WO 2012/136531 A1

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization llIIlIIlllIlIlllIlIllIllIllIIlIlllIlIllIlllllIlllIIIllllIIllIlIllIIlllIlllIlIIIIIIIIIIIIIIIIIII International Bureau (10) International Publication Number International Publication Date (43) A1 I

(Sl) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,

(51) International Patent Classification: C07D 4t71/04t (2006.01) A61P 35/00 (2006.01) A 61K 31/4t37 (2006.01)

CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.

(21) International Application Number PCT/EP2012/055471

(22) International

Filing Date:

28 March 2012 (28.03.2012)

(25) Filing Language:

English

(26) Publication Language:

English

States (unless otherwise indicated, for every of regional protection available): ARIPO (BW, GH,

(S4) Designated

(30) Priority Data:

11161332.9 6 April 11170305.4 17 June 11179044.0 26 August 11188997.8 14 November

WO 2012/136531

WIPO PCT

11 October 2012 (11.10.2012)

2011 (06.04.2011) 2011 (17.06.2011) 2011 (26.08.2011) 2011 (14.11.2011)

kind

EP EP EP EP

GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).

(71) Applicant (for all designated States except US): BAYER PHARMA AKTIENGESELLSCHAFT [DE/DE]; Miiller Strasse 178, 13353 Berlin (DE).

(72) Inventors; and Declarations under Rule 4.17: (for US only): KOPPITZ, Marcus (75) Inventors/Applicants as to applicant's entitlement to apply for and be granted a [DE/DE]; Scharnhorststr. 28, 10115 Berlin (DE). KLAR, patent (Rule 4. 1 7(ii)) Ulrich [DE/DE]; Isegrimsteig 8A, 13503 Berlin (DE). WENGNER, Antje [DE/DE]; Dunckerstr. 7, 10437 Berlin Published: (DE). NEUHAUS, Roland [DE/DE]; Lauenburger Str. 28, with international search report (Art. 21(3)) 12157 Berlin (DE). SIEMEISTER, Gerhard [DE/DE]; Reimerswalder Steig 26, 13503 Berlin (DE).

BAYER PHARMA AK(74) Common Representative: TIENGESELLSCHAFT; Law and Patents, Patents and Licensing, Miiller Strasse 178, 13353 Berlin (DE).

(54) Title: SUBSTITUTED IMIDAZOPYRIDINES AND INTERMEDIATES THEREOF

R NH N

R

N

A compounds of general formula (I) in which R', R' and A are as defined in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

(57) Abstract: The present invention relates to substituted imidazopyridine

WO 2012/136531

PC

T/EP2012/055471

SUBSTITUTED IMIDAZOPYRIDINES AND INTERMEDIATES THEREOF

relates to substituted

The present invention formula 5

10

as

I

described

and

defined

compounds

imidazopyridine

to methods of preparing

herein,

compounds,

to pharmaceutical

compounds,

to the use of said compounds for manufacturing

composition

for the treatment

intermediate

compounds

compositions

of general

combinations

and

said

comprising

a pharmaceutical

of a disease, as well as to

or prophylaxis

useful in the preparation

said

of said compounds.

BACKGROUND OF THE INVENTION

relates to chemical compounds that inhibit Mps-1 (Monopolar

The present invention

Spindle 1) kinase (also known as Tyrosine Threonine

Kinase, TTK). Mps-1 is a dual

specificity Ser/Thr kinase which plays a key role in the activation of the mitotic 15

proper chromosome

thereby ensuring Cell, 2001, 106,

replicated

apparatus. long

segregation

dividing

during

mitosis [Abrieu A

into the two daughter

cells. Upon entry into mitosis,

The mitotic checkpoint is a surveillance kinetochores

are present

and

mechanism

of the spindle

that is active as

prevents mitotic cells from

cell division with unattached chromosomes [Suijkerbuijk SJ and Kops GJ, Biochemica et Biophysica Acta, 2008, 1786, 24-31; Musacchio A and Salmon ED, Nat Rev Mol Cell Biol. , 2007, 8, 379-93]. Once all kinetochores are attached in a correct amphitelic, i. e. bipolar, fashion anaphase

and thereby completing

with the mitotic spindle,

and proceeds through

the checkpoint is satisfied and the cell enters anaphase

mitosis. The mitotic checkpoint consists of complex network

of a number of essential proteins, including members of the deficient,

30

et al. ,

cell has to ensure equal separation of the

are attached at their kinetochores to the microtubules

as unattached

entering

25

83-93]. Every

chromosomes

chromosomes

20

spindle assembly checkpoint)

(also known as spindle checkpoint,

checkpoint

families,

MAD

1-3) and Bub (Budding uninhibited

MAD

(mitotic arrest

by benzimidazole,

Bub

1-3)

the motor protein CENP-E, Mps-1 kinase as well as other components,

many of these being over-expressed

tissues [Yuan B

et al. ,

in proliferating

cells (e.g. cancer cells) and

Clinical Cancer Research, 2006, 12,

405-10]. The essential

role of Mps-1 kinase activity in mitotic checkpoint signalling

has been shown by

WO 2012/136531

et ai. ,

N

al. , 5

EMBO Reports,

There

et al. , Current Biology, et al. , Current Biology, 2005, 15, 1070-76; Schmidt M et

PLos ONE, 2008, 3,

2005, 15, 160-65; Dorer

RK

e2415; Jones

MH

2005, 6, 866-72].

mitotic checkpoint

evidence linking reduced but incomplete

is ample

T/EP2012/055471

of Mps-1 kinase

chemical genetics as well as chemical inhibitors

shRNA-silencing,

[Jelluma

PC

function with aneuploidy

and tumourigenesis

[Weaver

BA and

Cleveland

DW,

Cancer Research, 2007, 67, 10103-5; King RW, Biochimica et Biophysica Acta, 2008,

1786, 4-14].

In

of the mitotic checkpoint has been

contrast, complete inhibition

recognised to result in severe chromosome 10

Drug

M

of

and Medema RH, Cell Cycle, 2006, 5, 159-63; Schmidt M and Bastians H,

Resistance

abrogation

2007, 10, 162-81]. Therefore, mitotic checkpoint

Updates,

through

pharmacological

of Mps-1 kinase or other components

inhibition

of the mitotic checkpoint represents

a new approach

for the treatment

of

disorders including solid tumours such as carcinomas and sarcomas

proliferative

and leukaemias

and lymphoid

or other disorders associated with

malignancies

cellular proliferation.

uncontrolled

anti-mitotic

Established

20

and induction

apoptosis in tumour cells [Kops GJ et al. , Nature Reviews Cancer, 2005, 5, 773-85; Schmidt

15

missegregation

activate the

drugs

SAC inducing

such

as vinca

alkaloids,

a mitotic arrest either by stabilising

dynamics. This arrest prevents separation

microtubule

or epothilones

taxanes

or destabilising

of sister chromatids to form

the two daughter cells. Prolonged arrest in mitosis forces a cell either into mitotic

exit without cytokinesis or into mitotic catastrophe leading to cell death. In

25

contrast,

progression

inhibitors

of Mps-1 induce a SAC inactivation

that accelerates

of cells through mitosis resulting in severe chromosomal

missegregation

and finally in cell death.

These findings suggest that Mps-1 inhibitors should be of therapeutic

treatment 30

of proliferative

proliferative

disorders associated with enhanced

uncontrolled

cellular processes such as, for example, cancer, inflammation,

arthritis, viral diseases, neurodegenerative cardiovascular

value for the

diseases such as Alzheimer's

diseases, or fungal diseases in a warm-blooded

disease,

animal such as man.

WO 2012/136531

Therefore,

PC

of Mps-1

inhibitors

therapeutic

complement

represent valuable compounds

T/EP2012/055471

that should

options either as single agents or in combination

with

other drugs.

5

Different compounds

effect on

Mps-1 kinase. W02010/124826A1 discloses substituted

as inhibitors

substituted

aminoquinoxalines

as Mps-1 inhibitors.

derivatives

imidazole

imidazoquinoxaline

of Mps-1 kinase or TTK. W02011/026579A1 discloses

compounds

fused

10

have been disclosed in prior art which show an inhibitory

as

W02011/063908A1,

inhibitors.

Mps-1

W02011/064328A1 as well as W02011063907

W02011/013729A1 discloses

A1

disclose triazolopyridine

derivates

as inhibitors of Mps-1 kinase.

However,

Mps-1 kinase

15

inhibitors.

have not been disclosed in the context of

derivatives

imidazopyridine

derivates have been disclosed for the

Imidazopyridine

treatment or prophylaxis of different diseases: W02004/026867A2 and W02007/032936A2 disclose substituted as cyclin dependent

kinase (CDK) inhibitors

imidoazopyridines

for the treatment

of diseases and

disorders associated with CDKs.

20 W02008/029152A2 discloses bicyclic heterorayl

duchenne

muscular

imidoazopyridines

25

dystrophy.

Among

for the treatment

other compounds

of

also substituted

are mentioned.

W02008/082490A2 discloses substituted C-Jun-N-terminal

compounds

imidazopyridines

for the treatment

of

kinase (JNK1) mediated diseases.

W02008/134553A1 discloses substituted

treatment of sodium channel-mediated

imidazopyridines

and indolizines

for the

diseases.

30 Thus,

the state of the art described

substituted

imidazopyridine

invention,

or a stereoisomer,

salt thereof,

or a mixture

above does not describe the specifically

compounds

of general

a tautomer,

an N-oxide, a hydrate,

formula

I

of the

present

a solvate, or a

of same, as described and defined herein, and as

WO 2012/136531

PC

referred to as "compounds of the present invention",

hereinafter

or their

activity.

pharmacological

the state of the art described above does not describe the use of a

Furthermore,

of the present invention as Mps-1 inhibitor.

compound

It has now been found, and this constitutes

said

T/EP2012/055471

compounds

of the present

the basis of the present invention,

invention

that

and advantageous

have surprising

properties.

10

In

particular,

said compounds

of the present invention have surprisingly

been found

to effectively inhibit Mps-1 kinase and may therefore be used for the treatment or of diseases of uncontrolled

prophylaxis

cellular immune responses, or inappropriate

inappropriate

or diseases which are accompanied

responses

15

and/or

proliferation

survival,

cellular

inappropriate

inappropriate

inflammatory

responses, or inappropriate

Mps-1 kinase, such as, for example,

20

25

haemotological

particularly

head and neck tumours including

of the thorax including tumours,

non-small

endocrine tumours,

urological

tumours,

and sarcomas, and/or metastases

tumours

including

responses, which

in

or the

cellular

responses is mediated by

tumours,

solid tumours,

syndrome,

and/or

malignant

brain tumours and brain metastases,

cell and small cell lung tumours, mammary

and other gynaecological

renal, bladder and prostate

tumours,

cell growth,

inappropriate

e.g. leukaemias and myelodysplastic

lymphomas,

gastrointestinal

cellular immune

cellular inflammatory

thereof,

tumours


and/or survival,

metastases

and/or survival,

with uncontrolled

responses,

cell growth, proliferation

uncontrolled immune


thereof.

tumours,

skin

WO 2012/136531

SUMMARY

PC

of the

T/EP2012/055471

INVENTION


covers compounds of general formula

I

R NH N

R A

in which

A

represents a 4a

4a

H

4b

N

*

N

R

4d

R

Z

4c 4b

4c

H

group j

OI

10 wherein

* indicates the point of attachment

of said groups with the rest of

the molecule;

Z

represents a -C(=0)N(H)R' or a -C(=S)N(H)R" group;

R'

represents a hydrogen atom or a C~-C6-alkyl-, a C~-C6-cycloalkyl- or an aryl-

15

group j

wherein

said C&-C6-cycloalkyl-

identically or differently, 20

or aryl-

group

is optionally

substituted,

with 1, 2, 3 or 4 groups selected from: halogen,

-OH, -CN, C~-C6-alkyl-, C~-C6-alkoxy-, C~-C6-cycloalkyl-,

HO-C~-C6-alkyl-;

WO 2012/136531

wherein

PC

said

differently,

R~

identically or

1, 2, 3 or 4 groups selected from: halogen,

with

-OH,

-CN,

HO-C~-Ce-alkyl-;

C~-Ce-alkoxy-, C~-Ce-cycloalkyl-,

5

substituted,

group is optionally

C&-Ct;-alkyl-

T/EP2012/055471

represents a hydrogen atom, or a C~-C6-alkyl- or C~-C6-cycloalkyl- group; wherein said Cz-C6-cycloalkylwith 1, 2, 3, or 4

differently,

substituted,

group is optionally —

identically or

groups selected from: halogen, OH, -CN, -C&-

C6-alkyl, -C~ -C6-alkoxy;

wherein

10

said

differently,

1, 2, 3, or 4

with

substituted,

group is optionally

C&-Ct;-alkyl-

—

identically or

selected from: halogen,

groups

OH, -CN,

-C& -C6-alkoxy;

represents

a hydrogen

-(CH~) -Cz-Ce-alkenyl,

15

atom or a halogen atom or a -CN, C~-C6-alkyl-, -(CH&) -C&-C8-cycloalkenyl,

-(CH&) -C&-C6-cycloalkyl,

-(CH~) -(4-

to

-(CH&)

heteroaryl-C&-C6-alkyl-,

20

-C&

C~-Cs-cycloalkenyl-,

25

-C(=0)N(R")R'

a r y l-X-,

-C(=0)0-R'

-N(R")R'

30

3-

C&-Ce-cycloalkyl-,

C&-C8-cycloalkenyl-,

7-membered

-NO&,

-C6-alkyl-X-,

to

8-membered

-C(=0)N(H)R", -OR'

-N(H)C(=0)R'

-SR'

-S(=0)zN(R6b)R6', -S-(CHz) -N(R6')R6b or

group;

-(CH&)~-C&-C6-alkenyl,

to 7-membered

-(CH&)m-C&-C6-alkynyl,

heteroaryl-C~-C6-alkyl-,

aryl-C~-C6-alkyl-,

heterocycloalkyl-,

C&-C6-alkynyl-,

C&-C6-alkenyl-,

aryl-,

C&

-C6-alkyl-X-,

-X-(CHz)m-C&-C8-cycloalkenyl,

-X-(CHz)m-Cz-C6-alkenyl, -X-(CH&) -C~-C6-alkynyl,

to

-C(=0)R',

heteroaryl-X-,

heterocycloalkyl)

-Ct;-alkyl-,

-(CH~) -C~-C6-cycloalkyl,

C&

aryl-,

-X-(CH~) -(3-

-X-(CHz) -(4-

heterocycloalkyl),

C&

C~-C6-alkynyl-,

-X-(CHz) -C~-Ce-cycloalkyl,

-S-(CHz), -(3- to 7-membered said

7-membered

-X-(CH~)m-C~-C8-cycloalkenyl,

-S(=0)R6 -S(=0)&R6 -S(=0)(=NR6')R~b

wherein

to

heteroaryl-,

-Ct;-alkyl-heteroaryl,

-X-(CH&) -C~-C6-alkynyl,

heterocycloalkenyl),

3-

C~-C6-cycloalkyl-,

-X-(CH~) -C~-C6-alkenyl,

7-membered

aryl-C~ -C6-alkyl-, R6a(R6b)N-C&-C6-alkyl-,

halo-C&-C6-alkyl-,

C~-C6-alkenyl-,

-C& -Ct;-alkyl-aryl,

heterocycloalkyl),


halo-C~-C6-alkoxy-C~ -C6-alkyl-,

heterocycloalkyl-,

t o 7-membered

-(3-

8-membered

-(CHz) -C~-Ce-alkynyl,


heterocycloalkyl),

-X-(CHz) -(4-

-X-(CH~) -(3-

to

to

8-membered

WO 2012/136531

PC

identically or differently,

R',

R',

R

with

is

group

1, 2, 3, 4 or

-C&

-C6-alkyl-aryl,

optionally substituted,

5 R' groups;

R

represent, -CN,

heteroaryl-

or

-C~-C6-alkyl-heteroaryl

5

heteroaryl-X-,

a r y l-X-,


T/EP2012/055471

independently

from each other, a hydrogen halo-C~-C6-alkyl-,

C~-C6-alkoxy-,

-OH, C~-Ct;-alkyl-,

R6a(R6b)N C1 C6-alkyl-,

HO-C&

halo-C~-C6-alkoxy-,

-C6-alkyl-,

NC-C&-C6-alkyl-,

or halo-C&-Ct;-alkoxy-C&-C6-alkyl-

C&-Ct;-alkoxy-C&-C6-alkyl-

or halogen atom or a

group;

10 R'

represents

a hydrogen

-(CH&). -C&-C6-alkynyl,

atom

or

-(CH~). -C~-C6-alkenyl,

C~-C6-alkyl-,

-(CH&)m-C&-C6-cycloalkyl,

-(CH&)~-(3-

to 7-membered

aryl-C~ -C6-alkyl-, heteroaryl-C~ -C6-alkyl-, halo-C~-C6-alkyl-,

heterocycloalkyl),

R"(R")N-C&-Ce-alkyl-, 15

a

HO-C&

C&-Ct;-alkoxy-C&-C6-alkyl-,

to 7-membered

-C6-alkyl-,

-Cl C6 alkyl-CN,

halo-C&-C6-alkoxy-C&-C6-alkyl-,

heterocycloalkyl-,

C~-Ca-cycloalkenyl-,

Cz-C6-cycloalkyl-,

3-

aryl- or heteroaryl-

group j s a i d C~-C6-alkyl-,

wherein

20

-(CH~)m-C~-C6-cycloalkyl,

-(CH~) -(3-

aryl-C& -C6-alkyl-,


R"(R'

to 7-membered

7-membered

heterocycloalkyl), halo-C&-C6-alkyl-, -C& -C6-alkyl-CN,

halo-C~-Ce-alkoxy-C~-Ce-alkyl-,

heterocycloalkyl-,

group is optionally

to

-(CH~). -C~-C6-alkynyl,

HO-C~ -Ce-alkyl-,

)N-C&-C6-alkyl-,

C~-Ce-alkoxy-C~-Ce-alkyl-,

substituted,



C~-C6-cycloalkyl-,

3-

aryl- or heteroarylwith

1, 2, 3, 4 or 5

R' groups;

25

R

R',

R

R'

represent, C~

30


-Ce-alkyl-,

independently H

7-membered

0-C~ -C6-alkyl-,

heterocycloalkyl-,

heteroaryl-C&-C6-alkyl-

from each other, a hydrogen

C~-C6-alkenyl-,

C~-C6-cycloalkyl-,

aryl-,

atom or a

heteroaryl-,

3-

aryl-C&-C6-alkyl-

to or

group;

wherein said C~-C6-cycloalkyl-

group is optionally

substituted,

identically or

or 2 groups selected from: halogen, -OH, -CN, C&-C6-alkyl-,

differently with

1

HO-C&-C6-alkyl-,

C&-C6-alkoxy-, halo-C&-C6-alkyl-,

halo-C&-C6-alkoxy-;

WO 2012/136531

R'

represents

a hydrogen

Hp-C& -Ce-alkyl-,

C~-Ce-alkenyl-,

heteroaryl-,

-C( 0)Re

3- to 7-membered

-NOES)

-N(H)C(=0)R

-N(R ')C(=0)N(R ')R

-N(R6')S(=0)R6

-N(R

-S(=0)N(R")Reb

-N(R ')C(=0)OR

N(R6a)R6b

-N(H)S(=0)R

-N=S(=0)(R6')Reb

-S(=0)R

-SR

-0(C=O)OR

-S(=0)~R'

R6

aryl-,

-N(H)C(=0)N(R ')R

-N(R6')S(=0)&R6

-0(C=O)N(R ')R

-0(C=O)R

p)p

C(

')C(=0)R

-N(H)C(=0)OR

-N(H)S(=0)zR6

C~-Ce-alkoxy-,

heterocycloalkyl-,

C( p)N(R6a)R6b

C( 0)N(H)R6a

-CN,

halo-C&-Ce-alkoxy-C& -Ce-alkyl-,

C&-Ce-alkoxy-C& -Ce-alkyl-,

C~-Ce-alkynyl-,

T/EP2012/055471

R"(R")N-C&-Ce-alkyl-,

halo-C&-Ce-alkoxy-,

halo-C&-Ce-alkyl-,

C&-Ce-alkyl-,

10

or halogen atom or a Hp-,

PC

-OR6

-S(=0)N(H)R

or

-S(=0)~N(R")Reb

-S(=0)~N(H)R'

-S(=0)(=NR")R' group; wherein

said aryl- or heteroaryl-

or differently, 15

1, 2 or 3

with

substituted,

group is optionally

identically

C&-Ce-alkyl- groups;

or

when 2 R' groups are present ortho to each other on an aryl ring, said 2 R' groups together form a bridge:

* represent

*0(CHz)&0*, *0(CH&)0*, *NH(C(=0))NH*, wherein

attachment

the point of

to said aryl ring;

20 Rs

represents a hydrogen or halogen atom or a -CN, C~-Ce-alkoxy-, C~-Ce-alkyl-, halo-C~-Ce-alkyl-,

Rea(Reb)N-C&-Ce-alkyl-,

C&-Ce-alkoxy-C&-Ce-alkyl-,

halo-C&-Ce-alkoxy-C&-Ce-alkyl-,

3- to 7-membered

C~-Ce-alkynyl-,

25

C( 0)R6

-N(H)C(=0)R

-N(R

p(C p)N(R6a)R6b

p(C p)pR6

-S(=0&)R' -S(=0)&N(H)R'

7-membered wherein

S( p)R6

heteroaryl-,

N(R6a)R6b

Np

-N(R ')C(=0)N(R

-N(R -OR

S( p)N(H)R6

')R

')S(=0)R -0(C=O)R

S( p)N(R6a)R6b

-S(=0)(=NR")R' or -S(=0)&-(3- to

group;

said 3- to 7-membered

optionally substituted, groups j

SR6

-S(=0)&N(R")Reb

heterocycloalkyl)

R6

-N(H)S(=0)R

-N=S(=0)(R ')R

-N(R ')S(=0)2R

-N(H)S(=0)2R

0)0

C(

C2-Ce-alkenyl-,

aryl-,

-N(H)C(=0)N(R ')R

')C(=0)R

-N(R ')C(=0)OR

-N(H)C(=0)OR

30

heterocycloalkyl-,

C( 0)N(R6a)R6b

C( 0)N(H)R6a

HO-C&-Ce-alkyl-,

heterocycloalkyl-


or heteroaryl-

group

is

with 1, 2, 3 or 4 C&-Ce-alkyl-

WO 2012/136531

PC

m

is an integer of 0, 1, 2, 3, 4, 5 or

n

is an integer of 0, 1, 2, 3, 4 or

X

is S, S(=Q), S( Q)~ Q

or a stereoisomer,

NR6

a tautomer,

T/EP2012/055471

6;

5; and

CR6aR6b

C( CR6aR6b) C(=Q) or((QPI)(R6a)


.

a solvate, or a salt thereof,

or a mixture of same.

also relates to methods of preparing


10

pharmaceutical

compositions

use of said compounds

for manufacturing

the preparation

comprising

said compounds,

a pharmaceutical

to the

composition for the

of a disease, as well as to intermediate

treatment or prophylaxis in

and combinations

to

said compounds,

compounds

useful

of said compounds.

15

of the

DETAILED DESCRIPTION

The terms as mentioned

in

INVENTION

the present text have preferably

the following

meanings: 20 The term "halogen atom" or "halo-" is to be understood

as meaning a fluorine,

chlorine, bromine, or iodine atom.

The term "C&-C|;-alkyl" is to be understood 25

saturated,

branched, carbon

atoms,

e.g. a methyl,

1-ethylpropyl,

ethyl,

3-methylpentyl,

1-ethylbutyl,

3, 3-dimethylbutyl,

2, 3-dimethylbutyl,

pentyl,

1, 2, 3, 4, hexyl,

iso-propyl,

1-methylpentyl,

2-ethylbutyl,

1, 1-dimethylbutyl,

2, 2-dimethylbutyl,

group,

or an isomer

said group has 1, 2, 3 or 4 carbon atoms ("C&-C&-alkyl"),

propyl,

butyl,

iso-propyl,

iso-butyl,

or 6

1, 1-dimethylpropyl,

neo-pentyl,

or 1, 2-dimethylbutyl

5

1-methylbutyl,

2-methylbutyl,

2-methylpentyl,

1, 3-dimethylbutyl,

thereof. Particularly, ethyl,

iso-pentyl,

a linear or

meaning

group having butyl,

propyl,

1,2-dim ethylpropyl,

4-methylpentyl,

a methyl,

hydrocarbon

tert-butyl,

sec-butyl,

iso-butyl,

30

monovalent

as preferably

sec-butyl,

tert-butyl

e.g.

group,

WO 2012/136531

PC

or iso-propyl group.

n-propyl-

The term "halo-C&-C6-alkyl" is to be understood 5

saturated,

branched, is defined

halogen

atom,

halo-C& -C6-alkyl

in

or differently,

from another.

Particularly,

for

is,

example,

i. e. one

halogen atom being

said halogen -CF&,

-CHF&,

atom is F. Said or

-CFzCF&,

-CH&F,

-CHzCF&.

The term "C&-C6-alkoxy" is to be understood branched,

saturated,

n-butoxy,

sec-butoxy,

a linear or

meaning

-0-(C~-C6-alkyl), in which the

e.g. a methoxy, ethoxy,

supra,

tert-butoxy,

iso-butoxy,

as preferably

group of formula

monovalent,

term "alkyl" is defined

15

atoms is replaced by a

one or more hydrogen

identically

group

as preferably meaning a linear or

C~-C6-alkyl group in which the term "C~-C6-alkyl"

monovalent

and in which

supra,

independent 10

e.g. a methyl, ethyl,

2 or 3 carbon atoms ("C&-C&-alkyl"),

1,

more particularly

T/EP2012/055471

pentoxy,

n-propoxy,

iso-propoxy,

iso-pentoxy,

or n-hexoxy

group, or an isomer thereof.

The term "halo-C~-Ct;-alkoxy" is to be understood branched,

20

saturated,

monovalent

one or more of the hydrogen halogen atom. Particularly,

as preferably meaning a linear or

C&-C6-alkoxy group,

as defined supra, in which

atoms is replaced, in identically or differently, said halogen atom is F. Said halo-C~-C6-alkoxy

by a

group is,

for example, -OCF&, -OCHFz, -OCH~F, -OCF&CF~, or -OCH)CF3. The term "C~-C6-alkoxy-C~-C6-alkyl" is to be understood 25

linear or branched,

saturated,

monovalent

which one or more of the hydrogen by

30

a C~-C6-alkoxy

group,

iso-propoxyalkyl,

sec-butoxyalkyl,

pentyloxyalkyl,

meaning

a

as defined supra, in

C&-C6-alkyl group,

atoms is replaced, in identically or differently,

as defined

propyloxyalkyl,

as preferably

supra,

butoxyalkyl,

e.g. methoxyalkyl, iso-butoxyalkyl,

iso-pentyloxyalkyl,

ethoxyalkyl,

tert-butoxyalkyl,

hexyloxyalkyl

group, or an

isomer thereof.

The term "halo-C~-C6-alkoxy-C~-C6-alkyl" a linear defined

or branched, supra,

saturated,

in which

is to be understood

monovalent

C&

-C6-alkoxy-C& -C6-a lkyl group,

one or more of the hydrogen 10

as preferably meaning as

atoms is replaced, in

WO 2012/136531

identically Said

PC

or differently,

by a halogen

CH2CH20CF3~

said halogen atom is F.

atom. Particularly,

halo-C~ -Ct;-alkoxy-C~ -C|,-alkyl

for

is,

group CHIC H20CH2Fp

CH2CH20CHF2p

T/EP2012/055471

example,

CH2CH&OCF&CF3p

ol

-CHzCHzOCHzCF3.

The term "C&-Ct;-alkenyl" is to be understood branched,

monovalent

as preferably

meaning

group, which contains one or more double

hydrocarbon

bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly ("C&-C&-alkenyl"), it being understood

10

a linear or

2 or 3 carbon atoms

that in the case in which said alkenyl group

contains more than one double bond, then said double bonds may be isolated from,

or conjugated with, each other. Said alkenyl group is, for example, a vinyl, allyl, (E)-2-methylvinyl,

(E)-but-1-enyl,

(Z)-2-methylvinyl,

(Z)-but-1-enyl,

(E)-pent-2-enyl,

15

(E)-hex-4-enyl,

(Z)-hex-4-enyl,

(Z)-hex-2-enyl,

(E)-hex-1-enyl,

(Z)-1-methylprop-1-enyl,

(E)-hex-3-enyl, (Z)-hex-1-enyl,

(Z)-pent-3-enyl,

(Z)-pent-1-enyl, (Z)-hex-3-enyl,

hex-5-enyl,

(E)-hex-2-enyl,

2-methylprop-2-enyl,

isopropenyl,

(E)-1-methylprop-1-enyl,

3-methylbut-3-enyl,

2-methylbut-3-enyl,

3-methylbut-2-enyl,

(E)-2-methylbut-2-enyl,

(Z)-2-methylbut-2-enyl,









1-ethylprop-1-enyl,

1-propylvinyl,

3-methylpent-4-enyl,


30

(E)-pent-1-enyl,

(Z)-but-2-enyl,

1-methylbut-3-enyl,

1, 1-dimethylprop-2-enyl, 25

(E)-pent-3-enyl,



20

pent-4-enyl,

(Z)-pent-2-enyl,

(E)-but-2-enyl,

homoallyl,

1-isopropylvinyl,




(E)-3-methylpent-3-enyl,

(Z)-3-methylpent-3-enyl,





















3-ethylbut-3-enyl, (Z)-3-ethylbut-2-enyl,

2-ethylbut-3-enyl,

1-ethylbut-3-enyl,

(E)-2-ethylbut-2-enyl, 11

(E)-3-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl,

WO 2012/136531

PC

(E)-1-ethylbut-2-enyl,

(Z)-1-ethylbut-2-enyl,



2-ethylbut-1-enyl,



2-propylprop-2-enyl,

1-propylprop-2-enyl,

2-isopropylprop-2-enyl,

1-isopropylprop-2-enyl,

(E)-2-propylprop-1-enyl,

(Z)-2-propylprop-1-enyl,

(E)-1-propylprop-1-enyl,

(Z)-1-propylprop-1-enyl,

(E)-2-isopropylprop-1-enyl,

(E)-3, 3-dimethylprop-1-enyl,

(Z)-3, 3-dimethylprop-1-enyl,

penta-1, 4-dienyl,

(E)-1-isopropylprop-1-enyl,

(Z)-2-isopropylprop-1-enyl,

(Z)-1-isopropylprop-1-enyl,

10

1-(1,1-dimethylethyl)ethenyl,

hexa-1, 5-dienyl, or methylhexadienyl

buta-1, 3-dienyl,

group. Particularly,

branched,

monovalent

hydrocarbon

as preferably

("Cz-Cg-alkynyl"). prop-2-ynyl,

pent-3-ynyl,

Said C&-C|,-alkynyl

but-1-ynyl, pent-4-ynyl,

1-methylprop-2-ynyl,

3-methylbut-i-ynyl,

group is, for example,

but-3-ynyl,

but-2-ynyl,

hex-1-ynyl,

hex-2-inyl,

1-ethylprop-2-ynyl,

prop-1-ynyl,

pent-1-ynyl,

pent-2-ynyl,

hex-3-inyl, hex-4-ynyl,

hex-5-ynyl,

1-methylbut-2-ynyl,

2-methylpent-4-ynyl,








2-ethylbut-3-ynyl,

1, 1-dimethylbut-3-ynyl, Particularly,

1-ethylbut-3-ynyl,

1, 1-dimethylbut-2-ynyl,

said alkynyl group is ethynyl,

or 3, 3-dimethylbut-1-ynyl

prop-1-ynyl,

The term "C~-C|,-cycloalkyl" is to be understood monovalent, ("C3

Ct;

monocyclic hydrocarbon

cycloalkyl").

or prop-2-inyl.

as meaning

a

saturated,

group is for example a cyclopropyl,

or cyclohexyl ring.

The term "C~-C8-cycloalkenyl" is to be understood monovalent,

group.

ring which contains 3, 4, 5 or 6 carbon atoms

Said C~-C|, -cycloalkyl

cyclobutyl, cyclopentyl,

1-ethylbut-2-ynyl,

2, 2-dim ethylbut-3-inyl,

1-isopropylprop-2-ynyl,

1-propylprop-2-ynyl,

30

a linear or

2 or 3 carbon atoms

ethynyl,

1-methylbut-3-ynyl,

2-methylbut-3-ynyl,


25

meaning

group which contains one or more triple bonds,

and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly

20

said

group is vinyl or allyl.

The term "Cz-C|;-alkynyl" is to be understood

15

T/EP2012/055471

mono-, or bicyclic hydrocarbon

ring which

as preferably

a

contains 4, 5, 6, 7 or 8

carbon atoms and one, two, three or four double bonds, in conjugation 12

meaning

or not, as

WO 2012/136531

PC

the size of said cycloalkenyl a monocyclic

example,

hydrocarbon

The term "3- to 7-membered

saturated,

ring,

heterocycloalkyl",

is to be understood

mono- or bicyclic hydrocarbon

monovalent,

0,

C&-C|,-alkyl-

10

R' represents

S, S(=0), S(=0)z, NR', in which

or

as meaning a

ring which contains 2,

3, 4,

groups selected from

5 or 6 carbon atoms, and one or more heteroatom-containing

C(=0),

group is for

Said C&-C8-cycloalkenyl

e.g. a cyclobutenyl, cyclopentenyl, e.g. a cylooctadienyl ring.

ring,

or a bicyclic hydrocarbon

cyclohexenyl

5

ring allows.

T/EP2012/055471

atom, or a

a hydrogen

or halo-C&-C|, -alkyl- group; it being possible for said heterocycloalkyl

group to be attached to the rest of the molecule via any one of the carbon atoms

or, if present, the nitrogen atom. Particularly,


and one or more of the above-mentioned

carbon atoms, groups

15

(a

can contain 2, 3, 4, or 5

heterocycloalkyl

"3- to 6-membered can contain

heterocycloalkyl

heterocycloalkyl"),

heterocycloalkyl"),

wherein

two

(a

groups

adjacent

are optionally

heterocycloalkyl-group

more particularly

said

4 or 5 carbon atoms, and one or more of the

heteroatom-containing

above-mentioned

heteroatom-containing

of the

atoms

substituted

"5-

to

6-membered

3- to 7-membered

in such a way,

that an aryl- or

is formed.

heteroaryl-group

20

Particularly, 4-membered

without being limited thereto, said heterocycloalkyl ring, such as an azetidinyl,

tetrahydrofuranyl,

dioxolinyl,

or a 6-membered 25

dithianyl,

ring,

or a 5-membered

imidazolidinyl,

pyrrolidinyl,

ring, such as tetrahydropyranyl,

thiomorpholinyl,

a diazepanyl

oxetanyl,

piperazinyl,

for example.

or trithianyl,

Optionally,

ring, such as

pyrazolidinyl,

piperidinyl,

or a 7-membered

said heterocycloalkyl

can be a

pyrrolinyl,

morpholinyl, ring, such as

can be benzo

fused.

Said heterocyclyl

30

5, 5-membered 5, 6-membered

As

mentioned

unsaturated,

can be bicyclic, such as, without being limited thereto, a

ring,

e. g.

bicyclic ring,

supra,

i. e.

said

a hexahydrocyclopenta[c]pyrrol-2(1H)-yl)

e. g.

a hexahydropyrrolo[1,

nitrogen

ring, or a

2-a]pyrazin-2(1H)-yl

atom-containing

ring.

ring can be partially

it can contain one or more double bonds, such as, without being 13

WO 2012/136531

PC

thereto,

limited

a

4H-

[1,3, 4] thiadiazinyl, ring, for example, or, it may be

2, 5-dihydro-1H-pyrrolyl,

or 4H-[1, 4]thiazinyl

4, 5-dihydrooxazolyl,

T/EP2012/055471

such as, without being limited thereto, a dihydroisoquinolinyl

benzo-fused,

ring,

for example. The term "4- to 8-membered

heterocycloalkenyl",

an unsaturated,

mono- or bicyclic hydrocarbon

monovalent,

is to be understood

as meaning

ring which contains

4,

groups selected 5, 6, 7 or 8 carbon atoms, and one or more heteroatom-containing from C(=0), 0, S, S(=0), S(=0)&, NR', in which R' represents a hydrogen atom, or a

10

C~-C|, -alkyl-

or halo-C~-C|;-alkyl- group; it being possible for said heterocycloalkenyl

group to be attached to the rest of the molecule via any one of the carbon atoms

or, if present, the nitrogen atom. Examples of said heterocycloalkenyl one

or

double

more

4H-pyranyl,

4, 5-dihydrooxazolyl,

2, 5-dihydrofuranyl, 2, 3-dihydrothiophenyl,

2, 5-dihydrothiophenyl,

2, 3-dihydrofuranyl,

or 4H-[1, 4]thiazinyl group, or, it may be benzo fused.

The term "aryl" is to be understood

as preferably meaning a monovalent,

or partially aromatic, mono-, or bi- or tricyclic hydrocarbon

20

6, 7, 8, 9,

9 carbon atoms (a "C9-aryl" group), e.g. an indanyl or indenyl group, or

having

10 carbon

dihydronaphthyl,

or naphthyl

a

ring

group), group),

e.g. a e.g. an

optionally

atoms

or a ring having

anthranyl

group, wherein in

e.g. a tetra linyl,

group),

group, or a ring having 13 carbon atoms, (a "C~~-aryl"

group,

substituted

"C&o-aryl"

(a

fluorenyl


30

ring having

aromatic

10, 11, 12, 13 or 14 carbon atoms (a "Ct, -C&4-aryl" group), particularly a ring having 6 carbon atoms (a "C|;-aryl" group), e.g. a phenyl group; or a biphenyl group, or a ring having

25

3H-diazirinyl,

2H-pyranyl,

[1,3]dioxolyl, 4H-[1, 3, 4]thiadiazinyl,

2, 5-dihydro-1H-pyrrolyl,

15

e.g.

bonds,

may contain

such

a

14 carbon atoms,

(a "C&4-aryl"

two adjacent atoms of the aryl-group way,

that

a

3-

to

are

7-membered

is formed.

The term "heteroaryl" is understood

as preferably

meaning

a monovalent,

monocyclic-, bicyclic- or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11,

12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl" group), particularly 6 or 9 or 10 atoms, and which contains at least one heteroatom

identical or different, said heteroatom

which may be

being such as oxygen, nitrogen

14

5 or

or sulfur,

WO 2012/136531

and in addition

PC

case can be benzocondensed,

in each

of the heteroaryl-group 7-membered

pyrrolyl,

oxadiazolyl,

isothiazolyl,

triazolyl,

a way, that a 3- to

in such

heteroaryl is selected

imidazolyl,

pyrazolyl,

benzoxazolyl,

benzisoxazolyl,

etc. ; or

pyridyl,

pyridazinyl,

benzothienyl,

benzotriazolyl,

benzimidazolyl,

pyrimidinyl,

isoxazolyl,

etc. , and benzo

thia-4H-pyrazolyl

thiadiazolyl,

thereof, such as, for example, benzofuranyl,

derivatives isoindolyl,

substituted

oxazolyl, thiazolyl,

two adjacent atoms

wherein

is formed. Particularly,


from thienyl, furanyl, 5

are optionally

T/EP2012/055471

indazolyl,

triazinyl,

pyrazinyl,

indolyl,

etc. , and

thereof, such as, for example, quinolinyl, quinazolinyl, etc. ; or azocinyl, indolizinyl, purinyl, etc. , and benzo derivatives

benzo derivatives 10

isoquinolinyl,

thereof;

or cinnolinyl,

pteridinyl, xanthenyl,

15

In

phthalazinyl,

carbazolyl,

acridinyl,

quinoxalinyl,

quinazolinyl,

phenothiazinyl,

phenazinyl,

general, and unless otherwise mentioned,

the heteroarylic

thereof. Thus, for some illustrative

non-restricting

pyridinylene

includes

pyridin-2-ylene,

pyridin-4-yl

and

pyridin-2-yl,

e. g. the

of "C&-C|;-alkyl", "C&-Ct;-haloalkyl",

example, the term pyridinyl pyridin-3-yl,

this text,

e.g.

in

or

pyridin-3-ylene,

includes

the context of the definition

"C&-C|;-alkoxy", or "C&-C|;-haloalkoxy" is to be

as meaning an alkyl group having a finite number of carbon atoms of

to 6, i. e. 1, 2, 3, 4, 5, or 6 carbon atoms. It is to be understood term "C~-C|;" is to be interpreted

as any sub-range

comprised

C~-Cs, C~-C4, C~-Cz, C~-C~, C~-C~, C~-Cs, C~-Ce; particularly C&-Cs,

positional isomers

thien-3-yl and thien-3-ylene.

The term "C&-Ce", as used throughout

25

or heteroarylenic

or the term thienyl or thienylene

pyridin-4-ylene;

thien-2-yl, thien-2-ylene,

understood

phenoxazinyl,

or oxepinyl, etc. .

radicals include all the possible isomeric forms thereof,

20

naphthpyridinyl,

C&-C|, ,

more

particularly

C&-C&, in the

"C~-Ct;-haloalkoxy" even more particularly

1

further that said

therein,

e.g. C~-C|;,

C&-Cz, C&-Cg, C&-C4,

case of "C&-C|;-haloalkyl" or

C~-C~.

30 Similarly,

as used herein, the term "C&-C|,", as used throughout

the context of the definitions understood

this text,

e.g.

in

of "C~-C|;-alkenyl" and "C~-C|;-alkynyl", is to be

as meaning an alkenyl group or an alkynyl group having a finite number

of carbon atoms of 2 to 6,

i. e.

2, 3, 4, 5, or 6 carbon atoms. It is to be understood 15

WO 2012/136531

PC

further that said term "C&-C|," is to be interpreted

as any sub-range comprised

therein, e.g. C~-Ce, C~-Cs, C~-C~, Cz-C~, Cz-C~, Cz-Cs, particularly -

context of the definition

C~-C3.

e.g.

this text,

Further, as used herein, the term "C&-Ct;", as used throughout 5

T/EP2012/055471

of "C~-C|;-cycloalkyl", is to be understood

the

in

as meaning a

cycloalkyl group having a finite number of carbon atoms of 3 to 6, i. e. 3, 4, 5 or 6

carbon atoms. It is to be understood

further

interpreted

therein,

as any sub-range

C&-C|„Cs-Ct;, particularly

comprised

that said term "C~-Ct;" is to be

e.g.

C|;,

C3

C4

C5,

C3

C5,

C3

Cg,

Cz-C|, .

10 As used

herein,

the term "leaving group" refers to an atom or a group of atoms

that is displaced in a chemical reaction as stable species taking with it the bonding

15

electrons. Preferably,

a leaving group is selected from the group comprising:

in particular

bromo

chloro,

or iodo, methanesulfonyloxy,

benzene)sulfonyloxy,

(4-nitro-benzene)sulfonyloxy,

(4-bromo-

(2-nitro-benzene)-sulfonyloxy,

(2, 4, 6-tri-isopropyl-benzene)-sulfonyloxy,

(4-isop ropyl-benzene) sulfonyloxy,

(4-tertbutyl-benzene)

(2, 4, 6-trimethyl-benzene)sulfonyloxy, benzenesulfonyloxy,

p-toluenesulfonyloxy,

nonafluo rob utanesulfonyloxy,

trifluoromethanesulfonyloxy,

halo,

sulfonyloxy,

and (4-methoxy-benzene)sulfonyloxy.

20 The term "substituted" means that one or more hydrogens

on the designated

atom

is replaced with a selection from the indicated group, provided that the designated

atom's normal valency under the existing circumstances

the substitution 25

results in a stable compound.

variables are permissible

Combinations

only if such combinations

The term "optionally substituted"

is not exceeded, and that

of substituents

and/or

result in stable compounds.

means optional substitution

with the specified

groups, radicals or moieties.

30

Ring system

nonaromatic

substituent

means a substituent

ring system which,

attached to an aromatic or

for example, replaces an available hydrogen on the

ring system.

16

WO 2012/136531

PC

"one or more times", e.g. in the definition

the term

herein,

As used

as meaning "one, two, three, four or five times, particularly

understood

one or two times".

particularly

also includes all suitable isotopic variations of a compound

The invention

which

10

An

of the

isotopic variation of a compound of the invention is defined as one in

at least one atom is replaced by an atom having the same atomic number

but an atomic mass different from the atomic mass usually or predominantly in

include isotopes of hydrogen,

sulphur,

fluorine,

(tritium)

"C

and

""I,

chlorine,

"N

'4C

respectively.

bromine

found

into a compound of the

nature. Examples of isotopes that can be incorporated

invention

15

one, two,

one, two or three times, even more

three or four times, more particularly

invention.

of the

of the compounds of the general formulae of the present invention, is

substituents

5

T/EP2012/055471

carbon, nitrogen, oxygen, phosphorus, iodine,

and

"0 "0 "P "P "S

"S "S

'4S

as 'H

such

(deuterium),

"'F "Cl "Br

Certain isotopic variations of a compound

'"I

"4I

of the invention,

for example, those in which one or more radioactive isotopes such as 'H or

are useful

incorporated,

and/or substrate tissue distribution

in drug

Tritiated and carbon-14, i. e. , '4C, isotopes are particularly and detectability.

of preparation 20

deuterium metabolic

may afford certain therapeutic

stability,

conventional

25

illustrative

for example,

increased

advantages in vivo

and hence may be preferred

requirements

variations

Further, substitution

of a compound procedures

of the invention

known

by a person

methods or by the preparations

using appropriate

in

studies.

with isotopes such as

resulting

from greater

or reduced

circumstances.

can generally skilled

"C are

preferred for their ease

half-life

in some

'H

dosage

Isotopic

be prepared

by

the art such as by the

described in the examples hereafter

isotopic variations of suitable reagents.

Where the plural form of the word compounds,

salts, polymorphs,

hydrates,

solvates and the like, is used herein, this is taken to mean also a single compound,

30

salt, polymorph,

By

isomer, hydrate, solvate or the like.

"stable compound' or "stable structure" is meant a compound that is sufficiently

robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation

into an efficacious therapeutic

17

agent.

WO 2012/136531

In

PC

T/EP2012/055471

accordance with a first aspect, the present invention is directed to compounds

of general formula

I: R I

H, C~ NH N

N

in which

A

represents a 4a

4a

H

4b

N

*

N

R

4d

R

Z

4c 4b

4c

H

group j

OI

10 wherein



the molecule;

Z

represents a -C(=0)N(H)R' or a -C(=S)N(H)R' group;

R'

represents a hydrogen atom or a C~-Ce-alkyl-, a C~-Ce-cycloalkyi- or an aryl-

15

group j

wherein

said C&-Ce-cycloalkyl-

identically or differently, 20

or aryl-

group is optionally

substituted,


-OH, -CN, C&-Ce-alkyl-, C~-Ce-alkoxy-, C~-Ce-cycloalkyi-,

18

HO-C~-Ce-alkyl-;

WO 2012/136531

wherein

PC

said

differently,

R~

identically or


with

-OH,

-CN,

HO-C~-Ce-alkyl-;


5

substituted,

group is optionally

C&-Ct;-alkyl-

T/EP2012/055471


differently,

substituted,


identically or



wherein

10

said

differently,

C&-Ct;-alkyl-

1, 2, 3, or 4

with

—

identically

substituted,

is optionally

group


groups

or

OH, -CN,

-C& -C6-alkoxy;

represents

a hydrogen


15

atom or a halogen atom or a -CN, C~-C6-alkyl-, -(CH&) -C&-C8-cycloalkenyl,


-(CH~) -(4-

to

-(CH&)


20

-C&


25

-C(=0)N(R")R'

a r y l-X-,

-C(=0)0-R'

-N(R")R'

30

3-

C&-Ce-cycloalkyl-,


7-membered

-NO&,

-C6-alkyl-X-,

to

8-membered

-C(=0)N(H)R", -OR'

-N(H)C(=0)R'

-SR'

-S(=0)zN(R6b)R6', -S-(CHz) -N(R6')R6b or

group;


to 7-membered



aryl-C~-C6-alkyl-,

heterocycloalkyl-,

C&-C6-alkynyl-,

C&-C6-alkenyl-,

aryl-,

C&

-C6-alkyl-X-,



to

-C(=0)R',

heteroaryl-X-,

heterocycloalkyl)

-Ct;-alkyl-,


C&

aryl-,

-X-(CH~) -(3-

-X-(CHz) -(4-

heterocycloalkyl),

C&

C~-C6-alkynyl-,


-S-(CHz), -(3- to 7-membered

said

7-membered


-S(=0)R6 -S(=0)&R6 -S(=0)(=NR6')R~b

wherein

to

heteroaryl-,




3-

C~-C6-cycloalkyl-,


7-membered

aryl-C~ -C6-alkyl-, R6a(R6b)N-C&-C6-alkyl-,

halo-C&-C6-alkyl-,

C~-C6-alkenyl-,


heterocycloalkyl),



heterocycloalkyl-,

t o 7-membered

-(3-

8-membered


-X-(CHz) -C~-Ce-cycloalkyl, -X-(CHz) -(4-

heterocycloalkyl),

19

-X-(CH~) -(3-

to

to

8-membered

WO 2012/136531


aryl-X-,


R',

R',

R

substituted,

group is optionally

1, 2, 3, 4 or

with

-C&-C6-alkyl-aryl,

5 R' groups;

R

represent, independently -CN,

heteroaryl-X-,

heteroaryl-

or


5

T/EP2012/055471

PC

-OH, C~-Ct;-alkyl-,

from each other, a hydrogen halo-C~-C6-alkyl-,

C~-C6-alkoxy-,


or halogen atom, or a

HO-C&

-C6-alkyl-,

NC-C&-C6-alkyl-,

or halo-C&-Ct;-alkoxy-C&-C6-alkyl-


halo-C~-C6-alkoxy-,

group;

10 R'

represents

a hydrogen


atom

or


C~-C6-alkyl-,


-(CH&)~-(3-

to 7-membered


heterocycloalkyl),


a

HO-C&


to 7-membered

-C6-alkyl-,

-Cl C6 alkyl-CN,


heterocycloalkyl-,


Cz-C6-cycloalkyl-,

3-


group j wh e rein said

20


-(CH~) -(3-

aryl-C& -C6-alkyl-,


R"(R'

to 7-membered

7-membered



heterocycloalkyl-,

group is optionally

to


HO-C~ -Ce-alkyl-,

)N-C&-C6-alkyl-,




substituted,

C~-C6-cycloalkyl-,

3-


1, 2, 3, 4 or 5

R' groups;

25

R

R',

R

R'

represent, C~

30


C~-C6-alkyl-,

-Ce-alkyl-,

independently H

7-membered

0-C~ -C6-alkyl-,

heterocycloalkyl-,


wherein


C~-C6-alkenyl-,

C~-C6-cycloalkyl-,

aryl-,

atom, or a

heteroaryl-,

3-

aryl-C&-C6-alkyl-

to or

group;

said C~-C6-cycloalkyl-

group is optionally

substituted,

identically or


differently with

1

HO-C&-C6-alkyl-,


20

halo-C&-C6-alkoxy-;

WO 2012/136531

R'

represents

-C6-alkyl-,

C~-C6-alkenyl-,

3- to 7-membered

C~-C6-alkynyl-,

heteroaryl-,

-C( 0)R6

-NOES)

-N(H)C(=0)R

-N(R6')S(=0)R6

-N(R

-S(=0)N(R")R6b

R6

-N(R ')C(=0)OR

N(R6a)R6b

-N(H)S(=0)R

-N=S(=0)(R6')R6b

-S(=0)R

-SR

-0(C=O)OR

-S(=0)~R'

0)0

C(

aryl-,

-N(H)C(=0)N(R ')R

-N(R6')S(=0)&R6

-0(C=O)N(R ')R

-0(C=O)R

C~-C6-alkoxy-,

heterocycloalkyl-,

')C(=0)R

-N(H)C(=0)OR

-N(H)S(=0)zR6

-CN,

R"(R")N-C&-C6-alkyl-,

C( 0)N(R6a)R6b

C( 0)N(H)R6a

T/EP2012/055471

halo-C&-C6-alkoxy-C& -C6-alkyl-,

C&-C6-alkoxy-C& -C6-alkyl-,

-N(R ')C(=0)N(R ')R

10

or a HO-,

atom

halo-C&-C6-alkoxy-,

halo-C&-C6-alkyl-,

C&-C6-alkyl-, HO-C&

or halogen

a hydrogen

PC

-OR6

-S(=0)N(H)R

or

-S(=0)~N(R")R6b

-S(=0)~N(H)R'



or differently, 15

1, 2 or 3

with

identically

substituted,

group is optionally

C&-C6-alkyl- groups;

or


* represent


attachment

the point of

to said aryl ring;

20 Rs

represents a hydrogen or halogen atom or a -CN, C~-C6-alkoxy-, C~-C6-alkyl-, halo-C~-C6-alkyl-,

R6a(R6b)N-C&-C6-alkyl-,

C&-C6-alkoxy-C&-C6-alkyl-,


3- to 7-membered

C~-C6-alkynyl-,

25

C( 0)R6

-N(H)C(=0)R

-N(R

0(C 0)N(R6a)R6b 7-membered wherein

SR6

0(C 0)OR6

-S(=0&)R' -S(=0)&N(H)R'

heteroaryl-,

N(R6a)R6b

-N(R ')C(=0)N(R

-N(R -OR

S( 0)N(H)R6

NO

')R

')S(=0)R -0(C=O)R

S( 0)N(R6a)R6b

-S(=0)(=NR")R' or -S(=0)&-(3- to

group;



S( 0)R6

-S(=0)&N(R")R6b

heterocycloalkyl)

R6

-N(H)S(=0)R

-N=S(=0)(R ')R

-N(R ')S(=0)2R

-N(H)S(=0)2R

0)0

C(

C2-C6-alkenyl-,

aryl-,

-N(H)C(=0)N(R ')R

')C(=0)R

-N(R ')C(=0)OR

-N(H)C(=0)OR

30

heterocycloalkyl-,

C( 0)N(R6a)R6b

C( 0)N(H)R6a

HO-C&-C6-alkyl-,

heterocycloalkyl-


groups j 21

or heteroaryl-

group, is

with 1, 2, 3 or 4 C&-C6-alkyl-

WO 2012/136531

PC

m


n


X

is $, $(=Q), 5( Q)~ Q

In

a preferred embodiment,

NR6

T/EP2012/055471

6;

5; and

CR6aR6b

with respect

C( CR6aR6b) (-(=Q) or ((QH)(R6a)

to compounds of formula

I, supra,

represents a

A

4a 4b

R

4d

Z

4c

wherein

10

group j * indicates the point of attachment

of said group with the rest of

the molecule.

In

A

another preferred embodiment,

with respect to compounds

of formula

I, supra,

represents

H N

0

CH

15

wherein

1



the molecule. 20

In

R'



of formula

I, supra,

represents a C~-C6-alkyl- group;

wherein

said C~-C6-alkyl-

differently, C&

with

group is optionally

substituted,

identically or


-C&-alkoxy-, C&-C6-cycloalkyl-.

25 22

-QH,

-CN,

WO 2012/136531

In

R'

PC


said C&-C4-alkyl-

differently, C&

R'

group is optionally

1, 2 or 3 groups

substituted,

identically or


-OH,

-CN,


of formula

I, supra,

represents a methyl- or ethyl- group;

C&

R'

with


said methyl- or ethyl- group is optionally

differently,

In

I, supra,

-Cg-alkoxy-, C&-C6-cycloalkyl-.

wherein

10

of formula

represents a C~-C~-alkyl- group;

wherein

In


T/EP2012/055471

with

1, 2 or 3 groups

selected

identically or

substituted,

from: halogen,

-OH,

-CN,

-C)-alkoxy-, C&-C6-cycloalkyl-.



of formula

I, supra,

of formula

I, supra,

represents a methyl- or ethyl- group.

15 In

R'



represents a Cz-C6-cycloalkyl- group; wherein said C~-C6-cycloalkyl-

differently, 20

C&-Ct;-alkyl-, C&-C6-alkoxy-, C&-C6-cycloalkyl-,

In

R'

Preferably,

the C~-C6-cycloalkyl-

cyclopropyl-

or cyclobutyl-

identically or

cyclopropyl-

-OH,

-CN,

. or unsubstituted


group.


of formula

I, supra,

represents a C~-C6-cycloalkyl- group;

differently, C3 C6

with

1,

group is optionally

2 or 3 groups

cycloalkyl-, HO-C~-C6-alkyl-

Preferably,

the C&-C6-cycloalkyl-

cyclopropyl-

or cyclobutyl-

group is a substituted

In

More preferably,

or unsubstituted


HO-C&-C6-alkyl-


group.


30

substituted,



25

group is optionally


identically or

-CN, C&-C6-alkyl-,

. group is a substituted

group.

or unsubstituted


substituted,

More preferably,

cyclopropyl-

the Cz-C6-cycloalkyl-

group.


23

or unsubstituted

of formula

I, supra,

WO 2012/136531

R'

PC

represents a Cz-C6-cycloalkyl- group; group is optionally substituted


selected from: -F, -CN, C&-Cz-alkyl-, C~-C6-cycloalkyl-,

Preferably,

the C&-C6-cycloalkyl-

cyclopropyl-

or cyclobutyl-

In


R'

represents an arylgroup; wherein with

15

1, 2, 3 or 4 groups selected from: halogen, Cz-C6-cycloalkyl-,

HO-C&-C6-alkyl-

is a substituted

or unsubstituted

phenyl- group.

In


R'

represents an arylgroup; wherein

with 1, 2 or 3 groups alkyl-

20

.

-CN, C~-C6-alkyl-,

Preferably the arylgroup

of formula

I, supra,


substituted,


I, supra,

-CN, C~-C6-alkyl-,

Preferably the arylgroup is a substituted

or unsubstituted

HO-C~-C6-

phenyl-

gI oup.

In


R'

represents an arylgroup; wherein


said arylgroup is optionally

substituted,

with 1, 2 or 3 C&-C6-alkyl- groups. Preferably

25

or unsubstituted

In

R'

30

.

-OH,



of formula


substituted,

C&-Ct;-alkoxy-,

or unsubstituted

group.



.


group. More preferably, cyclopropyl-

with one group

HO-C&-Cz-alkyl-


or unsubstituted


10

T/EP2012/055471


methyl, ethyl,

4 Z* CH

C


the arylgroup is a substituted

is selected from:

H

I, supra,

phenyl- group.


*

of formula

*

NC

HO

)

24

of formula I, supra,

WO 2012/136531

PC

T/EP2012/055471

CH

CH

wherein



the molecule.

5

In



R'

of formula

I, supra,

represents a methyl- group or a cyclopropyl- group; wherein

said cyclopropyl-

group is optionally

substituted

with one fluorine

atom.

10

In



R' represents

an aryl- or heteroaryl-

group; wherein said aryl- or heteroaryl- group

is optionally

substituted,


aryl-

preferably

is a substituted

group

heteroaryl-


with

1, 2, 3 or 4 R' groups. The

or unsubstituted

group preferably is a substituted

phenyl-

or unsubstituted

group.

The

pyridyl- group.

15 In


R' represents

differently,


an arylgroup; wherein

with

unsubstituted

1


said arylgroup is substituted,

or 2 R' groups. The arylgroup preferably

identically or

is a substituted

or

phenyl- group.

20 In

R'


represents

heteroaryl-X-

25

an

aryl-X-

or

group is optionally


heteroaryl-X-

substituted,

group;

wherein

of formula I, supra, aryl-X-

said


with

or

1, 2, 3

or 4 R' groups. The arylgroup preferably is a substituted

or unsubstituted

phenyl-

group. The heteroaryl-

or unsubstituted

pyridyl-

gl

In

group preferably

is a substituted

oup.


R' represents



an aryl-X- group; wherein said aryl-X- group is substituted,

25

identically

WO 2012/136531

or differently, unsubstituted

In

5

R'

PC

with

T/EP2012/055471


1

or

phenyl- group.



represents

heteroaryl-0-

an

0- or heteroaryl 0-

aryl

wherein

said


substituted,

group is optionally

group;


0- or

aryl

with 1, 2, 3


or unsubstituted

phenyl-


or unsubstituted

pyridyl-

group preferably

is a substituted

gI oup.

10 In

R'



represents

an

aryl-0-

identically

or differently,

substituted

or unsubstituted

wherein

group; with

1

aryl-0-

said


group is substituted,

or 2 R' groups. The arylgroup preferably is a

phenyl- group.

15 In



R' represents

an aryl-S(=0),

or heteroaryl-S(=0),

-

-

or heteroaryl-S(=0)~- group; wherein said aryl-S(=0), -

group is optionally

1, 2, 3 or 4 R' groups. The integer 20

More preferably,

30

0. The


pyridyl-

group.

an aryl-S(=0),

identically

or differently,

Preferably,

p =

substituted

or unsubstituted

In

0 or p

=

-

heteroaryl-NR'-

1

or 2. Preferably,

p =

2. More preferably,

=

0 or p

is a substituted

or unsubstituted

is a substituted

or unsubstituted

2.


or 2 R' groups. The integer p equals 0, p =

0. The

1

or 2.

arylgroup preferably

is a

phenyl- group.


or heteroaryl-NR'-

group is optionally substituted,

3 or 4 R' groups.

1

with

said aryl-S(=0), - group is substituted,

group; wherein

with

an aryl-NR'-

0,




R' represents

p equals

group preferably


R' represents

substituted,

arylgroup preferably

phenyl-

In

25

p =


The arylgroup

preferably

26

group;


wherein

said aryl-NR'-

identically or differently, is a substituted

with

or

1, 2,

or unsubstituted

WO 2012/136531

phenyl-


pyridyl-

group.

In

5

PC

group preferably

R' represents

an

heteroaryl-NH-

group is optionally

or heteroaryl-NH-

aryl-NH-

3 or 4 R' groups.

substituted,

The arylgroup

phenyl-


pyridyl-

group.

or unsubstituted

is a substituted




wherein

group;

T/EP2012/055471

said


preferably

group preferably

or

aryl-NH-

with

1, 2,

is a substituted

or unsubstituted

is a substituted

or unsubstituted

10 In

R



represents

aryl-CR 'R -

an

or

aryl-CR"R"- or heteroaryl-CR"R"-

unsubstituted

an aryl-CH2-


pyridyl-

group.

30

pyridyl-

group.

group preferably


represents

-(CHz)m-C&-C6-alkenyl,

is a substituted

is a substituted

or

a

hydrogen

-(CH&)~-C&-C6-alkynyl,

27

said aryl-CH~-

or

with 1, 2,

is a substituted

or unsubstituted

is a substituted

or unsubstituted


group; wherein said aryl-C(=0)- or


with 1,

is a substituted

or unsubstituted

is a substituted

or unsubstituted


atom


wherein


groups. The arylgroup preferably


R'

preferably


phenyl-

In

said

identically or


an aryl-C(=0)- or heteroaryl-C(=0)-

heteroaryl-C(=0)R~

group;

group preferably


R' represents

substituted,

The arylgroup

phenyl-

2, 3 or 4

substituted,

group preferably

or heteroaryl-CH~-

group is optionally

heteroaryl-CH&-

In

group; wherein



3 or 4 R' groups.

25

-

group.

pyridyl-

R' represents

20

phenyl- group. The heteroaryl-

or unsubstituted

In

group is optionally

'R

with 1, 2, 3 or 4 R' groups. The arylgroup preferably

differently,

15

heteroaryl-CR


or

a

aryl-, heteroaryl-,

of formula I, supra, -CN,

C&-C6-aikyl-,

aryl-X- group;

WO 2012/136531

wherein said C&-C6-alkyl-, -(CH&)m-C&-C6-alkenyl,

or heteroaryl-

T/EP2012/055471

PC


aryl-, aryl-X-



with

1

or 2

R' groups.

5

In


R' represents

differently,

a heteroaryl-

with

1

or unsubstituted

10

In


substituted,

is optionally

group which

or 2 R' groups. The heteroaryl-


group preferably

identically

is a substituted

pyridyl- group.




R'is selected from: H) H3C CHz ) H3C S ) H3C

S(0)z

)

HO CHz CHz ) HO CHz CHz CHp

H3C CH(OH) ) HpC:CH )

Jl* * C=CH

H3C

OH 7

)

7

0 H~C~

I

CH3

OH

15

OH 7

0

7

CH3

!

~0 HGC

OH 7

0*

F 7

~0 F

or

F

CI

28

HBC

WO 2012/136531

PC

T/EP2012/055471

~O

CHB

~0 F

HBC

F

OH

! F

F~0

+F

!

F

F

7

OH

7

S

S

S

S

F

! F

S

H

C

0 CHG

CH

NH

NH

~CN

29

NH

~CH~

WO 2012/136531

H

PC

T/EP2012/055471

C

, NH

QH

OH

~NH H

C

OH

wherein

0



the molecule.

In

R'



the phenyl- group is either substituted

-C(=0)N(H)R" group, or with a

the

wherein

differently,

differently,

In

halogen,

20

phenyl-S-

with

1

and

group is optionally

group and a

identically

substituted,

or

HgC-;

identically

or

or 2 groups selected from: -F, H~C-O-, HO-, HgC-.

R" are selected,


independently

-CN, C~-Ce-alkyl-, C~-Ce-alkoxy-,


R" and R" represent,

substituted,

or 2 groups selected from: -F, H~C-O-, HO-,


R", R", R",

In

1

with a methyl-

HO-CHz- group;

group is optionally

phenyl-0-

with

the

wherein

15

I, supra,

represents a pyridyl-, phenyl-, phenyl-0- or phenyl-S- group; wherein

10

of formula

independently


from each other, from hydrogen,

halo-C~-Ce-alkyl-,

halo-C~-Ce-alkoxy-.


of formula


I, supra,

or halogen atom,

or a -CN, C&-C6-alkyl-, C&-Ct;-alkoxy-, halo-C&-Ct;-alkyl- or a halo-C&-C6-alkoxy- group.

30

WO 2012/136531

In

PC

of the present invention

another preferred embodiment


independently

C~-Ce-alkoxy- or a halo-C~-Ce-alkyl-

5

In

R

' and

T/EP2012/055471

represent,

R

or halogen atom, or a C~-C6-alkyl-,

group.



R" and R" represent


R" and R" represent

hydrogen.

In



independently

10

C~-C6-alkyl-,

In

and R

R

In

'is

C&-C6-alkoxy- group; with

In

from

each other,

a hydrogen

and R4' represents

a hydrogen

halo-,

from:

C& -C6-alkoxy-C&

In

-CN,

R4'

R"(R'

)N-C&

R

R

or a C~-C4-alkyl-

R" and R" is

-OH,

and R

'

represent

and R

'

represent

group; with the

not a hydrogen atom.

C~-C6-alkyl-,

-C6-alkyl-,

C~-C6-alkoxy-, HO-C&-C6-alkyl-,

R"

a group

halo-C~-C6-alkyl-, NC-C&-C6-alkyl-,

-C6-alkyl-, and halo-C& -C6-alkoxy-C& -Ce-alkyl-.

represents

a hydrogen

of the present invention one of the groups atom while

the other one represents

selected from: halo-, -CN, -OH, C~-C6-alkyl- and C~-C6-alkoxy-.

In

-CN,

atom while the other one represents

-OH,


and

represent

of the present invention one of the groups


halo-C&-C6-alkoxy-,

30

'

or a C~-C6-alkyl- group.



selected

and R

the proviso that at least one of the groups


proviso that at least one of the groups

25

R




independently

In

-OH,

not a hydrogen atom.

independently

20



independently 15

-CN,

-C6-alkoxy- group.

C~


C&-C6-alkyl-,



of the present invention 31

R"

a group

WO 2012/136531

either:

or:

In

5

= C&-C&-akyl- and R

R

R4b =

hydrogen

or: R4'=

R'

10

and R4' = C~-C~-akyl-.


R"= H, R"=CH~,

H,

I-I, R4b = CH&, R4' = I-I,

and

and R4' =

of formula

-(CH&). -C&-C6-alkenyl,

t o 7-membered heterocycloalkyl),

-(CH~) -(3-

aryl-C~ -C6-alkyl-,


to 7-membered

halo-C~-C6-alkyl-,

HO-C~ -C6-alkyl-,

-C& -C6-alkyl-CN,

halo-C~-C6-alkoxy-C~-C6-alkyl-,

heterocycloalkyl-,

I, supra,

-(CH&), -C&-C6-alkynyl,


C~-C6-alkoxy-C~-C6-alkyl-,

C~-C6-cycloalkyl-,

3-



group j


said -(CH&)

t o

-(3-

7-membered

heterocycloalkyl-,

R'

C~

with

-(CH&)

to

7-membered

group is optionally

1, 2, 3, 4 or 5 R' groups.


a C&-C6-alkyl-,

of formula

-(3- to 7-membered

I, supra,

heterocycloalkyl),

or halo-C~ -Ct;-alkyl- group;

-Ct;-alkoxy-C~-C6-alkyl-

wherein

3-


C~-C8-cycloalkenyl-,


represents


C&-C6-cycloalkyl-,


substituted,

aryl-C&-C6-alkyl-,

C~-Ce-alkoxy-C~-C6-alkyl-,

-Cl C6 alkyl-CN,


In

heterocycloalkyl),

halo-C~-C6-alkyl-,

HO-C~ -Ce-alkyl-,

20


-(CH~), -C~-C6-alkynyl,


25

I-I.


another preferred embodiment, represents

R"= H;

R"(R")N-C~-C6-alkyl-,

15

T/EP2012/055471

' = hydrogen;


eitherR"=

In

PC

said C~-C6-alkyl-,

-(CH~)

-(3- to 7-membered

heterocycloalkyl),

or halo-C&-C6-alkyl- group is optionally substituted,



with

1, 2 or 3 R' groups.

30 In



of formula

I, supra,

R' is selected from: Hp

(CH3)2CH

HO C(CH3)p

y

)

CHF2

p

CF3

p

CF3 CH2

)

CF3 CH2 CH2

)

HO C(CH3))CH) ) HO CHp CH(OH) ) H3C

32

CF3 CH(OH)

0 CHp

)

HpN

)

HO CH2 CHp CHp )

WO 2012/136531

HzN-C(CHg)z-)

S(=0)2

)

H3C

S(:0)2 CH2

y

(CH3)zN

H3C

&

S(:0)2 CH2

C(=0) N(H)

CH2 CH2 ) NC CH2 ) H3C

HzN-C(=0)-CHp

(CHg)zN-CHz-CHz-CHz-)

(CHg)zN-CHz-CHz-)

( C Hz)zN-CHz-)

(CH3)2N C(CH3)2 HO

T/EP2012/055471

PC

C(:0) CHz

H3C N(H)

)

CH2

CH2 H3C

HO

)

C(=0)

C(:0) N(CH3)

S(:0)2 CH2

N(H) CH2 CHp

CHz CHp

y

0 II

S

vU

Q

OH

CHG I

'

N

CH3

CH3

I

S

N

V V

N

N

I

I

CH2

CH2

C3 N

CH2 H~C

F

CH

"

CH~

F H I

N N

CH2

N=N

'

CH3

/

I

~ wherein

N~

N:N

N

NH

/

'-CH 2

N~~

NH

CH2



the molecule.

In


R' represents


a group selected from:

33

of formula

I, supra,

WO 2012/136531

PC

F

CH

F

0

F~F H

CH

wherein

T/EP2012/055471

H~H


of said groups with the rest of the

molecule.

5

In

R',



R", R", and R" represent, independently said C&-C6-cycloalkyl-

differently with

10

C&-C6-alkyl-,

In

R',

C&

1

R", R',

and

wherein

said C~-C6-cycioalkyl-

differently

with

1

or HO-

-OH, -CN, C~-C6-alkyl-,


R" represent, independently

identically

halo-C&-C6-alkoxy-.

of formula

I, supra,

atom, or


a C~-C6-alkyl-, C~-C6-cycloalkyl- or aryl-C~-C6-alkyl-

15

substituted,

or 2 groups selected from: halogen,


atom, or

group;

group is optionally

-C6-alkoxy-, halo-C&-C6-alkyl-,

I, supra,


a C~-C6-alkyl-, C~-C6-cycloalkyl- or aryl-C~-C6-alkyl-

wherein

of formula

group;

substituted,

group is optionally

or 2 groups selected from: halogen,

identically

-OH, -CN, C&-C6-alkyl-,

or HO-

C~-C6-alkyl-.

In

20


R" represents

a hydrogen

atom or methyl-

wherein said Cz-C6-cyclpropyl-

In

R'

25

C~-C6-alkenyl-,

30

-C( 0)R6

-NOES/

-N(H)C(=0)R

-N(R ')C(=0)N(R ')R

')S(=0)R

-N(R

-N(H)C(=0)OR

-N(H)S(=0)zR

(-( 0)N(R6a)R6b

')C(=0)R

of formula -CN,

I, supra,

C&-C6-aikoxy-,

R"(R")N-C~-C6-alkyl-,

heterocycloalkyl-, (-(

0)0

R6

aryl-,

N(R6a)R6b

-N(H)C(=0)N(R ')R

-N(R ')C(=0)OR

-N(R")S(=0)2R' 34

group;

halo-C~-C6-alkoxy-C& -C6-alkyl-,

3- to 7-membered

(-( 0)N(H)R6a

heteroaryl-,

-N(R

halo-C~-C6-alkoxy-,

C&-C6-alkoxy-C~ -C6-alkyl-,

C~-C6-alkynyl-,

I, supra,

with one -CN group.


halo-C~-C6-alkyl-,

HO-C~ -C6-alkyl-,

substituted

or halogen atom, or a HO-,

a hydrogen

C~-C6-alkyl-,

of formula

group or a C~-C6-cyclpropyl-

group is optionally


represents


-N(H)S(=0)R

-N=S(=0)(R")R'

-OR'

WO 2012/136531

PC

-0(C=O)N(R ')R

-0(C=O)R

-S(=0)N(R6')R6b

-S(=0)zR6

-S(=0)R

-SR

-0(C=O)OR

T/EP2012/055471

-S(=0)N(H)R -S(=0)zN(R6')R6b

-S(=0)zN(H)R6

-S(=0)(=NR")R' group; said aryl- or heteroaryl-

wherein

or differently,

In

with


an aryl- or aryl-X- group,

identically

which is substituted

of formula I, supra, with two R' groups

groups together form a bridge: *0(CH~)0*, *NH(C(=0))NH*, wherein * represent the point of attachment

ortho to each other,

10

substituted,

1, 2 or 3 C~-C6-alkyl- groups.


R' represents

group is optionally

said two R

*0(CH&)&0*,

to said aryl

ring.

In


R'

15

represents

C&-C6-alkyl-, halo-C&-C6-alkyl-,

N(H)C(=0)R6

In

20


a hydrogen

7-membered

HO-C&-C6-alkyl-,

-OR6

represents

halo-C~ -C6-alkyl-,

H&N-C&-Ct;-alkyl-,

-C(=0)N(H)R"

heterocycloalkyl-,

of formula -CN,

I, supra,

C&-C6-alkoxy-,

C&-C6-alkenyI, 3-

-N(R")R"

to

-C(=0)0-R'

or -SR' group


R'


a

halogen


atom, or

halo-C~ -C6-alkoxy-,

a HO-,

HO-C~ -C6-alkyl-,

of formula

C&-Ct;-alkoxy-,

I, supra,

C&-C6-alkyl-,

-C(=0) N(H) R", -N(R")R",

-C(=0)0-R' or -OR' group.

In

25


R'

represents

HO-C~-Ce-a[ky[,

a halogen


atom, or a

-C( 0)N(R6a)R6b

-CN,

N(R6a)R6b

-OH,

of formula

C&-C6-alkoxy-,

N(H)C( 0)R6

I, supra,

C&-C6-alkyl-,

N(R6c)C( 0)N(R6a)R6b

-S(=0)~R' or -S(=0)~OH group.

In

30


the invention

relates to compounds of formula I,

wherein X is S.

In


X is


S(=0).

35

of formula

I, supra,

WO 2012/136531

In

PC


T/EP2012/055471


of formula

I, supra,


of formula

I, supra,


of formula

I, supra,

X is S(=0)&.

In

5


XisO. In


X is NR'. Preferably,

10

In

NH

or N(CH~). Most preferably,


X is

In

X is


of formula

I, supra,


of formula

I, supra,


of formula

I, supra,


of formula

I, supra,


of formula

I, supra,

CR"R' . Preferably, X is CHz.


X is

X is NH.

C(=0).

15 In Z

In

20

another preferred embodiment, represents a -C(=0)N(H)R' group.


nis 1.

In


m is

25

0 or 1.

It is to be understood

that the present invention

the preferred embodiments

relates also to any combination

of

the invention

is

described above.

Some examples of combinations

are given hereinafter.

However,

not limited to these combinations.

30

In

a preferred

formula

embodiment

the present

I

36

invention

is related

to compounds

of

WO 2012/136531

PC

T/EP2012/055471

R NH N

R A

in which

A

represents 4a 4b

R

4d

Z

4c

wherein * indicates the point of attachment

10

15


the molecule;

Z

represents a -C(=0)N(H)R' group or a -C(=S)N(H)R" group;

R'

represents a C~-C6-alkyl-, a C~-C6-cycloalkyl- or an arylgroup;

wherein

said C&-C6-cycloalkyl-


or aryl-

group is optionally


-OH, -CN, C~-C6-alkyl-, C~-C6-alkoxy-, C~-C6-cycloalkyl-,

wherein

said

differently,

20

C&-Ct;-alkyl-

with

substituted,

group

is optionally

HO-C~-C6-alkyl-;

substituted,

identically


C~-C6-alkoxy-, C3-C6-cycloalkyl-,

HO-C~-C6-alkyl-;

37

-OH,

or -CN,

WO 2012/136531

represents a hydrogen

atom or a halogen atom, or a -CN, C&-C6-alkyl-,

-(CH~) -C~-C6-alkenyl,

-(CH~) -C~-Cs-cycloalkenyl,

-(CH~)m-C~-C6-cycloalkyl, -(CH&)

-(4-

to

-(CH&)

-(3-

8-membered

-C~

S( 0)R6

-S-(CH&), -(3-

15

wherein

0)(

S(

NR6a)R6b

-C6-alkyl-,

to 7-membered

C4-C~-cycloalkenyl-,

20

30

aryl-X-,

heteroaryl-X-,

or

C~

-C6-alkyl-X-,

-X-(CH2) -(3-

to

1, 2, 3, 4 or

to

8-membered -C&

-C6-alkyl-aryl,

substituted,

group is optionally

heteroaryl-

with

5 R' groups;

R


-OH, C~-C6-alkyl-,

C~-C6-alkoxy-,

Rea(Reb) N-C&-Ce-alkyl-,

HO-C&


R'

C~-C6-alkenyl-,

aryl-,

-X-(CHz) -(4-



heterocycloalkyl),


R'

or

-(CH~)m-C~-C6-alkynyl,



R

-SR

-X-(CH&)m-C&-C8-cycloalkenyl,


R'

-OR

group;

C~-C6-alkynyl-,

-X-(CH~) -C&-C6-alkynyl,

25

-C(=0)N(H)R",

heterocycloalkyl-,

-X-(CH&)m-C&-C6-alkenyl,

7-membered

to

S (CH&) -N(R6a)R6b

S( 0)&N(R6b)R6c

aryl-C&-Ct;-alkyl-,

3-

cycloalkyl-,

-C6-alkyl-X-,

8-membered

-N(H)C(=0)R

-NOz,

-(CH~)~-C~-C6-alkenyl,

-(CH&)m-C&-C6-cycloalkyl, C3 Ct;

to

-C(=0)R',

heteroaryl-X-,

to 7-membered heterocycloalkyl) C~

C~

aryl-,

-X-(CH~) -(3-

-X-(CH~) -(4-

-N(R ')R

-C(=0)0-R

said

C~-C6-alkynyl-,

-X-(CH~) -C~-C6-cycloalkyl,

a r y l-X-,

S( 0)&R6

7-membered


heterocycloalkyl),

-C(=0)N(R ')R

to

heteroaryl-,

-C6-alkyl-heteroaryl,

-X-(CH~) -C~-C6-alkynyl,


aryl-C& -C6-alkyl-,

3-



7-membered

heterocycloalkyl),

Rea(R6b)N-C&-C6-alkyl-,

C&-C6-cycloalkyl-,

C~-C6-alkenyl-,

-C~ -C6-alkyl-aryl,

7-membered



heterocycloalkyl-,

to

-(CH~) -C~-C6-alkynyl,

halo-C~-C6-alkyl-,


10

T/EP2012/055471

PC

represents

a hydrogen


halo-C~-C6-alkyl-,

halo-C~-C6-alkoxy-,

-C6-alkyl-,

NC-C&-C6-alkyl-,

halo-C&-C6-alkoxy-C&-C6-alkyl-

atom, or a

C~-Ce-alkyl-,

-(CHz)m-C&-C6-cycloalkyl,

38


group; -(CH~). -C~-Ce-alkenyl,

-(CH&)~-(3-

to 7-membered

WO 2012/136531

T/EP2012/055471

PC

aryl-C& -Ce-alkyl-,

heterocycloalkyl),

Rea(Reb)N C1 Ce-alkyl-,

0-C~ -Ce-alkyl-,

H

-C~ -Ce-alkyl-CN,



to 7-membered

heteroaryl-C& -Ce-alkyl-, halo-C&-Ce-alkyl-,

heterocycloalkyl-,

3-

C~-Ce-cycloalkyl-,



group j

wherein

said

-(CH~). -C~-Ce-alkenyl,

C&-Ce-alkyl-,

-(CH~) -C~-Ce-cycloalkyl,

-(CH~) -(3-

aryl-C~ -Ce-alkyl-,

heteroaryl-C&-Ce-alkyl-,

R"(R")N-C~-Ce-alkyl-, 10

heterocycloalkyl), halo-C~-Ce-alkyl-, -C& -Ce-alkyl-CN,


heterocycloalkyl-,

group is optionally

7-membered

Hp-C~ -Ce-alkyl-,


to 7-membered

to

-(CH~). -C~-Ce-alkynyl,


C4-CB-cycloalkenyl-,


substituted,

3-

C~-Ce-cycloalkyl-,

with

1, 2, 3, 4 or 5

R' groups;

15

R

R',

R

R'

represent, C&

independently

-Ce-alkyl-,

H

7-membered

0-C& -Ce-alkyl-,

25

C~-Ce-alkoxy-, halo-C~-Ce-alkyl-,

halo-C&-Ce-alkyl-,

C~-Ce-alkynyl-,

-C( 0)Re

-NOES)

-N(H)C(=0)R

')C(=0)N(R")R

-N(Re')S(=0)Re

-0(C=O)R

halo-C&-Ce-alkoxy-,

C~-Ce-alkoxy-C~ -Ce-alkyl-,

heteroaryl-,

-N(R

or

identically or

-N(R

(-( P)N(Rea)Reb

')C(=0)R

-0(C=O)N(R ')R

-N(Re')S(=0)&Re

-0(C=O)OR

S( 0)&Re

-SR

S( 0)&N(H)Re

-S(=0)(=NR")R' group; 39


heterocycloalkyl-, (-( P)P

Re

aryl-,

N(Rea)Reb

-N(H)C(=0)N(R ')R

-N(R")C(=0)OR'

-N(H)C(=0)OR

C~-Ce-alkoxy-,

-CN,

halo-C~-Ce-alkoxy-C~ -Ce-alkyl-,

3- to 7-membered

C( 0)N(H)Rea

-N(H)S(=0)&Re

S( 0)N(Rea)Reb

halo-C~-Ce-alkoxy-;


a hydrogen

C~-Ce-alkenyl-,

to

or 2 groups selected from: halogen, -OH, -CN, C~-Ce-alkyl-,

HO-C~-Ce-alkyl-,

C&-Ce-alkyl-,

aryl-C~-Ce-alkyl-,

substituted,

group is optionally

1

represents

3-

C&-Ce-alkenyl-,

heteroaryl-,

differently with

Hp-C~ -Ce-alkyl-,

30

aryl-,

atom, or a

group;

wherein said Cz-Ce-cycloalkyl-

R'

Cz-Ce-cycloalkyl-,

heterocycloalkyl-,

heteroaryl-C~-Ce-alkyl-

20


-N(H)S(=0)R'

-N=S(=0)(Re')Reb

-S(=0)R

-ORe

-S(=0)N(H)R S( 0)&N(Rea)Reb

WO 2012/136531

wherein

T/EP2012/055471

PC


or differently,

1, 2, or 3

with

group is optionally

substituted,

identically

C~-Cb-alkyl- groups;

or when 2 R' groups are present ortho to each other on an aryl ring, said 2 R' groups together form a bridge:

* represent

*0(CH&)&0*, *0(CH&)0*, *NH(C(=0))NH*, wherein

to said aryl ring;

attachment R'

represents a hydrogen or halogen atom, or a -CN, C&-Cb-alkoxy-, C&-C|;-alkyl-,

10

halo-C~-Cb-alkyl-,


C~-Cb-alkoxy-C~-Cb-alkyl-,

halo-C~-Cb-alkoxy-C~-Cb-alkyl-,

3- to 7-membered

C&-Ct;-alkynyl-,

-C(=0)Rb

-N(R")C(=0)R'

15

0(C 0)N(R6a)R6b 7-membered

25

heterocycloalkyl)

S( 0)R6

substituted,

-NQ~,

N(Roc)S(

-0(C=O)R

-OR

S( 0)N(H)R6

0)R

S( 0)N(R6a)R6b

-S(=0)(=NR|'c)R|' or -S(=0)z-(3- to

group;


optionally C&

SR6

heteroaryl-,

-N(Rb')Rbb

N(H)S( 0)Re

-S(=0)&N(R ')R

-S(=0)&N(H)Rt'

-S(=Op)R

wherein

0(C 0)OR6

aryl-,

-N(R")C(=0)N(R")R'

-N=S(=0)(R ')R

-N(R ')S(=0)zR

-N(H)S(=0)zR

C~-Cb-alkenyl-,

-C(=0)0-Rb

-N(H)C(=0)N(R")R'

N(Rec)C( 0)ORe

N(H)C( 0)ORe

HO-C&-C|;-alkyl-,

heterocycloalkyl-,

-C(=0)N(Rb')Rbb

-C(=0)N(H)Rb',

-N(H)C(=0)R'

20

the point of

heterocycloalkyl-

identically

or heteroaryl-

or differently,

group, is

with 1, 2, 3, or 4

-Cb-alkyl- groups;

m


n

isanintegerof0,

X

is S, S(=0), S(=0)&,

or a stereoisomer,

4or5;

1, 2, 3,

0,

and

C(=0) or CR"R'b

NR'

a tautomer,

6; '




30 In


formula

the present invention is related to compounds of

I:

40

WO 2012/136531

PC

T/EP2012/055471

R NH N

R A

in which

A

represents 4a 4b

R

4d

Z

4c

wherein

10

15


the molecule;

Z


R'

represents a C~-C6-alkyl- or a C3-C6-cycloalkyl- group; wherein said C~-C6-cycloalkyl-

differently, C~

-C6-alkyl-,

wherein

with C~

said

differently,

20


identically or


-C6-alkoxy-, C~-C6-cycloalkyl-, C&-Ct;-alkyl-

with

substituted,

group is optionally

HO-C~

group is optionally

HO-C~-C6-alkyl-;

41

-CN,

-C6-alkyl-;

substituted,

identically or


C~-C6-alkoxy-, C3-C6-cycloalkyl-,

-OH,

-OH,

-CN,

WO 2012/136531

atom or a halogen

represents a hydrogen -(CH~) -C~-C6-alkenyl,

-(4-

to

-(CH&)

-(3-

8-membered

7-membered

-C(=0)N(R ')R S( 0)R6

-S-(CH&), -(3-

15

wherein

0)(

S(

NR6a)R6b

-C6-alkyl-,

to 7-membered

C4-C~-cycloalkenyl-,

20

30

aryl-X-,

heteroaryl-X-,

or

C~

-C6-alkyl-X-,

-X-(CH2) -(3-

to

1, 2, 3, 4 or

to

8-membered -C&

-C6-alkyl-aryl,

substituted,

group is optionally

heteroaryl-

with

5 R' groups;

R


-OH, C~-C6-alkyl-,

C~-C6-alkoxy-,


HO-C&


R'

C~-C6-alkenyl-,

aryl-,

-X-(CHz) -(4-



heterocycloalkyl),


R'

or




R

-SR



R'

-OR

group;

C~-C6-alkynyl-,

-X-(CH~) -C&-C6-alkynyl,

25

-C(=0)N(H)R",

heterocycloalkyl-,


7-membered

to

S (CH&) -N(R6a)R6b

S( 0)&N(R6b)R6c

aryl-C&-Ct;-alkyl-,

3-

cycloalkyl-,

-C6-alkyl-X-,

8-membered

-N(H)C(=0)R

-NOz,

-(CH~)~-C~-C6-alkenyl,

-(CH&)m-C&-C6-cycloalkyl, C3 Ct;

to

-C(=0)R',

heteroaryl-X-,

to 7-membered heterocycloalkyl) C~

C~

aryl-,

-X-(CH~) -(3-

-X-(CH~) -(4-

-N(R ')R

-C(=0)0-R

said

C~-C6-alkynyl-,

-X-(CH~) -C~-C6-cycloalkyl,

a r y l-X-,

S( 0)&R6

7-membered


heterocycloalkyl),


to

heteroaryl-,

-C6-alkyl-heteroaryl,

-X-(CH~) -C~-C6-alkynyl,

7-membered

3-



10

aryl-C& -C6-alkyl-,

Rea(R6b)N-C&-C6-alkyl-,

C&-C6-cycloalkyl-,

C~-C6-alkenyl-, -C~

heterocycloalkyl),



-C~ -C6-alkyl-aryl,

to

C&-C6-alkyl-,

-CN,

-(CH~) -C~-C6-alkynyl,

halo-C~-C6-alkyl-,


heterocycloalkyl-,

atom, or a

-(CH~) -C~-Cs-cycloalkenyl,

-(CH~)m-C~-C6-cycloalkyl, -(CH&)

T/EP2012/055471

PC

represents

a hydrogen


halo-C~-C6-alkyl-,

halo-C~-C6-alkoxy-,

-C6-alkyl-,

NC-C&-C6-alkyl-,


atom, or a

C~-Ce-alkyl-,

-(CHz)m-C&-C6-cycloalkyl,

42


group; -(CH~). -C~-Ce-alkenyl,

-(CH&)~-(3-

to 7-membered

WO 2012/136531

T/EP2012/055471

PC

aryl-C& -Ce-alkyl-,

heterocycloalkyl),


0-C~ -Ce-alkyl-,

H

-C~ -Ce-alkyl-CN,



to 7-membered

heteroaryl-C& -Ce-alkyl-, halo-C&-Ce-alkyl-,

heterocycloalkyl-,

3-

C~-Ce-cycloalkyl-,



group j

wherein

said


C&-Ce-alkyl-,

-(CH~) -C~-Ce-cycloalkyl,

-(CH~) -(3-

aryl-C~ -Ce-alkyl-,

heteroaryl-C&-Ce-alkyl-,

R"(R")N-C~-Ce-alkyl-, 10

heterocycloalkyl), halo-C~-Ce-alkyl-, -C& -Ce-alkyl-CN,


heterocycloalkyl-,

group is optionally

7-membered

Hp-C~ -Ce-alkyl-,


to 7-membered

to

-(CH~). -C~-Ce-alkynyl,




substituted,

3-

C~-Ce-cycloalkyl-,

with

1, 2, 3, 4 or 5

R' groups;

15

R

R',

R

R'

represent, C&

independently

-Ce-alkyl-,

H

7-membered

0-C& -Ce-alkyl-,

25

C~-Ce-alkoxy-, halo-C~-Ce-alkyl-,

halo-C&-Ce-alkyl-,

C~-Ce-alkynyl-,

-C( 0)Re

-NOES)

-N(H)C(=0)R

')C(=0)N(R")R

-N(Re')S(=0)Re

-0(C=O)R

halo-C&-Ce-alkoxy-,

C~-Ce-alkoxy-C~ -Ce-alkyl-,

heteroaryl-,

-N(R

or

identically or

-N(R

(-( P)N(Rea)Reb

')C(=0)R

-0(C=O)N(R ')R

-N(Re')S(=0)&Re

-0(C=O)OR

S( 0)&Re

-SR

S( 0)&N(H)Re

-S(=0)(=NR")R' group; 43


heterocycloalkyl-, (-( P)P

Re

aryl-,

N(Rea)Reb

-N(H)C(=0)N(R ')R

-N(R")C(=0)OR'

-N(H)C(=0)OR

C~-Ce-alkoxy-,

-CN,

halo-C~-Ce-alkoxy-C~ -Ce-alkyl-,

3- to 7-membered

C( 0)N(H)Rea

-N(H)S(=0)&Re

S( 0)N(Rea)Reb

halo-C~-Ce-alkoxy-;


a hydrogen

C~-Ce-alkenyl-,

to


HO-C~-Ce-alkyl-,

C&-Ce-alkyl-,

aryl-C~-Ce-alkyl-,

substituted,

group is optionally

1

represents

3-

C&-Ce-alkenyl-,

heteroaryl-,

differently with

Hp-C~ -Ce-alkyl-,

30

aryl-,

atom, or a

group;


R'

Cz-Ce-cycloalkyl-,

heterocycloalkyl-,

heteroaryl-C~-Ce-alkyl-

20


-N(H)S(=0)R'

-N=S(=0)(Re')Reb

-S(=0)R

-ORe

-S(=0)N(H)R S( 0)&N(Rea)Reb

WO 2012/136531

wherein


or differently, R'

substituted,

identically

represents a hydrogen or halogen atom, or a -CN, C&-C6-alkoxy-, C&-C6-alkyl-, halo-C~-C6-alkyl-,




-C(=Q)R6

3- to 7-membered

-N(R

10

0(C 0)N(R6a)R6b

wherein

substituted,

N(R6c)S( -OR6

S( 0)N(H)R6

-NQ~,

')R

0)R

-0(C=O)R S( 0)N(R6a)R6b

group;


optionally C&

heterocycloalkyl)

-N(R6~)R6b

-S(=0)(=NR")R' or -S(=0)~-(3- to

-S(=0)~N(R")R6b

-S(=0~)R6 -S(=0)~N(H)R6

7-membered

S( 0)R6

heteroaryl-,

-N(R ')C(=0)N(R

-N=S(=0)(R ')R

SR6

0(C 0)OR6

aryl-,

N(H)S( 0)R6

N(R6c)C( 0)OR6

-N(R6C)S(=0)zR6

-N(H)S(=0)zR

C&-C6-alkenyl-,

-C(=Q)Q-R6

-N(H)C(=0)N(R ')R

')C(=0)R

N(H)C( 0)OR6

HO-C&-C6-alkyl-,

heterocycloalkyl-,

-C(=Q)N(R6')R6b

-C(=Q)N(H)R6',

-N(H)C(=0)R

20

group is optionally

1, 2 or 3 C~-C6-alkyl- groups;

with

C~-C6-alkynyl-,

15

T/EP2012/055471

PC

heterocycloalkyl-

identically

or heteroaryl-

or differently,

group, is

with 1, 2, 3, or 4

-C6-alkyl- groups;

m


n

isanintegerof0,

X

is S, S(=0), S(=0)z,

or a stereoisomer,

4or5;

1, 2, 3,

0,

and

C(=0) or CR"R'b

NR'

a tautomer,

6; '



or a mixture of same. 25 In


formula


I: R NH N

R A 44

WO 2012/136531

PC

T/EP2012/055471

in which

5

represents

A

4a 4b *

R

4d

Z

4c


wherein


the molecule;

10 Z


R'

represents a C&-C6-alkyl-, a C&-C6-cycloalkyl- or an arylgroup;

wherein 15

or C~-C6-cycloalkyl-

said C~-C6-alkyl-

substituted,

with 1, 2, 3 or 4 groups selected from:


Cz-C6-cycloalkyl-,

C&-C6-alkoxy-,

-OH, -CN, C&-C6-alkyl-,

halogen,

or arylgroup is optionally

HO-C&-C6-

alkyl-; R'

r

20

e

p r

ese

n

ts a

h y d

-(CH~)m-C~-C6-alkenyl,

rog e

a

n

tom o


or

differently,

25

R',

R

R',

group is optionally with 1, 2 or 3 R' groups; heteroaryl-

-CN,

C&-C6-alkyl-,

aryl-X- group;


substituted,

aryl-,

identically

or

R


a

aryl-, heteroaryl-,

wherein said C&-C6-alkyl-, -(CH&)m-C&-C6-alkenyl, aryl-X-

r

-OH, C&-Ct;-alkyl-,

from each other, a hydrogen C&-C6-alkoxy-,

45


halo-C&-C6-alkyl-,

halo-C&-C6-alkoxy-,

WO 2012/136531

R"(R")N-C~-Ct;-alkyl-,

R'

0-C~ -Ce-alkyl-,

H

NC-C&-C|;-alkyl-,

C~-Cb-alkoxy-C~-C|, -alkyl-, halo-C~-Cb-alkoxy-C~-Cb-alkyl-

group;

represents

-(CH&). -C&-C|,-alkenyl,

atom, or a

a hydrogen

-(CH~). -C~-C|, -alkynyl,

heterocycloalkyl),

aryl-C& -Cb-alkyl-,

-(CH~)~-(3- to 7-membered

heteroaryl-C& -Cb-alkyl-, halo-C&-Ct;-alkyl-,

HO-C~ -Ce-alkyl-,

-C~ -C|;-alkyl-CN,



to 7-membered

C&-Cb-alkyl-,

-(CH~)m-C~-Cb-cycloalkyl,


10

T/EP2012/055471

PC

heterocycloalkyl-,

3-

C~-Cb-cycloalkyl-,



group j

wherein

said

-(CH~), -C~-Cb-alkenyl,

C~-Cb-alkyl-,

to

7-membered

-(CH&) -C&-Cb-cycloalkyl,

-(CH&)

aryl-C~ -Cb-alkyl-,

heteroaryl-C&-Cb-alkyl-,


-(3-

-(CH~), -C~-Cb-alkynyl,

heterocycloalkyl), halo-C~-C|;-alkyl-,

-Cb-alkyl-,

HO-C&

-Cl Cb alkyl-CN,

3-

C&-Ct;-alkoxy-C&-C|, -alkyl-, halo-C&-Cb-alkoxy-C&-C|, -alkyl-,

Cz-C|;-cycloalkyl-,

to 7-membered


heterocycloalkyl-,

group is optionally



substituted,

1, 2, 3, 4 or 5

with

R' groups;

20

R

R',

R

R'

represent, C~

independently

-Ce-alkyl-,

H

7-membered


0-C~ -Ce-alkyl-,

heterocycloalkyl-,

C~-Ce-cycloalkyl-,

aryl-,

atom, or a 3-

to

aryl-C&-Ct, -alkyl-,

or

Cz-Ce-alkenyl-,

heteroaryl-,

heteroaryl-C~-C|, -alkyl- group;

wherein said C~-C|;-cycloalkyl- group is optionally substituted,

25

R'

30

or 2 groups selected from: halogen, -OH, -CN, C~-C|;-alkyl-,

differently with

1

HO-C~-Cb-alkyl-,

C~-Cb-alkoxy-, halo-C~-Cb-alkyl-,

HO-C&

halo-C&-Cb-alkyl-,

-Cb-alkyl-,

C~-Cb-alkenyl-,

halo-C~-Cb-alkoxy-;


represents a hydrogen C&-Cb-alkyl-,

identically or

halo-C&-Cb-alkoxy-,

C&-C|;-alkoxy-C& -Ct;-alkyl-,

C~-Cb-alkynyl-,

heteroaryl-,

-C( 0)Re

-NOES/

-N(H)C(=0)R

-N(R

46

C~-C|, -alkoxy-,

R"(R'

)N-C&-Cb-alkyl-,

halo-C&-Ct;-alkoxy-C& -C|;-alkyl-,

3- to 7-membered

C( 0)N(H)R6a

-CN,

C( 0)N(R6a)R6b

')C(=0)R

heterocycloalkyl-, C(

0)0

R6

aryl-,

N(R6a)R6b

-N(H)C(=0)N(R ')R

WO 2012/136531

PC

-N(R ')C(=0)N(R ')R N(R6~)S( 0)R6

N(R6~)S( 0)&R6

-0(C=O)N(R")R'

-0(C=O)R'

-N(R ')C(=0)OR

-N(H)C(=0)OR

N(H)S( 0)&R6

-S(=0)N(R ')R

-N(H)S(=0)R

S( 0)(R6~)R6b

N

-SR'

-0(C=O)OR'

-S(=0)2R

T/EP2012/055471

-S(=0)R'

OR6

-S(=0)N(H)R'

-S(=0)2N(R ')R

-S(=0)2N(H)R



or differently, R'

identically

1, 2, or 3 C~-C|;-alkyl- groups;

with

halo-C~-C|, -alkyl-,




3- to 7-membered

C&-Ct;-alkynyl-,

-C(=0)Rt'

-N(R")C(=0)R'

15

0(C 0)N(R6a)R6b 7-membered

heterocycloalkyl)

S( 0)R6

substituted,

-NQ~,

N(Roc)S(

-0(C=O)R

-OR

S( 0)N(H)R6

0)R

S( 0)N(R6a)R6b

-S(=0)(=NR|'c)R|' or -S(=0)z-(3- to

group;


optionally C&

SR6

heteroaryl-,

-N(R|")R|'b

N(H)S( 0)Re

-S(=0)&N(R ')R

-S(=0)&N(H)Rt'

-S(=Op)R

wherein

0(C 0)OR6

aryl-,

-N(R")C(=0)N(R")R'

-N=S(=0)(R ')R

-N(R ')S(=0)zR

-N(H)S(=0)zR

C~-Cb-alkenyl-,

-C(=0)0-R|'

-N(H)C(=0)N(R")R'

N(Rec)C( 0)ORe

N(H)C( 0)ORe

HO-C&-C|;-alkyl-,

heterocycloalkyl-,

-C(=0)N(Rt")Rt'b

-C(=0)N(H)Rt",

-N(H)C(=0)R'

25

substituted,

represents a hydrogen or halogen atom, or a -CN, C&-C|;-alkoxy-, C&-C|;-alkyl-,

10

20

group is optionally

heterocycloalkyl-

identically

or heteroaryl-

or differently,

group, is

with 1, 2, 3, or 4

-Cb-alkyl- groups;

m


n

isanintegerof0,

X

is S, S(=0), S(=0)&,

or a stereoisomer,

4or5;

1, 2, 3,

0,

and

C(=0) or CR"R'b

NR'

a tautomer,

6; '




30 In


formula


I:

47

WO 2012/136531

PC

T/EP2012/055471

R NH N

R A

in which

A

represents 4a 4b

R

4d

Z

4c


10


the molecule;

Z


R'

represents a C~-C6-alkyl-, a C~-C6-cycloalkyl- or an arylgroup;

wherein

15

said C&-C6-alkyl-

substituted, halogen,



-OH, -CN, C~-C6-alkyl-,



C~-C6-alkoxy-,

C~-C6-cycloalkyl-,

HO-C~-C6-

alkyl-; 20

R'

represents

a

-(CH&)m-C&-C6-alkenyl,

atom or

hydrogen


48

a

-CN,

aryl-, heteroaryl-,

C~-C6-alkyl-,

aryl-X- group;

WO 2012/136531

PC


or

aryl-X-

differently,

5

R',

R',

R


T/EP2012/055471

aryl-,


substituted,

identically

or

R

represent,


independently

or a

C&-C6-alkyl-

group j

R'

10

represents

a hydrogen


atom, or a


-(CH~) -(3-

to 7-membered


heterocycloalkyl),

HO-C~ -C6-alkyl-,


to 7-membered

-C& -C6-alkyl-CN,



15


C&-C6-alkyl-,

heterocycloalkyl-,


3-

C~-C6-cycloalkyl-,


group j

wherein

said

-(CH~), -C~-C6-alkenyl,

C~-C6-alkyl-,

to

7-membered


-(CH&)

aryl-C~ -C6-alkyl-,



20

-(3-

HO-C&


to 7-membered

heterocycloalkyl), halo-C~-C6-alkyl-,

-C6-alkyl-,

-C~ -C6-alkyl-CN,


heterocycloalkyl-,

group is optionally



Cz-C6-cycloalkyl-,

3-


1, 2, 3, 4 or 5


atom, or a

substituted,


R' groups;

25

R'

R",

R'

R"

represent, independently C~

-C6-alkyl-,

H

7-membered

0-C~ -C6-alkyl-,

heterocycloalkyl-,

heteroaryl-C~-C6-alkyl-

30

C~-C6-cycloalkyl-,

aryl-,

heteroaryl-,

C~-C6-alkenyl-,

3-

aryl-C&-C6-alkyl-,

to or

group;



identically or


differently with

1

HO-C~-C6-alkyl-,

C~-C6-alkoxy-, halo-C~-C6-alkyl-,

49

halo-C~-C6-alkoxy-;

WO 2012/136531

R'

represents


a hydrogen

HO-C~ -Ce-alkyl-,

C&-Ct;-alkenyl-,

C&-C6-alkoxy-C~ -Ce-alkyl-,

heteroaryl-,

-C( Q)R6

-NOES/

-N(H)C(=0)R'

-N(R ')C(=0)N(R ')R

-N(R«)S(=Q)R6

-S(=0)N(R ')R

10

-S(=0)2R

N(R6a)R6b

R6

-N(H)S(=0)R -QR6

-N=S(=Q)(R6')R6b

-N(R«)S(=0)&R6

-S(=0)R

-SR

-0(C=O)OR

aryl-,

-N(H)C(=0)N(R")R'

-N(R ')C(=0)OR

-N(H)C(=0)OR

-0(C=O)N(R ')R

-0(C=O)R

0)0

C(

-N(R«)C(=0)R'

-N(H)S(=0)&R6

C&-C6-alkoxy-,

heterocycloalkyl-,

C( 0)N(R6a)R6b

C( 0)N(H)R6a

-CN,

halo-C~-Ce-alkoxy-C& -C6-alkyl-,

3- to 7-membered

C&-Ct;-alkynyl-,

T/EP2012/055471

R"(R")N-C~-C«alkyl-,

halo-C~-C6-alkoxy-,

halo-C~-C6-alkyl-,

C~-C«alkyl-,

PC

-S(=0)N(H)R -S(=0)2N(R ')R

-S(=0)2N(H)R

-S(=0)(=NR«)R' group; wherein


or differently,

with

group is optionally

substituted,

identically

1, 2, or 3 C~-C6-alkyl- groups;

OI

when 2 R' groups are present ortho to each other on an aryl ring, said 2 R'

15

groups together form a bridge: *0(CH&)&0*, *0(CH&)0*, *NH(C(=0))NH*, wherein

R8

represents a hydrogen or halogen atom, or a -CN, C&-C6-alkoxy-, C&-C6-alkyl-, halo-C~-C6-alkyl-,




3- to 7-membered

C&-Ct;-alkynyl-,

-C(=Q)R6

25

-C(=Q)N(H)R6',

0(C 0)N(R6a)R6b -S(=Op)R

-S(=0)&N(H)R6

7-membered wherein

-S(=0)zN(R ')R

heterocycloalkyl)

substituted,

S( 0)R6

heteroaryl-,

-N(R6')R6b

-NQ~,

-N(R«)C(=0)N(R")R'

-N=S(=0)(R ')R SR6

N(R«)S( 0)R

-0(C=O)R

-OR

S( 0)N(H)R6

S( 0)N(R6a)R6b

-S(=0)(=NR«)R6 or -S(=0)z-(3- to

group;


optionally C&

0(C 0)OR6

aryl-,

N(H)S( 0)R6

N(R«)C( 0)OR6

-C«alkyl-,

C~-Ce-alkenyl-,

-C(=Q)Q-R6

-N(H)C(=0)N(R")R'

-N(R ')S(=0)zR

-N(H)S(=0)zR

HO-C&

heterocycloalkyl-,

-C(=Q)N(R6')R6b

-N(R«)C(=0)R'

-N(H)C(=0)R' N(H)C( 0)OR6

30

the point of

to said aryl ring;

attachment

20

* represent

heterocycloalkyl-

identically

-C6-alkyl- groups;

50

or heteroaryl-

or differently,

group, is

with 1, 2, 3, or 4

WO 2012/136531

5

PC

m


n


X

is S, S(=0), S(=0)&,

or a stereoisomer,

0,

6;

5; and

C(=0) or CR"R" '

NR'

a tautomer,

T/EP2012/055471




In



I:

formula

R NH N

R A

10

in which

15

A

represents 4a 4b

R

4d

Z

4c



the molecule; 20 Z


51

WO 2012/136531

R'

represents a C&-C6-alkyl-, a C&-C6-cycloalkyl- or an arylgroup;

wherein

said C~-C6-alkyl-

substituted,

re

p




-C6-alkyl-;

HO-C~

R'


-OH, -CN, C&-C6-alkyl-, C&-C6-alkoxy-, C&-C6-cycloalkyl-,

halogen,

resents

hydrogen

a


a

tom or


a

or

aryl-X-

15

heteroaryl-

optionally

is

group

differently,

with 1, 2 or 3 R' groups;

represent,

independently

C~-C6-alkyl-,

-CN,

aryl-, heteroaryl-,


10

T/EP2012/055471

PC

aryl-X- group;


substituted,


aryl-,

identically

or a

or

C&-C6-alkyl-

group j

represents

R'

a hydrogen




-(CH~) -(3-

HO-C~ -C6-alkyl-,



to 7-membered

C&-C6-alkyl-,

to 7-membered


heterocycloalkyl),

20

atom, or a


heterocycloalkyl-,


-C& -C6-alkyl-CN,

C~-C6-cycloalkyl-,

3-


group j

wherein 25

said

C~-C6-alkyl-,

-(3-

7-membered

-(CH&)

aryl-C~ -C6-alkyl-,


)N-C&-C6-alkyl-,


to 7-membered

HO-C&

substituted,



R' groups;

R"

R'

-C6-alkyl-,


heterocycloalkyl-,

group is optionally

R'

to


R"(R'

30


R"

52


heterocycloalkyl), halo-C~-C6-alkyl-, -C~ -C6-alkyl-CN,

Cz-C6-cycloalkyl-,

3-


with 1, 2, 3, 4 or 5

WO 2012/136531

represent, independently C3

T/EP2012/055471

PC


atom, a C&-Ce-alkyl-,

or aryl-C&-Ce-alkyl- group;

Ce-cycloalkyl-,

wherein said C~-Ce-cycloalkyl-

differently with

1

group is optionally

substituted,

identically or

or 2 groups selected from: halogen, -OH, -CN, C&-Ce-alkyl-,

Hp-C~ -Ce-alkyl-;

R'

represents

Hp-C& -Ce-alkyl-,

C~-Ce-alkenyl-,

heteroaryl-,

-C( 0)Re

3- to 7-membered

-NOES/

-N(H)C(=0)R

-N(Rec)S(=0)Re

-N(R

S( p)N(R6a)R6b

S( p)&R6

N(R6a)R6b

R6

-N(R ')C(=0)OR

-N(H)S(=0)R

-N=S(=0)(Rea)Reb

-S(=0)R

-SR

-0(C=O)OR

aryl-,

-N(H)C(=0)N(R ')R

-N(Rec)S(=0)&Re

-N(H)S(=0)zRe

(-( P)P

')C(=0)R

-N(H)C(=0)OR

-0(C=O)N(R ')R

-0(C=O)R

heterocycloalkyl-,

(-( P)N(R6a)R6b

C( 0)N(H)R6a

-N(R ')C(=0)N(R ')R

15

halo-C&-Ce-alkoxy-C& -Ce-alkyl-,

C&-Ce-alkoxy-C& -Ce-alkyl-,

C~-Ce-alkynyl-,

C~-Ce-alkoxy-,

-CN,

R"(R")N-C~-Ce-alkyl-,

halo-C~-Ce-alkoxy-,

halo-C~-Ce-alkyl-,

C~-Ce-alkyl-,

10


a hydrogen

-OR

-S(=0)N(H)R S( p)&N(Rea)Reb

S( p)&N(H)R6



or differently,

group is optionally

substituted,

identically

1, 2, or 3 C~-Ce-alkyl- groups;

with

20 Rs

represents a hydrogen or halogen atom, or a -CN, C~-Ce-alkoxy-, C~-Ce-alkyl-, halo-C~-Ce-alkyl-,

Rea(Reb)N-C&-Ce-alkyl-,



3- to 7-membered

C~-Ce-alkynyl-,

25

C( 0)R6

-N(R

-N(H)C(=0)R

p(C p)N(R6a)R6b

p(C p)pR6

S( 07)R6 -S(=0)&N(H)R'

7-membered wherein

C&

SR6

heterocycloalkyl)

substituted,

R6

N(R6a)R6b

-N(R ')C(=0)N(R

-N(H)S(=0)R

S( p)R6

heteroaryl-,

-N(R -OR

S( p)N(H)R6

Np

')R

')S(=0)R -0(C=O)R

S( p)N(R6a)R6b

-S(=0)&N(R")R" -S(=0)(=NR")R' or -S(=0)&-(3- to

group;


optionally

0)0

-N=S(=0)(R ')R

-N(R ')S(=0)2R

-N(H)S(=0)2R

C(

C2-Ce-alkenyl-,

aryl-,

-N(H)C(=0)N(R ')R

')C(=0)R

-N(R ')C(=0)OR

-N(H)C(=0)OR

30

heterocycloalkyl-,

C( 0)N(R6a)R6b

C( 0)N(H)R6a

HO-C&-Ce-alkyl-,

heterocycloalkyl-

identically

-Ce-alkyl- groups;

53

or heteroaryl-

or differently,

group, is

with 1, 2, 3, or 4

WO 2012/136531

PC

m


n


X

is S, S(=0), S(=0)z,

or a stereoisomer,

0,

a tautomer,

6;

5; and

C(=0) or CR"R6b

NR6

T/EP2012/055471

'




In

10



I:

formula

R NH N

R A

in which

15 A

represents 4a 4b *

R

4d

4c

wherein



the molecule;

20

Z

represents a -C(=0)N(H)R' or a -C(=S)N(H)R" group; 54

WO 2012/136531

R'

PC

represents a C~-C~-alkyl- or a C~-C6-cycloalkyl- group; wherein said C~-C6-cycloalkyl-

differently, C&

-Cg-alkyl-,

differently,

C~

-C~-alkoxy-, C~-C6-cycloalkyl-, C&-C&-alkyl-

with

represents

HO-C~

atom or


differently,

group is optionally

heteroaryl-

a

-OH,

-CN,

C~-C6-alkyl-,

-CN,

aryl-, heteroaryl-,


or

-CN,

HO-C~-C~-alkyl-;

hydrogen

a

-OH,

identically or



aryl-X-

identically or

-C~-alkyl-;

substituted,

group is optionally

C&-C&-alkoxy-, C~-C6-cycloalkyl-,

R'

substituted,

group is optionally


said

wherein

10

T/EP2012/055471

aryl-X- group;


substituted,

aryl-,

identically

or


15

R'

R

R'

R

represent,


independently

or a

C&-C6-alkyl-

group j

20

R'

represents

a hydrogen


heterocycloalkyl),

atom, or a


aryl-C~ -Ce-alkyl-,


to 7-membered


-(CH~) -(3-

to 7-membered

heteroaryl-C~ -Ce-alkyl-, halo-C&-C6-alkyl-,

HO-C~ -C6-alkyl-,


25

C&-C6-alkyl-,


heterocycloalkyl-,


-C& -C6-alkyl-CN,

C~-C6-cycloalkyl-,

3-


group j

wherein

30

said

C~-C6-alkyl-,

-(CH~), -C~-C6-alkenyl,

-(3-

to

7-membered


-(CH&)

aryl-C~ -C6-alkyl-,




to 7-membered group is optionally

HO-C&

substituted,



R' groups;

55

heterocycloalkyl), halo-C~-C6-alkyl-,

-C6-alkyl-,


heterocycloalkyl-,


-C& -C6-alkyl-CN,

Cz-C6-cycloalkyl-,

3-


1, 2, 3, 4 or 5

WO 2012/136531

Re

Rea 7

Rec

Reb 7

T/EP2012/055471

PC

7

represent, independently C3


Ce-cycloalkyl- or aryl-C&-Ce-alkyl-


differently with

1


group; identically or

substituted,

group is optionally


Hp-C~ -Ce-alkyl-;

R'

10

represents

a halogen

R'

15

C(

p)p

Re

-C(=0)N(H)R",

or -QRe group;




3- to 7-membered

-C(=Q)N(H)Re', -N(R

-N(H)C(=0)R

N(Rec)C( p)pRe

p(C p)N(Rea)Reb

p(C p)pRe

S( 02)Re -S(=0)2N(H)R'

7-membered wherein

C~

heterocycloalkyl)

substituted,

-N(Re')Reb

N(H)S( p)Re

S( p)Re

heteroaryl-, -Np~,

')R

N(Rec)S( p)Re -OR

S( p)N(H)Re

-0(C=O)R S( p)N(Rea)Reb

-S(=0)&N(R")R" -S(=0)(=NR")R' or -S(=0)z-(3- to

group;


optionally

aryl-,

-N(R ')C(=0)N(R

-N=S(=0)(R ')R SRe

C2-Ce-alkenyl-,

-C(=Q)Q-Re

-N(H)C(=0)N(R ')R

-N(R ')S(=0)2R

-N(H)S(=0)2R

HO-C&-Ce-alkyl-,

heterocycloalkyl-,

-C(=Q)N(Re')Reb

')C(=0)R

N(H)C( p)pRe

30

C&-Ce-alkyl-,

HO-C~-Ce-alkyl-,

halo-C~-Ce-alkyl-,

-C(=Q)Re

25

C&-Ce-alkoxy-,

represents a hydrogen or halogen atom, or a -CN, C~-Ce-alkoxy-, C~-Ce-alkyl-,

C~-Ce-alkynyl-,

20

a HO-,

halo-C~-Ce-alkoxy-,

halo-C~-Ce-alkyl-, N(Rea)Reb

atom, or

heterocycloalkyl-

identically

or heteroaryl-

or differently,

group, is

with 1, 2, 3, or 4

-Ce-alkyl- groups;

m


n


X

is S, S(=0), S(=0)&,

or a stereoisomer,

0,

NR'

a tautomer,

6;

5; and

C(=0) or CR"R'b

'



56


WO 2012/136531

In

PC


T/EP2012/055471


I:

formula

R NH N

R A

in which

A

represents 4a 4b *

R

4d

4c

10 wherein * indicates the point of attachment


the molecule;

Z


R'

represents a C&-C&-alkyl- or a cyclopropyl- group;

15

wherein

said

differently, C~

20

with

group is optionally

1, 2 or 3 groups

selected

substituted,

identically or

from: halogen,

-OH,

-CN,

-C~-alkyl-;

wherein

said C~-C3-alkyl-

differently, C&

cyclopropyl-

with

group

is optionally

1, 2 or 3 groups

-C3-alkoxy-;

57

selected

substituted,

identically

from: halogen,

-OH,

or -CN,

WO 2012/136531

re

R'

PC

resents

p

hydrogen

a


a

tom or

-(CH&) -C~-Ce-alkynyl,

a

aryl-X-

or

differently,

Rna

R4b

C~-Ce-alkyl-,

-CN,

aryl-, heteroaryl-,

wherein said C&-Ce-alkyl-, -(CH&)m-C&-Ce-alkenyl,


T/EP2012/055471

aryl-X- group;

-(CH&)m-C2-Ce-alkynyl,

substituted,

aryl-,

identically

or

R4d

represent a hydrogen atom;

10

R"

represents

halo-C&-C&-alkyl-, NC-C~

gl

atom, or a

a halogen

-C3-alkyl-,

halo-C&-C&-alkoxy-,

R

C~-C~-alkoxy-,

C~-C~-alkyl-,

-OH,

-CN,

'(R )N-C&-Cz-alkyl-,

HO-C&-C&-alkyl-,

halo-C~ -C~-alkoxy-C~-C~-alkyl-

C~-C~-alkoxy-C~ -C~-alkyl-,

oup j

15

represents

R'

a hydrogen

-(CH&). -C&-Ce-alkynyl,

heterocycloalkyl),

R"(R' 20

atom, or a

-(CH&)m-C&-Ce-cycloalkyl,

aryl-C~ -Ce-alkyl-,

)N-C&-Ce-alkyl-,


to 7-membered

C~-Ce-alkyl-,

-(CH&)~-(3-

to 7-membered

heteroaryl-C~ -Ce-alkyl-, halo-C~-Ce-alkyl-,

HO-C&

-Ce-alkyl-,


heterocycloalkyl-,



-C~ -Ce-alkyl-CN,

Cz-Ce-cycloalkyl-,

3-


gloUP j

wherein 25

said

C&-Ce-alkyl-,

-(CH&), -C2-Ce-alkenyl,

-(CH~) -C3-Ce-cycloalkyl,

-(CH~) -(3-

aryl-C~ -Ce-alkyl-,

heteroaryl-C~-Ce-alkyl-,

to 7-membered group is optionally

7-membered

heterocycloalkyl), halo-C&-Ce-alkyl-,

HO-C~ -Ce-alkyl-,



to

-(CH2), -C&-Ce-alkynyl,


heterocycloalkyl-,

substituted,



-C~ -Ce-alkyl-CN,

C~-Ce-cycloalkyl-,

3-


1, 2, 3, 4 or 5

R' groups;

30

Re

Rea 7

Rec

Reb 7

7

represent, independently C3 Ce


cycloalkyl- or aryl-C&-Ce-alkyl-

group; 58


WO 2012/136531

T/EP2012/055471

PC


differently with

1

substituted,

group is optionally

identically or


HO-C~ -Ce-alkyl-;

5

represents

R'

R'

C(

0)0

Re

C~-Ce-alkoxy-,

C~-Ce-alkyl-,

-C(=0)N(H)R",

HQ-C&-Ce-alkyl-,

or -ORe group;

halo-C~-Ce-alkyl-,




3- to 7-membered

C&-Ce-alkynyl-,

-C(=Q)Re

-N(R")C(=0)R'

15

0(C 0)N(Rea)Reb -S(=Op)R

wherein

C&

heterocycloalkyl)

substituted,

heteroaryl-,

-N(Re')Reb

-NQ~,

-N(R")C(=0)N(R")R' N(Rec)S(

-0(C=O)R

-OR

S( 0)N(H)Re

-S(=0)(=NRec)Re

0)R

S( 0)N(Rea)Reb

or -S(=0)z-(3- to

group;


optionally

S( 0)Re

-S(=0)&N(R ')R

-S(=0)&N(H)Re

7-membered

SRe

0(C 0)ORe

aryl-,

N(H)S( 0)Re

-N=S(=0)(R ')R

-N(R ')S(=0)zR

-N(H)S(=0)zR

C~-Ce-alkenyl-,

-C(=Q)Q-Re

-N(H)C(=0)N(R")R'

N(Rec)C( 0)ORe

N(H)C( 0)ORe

HO-C&-Ce-alkyl-,

heterocycloalkyl-,

-C(=Q)N(Re')Reb

-C(=Q)N(H)Re',

-N(H)C(=0)R'

25

HO-,

represents a hydrogen or halogen atom, or a -CN, C&-Ce-alkoxy-, C&-Ce-alkyl-,

10

20

a

halo-C&-Ce-alkoxy-,

halo-C&-Ce-alkyl-, N(Re~)Reb

atom, or

a halogen

heterocycloalkyl-

identically

or differently,

or heteroaryl-

group, is

with 1, 2, 3, or 4

-Ce-alkyl- groups;

m


n

isanintegerof0,

X

is S, S(=0), S(=0)&,

or a stereoisomer,

4or5;

1, 2, 3,

0,

and

C(=0) or CR"R'b

NR'

a tautomer,

6; '




30 In


formula


I:

59

WO 2012/136531

PC

T/EP2012/055471

R NH N

R A

in which

A

represents

H N

0

CH

wherein

1



the molecule;

10 R'

represents a methyl- group or a cyclopropyl- group; wherein

said cyclopropyl-

group is optionally

substituted

with one fluorine

atom; 15 R'

represents a pyridyl-, phenyl-, phenyl-0- or phenyl-S- group; wherein

the phenyl- group is either substituted

-C(=0)N(H)R" group, or with a wherein

20

differently, wherein

differently,

R'

the

phenyl-0-

with

the

1

1

group is optionally

group is optionally

substituted,

substituted,


represents a group selected from:

60

group and a

group;


phenyl-S-

with

HO-CH&-

with a methyl-

identically

or

HgC-;

identically HgC-;

or

WO 2012/136531

PC

F

CH~

F

0

F~F H

CH

H~H ; wherein

attachment

5

R"

represents a hydrogen atom or methyl- group or a C&-C6-cyclpropyl- group;

gl

group is optionally

a tautomer,

within I,

any embodiment



that the present invention

relates to any sub-combination


of compounds of general formula

supra.

More particularly

still, the present invention

which are disclosed in the Experimental

The compounds depending

in

of this invention the location

may contain

one or more asymmetric

of the various

carbon atoms may be present in the (R) or (S) configuration,

resulting

the case of multiple

in

may also be present due

asymmetry

centre, desired.

and

I

Section of this text, infra.

nature

racemic mixtures in the case of a single asymmetric

mixtures

of general formula

covers compounds

substituents

upon

Asymmetric

25

with one -CN


It is to be understood

20

substituted

oup j

or a stereoisomer,

15

* indicates the point of

of said groups with the rest of the molecule

wherein said C~-C6-cyclpropyl-

10

T/EP2012/055471

asymmetric

centre, and diastereomeric

centres.

In

certain

instances,

to restricted rotation about a given bond, for

example, the central bond adjoining two substituted

aromatic rings of the specified

compounds.

Substituents

that

30

all

on a ring may also be present in either cis or trans form. It is intended

such

configurations

enantiomers

(including

included within the scope of the present invention.

61

and

diastereomers),

are

WO 2012/136531

PC

Preferred

compounds

are those which

produce

the more desirable

activity.

Separated,

pure

or partially

purified

isomers

racemic or diastereomeric included 5

T/EP2012/055471

of the compounds

mixtures

the scope of the present

within

invention.

of such materials can be accomplished

separation

and

biological

stereoisomers

or

of this invention

are also

The purification

and the

techniques

known in

by standard

the art.

The optical isomers can be obtained

according to conventional

processes, for example, by the formation

of

covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of can be separated

diastereoisomers

of their physical and/or bases or acids are then

into their individual

chemical differences

example, by chromatography 15

of the racemic mixtures

salts using an optically active acid or base or formation of

diastereoisomeric 10

by resolution

diastereomers

by methods

known

or fractional crystallisation.

liberated

from the separated

in

on the basis

the art, for

The optically active

diastereomeric

salts.

A

different process for separation of optical isomers involves the use of chiral

(e.g. , chiral

chromatography

derivatisation,

optimally

HPLC

columns), with or without conventional

chosen to maximise

Suitable chiral HPLC columns are manufactured

20

the separation by Diacel,

of the enantiomers.

e.g. , Chiracel

OD and

Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without

derivatisation,

are also useful. The optically active compounds

of

can likewise be obtained by chiral syntheses utilizing optically active

this invention

starting materials.

25

In

order to limit different types of isomers from each other reference is made to

IUPAC Rules

Section

The invention

invention.

30

which

An

E

(Pure Appl Chem 45, 11-30, 1976).

also includes all suitable isotopic variations

of a compound of the

isotopic variation of a compound of the invention is defined as one in

at least one atom is replaced by an atom having the same atomic number

but an atomic mass different from the atomic mass usually or predominantly in

nature. Examples of isotopes that can be incorporated

invention

include isotopes of hydrogen,

found

into a compound of the

carbon, nitrogen, oxygen, phosphorus, 62

WO 2012/136531

PC

fluorine, chlorine, bromine and iodine, such as 'H (deuterium),

sulphur,

170 180 32P 33P 335

13C 14C 15N

and

""I,

T/EP2012/055471

18F 36Cl 828 r 123 I 124I 129I

345 355 365

Certain isotopic variations of a compound

respectively.

'H

of the invention,

for example, those in which one or more radioactive isotopes such as 'H or '4C are 5

are useful

incorporated,

in drug

and/or substrate tissue distribution

Tritiated and carbon-14, i. e. , '4C, isotopes are particularly

of preparation

deuterium metabolic

10

detectability.

with

may afford certain therapeutic

advantages

resulting

for example,

increased

conventional

procedures

known

using appropriate

can generally

by a person skilled in

methods or by the preparations

as

from greater

circumstances.

in some

of the invention

of a compound

such

half-life or reduced dosage

in vivo

and hence may be preferred

requirements

illustrative

isotopes

substitution

stability,

variations

preferred for their ease

Further,

and

studies.

described in

Isotopic

be prepared

by

the art such as by the the examples hereafter

isotopic variations of suitable reagents.

15 The present invention

or as any mixture of said stereoisomers,

present invention as single stereoisomers, in any

of the compounds of the

includes all possible stereoisomers

ratio. Isolation of a single stereoisomer,

e.g. a

single enantiomer

or a single

of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral diastereomer,

20

chromatography,

Further,

for example.

the compounds


may

exist as tautomers.

For

example, any compound of the present invention which contains a pyrazole moiety 25

as a heteroaryl even a mixture

group for example can exist as a 1H tautomer, in any amount

of the two tautomers,

example can exist as a 1H tautomer,

a 2H tautomer,

mixture in any amount of said 1H, 2H and 4H tautomers,

N

NH

30

1H-tautomer

2H-tautomer

63

or

or a triazole moiety for

or a 4H tautomer,

namely:

N

N

YN~g

or a 2H tautomer,

Y~/ 4H-tautomer

or even a

WO 2012/136531

The present

PC

includes

invention

all possible

present invention as single tautomers,

T/EP2012/055471

of the compounds

tautomers

or as any mixture of said tautomers,

of the in any

ratio.

5


the compounds

Further,

can exist as N-oxides, which are

defined in that at least one nitrogen of the compounds

of the present invention is

oxidised. The present invention includes all such possible N-oxides.

10

Furthermore,

the present invention

polymorphs,

of the compounds

The compounds

15


crystal lattice of the compounds. may

exist

in

stoichiometric

or non-stoichiometric

e.g. a hydrate, hemi-, (semi-),

tetra-, penta- etc. solvates or hydrates, 20

invention

In

an

respectively,

of formula

of the above-mentioned I, according

the form of or a stereoisomer, 25

ratio.

In

the case of di-, tri-,

mono-, sesqui-,

are possible. The present

aspects,

a tautomer,

relates

to

embodiments,

in

the invention

to any of the above-mentioned

a solvate, or a


salt thereof, or a mixture of same.

The compounds of the present invention

have surprisingly

been found to effectively

inhibit Mps-1 kinase and may therefore be used for the treatment

diseases of uncontrolled

30

element of the

includes all such hydrates or solvates.

embodiment

compounds

contain polar solvents, in

The amount of polar solvents, in particular water,

a stoichiometric

solvates,

or as a solvate,

or ethanol for example as structural

water, methanol

particular

ratio.

can exist as a hydrate,


the compounds

in any

forms, or

either as single

of the present invention,

or as a mixture of more than one polymorph,

polymorphs,

wherein

includes all possible crystalline


cellular immune responses, or inappropriate diseases

which

are accompanied

and/or survival, inappropriate

inflammatory

responses,

or prophylaxis



with uncontrolled

responses or



particularly

in which

64

of

the uncontrolled

cellular

cell growth,

WO 2012/136531

proliferation

and/or

inappropriate


as, for example,

thereof, 5

T/EP2012/055471

PC

haemotological

is mediated

responses

solid

tumours,



the thorax including

non-small

tumours,

endocrine

tumours,

urological

tumours

responses,

cellular immune

inappropriate

survival,

brain tumours

by Mps-1 kinase, such

tumours,

syndrome,

and/or metastases

malignant

other

and

tumours of

gastrointestinal

gynaecological

renal, bladder and prostate tumours,

including

lymphomas,

and brain metastases,


or

tumours,

skin tumours,

and/or metastases thereof.

and sarcomas,

10 Therefore,

the compounds

of formula

are expected to be valuable as

I, supra,

therapeutic agents.

Accordingly,

15

in

another

the present

embodiment,

compound

of general formula

a hydrate,

a solvate, or a salt thereof, particularly

or a stereoisomer,

I, supra,

is directed

invention

to a

a tautomer,

an N-oxide,

a pharmaceutically

acceptable

salt thereof, or a mixture of same, for use in the treatment

or prophylaxis

of a

disease. 20

In

another embodiment,


disorders associated with enhanced uncontrolled a patient in need of such treatment,

comprising

provides a method of treating proliferative

cellular processes in

to the patient an

administering

effective amount of a compound of formula I.

25

The term "treating" or "treatment" as stated throughout

conventionally, combating,

e. g. , the

alleviating,

or care of a subject for the purpose of

management

reducing,

this document is used

relieving,

improving

the condition of a disease or

disorder, such as a carcinoma.

30

The term "subject" or "patient" includes organisms which are capable of suffering

from a cell proliferative administration

disorder or who could otherwise

of a compound

of the invention,

benefit from the

such as human

and non-human

animals. Preferred humans include human patients suffering from or prone to 65

WO 2012/136531

PC

disorder or associated state, as described herein.

suffering from a cell proliferative animals"

"non-human

The term

e.g. ,

vertebrates,

includes

such as

mammals,

sheep, cow, dog, cat and rodents, e. g. , mice, and such as chickens, amphibians, reptiles, etc.

primates,

non-human non-mammals,

The terms "cell proliferative

disorder" or "disorder associated with enhanced

cellular processes" include disorders involving

proliferative

uncontrolled

10

T/EP2012/055471

the

of a cell. The compounds of the present

undesired

or uncontrolled

invention

can be utilized to prevent, inhibit, block, reduce, decrease, control,

proliferation

etc. , cell proliferation and/or cell division, and/or produce apoptosis. This method comprises administering to a subject in need thereof, including a mammal, a

including

pharmaceutically

of a compound

amount

an

human,

of this

acceptable salt, isomer, polymorph,

or a

invention,

metabolite,

hydrate or

solvate thereof which is effective to treat or prevent the disorder.

15 In

the present invention is directed to a compound of general

another embodiment,

formula I, or a stereoisomer,

thereof, particularly

a tautomer,

a

disease of uncontrolled cellular immune

inappropriate response,

particularly

survival,

inappropriate

inflammatory

25

in which

(MEK-ERK) pathway,

growth, proliferation


and/or survival,

response, or an inappropriate


the uncontrolled

is mediated

30

tumours,

tumours

tumours,

tumours,

skin tumours,

in which

e.g. leukaemias

tumours,

tumour,

and myelodysplastic

cell

non-small

a solid

syndrome,

brain tumours and brain

cell and small cell lung

endocrine tumours,

mammary

and other



66

protein kinase

cellular immune response, or

urological tumours including and sarcomas,

and/or

the disease of uncontrolled

response is a haemotological

of the thorax including

gastrointestinal

gynaecological

the mitogen-activated

an

cellular

response, or inappropriate


lymphomas,

metastases,



tumour and/or metastases thereof,

malignant

by

more particularly


inappropriate

of a disease, wherein said disease is

or prophylaxis

cellular immune

response

a solvate, or a salt

acceptable salt thereof, or a mixture of

a pharmaceutically

same, for use in the treatment

20


WO 2012/136531

also relates to useful forms of the compounds

The present invention herein,

such

as metabolites,

salts,

prodrugs,

as disclosed

inorganic or organic acid addition salt of a compound

example, see S. M. Berge, et ai. "Pharmaceutical

particular

in

esters, and co-precipitates.

salt" refers to a relatively

acceptable

"pharmaceutically

The term

solvates,

hydrates,

acceptable salts, in vivo hydrolysable

pharmaceutically 5

T/EP2012/055471

PC

non-toxic,

of the present invention.

Salts,

" J. Pharm.

For

Sci. 1977, 66,

1-19. A

10

suitable

invention

may be, for example,

invention

bearing a nitrogen

hydrochloric,

hydrobromic,

lauric,

trifluoroacetic, benzoic,

20

atom, in a chain or in a ring, for example, which is

hydroiodic,

propionic,

salicylic,

salt with an inorganic

sulfuric,

digluconic,

pectinic, persulfuric,

3-phenylpropionic,

sulfamic,

butyric,

acid, such as

phosphoric,

naphthalinedisulfonic,

or nitric

camphorsulfonic

undecanoic,

heptanoic, camphoric,

cinnamic,

nicotinic,

pamoic,

picric, pivalic, 2-hydroxyethanesulfonate,

trifluoromethanesulfonic,

ethansulfonic,

dodecylsulfuric,

methansulfonic,

2-naphthalenesulfonic,

acid, citric, tartaric, stearic, lactic, oxalic,

succinic, malic, adipic, alginic,

ascorbic, glucoheptanoic,

hexanoic,

3-hydroxy-2-naphthoic,

para-toluenesulfonic,

benzenesulfonic,

malonic,

bisulfuric,

2-(4-hydroxybenzoyl)-benzoic,

cyclopentanepropionic,

itaconic,

of the present

or with an organic acid, such as formic, acetic, acetoacetic,

acid, for example, pyruvic,

of the present

salt of a compound

an acid-addition

basic, such as an acid-addition

sufficiently

15

salt of the compounds

acceptable

pharmaceutically

glycerophosphoric,

maleic, fumaric,

D-gluconic,

aspartic, sulfosalicylic,

mandelic,

hemisulfuric,

or thiocyanic acid, for example. 25

Further,

another suitably pharmaceutically

present invention sodium

or potassium

magnesium

aminopropandiol,

acidic, is an alkali metal salt, for example a

salt or a salt with an organic base which affords a

acceptable cation, for example a salt with N-methyl-glucamine,

dimethyl-glucamine,

ethanolamine,

of the

salt, an alkaline earth metal salt, for example a calcium or

salt, an ammonium

physiologically

30

which is sufficiently

acceptable salt of a compound

ethyl-glucamine,

glucosamine,

lysine, dicyclohexylamine,

1, 6-hexadiamine,

sarcosine, serinol, tris-hydroxy-methyl-aminomethane,

sovak-base,

1-amino-2, 3, 4-butantriol.

67

Additionally,

basic

WO 2012/136531

PC

containing

nitrogen

sulfates

like dimethyl,

5

and dibutyl

diethyl,

such as decyl, lauryl,

long chain halides

with

such agents

myristyl

sulfate; and diamyl sulfates,

and strearyl

and iodides, aralkyl halides like benzyl and phenethyl

as lower alkyl

bromides and iodides;

ethyl, propyl, and butyl chlorides,

halides such as methyl, dialkyl

may be quaternised

groups

T/EP2012/055471

chlorides,

bromides

bromides and others.

Those skilled in the art will further recognise that acid addition salts of the claimed may be prepared

compounds

of the compounds

with the appropriate

or organic acid via any of a number of known methods.

inorganic

alkali and alkaline

10

by reaction

earth metal salts of acidic compounds

Alternatively,

of the invention

of the invention with the appropriate

prepared by reacting the compounds

are

base via

a variety of known methods.


As used

herein, the term "in vivo hydrolysable

ester" is understood as meaning

carboxy or hydroxy group, for example, a pharmaceutically is hydrolysed

cycloalkyl and optionally

acceptable esters for carboxy include for example alkyl, substituted

phenylalkyl,

esters, e.g. methoxymethyl,

pivaloyloxymethyl,

phthalidyl

esters,

5-methyl-1, 3-dioxolen-2-onylmethyl;

An

group

[alpha]-acyloxyalkyl

30

hydrolysis

esters,

cycloalkoxy-carbonyloxy-C&

e.g.

-C6 alkyl

1, 3-dioxolen-2-onylmethyl

esters, e.g.

and C~-C6-alkoxycarbonyloxyethyl

esters, e.g.

of this invention.

in vivo hydrolysable

hydroxy

benzyl esters, C&-C6

and may be formed at any carboxy group in the

1-methoxycarbonyloxyethyl, compounds

in particular

C~-C6 alkanoyloxymethyl

C~-C8

esters, e.g. 1-cyclohexylcarbonyloxyethyl; 25

acceptable ester which

or animal body to produce the parent acid or alcohol.

in the human

Suitable pharmaceutically

alkoxymethyl

an

ester of a compound of the present invention containing a

in viva hydrolysable

20

of the present

as single salts, or as any mixture of said salts, in any ratio.

invention

15

includes all possible salts of the compounds

ester of a compound of the present invention containing a

includes inorganic esters such as phosphate ethers and related compounds

of the ester breakdown

[alpha]-acyloxyalkyl

ethers

2, 2-dimethylpropionyloxymethoxy. groups for hydroxy include alkanoyl,

esters and

which as a result of the in vivo

to give the parent hydroxy group. Examples of include ace toxym e th oxy a n d A

selection of in vivo hydrolysable benzoyl, phenylacetyl

68

ester forming

and substituted

benzoyl

WO 2012/136531

PC

and phenylacetyl,

dialkylaminoacetyl

5

Compounds

I

of formula

as well as administration

therapeutic

I

pharmaceutical

I

where the

agents

of formula

pharmaceutical

I

agents,

and each additional

dosage formulation.

the patient together in a single oral dosage composition in

therapeutic

which

For

agent may be administered

and a therapeutic

capsule, or each agent may be administered

therapy

dosage formulation

and one or more additional

of the compound

of formula

agent or

adverse effects. This combination

agent in its own separate

example, a compound

therapeutic

additional

of a single

administration

covers all such esters.

as the sole pharmaceutical

may be administered

one or more

with

contains a compound

10

(to give carbamates),


causes no unacceptable

combination includes

and carboxyacetyl.

of formula

combination

in

(to give alkyl carbonate esters), dialkylcarbamoyl

alkoxycarbonyl

N-(dialkylaminoethyl)-N-alkylcarbamoyl

and

T/EP2012/055471

to

such as a tablet or

separate dosage formulations.

15 Where separate dosage formulations

or more additional therapeutic time (e. g. , concurrently)

20

In

hydrate,

agents may be administered

I

and one

at essentially the same

or at separately staggered times (e. g. , sequentially).

another aspect, the invention

of general formula

a compound

are used, the compound of formula

provides a pharmaceutical I, or a


stereoisomer,

particularly

composition

a tautomer,

a

an N-oxide,

a pharmaceutically

salt thereof, or a mixture of same, and a pharmaceutically

comprising

acceptable

acceptable diluent or

carrier. 25

Preferably, -

the pharmaceutical

one or more compounds N-oxide, a hydrate,

comprises:

combination

of general formula

I,

or a stereoisomer,


a tautomer,

an

a pharmaceutically

acceptable salt thereof, or a mixture of same; and -

30

one or more agents selected from: a taxane, such as Docetaxel, Paclitaxel, or

Taxol; an epothilone,

Predinisolone; Adriamycin;

Ifosfamide;

such as Ixabepilone,

Dexamethasone; Idarubicin;

Procarbazine;

Patupilone,

Estramustin;

Daunorubicin; Melphalan;

or Sagopilone; Mitoxantrone;

Vinblastin;

Vincristin;

Doxorubicin;

Bleomycin; Etoposide; Cyclophosphamide;

5-Fluorouracil;

69

Capecitabine;

Fludarabine;

WO 2012/136531

PC

2-Chloro-2'-deoxyadenosine;

Ara-C;

Cytarabine;

such as Flutamide,

derivative,

or Carboplatin;

such as Cisplatin,

an anti-androgen,

Thioguanine;

acetate, or Bicalutamide;

Cyproterone

T/EP2012/055471

Bortezomib; a platinum

Methotrexate;

Chlorambucil;

and

Rituximab.

In

still another aspect, the invention

pharmaceutical

composition.

one compound

of formula

I

provides a process for preparing

The process includes the step of combining

still another aspect, the invention

defined above for manufacturing

provides use of a compound

a pharmaceutical

of a cell proliferative

or prevention 15

disorder.

In

of formula

I

nasally, sublingually,

pulmonally,

the cell

lingually,

and/or locally. For this

for example orally, parenterally,

buccally, rectally, transdermally,

otically, or as an implant or stent.

conjunctivally,

When the compounds

are administered


as

to humans and animals, they can be given per se or as a composition containing, for example, 0. 1 to 99. 5/ (more

pharmaceuticals,

pharmaceutical preferably,

as

I

for the treatment

certain embodiments,

can act systemically

purpose, it can be applied in a suitable manner,

25

composition

of formula

disorder is cancer.

proliferative

The active component

20

into a suitable

form.

administration

In

at least

as defined above with at least one pharmaceutically

acceptable carrier, and bringing the resulting combination 10

a

0. 5 to 90%) of active ingredient

in combination

with a pharmaceutically

acceptable carrier.

selected, the compounds of the a suitable hydrated form, and/or the

Regardless of the route of administration

invention,

which may be used in

pharmaceutical

30

compositions

of the

present

invention,

acceptable dosage forms by conventional the art.

pharmaceutically those of skill in

Actual dosage levels and time course of administration

the pharmaceutical

compositions

are formulated

into

methods known to

of the active ingredients in

of the invention may be varied so as to obtain an 70

WO 2012/136531

PC

amount of the active ingredient

In

accordance

preparing

with

compounds

another aspect, the present invention


as described in the Experimental

In

10

patient, composition,

and mode of

without being toxic to the patient.

administration,

5

which is effective to achieve the desired

response for a particular

therapeutic

T/EP2012/055471

covers methods of

said methods comprising

the steps

Section herein.

also relates to methods

accordance with another aspect, the present invention

of preparing a compound of general formula I, supra.

In

accordance with a first embodiment,

of preparing

a compound

allowing an intermediate


relates to a method

of general formula I, the method comprises the step of compound

of general formula IY:

R NH N

R A

15 IV

in which R' and A

are as defined for general formula I, supra, and R' is a halogen

atom,

20

to react with a compound of general formula

I

I/'a:

IVa in which

25

R' is as defined for general formula

I, supra,

and Y is a substituent

is displaced in a coupling reaction, such as a hydrogen group, or an ester of a boronic acid group, for example, 71

which

atom, or a boronic acid

WO 2012/136531

PC

thereby giving, upon optional deprotection,

T/EP2012/055471

a compound of general formula

I

R NH N

R A

5

in which R', R' and A

In

accordance with a second embodiment,

method

10

are as defined for general formula

of preparing

comprising

a compound

I, supra.

the present invention also relates to a

of general

the step of allowing an intermediate

formula

compound

I, supra,

said method

of general formula

II:

R NH N

R Q

15

in which

R' and R' are as defined for general formula

atom

to react with a compound of general formula Ila:

72

I, supra,

and Q is a halogen

WO 2012/136531

PC

I

in which A is as defined in a coupling

displaced

T/EP2012/055471

la

for general formula I, supra, and

Y is a

substituent

which is

reaction, such as a boronic acid group, or an ester of a

boronic acid group, for example,



I

R NH N

R A



I, supra.

10 In

the present invention also relates to a

accordance with a third embodiment,

method

of preparing

comprising

a compound

of general


formula

compound

I, supra,

said method

of general formula VII:

V N

R A

15 VII

in which

R' and A


group, for example a halogen atom,

20 73

I, supra,

and V is a leaving

WO 2012/136531

PC

T/EP2012/055471

to react with a compound of general formula Vila: R5-CH2-NH2

VIIa in which R5 is as defined

for general formula I, supra,



I

R NH N

R A


In



accordance with a forth embodiment,

method

of preparing

comprising

a compound

I, supra.

of general


formula

compound

also relates to a

I, supra,

said method

of general formula VII:

N

R A VII

in which R' and A

are as defined for general formula 74

I, supra, and V is a NH&-group

WO 2012/136531

PC

T/EP2012/055471

to react with a compound of general formula Vllb: O=CHR5

VIIb

5

in which R5 is as defined

for general formula I, supra,



I

R NH N

R A

10


In

invention

In

I, supra.

accordance with a further aspect, the present invention covers intermediate

compounds

15


which

are useful in the preparation

of general formula I, particularly

particular,

in

of compounds

of the present

the methods described herein.

the present invention covers compounds of general formula IV:

75

WO 2012/136531

PC

T/EP2012/055471

R NH N

R A IV

in which R' and A

5

are as defined for general formula I, supra, and R' is a halogen

atom. The present invention

also covers compounds of general formula

II

R NH N

R Q 10

in which

R' and

R&

are as defined for general formula I, supra, and Q is a halogen

atom. 15


also covers compounds of general formula VII

N

R A VII

76

WO 2012/136531

PC

in which R' and R5


I,

supra, and

T/EP2012/055471

V

is a NH&-group

or a halogen atom.

5

EXPERIMENTAL SECTION

As

mentioned

supra, another aspect of the present invention

may be used for preparing

10

the compounds according to the present invention.

The following Table lists the abbreviations

section.

Examples

NMR

is a method which

used in this paragraph,

peak forms are stated

as they appear

in

and in the

the spectra,

possible higher order effects have not been considered. Names of compounds [MDL Information

15

labs.

In

were generated

using the Autonom

2000 add-in of ISIS/Draw

Systems Inc. (Elsevier MDL)] or the ICS naming tool 12.01 of ACD

some cases generally

accepted names of commercially available reagents

were used.

Abbreviation

Meaning

Ac

Acetyl

br

Broad

cycloDoublet dd

doublet of doublets

DCE

Dichloroethane

DCM

Dichloromethane

DIP EA

N,

DMAP

4-Dim ethylaminopyridine

DMF

N,

DMSO

dimethyl

DIP EA

N, N-Diisopropylethylamine

dppf

1, 1'-bis(di-phenylphosphino)ferrocene

EDC

N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide

eq

Equivalent

N-diisopropylethylamine

N-dimethylformamide

sulfoxide

77

WO 2012/136531

PC

ESI

electrospray ionisation

EtOAc

ethyl acetate

T/EP2012/055471

multiplet MeOH

methanol

MS

mass spectrometry

MW

molecular weight

NIS

N-

NMP

N-methylpyrrolidinone

NMR

nuclear magnetic

Iodosuccinimide

resonance spectroscopy:

chemical shifts (6)

are given in ppm. 2-(1H-7-Azabenzotriazol-1-yl)--1,

HATU

hexafluorophosphate

1, 3, 3-tetramethyl

uronium

Methanaminium

acid

Hcl

hydrochloric

MPLC

middle performance

MS

mass spectrometry

NMR

nuclear magnetic

liquid chromatography

resonance spectroscopy:

chemical shifts (6)

are given in ppm. The chemical shifts were corrected by setting the

DMSO signal

to 2. 50 ppm

using unless otherwise

Pd~dba~

Tris(dibenzylideneacetone)dipalladium(0)

Pd(dppf)Clz

1, 1'-bis(diphenylphosphino)

P(oTol)&

tri-o-tolylphosphine

ferrocenedichloropalladium(II)

quartet

rac-8

I

NAP

racemic-2, 2'-bis(diphenylphosphino)-1,

1'-binaphthyl

room temperature RT

retention time in minutes singlet

sept

septet triplet

TEA

triethylamine

TFA

trifluoroacetic acid

THF

tetrahydrofuran

UPLC

ultra performance

stated.

liquid chromatography

78

WO 2012/136531

PC

have their meanings

Other abbreviations

The various aspects of the invention

T/EP2012/055471

per se to the skilled person.

customary

are illustrated

described in this application

by

the following examples which are not meant to limit the invention in any way.

5

The schemes and procedures described below illustrate general synthetic routes to

of general formula

the compounds limiting.

in

transformations limiting.

In

protecting

of any of the substituents, after the exemplified

before and/or

can be such as the introduction

substitution,

for

allows

which

to the person skilled

in

are described in the subsequent successive

between

steps

said steps,

skilled in the

These

groups, halogenation,

of substituents.

further interconversion

and cleavage are well-known

the art (see for example T.W. Greene and P. G. M. Wuts in

Protective Groups in Organic Synthesis,

more

transformations.

include those which introduce

protecting groups and their introduction

Appropriate

or NH-CH~-R'

or other reactions known to

cyclization, condensation

the person skilled in the art. These transformations functionality

A, R'

of protecting groups, cleavage of

reduction or oxidation of functional

groups,

metallation,

20

to be

the Schemes is therefore not intended to be

in

addition, interconversion

modifications

a

and are not intended

the Schemes can be modified in various ways. The order of exemplified

can be achieved

15

of the invention

It is clear to the person skilled in the art that the order of transformations

as exemplified

10

I

may

3" edition,

paragraphs.

be performed

1999). Specific examples Further, it is possible that two or Wiley

work-up

without

e.g. a "one-pot" reaction, as

being performed

is well-known

to the person

art.

25

Synthesis of compounds Compounds

of general formula

with R', R', and A having

R', Q representing 30

NH2-group

of general formula I

I


can be synthesized

as depicted in the Scheme,

the meaning as given for general formula I, supra, and

leaving groups and

V

represents

an optionally

protected

or a leaving group. Examples for typical leaving groups include but are

not limited to halogen atoms like a chlorine, S(O)PR6-groups

like a methylsulfonyl-,

bromine or iodine atom or

trif late- or nonaf late-group,

79

p being

0,

1

or

WO 2012/136531

PC

routes that allow variations for R', R', R', Q,

The Scheme exemplifies

Functional moieties in R',

during the synthesis.

T/EP2012/055471

R', R',

V

and

A

Q, V and A can be converted

at every suitable stage of the synthesis. However, also other routes were used for synthesis of the target compounds.

Compounds

of formula

XI may

according to procedures 10

Tschitschibabin;

3524 -

—

et al. , Journal of Medicinal Chemistry, 1995, 38,

Fray, M. Jonathan

,

Journal of Medicinal Chemistry,

1997, 40, 3679

available or can be synthesized

of formula X may be commercially

according to procedures

to persons skilled in the art (see for example Loiseau, Philippe R. et al. European Journal of Medicinal Chemistry, 1987, 22, 457— 462 or WO 200426867 A2, 2004, 32-33). of formula

be commercially

known


to persons skilled in the art (see for example

Kristjan S. ; Johns, Brian A. , Organic Letters, 2003, 5, 1369 — 1372 or

Gudmundsson, WO

known

IX may

according to procedures

201070008 A1, 2010, 68).

A leaving

group Q can be introduced

formula

IX, V

or II.

As an

solvent

like

N,

VI

or

III

by

art to give compounds of general

N-bromosuccinimide

or

N-dimethylformamide

example, at temperatures

of general formula X,

example, halogens can be introduced

reagents like N-iodosuccinimide,

inert

in compounds

known to persons skilled in the

procedures 25

Obshchestva,

3686).

Compounds

20

Fiziko-Khimicheskago

Russkago

Zhurnal

3535 or Cai, Sui Xiong et al.

Compounds

15


to persons skilled in the art (see for example

known

Jegorow,

1928, 60, 689;

be commercially

using halogenation

or N-chlorosuccinimide, 1-methylpyrrolidin-2-on

ranging from room temperature

in an

e, f or

to the boiling point of

the solvent, for example.

30 Compounds

of general formula

general formula Y-A, in which

which

II, V

A is

the group

or

I, IV

or

VIII

can be obtained from compounds

reaction between a reagent of formula

IX via a coupling

defined supra and Y represents

A

can be transferred

of

a suitable functional

group by

to the Q-group bearing carbon atom of 80

WO 2012/136531

PC

of formula

compounds

II, V

or IX. Examples of suitable functional groups for

reactions are performed

Said coupling

as, for example, palladium

in

the presence of suitable catalysts, such

based catalysts like, for example,

bis(triphenylphosphine)-palladium

(II)

ferrocene)-dichloropalladium

(II) and

like,

phosphines

or

chloride

suitable

optionally

for example,

(0),

additives

as, for

such

or triphenylphosphine

P(oTol)&

and

carbonate, sodium

fluoride or tribasic potassium

tetrabutylammonium

2-methylpropan-2-olate,

(II)

(1, 1, -bis(diphenylphosphino)

optionally with a suitable base, such as, for example, potassium

10

Palladium

tetrakis(triphenylphosphine)palladium

acetate,

example,

Y in

boronic acids A-B(OH)~, or esters of boronic acids A-B(OC~-C|, -alkyl)~.

A-Y include

5

T/EP2012/055471

phosphate in a suitable solvent, such as, for example, tetrahydrofuran.

Examples of such coupling reactions may be found in the textbook entitled "Metal-Catalyzed

Cross-Coupling

Reactions", Armin de Meijere (Editor), Francois

Diederich (Editor) September 2004, Wiley Interscience ISBN: 978-3-527-30518-6.

15 Compounds

of general formula

I, II, III

or

VII

of

can be obtained from compounds

general formula IV, V, VI or VIII via a coupling reaction using a reagent of formula Y-R3 in which

which

20

the group

compounds

defined supra and Y represents

R3 is

R3

of formula

can be transferred IV, V, VI

a suitable functional

to the

group by

bearing carbon atom of

R3

or VIII. Examples of suitable functional groups

Y

for

of compounds of

the use in coupling reactions are given supra for the preparation

general formula I, IV or VIII from compounds of general formula II, V or IX.

The coupling reactions include metal catalyzed coupling reactions like Sonogashira coupling reactions with alkynes for alkyne introduction,

25

with alkenes for alkene introduction,

Hartwig

Heck coupling reactions

Buchwald coupling

reactions with

amines for amine introduction. Y in Y-R3 may

bases,

for example

tetrahydrofuran

30

also represent an acidic hydrogen

nucleophiles

sodium

hydride,

at temperatures

in

that can be removed by suitable

a suitable

as DMSO or

like, for example, primary or secondary amines, alkoxides, thiolates

IV, V, VI

carbon-atom

such

ranging from rt to the boiling point. The resulting

or carbon anion bearing groups can be used to replace formula

solvent,

or

VIII

R3 in

compounds

of general

to add secondary or tertiary amines, ethers, thioethers or

attached groups to give compounds of general formula I, II,

81

III

or VII.

WO 2012/136531

of general formula

Compounds

T/EP2012/055471

PC

or

I, II, III

primary or secondary

containing

VII

amines, ethers or thioether can also be build by Ullmann-type

coupling reactions in

the presence of suitable catalysts, such as, for example, copper based catalysts like copper(II)diacetate 5

in

of general formula

carbonate staring from compounds

atom. Optionally,

suitable

the case

V

by a reaction with suitable

15

N-dimethylformamide

room temperature

of

substitution

hydrogen

V in compounds

of a R5-CH2-group can be

of formula VII, VIII,

IX

or X

amines R~-CH&-NH& in the presence of a suitable

base, such as, for example N,

R3

VIII in which

or phenyl

like N, N-dimethylglycine

ligands

represents a leaving group, the introduction

achieved by nucleophilic

i. e.

or

can be added.

pyrrolidin-2-ylphosphonate

In

IV, V, VI

a leaving group such as, for example, an iodine, bromine or chlorine

represents

10

presence of a suitable base, like for example, caesium

suitable solvent such as

DIPEA in a

at temperatures

or 1-methylpyrrolidin-2-one,

ranging from

to the boiling point of the solvent to give amines of general

formula I, IV, V or VI. In

the case

represents a leaving group, the introduction

V

also be achieved in a coupling VIII, IX or X is

20

reaction in which

reacted with suitable amines

of a suitable catalyst, such as Pd~dba~ and a suitable base, such as, for example, such as, for example,

N,

V in

R~-CH&-NH&

BINAP

of a R5-CH2-group can

optionally in the presence

for example, and optionally with

tert-butylate

sodium

of formula VII,

compounds

in a suitable solvent,

or 1-methylpyrrolidin-2-one

N-dimethylformamide

to give

amines of general formula I, IV, V or VI.

25

In

the case

V

R~-CH&-group,

agent,

after deprotection

reaction

amination

for

using

example

cyanoborohydride

30

temperatures

to a

sodium

of formula

modified.

O=CHR',

a suitable

tris(acetato-kappaO)(hydrido)borate solvent like, for example,

ranging from room temperature

of formula I, For example,

reducing

or sodium

acetic acid at reaction

to the boiling point of the solvent.

II, III, IV, V, VI, VII, VIII, IX, X

thioethers 82

of a

can be achieved by a reductive

NH&-group,

an aldehyde

in a suitable

Residues in compounds

optionally

the introduction

represents an optionally protected NH2-group

can be oxidized

or XI can be

using oxidation

WO 2012/136531

PC

like 3-chlorobenzenecarboperoxoic

reagents

inert solvents

stoichiometric

acid, oxone or dimethyldioxirane

or acetone,

like dichloromethane

T/EP2012/055471

respectively.

on the

Depending

ratio of oxidation reagent to the afore mentioned

in

compounds

sulfoxides or sulfones or mixtures thereof will be obtained.

v NH2 N

XI

Ngi

NH

IX

VIII

NH

NH

Vll

N

N

~

di

VI

NH

V

IV

NH

NH N

N

~

3i

Further, the compounds

10

of formula

I

of the present invention can be converted to

any salt as described herein, by any method which is known to the person skilled in

the art. Similarly, any salt of a compound of formula

83

I

of the present invention can

WO 2012/136531

PC

be converted into the free compound,

and intermediates

The compounds invention

may require purification.

to the person skilled

10

in

produced according to the methods of the Purification of organic compounds

is well known

the art and there may be several ways of purifying the same

some cases, no purification

compound.

In

compounds

may be purified

may be necessary.

In

some cases, the

some cases, impurities

may be

removed by stirring using a suitable solvent. In some cases, the compounds

may be

purified by chromatography,

by crystallisation.

e.g. from Separtis

silica gel cartridges,

or Isolute

Flash NH2 silica gel in combination II

In

flash chromatography,

particularly

pre-packed

system such as a Flashmaster

the compounds autopurifier ionisation

with

mass spectrometer

such as Isolute

Flash silica gel

(Separtis) or an Isolera system (Biotage) and eluents

may be purified by preparative

equipped

using for example

with a suitable chromatographic

such as, for example, gradients of hexane/EtOAc

15

to the person

art.

skilled in the

5

by any method which is known

T/EP2012/055471

or DCM/methanol. HPLC using,

a diode array detector in combination

In

some cases,

for example, a Waters

and/or

with a suitable

on-line electrospray

pre-packed

reverse

phase column and eluants such as, for example, gradients of water and acetonitrile which may contain additives

20

such as trifluoroacetic

acid, formic acid or aqueous

ammonia.

Analytical

UPLC-MS was performed

as follows:

Method A: System: UPLC Acquity (Waters) with PDA Detector und Waters ZQ mass

spectrometer; 25

Column: Acquity BEH C18

0. 1% formic acid; Solvent B: acetonitrile; Gradient: 99 % A + 1 + 1 % A (0.4 min); Flow: 0. 8 mL/min; Injection Volume: 1.0 Ijl sample concentration); Detection: PDA scan range 210-400 nm-

Solvent A: Water % A

(1.6

min)

(0. 1mg-1mg/mL

1.7pm 2. 1x50mm; Temperature: 60'C;

+

Fixed and ESI (+), scan range 170-800 m/z

30

84

WO 2012/136531

Intermediate

PC

T/EP2012/055471

1-1: Preparation of 6, 8-dibromo-imidazo[1, 2-a]pyrazine

Example

CI

CI N

Br

To

stirred

a

of

solution

3-bromo-6, 8-dichloroimidazo[1, 2-a]pyridine 5

2. 31

subsequently

added

acid

(11.28

3 eq), 614 mg Pd(dppf)Cl~

min

mmol,

at 130'

(36.95

%)

'H-NMR

(300

mmol) in NMP (40 mL)

(0.75mmol, 0.2 eq)

C in

a microwave

and aqueous

oven, water was added and the precipitate was by preparative

HPLC yielded

Preparation

481 mg

N-cyclopropyl-4-(6, 8-dichloroimidazo[1, 2-a]pyridin-3-yl)benzamide: MHz, CDClz): 6 =

8. 51 (1H), 8.00

—

7.91 (3H), 7.81

—

0.68 (1H), 0. 57 (1H) ppm.

Intermediate 15

3. 76

[4-[(cyclopropylamino)carbonyl]phenyl]-boronic

filtered off, washed and dried. Purification

(1H),

g,

(Apollo)

carbonate solution (1M, 3 mL) in one portion at rt. After heating for 40

potassium

10

(1.00

was

g

available

commercially

Example

2-1:

of

N-cyclopropyl-4-(6, 8-dichloroimidazo[1, 2-a]pyridin-3-yI)benzamide

Y..

CI

N

N

CI

CI

0 HN

To a stirred solution of

85

7. 68 (4H), 2. 85

WO 2012/136531

PC

(320 mg, 0. 92

N-cyclopropyl-4-(6, 8-dichloroimidazo[1, 2-a]pyridin-3-yl)benzamide mmol) in NMP (30 mL) was subsequently

(0.92 mmol,

(3:2) (0. 185 5

1, 1'-binaphthalene-2, mg sodium

10

e

-

palladium

(0. 55

mmol,

0.6 eq)

mg

and 222. 1

(2. 31 mmol, 2. 5 eq) in one portion at rt. After heating for a microwave oven, the solution was filtered, evaporated and

tert-butylate

the residue triturated i

4-dien-3-one

0. 2 eq), 345. 3

mmol,

2'-diylbis(diphenylphosphane)

40 min at 150 C in

y

added 67. 6 mg 2-methylpropan-1-amine

eq), 169 mg (1E,4E)-1, 5-diphenylpenta-1,

1

T/EP2012/055471

e

d

l

of the residue by preparative

with water. Purification

7

d

0

m

4-[6-chloro-8- [(2-methylpropyl)amino]imidazo[1,

9

1

(

g

.

7

HPLC

%

)

2-a]pyridin-3-ylf-N-cyclopropylben

zamide: 'H-NMR (300 MHz, CDCl&): 6 7.88 (2H), 7.68 (1H), 7. 60 (2H), 7. 55 (1H), 6.28 (1H),

6. 10 (1H), 5.41 (1H), 3.09 (2H), 2. 95 (1H), 1.05 (6H), 0.91 (2H), 0. 66

Intermediate 15

Preparation

Example

3-1:

of 6-bromoimidazo[1, 2-a]pyridin-8-amine NHz

NHz NHz

To a stirred

solution

(2.2

L)

N

N

Br

isopropanol

N

of 5-bromopyridine-2,

at rt was added chloroacetaldehyde

mixture was stirred for an additional

the remaining

in

methanol

6-bromoimidazo[1, 2-a]pyridin-8-amine MHz, d|, -DMSO): 6

(255 g, 1626 mmol) in one under reflux overnight,

and

and dried in vaccuo

evaporation

=8. 39 (2H), 8. 12 (2H), 6. 92 (1H) ppm.

Preparation

Example

at 50'C.

yielded

as a brown solid (124 g, 40 %): 'H-NMR (300

25

Intermediate

the

60 min at rt. The suspension was filtered, and

solid was washed with isopropanol

Redissolution

3i

(278 g, 1478 mmol) in

3-diamine

portion. After stirring in an nitrogen atmosphere 20

(2H)

4-1:

of 6-bromo-3-iodoimidazo[1, 2-a]pyridin-8-amine NHz

NHz

86

WO 2012/136531

To a stirred

PC

of 6-bromoimidazo[1, 2-a]pyridin-8-amine

suspension

mmol) in THF 100 mL) at O'C was dropwise added a solution of NIS

1.16 eq)

for 2h, isolute sorbent (Biotage) was

added (20 g) and the mixture was evaporated

in vaccuo. The residue was loaded on

in

a flash column and the crude product purified

acetate

hexane)

/

(78.2 %).

"H-NMR

to yield 25. 6

Intermediate Preparation

g

Example

by flash chromatography

(ethyl

6-bromo-3-iodoimidazo[1, 2-a]pyridin-8-amine

(300 MHz, de-DMSO): 6

(2H) ppm. UPLC-MS: RT =

10

(20. 6 g, 97. 15 (25. 4 g, 112.87

mL THF. After stirring

mmol,

5

215

T/EP2012/055471

=

7 60 (1H), 7 54 (1H, d), 6 38 (1H), 6 12

0.98 min; m/z (ES+) 339.0 [MH']; required

MW =

338.0.

5-1:

of 4-(8-amino-6-bromoimidazo[1,

2-a]pyridin-3-yl)-

N-cyclopropyl-2-methylbenzamide NH~

NH~ N

Br

To a stirred solution of 6-bromo-3-iodoimidazo[1,

15

mmol)

in THF

(450 mL) was subsequently

1.05 eq), 3.706

g Pd(dppf)Cl&

4

1

added

7. 176

C

for 24 h, and, after addition of

3

4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

N-cyclopropyl-2-methyl-4-(4,

heated at 80 C for 48 h. After filtration through ALLOX and evaporation,

material was purified

by flash chromatography

'H-NMR

(2H),


7. 40+ 7. 38 (1H), 6. 41

to yield 4. 93

the crude g

(56 /)

2-a] pyridin-3-yl)-N-cyclopropyl-2-methylbenzamide:

4-(8-amino-6-bromoimidazo[1, 25

g

(4. 54 mmol, 0. 2 eq) and aqueous in one portion at rt. After stirring

carbonate solution (1M, 68 mL) overnight at rt, the mixture was heated at 60 potassium

20

(8.52 g, 22. 69

4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide


(23.82 mmol,

2-a]pyridin-8-amine

+

8. 31 (1H), 7.78 + 7.74 (1H), 7. 59 (1H), 7.45 + 7.44 6. 37 (1H), 6. 15+ 6. 10 (2H), 2. 81 (1H), 2. 36 (3H),

=

87

WO 2012/136531

PC

0.66 (1H), 0. 50 (1H) ppm. MW = 385. 3. Intermediate 5

Preparation

Example

UPLC-MS: RT =

0.82

T/EP2012/055471

min; m/z (ES+) 386. 3 [MH

]; required

6-1:

of

4-(6-bromo-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a]pyridin-3-yl]-

N-cyclopropyl-2-methylbenzamide F

F F

NH NH2 N N

Br

Br

0 HN

To a stirred solution of

10

4-(8-amino-6-bromoimidazo[1,

2-a]pyridin-3-yl)-N-cyclopropyl-2-methylbenzamide

(3 g, 5.87 mmol) in dichloroethane

(60 mL) at rt was added 3, 3, 3-trifluoropropanal

(4. 58 g, 40. 88 mmol, 7 eq). After stirring for 2 h, sodium triacetoxy borohydride (9.12 g, 40. 88 mmol, 7 eq) and trifluoroacetic acid (3.33 g, 29. 2 mmol, 5 eq) were added and the mixture was stirred for 1 h. After addition of DCM (100 mL), the 15

organic phase was washed with water and evaporated. by

flash

yielded

chromatography

4-[6-bromo-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

(66.9 %).

yl-2-methylbenzamide

(1H), 7. 60 (1H), 7.46

20

2. 81

1.22

'H-NMR

Purification

(300

88

2. 51

g

2-a]pyridin-3-yi]-N-cycloprop

MHz, d6-DMSO): 6 =

7.44 (2H), 7.41 + 7. 39 (1H), 6.63 (1H), 6. 32 (1H), 2. 64 (2H), 2. 36+ 2. 35 (3H), 0.66 (1H), 0.50 (1H) ppm. min; m/z (ES+) 482. 3 [MH ]; required MW = 481.3. +

of the residue

8. 32 (1H), 7.81 (1H), 3.49 (2H), UPLC-MS: RT =

WO 2012/136531

Intermediate

PC

Example

12:

of [4-(cyciopropyicarbamoyi)-3-methylphenyl]boronic

Preparation

T/EP2012/055471

acid

HO I

OH

Step A: Preparation

of 4-bromo-N-cyclopropyl-2-methylbenzamide

Br

To a stirred solution of 4-bromo-2-methylbenzoic L)

at rt was added cyclopropanamine

10

g

(73.4

mol) in DCM

EDC

(8.4

(320. 9 g, 1.67

the solution was washed with water

phase was reextracted with DCM. The combined organic phases

were dried over sodium sulfate, filtered and evaporated.

triturated

1.4

(79.64 g, 1.4 mol) and

mol) in one portion. After stirring overnight, and the aqueous

acid (300 g,

with diisopropyl

The remaining

ether, filtered, washed and dried

%) 4-bromo-N-cyclopropyl-2-methylbenzamide:

in

"H-NMR

solid was

vaccuo to yield 260

(300

MHz, CDCI~): 6

=7. 34 (s, 1H), 7.27 (d, 1H), 7. 14 (d, 1H), 5. 96 (bs, 1H), 2. 85 (m, 1H), 2. 38 (s, 3H),

0.85 (m, 2H), 0. 59 (m,

2H) ppm.

15

Step B: Preparation

of N-cyclopropyl-2-methyl-4-

(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)benzamide

o

B

0 20

To a solution dioxane

of 4-bromo-N-cyclopropyl-2-methylbenzamide

(2 L) at

rt was

2-dicyclohexylphosphino-2',

added

(260 g,

bis-(pinacolato)-diboron

4', 6'-triisopropylbiphenyl

(19.5

1.02

mol) in

(390 g, 1.53 mol),

g, 40. 9 mmol), potassium

acetate (150.6 g, 1.53 mol) and tris-(dibenzylidenaceton)-dipalladium(0) (9.37 g, 10.2 mmol) and the mixture was ref luxed for 6 h, After cooling to rt, water (3 L) 25

and ethyl

acetate (5

L) was added and the mixture stirred for 15 min. The organic

89

WO 2012/136531

T/EP2012/055471

PC

phase was washed with water, dried over Na&(SO&), filtered and evaporated.

(ethyl acetate/hexane)

chromatography

5

g

(56. 3

%)

4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide:

N-cyclopropyl-2-methyl-4-(4, 'H-NMR

308

yielded

Flash

(300 MHz, CDCl~): 6 =7.63 (s, 1H), 7.60 (d, 1H), 7. 28 (d, 1H), 5.94 (bs, 1H),

2. 87 (m, 1H), 2.41 (s, 3H), 1.33 (s, 6H), 0.85 (m, 2H), 0.59 (m, 2H) ppm. of [4-(cyclopropylcarbamoyl)-3-methylphenyl]boronic

Step C: Preparation

HO

acid

B I

OH

To a solution of

10

4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)benzamide


(20. 2 g, 67. 13 mol) in acetone (300 mL) at rt was added sodium periodate (43. 1 g, 201.40 mol) and ammonium acetate ( 134.26 mol, 134 mL 1M aqueous solution) and the mixture was stirred for 3h. More water was added (120 mL), and the mixture was stirred at

15

40'C for

2

h

more. After addition of 4

N

HCl

(32 mL), the organic

phase was removed in vaccuo and the reminder was extracted with ethyl

actate.

The organic phase was washed with sat. sodium chloride solution, filtered through

a Whatman

filter and evaporated. The residue was redissolved

evaporated

(two times) to yield

[4-(cyclopropylcarbamoyl)-3-methylphenyl]boronic

20

de DMSO): 6 =8 21

(2H),

0.47

Example

acid:

g

'H-NMR

toluene and

(94. 3

%) (3 00 MH z,

(1H), 8 04 (2H), 7 56 (2H), 7 17 (1H), 2 77 (1H), 2 25 (3H), 0 62

(2H) ppm.

1-1:

Preparation 25

14. 59

in

of N-cyclopropyl-4-(8-[(2-methylpropyl)amino]

imidazo[1, 2-a]pyridin-3-ylfbenzamide

90

WO 2012/136531

PC

Y..

T/EP2012/055471

Y.. N

N N

0 HN

To a solution of

4-[6-chloro-8- [(2-methylpropyl)amino]imidazo[1,

2-a]pyridin-3-ylf-N-cyclopropylben

zamide (50 mg, 0. 13 mmol) in ethanole (15 mL) was subsequently 5

TEA

(1.43

mmol) and 5 mg Pd/C (10%) at rt and the mixture subsequently

rt in a hydrogen

atmosphere

(

0

1

3

N-cyclopropyl-4-[8- [(2-methylpropyl)amino]imidazo[1,

HPLC

to yield 4. 7 )

2-a] pyridin-3-yl]benzamide:

8.46 (1H), 7.93 (2H), 7.80 (1H), 7.71 — 7.65 (3H), 6. 76 (1H), 6. 15 (1H), 5. 99 (1H), 3.03 (2H), 2. 84 (1H), 0. 92 (6H), 0. 67 (2H), 0. 56 'H-NMR


=

(2H).

Example

15

stirred at

at normal pressure for 2. 5 h. After filtration, the

and the residue purified by preparative

solution was evaporated

10

added 145 mg

2-1:

Preparation

of N-cyclopropyl-4-f6-[2-(hydroxymethyl)phenyl]2-a] pyridin-3-yl]-

8-[(3,3, 3-trifluoropropyl)amino]imidazo[1, 2-methylbenzamide

91

WO 2012/136531

F F

PC

F

T/EP2012/055471

F

F F

NH

NH

N

N N

Br

OH

0 HN

0.06

mmol 4-[6-bromo-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

N-cyclopropyl-2-methylbenzamide,

0. 13

mmol

acid (18.9 mg, 2 eq), 0.012 mmol Pd(dppf)Cl& 5

2-a]pyridin-3-yl]-

[2-(hydroxymethyl)phenyl]boronic

(10.18 mg, 0. 2 eq),

2 mL NMP and

0. 187 mmol potassium carbonate (0. 19 mL, 1M in water, 3 eq) were combined in a sealed vial and heated at 130 'C under microwave irradiation for 40 min. After additional

heating

at 120'C overnight

in a heating

solution was filtered and subjected to preparative

block and cooling to rt, the

to give 17.3

HPLC

mg

(55 %)

N-cyclopropyl-4-[6- [2-(hydroxym ethyl)phenyl] -8- [(3,3, 3-trifluoropropyl)amino]imid

10

azo[1, 2-a]pyridin-3-yl$-2-methylbenzamide:

"H-NMR

(300

MHz,

CDCl~): 6 =

7. 82

7.50 (3H), 7.48 — 7.30 (6H), 6.27 (1H), 6.02 (1H), 5. 84 (1H), 4. 64 (2H), 3.58 (2H), 3.40 (2H, tr), 2.90 (1H), 2. 56 (2H), 2. 45 (3H), 0.88 (2H), 0.61 (2H) ppm; UPLC-MS: RT = 1.02 min; m/z (ES+) 509.6 [MH']; required MW = 508. 6. (1H), 7.60

15

—

The following compound

examples were prepared in analogy to the procedure

described above using the appropriate boronic acid building

intermediate

example 6 and the appropriate

block [LC-MS data such as retention

time (RT in min) or

observed mass peak were collected using LC-MS Method A unless explicitly stated]:

92

WO 2012/136531

Example

T/EP2012/055471

PC

Structure

Analytical Data RT = 0.85 MWfound

Name F

=

480. 5MW„i, = 479.5 "H-NMR (300 MHz,

F

N-cyclopropyl-2-methyl-4-( 6-(pyridin-4-yl)-8-[(3, 3, 3-tr ifluoropropyl) amino]imidaz o[1,2-a] pyridin-3-yl)benza

N

N

2-2

8.60 8.34 (1H), 8.06 (1H), 7.71 (2H), 7. 66 (1H), 7.59 - 7.53 (2H), 7.42 (1H), 6.54 (1H). 6.47 (1H) 3.60 (2H), 2. 82 (1H), 2. 71 (2H), 2. 37 (3H), 0.66 (1H), 0.51 (1H)

dg-DMSO): 8 =

NH

N

mide

0

HN

(2H),

ppm

Example

3-1:

Preparation 5

of N-cyclopropyl-4-(6-[(3-fluoro-5-methylphenyl)sulfanyl]-

8-[(3,3, 3-trifluoropropyl)amino]imidazo[1,

2-a]pyridin-3-yl]-2-methylbenzamide

F

F F

F F

F

NH

NH

N

N

S

Br

F

0 HN

To a solution of 85. 5 mg (0.6 mmol) 3-fluoro-5-methylbenzenethiol

in

2. 0

mL DMSO

were added 24 mg (0.6 mmol) sodium hydride and the mixture was stirred for

1 h

at rt. 10

48 mg (0. 1 mmol) 4-[6-bromo-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, pyridin-3-ylf-N-cyclopropyl-2-methylbenzamide

heated at 160 'C for mg

were added and the mixture was

h. The mixture was filtered and purified by

(35 %) of the title compound.

UPLC-MS: RT =

1.47

HPLC

to yield 20

min; m/z (ES+) 543.6 [MH'];

8. 31 (1H), 7.87 (1H), 7. 66 (1H), 7.49 — 7.45 (2H), 7.39 (1H), 6. 93 (1H), 6.85 (2H), 6. 54 (1H), 6. 13 (1H), 3.44 (2H), 2. 81 (1H), 2. 55 (2H), 2. 35 (3H), 2. 21 (3H), 0.66 (2H), 0. 55 (2H) ppm. required

15

1

2-a]

MW =

542. 6.

"H-NMR

(300

MHz, d6-DMSO): 6 =

93

WO 2012/136531

PC

described

above

the appropriate

thiol

derivative

the appropriate

and

6 [LC-MS data such as retention time (RT in min) or observed mass

Br-intermediate 5

using

to the procedure

examples were prepared analogously

The following compound

T/EP2012/055471

peak were collected using LC-MS Method A unless explicitly stated]:

Example

Structure

Name

Data

Analytical

F F RT =

—547. 6 d 546. 6 MW„j, "H-NMR (300 MHz, d6-DMSO): 6 = 8. 29 (1H), 7.90 (1H), 7.66 (1H), 7.48 — 7.42 (2H), 7. 39 (1H), 7.30 (1H), 7. 12 (1H), 7.01 (1H), 6.56 (1H)6. 16 (1H), 3.43 (2H), 2. 81 (1H), 2. 54 (2H), 2. 35 (3H), 0. 66 (2H), =

NH N

N-cyclopropyl-4-l6-[(2, 3-di fluorophenyl)sulfanyl]-8-[( 3,3, 3-trifluoropropyl) amin o] imidazo [1,2-a] pyri din-3yl]-2-methylbenzamide

S

3-2

1.40 MWf

F F HN

0

0.49

(2H) ppm

F F RT =

NH N

3-3

N-cyclopropyl-2-methyl-4-l 6-(phenylsulfanyl)-8-[(3, 3, 3-trifluoropropyl) amino]im idazo[1, 2-a] pyridin-3-yl]be nzamide

S

HN

0

1.38 MWfognd 511.6 MW„j, = 510.6

(300 MHz, 8. 32 (1H), 7.75 (2H), 7.47 — 7.35 (3H), 7. 31 (4H), 7.23 (1H), 6.65 (1H), 6.23 (1H), 3.42 (2H), 2. 80 (1H), 2. 55 (2H), 2. 33 (3H), 0.65 (2H), 0.49 "H-NMR

d6-DMSO): 6 =

(2H) ppm

94

WO 2012/136531

Example

PC

Structure

Name

Analytical

T/EP2012/055471

Data

F F RT =

NH

526. 6

MW„j, = 525. 6 4-(6-[(2-aminophenyl)sulfa nyl]-8-[(3, 3, 3-trifluoroprop yl) amino]imidazo [1,2-a] pyr idin-3-yl)-N-cyclopropyl-2methylbenzamide

S HRN

HN

(300 MHz, 8.29 (1H), 7.57 (1H), 7.42 (1H), 7.36 — 7.27 (3H), 7. 12 (1H), 6.76 (1H), 6.53 (1H), 6.39 (1H), 6.06 (1H), 5.43 (2H), 5.40 (1H), 3.41 (2H), 2. 81 (1H), 2. 56 (2H), 2. 30 (3H), 0.66 (2H), 0.50 (2H) ppm "H-NMR

N

3-4

1.18 MWfpgpd

0

d6-DMSO): 6 =

F F RT =

1.40 MWfpgpd

529. 6

MW„j, = 528. 6

NH

(300 MHz, 8. 30 (1H), 7.89 (1H), 7.70 (1H), 7.50 — 7.44 (2H), 7. 39 (1H), 7.32 (1H), 7.08 (2H), 7.01 (1H), 6. 58 (1H), 6. 19 (1H), 3.42 (2H), 2. 80 (1H), 2. 55 (2H), 2. 34 (3H), 0. 65 (2H), 0.49 (2H) ppm H-NMR

N

N-cyclopropyl-4-[6-[(3-fluo rophenyl)sulfanyl]-8-[(3, 3, 3-trifluoropropyl) amino]im idazo[1, 2-a] pyridin-3-yl)-2methylbenzamide

S

3-5

F

d6-DMSO): 6 =

F F RT =

NH

527. 6

MW„j, = 526. 6

(300 MHz, 9.99 (1H), 7.67 (1H), 7.62 (1H), 7.41 — 7.35 (3H), 7. 10 — 7.02 (2H), 6. 85 (1H), 6. 72 (1H), 6.43 (1H), 6. 12 (1H), 3.43 (2H), 2. 80 (1H), 2. 57 (2H), 2. 33 (3H), 0.65 (2H), 0.49 "H-NMR

N

pyl-4-[6- [(2-hyd roxyphenyl) s ulf anyl] -8- [(3, 3, 3-trifluoropropyl) amino]i midazo[1, 2-a] pyridin-3-yl)2-methylbenzamide N-cyclo pro

3-6

1.14 MWfound

S HO

0 HN

d6-DMSO): 6 =

(2H) ppm

95

WO 2012/136531

PC

T/EP2012/055471

4-1:

Example

of N-cyclopropyl-2-methyl-4-f6-(methylsu

Preparation


lfanyl)-

2-a]pyridin-3-yl]benzamide F

F

F

F HN

HN

N

N

S

Br

H

H

To a solution of 170.0 mg (0.35 mmol) 4-[6-bromo-8-[(3, 3, 3-trifluoropropyl)amino]

imidazo[1, 2-a]pyridin-3-yl)-N-cyclopropyl-2-methylbenzamide

(1.77 mmol)

added 124 mg h

10

sodium thiomethylate

in

2. 0

mL DMSO were

and the mixture was stirred for

at 70' C. After stirring at 100 'C for 3 h, water was added and the mixture was

extracted with ethyl acetat. The organic phase was washed with water and sat sodium

chloride

solution,

(100 /0).

compound

dried

UPLC-MS: RT =

to yield

158

of the title

and

evaporated

1.08

min; m/z (ES+) 449. 5 [MH']; required MW =

mg

448. 5. 15

1

Example

5-1:

Preparation

of N-cyclopropyl-4-(6-[(3-fluoro-5-methylphenyl)sulfanyl]-

8-[(3,3, 3-trifluoropropyl)amino]imidazo[1, F

2-a]pyridin-3-yl]-2-methylbenzamide F

F F

F

HN

HN N

N

S

S

p

p

H

H

96

WO 2012/136531

To

PC

solution

a

of 158

zo[1, 2-a]pyridin-3-yl]benzamide

20 mL

DMF

mmol)

3, 3-trifluoropropyl)amino]imida were added 651 mg

(1.06

mmol)

persulfate

(oxone) and the mixture was stirred overnight at rt under

nitrogen atmosphere.

Water was added and the mixture was extracted with DCM.

potassium 5

in

(0. 35

mg

N-cyclopropyl-2-methyl-4-(6-(methylsulfanyl)-8-[(3,

T/EP2012/055471

The organic phase was washed with water and sat sodium chloride solution, dried

to yield 150

and evaporated

mg

of the title compound (88 %).

min; m/z (ES+) 481.5 [MH']; required

10

MW =

480. 5.

"H-NMR

UPLC-MS: RT =

1.08

(300 MHz, d6-DMSO): 6

=

8.37 (1H), 8. 12 (1H), 7.76 (1H), 7. 52 — 7.48 (2H), 7.45 (1H), 6. 82 (1H), 6. 50 (1H), 3.56 (2H), 3.27 (3H), 2.81 (1H), 2.69 (2H), 2. 37 (3H), 0.66 (2H), 0.51 (2H) ppm. Example

6-1: of N-cyclopropyl-4-(6-(3-fluorophenoxy)-

Preparation



F F

F

HN

HN N

N

0

Br

N

H

15 mixture

A

78

comprising

4-[6-bromo-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

20

according to intermediate

which was prepared

109 mg 3-fluorophenol

634 mg caesium carbonate, 3.3 mg

irradiation ethyl

and

1.5

mL

N,

1, 4-dioxane was heated at 120

6.4

C using microwave

for 4 hours. The mixture war poured into water and extracted with

acetate. The organic layer was dried over

(1%) of the title compound: (CDCl3): 6=

example 6-1,

N-dimethylglycine,

sodium sulfate. After filtration

removal of the solvent the residue war purified by chromatography

25

ljmol)

2-a]pyridin-3-yl]-N-cycloprop


mg copper(l)chloride

(162

mg

m/z (ES+) 513 [MH']; required

MW =

and

to give 1.2 mg

512.2.

"H-NMR

0. 62 (2H), 0. 90 (2H), 2. 49 (3H), 2. 51 (2H), 2. 92 (1H), 3.56 (2H), 5. 50

97

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(1H), 5.88 (1H), 5.99 (1H),

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6.75-6. 83 (2H), 7.22-7. 31 (2H), 7. 35 (1H), 7. 37 (1H),

7.43 (1H), 7.55 (1H), 7.60 (1H) ppm. Example 6-2: 5

of N-cyclopropyl-4-(6-(2-fluoro-4-methoxyphenoxy)-

Preparation



F F

F

HN

HN N

N

Br

F

H

H

A

mixture

50. 5

comprising

4-[6-bromo-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 10


74. 6

(105 ljmol)

2-a]pyridin-3-yl]-N-cycloprop

example 6-1,


which was prepared

171 mg caesium carbonate, 4. 77 mg (RS)-phenyl

mg 2-fluoro-4-methoxyphenol

hydrogen

mg

4. 2

pyrrolidin-2-ylphosphonate,

1,4-dioxane was heated at 120'C

using

mg

copper(l)chloride

microwave

irradiation

and

1

mL

for 2 hours. The

mixture war poured into water and extracted with a mixture of ethyl acetate and

15

methanol.

The organic layer was dried over sodium sulfate. After filtration and

removal of the solvent the residue war purified by chromatography

to give 7. 0

mg

(14%) of the title compound: m/z (ES+) 543 [MH']; required MW = 542. 2. 1H NMR (DMSO

d6) 6- 0 49 (2H) 0 65 (2H) 2 29 (3H) 2 62 (2H) 2 80 (1H) 3 47

3.72 (3H), 6. 12 (1H), 6. 54 (1H), 6.73 (1H), 7.00 (1H), 7.20 (1H), 7.29-7. 36 (3H), 7.43 (1H), 7. 59 (1H), 8.28 (1H) ppm. (2H),

20

Example 7 (alternative

route as described for Example 6-1)

N-cyc lopropyl-4-(6-(3-fluorophenoxy)-8-[(3,

trifluoropropyl)amino]imidazo[1,

3, 3-


98

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0

N

N

N

0

0

b

b

,

, N

N

To a solution of 31 mg (51 ljmol) tert-butyl (3-[4-(cyclopropylcarbamoyl)-3-

2-a] pyridin-8-yl](3, 3, 3-

methylphenyl]-6-(3-fluorophenoxy)imidazo[1,

trifluoropropyl)carbamate 5

which was prepared

7a in 0.5 mL dichloromethane


was added 58. 5 pL trifluoroacetic

mixture was heated at 50'C under microwave irradiation

were removed and the residue purified by chromatography

for

1

example

acid and the hour. The solvents

to give 19 mg (73%) of

the title compound. 1H NMR (DMSO

10

d6) 6- 0 48 (2H) 0 64 (2H) 2 33 (3H) 2 61 (2H) 2 79 (1H) 3 45

6. 10 (1H), 6. 58 (1H), 6.85-6.95 (3H), 7. 29-7.48 (4H), 7.60-7.70 (2H), 8.28 (1H)

(2H),

ppm.

Example 7a

tert-Butyl f3- [4-(cyclopropylcarbamoyl)-3-methylphenyl]

15

fluorophenoxy)imidazo[1,

N

-6-(3-

2-a]pyridin-8-yl](3, 3, 3-trifluoropropyl)carbamate

0

N

0 N

0

Br

N

P

b

,

N

200 mg (344 pmol) tert-butyl $6-bromo-3-[4-(cyclopropylcarbamoyl)-3methylphenyl]imidazo[1,

2-a]pyridin-8-yl](3, 3, 3-trifluoropropyl)carbamate

was prepared according to intermediate

20

to example 6-1 to give after working

example 7b were transformed

up and purification

compound.

Example 7b

99

which in analogy

32 mg (15%) of the title

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2-

tert-Butyl [6-bromo-3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]imidazo[1,

a] pyridin-8-yl](3, 3, 3-trifluoropropyl)carbamate

;j Jc 0

N

N

0

N

A

5

mixture comprising 2. 62

g

P

(4.91 mmol) tert-butyl (6-bromo-3-iodoimidazo[1, 2-

a]pyridin-8-yl)(3, 3, 3-trifluoropropyl)carbamate

intermediate

example 7c,

methylphenyl]boronic

1.61

g

according to

which was prepared

[4-(cyclopropylcarbamoyl)-3-

acid, which was prepared according to intermediate

12, 100 mg (1, 1, -bis(diphenylphosphino)ferrocene)-dichloropalladium aqueous 2M cesium carbonate solution and 30 mL tetrahydrofuran

10

55'C for 2 hours. 50

mg

(II),

example

6. 1

mL

was stirred at

(1, 1, -bis(diphenylphosphino)ferrocene)-dichloropalladium

(II) were added and stirring continued for additional

2 hours. Water was added and

the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the

residue was purified by chromatography

to give 2. 15 g (75/o) of the title compound.

15 Example 7c

tert-Butyl (6-bromo-3-iodoimidazo[1, 2-a]pyridin-8-yl)(3, 3, 3trifluoropropyl)carbamate

20

To a solution of

5.00 g (12.25

mmol) tert-butyl

yl)(3, 3, 3-trifluoropropyl)carbamate

which was prepared

example 7d in 75 mL N, N-dimethylformamide iodosuccinimide

(6-bromoimidazo[1, 2-a]pyridin-8-

and the mixture was stirred

were added 71.25 g

N-

at 23'C for 1.5 hours. Ethyl acetate

was added and the mixture was washed with saturated

25


sodium thiosulfate

solution,

water and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography

to give 5.92 100

g

(90/) of the title compound.

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Example 7d

tert-Butyl (6-bromoimidazo[1, 2-a]pyridin-8-yl)(3, 3, 3-trifluoropropyl)carbamate

0

N

5

To a solution of 16.24

g

(52, 71 mmol) 6-bromo-N-(3, 3, 32-a]pyridin-8-amine

trifluoropropyl)imidazo[1,

intermediate

example 7e in 62 mL tetrahydrofuran

butyl dicarbonate,

644 mg

N,

according to

which was prepared

were added 25. 31 g di-tert-

N-dimethylpyridin-4-amine

and the mixture was

stirred at 55'C for 4 hours. Ethyl acetate was added and the mixture was washed

10

with saturated

solution and dried over sodium sulfate.

sodium hydrogencarbonate

After filtration and removal of solvent the residue was purified by chromatography

to give 20. 9 g (97%) of the title compound. Example 7e

15

6-Bromo-N-(3, 3, 3-trifluoropropyl)imidazo[1,

2-a]pyridin-8-amine

NH

To a mixture comprising 21.7 g (102.3 mmol) 6-bromoimidazo[1, 2-a]pyridin-8amine which was prepared according to intermediate

trifluoropropanal,

20

total of 65. 07

18.16 mL acetic acid

g sodium

in

1.3

L

example 3-1, 13.05 mL 3,3, 3-

dichloromethane

tris(acetato-kappaO)(hydrido)borate(1-)

were added a in portions. After

the mixture was stirred at 23'C for 3 hours it was cooled to 3 C and 300 mL 4M aqueous ammonia was carefully added. The mixture was extracted with

dichloromethane,

the organic layer washed with brine and dried over sodium

sulfate. After filtration and removal of solvent the residue was purified by 25

chromatography

to give 16.26

g (52%)

of the title compound.

Example 8

4-(6-(3-F luorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 3-ylj-N, 2-dimethylbenzamide 101

2-a]pyridin-

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N

N

0

0

b

b

,

A

, OH

N

18 mg (38 pmol) 4-(6-(3-fluorophenoxy)-8-[(3, 3, 3-

mixture comprising


2-a]pyridin-3-ylf-2-methylbenzoic

acid which was

example 8a, 28. 5 pL methanamine

prepared according to intermediate 5

T/EP2012/055471

solution in

21.7 mg N-[(dimethylamino)(3H-[1, 2, 3]triazolo[4, 5-b]pyridin3-yloxy)methylene]-N-methylmethanaminium 7.0 mg N, Nhexafluorophosphate,

tetrahydrofuran

(2M),

dimethylpyridin-4-amine

and

0.9 mL

N,

N-dimethylformamide

was stirred at 23 C

overnight. The solvent was removed and the residue purified by chromatography give

10

16.1

mg (83%) of

1H NMR (CDCl3) 6

to

title compound.

2 41 2 68 (2H) 2 49 (3H) 3 02 (3H) 3 55 (2H) 5 49 (1H) 5 82

6.71 (1H), 6.75-6. 83 (1H), 7. 56 (1H), 7.61 (1H) ppm. (1H), 5.99 (1H),

(2H),

7.27 (1H), 7. 35 (1H), 7. 37 (1H), 7.46

Example 8a

15

4-(6-(3-Fluorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 2-methylbenzoic

N

acid

0 N

N

OH

OH

100 mg (205 pmol) 4-(8-[(tert-butoxycarbonyl)(3, fluorophenoxy)imidazo[1,

20

2-a]pyridin-3-ylf-

3, 3-trifluoropropyl)amino]-6-(3-

2-a] pyridin-3-ylf-2-methylbenzoic

prepared according to intermediate

acid which was


in analogy

example 7 to give after working up 97 mg (100%) of the title compound.

Example 8b

102

to

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4-I 8- [(tert-8utoxycarbonyl)(3,


3, 3-trifluorop ropyl)amino]-6-(3-

2-a] pyridin-3-yl]-2-methylbenzoic

0

N

T/EP2012/055471

acid

0

N

N

b

,

b

,

0

OH

3, 3-

To a solution of 50 mg (85 ljmol) methyl 4-(8-[(tert-butoxycarbonyl)(3, 5

trifluoropropyl)amino]-6-(3-fluorophenoxy)imidazo[1,

methylbenzoate

which was prepared

mL tetrahydrofurane

lithium

and

0.5

2-a]pyridin-3-yl]-2-


mL methanol

were added 1.28 mL of a 1M aqueous

hydroxide solution and the mixture was stirred at 23'C for

1

hour. Water

was added, the mixture was acidified by the addition of a 1M hydrochloric

10

extracted with dichloromethane

1.8

example 8c in

and methanol.

acid and

The organic layer was washed with

brine and dried over sodium sulfate. After filtration and removal of solvent the

residue was purified by chromatography

to give 107 mg (100%) of the title

compound.

15

Example Sc Methyl 4-(8- [(tert-butoxycarbonyl)(3,


N


2-a] pyridin-3-yl]-2-methylbenzoate

0

N

0

Br

0

0

550 mg (988 pmol) methyl 4-$6-bromo-8-[(tert-butoxycarbonyl)(3, 20


2-a]pyridin-3-yl$-2-methylbenzoate


intermediate

example 8d were transformed

example 7a to give after working up and purification

the title compound.

25

Example 8d

103

3, 3which was in analogy

to

287 mg (54%) of

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3, 3-

Methyl 4-[6-bromo-8- [(tert-butoxycarbonyl)(3,

imidazo[1, 2-a] pyridin-3-ylf-2-methylbenzoate

trifluoropropyl)amino]

;j .k N

N

T/EP2012/055471

0 N

0 Br

0

5

2. 50 g (4. 68 mmol) tert-butyl (6-bromo-3-iodoimidazo[1, 2-a]pyridin-8-yl)(3, 3, 3which was prepared according to intermediate example trifluoropropyl)carbamate 7c were transformed

in analogy

to intermediate

acid to give after working up and

(methoxycarbonyl)-3-methylphenyl]boronic purification

10

example 7b using [4-

1.83 g (67%) of the title compound.

Example 9

2-a]pyridine-3, 6-

4, 4'-(8-[(Tetrahydro-2H-pyran-4-ylmethyl)amino]imidazo[1, diyl]bis(N-cyclopropyl-2-methylbenzamide)

N

N

N

N

P

~NH 0

P

~NH 0

H

H

91 mg (134 ljmol) tert-butyl (3, 6-bis[4-(cyclopropylcarbamoyl)-3-

15

methylphenyl]imidazo[1,

ylmethyl)carbamate

were transformed

42. 3

mg (52%)

1H NMR (DMSO

20

2-a]pyridin-8-yl](tetrahydro-2H-pyran-4-

which was prepared in analogy


example 9a

to example 7 to give after working up and purification

of the title compound. d6) 6- 0 45 0 54 (4H) 0 60 0 70 (4H)

1

17

1

32 (2H)

1

59

1

69

1.95 (1H), 2. 35 (3H), 2. 36 (3H), 2. 75-2. 87 (2H), 3. 18-3.27 (4H), 3.78-3.87 (2H), 6.22 (1H), 6. 39 (1H), 7. 31 (1H), 7. 39-7. 55 (5H), 7.61 (1H), 7.84 (1H), 8.24 (1H), 8. 32 (1H) ppm. (2H),

Example 9a

104

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tert-Butyl (3, 6-bis[4-(cyclopropylcarbamoyl)-3-methylphenyl]imidazo[1,

2-a]pyridin-

8-ylf(tetrahydro-2H-pyran-4-ylmethyl)carbamate

N N

~NH 0

1.00 g (1.865 5

mmol) tert-butyl

(6-bromo-3-iodoimidazo[1, 2-a]pyridin-8-

yl)(tetrahydro-2H-pyran-4-ylmethyl)carbamate

intermediate

which was prepared


at 120'C to give after working

H

in analogy

up and purification

according to

to intermediate

example 7b


compound.

10

Example 9b

tert-Butyl (6-bromo-3-iodoimidazo[1, 2-a]pyridin-8-yl)(tetrahydro-2H-pyran-4ylm ethyl)carbamate

2. 22 15

g

(5.41 mmol) tert-butyl (6-bromoimidazo[1, 2-a]pyridin-8-yl)(tetrahydro-2H-

pyran-4-ylmethyl)carbamate

example 9c were transformed working up and purification



to intermediate

example 7c to give after

2. 87 g (99%) of the title compound.

Example 9c

20

tert-Butyl (6-bromoimidazo[1, 2-a]pyridin-8-yl)(tetrahydro-2H-pyran-4ylm ethyl)carbamate

105

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1.85 g (5.964 mmol) a]pyridin-8-amine

2-

6-bromo-N-(tetrahydro-2H-pyran-4-ylmethyl)imidazo[1,

which was prepared

transformed

in analogy

purification

1.41

g

T/EP2012/055471

to intermediate


example 9d were

example 7d to give after working up and

(58%) of the title compound.

Example 9d

6-Bromo-N-(tetrahydro-2H-pyran-4-ylm

ethyl)imidazo[1, 2-a] pyridin-8-amine

3.00 g (14.15 mmol) 6-bromoimidazo[1, 2-a]pyridin-8-amine 10


intermediate

example 3-1 were transformed


to give after

example 7e using tetrahydro-2H-pyran-4-carbaldehyde

working up and purification

to

2. 57 g (53%) of the title compound.

Example 10

15

N-ethyl-4-$6-(3-fluorophenoxy)-8-[(3,

2-

3, 3-trifluoropropyl)amino]imidazo[1,

a]pyridin-3-ylf-2-methylbenzamide

OH

N

18 mg (38 ljmol) 4-[6-(3-fluorophenoxy)-8-[(3, 3, 3trifluoropropyl)amino]imidazo[1,

20

2-a]pyridin-3-yl$-2-methylbenzoic

prepared according to intermediate example 8 using ethanamine

example 8a were transformed

to give after working

acid which was in analogy

up and purification

15.3

to

mg

(76%) of the title compound. 1H NMR (CDCl3)

6-

1

26 (3H) 2 46 2 58 (2H) 2 50 (3H) 3 50 (2H) 3 56 (2H) 5 48

(1H), 5.75 (1H), 5.99 (1H), 6.72 (1H), 6.76-6. 82 (2H), 7.27 (1H), 7. 36 (1H), 7. 38 25

(1H),

7.46 (1H), 7. 56 (1H), 7.61 (1H) ppm.

106

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Example 11

4-f6-(3-F luorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a]pyridin-

3-ylj-2-methyl-N-(1-methylcyclopropyl)benzamide

0

b

, 5

F

H

OH

18 mg (38 ljmol) 4-16-(3-fluorophenoxy)-8-[(3, 3, 32-a]pyridin-3-ylj-2-methylbenzoic




in analogy

to

chloride to give after working up and

example 8 using 1-methylcyclopropanaminium

13.7 mg (65%) of the title compound.

purification

10

acid which was

1H NMR (CDCl3) 6

0 76 (2H) 0 87 (2H)

1

52 (3H) 2 48 (3H) 2 51 (2H) 3 56 (2H)

5.47 (1H), 5.99 (1H), 6.08 (1H), 6.69-6.82 (3H), 7.27 (1H), 7.34 (1H), 7.36 (1H), 7.40 (1H), 7.55 (1H), 7.59 (1H) ppm. Example 12

15

N-[rel-(1S, 2S)-2-fluorocyclopropyl]-4-$6-(3-fluorophenoxy)-8-[(3,

3, 3-

2-a]pyridin-3-ylj-2-methylbenzamide

(rac-A), N-f [(1R,2R) or (1S,2S)]-2-fluorocyclopropylj-4-$6-(3-fluorophenoxy)-8-[(3, 3, 32-a]pyridin-3-ylj-2-methylbenzamide (ent-A or trifluoropropyl)amino]imidazo[1, trifluoropropyl)amino]imidazo[1,

A) and

20

N-([(1S, 2S) or (1R, 2R)]-2-fluorocyclopropyl j-4-$6-(3-fluorophenoxy)-8-

[(3,3, 3-trifluoropropyl)amino]imidazo[1, (A


or ent-A)

b

C.,

,

0

OH

rac-A

0

N

'-' H

0

b, 107

F

ant-A

H

0

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18 mg (38 pmol) 4-[6-(3-fluorophenoxy)-8-[(3, 3, 32-a]pyridin-3-ylf-2-methylbenzoic




working up and purification 1H NMR (CDCl3)

6-

1

14.1

02 (1H)

1

mg (66%)

in analogy

to

chloride to give after

example 8 using rel-(1S, 2S)-2-fluorocyclopropanaminium 5

acid which was

of the racemic title compound A.

27 (1H) 2 46 2 58 (2H) 2 51 (3H) 3 06 (1H) 3 56

4. 76 (1H), 5.48 (1H), 5.99 (1H), 6.03 (1H), 6.72 (1H), 6.75-6. 83 (2H), 7.27 (1H), 7. 37 (1H), 7. 39 (1H), 7.49 (1H), 7. 56 (1H), 7.61 (1H) ppm. 8.7 mg of rac-A (16 pmol) were separated by HPLC using a chiral column to give 2. 2 (2H),

10

mg (25%) ent-A

or

A and

2. 1

mg (24%) A or ent-A.

Example 13

3, 3-

N-(1-cyanocyc lopropyl)-4-(6-(3-fluorophenoxy)-8-[(3,



b

c5., '-'

,

N

+CN

OH

15

18 mg (38 ljmol) 4-[6-(3-fluorophenoxy)-8-[(3, 3, 32-a]pyridin-3-ylj-2-methylbenzoic




example 8 using 1-cyanocyclopropanaminium

20

purification

7. 5

1H NMR (CDCl3)

mg (35%) of

6-

1

in analogy

to


the title compound.

38 (2H)

1

66 (2H) 2 43 2 63 (2H) 2 51 (3H) 3 55 (2H) 5 49

6.00 (1H), 6.44 (1H), 6.71 (1H), 6.75-6. 84 7.55 (1H), 7.60 (1H). (1H),

25

acid which was

(2H),

7.27 (1H), 7. 33-7.47 (3H),

Example 14

4-(6-ethynyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, dimethylbenzamide

108

2-a] pyridin-3-yl]-N, 2-

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14 mg (36 ljmol) 4-[6-ethynyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a]pyridin-

N

OH

5

3-yl]-2-methylbenzoic

acid which was prepared according to intermediate

14a were transformed

in analogy

purification

12.4

1H NMR (CDCl3)

(1H),

mg (86%)

6-

to example 8 to give after working

example

up and


2 45 2 61 (2H) 2 54 (3H) 3 04 (4H) 3 61 (2H) 5 36 (1H) 5 82

6. 17 (1H), 7. 37 (1H), 7. 39 (1H), 7. 50 (1H), 7. 55 (1H), 7.91 (1H)

ppm.

Example 14a

10

4-[6-Ethynyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, methylbenzoic


acid

0

OH

93 mg (232 jjmol) methyl 4-[6-ethynyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, a]pyridin-3-yl]-2-methylbenzoate

15

example 14b were transformed working up and purification


70.8


to intermediate

mg (79%) of the

example 8b to give after

title compound.

Example 14b Methyl 4-(6-ethynyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

20

methylbenzoate

109

2-


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0

122.9

0

mg (245 pmol) methyl

4-[8-[(tert-butoxycarbonyl)(3,

which was prepared

3, 3-


trifluoropropyl)amino]-6-ethynylimidazo[1,

5

T/EP2012/055471


example 14c were transformed

analogy to example 7 to give after working up and purification

in

93 mg (85/) of the

title compound. Example 14c Methyl 4-(8-[(tert-butoxycarbonyl)(3,

10

ethynylimidazo[1,

3, 3-trifluoropropyl)amino]-6-

2-a]pyridin-3-yl]-2-methylbenzoate

;j .k 0

N

N N

~si

0 A

0

mixture comprising

169 mg (295 pmol) methyl 4-[8-[(tert-butoxycarbonyl)(3,

trifluoropropyl)amino]-6-

methylbenzoate

15

which was prepared

ljL tetra-n-butylammonium

tetrahydrofuran

[(trimethylsilyl)ethynyl]imidazo[1,

2-a]pyridin-3-yl$-2-


fluoride in tetrahydrofuran

3, 3-

(1M) and

example 14d, 295

1.4

mL

was stirred at 23'C for 20 minutes. Saturated ammoniumchloride

solution was added the mixture extracted with ethyl

acetate. The organic layer

was dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography

to give 122. 9

mg (75/o)


20 Example 14d Methyl 4-[8-[(tert-butoxycarbonyl)(3,

[(trimethylsilyl)ethynyl]imidazo[1,



110

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;j .k N

T/EP2012/055471

;j .k

0

0

N

N N

Br

~Si

0 A

0

50 mg (90 pmol) methyl 4-[6-bromo-8-[(tert-

mixture comprising

butoxycarbonyl)(3, 3, 3-trifluoropropyl)amino]imidazo[1,

methylbenzoate 5


which was prepared

6. 3

mg ethynyl(trimethyl)silane,

1.7 mg copper(l) iodide, 0.82

2-a] pyridin-3-yl]-2example 8d, 35.3

chloride,

mg bis(triphenylphosphine)palladium(ll)

mL N-isopropylpropan-2-amine

and

was heated at 80'C for 10 minutes under microwave irradiation.

removed and the residue purified by chromatography

0.82

mL dioxane

The solvents were

to give 59.9

mg (99%) of

the

title compound. 10 Example 15

N-ethyl-4-$6-ethynyl-8-[(3,


2-a]pyridin-3-

ylf-2-methylbenzamide

N

OH

15

14 mg (36 ljmol) 4-[6-ethynyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 3-yl$-2-methylbenzoic



in analogy

working up and purification 1H NMR (CDCl3) 6

20

2-a]pyridin-

(2H),

1

12.1

to example 8 using ethanamine mg (81%) of the

example

to give after

title compound.

28 (3H) 2 48 2 61 (2H) 2 54 (3H) 3 04 (1H) 3 52 (2H) 3 61

5. 36 (1H), 5.78 (1H), 6. 17 (1H), 7. 38 (1H), 7. 39 (1H), 7. 50 (1H), 7. 54 (1H),

7.91 (1H) ppm. Example 16

111

WO 2012/136531

PC

4-(6-ethynyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

T/EP2012/055471

2-a]pyridin-3-yl)-N-[rel-

(1R, 2R)-2-fluorocyclopropyl]-2-methylbenzamide

H N

OH

14 mg (36 ljmol) 4-[6-ethynyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 5

3-ylf-2-methylbenzoic



in analogy

fluorocyclopropanaminium mg (77%)

using

example

rel-(1S, 2S)-2-

chloride to give after working up and purification

12.3


1H NMR (CDCl3) 6

10

to example 8

2-a]pyridin-

1

04 (1H)

1

29 (1H) 2 49 2 60 (2H) 2 55 (3H) 3 05 (1H) 3 08

(1H), 3.61 (2H), 4. 78 (1H), 5. 37 (1H), 6.04 (1H), 6. 17 (1H), 7. 38 (1H), 7.40 (1H),

7.51-7.58 (2H), 7.91 (1H) ppm. Example 17

4-(6-ethynyl-8-[(3, 3, 3-tri flu oropropyl)amino]imidazo[1, 15

methyl-N-(1-methylcyclopropyl)ben

2-a] pyridin-3-yl)-2-

zamide

OH

14 mg (36 ljmol) 4-$6-ethynyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

20

3-yl$-2-methylbenzoic



in analogy

to example 8

112

example

using 1-methylcyclopropanaminium

chloride to give after working up and purification compound.

2-a]pyridin-

10.1

mg (63%) of

the title

WO 2012/136531

PC

1H NMR (CDCl3) 6

0 77 (2H) 0 89 (2H)

1

T/EP2012/055471

54 (3H) 2 45 2 60 (2H) 2 51 (3H) 3 04

(1H), 3.61 (2H), 5. 36 (1H), 6. 10 (1H), 6. 16 (1H), 7. 35 (1H), 7. 37 (1H), 7.44 (1H),

7.53 (1H), 7.89 (1H) ppm. 5

Example 18

N-(1-cyanocyc lopropyl)-4-(6-ethynyl-8-[(3,

3, 3-



NH

OH

+NN

14 mg (36 ljmol) 4-[6-ethynyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

10

3-yl$-2-methylbenzoic



in analogy

to example 8

2-a]pyridin-

example

using 1-cyanocyclopropanaminium


11.8 mg

(72%) of the title

compound. 1H NMR (CDCl3)

15

(2H),

6-

1

40 (2H)

1

68 (2H) 2 48 2 61 (2H) 2 55 (3H) 3 05 (1H) 3 61

5. 37 (1H), 6. 17 (1H), 6.46 (1H), 7. 36-7. 50 (3H), 7. 54 (1H), 7.89 (1H) ppm.

Example 19 N-cyc lopropyl-4-(6-(5-fluoro-2-methylphenoxy)-8-[(3,

3, 3-



N

0

20

N

OH

20 mg (41 ljmol) 4-[6-(5-fluoro-2-methylphenoxy)-8-[(3, trifluoropropyl)amino]imidazo[1,

3, 3-

2-a]pyridin-3-yl]-2-methylbenzoic



113


to

WO 2012/136531

PC

to give after working up and purification 20. 1

example 8 using cyclopropanamine mg (93%) of

T/EP2012/055471

the title compound.

1H NMR (CDCl3)

6- 0 62

(2H) 0 89 (2H) 2 27 (3H) 2 42 2 60 (2H) 2 48 (3H) 2 92

(1H), 3.57 (2H), 5. 50 (1H), 5.92 (1H), 6.00 (1H), 6. 57 (1H), 6. 73 (1H), 7. 17 (1H), 5

7.30-7. 37 (2H), 7.41 (1H), 7.45 (1H), 7. 53 (1H) ppm. Example 19a

4-16-(5-Fluoro-2-methylphenoxy)-8-[(3,


2-

acid

a]pyridin-3-yl]-2-methylbenzoic

N

0

0 0

OH

10 805 mg

(1.61




intermediate 15

3, 3-

mmol) methyl 4-(6-(5-fluoro-2-methylphenoxy)-8-[(3,

which was


example 8b to give after working up and purification

in analogy

to

736 mg (89%) of

the title compound.

Example 19b

[(3,3, 3-

Methyl 4-f6-(5-fluoro-2-methylphenoxy)-8-


N

imidazo[1, 2-a] pyridin-3-yl$-2-methylbenzoate

0 N

N

0

0

gv 20

0

0

1.06 g (1.77 mmol)

methyl 4-(8-[(tert-butoxycarbonyl)(3,

3, 3-

trifluoropropyl)amino]-6-(5-fluoro-2-methylphenoxy)imidazo[1,

methylbenzoate

which was prepared


114

2-a] pyridin-3-yl]-2example 19c were

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transformed mg (97%) of

PC

in analogy


T/EP2012/055471

861

up and purification

the title compound.

Example 19c 5

Methyl 4-(8-[(tert-butoxycarbonyl)(3,

methylphenoxy)imidazo[1,

N

2-a] pyridin-3-yl$-2-methylbenzoate

;j .k N

0

3, 3-trifluoropropyl)amino]-6-(5-fluoro-2-

0 N

0

1.36 g (2. 34 mmol) tert-butyl [6-(5-fluoro-2-methylphenoxy)-3-iodoimidazo[1, a]pyridin-8-yl](3, 3, 3-trifluoropropyl)carbamate

10

intermediate



1.12 g

according to

to intermediate

example

acid to give after working

7b using [4-(methoxycarbonyl)-3-methylphenyl]boronic up and purification

2-


Example 19d

15

2-a]pyridin-8-yl](3, 3, 3-

tert-Butyl [6-(5-fluoro-2-methylphenoxy)-3-iodoimidazo[1, trifluoropropyl)carbamate

.k N

0

1.10 g (2.43 mmol) tert-butyl [6-(5-fluoro-2-methylphenoxy)imidazo[1, S-yl](3, 3, 3-trifluoropropyl)carbamate 20

intermediate

which was prepared

example 19e were transformed

7c to give after working up and purification

in analogy

1.37 g

2-a]pyridin-

according to

to intermediate

example


Example 19e

tert-Butyl [6-(5-fluoro-2-methylphenoxy)-3-iodoimidazo[1, 25

trifluoropropyl)carbamate

115

2-a]pyridin-8-yl](3, 3, 3-

WO 2012/136531

PC

j

Jc

;

1.06 g (3.00 mmol) intermediate 5

N

0

3, 3-

6-(5-fluoro-2-methylphenoxy)-N-(3, 2-a]pyridin-8-amine

trifluoropropyl)imidazo[1,

T/EP2012/055471

example 19f were transformed

to give after working up and purification


1.17 g

according to

to intermediate

example 7d


Example 19f

6-(5-Fluoro-2-methylphenoxy)-N-(3,

3, 3-trifluoropropyl)imidazo[1,

2-a]pyridin-8-

amine

10

1.06 g (4. 11 mmol) 6-(5-fluoro-2-methylphenoxy)imidazo[1, which was prepared


analogy to intermediate g (73%)

2-a]pyridin-8-amine

example 19g were transformed

example 7e to give after working up and purification

in

1.06


15 Example 19g

6-(5-Fluoro-2-methylphenoxy)imidazo[1,

2-a] pyridin-8-amine

N H~

F




using 5-fluoro-2-methylphenol



116


to example 6-1

up and purification

1.10 g

WO 2012/136531

PC

T/EP2012/055471

Example 20

4-(6-(3-hydroxyprop-1-yn-1-yl)-8-[(3,


2-

a]pyridin-3-yl]-N, 2-dimethylbenzamide

JU

N N

N

OH

OH OH

5

N

14 mg (34 ljmol) 4-[6-(3-hydroxyprop-1-yn-1-yl)-8-[(3, trifluoropropyl)amino]imidazo[1,

3, 3-




example 8 using to give after working up and purification

7.3


mg (51%) of

to

the title

compound.

10

1H NMR (CD30D) 6

(1H),

2 46 (3H) 2 59 (2H) 2 92 (3H) 3 58 (2H) 4 36 (2H) 6 26

7.41-7.47 (2H), 7.49 (1H), 7.56 (1H), 7. 89 (1H) ppm.

Example 20a

4-[6-(3-Hydroxyprop-1-yn-1-yl)-8-[(3, 15


x


acid

J4

N

N

N

OH

OH

0

OH

83 mg (192 ljmol) methyl 4-j6-(3-hydroxyprop-1-yn-1-yl)-8trifluoropropyl)amino]imidazo[1,

intermediate

[(3,3, 3-



20

2-



the title compound.

Example 20b

117

which was in analogy

58. 1

to

mg (72%)

of

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T/EP2012/055471

PC

Methyl 4-[6-(3-hydroxyprop-1-yn-1-yl)-8-[(3,

2-


a] pyridin-3-yl]-2-methylbenzoate

N

0 J4

N

N

N

OH

OH

0

0

146 mg (275 pmol) methyl 4-$8-[(tert-butoxycarbonyl)(3, 5

6-(3-hydroxyprop-1-yn-1-yl)imidazo[1,




3, 3-trifluoropropyl)amino]which


up and purification

82. 9

mg (63%)

in analogy

of the title

compound.

10

Example 20c Methyl

4-[8- [(tert-butoxycarbonyl)(3,


hydroxyprop-

1-yn-1-yl)imidazo[1, 2-a] pyridin-3-yl]-2-methylbenzoate

;j .k N

;j .k

0

0

N

N N

Br OH

0

0

200 mg (359 pmol) methyl 4-$6-bromo-8-[(tert-butoxycarbonyl)(3, 15




intermediate purification

20



example 14d using prop-2-yn-1-ol to give after working up and

146. 1

mg (76%)


Example 21

N-ethyl-4-$6-(3-hydroxyprop-1-yn-1-yl)-8-[(3, trifluoropropyl)amino]imidazo[1,

3, 3-


118

to

WO 2012/136531

PC

J4

N

N

N

OH

OH OH

N

14 mg (34 ljmol) 4-[6-(3-hydroxyprop-1-yn-1-yl)-8-[(3, prepared according to intermediate

acid which was



example 8 using ethanamine

3, 3-



5

T/EP2012/055471

in analogy

up and purification

11.2

to

mg

(75%) of the title compound. 1H NMR (CDCl3) 6

1

28 (3H) 2 36 2 60 (2H) 2 52 (3H) 3 52 (2H) 3 59 (2H) 4 49

(2H), 5. 39 (1H), 5.86 (1H),

6. 12 (1H), 7. 34 (1H), 7. 36 (1H), 7.47 (1H), 7. 53 (1H),

7.83 (1H) ppm. 10 Example 22

4-(6-(3-hydroxyprop-1 -yn-1-yl)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-

a]pyridin-3-yl$-2-methyl-N-(1-methylcyclopropyl)benzamide

J4

N

N

N

OH

OH OH

15

14 mg (34 ljmol) 4-[6-(3-hydroxyprop-1-yn-1-yl)-8-[(3, trifluoropropyl)amino]imidazo[1,




20

11.6 mg

1H NMR (CDCl3) 6


to


example 8 using 1-methylcyclopropanaminium purification

3, 3-


0 77 (2H) 0 89 (2H)

1

53 (3H) 2 34 2 60 (2H) 2 50 (3H) 3 59

4.49 (2H), 5. 30 (1H), 5. 39 (1H), 6. 12 (1H), 6. 16 (1H), 7. 31 (1H), 7. 34 (1H), 7.41 (1H), 7.52 (1H), 7.81 (1H) ppm. (2H),

Example 23

119

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PC

N-(1-cyanocyc lopropyl)-4-(6-(3-hydroxyprop-1-yn-1-yl)-8-[(3,

T/EP2012/055471

3, 3-



J4

N

N

N

OH

OH CN

OH H

14 mg (34 pmol) 4-16-(3-hydroxyprop-1-yn-1-yl)-8-[(3, 5





example 8 using 1-cyanocyclopropanaminium purification

4. 0

mg

1H NMR (CDCl3)

10

(2H),

6-

3, 3acid which was

to

in analogy


(25/) of the title compound. 1

41 (2H)

1

68 (2H) 2 46 2 61 (2H) 2 49 (3H) 3 58 (2H) 4 48

5. 38 (1H), 6. 10 (1H), 6.79 (1H), 7.25-7. 45 (4H), 7. 51 (1H), 7.76 (1H) ppm.

Example 24 N-cyc lobutyl-4-$6-(3-flu

orophenoxy)-8-[(3, 3, 32-a]pyridin-3-yl]-2-methylbenzamide


F

0

15

OH

0

N H

17 mg (36 ljmol) 4-[6-(3-fluorophenoxy)-8-[(3, 3, 32-a]pyridin-3-yl]-2-methylbenzoic


prepared according to intermediate example 8 using cyclobutanamine

20

purification

16.5

mg (83/. )

1H NMR (CDCl3) 6

1




hydrochloride

to

up and


78 (2H)

1

94 (2H) 2 38 2 59 (4H) 2 49 (3H) 3 52 (2H) 4 59

(1H), 5. 50 (1H), 5.92 (1H), 5.99 (1H), 6.71 (1H), 6.76-6. 84 (2H), 7.27 (1H), 7. 35 (1H),

7. 37 (1H), 7.46 (1H), 7. 56 (1H), 7.60 (1H)

120

ppm.

WO 2012/136531

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T/EP2012/055471

Example 25

2-


4-f6-(5-Fluoro-2-methylphenoxy)-8-[(3, a]pyridin-3-yl]-N, 2-dimethylbenzamide

N

N

0

0

OH

5

N

20 mg (41 ljmol) 4-[6-(5-Fluoro-2-methylphenoxy)-8-[(3,

3, 3-




acid which was


example 8 to give after working up and purification

in analogy

to

16.0 mg (78%) of the title

compound.

10

1H NMR (CDCl3) 6

2 28 (3H) 2 40 2 61 (2H) 2 49 (3H) 3 02 (3H) 3 57 (2H) 5 50

(1H), 5.80 (1H), 5.99 (1H), 6. 58 (1H), 6.73 (1H), 7. 17 (1H), 7. 33 (1H), 7. 35 (1H),

7.45 (1H), 7.47 (1H), 7.54 (1H) ppm. Example 26

15

N-ethyl-4-$6-(5-fluoro-2-methylphenoxy)-8-[(3,

3, 3-



N

0

0

OH

N

20 mg (41 ljmol) 4-[6-(5-Fluoro-2-methylphenoxy)-8-[(3, trifluoropropyl)amino]imidazo[1,

20




3, 3acid which was




121

up and purification

in analogy

18.8

mg

to

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PC

1H NMR (CDCl3) 6

1

T/EP2012/055471

26 (3H) 2 28 (3H) 2 49 (3H) 2 50 2 59 (2H) 3 50 (2H) 3 57

(2H), 5.49 (1H), 5.74 (1H), 5. 99 (1H),

6. 58 (1H), 6.73 (1H), 7. 17 (1H), 7. 34 (1H),

7.35 (1H), 7.45 (1H), 7.47 (1H), 7.55 (1H) ppm. 5

Example 27

4-(6-(5-Fluoro-2-methylphenoxy)-8-[(3,

2-


a]pyridin-3-yl$-2-methyl-N-(1-methylcyclopropyl)benzamide

0

QH


10





18.6

mg (80%)

1H NMR (CDCl3) 6

15


to



3, 3-


0 76 (2H) 0 87 (2H)

1

52 (3H) 2 28 (3H) 2 43 2 62 (2H) 2 46

6.06 (1H), 6. 58 (1H), 6. 74 (1H), 7. 18 (1H), 7.32 (1H), 7.33 (1H), 7.39 (1H), 7.45 (1H), 7. 54 (1H) ppm. (3H), 3.57 (2H), 5.48 (1H), 5. 99 (1H),

Example 28

N-(1-cyanocyc lopropyl)-4-(6-(5-fluoro-2-methylphenoxy)-8-[(3, 20


3, 3-


N

N

OH

*CN


3, 3-


122

acid which was

WO 2012/136531

PC



example 8 using 1-cyanocyclopropanaminium

13.3

purification

mg (59%) of

1H NMR (CD30D) 6

5

(2H),

1

T/EP2012/055471

to

in analogy


the title compound.

33 (2H)

57 (2H) 2 23 (3H) 2 42 (3H) 2 58 (2H) 3 57

1

6. 16 (1H), 6.69 (1H), 6.79 (1H), 7.24 (1H), 7. 38-7.45 (4H), 7. 56 (1H) ppm.

Example 29

N-[rel-(1S, 2S)-2-fluorocyclopropyl]-4-(6-(5-fluoro-2-methylphenoxy)-8-[(3,

3, 3-

2-a]pyridin-3-yl)-2-methylbenzamide


0 0 OH

10

F






example 8 using rel-(1S, 2S)-2-fluorocyclopropanaminium

15


6-

1

3, 3acid which was in analogy

to



02 (1H)

1

27 (1H) 2 28 (3H) 2 42 2 61 (2H) 2 50 (3H) 3 05

3.57 (2H), 4. 73 (1H), 5. 52 (1H), 5.96-6. 08 (2H), 6. 57 (1H), 6.73 (1H), 7. 17 (1H), 7. 35 (1H), 7. 36 (1H), 7.47 (1H), 7.48 (1H), 7. 54 (1H) ppm. (1H),

20

Example 30 N-cyc lopropyl-4-(6-(2, 3-difluorophenoxy)-8-[(3,



Ql

OH

3, 3-

N

123

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PC

56 mg (114 pmol) 4-[6-(2, 3-difluorophenoxy)-8-[(3,


mg (69%) of



to


example 8 using cyclopropanamine 5

3, 3-



T/EP2012/055471

the title compound.

1H NMR (CDCl3)

6- 0 63

(2H) 0 90 (2H) 2 43 2 59 (2H) 2 48 (3H) 2 92 (1H) 3 57

5.49 (1H), 5.89 (1H), 6.03 (1H), 6.77 (1H), 6.90-7. 03 (2H), 7. 33 (1H), 7. 35 (1H), 7.42 (1H), 7. 54 (2H) ppm. (2H),

10

Example 30a

4-[6-(2, 3- Difluorophenoxy) -8- [(3,3, 3-trifluoropropyl)amino]imidazo[1, ylf-2-methylbenzoic

acid

0

OH

153 mg (303 pmol) methyl 4-(6-(2, 3-difluorophenoxy)-815


[(3,3, 3-





intermediate

2-a] pyridin-3-


112.7

mg (76%)


20

Example 30b Methyl

4-[6-(2, 3-difluorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

a] pyridin-3-ylf-2-methylbenzoate

;j .k '~ Cc, N

0

0

0

0

124

to

2-

WO 2012/136531

PC

191 mg (316 pmol) methyl 4-$8-[(tert-butoxycarbonyl)(3,

6-(2, 3-difluorophenoxy)imidazo[1,

3, 3-trifluoropropyl)amino]-





T/EP2012/055471


to


compound.

Example 30c Methyl 4-(8- [(tert-butoxycarbonyl)(3,

',

j.

k 0

N

0

N

Cr'-

Cr

0

10 305 mg (523 pmol) tert-butyl

[6-(2, 3-difluorophenoxy)-3-iodoimidazo[1,

8-yl](3, 3, 3-trifluoropropyl)carbamate intermediate

which was prepared


in analogy

up and purification

2-a]pyridin-

according to

to intermediate

example


7b using [4-(methoxycarbonyl)-3-methylphenyl]boronic

15

3-

2-a] pyridin-3-yl$-2-methylbenzoate

difluorophenoxy)imidazo[1,

N

3, 3-trifluoropropyl)amino]-6-(2,

202 mg (61%) of the title compound.

Example 30d

tert-Butyl [6-(2, 3-difluorophenoxy)-3-iodoimidazo[1,

2-a]pyridin-8-yl](3, 3, 3-


N

0

.k N

0

20 288 mg (630 pmol) tert-butyl

[6-(2, 3-difluorophenoxy)imidazo[1,

yl](3, 3, 3-trifluoropropyl)carbamate example 30e were transformed working up and purification

which was prepared

in analogy

to intermediate


example 7c to give after


25

125

2-a]pyridin-8-

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PC

T/EP2012/055471

Example 30e

tert-Butyl [6-(2, 3-difluorophenoxy)imidazo[1,

2-a]pyridin-8-yl](3, 3, 3-


N

5

290 mg (812 pmol) 6-(2, 3-difluorophenoxy)-N-(3, a]pyridin-8-amine transformed purification

10

0

which was prepared

in analogy



to intermediate

2-

example 30f were



Example 30f

6-(2, 3- Difluorophenoxy)

- N-(3,



Cr' 373 mg (1.43 mmol) 6-(2, 3-difluorophenoxy)imidazo[1, was prepared according to intermediate

15

to intermediate

2-a]pyridin-8-amine


which in analogy

example 7e to give after working up 500 mg of a crude material

that contained some incomplete reduction product. The compound mixture was solved in 20 mL ethanol, 76 mg palladium

on charcoal (10%) was added and the

mixture was stirred under an atmosphere

of hydrogen overnight. After filtration

and removal of the solvent the residue was purified by chromatography

20

294. 8 mg (52%) of the title compound. Example 30g

6-(2, 3- Difluorophenoxy)imidazo[1,


126

to give

WO 2012/136531

PC

T/EP2012/055471

NH~

5.00 g (23. 6 mmol) 6-bromoimidazo[1, 2-a]pyridin-8-amine according to intermediate using

5

2, 3-difluorophenol



to example 6-1

to give after working up and purification 373

mg (6%)

of

the title compound. Example 31

4-(S-(3-chlorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a]pyridin-

3-ylj-N-cyclopropyl-2-methylbenzamide

„b 10

0

„b

OH

0

N H

20 mg (41 ljmol) 4-[6-(3-chlorophenoxy)-8-[(3, 3, 3trifluoropropyl)amino]imidazo[1,

2-a]pyridin-3-ylj-2-methylbenzoic


example 8 using cyclopropanamine

15

mg (56%)




to

12.7


1H NMR (CDCl3)

6- 0 62

(2H) 0 99 (2H) 2 42 2 60 (2H) 2 49 (3H) 2 92 (1H) 3 56

6.90 (1H), 6.99 (1H), 7. 06 (1H), 7. 24 (1H), 7.34 (1H), 7.37 (1H), 7.43 (1H), 7.55 (1H), 7. 58 (1H) ppm. (2H), 5.49 (1H), 5.90 (1H), 5. 98 (1H),

20

Example 31a

4-[6-(3-Chlorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 2-methylbenzoic

acid

127

2-a] pyridin-3-yl]-

WO 2012/136531

PC

T/EP2012/055471

N

0 CI

0 0

0

OH

272 mg (540 pmol) methyl 4-$6-(3-chlorophenoxy)-8-[(3, 3, 3-






intermediate


to

260 mg (98%) of

the title compound. Example 31b Methyl 4-(6-(3-chlorophenoxy)-8-[(3,

10


2-

a]pyridin-3-yl]-2-methylbenzoate

;j .k 0

N

N

0 0

330 mg (546 pmol)

0 0 methyl 4-[8-[(tert-butoxycarbonyl)(3,

2-a]pyridin-3-yl)-2-methylbenzoate

chlorophenoxy)imidazo[1,


15

mg (100%) of

in analogy

Methyl 4-(8- [(tert-butoxycarbonyl)(3,

chlorophenoxy)imidazo[1,

0


2-a] pyridin-3-yl]-2- methylbenzoate

N

0

Br

/

CI

0 0

128

to example 7

the title compound.

31c

Example

20

which was prepared



N


WO 2012/136531

1.00 g (1.80 mmol)

methyl 4-(6-bromo-8-[(tert-butoxycarbonyl)(3,


according to intermediate using 3-chlorophenol

5

T/EP2012/055471

PC

2-a]pyridin-3-yl)-2-methylbenzoate


3, 3which was prepared

in analogy


to example 6-1 mg (30%) of

the

title compound. Example 32

4, 4'-(8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a] pyridine-3, 6-diyl/bis(N-

cyclopropyl-2-methylbenzamide)

N

N N

I

N

P

HN~

OH OH

0

10

0

H

20 mg (40 ljmol) 4, 4'-[8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, diyl]bis(2-methylbenzoic

acid) which was prepared according to intermediate

example 32a were transformed give

15

after working

1H NMR (DMSO

2-a]pyridine-3, 6-

in analogy

up and purification

to example 8

6.0 mg

using cyclopropanamine


d6) 6- 0 50 (4H) 0 66 (4H) 2 35 (3H) 2 37 (3H) 2 69 (2H) 2 81

3.59 (2H), 6. 36 (1H), 6.44 (1H), 7. 32 (1H), 7.41 (1H), 7.46-7. 55 (1H), 7.90 (1H), 8.23 (1H), 8. 31 (1H) ppm. (2H),

(4H),

7.63

Example 32a

20

4, 4'-[8-[(3, 3, 3-Trifluoropropyl)amino]imidazo[1,

2-a]pyridine-3, 6-diyl]bis(2-

acid)

methylbenzoic

N

N

N

N

l

0

0

OH

0

OH

930 mg (1.77 mmol) dimethyl 4, 4'-[8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, a]pyridine-3, 6-diyl]bis(2-methylbenzoate)

which was prepared

129

according to

2-

to

WO 2012/136531

PC


intermediate

in analogy

8b to give after working up and purification

T/EP2012/055471

to intermediate

example

743 mg (80/) of the title compound.

Example 32b 5

Dimethyl 4, 4'-(8- [(3,3, 3-trifluoropropyl)amino]imidazo[1,

2-a]pyridine-3, 6-

diyl]bis(2-methylbenzoate) ',

j.

k 0

N

N

N

N

N

o

o

0

1.15 g (1.84 mmol)

0

dimethyl

4, 4'-(8-[(tert-butoxycarbonyl)(3,

2-a]pyridine-3, 6-diyl]bis(2-methylbenzoate)


10

3, 3-




up and purification

which

in analogy

956 mg (94/. ) of the title

compound.

Example 32c

15

Dimethyl 4, 4'-(8- [(tert-butoxycarbonyl)(3,


2-

j.

a] pyridine-3, 6-diyl jbis(2-methylbenzoate) ',

.k N

k 0

N

N

0

N

o

0

1.31

g

(2.45 mmol) tert-butyl (6-bromo-3-iodoimidazo[1, 2-a]pyridin-8-yl)(3, 3, 3-


20

7c were transformed

which was prepared

in analogy

to intermediate



example

example 7b at 120'C using [4-


1.16 g (72/) of the title compound.

Example 33

130

WO 2012/136531

PC

N-cyc lopropyl-2-methyl-4-$6-phenoxy-8-[(3,


T/EP2012/055471

3, 3-

2-a]pyridin-3-yl]benzamide

0

0

OH

0

N H

10.0 mg (22 ljmol) 2-methyl-4-$6-phenoxy-8-[(3, 5

trifluoropropyl)amino]imidazo[1, according to intermediate using cyclopropanamine

3, 3-

2-a]pyridin-3-ylfbenzoic



acid which was prepared in analogy

up and purification

5.6

to example 8 mg (49%)

of

the title compound. 1H NMR (CDCl3)

10

(2H),

6- 0 62

(2H) 0 89 (2H) 2 40 2 60 (2H) 2 47 (3H) 2 92 (1H) 3 54

5.45 (1H), 5.92 (1H), 6.02 (1H), 7.01 (2H), 7.09 (1H), 7.28-7. 44 (5H), 7. 55

(2H), ppm.

Example 33a

2-Methyl-4-(6-phenoxy-8-[(3,

15


yl]benzoic acid

0 0

492 mg

(1.05

0


intermediate

OH

mmol) methyl 2-methyl-4-(6-phenoxy-8-[(3,


20

2-a]pyridin-3-

2-a]pyridin-3-yl]benzoate


3, 3which was prepared in analogy


the title compound.

Example 33b

131

to

352 mg (70%) of

WO 2012/136531

PC

Methyl 2-methyl-4-$6-phenoxy-8-

T/EP2012/055471

[(3,3, 3-trifluoropropyl)amino]imidazo[1,

2-

a] pyridin-3-ylfbenzoate

0

N

0

0 0 0

602 mg 5

(1.06

0 0

/

mmol) methyl 4-[8-[(tert-butoxycarbonyl)(3,

2-a]pyridin-3-ylf-2-methylbenzoate

trifluoropropyl)amino]-6-phenoxyimidazo[1, which was prepared

3, 3-




in

492 mg (99%) of the

title compound. 10

Example 33c Methyl 4-[8-[(tert-butoxycarbonyl)(3,


phenoxyimidazo[1, 2-a] pyridin-3-ylj-2-methylbenzoate ',

j

;j .k

.k N

N

0

N

b

c0 692 mg

15

0

0

(1.26

mmol) tert-butyl

trifluoropropyl)carbamate 33d were transformed

0

(3-iodo-6-phenoxyimidazo[1,

which was prepared

in analogy

20


to intermediate

example 7b using [4-


Example 33d

tert-Butyl (3-iodo-6-phenoxyimidazo[1,

example



2-a]pyridin-8-yl)(3, 3, 3-

2-a] pyridin-8-yl)(3, 3, 3-


132

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N

PC

T/EP2012/055471

;j .k

0

0

N

b 590 mg (1.40 mmol) tert-butyl (6-phenoxyimidazo[1, 2-a]pyridin-8-yl)(3, 3, 3trifluoropropyl)carbamate

33e were transformed 5

up and purification


which was prepared

in analogy

to intermediate

example

example 7c to give after working


Example 33e

tert-butyl

j.

(6-phenoxyimidazo[1, 2-a]pyridin-8-yl)(3, 3, 3-trifluoropropyl)carbamate ',

k

N

10

535 mg

0

(1.67 mmol) 6-phenoxy-N-(3, 3, 3-trifluoropropyl)imidazo[1,

amine which was prepared according to intermediate

15

to intermediate

example 33f were


transformed

in analogy

purification


Example 33f

6-Phenoxy-N-(3, 3, 3-trifluoropropyl)imidazo[1,

2-a]pyridin-8-amine

850 mg (3.27 mmol) 6-(3-chlorophenoxy)imidazo[1, prepared according to intermediate

20

2-a]pyridin-8-

intermediate

2-a]pyridin-8-amine


example 30f to give after working up and purification

the title compound.

133

which was

in analogy

to

638 mg (61%) of

WO 2012/136531

PC

T/EP2012/055471

Example 33g

6-(3-Chlorophenoxy)imidazo[1,



according to intermediate using 3-chlorophenol




to example 6-1

mg (216%) of

the

title compound. Example 34

10

4-(6-(3-chlorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a]pyridin-

3-ylj-N, 2-dimethylbenzamide

CI

0

N

OH


15

acid which was





14.3

mg (66%)

in analogy

to

of the title


6-

2 42 2 59 (2H) 2 50 (3H) 3 02 (3H) 3 56 (2H) 5 50 (1H) 5 82

6.90 (1H), 7.00 (1H), 7. 06 (1H), 7. 24 (1H), 7. 36 (1H), 7. 38 (1H), 7.46 (1H), 7.56 (1H), 7.59 (1H) ppm. (1H), 5.98 (1H),

20

Example 35

4-(6-(3-ch lorophenoxy)-8-[(3, 3, 3-tri flu oropropyl)amino]imidazo[1, 3-ylj-N-ethyl-2-methylbenzamide

134

2-a]pyridin-

WO 2012/136531

PC

T/EP2012/055471

CI

0

N








up and purification

13.4

to

mg

(60/) of the title compound. 1H NMR (CDCl3)

6-

1

26 (3H) 2 46 2 59 (2H) 2 50 (3H) 3 47 3 61 (4H) 5 51 (1H)

5.76 (1H), 5.98 (1H), 6.90 (1H), 7.00 (1H), 7.07 (1H), 7.23 (1H), 7. 36 (1H), 7.38 (1H), 7.46 (1H), 7. 56 (1H), 7. 59 (1H) ppm. 10 Example 36

4-(6-(3-ch lorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a]pyridin-

3-ylj-2-methyl-N-(1-methylcyclopropyl)benzamide

CI

0

15

OH





20

13.3

1H NMR (CDCl3)

mg (57%)

6- 0 76

in analogy

to



acid which was


(2H) 0 87 (2H)

1

52 (3H) 2 45 2 58 (2H) 2 48 (3H) 3 56

6.07 (1H), 6.90 (1H), 6.99 (1H), 7. 07 (1H), 7. 23 (1H), 7.34 (1H), 7.36 (1H), 7.40 (1H), 7.55 (1H), 7. 58 (1H) ppm. (2H), 5.48 (1H), 5.98 (1H),

135

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PC

T/EP2012/055471

Example 37

4-(6-(3-ch lorophenoxy)-8-[(3, 3, 3-tri flu oropropyl)amino]imidazo[1,

2-a]pyridin-

3-ylj-N-(1-cyanocyclopropyl)-2-methylbenzamide

CI

H N

CI

0 5

OH

+CN

35 mg (71 ljmol) 4-[6-(3-chlorophenoxy)-8-[(3, 3, 3-






10

20.4

mg (57%)

1H NMR (CDCl3) 6

1


to



37 (2H)

1

66 (2H) 2 43 2 64 (2H) 2 51 (3H) 3 55 (2H) 5 49

6.48 (1H), 6.90 (1H), 6.99 (1H), 7.07 (1H), 7.25 (1H), 7. 33-7.46 (3H), 7. 55 (1H), 7. 58 (1H) ppm. (1H), 5.98 (1H),

Example 38

15

4-(6-(3-fluorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a]pyridin-

3-ylj-2-methyl-N-(1-methylcyclobutyl)benzamide

0 CI

0

OH


20




example 8 using 1-methylcyclobutylamin

12.5

mg (52%)

acid which was



136

in analogy

to

up and purification

WO 2012/136531

1H NMR (CDCl3) 6

PC

1

60 (3H)

1

T/EP2012/055471

85 2 01 (2H) 2 09 2 18 (2H) 2 42 (2H) 2 47 2 58

2. 50 (3H), 3.56 (2H), 5. 50 (1H), 5.83 (1H), 5.99 (1H), 6.72 (1H), 6. 75-6. 83 (2H), 7.27 (1H), 7. 35 (1H), 7. 36 (1H), 7.46 (1H), 7. 56 (1H), 7.61 (1H) ppm. (2H),

5

Example 39

4-(6-(3-ch lorophenoxy)-8-[(3, 3, 3-tri flu oropropyl)amino]imidazo[1, 2-a]pyridin3-ylj-N-[rel-(1R, 2R)-2-fluorocyclopropyl]-2-methylbenzamide (rac-A), 4-f6-(3chlorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 10

2-a]pyridin-3-ylj-N-

(A or ent-A) and ([(15,25) or (1R, 2R)]-2-fluorocyclopropylj-2-methylbenzamide 4-(6-(3-chlorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 2-a]pyridin-

3-ylj-N-([(1R, 2R) or (1S,2S)]-2-fluorocyclopropylj-2-methylbenzamide

(ent-A or

A)

N

„b

CI

OH

N

0

-a

0

0 erat-a

35 mg (71 ljmol) 4-[6-(3-chlorophenoxy)-8-[(3, 3, 3-

15





example 8 using rel-(1S, 2S)-2-fluorocyclopropanaminium working up and purification 1H NMR (CDCl3) 6

1

22. 9

02 (1H)

1

mg (56%)


to



27 (1H) 2 46 2 57 (2H) 2 52 (3H) 3 06 (1H) 3 56

20

4. 77 (1H), 5. 51 (1H), 5.97-6.04 (2H), 6.90 (1H), 7.00 (1H), 7.07 (1H), 7.23 (1h), 7.37 (1H), 7. 39 (1H), 7.49 (1H), 7. 57 (1H), 7.60 (1H) ppm. 16.9 mg of rac-A (31 pmol) were separated by HPLC using a chiral column to give 7.2 mg (43%) ent. -A or A and 7.7 mg (46%) A or ent. -A.

25

Example 40

(2H),

N-(2, 6-diethylphenyl)-4-(6-(3-fluorophenoxy)-8-[(3,


3, 3-


137

WO 2012/136531

PC

T/EP2012/055471

N

0 F F

H N

OH

0

17 mg (36 ljmol) 4-[6-(3-fluorophenoxy)-8-[(3, 3, 32-a]pyridin-3-yl$-2-methylbenzoic



example 8 using 2, 6-diethylaniline mg (66%)

acid which was



in analogy

up and purification

to

15.0


1H NMR (CDCl3) 6

1

27 (6H) 2 48 (2H) 2 62 (3H) 2 73 (4H) 3 53 (2H) 5 44 (1H)

6.01 (1H), 6.71-6.84 (3H), 7.20 (2H), 7.24-7. 32 (3H), 7.44 (1H), 7.46 (1H), 7. 50 (1H), 7.65 (1H), 7.68 (1H) ppm. 10 Example 41

4, 4'-(8-[methyl(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a]pyridine-3, 6-

diyl]bis(N, 2-dimethylbenzamide)

N

N N

/

N

0 OH

HN

/

OH

15

0

20 mg (40 pmol) 4, 4'-(8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, diyl]bis(2-methylbenzoic

and purification

2-a]pyridine-3, 6-



in analogy

to example 8 to give after working up

4. 9 mg (22/) of the title compound.

d6). 6- 2 37 (3H) 2 39 (3H) 2 70 (2H) 2 74 (6H) 3 59 (2H) 6 36 (1H), 6.46 (1H), 7. 36 (1H), 7.45 (1H), 7.48-7. 56 (4H), 7.64 (1H), 7.92 (1H), 8. 12 1H NMR (DMSO

20

N H

(1H),

8.20 (1H) ppm.

Example 42

138

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PC

T/EP2012/055471

oxyphenoxy)-8-[(3, 3, 3-

N-cyc lopropyl-4-(S-(3-fluoro-4-meth



N

0

Br

F HN

A

5

HN

mixture comprising 200 mg (416 ljmol) 4-$6-bromo-8-[(3, 3, 3-

2-a]pyridin-3-ylf-N-cyclopropyl-2-

trifluoropropyl)amino]imidazo[1, methylbenzamide

which was prepared


975 mg caesium carbonate, 18.9 mg

mg 3-fluoro-4-methoxyphenol3-fluorophenol,

(RS) phenyl hydrogen mL

10

pyrrolidin-2-ylphosphonate,

1,4-dioxane was heated at 130'C

example 42a, 472

16.4

using microwave

mg copper(l)chloride

irradiation

and 4

for 4 hours. The

mixture was poured into water and extracted with ethyl acetate and methanol.

The organic layer was dried over sodium sulfate. After filtration and removal of the solvent the residue war purified by chromatography

to give 23. 2 mg (10%) of the

title compound. 1H NMR (CDCl3) 6

15

0 62 (2H) 0 90 (2H) 2 45 2 57 (2H) 2 48 (3H) 2 92 (1H) 3 56

3.87 (3H), 5.44 (1H), 5.90 (1H), 5.98 (1H), 6.74 (1H), 6. 83 (1H), 6. 91 (1H), 7.33 (1H), 7.35 (1H), 7.42 (1H), 7.49 (1H), 7. 53 (1H) ppm. (2H),

Example 42a

4-16-bromo-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 20

2-a]pyridin-3-yl]-N-

cyclopropyl-2-methylbenzamide

N

Br Br

HN

HO

750 mg (1.70 mmol) 4-(6-bromo-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, a]pyridin-3-yl]-2-methylbenzoic

2-


139

WO 2012/136531

PC

example 42b were transformed give

after working

in analogy

up and purification

T/EP2012/055471

to example 8 using cyclopropanamine

to


Example 42b 5

4-46-bromo-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,


acid

methylbenzoic

Br

Br

0

HO

787 mg (1.73 mmol) methyl 4-(6-bromo-8-[(3, 3, 32-a]pyridin-3-yl$-2-methylbenzoate


10



which was

to

in analogy

example 8b to give after working up 769 mg (96/) of the title

intermediate compound.

Example 42c

15

methyl 4-j6-bromo-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,


methylbenzoate

N

0 N

Br

Br

0

0

1000 mg (1.80 mmol) methyl 4-$6-bromo-8-[(tert-butoxycarbonyl)(3, trifluoropropyl)amino]imidazo[1,

20




example 7 to give after working up and purification compound.

Example 43

140


801 mg (93/) of the title

to

WO 2012/136531

PC

T/EP2012/055471

2-a]pyridine-3, 6-

4, 4'-(8-[methyl(3, 3, 3-trifluoropropyl)amino]imidazo[1, diyl]bis[N-(1-cyanocyclopropyl)-2-methylbenzamide]

N

N N

/

N

/

0 OH

HN~CN

0

OH

0

H

20 mg (40 ljmol) 4, 4'-[8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 5

2-a]pyridine-3, 6-


diyl]bis(2-methylbenzoic


in analogy

to example 8

using 1-

chlorid to give after working up and purification

cyanocyclopropanaminium

2. 9 mg

(4%) of the title compound. 1H NMR (DMSO

10

d6). 6-

1

25 (4H)

1

53 (4H) 2 38 (3H) 2 40 (3H) 2 62 2 79 (2H)

3.59 (2H), 6.38 (1H), 6.46 (1H), 7.39 (1H), 7.49 (1H), 7.54 (1H), 7.56-7. 61 (3H), 7.67 (1H), 7.94 (1H), 9.13 (1H), 9.21 (1H) ppm. Example 44

2-a]pyridine-3, 6-

4, 4'-(8-[methyl(3, 3, 3-trifluoropropyl)amino]imidazo[1, 15

diyl]bis[2-methyl-N-(1-methylcyclopropyl)benzamide]

N

N N

/

N

/

/ OH

0

OH

0

H

20 mg (40 ljmol) 4, 4'-[8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, diyljbis(2-methylbenzoic



20

methylcyclopropanaminium mg (33%) of

in analogy

to example 8

using 1-


8.4

the title compound.

1H NMR (DMSO

d6). 6- 0 56 (4H) 0 69 (4H)

1

36 (3H)

1

37 (3H) 2 33 (3H) 2 35

3.59 (2H), 6.36 (1H), 6.43 (1H), 7.27 (1H), 7. 37 (1H), 7.437.62 (1H), 7.88 (1H), 8.37 (1H), 8.46 (1H) ppm.

(3H), 2. 49-2. 77 (2H),

7.54 (4H),

2-a]pyridine-3, 6-

141

WO 2012/136531

PC

T/EP2012/055471

Example 45

4, 4'-(8-[methyl(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a]pyridine-3, 6-

diyl]bis(N-ethyl-2-methylbenzamide)

N

N N

/

N

0 HN~

OH

0

OH

N H

0

20 mg (40 ljmol) 4, 4'-j8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,


diyl]bis(2-methylbenzoic


after working 10

in analogy

up and purification

1H NMR (DMSO

d6) 6-

2-a]pyridine-3, 6-

1

5.3

09 (3H)

1

to example 8 using ethanamine

mg (23%)

10 (3H)

2

to give


37 (3H) 2 38 (3H) 2 70 (2H) 3 23

3.59 (2H), 6. 36 (1H), 6.45 (1H), 7. 34 (1H), 7.44 (1H), 7.48-7. 56 (1H), 7.91 (1H), 8. 18 (1H), 8.27 (1H) ppm. (4H),

(4H),

7.64

Example 46

15

N-(2, 6-diethylphenyl)-4-(6-(5-fluoro-2-methylphenoxy)-8-[(3,

3, 3-



0

OH


20


prepared according to intermediate example 8 using 2, 6-diethylaniline

3, 3-




142


up and purification

to

6.7

mg

WO 2012/136531

PC

1H NMR (CDCl3) 6

1

T/EP2012/055471

27 (6H) 2 29 (3H) 2 45 (2H) 2 60 (3H) 2 74 (4H) 3 51 (2H)

5.35 (1H), 6.00 (1H), 6.58 (1H), 6.74 (1H), 7. 14-7.24 (3H), 7.29 (1H), 7.37-7.40 (4H),

5

7. 50 (1H), 7.66 (1H) ppm.

Example 47 N-cyc lobutyl-4-$6-(5-fluoro-2-methylphenoxy)-8-[(3,

3, 3-



OH

15 mg (31 pmol) 4-16-(5-Fluoro-2-methylphenoxy)-8-[(3,

10




example 8 using cyclobutanamine

3, 3acid which was



in analogy

up and purification

to

14.7

mg


15

6-

1

70

1

84 (2H)

1

85 2 03 (2H) 2 28 (3H) 2 42 2 60 (4H) 2 48

(3H), 3.57 (2H), 4. 60 (1H), 5.46 (1H), 5.89 (1H), 5.99 (1H), 6. 57 (1H), 6. 73 (1H),

7. 17 (1H), 7.34 (1H), 7.35 (1H), 7.42-7. 49 (2H), 7.55 (1H) ppm. Example 48 Re l-4-(6-(3-flu oroph en oxy)-8-[(3, 3, 3-t ri flu oropropyl)amino]imidazo[1,

20

a]pyridin-3-yl]-2-methyl-N-[(1R,

2R)-2-methylcyclopropyl]benzamide

b

b

,

,

HO

~ 143

2-

WO 2012/136531

PC

T/EP2012/055471

20 mg (42 pmol) 4-I6-(3-fluorophenoxy)-8-[(3, 3, 3trifluoropropyl)amino]imidazo[1,




and purification 1H NMR (CDCl3)

15.5

mg (66%)

in analogy

to

to give after working up

example 8 using rel-(1R, 2R)-2-methylcyclopropanamine 5

acid which was


6- 0 66 (1H) 0 75 (1H) 0 98 (1H)

1

16 (3H) 2 44 2 58 (2H) 2 49

3.56 (2H), 5. 50 (1H), 5.85 (1H), 5.99 (1H), 6.72 (1H), 6. 79-6. 82 7.27 (1H), 7. 34 (1H), 7. 36 (1H), 7.42 (1H), 7. 55 (1H), 7.60 (1H) ppm.

(3H), 2. 60 (1H), (2H),

10

Example 49

N-[1, 1'-bi(cyclopropyl)-1-yl]-4-(6-(3-fluorophenoxy)-8-[(3,

3, 3-



b

b

,

,

HO

20 mg (42 ljmol) 4-[6-(3-fluorophenoxy)-8-[(3, 3, 3-

15




example 8 using 1, 1'-bi(cyclopropyl)-1-aminium and purification 1H NMR (CDCl3)

20

14.3

6- 0

mg (58%)

acid which was


in analogy

to

chloride to give after working up


22 (2H) 0 49 (2H) 0 72 (2H) 0 82 (2H)

1

57 (1H) 2 44 2 59

2.49 (3H), 3.56 (2H), 5.48 (1H), 5.99 (1H), 6. 10 (1H), 6.71 (1H), 6. 75-6. 83 (2H), 7.27 (1H), 7. 34 (1H), 7. 36 (1H), 7.43 (1H), 7. 55 (1H), 7.60 (1H) ppm. (2H),

Example 50

4-f6-(3-F luorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 25

3-ylj-N-[1-(hydroxymethyl)cyclopropyl]-2-methylbenzamide

144

2-a]pyridin-

WO 2012/136531

PC

T/EP2012/055471

N

b

0

b

,

,

HN

HO

I.

I

OW

30 mg (63 ljmol) 4-[6-(3-fluorophenoxy)-8-[(3, 3, 32-a]pyridin-3-yl]-2-methylbenzoic




example 8 using 1-(hydroxymethyl)cyclopropanaminium working up and purification 1H NMR (DMSO

23.3

mg (64%)


to



d6) 6- 0 65 (2H) 0 72 (2H) 2 33 (3H) 2 54 2 67 (2H) 3 46 (2H)

3.52 (2H), 4.70 (1H), 6. 10 (1H), 6.56 (1H), 6.86-6. 94 (3H), 7. 31-7.44 (4H), 7.63 (1H), 7.64 (1H), 8.43 (1H) ppm. 10 Example 51

N-(1-cyanocyc lobutyl)-4- f 6-(3-flu orophenoxy)-8-[(3, 3, 32-a]pyridin-3-yl]-2-methylbenzamide trifluoropropyl)amino]imidazo[1,

N N

b

0

b

,

,

N~

HO

15

20 mg (42 ljmol) 4-[6-(3-fluorophenoxy)-8-[(3, 3, 3trifluoropropyl)amino]imidazo[1,




example 8 using 1-aminocyclobutanecarbonitrile purification

20


to

to give after working up and


1H NMR (CDCl3) 6

2 11 2 36 (2H) 2 43 2 58 (4H) 2 53 (3H) 2 83 2 95 (2H) 3 56

5.49 (1H), 6.00 (1H), 6.23 (1H), 6.72 (1H), 6.77-6. 83 (2H), 7.28 (1H), 7. 39 (1H), 7.41 (1H), 7. 51 (1H), 7. 57 (1H), 7.60 (1H) ppm. (2H),

145

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PC

Example 52 N-cyc lopropyl-4-(6-(3-methoxyphenoxy)-8-[(3,

3, 3-



.b

.b

HN

HO

20 mg (41 pmol) 4-16-(3-methoxyphenoxy)-8-[(3, trifluoropropyl)amino]imidazo[1,



mg (58%)





10

3, 3-

to

13.1


1H NMR (CDCl3)

6- 0 62

(2H) 0 89 (2H) 2 42 2 60 (2H) 2 48 (3H) 2 91 (1H) 3 54

3.78 (3H), 5.48 (1H), 5.92 (1H), 6.02 (1H), 6. 54-6. 68 (3H), 7.21 (1H), 7. 33 (1H), 7. 36 (1H), 7.41 (1H), 7. 54 (1H), 7. 58 (1H) ppm. (2H),

15

Example 52a

4-16-(3-Methoxyphenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, yl]-2-methylbenzoic

acid

N

.b

N

0

.b HO

231 mg (95 ljmol) methyl 4-(6-(3-methoxyphenoxy)-8-[(3,

20


3, 3-



intermediate

2-a]pyridin-3-



the title compound.

146


to

211 mg (99%) of

WO 2012/136531

T/EP2012/055471

PC

Example 52b Methyl 4-(6-(3-methoxyphenoxy)-8-[(3,


2-


;j .k 0

N

N

..b 5

N

..b

0

0

536 mg (894pmol) methyl 4-(8-[(tert-butoxycarbonyl)(3,



6-(3-methoxyphenoxy)imidazo[1,




which was

to

in analogy


compound.

10 Example 52c Methyl 4-(8- [(tert-butoxycarbonyl)(3,

j.


j.

methoxyphenoxy)imidazo[1, ',

k

N

',

0

0

15

k

N

Br

1.00 g (1,80 mmol)


0

.b

0

methyl 4-(6-bromo-8-[(tert-butoxycarbonyl)(3,





example 6-1 using 3-methoxyphenol


mg (50%)


up and purification


20 Example 53

N-(1-cyanocyc lopropyl)-4-(6-(3-methoxyphenoxy)-8-[(3,


3, 3-


147

to 536

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PC

T/EP2012/055471

N

..b

..b

HN

HO

3, 3-

35 mg (72 ljmol) 4-[6-(3-methoxyphenoxy)-8-[(3,





15.1

1H NMR (CDCl3)

mg (36%) of

6-

1

37 (2H)

in analogy

to



acid which was

the title compound. 1

66 (2H) 2 43 2 59 (2H) 2 50 (3H) 3 55 (2H) 3 78

6.03 (1H), 6.42 (1H), 6. 54-6. 68 (3H), 7.22 (1H), 7. 35 (1H), 7. 39 (1H), 7.42 (1H), 7. 54 (1H), 7. 57 (1H) ppm. (3H), 5.44 (1H),

10 Example 54

4-(6-(3-Methoxyphenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-

a]pyridin-3-ylf-2-methyl-N-(1-methylcyclopropyl)benzamide

.b

.b HO

15

~ [(3,3, 3-

20 mg (41 ljmol) 4-[6-(3-methoxyphenoxy)-8trifluoropropyl)amino]imidazo[1,




20

in analogy

to



acid which was


1H NMR (CDCl3) 6

0 76 (2H) 0 86 (2H)

1

52 (3H) 2 42 2 59 (2H) 2 47 (3H) 3 55

3.78 (3H), 5.46 (1H), 6.02 (1H), 6.08 (1H), 6. 55-6. 68 (3H), 7.22 (1H), 7. 33 (1H), 7. 35 (1H), 7. 39 (1H), 7. 53 (1H), 7. 57 (1H) ppm. (2H),

148

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Example 55

4-(6-(3-Methoxyphenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-


N

.b

.b

HN

HO

20 mg (41 pmol) 4-[6-(3-methoxyphenoxy)-8-[(3,

3, 3-





12.5


10

acid which was

mg (58%)

in analogy

to

of the title


6-

2 42 2 59 (2H) 2 49 (3H) 3 02 (3H) 3 55 (2H) 3 78 (3H) 5 48

6.02 (1H), 6. 55-6. 67 (3H), 7.22 (1H), 7. 35 (1H), 7. 37 (1H), 7.45 (1H), 7. 55 (1H), 7. 59 (1H) ppm. (1H), 5.82 (1H),

15

Example 56

N-ethyl-4-$6-(3-methoxyphenoxy)-8-[(3,

2-


a]pyridin-3-yl$-2-methylbenzamide

N

..b

.b

HN

HO

20 mg (41 pmol) 4-[6-(3-methoxyphenoxy)-8-[(3,

20





3, 3acid which was




149

up and purification

in analogy

12.6

mg

to

WO 2012/136531

PC

1H NMR (CDCl3) 6

1

T/EP2012/055471

26 (3H) 2 42 2 59 (2H) 2 49 (3H) 3 45 3 61 (4H) 3 78 (3H)

5.47 (1H), 5.77 (1H), 6.02 (1H), 6.54-6. 68 (3H), 7.22 (1H), 7.35 (1H), 7.37 (1H), 7.45 (1H), 7.55 (1H), 7.59 (1H) ppm. 5

Example 57

N-(1-cyanocyc lopropyl)-2-methyl-4-$6-phenoxy-8-[(3,

3, 3-



0

0

d 0

OH

0

H

10 mg (22 pmol) 2-methyl-4-[6-phenoxy-8-[(3, 10


7. 6

1H NMR (CDCl3)

15

(1H),

mg

6-


to example 8



purification

3, 3-


trifluoropropyl)amino]imidazo[1, according to intermediate

N

(63/) of the title compound. 1

37 (2H)

1

65 (2H) 2 42 2 60 (2H) 2 49 (3H) 3 54 (2H) 5 45

6.03 (1H), 6. 51 (1H), 7.01 (2H), 7. 10 (1H), 7.28-7. 44 (5H), 7. 54

(2H) ppm.

Example 58

2-Methyl-N-(1-methylcyclopropyl)-4-$6-phenoxy-8-[(3,


b 20

'-' OH


b '-'~ 0

H

10 mg (22 ljmol) 2-methyl-4-[6-phenoxy-8-[(3, trifluoropropyl)amino]imidazo[1, according to intermediate

3, 3-

3, 3-

2-a]pyridin-3-yl/benzoic


150


to example 8

WO 2012/136531

PC



purification

8. 3

1H NMR (CDCl3)

mg (71%) of

6- 0 75

T/EP2012/055471

the title compound.

(2H) 0 86 (2H)

1

51 (3H) 2 42 2 59 (2H) 2 46 (3H) 3 54

5.46 (1H), 6.02 (1H), 6.08 (1H), 7.01 (2H), 7.09 (1H), 7.29-7. 42 (5H), 7. 53 (1H), 7. 55 (1H) ppm. (2H),

5

Example 59 N,


2-dimethyl-4-(6-phenoxy-8-[(3,

2-

a]pyridin-3-yl$benzamide

OH

10

0

N H

10 mg (22 ljmol) 2-methyl-4-[6-phenoxy-8-[(3, trifluoropropyl)amino]imidazo[1, according to intermediate

3, 3-




to example 8

to give after working up and purification 6.7 mg (62%) of the title compound. 15

1H NMR (CDCl3) 6

(1H),

2 42 2 59 (2H) 2 48 (3H) 3 01 (3H) 3 54 (2H) 5 46 (1H) 5 83

6.02 (1H), 7.01 (2H), 7.09 (1H), 7.29-7. 39 (4H), 7.44 (1H), 7. 54 (1H), 7. 57

(1H) ppm.

Example 60

20

N-ethyl-2-methyl-4-(6-phenoxy-8-[(3,


2-


0

OH

0

N H

10 mg (22 ljmol) 2-methyl-4-[6-phenoxy-8-[(3, trifluoropropyl)amino]imidazo[1,

3, 3-

2-a]pyridin-3-ylfbenzoic 151

acid which was prepared

WO 2012/136531

PC

according to intermediate using ethanamine



to example 8

in analogy

up and purification

6.4

T/EP2012/055471

mg (57%)

of the title

compound. 1H NMR (CDCl3) 6

5

1

26 (3H) 2 41 2 59 (2H) 2 48 (3H) 3 44 3 60 (4H) 5 46 (1H)

5.76 (1H), 6.03 (1H), 7.01 (2H), 7.09 (1H), 7.29-7. 39 (4H), 7.44 (1H), 7.55 (1H), 7.57 (1H) ppm. Example 61

3, 3-

Rel-4-(6-(5-fluoro-2-methylphenoxy)-8-[(3, 10

2R)-2-

2-a]pyridin-3-yl)-2-methyl-N-[(1R,

trifluoropropyl)amino]imidazo[1, methylcyclopropyl]benzamide

0

0

OH

0

N H




15



9.6

1H NMR (CDCl3) 6

mg (82%)



0 66 (1H) 0 75 (1H) 0 98 (1H)

1

16 (3H) 2 28 (3H) 2 46 2 57

3.57 (2H), 5.47 (1H), 5.86 (1H), 5. 99 (1H), 6. 57 (1H), 6.73 (1H), 7. 17 (1H), 7.32 (1H), 7.34 (1H), 7.40 (1H), 7.46 (1H), 7.54 (1H) ppm. (2H), 2. 48 (3H), 2. 60 (1H),

20

to


example 8 using rel-(1R, 2R)-2-methylcyclopropanamine and purification

3, 3-

Example 62

N-[1, 1'-bi(cyclopropyl)-1-yl]-4-(6-(5-fluoro-2-methylphenoxy)-8-[(3, trifluoropropyl)amino]imidazo[1,


152

3, 3-

WO 2012/136531

PC

"~

0

b

, 0

10 mg (21 ljmol) 4-[6-(5-Fluoro-2-methylphenoxy)-8-[(3, prepared according to intermediate 5

9.5

1H NMR (CDCl3) 6

mg (78%)

acid which was


example 8 using 1, 1'-bi(cyclopropyl)-1-aminium and purification

3, 3-



T/EP2012/055471

in analogy

to

chloride to give after working up


0 23 (2H) 0 49 (2H) 0 72 (2H) 0 82 (2H)

1

57 (1H) 2 28 (3H)

2.46-2. 59 (2H), 2. 48 (3H), 3.57 (2H), 5.47 (1H), 5.99 (1H), 6. 10 (1H), 6. 58 (1H), 6.73 (1H), 7. 17 (1H), 7.33 (1H), 7.34 (1H), 7.41 (1H), 7.46 (1H), 7.54 (1H) ppm. 10 Example 63

6-(5-fluoro-2-methylphenoxy)-8-[(3,

N-(1-cyanocyclobutyl)-4-f

3, 3-



b "q

, 0

15

OH

0

H

N





example 8 using 1-aminocyclobutanecarbonitrile purification

20

8. 1

mg (66%)

1H NMR (CDCl3) 6


to



2 11 2 35 (2H) 2 28 (3H) 2 43 2 59 (4H) 2 52 (3H) 2 89 (2H)

3.57 (2H), 5.48 (1H), 6.00 (1H), 6.25 (1H), 6.58 (1H), 6.74 (1H), 7. 18 (1H), 7.36 (1H), 7. 38 (1H), 7.46 (1H), 7.49 (1H), 7. 55 (1H) ppm. Example 64

153

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PC

3, 3-

N-cyclopropyl-2-methyl-4-$6-[4-(trifluoromethoxy)phenoxy]-8-[(3, 2-a]pyridin-3-yl)benzamide


0

0

HN

HO

F

3, 3-

20 mg (37 ljmol) 2-methyl-4-[6-[4-(trifluoromethoxy)phenoxy]-8-[(3, 5

T/EP2012/055471

trifluoropropyl)amino]imidazo[1, according to intermediate using cyclopropanamine





up and purification

to example 8

13.3

mg (59%) of


10

6- 0 62

(2H) 0 90 (2H) 2 43 2 59 (2H) 2 49 (3H) 2 92 (1H) 3 56

(2H), 5.49 (1H), 5.89 (1H), 5. 98 (1H),

7.00 (2H), 7. 18 (2H), 7. 33 (1H), 7. 35 (1H),

7.42 (1H), 7.55 (1H), 7.56 (1H) ppm. Example 64a

2-Methyl-4-[6- [4-(trifluoromethoxy)

15


F


acid

0

0

F~O

phenoxy]-8- [(3,3, 3-

0 0

HO

F

233 mg (421 pmol) methyl 2-methyl-4-[6-[4-(trifluoromethoxy)phenoxy]-8-[(3, trifluoropropyl)amino]imidazo[1, according to intermediate

20

intermediate

2-a]pyridin-3-ylfbenzoate


3, 3-


to

example 8b to give after working up 234 mg (max. 100%) of the title

compound.

Example 64b

154

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PC

Methyl 2-methyl-4-$6- [4-(trifluoromethoxy)phenoxy]-8-


[(3,3, 3-

imidazo[1, 2-a] pyridin-3-ylfbenzoate

0

N

0

0 0

F~O F

0 0

F~O F

292 mg (447 pmol) methyl 4-$8-[(tert-butoxycarbonyl)(3, 5


6-[4-(trifluoromethoxy)phenoxy]imidazo[1, which was prepared





in

239 mg (97%) of the

title compound. 10

Example 64c Methyl


(trifluoromethoxy)


[4-

phenoxy]imidazo[1, 2-a] pyridin-3-yl$-2-methylbenzoate

.J:

N

0

N

0 N

0

Br

0

F~O F

0

0

750 mg (1.35 mmol) methyl 4-46-bromo-8-[(tert-butoxycarbonyl)(3, 15





example 6-1 using 4-(trifluoromethoxy)phenol purification

20



to

up and


Example 65

N-(1-cyanocyclopropyl)-2-methyl-4-$6-[4-(trifluoromethoxy)phenoxy]-8-[(3, trifluoropropyl)amino]imidazo[1,

2-a]pyridin-3-yl)benzamide

155

3, 3-

WO 2012/136531

PC

T/EP2012/055471

0

~ HN

HO

F

~

30 mg (56 ljmol) 2-methyl-4-[6-[4-(trifluoromethoxy)phenoxy]-8-[(3, 2-a]pyridin-3-yl/benzoic

trifluoropropyl)amino]imidazo[1, according to intermediate 5


19.1

mg (54%)

6-

1H NMR (CDCl3)

(1H), 5.99 (1H),

1


to example 8

in analogy



purification

3, 3-


37 (2H)

1

66 (2H) 2 42 2 63 (2H) 2 50 (3H) 3 55 (2H) 5 50

6.45 (1H), 7.00 (2H), 7. 18 (2H), 7. 32-7. 47 (3H), 7. 55 (1H), 7. 57

(1H) ppm.

10 Example 66

2-Methyl-N-(1-methylcyclopropyl)-4-$6-[4-(trifluoromethoxy)phenoxy]-8-



N

0

0

F

15

HN

HO

20 mg (37 ljmol) 2-methyl-4-[6-[4-(trifluoromethoxy)phenoxy]-8-[(3, trifluoropropyl)amino]imidazo[1, according to intermediate




purification

20

13.8

mg (60%)

1H NMR (CDCl3) 6


to example 8



0 76 (2H) 0 86 (2H)

(2H), 5. 50 (1H), 5.98 (1H),

3, 3-

1

52 (3H) 2 43 2 59 (2H) 2 47 (3H) 3 56

6.06 (1H), 7.01 (2H), 7. 18 (2H), 7. 32 (1H), 7. 34 (1H),

7.39 (1H), 7.55 (1H), 7.56 (1H) ppm. 156

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PC

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Example 67 N,

2-dimethyl-4-(6-[4-(trifluoromethoxy)phenoxy]-8-[(3,


3, 3-


N

0

0

HO

5

HN

F

F

F

3, 3-





1H NMR (CDCl3) 6

11.8 mg


to example 8


2 43 2 59 (2H) 2 49 (3H) 3 02 (3H) 3 56 (2H) 5 50 (1H) 5 78

(1H), 5.99 (1H), 7.01 (2H), 7. 18 (2H), 7. 35 (1H), 7. 36 (1H), 7.46 (1H), 7. 56 (1H),

7.58 (1H) ppm. Example 68

15

3, 3-

N-ethyl-2-methyl-4-(6-[4-(trifluoromethoxy)phenoxy]-8-[(3, trifluoropropyl)amino]imidazo[1,


0

0

HN

HO

F

3, 3-

20 mg (37 ljmol) 2-methyl-4-[6-[4-(trifluoromethoxy)phenoxy]-8-[(3, trifluoropropyl)amino]imidazo[1,

20





up and purification

title compound.

157


12.6

to example 8

mg (57%)

of the

WO 2012/136531

1H NMR (CDCl3) 6

PC

1

T/EP2012/055471

26 (3H) 2 42 2 60 (2H) 2 49 (3H) 3 45 3 61 (4H) 5 50 (1H)

5.75 (1H), 5.99 (1H), 7.01 (2H), 7. 18 (2H), 7.35 (1H), 7. 36 (1H), 7.46 (1H), 7.56 (1H),

5

7. 58 (1H) ppm.

Example 69

oxyphenoxy)-8-[(3, 3, 3-

N-cyc lopropyl-4-(6-(2-fluoro-4-meth



N

0

Br

F

HN

HN

20 mg (37 ljmol) 4-46-bromo-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

10

3-yl$-N-cyclopropyl-2-methylbenzamide

intermediate

which was prepared


fluoro-4-methoxyphenol

in analogy


2-a]pyridin-

according to

to example 42

using 2-

17.8

mg (8%)

up and purification

of

the title compound. 1H NMR (CDCl3) 6

15

0 62 (2H) 0 90 (2H) 2 41 2 60 (2H) 2 46 (3H) 2 92 (1H) 3 57

3.80 (3H), 5.43 (1H), 5.91 (1H), 6.06 (1H), 6.64 (1H), 6. 75 (1H), 7. 02 (1H), 7.29 (1H), 7.31 (1H), 7.36 (1H), 7.39 (1H), 7. 50 (1H) ppm. (2H),

Example 70

N-(1-cyanocyc lopropyl)-4-(6-(2, 3-difluorophenoxy)-8-[(3, 3, 320



0 F

0

OH

0

H

N

10 mg (20 ljmol) 4-(6-(2, 3-difluorophenoxy)-8-[(3, 3, 3trifluoropropyl)amino]imidazo[1,


158

acid which was

WO 2012/136531

PC



8.4

1H NMR (DMSO

5

mg (71%) of

d6) 6

1

in analogy

to



T/EP2012/055471

the title compound.

23 (2H)

1

52 (2H) 2 35 (3H) 2 55 2 67 (2H) 3 46 (2H)

6. 18 (1H), 6.60 (1H), 6.94 (1H), 7.07-7. 18 (2H), 7.42 (1H), 7.47 (1H), 7.48 (1H), 7.67 (1H), 7.70 (1H), 9.17 (1H) ppm. Example 71

4-(6-(2, 3-Difluorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 10

2-


0 F

0

OH

0

H

10 mg (20 ljmol) 4-[6-(2, 3-difluorophenoxy)-8-[(3, 3, 32-a]pyridin-3-yl$-2-methylbenzoic



15



to



8. 9 mg (76%) of the title compound.

purification

1H NMR (CDCl3) 6

0 76 (2H) 0 87 (2H)

1

52 (3H) 2 45 2 59 (2H) 2 47 (3H) 3 57

5.49 (1H), 6.03 (1H), 6.07 (1H), 6.77 (1H), 6.90-7. 03 (2H), 7. 32 (1H), 7. 34 (1H), 7. 39 (1H), 7. 52-7. 56 (2H) ppm. (2H),

20 Example 72

4-(6-(2, 3-Difluorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, a]pyridin-3-yl]-N, 2-dimethylbenzamide

0

/ F

F

0

OH

0

N H

159

2-

WO 2012/136531

PC

T/EP2012/055471

10 mg (20 pmol) 4-[6-(2, 3-difluorophenoxy)-8-[(3, 3, 32-a]pyridin-3-ylf-2-methylbenzoic




example 8 to give after working up and purification 5

9.2

mg

in analogy

to

(85/) of the title


6-

2 46 2 58 (2H) 2 49 (3H) 3 02 (3H) 3 57 (2H) 5 51 (1H) 5 80

6.03 (1H), 6.77 (1H), 6.90-7.03 (1H), 7. 56 (1H) ppm. (1H),

10

acid which was

(2H),

7. 34 (1H), 7. 36 (1H), 7.45 (1H), 7. 55

Example 73

2-

4-(6-(2, 3-Difluorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, a]pyridin-3-yl$-N-ethyl-2-methylbenzamide

N

0

NQ F

F

0

OH

0

N H

10 mg (20 ljmol) 4-[6-(2, 3-difluorophenoxy)-8-[(3, 3, 315





acid which was



up and purification

in analogy

8.8

mg

to

(79/)

of the title compound. 1H NMR (CDCl3)

20

6-

1

26 (3H) 2 46 2 58 (2H) 2 49 (3H) 3 51 (2H) 3 57 (2H) 5 49

6.03 (1H), 6.78 (1H), 6.90-7. 03 (1H), 7. 55 (1H), 7. 56 (1H) ppm. (1H), 5.75 (1H),

(2H),

7. 34 (1H), 7. 36 (1H), 7.45

Example 74

N-cyclopropyl-2-methyl-4-$6-[3-(trifluoromethoxy)phenoxy]-8-[(3, 25



160

3, 3-

WO 2012/136531

PC

T/EP2012/055471

N N

;.b

;.b

HN

HO

3, 3-

20 mg (37 ljmol) 2-methyl-4-[6-[3-(trifluoromethoxy)phenoxy]-8-[(3, trifluoropropyl)amino]imidazo[1, according to intermediate 5






in analogy

up and purification

to example 8

12.2

mg (54%)

of


6- 0 62

(2H) 0 89 (2H) 2 43 2 59 (2H) 2 49 (3H) 2 92 (1H) 3 56

5. 52 (1H), 5.89 (1H), 5.98 (1H), 6.88 (1H, 6.90-6. 98 (2H), 7. 31 (1H), 7. 34 (1H), 7. 36 (1H), 7.43 (1H), 7. 56 (1H), 7. 59 (1H) ppm. (2H),

10 Example 74a

2-Methyl-4-f6- [3-(trifluoromethoxy)


;.b 15

phenoxy]-8- [(3,3, 3-

;.b

0

acid


HO

231 mg (417 pmol) methyl 2-methyl-4-16-[3-(trifluoromethoxy)phenoxy]-8-[(3,


intermediate

2-a]pyridin-3-yl]benzoate


3, 3-


to

example 8b to give after working up 233 mg (max. 100%) of the title

compound.

20 Example 74b Methyl 2-methyl-4-$6- [3-(trifluoromethoxy)phenoxy]-8-


[(3,3, 3-

imidazo[1, 2-a] pyridin-3-yl$benzoate 161

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0

N

N

;.b

N

;.b

0

0


which was prepared



6-[3-(trifluoromethoxy)phenoxy]imidazo[1,

5

T/EP2012/055471

PC




in

237 mg (93%) of the

title compound. Example 74c Methyl

10




(trifluoromethoxy)phenoxy]imidazo[1, ',

j.

k

N

',

0

[3-

j.

k

N

0 N

Br

0

;.b

0

750 mg (1.35 mmol) methyl 4-[6-bromo-8-[(tert-butoxycarbonyl)(3, trifluoropropyl)amino]imidazo[1,



15


example 6-1 using 3-(trifluoromethoxy)phenol purification


to



Example 75

N-(1-cyanocyclopropyl)-2-methyl-4-$6-[3-(trifluoromethoxy)phenoxy]-8-[(3, 20



162

3, 3-

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PC

T/EP2012/055471

N N

;.b

;.b

HN

HO

30 mg (56 ljmol) 2-methyl-4-[6-[3-(trifluoromethoxy)phenoxy]-8-[(3, 2-a]pyridin-3-yl/benzoic

trifluoropropyl)amino]imidazo[1, according to intermediate 5


18.5

1H NMR (CDCl3)

(1H), 5.99 (1H),

mg (52%)

6-

1


to example 8

in analogy



purification

3, 3-


37 (2H)

1

66 (2H) 2 43 2 58 (2H) 2 51 (3H) 3 55 (2H) 5 51

6.45 (1H), 6.85-7.01 (3H), 7. 30-7.46 (4H), 7. 56 (1H), 7.60 (1H)

ppm.

10 Example 76

2-Methyl-N-(1-methylcyclopropyl)-4-$6-[3-(trifluoromethoxy)phenoxy]-8-



N

;.b 15

b

;~.

HN

HO




purification

20


to example 8



1H NMR (CDCl3) 6

(2H),


3, 3-

0 76 (2H) 0 87 (2H)

1

52 (3H) 2 43 2 59 (2H) 2 48 (3H) 3 56

5. 50 (1H), 5.98 (1H), 6.06 (1H), 6.86-6. 98 (3H), 7.29-7.43 (4H), 7.55 (1H),

7.59 (1H) ppm. 163

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T/EP2012/055471

Example 77

3, 3-

N-ethyl-2-methyl-4-(6-[3-(trifluoromethoxy)phenoxy]-8-[(3, trifluoropropyl)amino]imidazo[1,


N N

;.b

;.b

HO

)

HN

20 mg (37 ljmol) 2-methyl-4-[6-[3-(trifluoromethoxy)phenoxy]-8-[(3,


10






3, 3-

up and purification

in analogy

to example 8

13.0 mg (59%) of the

title compound. 1H NMR (CDCl3)

6-

1

26 (3H) 2 42 2 59 (2H) 2 50 (3H) 3 45 3 62 (4H) 5 52 (1H)

5.76 (1H), 5.98 (1H), 6.86-7. 00 (3H), 7.29-7. 40 (3H), 7.46 (1H), 7. 56 (1H), 7.61 (1H) ppm.

15

Example 78 N,

3, 3-

2-dimethyl-4-(6-[3-(trifluoromethoxy)phenoxy]-8-[(3,



N

;.b

;.b HO

HN

20 mg (37 pmol) 2-methyl-4-[6-[3-(trifluoromethoxy)phenoxy]-8-[(3,

20






12.5

164

mg (58%)

3, 3-

in analogy

to example 8


WO 2012/136531

1H NMR (CDCl3) 6

(1H), 5.98 (1H),

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2 43 2 59 (2H) 2 50 (3H) 3 02 (3H) 3 56 (2H) 5 51 (1H) 5 79

6.86-6.98 (3H), 7.29-7.40 (3H), 7.46 (1H), 7.56 (1H), 7.61 (1H)

ppm.

5

Example 79 N-cyc lopropyl-4-(6-(2-methoxyphenyl)-8-[(3,

3, 3-



N N N

l

N

HN

HO

50 mg (107 ljmol) 4-(6-(2-methoxyphenyl)-8-[(3,

10




(2H),

(5H),


in analogy

to


1H NMR (CDCl3) 6

15

acid which was


example 8 using cyclopropanamine mg (72%)

3, 3-

0 62 (2H) 0 89 (2H) 2 49 2 62 (2H) 2 51 (3H) 2 92 (1H) 3 64

3.85 (3H), 5. 31 (1H), 5.97 (1H), 6. 38 (1H), 7.01 (1H), 7.04 (1H), 7. 30-7.45 7. 53 (1H), 7.88 (1H) ppm.

Example 79a

4-16-(2-Methoxyphenyl)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

20

2-methylbenzoic

2-a]pyridin-3-yl]-

acid

N

N

N

N

0 0

628 mg (max.

1.30 mmol)

HO

methyl 4-$6-(2-methoxyphenyl)-8-[(3,


3, 3-


165

which was

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to

in analogy


intermediate

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PC

337 mg (55%) of

the title compound.

5

Example 79b Methyl 4-(6-(2-methoxyphenyl)-8-[(3,


2-

a] pyridin-3-yl(-2-methylbenzoate

0

N

N N

N

l

N

0

0

3, 3-

759 mg (1.30 mmol) methyl 4-48-[(tert-butoxycarbonyl)(3,

10

trifluoropropyl)amino]-6-(2-methoxyphenyl)imidazo[1,

methylbenzoate transformed

example 79c were


which was prepared

in analogy



up 872 mg

of crude title

compound.

15


methoxyphenyl)imidazo[1,

N



0 N N

Br

0 A

20

0

mixture comprising 750 g

methyl 4-f6-bromo-8-[(tert-

butoxycarbonyl)(3, 3, 3-trifluoropropyl)amino]imidazo[1,

methylbenzoate

which was prepared

mg (2-methoxyphenyl)boronic

potassium


and

example 8d, 410


acid, 18 mL n-propanol,

1.35

carbonate solution, 1.0 mL 1-methyl-2-pyrrolidon,

triphenylphosphine,

25

(1.35 mmol)

mL

of an aqueous

35.4

94.9 mg bis(triphenylphosphine)palladium

2M

mg

was stirred at

120'C for 2 hours under microwave irradiation. The solution was cooled, water 166

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added and extracted with ethylacetate

and methanol.

T/EP2012/055471

The organic phase was

washed with brine and dried over sodium sulfate. After filtration and removal of

solvent the residue (915 mg) was used without further purification.

5

Example 80

4-(6-(2-Meth oxyphenyl)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a] pyridin-

3-yl$-2-methyl-N-(1-methylcyclopropyl)benzamide

N N

N

/

N

0 HN

HO

3, 3-

50 mg (107 ljmol) 4-[6-(2-methoxyphenyl)-8-[(3,

10





43.2

mg (74%)

1H NMR (CDCl3) 6

15

(2H),

(5H),

in analogy

to



acid which was


0 76 (2H) 0 87 (2H)

1

52 (3H) 2 48 2 63 (2H) 2 49 (3H) 3 64

3.85 (3H), 5. 30 (1H), 6. 12 (1H), 6. 38 (1H), 7.01 (1H), 7.04 (1H), 7. 30-7.44 7. 53 (1H), 7.87 (1H) ppm.

Example 81

4-(6-(2-Meth oxyphenyl)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 20

2-a] pyridin-


N

N

N

/

N

/

0 HO

HN

50 mg (107 ljmol) 4-[6-(2-methoxyphenyl)-8-[(3, trifluoropropyl)amino]imidazo[1,

3, 3-


167

acid which was

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38.7


mg (72%)

T/EP2012/055471

in analogy

to

of the title


5

(1H), 5.86 (1H),

2 50 2 63 (2H) 2 51 (3H) 3 02 (3H) 3 64 (2H) 3 85 (3H) 5 30

6. 38 (1H), 7.01 (1H), 7.05 (1H), 7. 31-7.48 (5H), 7. 54 (1H), 7.89

(1H) ppm.

Example 82

N-ethyl-4-$6-(2-methoxyphenyl)-8-[(3,

10

2-



N N

N

l

N

/

HN

HO

50 mg (107 ljmol) 4-[6-(2-methoxyphenyl)-8-[(3,




15


3, 3acid which was



in analogy

up and purification

40. 1

to

mg


1

26 (3H) 2 50 2 62 (2H) 2 52 (3H) 3 51 (2H) 3 64 (2H) 3 85

(3H), 5. 31 (1H), 5.81 (1H), 6. 38 (1H), 7.01 (1H), 7.05 (1H), 7. 31-7.48 (5H), 7. 55

(1H),

7.89 (1H) ppm.

20 Example 83 N-cyc lopropyl-4-(6-[3-fluoro-4-(trifluoromethoxy)


phenoxy]-8-[(3, 3, 3-


168

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T/EP2012/055471

N

0

0 F

F

F~O F

HN

HO

20 mg (36 ljmol) 4-16-[3-fluoro-4-(trifluoromethoxy)phenoxy]-8-[(3, 2-a]pyridin-3-yl$-2-methylbenzoic





example 8 using cyclopropanamine mg (58%)


3, 3-

to

13.0


1H NMR (CDCl3)

6- 0 62

(2H) 0 90 (2H) 2 44 2 60 (2H) 2 50 (3H) 2 92 (1H) 3 57

(2H), 5. 53 (1H), 5.89 (1H), 5. 96 (1H),

6.77 (1H)=, 6.83 (1H), 7.24 (1H), 7.34 (1H),

7.37 (1H), 7.43 (1H), 7.56 (1H), 7.61 (1H) ppm. 10 Example 83a

4-(6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-8-

[(3,3, 3-



acid

N

0

F~O

0

0

F

15

F~O

HO

F

221 mg (387 pmol) methyl 4-$6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-8-[(3,




intermediate



100%) of the title compound.

20 Example 83b Methyl 4-(6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-8-[(3,


3, 3-

imidazo[1, 2-a] pyridin-3-yl]-2-methylbenzoate

169

3, 3-


to

220 mg (max.

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T/EP2012/055471

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0

N

N

0

0

0

F~O

0

F~O

F

F

286 mg (426 pmol) methyl 4-$8-[(tert-butoxycarbonyl)(3, 6- [3-fluoro-4-(trifluoromethoxy)

methylbenzoate 5

transformed

phenoxy]imidazo[1, 2-a] pyridin-3-yl]-2-

which was prepared

in analogy




example 83c were

227

up and purification

the title compound.

mg (93%) of


10

3, 3-trifluoropropyl)amino]-6-[3-fluoro-42-a]pyridin-3-yl$-2-methylbenzoate

(trifluoromethoxy)phenoxy]imidazo[1,

;j Jc N

N

0

0 N

0

Br

0

F~O

0

F

750 mg (1.35 mmol) methyl 4-[6-bromo-8-[(tert-butoxycarbonyl)(3, trifluoropropyl)amino]imidazo[1,



15

example 6-1 using and purification


to


up


3-fluoro-4-(trifluoromethoxy)phenol

3, 3-


Example 84

N-(1-cyanocyclopropyl)-4-(6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-8-[(3, 20



170

3, 3-

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PC

0

0 F

F

F~O F

F~O

HO

HN

F

30 mg (54 ljmol) 4-[6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-8-[(3, 2-a]pyridin-3-yl$-2-methylbenzoic



T/EP2012/055471



19.3

1H NMR (CDCl3)

mg (55%)

6-

1


to



37 (2H)

1

67 (2H) 2 44 2 61 (2H) 2 52 (3H) 3 56 (2H) 5 53

(1H), 5.96 (1H), 6.43 (1H), 6.77 (1H), 6.83 (1H), 7.24 (1H), 7. 36 (1H), 7.40 (1H),

7.44 (1H), 7.57 (1H), 7.61 (1H) ppm. 10 Example 85

phenoxy]-8-[(3, 3, 3-

4-(6-[3-Fluoro-4-(trifluoromethoxy)

2-a]pyridin-3-yl)-2-methyl-N-(1-

trifluoropropyl)amino]imidazo[1, methylcyclopropyl)ben

zamide

N

0

0 F

F

F~O F

F~0

HO

HN

F

15

20 mg (36 ljmol) 4-[6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-8-[(3, trifluoropropyl)amino]imidazo[1,





20

purification

13.2

mg (55%)


to



171

3, 3-

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1H NMR (CDCl3) 6

PC

0 76 (2H) 0 87 (2H)

1

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52 (3H) 2 44 2 60 (2H) 2 48 (3H) 3 57

6.06 (1H), 6.77 (1H), 6.84 (1H), 7. 24 (1H), 7. 33 (1H), 7.35 (1H), 7.41 (1H), 7.56 (1H), 7.60 (1H) ppm. (2H), 5. 53 (1H), 5.96 (1H),

5

Example 86

4-(6-[3-Fluoro-4-(trifluoromethoxy)phenoxy]-8-[(3,

3, 3-

2-a]pyridin-3-yl)-N, 2-dimethylbenzamide


N

0

0 F

F

F~O F

F~O

HO

HN

F

20 mg (36 ljmol) 4-[6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-8-[(3,

10






12.3

mg (57%)


to

of the title


15

2 45 2 60 (2H) 2 51 (3H) 3 02 (3H) 3 57 (2H) 5 53 (1H) 5 78

(1H), 5.96 (1H), 6.78 (1H), 6.84 (1H), 7.24 (1H), 7. 36 (1H), 7. 38 (1H), 7.47 (1H),

7.57 (1H), 7.62 (1H) ppm. Example 87

N-ethyl-4-$6-[3-fluoro-4-(trifluoromethoxy) 20


phenoxy]-8-[(3, 3, 3-


N

0

0 F

F~O F

HO

F~O

HN

F

20 mg (36 ljmol) 4-[6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-8-[(3, trifluoropropyl)amino]imidazo[1,


172

3, 3acid which was

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up and purification

T/EP2012/055471

in analogy mg (%)

to of the

title compound. 1H NMR (CDCl3) 6

5

1

26 (3H) 2 43 2 61 (2H) 2 50 (3H) 3 45 3 62 (4H) 5 53 (1H)

5.76 (1H), 5.96 (1H), 6.77 (1H), 6.84 (1H), 7.24 (1H), 7. 36 (1H), 7. 37 (1H), 7.47 (1H),

7. 57 (1H), 7.62 (1H) ppm.

Example 88 N,

10

2-dimethyl-4-f 6-(pyridin-4-yl)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,


N

J4 N

N

/

N

N

HN

HO

20 mg (45 ljmol) 2-methyl-4-[6-(pyridin-4-yl)-8-[(3, according to intermediate



to give after working up and purification 1H NMR (DMSO

3, 3-



15

2-

10.5

mg (48%)

in analogy

to example 8


d6) 6 2 39 (3H) 2 62 2 79 (2H) 2 74 (3H) 3 60 (2H) 6 47 (1H)

6.54 (1H), 7.45 (1H), 7.52-7. 61 (2H), 7.67 (1H), 7.72 (2H), 8.08 (1H), 8.22 (1H), 8.59 (2H) ppm. 20

Example 88a

2-Methyl-4-[6-(pyridin-4-yl)-8-


3-yljbenzoic acid

N N

N

/

N

N

0

HO

173

2-a]pyridin-

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PC

399 mg (878 pmol) methyl 2-methyl-4-16-(pyridin-4-yl)-8-[(3, 2-a]pyridin-3-ylfbenzoate


5

3, 3which was prepared


in analogy


intermediate

T/EP2012/055471

to

300 mg (78%) of

the title compound.

Example 88b

[(3,3, 3- trifluoropropyl)amino]

Methyl 2-methyl-4-$6-(pyridin-4-yl)-8-

imidazo[1, 2-

a] pyridin-3-yl]benzoate

N

N

/

N

N

N

0

10

0



6-(pyridin-4-yl)imidazo[1,





to example 7

to give after working up 532 mg (max. 100%) of the crude title compound. 15 Example 88c Methyl 4-(8-[(tert-butoxycarbonyl)(3,

3, 3-trifluoropropyl)amino]-6-(pyridin-4-

yl)imidazo[1, 2-a] pyridin-3-yl]-2-methylbenzoate

N

0

0

N

N N

N

0

20

0

500 mg (899 pmol) methyl 4-$6-bromo-8-[(tert-butoxycarbonyl)(3, trifluoropropyl)amino]imidazo[1,



intermediate

example Sd were transformed

example 79c using pyridin-4-ylboronic

601 mg (max. 100%) of the crude title compound.

25

174


to

acid to give after working up

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Example 89

3, 3-

N-ethyl-2-methyl-4-(6-(pyridin-4-yl)-8-[(3,



N

N N

/

N

N

N

HN

HO

5

20 mg (45 ljmol) 2-methyl-4-[6-(pyridin-4-yl)-8-[(3,


trifluoropropyl)amino]imidazo[1, according to intermediate using ethanamine

3, 3-



up and purification


9.7 mg

to example 8

(43%) of the title

compound.

10

1H NMR (DMSO

d6) 6

09 (3H) 2 39 (3H) 2 62 2 79 (2H) 3 24 (2H) 3 60 (2H)

1

6.47 (1H), 6.54 (1H), 7.44 (1H), 7.52-7. 61 (2H), 7.66 (1H), 7.71 (2H), 8.08 (1H), 8.29 (1H), 8.59 (2H) ppm. Example 90

15

3, 3-

2-Methyl-N-(1-methylcyclopropyl)-4-$6-(pyridin-4-yl)-8-[(3,



N

N N

N N

N

HN

HO

20 mg (45 ljmol) 2-methyl-4-[6-(pyridin-4-yl)-8-[(3, trifluoropropyl)amino]imidazo[1,

20


7. 1

mg (32%)




purification

3, 3acid which was prepared in analogy

to example 8



175

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1H NMR (DMSO

PC

d6) 6 0 56 (2H) 0 70 (2H)

1

T/EP2012/055471

37 (3H) 2 36 (3H) 2 62 2 78 (2H)

3.60 (2H), 6.47 (1H), 6.54 (1H), 7.38 (1H), 7. 50-7. 58 (2H), 7.65 (1H), 7.71 (2H), 8.06 (1H), 8.48 (1H), 8.59 (2H) ppm. 5

Example 91

N-(1-cyanocyc lopropyl)-2-methyl-4-$6-(pyri

din-4-yl)-8-[(3, 3, 3-



N N

/

N

N

N

HN

HO

NC+

30 mg (68 ljmol) 2-methyl-4-[6-(pyridin-4-yl)-8-[(3,

10


2-a]pyridin-3-yljbenzoic


4. 2

1H NMR (DMSO

15

mg


to example 8



purification

3, 3-


d6) 6-

1

25 (2H)

1

54 (2H) 2 40 (3H) 2 49 2 78 (2H) 3 60 (2H)

6.48 (1H), 6.55 (1H), 7.49 (1H), 7.59 (1H), 7.62 (1H), 7.69 (1H), 7.72 (2H), 8.08 (1H), 8. 59 (2H), 9.23 (1H) ppm. Example 92

20

2-

3, 3-trifluoropropyl)amino]-6-vinylimidazo[1,

N-cyc lopropyl-2-methyl-4-$8-[(3,


N N N N

H N

0

OH

10 mg (26 ljmol) 2-methyl-4-[8-[(3, 3, 3-trifluoropropyl)amino]-6-vinylimidazo[1, a]pyridin-3-yl]benzoic


176

2-

example

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PC


after working

to example 8

in analogy

9.1

up and purification

1H NMR (CDCl3)

6- 0 64

to give


mg (83%) of the

title compound.

(2H) 0 91 (2H) 2 49 2 63 (2H) 2 52 (3H) 2 94 (1H) 3 64

(2H), 5. 28 (1H), 5. 33 (1H), 5. 68 (1H), 5

T/EP2012/055471

5.98 (1H), 6. 32 (1H), 6. 57 (1H), 7. 36 (1H),

7.39 (1H), 7.45 (1H), 7.47 (1H), 7.63 (1H) ppm. Example 92a

2-Methyl-4-[8- [(3,3, 3-trifluoropropyl)amino]-6-vinylimidazo[1,

2-a]pyridin-3-

ylfbenzoic acid

N

N

N

N

0

10

0

OH

240 mg (595 pmol) methyl 2-methyl-4-[8-[(3, 3, 3-trifluoropropyl)amino]-6vinylimidazo[1, 2-a]pyridin-3-ylfbenzoate

which was prepared


intermediate

8b to give after working up and purification

in analogy

183.7

according to

to intermediate

mg (75%)

example


15 Example 92b Methyl 2-methyl-4-$8-

[(3,3, 3-trifluoropropyl)amino]-6-vinylimidazo[1,

2-a] pyridin-3-

ylfbenzoate

0

N

N

N

N

N

0

20

0

363 mg (721 pmol) methyl 4-$8-[(tert-butoxycarbonyl)(3, 6-vinylimidazo[1, 2-a]pyridin-3-yl]-2-methylbenzoate

to intermediate

after working

example 92c were transformed up and purification


which was prepared

in analogy

to example 7 to give

242. 9 mg (79%) of the title compound.

177

according

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T/EP2012/055471


2-



0

N

0

N

N N

Br

0 5

0

500 mg (899 pmol) methyl 4-$6-bromo-8-[(tert-butoxycarbonyl)(3, 2-a]pyridin-3-yl$-2-methylbenzoate




example 79c using using 4, 4, 5, 5-tetramethyl-2-vinyl-1,

intermediate dioxaborolane

10

3, 3-


up and purification


to

3, 2-


compound.

Example 93 N,

2-dimethyl-4-(8-[(3, 3, 3-trifluoropropyl)amino]-6-vinylimidazo[1,

2-a] pyridin-

3-yljbenzamide

N

N N

N

0

15

H N

OH

2-




in analogy

purification

20

8. 1

1H NMR (CDCl3)

mg (78%)

6-


example

up and


2 49 2 63 (2H) 2 53 (3H) 3 04 (3H) 3 65 (2H) 5 29 (1H) 5 34

(1H), 5.69 (1H), 5.88 (1H), 6. 33 (1H), 6. 58 (1H), 7. 38 (1H), 7.40 (1H), 7.47-7. 53 (2H),

7.65 (1H) ppm.

Example 94

178

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N-ethyl-2-methyl-4-(8-[(3,

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2-


N

N N

N

0

H N

OH

2-

10 mg (26 ljmol) 2-methyl-4-[8-[(3, 3, 3-trifluoropropyl)amino]-6-vinylimidazo[1, 5

a]pyridin-3-yl]benzoic



in analogy


6-

1

to example 8

9.4 mg

using ethanamine

example

to give after


28 (3H) 2 50 2 62 (2H) 2 53 (3H) 3 52 (2H) 3 65 (2H) 5 28

(1H), 5. 34 (1H), 5.69 (1H), 5.84 (1H), 6. 32 (1H), 6. 57 (1H), 7. 38 (1H), 7. 39 (1H),

10

7.48 (1H). 7.49 (1H), 7.64 (1H) ppm. Example 95


2-Methyl-N-(1-methylcyclopropyl)-4-$8-[(3, vinylimidazo[1, 2-a]pyridin-3-yljbenzamide

N N N N

H N

15

0

OH

2-




in analogy

to example 8



20

example

6.8 mg

(60%) of the title


6- 0 77

(2H) 0 89 (2H)

1

53 (3H) 2 49 2 63 (2H) 2 51 (3H) 3 65

3.32 (1H), 5.68 (1H), 6. 13 (1H), 6. 32 (1H), 6. 57 (1H), 7. 36 (1H), 7.38 (1H), 7.44 (1H), 7.48 (1H), 7.63 (1H) ppm. (2H), 5. 29 (1H),

179

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Example 96


N-(1-cyanocyc lopropyl)-2-methyl-4-$8-[(3, vinylimidazo[1, 2-a] pyridin-3-yl jbenzamide

N N N N

H N

0

OH

+CN 2-

10 mg (26 ljmol) 2-methyl-4-[8-[(3, 3, 3-trifluoropropyl)amino]-6-vinylimidazo[1, a]pyridin-3-yljbenzoic



in analogy

to example 8



10

example

8.6 mg

(74/c) of the title


6-

1

39 (2H)

1

67 (2H) 2 48 2 63 (2H) 2 52 (3H) 3 64 (2H) 5 28

(1H), 5. 31 (1H), 5.69 (1H), 6. 33 (1H), 6. 56 (1H), 6.66 (1H), 7. 36 (1H), 7.40 (1H),

7.42-7. 48 (2H), 7.63 (1H) ppm. 15

Example 97

N-[rel-(1S, 2S)-2-fluorocyclopropyl]-2-methyl-4-(8-[(3, trifluoropropyl)amino]-6-vinylimidazo[1,

3, 3-

2-a] pyridin-3-ylfbenzamide

N N

N

N

0

rac.

OH

0

H N

2-





in analogy

fluorocyclopropanaminium mg (89/c)

to example 8

using

example

rel-(15, 25)-2-


of the title compound. 180

10.2

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1H NMR (CDCl3) 6

1

04 (1H)

T/EP2012/055471

28 (1H) 2 48 2 64 (2H) 2 54 (3H) 3 07 (1H) 3 64

1

4. 78 (1H), 5.29 (1H), 5. 33 (1H), 5.69 (1H), 6. 10 (1H), 6. 32 (1H), 6. 57 (1H), 7.38 (1H), 7.40 (1H), 7.48 (1H), 7.52 (1H), 7.64 (1H) ppm. (2H),

5

Example 98

2-Methyl-N-[rel-(1S, 2S)-2-methylcyclopropyl]-4-(8-[(3,

3, 3-

2-a] pyridin-3-yl/ben

trifluoropropyl)amino]-6-vinylimidazo[1,

zamide

N N

N

N

H N

OH





in analogy

methylcyclopropanamine

to example 8

2-

example

using rel-(1R, 2R)-2-


10.0

mg

(88/) of


15

6- 0 67 (1H) 0 77 (1H) 0 99 (1H)

1

17 (3H) 2 45 2 66 (3H) 2 51

(3H), 3.64 (2H), 5.28 (1H), 5. 34 (1H), 5.68 (1H), 5.96 (1H), 6. 32 (1H), 6. 57 (1H),

7.35 (1H), 7.37 (1H), 7.44 (1H), 7.47 (1H), 7.63 (1H) ppm. Example 99 N-cyc lopropyl-4-(6-ethyl-8-[(3,

20

2-a] pyridin-


3-yl$-2-methylbenzamide

N N N N

H N

0

OH

10 mg (26 pmol) 4-[6-ethyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, yl(-2-methylbenzoic

2-a]pyridin-3-


181

example

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after working

in analogy

up and purification

1H NMR (CDCl3)

6- 0 64

to example 8


6.8


mg (62%)

(2H) 0 91 (2H)

1

T/EP2012/055471

to give

24 (3H) 2 46 2 65 (4H) 2 52 (3H) 2 93

(1H), 3.60 (2H), 5.24 (1H), 5.97 (1H), 6.04 (1H), 7. 37 (1H), 7. 39 (1H), 7.45 (1H), 5

7.47 (1H), 7.53 (1H) ppm. Example 99a

4-I 6-Ethyl-8- [(3,3, 3-trifluorop ropyl)amino]imidazo[1,

methylbenzoic

2-a] pyridin-3-yl(-2-

acid

0

N

N

N

N

N

0

10

OH

0

OH

183 mg (372 pmol) 4-I 8-[(tert-butoxycarbonyl)(3,


ethylimidazo[1, 2-a]pyridin-3-yl]-2-methylbenzoic





150.8

in analogy

mg (93%) of the

to example 7

title compound.

15 Example 99b

4-I 8- [(tert-8utoxycarbonyl)(3,

3, 3-trifluorop ropyl)amino]-6-ethylimidazo[1, acid


0

N

0

N

N

N

N

N

0

20

2-

0

OH


6-ethylimidazo[1, 2-a]pyridin-3-yl]-2-methylbenzoate

to intermediate


Sb to give after working up and purification

182


which was prepared

in analogy

to intermediate

according

example


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T/EP2012/055471

Example 99c Methyl 4-(8-[(tert-butoxycarbonyl)(3,

3, 3-trifluoropropyl)amino]-6-ethylimidazo[1,

2-


;j .k

0

N

0

N

N

N

N

N

0 5

To a solution of 132 mg (262 pmol) methyl 4-(8-[(tert-butoxycarbonyl)(3,

3, 3-

trifluoropropyl)amino]-6-vinylimidazo[1,



example 92c in 5 mL ethanol were added

13.9 mg

on charcoal (10%) and the mixture was vigorously

palladium

an atmosphere

10

0

which

stirred under

of hydrogen for 1.5 hours at 23'C. After filtration and removal of

the solvent the residue was purified by chromatography

to give 112.1 mg (80%) of

the title compound. Example 100

4-(6-Ethyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 15

2-a]pyridin-3-ylj-N, 2-

dimethylbenzamide

N

N N

N

0

H N

OH

10 mg (26 pmol) 4-[6-ethyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, yl(-2-methylbenzoic


99a were transformed 20

purification

5.4

1H NMR (CDCl3)

(1H), 5.85 (1H),

in analogy

mg (52%)

6-

2-a]pyridin-3-

1


example

up and


24 (3H) 2 48 2 65 (4H) 2 53 (3H) 3 04 (3H) 3 60 (2H) 5 25

6.05 (1H), 7. 39 (1H), 7.40 (1H), 7.49 (2H), 7. 54 (1H)

Example 101

183

ppm.

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N-ethyl-4-$6-ethyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

T/EP2012/055471

2-a]pyridin-3-yl]-

2-methylbenzamide

N

N N

N

0

0

OH

H N

10 mg (26 ljmol) 4-[6-ethyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 5

yl]-2-methylbenzoic



(2H),

10

6-

to example 8

in analogy


2-a]pyridin-3-

1

7.6

24 (3H)

using ethanamine

example

to give after

the title compound.

mg (71%) of

27 (3H) 2 48 2 63 (4H) 2 53 (3H) 3 52 (2H) 3 60

1

5.25 (1H), 5.82 (1H), 6.04 (1H), 7. 39 (1H), 7.40 (1H), 7.45-7. 52 (2H), 7. 54

(1H) ppm.

Example 102

4-(S-Ethyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,


zamide

methyl-N-(1-methylcyclopropyl)ben

N N N N

H N

15

0

OH

10 mg (26 ljmol) 4-[6-ethyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, yl]-2-methylbenzoic


acid which was prepared according to intermediate in analogy

to example 8

example



20

2-a]pyridin-3-

8.7 mg

(77%) of the title


0 77 (2H) 0 88 (2H)

(3H), 3.60 (2H), 5.26 (1H), 6.04 (1H),

1

24 (3H)

1

53 (3H) 2 47 2 64 (4H) 2 50

6. 15 (1H), 7. 36 (1H), 7. 38 (1H), 7.43 (1H),

7.47 (1H), 7.52 (1H) ppm. 184

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Example 103

N-(1-cyanocyc lopropyl)-4-(6-ethyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-


N N N N

N

OH

+CN

10 mg (26 ljmol) 4-[6-ethyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, yl(-2-methylbenzoic



to example 8

in analogy

example



10

2-a]pyridin-3-

9.5

mg (82%)

of the title


(2H),

6-

1

24 (3H)

39 (2H)

1

1

67 (2H) 2 48 2 63 (4H) 2 53 (3H) 3 61

5.28 (1H), 6.05 (1H), 6.64 (1H), 7. 36-7.48 (4H), 7. 53 (1H) ppm.

Example 104

15

4-(6-Ethyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a]pyridin-3-ylj-N-[rel-

(1S,2S)-2-fluorocyclopropyl]-2-methylbenzamide

N N

N

N

H N

0

OH

F


20



fluorocyclopropanaminium mg (81%) of

2-a]pyridin-3-

to example 8

using

example

rel-(1S, 2S)-2-


the title compound.

185

9.3

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1H NMR (CDCl3) 6

PC

1

04 (1H)

1

19

34 (1H)

1

1

T/EP2012/055471

25 (3H) 2 47 2 63 (4H) 2 54 (3H)

3.07 (1H), 3.61 (2H), 4.78 (1H), 5.28 (1H), 6.03-6. 13 (2H), 7. 38-7. 56 (5H) ppm. Example 105 5

4-(6-Ethyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a]pyridin-3-ylj-2-

methyl-N-[rel-(1S, 2S)-2-methylcyclopropyl]benzamide

N N

N

N

0

0

OH

N


10

2-a]pyridin-3-



in analogy

methylcyclopropanamine

to example 8

example

using rel-(1R, 2R)-2-

10.4


mg (92%)

of

the title compound. 1H NMR (CDCl3) 6

0 68 (1H) 0 77 (1H) 0 99 (1H)

1

17 (3H)

1

24 (3H) 2 46 2 65

3.60 (2H), 5.27 (1H), 5.94 (1H), 6.04 (1H), 7. 36 (1H), 7. 39 (1H), 7.44 (1H), 7.47 (1H), 7.53 (1H) ppm. (5H), 2. 52 (3H),

15

Example 106

3, 3-

4-(6-(3-Fluoro-4-methoxyphenoxy)-8-[(3,



0 F

F OH

20

H N

~0

30 mg (60 ljmol) 4-[6-(3-fluoro-4-methoxyphenoxy)-8-[(3, trifluoropropyl)amino]imidazo[1,

3, 3-




186


to

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12.5

T/EP2012/055471

mg (39%) of the

title


6-

2 42 2 60 (2H) 2 49 (3H) 3 02 (3H) 3 55 (2H) 3 87 (3H) 5 47

(1H), 5.83 (1H), 5.98 (1H), 6.74 (1H), 6.82 (1H), 6.92 (1H), 7. 33 (1H), 7. 35 (1H), 5

7.45 (1H), 7.50 (1H), 7.53 (1H) ppm. Example 106a

4-16-(3-Fluoro-4-methoxyphenoxy)-8-[(3,


2-

acid


N

0

0

F

10

F

0

~0

~0

OH

0

966 mg (1.87 mmol) methyl 4-f6-(3-fluoro-4- methoxyphenoxy)-8trifluoropropyl)amino]imidazo[1,





intermediate 15

[(3,3, 3which was in analogy

to

201 mg (21%) of

the title compound.

Example 106b Methyl 4-f6-(3-fluoro-4-methoxyphenoxy)-8-


[(3,3, 3-


0

Br

0

F

0

20

850 mg (1.86 mmol) methyl 4-j6-bromo-8-[(3, 3, 3trifluoropropyl)amino]imidazo[1,



intermediate


example 6-1 using 3-fluoro-4-methoxyphenol

187


to


up

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g

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of a crude product that contained about 40% of the title compound and was

used without further purification.

Example 106c 5

Methyl 4-(6-bromo-8-



methylbenzoate

;j .k N

0

Br

Br

0

0

2. 90 g (5.21 mmol) methyl 4-[6-bromo-8-[(tert-butoxycarbonyl)(3, 2-a]pyridin-3-yl]-2-methylbenzoate


10

3, 3-




2. 33


mg (98%) of the

to

title

compound.

Example 107

15

N-ethyl-4-$6-(3-fluoro-4-methoxyphenoxy)-8-[(3,

3, 3-



N N

0

0 F

F

~0

0

H N

OH

30 mg (60 ljmol) 4-[6-(3-fluoro-4-methoxyphenoxy)-8-[(3, trifluoropropyl)amino]imidazo[1,

20



3, 3acid which was




188

up and purification

in analogy

11.6

mg

to

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1H NMR (CDCl3) 6

1

T/EP2012/055471

26 (3H) 2 42 2 59 (2H) 2 49 (3H) 3 45 3 61 (4H) 3 87 (3H)

5.48 (1H), 5.78 (1H), 5.99 (1H), 6.74 (1H), 6.83 (1H), 6.91 (1H), 7. 34 (1H), 7.35 (1H), 7.45 (1H), 7. 50 (1H), 7. 54 (1H) ppm.

mg (85%)


1H NMR (CDCl3)

(2H),

6- 0 62

(2H) 0 89 (2H) 2 44 2 58 (2H) 2 47 (3H) 2 92 (1H) 3 55

5.04 (2H), 5.48 (1H), 5.92 (1H), 6.02 (1H), 6.92-7. 00 (4H), 7.29-7.48 (9H),

7.51 (1H) ppm. 10 Example 109a

4-[6- [4-(Benzyloxy) phenoxy] -8- [(3,3, 3-trifluoropropyl)amino]imidazo[1, 3-ylj-2-methylbenzoic

acid

N

N

0

0 0

15

a]pyridin-3-ylf-2-methylbenzoate example 109b were transformed

20

0

Methyl 4-(6-[4-(benzyloxy)phenoxy]-8-[(3,

after working

2-a] pyridin-

up and purification

OH



16.3


to intermediate

mg (3%) of the

2-

example 8b to give

title compound.

Example 109b Methyl 4-[6-[4-(benzyloxy)phenoxy]-8-[(3,


a]pyridin-3-ylJ-2-methylbenzoate

189

2-

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0

N

N

N

0

0 0

0

3, 3-

Methyl 4-[6-[4-(benzyloxy)phenoxy]-8-[(tert-butoxycarbonyl)(3,




T/EP2012/055471

PC

which was


in analogy

to

example 7 to give after working up the title compound as crude product that was used without further purification.

Example 109c

3, 3-

Methyl 4-[6-[4-(benzyloxy)phenoxy]-8-[(tert-butoxycarbonyl)(3,

10



',

j.

k

N

0

N

0

0 0

3, 3-




15

which was


example 6-1 using 4-(benzyloxy)phenol


up

in analogy

the title compound

that was used without further purification.

Example

110

N-cyc lopropyl-4-(6-(4-hydroxyphenoxy)-8-[(3,

20


3, 3-


190

to

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T/EP2012/055471

N N

0

0 H N

To a solution of

H

8.0 mg (13 pmol) 4-$6-[4-(benzyloxy)phenoxy]-8-[(3, 3, 3-

trifluoropropyl)amino]imidazo[1, methylbenzamide 5

2-a]pyridin-3-ylf-N-cyclopropyl-2-

which was prepared

were added 0.54 pL pyridine and

according to example 109 in 254 ljL ethanol

mg palladium

1

vigorously stirred under an atmosphere

on charcoal. The mixture was

of hydrogen at 23'C for 16 hours. After

filtration and removal of the solvents the residue was purified by chromatography

to give 4. 6 mg (68%) of the title compound. 1H NMR (CDCl3)

10

6- 0 63

(2H) 0 89 (2H) 2 43 2 56 (2H) 2 46 (3H) 2 91 (1H) 3 54

3.86 (1H), 5.46 (1H), 5.97 (1H), 6.04 (1H), 6.83 (2H), 6. 93 (2H), 7. 30 (1H), 7.32 (1H), 7.39 (1H), 7.41 (1H), 7.52 (1H) ppm. (2H),

Example 111 N-cyc lopropyl-2-methyl-4-$6-[(1E)-prop-1-en-1-yl]-8-[(3,

15


3, 3-


N N N N

0

OH

10 mg (25 ljmol) 2-methyl-4-[6-[(1E)-prop-1-en-1-yl]-8-[(3, 3, 3trifluoropropyl)amino]imidazo[1, according to intermediate

20





the title compound.

191


up and purification

to example 8

7.7 mg (70%) of

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PC

1H NMR (CDCl3) 6

3.63

(1H),

(2H),

0 64 (2H) 0 91 (2H)

1

T/EP2012/055471

89 (3H) 2 48 2 62 (2H) 2 52 (3H) 2 94

5.29 (1H), 5.97 (1H), 6. 11-6.33 (3H), 7. 36 (1H), 7. 39 (1H), 7.43-

7.49 (2H), 7.57 (1H) ppm. 5

Example 111a

2-Methyl-4-f6- [(1E)-prop-1-en-1-yl]-8- [(3,3, 3-trifluoropropyl)amino]imidazo[1,

a]pyridin-3-ylIbenzoic

2-

acid

N

N

N

N

0

0

OH

400 mg (958 pmol) methyl 2-methyl-4-16-[(1E)-prop-1-en-1-yl]-8-[(3, 3, 3-

10


2-a]pyridin-3-ylfbenzoate




intermediate

to

259. 3

mg (64%)

of the title compound. 15

Example 111b Methyl 2-methyl-4-$6- [(1E)-prop-1-en-1-yl]-8-


imidazo[1, 2-a] pyridin-3-yl$benzoate

0

N

N

N

N

N

0

522 mg

20

[(3,3, 3-

(1.01

0

mmol) methyl 4-(8-[(tert-butoxycarbonyl)(3,

trifluoropropyl)amino]-6-

methylbenzoate transformed mg (91%) of

[(1E)-prop-1-en-1-yl]imidazo[1, 2-a] pyridin-3-ylj-2-

which was prepared

in analogy

3, 3-



the title compound.

192

example 111c were

up and purification

403

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T/EP2012/055471

PC

111c

Example

3, 3-trifluoropropyl)amino]-6-[(1E)-prop-1-en-

Methyl 4-(8-[(tert-butoxycarbonyl)(3,

1-yl]imidazo[1, 2-a] pyridin-3-yl]-2-methylbenzoate

0

N

N N

Br

0 5

0





example 79c using (1E)-prop-1-en-1-ylboronic

intermediate



to

acid to give after


10 Example 112 N,

2-dimethyl-4-(6-[(1E)-prop-1-en-1-yl]-8-[(3, 3, 3-



N

N N

N

H N

OH

15

10 mg (25 pmol) 2-methyl-4-[6-[(1E)-prop-1-en-1-yl]-8-[(3, 3, 3trifluoropropyl)amino]imidazo[1, according to intermediate




to example 8

to give after working up and purification 8.7 mg (84%) of the title compound. 1H NMR (CDCl3)

20

(1H), 5.89 (1H),

6-

1

89 (3H) 2 49 2 62 (2H) 2 53 (3H) 3 04 (3H) 3 63 (2H) 5 29

6. 12-6.32 (3H), 7.37 (1H), 7. 39 (1H), 7.47 (1H), 7.49 (1H), 7. 58

(1H) ppm.

Example 113

193

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N-ethyl-2-methyl-4-(6-[(1E)-prop-1-en-1-yl]-8-[(3,

T/EP2012/055471

3, 3-



N N

N N

0

H N

OH

10 mg (25 ljmol) 2-methyl-4-[6-[(1E)-prop-1-en-1-yl]-8-[(3, 3, 35







up and purification

in analogy

9.4 mg

to example 8

(88%) of the title


10

6-

1

28 (3H)

1

90 (3H) 2 48 2 63 (2H) 2 53 (3H) 3 52 (2H) 3 63

5.29 (1H), 5.82 (1H), 6. 12-6.32 (3H), 7. 38 (1H), 7. 39 (1H), 7.47 (1H), 7.49 (1H), 7. 58 (1H) ppm. (2H),

Example 114

2-Methyl-N-(1-methylcyclopropyl)-4-$6-[(1E)-prop-1 15


-en-1-yl]-8-[(3, 3, 3-


N N N N

0

H N

OH

10 mg (25 ljmol) 2-methyl-4-[6-[(1E)-prop-1-en-1-yl]-8-[(3, 3, 32-a]pyridin-3-ylfbenzoic


20



purification

10.5

mg (93%) of


to example 8


the title compound.

194

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1H NMR (CDCl3) 6

0 77 (2H) 0 89 (2H)

3.63 (2H), 5.26 (1H), 6.08-6. 31 (1H), 7. 56 (1H) ppm. (3H),

5

1

54 (3H)

1

T/EP2012/055471

90 (3H) 2 46 2 63 (2H) 2 51

7. 36 (1H), 7. 38 (1H), 7.43 (1H), 7.47

(4H),

Example 115

N-(1-cyanocyclopropyl)-2-methyl-4-$6-[(1E)-prop-1

-en-1-yl]-8-[(3, 3, 3-



N N N N

0

H N

OH NC

10 mg (25 pmol) 2-methyl-4-[6-[(1E)-prop-1-en-1-yl]-8-[(3, 3, 310




9.4

1H NMR (CDCl3)

15

mg (81%) of

6-

1

in analogy

the title compound.

39 (2H)

1

68 (2H)

1

90 (3H) 2 48 2 63 (2H) 2 54 (3H) 3 63

5.26 (1H), 6. 11-6.31 (3H), 6.48 (1H), 7. 38 (1H), 7.42 (1H), 7.45 (1H), 7.46 (1H), 7. 57 (1H) ppm. (2H),

116

Example

N-[rel-(1S, 2S)-2-fluorocyclopropyl]-2-methyl-4-(6-[(1E)-prop-i 20

to example 8



purification



-en-1-yl]-8-


N N N N

0

OH

rac.

0

H N

F

10 mg (25 ljmol) 2-methyl-4-[6-[(1E)-prop-1-en-1-yl]-8-[(3, 3, 3trifluoropropyl)amino]imidazo[1,


195


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according to intermediate using

7. 5

mg (66%)

1H NMR (CDCl3) 6

1

in analogy


04 (1H)

1

28 (1H)

1

89 (3H) 2 47 2 63 (2H) 2 54 (3H) 3 08

3.63 (2H), 4. 78 (1H), 5.27 (1H), 6.06 (1H), 6. 10-6.32 (3H), 7. 39 (1H), 7.40 (1H), 7.47 (1H), 7. 52 (1H), 7. 58 (1H) ppm. (1H),

117

Example

-en-1-yl]-8-

2-Methyl-N-[rel-(15, 25)-2-methylcyclopropyl]-4-(6-[(1E)-prop-i

10

to example 8


rel-(15, 25)-2-fluorocyclopropanaminium

purification

5


T/EP2012/055471



N N N N

H N

0

OH

10 mg (25 ljmol) 2-methyl-4-[6-[(1E)-prop-1-en-1-yl]-8-[(3, 3, 3trifluoropropyl)amino]imidazo[1, according to intermediate

15


9.4

mg (83%) of

1H NMR (CDCl3) 6

in analogy


using rel-(1R, 2R)-2-methylcyclopropanamine

purification



to example 8

up and

the title compound.

0 67 (1H) 0 77 (1H)

1

00 (1H)

1

17 (3H)

1

90 (3H) 2 46 2 65

2. 52 (3H), 3.63 (2H), 5.26 (1H), 5.89 (1H), 6. 11-6.30 (3H), 7. 36 (1H), 7. 38 (1H), 7.45 (1H), 7.47 (1H), 7. 57 (1H) ppm. (2H),

20 Example

118

N-[rel-(1R, 2R)-2-fluorocyclopropyl]-4-(6-[(1Z)-3-hydroxyprop-1-en-1-yl]-8-



196

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N N

N

N

OH H N

OH

0

OH

10 mg (24 ljmol) 4-[6-[(1Z)-3-hydroxyprop-i-en-1-yl]-8-[(3, 3, 32-a]pyridin-3-yl]-2-methylbenzoic




example 8 using rel-(1S, 2S)-2-fluorocyclopropanaminium working up and purification 1H NMR (CDCl3) 6

1

8. 1

05 (1H)

mg (71%) of 1


to


the title compound.

28 (1H) 2 48 2 60 (2H) 2 52 (3H) 3 06 (1H) 3 60

4. 38 (2H), 4. 77 (1H), 5. 37 (1H), 5.94 (1H), 6.07 (1H), 6. 15 (1H), 6.46 (1H), 7.36 (1H), 7.40 (1H), 7.49 (1H), 7.51 (1H), 7.66 (1H), ppm. (2H),

10

119

Example

4-(6-[(1Z)-3-hydroxyprop-1-en-1-yl]-8-[(3, 3, 32-a]pyridin-3-yl]-N, 2-dimethylbenzamide


N

N

N

N

OH

OH

0

15

H N

OH

10 mg (24 ljmol) 4-[6-[(1Z)-3-hydroxyprop-1-en-1-yl]-8-[(3, 3, 3trifluoropropyl)amino]imidazo[1,





8. 5

mg


to

(82/) of the title

compound.

20

1H NMR (CDCl3) 6

2 48 2 61 (2H) 2 50 (3H) 3 02 (3H) 3 59 (2H) 4 37 (2H) 5 41

(1H), 5.90-6.01 (2H), (1H),

6.07 (1H), 6.45

(2H),

7. 34 (1H), 7. 39 (1H), 7.45 (1H), 7. 50

7.66 (1H) ppm.

197

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Example 120

N-ethyl-4-$6-[(1Z)-3-hydroxyprop-1-en-1-yl]-8-[(3,

3, 3-



N N

N N

OH

OH

0 5

H N

OH

10 mg (24 pmol) 4-[6-[(1Z)-3-hydroxyprop-i-en-1-yl]-8-[(3, 3, 3prepared according to intermediate


acid which was





up and purification

in analogy

7.0

to

mg (66%)


10

1H NMR (CDCl3)

6-

1

27 (3H) 2 48 2 61 (2H) 2 51 (3H) 3 51 (2H) 3 60 (2H) 4 38

(2H), 5.40 (1H), 5.88 (1H), 5. 94 (1H),

6.08 (1H), 6.46 (1H), 7. 35 (1H), 7. 39 (1H),

7.46 (1H), 7.51 (1H), 7.66 (1H) ppm. Example 121

15

4-(6-(3-Fluoro-4-methoxyphenoxy)-8-[(tetrahydro-2H-pyran-4ylmethyl)amino]imidazo[1,

2-a] pyridin-3-ylf-N, 2-dimethylbenzamide

N

0

0

F

F

~O

0

OH

~0

0

H N

10 mg (20 ljmol) 4-[6-(3-fluoro-4-methoxyphenoxy)-8-[(tetrahydro-2H-pyran-4ylmethyl)amino]imidazo[1,

20



acid which was


example 8 to give after working up and purification compound.

198

8.2

mg (76%)

in analogy

of the title

to

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1H NMR (CDCl3) 6

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PC

1

40 (2H)

75 (2H)

1

1

94 (1H) 2 49 (3H) 3 01 (3H) 3 14 (2H)

3.39 (2H), 3.87 (3H), 3.99 (2H), 5.42 (1H), 5.85 (1H), 5.97 (1H), 6.74 (1H), 6.83 (1H), 6.90 (1H), 7. 34 (1H), 7. 36 (1H), 7.44 (1H), 7.47 (1H), 7. 52 (1H) ppm. 5

Example 121a

4-I6-(3-Fluoro-4-methoxyphenoxy)-8-[(tetrahydro-2H-pyran-4ylmethyl)amino]imidazo[1,


acid

N

0

0

F

F

40. 9 10

0

mg

~0

0

OH

(79 ljmol) methyl 4-(6-(3-fluoro-4-methoxyphenoxy)-8-[(3, 2-a]pyridin-3-yl$-2-methylbenzoate



which was



intermediate

3, 3-

in analogy

31.1

to

mg (78%)

of

the title compound.

15

Example 121b Methyl 4-f6-(3-fluoro-4-methoxyphenoxy)-8-


[(3,3, 3-

imidazo[1, 2-a] pyridin-3-yl$-2-methylbenzoate

Br

F

0

373.5 20

mg

0

(815 pmol) methyl 4-f6-bromo-8-[(tetrahydro-2H-pyran-4-

ylmethyl)amino]imidazo[1,




6-1 using 3-fluoro-4-methoxyphenol mg (9%) of


the title compound.

199


to example

up and purification

40. 9

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Example 121c 2-

Methyl 4-f6-bromo-8- [(tetrahydro-2H-pyran-4-ylmethyl)amino]imidazo[1,

a]pyridin-3-yl]-2-methylbenzoate

methyl

N

Br

Br

0 5

581.5

mg

0

(1.04 mmol)

methyl 4-[6-bromo-8-[(tert-butoxycarbonyl)(tetrahydro-2H-


pyran-4-ylmethyl)amino]imidazo[1,


which was



in analogy

to

458 mg (89/) of the title

compound.

10 Example 121d Methyl 4-[6-bromo-8- [(tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-



Br

0

15

863 mg (1.61 mmol) tert-butyl

(6-bromo-3-iodoimidazo[1, 2-a]pyridin-8-

yl)(tetrahydro-2H-pyran-4-ylmethyl)carbamate

intermediate



using [4-(methoxycarbonyl)-3-methylphenyl]boronic

and purification

689.4

mg

to intermediate


Example 122

N-ethyl-4-$6-(3-fluoro-4-methoxyphenoxy)-8-[(tetrahydro-2H-pyran-42-a]pyridin-3-yl$-2-methylbenzamide

200

example 7b


20


according to

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N

0

0

F

F

~O

0

~0

OH

0

H N







acid which was

up and purification

in analogy

9.1

to

mg (82%)


6-

1

26 (3H)

1

40 (2H)

1

76 (2H)

1

94 (1H) 2 49 (3H) 3 14 (2H)

3.39 (2H), 3.50 (2H), 3.87 (3H), 4.00 (2H), 5.42 (1H), 5.79 (1H), 5.97 (1H), 6.75 (1H), 6.82 (1H), 6.90 (1H), 7. 34 (1H), 7. 36 (1H), 7.44 (1H), 7.47 (1H), 7. 52 (1H) 10

ppm.

Example 123 N-cyc lopropyl-4-(6-(3-fluoro-4-meth

oxyphenoxy)-8-[(tetrahydro-2H-pyran-4-

2-a]pyridin-3-yl$-2-methylbenzamide


0 F

F

~0

0

H

OH

15



prepared according to intermediate example 8 using cyclopropanamine

20

acid which was



in analogy

up and purification

to

9.6 mg


0 63 (2H) 0 89 (2H)

1

40 (2H)

1

75 (2H)

1

94 (1H) 2 48 (3H)

2. 92 (1H), 3. 14 (2H), 3.39 (2H), 3.87 (3H), 3.99 (2H), 5.41 (1H), 5.94 (1H), 5.97

201

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(1H), 6.74 (1H), 6.82 (1H), 6.90 (1H), 7. 32 (1H), 7. 35 (1H), 7.41 (1H), 7.46 (1H),

7.52 (1H) ppm. Example 124 5

N-[rel-(1S, 2S)-2-fluorocyclopropyl]-4-(6-(3-fluoro-4-methoxyphenoxy)-8-



0 F

H

F

~0

0

OH

20 mg (40 ljmol) 4-[6-(3-fluoro-4-methoxyphenoxy)-8-[(3,



10



example 8 using rel-(1S, 2S)-2-fluorocyclopropanaminium working up and purification 1H NMR (DCDCl3)

15

6

1

3, 3-

11.9 mg (51%) of the title

03 (1H)

1


to

chloride to give after compound.

27 (1H) 2 46 2 57 (2H) 2 51 (3H) 3 06 (1H)

3.56 (2H), 3.87 (3H), 4.77 (1H), 5.47 (1H), 5.99 (1H), 6.01 (1H), 6.74 (1H), 6.83 (1H), 6.91 (1H), 7. 35 (1H), 7. 37 (1H), 7.48 (1H), 7. 51 (1H), 7. 54 (1H) ppm. Example 125

4-(6-(3-fluoro-4-meth

oxyphenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

a]pyridin-3-yl]-2-methyl-N-[rel-(1S,

2S)-2-methylcyclopropyl]benzamide

0 0 F F

~0

0

OH

20 20 mg (40 pmol) 4-[6-(3-fluoro-4-methoxyphenoxy)-8-[(3, trifluoropropyl)amino]imidazo[1,

3, 3-


202

acid which was

2-

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PC



to


1H NMR (CDCl3) 6

5

in analogy


example 8 using rel-(1R, 2R)-2-methylcyclopropanamine and purification

T/EP2012/055471

0 66 (1H) 0 76 (1H) 0 98 (1H)

1

16 (3H) 2 43 2 57 (2H) 2 48

(3H), 2. 60 (1H), 3.55 (2H), 3.87 (3H), 5.47 (1H), 5.87 (1H), 5. 99 (1H), 6. 74 (1H),

6.83 (1H), 6.91 (1H), 7.32 (1H), 7.34 (1H), 7.41 (1H), 7.50 (1H), 7.53 (1H) ppm. Example 126

2-a] pyridin-

4-(6-(3-hydroxypropyl)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 10


N

N

N

N

OH

OH

0

H N

OH

10 mg (24 ljmol) 4-(6-(3-hydroxypropyl)-8-[(3, 3, 3-trifluoropropyl)amino] imidazo[1, 2-a]pyridin-3-yl$-2-methylbenzoic example 126a were transformed

intermediate 15

6-

1

in analogy

to example 8 to give after


working up and purification 1H NMR (CD30D)

acid which was prepared according to

84 (2H) 2 46 (3H) 2 54 2 68 (4H) 2 79 (2H) 2 91 (3H)

3.58 (4H), 6.24 (1H), 7.43-7. 51 (4H), 7.66 (1H) ppm. Example 126a

20

4-[6-(3-hydroxypropyl)-8-[(3, 3, 3-trifluoropropyl)amino] 2-methylbenzoic

acid

N

N

N

N

OH

OH

0

69.6

mg

imidazo[1, 2-a]pyridin-3-yl]-

OH

0

OH

(166 ljmol) 4-[6- [(1Z)-3-hydroxyprop-1-en-1-yl]-8-[(3, 3, 3-



203

acid which was

WO 2012/136531



example 99c to give after working up and purification

intermediate

T/EP2012/055471

PC

in analogy

58. 6

to

mg (84%)


5

Example 127


N-ethyl-4-$6-(3-hydroxypropyl)-8-[(3,

2-


N

N

N

N

OH

OH

0

H N

OH

10 mg (24 ljmol) 4-[6-(3-hydroxypropyl)-8-[(3, 3, 3-trifluoropropyl)amino] 10

imidazo[1, 2-a]pyridin-3-yl$-2-methylbenzoic example 126a were transformed

intermediate ethanamine

acid which was prepared according to in analogy


to example 8 using

10.1

mg (95%)

of the title

compound. 1H NMR (CD30D) 6

15

1

23 (3H)

1

84 (2H) 2 46 (3H) 2 54 2 67 (4H) 2 79 (2H)

3.40 (2H), 3.58 (4H), 6.26 (1H), 7.43-7. 49 (3H), 7.50 (1H), 7.65 (1H) ppm. Example 128 N-cyc lopropyl-4-(6-(3-hydroxypropyl)-8-[(3,

3, 3-



N

N

N

N

OH

OH

0

OH

H N

20

10 mg (24 ljmol) 4-[6-(3-hydroxypropyl)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo

[1,2-a]pyridin-3-yl]-2-methylbenzoic intermediate

acid which was prepared according to


204

in analogy

to example 8

using

WO 2012/136531

PC

to give after working up and purification 9.7

cyclopropanamine

T/EP2012/055471

mg (89%) of

the

title compound.

6- 0 62

1H NMR (CD30D)

(2H) 0 81 (2H)

1

84 (2H) 2 45 (3H) 2 54 2 66 (4H)

2. 87 (1H), 3.52-3. 63 (4H), 6.25 (1H), 7.42-7. 48 (3H), 7. 50 (1H), 7.65 (1H) ppm. Example 129 N-cyc lopropyl-4-(6-(3-fluoro-4-hydroxyphenoxy)-8-[(3,


10

N

To a solution of 15.2 mg (28 ljmol) N-cyclopropyl-4-j6-(3-fluoro-4methoxyphenoxy)-8methylbenzamide

15


OH

N

3, 3-

[(3,3, 3-trifluoropropyl)amino]imidazo[1, 2-a] pyridin-3-yl]-2which was prepared according to example 42 in 2. 4 mL

dichloromethane

were added 89.7 ljL of a 2M boron tribromide solution in

dichloromethane

and the mixture was stirred

of 56 pL

2M boron tribromide

continued for additional

at 23'C overnight.

solution in dichloromethane

A

second portion

was added and stirring

6 hours. Methanol was added and solvents were removed.

to give 7.4

The residue was purified by chromatography

mg (47%)

of the title

compound. 1H NMR (DMSO

20

d6) 6- 0 49 (2H) 0 65 (2H) 2 31 (3H) 2 61 (2H) 2 80 (1H) 3 45

6.06 (1H), 6.49 (1H), 6.74 (1H), 6.89 (1H), 6.98 (1H), 7. 31-7.47 (4H), 7. 59 (1H), 8.27 (1H), 9.62 (1H) ppm. (2H),

Example 130

4-(6-(3-Fluoro-4-hydroxyphenoxy)-8-[(3, 25



205

2-

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N

N

0

0

F

0~

8.8

mg

0

F

H N

H N

OH

(17 pmol) 4-[6-(3-fluoro-4-methoxyphenoxy)-8-[(3,

3, 3-

2-a]pyridin-3-yl]-N, 2-dimethylbenzamide


was prepared according to example 106 were transformed 5

T/EP2012/055471

129 to give after working up and purification 1H NMR (DMSO

5.3

mg (59%)

in analogy

which

to example


d6) 6- 2 33 (3H) 2 55 2 67 (2H) 2 72 (3H) 3 45 (2H) 6 06 (1H)

6.50 (1H), 6.75 (1H), 6.89 (1H), 6.98 (1H), 7. 36-7.42 (3H), 7.44 (1H), 7.61 (1H), 8. 17 (1H), 9.62 (1H) ppm. 10

Example 131

3, 3-

N-ethyl-4-$6-(3-fluoro-4-hydroxyphenoxy)-8-[(3, trifluoropropyl)amino]imidazo[1,


N

0

0

F

H N

~0

11.8 mg 15

0



prepared according to example 107 were transformed give

after working

1H NMR (DMSO

20

3, 3-

(22 ljmol) N-ethyl-4-(6-(3-fluoro-4-methoxyphenoxy)-8-[(3,

up and purification

d6). 6-

1

5.8

mg (48%)

in analogy

which was

to example 129 to


08 (3H) 2 33 (3H) 2 53 2 70 (2H) 3 22 (2H) 3 45 (2H)

6.07 (1H), 6.50 (1H), 6.75 (1H), 6.89 (1H), 6.98 (1H), 7.35-7.44 (4H), 7.60 (1H), 8.23 (1H), 9.62 (1H) ppm. Example 132 N-cyc lopropyl-4-(6-(2-hydroxyphenyl)-8-[(3,


3, 3-

2-a]pyridin-3-yl]-2-methylbenzamide 206

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N N

/

N

/

N

OH OH H N

0

OH

10 mg (22 ljmol) 4-[6-(2-hydroxyphenyl)-8-[(3,



5

3, 3acid which was





mg (67%)

in analogy

up and purification

to

7.7


1H NMR (CDCl3) 6

0 63 (2H) 0 87 (2H) 2 35 2 53 (2H) 2 39 (3H) 2 90 (1H) 3 55

5. 30 (1H), 5. 33 (1H), 6.21 (1H), 6. 30 (1H), 6.98 (1H), 7.05 (1H), 7. 22-7. 35 (4H), 7.40 (1H), 7.81 (1H) ppm. (2H),

10 Example 132a

4-[6-(2-Hydroxyphenyl)-8-[(3, 2-methylbenzoic


2-a] pyridin-3-yl(-

acid

0

N

N

N

N

/

N

/

OH

0

15

OH

0

OH

241 mg (423 pmol) 4-(8-[(tert-butoxycarbonyl)(3,





acid which was




compound.

20 Example 132b 4-4 8- [(tert-8utoxycarbonyl)(3,


3, 3-trifluorop ropyl)amino]-6-(2-


207

in analogy

acid

to

WO 2012/136531

PC

0

N

0

N

P

N

/

N

/

N

~

0

0

0

OH

524 mg (max. 899 pmol) methyl 4-[8- [(tert-butoxycarbonyl)(3,

-6-(2-methoxyphenyl)imidazo[1,


methylbenzoate 5

T/EP2012/055471

which was prepared

3, 3-

2-a] pyridin-3-yl j-2-


to intermediate

example 79c were

example 8b to give after working up and

transformed

in analogy

purification


Example 133

4-(6-(2-Hydroxyphenyl)-8-[(3, 10

3, 3-tri flu oropropyl)amino]imidazo[1,


N

N

N

/

N

/

OH

OH

0

H N

OH

10 mg (22 pmol) 4-[6-(2-hydroxyphenyl)-8-[(3, trifluoropropyl)amino]imidazo[1,

3, 3-



15

2-a] pyridin-



6.4

acid which was

to

in analogy

mg (59%) of the

title


6-

2 38 2 54 (2H) 2 41 (3H) 3 00 (3H) 3 57 (2H) 5 30 (1H) 5 34

6.08 (1H), 6. 30 (1H), 6.98 (1H), 7.04 (1H), 7.23-7. 32 (3H), 7. 36 (1H), 7.42 (1H), 7.82 (1H) ppm. (1H),

20 Example 134

N-ethyl-4-$6-(2-hydroxyphenyl)-8-[(3,



208

2-

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N

N

N

/

/

N

OH

OH

OH

0

H N


3, 3-




T/EP2012/055471

PC





5.2

up and purification

to

mg (47%)


(1H), 5.97 (1H), (1H),

6-

1

25 (3H) 2 38 2 55 (2H) 2 42 (3H) 3 49 (2H) 3 57 (2H) 5 35

6.28 (1H), 6.99 (1H), 7.04 (1H), 7.22-7. 33 (4H), 7. 38 (1H), 7.45

7.81 (1H) ppm.

10 Example 135

N-[rel-(1S, 2S)-2-fluorocyclopropyl]-4-(6-(2-hydroxyphenyl)-8-[(3,

3, 3-



N N

N

N

/

/ OH

OH H N

0

15

OH


3, 3-





example 8 using rel-(1S, 2S)-2-fluorocyclopropanaminium working up and purification

20

1H NMR (CDCl3)

6-

1

6. 1

05 (1H)

mg 1


to



25 (1H) 2 28 2 56 (2H) 2 45 (3H) 3 04 (1H) 3 57

4. 75 (1H), 5. 36 (1H), 6. 18 (1H), 6.28 (1H), 6.95-7. 11 (2H), 7.23-7. 36 (4H), 7.38-7. 50 (2H), 7.83 (1H) ppm. (2H),

209

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Example 136 N-cyc lopropyl-4-(6-(3-hydroxyphenoxy)-8-[(3,

3, 3-



0 0 0 5

18.8

mg

(36 ljmol) N-cyclopropyl-4-f6-(3-methoxyphenoxy)-8-



prepared according to example 52 were transformed

after working

give

1H NMR (DMSO

10

[(3,3, 3-

up and purification

9.1

in analogy

mg (47%)

which was

to example 129 to


d6) 6- 0 49 (2H) 0 65 (2H) 2 32 (3H) 2 52 2 70 (2H) 2 79 (1H)

3.46 (2H), 6.09 (1H), 6.39 (1H), 6.42-6. 48 (2H), 6.51 (1H), 7.09 (1H), 7.34 (1H), 7.40 (1H), 7.41 (1H), 7.53 (1H), 7.62 (1H), 8.26 (1H), 9.49 (1H) ppm. Example 137

4-(6-(3-Hydroxyphenoxy)-8-[(3, 15


2-


0

0

12.8

0

mg (24 pmol) 4-$6-(3-methoxyphenoxy)-8-[(3,

trifluoropropyl)amino]imidazo[1, methylcyclopropyl)benzamide

20

transformed

5. 1

in analogy

mg (39%) of the

3, 3-

2-a]pyridin-3-yl$-2-methyl-N-(1which was prepared

according to example 54 were


title compound.

210

up and purification

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1H NMR (DMSO

PC

d6) 6 0 55 (2H) 0 68 (2H)

1

T/EP2012/055471

35 (3H) 2 31 (3H) 2 61 (2H) 3 45

6.08 (1H), 6. 39 (1H), 6.43-6.48 (2H), 6. 51 (1H), 7.09 (1H), 7. 31 (1H), 7. 38 (1H), 7.40 (1H), 7. 52 (1H), 7.61 (1H), 8.41 (1H), 9.49 (1H) ppm. (2H),

5

Example 138

N-ethyl-4-$6-(3-hydroxyphenoxy)-8-[(3,


2-


N

20. 5 10

mg

0

N

(40 ljmol) N-ethyl-4-[6-(3-methoxyphenoxy)-8-[(3,



prepared according to example 56 were transformed give

after working

1H NMR (DMSO

15

12. 1

up and purification

d6).

6-1

3, 3-

mg (58%)

in analogy

which was

to example 129 to


08 (3H) 2 34 (3H) 2 53 2 70 (2H) 3 22 (2H) 3 46 (2H)

6.09 (1H), 6.40 (1H), 6.42-6. 48 (2H), 6. 51 (1H), 7.09 (1H), 7.34-7. 46 (3H), 7. 54 (1H), 7.62 (1H), 8.22 (1H), 9.49 (1H) ppm. Example 139

4-(6-(3-Hydroxyphenoxy)-8-[(3,


2-


0

N

N

20

22. 4 mg (45 ljmol) 4-$6-(3-methoxyphenoxy)-8-[(3, trifluoropropyl)amino]imidazo[1,

3, 3-


was prepared according to example 55 were transformed

in analogy

which

to example 129

to give after working up and purification 6.7 mg (31%) of the title compound. 211

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1H NMR (DMSO

PC

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d6) 6 2 34 (3H) 2 53 2 68 (2H) 2 72 (3H) 3 45 (2H) 6 08 (1H)

6.39 (1H), 6.44 (1H), 6.46 (1H), 6.54 (1H), 7.09 (1H), 7.38-7.45 (3H), 7.55 (1H), 7.63 (1H), 8. 18 (1H), 9.51 (1H) ppm. 5

Example 140 Methyl 2-methyl-4-(3-[3-methyl-4-(methylcarbamoyl)phenyl]-8-[(3,

3, 3-

2-a]pyridin-6-yl)benzoate


N N

Br

0 H N

H N

408 mg (905 pmol) 4-[6-bromo-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

10


which was prepared


intermediate

in analogy

79c using [4-(methoxycarbonyl)-3-methylphenyl]boronic

15

according to

to intermediate

example



up and purification 1H NMR (DMSO

2-

d6). 6- 2 38 (3H) 2 56 (3H)

2 62 2

78 (2H) 2 74 (3H) 3 59 (2H)

3.80 (3H), 6.40 (1H), 6.50 (1H), 7.45 (1H), 7. 50-7. 66 (5H), 7.87 (1H), 7.97 (1H), 8.22 (1H) ppm. Example 140a

4-[6-Bromo-8- [(3,3, 3-trifluoropropyl)amino]imidazo[1, 20

dim ethylbenza mid

2-a]pyridin-3-yl]-N, 2-

e

N

Br

Br

OH

H N

400 mg (904 pmol) 4-[6-bromo-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, a]pyridin-3-ylI-2-methylbenzoic

2-


212

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in analogy

409mg (99%) of the title compound.

and purification

Example 141 5

3, 3-

N-cyclopropyl-4-(6-(2-hydroxyethyl)-8-[(3,



N N

x

N N

HO HO H N

0

OH

10 mg (25 ljmol) 4-[6-(2-hydroxyethyl)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, a]pyridin-3-yl(-2-methylbenzoic

10



to give after working up and purification 1H NMR (CD30D) 6

(1H),

15

3.60

(2H),

3.78

to example 8



0 62 (2H) 0 81 (2H) 2 45 (3H) 2 60 (2H) 2 74 (2H) 2 86 (2H),

6.27 (1H), 7.42-7. 54 (4H), 7.70 (1H), ppm.

Example 141a

4-[6-(2-Hydroxyethyl)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

N

x

N

N

N

HO

HO

0 0

23.6


acid

methylbenzoic

20

2-

mg

/

0

OH

(56 ljmol) methyl 4-(6-(2-hydroxyethyl)-8-




intermediate

[(3,3, 3-



example 8b to give after working up 21 mg (83%) of the title

compound.

213

to

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Example 141b Methyl 4-(6-(2-hydroxyethyl)-8-[(3,

3-ylf-2-methylbenzoate


(A) and

methyl 4-f6- [(1RS)-1- hydroxyethyl]-85

a]pyridin-3-ylf-2-methylbenzoate

0

N

[(3,3, 3- trifluoropropyl)amino]

(B)

N

HO

imidazo[1, 2-

0

N

N N

x

N

N

N

xN

HO

N

HO

HO

0 0

0 0

0 0

/

0 0

218 mg (418 pmol) of a mixture of methyl 4-(8-[(tert-butoxycarbonyl)(3, trifluoropropyl)amino]

methylbenzoate

10

and methyl 4-(8-[(tert-butoxycarbonyl)(3,

transformed mg (13%) of

in analogy


the title compound

3, 3-

3, 32-a]pyridin-3-yl)-2-


which was prepared

/

2-a] pyridin-3-ylf-2-

-6-(2-hydroxyethyl)imidazo[1,

trifluoropropyl)amino]-6-[(1RS)-1-hydroxyethyl]imidazo[1, methylbenzoate

15

2-a]pyridin-

example 141c were

up and purification

23. 6

34. 9 mg (20%) of the title compound B.

A and


hydroxyethyl)imidazo[1,


2-a]pyridin-3-ylj-2-methylbenzoate

3, 3-trifluoropropyl)amino]-6-[(1RS)-1-

methyl 4-j8-[(tert-butoxycarbonyl)(3,

hydroxyethyl]imidazo[1,

2-a]pyridin-3-ylj-2-methylbenzoate

0

N N

(B)

0

N

N

N

(A) and

N

HO

N

x

N

HO

20

0 0

0

0 0

To a solution of 217 mg (431 pmol) methyl 4-(8-[(tert-butoxycarbonyl)(3, trifluoropropyl)amino]-6-vinylimidazo[1,



example 92c in 7.4 mL tetrahydrofuran

were added 2. 16 mL of a 1M boran-tetrahydrofuran 25

3, 3-

solution. The mixture was

stirred for two days at 23'C. After cooling to 3'C, 325 ljL water and 325 ljL

214

which

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peroxide solution (30% in water) were added and stirring continued at

hydrogen

23'C for two hours. The mixture was poured into water and extracted with ethyl

acetate. The combined organic layers were dried over sodiumsulfate.

After

filtration and removal of the solvent the crude product containing a mixture of the 5

title compounds was used without purification. Example 142

4-(6-(2-Hydroxyethyl)-8-[(3, 3, 3-tri flu oropropyl)amino]imidazo[1,

2-a] pyridin-3-

ylf-N, 2-dimethylbenzamide

N N N N

HO HO H N

0

10

OH

10 mg (25 ljmol) 4-[6-(2-hydroxyethyl)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,



example 141a were transformed and purification

15

1H NMR (CD30D)

(2H),

8.2

6-

2-

mg (79%) of

in analogy


the title compound.

2 46 (3H) 2 60 (2H) 2 74 (2H) 2 91 (3H) 3 60 (2H) 3 78

6.27 (1H), 7.45-7. 51 (4H), 7.71 (1H) ppm.

Example 143 N-cyc lopropyl-4-(6-[(1RS)-1-hydroxyethyl]-8-[(3,

20

3, 3-



N N

HO

HO

xN

xN H N

0

OH

11 mg (27 ljmol) 4-[6-[(1RS)-1-hydroxyethyl]-8-[(3, 3, 3-



215

acid which was

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to

11.7

the title compound.

1H NMR (CD30D) 6

5

in analogy


example 8 using cyclopropanamine mg (97%) of

T/EP2012/055471

0 62 (2H) 0 81 (2H)

1

46 (3H) 2 45 (3H) 2 52 2 69 (2H)

2. 86 (1H), 3.61 (2H), 4.79 (1H), 6.32 (1H), 7.43-7.49 (3H), 7. 52 (1H), 7.82 (1H) ppm.

Example 143a

4-[6- [(1RS)-1-Hydroxyethyl] -8- [(3,3, 3-trifluoropropyl)amino]imidazo[1, 10

3-ylf-2-methylbenzoic

2-a] pyridin-

acid

N N

HO

w

HO N

xN

OH

0

34.9

mg

(83 ljmol) methyl 4-[6-[(1RS)-1-hydroxyethyl]-8-[(3, 3, 32-a]pyridin-3-yl$-2-methylbenzoate



15



to

example 8b to give after working up 34. 1 mg of the title compound

intermediate

that was used without further purification. Example 144

4-(6-[(1RS)-1-Hydroxyethyl]-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 20

2-

a]pyridin-3-yl)-N, 2-dimethylbenzamide

N N

HO

HO

xN

x

N

H N

0

OH

11 mg (27 pmol) 4-[6- [(1RS)-1-hydroxyethyl]-8- [(3,3, 3-





216


to

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7. 5


mg (63%) of

the title

compound. 1H NMR (CD30D)

6-

1

46 (3H) 2 46 (3H) 2 53 2 69 (2H) 2 91 (3H) 3 61 (2H)

4.80 (1H), 6.32 (1H), 7.44-7. 55 (4H), 7.83 (1H) ppm. Example 145

N-ethyl-4-$6-[(1RS)-1-hydroxyethyl]-8-[(3,

3, 3-



N N

HO

HO

wN

w

N

H N

OH

0

10

11 mg (27 ljmol) 4-16-[(1RS)-1-hydroxyethyl]-8-[(3, 3, 3-




acid which was



in analogy

up and purification

11.4

to

mg


15

1H NMR (CD30D)

6-

1

23 (3H)

1

46 (3H) 2 46 (3H) 2 52 2 69 (2H) 3 40 (2H)

3.61 (2H), 4.80 (1H), 6.33 (1H), 7.45-7. 55 (4H), 7.83 (1H) ppm. Example 146 N-cyc lopropyl-4-(6-(3-fluoro-2-meth

20


oxyphenoxy)-8-[(3, 3, 32-a]pyridin-3-yl]-2-methylbenzamide

0

Br

N

P

N

50 mg (104 ljmol) 4-[6-bromo-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, a]pyridin-3-yl(-N-cyclopropyl-2-methylbenzamide

intermediate


217


to intermediate

2-

according to

example 6-

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1

PC


using 3-fluoro-2-methoxyphenol

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up and purification

10.0 mg


6- 0 62

(2H) 0 89 (2H) 2 43 2 58 (2H) 2 47 (3H) 2 91 (1H) 3 56

3.97 (3H), 5.49 (1H), 5.92 (1H), 6.03 (1H), 6.73 (1H), 6.86-6. 98 (2H), 7. 31 (1H), 7. 33 (1H), 7.40 (1H), 7.48 (1H), 7. 53 (1H) ppm. (2H),

5

Example 147

4-(3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(3,



N

N N

3, 3-

/

N

0 OH

P

~NH N

10

H

3, 3-

10 mg (19 ljmol) 4-[3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(3, prepared according to intermediate



15

acid which was



9.3

mg (86%)

in analogy

of the title

compound.

6- 0 63

1H NMR (CD30D)

(2H) 0 82 (2H) 2 44 (3H) 2 46 (3H) 2 57 2 72 (2H)

2. 88 (1H), 2.90 (3H), 3.68 (2H), 6.51 (1H), 7. 37-7. 52 (6H), 7. 56 (1H), 7.90 (1H) ppm.

20

Example 147a

4-[3- [4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-



N

N

N

N

/

0 0

[(3,3, 3-

OH N

H

218

P

acid

to

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363 mg (659 pmol) methyl 4-$3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-

2-a] pyridin-6-ylf-2-methylbenzoate [(3,3, 3-trifluoropropyl)amino]imidazo[1, was prepared according to intermediate example 147b were transformed

to intermediate 5


which in analogy

265 mg (67%)

of the title compound. Example 147b

3, 3-

methyl 4-[3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(3,



N N

N

10

/

'-

P

N

P

437 mg (907 pmol) 4-[6-bromo-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, a]pyridin-3-yl]-N-cyclopropyl-2-methylbenzamide


intermediate

79c using [4-(methoxycarbonyl)-3-methylphenyl]boronic 15

up and purification

according to


2-

to intermediate

example



Example 148


2-a]pyridin-6-yl]-N-ethyl-2-methylbenzamide


N

N N

3, 3-

/

N

0

P

OH

20

N

H

3, 3-

10 mg (19 ljmol) 4-[3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(3, trifluoropropyl)amino]imidazo[1,



example 8 using ethanamine 25

acid which was




219

up and purification

in analogy

10.4

mg

to

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1H NMR (CD30D) 6

0 63 (2H) 0 82 (2H)

1

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22 (3H) 2 44 (3H) 2 46 (3H) 2 55

2. 73 (2H), 2.88 (1H), 3.39 (2H), 3.68 (2H), 6. 52 (1H), 7.37-7. 52 (6H), 7.56 (1H), 7.90 (1H) ppm. 5

Example 149


3, 3-

2-a] pyridin-6-yl]-2-methyl-N-(1-

trifluoropropyl)amino]imidazo[1, methylcyclopropyl)benzamide

N

N

N

N

0

0 OH

P

QNH N

H

10




9. 1

purification

mg (83/o)

1H NMR (CDCl3) 6

acid which was


in analogy


0 64 (2H) 0 76 (2H) 0 82 0 94 (4H)

(3H), 2. 58 (2H), 2. 94 (1H), 3.67 (2H), 5. 51 (1H),

1

52 (3H) 2 49 (3H) 2 51

6.00 (1H), 6. 08 (1H), 6. 32 (1H),

7.28-7. 43 (5H), 7.47 (1H), 7. 54 (1H), 7.81 (1H) ppm. Example 150

20

4-(6-$4-[(1-cyanocyclopropyl)carbamoyl]-3-methylphenyl$-8-[(3, trifluoropropyl)amino]imidazo[1,

N

N

N

N

3, 3-

2-a] pyridin-3-yl)-N-cyc lopropyl-2-

methylbenzamide

0

P

+NH

OH

to



15

3, 3-

10 mg (19 ljmol) 4-[3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(3,

N

H

220

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3, 3-

10 mg (19 pmol) 4-[3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(3, trifluoropropyl)amino]imidazo[1,




5. 3

purification

mg (45%)

(2H),

to


6- 0 62

1H NMR (CD30D)

in analogy


example 8 using 1-cyanocyclopropanaminium 5

acid which was

(2H) 0 81 (2H)

1

34 (2H)

1

57 (2H) 2 45 (6H) 2 64

2. 87 (1H), 3.67 (2H), 6. 51 (1H), 7. 39-7.57 (7H), 7.90 (1H) ppm.

Example 151

10


3, 3-

2-a]pyridin-6-yl]-N-[1-


(hydroxymethyl)cyclopropyl]-2-methylbenzamide

N

N N

/

N

9"'

OH

P

~

H

H

3, 3-

10 mg (19 pmol) 4-[3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(3, 15





example 8 using 1-(hydroxymethyl)cyclopropanaminium working up and purification 1H NMR (CD30D)

20

6- 0 63



7.0 mg (59%) of the title compound. (2H) 0 82 (2H) 0 86 0 92 (4H) 2 44 (3H) 2 46 (3H)

2. 56-2. 73 (2H), 2. 88 (1H), 3.63-3.74 (4H), 6. 51 (1H), 7. 39-7.52 (6H), 7. 56 (1H), 7.89 (1H) ppm. Example 152

4-(3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(3, 25


3, 3-

2-a]pyridin-6-yl]-N-[rel-(15, 25)-2-

fluorocyclopropyl]-2-methylbenzamide

221

to

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N

N N

N

0

0 OH N

P

P H

3, 3-

10 mg (19 pmol) 4-[3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(3, trifluoropropyl)amino]imidazo[1,



T/EP2012/055471


to



6- 0 62

in analogy


example 8 using rel-(1S, 2S)-2-fluorocyclopropanaminium

1H NMR (CD30D)

acid which was

(2H) 0 81 (2H)

(3H), 2. 64 (2H), 2. 86 (2H), 3.67 (2H),

05 (1H)

1

1

18 (1H) 2 44 (3H) 2 45

4. 69 (1H), 6. 51 (1H), 7.40 (1H), 7.42 (1H),

7.43-7. 51 (4H), 7. 55 (1H), 7.90 (1H) ppm. 10 Example 153

3, 3-

4-(6-(4-carbamoyl-3-methylphenyl)-8-[(3,

2-a] pyridin-3-yl]-N-cyc lopropyl-2-

trifluoropropyl)amino]imidazo[1, methylbenzamide

N N

N

/

N

OH

P

NH2

15

H

H

10 mg (19 ljmol) 4-[3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(3, trifluoropropyl)amino]imidazo[1,





example 8 using ammonia (0.5M in dioxane) to give after working up and

20

purification

8. 7

mg (83%) of

1H NMR (CD3OD)

the title compound.

6 0 63 (2H) 0 82 (2H) 2 48 (3H) 2 49 (3H) 2 55 2 73 (2H)

2. 88 (1H), 3.68 (2H), 6.52 (1H), 7.41-7.53 (6H), 7.56 (1H), 7.91 (1H) ppm. Example 154 222

to

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4-(6-(4-([rel-(1S, 2S)-2-fluorocyclopropyl]carbamoylj-3-methylphenyl)-8-[(3, 2-a]pyridin-3-yl)-N, 2-dimethylbenzamide


N

N N

3, 3-

/

N

OH H N

H N

phenyl] -8- [(3,3, 3-

10 mg (20 ljmol) 2-methyl-4-[3- [3-methyl-4-(methylcarbamoyl) 5

according to intermediate using


7. 1

1H NMR (CDCl3)

mg (61%) of

6-

1


to example 8


rel-(1S, 2S)-2-fluorocyclopropanaminium

purification

10



the title compound.

04 (1H)

1

27 (1H) 2 52 2 64 (2H) 2 52 (6H) 3 02 3 09 (1H)

3.03 (3H), 3.67 (2H), 4.76 (1H), 5.42 (1H), 5.90 (1H), 6.07 (1H), 6. 32 (1H), 7.33 (1H), 7. 35 (1H), 7. 38-7.47 (3H), 7.50 (1H), 7. 55 (1H), 7.83 (1H) ppm. Example 154a phenyl] -8- [(3,3, 3-

2-methyl-4-[3- [3-methyl-4-(methylcarbamoyl) 15



N

acid

N

N

N

0

OH H N

H N

322 mg (614 pmol) methyl 2-methyl-4-[3-[3-methyl-4-(methylcarbamoyl)phenyl]-8-

2-a] pyridin-6-yl]benzoate which was [(3,3, 3-trifluoropropyl)amino]imidazo[1, prepared according to example 140 were transformed in analogy to intermediate 20

example 8b to give after working up and purification compound.

Example 155

223


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4-(6-(4-([1-(hydroxymethyl)cyclopropyl]carbamoyl

j-3-methylphenyl)-8-[(3,

3, 3-



N N

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N

I

N

OH H N

H N

phenyl] -8- [(3,3, 3-

10 mg (20 pmol) 2-methyl-4-[3- [3-methyl-4-(methylcarbamoyl) 5



7. 5

mg (63%) of

6- 0 87

1H NMR (CD30D)

10

in analogy

to example 8


using 1-(hydroxymethyl)cyclopropanaminium

purification




the title compound.

(4H) 2 43 (3H) 2 46 (3H) 2 58 2 71 (2H) 2 91 (3H)

3.64-3. 71 (4H), 6. 50 (1H), 7. 38-7.45 (3H), 7. 50 (3H), 7. 55 (1H), 7.90 (1H) ppm. Example 156

4-(6-f 4-[(1-cyanocyclopropyl)carbamoyl]-3-methylphenyl$-8-[(3, 2-a]pyridin-3-yl)-N,


3, 3-

2-dimethylbenzamide

N

N

N

+NH

OH H N

H N

CN

15

10 mg (20 ljmol) 2-methyl-4-[3- [3-methyl-4-(methylcarbamoyl) 2-a]pyridin-6-ylfbenzoic



purification

6. 0

mg (53%) of

1H NMR (CD30D)

6-

1


to example 8



20

phenyl] -8- [(3,3, 3-

the title compound.

34 (2H)

1

57 (2H) 2 45 (3H) 2 46 (3H) 2 56 2 72 (2H)

2. 91 (3H), 3.67 (2H), 6.50 (1H), 7.38-7. 52 (6H), 7.56 (1H), 7.91 (1H) ppm. Example 157

224

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2-methyl-N-(1-methylcyclopropyl)-4-(3-[3-methyl-4-(methylcarbamoyl)phenyl]-


2-a] pyridin-6-yl]benzamide

JV

N

N

N

l

0 OH

PNH

H N

H N

phenyl] -8- [(3,3, 3-



5. 2

1H NMR (CDCl3)

10

(3H), (5H),

mg (47%)

6- 0 76




purification


in analogy

to example 8


of the title compound. (2H) 0 87 (2H)

52 (3H) 2 43 2 68 (2H) 2 49 (3H) 2 52

1

3.04 (3H), 3.66 (2H), 5.82 (1H), 5.91 (1H), 6. 10 (1H), 6. 34 (1H), 7. 28-7. 43 7. 50 (1H), 7. 54 (1H), 7.81 (1H) ppm.

Example 158

3, 3-

4-(6-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(3, 15



N N

N

/

N

OH H N

~NH

H N

10 mg (20 ljmol) 2-methyl-4-[3- [3-methyl-4-(methylcarbamoyl) trifluoropropyl)amino]imidazo[1, according to intermediate

20





phenyl] -8- [(3,3, 3-


up and purification

7.4

to example 8 mg (65%)

of


6- 0 63

(2H) 0 89 (2H) 2 44 2 65 (2H) 2 50 (3H) 2 51 (3H) 2 91

3.04 (3H), 3.66 (2H), 5.43 (1H), 5.89-6. 02 7.49 (1H), 7.54 (1H), 7.82 (1H) ppm. (1H),

225

(2H),

6. 32 (1H), 7.27-7. 43 (5H),

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Example 159

3, 3-

4-(6-[4-(ethylcarbamoyl)-3-methylphenyl]-8-[(3, trifluoropropyl)amino]imidazo[1,


N N

N

/

N

OH H N

H N

phenyl] -8- [(3,3, 3-

10 mg (20 ljmol) 2-methyl-4-[3- [3-methyl-4-(methylcarbamoyl) 2-a]pyridin-6-yl/benzoic


10



using ethanamine


7.6

up and purification

to example 8

mg (69%) of

the title


6-

1

26 (3H) 2 49 2 65 (2H) 2 51 (6H) 3 04 (3H) 3 50 (2H) 3 67

5.44 (1H), 5.81 (1H), 5.94 (1H), 6. 34 (1H), 7. 30-7.45 (5H), 7.49 (1H), 7. 55 (1H), 7.83 (1H) ppm. (2H),

15

Example 160

3, 3-

4-(6-(4-carbamoyl-3-methylphenyl)-8-[(3, trifluoropropyl)amino]imidazo[1,


N N

N

/

N

OH

NH2 H N

H N





(0.5M in dioxane) to give after (60%) of the title compound.

using ammonia

226

phenyl] -8- [(3,3, 3-


to example 8


6.3

mg

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1H NMR (CD3OD)

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6 2 46 (3H) 2 48 (3H) 2 55 2 72 (2H) 2 91 (3H) 3 67 (2H)

6.51 (1H), 7.41-7.52 (6H), 7. 56 (1H), 7.91 (1H) ppm. Example 161 5

N-cyclopropyl-4-(8-[(2, 2-difluoroethyl)amino]-6-(3-fluorophenoxy)imidazo[1,

2-


N

0

HN

0

HN

0

To a solution of 174.18 mg (0.3 mmol) tert-butyl f3-[4-(cyclopropylcarbamoyl)-3-

2-a] pyridin-8-ylj(2, 2-

methylphenyl]-6-(3-fluorophenoxy)imidazo[1,

10

difluoroethyl)carbamate

in

the mixture was stirred for After evaporation,

15

1H-NMR

1 h

DCM

were added 3 mL TFA and 200 pL water and

at overnight.

the residue was purified by UPLC MS: RT =

title compound.

480. 5.

1.0 mL

1.18 min;

HPLC

to yield 36

mg

(24%) of the

m/z (ES+) 481.5 [MH+]; required MW =

(300 MHz, DMSO-d6), 6 [ppm]= 0.43-0. 54 (2H), 0.60-0. 70 (2H), 2. 33

3.60-3.81 (3H), 6.32 (1H), 6. 66 (1H), 6.81-6.94 (3H), 7.29-7.40 7.40-7. 50 (2H), 7.63-7.75 (2H), 8.28 (1H).

(3H), 2. 79 (1H), (2H),

Example 161a

tert-butyl f3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(3-

20


HN

0

2-a]pyridin-8-ylj(2, 2-difluoroethyl)carbamate

HN

To a solution of 164.83 mg (0.3 mmol) tert-butyl f6-bromo-3-[4(cyclopropylcarbamoyl)-3-methylphenyl]imidazo[1,

227

2-a] pyridin-8-ylj(2, 2-

WO 2012/136531

PC

difluoroethyl)carbamate

in

4.0 mL dioxane were added 782

mg

T/EP2012/055471

(2. 4 mmol) cesium

carbonate, 11.88 mg (0. 12 mmol) copper(l) chloride and 12.37 mg (0. 12 mmol) and the mixture was stirred for

dimethylglycine

1 h

at 160'C. The solvent was

removed in vaccuo and the residue was used in the next step without further

purification. UPLC MS: RT =

1.37 min;

m/z (ES+) 581.6 [MH+]; required MW = 580. 6.

Example 161b 2-

tert-butyl [6-bromo-3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]imidazo[1,

10

a] pyridin-8-ylf(2, 2-difluoroethyl)carbamate

N

0

HN

To a solution of

3.5 g (6.97 mmol) tert-butyl (6-bromo-3-iodoimidazo[1,

8-yl)(2, 2-difluoroethyl)carbamate

in

100 mL THF were added 2. 29

[4-(cyclopropylcarbamoyl)-3-methylphenyl]boronic

15

acid,

g

2-a]pyridin-

(10.46

0.569 g (0.697 mmol)

Pd(dppf)Clz and 20. 91 mL (20. 91 mmol, 1M aqueous solution) potassium and the mixture was stirred for 2

purification,

2.41

UPLC MS: RT =

g

1.28

h

mmol)

carbonate

at 55'C to give, after working up and

(62. 9%) of the title compound. min; m/z (ES+) 550.46 [MH+]; required MW =

549.4.

1H-NMR

(300 MHz, DMSO-d6), 6 [ppm]= 0.46-0. 55 (2H), 0.62-0. 71 (2H), 1.33 (10H), 2. 37 20

(3H), 2. 76-2. 87 (1H),

(1H),

4. 17 (2H), 7.38-7.45 (2H), 7.48-7. 57 (2H), 7.79 (1H), 8.34

8. 56 (1H).

Example 161c

tert-butyl

(6-bromo-3-iodoimidazo[1, 2-a]pyridin-8-yl)(2, 2-difluoroethyl)carbamate

25

228

WO 2012/136531

PC

5.9 g (15.68

To a solution of

mmol) tert-butyl

yl)(2, 2-difluoroethyl)carbamate working up and purification, UPLC MS: RT =

(6-bromoimidazo[1, 2-a]pyridin-8-

mL DMF were added

1.39 min;

MHz, DMSO-d6), 6 [ppm]=

5.91

(78.41 mmol) 1at 40'C to give, after

17.64

5-dione and the mixture was stirred for 2

iodopyrrolidine-2,

5

80

in

T/EP2012/055471

h

g


g

m/z (ES+) 503. 1 [MH+]; required MW = 502. 1. 1H-NMR (300

1.29 (10H), 4. 12 (2H), 7.45 (1H), 7.72 (1H), 8.43 (1H).

Example 161d

tert-butyl

(6-bromoimidazo[1, 2-a]pyridin-8-yl)(2, 2-difluoroethyl)carbamate

5.39 g (19.52

To a solution of

250 mL THF were added 19.76

a]pyridin-8-amine

in

0.48

DIPEA and a solution

g

(3.9 mmol)

dicarbonate in 50 mL THF and 15

after working

1.20 min;


(1H),

of 29. 82

g

2-

(27 mL, 195.23 mmol) TEA,

(136.66 mmol) di-tert-butyl the mixture was stirred for 48 h at 40'C to give,

up and purification,

UPLC MS: RT =

20

mmol) 6-bromo-N-(2, 2-difluoroethyl)imidazo[1,

7.42

g

g

(94.2%) of the title compound.

m/z (ES+) 377.2 [MH+]; required MW = 376.2. 1H-NMR (300

1.22-1.40 (10H), 4. 14 (2H), 7. 31 (1H), 7. 57 (1H), 7. 94

8.86 (1H).

Example 161e

6-bromo-N-(2, 2-difluoroethyl)imidazo[1,


NH~

To a solution of DCM

25

was added

8.00 g (100 mmol)

freshly prepared difluoroacetaldehyde

5.30 g (25 mmol) 6-bromoimidazo[1, 2-a]pyridin-8-amine,

purification,

4. 0

g

h

26.49

(18.56 mL, 250 mmol) at rt to give, after working up and

(125 mmol) sodium triacetoxy borohydride and the mixture was stirred for 72

and 28. 5 g

in 560 mL


229

g

TFA

WO 2012/136531

UPLC MS: RT =

PC

0.71

min; m/z (ES+) 277. 1 [MH+]; required MW =


T/EP2012/055471

276. 1. 1H-NMR (300

3.69 (2H), 6. 36 (1H), 6. 54 (1H), 7.41 (1H), 7. 77 (1H),

8. 10 (1H). 5

Example 161f

difluoroacetaldehyde

To a solution of 13.96 g (110 mmol) oxalyl chloride in 280 mL

DCM

was added

dropwise at -78'C 52. 28 mL (220 mmol) DMSO. After stirring for 2 min,

10

mmol) 2, 2-difluoroethanol

stirred for

1 h

in

283 mL

at -78 C. 30. 35

g

DCM

8.21

g

(100

were slowly added and the mixture was

(300 mmol) TEA were added and the mixture was

left to come to rt over 90 min to yield the title compound in solution, which was used without further work-up in the next step.

15

Example 162 N-cyc lopropyl-4-(8-[(2, 2-difluoroethyl)amino]-6-(4-

methoxyphenoxy)imidazo[1,

HN


0

HN

0

178 mg (300 pmol) tert-butyl $3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(420


2-a]pyridin-8-yl](2, 2-difluoroethyl)carbamate



which in analogy

to example 161 using TFA to give after working up and purification 6. 3 mg (3%) of the title compound. UPLC MS: RT =

25

1.11


492. 5.

1H-NMR

(300

0.44-0. 54 (2H), 0.61-0.69 (2H), 2. 30 (3H), 2. 79 (1H), 3.65 (3H), 3.67-3.71 (3H), 6.49 (1H), 6.52-6. 59 (1H), 6.75-6. 80 (2H), 6.87-6. 94 (2H), 7.00-7. 06 (2H), 7. 32-7. 42 (2H), 7.74 (1H), 8. 29 (1H)


230

WO 2012/136531

PC

T/EP2012/055471

Example 162a

tert-butyl f3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(42-a]pyridin-8-ylj(2, 2-difluoroethyl)carbamate


HN

0 HN

0



prepared according to intermediate example 161a using 4-methoxyphenol

10

compound


1.34 min;

in analogy

to

to give after evaporation the crude title

which was used without purification

UPLC MS: RT =

which was

in

the next step.

m/z (ES+) 593.6 [MH+]; required MW = 592. 6.

Example 163 N-cyc lopropyl-4-(8-[(2, 2-difluoroethyl)amino]-6-(2,

15


HN

3-


0

~N

0

179 mg (300 pmol) tert-butyl $3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(2, difluorophenoxy)imidazo[1,

2-a]pyridin-8-yl$(2, 2-difluoroethyl)carbamate


20


example 161 using TFA to give after working up and purification

the title compound. 231

3-

which was

in analogy

to

17.9 mg (11 %) of

WO 2012/136531

UPLC MS: RT =

PC

1.25


T/EP2012/055471

498. 5.

1H-NMR

(300

0.44-0. 54 (2H), 0.60-0. 70 (2H), 2. 33 (3H), 2. 79 (1H), 3.63-3.81 (3H), 6. 39-6.44 (1H), 6.67-6. 74 (1H), 6. 93 (1H), 7. 05-7.21 (2H), 7. 32-7. 39 (1H), 7.40-7.47 (2H), 7.71 (2H), 8.29 (1H)


Example 163a

tert-butyl (3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(2, difluorophenoxy)imidazo[1,

3-

2-a] pyridin-8-yl$(2, 2-difluoroethyl)carbamate

F

HN

10

0 HN





compound


UPLC MS: RT =

1.37 min;

in

m/z (ES+) 599.6 [MH+]; required MW = 598.6.

N-cyc lopropyl-4-(8-[(2, 2-difluoroethyl)amino]-6-(5-fluoro-2-

HN

0

in analogy

the next step.

Example 164


which was


example 161a using 2, 3-difluorophenol

15

0


I-IN

0

20

232

to

WO 2012/136531

PC

T/EP2012/055471

179 mg (300 pmol) tert-butyl $3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(5fluoro-2-methylphenoxy)imidazo[1, which was prepared




analogy to example 161 using TFA to give after working up and purification 5

mg

in

19.6


UPLC MS: RT =

1.30 min;


0.44-0. 52 (2H), 0.60-0. 69 (2H), 2. 20 (3H), 2. 31 (3H), 2.79 (1H), 3.71 (3H), 6. 30-6.35 (1H), 6.65 (1H), 6. 74 (1H), 6.84 (1H), 7.23-7. 31 (1H), 7.32-7. 37 (1H), 7. 37-7.44 (2H), 7. 50 (1H), 7. 67 (1H), 8.28 (1H).


10 Example 164a

tert-butyl [3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(5-fluoro-2-

2-a] pyridin-8-ylf(2, 2-difluoroethyl)carbamate


HN

15

0

HN





example 161a using 5-fluoro-2-methylphenol

UPLC MS: RT =

1.42

in

the next step.

min; m/z (ES+) 595.6 [MH+]; required MW =



5-


233

in analogy

to give after evaporation the crude

title compound which was used without purification 20

which was

594. 6.

to

WO 2012/136531

HN

PC

0

T/EP2012/055471

0

HN

179 mg (300 pmol) tert-butyl (3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(5fluoro-2-methylphenoxy)imidazo[1, which was prepared 5




analogy to example 161 using TFA to give after working up and purification mg

in

11.6

(7 %) of the title compound.

UPLC MS: RT =

1.24


498. 5.

1H-NMR

(300

0.44-0. 53 (2H), 0.60-0. 69 (2H), 2. 33 (3H), 2. 79 (1H), 3.63-3.81 (3H), 6.40 (1H), 6.66-6. 75 (1H), 6. 91-7.07 (2H), 7. 33-7.48 (4H), 7.67-7. 76 (2H), 8.29 (1H).


10

Example 165a

tert-butyl f3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(5-fluoro-2methylphenoxy)imidazo[1,

HN

2-a] pyridin-8-yl$(2, 2-difluoroethyl)carbamate

0

HN

0

15





example 161a using 2, 5-difluorophenol

20

compound

1.36 min;

in analogy



UPLC MS: RT =

which was

in

the next step.

m/z (ES+) 599.6 [MH+]; required MW = 598.6.

234

to

WO 2012/136531

PC

T/EP2012/055471



HN

5

5-


0

HN

0

179 mg (300 pmol) tert-butyl $3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(32-a]pyridin-8-yl](2, 2-difluoroethyl)carbamate

fluoro-2-methylphenoxy)imidazo[1, which was prepared



analogy to example 161 using TFA to give after working up and purification mg

10

in

44. 7


UPLC MS: RT =

1.31


494. 5.

1H-NMR

(300

0.43-0. 53 (2H), 0.65 (2H), 2. 15 (3H), 2. 31 (3H), 2. 79 (1H), 3.72 (3H), 6. 30-6.37 (1H), 6.64 (1H), 6. 74 (1H), 6.87-6. 97 (1H), 7. 14 (1H), 7.30-7.43 (3H), 7.48 (1H), 7.66 (1H), 8.28 (1H).


15

Example 166a

tert-butyl [3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(3-fluoro-2methylphenoxy)imidazo[1,

F

~N

0

2-a] pyridin-8-ylf(2, 2-difluoroethyl)carbamate

N

0

HN

0

165 mg (300 pmol) tert-butyl $6-bromo-3-[4-(cyclopropylcarbamoyl)-320





235


to

WO 2012/136531

PC


example 161a using 3-fluoro-2-methylphenol

title compound which was used without purification

1.43

UPLC MS: RT =

5

T/EP2012/055471

in

the next step.


594. 6.

Example 167 N-cyc lopropyl-4-(8-[(2, 2-difluoroethyl)amino]-6-(3-fluoro-4-


N


0 N

N

HN

0

HN

0

179 mg (300 ljmol) N-cyclopropyl-4-[8-[(2, 2-difluoroethyl)amino]-6-(3-fluoro-410


2-a]pyridin-3-ylf-2-methylbenzamide


which was



in analogy

10.8

mg

to

(4 %) of

the title compound. UPLC MS: RT =

15

1.22


1H-NMR

(300

0.45-0. 53 (2H), 0.62-0. 69 (2H), 2. 32 (3H), 2. 76-2. 83 (1H), 3.66 (3H), 3.68-3.74 (3H), 6. 36 (1H), 6.60-6. 63 (1H), 6.85-6. 91 (1H), 7.03-7. 14 (2H), 7. 33-7.39 (1H), 7.40-7. 45 (2H), 7.54 (1H), 7.72 (1H), 8.28 (1H).


Example 167a

20

510.5.

N-cyclopropyl-4-[8- [(2, 2-difluoroethyl)amino]-6-(3-fluoro-4-


~N

0

2-a] pyridin-3-yl]-2-methylbenzamide

HN

0

236

WO 2012/136531

PC

T/EP2012/055471





example 161a using 3-fluoro-4-methoxyphenol 5

1.34 min;

to

in analogy


title compound which was used without purification UPLC MS: RT =

which was

in

the next step.


610.6.

Example 168

tert-butyl (3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(210

hydroxybenzoyl)imidazo[1,


N N

N N

OH

0

HN

0

HN

0

179 mg (300 ljmol) tert-butyl $3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(2hydroxybenzoyl)imidazo[1,



15



7.2

which was

to

in analogy

mg

(4%) of


1.23


490. 5.

(300

0.43-0. 54 (2H), 0. 59-0.69 (2H), 2. 36 (3H), 2. 74-2. 86 (1H), 3.80 (3H), 6.72 (1H), 6.83 (1H), 7.24 (2H), 7.29 (1H), 7.40-7. 48 (3H), 7.50-7. 56 (2H), 7.78 (1H), 8. 34 (1H), 8. 51 (1H)


20

1H-NMR

Example 168a

tert-butyl f3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(2hydroxybenzoyl)imidazo[1,

2-a] pyridin-8-ylj(2, 2-difluoroethyl)carbamate

237

WO 2012/136531

PC

T/EP2012/055471

N N

OH

0

HN

0

HN

To a suspension

of 240 mg (437 pmol) tert-butyl [6-bromo-3-[42-a] pyridin-8-ylj(2, 2-

(cyclopropylcarbamoyl)-3-methylphenyl]imidazo[1,

difluoroethyl)carbamate 5

which was prepared


example

161b in 10 mL toluene were added 3 mg (7 pmol) butyldi-1-adamantylphosphine, mg

(4. 37 pmol) palladium(ll)

acid and 70 pL (437 pmol)

1

acetate, 90 mg (655 ljmol) 2-hydroxyphenylboronic

N, N, N',

N'-tetramethylenediamine

and the mixture was

heated in an autoclave at 100'C at 12 bar carbon monoxide pressure for 22h. The oranic solvent was removed in vaccuo, dissolved in ethyl acetate, washed with 1N

10

NaOH and

water, dried and evaporated to yield 190 mg (73%) of the crude title

compound

which was used in the next step without further purification.

UPLC MS: RT =

1.34 min;


610.6.

1H-NMR

(300

0.45-0. 54 (2H), 0.61-0.69 (2H), 1.29-1.43 (9H), 2. 37 (3H), 2. 80 (1H), 4. 14-4. 30 (2H), 7.23-7. 31 (3H), 7.45 (3H), 7. 59 (1H), 7. 74 (1H), 7. 93 (1H), 8. 36 (1H), 9.07 (1H)


15

Example 169 N-cyc lopropyl-4-(6-(3-fluorophenoxy)-8-[(2-meth

oxyethyl)amino]imidazo[1,

2-


HN

0

HN

0

20

163.04

mg

(0.284 mmol) tert-butyl [3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-

6-(3-fluorophenoxy)imidazo[1,

2-a]pyridin-8-ylj(2-methoxyethyl)carbamate

238

which

WO 2012/136531

PC


T/EP2012/055471


to example 161 using TFA to give after working up and purification

14.7

in analogy mg

(10 %)

of the title compound. UPLC MS: RT =

1.12 min;

m/z (ES+) 475. 5 [MH+]; required MW = 474. 5.

Example 169a

tert-butyl f3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(3fluorophenoxy)imidazo[1,

~N

10

163.04

mg

2-a] pyridin-8-yl](2-methoxyethyl)carbamate

0

(0.3 mmol) tert-butyl I6-bromo-3-[4-(cyclopropylcarbamoyl)-3-



prepared according to intermediate example 161a using 3-fluorophenol compound

15

0

HN


1.22

in analogy

to



UPLC MS: RT =

which was

in

the next step.

min; m/z (ES+) 575. 7 [MH+]; required MW = 574. 7.

Example 169b

tert-butyl f6-bromo-3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]imidazo[1,

2-

a] pyridin-8-yl](2-methoxyethyl)carbamate

N

0

HN

20

4.76 g (9.59 mmol) tert-butyl (6-bromo-3-iodoimidazo[1, 2-a]pyridin-8-yl)(2which was prepared according to intermediate example methoxyethyl)carbamate 239

WO 2012/136531

PC

169c were transformed

in analogy

T/EP2012/055471

to example 161b using [4acid to give, after working up and

(cyclopropylcarbamoyl)-3-methylphenyl]boronic

3.96 g (73.7 /o) of the title compound. RT = 1.17 min; m/z (ES+) 544. 5 [MH+]; required

purification, UPLC MS:

MW =

543. 5.

1H-NMR

(300

0.46-0. 54 (2H), 0.62-0. 71 (2H), 1.31 (9H), 2. 37 (3H), 2.82 (1H), 3. 15 (3H), 3.42 (2H), 3.85 (2H), 7. 34 (1H), 7. 39-7.44 (1H), 7.49-7. 55 (2H), 7.76 (1H), 8.33 (1H), 8.52 (1H).


Example 169c

10

tert-butyl

9.61

g

(6-bromo-3-iodoimidazo[1, 2-a]pyridin-8-yl)(2-methoxyethyl)carbamate

(25. 96 mmol) tert-butyl (6-bromoimidazo[1, 2-a]pyridin-8-yl)(2-

methoxyethyl)carbamate

169d were transformed 15



example

to example 161c using 1-iodopyrrolidine-2, 5-

dione to give, after working up and purification,

9.62

g

(74.7 /) of the title

compound. UPLC MS: RT =

1.34 min;



1.27 (9H), 3. 11 (3H), 3. 39 (2H), 3.80 (2H), 7. 38 (1H),

7.70 (1H), 8.40 (1H). 20 Example 169d

tert-butyl

(6-bromoimidazo[1, 2-a]pyridin-8-yl)(2-methoxyethyl)carbamate

7.3 g (27. 02 mmol) 6-bromo-N-(2-methoxyethyl)imidazo[1, 25

which was prepared


analogy to example 161d using di-tert-butyl and purification,

9.62

g

example 169e were transformed

in

dicarbonate to give, after working up

(90.9 /) of the title compound. 240

2-a]pyridin-8-amine

WO 2012/136531

UPLC MS: RT =

PC

1.13 min;

T/EP2012/055471

m/z (ES+) 371.2 [MH+]; required MW = 370.2. 1H-NMR (300


1.27 (9H), 3. 12 (3H), 3. 39 (2H), 3.82 (2H), 7. 24 (1H),

7.55 (1H), 7.91 (1H), 8.81 (1H). 5

Example 169e

6-bromo-N-(2-methoxyethyl)imidazo[1,


NH2 N

Ng~

8.2

g

(38.72 mmol) 6-bromoimidazo[1, 2-a]pyridin-8-amine

analogy to example 161e using methoxyacetaldehyde

10

g

(72. 2

%)

in

which was prepared

example 169f to give, after working up and purification,


7.55

were transformed


MHz,

0.69 min; m/z (ES+) 271. 1 [MH+]; required MW = 270. 1. 1H-NMR (300 DMSO-d6), 6 [ppm]= 3.25 (3H), 3.32-3. 38 (2H), 3.46-3. 56 (2H), 6.08 (1H), 6. 18

(1H),

7. 38 (1H), 7.75 (1H), 8.03 (1H).

UPLC MS: RT =

15 Example 169f

~

methoxyacetaldehyde

HO~ 0 w 15.2 20

g

0~~

0

(200 mmol) 2-methoxyethanol

using 2-methoxyethanol

were transformed

to give the title compound

in analogy

in solution,

which was used

without further work-up in the next step.

Example 170 N-cyc lopropyl-4-(8-[(2, 2-difluoroethyl)amino]-6-(4-

25



241

to example 161f

WO 2012/136531

PC

T/EP2012/055471

D.&; HN

0

0

HN

163 mg (286 pmol) tert-butyl $3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(2methylphenoxy)imidazo[1,

2-a]pyridin-8-ylf(2-methoxyethyl)carbamate





20. 2

mg

to

(15%) of


1.11


470. 6.

1H-NMR

(300

0.44-0. 52 (2H), 0. 59-0.69 (2H), 2. 21 (3H), 2. 28 (3H), 2.79 (1H), 3.25 (3H), 3.32-3.39 (2H), 3.50-3.58 (2H), 6.07-6. 16 (2H), 6.92 (1H), 6.987.06 (1H), 7. 13 (1H), 7.23-7. 30 (2H), 7. 30-7. 38 (3H), 7. 58 (1H), 8.25 (1H)


10

Example 170a

tert-butyl f3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(2methylphenoxy)imidazo[1,

HN

2-a] pyridin-8-ylf(2-methoxyethyl)carbamate

0

HN

0

15


20

2-a]pyridin-8-yl](2-methoxyethyl)carbamate

which was



example 161a using 2-methylphenol


compound


UPLC MS: RT =

1.22

in

the next step.


242

in analogy

570. 7.

to

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PC

T/EP2012/055471

Example 171 N-cyc lopropyl-4-(6-(3, 4-difluorophenoxy)-8-[(2-

methoxyethyl)amino]imidazo[1,

HN


0

HN

0






10

8. 5

4-


mg

to

(6 %) of


1.14 min;


0.44-0. 53 (2H), 0.60-0. 70 (2H), 2. 33 (3H), 2. 80 (1H), 3.24 (3H), 3.32-3.39 (2H), 3.48-3. 55 (2H), 6.07 (1H), 6. 15-6.24 (1H), 6.84-6. 92 (1H), 7.21 (1H), 7.31-7.40 (2H), 7.40-7. 47 (2H), 7. 57-7. 66 (2H), 8. 26 (1H)


15 Example 171a

tert-butyl [3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(3, difluorophenoxy)imidazo[1,

HN

20

0

4-


HN

0





243


to

WO 2012/136531

PC


example 161a using 3, 4-difluorophenol compound


UPLC MS: RT =

5

1.24

T/EP2012/055471

in

the next step.


592. 7.



HN


0

HN

0

163 mg (277 pmol) tert-butyl $3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(5-

10


fluoro-2-methylphenoxy)imidazo[1, which was prepared



analogy to example 161 using TFA to give after working up and purification

in

16.9 mg

(12 %) of the title compound. UPLC MS: RT =

15

1.15 min;


0.46-0. 52 (2H), 0.61-0.68 (2H), 2. 20 (3H), 2. 31 (3H), 2.79 (1H), 3.24 (3H), 3.36 (2H), 3.48-3. 56 (2H), 6. 08 (1H), 6. 17 (1H), 6.75 (1H), 6. 796.88 (1H), 7.27 (1H), 7.33-7.42 (3H), 7.45 (1H), 7.60 (1H), 8.26 (1H).


Example 172a

20

tert-butyl [3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(5-fluoro-2methylphenoxy)imidazo[1,

HN

2-a] pyridin-8-ylf(2-methoxyethyl)carbamate

0 ~N

0

244

WO 2012/136531

PC

T/EP2012/055471





example 161a using 5-fluoro-2-methylphenol 5

1.26

in analogy

to


title compound which was used without purification UPLC MS: RT =

which was

in

the next step.


588. 7.


10



HN

0

HN

0

3-


2-a]pyridin-8-yl$(2-methoxyethyl)carbamate


15



10.6


mg

(7.5

%)

to

of


1.14 min;


0.45-0. 52 (2H), 0.61-0.69 (2H), 2. 33 (3H), 2. 79 (1H), 3.24 (3H), 3.36 (2H), 3.48-3. 55 (2H), 6. 18 (1H), 6. 24 (1H), 6.95 (1H), 7.06-7. 20 (2H), 7.32-7. 38 (1H), 7. 39-7.45 (2H), 7.63-7.68 (2H), 8. 27 (1H)


20

Example 173a

tert-butyl [3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(2, difluorophenoxy)imidazo[1,

3-

2-a] pyridin-8-yl$(2-methoxyethyl)carbamate

245

WO 2012/136531

PC

0

HN

T/EP2012/055471

0

HN





example 161a using 2, 3-difluorophenol UPLC MS: RT =

1.24

in analogy

to



compound

which was

in

the next step.


592. 7.

Example 174

10

N-cyclopropyl-4-(6-(5-fluoro-2-hydroxybenzoyl)-8-[(22-a]pyridin-3-yl]-2-methylbenzamide


N

HN

0

260 mg (431 pmol) tert-butyl $3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(5fluoro-2-hydroxybenzoyl)imidazo[1,

15

which was prepared




analogy to example 161 using TFA to give after working up and purification

in

184 mg

(85 %) of the title compound. UPLC MS: RT =

1.18 min;

m/z (ES+) 503.6 [MH+]; required MW = 502. 6. 1H-NMR (300

0.46-0. 53 (2H), 0.61-0.69 (2H), 2. 36 (3H), 2. 80 (1H), 3.26-3. 29 (3H), 3.42-3. 50 (2H), 3.56-3.63 (2H), 6. 23 (1H), 6. 62-6. 67 (1H), 7.23-7. 33 (3H), 7.41-7.47 (1H), 7.48-7. 53 (2H), 7.73 (1H), 8.32 (1H), 8.47 (1H)


20

246

WO 2012/136531

PC

T/EP2012/055471

Example 174a

tert-butyl f3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-6-(5-fluoro-2hydroxybenzoyl)imidazo[1,

~N

5

2-a] pyridin-8-ylj(2-methoxyethyl)carbamate

0

0

HN

300 mg (552 ljmol) tert-butyl $6-bromo-3-[4-(cyclopropylcarbamoyl)-3methylphenyl]imidazo[1,



which was


example 168a using (5-fluoro-2-hydroxyphenyl)boronic

in analogy

to



10

UPLC MS: RT =

1.28


602. 7.

Example 175 N-cyc lopropyl-4-(6-(5-fluoro-2-hydroxyphenoxy)-8-[(3,


trifluoropropyl)amino]imidazo[1, F

F

F

3, 3-

F

NH

NH N

N

0

0 OH

F HN

0

0

HN

15

17 mg (31 ljmol) N-cyclopropyl-4-[6-(5-fluoro-2-methoxyphenoxy)-8-[(3, trifluoropropyl)amino]imidazo[1,





example 129 using boron tribromide to give after working up and purification

20

mg

to

1.7


UPLC MS: RT =

1.08 min;

m/z (ES+) 529. 5 [MH+]; required MW = 528. 5. 5. 1H-NMR

(400 MHz, DMSO-d6), Shift [ppm]= 0.46-0. 52 (2H), 0.62-0. 68 (2H), 2. 29 (3H), 2. 57247

WO 2012/136531

PC

T/EP2012/055471

2. 69 (2H), 2.79 (1H), 3.47 (2H), 6. 11 (1H), 6.47-6. 53 (1H), 6.77-6. 85 (1H), 6.876.95 (2H), 7.29-7. 38 (3H), 7. 55-7. 63 (1H), 8. 27 (1H), 9.50 (1H)

5

Example 175a

N-cyclopropyl-4-[6-(5-fluoro-2-methoxyphenoxy)-8trifluoropropyl)amino]

[(3,3, 3-

imidazo[1, 2-a] pyridin-3-yl$-2-methylbenzamide

FQ

NH N N

0

Br

0

HN

0

0

HN

100 mg (208 pmol) 4-(6-bromo-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 10

a]pyridin-3-yl]-N-cyclopropyl-2-methylbenzamide

intermediate


fluoro-2-methoxyphenol


was used without further purification

15

I


up

the crude title compound which

the next step.

N-cyc lopropyl-4-(6-(3-fluoro-2-hydroxyphenoxy)-8-[(3,

NH N

N

0

Br HO

HN

0

3, 3-


NH

HN

0

248

according to

to example 6-1 using 5-

Example 176


2-

WO 2012/136531

T/EP2012/055471

PC

N-cyclop ropyl-4-[6- (3- fluoro-2- hydroxyp hen oxy) -8- [(3,3, 3-

2-a]pyridin-3-ylf-2-methylbenzamide

trifluoropropyl)amino]imidazo[1, in analogy

to give after

to example 175 and 175a using 3-fluoro-2-methoxyphenol

2. 3

working up and purification 5

was prepared

UPLC MS: RT =

1.08 min;

mg


m/z (ES+) 529. 5 [MH+]; required MW = 528. 5. 5. 1H-NMR

(400 MHz, DMSO-d6), Shift [ppm]= 0.45-0. 52 (2H), 0.61-0.69 (2H), 2. 28 (3H), 2. 57-

2. 69 (2H), 2.79 (1H), 3.47 (2H), 6. 11 (1H), 6.42-6. 54 (1H), 6.70-6. 86 (1H), 6.866.93 (2H), 7.29-7. 38 (3H), 7. 57-7. 61 (1H), 8. 27 (1H), 9.50 (1H) 10

Example 177 N-cyc lopropyl-4-(6-[(5-fluoropyridin-3-yl)oxy]-8-[(3,


trifluoropropyl)amino]imidazo[1, F

3, 3-

F NH

NH

N

N

0

Br

F

~0

0

HN

2-

96 mg (200 ljmol) 4-[6-bromo-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 15

a]pyridin-3-yl(-N-cyclopropyl-2-methylbenzamide

intermediate


fluoropyridin-3-ol



according to


up and purification


compound. UPLC MS: RT =

20

1.13 min;


513.5. 5.

1H-NMR

(300 MHz, DMSO-d6), Shift [ppm]= 0.49 (2H), 0.65 (2H), 2. 33 (3H), 2. 56-2. 68 (2H),

2. 79 (1H), 3.42-3. 51 (2H), 6. 16 (1H), 6. 59 (1H), 7.32-7. 39 (1H), 7.40-7. 55 (3H), 7.65 (1H), 7.74 (1H), 8.23-8. 32 (3H) Example 178 25

N-cyclopropyl-4-(6-[(5-fluoro-6-methoxypyridin-3-yl)oxy]-8-[(3, trifluoropropyl)amino]imidazo[1,

3, 3-


249

WO 2012/136531

PC

T/EP2012/055471

FQ

FQ

NH

NH

N

N

0

Br

&N

F

0

0

HN

~0

HN

96 mg (200 ljmol) 4-(6-bromo-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, a]pyridin-3-yl]-N-cyclopropyl-2-methylbenzamide


intermediate 5

which was prepared

fluoro-6-methoxypyridin-3-ol

in analogy


2-

according to


up and purification

15 mg (15 %)


1.21

UPLC MS: RT =


543. 5. 5.

1H-NMR

(300 MHz, DMSO-d6), Shift [ppm]= 0.44-0. 53 (2H), 0.60-0. 69 (2H), 2. 32 (3H), 2. 56-

10

2. 71 (2H), 2.79 (1H), 3.45 (2H), 3.88 (3H), 6. 12 (1H), 6.57 (1H), 7.32-7. 38 (1H), 7.39-7.46 (2H), 7. 56 (1H), 7.62 (1H), 7.70 (1H), 7.87 (1H), 8.29 (1H)

compositions of the compounds

Pharmaceutical

also relates to pharmaceutical

This invention

15

compounds

effect

by administration

patient, for the purpose of this invention,

need of treatment invention

20

compositions

containing

one or more

of the present invention. These compositions can be utilised to achieve

the desired pharmacological A

of the invention

pharmaceutical

including

compositions

that

are

acceptable carrier and a pharmaceutically

or salt

compound,

is a mammal,

in need

thereof.

a human,

in

for the particular condition or disease. Therefore, the present

includes

pharmaceutically

to a patient

thereof,

of the

present

invention.

comprised

of a

effective amount of a A

pharmaceutically

acceptable carrier is preferably a carrier that is relatively non-toxic and innocuous

to a patient ingredient 25

at concentrations

consistent

so that any side effects ascribable

beneficial effects of the active ingredient. compound

with

is preferably

A

effective activity of the active

to the carrier do not vitiate the

pharmaceutically

effective amount of

that amount which produces a result or exerts an influence 250

WO 2012/136531

on the particular

PC

condition being treated. The compounds

art using any effective conventional

5

release

timed

and

ophthalmically,

optically, sublingually,

solutions,

10

In

another embodiment,

troches, lozenges,

of pharmaceutical

melts, powders,

according to methods

compositions.

The solid

and inert fillers such

lubricants,

and corn starch.

the compounds

of this invention

may be tableted

tablet bases such as lactose, sucrose and cornstarch

conventional

with binders such as acacia, corn starch or gelatine,

disintegrating

with

in combination

agents intended

to assist the break-up and dissolution of the tablet following administration

such as

potato starch, alginic acid, corn starch, and guar gum, gum tragacanth,

acacia,

and to prevent

the

of tablet material to the surfaces of the tablet dies and punches,

for

intended

lubricants adhesion

to improve the flow of tablet granulation

example talc, stearic acid, or magnesium,

agents,

them

more acceptable

to the patient. Suitable excipients for use

dosage forms include dicalcium phosphate

without

ethanol,

the addition

agent or emulsifying

to otherwise

oil of wintergreen,

or cherry

to enhance the aesthetic qualities of the tablets and make

intended

for example,

calcium or zinc stearate, dyes, colouring

agents such as peppermint,

and flavouring

flavouring,

25

into solid or liquid

can be formulated

for example, surfactants,

as lactose, sucrose, calcium phosphate,

20

nasally,

unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled

gelatine type containing,

15

slow

and the like.

and may be prepared

to the art for the manufacture

known

immediate,

topically,

parenterally,

rectally, vaginally,

pills, tablets,

or emulsions,

suspensions,

orally,

the compounds

such as capsules,

preparations

dosage unit forms, including

preparations,

For oral administration,


carriers well known in the

with pharmaceutically-acceptable

can be administered

T/EP2012/055471

benzyl

in oral liquid

and diluents such as water and alcohols,

alcohol, and polyethylene

of a pharmaceutically

alcohols,

acceptable

either with or

surfactant,

suspending

agent. Various other materials may be present as coatings or

modify the physical

form of the dosage unit.

For instance tablets,

pills or capsules may be coated with shellac, sugar or both.

30

are suitable for the preparation

Dispersible

powders

suspension.

They provide the active ingredient

wetting

agent,

and granules

a suspending

agent

and

251

in admixture

one or more

of an aqueous

with a dispersing

preservatives.

or

Suitable

WO 2012/136531

or wetting

dispersing

already

PC

and

excipients,

by those

for example those sweetening,

and colouring agents described above, may also be present.

The pharmaceutical

oil-in-water

The oily phase

emulsions.

naturally

occurring

occurring

phosphatides

gums

may also be in the form of

of this invention

compositions

or a mixture of vegetable

paraffin

be a vegetable

may

oil such as liquid

agents may be (1)

oils. Suitable emulsifying

acacia and gum tragacanth,

such as gum

(2) naturally

(3) esters or partial esters

such as soy bean and lecithin,

for example, sorbitan monooleate,

derived form fatty acids and hexitol anhydrides,

10

are exemplified

agents

suspending

above. Additional

mentioned

flavouring

5

agents

T/EP2012/055471

(4) condensation

products of said partial esters with ethylene oxide, for example,

polyoxyethylene

sorbitan monooleate.

may also contain sweetening

agents.

and flavouring Oily

The emulsions

suspensions

may

be formulated

by suspending

the active ingredient

in a

vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, 15

or in a mineral thickening

agent such as, for example,

The suspensions

agents;

flavouring

20

beeswax,

and

or more

one

for example, ethyl or

one or more

agents;

colouring

sweetening

a

or cetyl alcohol.

hard paraffin,

may also contain one or more preservatives,

p-hydroxybenzoate;

n-propyl

may contain

The oily suspensions

paraffin.

oil such as liquid

agents

one

or more

as sucrose

such

or

saccharin. Syrups and elixirs may be formulated

glycerol, propylene

a demulcent,

with sweetening

agents such as, for example,

glycol, sorbitol or sucrose. Such formulations

and preservative,

may also contain

such as methyl and propyl parabens

and flavouring

and colouring agents.

25

The compounds

of this invention

subcutaneously,

intravenously,

interperitoneally, physiologically

30

as

may also be administered

intraocularly,

injectable

dosages

parenterally,

or

intramuscularly,

intrasynovially,

of the

that is,

compound

in

preferably

a

carrier which can be a

acceptable diluent with a pharmaceutical

sterile liquid or mixture

of liquids such as water, saline, aqueous dextrose and

related

an alcohol

sugar

solutions,

alcohol, glycols such as propylene such

such as ethanol,

isopropanol,

glycol or polyethylene

as 2, 2-dimethyl-1, 1-dioxolane-4-methanol,

252

ethers

or hexadecyl

glycol, glycerol such

ketals

as poly(ethylene

WO 2012/136531

PC

T/EP2012/055471

glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride,

or an

acetylated fatty acid glyceride, with or without the addition of a pharmaceutically

acceptable surfactant carbomers,

pectin, 5

methycellulose,

of oils which

are those of petroleum,

example,

peanut

petrolatum

myristate.

and

detergents,

for example

olefin

Suitable

for

origin,

oil, corn oil, olive oil,

sulfonates,

dimethyl

detergents

alkyl

acetates; anionic detergents, for example,

alkyl,

ether,

olefin,

non-ionic detergents,

alkanolamides,

and

alkyl-beta-aminopropionates,

alkyl, aryl, and

and

for example, fatty amine oxides, fatty acid or

poly(oxyethylene-oxypropylene)s

copolymers;

pyridinium

sulfates,

monoglyceride

and

cationic

include

halides,

ammonium

dialkyl

sulfosuccinates;

oxide

fatty acid alkali metal,

soaps include

salts and suitable

triethanolamine

ammonium,

propylene

and

and 2-alkylimidazoline

for

detergents,

amphoteric

oxide

ethylene

quarternary

or

example,

salts,

ammonium

as well as mixtures.

compositions of this invention

The parenteral

will typically contain from about

to about 25% by weight of the active ingredient buffers

may

irritation 25

or synthetic

vegetable,

of this

formulations

isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl

halides, and alkylamine

20

animal,

the parenteral

adjuvants.

oil. Suitable fatty acids include oleic acid, stearic acid,

and mineral

oleate and isopropyl

15

in

oil, sesame oil, cottonseed

oil, soybean

or

hydroxypropylmethylcellulose,

can be used

invention

agent such as

suspending

agent and other pharmaceutical

or emulsifying

carboxymethylcellulose, Illustrative

10

such as a soap or a detergent,

also be used

advantageously.

at the site of injection,

surfactant having a hydrophile-lipophile

such

In

in solution.

Preservatives

order to minimise

compositions

may contain

0. 5% and

or eliminate a non-ionic

balance (HLB) preferably of from about 12

to about 17. The quantity of surfactant in such formulation

preferably

ranges from

about 5% to about 15% by weight. The surfactant can be a single component having

the above

HLB

or can be a mixture of two or more components

having the desired

HLB.

30

Illustrative

polyethylene

of surfactants

used

in

parenteral

formulations

sorbitan fatty acid esters, for example,

253

are the class of

sorbitan monooleate

and the

WO 2012/136531

high molecular

compositions

may be in the form of sterile injectable aqueous

may be formulated

Such suspensions

suitable

using

or wetting

dispersing

and gum

acacia;

oxide

ethylene

heptadeca-ethyleneoxycetanol,

ester derived

partial

sorbitol monooleate,

ester

derived

polyoxyethylene

a

stearate, a condensation

acid

product of ethylene

product

example,

oxide with a

such as polyoxyethylene

product of an ethylene oxide with a partial and

a

hexitol

for

anhydride,

example

sorbitan monooleate. may also be a sterile

preparation

in a non-toxic

parenterally

oils are conventionally

injectable

solution

or

acceptable diluent or solvent. Diluents and

are, for example, water, Ringer's solution, isotonic

chloride solutions and isotonic glucose solutions.

In

employed as solvents or suspending

any bland, fixed oil may be employed

including

addition,

sterile fixed

media. For this purpose,

synthetic mono- or diglycerides.

fatty acids such as oleic acid can be used

addition,

for

alcohol,

aliphatic

a condensation

fatty

solvents that may be employed sodium

chain

long

or a condensation

from

gum

product of an alkylene oxide

form a fatty acid and a hexitol

The sterile injectable suspension

polyoxyethylene

a

polyvinylpyrrolidone,

or wetting agents which may be a naturally

dispersing

with

methylcellulose,

alginate,

sodium

with a fatty acid, for example,

of

agents such as, for

agents and suspending

such as lecithin, a condensation

occurring phosphatide

to known methods

according

carboxymethylcellulose,

sodium

tragacanth

20

base, formed

The pharmaceutical

hydroxypropylmethyl-cellulose,

15

oxide with a hydrophobic

of propylene oxide with propylene glycol.

example,

10

T/EP2012/055471

by the condensation

suspensions. 5

weight adducts of ethylene

PC

the preparation

in

In

of

inj ectables.

25

A

composition

suppositories

prepared

of the invention

may

for rectal administration

non-irritation

butter and polyethylene Another

formulation

transdermal

delivery

the form

of

can be

excipient which is solid

but liquid at the rectal temperature

melt in the rectum to release the drug. Such materials

30

in

of the drug. These compositions

by mixing the drug with a suitable

at ordinary temperatures

be administered

also

and will therefore

are, for example, cocoa

glycol.

employed

in

the methods


devices ("patches"). Such transdermal

254

employs

patches may be used

WO 2012/136531

to provide continuous invention

or discontinuous

of the compounds

infusion

release formulations

15

ventricular

system

to bypass

delivery

system,

used

for the

regions of the body, is described

April

30, 1991.

The

compositions

of the

can

invention

acceptable

pharmaceutically

Such

compositions ingredients

procedures

and

include

Pharmaceutical

"Parenteral

Science

Formulations

States (1999)-Part-1"

for

agents

a drug directly

catheter barrier.

into the One

such

to specific

in US

Patent No. 5, 011,472, issued

also

contain

those

other

conventional

referred

generally

to as

procedures for preparing can

forms

described

in

be

utilized.

the

following

Formulations"

et al. ,

Journal

PDA

1998, 52(5), 238-311; Strickley,

B. Technology

of Small Molecule Therapeutics

PDA

is well

herein by reference: Powell, M. F.

Parenteral

to

use of

and

of agents

transport

dosage

appropriate

in

of Excipients

"Compendium

30

blood-brain

ingredients,

compounding

references, each of which is incorporated

25

The construction

carriers or diluents, as necessary or desired. Conventional such

composition

of pharmaceutical

the

liposomal,

that are known in the art.

of a drug delivery

placement

involve

anatomical

20

device.

delivery

usually

implantable

include

administration

art. Direct techniques for, for example, administering

to the brain patient's

for parenteral

devices for the delivery

delivery

known in the

or on demand delivery

pulsatile,

and polymeric gel formulations

a mechanical

via

mechanical

US

reference).

by

or necessary to introduce the pharmaceutical

It may be desirable

the patient

herein

e.g. ,

agents.

polymeric microsphere

10

for continuous,

Such patches may be constructed

Controlled

patches

agents is well known in the art (see,

Patent No. 5, 023, 252, issued June 11, 1991, incorporated

of pharmaceutical

of the present

and use of transdermal

amounts. The construction

in controlled

for the delivery of pharmaceutical

5

T/EP2012/055471

PC

Journal of Pharmaceutical

Marketed

Science

in

of R. G

the United

& Technology

1999,

53(6), 324-349; and Nema, S. et al. , "Excipients and Their Use

in

Products"

1997, 51(4),

PDA

Journal

of Pharmaceutical

Science R Technology

Injectable

166-171. Commonly

used pharmaceutical

ingredients

formulate the composition for its intended

that can be used as appropriate

route of administration

255

include:

to

WO 2012/136531

PC

T/EP2012/055471

acidifying agents (examples include but are not limited to acetic acid, citric acid,

acid, nitric acid);

fumaric acid, hydrochloric

agents (examples include but are not limited to ammonia solution,

alkalinizing

carbonate, diethanolamine,

ammonium 5

sodium borate, sodium carbonate,

monoethanolamine,

potassium

trolamine);

triethanolamine,

sodium hydroxide,

(examples include but are not limited to powdered

adsorbents

hydroxide,

cellulose and

activated charcoal);

(examples include but are not limited to carbon dioxide,

aerosol propellants

CCbF~, F~ClC-CClF~ and CClF~)

10

agents (examples include but are not limited to nitrogen and

air displacement

argon); antifungal

ethylparaben,

butylparaben,

benzalkonium

methylparaben,

preservatives

antimicrobial 15

(examples include but are not limited to benzoic acid,

preservatives

(examples

chloride, benzethonium

chloride, chlorobutanol,

propylparaben, includ

e

bu

sodium

t a re

n

benzoate);

o t li m

i

ted to

chloride, benzyl alcohol, cetylpyridinium

phenol, phenylethyl

alcohol, phenylmercuric

nitrate and

thimerosal); antioxidants

palmitate, 20

(examples

butylated

sulfoxylate,

buffering

hypophosphorus

sodium metabisulfite);

polyurethanes,

natural

silicones, polysiloxanes

and

copolymers);

(examples include but are not limited to potassium dipotassium phosphate, sodium acetate, sodium citrate anhydrous

agents

metaphosphate,

hydroxytoluene,

propyl gallate, sodium ascorbate, sodium bisulfite, sodium

rubber, polyacrylates,

styrene-butadiene 25

butylated

to ascorbic acid, ascorbyl

(examples include but are not limited to block polymers,

binding materials and synthetic

but are not limited

hydroxyanisole,

acid, monothioglycerol, formaldehyde

include

and sodium citrate dihydrate)

256

WO 2012/136531

PC

T/EP2012/055471

carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil,

mineral oil, peanut oil, sesame oil, bacteriostatic

sodium chloride injection and

bacteriostatic water for injection) 5

agents (examples include but are not limited to edetate disodium and

chelating

edetic acid) colourants (examples include but are not limited to FDBC Red No. 3, FDBC Red No. 20, FDBC Yellow No. 6, FDBC Blue No. 2, DBC Green No. 5, DBC Orange No. 5, DBC Red No. 8, caramel and ferric oxide

10

red);

clarifying agents (examples include but are not limited to bentonite);

agents (examples include but are not limited to acacia, cetomacrogol,

emulsifying

cetyl alcohol, glyceryl monostearate, polyoxyethylene

encapsulating 15

lecithin, sorbitan monooleate,

50 monostearate);

agents

(examples include but are not limited to gelatin and

cellulose acetate phthalate)

(examples include but are not limited to anise oil, cinnamon

flavourants

cocoa, menthol, orange oil, peppermint

oil and vanillin);

(examples include but are not limited to glycerol, propylene

humectants

oil,

glycol

and sorbitol);

20

levigating

agents

(examples include but are not limited to mineral oil and

glycerin); oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable

25

ointment

bases (examples

ointment,

polyethylene

limited

enhancers

to monohydroxy

but are not limited

petrolatum,

glycol ointment,

ointment, yellow ointment,

penetration

include

oil); to lanolin, hydrophilic

hydrophilic

petrolatum,

white

and rose water ointment);

(transdermal

delivery)

or polyhydroxy

alcohols,

257

(examples include but are not mono-or polyvalent

alcohols,

WO 2012/136531

saturated or unsaturated

T/EP2012/055471

fatty alcohols, saturated or unsaturated

fatty esters,

saturated

or unsaturated

derivatives,

cephalin, terpenes, amides, ethers, ketones and ureas)

dicarboxylic acids, essential oils, phosphatidyl

(examples include but are not limited to diethyl phthalate

plasticizers 5

PC

and

glycerol); solvents (examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol,

mineral oil, oleic acid, peanut oil, purified water, water for

injection, sterile water for injection and sterile water for irrigation); stiffening

10

agents (examples include but are not limited to cetyl alcohol, cetyl

esters wax, microcrystalline

stearyl alcohol, white wax and yellow

wax, paraffin,

wax);

15

suppository

bases (examples include but are not limited to cocoa butter and

polyethylene

glycols (mixtures));

surfactants

(examples include but are not limited to benzalkonium

nonoxynol

10, oxtoxynol

80, sodium

9, polysorbate

lauryl

chloride,

sulfate and sorbitan

mono-palmitate); suspending

(examples include but are not limited to agar, bentonite,

agents

carbomers, carboxymethylcellulose cellulose,

20

hydroxypropyl

sodium, hydroxyethyl

cellulose, hydroxypropyl

kaolin, methylcellulose,

methylcellulose,

tragacanth

and

veegum); sweetening

agents (examples include but are not limited to aspartame,

glycerol, mannitol,

tablet

dextrose,

propylene glycol, saccharin sodium, sorbitol and sucrose);

anti-adherents

(examples

include

but

are not limited

to magnesium

stearate and talc); 25

tablet binders

(examples include but are not limited to acacia, alginic acid,

carboxymethylcellulose glucose, methylcellulose,

sodium, compressible

non-crosslinked

sugar, ethylcellulose,

polyvinyl

starch);

258

pyrrolidone,

gelatin, liquid

and pregelatinized

WO 2012/136531

PC

(examples include but are not limited to dibasic

tablet and capsule diluents

kaolin, lactose, mannitol,

calcium phosphate,

cellulose,

precipitated

T/EP2012/055471

carbonate,

calcium

cellulose, powdered

microcrystalline

carbonate,

sodium

sodium

phosphate,

sorbitol and starch); 5

tablet coating agents (examples include but are not limited to liquid glucose, cellulose, hydroxypropyl

hydroxyethyl

cellulose acetate phthalate

ethylcellulose,

methylcellulose,

tablet direct compression

cellulose, hydroxypropyl

excipients

methylcellulose,

and shellac);

(examples include but are not limited to

dibasic calcium phosphate);

10

tablet

(examples include but are not limited to alginic acid,

disintegrants

carboxymethylcellulose

cross-linked

calcium,

polyvinylpyrrolidone,

cellulose,

microcrystalline

sodium alginate,

polacrillin

potassium,

sodium starch glycollate and

starch); tablet glidants (examples include but are not limited to colloidal silica, corn starch 15

and

talc);

tablet lubricants magnesium

(examples

include

but are not limited to calcium

stearate,

stearate, mineral oil, stearic acid and zinc stearate);

tablet/capsule

opaquants

(examples include but are not limited to titanium

dioxide); 20

tablet polishing agents (examples include but are not limited to carnuba wax and white wax);

thickening

agents (examples include but are not limited to beeswax, cetyl alcohol

and paraffin);

tonicity agents (examples include but are not limited to dextrose and sodium 25

chloride); viscosity increasing agents (examples include but are not limited to alginic acid,

bentonite, pyrrolidone,

carbomers, carboxymethylcellulose sodium alginate and tragacanth);

259

sodium, methylcellulose, and

polyvinyl

WO 2012/136531

PC

(examples include but are not limited to heptadecaethylene

agents

wetting

lecithins, sorbitol monooleate,

oxycetanol,

5

polyoxyethylene

compositions

according to the present invention

Solution:

IV

A 5 mg/mL

solution of the desired compound

can be made using sterile, injectable water, and the

to

The solution is diluted for administration

as an

and is administered

owder for

o hilised

L

with (i) 100 - 1000 mg

IV

concentration 5/o —

to 0.2

—

with sterile 5/ dextrose

2 mg/mL

A

sterile preparation

can be prepared

—

3000 mg Dextran 40. The

with sterile, injectable saline or dextrose

5/o

to a

of 10 to 20 mg/mL, which is further diluted with saline or dextrose

0.4

mg/mL,

either

and is administered

IV

bolus or by

IV

infusion over 15

60 minutes.

Intramuscular

The following solution or suspension

sus ension:

for intramuscular

can be prepared,

injection:

50 mg/mL of the desired, water-insoluble

20

adjusted if necessary.

of the desired compound of this invention as a lyophilised

is reconstituted

formulation

of this invention

infusion over about 60 minutes.

administration:

IV

1 —

pH is

powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300

15

can be illustrated

as follows:

Sterile

10

sorbitol monooleate,

stearate).

and polyoxyethylene

Pharmaceutical

T/EP2012/055471

compound

of this invention

5 mg/mL sodium carboxymethylcellulose

4 mg/mL TWEEN 80

9 mg/mL sodium chloride 9 mg/mL benzyl alcohol Hard Shell Ca sules:

25

standard

ingredient,

A

large number of unit capsules are prepared

by filling

two-piece hard galantine capsules each with 100 mg of powdered active

150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium

Soft Gelatin Ca sules:

A

mixture of active ingredient

soybean oil, cottonseed oil or olive oil is prepared

260

in a digestible

stearate. oil such as

and injected by means of a

WO 2012/136531

PC

positive displacement

to form soft gelatin capsules

pump into molten gelatin

The capsules are washed and dried.

100 mg of the active ingredient.

containing

can be dissolved in a mixture of polyethylene

The active ingredient

T/EP2012/055471

glycol, glycerin

and sorbitol to prepare a water miscible medicine mix. 5

Tablets:

A

large number of tablets are prepared

by conventional

that the dosage unit is 100 mg of active ingredient, dioxide, 5 mg of magnesium

stearate, 275

mg

of starch, and 98.8 mg of lactose. Appropriate may be applied

10

to increase palatability,

mg. of colloidal silicon

of microcrystalline

cellulose, 11 mg.

aqueous and non-aqueous

coatings

improve elegance and stability or delay

absorption.

Release Tablets/Ca

Immediate

immediate

sules: These are solid oral dosage forms made by

and novel processes. These units are taken orally without

conventional

dissolution

and delivery of the medication.

mixed in a liquid containing 15

0. 2

procedures so

ingredient

water for

The active ingredient

is

pectin and

such as sugar, gelatin,

sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed

with

viscoelastic

and

thermoelastic

sugars

and

polymers

or

effervescent components to produce porous matrices intended for immediate release, without the need of water. 20

therapies

Combination

The compounds

of this invention can be administered

agent or in combination 25

with one or more other pharmaceutical

causes no unacceptable

combination

also to such combinations. combined

with known

30

alkylating

inhibitors,

but

are not

anti-hyper-proliferative

agents,

limited

cell cycle inhibitors,

DNA-intercalating

enzyme inhibitors,

261

of this invention can be

thereof. Other indication agents

to, anti-angiogenic

biological response modifiers, or anti-hormones.

relates

or other indication agents, and the

and combinations

anti-metabolites,

agents where the

adverse effects. The present invention

For example, the compounds

like, as well as with admixtures

include,

as the sole pharmaceutical

agents,

mitotic

inhibitors,

antibiotics, growth factor

toposisomerase

inhibitors,

WO 2012/136531

The additional

pharmaceutical

agent can be 131l-chTNT, abarelix, abiraterone,

aclarubicin,

aldesleukin,

alemtuzumab,

aminoglutethimide,

(RDEA

folinate,

catumaxomab,

celecoxib, celmoleukin,

chlormethine,

cisplatin, cladribine,

alfa, dasatinib,

doxorubicin,

doxorubicin

epoetin beta, eptaplatin,

exemestane,

everolimus, flutamide,

formestane,

gefitinib,

gemcitabine, tiuxetan,

ibritumomab

lisuride,

nimotuzumab,

30

oxaliplatin,

p53

pamidronic

acid,

(methoxy

porfimer

plicamycin,

fluorouracil,

nitrate, ganirelix,

gallium

imatinib,

lomustine,

mitobronitol,

nitracrine,

pazopanib,

pegaspargase,

poliglusam,

pralatrexate,

peginterferon

polyestradiol

prednimustine, 262

nilutamide,

oprelvekin,

seed, PEG-epoetin beta

palladium-103

palifermin,

perfosfamide,

nilotinib,

omeprazole,

paclitaxel,

peplomycin,

mitolactol,

mitoguazone,

ofatumumab,

beta), pegfilgrastim,

mercaptopurine,

methyltestosterone,

nelarabine,

nedaplatin,

letrozole, masoprocol,

lonidamine,

mepitiostane,

melphalan,

miriplatin,

lentinan,

lenograstim,

Methyl aminolevulinate,

therapy,

pentostatin,

sodium,

lobaplatin,

panitumumab,

PEG-epoetin

pentazocine, plerixafor,

gene

fludarabine,

etoposide,

goserelin, histamine l-125 seeds, ibandronic acid,

lenalidomide,

mitoxantrone,

nimustine,

epoetin alfa,

glutoxim,

ifosfamide,

megestrol,

methoxsalen,

mitotane,

epitiostanol,

irinotecan,

levamisole,

mitomycin,

acetate,

elliptinium

beta, interferon gamma, ipilimumab,

leuprorelin,

miltefosine,

dactinomycin,

improsulfan,

lapatinib,

mifamurtide,

crisantaspase,

imiquimod,

lanreotide,

methotrexate,

edrecolomab,

hydroxycarbamide,

ixabepilone,

medroxyprogesterone,

chlormadinone,

chloride, docetaxel, doxifluridine,

epirubicin,

gemtuzumab,

idarubicin,

alfa, interferon

interferon

carmustine,

carmofur,

dacarbazine,

fadrozole, filgrastim, fotemustine, fulvestrant,

histrelin,

dihydrochloride,

cabazitaxel, calcium

erlotinib, estradiol, estramustine,

eribulin,

86-9766

decitabine, degarelix, denileukin

dibrospidium

enocitabine,

endostatin,

eltrombopag,

BAY

bexarotene, bicalutamide,

chlorambucil,

cytarabine,

estrone, eculizumab,

+

1000394,

BAY

carboplatin,

daunorubicin,

deslorelin,

arsenic trioxide,

arglabin,

busulfan,

cetuximab,

altretamine,

clodronic acid, clofarabine,

cyproterone,

cyclophosphamide,

diftitox, denosumab,

25

buserelin,

capecitabine,

levofolinate,

calcium

80-6946,

bevacizumab,

bortezomib,

bleomycin,

darbepoetin

20

BAY

119), belotecan, bendamustine,

bisantrene,

15

basiliximab,

alitretinoin,

anastrozole,

amsacrine,

amrubicin,

azacitidine,

asparaginase,

10

T/EP2012/055471

PC

alfa-2b,

pemetrexed,

picibanil,

pirarubicin,

phosphate,

polysaccharide-K,

procarbazine,

quinagolide,

WO 2012/136531

raloxifene, raltitrexed, rituximab,

romidepsin,

sobuzoxane,

sodium

tamibarotene, 5

trilostane,

zinostatin,

15

teniposide,

testosterone,

thiotepa,

thymalfasin,

tioguanine,

tocilizumab,

trabectedin,

trastuzumab,

tositumomab,

vorinostat,

aldesleukin,

alendronic

altretamine,

aminoglutethimide,

acid, alfaferone,

calcitonin,

cerubidine,

dexrazoxane,

dacarbazine,

cytarabine,

delestrogen,

ergamisol,

finasteride,

filgrastim,

5-fluorodeoxyuridine

gemcitabine,

gemtuzumab,

hydrocortone, idarubicin,

alfa-2A, interferon

bortezomib,

fligrastim,

epirubicin,

epoetin alfa, sodium,

fludarabine,

fulvestrant,

gammagard,

granisetron

HCl, histrelin,

hydroxyurea,

ibritumomab

eyrthro-hydroxynonyladenine,

interferon-alpha

alfa-n1, interferon 263

doxorubicin,

(5-FU), fluoxymesterone,

gleevec, gliadel, goserelin,

alfa-2B, interferon

deslorelin,

phosphate

fluconazole,

5-fluorouracil

alpha,

decadron,

etoposide, fadrozole, farston,

floxuridine,

interferon

busulfan,

DaunoXome,

depo-medrol,

diftitox,

fosteabine, fotemustine,

ifosfamide,

sodium

clodronic acid,

cladribine,

estrace, estradiol, estramustine

monophosphate,

formestane,

flutamide,

tiuxetan,

betamethasone

dif lucan, docetaxel, doxifluridine,

diethylstilbestrol,

epogen, eptaplatin,

hycamtin,

azathioprine,

casodex, cefesone, celmoleukin,

ethinyl estradiol, ethyol, etidronic acid, etopophos,

30

5-azacytidine,

DW-166HC, eligard, elitek, ellence, emend,

dronabinol,

aloprim, aloxi,

anastrozole,

dactinomycin,

denileukin

afinitor,

amsacrine,

acetate,

cisplatin, cladribine,

chlorambucil,

phosphate,

carboplatin,

from:

allopurinol,

amrubicin,

betamethasone

capecitabine,

campath,

cyclophosphamide,

25

alitretinoin,

bexarotene, bleomycin sulfate, broxuridine,

phosphate,

vindesine,

glass microspheres,

is selected

agent

amifostine,

or tice BCG, bestatin,

decadron

vincristine,

yttrium-90

arsenic trioxide, aromasin,

anzmet, aranesp, arglabin,

20

pharmaceutical

additional

valrubicin,

zoledronic acid, zorubicin.

zinostatin stimalamer,

the

vorozole,

+

treosulfan,

ubenimex,

tryptophan,

vinblastine,

vemurafenib,

Preferably,

BCG

trofosfamide,

triptorelin,

vinorelbine,

vinflunine,

gimeracil

+

temsirolimus,

vapreotide,

vandetanib,

talaporfin,

sunitinib,

temozolomide,

toremifene,

tretinoin,

streptozocin,

teceleukin, tegafur, tegafur

tasonermin,

thalidomide,

topotecan,

10

tamoxifen,

sipuleucel- T, sizofira n,

sargramostim,

sorafenib,

glycididazole,

risedronic acid,

razoxane, regorafenib,

ranimustine, romiplostim,

oteracil, temoporfin, tetrofosmin,

T/EP2012/055471

PC

2, interferon

alfa-n3, interferon

beta,

WO 2012/136531

interferon

PC

intron A, iressa, irinotecan,

interleukin-2,

gamma-1a,

sulfate, letrozole, leucovorin,

levofolinic acid calcium salt, levothroid,

mecobalamin,

mechlorethamine, 5

acetate, melphalan, miltefosine,

minocycline,

nedaplatin,

neulasta,

10

neumega,

procarbazine,

strontium-89

15

20

RDEA

paclitaxel, pediapred, HCl, pirarubicin,

prednisone,

prednisolone,

premarin,

rhenium-186

etidronate,

sargramostim,

semustine,

119, rebif,

tamoxifen, tamsulosin,

thioguanine,

thiotepa, thyrotropin,

tositumomab,

trastuzumab,

trimetrexate,

triptorelin

vesnarinone,

vinblastine,

tretinoin,

trexall, trimethylmelamine,

acetate, triptorelin pamoate, vincristine,

vindesine,

arzoxifene, asoprisnil,

vinorelbine,

atamestane,

valrubicin,

UFT, uridine,

ABI-007, acolbifene,

zofran,

testred,

propionate,

acid, topotecan, toremifene,

tiludronic

treosulfan,

tastolactone,

tasonermin,

teniposide, testosterone

taxotere, teceleukin, temozolomide,

aminopterin,

NSC-631570,

nolvadex,

sparfosic acid, stem-cell therapy, streptozocin,

solu-medrol,

stimalamer,

metvix,

Modrenal, Myocet,

pilocarpine

salagen, sandostatin,

chloride, synthroid,

zinostatin

mitoxantrone,

picibanil,

prednimustine,

romurtide,

sizofiran, sobuzoxane,

Mesna, methotrexate,

orapred, oxaliplatin,

HCl,

marinol,

acetate, megestrol

nilutamide,

neupogen,

raltitrexed,

procrit,

roferon-A,

rituximab,

C, mitotane,

Pegasys, pentostatin,

porfimer sodium,

plicamycin,

lonidamine,

medroxyprogesterone

mitomycin

OCT-43, octreotide, ondansetron

pegaspargase,

levoxyl, lomustine,

6-mercaptopurine,

menest,

kytril, lentinan

acetate, levamisole,

leuprolide

leuprolide,

T/EP2012/055471

zinecard,

virulizin,

affinitak,

actimmune,

atrasentan,

sorafenib (BAY

43-9006), avastin, CCI-779, CDC-501, celebrex, cetuximab, crisnatol, cyproterone

acetate, decitabine,

exatecan, fenretinide,

eflornithine, 25

implant,

holmium-166

ixabepilone, lonafarnib,

neovastat,

raloxifene,

pamidronate

ranpirnase,

taxoprexin,

TLK-286,

verteporfin,

nolatrexed,

toremifene, vinflunine,

hydrogel

intron-PEG,

gamma,

L-651582, lanreotide,

lasofoxifene,

libra,

MS-209, liposomal MTP-PE, MX-6, nafarelin,

oblimersen, PN-401,

disodium,

alpha

histrelin

dihydrochloride,

onco-TCS, osidem, paclitaxel QS-21,

13-cis -retinoic acid, satraplatin, thymosin

edotecarin,

dutasteride,

dSLIM,

acid, interferon

ibandronic

minodronate,

miproxifene,

polyglutamate,

tarceva,

DOTMP,

histamine

keyhole limpet hemocyanin,

nemorubicin,

30

DN-101, doxorubicin-MTC,

1, tiazofurine,

TransMID-107R,

valspodar,

seocalcitol,

T-138067,

tirapazamine,

tipifarnib,

vapreotide,

Z-100, and zoledronic acid or combinations

264

R-1549,

quazepam,

vatalanib,

thereof.

WO 2012/136531

PC

agents which can be added to the composition

anti-hyper-proliferative

Optional

include but are not limited to compounds regimens

in

incorporated 5

11'" Edition

the

dacarbazine,

dactinomycin,

daunorubicin,

mitoxantrone,

6-mercaptopurine, prednisolone,

the

of neoplastic

treatment

diseases

Basis of Therapeutics

Pharmacological by

McGraw-Hill,

pages

cladribine,

adenine,

erythrohydroxynonyl

5-fluorodeoxyuridine

flutamide,

acetate,

25

pentostatin,

semustine,

teniposide,

streptozocin,

and vindesine.

of the

Goodman

is

to be used

acknowledged

Gilman's

and

hereby

The

et al. , publ.

incorporated

by

5-azacytidine

2', 2'-difluorodeoxycytidine,

docetaxel,

estradiol,

fludarabine

5-fluorodeoxyuridine,

fluoxymesterone,

phosphate,

caproate,

interferon,

idarubicin,

acetate,

melphalan,

mitotane,

N-phosphonoacetyl-L-aspartate

(PALA),

plicamycin,

megestrol

testosterone

propionate,

thiotepa,

trimethylmelamine,

uridine, and vinorelbine.

Other anti-hyper-proliferative invention

include

but

The compounds protein

include,

to other anti-cancer

disorders

agents

such

as

raloxifen and topotecan.

may also be administered

Such protein

cancer or other angiogenic invention

irinotecan,

of the invention

therapeutics.

of the

agents suitable for use with the composition

are not limited

epothilone and its derivatives,

30

in

C,

azathioprine,

ethinyl

hydroxyprogesterone

paclitaxel,

lomustine,

mitomycin

raloxifen,

vincristine,

L-asparaginase,

monophosphate,

medroxyprogesterone

leucovorin,

methotrexate,

1225-1287, (1996), which diethylstilbestrol,

busulfan,

5-fluorouracil,

(Ninth Edition), editor Molinoff

reference, such as aminoglutethimide,

20

irinotecan,

include but are not limited to those compounds

invention

epirubicin,

(adriamycine),

agents suitable for use with the composition

Other anti-hyper-proliferative

in

cytarabine,

procarbazine,

prednisone,

topotecan, vinblastine,

tamoxifen, thioguanine,

cyclophosphamide,

etoposide,

mesna,

is hereby

carboplatin,

doxorubicin

ifosfamide,

hydroxyurea,

drug

bleomycin,

derivative,

epothilone

mechlorethamine,

15

colaspase,

cisplatin,

an

(1996), which

Index,

asparaginase,

chlorambucil,

hexamethylmelamine,

10

as

such

carmustine,

epothilone,

listed on the cancer chemotherapy

of the Merck

reference,

by

T/EP2012/055471

therapeutics

suitable

and for use with

but are not limited to, an interferon

265

in combination

with

for the treatment

the compositions

(e. g. , interferon

of

of the

.alpha.

,

WO 2012/136531

.beta. , or .gamma. cetuximab,

trastuzumab,

mecasermin,

bevacizumab, 5

MFE-CP1

MDX-1307, Her-2

mecasermin

rinfabate, oprelvekin,

APC-8024,

celmoleukin,

melanoma,

ofatumumab,

oregovomab,

aflibercept,

WX-G250, Albuferon,

1311-chTNT-1/B. Monoclonal but are not limited

alemtuzumab,

adalimumab,

omalizumab,

palivizumab,

basiliximab,

agents,

recombinant

ibritumomab,

EM-1421,

HPV-16-E7,

-

Javelin

prostate

EGF vaccine, CYT-004-MelQbG10,

besudotox,

cintredekin

vaccine,

CTP-37, efungumab,

or

include,

edrecolomab,

daclizumab,

cetuximab,

bevicizumab,

efalizumab,

rituximab,

trastuzumab,

daclizumab,

and infliximab. may also be combined

(e.g. avastin,

with biological therapeutic

rituxan,

erbitux,

of the invention

may also be in combination

herceptin),

or

with

inhibitors

axitinib,

DAST,

of proteasomes

with antiangiogenesis

recentin,

sorafenib or

or mTOR inhibitors,

or

or steroidal metabolic enzyme inhibitors are also possible.

cytostatic agents in combination

Generally,

the use of cytotoxic and/or

compound

or composition of the present invention will serve to:

(1)

HyperAcute

abciximab,

muromomab-CD3,

antibodies

Combinations

anti-hormones

30

aviscumine,

useful as the protein therapeutic

agents, such as, for example, with avastin, sunitinib.

AC-9301,

proteins.

The compounds 25

denosumab,

antibodies

of the invention as

such

SGN-35, MT-103,

CAT-3888, labetuzumab,

zalutumumab,

to, muromonab-CD3,

gentuzumab,

The compounds

NY-ESO-1 vaccine,

rhMBL,

EMD-273063, L19-IL-2

lintuzumab,

galiximab,

1,

rhH1. 3, IGN-311, Endostatin,

SGN-40, pertuzumab,

vaccine,

-

natalizumab,

immunotoxin,

NGR-hTNF,

radioisotope-llinked

tucotuzumab

alpha

thymosin

IMC-1C11, CT-322, rhCC10, r(m)CRP, MORAb-009,

vaccine,

TRP-1

infliximab,

L-19 based radioimmunotherapeutics,

alpha-particle-emitting

WT1 peptide,

20

rituximab,

PRX-321, CNT0-328, MDX-214, tigapotide,

fusion protein,

cancer, Javelin 15

diftitox,

PRO-1762, lexatumumab,

volociximab,

Tuebingen,

YH-16, gemtuzumab,

antibody,

denileukin

AS-1402, B43-genistein,

NY-ESO-1 vaccine,

10

anti-FAP

ZD-2767-P, ABT-828, ErbB2-specific

+

rinfabate,

antibodies,

monoclonal

supraagonistic

)

vaccine, Colostrinin,

protein

T/EP2012/055471

PC

yield better efficacy in reducing

the tumour as compared to administration

with

the growth of a tumour or even eliminate

of either agent alone,

266

a

WO 2012/136531

PC

provide for the administration

(2)

T/EP2012/055471

of lesser amounts of the administered

chemo-

therapeutic agents,

for a chemotherapeutic

provide

(3)

patient with fewer deleterious pharmacological 5

provide for treating a broader spectrum

than observed with

of different cancer types in

especially humans,

mammals,

10

complications

and certain other combined therapies,

single agent chemotherapies

(4)

that is well tolerated in the

treatment

(5)

provide for a higher response rate among treated patients,

(6)

provide for a longer survival time among treated patients compared to

standard chemotherapy

treatments,

(7)

provide a longer time for tumour progression,

(8)

yield efficacy and tolerability used

alone,

combinations

compared

to

and/or

results at least as good as those of the agents

instances

known

where

other

cancer agent

effects.

produce antagonistic

15 Methods of Sensitizing Cells to Radiation

In

a distinct

invention

20

embodiment

may be used to sensitize a cell to radiation.

with a compound

renders


a compound

of the present

That is, treatment

of a cell

of the present invention prior to radiation treatment of the cell

the cell more susceptible

to

DNA

would be in the absence of any treatment

damage and cell death than the cell

with a compound

of the invention.

In

one

aspect, the cell is treated with at least one compound of the invention. Thus, the present invention

25

is administered conventional

also provides a method of killing a cell, wherein a cell

one or more compounds

of the invention in combination

with

radiation therapy.


also provides a method of rendering

a cell more susceptible

to cell death, wherein the cell is treated one or more compounds of the invention prior to the treatment

of the cell to cause or induce cell death. 267

In

one aspect,

WO 2012/136531

PC

T/EP2012/055471

after the cell is treated with one or more compounds of the invention, the cell is treated with at least one compound, thereof, in order to cause

DNA

or at least one method,

or a combination

the function of

damage for the purpose of inhibiting

the normal cell or killing the cell. 5

In

agent. That is, after treating a cell with one or more compounds of the

invention

to sensitize the cell to cell death, the cell is treated with at least one

damaging

invention

but

are not

ionizing radiation

cisplatinum),

In

agent to kill the cell.

include,

and mutagenic

DNA

agents useful in the present

damaging

to, chemotherapeutic

limited

(X-rays, ultraviolet

radiation), carcinogenic agents,

a cell is killed by treating

another embodiment,

DNA

pathway is activated, inhibiting damage when the pathway

in DNA damage when

the

of a cell signalling pathway that results in

DNA

is inhibited,

cell, wherein the change results in DNA

DNA

20

In

DNA

and inducing

a compound

concomitantly

to a cell immediately

DNA

damage in a cell.

DNA

damage in the cell.

or other induction of

yet another aspect of the invention,

of

example,

the repair of

of the invention is administered

a compound

with the radiation

change in a

to a


cell prior to the radiation or other induction of

25

thereby preventing

damage and resulting in an abnormal accumulation

one aspect of the invention,

a biochemical

damage. By way of a non-limiting

repair pathway in a cell can be inhibited,

aspect of the invention,

the cell with at least one

damage. Such methods include, but are not limited

to, activation of a cell signalling pathway that results

a

(e.g. ,

agents

agents.

method to cause or induce

15

DNA

damaging

DNA

10

a cell is killed by treating the cell with at least one

one embodiment,

a compound

In

another

to a cell

damage in the cell.

DNA

In


after radiation or other induction of

DNA

damage in the cell

has begun. In

another aspect, the cell is in vitro.

As mentioned

supra, the compounds

In

another embodiment,

the cell is in vivo.

of the present invention have surprisingly

been

found to effectively inhibit Mps-1 and may therefore be used for the treatment

30

prophylaxis

inappropriate

of diseases of uncontrolled


cellular immune responses, or inappropriate 268

or

and/or survival,


WO 2012/136531

responses, or diseases which are accompanied and/or

proliferation

inappropriate immune



Mps-1, such as, for example,


leukaemias

cellular immune


non-small

endocrine tumours,

responses,

particularly

in which

tumours,

and sarcomas, and/or metastases

the

responses is mediated by

solid tumours,

tumours,

and/or malignant

syndrome,


brain tumours

cell and small cell lung tumours, and other gynaecological

mammary


urological tumours including

or

cellular

inappropriate

myelodysplastic

and

tumours,

In

15

haematological

lymphomas,

tumours,

cell growth,


thereof,

gastrointestinal

with uncontrolled

and/or survival,

metastases

tumours

10

e. g.

T/EP2012/055471

responses,


uncontrolled 5

inappropriate

survival,

PC

skin

thereof.

accordance with another aspect therefore, the present invention covers a

compound

hydrate,

of general formula

I,

or a stereoisomer,


particularly

an N-oxide, a

a tautomer,

acceptable

a pharmaceutically

salt thereof, or a mixture of same, as described and defined herein, for use in the treatment or prophylaxis of a disease, as mentioned

20

Another particular compound

aspect of the present invention is therefore the use of a

of general formula

N-oxide, a hydrate,

supra.

I, described supra, or a

stereoisomer,


a tautomer,

an

a pharmaceutically

acceptable salt thereof, or a mixture of same, for the prophylaxis

or treatment

of a disease. 25 Another compound

particular

aspect of the present invention

of general formula

I

composition for the treatment

30

The diseases

uncontrolled immune

referred

to

described supra for manufacturing or prophylaxis

in

the two



which are accompanied

is therefore the use of a

of a disease.

preceding

paragraphs

and/or survival,


with uncontrolled

269

a pharmaceutical

are diseases of

inappropriate

cellular

responses, or diseases


and/or

WO 2012/136531

inflammatory

responses,

proliferation

and/or survival,

example, haematological leukaemias tumours

brain

including

non-small

syndrome,

tumours

and

malignant

brain

mammary

responses,

or

by Mps-1, such as,

for

and/or metastases thereof,

solid tumours,

metastases,

gastrointestinal


including

of the thorax

tumours


e. g.

head and neck

lymphomas,

cell and small cell lung tumours,

endocrine tumours, tumours

cellular immune

responses is mediated

cellular

cell growth,

the uncontrolled

in which

inappropriate

tumours,

and myelodysplastic

including

10

particularly


inappropriate

T/EP2012/055471


inappropriate

survival,

5

PC

tumours,

tumours,

urological

skin tumours,

and

sarcomas, and/or metastases thereof.

The term "inappropriate" in

15

within the context of the present invention,

the context of "inappropriate


responses", as used herein, is to be understood


a response which is less than, or greater than normal,

meaning

in particular

as preferably and which is

associated with, responsible for, or results in, the pathology of said diseases.

Preferably, 20

the use is in the treatment

diseases are haemotological

compositions

and

disorders.

comprises

30

amount

and/or

administering

of a compound

isomer, polymorph,

prostate

e.g. ,

psoriasis,

hyperplasia

and/or

to a mammal

produce

in need

of this invention,

metabolite,

mammalian

hydrate,

This method

apoptosis.

thereof, including

or a pharmaceutically

a human,

270

such

etc.

which is

disorders include but are not

keloids, and other hyperplasias tumours,

an

acceptable salt,

solvate or ester thereof;

Hyper-proliferative

(BPH), solid

hyper-proliferative

to inhibit, block, reduce, decrease, etc. ,

cell division,

effective to treat the disorder. limited,

to treat

thereof,

can be utilized

Compounds

cell proliferation

disorders

relates to a method for using the compounds of the present

The present invention invention

of diseases, wherein the

solid tumours and/or metastases thereof.

tumours,

Method of treating hyper-proliferative

25

or prophylaxis

affecting the skin, benign

as cancers

of the breast,

WO 2012/136531

PC

tract, brain, reproductive

respiratory

liver, skin, head and neck, thyroid,

of breast

5

carcinoma,

lobular

tract, urinary tract, eye,

and their distant metastases.

parathyroid

cancer include,

invasive

digestive

Those

sarcomas, and leukaemias.

disorders also include lymphomas, Examples

organs,

T/EP2012/055471

carcinoma,

to invasive

are not limited

but

ductal

carcinoma

situ,

in

ductal lobular

and

carcinoma in situ. Examples

of cancers of the respiratory

small-cell

and non-small-cell

pleuropulmonary

10

Examples

lung

carcinoma,

as well as bronchial

of brain

cancers

but

include,

adenoma

cerebellar

cerebral

and

glioma,

ependymoma,

as well as neuroectodermal

of the male reproductive

not limited to endometrial,

to brain

are not limited astrocytoma,

and

stem

and

medulloblastoma,

and pineal tumour.

but are not limited to prostate

organs include,

and testicular cancer. Tumours of the female reproductive

15

to

but are not limited

blastoma.

hypophtalmic

Tumours

tract include,

organs include, but are

cervical, ovarian, vaginal, and vulvar cancer, as well as

sarcoma of the uterus. Tumours

tract include,

of the digestive

colorectal, oesophageal,

but are not limited

rectal, small-intestine,

gastric, pancreatic,

gallbladder,

to anal, colon,

and salivary gland cancers.

20

Tumours

of the urinary

tract include,

kidney, renal pelvis, ureter, urethral Eye

cancers

include,

but

are

but are not limited

and human papillary

not

limited

to bladder,

penile,

renal cancers.

to intraocular

melanoma

and

retinoblastoma. Examples of liver cancers include,

25

(liver cell carcinomas

(intrahepatic Skin

with or without

fibrolamellar

variant),

bile duct carcinoma), and mixed hepatocellular

cancers include,

sarcoma,

but are not limited to hepatocellular

malignant

but are not limited

melanoma,

to squamous

carcinoma

cholangiocarcinoma

cholangiocarcinoma.

cell carcinoma,

Kaposi's

Merkel cell skin cancer, and non-melanoma

cancer. 271

skin

WO 2012/136531

cancers include, but are not limited to laryngeal,

Head-and-neck

non-Hodgkin's 5

limited

T-cell

cutaneous

lymphoma,

hypopharyngeal,

to AIDS-related

lymphoma,

Burkitt

lymphoma,

lymphoma,

of the central nervous system.

disease, and lymphoma

Hodgkin's

are not

but

include,

Lymphomas

T/EP2012/055471

cancer, lip and oral cavity cancer and squamous

oropharyngeal

nasopharyngeal,

cell.

PC

Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, fibrous histiocytoma,

malignant

10

lymphocytic

leukemia,

have been well characterized

in humans,

These disorders etiology

chronic

acute

myelogenous

other

in

The term "treating" or "treatment"

be treated

as stated throughout

e.g. , the management

conventionally,

combating,

can

and

mammals,

but also exist with a by

administering

compositions of the present invention.

pharmaceutical

15

leukemia,

and hairy cell leukemia.

leukemia,

similar

chronic

leukemia,

lymphoblastic

to acute myeloid

are not limited

but

include,

Leukemias

and rhabdomyosarcoma.

lymphosarcoma,

alleviating,

reducing,

this document

is used

or care of a subject for the purpose

relieving,

improving

of

the condition of, etc. , of a

disease or disorder, such as a carcinoma.

Methods of treating kinase disorders

20 The present

also provides

invention

associated with aberrant

mitogen

methods

extracellular

limited to stroke, heart failure, hepatomegaly,

disease, cystic fibrosis, 25

kinase activity,

cardiomegaly,

of xenograft rejections,

Effective amounts of compounds of the present invention disorders,

including

section above. compounds

The phrase

Nonetheless,

of disorders

including,

but not

diabetes, Alzheimer' s

septic shock or asthma. can be used to treat such

those diseases (e.g. , cancer) mentioned

in

the Background

such cancers and other diseases can be treated with


the relationship

30

symptoms

for the treatment

regardless of the mechanism

of action and/or

between the kinase and the disorder.

"aberrant

includes any abnormal

kinase

activity"

or "aberrant

tyrosine

kinase

activity,

"

expression or activity of the gene encoding the kinase or of

272

WO 2012/136531

it encodes.

the polypeptide

deletions, substitutions,

mutations,

The present

especially of mitogen amount

diastereoisomeric

of inhibiting

forms thereof.

invention,

prodrugs

a kinase activity,

including

(e.g. :

salts, polymorphs,

esters)

Kinase activity can be inhibited

vitro), or in the cells of a mammalian

an effective

administering

kinase, comprising

solvates,

hydrates,

kinase activity; gene

etc.

for methods

of the present

of a compound

metabolites,

10

extracellular

gene amplification;

or hyperactive

additions,

also provides

invention

but are

activity, include,

of the gene or polypeptide;

which produce constitutively-active

mutations

5

Examples of such aberrant

to, over-expression

not limited

T/EP2012/055471

PC

thereof, in

and

cells (e.g. , in

subject, especially a human patient in need

of treatment.

Methods of treating angiogenic disorders

15

The present

invention

methods

also provides

of treating

and diseases

disorders

associated with excessive and/or abnormal angiogenesis.

organism.

A

of angiogenesis

and ectopic expression

Inappropriate

number of pathological

retinal-vein

to an

conditions are associated with the growth of

extraneous blood vessels. These include, 20

can be deleterious

e. g. , diabetic retinopathy,

of prematurity

occlusion, and retinopathy

[Aiello

et al.

ischemic

New Engl.

J.

1994, 331, 1480; Peer et al. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD; see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996,

Med.

37, 855], neovascular inflammation,

25

graft restenosis, etc. cancerous

and

angiofibroma,

in-stent restenosis, vascular

addition, the increased blood supply associated with

neoplastic

the consequence

invention

(RA), restenosis,

fibroplasias,

tissue,

encourages

growth,

leading to rapid tumour

Moreover, the growth of new blood and lymph vessels

provides an escape route for renegade cells, encouraging

in a tumour

30

In

and metastasis.

enlargement

and

arthritis

rheumatoid

retrolental

psoriasis,

glaucoma,

spread

of the cancer. Thus, compounds

metastasis

of the present

can be utilized to treat and/or prevent any of the aforementioned

angiogenesis by inhibiting,

disorders,

e. g. ,

by inhibiting

blocking, reducing,

and/or reducing blood vessel formation;

decreasing,

273

etc. endothelial cell proliferation or

WO 2012/136531

T/EP2012/055471

PC

as well as causing cell death or apoptosis of

other types involved in angiogenesis, such cell types.

Dose and administration

Based upon standard

tests

toxicity

and

disorders

standard

by

to evaluate compounds

known

pharmacological

assays

for

in mammals,

of these results with the results of known medicaments

comparison

useful

disorders,

and angiogenic

of treatment of the conditions identified above

determination

10

techniques

of hyper-proliferative

for the treatment standard

laboratory

by

the

and by

that are used

to treat these conditions, the effective dosage of the compounds of this invention for treatment

can readily be determined

to be administered

of the active ingredient

15

of each desired indication. in

of one of these

the treatment

to such considerations

The amount

as the particular

conditions

can vary widely

compound

and dosage unit employed,

treatment,

the age and sex of the patient treated, and the nature and extent of

according

the period of

the mode of administration,

the condition treated.

to be administered

The total amount of the active ingredient

20

from about

0.001

from about

0.01

will generally

range

to about 200 mg/kg body weight per day, and preferably

mg/kg

to about 20 mg/kg body weight per day. Clinically useful

mg/kg

dosing schedules will range from one to three times a day dosing to once every four

weeks dosing.

In

addition,

drug for a certain period

mg

to about 1500

mg

is not dosed with a

of time, may be beneficial to the overall balance between

effect and tolerability.

pharmacological

25

"drug holidays" in which a patient

A unit

of active ingredient,

dosage may contain from about 0. 5

one or more

and can be administered

times per day or less than once a day. The average daily dosage for administration by injection,

injections, mg/kg

30

intravenous,

and use of infusion

of total

preferably vaginal

including

body

weight.

techniques

will

The average

be from 0.01 to 200 mg/kg

dosage regimen

will preferably

administered

between

one

preferably

daily

and parenteral

be from 0.01 to 200

rectal dosage

regimen

will

of total body weight. The average daily be from 0.01 to 200 mg/kg of total body

weight. The average daily topical dosage regimen

200 mg

subcutaneous

intramuscular,

to four 274

will preferably

times

daily.

be from 0. 1 to

The

transdermal

WO 2012/136531

concentration

PC

be that required

will preferably

to maintain

a daily dose of from

0.01 to 200 mg/kg. The average daily inhalation dosage regimen from 0.01 to 100 mg/kg of total body weight. Of course the specific initial and continuing 5

and

diagnostician,

10

mode of treatment

and number

or a pharmaceutically

invention

of administration,

time

patient,

by the

the age route

of

and the like. The

of doses of a compound

of the present

acceptable salt or ester or composition thereof can

be ascertained by those skilled in the art using conventional

Preferably,

employed,

rate of excretion of the drug, drug combinations,

administration,

desired

of the

be

dosage regimen for each patient will

the activity of the specific compound

condition

general

will preferably

to the nature and severity of the condition as determined

vary according

attending

T/EP2012/055471

the diseases of said method are haematological

treatment tests.

solid tumour

tumours,


15

of the present invention can be used

The compounds prevention, tumours

i. e.

in

particular in therapy and

of tumour growth and metastases,

prophylaxis,

especially in solid

of all indications and stages with or without pre-treatment

of the tumour

growth.

20 Methods of testing for a particular

or pharmaceutical

pharmacological

property are

well known to persons skilled in the art.

The example testing experiments 25

invention

and the invention

is not limited to the examples given.

Biological assay: Proliferation

30

Cultivated

described herein serve to illustrate the present

Assay

tumour cells (MCF7, hormone dependent

cells, ATCC HTB22; NCI-H460, human DU

HTB-81;

HeLa-MaTu,

human

mammary

carcinoma

non-small

cell lung carcinoma cells, ATCC

human

prostate carcinoma cells, ATCC

145, hormone-independent

HTB-177;

human

cervical

carcinoma

275

cells,

EPO-GmbH,

Berlin;

WO 2012/136531

HeLa-MaTu-ADR,

PC

multidrug-resistant

Berlin; HeLa human

cervical carcinoma

human

cells, EPO-GmbH,

cervical tumour cells, ATCC CCL-2; 816F10 mouse melanoma

cells, ATCC CRL-6475) were plated at a density of 5000 cells/well HeLa-MaTu-ADR), 5

3000 cells/well

(NCI-H460, HeLa-MaTu,

(816F10) in a 96-well multititer plate supplemented

10%

T/EP2012/055471

(MCF7, DU145,

HeLa), or 1000 cells/well

200 IjL of their respective growth medium

in

fetal calf serum. After 24 hours, the cells of one plate

(zero-point plate) were stained with crystal violet (see below), while the medium

of the other plates was replaced by fresh culture medium

test substances were added 10

of 0.01-30 IjM; the final concentration The cells were incubated

proliferation

in

the presence of test substances.

15 minutes at room temperature.

point of an 11% glutaric aldehyde solution for

After three washing cycles of the fixed cells with

water, the plates were dried at room temperature. adding 100 Ijl/measuring washing

point of a

cycles of the stained

temperature.

0. 1% crystal violet

The cells were stained by solution (pH

3.0). After three

cells with water, the plates were dried at room

The dye was dissolved

100 Ijl/measuring

by adding

acetic acid solution. The extinction was determined 20

Cell

the cells with crystal violet: the cells

by staining

were fixed by adding 20 Ijl/measuring

15

of the solvent dimethyl sulfoxide was 0. 5%).

for 4 days

was determined

(0 pM, as well as in the range

concentrations

in various

(200 Ijl), to which the

by photometry

point of a 10%

at a wavelength

of 595 nm. The change of cell number, in percent, was calculated by normalization of the measured

of the untreated

the extinction determined

values to the extinction

values of the zero-point plate (=0%) and

(0 Ijm) cells (=100%). The IC50 values

by means of a 4 parameter

were

fit using the company's own software.

25 Mps-1 kinase assay

The human kinase Mps-1 phosphorylates

of the phosphorylated

30

energy transfer

antibody

substrate peptide. Detection

product is achieved by time-resolved

(TR-FRET) from Europium-labelled

as donor

(SA-XLent) as

a biotinylated

to streptavidin

labelled

with

fluorescence resonance

anti-phospho-Serine/Threonine

cross-linked

allophycocyanin

acceptor. Compounds are tested for their inhibition of the kinase

activity.

276

WO 2012/136531

N-terminally

PC

GST-tagged human Karslruhe,

from Invitrogen,

the

reaction

kinase

a

biotinylated

no PV4071) was used. As substrate for

sequence

amino-acid

of the

peptide

in amide form, purchased

(C-terminus

PWDPDDADITEILG

cat.

Germany,

Mps-1 kinase (purchased

recombinant

full length

T/EP2012/055471

from Biosynthan

GmbH,

Berlin) was used.

solution of the test compound

For the assay 50 nL of a 100-fold concentrated DMSO was

pipetted into a black low volume 384well microtiter plate (Greiner

Bio-One, Frickenhausen,

10

in

2 pl

Germany),

of Mps-1 in assay buffer

of a solution

10 mM MgCl&, 2 mM DTT, 25 mM Hepes pH 7. 7, [0.1 mM sodium-ortho-vanadate, 0.05% BSA, 0.001% Pluronic F-127] were added and the mixture was incubated for 15 min at 22'C to allow pre-binding

of the test compounds

to

Mps-1

before the

start of the kinase reaction. Then the kinase reaction was started by the addition of 3 Ijl of a solution of 16.7 adenosine-tri-phosphate

(1.67 IjM

the 5 pl assay volume is 10 IjM) and peptide substrate 15

5 Ijl assay volume is

1

IjM) in assay buffer and

16.7

(ATP,

pM =& =&

final conc. in the

the resulting mixture was incubated

for a reaction time of 60 min at 22 C. The concentration

of Mps-1

the assay was

in

adjusted to the activity of the enzyme lot and was chosen appropriate

20

nM

0. 1%

The reaction was stopped by the

(final conc. in the 5 Ijl assay volume).

addition

of 3

pl

40

BSA,

to have the

were in the range of about

assay in the linear range, typical enzyme concentrations 1

final conc. in

of a solution of HTRF detection reagents (100 mM Hepes mM

EDTA,

140

nM

anti-phospho(Ser/Thr)-Europium-a Rodgau- Jugesheim,

n

7. 4,

[¹61GSTXLB, Fa. Cis France], 1. nM

Streptavidin-XLent

Marcoule,

Biointernational,

pH

5

t i b o d y [ ¹A D 01 8 0,

P

erkin

Elm

er

LA

S,

Germany].

25

The resulting phosphorylated

Subsequently

peptide

to

the

1 h

at 22

energy

anti-phospho(Ser/Thr)

antibody

to

fluorescence

emissions

at 620

nm and

measured

in

a Viewlux

Germany).

The "blank-corrected

similar to the traditional

to allow the binding of the

substrate was evaluated

the amount of phosphorylated of the

C

anti-phospho(Ser/Thr)-Europium-antibody.

resonance

measurement

30

mixture was incubated

the

transfer

normalized

the

Europium-labelled

Therefore, the after excitation at 350 nm was

Streptavidin-XLent.

665 nm

TR-FRET reader

from

by

(PerkinElmer

ratio"

(

LAS,

Rodgau-Jugesheim,

a Viewlux specific readout,

ratio of the emissions at 665 nm and at 622 nm, in which

277

WO 2012/136531

PC

blank and Eu-donor crosstalk are subtracted

T/EP2012/055471

from the 665 nm signal before the

ratio is calculated) was taken as the measure for the amount of phosphorylated substrate.

5

The data were normalised

reaction without

(enzyme

0

all other assay components

compounds

were tested on the same microtiter plate at 10 different concentrations

the range of 20

27 nM,

9.2

nM,

3. 1

IjM

to

nM and

1

nM 1

(20

6.7

IjM,

nM, dilution

IjM,

2.2

0.74

pM,

series prepared

level of the 100fold conc. stock solutions by serial

for each concentration

=

but no enzyme

IjM,

0.25

IjM, 82 nM,

before the assay at the

1:3 dilutions)

and ICso values were calculated

%

100 /o inhibition). Test

inhibition,

in

10

=

inhibitor

in duplicate

by a 4 parameter

values

fit using

an in-house software.

It was surprisingly formula

I

found that the inhibitory

can be positively influenced

activity of compounds

of general

by R' being an aryl-X- or heteroaryl-X-

group.

Therefore, compounds of general formula I, supra, in which R' represents an aryl15

X- or heteroaryl-X-

group (X being selected from

are preferred.

20

25

30

278

0,

S, S(=0), S(=0)&, NR, CR'R")

WO 2012/136531

PC

T/EP2012/055471

Table

Example

2-1

2-2

3-1

3-2

3-3

Mps-1 [nM]

ICED

10.5 0.9 0. 3 0.6 0. 3 0. 5

Mps-1 [nM]

Example

ICED

27

4. 2 13.9 1.3 0.4 1.3 0.9 0.7 6.2 6. 3

28

29

30 31

32

33

3-4

Example

59

1.5

60

64

2. 3 4. 9 49.3 59.7 8.6

65

131

66

161

67

72. 8

68

124

61

62

63

34

3-6

0.8 0.4

5-1

84. 1

36

0. 3 0. 3 3.4 0.4 2. 9 3.8

37

23

69

38

29.6

70

3-5

6-1

10 12 (rac. -

35

39 (rac.

-

2. 9 5. 3 0.4 17.6 25. 2

42

0.8

44 45

11.9

65. 2

47

55

48

29.4

49

17

108

50

18

65. 5

51

19

52

21

0.7 41. 1 33.7

7.6 2. 1 97.6 7. 3 40. 6 0.9 19.5

54

16

22

50

55

2. 9 7.8 12.6 5.7

25 25

53

2. 9

57

1.9

58

78

83

30.3 2. 1 35.6 19.8 21.3 68.7

84

243

85

199

86

56.7 70. 3

79 80 81

82

87 88

56

24

51

73

ent. -A)

20

105

77

4. 9

43

15

76

72

0.7

14

157

39 (ent. -A or A) 39 (A or

12 (ent. -A or A) 12 (A or

13

75

71

3. 1

41

A)

74

3.8 1.8 0.6 1.2 6.8

A)

ent. -A)

279

Mps-1 [nM]

ICED

89

90 91

9.8 6.9 15.9 20. 6

WO 2012/136531

PC

Mps-1

Example

ICED

[nM]

Mps-1

Example

ICED

[nM]

13.2

127

62. 5

128

94

68. 6 84. 3

95

140

130

123

131

9.5 0. 5 0.9 1.4

47. 4 29.4

132

99 100

13.3

134

106

135

101

123

136

102

103

92

93

T/EP2012/055471

Mps-1

Example 162

ICED

[nM]

167

8.6 1.3 13.8 48. 3 4. 6 6.2

168

279

169

21.7

170

176

171

131

137

12.6 13.7 8.4 0. 5 2. 2

172

115 77.8

156

138

1.3

173

8.2

65. 3 49. 8

139

174

816

175

3.0

1.6 1.8 6. 3

141

36. 1 26. 2

176

1.8

142

244

177

20.4

143

33.2

178

2.2

17.8 0.6 5.8 21.8 45. 1 75. 3 59.4 19.9

144

233

145

250

146

3.2 0. 5

9.4 19.9

152

54. 7

154

120

42. 2

155

121

1.5 1.9 0.8 0.7

156

97 98

104 105

106

107 108

109

110 112

113 114 115 116 117 118 119

122

123 124 125

126

146

129

133

140

147 148

149

150

160

0.8 2. 6 0.8 0. 5 12.7 21.1 21.3 15.3 6.2 9. 1 2. 3

161

2. 3

151

153

157 158

159

280

163 164 165

166

WO 2012/136531

T/EP2012/055471

PC

Spindle Assembly Checkpoint Assay The spindle assembly

begin to condensate which is

during mitosis. Upon entry into mitosis, chromosomes 5

by the phosphorylation

accompanied

of histone

H3 on

of histone

H3 on

of histone

serine 10 can be utilized as a marker

H3 on

of cells in mitosis. Nocodazole is a microtubule interferes

nocodazole

10

checkpoint.

assembly

the

mobilises

and

dynamics

The cells arrest in mitosis at G2/M transition

spindle

and exhibit

of the spindle assembly

overrides the mitotic blockage in the presence of

by Mps-1 inhibitors

nocodazole, and the cells complete mitosis prematurely.

This alteration

decrease of cells with phosphorylation

H3 on

by the

15

microtubule

with

substance. Thus,

destabilizing

histone H3 on serine 10. An inhibition

phosphorylated checkpoint

serine 10. Dephosphorylation

serine 10 begins in anaphase and ends at early telophase.

phosphorylation

Accordingly,

of chromosomes

assures the proper segregation

checkpoint

decline is used as a marker to determine

of histone

is detected

serine 10. This

the capability of compounds of the

present invention to induce a mitotic breakthrough.

cells of the human

Cultivated

at a density of 2500 cells/well

plated

20

cervical tumour cell line HeLa (ATCC CCL-2) were

Dulbeco's Medium (w/o phenol red, w/o sodium pyruvate,

supplemented

w pyridoxine)

streptomycin

with 1% (v/v) glutamine,

24

h

concentrations

concentration in

solubilised

(0

and blocked in

15

1% (v/v) penicillin,

1% (v/v)

overnight at 37'C, 10

of 0. 1 Ijg/ml were added to cells. After

in dimethyl

sulfoxide

as well as in the range of 0. 005 IjM DMSO was

0.5% (v/v)).

at various

(DMSO) were added —

10

IjM;

min.

in

buffered saline (PBS) at 4

in phosphate

0. 1%

(v/v) Triton

0. 5% (v/v) bovine After

washing

X™ 100 in with

C

PBS,

(BSA) in PBS

20

Ijl/well

h

at

4% (v/v)

overnight

PBS at room temperature

serum albumin

the final

Cells were incubated for 4

the presence of test compounds. Thereafter, cells were fixed in

permeabilised

for

pM,

of the solvent

paraformaldehyde

30

1000 mg/ml glucose,

cells were arrested at G2/M phase of the cell cycle progression.

incubation,

Test compounds

37'C

w

and 10% (v/v) fetal calf serum. After incubation

Ijl/well nocodazole at a final concentration

25

384-well microtiter plate in 20 Ijl

in a

then

for 20 min

at room temperature antibody

solution

Cat¹ 16-222; 1:200 dilution) was added to cells, which were incubated for 2 h at room temperature. (anti-phospho-histone

H3

clone 3H10, FITC; Upstate,

281

WO 2012/136531

cells were washed

Afterwards,

20 pl/well

PBS and

with

12 min at room

the dark. Cells were washed twice with PBS then covered with PBS

in

at 4'C until analysis. Images were acquired with a Perkin Elmer OPERA™

and stored 5

33342 dye

HOECHST

solution (5 pg/ml) was added to cells and cells were incubated

temperature

T/EP2012/055471

PC

High-Content

Analysis reader. Images were analyzed

with image analysis software

MetaXpress™ from Molecular devices utilizing the Cell Cycle application module. this assay both labels HOECHST 33342 and phosphorylated

were measured.

33342 labels

HOECHST

staining of phosphorylated

10

DNA

and is used to count cell number. The

Histone H3 on serine 10 determines

presence of nocodazole indicating

15

logistic regression analysis to

value for each tested compound.

to persons skilled

It will be apparent may be performed

in analogy using

25

cell growth,


in which

the uncontrolled

cellular

immune

syndrome,


30

lung tumours,

gynaecological tumours,

responses

thereof,

lymphomas,

tumours,

inappropriate

cell

cellular immune responses, or

are haemotological

tumours,

solid

e.g. leukaemias and myelodysplastic non-small

endocrine tumours,

urological tumours including and sarcomas,

responses is

the diseases of uncontrolled


tumours,

cellular

responses, particularly


tumours of the thorax including

gastrointestinal

skin tumours,

in which

of diseases of



metastases

malignant

and/or survival,

or inappropriate


and/or

or prophylaxis


by Mps-1, more particularly

inappropriate

reagents.


responses,

growth, proliferation

tumours

the appropriate

proliferation

immune

mediated

the art that assays for other Mps kinases

suitable for the treatment

kinases and are therefore

uncontrolled

in

of the present invention effectively inhibit one or more Mps-1

Thus the compounds

20

the number of

mitotic progression. The raw

an inappropriate

assay data were further analysed by four parameter ICED

Histone H3 on serine 10

of Mps-1 decreases the number of mitotic cells in the

mitotic cells. Inhibition

determine the

In

cell and small cell

mammary

and other



282

brain tumours

WO 2012/136531

PC

of in

Investigation

vi

tro metabolic

stability

in

T/EP2012/055471

rat hepatocytes

(including

calculation of hepaticin vivo blood clearance (CL))

After perfusion,

were gently shaken out into a Petri dish with ice-cold

was filtered through

cell suspension

WME. The resulting

at 50

falcon tubes and centrifuged

pellet was resuspended

in

30 ml

sterile gaze in 50 ml

for 3 min at room temperature.

xg

centrifuged

WME and

(WME) and resuspended

a Percoll

through

containing

in medium

5% FCS. Cell

For the metabolic stability assay liver cells were distributed FCS

to glas vials at a density of 1.0

added

to a final concentration

x

of

in WME containing

IjM.

1

HPLC-system

rpm

and the supernatant

were immediately

was analyzed

From the half-life the intrinsic

parameters

centrifuged

with

for 15

an Agilent

from the concentration-time

L/h/kg

liver blood flow, amount

parameter

The following

rat; specific liver weight

10' cells/g liver, liver cells in It was surprisingly formula

I

vi

—

tro

values were used: Liver blood flow

32 g/kg rat body weight; liver cells in vivo—

R"(R")N-C&-Cp-alkyl-,

)

—

4. 2

1.1 x

atom. Therefore, C~-C~-alkoxy-,

R

and/or

halo-C~-C~-alkyl-,

NC-C&-Ce-alkyl-,

Preferably,

of general

at least one of the groups R" and R"

by

HO-C&-Cp-alkyl-,

halo-C~-C~-alkoxy-C~-C~-alkyl-.

(F

0.5 x 10'/ml.


-CN, -OH, C~-C~-alkyl-,

plot.

of liver cells in vivo and in vitro.

found that the metabolic stability of compounds

being different from a hydrogen

halo-,

1200

clearances were calculated. Together with the

The hepatic in vivo blood clearance (CL) and the maximal oral bioavailability was calculated.

30

added.

with LCMS/MS detection.

The half-life of a test compound was determined

additional

the hepatocyte

During incubation,

Samples were frozen at -20' C over night, after subsequently

at 3000

5%

10' vital cells/ml. The test compound was

and 90 min, to which equal volumes of cold methanol

minutes

viability was

shaken and aliquots were taken at 2, 8, 16, 30, 45

were continuously

suspensions

25

gradient

by trypan blue exclusion.

determined

20

The cell

for 2 times at 100 x g. The hepatocytes were washed again with Williams' medium E

15

method.

the liver was carefully removed from the rat: the liver capsule was

opened and the hepatocytes

10

via a 2-step perfusion

from Han Wistar rats were isolated

Hepatocytes

R" and/or

283

R

' are

selected from

halo-C~-C~-alkoxy-,

C&-Ce-alkoxy-C&-Cp-alkyl-,

R~ are selected from halo-,

WO 2012/136531

PC

T/EP2012/055471

'

are selected

R" and/or R" are selected

from halo-,

found that the metabolic stability of compounds

of general

-CN, -OH, C&-C6-alkyl-, C&-C6-alkoxy-; more

from halo-, C~-C6-alkyl-; most preferably,

preferably,

R

and/or

R

C&-C~-alkyl-.

It was surprisingly 5

formula

I

Compounds

of formula

I

by R' being a

1, 1, 1-trifluoroethyl group. with R' being a 1,1, 1-trifluoroethyl group are therefore


preferred.

10

284

WO 2012/136531

PC

T/EP2012/055471

CLAIMS

1. A compound of general

formula

I

R NH N

R A

in which

A

represents a 4a

4a

H

4b

R

4d

N

R

Z

N

/

4c 4b

4c

H

10

gloup j

OI

wherein



the molecule; 15

Z


R'

represents a hydrogen atom or a C~-C6-alkyl-, a C~-C6-cycloalkyl- or an arylgroup j

wherein 20

identically

said C~-C6-cycloalkyl-

or differently,

or aryl-

group is optionally

substituted,


-OH, -CN, C&-C6-alkyl-, C&-C6-alkoxy-, Cz-C6-cycloalkyl-,

285

HO-C&-C6-alkyl-;

WO 2012/136531

wherein

PC

said

differently,

R~

identically or


with

-OH,

-CN,

HO-C~-Ce-alkyl-;


5

substituted,

group is optionally

C&-Ct;-alkyl-

T/EP2012/055471


differently,

substituted,


identically or



wherein

10

said

differently,

1, 2, 3, or 4

with

substituted,

group is optionally

C&-Ct;-alkyl-

—

identically or


groups

OH, -CN,

-C& -C6-alkoxy;

15

represents a hydrogen

atom or a halogen atom, or a -CN, C~-C6-alkyl-,


-(CH&) -C&-C8-cycloalkenyl,


-(CH~) -(4-

to

-(CH&)

8-membered


heterocycloalkyl-,

7-membered

-C&


25

-C(=0)N(R")R'

a r y l-X-,

-C(=0)0-R'

-N(R")R'

30

3-

C&-Ce-cycloalkyl-,


7-membered

-NO&,

-C6-alkyl-X-,

to

8-membered

-C(=0)N(H)R", -OR'

-N(H)C(=0)R'

-SR'

-S(=0)zN(R~b)R6', -S-(CHz) -N(R6')R6b



aryl-C~-C6-alkyl-,

to 7-membered

heterocycloalkyl-,

C&-C6-alkynyl-,

or

group;


C&-C6-alkenyl-,

aryl-,

C&

-C6-alkyl-X-,



to

-C(=0)R',

heteroaryl-X-,

heterocycloalkyl)

-Ct;-alkyl-,


C&

aryl-,

-X-(CH~) -(3-

-X-(CHz) -(4-

heterocycloalkyl),

C&

C~-C6-alkynyl-,


-S-(CHz), -(3- to 7-membered

said

7-membered


-S(=0)R6 -S(=0)zR6 -S(=0)(=NR6')R6b

wherein

to

heteroaryl-,




aryl-C~ -C6-alkyl-,

3-

C~-C6-cycloalkyl-,


7-membered

heterocycloalkyl),


halo-C&-C6-alkyl-,

C~-C6-alkenyl-,


to



20

-(3-


-X-(CHz) -C~-Ce-cycloalkyl, -X-(CHz) -(4-

heterocycloalkyl),

286

-X-(CH~) -(3-

to

to

8-membered

WO 2012/136531


aryl-X-,


R',

R',

R

-C&-C6-alkyl-aryl,

substituted,

group is optionally

1, 2, 3, 4 or

with

5 R' groups;

R



heteroaryl-X-,

heteroaryl-

or


5

T/EP2012/055471

PC

C~-C6-alkoxy-,

-OH, C~-Ct;-alkyl-,


HO-C&



halo-C~-C6-alkyl-,

halo-C~-C6-alkoxy-,

-C6-alkyl-,

NC-C&-C6-alkyl-,


group;

10 R'

represents

atom, or a

a hydrogen



-(CH&)~-(3-

to 7-membered


heterocycloalkyl),



C~-C6-alkyl-,

HO-C&


to 7-membered

-C6-alkyl-,

-Cl C6 alkyl-CN,


heterocycloalkyl-,


3-

Cz-C6-cycloalkyl-,


group j

wherein 20

said


-(CH~) -(3-

aryl-C& -C6-alkyl-,


R"(R'

to 7-membered

7-membered



heterocycloalkyl-,

group is optionally

to


HO-C~ -Ce-alkyl-,

)N-C&-C6-alkyl-,




substituted,

C~-C6-cycloalkyl-,

3-


1, 2, 3, 4 or 5

R' groups;

25

R

R',

R

R'

represent, C~

30


C~-C6-alkyl-,

-Ce-alkyl-,

independently H

7-membered


0-C~ -C6-alkyl-,

heterocycloalkyl-,


C~-C6-alkenyl-,

C~-C6-cycloalkyl-,

aryl-,

atom, or a

heteroaryl-,

3-

aryl-C&-C6-alkyl-,

to or

group;


group is optionally

substituted,

identically or


differently with

1

HO-C&-C6-alkyl-,


287

halo-C&-C6-alkoxy-;

WO 2012/136531

R'

represents

a hydrogen

-C6-alkyl-,

C~-C6-alkenyl-,

heteroaryl-,

-C( 0)R6

-N02i

-N(H)C(=0)R

-N(R ')C(=0)N(R ')R

-N(R6')S(=0)R6

10

3- to 7-membered

-N(R

-S(=0)N(R")R6b

-N(R ')C(=0)OR

N(R6a)R6b

-N(H)S(=0)R

-N=S(=0)(R6')R6b

-S(=0)R

-SR

-0(C=O)OR

-S(=0)~R'

R6

aryl-,

-N(H)C(=0)N(R ')R

-N(R6')S(=0)&R6

-0(C=O)N(R ')R

-0(C=O)R

0)0

C(

')C(=0)R

-N(H)C(=0)OR

-N(H)S(=0)zR6

C~-C6-alkoxy-,

heterocycloalkyl-,

C( 0)N(R6a)R6b

C( 0)N(H)R6a

-CN,


C&-C6-alkoxy-C& -C6-alkyl-,

C~-C6-alkynyl-,

T/EP2012/055471

R"(R")N-C&-C6-alkyl-,

halo-C&-C6-alkoxy-,

halo-C&-C6-alkyl-,

C&-C6-alkyl-, HO-C&

or halogen atom or a HO-,

PC

-OR6

-S(=0)N(H)R

or

-S(=0)~N(R")R6b

-S(=0)~N(H)R'



or differently, 15

1, 2 or 3

with

substituted,

group is optionally

identically

C&-C6-alkyl- groups;

or


* represent


attachment

the point of

to said aryl ring;

20 Rs

represents a hydrogen or halogen atom or a -CN, C~-C6-alkoxy-, C~-C6-alkyl-, halo-C~-C6-alkyl-,




3- to 7-membered

C~-C6-alkynyl-,

25

C( 0)R6

-N(H)C(=0)R

-N(R

0(C 0)N(R6a)R6b 7-membered wherein

SR6

0(C 0)OR6

-S(=0&)R' -S(=0)&N(H)R'

heteroaryl-,

N(R6a)R6b

-N(R ')C(=0)N(R

-N(R -OR

S( 0)N(H)R6

NO

')R

')S(=0)R -0(C=O)R

S( 0)N(R6a)R6b

-S(=0)(=NR")R' or -S(=0)&-(3- to

group;



S( 0)R6

-S(=0)&N(R")R6b

heterocycloalkyl)

R6

-N(H)S(=0)R

-N=S(=0)(R ')R

-N(R ')S(=0)2R

-N(H)S(=0)2R

0)0

C(

C2-C6-alkenyl-,

aryl-,

-N(H)C(=0)N(R ')R

')C(=0)R

-N(R ')C(=0)OR

-N(H)C(=0)OR

30

heterocycloalkyl-,

C( 0)N(R6a)R6b

C( 0)N(H)R6a

HO-C&-C6-alkyl-,

heterocycloalkyl-


groups j

288

or heteroaryl-

group, is

with 1, 2, 3 or 4 C&-C6-alkyl-

WO 2012/136531

PC

m


n


X

is S, S(=0), S(=0)z,

or a stereoisomer,

0,

a tautomer,

6;

5; and

C(=0) or CR"Reb

NRe

T/EP2012/055471

'




10

2. A compound according to claim 1, wherein R'

represents C~-Ce-cycloalkyl- or a C~-C4-alkyl- group; wherein said Cz-Ce-cycloalkyl-

differently, C~

-Ce-alkyl-,

wherein

15

C&

C&

-Ce-alkoxy-, C~-Ce-cycloalkyl-,

group is optionally

C&-C&-alkyl-

with

HO-C~

1, 2, 3 or 4 groups

-OH,

-CN,

-Ce-alkyl-;

substituted,

selected

from:

identically or halogen,

-CN,

-Cp-alkoxy-, C&-Ce-cycloalkyl-;

or a stereoisomer,

20

identically or


said

differently,

substituted,

group is optionally

a tautomer,




3. A compound A

according to claim

1

or 2, wherein

represents a 4a 4b

R

4d

Z

4c group

j

25 wherein


the molecule; and Z

represents a -C(=0)N(H)R' group;

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or a stereoisomer,

a tautomer,

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4. A compound R'

r

e

p r

according to claim 1, 2 or 3, wherein:

ese

n

ts a

rog e

h y d

-(CH~)m-C~-C|;-alkenyl,

a

n

tom o

-(CH~)m-C~-C|;-alkynyl,

r

aryl-X-

or

differently,

or a stereoisomer,


a tautomer,

C&-C|;-alkyl-,

-CN,

aryl-, heteroaryl-,

wherein said C&-C|;-alkyl-, -(CH&)m-C&-C|;-alkenyl,

10

a

aryl-X- group;

-(CH&)m-C&-C|, -alkynyl,

substituted,


aryl-,

identically

or



15

5. A compound R'

according to any one of claims 1, 2 or 3, wherein

represents a an aryl- or aryl-X- group; wherein

or a stereoisomer,

a tautomer,




6. A compound R'

according to claim 1, 2, 3, 4 or 5, wherein:

represents

a C&-Ct;-alkyl-,

halo-C~-C|, -alkyl- or

25

identically or


differently,

20

substituted,

said aryl- or aryl-X- group is optionally

wherein

C~

-(CH&)

-(3- to 7-membered

heterocycloalkyl),

-C|;-alkoxy-C~ -Ct;-alkyl- group;

said C&-C|;-alkyl-,

-(CHz) -(3-

to 7-membered

heterocycloalkyl),

halo-C~-C|, -alkyl- or C~-Ct;-alkoxy-C~-C|, -alkyl- group is optionally


or a stereoisomer,

a tautomer,

with

1, 2, 3, 4 or

substituted,

5 R' groups;




30

7. A compound R4' and R4'

according to claim 1, 2, 3, 4 or 5, wherein

represent a hydrogen atom; and

one of the groups R" and R" represents

a hydrogen

atom while the other one

represents a group selected from: halo-, -CN, -OH, C&-C|;-alkyl- and C&-Ct;-alkoxy-;

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or a stereoisomer,

a tautomer,

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5

8. A compound R' R R', R

according to any one of the claims

represent, independently C3 Ce


10

1

to 7, wherein


cycloalkyl- or aryl-C~-Ce-alkyl-

differently with

1


group;

group is optionally

substituted,

identically or


HO-C~ -Ce-alkyl-;

or a stereoisomer,

a tautomer,




9. A compound 15

R'


represents

a halogen

halo-C~-Ce-alkyl-, N(Rea)Reb

or a stereoisomer,

atom, or

halo-C~-Ce-alkoxy-,

1

to 8, wherein

a HO-,

C&-Ce-alkoxy-,

HO-C~-Ce-alkyl-,

C&-Ce-alkyl-,

-C(=O)N(H)R",

C( O)O Re or -ORe group;

a tautomer,




20

10. A

compound

according to claim 1, which is selected from the group consisting

of: N-cyclopropyl-4-[8- [(2-methylpropyl)amino]imidazo[1,

2-a] pyridin-3-yl/benzamide,

N-cyclopropyl-4-[6- [2-(hydroxymethyl)phenyl]-8[(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

N-cyclopropyl-2-methyl-4-[6-(pyridin-4-yl)-8[(3,3, 32-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1,

N-cyclopropyl-4-[6-[(3-fluoro-5-methylphenyl)sulfanyl]-8[(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

N-cyclopropyl-4-[6-[(2, 3-difluorophenyl)sulfanyl]-8-[(3, 3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1, N-cyclopropyl-2-methyl-4-[6-(phenylsulfanyl)-8-[(3, 3, 32-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1,

291

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4-[6-[(2-aminophenyl)sulfanyl]-8[(3,3, 3-trifluoropropyl)amino]imidazo[1, pyridin-3-ylf-N-cyclopropyl-2-methylbenzamide, a]

2-

N-cyclopropyl-4-[6- [(3-fluorophenyl)sulfanyl] -8- [(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1, -8- [(3,3, 3N-cyclopropyl-4-[6- [(2- hydroxyphenyl)sulfanyl] 2-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

N-cyclopropyl-2-methyl-4-[6-(methylsulfonyl)-8-[(3, 3, 32-a] pyridin-3-yl]benzamide, trifluoropropyl)amino]imidazo[1,

N-cyclopropyl-4-[6-(2-fluoro-4-methoxyphenoxy)-8-[(3, 3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

N-cyclopropyl-4-[6-(3-fluorophenoxy)-8-[(3, a] pyridin-3-ylf-2-methylbenzamide,


4-[6-(3-fluorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-

2-a]pyridin-3-yl)-

N, 2-dimethylbenzamide,

4, 4'-[8- [(tetra hydro-2H-pyran-4-ylmethyl)amino]imidazo[1,

2-a] pyridine-3, 6-

diyl]bis(N-cyclopropyl-2-methylbenzamide),

N-ethyl-4-[6-(3-fluorophenoxy)-8-[(3, a] pyridin-3-yl]-2-methylbenzamide,


4-[6-(3-fluorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-

2-a]pyridin-3-yl)-

2-methyl-N-(1-methylcyclopropyl)benzamide,

[rel-(1S, 2S)-2-fluorocyclopropyl]-4-$6-(3-fluorophenoxy)-8[(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1, N-

N-[[(1R, 2R) or (1S,2S)]-2-fluorocyclopropyl$-4-$6-(3-fluorophenoxy)-82-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

[(3,3, 3-

N-[[(1S,2S) or (1R, 2R)]-2-fluorocyclopropyl$-4-$6-(3-fluorophenoxy)-82-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

[(3,3, 3-

N-(1-cyanocyclopropyl)-4-(6-(3-fluorophenoxy)-8[(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1, 4-(6-ethynyl-8- [(3,3, 3-trifluoropropyl)amino]imidazo[1, dim ethylbenzamide, N-ethyl-4-[6-ethynyl-8methylbenzamide,

2-a] pyridin-3-ylf-


N,

2-

2-a] pyridin-3-ylI-2-

4-[6-ethynyl-8- [(3,3, 3-trifluoropropyl)amino]imidazo[1, (1R, 2R)-2-fluorocyclopropyl]-2-methylbenzamide,

2-a] pyridin-3-ylf-

4-[6-ethynyl-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a]pyridin-3-ylf-2-methyl-N-

N-

[rel-

(1-methylcyclopropyl)benzamide,

N-(1-cyanocyclopropyl)-4-[6-ethynyl-8a] pyridin-3-ylf-2-methylbenzamide,


N-cyclopropyl-4-[6-(5-fluoro-2-methylphenoxy)-8[(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

292

2-

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T/EP2012/055471

2-

4-(6-(3-hydroxyprop-1-yn-1-yl)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, a] pyridin-3-yl]-N, 2-dimethylbenzamide, N-ethyl-4-(6-(3-hydroxyprop-1-yn-1-yl)-8-[(3, a] pyridin-3-yl)-2-methylbenzamide,

2-

4-(6-(3-hydroxyprop-1-yn-1-yl)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, a] pyridin-3-yl]-2-methyl-N-(1-methylcyclopropyl)benzamide, N-(1-cyanocyclopropyl)-4-f6-(3trifluoropropyl)amino]imidazo[1,

2-


hydroxyprop-1-yn-1-yl)-8- [(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide,

N-cyclobutyl-4-f6-(3-fluorophenoxy)-8a] pyridin-3-yl]-2-methylbenzamide,


4-(6-(5-fluoro-2-methylphenoxy)-8-[(3, a] pyridin-3-ylf-N, 2-dimethylbenzamide,


22-

N-ethyl-4-f6-(5-fluoro-2-methylphenoxy)-8[(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

4-(6-(5-fluoro-2-methylphenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, a] pyridin-3-ylf-2-methyl-N-(1-methylcyclopropyl)benzamide,

2-

N-(1-cyanocyclopropyl)-4-f6-(5-fluoro-2-methylphenoxy)-8[(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

N-[rel-(1S, 2S)-2-fluorocyclopropyl]-4-$6-(5-fluoro-2-methylphenoxy)-82-a] pyridin-3-yl]-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

[(3,3, 3-

N-cyclopropyl-4-(6-(2, 3-difluorophenoxy)-8-[(3, 3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,


2-a]pyridin-3-yl)-

N-cyclopropyl-2-methylbenzamide,

4, 4'-I 8-[(3,3, 3-trifluoropropyl)amino]imidazo[1,

2-a]pyridine-3, 6-diyl/bis(N-

cyclopropyl-2-methylbenzamide),

N-cyclopropyl-2-methyl-4-(6-phenoxy-8-[(3, a] pyridin-3-yl]benzamide,


4-(6-(3-chlorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, N,

2-

2-a]pyridin-3-ylj-

2-dimethylbenzamide,


2-a]pyridin-3-yl)-

N-ethyl-2-methylbenzamide,


2-a]pyridin-3-yl)-

2-methyl-N-(1-methylcyclopropyl)benzamide,


2-a]pyridin-3-ylf-

N-(1-cyanocyclopropyl)-2-methylbenzamide,

4-(6-(3-fluorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a]pyridin-3-yl)-

2-methyl-N-(1-methylcyclobutyl)benzamide,

4-(6-(3-chlorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, N- [rel-(1R, 2R)-2-fluorocyclopropyl] -2-methylbenzamide,

2-a]pyridin-3-ylf-

4-(6-(3-chlorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, N-I [(1S,2S) or (1R, 2R)]-2-fluorocyclopropyl$-2-methylbenzamide,

2-a]pyridin-3-ylI-

293

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T/EP2012/055471

4-[6-(3-chlorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, 2-a]pyridin-3-yljN-[[(1R, 2R) or (1S,2S)]-2-fluorocyclopropylj-2-methylbenzamide, N-(2, 6-diethylphenyl)-4-[6-(3-fluorophenoxy)-8[(3,3, 32-a] pyridin-3-ylj-2-methylbenzamide, trifluoropropyl)amino]imidazo[1, 4, 4'-[8-[methyl(3, 3, 3-trifluoropropyl)amino]imidazo[1, dim ethylbenzamide),

2-a] pyridine-3, 6-diyljbis(N, 2-

N-cyclopropyl-4-[6-(3-fluoro-4-methoxyphenoxy)-8-[(3, 3, 32-a] pyridin-3-ylj-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

4, 4'-[8-[methyl(3, 3, 3-trifluoropropyl)amino]imidazo[1, cyanocyclopropyl)-2-methylbenzamide],

2-a] pyridine-3, 6-diyljbis[N-(1-

4, 4'-[8-[methyl(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a] pyridine-3, 6-diyljbis[2-

methyl-N-(1-methylcyclopropyl)benzamide],

4, 4'-[8-[methyl(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a] pyridine-3, 6-diyljbis(N-

ethyl-2-methylbenzamide), N-(2, 6-diethylphenyl)-4-[6-(5-fluoro-2-methylphenoxy)-8-[(3, 3, 32-a] pyridin-3-ylj-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

N-cyclobutyl-4-[6-(5-fluoro-2-methylphenoxy)-8[(3,3, 32-a] pyridin-3-ylj-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

rel-4-[6-(3-fluorophenoxy)-8- [(3,3, 3-trifluoropropyl)amino]imidazo[1, ylj-2-methyl-N-[(1R, 2R)-2-methylcyclopropyl]benzamide, N-

[(3,3, 32-a] pyridin-3-ylj-2-methylbenzamide,

[1,1'-bi(cyclopropyl)-1-yl]-4-[6-(3-fluorophenoxy)-8-


4-[6-(3-fluorophenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, N-

2-a]pyridin-3-

2-a]pyridin-3-ylj-

[1-(hydroxym ethyl)cyclopropyl]-2-methylbenzamide,

N-(1-cyanocyclobutyl)-4-[6-(3-fluorophenoxy)-8-[(3, 3, 32-a] pyridin-3-ylj-2-methylbenzamide, trifluoropropyl)amino]imidazo[1, -8- [(3,3, 3N-cyclopropyl-4-[6-(3-methoxyphenoxy) 2-a] pyridin-3-ylj-2-methylbenzamide, trifluoropropyl)amino]imidazo[1, N-(1-cyanocyclopropyl)-4-[6-(3-methoxyphenoxy)-8[(3,3, 32-a] pyridin-3-ylj-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

4-[6-(3-methoxyphenoxy)-8- [(3,3, 3-trifluoropropyl)amino]imidazo[1, ylj-2-methyl-N-(1-methylcyclopropyl)benzamide,

2-a]pyridin-3-

4-[6-(3-methoxyphenoxy)-8ylj-N, 2-dimethylbenzamide,

2-a]pyridin-3-


N-ethyl-4-[6-(3-methoxyphenoxy)-8-[(3, a] pyridin-3-yl j-2-methylbenzamide,


2-

N-(1-cyanocyclopropyl)-2-methyl-4-$6-phenoxy-8[(3,3, 32-a] pyridin-3-yljbenzamide, trifluoropropyl)amino]imidazo[1,

2-methyl-N-(1-methylcyclopropyl)-4-(6-phenoxy-8-[(3, 3, 32-a] pyridin-3-yljbenzamide, trifluoropropyl)amino]imidazo[1, N,

2-dimethyl-4-[6-phenoxy-8-


yl jbenzamide,

294

2-a] pyridin-3-

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N-ethyl-2-methyl-4-[6-phenoxy-8-[(3, a] pyridin-3-yl]benzamide,

T/EP2012/055471


22-

rel-4-[6-(5-fluoro-2-methylphenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, a]pyridin-3-ylJ-2-methyl-N-[(1R, 2R)-2-methylcyclopropyl]benzamide, N-

methylphenoxy)-8- [(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide,

[1,1'-bi(cyclopropyl)-1-yl]-4-[6-(5-fluoro-2-


N-(1-cyanocyclobutyl)-4-[6-(5-fluoro-2-methylphenoxy)-8[(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1, N-cyclopropyl-2-methyl-4- [6- [4-(trifluoromethoxy)phenoxy]-8-[(3, 2-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1,

N-(1-cyanocyclopropyl)-2-methyl-4-$6[4-(trifluoromethoxy) 2-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1,

3, 3-

phenoxy] -8- [(3,3, 3-

2-methyl-N-(1-methylcyclopropyl)-4-(6-[4-(trifluoromethoxy)phenoxy]-8-[(3, 2-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1,

3, 3-

N, 2-dimethyl-4-[6-[4-(trifluoromethoxy)phenoxy]-8[(3,3, 32-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1,

N-ethyl-2-methyl-4-[6-[4-(trifluoromethoxy)phenoxy]-8-[(3, 3, 32-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1, N-cyclopropyl-4-[6-(2-fluoro-4-methoxyphenoxy)-8-[(3, 3, 32-a] pyridin-3-yl]-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

N-(1-cyanocyclopropyl)-4-[6-(2, trifluoropropyl)amino]imidazo[1,

3-difluorophenoxy)-8- [(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide,


2-a]pyridin-3-

ylf-2-methyl-N-(1-methylcyclopropyl)benzamide,


2-a]pyridin-3-

yl)-N, 2-dimethylbenzamide,


2-a]pyridin-3-

yl)-N-ethyl-2-methylbenzamide,

N-cyclopropyl-2-methyl-4-[6- [3-(trifluoromethoxy)phenoxy]-8-[(3, 2-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1,

3, 3-

N-(1-cyanocyclopropyl)-2-methyl-4-$6[3-(trifluoromethoxy) phenoxy] -8- [(3,3, 32-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1,

2-methyl-N-(1-methylcyclopropyl)-4-[6-[3-(trifluoromethoxy)phenoxy]-8-[(3, 2-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1,

3, 3-

N-ethyl-2-methyl-4-[6-[3-(trifluoromethoxy)phenoxy]-8-[(3, 3, 32-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1, 2-dimethyl-4-[6-[3-(trifluoromethoxy)phenoxy]-8[(3,3, 32-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1, N,

N-cyclopropyl-4-[6-(2-methoxyphenyl)-8-[(3, a] pyridin-3-ylf-2-methylbenzamide,


4-[6-(2-methoxyphenyl)-8- [(3,3, 3-trifluoropropyl)amino]imidazo[1, 2-methyl-N-(1-methylcyclopropyl)benzamide,

295

2-

2-a] pyridin-3-yl]-

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4-(6-(2-methoxyphenyl)-8-[(3, N, 2-dimethylbenzamide,


N-ethyl-4-(6-(2-methoxyphenyl)-8-[(3, a] pyridin-3-yl)-2-methylbenzamide,

T/EP2012/055471

2-a]pyridin-3-ylj2-


N-cyclopropyl-4-(6- [3-fluoro-4-(trifluoromethoxy)phenoxy]-8[(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

N-(1-cyanocyclopropyl)-4-f6- [3-fluoro-4-(trifluoromethoxy) phenoxy] -8- [(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1, 4-f6- [3-fluoro-4-(trifluo rom ethoxy) phenoxy] -8- [(3,3, 32-a] pyridin-3-yl)-2-methyl-N-(1trifluoropropyl)amino]imidazo[1, methylcyclopropyl)benzamide, 4-f6- [3-fluoro-4-(trifluo rom ethoxy) phenoxy] -8- [(3,3, 32-a] pyridin-3-yl)-N, 2-dimethylbenzamide, trifluoropropyl)amino]imidazo[1, N-ethyl-4-f6- [3-fluoro-4-(trifluoromethoxy)phenoxy]-8[(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

2-dimethyl-4-I6-(pyridin-4-yl)-8-[(3, a] pyridin-3-ylfbenzamide, N,

N-ethyl-2-methyl-4-(6-(pyridin-4-yl)-8-[(3, a] pyridin-3-ylfbenzamide,

2-



2-

2-methyl-N-(1-methylcyclopropyl)-4-f6-(pyridin-4-yl)-8[(3,3, 32-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1, N-(1-cyanocyclopropyl)-2-methyl-4-$6-(pyridin-4-yl)-8[(3,3, 32-a] pyridin-3-yl]benzamide, trifluoropropyl)amino]imidazo[1, N-cyclopropyl-2-methyl-4a] pyridin-3-ylfbenzamide,

j8- [(3,3, 3-trifluoropropyl)amino]

-6-vinylimidazo[1, 2-

N, 2-dimethyl-4-I8-[(3, 3, 3-trifluoropropyl)amino]-6-vinylimidazo[1, ylfbenzamide,

N-ethyl-2-methyl-4-f8yl/benzamide,

2-a] pyridin-3-

2-a] pyridin-3-

[(3,3, 3-trifluoropropyl)amino]-6-vinylimidazo[1,

2-methyl-N-(1-methylcyclopropyl)-4-(8[(3,3, 3-trifluoropropyl)amino]-6vinylimidazo[1, 2-a] pyridin-3-yl/benzamide, N-(1-cyanocyclopropyl)-2-methyl-4-$8[(3,3, 3-trifluoropropyl)amino]-6vinylimidazo[1, 2-a] pyridin-3-yl/benzamide,

[rel-(1S, 2S)-2-fluorocyclopropyl]-2-methyl-4-I8-[(3, vinylimidazo[1, 2-a] pyridin-3-yl/benzamide, N-

2-methyl-N- [rel-(1S, 2S) -2-methylcyclopropyl]-4-$8vinylimidazo[1, 2-a] pyridin-3-yl/benzamide,

N-cyclopropyl-4-(6-ethyl-8yl)-2-methylbenzamide,

3, 3-trifluoropropyl)amino]

[(3,3, 3-trifluoropropyl)amino]


4-f6-ethyl-8- [(3,3, 3-trifluoropropyl)amino]imidazo[1, dim ethylbenzamide,

296

-6-

2-a] pyridin-3-

2-a]pyridin-3-ylf-N,

2-

-6-

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N-ethyl-4-f6-ethyl-8methylbenzamide,

PC


4-f6-ethyl-8- [(3,3, 3-trifluoropropyl)amino]imidazo[1, (1-methylcyclopropyl)benzamide, N-(1-cyanocyclopropyl)-4-f6-ethyl-8a] pyridin-3-yl]-2-methylbenzamide,

T/EP2012/055471

2-a] pyridin-3-ylJ-2-

2-a]pyridin-3-yl)-2-methyl-N-

[(3,3, 3-trifluorop ropyl)amino]imidazo[1, 2-

4-f6-ethyl-8- [(3,3, 3-trifluoropropyl)amino]imidazo[1, (1S,2S)-2-fluorocyclopropyl]-2-methylbenzamide,

2-a]pyridin-3-yl)-N-[rel-

4-f6-ethyl-8- [(3,3, 3-trifluoropropyl)amino]imidazo[1, [rel-(1S, 2S)-2-methylcyclopropyl] benzamide,

2-a] pyridin-3-ylf-2-methyl-N-

4-(6-(3-fluoro-4-methoxyphenoxy)-8-[(3, a] pyridin-3-ylf-N, 2-dimethylbenzamide,

3, 3-trifluoropropyl)amino]

imidazo[1, 2-

N-ethyl-4-f6-(3-fluoro-4-methoxyphenoxy)-8[(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

N-cyclopropyl-4-(6-[(1Z)-3-hydroxyprop-1-en-1-yl]-8[(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

4-(6- [4-(benzyloxy)phenoxy]-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a] pyridin-

3-ylj-N-cyclopropyl-2-methylbenzamide,

N-cyclopropyl-4-(6-(4-hydroxyphenoxy)-8-[(3, a] pyridin-3-ylf-2-methylbenzamide,


N-cyclopropyl-2-methyl-4- j6- [(1E)-prop-1-en-1-yl]-8-[(3, 3, 32-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1,

2-dimethyl-4-I6-[(1E)-prop-1-en-1-yl]-8-[(3, 3, 32-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1, N-ethyl-2-methyl-4-f6- [(1E)-prop-1-en-1-yl]-8-[(3, 3, 32-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1, N,

3, 3-

2-methyl-N-(1-methylcyclopropyl)-4-f6-[(1E)-prop-1-en-1-yl]-8-[(3, 2-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1, N-(1-cyanocyclopropyl)-2-methyl-4-$6-[(1E)-prop-1-en-1-yl]-82-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1,

[(3,3, 3-

N-[rel-(1S, 2S)-2-fluorocyclopropyl]-2-methyl-4-I6-[(1E)-prop-i 2-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1,

-en-1-yl]-8-[(3, 3, 3-

2-methyl-N-[rel-(1S, 2S)-2-methylcyclopropyl]-4-$6-[(1E)-prop-1-en-1-yl]-82-a] pyridin-3-yl)benzamide, trifluoropropyl)amino]imidazo[1,

[(3,3, 3-

[rel-(1R, 2R)-2-fluorocyclopropyl]-4-(6- [(1Z)-3-hydroxyprop-1-en-1-yl]-8- [(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1, N-

4-(6-[(1Z)-3-hydroxyprop-1-en-1-yl]-8-[(3, 3, 3-trifluoropropyl) amino]imidazo[1, 2a] pyridin-3-ylf-N, 2-dimethylbenzamide, N-ethyl-4-(6- [(1Z)-3-hydroxyprop-1-en-1-yl]-8- [(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1, 4-f6-(3-fluoro-4-methoxyphenoxy)-8-[(tetrahydro-2H-pyran-4ylmethyl)amino]imidazo[1, 2-a] pyridin-3-ylf-N, 2-dimethylbenzamide,

297

2-

WO 2012/136531

PC

T/EP2012/055471

N-ethyl-4-[6-(3-fluoro-4-methoxyphenoxy)-8[(tetrahydro-2H-pyran-4ylmethyl)amino]imidazo[1, 2-a] pyridin-3-yl)-2-methylbenzamide, N-cyclopropyl-4-[6-(3-fluoro-4-methoxyphenoxy)-8-[(tetrahydro-2H-pyran-4ylmethyl)amino]imidazo[1, 2-a] pyridin-3-yl)-2-methylbenzamide,

[(3,3, 3-

[rel-(1S, 2S)-2-fluorocyclopropyl]-4-$6-(3-fluoro-4-methoxyphenoxy)-82-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1, N-

2-

4-[6-(3-fluoro-4-methoxyphenoxy)-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1, a] pyridin-3-yl]-2-methyl-N- [rel-(1 S, 2S)-2-methylcyclopropyl] benzamide,


4-[6-(3-hydroxypropyl)-8N, 2-dimethylbenzamide,

N-ethyl-4-f6-(3-hydroxypropyl)-8a] pyridin-3-ylf-2-methylbenzamide,

2-a] pyridin-3-ylj-


22-


N-cyclopropyl-4-[6-(3-hydroxypropyl)-8-[(3, a] pyridin-3-ylf-2-methylbenzamide,

N-cyclopropyl-4-[6-(3-fluoro-4-hydroxyphenoxy)-8[(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1, 2-

4-[6-(3-fluoro-4-hydroxyphenoxy)-8[(3,3, 3-trifluoropropyl)amino]imidazo[1, pyridin-3-ylf-N, 2-dimethylbenzamide, a] N-ethyl-4-[6-(3-fluoro-4- hydroxyphenoxy)-8- [(3,3, 32-a] pyridin-3-yl]-2-methylbenzamide, trifluoropropyl)amino]imidazo[1, N-cyclopropyl-4-[6-(2-hydroxyphenyl)-8-[(3, a] pyridin-3-ylf-2-methylbenzamide,

4-[6-(2-hydroxyphenyl)-8-[(3, N, 2-dimethylbenzamide,


N-ethyl-4-[6-(2-hydroxyphenyl)-8a] pyridin-3-yl]-2-methylbenzamide,

2-


2-a] pyridin-3-ylJ-


2-

[rel-(1S, 2S)-2-fluorocyclopropyl]-4-$6-(2-hydroxyphenyl)-8[(3,3, 32-a] pyridin-3-yl)-2-methylbenzamide, trifluoropropyl)amino]imidazo[1, N-

4-[6-(3- hydroxyphenoxy)-8-

2-


N-cyclopropyl-4-[6-(3-hydroxyphenoxy)-8-[(3, a] pyridin-3-yl)-2-methylbenzamide,


2-a] pyridin-3-

yl)-2-methyl-N-(1-methylcyclopropyl)benzamide, -8- [(3,3, 3-trifluoropropyl)amino]imidazo[1, N-ethyl-4-[6-(3-hydroxyphenoxy) a] pyridin-3-yl]-2-methylbenzamide,

4-[6-(3- hydroxyphenoxy)-8-


2-

2-a] pyridin-3-

yl)-N, 2-dimethylbenzamide,

methyl 2-methyl-4-[3- [3-methyl-4-(methylcarbamoyl) phenyl] -8- [(3,3, 32-a] pyridin-6-yl)benzoate, trifluoropropyl)amino]imidazo[1,

N-cyclopropyl-4-[6-(2-hydroxyethyl)-8-[(3, a] pyridin-3-ylf-2-methylbenzamide,

4-[6-(2-hydroxyethyl)-8N, 2-dimethylbenzamide,


[(3,3, 3-trifluoropropyl)amino]imidazo[1, 298

2-

2-a]pyridin-3-ylf-

WO 2012/136531

PC

T/EP2012/055471

N-cyclopropyl-4-(6-[(1RS)-1-hydroxyethyl]-8-[(3, 3, 32-a] pyridin-3-yl]-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

4-(6-[(1RS)-1-hydroxyethyl]-8-[(3, 3, 3-trifluoropropyl)amino]imidazo[1,

2-a]pyridin-3-

yl]-N, 2-dimethylbenzamide,

N-ethyl-4-f6- [(1RS)-1- hydroxyethyl]-8a] pyridin-3-yl]-2-methylbenzamide,

2-


N-cyclopropyl-4-(6-(3-fluoro-2-methoxyphenoxy)-8-[(3, 3, 32-a] pyridin-3-yl]-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

4-f3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(3, 3, 32-a] pyridin-6-yl]-N, 2-dimethylbenzamide, trifluoropropyl)amino]imidazo[1, 4-f3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(3, 3, 32-a] pyridin-6-yl]- N-ethyl-2-methylbenzamide, trifluoropropyl)amino]imidazo[1, 4-f3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(3, 3, 32-a] pyridin-6-yl]-2-methyl-N-(1trifluoropropyl)amino]imidazo[1, methylcyclopropyl)benzamide,

4-(6-f4- [(1-cyanocyclopropyl)carbamoyl]-3-methylphenyl]-8-[(3, 3, 32-a] pyridin-3-yl)- N-cyclopropyl-2trifluoropropyl)amino]imidazo[1, methylbenzamide,

4-f3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(3, 3, 32-a] pyridin-6-yl]- N- [1-(hydroxym ethyl)cyclopropyl]trifluoropropyl)amino]imidazo[1, 2-methylbenzamide, 4-f3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(3, 3, 32-a] pyridin-6-yl]- N- [rel-(1S, 2S)-2trifluoropropyl)amino]imidazo[1, fluorocyclopropyl]-2-methylbenzamide, 4-f6-(4-carbamoyl-3-methylphenyl)-8[(3,3, 3-trifluoropropyl)amino] a] pyridin-3-yl]-N-cyclopropyl-2-methylbenzamide,

imidazo[1, 2-

4-(6-(4-I [rel-(1S, 2S)-2-fluorocyclopropyl]carbamoyl]-3-methylphenyl)-8-[(3, ethyl)cyclopropyl]carbarn 2-a] pyridin-3-yl]-N, 2-dimethylbenzamide, trifluoropropyl)amino]imidazo[1, 4-f6-(4-([1-(hydroxym trifluoropropyl)amino]imidazo[1,

3, 3-

oyl]-3-methylphenyl)-8- [(3,3, 32-a] pyridin-3-yl]-N, 2-dimethylbenzamide,

4-(6-f4- [(1-cyanocyclopropyl)carbamoyl]-3-methylphenyl]-8-[(3, 3, 32-a] pyridin-3-yl)- N, 2-dimethylbenzamide, trifluoropropyl)amino]imidazo[1, 2-methyl-N-(1-methylcyclopropyl)-4-f3-[3-methyl-4-(methylcarbamoyl)phenyl]-82-a] pyridin-6-ylfbenzamide, [(3,3, 3-trifluoropropyl)amino]imidazo[1,

4-f6-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(3, 3, 32-a] pyridin-3-yl]-N, 2-dimethylbenzamide, trifluoropropyl)amino]imidazo[1,

4-f6-[4-(ethylcarbamoyl)-3-methylphenyl]-8-[(3, 3, 32-a] pyridin-3-yl]-N, 2-dimethylbenzamide, trifluoropropyl)amino]imidazo[1, 4-f6-(4-carbamoyl-3-methylphenyl)-8[(3,3, 3-trifluoropropyl)amino]imidazo[1, a] pyridin-3-yl]-N, 2-dimethylbenzamide, N-cyclopropyl-4-(8- [(2, 2-difluoroethyl)amino]-6-(3-fluorophenoxy)imidazo[1, a] pyridin-3-yl]-2-methylbenzamide,

299

22-

WO 2012/136531

PC

T/EP2012/055471

2-

N-cyclopropyl-4-[8- [(2, 2-difluoroethyl)amino]-6-(4-methoxyphenoxy)imidazo[1, a] pyridin-3-yl j-2-methylbenzamide, N-cyclopropyl-4-[8- [(2, 2-difluoroethyl)amino]-6-(2, a] pyridin-3-yl j-2-methylbenzamide,

2-

3-difluorophenoxy)imidazo[1,

N-cyclopropyl-4-[8- [(2, 2-difluoroethyl)amino]-6-(5-fluoro-2methylphenoxy)imidazo[1, 2-a] pyridin-3-ylj-2-methylbenzamide, N-cyclopropyl-4-[8- [(2, 2-difluoroethyl)amino]-6-(2, a] pyridin-3-yl j-2-methylbenzamide,

2-

5-difluorophenoxy)imidazo[1,

N-cyclopropyl-4-[8- [(2, 2-difluoroethyl)amino]-6-(3-fluoro-2methylphenoxy)imidazo[1, 2-a] pyridin-3-ylj-2-methylbenzamide, N-cyclopropyl-4-[8- [(2, 2-difluoroethyl)amino]-6-(3-fluoro-42-a] pyridin-3-ylj-2-methylbenzamide, methoxyphenoxy)imidazo[1, 2-

N-cyclopropyl-4-[8- [(2, 2-difluoroethyl)amino]-6-(2-hydroxybenzoyl)imidazo[1, a] pyridin-3-yl j-2-methylbenzamide, 2-

N-cyclopropyl-4-[6-(3-fluorophenoxy)-8-[(2-methoxyethyl)amino]imidazo[1, a] pyridin-3-yl j-2-methylbenzamide,

2-

N-cyclopropyl-4-[8- [(2-methoxyethyl)amino]-6-(2-methylphenoxy)imidazo[1, a] pyridin-3-yl j-2-methylbenzamide,

2-

N-cyclopropyl-4-[6-(3, 4-difluorophenoxy)-8-[(2-methoxyethyl)amino]imidazo[1, a] pyridin-3-yl j-2-methylbenzamide, N-cyclopropyl-4-[6-(5-fluoro-2-methylphenoxy)-8[(22-a] pyridin-3-ylj-2-methylbenzamide, methoxyethyl)amino]imidazo[1,

2-

N-cyclopropyl-4-[6-(2, 3-difluorophenoxy)-8-[(2-methoxyethyl)amino]imidazo[1, a] pyridin-3-yl j-2-methylbenzamide, N-cyclopropyl-4-[6-(5-fluoro-2-hydroxybenzoyl)-8-[(22-a] pyridin-3-ylj-2-methylbenzamide, methoxyethyl)amino]imidazo[1, 2-

N-cyclopropyl-4-[8- [(2, 2-difluoroethyl)amino]-6-(3-fluorophenoxy)imidazo[1, a] pyridin-3-yl j-2-methylbenzamide, N-cyc lop ropyl-4-[6- (5- fluoro-2- hydroxyphenoxy) -8- [(3,3, 32-a] pyridin-3-ylj-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

N-cyclopropyl-4-[6-(3-fluoro-2-hydroxyphenoxy)-8[(3,3, 32-a] pyridin-3-ylj-2-methylbenzamide, trifluoropropyl)amino]imidazo[1, N-cyclopropyl-4-[6- [(5-fluoropyridin-3-yl)oxy]-8-[(3, 3, 32-a] pyridin-3-ylj-2-methylbenzamide, trifluoropropyl)amino]imidazo[1, N-cyclopropyl-4-[6- [(5-fluoro-6-methoxypyridin-3-yl)oxy]-8-[(3, 3, 32-a] pyridin-3-ylj-2-methylbenzamide, trifluoropropyl)amino]imidazo[1,

or a stereoisomer,

a tautomer,




11. A 5

method of preparing

method comprising

the

a compound according to any one of claims

step: 300

1

to 10, said

WO 2012/136531

-

PC


T/EP2012/055471

of general formula IV:

compound

R NH N

R A IV

in which

R' and A are as defined for general formula and

R'

is a halogen

I

in any one

of claims

atom;

to react with a compound of general formula IVa:

IVa in which

R' is as defined for general formula Y is a substituent

I

in any one

which is displaced in a coupling

thereby giving a compound of general formula

301

I

of claims

1

reaction;

to

10;

1

to

10;

WO 2012/136531

PC

T/EP2012/055471

R NH N

R A

in which

R', R', and A are as defined for general formula

I

in any one

of claims

1

to

10.

12.

method

A

of preparing

said method comprising

10

-

a compound

according to any one of claims

1

to 10,

the step:


compound

of general formula

II

R NH N

R Q in which

15

R3 and R5


and Q is a halogen

I

in any one

atom;

to react with a compound of general formula Ila: 20

A-Y

302

of claims

1

to

10;

WO 2012/136531

T/EP2012/055471

PC

I

la

in which A is

as defined for general formula

Y is a substituent

I

one of claims

in any

which is displaced in a coupling


to

1

10;

reaction;

I

R NH N

R

in which

10

claims

13.

1

method

A

R', R' and A are as defined for general formula

-

in any one of

to 10. of preparing


15

I


a compound

1

to 10,

the step:


compound

of general formula

Vll

V N

R A VII

in which

20

R3 and A


and V is a leaving group;

303

I

in any one

of claims

1

to

10;

WO 2012/136531

to react with a compound of general formula

PC

T/EP2012/055471

to

10;

Ila

R5-CH2-NH2

Vila in which R5 is


I

in any one


of claims

1

I

R NH N

R A 10 in which

claims

14. 15

1

method

A


of preparing


a compound

the step:


compound

of general formula

V N

R A 20

in any one of

to 10.


-

I

VII

in which

304

Vll

1

to 10,

WO 2012/136531

PC


R3 and A

and Vis a

~NH

I

in any one

T/EP2012/055471

of claims

1

to

10;

-group;

to react with a compound of general formula Vllb: O=CHR5

VIIb in which R5 is


I

in any one

of claims

1

to

10;

10 thereby giving a compound of general formula

I

R NH N

R


in which

15

claims

15. A

an


N-oxide,

pharmaceutically

20

a hydrate,

a solvate,

1

to 10, or a stereoisomer,

or a salt thereof,

particularly

acceptable salt thereof, or a mixture of same, for use

in

a a

the

treatment or prophylaxis of a disease.

16. A pharmaceutical the claims

1

composition

comprising

a compound

according to any one of

to 10, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate,

or a salt thereof, 25

in any one of

to 10.

1

compound

tautomer,

I

particularly

a pharmaceutically

mixture of same, and a pharmaceutically

acceptable salt thereof, or a

acceptable diluent or carrier.

305

WO 2012/136531

17. A pharmaceutical -

5

composition comprising:

according

stereoisomer,


a tautomer,

a pharmaceutically

1

to 10, or a


acceptable salt thereof, or a mixture of same;

and -

one or more agents selected from: a taxane, such as Docetaxel, Paclitaxel, or

Taxol; an epothilone,

such as Ixabepilone,

Dexamethasone;

Predinisolone;

10

to any one of the claims

one or more compounds

particularly

T/EP2012/055471

PC

Adriamycin;

Idarubicin;

Ifosfamide;

Procarbazine;

Cytarabine;

Ara-C;

such as Flutamide,

derivative,

Estramustin;

Daunorubicin; Melphalan;

2-Chloro-2

Cyproterone

such as Cisplatin,

or Sagopilone; Mitoxantrone;

Patupilone,

Vincristin;

Vinblastin;

Doxorubicin;

Bleomycin; Etoposide; Cyclophosphamide;

5-Fluorouracil;

-deoxyadenosine;

Capecitabine;

Thioguanine;

acetate, or Bicalutamide; or Carboplatin;

Fludarabine;

an anti-androgen,

Bortezomib; a platinum

Chlorambucil;

Methotrexate;

and

Rituximab.

15

18.

Use of a compound

stereoisomer,

according

a tautomer,

1

to 10, or a



a pharmaceutically

particularly


acceptable salt thereof, or a mixture of same, for

the prophylaxis or treatment of a disease. 20

19.

Use of a compound

stereoisomer,

according

a tautomer,

1

to 10, or a



a pharmaceutically

particularly


acceptable salt thereof, or a mixture of same, for

of a medicament for the prophylaxis or treatment of a disease.

the preparation 25

20.


uncontrolled

30

to claim 15, 18 or 19, wherein

Use according

immune

response, or an inappropriate

in which

the uncontrolled

cellular immune mediated particularly survival,

by the

the disease of uncontrolled

inappropriate

cellular immune

and/or survival,

kinase

inappropriate

response is

(MEK-ERK) pathway,



response is a haemotological 306

response, particularly


protein

cellular

an inappropriate



in which

inflammatory

and/or survival,


mitogen-activated

said disease is a disease of

tumour,

a solid tumour

more and/or

cellular and/or

WO 2012/136531


metastases

thereof,

lymphomas,


tumours


gastrointestinal 5

PC

urological

tumours,

and sarcomas,

21. A

compound

endocrine tumours,

tumours,

tumours,

non-small

tumours

including

brain tumours

T/EP2012/055471

syndrome,

malignant





tumours,

skin


of general formula IV:

R NH N

R A

10 IV

in which R' and A


and R3 is a halogen atom.

15

22. A compound of general formula

II

R NH N

R Q 20

307

I

in any one

of claims

1

to 10,

WO 2012/136531

PC

in which R' and R'


I

T/EP2012/055471

in any one

of claims

1

to 10

in any one

of claims

1

to 10

and Q is a halogen atom.

23. A

compound

of general formula

VII

N

R A VII

in which R' and A

10


and V is a NH2-group

or a halogen atom.

308

I

SEARCH REPORT

INTERNATIONAL

International

application No

PCT/ E P2812/855471 A. CLASSIFICATION OF SUBJECT MATTER

According to International

A61P38/88

A61K31/437

C87D471/84

I NV. ADD.

Patent Classification (IPC) or to both national classification and IPC

B. FIELDS SEARCHED Minimum

documentation

searched (classification system followed by classification symbols)

C87D

Documentation

searched other than minimum documentation

Electronic data base consulted during the international

EPO-Internal,

WPI

to the extent that such documents

are included

in

the fields searched

search (name of data base and, where practicable, search terms used)

Data

C. DOCUMENTS CONSIDERED TO BE RELEVANT Category*

Citation of document, with indication,

where appropriate,

of the relevant passages

2884/826867 A2 (SCHERING 2884 (2884-84-81) cited in the application abstract; claims 1-38

X

WO

CORP

Relevant to claim No.

[US])

22

1 April

A

tables 8, 18-13 Compounds of general formula F wherein (present g in claim 22) is Br or Cl

A

WO

2887/832936

A2

X

CORP [US]; IUIADISON VINCENT [US]

(SCHERING

[US] .

IUIALLAIUIS

ALAN

PARUCH)

22 March 2887

K

1-21,23

1-23

.

(2887-83-22)

cited in the application abstract table 5

* Special categories of cited documents: "A" document defining the general state of the art which is not considered to be of particular relevance

"E" earlier application or patent but published on or after the international filing date "L" document which may throw doubts on priority claim(s) or which is cited to establish the publication date of another citation or other special reason (as specified)

"0" document

referring to an oral disclosure, use, exhibition or other

means

"P" document published prior to the international

filing

date but later than

the priority date claimed Date of the actual completion of the international

search

2280

"8" document member of the same patent

85/87/2812

Name and mailing address of the ISA/ NL -

"X" document of particular relevance; the claimed invention cannot be considered novel or cannot be considered to involve an inventive step when the document is taken alone "Y" document of particular relevance; the claimed invention cannot be considered to involve an inventive step when the document is combined with one or more other such documents, such combination being obvious to a person skilled in the art

Date of mailing of the international

29 June 2812 European Patent Office, P. B. 5818 Patentlaan

"T" later document published after the international filing date or priority date and not in conflict with the application but cited to understand the principle or theory underlying the invention

Authorized

officer

2

HV Rijswijk

Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 Form PCT/ISA/2t 0 (second sheet) (Apnl 2005)

Goss,

Ilaria

family

search report

INTERNATIONAL Information

Patent document cited in search report WO

2884826867

SEARCH REPORT

date

81-84-2884

AR

AT AU

CA CN

DE

EP ES HK

IL JP JP KR

A2

22-83-2887

NZ

538566 2884897517 2886838555 2884826867 288582278

A

AT CA CN

EP ES HK

JP US US US WO

Form PCT/ISA/2t 0 (patent family annex) (Apnl 2005)

841291 A1 378336 T 2883295332 A1 2499639 A1 1783414 A 68317529 T2 1539756 A2 2293868 T3 1871757 A1 167433 A 4845379 B2 2886587254 A 28858852588 A A

ZA

2887832936

date

PA85883858

WO

WO

Publication

HX

US US

application No

PCT/ E P2812/855471 Patent family member(s)

Publication

A2

International

on patent family members

478852 2621983

A1 A1 A2 A

T A1

181388233 A 1931641 A2 2349476 T3 1112229 A1 2889587843 A 2887866621 A1 2818137326 A1 2818143384 A1 2887832936 A2

11-85-2885 15-11-2887 88-84-2884 81-84-2884 38-11-2885 25-89-2888 15-86-2885 16-83-2888 18-81-2888 31-83-2811 28-12-2811 82-83-2886 82-86-2885 27-85-2885 29-82-2888 28-85-2884 89-82-2886 81-84-2884 31-85-2886

15-89-2818 22-83-2887 85-11-2888 18-86-2888

83-81-2811 19-11-2818 26-82-2889 22-83-2887 83-86-2818 18-86-2818 22-83-2887