NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF FIBROSIS

1 ) A compound according to Formula Ia:

wherein

X is ═O, or ═N—CN;

R 1a is selected from:

C 1-4 alkyl optionally substituted with one or more groups independently selected from

OH,

C 1-4 alkoxy optionally substituted with one or more independently selected OH, or C 1-4 alkoxy,

—SO 2 —C 1-4 alkyl,

—O—C 3-7 monocyclic cycloalkyl, and

—O-heterocycloalkyl wherein said heterocycloalkyl is a 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S;

NR 6a R 6b ,

C 1-4 alkoxy,

C 3-7 monocyclic cycloalkyl,

4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, optionally substituted with one or more halo,

—O—C 3-7 monocyclic cycloalkyl, and

—O-heterocycloalkyl wherein said heterocycloalkyl is a 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S;

R 1b is H, or C 1-4 alkyl;

Cy 1 is a 5 membered monocyclic heteroaryl ring, comprising one, two, or three heteroatoms independently selected from N, O, or S, or

Cy 1 is 4-7 membered monocyclic heterocycloalkyl ring comprising one, two, or three heteroatoms independently selected from N, O, or S, or 4-7 membered monocyclic heterocycloalkyl ring comprising one, two, or three heteroatoms independently selected from N, O, or S, fused to a 5-6 membered heteroaryl ring comprising one, two, or three heteroatoms independently selected from N, O, or S, which heteroaryl may optionally substituted with one C 1-4 alkyl;

each R 2a and R 2b is independently selected from H, and C 1-4 alkyl optionally substituted with one or more independently selected —OH, or C 1-4 alkoxy;

R 3 is selected from:

C 1-4 alkyl optionally substituted with one or more independently selected:

halo,

—CN,

—OH,

—C 1-4 alkoxy, or

—NR 7a R 7b ;

C 1-4 alkoxy substituted with one or more halo,

C 3-7 monocyclic cycloalkyl,

4-7-membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S,

—CN,

—S(O) 2 —C 1-4 alkyl,

—NR 8a R 8b , and

—C(═O)NR 8c R 8d ;

each R 4 is independently selected from:

C 1-4 alkyl optionally substituted with one or more independently selected R 12 groups,

C 3-7 monocyclic cycloalkyl, and

4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S;

Cy 2 is phenyl or 5-6 membered monocyclic heteroaryl comprising one or two heteroatoms independently selected from N, O, and S;

each R 5 is independently selected from:

halo,

—CN,

—OH,

C 1-4 alkyl optionally substituted with one or more independently selected R 13 groups,

C 1-4 alkoxy optionally substituted with one or more independently selected R 13 groups,

C 3-7 monocyclic cycloalkyl optionally substituted with one or more independently selected R 14 groups,

4-11 membered monocyclic, or fused or spiro bicyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, optionally substituted with one or more independently selected R 14 groups,

—O—C 3-7 monocyclic cycloalkyl optionally substituted with one or more independently selected R 14 groups,

—O-heterocycloalkyl wherein said heterocycloalkyl is a 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, optionally substituted with one or more independently selected R 14 groups, and wherein if a N heteroatom is present, said N heteroatom, is further substituted with one —C(═O)—C 1-4 alkyl, —C(═O)—C 1-4 alkoxy, —SO 2 —C 1-4 alkyl, —C(═O)—NH 2 , —C(═O)NHC 1-4 alkyl, or —C(═O)N(C 1-4 alkyl) 2 ,

—SO 2 —C 1-4 alkyl,

—SO 2 NR 15a R 15b ,

—C(═O)NR 15c R 15d , and

—NR 17a R 17b ;

each R 12 is independently selected from:

halo,

OH,

C 1-4 alkoxy,

—SO 2 —C 1-4 alkyl,

C 3-7 monocyclic cycloalkyl optionally substituted with one or more independently selected —OH, halo, —CN, C 1-4 alkyl, C 1-4 alkoxy or ═O,

4-7 membered monocyclic heterocycloalkyl, comprising one, two, or three heteroatoms independently selected from N, O, and S, optionally substituted with one or more independently selected —OH, halo, —CN, C 1-4 alkyl, C 1-4 alkoxy or ═O,

—NR 9a R 9b , and

—CN;

each R 13 is independently selected from:

halo,

—CN,

—OH,

C 1-4 alkoxy optionally substituted with one or more independently selected OH, C 1-4 alkoxy, or halo,

—C(═O)NR 16a R 16b ,

—NR 16c C(═O)—C 1-4 alkyl,

—NR 16d C(═O)—C 1-4 alkoxy,

—SO 2 —C 1-4 alkyl

—SO 2 NR 16e R 16f ,

—NR 16g SO 2 —C 1-4 alkyl,

C 3-7 monocyclic cycloalkyl optionally substituted with one or more independently selected halo, or C 1-4 alkyl optionally substituted with one or more halo, and

4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, optionally substituted with one or more independently selected halo, or C 1-4 alkyl optionally substituted with one or more halo, and wherein if a N heteroatom is present, said N heteroatom, is further substituted with one —C(═O)—C 1-4 alkyl, —C(═O)—C 1-4 alkoxy, —SO 2 —C 1-4 alkyl, —C(═O)—NH 2 , —C(═O)NHC 1-4 alkyl, or —C(═O)N(C 1-4 alkyl) 2 ;

each R 14 is independently selected from:

halo,

—CN,

—OH,

C 1-4 alkoxy optionally substituted with one or more halo, and

C 1-4 alkyl optionally substituted with one or more halo;

each R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , R 15a , R 15b , R 15c , R 15d , R 16a , R 16b , R 16c , R 16d , R 16e , R 16f , and R 16g is independently selected from H and C 1-4 alkyl;

each R 17a and R 17b is independently selected from H and C 1-4 alkyl optionally substituted with one or more independently selected halo, OH, or C 1-4 alkoxy;

the subscript n is 0, 1, 2, or 3; and

the subscript m is 0, 1, 2, 3 or 4;

or a pharmaceutically acceptable salt thereof or the solvate or the salt of a solvate thereof.

2 ) A compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is according to Formula Ib:

wherein

R 1a is selected from:

C 1-4 alkyl optionally substituted with one or more groups independently selected from

OH,

C 1-4 alkoxy optionally substituted with one or more independently selected OH, or C 1-4 alkoxy,

—SO 2 —C 1-4 alkyl,

—O—C 3-7 monocyclic cycloalkyl, and

—O-heterocycloalkyl wherein said heterocycloalkyl is a 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S;

NR 6a R 6b ,

C 1-4 alkoxy,

C 3-7 monocyclic cycloalkyl,

4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, optionally substituted with one or more halo,

—O—C 3-7 monocyclic cycloalkyl, and

—O-heterocycloalkyl wherein said heterocycloalkyl is a 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S;

R 1b is H, or C 1-4 alkyl;

Cy 1 is a 5 membered monocyclic heteroaryl ring, comprising one, two, or three heteroatoms independently selected from N, O, or S, or

each R 2a and R 2b is independently selected from H, and C 1-4 alkyl optionally substituted with one or more independently selected —OH, or C 1-4 alkoxy;

R 3 is selected from:

C 1-4 alkyl optionally substituted with one or more independently selected:

halo,

—CN,

—OH,

—C 1-4 alkoxy, or

—NR 7a R 7b ;

C 1-4 alkoxy substituted with one or more halo,

C 3-7 monocyclic cycloalkyl,

4-7-membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S,

—CN,

—NR 8a R 8b , and

—C(═O)NR 8c R 8d ;

each R 4 is independently selected from:

C 1-4 alkyl optionally substituted with one or more independently selected R 12 groups,

C 3-7 monocyclic cycloalkyl, and

4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S;

Cy 2 is phenyl or 5-6 membered monocyclic heteroaryl comprising one or two heteroatoms independently selected from N, O, and S;

each R 5 is independently selected from:

halo,

—CN,

—OH,

C 1-4 alkyl optionally substituted with one or more independently selected R 13 groups,

C 1-4 alkoxy optionally substituted with one or more independently selected R 13 groups,

C 3-7 monocyclic cycloalkyl optionally substituted with one or more independently selected R 14 groups,

4-11 membered monocyclic, or fused or spiro bicyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, optionally substituted with one or more independently selected R 14 groups,

—O—C 3-7 monocyclic cycloalkyl optionally substituted with one or more independently selected R 14 groups,

—O-heterocycloalkyl wherein said heterocycloalkyl is a 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, optionally substituted with one or more independently selected R 14 groups, and wherein if a N heteroatom is present, said N heteroatom, is further substituted with one —C(═O)—C 1-4 alkyl, —C(═O)—C 1-4 alkoxy, —SO 2 —C 1-4 alkyl, —C(═O)—NH 2 , —C(═O)NHC 1-4 alkyl, or —C(═O)N(C 1-4 alkyl) 2 ,

—SO 2 —C 1-4 alkyl,

—SO 2 NR 15a R 15b ,

—C(═O)NR 15c R 15d , and

—NR 17a R 17b ;

each R 12 is independently selected from:

halo,

OH,

C 1-4 alkoxy,

—SO 2 —C 1-4 alkyl,

C 3-7 monocyclic cycloalkyl optionally substituted with one or more independently selected —OH, halo, —CN, C 1-4 alkyl, C 1-4 alkoxy or ═O,

4-7 membered monocyclic heterocycloalkyl, comprising one, two, or three heteroatoms independently selected from N, O, and S, optionally substituted with one or more independently selected —OH, halo, —CN, C 1-4 alkyl, C 1-4 alkoxy or ═O,

—NR 9a R 9b , and

—CN;

each R 13 is independently selected from:

halo,

—CN,

—OH,

C 1-4 alkoxy optionally substituted with one or more independently selected OH, C 1-4 alkoxy, or halo,

—C(═O)NR 16a R 16b ,

—NR 16c C(═O)—C 1-4 alkyl,

—NR 16d C(═O)—C 1-4 alkoxy,

—SO 2 —C 1-4 alkyl

—SO 2 NR 16e R 16f ,

—NR 16g SO 2 —C 1-4 alkyl,

C 3-7 monocyclic cycloalkyl optionally substituted with one or more independently selected halo, or C 1-4 alkyl optionally substituted with one or more halo, and

4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, optionally substituted with one or more independently selected halo, or C 1-4 alkyl optionally substituted with one or more halo, and wherein if a N heteroatom is present, said N heteroatom, is further substituted with one —C(═O)—C 1-4 alkyl, —C(═O)—C 1-4 alkoxy, —SO 2 —C 1-4 alkyl, —C(═O)—NH 2 , —C(═O)NHC 1-4 alkyl, or —C(═O)N(C 1-4 alkyl) 2 ;

each R 14 is independently selected from:

halo,

—CN,

—OH,

C 1-4 alkoxy optionally substituted with one or more halo, and

C 1-4 alkyl optionally substituted with one or more halo;

each R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , R 15a , R 15b , R 15c , R 15d , R 16a , R 16b , R 16c , R 16d , R 16e , R 16f , and R 16g is independently selected from H and C 1-4 alkyl;

each R 17a and R 17b is independently selected from H and C 1-4 alkyl optionally substituted with one or more independently selected halo, OH, or C 1-4 alkoxy;

the subscript n is 0, 1, 2, or 3; and

the subscript m is 0, 1, 2, 3 or 4;

or a pharmaceutically acceptable salt thereof or the solvate or the salt of a solvate thereof.

3 ) A compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2 , wherein the compound is according to Formula IV:

4 ) A compound or a pharmaceutically acceptable salt thereof according to claim 1 , 2 or 3 , wherein R 3 is —CH 3 , —CH 2 CH 3 , or —(CH 2 ) 2 CH 3 , each of which is substituted with one, two or three independently selected halo, —CN, —C 1-4 alkoxy, or —NR 7 R 7b .

5 ) A compound or a pharmaceutically acceptable salt thereof according to claim 1 , 2 or 3 , wherein R 3 is C 3-7 monocyclic cycloalkyl.

6 ) A compound or a pharmaceutically acceptable salt thereof according to claim 1 , 2 or 3 , wherein the compound is according to any one of Formula Va-Vb:

7 ) A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 6 , wherein R 4 is C 1-4 alkyl.

8 ) A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 7 , wherein Cy 2 is pyridinyl.

9 ) A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 8 , wherein the subscript m is 1, 2, 3, or 4.

10 ) A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 9 , wherein R 5 is C 1-4 alkyl substituted with one or more independently selected R 13 groups.

11 ) A compound or a pharmaceutically acceptable salt thereof according to claim 10 , wherein R 13 is F, —CN, —OH, —OCH 3 , —OCF 3 , —OCH 2 CH 3 , —OCH 2 CF 3 , —OCH 2 CH 2 OH, or —OCH 2 CH 2 OCH 3 .

12 ) A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 11 , wherein R 5 is C 1-4 alkoxy.

13 ) A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 12 , and a pharmaceutically acceptable carrier.

14 ) A pharmaceutical composition according to claim 13 comprising a further therapeutic agent.

15 ) A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 - 12 , or a pharmaceutical composition according to claim 13 or 14 for use in medicine.

16 ) A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 12 , or a pharmaceutical composition according to claim 13 or 14 for use in the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases.

17 ) A pharmaceutical composition according to claim 14 , wherein the further therapeutic agent is an agent for the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases.