IP Library › Granted Patent US 12,331,023

Granted Patent B2

US 12,331,023 · App. 17/496,452 · Granted Jun 17, 2025

Substituted heterocyclyl derivatives as CDK inhibitors

Inventors: Susanta Samajdar (Bangalore, IN); Ramulu Poddutoori (Karimnagar, IN); Chetan Pandit (Bangalore, IN); Subhendu Mukherjee (Hooghly, IN); Rajeev Goswami (Deharadun, IN)

Assignee: Aurigene Oncology Limited

C07D231/40 A61K31/415 A61K31/4155 A61K31/416 A61K31/4439 A61K31/454 A61K31/4545 A61K31/4725 A61K31/496 A61K31/497 A61K31/5377 A61K45/06 C07D231/56 C07D401/04 C07D401/12 C07D401/14 C07D403/12 C07D413/12 C07D471/04

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Quick Facts

Patent No.: US 12,331,023
App. No.: 17/496,452
Granted: Jun 17, 2025
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention provides substituted heterocyclylderivatives of formula (I), which are therapeutically useful, particularly as selective transcriptional CDK inhibitors including CDK7, CDK9, CDK12, CDK13 and CDK18, more particularly transcriptional CDK7 inhibitors. These compounds are useful in the treatment and prevention of diseases and/or disorders associated with selective transcriptional CDKs in a mammal. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of the substituted heterocyclyl derivatives of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof.

Claims (344)

1. A process for preparing a compound of formula (IC-1),

the process comprising the steps:

a) reacting a compound of formula (a) with a compound of formula (b) to afford a compound of formula (c):

b) reacting the compound of formula (c) with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (g) to afford a compound of formula (h):

and

c) coupling the compound of formula (h) with a compound of formula (i) to afford a compound of formula (IC-1):

wherein,

ring A is 1,3-phenylene;

ring B is phenyl, piperidinyl, pyridinyl, 1,2,3-6-tetrahydropyridinyl, piperazinyl, pyrazinyl, pyrazolyl, morpholinyl, indolinyl or pyrrolidinyl;

R 1 is hydrogen;

R 2 is (C 1 -C 6 ) alkyl or (C 3 -C 10 ) cycloalkyl;

R 3 is hydrogen or (C 1 -C 6 ) alkyl;

R 4 at each occurrence is fluoro;

R 5 is

wherein R 5 ′ is hydrogen, halo, methoxymethyl, or —CH 2 NR a R b ; and R 5 ″ is H;

R a and R b are each independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy or methyloxyethyl; alternatively, R a and R b together with the nitrogen atom to which they are attached form an optionally substituted 5 to 6 membered ring containing 0-2 additional heteroatoms that are independently N, O or S; wherein the 5 to 6 membered ring is optionally substituted with one or more substituents selected from halo, cyano, cyano (C 1 -C 6 ) alkyl, methyloxymethyl or —COO—(C 1 -C 6 ) alkyl;

R 6 at each occurrence is fluoro, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy;

L 1 is *—CR c R d —C(O)—; wherein * is the point of attachment with the phenyl ring;

R c and R d independently are hydrogen or (C 1 -C 6 ) alkyl; alternatively, R c and R d together with the carbon atom to which they are attached form a (C 3 -C 10 ) cycloalkyl ring;

m is 0, or 1; and

q is 0 to 2.

2. The process of claim 1 , wherein the compound of formula (IC-1) is a compound of formula (IF):

wherein,

R 3 is hydrogen,

R 5 is

and

m is 0.

3. The process of claim 1 , wherein ring B is phenyl or pyridinyl.

4. The process of claim 1 , wherein R 2 is (C 3 -C 10 ) cycloalkyl.

5. The process of claim 1 , wherein R 5 is

6. The process of claim 5 , wherein R 5 ′ is-CH 2 NR a R b ; wherein R a and R b are each independently (C 1 -C 6 ) alkyl; or alternatively, R a and R b together with the nitrogen atom to which they are attached form an optionally substituted 5 to 6 membered ring containing 0-2 additional heteroatoms that are independently N, O or S; wherein the 5 to 6 membered ring is optionally substituted with one or more substituents selected from halo, cyano, cyano (C 1 -C 6 ) alkyl, methoxymethyl or —COO—(C 1 -C 6 ) alkyl.

7. The process of claim 6 , wherein R a and R b together with the nitrogen atom to which they are attached form a 5 to 6 membered heterocyclic ring containing 0-2 additional heteroatoms that are independently O, S or N.

8. The process of claim 1 , wherein the compound of formula (IC-1) is a compound selected from:

Compound

No.

IUPAC name

(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-

biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide;

(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-

biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide (Isomer-1 of compound-1);

(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-

biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide (Isomer-2 of compound-1);

(E)-N-(5′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-2′-fluoro-

[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide;

(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-4′-fluoro-

[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide;

(E)-N-(3′-(2-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-oxoethyl)-[1,1′-biphenyl]-4-

yl)-4-(dimethylamino)but-2-enamide;

(E)-4-(dimethylamino)-N-(3′-(1-((5-ethyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)-[1,1′-biphenyl]-4-yl)but-2-enamide;

(E)-N-(3′-(1-((5-(tert-butyl)-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-

biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide;

10.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide;

11.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide (Isomer-1 of compound-10);

12.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide (Isomer-2 of compound-10);

13.

(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxobutan-2-yl)-[1,1′-

biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide;

14.

(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-

[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide;

15.

(E)-N-(3′-(1-((5-cyclobutyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-

biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide;

16.

(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-3-yl)-4-(dimethylamino)but-2-enamide;

17.

(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-2-fluoro-

[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide;

18.

N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-

biphenyl]-4-yl)acrylamide;

19.

N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-[1,1′-

biphenyl]-4-yl)acrylamide;

20.

N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)acrylamide;

21.

N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)acrylamide (Isomer-1 of compound-20);

22.

N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)acrylamide (Isomer-2 of compound-20);

23.

N-(5′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-2′,3-difluoro-

[1,1′-biphenyl]-4-yl)acrylamide;

24.

N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-3-yl)acrylamide;

25.

2-(4′-acrylamido-3′-fluoro-[1,1′-biphenyl]-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-

3-methylbutanamide;

26.

2-(3-(5-acrylamidopyridin-2-yl)phenyl)-N-(5-cyclopropyl-1H-pyrazol-3-

yl)butanamide;

27.

2-(4′-acrylamido-3′-fluoro-[1,1′-biphenyl]-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-

yl)butanamide;

28.

(E)-N-(3′-(1-((5-cyclopentyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-

[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide;

29.

(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1-(4-(dimethylamino)but-2-

enoyl)indolin-5-yl)phenyl)propanamide;

30.

N-(3′-(1-((5-cyclopropyl-4-methyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-

biphenyl]-4-yl)acrylamide;

31.

(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxobutan-2-yl)-3-fluoro-

[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide;

32.

(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-

[1,1′-biphenyl]-4-yl)-4-(diethylamino)but-2-enamide;

33.

(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-

[1,1′-biphenyl]-4-yl)-4-(pyrrolidin-1-yl)but-2-enamide;

34.

(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-

[1,1′-biphenyl]-4-yl)-4-morpholinobut-2-enamide;

35.

(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-3-yl)-4-morpholinobut-2-enamide;

36.

(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-

yl)phenyl)pyridin-3-yl)-4-(dimethylamino)but-2-enamide;

37.

(E)-4-((6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-3-yl)amino)-N,N-dimethylbut-2-enamide;

38.

(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-

2-fluoropyridin-3-yl)-4-(dimethylamino)but-2-enamide;

39.

(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-3-yl)-4-(piperidin-1-yl)but-2-enamide;

40.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-(piperidin-1-yl)but-2-enamide;

41.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-methoxybut-2-enamide;

42.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide;

43.

(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)-3-

fluoro-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide;

44.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-

yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide;

45.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-(3-fluoropyrrolidin-1-yl)but-2-enamide;

46.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-((S)-3-fluoropyrrolidin-1-yl)but-2-enamide;

47.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-((S)-3-fluoropyrrolidin-1-yl)but-2-enamide

(Isomer-1 of compound-46);

48.

E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-((S)-3-fluoropyrrolidin-1-yl)but-2-enamide

(Isomer-2 of compound-46);

49.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-((R)-3-fluoropyrrolidin-1-yl)but-2-enamide

50.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-((R)-3-fluoropyrrolidin-1-yl)but-2-enamide

(Isomer-1 of compound-49);

51.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-((R)-3-fluoropyrrolidin-1-yl)but-2-enamide

(Isomer-2 of compound-49);

52.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide;

53.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-

phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide (Isomer-1 of compound-52);

54.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-

phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide (Isomer-2 of compound-52);

55.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-(diethylamino)but-2-enamide;

56.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-

yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide;

57.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-(3-fluoropiperidin-1-yl)but-2-enamide;

58.

(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-

2-fluoropyridin-3-yl)-4-morpholinobut-2-enamide;

59.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-

6-fluoropyridin-2-yl)-4-morpholinobut-2-enamide;

60.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-3-yl)-4-morpholinobut-2-enamide;

61.

(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-

biphenyl]-3-yl)-4-morpholinobut-2-enamide;

62.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-(methoxy(methyl)amino)but-2-enamide;

63.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-

3-fluoropyridin-2-yl)-4-morpholinobut-2-enamide;

64.

(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-

2-fluoropyridin-3-yl)-4-(3-fluoropyrrolidin-1-yl)but-2-enamide;

65.

N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3 -yl)amino)-1-oxopropan-2-yl)-3-methoxy-

[1,1′-biphenyl]-4-yl)acrylamide;

66.

N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-methyl-[1,1′-

biphenyl]-4-yl)acrylamide;

67.

N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3,5-dimethyl-

[1,1′-biphenyl]-4-yl)acrylamide;

68.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-((2-methoxyethyl)(methyl)amino)but-2-enamide;

69.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-(1H-imidazol-1-yl)but-2-enamide;

70.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-((S)-2-(methoxymethyl)pyrrolidin-1-yl)but-2-enamide ;

71.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-((S)-2-(methoxymethyl)pyrrolidin-1-yl)but-2-enamide

(Isomer-1 of compound-70);

72.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-((S)-2-(methoxymethyl)pyrrolidin-1-yl)but-2-enamide

(Isomer-2 of compound-70);

73.

N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-2-methoxy-

[1,1′-biphenyl]-4-yl)acrylamide;

74.

N-((5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)methyl)acrylamide;

75.

N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-2-methyl-[1,1′-

biphenyl]-4-yl)acrylamide;

76.

2-(3-(1-acryloylindolin-5-yl)phenyl)-N-(5-cyclopropyl-1H-pyrazol-3-

yl)propanamide;

77.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-((2S,4S)-4-fluoro-2-(methoxymethyl)pyrrolidin-1-yl)but-

2-enamide;

78.

(E)-4-(3-cyanopyrrolidin-1-yl)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-

1-oxopropan-2-yl)phenyl)pyridin-2-yl)but-2-enamide;

79.

N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyrazin-2-yl)acrylamide;

80.

(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-

[1,1′-biphenyl]-4-yl)-4-((S)-3-fluoropyrrolidin-1-yl)but-2-enamide;

81.

methyl ((E)-4-((5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)amino)-4-oxobut-2-en-1-yl)-L-prolinate;

82.

(E)-4-((S)-2-(cyanomethyl)pyrrolidin-1-yl)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-

3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)but-2-enamide;

83.

4-acrylamido-N-(3-((5-ethyl-1H-pyrazol-3-yl)amino)phenyl)benzamide;

84.

(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)-

1,2,3,6-tetrahydropyridin-4-yl)phenyl)propanamide;

85.

(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1-(4-(dimethylamino)but-2-

enoyl)piperidin-4-yl)phenyl)propanamide;

86.

N-(3′-(2-((5-methyl-1H-pyrazol-3-yl)amino)-2-oxoethyl)-[1,1′-biphenyl]-4-

yl)acrylamide;

87.

N-(3′-(1-((5-ethyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-

yl)acrylamide;

88.

N-(3′-(1-((5-(tert-butyl)-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-

4-yl)acrylamide;

89.

(E)-N-(3-((1H-indazol-3-yl)amino)phenyl)-4-(4-(dimethylamino)but-2-

enamido)benzamide;

90.

N-(3′-(1-((1H-indazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-

yl)acrylamide;

91.

(E)-N-(3′-(1-((1H-indazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-

(dimethylamino)but-2-enamide;

92.

(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyrazin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide;

93.

(S,E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide;

94.

(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-1-(3-(6-(4-(pyrrolidin-1-yl)but-2-

enamido)pyridin-3-yl)phenyl)cyclopropane-1-carboxamide; and

95.

(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-methyl-1-oxopropan-2-

yl)phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide;

9. The process of claim 1 , comprising:

a) reacting a compound of formula (1a) with a compound of formula (1-B) to form a compound of formula (1b):

b) reacting the compound of formula (1b) with the 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to afford a compound of formula (2a):

and

c) coupling the compound of formula (2a) with a compound of formula (3-B) to afford (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide:

10. The process of claim 1 , comprising:

a) reacting a compound of formula (1a) with 2-(3-bromophenyl)-3-methylbutanoic acid to form tert-butyl 3-(2-(3-bromophenyl)-3-methylbutanamido)-5-cyclopropyl-1H-pyrazole-1-carboxylate:

b) reacting the tert-butyl 3-(2-(3-bromophenyl)-3-methylbutanamido)-5-cyclopropyl-1H-pyrazole-1-carboxylate with the 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to afford tert-butyl 5-cyclopropyl-3-(3-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) butanamido)-1H-pyrazole-1-carboxylate:

and

c) coupling the tert-butyl 5-cyclopropyl-3-(3-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) butanamido)-1H-pyrazole-1-carboxylate with a compound of formula (3-B) to afford (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide:

11. The process of claim 9 , wherein (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide is afforded as a racemic mixture.

12. The process of claim 9 , further comprising isolating the(S) enantiomer of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide.

13. The process of claim 9 , further comprising isolating the (R) enantiomer of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide.

14. The process of claim 10 , wherein (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide is afforded as a racemic mixture.

15. The process of claim 10 , further comprising isolating an enantiomer of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide.

16. The process of claim 1 , wherein the compound of formula (a) is tert-butyl 3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate, and

wherein step a) is carried out by (i) converting the compound of formula (b) in the presence of dichloromethane, a catalytic amount of dimethylformamide and oxalyl chloride to the corresponding acid chloride, followed by (ii) reacting the obtained acid chloride with the tert-butyl 3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate in presence of either (1)pyridine or (2) a combination of dichloromethane and triethylamine.

17. The process of claim 1 , wherein step b) is carried out in the presence of (1) 1,4-dioxane, (2) potassium acetate, and (3) PdCl 2 (dppf)·DCM complex or PdCl 2 (PPh 3 ) 2 .

18. The process of claim 1 , wherein the compound of formula (i) is (E)-N-(5-bromopyridin-2-yl)-4-morpholinobut-2-enamide, and

wherein step c) is carried out in the presence of (1) 1,4-dioxane, (2) water, (3) Cs 2 CO 3 and (4) PdCl 2 (dppf)·DCM complex or PdCl 2 (PPh 3 ) 2 .

Assignments (2)

CHANGE OF NAME Recorded Apr 13, 2023

From: AURIGENE DISCOVERY TECHNOLOGIES LIMITED

To: AURIGENE ONCOLOGY LIMITED

Reel/Frame 063312/0927 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 18, 2021

From: SAMAJDAR, SUSANTA; PODDUTOORI, RAMULU; PANDIT, CHETAN; MUKHERJEE, SUBHENDU; GOSWAMI, RAJEEV

To: AURIGENE DISCOVERY TECHNOLOGIES LIMITED

Reel/Frame 057813/0422 →

Priority Claims (2)

IN 2803/CHE/2015 · Jun 4, 2015 · national

IN 6214/CHE/2015 · Nov 18, 2015 · national

Continuity (4)

Continuation 16867761 · May 6, 2020

Continuation 15579246

Related Publication 20220098156A1 · Mar 31, 2022

Related Publication 20230250062A9 · Aug 10, 2023

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