IP Library › Patent Application 18794848
Patent Application
App. No. 18/794,848

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US None
App. No.
18/794,848
Abstract

This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing at least one such modulator, methods of treatment of cystic fibrosis using such modulators and pharmaceutical compositions, and processes for making such modulators.

Claims (157)

1 .- 62 . (canceled)

63 . A process for preparing a compound of Formula S4-4:

comprising converting a compound of Formula S4-3:

into a compound of Formula S4-4, wherein:

each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and;

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl

 (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —NR Y1 —; or two instances of R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;

Ring B is selected from:

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy),

C 3 -C 8 cycloalkyl,

5- to 10-membered heteroaryl, and

3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);

each Q is independently selected from:

C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:

halogen,

oxo,

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and

C 3 -C 8 cycloalkyl,

C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:

halogen,

CN,

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe),

C 1 -C 6 alkoxy,

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and

C 3 -C 8 cycloalkyl,

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:

halogen,

CN,

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy),

C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:

halogen,

C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and

C 6 -C 10 aryl,

5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

halogen,

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and

3- to 10-membered heterocyclyl,

3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and

oxo;

each R 1 is independently selected from halogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen and hydroxy), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;

each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen); and

m is selected from 0, 1, 2, and 3.

64 . The process of claim 63 , wherein the compound of Formula S4-3 is produced by converting a compound of Formula S4-2:

into a compound of Formula S4-3.

65 . The process according to claim 63 , wherein each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 3 -C 8 cycloalkyl, and —OR Y1 .

66 . The process according to claim 63 , wherein each R Y is independently selected from:

hydrogen, fluorine,

67 . The process according to claim 63 , wherein each Q is independently selected from:

C 3 -C 8 cycloalkyl, and

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alky.

68 . The process according to claim 63 , wherein each Q is independently selected from:

69 . The process according to claim 63 , wherein Ring B is selected from C 3 -C 8 cycloalkyl and phenyl optionally substituted with 1-3 groups independently selected from halogen.

70 . The process according to claim 63 , wherein Ring B is selected from:

71 . The process according to claim 63 , wherein each R 1 is independently selected from C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen and hydroxy), —N(R 2 ) 2 , and —CO 2 R 2 .

72 . The process according to claim 63 , wherein each R 2 is independently selected from hydrogen and C 1 -C 6 alkyl.

73 . The process according to claim 63 , wherein each R 1 is independently selected from —CF 3 , —NH 2 , —NH(CH 2 CH 3 ), CO 2 H, and CH 2 OH.

74 . The process according to claim 63 , wherein the compound of Formula S4-4 is selected from:

Comp.

No.

Structure

1

2

enantiomer 1

3

enantiomer 2

4

5

6

7

diastereomer pair 1

8

diastereomer pair 2

11

12

13

14

18

diastereomer pair

25

34

enantiomer 1

35

enantiomer 2

36

37

40

diastereomer 1

41

diastereomer 2

42

diastereomer 1

43

regioisomeric diastereomer 1

44

45

diastereomer 2

46

diastereomer 2

47

enantiomer 1

48

enantiomer 2

49

enantiomer 1

50

enantiomer 2

51

enantiomer 1

52

enantiomer 2

53

diastereomer 1

54

enantiomer 1

55

enantiomer 2

56

enantiomer 1

57

enantiomer 2

58

diastereomer 2

59

60

61

62

enantiomer 3

65

enantiomer 1

66

enantiomer 2

67

68

enantiomer 1

69

enantiomer 2

70

diastereomer 1

71

diastereomer 2

75

76

77

diastereomer 1

and a pharmaceutically acceptable salt thereof.

75 . The process according to claim 63 , wherein the conversion occurs in a solvent.

76 . The process according to claim 75 , wherein the solvent is selected from methanol, ethanol, ethyl acetate, and a combination thereof.

77 . The process according to claim 75 , wherein the solvent is ethanol.

78 . The process according to claim 63 , wherein the conversion occurs in the presence of a catalyst.

79 . The process according to claim 78 , wherein the catalyst is palladium on carbon or palladium on silica.

80 . The process according to claim 63 , wherein the conversion occurs at room temperature.

81 . The process according to claim 64 , wherein the compound of Formula S4-2 is converted into the compound of Formula S4-3 in the presence of a catalyst.

82 . The process according to claim 81 , wherein the catalyst is selected from Dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II), [1,3-Bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-[(2-isopropoxyphenyl)methylene]ruthenium, and Dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II).