Granted Patent B2

US 12,612,424 · App. 17/624,514 · Granted Apr 28, 2026

Inventors: Wenge Zhong (Thousand Oaks, CA); Xiaotian Zhu (Newton, MA); Song Feng (Shanghai, CN); Lei Wu (Shanghai, CN); Wei Huang (Shanghai, CN); Hao Liu (San Diego, CA); Rongqiang Liu (Kendall Park, NJ); Kate Xin Wen (Shanghai, CN); Hua Zhou (Shanghai, CN)

Assignee: Regor Pharmaceuticals, Inc.

C07F9/6561A61K45/06A61P35/00C07D401/14C07D405/14C07D471/04C07D473/32C07D487/04C07D491/107C07D498/04C07D519/00C07F9/65583

Abstract

Claims (135)

1 . A compound represented by structural formula (I-2):

or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein

A is CR 2 or N;

(i) R is

 wherein the bond connects with the pyrimidine ring;

each instance of R a is independently H, F, or Cl;

R a1 is independently H, C 1-4 alkyl, or C 1-4 hydroxyalkyl:

R a1 ′ is independently —(CHR aa ) k OH, —(CHR aa ) k CN, —(CHR aa ) k C(O)OR 11 , —(CHR aa ) k C(O)NR 11 R 12 , —(CHR aa ) k C(O)NR 11 OR 12 , —(CHR aa ) k C(O)NR 11 S(═O) 2 R 12 , —(CHR aa ) k S(═O) 2 R 11 , —(CHR aa ) k S(═O) 2 NR 11 R 12 , —(CHR aa ) k NR 11 S(═O) 2 R 12 , —(CHR aa ) k -5-6 membered heteroaryl, or —(CHR aa ) k P(═O)R 11 R 12 ;

R aa is independently H or C 1-3 alkyl optionally substituted with halogen;

R 1 is H, deuterium, halogen, OH, CN, NH 2 , NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, NR 11 R 12 , C(O)NR 11 R 12 , C(O)C 1-6 alkyl, C(O)OC 1-6 alkyl, NR 11 C(O)C 1-6 alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, or 3-7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl, or heterocyclyl represented by R 1 or in the group represented by R 1 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, and NR 11 R 12 ; or

(ii) R and R 1 , together with the carbon atoms to which they are attached, form a ring represented below:

wherein the bonds connect with the pyrimidine ring;

each instance of R b is independently H, deuterium, halogen, OH, CN, NH 2 , NO 2 , COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, NR 11 R 12 , C(O)NR 11 R 12 , C(O)NR 11 OR 12 , C(O)NR 11 S(═O) 2 R 12 , C(O)C 1-6 alkyl, C(O)OR 11 , NR 11 C(O)R 12 , S(═O) 2 R 11 , S(═O) 2 NR 11 R 12 , NR 11 S(═O) 2 R 12 , P(═O)R 11 R 12 , C 3-6 cycloalkyl, 3-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, or heteroaryl represented by R b or in the group represented by R b is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, NR 11 R 12 , C(O)NR 11 R 12 , C(O)NR 11 OR 12 , C(O)NR 11 S(═O) 2 R 12 , C(O)OR 11 , NR 11 S(═O) 2 R 12 , P(═O)R 11 R 12 , S(═O) 2 R 11 , S(═O) 2 NR 11 R 12 , and 5-6 membered heteroaryl;

each instance of R c is independently phenyl, 5-6 membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N and 0; 5-6 membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N and O; wherein the phenyl, heterocyclyl, or heteroaryl represented by R c is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, NR 11 R 12 , C(O)NR 11 R 12 , and P(O)di-C 1-6 alkyl;

each instance of R 2 is independently H, deuterium, halogen, OH, CN, NH 2 , NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, NR 11 R 12 , C(O)NR 11 R 12 , C(O)C 1-6 alkyl, C(O)OC 1-6 alkyl, NR 11 C(O)C 1-6 alkyl, P(═O)R 11 R 12 , S(═O) 2 R 11 , or S(═O) 2 NR 11 R 12 , wherein the alkyl, alkenyl, alkynyl, or alkoxy represented by R 2 or in the group represented by R 2 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, and NR 11 R 12 ;

R 3 is H, C 1-6 alkyl, C(O)C 1-6 alkyl, C 3-6 cycloalkyl, or 3-7 membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl represented by R 3 or in the group represented by R 3 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, and NR 11 R 12 ;

each instance of R 11 and R 12 is independently H or C 1-4 alkyl;

m is 0, 1, 2, or 3; and

k is 0 or 1.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein

R 1 is H, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, NR 11 R 12 , C(O)NR 11 R 12 , C(O)C 1-6 alkyl, C(O)OC 1-6 alkyl, NR 11 C(O)C 1-6 alkyl, wherein the alkyl, alkenyl, or alkoxy represented by R 1 or in the group represented by R 1 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, and NR 11 R 12 .

3 . The compound of claim 2 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein

R 1 is H, halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 1-4 alkoxy, or C 1-4 haloalkoxy.

4 . The compound of claim 3 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein

R 1 is H, F, Cl, CN, or CF 3 .

5 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R is

wherein the bond connects with the pyrimidine ring,

R a1 is independently H, C 1-4 alkyl, or C 1-4 hydroxyalkyl;

R a1 ′ is independently —(CHR aa ) k OH, —(CHR aa ) k CN, —(CHR aa )C(O)OR 11 , —(CHR aa ) k C(O)NR 11 R 12 , —(CHR aa ) k C(O)NR 11 OR 12 , —(CHR aa ) k C(O)NR 11 S(═O) 2 R 12 , —(CHR aa ) k S(═O) 2 R 11 , —(CHR aa ) k S(═O) 2 NR 11 R 12 , —(CHR aa ) k NR 11 S(═O) 2 R 12 , —(CHR aa ) k -5-6 membered heteroaryl, or —(CHR aa ) k P(═O)R 11 R 12 ;

R aa is independently H or C 1-3 alkyl optionally substituted with halogen;

R a is independently H, F, or Cl;

R 11 and R 12 are independently H or C 1-4 alkyl;

k is 0 or 1.

6 . The compound of claim 5 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein

R a1 is independently H, CH 3 , or CH 2 OH;

R a1 ′ is independently —(CHR aa ) k OH, —(CHR aa ) k CN, —(CHR aa ) k C(O)OR 11 , —(CHR aa ) k C(O)NR 11 R 12 , —(CHR aa ) k C(O)NR 11 OR 12 , —(CHR aa ) k C(O)NR 11 S(═O) 2 R 12 , —(CHR aa ) k S(═O) 2 R 11 , —(CHR aa ) k S(═O) 2 NR 11 R 12 , —(CHR aa ) k NR 11 S(═O) 2 R 12 , —(CHR aa ) k -tetrazole, or —(CHR aa ) k P(═O)R 11 R 12 ;

R aa is independently H, CH 3 , or CF 3 ;

R 11 and R 12 are independently H or C 1-2 alkyl;

each instance of R a is independently H or F; and

k is 0 or 1.

7 . The compound of claim 6 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1 is Cl.

8 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein

(i) R and R 1 , together with the carbon atoms to which they are attached, form a ring represented below:

(ii) R and R 1 , together with the carbon atoms to which they are attached, form a ring represented below:

wherein the bonds connect with the pyrimidine ring.

9 . The compound of claim 8 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein

(i) each instance of R b is independently H, halogen, OH, CN, NH 2 , COOH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, NR 11 R 12 , C(O)NR 11 R 12 , C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)NR 11 OR 12 , S(═O) 2 R 11 , S(═O) 2 NR 11 R 12 , NR 11 (S═O) 2 R 12 , C(O)NR 11 S(═O) 2 R 12 , P(═O)R 11 R 12 , 5-6 membered heteroaryl, or NR 11 C(O)C 1-4 alkyl; and

each instance of R c is phenyl or pyridinyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of halogen, OH, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, NR 11 R 12 , C(O)NR 11 R 12 , and P(═O)di-C 1-6 alkyl;

(ii) each instance of R b is independently H, halogen, CN, COOH, C 1-2 alkyl, or C 1-2 haloalkyl;

each instance of R c is phenyl or pyridinyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, NR 11 R 12 , C(O)NR 11 R 12 , and P(═O)di-C 1-6 alkyl;

(iii) each instance of R b is independently H, CN, or COOH; and

each instance of R c is phenyl or pyridinyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of C 1-4 alkyl, C(O)N(CH 3 ) 2 , and P(═O)(CH 3 ) 2 .

10 . The compound of claim 7 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein

m is 0 or 1; and/or

each instance of R 2 is H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy; and

R 3 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, or COCH 2 NR 11 R 12 .

11 . The compound of claim 10 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein each instance of R 2 is H, F, Cl, or OCH 3 ; and R 3 is H or C 1-4 alkyl.

12 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

13 . A combination comprising a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, and one or more therapeutically active co-agents.

14 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein each instance of R 2 is independently H, halogen, OH, CN, NH 2 , NO 2 , C 1-4 alkyl, C 1-4 alkoxy, NR 11 R 12 , C(O)NR 11 R 12 , C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, NR 11 C(O)C 1-4 alkyl, P(═O)R 11 R 12 , S(═O) 2 R 11 , or S(═O) 2 NR 11 R 12 , wherein the alkyl or alkoxy represented by R 2 or in the group represented by R 2 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, and NR 11 R 12 .

15 . The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is H, C 1-6 alkyl, or C(O)C 1-6 alkyl, wherein the alkyl represented by R 3 or in the group represented by R 3 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, and NR 11 R 12 .

16 . The compound of claim 11 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein

R a1 is independently H, CH 3 , or CH 2 OH;

R a1 ′ is —CH 2 COOH; and

each instance of R a is independently H or F.

17 . A compound, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the compound is

Exam-

ple

No.

Structure

36

37

43

44

45

38

39

47

46

111

40

41

33

32

95

96

87

115

88

121

81

99

120

117

118

119

116

97

122

101

102

100

127

123

103

128

124

98

110

163

109

112

105

104

126

125

172

171

166

145

149

164

150

151

152

153

154

160

157

155

158

156

165

18 . A compound, or a pharmaceutically acceptable salt, wherein the compound is

19 . A stereoisomer of a compound, wherein the compound is

Assignments (2)

Priority Claims (1)

Continuity (1)

References Cited (42)