IP Library › Granted Patent US 10,442,798

Granted Patent B2

US 10,442,798 · App. 15/890,648 · Granted Oct 15, 2019

Tetrahydroquinoline sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease

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Quick Facts

Patent No.: US 10,442,798
App. No.: 15/890,648
Granted: Oct 15, 2019
Kind: B2

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Abstract

The invention provides tetrahydroquinoline sulfonamide compounds, tetrahydronaphthalene sulfonyl compounds, and related compounds, pharmaceutical compositions, methods of promoting RORy activity, methods of increasing the amount of IL-17 in a subject, and methods of treating cancer and other medical disorders using such compounds.

Claims (404)

1. A compound represented by Formula I:

or a pharmaceutically acceptable salt thereof; wherein:

A is phenylene, 5-6 membered heteroarylene, or C 3-6 heterocycloalkylene;

R 1 represents independently for each occurrence halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;

R 2A is one of the following:

(i) C 1-6 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 1-6 alkylene)-CO 2 R 4 , —O—(C 1-6 alkylene)-C(O)—(C 1-6 alkyl), —N(R 4 )—(C 1-6 alkylene)-CO 2 R 4 , or —N(R 4 )—(C 1-6 alkylene)-C(O)—(C 1-6 alkyl), wherein the C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 alkylene are optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —C(O)N(R 4 )(R 5 ), —C(O)—N(R 4 )—(C 1-4 alkylene)-CO 2 R 4 , —N(R 4 )C(O)R 8 , —CN, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, —N(R 4 )(R 5 ), —N(R 4 )C(O)N(R 4 )(R 5 ), —N(R 4 )CO 2 R 9 , —N(R 4 )S(O) 2 R 9 , and —N(R 4 ) S(O) 2 N(R 4 )(R 5 ); or

(ii) —CO 2 R 4 , —N(R 4 )C(O)R 9 , —N(R 4 )CO 2 R 9 , —N(R 4 )C(O)N(R 4 )(R 5 ), —N(R 4 )C(O)N(R 4 )(heteroaryl), —N(R 4 )S(O) 2 R 9 , —N(R 4 )(R 5 ), or —OH;

R 2B is C 1-6 alkyl, C 1-3 haloalkyl, or fluoro;

R 3 represents independently for each occurrence hydrogen, C 1-6 haloalkyl, halogen, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —N(R 4 )(R 8 ), —O—(C 1-6 hydroxyalkyl), or —O—(C 1-6 alkylene)-CO 2 R 4 ; or two vicinal occurrences of R 3 are taken together with intervening atoms to form a 4-6 membered ring;

R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or an occurrence of R 4 and R 5 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-8 membered heterocyclic ring;

R 6 and R 7 each represent independently for each occurrence hydrogen, fluoro, or C 1-6 alkyl, or R 6 and R 7 are taken together with the carbon atom to which they are attached to form a 3-6 membered carbocyclic ring; or R 6 and a vicinal occurrence of R 2B are taken together to form a bond;

R 8 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), or aryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, and —CO 2 R 4 ; or R 8 is —CO 2 R 4 ;

R 9 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), C 1-6 haloalkyl, or C 1-6 hydroxyalkyl;

X is one of the following:

(i) —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), or —N(R 4 )—(C 1-6 alkylene)-(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;

(ii) —S-aralkyl, —S-heteroaralkyl, —S-phenyl, —S-heteroaryl, —S-(partially unsaturated bicyclic carbocyclyl), —S—(C 1-6 alkylene)-(C 3-6 cycloalkyl), or —S—(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;

(iii) —(C 2-6 alkenylene)-phenyl, —(C 2-6 alkenylene)-heteroaryl, —(C 2-6 alkenylene)-(partially unsaturated 8-10 membered bicyclic ring containing 0-3 heteroatoms), —(C 1-6 alkylene)-phenyl, —(C 1-6 alkylene)-heteroaryl, —(C 1-6 alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C 1-6 alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), —(C 1-6 alkylene)-(C 3 -C 6 cycloalkyl), -(5-6 membered heterocycloalkylene)-phenyl, or —(C 3-6 cycloalkylene)-phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;

(iv) —(C 2-6 alkenylene)-(C 1-6 alkyl), —(C 2-6 alkenylene)-(C 3-6 cycloalkyl), or

each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 , wherein A* is a 5-8 membered, partially saturated carbocyclic or heterocyclic ring; or

(v) —(C 1-6 alkylene)-Z 1 or —(C 2-6 alkenylene)-Z 1 , wherein Z 1 is —O-aralkyl, —O— heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), —N(R 4 )—(C 1-6 alkylene)-(C 3-6 cycloalkyl), or —N(R 4 )—(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;

Y is —C(R 6 )(R 7 )—, —C(O)—, or —S(O) p —;

m and p each represent independently for each occurrence 0, 1, or 2; and

n is 1, 2, or 3.

2. The compound of claim 1 , wherein the compound is represented by Formula I-A:

or a pharmaceutically acceptable salt thereof; wherein:

A is phenylene or a 5-6 membered heteroarylene;

R 1 represents independently for each occurrence halogen, C 1-6 alkyl, or C 3-6 cycloalkyl;

R 2A is C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —N(R 4 )C(O)(C 1-6 alkyl), —CN, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, and —N(R 4 )(R 5 ); or R 2A is —CO 2 R 4 or —N(R 4 )C(O)(C 1-6 alkyl);

R 2B is C 1-6 alkyl or C 1-3 haloalkyl;

R 3 represents independently for each occurrence hydrogen, C 1-6 haloalkyl, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or —O—(C 1-6 alkylene)-OH; or two vicinal occurrences of R 3 are taken together with intervening atoms to form a 4-6 membered ring;

R 6 and R 7 each represent independently for each occurrence hydrogen or C 1-6 alkyl, or R 6 and R 7 are taken together with the carbon atom to which they are attached to form a 3-6 membered carbocyclic ring;

X is one of the following:

(i) —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)-(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), or —N(R 4 )—(C 1-6 alkylene)-(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;

(ii) —(C 2-6 alkenylene)-phenyl, —(C 2-6 alkenylene)-heteroaryl, —(C 1-6 alkylene)-phenyl, —(C 1-6 alkylene)-heteroaryl, —(C 1-6 alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C 1-6 alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), or -(5-6 membered heterocycloalkylene)-phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; or

(iii) —(C 1-6 alkylene)-Z 1 or —(C 2-6 alkenylene)-Z 1 , wherein Z 1 is —O-aralkyl, —O— heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), or —N(R 4 )—(C 1-6 alkylene)-(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;

Y is —C(R 6 )(R′)—;

m and p are independently 0, 1, or 2; and

n is 1, 2, or 3.

3. The compound of claim 2 , wherein R 2A is C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —N(R 4 )C(O)(C 1-6 alkyl), —CN, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and —N(R 4 )(R 5 ).

4. The compound of claim 2 , wherein R 2A is C 1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —N(R 4 )C(O)(C 1-6 alkyl), —CN, hydroxyl, and C 1-6 alkoxy.

5. The compound of claim 2 , wherein R 2A is —CO 2 R 4 .

6. The compound of claim 2 , wherein R 2B is methyl.

7. The compound of claim 2 , wherein A is phenylene.

8. The compound of claim 7 , wherein n is 1.

9. The compound of claim 7 , wherein R 3 represents independently for each occurrence C 1-6 haloalkyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, or —O—(C 1-6 alkylene)-OH.

10. The compound of claim 8 , wherein R 3 is trifluoromethyl.

11. The compound of claim 7 , wherein X is —O-aralkyl or —N(R 4 )-aralkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

12. The compound of claim 9 , wherein X is —O-benzyl or —N(R 4 )-benzyl, each of which is substituted with 1 or 2 substituents independently selected from the group consisting of chloro, bromo, and fluoro.

13. The compound of claim 7 , wherein X is —(C 2-6 alkenylene)-phenyl, —(C 2-6 alkenylene)-heteroaryl, —(C 1-6 alkylene)-phenyl, —(C 1-6 alkylene)-heteroaryl, —(C 1-6 alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C 1-6 alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), or -(5-6 membered heterocycloalkylene)-phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

14. The compound of claim 9 , wherein X is —(C 2-6 alkenylene)-phenyl, —(C 1-6 alkylene)-phenyl, or —(C 1-6 alkylene)-heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

15. The compound of claim 1 , wherein Y is —C(R 6 )R 7 )—.

16. The compound of claim 2 , wherein R 6 and R 7 are independently hydrogen or methyl.

17. The compound of claim 7 , wherein Y is —C(R 6 )(R 7 )—, R 6 and R 7 are independently hydrogen or methyl, and X is attached at the 7-position of the 1,2,3,4-tetrahydroquinolinyl ring.

18. The compound of claim 10 , wherein m is 0.

19. The compound of claim 10 , wherein p is 0.

20. The compound of claim 6 , wherein p is 1.

21. A compound in Table 1-1, 1-A-1, 24-1, or 25-1 below, or a pharmaceutically acceptable salt thereof:

TABLE 1-1

No.

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

TABLE 1-A-1

No.

I-A1

I-A2

I-A3

I-A4

I-A5

I-A6

I-A7

I-A8

I-A9

I-A10

I-A11

I-A12

I-A13

I-A14

I-A15

I-A16

I-A17

I-A18

I-A19

I-A20

I-A21

I-A22

I-A23

I-A24

I-A25

I-A26

I-A27

I-A28

I-A29

I-A30

I-A31

I-A32

I-A33

I-A34

I-A35

I-A36

I-A37

I-A38

I-A39

I-A40

I-A41

I-A42

I-A43

I-A44

I-A45

I-A46

I-A47

I-A48

I-A49

I-A50

I-A51

I-A52

I-A53

I-A54

I-A55

I-A56

I-A57

I-A58

I-A59

I-A60

I-A61

I-A62

I-A63

I-A64

I-A65

I-A66

I-A67

I-A68

I-A69

I-A70

I-A71

I-A72

I-A73

I-A74

I-A75

I-A76

I-A77

I-A78

I-A79

I-A80

I-A81

I-A82

I-A83

I-A84

I-A85

I-A86

I-A87

I-A88

I-A89

I-A90

I-A91

I-A92

I-A93

I-A94

I-A95

I-A96

I-A97

I-A98

I-A99

I-A100

I-A101

I-A102

I-A103

I-A104

I-A105

I-A106

TABLE 24-1

Compound Structure

TABLE 25-1

Title

Com-

pound

from

Example

Compound

No.

Structure

15B

15C

15D

25A

25B

25C

25D

25E

25J

25K

25L

25M

25N

25O

25P

25Q

25R

25S

25T

25U

25V

25W

28A

28B

28C

28D

28F

116F

116G

116H

116I

116J

116L

116M

138

139

140

142

143

145

146

147

148

149

150

151

152

153

154A

154B

154C

155

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173A

173B

173C

173D

173E

173F

174

175

176

177

187

188

189

22. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

23. A method of treating a disorder selected from the group consisting of cancer, bacterial infection, and fungal infection, comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof to ameliorate a symptom of the disorder, wherein the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer, esophagus cancer, liver cancer, an acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma.

24. The method of claim 23 , wherein the disorder is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer, esophagus cancer, liver cancer, an acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma.

25. A method of increasing the amount of IL-17 in a subject, comprising administering to a subject an effective amount of a compound of claim 1 to increase the amount of IL-17 in the subject.

26. The method of claim 23 , wherein the subject is a human.

27. A method of promoting the activity of RORγ, comprising exposing a RORγ to an effective amount of a compound of claim 1 to promote the activity of said RORγ.

28. A compound represented by Formulae III or IV:

or a pharmaceutically acceptable salt thereof; wherein:

A is phenylene, 5-6 membered heteroarylene, or C 3-6 heterocycloalkylene;

R 1 represents independently for each occurrence halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;

R 2A is —(C 1-2 alkylene)-(2-8 membered heteroalkylene)-CO 2 R 4 , —(C 1-6 alkylene)-C(O)N(R 4 )(C 1-6 hydroxyalkyl ene)-CO 2 R 4 , or —(C 1-6 alkylene)-N(R 4 )C(O)N(R 4 )—(C 1 -6 alkylene)-CO 2 R 4 ; wherein the C 1-6 alkylene is optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —C(O)N(R 4 )(R 5 ), —CN, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, and —N(R 4 )(R 5 );

R 2B is C 1-6 alkyl, C 1-3 haloalkyl, or fluoro;

R 3 represents independently for each occurrence hydrogen, C 1-6 haloalkyl, halogen, hydroxyl, C 1-6 alkyl, C 3 -6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —N(R 4 )(R 8 ), —O—(C 1-6 hydroxyalkyl), or —O—(C 1-6 alkylene)-CO 2 R 4 ; or two vicinal occurrences of R 3 are taken together with intervening atoms to form a 4-6 membered ring;

R 9 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), C 1-6 haloalkyl, or C 1-6 hydroxyalkyl;

X is one of the following:

(ii) —S-aralkyl, —S-heteroaralkyl, —S-phenyl, —S-heteroaryl, —S-(partially unsaturated bicyclic carbocyclyl), —S—(C 1-6 alkylene)-(C 3-6 cycloalkyl), or —S—(C 3 -6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;

(iii) —(C 2-6 alkenylene)-phenyl, —(C 2-6 alkenylene)-heteroaryl, —(C 2-6 alkenylene)-(partially unsaturated 8-10 membered bicyclic ring containing 0-3 heteroatoms), —(C 1-6 alkylene)-phenyl, —(C 1-6 alkylene)-heteroaryl, —(C 1-6 alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C 1-6 alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), —(C 1-6 alkylene)-(C 3 -C 6 cycloalkyl), -(5-6 membered heterocycloalkylene)-phenyl, or —(C 3-6 cycloalkyl ene)-phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;

(iv) —(C 2-6 alkenylene)-(C 1-6 alkyl), —(C 2-6 alkenylene)-(C 3-6 cycloalkyl), or

Y is —C(R 6 )(R 7 )—, —C(O)—, or —S(O) p —;

m and p each represent independently for each occurrence 0, 1, or 2; and

n is 1, 2, or 3; and

Formula IV is represented by:

or a pharmaceutically acceptable salt thereof; wherein:

A is phenylene, 5-6 membered heteroarylene, or C 3-6 heterocycloalkylene;

R 1 represents independently for each occurrence halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;

R 2A is one of the following:

(i) hydrogen, C 1-6 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 1-6 alkylene)-CO 2 R 4 , —O—(C 1-6 alkylene)-C(O)—(C 1-6 alkyl), —N(R 4 )—(C 1-6 alkylene)-CO 2 R 4 , or —N(R 4 )—(C 1-6 alkylene)-C(O)—(C 1-6 alkyl), wherein the C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 alkylene are optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —C(O)N(R 4 )(R 5 ), —C(O)—N(R 4 )—(C 1-4 alkylene)-CO 2 R 4 , —N(R 4 )C(O)R 8 , —CN, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, —N(R 4 )(R 5 ), —N(R 4 )C(O)N(R 4 )(R 5 ), —N(R 4 )CO 2 R 9 , —N(R 4 )S(O) 2 R 9 , and —N(R 4 ) S(O) 2 N(R 4 )(R 5 ); or

(ii) —CO 2 R 4 , —N(R 4 )C(O)R 9 , —N(R 4 )CO 2 R 9 , —N(R 4 )C(O)N(R 4 )(R 5 ), —N(R 4 )C(O)N(R 4 )(heteroaryl), —N(R 4 )S(O) 2 R 9 , —N(R 4 )(R 5 ), —OH, or —(C 1-2 alkylene)-(2-8 membered heteroalkylene)-CO 2 R 4 ;

R 2B is C 1-6 alkyl, C 1-3 haloalkyl, or fluoro;

R 3 represents independently for each occurrence hydrogen, C 1-6 haloalkyl, halogen, hydroxyl, C 1-6 alkyl, C 3 -6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —N(R 4 )(R 8 ), —O—(C 1-6 hydroxyalkyl), or —O—(C 1-6 alkylene)-CO 2 R 4 ; or two vicinal occurrences of R 3 are taken together with intervening atoms to form a 4-6 membered ring;

R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-6 alkyl, or C 3 -6 cycloalkyl; or an occurrence of R 4 and R 5 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-8 membered heterocyclic ring;

R 9 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), C 1-6 haloalkyl, or C 1-6 hydroxyalkyl;

X is C 4-7 cycloalkenyl, C 3-7 cycloalkyl, or an 8-10 membered, bicyclic partially saturated carbocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;

Y is —C(R 6 )(R 7 )—, —C(O)—, or —S(O) p —;

m and p each represent independently for each occurrence 0, 1, or 2; and

n is 1, 2, or 3.

29. A pharmaceutical composition comprising a compound of claim 28 , and a pharmaceutically acceptable carrier.

30. A method of treating a disorder selected from the group consisting of cancer, bacterial infection, and fungal infection, comprising administering a therapeutically effective amount of a compound of claim 28 to a subject in need thereof to ameliorate a symptom of the disorder, wherein the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer, esophagus cancer, liver cancer, an acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 1, 2019

From: AICHER, THOMAS DANIEL; TAYLOR, CLARKE B.; VANHUIS, CHAD A.

To: LYCERA CORPORATION

Reel/Frame 049932/0437 →

SECURITY INTEREST Recorded Jan 3, 2019

From: LYCERA CORP.

To: WILMINGTON TRUST, NATIONAL ASSOCIATION

Reel/Frame 048002/0201 →