Compounds and compositions for treating conditions associated with NLRP activity

Patent metadata

Field	Value
Publication number	US-11370763-B2
Application number	US-201816632850-A
Country	US
Kind code	B2
Filing date	Jul 23, 2018
Priority date	Jul 24, 2017
Publication date	Jun 28, 2022
Grant date	Jun 28, 2022

Abstract

In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured. The variables shown in Formula AA are as defined in the claims. The compounds of formula AA are NLRP3 activity modulators and, as such, can be used in the treatment of metabolic disorders (e.g. Type 2 diabetes, atherosclerosis, obesity or gout), a disease of the central nervous system (e.g. Alzheimer's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis or Parkinson's disease), lung disease (e.g. asthma, COPD or pulmonary idiopathic fibrosis), liver disease (e.g. NASH syndrome, viral hepatitis or cirrhosis), pancreatic disease (e.g. acute pancreatitis or chronic pancreatitis), kidney disease (e.g. acute kidney injury or chronic kidney injury), intestinal disease (e.g. Crohn's disease or Ulcerative Colitis), skin disease (e.g. psoriasis), musculoskeletal disease (e.g. scleroderma), a vessel disorder (e.g. giant cell arteritis), a disorder of the bones (e.g. osteoarthritis, osteoporosis or osteopetrosis disorders), eye disease (e.g. glaucoma or macular degeneration), a disease caused by viral infection (e.g. HIV or AIDS), an autoimmune disease (e.g. Rheumatoid Arthritis, Systemic Lupus Erythematosus or Autoimmune Thyroiditis), cancer or aging.

First claim

We claim:

1. A compound of Formula AA

wherein
m=0, 1, or 2;
n=0, 1, or 2;
o=1 or 2;
p=0, 1, 2, or 3;
wherein
A is:
thiophenyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 ;
phenyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 ;
thiazolyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 ;
oxazolyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 ;
pyridyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 ;
pyrazolyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 ;
B is phenyl, pyridyl, or pyrimidinyl;
wherein
at least one R 6 is ortho to the bond connecting the B ring to the C(R 4 R 5 ) group of Formula AA;
R 1 and R 2 are each independently selected from C 1 -C 6 alkyl, halo, CN, COC 1 -C 6 alkyl, CO 2 C 1 -C 6 alkyl, C 6 -C 10 aryl, S(O)C 1 -C 6 alkyl, 5- to 10-membered heteroaryl, and 3- to 7-membered heterocycloalkyl,
wherein the C 1 -C 6 alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy and oxo;
R 6 and R 7 are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CN, NO 2 COC 1 -C 6 alkyl, CO 2 C 1 -C 6 alkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, CONR 8 R 9 , and 3- to 7-membered heterocycloalkyl,
wherein the C 1 -C 6 alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy or oxo, or at least one pair of R 6 and R 7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C 5 -C 8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more hydroxy or oxo;
each of R 4 and R 5 is independently selected from hydrogen and C 1 -C 6 alkyl;
R 10 is C 1 -C 6 alkyl;
each of R 8 and R 9 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, (C═NR 13 )NR 11 R 12 , S(O 2 )C 1 -C 6 alkyl, S(O 2 )NR 11 R 12 , COR 13 , CO 2 R 13 and CONR 11 R 12 ; wherein the C 1 -C 6 alkyl is optionally substituted with one or more hydroxy, halo, C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl or 3- to 7-membered heterocycloalkyl; or R 8 and R 9 taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;
R 13 is C 1 -C 6 alkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl;
each of R 11 and R 12 at each occurrence is independently selected from hydrogen and C 1 -C 6 alkyl;
R 3 is hydrogen,
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein A is any one of:
thiophenyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 ;
oxazolyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2R 2 ;
thiazolyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2R 2 ; or
phenyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2R 2 .

3. The compound of claim 1 , wherein m=1 and n=0; optionally wherein the substituted ring A is any one of:

4. The compound of claim 1 , wherein m=1 and n=1; optionally wherein the substituted ring A is any one of:

5. The compound of claim 1 , wherein m=2 and n=1; optionally wherein the substituted ring A is any one of:

6. The compound of claim 1 , wherein R 1 is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH 3 ; COCH 2 CH 3 ; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O 2 )CH 3 ; and S(O 2 )NR 11 R 12 .

7. The compound of claim 1 , wherein R 2 is selected from the group consisting of fluoro; chloro; cyano; methyl; methoxy; ethoxy; isopropyl; 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; COCH 3 ; COPh; 2-methoxy-2-propyl; (dimethylamino)methyl; S(O 2 )CH 3 ; and S(O 2 )NR 11 R 12 .

8. The compound of claim 1 , wherein B is phenyl substituted with 1 or 2 R 6 and optionally substituted with 1, 2, or 3 R 7 ; optionally wherein the substituted ring B is any one of

9. The compound of claim 1 , wherein B is pyridyl; o=1 or 2; and p=0, 1, or 2; optionally wherein the substituted ring B is

10. The compound of claim 1 , wherein each of R 4 and R 5 is hydrogen.

11. The compound, selected from the group consisting of the compounds below:

Compound
Structure

101

101a

101b

102

103

104

Assignees

• Novartis Ag

Inventors

• Franchi Luigi
• Ghosh Shomir
• Glick Gary
• Katz Jason
• Opipari Jr Anthony William
• Roush William
• Seidel Hans Martin
• Shen Dong-Ming
• Venkatraman Shankar
• Winkler David Guenther

Classifications

• C07C2601/02

  with a three-membered ring · CPC title

• C07C2601/10

  the ring being unsaturated · CPC title

• C07C381/10

  Compounds containing sulfur atoms doubly-bound to nitrogen atoms · CPC title

• C07D277/36 Primary

  Sulfur atoms · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title