Quinazoline and indole compounds to treat medical disorders

Patent metadata

Field	Value
Publication number	US-10961252-B2
Application number	US-201816226378-A
Country	US
Kind code	B2
Filing date	Dec 19, 2018
Priority date	Jun 27, 2016
Publication date	Mar 30, 2021
Grant date	Mar 30, 2021

Abstract

Compounds, methods of use, and processes for making inhibitors of Complement Factor B are provided.

First claim

We claim:

1. A compound of formula:

or a pharmaceutically acceptable salt thereof;
wherein:
D is D1;
E is selected from: E1 and E2;
F is selected from: F1 and F2;
wherein at least one of E or F is selected from: E2 or F2 respectively;
D1 is

R 51 is independently selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, (C 1 -C 6 alkoxy)(C 1 -C 6 alkyl), (C 1 -C 6 alkoxy)(C 1 -C 6 alkoxy), C 1 -C 6 haloalkoxy, —S(C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —S(O) 2 (C 1 -C 6 alkyl), —CH 2 NHC(O)(C 1 -C 6 alkyl), and —OCH 2 C(O)R 57 ;
R 52 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, and halogen;
R 53 is selected from hydrogen; halogen; cyano; C 1 -C 6 alkyl optionally substituted with hydroxy; C 1 -C 6 haloalkyl optionally substituted with hydroxy; —CH 2 C(O)R 57 ; C 6 -C 14 aryl; and 5- to 10-membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron, wherein the aryl and heteroaryl group is optionally substituted with C 1 -C 6 alkyl groups;

E1 is

E2 is

F1 is phenyl; napthyl; or 5- to 10-membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron, wherein F1 is optionally substituted by R 55 and further optionally substituted with a substituent selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, and cyanomethyl;
F2 is selected from

and a 5- to 10-membered heteroaryl group having 1-3 heteroatoms selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron with a R 62 substituent;
wherein each F2 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 55 and R 62 ;
R 54 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 hydroxyalkyl;
R 55 is selected from C(O)R 58 ; —CH 2 C(O)R 58 ; R 59 ; —C(O)NHSO 2 (C 1 -C 6 alkyl); —SO 2 NR 25 C(O)(C 1 -C 6 alkyl); —SO 2 N(R 25 ) 2 ; —SO 2 (C 1 -C 6 alkyl); cyano; halogen; C 1 -C 6 hydroxyalkyl; and 5- to 10-membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron;
m is independently 0, 1, or 2;
n is 0, 1, 2, 3, or 4;
R 25 is independently selected from hydrogen and C 1 -C 4 alkyl;
R 56 is independently selected at each occurrence from hydrogen, hydroxy, —N(R 25 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, and C 1 -C 6 alkyoxy;
or C(R 56 ) 2 , taken in combination, forms a spirocyclic carbocycle having 3, 4, 5, or 6 ring atoms;
R 57 is hydroxy, C 1 -C 6 alkoxy, or —N(R 25 ) 2 ;
R 58 is hydroxy; C 1 -C 6 alkoxy; —N(R 25 ) 2 ; or 3- to 12-membered heterocycle having at least one ring atom selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron; wherein each R 58 other than hydroxy is optionally substituted with halogen, hydroxy, or C 1 -C 6 alkyl;
R 59 is 5- to 10-membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron optionally substituted with one or more C 1 -C 6 alkyl groups;
R 60 is halogen;
R 61 is independently selected at each occurrence from hydrogen, halogen, hydroxy, —N(R 25 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, and C 1 -C 6 alkyloxy;
R 62 is selected from

P(O)R 65 R 65 , C(O)NR 25 OR 25 and SF 5 ;
R 63 and R 64 are independently selected at each occurrence from hydrogen; hydroxyl; cyano; amino; C 1 -C 6 alkyl; C 1 -C 6 haloalkyl; C 1 -C 6 alkoxy; (C 3 -C 6 cycloalkyl)(C 1 -C 6 alkyl); (phenyl)C 0 -C 4 alkyl; —C 1 -C 4 alkylOC(O)OC 1 -C 6 alkyl; —C 1 -C 4 alkylOC(O)C 1 -C 6 alkyl; —C 1 -C 4 alkylC(O)OC 1 -C 6 alkyl; C 6 -C 14 aryl; 5- to 10-membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron; 3- to 12-membered heterocycle having at least one ring atom selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron; (C 6 -C 14 aryl)alkyl; (5- to 10-membered heteroaryl)(C 1 -C 6 alkyl) having 1-3 ring atoms selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron; and (3- to 12-membered heterocyclo)(C 1 -C 6 alkyl) having at least one ring atom selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron; and
R 65 is independently selected at each occurrence from hydroxy; C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 alkyl; (C 3 -C 6 cycloalkyl)(C 1 -C 6 alkyl); C 6 -C 14 aryl; (C 6 -C 14 aryl)(C 1 -C 6 alkyl); —O—(C 5 -C 14 aryl)(C 1 -C 6 alkyl); —O—(C 5 -C 14 aryl); 3- to 12-membered heterocycle having at least one ring atom selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron; (3- to 12-membered heterocyclo)(C 1 -C 6 alkyl) having at least one ring atom selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron; 5- to 10-membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron; (5- to 10-membered heteroaryl)(C 1 -C 6 alkyl) having 1-3 ring atoms selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron; O-(5- to 10-membered heteroaryl) having 1-3 ring atoms selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron; O-(3- to 12-membered heterocycle) having at least one ring atom selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron; and —N(R 25 ) 2 .

2. The compound of claim 1 , wherein R 51 is hydrogen.

3. The compound of claim 2 , wherein F is F2.

4. The compound of claim 3 , wherein the compound is selected from:

5. The compound of claim 4 , wherein the compound is selected from

6. The compound of claim 5 , wherein m is 1.

7. The compound of claim 6 , wherein R 56 is independently selected at each occurrence from hydrogen and C 1 -C 6 alkyl.

8. The compound of claim 7 , wherein R 54 is hydrogen.

9. The compound of claim 8 , wherein the compound is of formula

10. The compound of claim 1 , wherein F2 is selected from:

wherein each F2 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 55 and R 62 .

11. The compound of claim 10 , wherein the compound is selected from:

12. The compound of claim 11 , wherein m is 1.

13. The compound of claim 12 , wherein R 56 is independently selected at each occurrence from hydrogen and C 1 -C 6

Assignees

• Achillion Pharmaceuticals Inc

Inventors

• Wiles Jason Allan
• Phadke Avinash

Classifications

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K31/662

  Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon · CPC title