Amino compounds for treatment of immune and inflammatory disorders

Patent metadata

Field	Value
Publication number	US-11649223-B2
Application number	US-202017135184-A
Country	US
Kind code	B2
Filing date	Dec 28, 2020
Priority date	Aug 26, 2015
Publication date	May 16, 2023
Grant date	May 16, 2023

Abstract

Compounds, methods of use, and processes for making inhibitors of complement Factor D are provided comprising Formula I, I″ and I′″ or a pharmaceutically acceptable salt or composition thereof. The inhibitors described herein target Factor D and inhibit or regulate the complement cascade. The inhibitors of Factor D described herein reduces the excessive activation of complement.

First claim

We claim:

1. A method for the treatment of a disorder mediated by complement factor D, comprising administering to a host in need thereof an effective amount of a compound of formula

or a pharmaceutically acceptable salt thereof, wherein
A is A1;
B is B1 or B4;
L is L1;
L3 is L4 or L5;
A1 is

B1 is selected from the group consisting of a monocyclic or bicyclic carbocyclic; a monocyclic or bicyclic carbocyclic-oxy group; a monocyclic, bicyclic, or tricyclic heterocyclic group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and from 4 to 7 ring atoms per ring; —(C 0 -C 4 alkyl)(aryl); —(C 0 -C 4 alkyl)(heteroaryl); and —(C 0 -C 4 alkyl)(biphenyl), each of which B1 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of R 33 and R 34 , and 0 or 1 substituents selected from the group consisting of R 35 and R 36 ;
B4 is selected from the group consisting of:
(i) a 4-membered carbocyclic fused to a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S;
(ii) a 4-membered carbocyclic fused to a 6-membered aryl ring; and
(iii) (cycloalkyl)-(aryl), (cycloalkyl)-(heteroaryl), (cycloalkyl)-(heterocycle), (alkyl)-alkenyl, or cycloalkyl-alkenyl;

wherein B4 can be substituted 1, 2, 3 or 4 times with the substituents independently selected from the group consisting of R 33 , R 34 , R 35 , R 36 and R 48 ;
L1 is a bond or is selected from the group consisting of formulas

L4 is —C(O)—;
L5 is —C(S)—, —P(O)OH—, —S(O)—, —S(O) 2 — or —C(R 52 ) 2 —;
X 11 is N or CR 11 ;
X 12 is CR 12 ;
X 13 is CR 13 ;
X 14 is N or CR 14 ;
R 6 is selected from the group consisting of hydrogen, -JCHO, -JC(O)NH 2 , -JC 2 -C 6 alkanoyl, -JC(O)NH(CH 3 ), -J-COOH, -JP(O)(OR 9 ) 2 , -JOC(O)R 9 , -JC(O)OR 9 , -JC(O)N(CH 2 CH 2 R 9 )(R 10 ), -JNR 9 C(O)R 10 , -JSO 2 NH 2 , -JS(O)NH 2 , -JC(CH 3 ) 2 F, -JCH(CF 3 )NH 2 , -JC(O)C 0 -C 2 alkyl(C 3 -C 7 cycloalkyl), -JNR 9 (C 2 -C 6 alkanoyl), -JNR 9 C(O)NR 9 R 10 , -JSO 2 (C 1 -C 6 alkyl), -JSO 2 (C 1 -C 6 haloalkyl), -JSO 2 NR 7 R 7 , -JSO═NH(C 1 -C 6 alkyl), -J-nitro, -J-halogen, -J-hydroxyl, -J-phenyl, a 5- to 6-membered heteroaryl, -J-cyano, -J-cyanoimino, -J-amino, -J-imino, —C 1 -C 6 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 heterocycloalkyl), —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl),

each R 6 other than hydrogen, nitro, halogen, cyano, cyanoimino, or —CHO is unsubstituted or substituted with one or more substituents selected from the group consisting of amino, imino, halogen, hydroxyl, cyano, cyanoimino, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, —C 0 -C 2 alkyl(mono- and di-C 1 -C 4 alkylamino), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;
R 7 is hydrogen, C 1 -C 6 alkyl, or —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl);
R 8 and R 8′ are independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), C 1 -C 6 alkoxy, and (C 1 -C 4 alkylamino)C 0 -C 2 alkyl; or R 8 and R 8′ are taken together to form an oxo group; or R 8 and R 8′ can be taken together with the carbon that they are bonded to form a 3-membered carbocyclic ring;
R 9 and R 10 are independently selected at each occurrence from the group consisting of hydrogen, C 1 -C 6 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), and —O—C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl);
R 11 and R 14 are independently selected at each occurrence from the group consisting of hydrogen, halogen, hydroxyl, nitro, cyano, —O(PO)(OR 9 ) 2 , —(PO)(OR 9 ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkenyl(aryl), C 2 -C 6 alkenyl(cycloalkyl), C 2 -C 6 alkenyl(heterocycle), C 2 -C 6 alkenyl(heteroaryl), C 2 -C 6 alkynyl, C 2 -C 6 alkynyl(aryl), C 2 -C 6 alkynyl(cycloalkyl), C 2 -C 6 alkynyl(heterocycle), C 2 -C 6 alkynyl(heteroaryl), C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkyl, —C 0 -C 4 alkyl(mono- and di-C 1 -C 6 alkylamino), —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —C 0 -C 4 alkoxy(C 3 -C 7 cycloalkyl), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;
one of R 12 and R 13 is chosen from R 31 and the other of R 12 and R 13 is chosen from R 32 or both R 12 and R 13 are each independently selected from a R 32 ;
R 17 is hydrogen, C 1 -C 6 alkyl, or —C 0 -C 2 alkyl(C 3 -C 7 cycloalkyl);
R 18 and R 18′ are independently selected from the group consisting of hydrogen, halogen, hydroxymethyl, and methyl;
m is 0, 1, 2, or 3;
R 21 and R 22 are independently selected at each occurrence from the group consisting of hydrogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 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, (4- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S;
R 23 is independently selected at each occurrence from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (aryl)C 0 -C 4 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (phenyl)C 0 -C 4 alkyl, (4- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S;
R 31 is selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, cyano, amino, —COOH, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, —C(O)OR 9 , C 1 -C 6 thioalkyl, —C 0 -C 4 alkylNR 9 R 10 , —C(O)NR 9 R 10 , —SO 2 R 9 , —SO 2 NR 9 R 10 , —OC(O)R 9 , and —C(NR 9 )NR 9 R 10 , each of which R 31 other than hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, amino, —COOH, —CONH 2 , C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy, and each of which R 31 is also optionally substituted with one substituent selected from the group consisting of phenyl and 4- to 7-membered heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; which phenyl or 4- to 7-membered heterocycle is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, (mono- and di-C 1 -C 6 alkylamino)C 0 -C 4 alkyl, C 1 -C 6 alkylester, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;
R 32 is selected from the group consisting of NR 72 R 73 , NR 9 SOR 73 , and N(SO 2 R 9 )CH 2 C(O)R 74 ;
R 72 is selected at each occurrence from the group consisting of aryl, heteroaryl, heterocycle, alkynyl, hydroxyl, C 1 -C 6 alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (aryl)C 0 -C 4 alkyl, (heterocycle)C 0 -C 4 alkyl, (heteroaryl)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)O

Assignees

• Achillion Pharmaceuticals Inc

Inventors

• Wiles Jason Allan
• Phadke Avinash S
• Deshpande Milind
• Agarwal Atul
• Chen Dawei
• Gadhachanda Venkat Rao
• Hashimoto Akihiro
• Pais Godwin
• Wang Qiuping
• Wang Xiangzhu
• Greenlee William

Classifications

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D401/12

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

• C07D403/12

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

• C07D487/04

  Ortho-condensed systems · CPC title