US 2018/0022767 A1 · Compounds for Treatment of Complement Mediated Disorders

Abstract

Compounds, methods of use, and processes for making inhibitors of complement factor D comprising Formula I, or a pharmaceutically acceptable salt or composition thereof are provided. The inhibitors described herein target factor D and inhibit or regulate the complement cascade at an early and essential point in the alternative complement pathway, and reduce factor D's ability to modulate the classical and lectin complement pathways. The inhibitors of factor D described herein are capable of reducing the excessive activation of complement, which has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer.

A pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier:

or a pharmaceutically acceptable salt thereof, wherein
Q1 is C(R1R1′);
Q2 is C(R2R2′);
Q3 is C(R3R3′);
X1 is N and X2 is CH;
R1, R1′, R2, R2′, R3, and R3′ are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, C2-C6alkynyl, C2-C6alkanoyl, C1-C6thioalkyl, hydroxyC1-C6alkyl, aminoC1-C6alkyl, —C0-C4alkylNR9R10, —C(O)OR9, —OC(O)R9, —NR9C(O)R10, —C(O)NR9R10, —OC(O)NR9R10, —O(heteroaryl), —NR9C(O)OR10, C1-C2haloalkyl, C0-C4alkyl(C3-C7cycloalkyl), —O—C0-C4alkyl(C3-C7cycloalkyl) and C1-C2haloalkoxy;
or R1 and R1′ or R3 and R3′ may be taken together to form a 3- to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, or S;
or R2 and R2′ may be taken together to form a 3- to 6-membered carbocyclic spiro ring, or R2 and R2′may be taken together to form a 3- to 6-membered heterocyclic spiro ring, each of which spiro ring is unsubstituted or substituted with one or more halogen or methyl substituents;
or R1 and R2 may be taken together to form a 3-membered carbocyclic ring;
or R1 and R2 may be taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently chosen from N, O, and S;
or R2 and
(q) hydrogen, halogen, hydroxyl, nitro, cyano, amino, —COOH, C1-C2haloalkyl, and C1-C2haloalkoxy,
(r) C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, C2-C6alkenyloxy, —C(O)OR9, C1-C6thioalkyl, —C0-C4alkylNR9R10, —C(O)NR9R10, —SO2R9, —SO2NR9R10, —OC(O)R9, and —C(NR9)NR9R10, each of which (r) is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, —COOH, —CONH2, C1-C2haloalkyl, and C1-C2haloalkoxy, and each of which (r) is also optionally substituted with one substituent chosen from phenyl and 4- to 7-membered heterocycle containing 1, 2, or 3 heteroatoms independently chosen from N, O, and S;
which phenyl or 4- to 7-membered heterocycle is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, (mono- and di-C1-C6alkylamino)C0-C4alkyl, C1-C6alkylester, —C0-C4alkyl(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy;
L is
where R17 is hydrogen or C1-C6alkyl and R18 and R18′ are independently chosen from hydrogen, halogen, and methyl;
and m is 0, 1, 2, or 3;
B is a monocyclic or bicyclic carbocyclic or carbocyclic-oxy group or 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, or
B is a C2-C6alkenyl or C2-C6alkynyl group;
or
B is —(C0-C4alkyl)(aryl), —(C0-C4alkyl)(heteroaryl), or —(C0-C4alkyl)(biphenyl)
each of which B is unsubstituted or substituted with one or more substituents independently chosen from (w) and (x) and 0 or 1 substituents chosen from (y) and (z)
(w) halogen, hydroxyl, —COOH, cyano, C1-C6alkyl, C2-C6alkanoyl, C1-C6alkoxy, —C0-C4alkylNR9R10, —SO2R9, C1-C2haloalkyl, and C1-C2haloalkoxy;
(x) nitro, C2-C6alkenyl, C2-C6alkynyl, C1-C6thioalkyl, -JC3-C7cycloalkyl, —B(OH)2, -JC(O)NR9R23, -JOSO2OR21, SR9, —C(O)(CH2)1-4S(O)R21, —O(CH2)1-4S(O)NR21R22, -JOP(O)(OR21)(OR22), -JP(O)(OR21)(OR22), -JOP(O)(OR21)R22, -JP(O)(OR21)R22, -JOP(O)R21R22, -JP(O)R21R22, -JSP(O)(OR21)(OR22), -JSP(O)(OR21)(R22), R3, if bound to adjacent carbon atoms, may be taken together to form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring;
each of which non-spiro ring may be unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, cyano, —COOH, C1-C4alkyl, C2-C4alkenyl, C1-C4alkoxy, C2-C4alkanoyl, hydroxyC1-C4alkyl, (mono- and di-C1-C4alkylamino)C0-C4alkyl, —C0-C4alkyl(C3-C7cycloalkyl), —O—C0-C4alkyl(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy;
R9 and R10 are independently chosen at each occurrence from hydrogen, C1-C6alkyl, and (C3-C7cycloalkyl)C0-C4alkyl;
A is
R6 is independently chosen from CHO, —C(O)NH2, —C(O)NH(CH3), C2-C6alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, —COOH, —SO2NH2, —C(NH2)C1-C3alkyl, —C(NH2)C1-C3haloalkyl, —CF(C═CH2), —C(═NCN)C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, —C0-C4alkyl(C3-C7cycloalkyl), —C(O)C0-C4alkyl(C3-C7cycloalkyl), —P(O)(OR9)2, —OC(O)R9, —C(O)OR9,)—C(O)N(CH2CH2R9)(R10), —NR9C(O)R10, phenyl, or 5- to 6-membered heteroaryl each R6 other than hydrogen, hydroxyl, cyano, and —COOH is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, imino, cyano, cyanoimino, C1-C2alkyl, C1-C4alkoxy, —C0-C2alkyl(mono- and di-C1-C4alkylamino), C1-C2haloalkyl, C1-C2haloalkoxy, C(O)alkyl, C(O)cycloalkyl, C(O)aryl, C(O)heterocycle, and C(O)heteroaryl;
R8 and are independently chosen from hydrogen, halogen, hydroxyl, C1-C6alkyl, C1-C6alkoxy, and (C1-C4alkylamino)C0-C2alkyl, or R8 and R8′ are taken together to form an oxo group;
X12 is N or CR12;
X13 is N or CR13;
R12 and R13 are independently chosen from (q) and (r),
-JSP(O)(R21)(R22), -JNR9(O)(NHR21)(NHR22), -JNR9P(O)(OR21)(NHR22), -JNR9P(O)(OR21)(OR22), -JC(S)R21, -JNR21SO2R22, -JSO2NR9COR22, -JSO2NR9CONR21R22, -JNR21SO2R22, -JC(O)NR21SO2R22, -JC(NH2)NR22, -JC(NH2)NS(O)2R22, -JOC(O)NR21R22, -JNR21C(O)OR22, -JNR21OC(O)R22, —(CH2)1-4C(O)NR21R22, -JNR9C(O)R21, -JC(O)R21, -JNR9C(O)NR10R22, —CCR21, —(CH2)1-4OC(O)R21, and -JC(O)OR23;
each of which (x) may be unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH)2, —Si(CH3)3, —COOH, —CONH2, —P(O)(OH)2, C1-C6alkyl, C1-C6alkoxy, —C0-C2alkyl(mono- and di-C1-C4alkylamino), C1-C6alkylester, C1-C4alkylamino, C1-C4hydroxylalkyl, C1-C2haloalkyl, and C1-C2haloalkoxy;
(y) naphthyl, naphthyloxy, indanyl, (4- to 7-membered heterocycloalkyl)C0-C4alkyl containing 1 or 2 heteroatoms chosen from N, O, and S, and bicyclic heterocycle containing 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and containing 4- to 7-ring atoms in each ring;
each of which (y) is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, (mono- and di-C1-C6alkylamino)C0-C4alkyl, C1-C6alkylester, —C0-C4alkyl(C3-C7cycloalkyl), —SO2R9, C1-C2haloalkyl, and C1-C2haloalkoxy;
and
(z) tetrazolyl, (phenyl)C0-C2alkyl, (phenyl)C1-C2alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently chosen from N, O, B, and S, each of which (z) is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, (mono- and di-C1-C6alkylamino)C0-C4alkyl, C1-C6alkylester, —C0-C4alkyl(C3-C7cycloalkyl), —SO2R9, —OSi(CH3)2C(CH3)3, C1-C2haloalkyl, and C1-C2haloalkoxy;
J is independently chosen at each occurrence from a covalent bond, C1-C4alkylene, —OC1-C4alkylene, C2-C4alkenylene, and C2-C4alkynylene;
R21 and R22 are independently chosen at each occurrence from hydrogen, hydroxyl, cyano, amino, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, (C3-C7cycloalkyl)C0-C4alkyl, (phenyl)C0-C4alkyl, —C1-C4alkylOC(O)OC1-C6alkyl, —C1-C4alkylOC(O)C1-C6alkyl, —C1-C4alkylC(O)OC1-C6alkyl, (4- to 7-membered heterocycloalkyl)C0-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C0-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S;
and
R23 is independently chosen at each occurrence from (C3-C7cycloalkyl)C0-C4alkyl, (phenyl)C0-C4alkyl, (4- to 7-membered heterocycloalkyl)C0-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C0-C4alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S.

39 more elements

Compounds for Treatment of Complement Mediated Disorders

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Compounds for Treatment of Complement Mediated Disorders

Life of this patent

Abstract

Claims21