US 2020/0262818 A1 · ARYL, HETEROARYL, AND HETEROCYCLIC COMPOUNDS FOR TREATMENT OF IMMUNE AND INFLAMMATORY DISORDERS

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.

A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein
A is selected from the group consisting of A1 and A2;
B is selected from the group consisting of B1, B1′, B2, B3, and B4;
C is selected from the group consisting of C1, C2, and C3;
L is selected from the group consisting of L1 and L2;
L3 is selected from the group consisting of L4 and L5;
at least one of A, B, C, L, or L3 is selected from the group consisting of A2, B3, C3, L2, or L5;
A1 is selected from the group consisting of:
A2 is selected from the group consisting of:
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;
C2-C6alkenyl;
C2-C6alkynyl;
—(C0-C4alkyl)(aryl);
—(C0-C4alkyl)(heteroaryl);
or —(C0-C4alkyl)(biphenyl), each of which B1 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of R33 and R34, and 0 or 1 substituents selected from the group consisting of R35 and R36;
B1′ is selected from the group consisting of:
B2 is selected from the group consisting of:
B3 is selected from the group consisting of:
(I) 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;
C2-C6alkenyl;
C2-C6alkynyl;
—(C0-C4alkyl)(aryl);
—(C0-C4alkyl)(heteroaryl);
or —(C0-C4alkyl)(biphenyl);
each of which B3 is substituted with one or more of the following:
S(O)═NHR21, SF5, and JC(R9)═NR21;
(II) a monocyclic, bicyclic, or tricyclic heterocyclic group that has at least one boron or silicon atom in the ring or a monocyclic, bicyclic, or tricyclic heteroaryl group that has at least one boron in the ring;
(III) a 6-membered aryl group fused to a 5-membered saturated cyclic group that optionally contains 1 or 2 heteroatoms independently selected from the group consisting of N and S wherein one of the CH2 groups of the 5-membered cyclic group is substituted by oxo, excluding dihydrobenzofuran;
and
(IV) (alkyl)-(cycloalkyl), (alkenyl)-(cycloalkyl), or (alkynyl)-(cycloalkyl);
wherein B3 can be further substituted one or more times with the substituents independently selected from the group consisting of R35, R36 and R48;
B4 is selected from the group consisting of the following:
(I) a 4-membered carbocyclic fused to a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S;
(II) a 4-membered carbocyclic fused to a 6-membered aryl ring;
(III) 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;
C2-C6alkenyl;
C2-C6alkynyl;
—(C0-C4alkyl)(aryl);
—(C0-C4alkyl)(heteroaryl);
or —(C0-C4alkyl)(biphenyl);
each of which B3 is substituted one or more times with S(O)2OR21;
(IV) (cycloalkyl)-(aryl), (cycloalkyl)-(heteroaryl), (cycloalkyl)-(heterocycle), (alkyl)-alkenyl, cycloalkyl-alkenyl;
(V) alkyl, (alkyl)-(alkenyl), alkyl(alkynyl), or cycloalkyl-;
(VI) (alkyl)-(cycloalkyl), (alkenyl)-(cycloalkyl), (alkynyl)-(cycloalkyl), or (cycloalkyl)-(cycloalkyl);
wherein B4 can be substituted 1, 2, 3 or 4 times or more with the substituents independently selected from the group consisting of R33, R34, R35 R36 and R48;
C1 is
C2 is selected from the group consisting of:
wherein q is 0, 1, 2 or 3 and r is 1, 2 or 3;
C3 is selected from the group consisting of:
L1 is a bond or is selected from the group consisting of the formulas
L2 is selected from the group consisting of:
L3 is selected from the group consisting of L4 or L5;
L4 is —C(O)—;
L5 is —C(S)—, —P(O)OH—, —S(O)—, —S(O)2— or —C(R52)2—;
Q1 is N(R1) or C(R1R1′);
Q2 is C(R2R2′), C(R2R2′)—C(R2R2′), S, O, N(R2) or C(R2R2′)O;
Q3 is N(R3), S, or C(R3R3′);
X1 and X2 are independently N, CH, or CZ, or X1 and X2 together are C═C;
Z is F, Cl, NH2, CH3, CH2D, CHD2, or CD3;
X11 is N or CR11;
X12 is N or CR12;
X13 is N or CR13;
X14 is N or CR14, and wherein no more than 2 of X11, X12, X13, and X14 are N;
X15 is NH, O, or S;
X16 is CR12;
X17 is N or CR13;
X18 is CR12;
X19 is N or CR13;
X20 is NH or O;
R and R′ are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl;
R1, R1′, R2, R2′, R3, and R3′ are independently chosen at each occurrence from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, 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, —NR9C(O)OR10, C1-C2haloalkyl, and C1-C2haloalkoxy;
or R1 and R2 are linked to form a 3- to 6-membered carbocyclic or aryl ring;
or R2 and R3 are linked to form a 3- to 6-membered carbocyclic ring;
or R1 and R1′, or R2 and R2′, or R3 and R3′ are linked to form a 3- to 6-membered carbocyclic spiro ring;
or R1 and R1′, R2 and R2′ or R3 and R3′ are linked to form a 3- to 6-membered heterocyclic spiro ring;
each of which ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, cyano, —COOH, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, 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;
or R1 and R1′ or R2 and R2′ are linked to form a carbonyl group;
or R1 and R2 or R2 and R3 can be taken together to form a carbon-carbon double bond;
R4, R5, and R6 are selected from the group consisting of hydrogen, -JCHO, -JC(O)NH2, -JC2-C6alkanoyl, -JC(O)NH(CH3), -J-COOH, -JP(O)(OR9)2, -JOC(O)R9, -JC(O)OR9, -JC(O)N(CH2CH2R9)(R10), -JNR9C(O)R10, -JSO2NH2, -JS(O)NH2, -JC(CH2)2F, -JCH(CF3)NH2, -JC(O)C0-C2alkyl(C3-C7cycloalkyl), -JNR9(C2-C6alkanoyl), -JNR9C(O)NR9R10, -JSO2(C1-C6alkyl), -JSO2(C1-C6haloalkyl), -JSO2NR7R7, -JSO═NH(C1-C6alkyl), -J-nitro, -J-halogen, -J-hydroxyl, -J-phenyl, a 5- to 6-membered heteroaryl, -J-cyano, -J-cyanoimino, -J-amino, -J-imino, —C1-C6alkyl, —C0-C4alkyl(C3-C7heterocycloalkyl), —C0-C4alkyl(C3-C7cycloalkyl),
each of which R4, R5 and R6 other than hydrogen, nitro, halogen, cyano, cyanoimino, or —CHO, is unsubstituted or substituted with one or more of amino, imino, halogen, hydroxyl, cyano, cyanoimino, C1-C2alkyl, C1-C2alkoxy, —C0-C2alkyl(mono- and di-C1-C4alkylamino), C1-C2haloalkyl, and C1-C2haloalkoxy;
R7 is hydrogen, C1-C6alkyl, or —C0-C4alkyl(C3-C7cycloalkyl);
R8 and R8′ are independently selected from the group consisting of hydrogen, halogen, hydroxyl, C1-C6alkyl, —C0-C4alkyl(C3-C7cycloalkyl), C1-C6alkoxy, and (C1-C4alkylamino)C0-C2alkyl;
or R8 and R8′ are taken together to form an oxo group;
or R8 and R8′ can be taken together with the carbon that they are bonded to form a 3-membered carbocyclic ring;
R9 and R10 are independently chosen at each occurrence from hydrogen, C1-C6alkyl, (C3-C7cycloalkyl)C0-C4alkyl, —C0-C4alkyl(C3-C7cycloalkyl), and —O—C0-C4alkyl(C3-C7cycloalkyl);
R11 and R14 are independently chosen at each occurrence from hydrogen, halogen, hydroxyl, nitro, cyano, —O(PO)(OR9)2, —(PO)(OR9)2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C6alkenyl(aryl), C2-C6alkenyl(cycloalkyl), C2-C6alkenyl(heterocycle), C2-C6alkenyl(heteroaryl), C2-C6alkynyl, C2-C6alkynyl(aryl), C2-C6alkynyl(cycloalkyl), C2-C6alkynyl(heterocycle), C2-C6alkynyl(heteroaryl), C2-C6alkanoyl, C1-C6alkoxy, C1-C6thioalkyl, —C0-C4alkyl(mono- and di-C1-C6alkylamino), —C0-C4alkyl(C3-C7cycloalkyl), —C0-C4alkoxy(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy;
one of R12 and R13 is chosen from R31 and the other of R12 and R13 is chosen from R32 or both R12 and R13 are each independently R32;
R16 is absent or selected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, —C0-C4alkyl(mono- and di-C1-C6alkylamino), —C0-C4alkyl(C3-C7cycloalkyl), C1-C2haloalkyl, and C1-C2haloalkoxy;
R17 is hydrogen, C1-C6alkyl, or —C0-C4alkyl(C3-C7cycloalkyl);
R18 and R18′ are independently selected from the group consisting of hydrogen, halogen, hydroxymethyl, and methyl;
and m is 0, 1, 2, or 3;
R19 is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, —SO2C1-C6alkyl, (mono- and di-C1-C6alkylamino)C1-C4alkyl, —C0-C4alkyl(C3-C7cycloalkyl), —C0-C4alkyl(C3-C7heterocycloalkyl), —C0-C4alkyl(aryl), C0-C4alkyl(heteroaryl), and wherein R19 other than hydrogen is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, amino, —COOH, and —C(O)OC1-C4alkyl;
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;
R23 is independently chosen at each occurrence from C1-C6alkyl, C1-C6haloalkyl, (aryl)C0-C4alkyl, (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;
R31 is selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, cyano, amino, —COOH, C1-C2haloalkyl, C1-C2haloalkoxy, C1-C6alkyl, —C0-C4alkyl(C3-C7cycloalkyl), 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 R31 other than hydrogen, halogen, hydroxyl, nitro, cyano, C1-C2haloalkyl, and C1-C2haloalkoxy is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, amino, —COOH, —CONH2 C1-C2haloalkyl, and C1-C2haloalkoxy, and each of which R31 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 selected from the group consisting of 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;
R32 is selected from the group consisting of aryl;
5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S;
or a 4- to 7-membered heterocycle having 1, 2, or 3 heteroatoms independently chosen from N, O, and S;
wherein the heterocycle is bonded through a carbon atom in the heterocycle ring to a carbon atom of ring A in the R12 or R13 position;
and wherein the aryl, heteroaryl, and heterocycle can be optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, amino, cyano, —CHO, —COOH, —CONH2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, —C1-C6alkoxy, C2-C6alkanoyl, C1-C6alkylester, (mono- and di-C1-C6alkylamino)C0-C2alkyl, C1-C2haloalkyl, hydoxyC1-C6alkyl, ester, carbamate, urea, sulfonamide, —C1-C6alkyl(heterocyclo), C1-C6alkyl(heteroaryl), —C1-C6alkyl(C3-C7cycloalkyl), O—C1-C6alkyl(C3-C7cycloalkyl), B(OH)2, phosphate, phosphonate, and C1-C2haloalkoxy;
R33 is independently selected from the group consisting of halogen, hydroxyl, —COOH, cyano, C1-C6alkyl, C2-C6alkanoyl, C1-C6alkoxy, —C0-C4alkylNR9R10, —SO2R9, C1-C2haloalkyl, and C1-C2haloalkoxy;
R34 is independently selected from the group consisting of nitro, C2-C6alkenyl, C2-C6alkynyl, C1-C6thioalkyl, -JC3-C7cycloalkyl, —B(OH)2, -JC(O)NR9R23, -JOSO2OR21, —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), -JSP(O)(R21)(R22), -JNR9P(O)(NHR21)(NHR22) -JNR9P(O)(OR21)(NHR22), -JNR9P(O)(OR21)(OR22), -JC(S)R21, -JNR21SO2R22, -JNR9S(O)NR10R22, -JNR9SO2NR10R22, -JSO2NR9COR22, -JSO2NR9CONR21R22, -JNR21SO2R22, -JC(O)NR21SO2R22, -JC(NH2)═NR22, -JCH(NH2)NR9S(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 R34 may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH)2, —Si(CH3)3, —COOH, —CONH2, —P(O)(OH)2, C1-C6alkyl, —C0-C4alkyl(C3-C7cycloalkyl), C1-C6alkoxy, —C0-C2alkyl(mono- and di-C1-C4alkylamino), C1-C6alkylester, C1-C4alkylamino, C1-C4hydroxylalkyl, C1-C2haloalkyl, and C1-C2haloalkoxy;
R35 is independently selected from the group consisting of 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 R35 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of 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;
R36 is independently selected from the group consisting of 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 R36 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, —Si(CH3)2C(CH3)3, C1-C2haloalkyl, and C1-C2haloalkoxy;
R48 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, cyano, amino, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6thioalkyl, C1-C6alkoxy, -JC3-C7cycloalkyl, —B(OH)2, -JC(O)NR9R23,-JOSO2OR21, —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), -JSP(O)(R21)(R22), -JNR9P(O)(NHR21)(NHR22) -JNR9P(O)(OR21)(NHR22) -JNR9P(O)(OR21)(OR22), -JC(S)R21, -JNR21SO2R22, -JNR9S(O)NR10R22, -JNR9SO2NR10R22, -JSO2NR9COR22, -JSO2NR9CONR21R22, -JNR21SO2R22, -JC(O)NR21SO2R22, -JC(NH2)═NR22, -JCH(NH2)NR9S(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, -JC(O)OR23;
SC1-C6alkyl(O)═NH;
each of which R48 may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH)2, —Si(CH3)3, —COOH, —CONH2, —P(O)(OH)2, C1-C6alkyl, —C0-C4alkyl(C3-C7cycloalkyl), C1-C6alkoxy, —C0-C4alkyl(mono- and di-C1-C4alkylNR9R10), C1-C6alkylester, C1-C4alkylamino, C1-C4hydroxylalkyl, C1-C2haloalkyl, C1-C2haloalkoxy, —OC(O)R9, —NR9C(O)R10, —C(O)NR9R10, —OC(O)NR9R10, —NR9C(O)OR10, C1-C2haloalkyl, and C1-C2haloalkoxy;
R51 is CH3, CH2F, CHF2 or CF3;
R52 is independently selected from the group consisting of halo, hydrogen, or C1-C6alkyl;
and
J is independently chosen at each occurrence from a covalent bond, C1-C4alkylene, —OC1-C4alkylene, C2-C4alkenylene, and C2-C4alkynylene.

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Abstract

Claims20