US 12,065,459 B2
Aryl, heteroaryl, and heterocyclic compounds for treatment of complement mediated disorders
Jason Allan Wiles, Madison, CT (US); Venkat Rao Gadhachanda, Hamden, CT (US); Qiuping Wang, Bethany, CT (US); Godwin Pais, Hamden, CT (US); Akihiro Hashimoto, Branford, CT (US); Dawei Chen, Guilford, CT (US); Xiangzhu Wang, Branford, CT (US); Atul Agarwal, Hamden, CT (US); Milind Deshpande, Madison, CT (US); and Avinash S. Phadke, Branford, CT (US)
Assigned to Achillion Pharmaceuticals, Inc., Boston, MA (US)
Filed by Achillion Pharmaceuticals, Inc., Blue Bell, PA (US)
Filed on Nov. 1, 2019, as Appl. No. 16/672,114.
Application 16/672,114 is a continuation of application No. 16/276,139, filed on Feb. 14, 2019, granted, now 10,464,956.
Application 16/276,139 is a continuation of application No. 16/140,148, filed on Sep. 24, 2018, granted, now 10,253,053, issued on Apr. 9, 2019.
Application 16/140,148 is a continuation of application No. 15/711,794, filed on Sep. 21, 2017, granted, now 10,081,645, issued on Sep. 25, 2018.
Application 15/711,794 is a continuation of application No. 14/631,625, filed on Feb. 25, 2015, granted, now 9,796,741, issued on Oct. 24, 2017.
Claims priority of provisional application 62/046,783, filed on Sep. 5, 2014.
Claims priority of provisional application 62/022,916, filed on Jul. 10, 2014.
Claims priority of provisional application 61/944,189, filed on Feb. 25, 2014.
Prior Publication US 2020/0062790 A1, Feb. 27, 2020
Int. Cl. C07F 9/572 (2006.01); A61K 9/00 (2006.01); A61K 31/404 (2006.01); A61K 31/4045 (2006.01); A61K 31/407 (2006.01); A61K 31/4162 (2006.01); A61K 31/4178 (2006.01); A61K 31/4184 (2006.01); A61K 31/4188 (2006.01); A61K 31/4192 (2006.01); A61K 31/437 (2006.01); A61K 31/4439 (2006.01); A61K 31/444 (2006.01); A61K 31/4709 (2006.01); A61K 31/496 (2006.01); A61K 31/501 (2006.01); A61K 31/506 (2006.01); A61K 31/519 (2006.01); A61K 31/549 (2006.01); A61K 31/55 (2006.01); A61K 31/675 (2006.01); A61K 31/683 (2006.01); C07B 59/00 (2006.01); C07D 209/12 (2006.01); C07D 209/14 (2006.01); C07D 209/30 (2006.01); C07D 209/40 (2006.01); C07D 209/42 (2006.01); C07D 209/44 (2006.01); C07D 209/88 (2006.01); C07D 401/14 (2006.01); C07D 403/06 (2006.01); C07D 403/08 (2006.01); C07D 403/12 (2006.01); C07D 403/14 (2006.01); C07D 405/12 (2006.01); C07D 405/14 (2006.01); C07D 413/06 (2006.01); C07D 413/14 (2006.01); C07D 417/06 (2006.01); C07D 417/12 (2006.01); C07D 417/14 (2006.01); C07D 471/04 (2006.01); C07D 471/08 (2006.01); C07D 487/04 (2006.01); C07D 487/14 (2006.01); C07D 491/113 (2006.01); C07D 495/04 (2006.01); C07D 513/04 (2006.01); C07F 5/02 (2006.01); C07F 7/08 (2006.01); C07F 9/6558 (2006.01); C07F 9/6561 (2006.01)
CPC C07F 9/5728 (2013.01) [A61K 9/0014 (2013.01); A61K 9/0019 (2013.01); A61K 9/0048 (2013.01); A61K 9/0053 (2013.01); A61K 31/404 (2013.01); A61K 31/4045 (2013.01); A61K 31/407 (2013.01); A61K 31/4162 (2013.01); A61K 31/4178 (2013.01); A61K 31/4184 (2013.01); A61K 31/4188 (2013.01); A61K 31/4192 (2013.01); A61K 31/437 (2013.01); A61K 31/4439 (2013.01); A61K 31/444 (2013.01); A61K 31/4709 (2013.01); A61K 31/496 (2013.01); A61K 31/501 (2013.01); A61K 31/506 (2013.01); A61K 31/519 (2013.01); A61K 31/549 (2013.01); A61K 31/55 (2013.01); A61K 31/675 (2013.01); A61K 31/683 (2013.01); C07B 59/002 (2013.01); C07D 209/12 (2013.01); C07D 209/14 (2013.01); C07D 209/30 (2013.01); C07D 209/40 (2013.01); C07D 209/42 (2013.01); C07D 209/44 (2013.01); C07D 209/88 (2013.01); C07D 401/14 (2013.01); C07D 403/06 (2013.01); C07D 403/08 (2013.01); C07D 403/12 (2013.01); C07D 403/14 (2013.01); C07D 405/12 (2013.01); C07D 405/14 (2013.01); C07D 413/06 (2013.01); C07D 413/14 (2013.01); C07D 417/06 (2013.01); C07D 417/12 (2013.01); C07D 417/14 (2013.01); C07D 471/04 (2013.01); C07D 471/08 (2013.01); C07D 487/04 (2013.01); C07D 487/14 (2013.01); C07D 491/113 (2013.01); C07D 495/04 (2013.01); C07D 513/04 (2013.01); C07F 5/025 (2013.01); C07F 5/027 (2013.01); C07F 7/0812 (2013.01); C07F 9/65583 (2013.01); C07F 9/6561 (2013.01); C07F 9/65616 (2013.01); C07B 2200/05 (2013.01)] 20 Claims
 
1. A compound of Formula I

OG Complex Work Unit Chemistry
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 chosen from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxyl, C2-C6alkynyl, C2-C6alkanoyl, C1-C6thioalkyl, —C(O)OR9, —OC(O)R9, —NR9C(O)R10, —C(O)NR9R10, —OC(O)NR9R10, —NR9C(O)OR10, C1-C2haloalkyl, and C1-C2haloalkoxy;
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);
A is a group selected from:

OG Complex Work Unit Chemistry
R6 is selected from —CHO, —C(O)NH2, —C(O)NH(CH3), C2-C6alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, —COOH, —SO2NH2, vinyl, 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, and 5- to 6-membered heteroaryl;
R6′ is hydrogen, halogen, hydroxyl, C1-C4alkyl, —C0-C4alkyl(C3-C7cycloalkyl), or C1-C4alkoxy; or R6 and R6′ may be taken together to form an oxo, vinyl, or imino group;
R7 is hydrogen, C1-C6alkyl, or —C0-C4alkyl(C3-C7cycloalkyl);
R8 and R8′ are independently chosen from 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;
X11 is N or CR11;
X12 is CR12;
X13 is CR13;
X14 is N or CR14;
one of R12 and R13 is chosen from R31 and the other of R12 and R13 is chosen from R32:
R31 is chosen from 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;
R32 is 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S wherein the heteroaryl ring can be optionally substituted with one or more substituents independently chosen from 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), and C1-C2haloalkoxy;
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-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;
R16 is absent or may include one or more substituents independently chosen from 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;
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 chosen from 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-C17cycloalkyl)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;
L is

OG Complex Work Unit Chemistry
where R17 is hydrogen, C1-C6alkyl, or —C0-C4alkyl(C3-C7cycloalkyl), and R18 and R18′ are independently chosen from hydrogen, halogen, hydroxymethyl, and methyl; and m is 0, 1, 2, or 3;
B is 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); or —(C0-C4alkyl)(heteroaryl); each of which B is unsubstituted or substituted with one or more substituents independently chosen from R33 and R34, and 0 or 1 substituents chosen from R35 and R36;
R33 is independently chosen from halogen, hydroxyl, —COOH, cyano, C1-C6alkyl, C2-C6alkanoyl, C1-C6alkoxy, —C0-C4alkylNR9R10, —SO2R9, C1-C2haloalkyl, and C1-C2haloalkoxy;
R34 is independently chosen from nitro, C2-C6alkenyl, C2-C6alkynyl, C1-C6thioalkyl, -JC3-C7cycloakyl, —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, -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 chosen from 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 chosen from 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 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
R36 is independently chosen from tetrazolyl, (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; and
J is independently selected at each occurrence from a covalent bond, C1-C4alkylene, —OC1-C4alkylene, C2-C4alkenylene, and C2-C4alkynylene.