# US 10,370,394 B2 · Carbamate, ester, and ketone compounds for treatment of complement mediated disorders

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- Number: US 10,370,394 B2
- Document ID: US10370394B2
- Status: Granted
- Kind: B2
- Application number: 15/638,081
- Filed: 2017-06-29
- Published: 2017-10-19
- Granted: 2019-08-06
- Earliest claimed: 2014-02-25
- Assignees: Achillion Pharmaceuticals, Inc.
- Applicants: Achillion Pharmaceuticals, Inc.
- Inventors: Jason Allan Wiles; Venkat Rao Gadhachanda; Godwin Pais; Akihiro Hashimoto; Qiuping Wang; Dawei Chen; Xiangzhu Wang; Atul Agarwal; Milind Deshpande; Avinash S. Phadke
- Web page: https://patentgrep.com/patent/US10370394B2

## CPC

- C07F 9/5728: {condensed with carbocyclic rings or carbocyclic ring systems}
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/4045: Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 31/4162: condensed with heterocyclic ring systems
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/4188: condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
- A61K 31/4192: 1,2,3-Triazoles
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/549: having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 31/683: Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/12: of the kidneys
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07B 59/002: {Heterocyclic compounds}
- C07D 209/12: Radicals substituted by oxygen atoms
- C07D 209/14: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 209/30: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D 209/40: Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
- C07D 209/42: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 209/44: Iso-indoles; Hydrogenated iso-indoles
- C07D 209/88: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
- C07D 401/14: containing three or more hetero rings
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/08: linked by a carbon chain containing alicyclic rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/14: containing three or more hetero rings
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 471/08: Bridged systems
- C07D 487/04: Ortho-condensed systems
- C07D 487/14: Ortho-condensed systems
- C07D 491/113: with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
- C07D 495/04: Ortho-condensed systems
- C07D 513/04: Ortho-condensed systems
- C07F 5/025: {Boronic and borinic acid compounds}
- C07F 5/027: {Organoboranes and organoborohydrides}
- C07F 7/0812: {comprising a heterocyclic ring}
- C07F 9/65583: {each of the hetero rings containing nitrogen as ring hetero atom}
- C07F 9/6561: containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F 9/65616: {containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs}
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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, wherein R12 or R13 on the A group is a carbamate, ester, or ketone substituent (R32) 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.

## Claims

### Claim 1

A method for the treatment of a disorder mediated by the complement factor D pathway, comprising administering an effective amount of a compound of Formula I to a host in need thereof of, or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, wherein the disorder is selected from age-related macular degeneration (AMD), retinal degeneration, ophthalmic disease, multiple sclerosis, arthritis, chronic obstructive pulmonary disease (COPD), atypical or typical hemolytic uremic syndrome, rheumatoid arthritis, C3 glomerulonephritis, and MPGN II; and wherein Formula I is:
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, 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, where 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);
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 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 1 or more substituents independently chosen from 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;
A is a group selected from:
R5 and R6 are independently selected from —CHO, —C(O)NH2, —C(O)NH(CH3), C2-C6alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, —COOH, —SO2NH2, vinyl, C1-C6alkyl (including methyl), 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;
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 linked to form an oxo group; or R8 and R8′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, 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 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 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;
R32 is selected from —OC(O)NR21R22, —OC(O)NR24R25, and —OC(O)NR9(CH2)1-4P(O)(OR21)(OR22);
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;
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;
R24 and R25 are taken together with the nitrogen to which they are attached to form a 4- to 7-membered monocyclic heterocycloalkyl group, or a 6- to 10-membered bicyclic heterocyclic group having fused, spiro, or bridged rings;
L is
R17 is hydrogen, C1-C6alkyl, or —C0-C4alkyl(C3-C7cycloalkyl);
R18 and R18′are independently chosen from hydrogen, halogen, hydroxymethyl, and methyl;
m is 0, 1, 2, or 3;
B is 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 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;
R26, R27, and R28 are independently chosen from hydrogen, halogen, hydroxyl, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, C1-C6alkoxy, C1-C6thioalkyl, (mono- and di-C-1-C6alkylamino)C0-C4alkyl, (C3-C7cycloalkyl)C0-C4alkyl, (aryl)C0-C4alkyl-, (heteroaryl)C0-C4alkyl-, and —C0-C4alkoxy(C3-C7cycloalkyl); each of which R26, R27, and R28 other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, C1-C2alkoxy, C1-C2haloalkyl, (C3-C7cycloalkyl)C0-C4alkyl-, and C1-C2haloalkoxy;
R29 is hydrogen, C1-C2alkyl, C1C2haloalkyl or —Si(CH3)2C(CH3)3,
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-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, -JC(NH2)NR9S(O)2R22, -JOC(O)NR21R22, -JNR21C(O)OR22, -JNR21OC(O)R22, —(CH2)1-4C(O)NR21R22, -JC(O)R24R25, -JNR9C(O)R21, -JC(O)R21, -JNR9C(O)NR10R22, —CCR21, —(CH2)1-4OC(O)R21, and -JC(O)OR23; each of which R34 is 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)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; and
J is independently selected at each occurrence from a covalent bond, C1-C4alkylene, —OC1-C4alkylene, C2-C4alkenylene, and C2-C4alkynylene.

### Claim 2 (depends on 1)

The method of claim 1, wherein the disorder is age-related macular degeneration (AMD).

### Claim 3 (depends on 1)

The method of claim 1, wherein the disorder is retinal degeneration, ophthalmic disease, multiple sclerosis, arthritis, or COPD.

### Claim 4 (depends on 1)

The method of claim 1, wherein the disorder is an ophthalmic disease.

### Claim 5 (depends on 1)

The method of claim 1, wherein the disorder is paroxysymal nocturnal hemoglobinuria (PNH).

### Claim 6 (depends on 1)

The method of claim 1, wherein the disorder is a respiratory disease.

### Claim 7 (depends on 1)

The method of claim 1, wherein the disorder is a cardiovascular disease.

### Claim 8 (depends on 1)

The method of claim 1, wherein the disorder is atypical or typical hemolytic uremic syndrome.

### Claim 9 (depends on 1)

The method of claim 1, wherein the disorder is rheumatoid arthritis.

### Claim 10 (depends on 1)

The method of claim 1, wherein the disorder is C3 glomerulonephritis.

### Claim 11 (depends on 1)

The method of claim 1, wherein the disorder is MPGN II.

### Claim 12 (depends on 1)

The method of claim 1, wherein the host is a human.

### Claim 13 (depends on 1)

The method of claim 1, wherein the
ring is selected from:

### Claim 14 (depends on 1)

The method of claim 1, wherein the
ring is selected from:

### Claim 15 (depends on 1)

The method of claim 1, wherein B is selected from:

### Claim 16 (depends on 1)

The method of claim 1, wherein B is selected from:

### Claim 17 (depends on 1)

The method of claim 1, wherein R32 is selected from:

### Claim 18 (depends on 1)

The method of claim 1, wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 18)

The method of claim 18, wherein R13 is R32 and R12 is hydrogen.

### Claim 20 (depends on 19)

The method of claim 19, wherein B is selected from:

### Claim 21 (depends on 20)

The method of claim 20, wherein R32 is selected from:

### Claim 22 (depends on 18)

The method of claim 18, wherein R31 is hydrogen, and wherein 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 R33 and R34, and 0 or 1 substituents chosen from R35 and R36.

### Claim 23 (depends on 22)

The method of claim 22, wherein B is aryl, heteroaryl, or biphenyl 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.

### Claim 24 (depends on 23)

The method of claim 23, wherein R33 is halogen.

### Claim 25 (depends on 23)

The method of claim 23, wherein there are two substituents chosen from R33 and wherein one is halogen and the other is C1-C6alkyl.

### Claim 26 (depends on 25)

The method of claim 25, wherein C1-C6alkyl is methyl.

### Claim 27 (depends on 1)

The method of claim 1, wherein 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 R33 and R34, and 0 or 1 substituents chosen from R35 and R36.

### Claim 28 (depends on 27)

The method of claim 27, wherein B is aryl, heteroaryl, or biphenyl 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.

### Claim 29 (depends on 28)

The method of claim 28, wherein R33 is halogen.

### Claim 30 (depends on 28)

The method of claim 28, wherein there are two substituents chosen from R33 and wherein one is halogen and the other is C1-C6alkyl.

### Claim 31 (depends on 30)

The method of claim 30, wherein C1-C6alkyl is methyl.

### Claim 32 (depends on 18)

The method of claim 18, wherein R12 is R32 and R13 is hydrogen.

### Claim 33 (depends on 32)

The method of claim 32, wherein B is selected from:

### Claim 34 (depends on 33)

The method of claim 33, wherein R32 is selected from:

### Claim 35 (depends on 1)

The method of claim 1, wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.