# US 2017/0283403 A1 · Diamide macrocycles that are fxia inhibitors

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- Number: US 2017/0283403 A1
- Document ID: US20170283403A1
- Status: Published application
- Kind: A1
- Application number: 15/508,122
- Filed: 2015-09-03
- Published: 2017-10-05
- Earliest claimed: 2014-09-04
- Assignees: Bristol-Myers Squibb Company
- Applicants: Bristol-Myers Squibb Company
- Inventors: Jun Shi; William R. Ewing; Laura Nielsen; Zilun HU; Mimi L. Quan
- Web page: https://patentgrep.com/patent/US20170283403A1

## CPC

- C07D 409/12: linked by a chain containing hetero atoms as chain links
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- 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 13/12: of the kidneys
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides compounds of Formula (I) or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective Factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.

## Claims

### Claim 1

A compound of Formula (I):
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
is an optional bond;
ring A is independently selected from a C3-10 carbocycle and a 5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NH, N(C1-4 alkyl), NC(═NH)NH2, O, and S;
ring B is independently selected from a aryl and a 5- to 10-membered heterocycle;
L1 is independently selected from a
bond, —CR5R5—, —CHR5CHR5—, —CR5═CR5—, —C≡C—, —OCH2—, —CHR5NH—, —CH2O—, —SCH2—, —SO2CH2—, and —CH2NH—;
R1 is, independently at each occurrence, selected from halogen, C1-6 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 haloalkyl, OH, ═O, OCH2F, OCHF2, OCF3, CF3, CN, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, CO2(C1-4 alkyl), CO(C1-4 alkyl), —CH2NH2, —CONH2, —CONH(C1-4 alkyl), —OCH2CO2H, —NHCO(C1-4 alkyl), —NHCO2(C1-4 alkyl), —NHSO2(C1-4 alkyl), —SO2NH2, and —C(═NH)NH2;
R2 is a 5- to 7-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C1-4 alkyl), O, and S(O)2, wherein said heterocycle is substituted with 0-2 R2a;
R2a is, independently at each occurrence, selected from halogen, C1-4 alkyl, —CH2OH, C1-4 alkoxy, OH, CF3, OCF3, OCH2F, OCHF2, CN, NH2, CO2H, CO2(C1-4 alkyl), COC1-4 alkyl, —CONH2, —CONH(C1-4 alkyl), —CON(C1-4 alkyl)2, —SO2(C1-4 alkyl), —SO2NH2, —SO2NH(C1-4 alkyl), and —SO2N(C1-4 alkyl)2;
R3 is independently selected from H and C1-4 alkyl;
alternatively, L1 and R3, together with the nitrogen atom to which they are attached, form a ring;
R4 is selected from H, C1-4 alkyl, hydroxyl, F, CF3, and C3-6 cycloalkyl;
R5 is selected from H and C1-4 alkyl;
R6 is selected from H, halogen, C(O)OH, and C(O)O(C1-4 alkyl);
R7 is selected from H, C1-4 alkyl, and CF3;
alternatively, R6 and R7 together are ═O; and
R8 is, independently at each occurrence, selected from H, halogen, NHCO2C1-4 alkyl, CN, OH, O—C1-4 alkyl, CF3, —OCF3, —OCHF2, —CHF2, —CH2F, CO2H, CO2(C1-4 alkyl), —CH2CO2H, —(CH2)2CO2H, —CH2CO2(C1-4 alkyl), —(CH2)2CO2(C1-4 alkyl), NH2, —CH2NH2, —NHCO(C1-4 alkyl), —NHCO2(CH2)1-2O(C1-4 alkyl), —NHCO2(CH2)1-3O(C1-4 alkyl), NHCO2CH2CH(C1-4 alkyl)O(C1-4 alkyl), —NHCO2(CH2)1-2OH, —NHCO2CH2CO2H, —CH2NHCO2(C1-4 alkyl), —NHC(O)NH(C1-4 alkyl), —NHC(O)N(C1-4 alkyl)2, NHC(O)NH(C1-4 alkyl)N(5- to 6-membered heterocycle), —NHSO2(C1-4 alkyl), —CONH2, —CONH(C1-4 alkyl), —CON(C1-4 alkyl)2, and —CH2CONH2.

### Claim 2 (depends on 1)

The compound of claim 1 having Formula (II):
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
is an optional bond;
ring A is independently selected from a C3-10 carbocycle and a 5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NH, N(C1-4 alkyl), NC(═N)NH2, and S;
L1 is independently selected from a bond, —CR5R5—, and —CHR5CHR5—;
R1 is, independently at each occurrence, selected from halogen, C1-6 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 haloalkyl, OH, ═O, OCH2F, OCHF2, OCF3, CN, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, CO2(C1-4 alkyl), CO(C1-4 alkyl), —CH2NH2, —CONH2, —CONH(C1-4 alkyl), —OCH2CO2H, —NHCO(C1-4 alkyl), —NHCO2(C1-4 alkyl), —NHSO2(C1-4 alkyl), —SO2NH2, and —C(═NH)NH2;
R2 is a 5- to 7-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, and N(C1-4 alkyl);
R3 is independently selected from H and C1-4 alkyl;
alternatively, L1 and R3, together with the nitrogen atom to which they are attached, form a ring;
R4 is selected from H, C1-4 alkyl, hydroxyl, and C3-6 cycloalkyl;
R5 is selected from H and C1-4 alkyl; and
R8 is independently selected from H, halogen, NHCO2C1-4 alkyl, CN, OH, O—C1-4 alkyl, CF3, —OCF3, —OCHF2, —CHF2, —CH2F, CO2H, CO2(C1-4 alkyl), —CH2CO2H, —(CH2)2CO2H, —CH2CO2(C1-4 alkyl), —(CH2)2CO2(C1-4 alkyl), NH2, —CH2NH2, —NHCO(C1-4 alkyl), —NHCO2(CH2)1-2O(C1-4 alkyl), —NHCO2(CH2)1-3O(C1-4 alkyl), NHCO2CH2CH(C1-4 alkyl)O(C1-4 alkyl), —NHCO2(CH2)1-2OH, —NHCO2CH2CO2H, —CH2NHCO2(C1-4 alkyl), —NHC(O)NH(C1-4 alkyl), —NHC(O)N(C1-4 alkyl)2, NHC(O)NH(C1-4 alkyl)N[5- to 6-membered heterocycle)], —NHSO2(C1-4 alkyl), —CONH2, —CONH(C1-4 alkyl), —CON(C1-4 alkyl)2, and —CH2CONH2.

### Claim 3 (depends on 2)

The compound of claim 2 having Formula (III):
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
is an optional bond;
L1 is independently selected from a bond, —CR5R5—, and —CHR5CHR5—;
R1 is, independently at each occurrence, selected from halogen, C1-6 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 haloalkyl, OH, ═O, OCH2F, OCHF2, OCF3, CN, NH2, NH(C1-4 alkyl), and N(C1-4 alkyl)2;
R2 is a 5- to 7-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N and NH;
R3 is independently selected from H and C1-4 alkyl;
R4 is selected from H, C1-4 alkyl, hydroxyl, and C3-6 cycloalkyl;
R5 is selected from H and C1-4 alkyl; and
R8 is independently selected from H, halogen, NHCO2C1-4 alkyl, CN, OH, O—C1-4 alkyl, CF3, —OCF3, —OCHF2, —CHF2, —CH2F, CO2H, and CO2(C1-4 alkyl).

### Claim 4 (depends on 3)

The compound of claim 3 having Formula (IV):
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
is an optional bond;
R1a is selected from H, F, and Cl;
R1b is selected from H and F;
R4 is selected from H, C1-4 alkyl, and hydroxyl;
R5 is selected from H and C1-4 alkyl; and
R8 is independently selected from H, halogen, NHCO2C1-4 alkyl, CN, OH, O—C1-4 alkyl, CF3, —OCF3, —OCHF2, —CHF2, —CH2F, CO2H, and CO2(C1-4 alkyl).

### Claim 5 (depends on 2)

The compound of claim 2, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
is an optional bond;
ring A is a 5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NH, N(C1-4 alkyl), and NC(═NH)NH2;
L1 is independently selected from a bond, —CR5R5—, and —CHR5CHR5—;
R1 is, independently at each occurrence, selected from halogen, C1-6 alkyl, and ═O;
R3 is independently selected from H and C1-4 alkyl;
R4 is selected from H, C1-4 alkyl, hydroxyl, and C3-6 cycloalkyl;
R5 is selected from H and C1-4 alkyl; and
R8 is independently selected from H, halogen, and NHCO2C1-4 alkyl.

### Claim 6 (depends on 5)

The compound of claim 5, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
L1 is independently selected from a bond, —CH—, and —CH2CH2—;
ring A is a 5- to 10-membered heterocycle selected from
and
R1 is, independently at each occurrence, selected from halogen and ═O.

### Claim 7 (depends on 2)

The compound of claim 2, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
is an optional bond;
ring A is phenyl;
R1 is, independently at each occurrence, selected from halogen, C1-6 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and OH;
L1 and R3, together with the nitrogen atom to which they are attached, form a ring;
R4 is selected from H, C1-4 alkyl, hydroxyl, and C3-6 cycloalkyl;
R5 is selected from H and C1-4 alkyl; and
R8 is independently selected from H, halogen, and NHCO2C1-4 alkyl.

### Claim 8 (depends on 1)

A compound of claim 1 selected from:
(±)-methyl N-[8-({2-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]ethyl} carbamoyl)-2,10-dioxo-1,2,3,4,5,6,7,8,9,10-decahydro-1,9-benzodiazacyclododecin-13-yl]carbamate;
methyl N-[8-({2-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]ethyl}carbamoyl)-2,10-dioxo-1,2,3,4,5,6,7,8,9,10-decahydro-1,9-benzodiazacyclododecin-13-yl]carbamate;
methyl N-[8-({2-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]ethyl}carbamoyl)-2,10-dioxo-1,2,3,4,5,6,7,8,9,10-decahydro-1,9-benzodiazacyclododecin-13-yl]carbamate;
(±)-methyl N-{8-[(1-carbamimidoylpiperidin-4-yl)carbamoyl]-2,10-dioxo-1,2,3,4,5,6,7,8,9,10-decahydro-1,9-benzodiazacyclododecin-13-yl}carbamate;
(±)-methyl N-(8-{[(1-carbamimidoylpiperidin-4-yl)methyl]carbamoyl}-2,10-dioxo-1,2,3,4,5,6,7,8,9,10-decahydro-1,9-benzodiazacyclododecin-13-yl)carbamate;
(±)-methyl N-(8-{[2-(1-carbamimidoylpiperidin-4-yl)ethyl]carbamoyl}-2,10-dioxo-1,2,3,4,5,6,7,8,9,10-decahydro-1,9-benzodiazacyclododecin-13-yl)carbamate;
(±)-methyl N-{2,10-dioxo-8-[(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamoyl]-1,2,3,4,5,6,7,8,9,10-decahydro-1,9-benzodiazacyclododecin-13-yl}carbamate;
(±)-methyl N-(8-{[(5-chloro-1-benzothiophen-3-yl)methyl]carbamoyl}-2,10-dioxo-1,2,3,4,5,6,7,8,9,10-decahydro-1,9-benzodiazacyclododecin-13-yl)carbamate;
(±)-methyl N-{8-[3-(3-chlorophenyl)pyrrolidine-1-carbonyl]-2,10-dioxo-1,2,3,4,5,6,7,8,9,10-decahydro-1,9-benzodiazacyclododecin-13-yl}carbamate;
(±)-methyl N-{8-[3-(3-methoxyphenyl)piperidine-1-carbonyl]-2,10-dioxo-1,2,3,4,5,6,7,8,9,10-decahydro-1,9-benzodiazacyclododecin-13-yl}carbamate;
(±)-methyl N-[8-({2-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]ethyl}carbamoyl)-4-methyl-2,10-dioxo-1,2,3,4,5,6,7,8,9,10-decahydro-1,9-benzodiazacyclododecin-13-yl]carbamate;
methyl N-[8-({2-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]ethyl}carbamoyl)-4-methyl-2,10-dioxo-1,2,3,4,5,6,7,8,9,10-decahydro-1,9-benzodiazacyclododecin-13-yl]carbamate;
(±)-methyl N-[8-({2-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]ethyl} carbamoyl)-3-methyl-2,10-dioxo-1,2,3,4, 5,6,7,8,9,10-decahydro-1,9-benzodiazacyclododecin-13-yl]carbamate;
methyl N-[8-({2-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]ethyl}carbamoyl)-3-methyl-2,10-dioxo-1,2,3,4,5,6,7,8,9,10-decahydro-1,9-benzodiazacyclododecin-13-yl]carbamate;
(E/Z)-(±)-methyl N-[8-({2-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]ethyl} carbamoyl)-2,10-dioxo-1,2,3,4,7,8,9,10-octahydro-1,9-benzodiazacyclododecin-13-yl]carbamate;
(Z)-methyl N-[8-({2-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]ethyl} carbamoyl)-2,10-dioxo-1,2,3,4,7,8,9,10-octahydro-1,9-benzodiazacyclododecin-13-yl]carbamate;
(E)-methyl N-[8-({2-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]ethyl} carbamoyl)-2,10-dioxo-1,2,3,4,7,8,9,10-octahydro-1,9-benzodiazacyclododecin-13-yl]carbamate;
(E/Z)-(±)-N-{2-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]ethyl}-2,10-dioxo-1,2,3,4,7,8,9,10-octahydro-1,9-benzodiazacyclododecine-8-carboxamide;
(±)-N-{2-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]ethyl}-2,10-dioxo-1,2,3,4,5,6,7,8,9,10-decahydro-1,9-benzodiazacyclododecine-8-carboxamide;
(E/Z)-(±)-N-[(1-carbamimidoylpiperidin-4-yl)methyl]-2,10-dioxo-1,2,3,4,7,8,9,10-octahydro-1,9-benzodiazacyclododecine-8-carboxamide;
(Z)-(±)-N-(1-carbamimidoylpiperidin-4-yl)-2,10-dioxo-1,2,3,4,7,8,9,10-octahydro-1,9-benzodiazacyclododecine-8-carboxamide;
(E)-(±)-N-(1-carbamimidoylpiperidin-4-yl)-2,10-dioxo-1,2,3,4,7,8,9,10-octahydro-1,9-benzodiazacyclododecine-8-carboxamide;
(Z)-(±)-methyl N-[8-({2-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]ethyl} carbamoyl)-4-methyl-2,10-dioxo-1,2,3,4,7,8,9,10-octahydro-1,9-benzodiazacyclododecin-13-yl]carbamate;
(E)-(±)-methyl N-[8-({2-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]ethyl} carbamoyl)-4-methyl-2,10-dioxo-1,2,3,4,7,8,9,10-octahydro-1,9-benzodiazacyclododecin-13-yl]carbamate; and
(E)-methyl N-[8-({2-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]ethyl} carbamoyl)-4-methyl-2,10-dioxo-1,2,3,4,7,8,9,10-octahydro-1,9-benzodiazacyclododecin-13-yl]carbamate.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising one or more compounds according to claim 1 and a pharmaceutically acceptable carrier or diluent.

### Claim 10 (depends on 1)

A method for the treatment and/or prophylaxis of a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 10)

A method according to claim 10, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart or in the peripheral circulation.

### Claim 12 (depends on 11)

A method according to claim 11, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis.

### Claim 13

(canceled)