# US 11,078,198 B2 · Spirocyclic compounds as farnesoid X receptor modulators

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- Number: US 11,078,198 B2
- Document ID: US11078198B2
- Status: Granted
- Kind: B2
- Application number: 16/175,910
- Filed: 2018-10-31
- Published: 2019-05-02
- Granted: 2021-08-03
- Earliest claimed: 2017-11-01
- Assignees: Bristol-Myers Squibb Company
- Applicants: Bristol-Myers Squibb Company
- Inventors: Joseph E. Carpenter; Yanting Huang; Ying Wang; Gang Wu
- Web page: https://patentgrep.com/patent/US11078198B2

## CPC

- C07D 417/14: containing three or more hetero rings
- A61K 31/42: Oxazoles
- A61K 31/428: condensed with carbocyclic rings
- A61K 31/429: condensed with heterocyclic ring systems
- C07D 261/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 263/32: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 401/14: containing three or more hetero rings
- C07D 413/08: linked by a carbon chain containing alicyclic rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 487/10: Spiro-condensed systems
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D 491/113: with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
- C07D 491/20: Spiro-condensed systems
- C07D 513/04: Ortho-condensed systems
- C07H 15/26: Acyclic or carbocyclic radicals, substituted by hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein all the variables are as defined herein. These compounds modulate the activity of famesoid X receptor (FXR), for example, as agonists. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating a disease, disorder, or condition associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.

## Claims

### Claim 1

A compound of Formula (I):
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof; wherein:
the
moiety is
E ring is a 4- to 6-membered carbocyclyl or heterocyclyl, wherein the carbocyclyl and heterocyclyl are each independently substituted with 0 to 3 R3;
* denotes a spiro carbon atom;
Y is CR7 or N;
m and n are each independently an integer of 0, 1, or 2;
f is an integer of 0, 1, 2, or 3;
Z is 6- to 10-membered aryl, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, 3- to 10-membered carbocyclyl, or 4- to 10-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein the aryl, heteroaryl carbocyclyl, and heterocyclyl are independently substituted with 0 to 5 R8;
L1 is a covalent bond, O, S, —NR16—, —S(O)2—, C1-3 alkylene, C1-3 heteroalkylene, C2-4 alkenylene, C2-4 alkynylene, aryl, or a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein the alkylene, alkenylene, aryl, heteroalkylene, and heteroaryl are each independently substituted with 0 to 3 R11;
L2 is a covalent bond, O, S, —NR17—, C1-3 alkylene, or C1-3 heteroalkylene, wherein the alkylene and heteroalkylene are independently substituted with 0 to 3 R15;
RX is -L3-RZ;
L3 is a covalent bond, C1-3 alkylene, —C(O)NR12—CH2—, or —OCH2—, wherein the C1-3 alkylene is substituted with 0 to 3 R4;
RZ is —CN, —C(O)OR13, —C(O)NR14aR14b,
Re is C1-6 alkyl, C3-6 cycloalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, or aryl;
RY is each independently hydrogen, halo, cyano, hydroxyl, amino, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; or alternatively two RY, together with the carbon atoms to which they are attached, form a bridge moiety; and with the proviso that when Y is N and RY is attached to a carbon atom adjacent to Y, then RY is not halo, cyano, hydroxyl, amino, alkoxy, or haloalkoxy;
R1 is C1-6 alkyl, C3-5 cycloalkyl, or C4-6 heterocyclyl, wherein the alkyl, cycloalkyl, and heterocyclyl are each substituted with 0 to 3 R9;
R2 is 6- to 10-membered aryl, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, 3- to 10-membered carbocyclyl, or 4- to 10-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein the aryl, heteroaryl, carbocyclyl, and heterocyclyl are independently substituted with 0 to 5 R10;
R3, R5, and R7 are each independently hydrogen, halo, cyano, hydroxyl, amino, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;
R4 is each independently halo, oxo, cyano, hydroxyl, amino, alkyl, alkoxy, or alkylamino; or alternatively, two R4, taken together with the atom(s) to which they are attached, form a carbocyclyl or heterocyclyl moiety;
R6, R16 and R17 are each independently hydrogen, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, or haloalkoxyalkyl;
R8 and R10 are each independently halo, cyano, hydroxyl, amino, oxo, —ORa, —SRa, ═S, NRcRc, ═NH, ═N—OH, ═NRa, ═N—ORa, —NO2, —S(O)2Ra, —S(O)2NHRb, —S(O)2NRcRc, —S(O)2ORb, —OS(O)2Rb, —OS(O)2ORb, —P(O)(ORb)(ORb), —C(O)Rb, —C(NRb)Rb, —C(O)ORb, —C(O)NRcRc, —C(NRb)NRcRc, —OC(O)Rb, —NRbC(O)Rb, —OC(O)ORb, —NRbC(O)ORb, —NRbC(O)NRcRc, —NRbC(NRb)Rb, —NRbC (NRb)NRcRc, C1-6 alkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, carbocyclyl, or heterocyclyl; wherein the alkyl, aryl, heteroaryl, carbocyclyl, and heterocyclyl, by themselves or as part of another group, are each independently substituted with 0 to 5 Rd;
Ra is each independently C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, or heterocyclylalkyl;
Rb is each independently hydrogen or Ra;
Rc is each independently Rb or alternatively, the two Rc are taken together with the nitrogen atom to which they are bonded form a 4-, 5-, 6- or 7-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S;
Rd is each independently Ra, alkoxy, haloalkoxy, alkylamino, cycloalkylamino, heterocyclylamino, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkoxy, heterocyclyloxy, haloalkoxy, alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, arylamino, aralkylamino, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, alkylthio, halo, cyano, hydroxyl, amino, oxo, —ORa, —SRa, ═S, —NRcRc, ═NH, ═N—OH, ═NRa, ═N—ORa, —NO2, —S(O)2Ra, —S(O)2NHRb, —S(O)2NRcRc, —S(O)2ORb, —OS(O)2Rb, —OS(O)2ORb, —P(O)(oRb)(ORb), —C(O)Rb, —C(NRb)Rb, —C(O)ORb, —C(O)NRcRc, —C(NRb)NRcRc, —OC(O)Rb, —NRbC(O)Rb, —OC(O)ORb, —NRbC(O)ORb, —NRbC(O)NRcRc, —NRbC(NRb)Rb, or —NRbC(NRb)NRcRc;
R9 is each independently halo, cyano, hydroxyl, amino, or C1-6 alkyl;
R11 and R15 are each independently halo, oxo, cyano, hydroxyl, amino, C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;
R12 is hydrogen or C1-4 alkyl;
R13 is hydrogen, C1-10 alkyl, glycosyl, or carboxy(trihydroxy)tetrahydropyranyl; and
R14a and R14b are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy.

### Claim 2 (depends on 1)

The compound according to claim 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof; wherein:
L1 is a covalent bond, O, S, NH, or C1-3 alkylene, wherein the C1-3 alkylene is substituted with 0 to 3 R11;
and
L2 is a covalent bond.

### Claim 3 (depends on 1)

The compound according to claim 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof; wherein:
the
moiety is selected from:

### Claim 4 (depends on 1)

The compound according to claim 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof; wherein Z is phenyl or 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein the phenyl and heteroaryl are independently substituted with 0 to 5 R8.

### Claim 5 (depends on 1)

The compound according to claim 1, which is represented by Formula (III):
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof; wherein:
Z is 6-membered monocyclic heteroaryl containing 1 or 2 nitrogen atoms, or a 9- to 10-membered bicyclic heteroaryl containing 1 or 3 heteroatoms independently selected from N, O, and S, wherein the monocyclic or bicyclic heteroaryl is independently substituted with 0 to 3 R8;
R2 is phenyl or pyridinyl, wherein the phenyl and pyridinyl are each independently substituted with 0 to 2 R10;
R8 is each independently halo, cyano, hydroxyl, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, or C1-4 haloalkoxy;
R10 is each independently halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, or C1-4 haloalkoxy;
RX is —C(O)OH or —C(O)NH—S(O)2Re; and
Re is C1-6 alkyl or C3-6 cycloalkyl.

### Claim 6 (depends on 1)

The compound according to claim 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof; wherein:
Y is CH or N;
the
moiety is selected from:
L1 is a covalent bond, O, or —OCH2—, provided that L1 is a covalent bond when Y is N;
Z is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzo[d]imidazolyl, benzo[d]isoxazolyl, benzo[d]oxadiazolyl, benzo[d]thiazolyl, imidazolo[1,5-a] pyridinyl, indazolyl, indolyl, pyrazolo[4,3-b]pyridinyl, pyrrolo[2,1-f][1,2,4]triazinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrrolo[3,2-c]pyridinyl, thiazolo[4,5-b]pyridinyl, thiazolo[5,4-b]pyridinyl, cinnolinyl, isoquinolinyl, quinolinyl, or quinoxalinyl, each substituted with zero to 1 R8;
R8 is F, —CH3, —CF3, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCHF2, —OCF3, —OCH2CH2OH, or —CH2OCH2CH2Si(CH3)3;
Rx is —CN, —C(O)OH, —C(O)OCH2CH3, —C(O)NH2, —C(O)NH(CH3), —C(O)NHCH2CH3, —C(O)NHCH(CH3)2, —C(O)NH(cyclopropyl), —C(O)NHCH2C(O)OH, —C(O)NHS(O)2CH3, —C(O)NHS(O)2(cyclopropyl), —OCH2C(O)OH, or —C(O)O(carboxy(trihydroxy)tetrahydropyranyl);
L2 is a covalent bond;
R1 is —CHF2, —CH(CH3)2, cyclopropyl, or methylcyclopropyl;
R2 is cyclohexyl, phenyl, or pyridinyl, wherein the phenyl and the pyridinyl are independently substituted with 1 to 3 R10; and
R10 is each independently F, Cl, —CH3, —CF3, —OCH3, or —OCF3.

### Claim 7 (depends on 1)

The compound according to claim 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, selected from:

### Claim 8 (depends on 1)

The compound according to claim 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, selected from:

### Claim 9 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

### Claim 10 (depends on 8)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 8, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

### Claim 11

A compound having the structure:
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

### Claim 12 (depends on 11)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 11 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.