# US 11,440,897 B2 · Bicyclic carboxamides and methods of use thereof

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- Number: US 11,440,897 B2
- Document ID: US11440897B2
- Status: Granted
- Kind: B2
- Application number: 17/070,554
- Filed: 2020-10-14
- Published: 2021-01-28
- Granted: 2022-09-13
- Earliest claimed: 2018-04-17
- Assignees: Tempest Therapeutics, Inc.
- Applicants: Tempest Therapeutics, Inc.
- Inventors: Yalda Bravo; Austin Chih-Yu Chen; Jinyue Ding; Robert Gomez; Heather Lam; Joe Fred Nagamizo; Renata Marcella Oballa; David Andrew Powell; Tao Sheng
- Web page: https://patentgrep.com/patent/US11440897B2

## CPC

- C07D 401/10: linked by a carbon chain containing aromatic rings
- 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 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 417/10: linked by a carbon chain containing aromatic rings
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Compounds, compositions and methods are provided for modulating the activity of EP2 and EP4 receptors, and for the treatment, prevention and amelioration of one or more symptoms of diseases or disorders related to the activity of EP2 and EP4 receptors. In certain embodiments, the compounds are antagonists of both the EP2 and EP4 receptors.

## Claims

### Claim 1

A method for the treatment of an EP4-mediated cancer in a patient comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, isotopic variant, or prodrug thereof:
wherein:
X1 is N;
X3 is CR3;
X4 is CR4;
X5 is CR5;
L1 is —CRb2—;
Ring A is aryl;
R1 is aryl optionally substituted with one, two, or three Ry;
each Ry is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halogen, —OR8, —NR8R9, —CN, —C(O)R11, —C(O)NR8R9, —NR8C(O)R11, —NR8C(O)OR9, —NR10C(O)NR8R9, —OC(O)NR8R9, —S(O)2R11, —S(O)R11, —SR8, —S(O)2NR8R9, —S(O)NR8R9, —NR8S(O)R11, —NR8S(O)2R11, or —NR10S(O)2NR8R9; wherein the alkyl is optionally substituted with —OR8 or —NR8R9 and wherein the cycloalkyl and heterocyclyl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl;
each Rx is independently halogen, methyl, C1haloalkyl, or —CN;
R2, R3, R4, and R5 are each independently hydrogen, alkyl, halogen, —OR, —NR8R9, —SR8, —S(O)R11, —S(O)2R11, —CN, cycloalkyl, or haloalkyl;
R6 is hydrogen, alkyl, or haloalkyl;
R7 is hydrogen, halogen, alkyl, alkoxy, haloalkoxy, hydroxyl, or haloalkyl;
each R8 and each R9 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl; or
R8 and R9, together with the atom or atoms to which they are attached, form a heterocyclyl optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl;
each R10 is independently hydrogen or alkyl;
each R11 is independently alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl;
Y1 and Y2 are each independently a bond or —(CRa2)n—, provided that Y1 and Y2 are not both a bond;
Z1 and Z2 are each —CRa2—;
L2 is —(CRc2)m—;
G is —C(O)OR12, —C(O)NHOH, —SO3H, —SO2NH2, —SO2NHRd, —SO2NHC(O)Rd, —NHC(O)NHSO2Rd, -1H-tetrazolyl, —P(O)(OH)2, -1,2,4-oxadiazol-5(4H)-one, -tetrazol-5(4H)-one, or —C(O)NHSO2Rd;
R12 is selected from H, C1-C6alkyl, aryl, aralkyl, CH(R13)OC(═O)R14, CH(R13)OC(═O)OR14 and a (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl group having the following formula:
wherein Rc is C1-C6 alkyl;
R13 is hydrogen or C1-C6 alkyl;
R14 is C1-C6 alkyl or C3-C6-cycloalkyl;
each Ra is independently hydrogen, alkyl, halogen, or haloalkyl;
each Rb is independently hydrogen, alkyl or haloalkyl, or two Rbs, together with the carbon atom to which they are attached, form a cycloalkyl or a heterocyclyl;
each Rc is independently hydrogen or halogen;
Rd is alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl;
m is 0, 1, or 2;
each n is independently 1, 2, or 3;
p is 1; and
q is 0, 1, or 2.

### Claim 2 (depends on 1)

The method of claim 1, wherein:
R2, R3, R4, and R5 are each independently hydrogen, alkyl, halogen, —OR8, —CN, cycloalkyl, or haloalkyl; each Rb is independently hydrogen, deuterium, optionally deuterated alkyl or haloalkyl, or two Rbs, together with the carbon atom to which they are attached, form optionally deuterated cycloalkyl; and
each R8 is independently hydrogen, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl.

### Claim 3 (depends on 1)

The method of claim 1, wherein:
each Ry is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halogen, —OR8, —NR8R9, —CN, —C(O)R11, —C(O)NR8R9, —NR8C(O)R11, —NR8C(O)OR9, —NR10C(O)NR8R9, —OC(O)NR8R9, —S(O)2R11, —S(O)R11, —SR8, —S(O)2NR8R9, —NR8S(O)2R11, or —NR10S(O)2NR8R9 wherein alkyl is optionally substituted with —OR8 or —NR8R9 and wherein cycloalkyl and heterocyclyl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl;
each R8 and each R9 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl; or
R8 and R9, together with the atom or atoms to which they are attached, form a heterocyclyl optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl;
each R10 is independently hydrogen or alkyl;
each R11 is independently alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl; and
each Rb is independently hydrogen or deuterium.

### Claim 4 (depends on 3)

The method of claim 3, wherein the compound is of Formula (II):
or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, or prodrug thereof, wherein L1 is —CRb2— and each Rb is independently hydrogen or deuterium.

### Claim 5 (depends on 3)

The method of claim 3, wherein the compound is of Formula (IIc):
or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, or prodrug thereof, wherein L1 is —CRb2— and each Rb is independently hydrogen or deuterium.

### Claim 6 (depends on 5)

The method of claim 5 wherein:
R3, R4, and R5 are each independently hydrogen, alkyl, halogen, —OR8, —NR8R9, —S(O)R11, —S(O)2R11, —CN, cycloalkyl, or haloalkyl; and
each R8 and each R9 are independently hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl; or
R8 and R9, together with the atom or atoms to which they are attached, form a heterocyclyl optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl; and
each R11 is independently alkyl, deuterated alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl.

### Claim 7 (depends on 6)

The method of claim 6, wherein:
one of R3, R4, and R5 is alkyl, halogen, —OR8, —NR8R9, —SR8, —S(O)R11, —S(O)2R11, —CN, cycloalkyl, or haloalkyl and the remainder of R3, R4, and R5, when present, are hydrogen.

### Claim 8 (depends on 7)

The method of claim 7, wherein:
one of R3 or R4 is halogen and the other of R3 and R4, when present, is hydrogen and R5 is hydrogen.

### Claim 9 (depends on 8)

The method of claim 8, wherein:
R1 is aryl optionally deuterated and optionally substituted with one or two Ry;
each Ry is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halogen, —OR8, —NR8R9, —CN, —C(O)R11, —C(O)NR8R9, —NR8C(O)R11, —NR8C(O)OR9, —NR10C(O)NR8R9, —OC(O)NR8R9, —S(O)2R11, —S(O)R11, —SR8, —S(O)2NR8R9, —S(O)NR8R9, —NR8S(O)R11, —NR8S(O)2R11, or —NR10S(O)2NR8R9; wherein alkyl is optionally substituted with —OR8 or —NR8R9 and wherein cycloalkyl and heterocyclyl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl;
each R8 and each R9 are independently hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl; or
R8 and R9, together with the atom or atoms to which they are attached, form a heterocyclyl optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl;
each R10 is independently hydrogen, deuterium, alkyl or deuterated alkyl; and
each R11 is independently alkyl, deuterated alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl.

### Claim 10 (depends on 1)

The method of claim 1, wherein Ring A is phenyl and R1 is phenyl.

### Claim 11 (depends on 10)

The method of claim 10, wherein R7 is hydrogen or deuterium.

### Claim 12 (depends on 11)

The method of claim 11, wherein q is 0 or 1.

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound is selected from:
or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, isotopic variant, or prodrug thereof.

### Claim 14 (depends on 1)

The method of claim 1, further comprising administering a pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier.

### Claim 15 (depends on 1)

The method of claim 1, wherein said EP4-mediated cancer is selected from glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer and prostate cancer.

### Claim 16 (depends on 15)

The method of claim 15, wherein said EP4-mediated cancer is selected from colon cancer, bladder cancer, hepatocellular carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer.

### Claim 17 (depends on 1)

The method of claim 1, wherein said EN-mediated cancer selected from colorectal cancer (CRC), lung cancer, squamous cell carcinoma of the head and neck (SCCHN), bladder cancer, endometrial cancer, and gastric cancer.

### Claim 18 (depends on 1)

The method of claim 1, wherein said EP4-mediated cancer is colorectal cancer (CRC).