# US 11,306,088 B2 · CXCR4 inhibitors and uses thereof

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- Number: US 11,306,088 B2
- Document ID: US11306088B2
- Status: Granted
- Kind: B2
- Application number: 16/939,723
- Filed: 2020-07-27
- Published: 2021-02-18
- Granted: 2022-04-19
- Earliest claimed: 2016-06-21
- Assignees: X4 Pharmaceuticals, Inc.
- Applicants: X4 Pharmaceuticals, Inc.
- Inventors: Elyse Marie Josee Bourque; Renato Skerlj
- Web page: https://patentgrep.com/patent/US11306088B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/41: having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61P 35/00: Antineoplastic agents
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

## Claims

### Claim 1

A method of treating a CXCR4-mediated disease, disorder, or condition, comprising administering to a patient in need thereof a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein the compound inhibits CXCR4 and the disease, disorder, or condition is treated by inhibition of CXCR4, wherein:
Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R1 is independently —R, halogen, —CN, —OR, —N(R)2, —NO2, —N3, —SR, or -L1-R6;
each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each L1 and L2 is independently a covalent bond or a C1-8 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO2—, —SO2N(R)—, —(R)NSO2—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, —(R)NC(S)N(R)—, or -Cy-;
each -Cy- is independently a bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R2 is hydrogen, halogen, —CN, —OR, —N(R)2, —NO2, —N3, —SR, -L2-R6, or optionally substituted C1-8 aliphatic;
R3 is hydrogen, optionally substituted C1-6 aliphatic, or -L3-R6;
L3 is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —S—, —SO—, —SO2—, —C(S)—, or -Cy-;
each R4 is independently hydrogen, deuterium, halogen, —CN, —OR6, or C1-4 alkyl, or two R4 groups on the same carbon are optionally taken together to form ═NR6, ═NOR6, ═O, or ═S;
each R5 is independently R, halogen, —CN, —OR, —N(R)2, —NO2, —N3, —SR, or -L1-R6, or two R5 groups on the same saturated carbon atom are optionally taken together to form ═NR, ═NOR, ═O, ═S, or a spirocyclic 3-6 membered carbocyclic ring;
each R6 is independently hydrogen or C1-6 alkyl optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms;
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, 3, or 4; and
p is 0, 1, 2, 3, or 4.

### Claim 2 (depends on 1)

The method of claim 1, wherein Ring A is selected from:

### Claim 3 (depends on 1)

The method of claim 1, wherein Ring A is selected from

### Claim 4 (depends on 3)

The method of claim 3, wherein R1 is selected from hydrogen, halogen, C1-6 alkyl (optionally substituted with 1, 2, or 3 halogens), —CN, —N(R)2, —OR, —SR, —S(O)R6, —SO2R6, —SO2NHR6,
and each R is independently hydrogen, —CH2-phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CH2F, —CHF2, —CF3, —CH2CHF2, or —CH2CF3.

### Claim 5 (depends on 4)

The method of claim 4, wherein L1 is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —N(R)—, —S—, —SO—, —SO2—, —SO2N(R)—, —(R)NSO2—, —C(S)—, or -Cy-, wherein each R is independently hydrogen, —CH2-phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CH2F, —CHF2, —CF3, —CH2CHF2, or —CH2CF3.

### Claim 6 (depends on 5)

The method of claim 5, wherein L2 is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —N(R)—, —S—, —SO—, —SO2N(R)—, —(R)NSO2—, —C(S)—, or -Cy-, and each R is independently hydrogen, —CH2-phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CH2F, —CHF2, —CF3, —CH2CHF2, or —CH2CF3.

### Claim 7 (depends on 6)

The method of claim 6, wherein R2 is hydrogen, halogen, —CN, —OR, —N(R)2, —SR, optionally substituted C1-6 aliphatic, or -L2-R6, wherein L2 is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —N(R)—, —S—, —SO—, —SO2—, —C(S)—, or -Cy-; wherein the C1-6 aliphatic group is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —CN, —N(R)2, —NO2, —N3, ═NR, ═NOR, ═O, ═S, —OR, —SR, —SO2R, —S(O)R, —R, -Cy-R, —C(O)R, —C(O)OR, —OC(O)R, —C(O)N(R)2, —(R)NC(O)R, —OC(O)N(R)2, —(R)NC(O)OR, —N(R)C(O)N(R)2, —SO2N(R)2, —(R)NSO2R, —C(S)R, or —C(S)OR; wherein each R is independently hydrogen, —CH2-phenyl, phenyl, C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CH2F, —CHF2, —CF3, —CH2CHF2, or —CH2CF3.

### Claim 8 (depends on 6)

The method of claim 6, wherein R2 is hydrogen, —NH2, C2-4 alkynyl, F, Cl, Br, or I.

### Claim 9 (depends on 7)

The method of claim 7, wherein R3 is C1-4 alkyl optionally substituted with
pyridyl, —N(R)2, —CN, or 1, 2, or 3 deuterium or halogen atoms, wherein R is hydrogen or C1-3 alkyl.

### Claim 10 (depends on 7)

The method of claim 7, wherein R3 is methyl.

### Claim 11 (depends on 10)

The method of claim 10, wherein R5 is hydrogen, C1-6 alkyl, halogen, —CN, —OCF3, cyclopropyl, ethynyl, —OCH3, —CF3, —CD3, or

### Claim 12 (depends on 9)

The method of claim 9, wherein the compound is of Formula VII:
or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound is of Formulae VIII-a or VIII-b:
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

The method of claim 1, wherein the compound is of Formulae XIV-a, XIV-b, or XIV-c:
or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1)

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

### Claim 16 (depends on 1)

The method of claim 1, wherein the CXCR4-mediated disease, disorder, or condition is a cancer selected from a leukemia, polycythemia vera, a lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, or heavy chain disease; or a solid tumor selected from fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, or epithelial carcinoma.

### Claim 17 (depends on 1)

The method of claim 1, wherein the CXCR4-mediated disease, disorder, or condition is a leukemia selected from acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, or chronic lymphocytic leukemia; or a lymphoma selected from Hodgkin's disease or non-Hodgkin's disease.

### Claim 18 (depends on 1)

The method of claim 1, wherein the CXCR4-mediated disease, disorder, or condition is a cancer selected from liver cancer, kidney cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), colon cancer, prostate cancer, testicular cancer, rectal cancer, anal cancer, colon cancer, lung cancer, gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; or neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST).

### Claim 19 (depends on 1)

The method of claim 1, wherein the CXCR4-mediated disease, disorder, or condition is a cancer selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, melanoma, breast cancer, colorectal carcinoma, colorectal cancer, non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC), fallopian tube cancer, papillary serous cystadenocarcinoma, or uterine papillary serous carcinoma (UPSC).

### Claim 20 (depends on 1)

The method of claim 1, wherein the CXCR4-mediated disease, disorder, or condition is a primary immune deficiency selected from: warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome; severe congenital neutropenia (SCN); GATA2 deficiency (Mono MAC syndrome); idiopathic CD4+ T lymphocytopenia (ICL); or Wiskott-Aldrich Syndrome.

### Claim 21

A method of inhibiting activity of CXCR4 or a mutant thereof in a biological sample comprising the step of contacting the biological sample with a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R1 is independently —R, halogen, —CN, —OR, —N(R)2, —NO2, —N3, —SR, or -L1-R6;
each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each L1 and L2 is independently a covalent bond or a C1-8 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO2—, —SO2N(R)—, —(R)NSO2—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, —(R)NC(S)N(R)—, or -Cy-;
each -Cy- is independently a bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R2 is hydrogen, halogen, —CN, —OR, —N(R)2, —NO2, —N3, —SR, -L2-R6, or optionally substituted C1-8 aliphatic;
R3 is hydrogen, optionally substituted C1-6 aliphatic, or -L3-R6;
L3 is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —S—, —SO—, —SO2—, —C(S)—, or -Cy-;
each R4 is independently hydrogen, deuterium, halogen, —CN, —OR6, or C1-4 alkyl, or two R4 groups on the same carbon are optionally taken together to form ═NR6, ═NOR6, ═O, or ═S;
each R5 is independently R, halogen, —CN, —OR, —N(R)2, —NO2, —N3, —SR, or -L1-R6, or two R5 groups on the same saturated carbon atom are optionally taken together to form ═NR, ═NOR, ═O, ═S, or a spirocyclic 3-6 membered carbocyclic ring;
each R6 is independently hydrogen or C1-6 alkyl optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms;
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, 3, or 4; and
p is 0, 1, 2, 3, or 4.