# US 2021/0276982 A1 · Tgf-ß inhibitors

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- Number: US 2021/0276982 A1
- Document ID: US20210276982A1
- Status: Published application
- Kind: A1
- Application number: 17/324,320
- Filed: 2021-05-19
- Published: 2021-09-09
- Earliest claimed: 2015-04-01
- Assignees: Rigel Pharmaceuticals, Inc.
- Applicants: Rigel Pharmaceuticals, Inc.
- Inventors: Marina Gelman; Pingyu Ding; Todd Kinsella; Rajinder Singh; Somasekhar Bhamidipati; Jeffrey Clough
- Web page: https://patentgrep.com/patent/US20210276982A1

## CPC

- C07D 403/12: linked by a chain containing hetero atoms as chain links
- A61P 35/02: specific for leukemia
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed are aryl pyrimidine compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein A, Z, R and R′ are as described herein. In certain embodiments, a compound disclosed herein inhibits the activity of one or more members of the TGF-β superfamily, and can be used to treat disease by blocking such activity.

## Claims

### Claim 1

A method for treating a disease or condition mediated by or involving a member of the TGF-β receptor superfamily in a subject in need thereof, comprising administering an effective TGF-β receptor superfamily inhibiting amount of a compound having the structure of formula (I):
or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
A is phenyl optionally substituted with one to five R1 groups, wherein each R1 is independently halogen, cyano, —ORa, —SRa, —N(Ra)2, C1-6 alkyl, C1-6haloalkyl or C3-8cycloalkyl,
wherein each Ra is independently hydrogen, C1-6 alkyl or C1-6 haloalkyl;
Z is
a fused bicyclic ring of the formula,
wherein
ring A is phenyl or pyrazole,
optionally substituted with one to four R2 groups, wherein each R2 is independently halogen, C1-6alkyl, C1-6haloalkyl, —ORb, —C(O)NRb2, —C(O)CH2NRb2, —CH2—OP(O)(ORc)2, or heteroaryl,
wherein each Rb is independently hydrogen, C1-6 alkyl or C1-6haloalkyl, and
wherein each Rc is independently hydrogen or C1-6 alkyl;
ring B is phenyl or pyridyl, each optionally substituted with one to three R3 groups,
wherein each R3 is independently halogen, C1-6alkyl, C1-6haloalkyl, cycloalkyl or heteroaryl;
R and R′ are independently hydrogen, halogen, C1-6alkyl or C1-6 haloalkyl; and
wherein each alkyl, haloalkyl cycloalkyl or heteroaryl group is optionally substituted with one or two —RZ groups that are each independently halogen, C1-6alkyl or C1-6haloalkyl.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound has a structure according to formula (II)
or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof;
wherein:
R and R′ are independently hydrogen, halogen, C1-6alkyl or C1-6 haloalkyl;
R1 is halogen, cyano, —SRa, —N(Ra)2, C1-6 alkyl, C1-6haloalkyl or C3-8cycloalkyl,
wherein each Ra is independently hydrogen, C1-6 alkyl or C1-6 haloalkyl;
m is 0, 1, 2, 3 or 4;
X is N or C(H);
R2 is hydrogen, —C(O)CH2NRb2, —CH2—OP(O)(ORc)2, C1-6 alkyl, C1-6haloalkyl, or heteroaryl, wherein each Rb is independently hydrogen or C1-6 alkyl, and wherein each Rc is independently hydrogen or C1-6 alkyl; and
R3 is halogen, C1-6alkyl, C1-6haloalkyl, cycloalkyl or heteroaryl.

### Claim 3 (depends on 2)

The method of claim 2, wherein the compound has a structure according to formula (IIa):
wherein
R is hydrogen, halogen, C1-6 alkyl or C1-6 haloalkyl;
R1 is halogen, cyano, C1-6 alkyl, —NH2, C1-6 haloalkyl or C3-6 cycloalkyl;
m is 0, 1, 2, 3 or 4;
R2 is hydrogen, C1-6 alkyl, —C(O)CH2NRb2, —CH2—OP(O)(ORc)2, C1-6 haloalkyl, or C5-6 heteroaryl,
wherein each Rb is independently hydrogen or C1-6 alkyl, and
wherein each Rc is independently hydrogen or C1-6 alkyl; and
R3 is halogen, C1-6 alkyl or C1-6 haloalkyl.

### Claim 4 (depends on 3)

The method of claim 3, wherein:
R is hydrogen, halogen, C1-6 alkyl or C1-6 haloalkyl;
R1 is halogen, cyano, C1-6 alkyl or —NH2;
m is 0, 1, 2, 3 or 4;
R2 is hydrogen, C1-6 alkyl, —C(O)CH2NRb2, or —CH2—OP(O)(ORc)2,
wherein each Rb is independently hydrogen or C1-6 alkyl, and
wherein each Rc is independently hydrogen or C1-6 alkyl; and
R3 is halogen or C1-6 alkyl.

### Claim 5 (depends on 2)

The method of claim 2, wherein the compound has the structure

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound has a structure according to formula (IV):
or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
Z is:
wherein
R2 is —C(O)CH2NRb2,
wherein Rb is C1-6 alkyl; and
R3 is C1-6alkyl; or
wherein
R2 is hydrogen or —ORb,
wherein Rb is hydrogen or C1-6 alkyl; and
n is 0, 1 or 2;
R and R′ are independently hydrogen or C1-6alkyl;
R1 is halogen, cyano, or C1-6 alkyl; and
m is 0, 1 or 2.

### Claim 7 (depends on 6)

The method of claim 6, wherein the compound has a structure

### Claim 8 (depends on 1)

The method of claim 1, wherein the compound is selected from:
2-(Dimethylamino)-1-(5-((2-(2,5-dimethylphenyl)pyrimidin-4-yl)amino)-1H-indazol-1-yl)ethan-1-one;
N-(2-(3,4-Difluorophenyl)pyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;
N-(2-(4-Fluorophenyl)pyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;
N-(5-Fluoro-2-(4-fluoro-2-methylphenyl)pyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;
N-(2-(3-Fluorophenyl)-5-methylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;
N-(2-(4-Fluorophenyl)-5-methylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;
N-(2-(3,4-Difluorophenyl)-5-methylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;
N-(2-(3-Methylphenyl)-5-methylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;
N-(2-(2-Fluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(3-Fluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-Phenylpyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(2-Methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
6-Fluoro-N-(2-(2-fluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(5-Fluoro-2-(2-fluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(5-fluoro-2-methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(3,5-Difluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(3-Fluoro-4-methoxyphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(3-Cyanophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(2,5-Dimethylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(3-Aminophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(3-Methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(4-Fluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(5-Fluoro-2-(methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(3,4-Difluorophenyl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine;
N-(5-Fluoro-2-(3-fluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(5-Fluoro-2-phenylpyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(2-Fluorophenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(2-Methylphenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(3,4-Difluorophenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(2,5-Dimethylphenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(4-Fluoro-2-methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(4-Fluoro-3-methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(2-Aminophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(3-Trifluoromethylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(4-Methoxy-2-methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(4-Fluoro-2-methylphenyl)pyrimidin-4-yl)-6,7-dimethoxyquinolin-4-amine;
N-(2-(2-Fluoro-5-methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(4-Fluoro-3-methylphenyl)-5-methylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;
N-(2-(4-Fluoro-3-methylphenyl)-5-methylpyrimidin-4-yl)-6-methyl-1H-indazol-5-amine;
N-(2-(3-Methylphenyl)-5-methylpyrimidin-4-yl)-6-methyl-1H-indazol-5-amine;
N-(2-(4-Fluorophenyl)-5-methylpyrimidin-4-yl)-6-methyl-1H-indazol-5-amine;
N-(2-(3,4-Difluorophenyl)-5-methylpyrimidin-4-yl)-6-methyl-1H-indazol-5-amine;
N-(2-(2,5-Dimethylphenyl)-5-methylpyrimidin-4-yl)-6-methyl-1H-indazol-5-amine;
N-(2-(4-Fluoro-3-methylphenyl)-5-methylpyrimidin-4-yl)-6-methyl-1H-indazol-5-amine;
6-Fluoro-N-(2-(3-fluorophenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;
6-Fluoro-N-(2-(3-methylphenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;
6-Fluoro-N-(2-(2,5-dimethylphenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;
6-Fluoro-N-(2-(3,4-difluorophenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;
6-Fluoro-N-(2-(4-fluoro-3-methylphenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(2-Fluorophenyl)-5-methylpyrimidin-4-yl)-6-methoxy-1H-indazol-5-amine;
N-(2-(3,4-Difluorophenyl)-5-methylpyrimidin-4-yl)-6-methoxy-1H-indazol-5-amine;
or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof.

### Claim 9 (depends on 1)

The method of claim 1, wherein the disease or condition is mediated by or involves GDF-8 or TGF-β.

### Claim 10 (depends on 9)

The method of claim 9, wherein the disease or condition is pulmonary hypertension, chronic renal disease, acute renal disease, wound healing, arthritis, osteoporosis, kidney disease, congestive heart failure, ulcer, ocular disorder, corneal wound, diabetic nephropathy, impaired neurological function, Alzheimer's disease, atherosclerosis, peritoneal or sub-dermal adhesion, kidney fibrosis, lung fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, hepatitis B, hepatitis C, alcohol-induced hepatitis, cancer, haemochromatosis, primary biliary cirrhosis, restenosis, retroperitoneal fibrosis, mesenteric fibrosis, endometriosis, keloids, cancer, abnormal bone function, inflammatory disorder, scarring or photoaging of the skin.

### Claim 11 (depends on 9)

The method of claim 9, wherein the disease or condition is benign or malignant tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina or thyroid, sarcoma, glioblastomas, multiple myeloma or gastrointestinal cancer, colon carcinoma or colorectal adenoma, tumor of the neck and head, epidermal hyperproliferation, melanoma, psoriasis, prostate hyperplasia, neoplasia, neoplasia of epithelial character, leukemias, lymphomas, mammary carcinoma or leukemia.

### Claim 12 (depends on 9)

The method of claim 9, wherein the disease or condition is Cowden syndrome, Lhermitte-Dudos disease, Bannayan-Zonana syndrome, or other disease in which the PI3K/PKB pathway is aberrantly activated.

### Claim 13 (depends on 9)

The method of claim 9, wherein the disease is cancer, and the compound is administered in combination with the administration of a therapeutically effective amount of one or more chemotherapeutic agents.

### Claim 14 (depends on 13)

The method of claim 13, wherein the one or more chemotherapeutic agents is independently selected from the group consisting of antimetabolites, alkylating agents, coordination compounds, platinum complexes, DNA cross-linking compounds, inhibitors of transcription enzymes, tyrosine kinase inhibitors, protein kinase inhibitors, topoisomerase inhibitors, DNA minor-groove binding compounds, vinca alkyloids, taxanes, antitumor antibiotics, hormones, aromatase inhibitors, enzymes, growth factor receptors antibodies, cytokines, cell surface markers antibodies, HDAC inhibitors, HSP 90 inhibitors, BCL-2 inhibitors, B-raf inhibitors, MEK inhibitors, mTOR inhibitors, proteasome inhibitors and monoclonal antibodies.

### Claim 15 (depends on 13)

The method of claim 13, wherein the one or more chemotherapeutic agents is independently selected from the group consisting of ABT-199, mechlorothamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines, procarbazine, dacarbazine, temozolomide, busulfan, carmustine, lomustine, methotrexate, fluorouracil, capecitabine, cytarabine, gemcitabine, cytosine arabinoside, mecaptopurine, fludarabine, cladribine, thioguanine, azathioprine, vinblastine, vincristine, paclitaxel, docetaxel, colchicine, actinomycin D, daunorubicin, bleomycin, L-asparaginase, cisplatin, carboplatin, oxaliplatin, prednisone, dexamethasone, amino glutethimide, formestane, anastrozole, hydroxyprogesterone caproate, medroxyprogesterone, tamoxifen, amsacrine, mitoxantrone, topotecan, irinotecan, camptothecin, afatinib, axitinib, bosutinib, bortezomib, carfilzomib, cabozantinib, cediranib, crizotinib, dasatinib, dabrafenib, evorolimus, ibrutinib, LDK378, LGX818, MEK162, regorafenib, ruxolitinib, selumetinib, sorafenib, trametinib, vemurafenib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, palbociclib, pazopanib, pomatinib, semaxanib, sirolimus, sunitinib, temsirolimus, vatalanib, vandetanib, anti Her2 antibodies, interferon-α, interferon-γ, interleukin 2, GM CSF, anti CTLA 4 antibodies, rituximab, anti CD33 antibodies, MGCD0103, vorinostat, 17-AAG, thalidomide, lenalidomide, rapamycin, CCI-779, doxorubicine, gemcitabine, melphalan, NPI052, gemtuzumab, alemtuzumab, cetuximab, ibritumomab tiuxaetan, tositumomab, iodine-131 tositumomab, trastuzumab, ado-trastuzumab emtansine, obinutuzumab, bevacizumab, rituximab, and anti-TRAIL death receptor antibodies.