CN-121986106-A - Myt1 inhibitors based on fused thiazole or pyridine rings

Abstract

The present invention provides a compound of formula (I): (I) Or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically labeled compound thereof, wherein ring a, ring B, ring C, Y, R A 、R B 、R C , m, n, p and q are as disclosed in the specification. The invention also provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically-labeled compound thereof, as an inhibitor of Myt1, and methods of use thereof.

Inventors

• LIU ZHENGHAO
• Lin Longzha
• WANG HONGREN
• XUN GUOLIANG
• SUN YINA
• YANG JINYU
• ZHOU JIANLAI
• CHEN BIN

Assignees

• 智擎生技制药股份有限公司

Dates

Publication Date

20260505

Application Date

20241009

Priority Date

20231011

Claims (20)

1. 1. A compound of formula (I), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically-labeled compound thereof, (I) Wherein: Ring a is a 5-7 membered monocyclic aryl, heterocyclyl or heteroaryl group or an 8-11 membered fused bicyclic aryl, heterocyclyl or heteroaryl group; ring B is a 5-6 membered monocyclic aryl, heterocyclyl or heteroaryl group; Ring C is a 5-7 membered monocyclic aryl, heterocyclyl or heteroaryl group or an 8-11 membered fused bicyclic aryl, heterocyclyl or heteroaryl group, wherein one or two ring carbon atoms in the heterocyclyl or heteroaryl group may be replaced by a-C (O) -, -C (S) -or-C (=nh) -group; R A is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, hydroxy, oxo, cyano or amino; R B is hydrogen, C 1 -C 6 alkyl, halogen, hydroxy, oxo, cyano or amino; R C is L-Q-R 1 , hydrogen, halogen, hydroxy, oxo, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, -O- (C 1 -C 6 haloalkyl), -NH- (C 1 -C 6 haloalkyl), - -N (C 1 -C 6 haloalkyl) (C 1 -C 6 haloalkyl), Sulfur pentafluoride, C 1 -C 6 haloalkoxy or halocycloalkyl, -NH-S (O) 2 -(C 1 -C 6 alkyl), -NHP (=O) - (C 1 -C 6 alkyl), -NHC (O) - (C 1 -C 6 alkyl), -C (O) NH- (C 1 -C 6 alkyl), -NHC (O) NH- (C 1 -C 6 alkyl), -S (O) 2 -(C 1 -C 6 alkyl), -P (=O) (C 1 -C 6 alkyl) 2 、-NHC(O)-(C 3 -C 6 cycloalkyl), optionally substituted with one or two substituents selected from the group consisting of halo, Cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C 1 -C 6 alkylamino, -NH (C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) (C 1 -C 6 alkyl), C 1 -C 6 hydroxyalkyl, -C (O) (C 1 -C 6 alkyl), C 1 -C 6 alkoxyhydroxy, (C 1 -C 6 alkoxy) (C 1 -C 6 alkoxy); l is a direct bond, O or NH; q is absent, a direct bond or C 1 -C 6 alkyl; R 1 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl containing one or two heteroatoms selected from N, O, S, -S (O) x - (x is 0,1 or 2), wherein alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or two substituents R 2 ; R 2 is C 1 -C 6 alkyl, halogen, hydroxy, oxo, cyano, amino, - (c=o) (C 1 -C 6 alkyl) or-N (C 1 -C 6 alkyl) (C 1 -C 6 alkyl); Y is O, CR 3 、CR 3 R 4 , N or NH; R 3 and R 4 are independently hydrogen, C 1 -C 6 alkyl, halogen, hydroxy, oxo, cyano or amino, or R 3 and R 4 attached to the same carbon atom together with the carbon atom to which they are attached form a C 3 -C 7 cycloalkyl group, or R 3 and R 4 attached to different carbon atoms together with the carbon atom to which they are attached form a C 3 -C 7 cycloalkyl group; m is 1, 2, 3 or 4; n is 0 or 1; p is 1, 2 or 3, and Q is 1 or 2.
2. 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically-labeled compound thereof, wherein Q is 1, and the number of the groups is 1, Y is CR 3 R 4 or NH, and R 3 and R 4 are as defined in claim 1.
3. 3. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically-labeled compound thereof, wherein q is 2; y is CR 3 R 4 、CR 3 or N, and R 3 and R 4 are as defined in claim 1.
4. 4. The compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically labeled compound thereof, wherein, Ring B is thiazole or pyridine.
5. 5. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically labeled compound thereof, wherein, Ring a is selected from phenyl, a 5-6 membered heteroaryl group containing at least one N atom, or an 8-11 membered fused bicyclic heteroaryl group containing at least two N atoms.
6. 6. The compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically labeled compound thereof according to claim 5, wherein, Ring A is selected from 、 、 、 、 、 Or (b) ; R A and m are as defined in claim 1.
7. 7. The compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically labeled compound thereof according to claim 6, wherein, Ring A is selected from 、 、 、 、 、 Or (b) ; And R A1 、R A2 、R A3 、R A4 、R A5 and R A6 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, hydroxy, oxo, cyano or amino.
8. 8. The compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically labeled compound thereof according to claim 7, wherein, Ring A is And R A1 and R A2 are methyl.
9. 9. The compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically labeled compound thereof according to claim 7, wherein, Ring A is ; R A1 、R A2 is methyl, and R A3 is halogen.
10. 10. The compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically labeled compound thereof according to claim 7, wherein, Ring A is And (C) sum R A5 is methyl.
11. 11. A compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically-labeled compound thereof, wherein ring a is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
12. 12. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically-labeled compound thereof, wherein ring C is a 5-7 membered monocyclic heteroaryl or an 8-11 membered fused bicyclic heteroaryl containing at least two N atoms.
13. 13. A compound of formula (I) according to claim 12, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically-labeled compound thereof, wherein ring C is a 9-membered fused bicyclic heteroaryl containing at least two N atoms.
14. 14. A compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically-labeled compound thereof, wherein ring C is selected from 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) And R C and p are as defined in claim 1.
15. 15. A compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically-labeled compound thereof, wherein R C is selected from hydrogen, -CH 3 、-CH 2 CH 3 、-CH 2 CF 3 、-NH 2 , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
16. 16. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically-labeled compound thereof, wherein the compound of formula (I) is selected from: 。
17. 17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically labeled compound thereof, and one or more pharmaceutically acceptable carriers or excipients.
18. 18. Use of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically-labeled compound thereof, for the manufacture of a medicament for treating cancer in a subject in need thereof.
19. 19. The use of claim 18, wherein the compound or pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically labeled compound is co-administered to the individual with a second anticancer agent, wherein the second anticancer agent is selected from the group consisting of a targeted cancer drug, such as Qu Tuo bead monoclonal antibody (trastuzumab), ramucirumab (ramucirumab), bevacizumab, everolimus (everolimus), a pharmaceutical composition comprising a pharmaceutical composition, Tamoxifen (tamoxifen), toremifene (toremifene), fulvestrant (fulvestrant), anastrozole (anastrozole), exemestane (exemestane), lapatinib (lapatinib), letrozole (letrozole), pertuzumab, ado Qu Tuo-bead monoclonal antibody entaxin (ado-trastuzumabemtansine), parecoxib (palbociclib), cetuximab (cetuximab), Panitumumab, ziv-aflibercept, regorafenib (regorafenib), imatinib mesylate (lmatinibmesylate), lanreotide acetate (lanreotideacetate) sunitinib, regorafenib (regorafenib), denox monoclonal antibody (denosumab), aliskiric acid (alitretinoin), sorafenib (sorafenib), Panzepam (pazopanib), temsirolimus (temsirolimus), everolimus (everolimus), retinoic acid (tretinoin), dasatinib (dasatinib), nilotinib (nilotinib), bosutinib (bosutinib), rituximab, alemtuzumab, ofatumumab, obunobtuzumab (obinutuxumab), ibrutinib (ibrutinib), Ai Dexi cloth (idelalisib), brinatumomab (blinatumomab), su Lani cloth (soragenib), crizotinib (crizotinib), erlotinib (erlotinib), gefitinib (gefitinib), afatinib dimaleate (afatinibdimaleate), ceritinib (ceritnib), ramucirumab monoclonal antibody (ramucirumab), nivolumab, paribead monoclonal antibody (pembrolizumab), afatinib dimaleate (afatinibdimaleate), Ornitinib (osimertinib) and Leishmania monoclonal antibody (necitumumab), alkylating agents such as busulfan (busulfan), chlorambucil, cyclophosphamide, ifosfamide, melphalan (melphalan), mechlorethamine, streptozotocin, thiotepa (thiotepa), uracil mustard, triethylmelamine, temozolomide and 2-chloroethyl-3-creatinamide-1-nitrosourea (SarCNU), antibiotics or plant alkaloids such as actinomycin-D, bleomycin (bleomycin), bleomycin, Candidiasis, daunomycin (daunorubicin), rubus parvius (doxorubicin), ada mycin (idarubicin), irinotecan (irinotecan), L-asparaginase (L-ASPARAGINASE), mitomycin-C (mitomycin-C), mithramycin (mitramycin), noveltine (novelline), paclitaxel (paclitaxel), docetaxel (docetaxel), topotecan (topotecan), Vinblastine (vinblastine), vincristine (vincristine), teniposide (teniposide) (VM-26) and etoposide (etoposide) (VP-16), hormones or steroids such as 5α -reductase inhibitors, aminoglutethimide (aminoglutethimide), anastrozole (anastrozole), bicalutamide (bicalutamide), chlorotriarene, diethylstilbestrol (diethylstilbestrol) (DES), drotaandrosterone (dromostanolone), Estramustine (estramustine), ethinyl estradiol, flutamide (flutamide), fluoxymesterone (fluoxymesterone), goserelin (goserelin), hydroxyprogesterone, letrozole, leuprolide (leuprolide), medroxyprogesterone acetate (medroxyprogesterone acetate), megestrol acetate (megestrol acetate), methylprednisolone (methylprednisolone), and pharmaceutical compositions, Methyltestosterone (methyltestosterone), mitotane (mitotane), nilamide (nilutamide), prednisolone (prednisolone), arzoxifene (SERM-3), tamoxifen (tamoxifen), testosterone (testolactone), testosterone (testosterone), triamcinolone (triamicnolone) and norrad (zoladex), synthetic formulations such as all-trans retinoic acid, carmustine (carmustine) (BCNU), Carboplatin (CBDCA), lomustine (lomustine) (CCNU), cis-diamminedichloroplatin (cisplatin), dacarbazine (dacarbazine), golidel (gliadel), altretamine (hexamethylmelamine), hydroxyurea, levamisole, mitoxantrone (mitoxantrone), o, p '-dichloro-diphenyl-dichloroethane (o, p' -DDD) (also known as nephrite (lysodren) or mitotane (mitotane)), oxaliplatin (oxaliplatin), Porphin sodium (porfimersodium), procarbazine and imatinib mesylate (imatinib mesylate) (Gleevec ® ), antimetabolites such as chlorodeoxyadenosine, cytosine arabinoside, 2'-deoxy Ke Fumei (2' -deoxycoformycin), fludarabine phosphate (fludarabine phosphate), 5-fluorouracil (5-FU), and, 5-fluoro-2' -deoxyuridine (5-FUdR), gemcitabine (gemcitabine), camptothecins, 6-mercaptopurine, methotrexate and thioguanine, and biological agents such as interferon-alpha, BCG (Bacillus Calmette-Guerin, BCG), granulocyte colony-stimulating factor (granulocyte colony stimulating factor, G-CSF), granulocyte-macrophage colony-stimulating factor (granulocyte-macrophage colony-stimulating factor, GM-CSF), Interleukin-2 and herceptin (herceptin).
20. 20. The use of claim 18, wherein the cancer is a heart cancer such as sarcomas (e.g., hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas, lung cancer such as bronchogenic cancer (e.g., squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, and adenocarcinoma), alveolar cancer (e.g., bronchiolar carcinoma), bronchogenic adenoma, sarcoma, lymphoma, chondromisstructured tumor, and mesothelioma), gastrointestinal cancer such as esophageal cancer (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma), gastric cancer (e.g., lymphoma, and leiomyosarcoma), gastric cancer (e.g., leiomyosarcoma), Pancreatic cancer (e.g., ductal adenocarcinoma, insulinoma, glyconoma, gastrinoma, carcinoid and vasoactive intestinal peptide tumor), small intestine cancer (e.g., adenocarcinoma, lymphoma, carcinoid, karposi's sarcoma, smooth myoma, hemangioma, lipoma, neurofibroma and fibroma), large intestine cancer (e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma and smooth myoma), genitourinary tract cancer such as kidney cancer (e.g., adenocarcinoma, wilm's tumor [ Wilm's tumor ], lymphoma and leukemia), bladder and urethra cancer (e.g., squamous cell carcinoma), Transitional cell carcinoma and adenocarcinoma), prostate cancer (e.g., adenocarcinoma and sarcoma), testicular cancer (e.g., sperm cell carcinoma, teratoma, embryonal tumor, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors and lipoma), liver cancer such as liver cancer (e.g., hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatoblastoma and hemangioma, bone cancer such as osteogenic sarcoma (e.g., osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma), malignant lymphoma (e.g., reticulosarcoma), hepatoma, Multiple myeloma, malignant giant cell tumor chordoma, osteochondral tumor (e.g., osteochondral exogenesis warts), benign chondria, chondroblastoma, cartilage myxofibroma, osteoid tumor and giant cell tumor, cancers of the nervous system such as craniocerebral cancers (e.g., osteoma, hemangioma, granuloma, xanthoma and osteomyelitis deformity), meningioma (e.g., meningioma and gliosis), brain cancers (e.g., astrocytoma, medulloblastoma, neuroglioma, ependymoma, blastoma (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma and congenital tumor), meningioma, and the like, Spinal neurofibromas, meningiomas, neurogliomas, and sarcomas, gynaecological cancers such as uterine cancers (e.g., endometrial cancers), cervical cancers (e.g., cervical cancers and pre-neoplastic cervical dysplasias), ovarian cancers (e.g., ovarian cancers [ e.g., serous cystic adenocarcinoma, bursal adenocarcinoma, and categorical unknown cancers ], granulosa cell tumors, shi Tuoli-lediglobular tumors (seltoli-LEYDIG CELL tumor), asexual cell tumors, and malignant teratomas), vulvar cancers (e.g., squamous cell carcinoma, intraepithelial cancers, adenocarcinoma, fibrosarcoma, and melanoma), vaginal cancers (e.g., clear cell carcinoma, vaginal cancer, Squamous cell carcinoma, botryoid sarcoma [ e.g., embryonal rhabdomyosarcoma ] and fallopian tube carcinoma), hematological cancers such as hematological cancers (myeloleukemia [ acute and chronic ], acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative diseases, multiple myeloma and myelodysplasia), hodgkin's disease, non-Hodgkin's lymphoma [ malignant lymphoma ], skin cancers such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, cutaneous fibromas, keloids, psoriasis, adrenal gland cancers such as neuroblastoma, or breast cancer.

Description

Myt1 inhibitors based on fused thiazole or pyridine rings Technical Field The present invention relates to methods of using inhibitors of membrane-associated tyrosine and threine-specific cdc2 inhibitory kinase (Myt 1) (gene name PKMYT) e.g., for the treatment of diseases or disorders, such as cancer, in particular, diseases or disorders that depend on Myt1 activity (e.g., cancer with CCNE1 amplification/overexpression or FBXW7 mutation). In particular, the invention relates to fused thiazole or fused pyridine ring based Myt1 inhibitors, pharmaceutical compositions comprising the compounds and methods of using the compounds. Background Since human DNA is continually damaged by various internal factors (e.g., stagnant replication forks and reactive oxygen species) or external factors (uv light, ionizing radiation and chemicals), to cope with these potential risks, cells evolve complex mechanisms to counteract these deleterious events to prevent them from compromising the integrity of the genome, thereby causing genome-unstable diseases such as cancer. These mechanisms are collectively known as the DNA Damage Response (DDR). DDR regulates specific DNA repair mechanisms, including G1, S, G and mitotic checkpoints, at various stages of the cell cycle by initiating various checkpoints pathways. Because most cancer cells have lost the G1 checkpoint due to p53 mutations, DNA damage correction is necessary depending on the G2 checkpoint before entering mitosis and dividing into 2 sub-cells. MYT1 (myelin transcription factor 1 ) inhibits the progression of the cell cycle by inhibiting the activity of cyclin-related proteins such as cyclin A, CDK1 (i.e. cdc 2) and CDK2, allowing multiple tumour cells to repair their DNA damage and continue to proliferate. Cdc2 (i.e. CDK 1) is a cyclin-dependent kinase (cyclin-DEPENDENT KINASE) that controls cell entry into mitosis. Upon G2-M transition, cdc2 dephosphorylates at Tyr-15 and Thr-14, allowing mitosis to proceed. Since phosphorylation of cdc2 at threonic acid 14 (Thr-14) and tyrosine 15 (Tyr-15) inhibits the activity of enzymes and prevents premature initiation of mitosis, the point in time of cdc2 dephosphorylation is important for initiation of mitosis. Cells will utilize arrest in the G2 phase of the cell cycle for pre-mitotic DNA damage repair to avoid death. Studies have shown that cdc2, if dephosphorylated prematurely, can lead to mitotic disasters and cell death. Myt1 is an important cell cycle regulator in the G2-M phase, and inhibition of Myt1 blocking the phosphorylation of cdc2 at Tyr-15 and Thr-14 can lead to the premature initiation of mitosis of cells by cdc2 leading to rapidly proliferating cell death. Furthermore, myt1 provides an intervention point to inhibit tumor cells from repairing DNA by the mechanism, thereby creating resistance to chemotherapeutic drugs. In summary, inhibition of Myt1 can reduce tumor cell proliferation, which is useful in therapy, and can overcome the resistance of tumor cells to chemotherapeutic agents by the combination of Myt1 inhibitors and chemotherapeutic agents. Thus, there remains a need to develop an effective Myt1 kinase inhibitor for the treatment of cancer. Disclosure of Invention One aspect of the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically-labeled compound thereof: (I) Wherein ring A, ring B, ring C, Y, R A、RB、RC, m, n, p, and q are as defined in the specification. Another aspect of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically labeled compound thereof, and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition of the invention is useful as an inhibitor of Myt 1. Another aspect of the invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically-labeled compound thereof for the preparation of a medicament for use as a Myt1 inhibitor. Another aspect of the invention is to provide a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotopically-labeled compound thereof, to inhibit the growth of cancer in the subject. The compounds of formula (I) may be used alone or in combination with another therapeutic agent and/or therapy. Detailed Description The invention may be understood more readily by reference to the following detailed descriptio