TGF-β inhibitors
Disclosed are pyrazole 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, X, Z, m, p, and R 2 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.
1. A compound having the structure of formula (I):
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof,
wherein
m is 1 or 2;
p is 0 or 1;
X is —CH 2 — or —O—;
A is
n is 0, 1, 2, 3, 4, or 5;
wherein each R 1 is independently halogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, C 3-8 Cak(C 0-6 alkyl), Hca(C 0-6 alkyl), Ar(C 0-6 alkyl), Het(C 0-6 alkyl), —O—(C 0 -C 6 alkyl)-Ar, —O—(C 0 -C 6 alkyl)-Het, —O—(C 0 -C 6 alkyl)-Cak, —O—(C 0 -C 6 alkyl)-Hca, —NO 2 , or —CN, wherein the Ar, Het, Cak, Hca, and alkyl are optionally substituted with 1, 2, 3, or 4 groups that are each independently halogen, cyano, nitro, —OR a , —SR a , —NR a 2 , —C(O)OR a , —C(O)NR a 2 , —C(O)R a , —S(O)R a , —S(O) 2 R a , —S(O)OR a , —S(O) 2 OR a , —S(O)NR a 2 , —S(O) 2 NR a 2 , —OC(O)R a , —OC(O)OR a , —OC(O)NR a 2 , —N(R)C(O)R a , —N(R)C(O)OR a , —N(R)C(O)NR a 2 , —N(R)S(O)R a , —N(R a )S(O) 2 R a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
each R a is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, or —(C 0 -C 6 alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano; or
wherein the Y ring is a 5- to 9-membered Hca optionally substituted by halo or C 1 -C 6 alkyl;
each R 2 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR c , —SR c , —NR c 2 , C 3-8 Cak, —NO 2 or —CN, wherein each R c is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and
Z is a fused bicyclic ring of the formula
wherein
ring A is Ar or 5- or 6-membered Het,
wherein
Z is optionally substituted by one or two —R Z groups that are each independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —OR, —SR, —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)S(O) 2 R, —O—C 1-6 alkyl-OR, —O—C 1-6 alkyl-SR, —O—C 1-6 alkyl-NR 2 , or C 3-8 Cak wherein each Cak and alkyl group is optionally substituted by one or two —R Z2 groups;
wherein each —R Z2 is independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR b , —NR b 2 , —C(O)R b , —C(O)OR b , —C(O)NR b 2 , —S(O) 2 NR b 2 , or —S(O) 2 R b ;
each R is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, or —(C 0 -C 6 alkyl)-Hca, wherein Ar, Het, Cak, Hca, and alkyl are optionally substituted with C 1 -C 6 alkyl, halogen, or C 1 -C 6 haloalkyl; and
each R b is independently hydrogen or C 1 -C 6 alkyl.
2. The compound of claim 1 , wherein Z is
3. The compound of claim 2 , wherein n is 1 or 2.
4. The compound of claim 2 , wherein n is 1.
5. The compound of claim 2 , wherein n is 2.
6. The compound of claim 2 , wherein n is 0.
7. The compound of claim 2 , wherein p is 1.
8. The compound of claim 2 , wherein p is 0.
9. The compound of claim 1 , wherein each R 2 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or —OR c .
10. The compound of claim 1 , wherein m is 1.
11. The compound of claim 1 , wherein m is 2.
12. The compound of claim 1 , wherein the compound has the formula:
13. The compound of claim 1 , which is of the formula:
14. 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 according to claim 1 .
15. The method of claim 14 , wherein 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; or 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; or the disease or condition is Cowden syndrome, Lhermitte-Dudos disease, or Bannayan-Zonana syndrome.
16. A method for treating cancer in which TGF-β signaling is implicated in a subject in need thereof, comprising administering an effective GDF-8 or TGF-β inhibiting amount of a compound according to claim 1 in combination with the administration of a therapeutically effective amount of one or more chemotherapeutic agents.
17. The method of claim 16 , 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; or 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.
18. The compound of claim 1 , wherein each R Z is independently halogen, C 1-6 alkyl, or C 1-6 haloalkyl.
19. The compound of claim 1 , wherein each R Z is independently C 1-3 alkyl or C 1-3 haloalkyl.
20. The compound of claim 1 , wherein each R Z is independently methyl or trifluoroalkyl.
21. The compound of claim 1 , wherein the compound is selected from
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof.
22. The compound of claim 1 having formula:
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof.