2,3-Disubstituted pyridine compounds as TGF-β inhibitors and methods of use

1. A method of inhibiting GDF8 in a cell, the method comprising contacting the cell with a compound of formula (IV):

or a pharmaceutically acceptable salt thereof, wherein

Cy 1 is phenyl substituted with 2, 3, or 4 moieties independently selected from halo, C 1-3 alkyl optionally substituted with 1, 2, or 3 halo, ethynyl, or (trimethylsilyl)ethynyl, and —O—C 1-3 alkyl optionally substituted with 1-3 halo; benzofuranyl; 2,3-dihydrobenzofuranyl; or phenylethenyl; or Cy 1 is phenyl substituted with a single substituent selected from halo, C 1-3 alkyl optionally substituted with 1, 2, or 3 halo, ethynyl, or (trimethylsilyl)ethynyl, —O—C 1-3 alkyl optionally substituted with 1-3 halo, —O—(C 0-3 alkyl)R IIIe , and —C(O)N(R x ) 2 ,

wherein R IIIe is phenyl, heteroaryl or heterocycloalkyl and each R x is independently H or C 1-3 alkyl;

Cy 2 is pyrazolo[1,5-a]pyrimidinyl; benzo[d]thiazolyl; imidazo[1,2-a]pyridinyl optionally substituted with phenyl-S(O) 2 -; [1,2,4]triazolo[1,5-a]pyridinyl; pyridinyl; quinazolinyl; 1H-pyrrolo[2,3-b]pyridinyl; pyrido[3,2-d]pyrimidinyl optionally substituted with amino, methylamino, or methoxy; or pyrido[3,2-d]pyrimidin-4(3H)-one,

wherein the quinazolinyl is optionally substituted with 1 or 2 substituents independently selected from N(R IIIa ) 2 ; R IIId ; C 1-3 alkyl optionally substituted with 1-3 halo; halo; methoxy; and N(H)(C 1-3 alkyl)R IV

each R IIIa is independently H; C 1-6 alkyl optionally substituted with —C(O)OH, —C(O)O(C 1-3 alkyl), or —CONH 2 ; or heteroaryl optionally substituted with C 1-3 alkyl;

R IIId is H or C 1-3 alkyl optionally substituted with 1-3 halo;

R IV is H, C 1-3 alkyl, -pyrrolidonyl, 4-methylpiperzinyl,

—N(C 1-2 alkyl)(C 1-2 alkyl), or morpholinyl;

and

R IIIc is H, halo, —OH, C 1-3 alkyl optionally substituted with 1-3 halo, or —O—C 1-3 alkyl optionally substituted with 1-3 halo

provided the compound is not one of compounds 1-974:

2. The method according to claim 1 , wherein the compound is of formula (IIIa):

or a pharmaceutically acceptable salt thereof, wherein

each R IIIa is independently H; C 1-6 alkyl optionally substituted with —C(O)OH, —C(O)O(C 1-3 alkyl), or —CONH 2 ; or heteroaryl optionally substituted with C 1-3 alkyl;

x is 0, 1, 2, or 3;

each R IIb is independently selected from halo, —OH, C 1-3 alkyl optionally substituted with 1-3 halo, —O—C 1-3 alkyl optionally substituted with 1-3 halo, or, when x is 1, R IIIb is also selected from —O—(C 0-3 alkyl)R IIIe and —C(O)N(R x ) 2

wherein R IIIe is phenyl, heteroaryl, or heterocycloalkyl, and each

R x is independently H or C 1-3 alkyl;

R IIIc is H, halo, —OH, C 1-3 alkyl optionally substituted with 1-3 halo, or —O—C 1-3 alkyl optionally substituted with 1-3 halo; and

R IIId is H or C 1-3 alkyl optionally substituted with 1-3 halo,

provided the compound is not one of compounds 1-974:

3. The method according to claim 2 , wherein

a) both R IIIa are H,

b) R IIId and R IIIc are each H,

c) x is 1, 2, or 3 and each R IIIb is independently selected from halo, methyl, methoxy, and hydroxy,

d) both R IIIa are H and R IIId and R IIIc are each H,

e) both R IIIa are H, R IIId and R IIIc are each H, and x is 1, 2, or 3 and each R IIIb is independently selected from halo, methyl, methoxy, -difluoromethyl, and hydroxy; or

f) x is 1, 2, or 3 and at least one R IIb is difluoromethyl.

4. The method according to claim 2 wherein the compound is selected from

#

Structure

 975

 976

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1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

and

1036

or a pharmaceutically acceptable salt thereof.

5. A method of inhibiting GDF8 in a cell, the method comprising contacting the cell with a compound of the formula,

or a pharmaceutically acceptable salt thereof, wherein

X is CH and each R Z is independently —OH, —C 1-3 alkyl optionally substituted with one or more halo, or C 1-3 alkyloxy optionally substituted with one or more halo, or

X is N and each R Z is independently halo, —OH, —C 1-3 alkyl optionally substituted with one or more halo, or C 1-3 alkyloxy optionally substituted with one or more halo, and

a is 1, 2, or 3,

provided the compound is not one of the following compounds:

6. The method according to claim 5 , wherein the compound is administered to a subject in need thereof in an amount effective to treat muscle wasting.

7. The method according to claim 6 , wherein the compound is administered to the subject in an amount effective to treat muscle wasting associated with cancer and other disorders.

8. The method according to claim 6 , wherein the muscle wasting is associated with small cell lung cancer, non-small cell lung cancer, triple-negative breast cancer, ovarian cancer, colorectal cancer, prostate cancer, melanoma, pancreatic cancer, multiple myeloma, T-acute lymphoblastic leukemia or AML.

9. The method according to claim 7 , further comprising administering a therapeutically effective amount of the compound to the subject in conjunction with another therapeutic cancer treatment of the subject.

10. The method according to claim 9 wherein the other therapeutic treatment comprises administration of a therapeutically effective amount of one or more chemotherapeutic agents, wherein the one or more chemotherapeutic agents is 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.

11. The method of claim 10 wherein the BCL-2 inhibitor is ABT-199.

12. The method according to claim 9 wherein the other therapeutic treatment comprises administration of a therapeutically effective amount of one or more chemotherapeutic agents, the one or more chemotherapeutic agents being independently selected from the group consisting of 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.

13. The method of claim 12 wherein the CTLA-4 antibody is ipilimumab.

14. The method of claim 9 , wherein the other cancer treatment comprises administration of a therapeutically effective amount of a checkpoint pathway inhibitor.

15. The method of claim 14 wherein the checkpoint pathway inhibitor is a PD-1 inhibitor, a PD-L1 inhibitor, an anti-LAG-3 agent, an anti-SLAMF7 agent, an anti-KIR agent, or an anti-CD137 agent.

16. The method of claim 15 wherein the checkpoint pathway inhibitor is nivolumab, lambrolizumab, pembrolizumab, MEDI-4736, MPDL3280A/RG7446, BMS-986016 (MDX-1408), elotuzumab (BMS-901608), lirilumab (BMS-986015), or urelumab (BMS-663513).

17. The method according to claim 9 wherein the cancer and other cancer treatment are selected from one of the following combinations:

Cancer

Drug or Treatment

Glioma

lomustine, temozolide and/or radiation

hepatocellular carcinoma

sorafenib, and/or regorafenib

myelodysplastic syndromes

decitabine and/or or azacytidine

pancreatic cancer

Gemcitabine

ovarian cancer,

carboplatin, cisplatin, doxorubicin,

gemcitabine and/or, paclitaxel

breast cancer

Trastuzumab

basal and squamous skin

5-fluorouracil, imiquimod, 5-

carcinomas

aminolevulinic acid and/or

photodynamic therapy

head and neck carcinoma

bleomycin, cisplatin, cetuximab,

docetaxel, fluorouracil, and/or

methotrexate

triple negative breast cancer

Paclitaxel

and

Prostate

abiraterone, and/or enzalutamide.