KRAS modulators and uses thereof

1. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof wherein:

M is selected from O, and NR 3 ;

R 1 is selected from 7- to 10-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, —B(OR 20 ) 2 , —OR 20 , —SR 20 , —S(O) 2 (R 20 ), —S(O) 2 N(R 20 ) 2 , —S(O)N(R 20 ) 2 , —S(O)R 20 (═NR 20 ), —NR 20 S(O) 2 R 20 , —C(O)N(R 20 ) 2 , —C(═NR 20 )N(R 20 ) 2 , —C(O)NR 20 OR 20 , —N(R 20 )C(O)R 20 , —N(R 20 )C(O)N(R 20 ) 2 , —N(R 20 )C(O)OR 20 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —OC(O)R 20 , —OC(O)N(R 20 ) 2 , —NO 2 , ═O, ═N(R 20 ), ═NO(R 20 ), —CN, —NHCN, C 1-6 alkyl-N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 1-6 alkyl-SO 2 R 20 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -C 12 carbocycle and 5- to 12-membered heterocycle, wherein the C 3 -C 12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R 1 *;

each R 1 * is independently selected from halogen, —B(OR 20 ) 2 , —OR 20 , —SR 20 , —S(O) 2 (R 20 ), —S(O) 2 N(R 20 ) 2 , —S(O)N(R 20 ) 2 , —S(O)R 20 (═NR 20 ), —NR 20 S(O) 2 R 20 , —C(O)N(R 20 ) 2 , —C(O)NR 20 OR 20 , —N(R 20 )C(O)R 20 , —N(R 20 )C(O)N(R 20 ) 2 , —N(R 20 )C(O)OR 20 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —OC(O)R 20 , —OC(O)N(R 20 ) 2 , —NO 2 , =0, ═N(R 20 ), ═NO(R 20 ), —CN, —NHCN, C 1-6 alkyl-N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3 -C 12 carbocycle;

Y is O;

R 2 is selected from -L-N(R 21 ) 2 and -L-heterocycle, wherein the heterocycle portion of -L-heterocycle, is optionally substituted with one or more R 6 ,

each L is independently selected from a C 1 -C 4 alkylene optionally substituted with one or more substituents selected from hydroxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkyl, C 3 -C 6 carbocycle, and 3- to 8-membered heterocycle, wherein the C 3 -C 6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, —OH, —NO 2 , ═O, ═S, —CN, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle or 3- to 8-membered heterocycle, wherein the C 3 -C 6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, —OH, —NO 2 , ═O, ═S, —CN, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl;

R 3 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 1-6 alkoxyalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, wherein C 3-12 carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , —N(C 1-6 alkyl) 2 , C 1-10 alkyl, —C 1-10 haloalkyl, —O—C 1-10 alkyl, oxo, C 3-12 carbocycle, and 3- to 12-membered heterocycle;

n is selected from 0 to 2;

each R 4 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, hydroxyl, halogen, C 3-12 carbocycle, and 3- to 12-membered heterocycle, wherein the C 1 -C 6 alkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, OR 5 , and N(R 5 ) 2 ;

each R 5 is independently selected from hydrogen and C 1 -C 6 alkyl;

each R 6 is independently selected from halogen, hydroxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, oxo, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, cyano, ═CH 2 , ═NO—C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, —N(R 5 )S(O) 2 (R 5 ), -Q-phenyl, -Q-phenylSO 2 F, —NHC(O)phenyl, —NHC(O)phenylSO 2 F, C 1 -C 3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH 2 -, —N(R 5 ) 2 , (C 1 -C 3 alkoxy)C 1 -C 3 alkyl-, (C 1 -C 3 alkyl)C(═O), oxo, (C 1 -C 3 haloalkyl)C(═O)—, —SO 2 F, (C 1 -C 3 alkoxy)C 1 -C 3 alkoxy, —CH 2 OC(O)N(R 5 ) 2 , —CH 2 NHC(O)OC 1 -C 6 alkyl, —CH 2 NHC(O)N(R 5 ) 2 , —CH 2 NHC(O)C 1 -C 6 alkyl, —CH 2 (pyrazolyl), —CH 2 NHSO 2 C 1 -C 6 alkyl, —CH 2 OC(O)heterocycle, —OC(O)N(R 5 ) 2 , —OC(O)NH(C 1 —C 3 alkyl)O(C 1 -C 3 alkyl), —OC(O)NH(C 1 -C 3 alkyl)O(C 1 -C 3 alkyl)phenyl(C 1 -C 3 alkyl)N(CH 3 ) 2 , —OC(O)NH(C 1 -C 3 alkyl)O(C 1 -C 3 alkyl)phenyl, —OC(O)heterocycle, —O—C 1 -C 3 alkyl, and —CH 2 heterocycle, wherein the phenyl of —NHC(O)phenyl and —OC(O)NH(C 1 -C 3 alkyl)(C 1 -C 3 alkyl)phenyl are each optionally substituted with one or more substituents selected from —C(O)H and OH, and wherein the alkyl of —O—C 1 -C 3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH 2 heterocyclyl is optionally substituted with oxo;

each Q is independently selected from a bond, S, and O;

each R 20 is independently selected from hydrogen; and C 1-6 alkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , —N(C 1-6 alkyl) 2 , C 1-10 alkyl, —C 1-10 haloalkyl, —O—C 1-10 alkyl, oxo, ═NH, C 3-12 carbocycle, and 3- to 12-membered heterocycle;

each R 21 is independently selected from hydrogen; and C 1-6 alkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , —N(C 1-6 alkyl) 2 , C 1-10 alkyl, —C 1-10 haloalkyl, —O—C 1-10 alkyl, oxo, C 3-12 carbocycle, and 3- to 12-membered heterocycle; and

B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle is are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, ═O, —NO 2 , C 1 -C 4 alkyl, C 1-6 aminoalkyl, —S—C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 2 -C 4 hydroxyalkynyl, C 1 -C 3 cyanoalkyl, triazolyl, C 1 -C 3 haloalkyl, —O—C 1 -C 3 haloalkyl, —S—C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 hydroxyalkyl, —CH 2 C(═O)N(R 5 ) 2 , —C 3 -C 4 alkynyl(NR 5 ) 2 , —N(R 5 ) 2 , (C 1 -C 3 alkoxy)haloC 1 -C 3 alkyl-, C 1-6 alkyl-N(R 20 ) 2 , C 3 -C 12 carbocycle and 5- to 12-membered heterocycle, wherein C 3 -C 12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, —OH, —NO 2 , —NH 2 , ═O, ═S, —CN, C 1-6 alkyl-N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl.

2. The compound or salt of claim 1 , wherein R 1 is selected from an optionally substituted 10-membered heterocycle.

3. The compound or salt of claim 2 , wherein R 1 is

which is optionally substituted with one or more substituents independently selected from halogen, —OH, —S(O) 2 (R 20 ), —S(O) 2 N(R 20 ) 2 , —S(O)N(R 20 ) 2 , —S(O)R 20 (═NR 20 ), —C(O)N(R 20 ) 2 , —C(═NR 20 )N(R 20 ) 2 , —C(O)OR 20 , —C(O)NR 20 OR 20 , —N(R 20 ) 2 , —C(O)R 20 , —NO 2 , ═O, —CN, C 1-6 alkyl-N(R 20 ) 2 , C 1 0.6 aminoalkyl, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkynyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, —OR 20 , and C 1-6 alkyl.

4. The compound or salt of claim 3 , wherein R 1 is selected from

5. The compound or salt of claim 4 , wherein R 1 is selected from

6. The compound or salt of claim 5 , wherein R 1 is selected from

7. The compound or salt of claim 6 , wherein R 1 is

8. The compound or salt of claim 1 , wherein R 1 is

9. The compound or salt of claim 1 , wherein R 1 is selected from an optionally substituted 7- to 8-membered bridged heterocycle.

10. The compound or salt of claim 9 , wherein R 1 is selected from

11. The compound or salt of claim 1 , wherein R 1 is selected from

each of which is optionally substituted.

12. The compound or salt of claim 11 , wherein R 1 is selected from

13. The compound or salt of claim 1 , wherein M is O.

14. The compound or salt of claim 1 , wherein M is NMe.

15. The compound or salt of claim 1 , wherein B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C 8 -C 15 fused carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —NH 2 , C 1 -C 3 alkyl, hydroxy, ═O, cyano, C 1 -C 3 alkoxy, C 1 -C 3 hydroxyalkyl, and C 2 -C 4 alkynyl.

16. The compound or salt of claim 15 , wherein B is selected from

17. The compound or salt of claim 16 , wherein B is selected from

18. The compound or salt of claim 1 , wherein R 2 is -L-heterocycle, optionally substituted with one or more R 6 , wherein each R 6 is independently selected from halogen, hydroxy, C 1 -C 3 alkyl, —N(R 5 )S(O) 2 (R 5 ), —OC(O)N(R 5 ) 2 , ═CH 2 , oxo, ═NO—C 1 -C 3 alkyl, —CH 2 OC(O)heterocycle, —CH 2 heterocycle, —CH 2 OC(O)N(R 5 ) 2 , and —O—C 1 -C 3 alkyl, wherein the alkyl of —O—C 1 -C 3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy.

19. The compound or salt of claim 18 , wherein each L is independently selected from unsubstituted C 1 -C 4 alkylene,

20. The compound or salt of claim 19 , wherein Y—R 2 is selected from

21. The compound or salt of claim 1 , wherein Y—R 2 is

22. The compound or salt of claim 1 , wherein Y—R 2 is

23. The compound or salt of claim 1 , wherein the compound is selected from:

or a salt of any one thereof.

24. The compound or salt of claim 1 , wherein the compound is selected from:

or a salt of any one thereof.

25. The compound or salt of claim 1 , wherein the compound is selected from:

26. A pharmaceutical composition comprising a compound or salt of claim 1 and a pharmaceutically acceptable excipient.

27. A method of treating a disease or disorder, comprising administering to a patient in need thereof the pharmaceutical composition of claim 26 , wherein the disease or disorder is a cancer selected from:

Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma;

Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;

Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomvosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomvoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);

Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma;

Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;

Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);

Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma);

Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and

Adrenal glands: neuroblastoma.

28. The method of claim 27 , wherein the disease or disorder is a cancer, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer; or wherein the cancer is a tumor cancer.

29. The compound or salt of claim 1 , wherein compound is

or a salt thereof.

30. The compound or salt of claim 1 , wherein compound is

or a salt thereof.

31. The compound or salt of claim 1 , wherein compound is

or a salt thereof.

32. The compound or salt of claim 1 , wherein compound is

or a salt thereof.

33. The compound or salt of claim 1 , wherein compound is

or a salt thereof.

34. The compound or salt of claim 1 , wherein compound is

or a salt thereof.

35. The compound or salt of claim 1 , wherein compound is

or a salt thereof.

36. The compound or salt of claim 1 , wherein compound is

or a salt thereof.

37. The compound or salt of claim 1 , wherein compound is

or a salt thereof.

38. The compound or salt of claim 1 , wherein compound is

or a salt thereof.

39. The compound or salt of claim 1 , wherein compound is

or a salt thereof.