KRas G12D inhibitors

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof:

wherein:

each R 1 is independently hydrogen, hydroxy, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, (C1-C3 alkoxy)-C1-C3 alkyl-, C1-C3 alkyl-N(R 5 ) 2 , cyano, C1-C3 cyanoalkyl, C2-C4 cyanoalkenyl, C1-C3 hydroxyalkyl, HC(═O)—, —CO 2 R 5 , or —CO 2 N(R 5 ) 2 ;

X is N or CR 5 ;

Y is a bond, O or NR 5 ;

R 2 is hydrogen, —N(R 5 ) 2 , heterocyclyl, C1-C6 alkyl, -L-heterocyclyl, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(═NH)NH 2 , -L-C(O)N(R 5 ) 2 , -L-C1-C6 haloalkyl, -L-OR 5 , -L-(CH 2 OR 5 )(CH 2 ) n OR 5 , -L-NR 5 C(O)-aryl, or -L-COOH, wherein the heterocyclyl, the aryl portion of -L-NR 5 C(O)-aryl, the heterocyclyl portion of -L-heterocyclyl and the cycloalkyl portion of -L-cycloalkyl is optionally substituted with one or more R 6 , and wherein the aryl portion of -L-aryl and heteroaryl portion of -L-heteroaryl is optionally substituted with one or more R 7 ,

wherein the heterocyclyl is hexahydro-1H-pyrrolizinyl, hexahydro-3H-pyrrolizin-3-one, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, hexahydropyrrolizine 4(1H)-oxide, azetidinyl, pyrrolidin-2-one, oxetanyl, piperidinyl, 1-azabicyclo[2.2.1]heptanyl, morpholinyl, oxa-5-azabicyclo[2.2.1]heptan-5-yl, thiopyranyl, 6-oxa-2-azaspiro[3.4]octanyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2′,3′-dihydrospiro[cyclopropane-1,1′-indenyl], (2S)-1-azabicyclo[2.2.1]heptan-2-yl, or tetrahydrofuranyl;

R 3 is-L-aryl, aryl, -L-heteroaryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted with one or more R 8 ;

each L is independently a C1-C4 alkylene optionally substituted with hydroxy, C1-C4 hydroxyalkyl or heteroaryl;

each R 5 is independently hydrogen, C1-C3 alkyl or C1-C3hydroxyalkyl, or two R 5 together with the atom to which they are both attached optionally join to form a heterocyclyl ring, wherein the heterocyclic ring formed by two R 5 is optionally substituted with one or more substituents independently selected from C1-C3 alkyl, hydroxy and C1-C3 alkoxy;

each R 6 is independently halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -Q-phenyl, -Q-phenylSO 2 F, —NHC(O)phenyl, —NHC(O)phenylSO 2 F, C1-C3 alkyl substituted pyrazolyl, araC1-C3 alkyl-, tert-butyldimethylsilyloxyCH 2 —, —N(R 5 ) 2 , (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(═O)—, oxo, (C1-C3 haloalkyl)C(═O)—, —SO 2 F, (C1-C3 alkoxy)C1-C3 alkoxy, (C1-C3)alkyl-O(C═O)—N(R 5 ) 2 or (C1-C3)alkyl-O(C═O)—N(OR 5 )R 5 ;

Q is a bond or O;

each R 7 is independently halogen, hydroxy, HC(═O)—, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or —N(R 5 ) 2 ;

each R 8 is independently halogen, cyano, hydroxy, C1-C4 alkyl, —S—C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, —O—C1-C3 haloalkyl, cyclopropyl, N(R 5 ) 2 , C1-C4hydroxyalkyl, —S—C1-C3 haloalkyl or —O—C1-C3alkyl; and

R 9 is hydrogen or oxo.

2 . The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein each R 1 is independently hydrogen, hydroxy, halogen, C1-C3 alkoxy, C1-C3alkyl-N(R 5 ) 2 , C1-C3 cyanoalkyl, dihalo-C1-C3alkyl, C1-C3alkyl, cyano, C2-C4alkenyl-cyano, C1-C3 hydroxyalkyl, hydroxy or (C1-C3 alkoxy)-C1-C3alkyl.

3 . The compound or pharmaceutically acceptable salt thereof of claim 2 , wherein X is N.

4 . The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein X is CR 5 , R 5 is hydrogen or C1-C3 alkyl, and each R 1 is independently hydrogen or hydroxy.

5 . The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Y is O.

6 . The compound or pharmaceutically acceptable salt thereof of claim 5 , wherein R 2 is C1-C6 alkyl, heterocyclyl or -L-heterocyclyl.

7 . The compound or pharmaceutically acceptable salt thereof of claim 6 , wherein L, if present, is methylene optionally substituted with methyl, and R 2 is heterocyclyl optionally substituted with one or more R 6 .

8 . The compound or pharmaceutically acceptable salt thereof of claim 7 , wherein the heterocyclyl is hexahydro-1H-pyrrolizinyl optionally substituted with one or more R 6 .

9 . The compound or pharmaceutically acceptable salt thereof of claim 8 , wherein said one or more R 6 groups are each independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, (C1-C3)alkyl-O(C═O)—N(R 5 ) 2 or (C1-C3)alkyl-O(C═O)—N(OR 5 )R 5 .

10 . The compound or pharmaceutically acceptable salt thereof of claim 9 , wherein two R 5 join to form a heterocycle.

11 . The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is -L-aryl or aryl, wherein aryl is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl or 2,3-dihydro-1H-indenyl, each optionally substituted with one or more R 8 .

12 . The compound or pharmaceutically acceptable salt thereof of claim 11 , wherein each R 8 is independently halogen, hydroxy, C1-C4 alkyl, C1-C3 haloalkyl, —O—C1-C3 haloalkyl or cyclopropyl.

13 . The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is-L-heteroaryl or heteroaryl, wherein heteroaryl is isoquinoline or quinazoline, each optionally substituted with one or more R 8 .

14 . The compound or pharmaceutically acceptable salt thereof of claim 13 , wherein each R 8 is independently halogen, hydroxy, C1-C4 alkyl, C1-C3 haloalkyl, —O—C1-C3 haloalkyl or cyclopropyl.

15 . The compound of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

16 . A pharmaceutical composition, comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

17 . A method for inhibiting KRas G12D activity in a cell, comprising contacting the cell in which inhibition of KRas G12D activity is desired with an effective amount of a compound of according to claim 1 or a pharmaceutically acceptable salt thereof.

18 . A method for treating a KRas G12D-associated cancer comprising administering to a patient having a KRas G12D-associated cancer a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

19 . The method of claim 18 , wherein the KRas G12D-associated cancer is selected from the group consisting of Cardiac: sarcoma myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma, alveolar carcinoma, bronchiolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus squamous cell carcinoma, esophagus adenocarcinoma, esophagus leiomyosarcoma, esophagus lymphoma, stomach carcinoma, stomach lymphoma, stomach leiomyosarcoma, pancreas ductal adenocarcinoma, pancreas insulinoma, pancreas glucagonoma, pancreas gastrinoma, pancreas carcinoid tumors, pancreas vipoma, small bowel adenocarcinoma, small bowel lymphoma, small bowel carcinoid tumors, small bowel Kaposi's sarcoma, small bowel leiomyoma, small bowel hemangioma, small bowel lipoma, small bowel neurofibroma, small bowel fibroma, large bowel adenocarcinoma, large bowel tubular adenoma, large bowel villous adenoma, large bowel hamartoma, large bowel leiomyoma; Genitourinary tract: kidney adenocarcinoma, Wilm's tumor, nephroblastoma, kidney lymphoma, kidney leukemia, bladder and urethra squamous cell carcinoma, bladder and urethra transitional cell carcinoma, bladder and urethra adenocarcinoma, prostate adenocarcinoma, prostate sarcoma, testicular seminoma, testicular teratoma, testicular embryonal carcinoma, testicular teratocarcinoma, testicular choriocarcinoma, testicular sarcoma, testicular interstitial cell carcinoma, testicular fibroma, testicular fibroadenoma, testicular adenomatoid tumors, testicular lipoma; Liver: hepatoma, liver cholangiocarcinoma, hepatoblastoma, liver angiosarcoma, hepatocellular adenoma, liver hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, biliary tract cholangiocarcinoma; Bone: osteogenic sarcoma, bone fibrosarcoma, bone malignant fibrous histiocytoma, bone chondrosarcoma, Ewing's sarcoma, bone malignant lymphoma, bone reticulum cell sarcoma, bone multiple myeloma, malignant giant cell tumor chordoma, osteochondroma, osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull osteoma, skull hemangioma, skull granuloma, skull xanthoma, skull osteitis deformans, meningioma, meningiosarcoma, gliomatosis, brain astrocytoma, brain medulloblastoma, brain glioma, brain ependymoma, brain germinoma brain pinealoma, brain glioblastoma multiform, brain oligodendroglioma, brain schwannoma, brain retinoblastoma, brain congenital tumors, spinal cord neurofibroma, spinal cord meningioma, spinal cord glioma, spinal cord sarcoma; Gynecological: uterus endometrial carcinoma, uterus serous cystadenocarcinoma, uterus mucinous cystadenocarcinoma, uterus unclassified carcinoma, granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma, vulva squamous cell carcinoma, vulva intraepithelial carcinoma, vulva adenocarcinoma, vulva fibrosarcoma, vulva melanoma, vagina clear cell carcinoma, vagina squamous cell carcinoma, vagina botryoid sarcoma, vagina embryonal rhabdomyosarcoma, fallopian tube carcinoma; Hematologic: acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, malignant lymphoma; Skin: skin malignant melanoma, basal cell carcinoma, skin squamous cell carcinoma, skin Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

20 . A compound selected from:

or a pharmaceutically acceptable salt thereof.

21 . The method of claim 18 , wherein the cancer is selected from the group consisting of cardiac, lung, esophagus, stomach, pancreas, small bowel, large bowel, kidney, bladder, urethra, prostate, testis, liver, biliary tract, bone, skull, meninges, brain, spinal cord, uterus, vulva, vagina, fallopian tubes, blood, skin, and adrenal gland cancer.

22 . The method of claim 18 , wherein the cancer is selected from the group consisting of cardiac angiosarcoma, cardiac fibrosarcoma, cardiac rhabdomyosarcoma, cardiac liposarcoma, squamous cell bronchogenic carcinoma, undifferentiated small cell bronchogenic carcinoma, undifferentiated large cell bronchogenic carcinoma, and bronchogenic adenocarcinoma.