WANG WEIPING (US)
WO2018175474A1 | 2018-09-27 | |||
WO2020061252A1 | 2020-03-26 |
US20180215765A1 | 2018-08-02 |
DATABASE PubChem COMPOUND 24 December 2015 (2015-12-24), "2-Tosyl-6-ethyl-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine", XP055807465, retrieved from NCBI Database accession no. CID102038714
CLAIMS 1. A method of treating cancer in a patient in need thereof, comprising administering to the patient a USP9X Inhibitor, wherein the patient is receiving or has received an immune checkpoint pathway inhibitor, wherein the USP9X Inhibitor is selected from the group consisting of: ; ; ; ; ; ; ; or a pharmaceutically acceptable salt thereof. 2. A method of treating cancer in a patient in need thereof, comprising administering to the patient an immune checkpoint pathway inhibitor, wherein the patient is receiving or has received a USP9X Inhibitor, wherein the USP9X Inhibitor is selected from the group consisting of: ; ; ; ; and or a pharmaceutically acceptable salt thereof. 3. The method of claim 1, comprising administering the USP9X Inhibitor to the patient, wherein the cancer has progressed while receiving the immune checkpoint pathway inhibitor. 4. The method of claim 1, wherein the patient has relapsed after previously being administered the immune checkpoint pathway inhibitor for the cancer. 5. The method of claim 1, wherein the method comprises administering the USP9X Inhibitor to the patient while the patient continues to receive the immune checkpoint pathway inhibitor after being diagnosed with a cancer that is refractory to the immune checkpoint pathway inhibitor. 6. The method of claim 1 or 2, wherein the cancer comprises a tumor that expresses PD-L1. 7. The method of claim 1 or 2, wherein the cancer comprises a tumor that expresses PD-1. 8. The method of claim 1 or 2, wherein the cancer comprises a tumor that expresses CTLA-4. 9. The method of claim 1 or 2, wherein the cancer is selected from unresectable or metastatic melanoma, cutaneous melanoma, advanced renal cell carcinoma, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, metastatic squamous non-small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, cervical cancer, hepatocellular carcinoma, or Merkel cell carcinoma. 10. The method of claim 1 or 2, wherein the patient has received one or more prior lines of chemotherapy. 11. The method of claim 1 or 2, wherein the immune checkpoint pathway inhibitor is selected from the group consisting of ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, and avelumab. 12. The method of claim 1 or 2, wherein the patient has not responded to prior therapy with an immune checkpoint pathway inhibitor. 13. The method of claim 1 or 2, comprising administering two or more immune checkpoint pathway inhibitors. 14. The method of claim 1 or 2, wherein the USP9X Inhibitor is selected from the group consisting of: ; nd 15. The method of claim 1 or 2, wherein the USP9X Inhibitor is selected from the group consisting of: ; ; ; ; ; ; . 16. A method of treating cancer in a patient in need thereof, comprising administering to the patient a USP9X Inhibitor of Formula I: or a pharmaceutically acceptable salt thereof, wherein: X is CR5R6, CR5, NR5, or N, as valency permits; dashed bonds are each independently a single or a double bond, as valency permits; Y1, Y2, and Y3 are each independently N or CRa; each Ra is independently -H, halogen, or -CN; Ring A is a 5- to 6-membered aryl, 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, 5- to 7-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, or 5- to 7-membered cycloalkyl, wherein each aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally substituted with one or more halogen, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, oxo, or -C(O)R’; Z1 is O, S, or NR; Z2 is O or NR; W is CR1’R2’, O, S, or NR; m is 0 or 1; R1 and R2 are each independently -H, halogen, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -(CRbRc)nC3-C12cycloalkyl, -(CRbRc)nC4-C12cycloalkenyl, -(CRbRc)nheterocyclyl, -(CRbRc)nC6-C14aryl, -(CRbRc)nheteroaryl, -OR, -OC(O)R’, -OS(O)2R’, -OS(O)2NR2, -OC(O)NR2, -OC(O)OR, -(CRbRc)nNR2, -(CRbRc)nNRC(O)R’, -(CRbRc)nNRS(O)2R’, -(CRbRc)nNRC(O)NR2, -(CRbRc)nNRC(O)OR, -(CRbRc)nCN, -(CRbRc)nNO2, -(CRbRc)nSR, -(CRbRc)nC(O)R’, -(CRbRc)nC(O)OR, -(CRbRc)nC(O)NR2, -(CRbRc)nSO2R’, -(CRbRc)nSO2NR2, or -(CRbRc)nSO2OR, wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Re, wherein each alkyl, alkenyl, or alkynyl is optionally substituted with one or more halogen, wherein each heterocyclyl is 3- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z1), and wherein each heteroaryl is 5- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S; or R1 and R2 combine with the carbon to which they are attached to form oxo, a C3-C8cycloalkyl, or a 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z1), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more Re; R1’ and R2’ are each independently -H, halogen, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -(CRbRc)nC3-C12cycloalkyl, -(CRbRc)nC4-C12cycloalkenyl, -(CRbRc)nheterocyclyl, -(CRbRc)nC6-C14aryl, -(CRbRc)nheteroaryl, -(CRbRc)nNR2, -(CRbRc)nNRC(O)R’, -(CRbRc)nNRS(O)2R’, -(CRbRc)nNRC(O)NR2, -(CRbRc)nNRC(O)OR, -(CRbRc)nCN, -(CRbRc)nNO2, -(CRbRc)nSR, -(CRbRc)nC(O)R’, -(CRbRc)nC(O)OR, -(CRbRc)nC(O)NR2, -(CRbRc)nSO2R’, -(CRbRc)nSO2NR2, or -(CRbRc)nSO2OR, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Re, wherein each heterocyclyl is 3- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein each heteroaryl is 5- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S; or R1’ and R2’ combine with the carbon to which they are attached to form oxo, a C3-C8cycloalkyl, or a 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S, wherein each heterocyclyl does not contain an O in the g-position relative to C(=Z1), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more Re; or R1 and R1’ combine with the carbons to which they are attached to form a C3-C8cycloalkyl or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S, wherein each heterocyclyl does not contain an O in the g-position relative to C(=Z1), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more Re; Rb and Rc are each independently selected from the group consisting of -H, halogen, and -C1-C6alkyl; each n is independently 0, 1, 2, 3, or 4; each Re is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -C3-C12cycloalkyl, -C4-C12cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C6-C14aryl, and 5- to 14- membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein -OR of Re does not result in an O in the g-position relative to C(=Z1), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -C1-C6alkyl optionally substituted with one or more halogen, -C2-C6alkenyl, -C2-C6alkynyl, -OR, -C3-C12cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; B is a monocyclic or bicyclic 3- to 14-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein the ring is optionally substituted with one or more Rd, and when m is 0 and the ring is saturated or partially unsaturated, then the ring does not contain an O in the g-position relative to C(=Z1); each Rd is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -C3-C12cycloalkyl, -C4-C12cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C6-C14aryl, and 5- to 14- membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -C1-C6alkyl optionally substituted with one or more halogen, -C2-C6alkenyl, -C2-C6alkynyl, -OR, -C3-C12cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; each R3, R4, R5, R6, R7, R8, R9, and R10 is independently -H, -C1-C6alkyl, -C3-C8cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more halogen, oxo, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2,-C3-C8cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein R3, R7, and R9 are each independently present or absent, as valency permits; or R3 and R4, R5 and R6, R7 and R8, R9 and R10, or combinations thereof, combine with the carbon to which they are attached to form an oxo, C3-C8cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; each R is independently selected from the group consisting of -H, -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -C3-C12cycloalkyl, -C4-C12cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C6-C14aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, oxo, -O-C1-C6alkyl, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -C1-C6alkyl optionally substituted with one or more oxo or -OH, -C2-C6alkenyl, -C2-C6alkynyl, -C3-C12cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; and each R’ is independently selected from the group consisting of -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -C3-C12cycloalkyl, -C4-C12cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, oxo, -C1-C6alkyl optionally substituted with one or more oxo or -OH, -C2-C6alkenyl, -C2-C6alkynyl, -O-C1-C6alkyl, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2; wherein the patient is receiving or has received an immune checkpoint pathway inhibitor selected from the group consisting of cemiplimab, atezolizumab, durvalumab, and avelumab. 17. A method of treating cancer in a patient in need thereof, comprising administering to the patient an immune checkpoint pathway inhibitor, wherein the patient is receiving or has received an USP9X Inhibitor of Formula I: or a pharmaceutically acceptable salt thereof, wherein: X is CR5R6, CR5, NR5, or N, as valency permits; dashed bonds are each independently a single or a double bond, as valency permits; Y1, Y2, and Y3 are each independently N or CRa; each Ra is independently -H, halogen, or -CN; Ring A is a 5- to 6-membered aryl, 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, 5- to 7-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, or 5- to 7-membered cycloalkyl, wherein each aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally substituted with one or more halogen, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, oxo, or -C(O)R’; Z1 is O, S, or NR; Z2 is O or NR; W is CR1’R2’, O, S, or NR; m is 0 or 1; R1 and R2 are each independently -H, halogen, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -(CRbRc)nC3-C12cycloalkyl, -(CRbRc)nC4-C12cycloalkenyl, -(CRbRc)nheterocyclyl, -(CRbRc)nC6-C14aryl, -(CRbRc)nheteroaryl, -OR, -OC(O)R’, -OS(O)2R’, -OS(O)2NR2, -OC(O)NR2, -OC(O)OR, -(CRbRc)nNR2, -(CRbRc)nNRC(O)R’, -(CRbRc)nNRS(O)2R’, -(CRbRc)nNRC(O)NR2, -(CRbRc)nNRC(O)OR, -(CRbRc)nCN, -(CRbRc)nNO2, -(CRbRc)nSR, -(CRbRc)nC(O)R’, -(CRbRc)nC(O)OR, -(CRbRc)nC(O)NR2, -(CRbRc)nSO2R’, -(CRbRc)nSO2NR2, or -(CRbRc)nSO2OR, wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Re, wherein each alkyl, alkenyl, or alkynyl is optionally substituted with one or more halogen, wherein each heterocyclyl is 3- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z1), and wherein each heteroaryl is 5- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S; or R1 and R2 combine with the carbon to which they are attached to form oxo, a C3-C8cycloalkyl, or a 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z1), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more Re; R1’ and R2’ are each independently -H, halogen, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -(CRbRc)nC3-C12cycloalkyl, -(CRbRc)nC4-C12cycloalkenyl, -(CRbRc)nheterocyclyl, -(CRbRc)nC6-C14aryl, -(CRbRc)nheteroaryl, -(CRbRc)nNR2, -(CRbRc)nNRC(O)R’, -(CRbRc)nNRS(O)2R’, -(CRbRc)nNRC(O)NR2, -(CRbRc)nNRC(O)OR, -(CRbRc)nCN, -(CRbRc)nNO2, -(CRbRc)nSR, -(CRbRc)nC(O)R’, -(CRbRc)nC(O)OR, -(CRbRc)nC(O)NR2, -(CRbRc)nSO2R’, -(CRbRc)nSO2NR2, or -(CRbRc)nSO2OR, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Re, wherein each heterocyclyl is 3- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein each heteroaryl is 5- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S; or R1’ and R2’ combine with the carbon to which they are attached to form oxo, a C3-C8cycloalkyl, or a 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S, wherein each heterocyclyl does not contain an O in the g-position relative to C(=Z1), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more Re; or R1 and R1’ combine with the carbons to which they are attached to form a C3-C8cycloalkyl or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S, wherein each heterocyclyl does not contain an O in the g-position relative to C(=Z1), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more Re; Rb and Rc are each independently selected from the group consisting of -H, halogen, and -C1-C6alkyl; each n is independently 0, 1, 2, 3, or 4; each Re is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -C3-C12cycloalkyl, -C4-C12cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C6-C14aryl, and 5- to 14- membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein -OR of Re does not result in an O in the g-position relative to C(=Z1), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -C1-C6alkyl optionally substituted with one or more halogen, -C2-C6alkenyl, -C2-C6alkynyl, -OR, -C3-C12cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; B is a monocyclic or bicyclic 3- to 14-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein the ring is optionally substituted with one or more Rd, and when m is 0 and the ring is saturated or partially unsaturated, then the ring does not contain an O in the g-position relative to C(=Z1); each Rd is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -C3-C12cycloalkyl, -C4-C12cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C6-C14aryl, and 5- to 14- membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -C1-C6alkyl optionally substituted with one or more halogen, -C2-C6alkenyl, -C2-C6alkynyl, -OR, -C3-C12cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; each R3, R4, R5, R6, R7, R8, R9, and R10 is independently -H, -C1-C6alkyl, -C3-C8cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more halogen, oxo, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2,-C3-C8cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein R3, R7, and R9 are each independently present or absent, as valency permits; or R3 and R4, R5 and R6, R7 and R8, R9 and R10, or combinations thereof, combine with the carbon to which they are attached to form an oxo, C3-C8cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; each R is independently selected from the group consisting of -H, -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -C3-C12cycloalkyl, -C4-C12cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C6-C14aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, oxo, -O-C1-C6alkyl, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -C1-C6alkyl optionally substituted with one or more oxo or -OH, -C2-C6alkenyl, -C2-C6alkynyl, -C3-C12cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; and each R’ is independently selected from the group consisting of -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -C3-C12cycloalkyl, -C4-C12cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, oxo, -C1-C6alkyl optionally substituted with one or more oxo or -OH, -C2-C6alkenyl, -C2-C6alkynyl, -O-C1-C6alkyl, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2; and wherein the immune checkpoint pathway inhibitor selected from the group consisting of cemiplimab, atezolizumab, durvalumab, and avelumab. 18. The method of claim 16 or claim 17, with the proviso that the USP9X Inhibitor is not a compound of Figure 14. 19. A method of treating cancer in a patient in need thereof, comprising administering to the patient a USP9X Inhibitor of Formula II: or a pharmaceutically acceptable salt thereof, wherein: X1 is NR or O; Y1 is CR7 or N; Y2 is CR8 or N; Y3 is CR9 or N; wherein the heteroaryl formed when at least one of Y1, Y2, or Y3 is N may comprise an N- oxide; Ring A is a monocyclic or bicyclic 3- to 12-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of N, O, and S, and wherein Ring A is optionally substituted with one or more Ra; each Ra is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2, optionally substituted C1-C6 aliphatic, optionally substituted C3-C10cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted Ra group may be substituted with one or more substituents selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2, and C1-C6aliphatic; Ring B is a monocyclic or bicyclic 3- to 12-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of N, O, and S, and wherein Ring B is optionally substituted with one or more Rb; each Rb is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2, optionally substituted C1-C6 aliphatic, optionally substituted C3-C10cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted Rb group may be substituted with one or more substituents selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2, and C1-C6aliphatic; R1 and R2 are each independently selected from the group consisting of -H, halogen, -OR, -OC(O)R’, -OS(O)2R’, -OS(O)2NR2, -OC(O)NR2, -OC(O)OR, -NR2, -NRC(O)R’, -NRS(O)2R’, -NRC(O)NR2, -NRC(O)OR, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -SO2NR2, -S(O)2OR, optionally substituted C1-C6aliphatic, optionally substituted C3-C10cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, or R1 and R2 combine with the carbon to which they are attached to form an optionally substituted C3-C8cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S, wherein an optionally substituted R1 and R2 group may be substituted with one or more of halogen, oxo, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2, and C1-C6aliphatic; R3, R4, R5, and R6 are each independently selected from the group consisting of -H, optionally substituted C1-C6aliphatic, optionally substituted C3-C8cycloalkyl, and optionally substituted 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S, or R3 and R4, or R5 and R6, or a combination thereof, combine with the carbon to which they are attached to form an optionally substituted C3-C8cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S, wherein an optionally substituted R3, R4, R5, and R6 group may be substituted with one or more of halogen, oxo, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2, and C1-C6 aliphatic; R7, R8, and R9 are each independently selected from the group consisting of -H, halogen, -OR, -OC(O)R’, -OS(O)2R’, -OS(O)2NR2, -OC(O)NR2, -OC(O)OR, -NR2, -NRC(O)R’, -NRS(O)2R’, -NRC(O)NR2, -NRC(O)OR, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -SO2NR2, -S(O)2OR, and optionally substituted C1-C6aliphatic, wherein an optionally substituted R7, R8, and R9 group may be substituted with one or more of halogen, oxo, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2, and C1-C6aliphatic; each R is independently selected from the group consisting of -H, optionally substituted C1-C6aliphatic, optionally substituted C3-C10cycloalkyl, optionally substituted 3- to 10- membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R group may be optionally substituted with one or more of halogen, oxo, -OH, -O(C1-C6aliphatic), -NH2, -NH(C1-C6aliphatic), -N(C1-C6aliphatic)2, -CN, and C1-C6aliphatic; each R’ is independently selected from the group consisting of optionally substituted C1-C6aliphatic, optionally substituted C3-C10cycloalkyl, optionally substituted 3- to 10- membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R’ group may be substituted with one or more of halogen, oxo, -OH, -O(C1-C6aliphatic), -NH2, -NH(C1-C6aliphatic), -N(C1-C6aliphatic)2, -CN, and C1-C6aliphatic; m is 0, 1, or 2; and n is 0, 1, or 2; wherein the patient is receiving or has received an immune checkpoint pathway inhibitor selected from the group consisting of cemiplimab, atezolizumab, durvalumab, and avelumab. 20. A method of treating cancer in a patient in need thereof, comprising administering to the patient an immune checkpoint pathway inhibitor, wherein the patient is receiving or has received an USP9X Inhibitor of Formula II: or a pharmaceutically acceptable salt thereof, wherein: X1 is NR or O; Y1 is CR7 or N; Y2 is CR8 or N; Y3 is CR9 or N; wherein the heteroaryl formed when at least one of Y1, Y2, or Y3 is N may comprise an N- oxide; Ring A is a monocyclic or bicyclic 3- to 12-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of N, O, and S, and wherein Ring A is optionally substituted with one or more Ra; each Ra is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2, optionally substituted C1-C6 aliphatic, optionally substituted C3-C10cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted Ra group may be substituted with one or more substituents selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2, and C1-C6aliphatic; Ring B is a monocyclic or bicyclic 3- to 12-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of N, O, and S, and wherein Ring B is optionally substituted with one or more Rb; each Rb is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2, optionally substituted C1-C6 aliphatic, optionally substituted C3-C10cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted Rb group may be substituted with one or more substituents selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2, and C1-C6aliphatic; R1 and R2 are each independently selected from the group consisting of -H, halogen, -OR, -OC(O)R’, -OS(O)2R’, -OS(O)2NR2, -OC(O)NR2, -OC(O)OR, -NR2, -NRC(O)R’, -NRS(O)2R’, -NRC(O)NR2, -NRC(O)OR, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -SO2NR2, -S(O)2OR, optionally substituted C1-C6aliphatic, optionally substituted C3-C10cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, or R1 and R2 combine with the carbon to which they are attached to form an optionally substituted C3-C8cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S, wherein an optionally substituted R1 and R2 group may be substituted with one or more of halogen, oxo, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2, and C1-C6aliphatic; R3, R4, R5, and R6 are each independently selected from the group consisting of -H, optionally substituted C1-C6aliphatic, optionally substituted C3-C8cycloalkyl, and optionally substituted 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S, or R3 and R4, or R5 and R6, or a combination thereof, combine with the carbon to which they are attached to form an optionally substituted C3-C8cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S, wherein an optionally substituted R3, R4, R5, and R6 group may be substituted with one or more of halogen, oxo, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2, and C1-C6 aliphatic; R7, R8, and R9 are each independently selected from the group consisting of -H, halogen, -OR, -OC(O)R’, -OS(O)2R’, -OS(O)2NR2, -OC(O)NR2, -OC(O)OR, -NR2, -NRC(O)R’, -NRS(O)2R’, -NRC(O)NR2, -NRC(O)OR, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -SO2NR2, -S(O)2OR, and optionally substituted C1-C6aliphatic, wherein an optionally substituted R7, R8, and R9 group may be substituted with one or more of halogen, oxo, -OR, -OC(O)R’, -NR2, -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR2, -S(O)2R’, -S(O)2NR2, and C1-C6aliphatic; each R is independently selected from the group consisting of -H, optionally substituted C1-C6aliphatic, optionally substituted C3-C10cycloalkyl, optionally substituted 3- to 10- membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R group may be optionally substituted with one or more of halogen, oxo, -OH, -O(C1-C6aliphatic), -NH2, -NH(C1-C6aliphatic), -N(C1-C6aliphatic)2, -CN, and C1-C6aliphatic; each R’ is independently selected from the group consisting of optionally substituted C1-C6aliphatic, optionally substituted C3-C10cycloalkyl, optionally substituted 3- to 10- membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R’ group may be substituted with one or more of halogen, oxo, -OH, -O(C1-C6aliphatic), -NH2, -NH(C1-C6aliphatic), -N(C1-C6aliphatic)2, -CN, and C1-C6aliphatic; m is 0, 1, or 2; and n is 0, 1, or 2; and wherein the immune checkpoint pathway inhibitor selected from the group consisting of cemiplimab, atezolizumab, durvalumab, and avelumab. 21. The method of claim 19 or claim 20, with the proviso that the USP9X Inhibitor is not a compound of Figure 15. |
Synthesis of Intermediate D1 Step 1. Tert-butyl 6-[(3-bromophenyl)(cyano)methyl]-1H,2H,3H-pyrrolo[3,4-c]pyri dine-2- carboxylate [00240] To a solution of tert-butyl 6-chloro-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxylate (2.0 g, 7.79 mmol) in tetrahydrofuran (20 mL) was added NaNH2 (2.0 g, 7.87 mmol), and 2-(3- bromophenyl)acetonitrile (2.32 g, 11.8 mmol). The resulting mixture was stirred for 16 h at 50 °C and then cooled to room temperature. The reaction mixture was poured into water (20 mL) and then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 20:80 ethyl acetate/petroleum ether) to afford tert-butyl 6-[(3-bromophenyl)(cyano)methyl]-1H,2H,3H-pyrrolo[3,4-c]pyri dine- 2-carboxylate (1.1 g, 34 %). LCMS (ES, m/z) 414, 416 [M+H] + . Step 2. Tert-butyl 6-(3-bromobenzoyl)-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxy late [00241] To a solution of sodium hydroxide (128 mg, 0.012 mmol) in water (0.13 mL) was added DMSO (8 mL), benzyltriethylammonium chloride (27 mg, 0.12 mmol) and a solution of tert-butyl 6-[(3-bromophenyl)(cyano)methyl]-1H,2H,3H-pyrrolo[3,4-c]pyri dine-2-carboxylate (1.1 g, 2.66 mmol) in DMSO ( 10 mL). The resulting solution was stirred for 3 h at room temperature while oxygen was bubbling in. The reaction mixture was poured into water (20 mL) and then extracted with EtOAc (3 x 20 mL). The combined organic layers were washed by brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 20:80 ethyl acetate/petroleum ether) to afford tert-butyl 6-(3-bromobenzoyl)-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxy late (640 mg, 60%). LCMS (ES, m/z) 403, 405 [M+H] + . Step 3. Tert-butyl 6-[(3-bromophenyl)(hydroxy)methyl]-1H,2H,3H-pyrrolo[3,4-c]py ridine- 2-carboxylate [00242] To a solution of tert-butyl 6-(3-bromobenzoyl)-1H,2H,3H-pyrrolo[3,4-c]pyridine-2- carboxylate (500 mg, 1.24 mmol) in tetrahydrofuran (10 mL) was added NaBH4 (95 mg, 2.49 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. The reaction mixture was poured into water (10 mL) and then extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 25:80 ethyl acetate/petroleum ether) to afford tert-butyl 6-[(3- bromophenyl)(hydroxy)methyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine -2-carboxylate (400 mg, 80%). LCMS (ES, m/z) 405, 407 [M+H] + . Step 4. (3-bromophenyl)(2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)me thanol (D1) [00243] To a solution of tert-butyl 6-[(3-bromophenyl)(hydroxy)methyl]-1H,2H,3H- pyrrolo[3,4-c]pyridine-2-carboxylate (1 equiv) in DCM was added TFA. The resulting solution was stirred for 1 h at rt and then concentrated under vacuum. The resulting mixture was then basified to pH 8 with saturated aqueous potassium carbonate solution. The resulting mixture was extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford (3-bromophenyl)(2,3-dihydro-1H-pyrrolo[3,4- c]pyridin-6-yl)methanol (D1). LCMS (ES, m/z) 305 [M+H] + .
Synthesis of Compound 4 Step 1. (3-bromophenyl)(2-((4-(oxazol-2-yl)phenyl)sulfonyl)-2,3-dihy dro-1H-pyrrolo[3,4- c]pyridin-6-yl)methanol [00244] To a solution of 4-(1,3-oxazol-2-yl)benzene-1-sulfonyl chloride (C1) (1.5 equiv) in DCM was added (3-bromophenyl)(2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)me thanol (D1) (1 equiv) and TEA (3.0 equiv). The resulting solution was stirred for 2 h at 25 °C. The reaction mixture was poured into water and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography to afford (3-bromophenyl)(2-((4-(oxazol- 2-yl)phenyl)sulfonyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6 -yl)methanol. LCMS (ES, m/z) 512, 514 [M+H] + . Step 2. Tert-butyl 4-(3-(hydroxy(2-((4-(oxazol-2-yl)phenyl)sulfonyl)-2,3-dihydr o-1H- pyrrolo[3,4-c]pyridin-6-yl)methyl)phenyl)piperazine-1-carbox ylate [00245] To a solution of (3-bromophenyl)(2-((4-(oxazol-2-yl)phenyl)sulfonyl)-2,3-dihy dro- 1H-pyrrolo[3,4-c]pyridin-6-yl)methanol (1 equiv) in toluene was added N-Boc-piperidine (1.4 equiv), XPhos (25 mol%), Cs2CO3 (3.3 equiv) and Pd2(dba)3 . CHCl3 (12 mol%). The resulting mixture was stirred for 16 h at 100 °C and then cooled to room temperature. The reaction mixture was filtered and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography to afford tert-butyl 4-(3-(hydroxy(2-((4-(oxazol-2-yl)phenyl)sulfonyl)-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)methyl)phenyl)piperazi ne-1-carboxylate. LCMS (ES, m/z) 618 [M+H] + . Step 3. [2-[4-(1,3-oxazol-2-yl)benzenesulfonyl]-1H,2H,3H-pyrrolo[3,4 -c]pyridin-6-yl][3- (piperazin-1-yl)phenyl] methanol (4) [00246] To a solution of HCl in 1,4-dioxane (4 N) was added tert-butyl 4-(3-(hydroxy(2-((4- (oxazol-2-yl)phenyl)sulfonyl)-2,3-dihydro-1H-pyrrolo[3,4-c]p yridin-6- yl)methyl)phenyl)piperazine-1-carboxylate (1 equiv) and water. The resulting mixture was stirred for 4 h at room temperature. The reaction mixture was concentrated and lyophilized. The resulting crude product was purified by reverse phase chromatography. The product fractions were concentrated and lyophilized to afford tert-butyl 4-(3-(hydroxy(2-((4-(oxazol-2- yl)phenyl)sulfonyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-y l)methyl)phenyl)piperazine-1- carboxylate as a white solid (79%). 1 H-NMR (DMSO-d6, 400 MHz) d (ppm): 9.09 (br s, 2H), 8.33 (d, J = 2.8 Hz, 2H), 8.16 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 3.2 Hz, 2H), 7.12-7.08 (m, 1H), 7.03-7.01 (m, 1H), 6.80-6.77 (m, 2H), 6.07 (br s, 1H), 5.62 (s, 1H), 4.69-4.58 (m, 4H), 3.52-3.35 (m, 4H), 3.30-3.19 (m, 4H). LCMS (ES, m/z) 518 [M+H] + . The two enantiomers were further separated by Chiral Prep-HPLC (Column: CHIRALPAK IF, 5 µm, 20x250 mm; Mobile Phase, A: MTBE (containing 0.2% IPA) and B: EtOH (keep 50% B over 25 min); Detector: UV 254/220 nm; Retention time: 1 st eluting isomer, 10.759 min; 2 nd eluting isomer (4), 17.742 min).
Synthesis of Compounds of Formula I [00247] In some embodiments, the USP9X inhibitor may be a compound of Table 1: Table 1
Intermediates for Compounds of Table 1 Intermediate 2-2. 2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,2,3,4,5, 6- hexahydropyrrolo[3,4-c]pyrrole Step 1. 1,4-dibromo-2,3-bis(bromomethyl)but-2-ene [00248] To a solution of 2,3-dimethylbut-2-ene (1000 g, 11.9 mol) in DCM (1000 mL) in a 4 L 4-necked round bottom flask was added aqueous hydrogen bromide solution (150 mL, 48%) with stirring at 10-15 °C. To the reaction was added bromine (9.90 kg, 62.0 mol) with stirring at 0 °C. The resulting mixture was stirred for 2 days at 45 °C in an oil bath. After cooling to room temperature, the reaction mixture was carefully poured into saturated aqueous sodium hydrogen sulfite solution (10 L). The precipitate was collected by filtration and dried in oven to afford 1,4- dibromo-2,3-bis(bromomethyl)but-2-ene as a light yellow solid (3000 g, 44%). GCMS: (EI, m/z): 398, 400, 402 [M] + . Step 2. 2,5-ditosyl-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole [00249] To a solution of 1,4-dibromo-2,3-bis(bromomethyl)but-2-ene (2000 g, 3.50 mol) in DMF (20 L) was added 4-methylbenzene-1-sulfonamide (2137 g, 12.5 mol), and potassium carbonate (5175 g, 37.4 mol). The resulting mixture was stirred for 2 days at room temperature. The reaction mixture was slowly poured into water/ice (20 L). The precipitate was collected by filtration, washed with ethanol and dried in an oven to afford 2,5-ditosyl-1,2,3,4,5,6- hexahydropyrrolo[3,4-c]pyrrole as a light yellow solid (1345 g, 78%). LCMS: (ES, m/z): 419 [M+H] + . Step 3. 1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole hydro bromide salt [00250] To a solution of 2,5-ditosyl-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (1345 g, 2.73 mol) in aqueous hydrogen bromide solution (4500 mL, 48%) in 10 L 4-necked round-bottom flask, was added phenol (1270 g, 13.5 mol). The resulting mixture was stirred for 2 days at 120 °C. After cooling to room temperature, the aqueous layer was collected and concentrated under vacuum. The resulting solids were washed with DCM/MeOH (v:v = 10:1, 3 x 300 mL) and dried in an oven to afford 1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole hydrogen bromide salt as a yellow solid (480 g, 61%). LCMS: (ES, m/z): 111 [M+H] + . Step 4. Di-tert-butyl pyrrolo[3,4-c]pyrrole-2,5(1H,3H,4H,6H)-dicarboxylate [00251] To a suspension of 1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole hydrogen bromide salt (458 g, 1.52 mol) in water (4 L) was added sodium bicarbonate (424 g, 5.05 mol) followed by dropwise addition of a solution of di-tert-butyl dicarbonate (807 g, 3.70 mol) in methanol (500 mL) with stirring at 0 °C. The resulting solution was stirred for 16 h at 25 °C. The precipitate was collected by filtration and dried in an oven to afford di-tert-butyl pyrrolo[3,4-c]pyrrole- 2,5(1H,3H,4H,6H)-dicarboxylate as a white solid (300 g, 61%). LCMS (ES, m/z): 311[M+H] + . Step 5. Tert-butyl 4,5-dihydropyrrolo[3,4-c]pyrrole-2(1H,3H,4H)-carboxylate 4- methylbenzene-1-sulfonic acid salt [00252] To a solution of di-tert-butyl pyrrolo[3,4-c]pyrrole-2,5(1H,3H,4H,6H)-dicarboxylate (200 g, 612 mmol) in propan-2-yl acetate (5 L) was added 4-methylbenzene-1-sulfonic acid (123 g, 647 mmol) in portions at 0 °C. The resulting mixture was stirred for 16 h at 55 °C in an oil bath. After cooling to room temperature, the precipitate was collected by filtration and dried in an oven to afford tert-butyl 4,5-dihydropyrrolo[3,4-c]pyrrole-2(1H,3H,4H)-carboxylate 4-methylbenzene- 1-sulfonic acid salt as a yellow solid (197 g, 80%). LCMS: (ES, m/z): 211[M+H] + . Step 6. Tert-butyl 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)-4,5-dihydrop yrrolo[3,4- c]pyrrole-2(1H,3H,4H)-carboxylate [00253] To a suspension of tert-butyl 4,5-dihydropyrrolo[3,4-c]pyrrole-2(1H,3H,4H)- carboxylate 4-methylbenzene-1-sulfonic acid salt (61 g, 142 mmol) in water (100 mL) and tetrahydrofuran (30 mL) was added sodium hydroxide (13 g, 325 mmol) followed by portion-wise addition of 2,3-dihydro-1,4-benzodioxine-6-sulfonyl chloride (25 g, 95.9 mmol) at 0 °C. The resulting mixture was stirred for 2 h at 25 °C. The product was extracted with ethyl acetate (3 x 200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting material was purified by silica gel chromatography (eluting with 1:10 ethyl acetate/petroleum ether) to afford tert-butyl 5-(2,3- dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)-4,5-dihydropyrrolo[ 3,4-c]pyrrole-2(1H,3H,4H)- carboxylate as a white solid (30 g, 73%). LCMS: (ES, m/z): 409 [M+H] + . Step 7. 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)-1,2,3,4,5,6- hexahydropyrrolo[3,4- c]pyrrole hydrochloric salt [00254] To a solution of tert-butyl 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)-4,5- dihydropyrrolo[3,4-c]pyrrole-2(1H,3H,4H)-carboxylate (30.0 g, 69.8 mmol) in 1,4-dioxane (100 mL) was added hydrochloric acid (200 mL, 4 M in 1,4-dioxane). The resulting solution was stirred for 2 h at 25 °C and then concentrated under vacuum to afford 2-(2,3-dihydrobenzo[b][1,4]dioxin- 6-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole hydrochloric salt as a yellow solid (20 g, 79%). LCMS: (ES, m/z): 309 [M+H] + . Intermediate 2-4. Methyl 2-(2-methyl-1,3-benzothiazol-4-yl)prop-2-enoate Step 1. 2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3 -benzothiazole [00255] To a solution of 4-bromo-2-methyl-1,3-benzothiazole (3.00 g, 12.9 mmol) in 1,4- dioxane (20 mL) was added 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2- dioxaborolane (4.01 g, 15.5 mmol), Pd(dppf)Cl2 (960 mg, 1.29 mmol) and potassium acetate (2.58 g, 25.8 mmol). The resulting mixture was stirred for 16 h at 100 °C and then cooled to room temperature. The reaction mixture was poured into water (30 mL) and then extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 20:80 ethyl acetate/petroleum ether) to afford 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiaz ole as a light yellow oil (2.00 g, 46%). LCMS (ES, m/z) 276 [M+H] + . Step 2. Methyl 2-(2-methyl-1,3-benzothiazol-4-yl)prop-2-enoate [00256] To a solution of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3 - benzothiazole (600 mg, 1.86 mmol) in 1,4-dioxane (10 mL) was added methyl 2-bromoprop-2- enoate (447 mg, 2.66 mmol), XPhos 3G (80 mg, 0.11mmol), potassium phosphate (1.4 g, 6.46 mmol) and water (1 mL). The resulting mixture was stirred for 16 h at 100 °C and then cooled to room temperature. The reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 20:80 ethyl acetate/petroleum ether) to afford methyl 2-(2- methyl-1,3-benzothiazol-4-yl)prop-2-enoate as light yellow oil (280 mg, 55%). LCMS (ES, m/z) 234 [M+H] + . [00257] The Intermediates in Table 2 were synthesized according to the procedure described for Intermediate 2-4 above. Table 2 Intermediate 3-1. methyl 2-(3-methoxyphenyl)acrylate [00258] In a 250 mL round-bottom flask was placed methyl 2-(3-methoxyphenyl)acetate (5 g, 27.2 mmol), paraformaldehyde (3 g, 33.3 mmol), n-Bu4NI (1 g, 2.7 mmol), potassium carbonate (9.6 g, 69.5 mmol) and N,N-dimethylformamide (60 mL). The resulting solution was stirred for 10 min at 60 °C in an oil bath. After cooling to room temperature, the solution was diluted with 100 mL of water and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 3 g (57%) of methyl 2-(3-methoxyphenyl)prop-2-enoate as a yellow oil. MS: (ESI, m/z): 193[M+H] + . [00259] The Intermediate in Table 3 was synthesized according to the procedure described for Intermediate 3-1 above. Table 3. Intermediate 5-1. 1-bromo-5-chloro-2-methoxy-4-methylbenzene [00260] To a solution of 2-bromo-4-chloro-5-methylphenol (2.0 g, 8.1 mmol) in acetone (20 mL) was added potassium carbonate (2.5 g,16 mmol), and iodomethane (0.66 mL, 9.5 mmol). The resulting mixture was stirred for 2 h at 25 °C. The reaction mixture was poured into water (30 mL) and then extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 20:80 ethyl acetate/petroleum ether) to afford 1-bromo-5-chloro-2-methoxy-4-methylbenzene as a light yellow oil (1.87 g, 82%). GCMS (EI, m/z): 234, 236 [M] + . [00261] The Intermediates in Table 4 were synthesized according to the procedure described for Intermediate 5-1 above. Table 4.
Intermediate 7-1. 2-{2-[(tert-butoxy)carbonyl]-2,3-dihydro-1H-isoindol-4-yl}-2 -oxoacetic acid Step 1. tert-butyl 4-(2-ethoxy-2-oxoacetyl)-2,3-dihydro-1H-isoindole-2-carboxyl ate [00262] To a solution of tert-buty 4-bromo-2,3-dihydro-1H-isoindole-2-carboxylatein (2.0 g, 6.4 mmol) in THF (20 mL) was added a solution of n-BuLi (2.6 mL, 2.5 M in THF) dropwise with stirring at -78 °C. After stirring for 15 min at -78 °C, diethyl oxalate (3.1 mL, 32 mmol) was added in. The resulting mixture was stirred for 1 h at -60 °C. The reaction mixture was poured into saturated ammonium chloride solution (20 mL) and then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 20:80 ethyl acetate/petroleum ether) to afford tert-butyl 4-(2-ethoxy-2-oxoacetyl)- 2,3-dihydro-1H-isoindole-2-carboxylate as a light yellow solid (1.12 g, 47%). LCMS (ES, m/z) 320 [M+H] + . Step 2. 2-{2-[(tert-butoxy)carbonyl]-2,3-dihydro-1H-isoindol-4-yl}-2 -oxoacetic acid [00263] To a solution of tert-butyl 4-(2-ethoxy-2-oxoacetyl)-2,3-dihydro-1H- isoindole-2 - carboxylate (1.12 g, 2.98 mmol) in tetrahydrofuran (6 mL) was added water (6 mL) and LiOH (421 mg, 16.70 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction mixture was washed with diethyl ether (1 x 10 mL) and then acidified to pH = 5 with saturated citric acid. The resulting solution was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 2-[2-[(tert-butoxy)carbonyl]-2,3-dihydro-1H-isoindol- 4-yl]- 2-oxoacetic acid as a light yellow solid (1.0 g, crude). LCMS (ES, m/z) 292 [M+H] + . [00264] The Intermediate in Table 5 was synthesized according to the procedure described for Intermediate 7-1 above. Table 5. Intermediate 14-1. methyl 3-{[(tert-butoxy)carbonyl](methyl)amino}-2-(3-chloro-4-fluor o- 2-methoxyphenyl)propanoate [00265] To a solution of methyl 3-{[(tert-butoxy)carbonyl](methyl)amino}-2-(4-fluoro-2- methoxyphenyl)propanoate (180 mg, 0.53 mmol) in dichloromethane (3 mL) was added NCS (211 mg, 1.58 mmol). The resulting solution was stirred for 16 h at room temperature. The reaction mixture were filtered, and concentrated under vacuum. The resulting crude product was purified by prep-TLC (eluting with 1:5 ethyl acetate/petroleum ether) to afford methyl 3-{[(tert- butoxy)carbonyl](methyl)amino}-2-(3-chloro-4-fluoro-2-methox yphenyl)propanoate as a light yellow oil (160 mg, 81%). LCMS (ES, m/z) 376, 378 [M+H] + . Intermediate 27-1. Methyl 2-(3-cyclopropyl-4,5-difluorophenyl)prop-2-enoate Step 1. Methyl 2-(3-bromo-4,5-difluorophenyl)acetate [00266] To a solution of 3-bromo-4,5-difluorobenzoic acid (2.50 g, 10.6 mmol) in toluene (15 mL), was added thionyl chloride (15 mL). The resulting solution was refluxed for 3 h, then cooled to room temperature and concentrated under vacuum. The resulting mixture was dissolved in THF (15 mL) and treated with triethylamine (2.47 mL, 17.9 mmol) and (diazomethyl)trimethylsilane (8.8 mL, 2.0 M in THF) at 0 °C. The resulting mixture was stirred for 16 h at room temperature and then poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting mixture was dissolved in methanol (40 mL) and treated with triethylamine (2.47 mL, 17.9 mmol) and silver (I) benzoate (1.40 g, 6.33 mmol) at 0 °C. The mixture was stirred for 16 h at room temperature and then concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with 0:100 to 10:90 ethyl acetate/petroleum ether) to afford methyl 2-(3-bromo-4,5-difluorophenyl)acetate as a colorless oil (0.98 g, 35%). LCMS (ES, m/z): 265, 267 [M+H] + . Step 2. Methyl 2-(3-cyclopropyl-4,5-difluorophenyl)acetate [00267] To a solution of methyl 2-(3-bromo-4,5-difluorophenyl)acetate (1.70 g, 6.72 mmol) in 1,4-dioxane (40 mL) was added cyclopropylboronic acid (865 mg, 10.1 mmol), potassium phosphate (4.20 g, 20.1 mmol), Pd(dppf)Cl2 (246 mg, 0.34 mmol) and water (8 mL). The mixture was stirred for 16 h at 90 °C and cooled to room temperature. The reaction mixture was poured into water (50 mL) and then extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with 0:100 to 30:70 ethyl acetate/petroleum ether) to afford methyl 2-(3-cyclopropyl-4,5-difluorophenyl)acetate as a colorless oil (550 mg, 36%). LCMS (ES, m/z): 227 [M+H] + . Step 3. Methyl 2-(3-cyclopropyl-4,5-difluorophenyl)prop-2-enoate [00268] To a solution of methyl 2-(3-cyclopropyl-4,5-difluorophenyl)acetate (550 mg, 2.43 mmol) in DMF (15 mL), was added potassium carbonate (840 mg, 6.08 mmol), tetrabutylamonium iodide (90 mg, 0.24 mmol) and paraformaldehyde (263 mg, 2.92 mmol). The resulting mixture was stirred for 10 min at 60 °C and then cooled to room temperature. The reaction mixture was poured into water (30 mL) and then extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 30:70 ethyl acetate/petroleum ether) to afford methyl 2-(3-cyclopropyl-4,5-difluorophenyl)prop-2- enoate as a colorless oil (159 mg, 27 %). LCMS (ES, m/z): 239 [M+H] + . Intermediate 33-1. 2-{1-[(tert-butoxy)carbonyl]pyrrolidin-2-yl}-2-(3-chlorophen yl)acetic acid Step 1. Methyl 2-(3-chlorophenyl)-2-diazoacetate [00269] To a solution of methyl 2-(3-chlorophenyl)acetate (5.00 g, 25.7 mmol) in CH3CN (50 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.87 mL, 32.6 mmol) dropwise with stirring at 0 °C followed by the addition of 4-methylbenzene-1-sulfonyl azide (6.40 g, 32.5 mmol) added dropwise with stirring at 0 °C. The solution was stirred for 4 h at 25 °C. The reaction mixture was treated with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 10:90 ethyl acetate/dichloromethane) to afford methyl 2-(3-chlorophenyl)-2-diazoacetate as a yellow solid (5.00 g, 83%). LCMS (ES, m/z): 211, 213 [M+H] + . Step 2. Tert-butyl 2-[1-(3-chlorophenyl)-2-methoxy-2-oxoethyl]pyrrolidine-1-car boxylate [00270] To a solution of tert-butyl pyrrolidine-1-carboxylate (894 mg, 5.22 mmol) in hexane (150 mL) was added tetrakis [(R)-(+)-N-(P-dodecylphenylsulfonyl)prolinato]dirhodium (II) (49 mg, 0.026 mmol) followed by treatment with methyl 2-(3-chlorophenyl)-2-diazoacetate (550 mg, 2.61 mmol) as a solution in hexane (100 mL) over 60 min with stirring at -50 °C. The resulting solution was stirred for 10 h at -50 °C and then 16 h at room temperature. The reaction was poured into saturated ammonium chloride solution (100 mL) and then extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 10:90 ethyl acetate/petroleum ether) to afford tert-butyl 2-[1-(3- chlorophenyl)-2-methoxy-2-oxoethyl]pyrrolidine-1-carboxylate as a yellow solid (400 mg, 39%). LCMS (ES, m/z): 354, 356 [M+H] + . Step 3. 2-{1-[(tert-butoxy)carbonyl]pyrrolidin-2-yl}-2-(3-chlorophen yl)acetic acid [00271] To a solution of tert-butyl 2-[1-(3-chlorophenyl)-2-methoxy-2-oxoethyl]pyrrolidine-1- carboxylate (400 mg, 1.13 mmol) in tetrahydrofuran (20 mL) and water (5 mL) was added lithium hydroxide (135 mg, 5.65 mmol). The resulting mixture was stirred for 18 h at room temperature. The reaction mixture was washed with diethyl ether (1 x 10 mL) and then acidified to pH = 6 with saturated citric acid. The resulting solution was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 2-{1-[(tert-butoxy)carbonyl]pyrrolidin-2-yl}-2-(3-chlorophen yl)acetic acid as yellow oil (300 mg, 78%). LCMS (ES, m/z): 340, 342 [M+H] + . Intermediate 38-1. 1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole hydrogen bromide salt Step 1. 1,4-dibromo-2,3-bis(bromomethyl)but-2-ene [00272] To a solution of 2,3-dimethylbut-2-ene (1000 g, 11.9 mol) in DCM (500 mL) in 4 L 4- necked round bottom flask was added aqueous hydrogen bromide solution (150 mL, 48%). The reaction was treated with bromine (9.90 kg, 62.0 mol) while stirring at 0 °C and then heated to 45 °C in an oil bath and stirred for an additional 2 days. After cooling to room temperature, the reaction mixture was carefully poured into saturated sodium hydrogen sulfite solution (10 L). The precipitate was collected by filtration and dried in oven to afford 1,4-dibromo-2,3- bis(bromomethyl)but-2-ene as a light yellow solid (3345 g, 49%). GCMS: (EI, m/z): 398, 400, 402 [M] + . Step 2. 2,5-ditosyl-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole [00273] To a solution of 1,4-dibromo-2,3-bis(bromomethyl)but-2-ene (2000 g, 3.50 mol) in DMF (20 L) was added 4-methylbenzene-1-sulfonamide (2137 g, 12.5 mol), and potassium carbonate (5175 g, 37.4 mol). The resulting mixture was stirred for 2 days at room temperature. The reaction mixture was then slowly poured into water/ice (20 L). The precipitate was collected by filtration, washed with ethanol and dried in oven to afford 2,5-ditosyl-1,2,3,4,5,6- hexahydropyrrolo[3,4-c]pyrrole as a light yellow solid (1345 g, 78%). LCMS: (ES, m/z): 419 [M+H] + . Step 3. 1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole hydro bromide salt [00274] To a solution of 2,5-ditosyl-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (1345 g, 2.73 mol) in aqueous hydrogen bromide solution (4500 mL, 48%) in 10 L 4-necked round-bottom flask, was added phenol (1270 g, 13.5 mol). The resulting mixture was stirred for 2 days at 120 °C. After cooling to room temperature, the aqueous layer was collected and concentrated under vacuum. The resulting solids were washed with DCM/MeOH (v:v = 10:1, 3 x 300 mL) and dried in an oven to afford 1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole hydrogen bromide salt as a yellow solid (480 g, 61%). LCMS: (ES, m/z): 111 [M+H] + . Intermediate 43-1. 2-hydroxy-2-(2-methyl-1,3-benzoxazol-4-yl)acetic acid Step 1. 3-hydroxy-2-nitrobenzaldehyde [00275] To a solution of 3-methyl-2-nitrophenol (200 g, 1.29 mol) in acetic anhydride (1600 mL) was added sulfuric acid (240 mL) and acetic acid (1620 mL). This was followed by the addition of chromium trioxide (280 g, 2.77 mol) in several batches with stirring at 0 °C. The resulting mixture was stirred for 2.5 h at 0 °C and then poured into ice/ water (5000 mL). The solids were collected by filtration and then washed with water (3 x 1 L), saturated sodium carbonate solution (3 x 800 mL), and water (3 x 1 L). The solids were dissolved in ethanol (380 mL) and concentrated hydrochloric acid (617 mL). The resulting solution was stirred for 1.5 h at 110 °C and then cooled to room temperature. The reaction mixture was concentrated under vacuum to afford 3-hydroxy-2-nitrobenzaldehyde as a yellow solid (38.0 g, 18%). LCMS (ES, m/z): 166 [M-H]-. Step 2. 2-hydroxy-2-(3-hydroxy-2-nitrophenyl)acetonitrile [00276] To a solution of 3-hydroxy-2-nitrobenzaldehyde (38.0 g, 204 mmol) in dichloromethane (500 mL) was added ZnI2 (14.5 g, 44.5 mmol). The reaction was treated with trimethylsilyl cyanide (100 mL, 708 mmol) added dropwise with stirring at 0 °C. The resulting mixture was stirred for 2.5 h at 25 °C. The reaction was poured into brine (200 mL) and then extracted with ethyl acetate (3 x 500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 2-hydroxy-2-(3-hydroxy-2- nitrophenyl)acetonitrile as a yellow solid (34.0 g, 73%). LCMS (ES, m/z): 195 [M+H] + . Step 3. Methyl 2-hydroxy-2-(3-hydroxy-2-nitrophenyl)acetate [00277] To a solution of 2-hydroxy-2-(3-hydroxy-2-nitrophenyl)acetonitrile (34.0 g, 157 mmol) in methanol (80 mL) was added hydrochloric acid (80 mL, 4 N in 1,4-dioxane). The resulting solution was stirred for 45 min at 60 °C and cooled to room temperature. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography (eluting with 0:100 to 35:65 ethyl acetate/petroleum ether) to afford methyl 2-hydroxy-2-(3-hydroxy-2- nitrophenyl)acetate as a yellow solid (23.0 g, 58%). LCMS (ES, m/z): 228 [M+H] + . Step 4. Methyl 2-(2-amino-3-hydroxyphenyl)-2-hydroxyacetate [00278] To a solution of methyl 2-hydroxy-2-(3-hydroxy-2-nitrophenyl)acetate (23.0 g, 0.11 mol) in methanol (500 mL) was added anhydrous palladium carbon (2.3 g, 10wt% Pd). The resulting mixture was stirred for 16 h at 25 °C under hydrogen atmosphere (3 atm). The reaction mixture was filtered and concentrated under vacuum to afford methyl 2-(2-amino-3- hydroxyphenyl)-2-hydroxyacetate as a yellow solid (14.0 g, 60%). LCMS (ES, m/z): 198 [M+H] + . Step 5. Methyl 2-hydroxy-2-(2-methyl-1,3-benzoxazol-4-yl)acetate [00279] To a solution of methyl 2-(2-amino-3-hydroxyphenyl)-2-hydroxyacetate (9.0 g, 43.4 mmol) in 1,1,1-triethoxyethane (150 mL) was added bismuth (III) trifluoromethanesulfonate (800 mg, 1.18 mmol). The resulting mixture was stirred for 10 min at 85 °C. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 50:50 ethyl acetate/petroleum ether) to afford methyl 2-hydroxy-2-(2-methyl-1,3-benzoxazol-4-yl)acetate as a white solid (6.3 g, 63%). LCMS (ES, m/z): 222 [M+H] + . Step 6. 2-hydroxy-2-(2-methyl-1,3-benzoxazol-4-yl)acetic acid [00280] To a solution of methyl 2-hydroxy-2-(2-methyl-1,3-benzoxazol-4-yl)acetate (500 mg, 2.26 mmol) in tetrahydrofuran (20 mL) and water (2 mL) was added lithium hydroxide (271 mg, 11.3 mmol). The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was washed with diethyl ether (1 x 10 mL) and then acidified to pH = 6 with hydrochloric acid (1 N). The resulting solution was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 2-hydroxy-2-(2-methyl-1,3-benzoxazol-4-yl)acetic acid as a white solid (386 mg, 82%). LCMS (ES, m/z): 208 [M+H] + . Intermediate 44-1. 2-methyl-1,3-benzothiazole-4-carbaldehyde Step 1. (2-methyl-1,3-benzothiazol-4-yl)methanol [00281] To a solution of 4-bromo-2-methyl-1,3-benzothiazole (2.10 g, 9.21 mmol) in 1,4- dioxane (70 mL) was added (tributylstannyl)methanol (3.84 g, 12.0 mmol), and Pd(PPh3)4 (1.60 g, 1.38 mmol). The resulting mixture was stirred for 16 h at 100 °C and then cooled to room temperature. The reaction mixture was poured into water (50 mL) and then extracted with ethyl acetate (3 x 70 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with 0:100 to 80:20 ethyl acetate/petroleum ether) to afford (2-methyl- 1,3-benzothiazol-4-yl)methanol as a yellow oil (1.20 g, 73%). LCMS (ES, m/z): 180 [M+H] + . Step 2. 2-methyl-1,3-benzothiazole-4-carbaldehyde [00282] To a solution of oxalyl chloride (1.39 mL, 13.39 mmol) in dichloromethane (30 mL) was added DMSO (1.43 mL, 20.1 mmol) dropwise with stirring at -78 °C. The resulting mixture was stirred for 30 min at -78 °C. The reaction was treated with (2-methyl-1,3-benzothiazol-4- yl)methanol (1.20 g, 6.69 mmol) in dichloromethane (10 mL) added slowly at -78 °C. After 2 h TEA (5.58 mL, 40.1 mmol) was added and the mixture was warmed to room temperature and stirred for 2 h. The reaction was poured into brine (30 mL) and then extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 2-methyl-1,3-benzothiazole-4-carbaldehyde as a yellow oil (900 mg, 76%). LCMS (ES, m/z): 178 [M+H] + . Intermediate 63-1. tert-butyl (R)-(3-(5-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)- 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-oxo-2-phe nylpropyl)carbamate [00283] In a dry 25 ml RBF under N2 was added 2-((2,3-dihydrobenzo[b][1,4]dioxin-6- yl)sulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (200 mg, 0.649 mmol), (R)-3-((tert- butoxycarbonyl)amino)-2-phenylpropanoic acid (189 mg, 0.713 mmol), DMF (1 mL), DIEA (170 µl, 0.973 mmol) and HATU (271 mg, 0.713 mmol). After 3 h, the reaction was diluted with 50 ml of saturated aqueous bicarbonate solution (50 mL) and extracted with EtOAc (4 x 20 mL). The extracts were dried over Na 2 SO 4, filtered and the solvent was removed in vacuo to afford 524 mg of a brown gummy solid. The crude material was purified by a Biotage SNAP-25 Silica column and eluted with an EtOAc/Hexane gradient (0-100% EtOAc). The desired product was isolated affording 309 mg of a white solid. [00284] The Intermediate in Table 6 was synthesized according to the procedure described for Intermediate 63-1 above.
Table 6. Intermediate 66. tert-butyl 5-[3-[(1S)-2-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-1-hydroxy-2-oxo ethyl]phenyl]- octahydropyrrolo[3,4-c]pyrrole-2-carboxylate [00285] To a solution of (2S)-2-(3-bromophenyl)-1-[5-(2,3-dihydro-1,4-benzodioxine-6- sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2-hyd roxyethan-1-one (100 mg, 0.20 mmol) in toluene (5 mL) was added tert-butyl octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (609 mg, 2.87 mmol), RuPhos 2G (15 mg, 0.02 mmol), RuPhos (18 mg, 0.04 mmol), and cesium carbonate (189 mg, 0.58 mmol). The resulting mixture was stirred overnight at 100 °C. After cooling to room temperature, the reaction was concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with 1:25 MeOH/DCM) to afford tert-butyl 5-[3- [(1S)-2-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3 H,4H,5H,6H-pyrrolo[3,4- c]pyrrol-2-yl]-1-hydroxy-2-oxoethyl]phenyl]-octahydropyrrolo -[3,4-c] pyrrole-2-carboxylate as a light yellow solid (100 mg, 80%). LCMS (ES, m/z): 653 [M+H] + . [00286] The Intermediates in Table 7 were synthesized according to the procedure described for Intermediate 66 above. Table 7. Intermediate 75. 4-[[(tert-butoxy)carbonyl]amino]-2-(3,5-dichlorophenyl)butan oic acid Step 1. Methyl 3-cyano-2-(3,5-dichlorophenyl)propanoate [00287] To a solution of methyl 2-(3,5-dichlorophenyl)acetate (2.00 g, 8.67 mmol) in tetrahydrofuran (20 mL) was added LDA (5.5 mL, 2 M in THF) dropwise with stirring at -78 °C. The solution was stirred for 30 min at -78 °C. The reaction was treated with 2-iodoacetonitrile (2.30 g, 13.8 mmol) and stirred for 1 h at -78 °C. The contents were poured into saturated aqueous ammonium chloride solution (50 mL) and then extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with 0:100 to 20:80 ethyl acetate/petroleum ether) to afford methyl 3-cyano-2-(3,5- dichlorophenyl)propanoate as a yellow oil (1.30 g, 58%). LCMS (ES, m/z): 258, 260 [M+H] + . Step 2. Methyl 4-[[(tert-butoxy)carbonyl]amino]-2-(3,5-dichlorophenyl)butan oate [00288] To a solution of methyl 3-cyano-2-(3,5-dichlorophenyl)propanoate (1.50 g, 5.52 mmol) in methanol (20 mL) was added Raney Ni (946 mg, 11.0 mmol), and di-tert-butyl dicarbonate (6.03 g, 27.6 mmol). The resulting mixture was stirred for 4 h at room temperature under hydrogen (2-3 atm). The reaction mixture was filtered and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 20:80 ethyl acetate/petroleum ether) to afford methyl 4-[[(tert-butoxy)carbonyl]amino]-2-(3,5- dichlorophenyl)butanoate as a yellow oil (1.80 g, 90%). LCMS (ES, m/z): 362, 364 [M+H] + . Step 3. 4-[[(tert-butoxy)carbonyl]amino]-2-(3,5-dichlorophenyl)butan oic acid [00289] To a solution of methyl 4-[[(tert-butoxy)carbonyl]amino]-2-(3,5- dichlorophenyl)butanoate (300 mg, 0.79 mmol) in tetrahydrofuran (2 mL) and water (2 mL) was added lithium hydroxide (94 mg, 3.93 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction mixture was washed with diethyl ether (1 x 10 mL) and then acidified to pH = 7 with saturated aqueous citric acid. The product was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 4-[[(tert-butoxy)carbonyl]amino]-2-(3,5- dichlorophenyl)butanoic acid as a yellow oil (180 mg, 66%). LCMS (ES, m/z): 348, 350 [M+H] + . Intermediate 80. Methyl 3-(azetidin-1-yl)-2-(2-methyl-1,3-benzothiazol-4-yl)propanoa te [00290] To a solution of methyl 2-(2-methyl-1,3-benzothiazol-4-yl)prop-2-enoate (200 mg, 0.86 mmol) in tetrahydrofuran (2 mL) was added azetidine (98 mg, 1.72 mmol). The resulting mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated under vacuum. The resulting crude product was purified by prep-TLC (eluting with 20:1 dichloromethane/methanol) to afford methyl 3-(azetidin-1-yl)-2-(2-methyl-1,3-benzothiazol-4- yl)propanoate as a brown oil (170 mg, 68%). LCMS (ES, m/z): 305 [M+H] + . Intermediate 83. 2-(3-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]-1-[5-(2,3 -dihydro-1,4- benzodioxine-6-sulfonyl) -1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one [00291] To a solution of 2-(3-bromophenyl)-1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfo nyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2-hydroxyethan- 1-one (800 mg, 1.53 mmol) in DMF (10 mL) was added imidazole (314 mg, 4.61 mmol), tert-butyl(chloro)dimethylsilane (0.43 mL, 2.30 mmol) and DMAP (20 mg, 0.164 mmol). The resulting solution was stirred for 2 h at 70 °C and then cooled to room temperature. The reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 50:50 ethyl acetate/petroleum ether) to afford 2-(3-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]-1-[5-(2,3 -dihydro-1,4- benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyr rol-2-yl]ethan-1-one as a light yellow oil (750 mg, 69%). LCMS (ES, m/z): 635, 637 [M+H] + . [00292] The Intermediates in Table 8 were synthesized according to the procedure described for Intermediate 83 above. Table 8. Intermediate 85. Tert-butyl 7-(3-{2-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo [3,4-c]pyrrol-2-yl]-1-hydroxy-2-oxoethyl}phenyl)-9,9- difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate [00293] To 2-[(tert-butyldimethylsilyl)oxy]-2-(3-{9,9-difluoro-3,7-diaz abicyclo[3.3.1]nonan- 3-yl}phenyl)-1- [5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H, 6H-pyrrolo[3,4- c]pyrrol-2-yl]ethan-1-one (280 mg, 0.34 mmol) was added TBAF (5 mL, 1 M in THF). The resulting solution was stirred for 30 min at room temperature. The reaction mixture was poured into water (5 mL) and then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by prep-TLC (eluting with 3:1 ethyl acetate/petroleum ether) to afford tert-butyl 7-(3-[2-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3 H,4H,5H,6H- pyrrolo[3,4-c]pyrrol-2-yl]-1-hydroxy-2-oxoethyl]phenyl)-9,9- difluoro-3,7- diazabicyclo[3.3.1]nonane-3-carboxylate as a yellow oil (220 mg, 82%). LCMS (ES, m/z): 703 [M+H] + . Intermediate 87. Tert-butyl 4-(3-{1-[(tert-butyldimethylsilyl)oxy]-2-[5-(2,3-dihydro-1,4 - benzodioxine-6-sulfonyl) -1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2- sulfanylideneethyl}phenyl)piperazine-1-carboxylate [00294] To a solution of tert-butyl 4-(3-[1-[(tert-butyldimethylsilyl)oxy]-2-[5-(2,3-dihydro- 1,4-benzodioxine-6-sulfonyl) -1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2- oxoethyl]phenyl)piperazine-1-carboxylate (320 mg, 0.43 mmol) in dichloromethane (5 mL), was added Lawesson Reagent (88 mg, 0.22 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction mixture was concentrated under vacuum. The resulting crude product was purified by Prep-TLC eluting with 1:1 ethyl acetate/petroleum ether to give the product as a light yellow oil (130 mg, 36%). LCMS (ES, m/z) 757 [M+H] + . Intermediate 89. 2-[2,3-dihydro(2,2,3,3-2D4)-1,4-benzodioxine-6-sulfonyl]- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole Step 1. 2,3-dihydro(2,2,3,3-2H4)-1,4-benzodioxine-6-sulfonyl chloride [00295] To a solution of n-BuLi (5.6 mL, 2.5 M in THF) was added n-Bu 2 Mg (14 mL, 1 M in THF) at room temperature. The resulting mixture was stirred for 10 min at room temperature and treated with 6-bromo-2,3-dihydro(2,2,3,3-2H4)-1,4-benzodioxine (2.0 g, 9.04 mmol) in tetrahydrofuran (10 mL) added dropwise with stirring at -10 °C. The resulting mixture was stirred for 1 h and then added to a solution of sulfuryl chloride (16 mL) in toluene (8 mL) with stirring at -10 °C. The resulting mixture was stirred for 0.5 h and quenched with saturated aqueous ammonium chloride solution (30 mL). The product was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0 to 50% ethyl acetate/petroleum ether) to afford 2,3-dihydro(2,2,3,3-2H4)-1,4- benzodioxine-6-sulfonyl chloride as a yellow oil (1.3 g, 60%). Step 2. 1-[2,3-dihydro(2,2,3,3-2H4)-1,4-benzodioxine-6-sulfonyl]-1H- imidazole [00296] To a solution of 2,3-dihydro(2,2,3,3-H)-1,4-benzodioxine-6-sulfonyl chloride (1.3 g, 5.01 mmol) in DCM (20 mL) was added 1H-imidazole (742 mg, 10.9 mmol). The resulting solution was stirred for 2 h at room temperature. Then the reaction mixture was filtered and concentrated under vacuum to afford 1-[2,3-dihydro(2,2,3,3-2H4)-1,4-benzodioxine-6-sulfonyl]- 1H-imidazole as a white solid (1.2 g, 89%). LCMS (ES, m/z): 271 [M+H] + . Step 3. 2-[2,3-dihydro(2,2,3,3-2H4)-1,4-benzodioxine-6-sulfonyl]-1H, 2H,3H,4H,5H,6H- pyrrolo[3,4-c]pyrrole [00297] To a solution of 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole dihydrobromide (3.6 g, 13.2 mmol) in water (15 mL) and ethanol (15 mL) was added 1-[2,3-dihydro(2,2,3,3-2H4)-1,4- benzodioxine-6-sulfonyl]-1H-imidazole (1.2 g, 4.08 mmol). The resulting solution was stirred for 18 h at room temperature and then 48 h at 60 °C. After cooling to room temperature, the solution was basified to pH = 14 with sodium hydroxide and then extracted with DCM (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 2-[2,3-dihydro(2,2,3,3-2H4)-1,4-benzodioxine-6-sulfonyl]- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole as a yellow solid (500 mg, 39%). LCMS (ES, m/z): 313 [M+H] + . Methods for Preparing Final Compounds Method A (2S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H, 2H,3H,5H-pyrrolo[3,4- c]pyrrol-2-yl)-2-hydroxy-2-(2-methyl-1,3-benzoxazol-4-yl)eth an-1-one and (2R)-1-(5- [2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,5H-p yrrolo[3,4-c]pyrrol-2-yl)-2- hydroxy-2-(2-methyl-1,3-benzoxazol-4-yl)ethan-1-one Example 94-1. 1 st eluting isomer; Example 94-2. 2 nd eluting isomer [00298] To a solution of 5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,5H - pyrrolo[3,4-c]pyrrole (180 mg, 0.43 mmol) in N,N-dimethylformamide (10 mL) was added 2- hydroxy-2-(2-methyl-1,3-benzoxazol-4-yl)acetic acid (89 mg, 0.43 mmol), DIEA (110.4 mg, 0.86 mmol), HOBt (63.5 mg, 0.47 mmol) and EDCI (90 mg, 0.47 mmol). The resulting mixture was stirred for 2 h at room temperature and poured into water (50 mL). The resulting solution was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting crude product was purified by prep-TLC (eluting with 1:10 MeOH/DCM). The two enantiomers were separated by Chiral Prep-HPLC (Column: CHIRALPARK IC, 5 µm, 20 x 250 mm; Mobile Phase, A: DCM and B: MeOH (hold 85% B for 25 min); flow rate: 20 mL/min; Detector: UV 254/220 nm; RT: A (1 st ), 16.24 min; B (2 nd ), 21.61 min). The fractions of A were concentrated and lyophilized to afford 1- (5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,5 H-pyrrolo[3,4-c]pyrrol-2-yl)-2- hydroxy-2-(2-methyl-1,3-benzoxazol-4-yl)ethan-1-one, 1 st eluting isomer, as a white solid (39.8 mg, 19%). The fractions of B were concentrated and lyophilized to afford 1-(5-[2H,3H- [1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,5H-pyrrolo[ 3,4-c]pyrrol-2-yl)-2-hydroxy-2- (2-methyl-1,3-benzoxazol-4-yl)ethan-1-one, 2 nd eluting isomer, as a white solid (31.7 mg, 15%). Method B (2R)-2-(3-cyclopropyl-4-methoxyphenyl)-1-[5-(2,3-dihydro-1,4 -benzodioxine-6-sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-3-(methylamino) propan-1-one) and (2S)-2- (3-cyclopropyl-4-methoxyphenyl)-1-[5-(2,3-dihydro-1,4-benzod ioxine-6-sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-3-(methylamino) propan-1-one) Example 95-1. 1st eluting isomer; Example 95-2. 2 nd eluting isomer Step 1. methyl 3-{[(tert-butoxy)carbonyl](methyl)amino}-2-(3-cyclopropyl-4- methoxyphenyl)propanoate [00299] To a solution of methyl 2-(3-cyclopropyl-4-methoxyphenyl)prop-2-enoate (300 mg, 1.29 mmol) in tetrahydrofuran (10 mL) was added methylamine (2 mL). The resulting mixture was stirred for 30 min at room temperature and concentrated under vacuum to remove excess methylamine. The residue was dissolved in tetrahydrofuran (5 mL) and treated with di-tert-butyl dicarbonate (423 mg, 1.94 mmol). The reaction stirred for 16 h and was concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 5:95 ethyl acetate/petroleum ether) to afford methyl 3-{[(tert-butoxy)carbonyl](methyl)amino}- 2-(3-cyclopropyl-4- methoxyphenyl)propanoate as a light yellow oil (200 mg, 43%). LCMS (ES, m/z) 364 [M+H] + . Step 2. 3-{[(tert-butoxy)carbonyl](methyl)amino}-2-(3-cyclopropyl-4- methoxyphenyl)propanoic acid [00300] To a solution of methyl 3-{[(tert-butoxy)carbonyl](methyl)amino}-2-(3-cyclopropyl- 4- methoxyphenyl)propanoate (200 mg, 0.55 mmol) in tetrahydrofuran (5 mL) was added water (5 mL), and lithium hydroxide (66 mg, 2.75 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction mixture was washed with diethyl ether (1 x 5 mL) and then acidified to pH = 5 with saturated citric acid. The resulting solution was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 3-{[(tert-butoxy)carbonyl](methyl)amino}-2-(3- cyclopropyl-4-methoxyphenyl)propanoic acid as a light yellow oil (150 mg, 87%). LCMS (ES, m/z) 350 [M+H] + . Step 3. tert-butyl N-[2-(3-cyclopropyl-4-methoxyphenyl)-3-[5-(2,3-dihydro-1,4- benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyr rol-2-yl]-3-oxopropyl]-N- methylcarbamate [00301] To a solution of 3-{[(tert-butoxy)carbonyl](methyl)amino}-2-(3-cyclopropyl-4- methoxyphenyl)propanoic acid (150 mg, 0.43 mmol) in DMF (5 mL) was added 2-(2,3-dihydro- 1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c ]pyrrole (177 mg, 0.51 mmol), DIEA (0.23 mL, 1.29 mmol) and HATU (196 mg, 0.51 mmol). The resulting solution was stirred for 1 h and poured into water (5 mL). The product was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by prep-TLC (eluting with 1:1 ethyl acetate/petroleum ether) to afford tert-butyl N-[2-(3-cyclopropyl-4-methoxyphenyl)-3-[5-(2,3- dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrro lo[3,4-c]pyrrol-2-yl]-3- oxopropyl]-N-methylcarbamate as a light yellow oil (150 mg, 55%). LCMS (ES, m/z) 640 [M+H] + . Step 4. (2R)-2-(3-cyclopropyl-4-methoxyphenyl)-1-[5-(2,3-dihydro-1,4 -benzodioxine-6- sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-3-(me thylamino)propan-1-one) and (2S)-2-(3-cyclopropyl-4-methoxyphenyl)-1-[5-(2,3-dihydro-1,4 -benzodioxine-6- sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-3-(me thylamino)propan-1-one) [00302] To a solution of tert-butyl N-[2-(3-cyclopropyl-4-methoxyphenyl)-3-[5-(2,3-dihydro- 1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c ]pyrrol-2-yl]-3-oxopropyl]-N- methylcarbamate (150 mg, 0.16 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL). The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum. The reaction was quenched with saturated potassium carbonate solution (5 mL) and then extracted with dichloromethane (3 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5 µm, 19 x150 mm; Mobile Phase, A: water (containing 10 mmol/L NH4HCO3) and B: CH3CN (30% to 58% over 7 min); Flow rate: 20 mL/min; Detector: UV 254 nm). The product fractions were concentrated under vacuum. The two enantiomers were further separated by (Column: CHIRALPAK IC, 5 µm, 20x250 mm; Mobile Phase, A: MTBE (containing 0.1% DEA) and B: EtOH (keep 50% B over 18 min); Detector: UV 254/220 nm; Retention time: A (1 st ), 9.54 min; B (2 nd ), 12.96 min). The product fractions were concentrated and lyophilized to afford 2-(3-cyclopropyl-4- methoxyphenyl)-1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl )-1H,2H,3H,4H,5H,6H- pyrrolo[3,4-c]pyrrol-2-yl]-3-(methylamino)propan-1-one), 1 st eluting isomer, as a white solid (44.3 mg, 70%), and 2-(3-cyclopropyl-4-methoxyphenyl)-1-[5-(2,3-dihydro-1,4-benz odioxine-6- sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-3-(me thylamino)propan-1-one), 2 nd eluting isomer, as a white solid (30.2 mg 48%). Method C (2S)-2-(3-chlorophenyl)-1-[5-(2,3-dihydro-1,4-Benzodioxine-6 -sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2-fluoro-3-(met hylamino)propan-1-one and (2R)-2-(3-chlorophenyl)-1-[5-(2,3-dihydro-1,4-Benzodioxine-6 -sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2-fluoro-3-(met hylamino)propan-1-one Example 96-1. 1 st eluting isomer; Example 96-2. 2 nd eluting isomer Step 1. Tert-butyl N-[2-(3-chlorophenyl)-3-[5-(2,3-dihydro-1,4-benzodioxine-6-s ulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2-fluoro-3-oxop ropyl]carbamate [00303] To a solution of 3-[[(tert-butoxy)carbonyl]amino]-2-(3-chlorophenyl)-2- fluoropropanoic acid (120 mg, 0.34 mmol) in DMF (2 mL) was added HATU (155 mg, 0.41 mmol), 2-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6 H-pyrrolo[3,4-c]pyrrole (110 mg, 0.34 mmol) and DIEA (132 mg, 1.02 mmol). The resulting solution was stirred for 1 h at room temperature. The reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by prep-TLC (eluting with 2:1 ethyl acetate/petroleum ether) to afford tert-butyl N-[2-(3-chlorophenyl)-3-[5- (2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H- pyrrolo[3,4-c]pyrrol-2-yl]-2- fluoro-3-oxopropyl]carbamate as a yellow oil (120 mg, 58%). LCMS (ES, m/z) 608, 610 [M+H] + . Step 2. Tert-butyl N-[2-(3-chlorophenyl)-3-[5-(2,3-dihydro-1,4-benzodioxine-6-s ulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2-fluoro-3-oxop ropyl]-N-methylcarbamate [00304] To a solution of tert-butyl N-[2-(3-chlorophenyl)-3-[5-(2,3-dihydro-1,4-benzodioxine- 6-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2-f luoro-3-oxopropyl]carbamate (120 mg, 0.20 mmol) in THF (2 mL) was added sodium hydride (10 mg, 0.25 mmol, 60% dispersion in mineral oil) at 0 °C. The resulting solution was stirred for 30 min at 0 °C and then treated with iodomethane (28 mg, 0.20 mmol). The resulting mixture was stirred for 6 h at room temperature. The reaction mixture was poured into aqueous ammonium chloride solution (10 mL) and then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford tert-butyl N-[2-(3- chlorophenyl)-3-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl) -1H,2H,3H,4H,5H,6H- pyrrolo[3,4-c] pyrrol-2-yl]-2-fluoro-3-oxopropyl]-N-methylcarbamate as a yellow oil (120 mg, 98%). LCMS (ES, m/z) 622, 624 [M+H] + . Step 3. (2S)-2-(3-chlorophenyl)-1-[5-(2,3-dihydro-1,4-Benzodioxine-6 -sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2-fluoro-3-(met hylamino)propan-1-one and (2R)-2-(3-chlorophenyl)-1-[5-(2,3-dihydro-1,4-Benzodioxine-6 -sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2-fluoro-3-(met hylamino)propan-1-one [00305] To a solution of tert-butyl N-[2-(3-chlorophenyl)-3-[5-(2,3-dihydro-1,4-benzodioxine- 6-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c] pyrrol-2-yl]-2-fluoro-3-oxopropyl]-N-methyl carbamate (120 mg, 0.18 mmol) in dichloromethane (2 mL) was added TFA (0.4 mL). The resulting solution was stirred for 1 h at room temperature and concentrated under vacuum. The resulting crude product was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5 µm, 19 x 150 mm; Mobile Phase, A: water (containing 10 mmol/L NH 4 HCO 3 ) and B: CH 3 CN (28% to 50% over 15 min); Flow rate: 20 mL/min; Detector: UV 254 nm). The two enantiomers were further separated by (Column: CHIRALPAK IF, 5 µm, 20 x 250 mm; Mobile Phase, A: methanol (containing 0.1% DEA) and B: DCM (hold 50% B over 15 min); Detector: UV 254/220 nm; Retention time: A (1 st ), 8.817 min; B (2 nd ), 11.059 min). The product fractions of A were concentrated and lyophilized to afford 2-(3-chlorophenyl)-1-[5-(2,3-dihydro-1,4- benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyr rol-2-yl]-2-fluoro-3- (methylamino)propan-1-one, 1 st eluting isomer, as a white solid (24.4 mg, 26%). The product fractions of B were concentrated and lyophilized to afford 2-(3-chloro-4-cyclopropoxyphenyl)-1- [5-(2,3-Dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H, 6H-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(methylamino)propan-1-one, 2 nd eluting isomer, as a white solid (11.9 mg, 12%). Method D (2S)-1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H ,4H,5H,6H-pyrrolo[3,4- c]pyrrol-2-yl]-2-(7-fluoro-2-methyl-2,3-dihydro-1H-isoindol- 4-yl)-2-hydroxyethan-1-one and (2R)-1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H ,4H,5H,6H-pyrrolo[3,4- c]pyrrol-2-yl]-2-(7-fluoro-2-methyl-2,3-dihydro-1H-isoindol- 4-yl)-2-hydroxyethan-1-one Example 97-1. 1 st eluting isomer; Example 97-2. 2 nd eluting isomer Step 1. 1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5 H,6H-pyrrolo[3,4- c]pyrrol-2-yl]-2-(2,3- dihydro-1H-isoindol-4-yl)-2-hydroxyethan-1-one [00306] To a solution of tert-butyl 4-[2-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c] pyrrol-2-yl]-1-hydroxy-2-oxoethyl]-2,3-dihydro-1H- isoindole-2-carboxylate (780 mg, 1.34 mmol) in dichloromethane (6 mL) was added hydrochloric acid (6 mL, 4 N in 1,4-dioxane). The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum to afford 1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2-(2,3-dihydro- 1H-isoindol-4-yl)-2- hydroxyethan-1-one HCl salt as a dark red solid (680 mg, 62%). LCMS (ES, m/z) 484 [M+H] + . Step 2. (2R)-1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H ,4H,5H,6H- pyrrolo[3,4-c]pyrrol-2-yl]-2-hydroxy-2-(2-methyl-2,3-dihydro -1H-isoindol-4-yl)ethan-1-one and (2S)-1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H ,4H,5H,6H-pyrrolo[3,4- c]pyrrol-2-yl]-2-hydroxy-2-(2-methyl-2,3-dihydro-1H-isoindol -4-yl)ethan-1-one [00307] To a solution of 1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl] -2-(2,3-dihydro-1H-isoindol-4-yl)-2- hydroxyethan-1-one (680 mg, 1.40 mmol) in methanol (7 mL) was added formaldehyde (7 mL, 40wt% in water). The resulting solution was stirred for 2 h at room temperature and then treated with sodium triacetoxyborohydride (893 mg, 4.21 mmol). The resulting mixture was stirred for 16 h at room temperature and concentrated under vacuum. The crude product was purified by prep- TLC (eluting with 1:10 MeOH/DCM). The enantiomers were separated by prep-Chiral HPLC (Column: CHIRAL ART Cellulose-SB, 5 µm, 20 x 250 mm; Mobile Phase, A: DCM and B: EtOH (0.1% DEA) (keep 40% B over 10 min); Detector: UV 254/220 nm; Retention time: 1 st , 6.63 min; 2 nd , 8.63 min. The product fractions were concentrated and lyophilized to afford 1-[5-(2,3- dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrro lo[3,4-c]pyrrol-2-yl]-2- hydroxy-2-(2-methyl-2,3-dihydro-1H-isoindol-4-yl)ethan-1-one , 1 st eluting isomer, as a white solid (41.2 mg, 6%), and 1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5 H,6H- pyrrolo[3,4-c]pyrrol-2-yl]-2-hydroxy-2-methyl-2,3-dihydro-1H -isoindol-4-yl)ethan-1-one, 2 nd eluting isomer, as a white solid (42.4 mg , 5%). Method E (2S)-2-(2-cyclopropyl-2,3-dihydro-1H-isoindol-4-yl)-1-[5-(2, 3-dihydro-1,4-benzodioxine-6- sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2-hyd roxyethan-1-one and (2R)- 2-(2-cyclopropyl-2,3-dihydro-1H-isoindol-4-yl)-1-[5-(2,3-dih ydro-1,4-benzodioxine-6- sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2-hyd roxyethan-1-one
Example 98-1. 1 st eluting isomer; Example 98-2. 2 nd eluting isomer Step 1. Tert-butyl4-{2-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)- 1H,2H,3H,4H,5H,6H- pyrrolo[3,4-c]pyrrol -2-yl]-2-oxoacetyl}-2,3-dihydro-1H-isoindole-2-carboxylate [00308] To a solution of 2-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6 H- pyrrolo [3,4-c]pyrrole (529 mg, 1.63 mmol) in DMF (3 mL) was added 2-[2-[(tert- butoxy)carbonyl]- 2,3-dihydro-1H-isoindol-4-yl]-2-oxoacetic acid (500 mg, 1.46 mmol), DIEA (665 mg, 4.89 mmol) and HATU (783 mg, 1.96 mmol). The resulting solution was stirred for 1 h at room temperature. The reaction mixture was poured into water (5 mL) and then extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by prep-TLC (eluting with 3:1 ethyl acetate/petroleum ether) to afford tert-butyl 4-[2-[5-(2,3-dihydro-1,4- benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyr rol-2-yl] -2-oxoacetyl]-2,3- dihydro-1H-isoindole-2-carboxylate as a yellow oil (300 mg, 30%). LCMS (ES, m/z) 582 [M+H] + . Step 2. 1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5 H,6H-pyrrolo[3,4- c]pyrrol-2-yl] -2-(2,3-dihydro-1H-isoindol-4-yl)ethane-1,2-dione [00309] To a solution of tert-butyl 4-[2-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo [3,4-c]pyrrol-2-yl]-2-oxoacetyl]-2,3-dihydro-1H-isoindole-2- carboxylate (300 mg, 0.45 mmol) in DCM (6 mL) was added TFA (1.5 mL). The resulting mixture was stirred for 2 h at room temperature and concentrated under vacuum. The resulting mixture was basified to pH = 8 with saturated potassium carbonate solution and then extracted with dichloromethane (2 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 1-[5-(2,3-dihydro-1,4-benzodioxine-6- sulfonyl)-1H,2H,3H,4H,5H,6H -pyrrolo[3,4-c]pyrrol-2-yl]-2-(2,3-dihydro-1H-isoindol-4- yl)ethane-1,2-dione as a yellow solid (200 mg, crude). LCMS (ES, m/z) 482 [M+H] + . Step 3. 1-(2-cyclopropyl-2,3-dihydro-1H-isoindol-4-yl)-2-[5-(2,3-dih ydro-1,4-benzodioxine- 6-sulfonyl) -1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethane-1,2-dion e [00310] To a solution of 1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl] -2-(2,3-dihydro-1H-isoindol-4-yl)ethane-1,2- dione (217 mg, 0.38 mmol) in 1,2-dichloroethane (15 ml) was added copper (II) acetate (90 mg, 0.43 mmol), 2,2’-bipyridine (70 mg, 0.43 mmol), cyclopropylboronic acid (77 mg, 0.85 mmol) and sodium carbonate (95 mg, 0.86 mmol). The resulting mixture was stirred for 16 h at 70 °C under air atmosphere and cooled to room temperature. The reaction mixture was filtered and poured into water (10 mL). The resulting solution was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting crude product was purified by prep-TLC (eluting with 3:1 ethyl acetate/petroleum ether) to afford 1-(2-cyclopropyl-2,3-dihydro-1H-isoindol-4-yl)-2-[5-(2,3- dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrro lo[3,4-c]pyrrol-2-yl]ethane- 1,2-dione as a white solid (60 mg, 26%). LCMS (ES, m/z) 522 [M+H] + . Step 4. (2S)-2-(2-cyclopropyl-2,3-dihydro-1H-isoindol-4-yl)-1-[5-(2, 3-dihydro-1,4- benzodioxine-6-sulfonyl) -1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2-hydroxyethan - 1-one and (2R)-2-(2-cyclopropyl-2,3-dihydro-1H-isoindol-4-yl)-1-[5-(2, 3-dihydro-1,4- benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyr rol-2-yl]-2-hydroxyethan- 1-one [00311] To a solution of 1-(2-cyclopropyl-2,3-dihydro-1H-isoindol-4-yl)-2-[5-(2,3-dih ydro- 1,4-benzodioxine-6-sulfonyl) -1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethane-1,2-dion e (60 mg, 0.10 mmol) in methanol (1.5 mL) was added sodium borohydride (9 mg, 0.23 mmol). The resulting solution was stirred for 2 h at room temperature. The reaction mixture was poured into water (5 mL) and then extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 10:1 DCM/MeOH) and further purified by Prep-HPLC (Column: XBridge Prep C18 OBD Column (19 × 150 mm) 5 um; Mobile Phase A: Water (10 mmoL/L NH4HCO3), Mobile Phase B: MeCN (30% B to 55% B over 7 min); Flow rate: 20 mL/min; Detector: 254/220 nm). The two enantiomers were further separated by Chiral-Prep-HPLC (Column: CHIRALPAK IE, 2 x 25 cm, 5 µm; Mobile Phase A: MeOH (containing 0.1% DEA), Mobile Phase B: DCM (Hold 35% B over 14 min); Flow rate: 19 mL/min; Detector: 220/254 nm; A: 9.39 min; B: 12.4 min). The fractions of A were concentrated and lyophilized to afford 2-(2-cyclopropyl-2,3-dihydro-1H-isoindol-4-yl)-1-[5-(2,3-dih ydro-1,4- benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyr rol-2-yl]-2-hydroxyethan-1- one, 1 st eluting isomer, as a white solid (5.0 mg, 10%). The fractions of B were concentrated and lyophilized to afford 2-(2-cyclopropyl-2,3-dihydro-1H-isoindol-4-yl)-1-[5-(2,3-dih ydro-1,4- benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyr rol-2-yl]-2-hydroxyethan-1- one, 2 nd eluting isomer, as a white solid (5.3 mg, 10%). Method F Example 99-1. (2S)-2-(3-chlorophenyl)-1-[5-(2,3-dihydro-1,4-benzodioxine-6 -sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-3-(methylamino) propan-1-one Step 1. Tert-butyl N-[(2S)-2-(3-chlorophenyl)-3-[5-(2,3-Dihydro-1,4-benzodioxin e-6- sulfonyl)1H,2H,3H,4H,5H, 6H-pyrrolo[3,4-c]pyrrol-2-yl]-3-oxopropyl]-N-methylcarbamate [00312] To a solution of (2R)-3-{[(tert-butoxy)carbonyl](methyl)amino}-2-(3- chlorophenyl)propanoic acid (2.30 g, 7.34 mmol) in N,N-dimethylformamide (20 mL) was added HATU (3.07 g, 8.08 mmol), 2-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6 H- pyrrolo[3,4-c]pyrrole hydrochloride (2.52 g, 7.34 mmol), and DIEA (3.82 mL, 22.1 mmol). The resulting solution was stirred for 2 h at rt. The reaction mixture was poured into water (100 mL) and then extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with 1:15 ethyl acetate/dichloromethane) to afford tert-butyl N-[(2S)-2-(3-chlorophenyl)-3-[5-(2,3-Dihydro-1,4-benzodioxin e-6-sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-3-oxopropyl]-N- methylcarbamate as a white solid (3.5 g, 79%). 1 H-NMR (DMSO-d6, 400 MHz) d (ppm): 7.40-7.18 (m, 6H), 7.07-7.06 (m, 1H), 4.45-4.22 (m, 5H), 4.11-3.88 (m, 7H), 3.88-3.58 (m, 2H), 3.44-3.36 (m, 1H), 2.75-2.67 (m, 3H), 1.27-1.16 (m, 9H). LCMS (ES, m/z) 604, 606 [M+H] + . Step 2. (2S)-2-(3-chlorophenyl)-1-[5-(2,3-dihydro-1,4-Benzodioxine-6 -sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-3-(methylamino) propan-1-one [00313] To a solution of tert-butyl N-[(2S)-2-(3-chlorophenyl)-3-[5-(2,3-Dihydro-1,4- benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyr rol-2-yl]-3-oxopropyl]-N- methylcarbamate (1.5 g, 2.49 mmol) in ethyl acetate (10 mL) was added a solution of hydrochloric acid (10 mL, 4 N in 1,4-dioxane). The resulting solution was stirred for 3 h at 25 °C. The mixture was concentrated under vacuum to about 1/3 volume and the solids were collected by filtration. The solids were treated with EtOAc (10 mL) at 70 °C, filtered at room temperature, and dissolved with saturated potassium carbonate solution/EA (1:1, 10 mL). The resulting solution was stirred for 3 h and then extracted with EA (3 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford (2S)-2-(3- chlorophenyl)-1-[5-(2,3-dihydro-1,4-Benzodioxine-6-sulfonyl) -1H,2H,3H,4H,5H,6H- pyrrolo[3,4-c]pyrrol-2-yl]-3-(methylamino)propan-1-one as a white solid (1 g, 80%). 1 H-NMR (DMSO-d6, 400 MHz) d (ppm): 7.36-7.25 (m, 6H), 7.07-7.06 (m, 1H), 4.40-4.29 (m, 5H), 4.06- 3.88 (m, 8H), 3.06-3.01 (m, 1H), 2.60-2.50 (m, 1H), 2.23 (s, 3H), 1.66 (s, 1H). LCMS (ES, m/z) 504, 506 [M+H] + . Method J (2R)-1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H ,4H,5H,6H-pyrrolo[3,4- c]pyrrol-2-yl]-3-[(oxetan-3-yl)amino]-2-phenylpropan-1-one and (2S)-1-[5-(2,3-dihydro-1,4- benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyr rol-2-yl]-3-[(oxetan-3- yl)amino]-2-phenylpropan-1-one Example 103-1.1 st eluting isomer; Example 103-2.2 nd eluting isomer [00314] To a solution of 3-[(oxetan-3-yl)amino]-2-phenylpropanoic acid (60 mg, 0.27 mmol) in DMF (10 mL) was added HATU (123 mg, 0.32 mmol), 2-(2,3-dihydro-1,4-benzodioxine-6- sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole hydrochloride (93 mg, 0.27 mmol) and DIEA (0.13 mL, 0.81 mmol). The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was poured into water (5 mL) and then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5 µm, 30 x 150 mm; Mobile Phase, A: water (containing 10 mmol/L NH4HCO3) and B: CH3CN (25% to 45% over 7 min); Flow rate: 60 mL/min; Detector: UV 254 nm). The product fractions were concentrated under vacuum. The two enantiomers were further separated by Chiral Prep-HPLC (Column: CHIRALPAK IF, 5 µm, 20 x 250 mm; Mobile Phase, A: MeOH (containing 0.1% DEA) and B: DCM (keep 10% B over 16 min); Flow rate: 20 mL/min; Detector: UV 254/220 nm; Retention time: 1 st , 17.285 min; 2 nd , 21.532 min). The product fractions were concentrated and lyophilized to afford 1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-3-[(oxetan-3-yl )amino]-2-phenylpropan-1-one, 1 st eluting isomer, as a white solid (1 mg, 1.4%), and 1-[5-(2,3-dihydro-1,4-benzodioxine-6- sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-3-[(o xetan-3-yl)amino]-2- phenylpropan-1-one, 2 nd eluting isomer, as a white solid (1 mg, 1.4%). Method R (2S)-2-(2,3-dihydro-1-benzofuran-7-yl)-1-(5-{2H,3H-[1,4]diox ino[2,3-b]pyridine-7- sulfonyl}-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-2-hyd roxyethan-1-one and (2R)- 2-(2,3-dihydro-1-benzofuran-7-yl)-1-(5-{2H,3H-[1,4]dioxino[2 ,3-b]pyridine-7-sulfonyl}- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-2-hydroxyethan- 1-one Example 112-1. 1 st eluting isomer; Example 112-2. 2 nd eluting isomer Step 1. 1-(2,3-dihydro-1-benzofuran-7-yl)-2-(5-{2H,3H-[1,4]dioxino[2 ,3-b]pyridine-7- sulfonyl}-1H,2H,3H,4H,5H,6H -pyrrolo[3,4-c]pyrrol-2-yl)ethane-1,2-dione [00315] To a solution of 2-(2,3-dihydro-1-benzofuran-7-yl)-2-oxoacetic acid (250 mg, 1.30 mmol) in DMF (4 mL) was added 2-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole (450 mg, 1.30 mmol), DIEA (0.43 mL, 2.60 mmol), and HATU (544 mg, 1.43 mmol). The resulting solution was stirred for 1 h at room temperature. The reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by prep-TLC (eluting with 1:1 ethyl acetate/petroleum ether) to afford 1-(2,3-dihydro-1-benzofuran-7-yl)-2-(5-{2H,3H- [1,4]dioxino[2,3-b]pyridine-7-sulfonyl}-1H,2H,3H,4H,5H,6H-py rrolo[3,4-c]pyrrol-2-yl)ethane- 1,2-dione as a light yellow solid (200 mg, 32%). LCMS (ES, m/z): 484 [M+H] + . Step 2. (2S)-2-(2,3-dihydro-1-benzofuran-7-yl)-1-(5-{2H,3H-[1,4]diox ino[2,3-b]pyridine-7- sulfonyl}-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-2-hyd roxyethan-1-one and (2R)- 2-(2,3-dihydro-1-benzofuran-7-yl)-1-(5-{2H,3H-[1,4]dioxino[2 ,3-b]pyridine-7-sulfonyl}- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-2-hydroxyethan- 1-one [00316] To a solution of 1-(2,3-dihydro-1-benzofuran-7-yl)-2-(5-{2H,3H-[1,4]dioxino[2 ,3- b]pyridine-7-sulfonyl}-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrro l-2-yl)ethane-1,2-dione (200 mg, 0.41 mmol) in tetrahydrofuran (2 mL) was added sodium borohydride (8 mg, 0.21 mmol). The resulting solution was stirred for 30 min at 0 °C. The reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5 µm, 19 x 150 mm; Mobile Phase, A: water (containing 10 mmol/L NH4HCO3) and B: MeCN (15% to 45% over 10 min); Flow rate: 20 mL/min; Detector: UV 254 nm). The product fractions were concentrated under vacuum. The two enantiomers were separated by Chiral Prep-HPLC (Column: CHIRALPAK IF, 5 µm, 20 x 250 mm; Mobile Phase, A: MeOH (containing 0.1% DEA) and B: DCM (keep 40% B over 50 min); Flow rate: 15 mL/min; Detector: UV 254/220 nm; Retention time: 1 st , 19.223 min; 2 nd , 29.404 min). The product fractions were concentrated and lyophilized to afford 2-(2,3-dihydro-1-benzofuran-7-yl)-1-(5-{2H,3H-[1,4]dioxino[2 ,3-b]pyridine-7- sulfonyl}-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-2-hyd roxyethan-1-one, 1 st eluting isomer, as a white solid (30.5 mg, 15%), and 2-(2,3-dihydro-1-benzofuran-7-yl)-1-(5-{2H,3H- [1,4]dioxino[2,3-b]pyridine-7-sulfonyl}-1H,2H,3H,4H,5H,6H-py rrolo[3,4-c]pyrrol-2-yl)-2- hydroxyethan-1-one, 2 nd eluting isomer, as a white solid (33.5 mg, 17%). Method S Example 114-1. (R)-3-((cyclopentylmethyl)amino)-1-(5-((2,3-dihydrobenzo[b][ 1,4]dioxin-6- yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl )-2-phenylpropan-1-one [00317] To tert-butyl (R)-(3-(5-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-oxo-2-phenylpropy l)carbamate (180 µl, 36.0 µmol; 0.2M in dioxane) was added acetic acid (150 µl, 30.0 µmol; 0.2M in dioxane) and DCE, cyclopentanecarbaldehyde (180 µl, 36.0 µmol; 0.2M in dioxane) and sodium triacetoxyborohydride (300 µl, 60.0 µmol; 0.2M in dioxane). The reaction was heated at 50 °C for 4 h. The reaction was run through an SCX-SPE cartridge and eluted with 2 ml of 10% MeOH/EtOAc (ETW) followed by 2 ml of 2M Ammonia/MeOH (ETC). The basic eluent was dried under a stream of N2 and the product was purified by reverse phase HPLC. Method W (2S)-2-{3-[(3aR,6aR)-3a-fluoro-5-methyl-octahydropyrrolo[3,4 -c]pyrrol-2-yl]phenyl}-1-[5- (2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H- pyrrolo[3,4-c]pyrrol-2-yl]- 2-hydroxyethan-1-one (first eluting isomer); and (2R)-2-{3-[(3aR,6aR)-3a-fluoro-5-methyl- octahydropyrrolo[3,4-c]pyrrol-2-yl]phenyl}-1-[5-(2,3-dihydro -1,4-benzodioxine-6-sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2-hydroxyethan- 1-one (second eluting isomer); and (2S)-2-{3-[(3aS,6aS)-3a-fluoro-5-methyl-octahydropyrrolo[3,4 -c]pyrrol-2- yl]phenyl}-1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H ,2H,3H,4H,5H,6H- pyrrolo[3,4-c]pyrrol-2-yl]-2-hydroxyethan-1-one (third eluting isomer); and (2R)-2-{3- [(3aS,6aS)-3a-fluoro-5-methyl-octahydropyrrolo[3,4-c]pyrrol- 2-yl]phenyl}-1-[5-(2,3- dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrro lo[3,4-c]pyrrol-2-yl]-2- hydroxyethan-1-one (fourth eluting isomer) Example 109-2. 1 st eluting isomer; Example 109-3. 2 nd eluting isomer; Example 109-4. 3 rd eluting isomer; Example 109-5.4 th eluting isomer Step 1. Ethyl (2E)-4-{[(tert-butoxy)carbonyl]amino}-2-fluorobut-2-enoate [00318] To a solution of ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (10 g, 40.5 mmol) in THF (60 mL), was added n-BuLi (16.5 mL, 2.5 M in hexnae) at -78 °C and stirred for 1 h, then tert-butyl N-(2-oxoethyl)carbamate (6.57 g, 40.4 mmol) in THF (10 mL) was added. The resulting solution was stirred for 3 h at -78 °C. The reaction mixture was poured into saturated sodium bicarbonate (100 mL) and then extracted with ethyl acetate (3x100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 20:80 ethyl acetate/petroleum ether) to afford ethyl (2E)-4-{[(tert-butoxy)carbonyl]amino}-2-fluorobut- 2-enoate as light yellow oil (4.1 g, 38.93%). LCMS (ES, m/z): 248 [M+H] + . Step 2. Ethyl (3S,4R)-1-benzyl-4-({[(tert-butoxy)carbonyl]amino}methyl)-3- fluoropyrrolidine-3-carboxylate [00319] To a solution of ethyl (2E)-4-[[(tert-butoxy)carbonyl]amino]-2-fluorobut-2-enoate (2.5 g, 10.111 mmol) in TFA (100 mL) and DCM (0.1 mL) was added benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (2.64 mg, 11.1 mmol). The resulting solution was stirred for 16 h at 25 °C and then concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with 0:100 to 10:90 ethyl acetate/petroleum ether) to afford ethyl (3S,4R)-1-benzyl-4-({[(tert-butoxy)carbonyl]amino}methyl)-3- fluoropyrrolidine- 3-carboxylate as light yellow oil (1.2 g, 31.20%). LCMS (ES, m/z): 381 [M+H] + . Step 3. (3aR,6aS)-5-benzyl-6a-fluoro-octahydropyrrolo[3,4-c]pyrrol-1 -one [00320] To a solution of ethyl (3S,4R)-1-benzyl-4-({[(tert-butoxy)carbonyl]amino}methyl)-3- fluoropyrrolidine-3-carboxylate (1.20 g, 3.15 mmol) in DCM (20 mL) was added TFA (10 mL). The resulting solution was stirred for 2 h at 25 °C and then concentrated under vacuum. The reaction mixture was poured into saturated sodium bicarbonate (100 mL) and then extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford (3aR,6aS)-5-benzyl-6a-fluoro- octahydropyrrolo[3,4-c]pyrrol-1-one as a white solid (510 mg, 69.02%). LCMS (ES, m/z): 235 [M+H] + . Step 4. (3aR,6aR)-2-benzyl-3a-fluoro-octahydropyrrolo[3,4-c]pyrrole [00321] To a solution of (3aR,6aS)-5-benzyl-6a-fluoro-octahydropyrrolo[3,4-c]pyrrol-1 -one (500 mg, 2.13 mmol) in THF (10 mL) was added 1.0 M BH 3 -THF (10.8 mL, 10.7 mmol). The resulting solution was stirred for 16 h at 60 °C and quenched by the addition of 10 mL of 1.0 M HCl and stirred for 2 h at 60 °C, concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 10:90 methylene chloride/methanol) to afford (3aR,6aR)-2-benzyl-3a-fluoro-octahydropyrrolo[3,4-c]pyrrole as light yellow oil (300 mg, 63.81%). LCMS (ES, m/z): 221 [M+H] + . Step 5. (3aR,6aR)-2-benzyl-3a-fluoro-5-methyl-octahydropyrrolo[3,4-c ]pyrrole [00322] To a solution of (3aR,6aR)-2-benzyl-3a-fluoro-octahydropyrrolo[3,4-c]pyrrole (300 mg, 1.36 mmol) in MeOH (15 mL) was added HCHO (2 mL) and stirred for 30 min, then STAB (865 mg, 4.09 mmol) was added. The resulting solution was stirred for 16 h at 25 °C and then concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 10:90 methylene chloride/methanol) to afford (3aR,6aR)-2-benzyl-3a- fluoro-5-methyl-octahydropyrrolo[3,4-c]pyrrole as colorless oil (220 mg, 68.94%). LCMS (ES, m/z): 235 [M+H] + . Step 6. (3aS,6aS)-3a-fluoro-2-methyl-octahydropyrrolo[3,4-c]pyrrole [00323] To a solution of (3aR,6aR)-2-benzyl-3a-fluoro-5-methyl-octahydropyrrolo[3,4- c]pyrrole (220 mg, 0.939 mmol) in MeOH (15 mL), was added Pd/C (21.9 mg) under hydrogen. The resulting solution was stirred for 3 h at 25 °C. The reaction mixture was filtered and concentrated to afford (3aS,6aS)-3a-fluoro-2-methyl-octahydropyrrolo[3,4-c]pyrrole as light yellow oil (100 mg, 73.87%). LCMS (ES, m/z): 145 [M+H] + . Step 7. (2S)-2-{3-[(3aR,6aR)-3a-fluoro-5-methyl-octahydropyrrolo[3,4 -c]pyrrol-2- yl]phenyl}-1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H ,2H,3H,4H,5H,6H- pyrrolo[3,4-c]pyrrol-2-yl]-2-hydroxyethan-1-one (first eluting isomer) (2R)-2-{3-[(3aR,6aR)-3a-fluoro-5-methyl-octahydropyrrolo[3,4 -c]pyrrol-2-yl]phenyl}-1-[5- (2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H- pyrrolo[3,4-c]pyrrol-2-yl]- 2-hydroxyethan-1-one (second eluting isomer) (2S)-2-{3-[(3aS,6aS)-3a-fluoro-5-methyl-octahydropyrrolo[3,4 -c]pyrrol-2-yl]phenyl}-1-[5- (2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H- pyrrolo[3,4-c]pyrrol-2-yl]- 2-hydroxyethan-1-one (third eluting isomer) (2R)-2-{3-[(3aS,6aS)-3a-fluoro-5-methyl-octahydropyrrolo[3,4 -c]pyrrol-2-yl]phenyl}-1-[5- (2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H- pyrrolo[3,4-c]pyrrol-2-yl]- 2-hydroxyethan-1-one (fourth eluting isomer) [00324] To a solution of (3aS,6aS)-3a-fluoro-2-methyl-octahydropyrrolo[3,4-c]pyrrole (85 mg, 0.59 mmol) in toluene (15 mL), was added RuPhos (27.5 mg, 0.06 mmol ), RuPhos Palladacycle Gen.3 (49.3 mg, 0.06 mmol), 2-(3-bromophenyl)-1-[5-(2,3-dihydro-1,4-benzodioxine-6- sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2-hyd roxyethan-1-one (307 mg, 1.77 mmol) and cesium carbonate (577 mg, 1.77 mmol). The resulting solution was stirred for 16 h at 100 °C and cooled to room temperature. The reaction mixture was poured into water (50 mL) and then extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5 µm, 19 x 150 mm; Mobile Phase, A: water (containing 10 mmol/L NH4HCO3) and B: CH3CN (30% to 60% over 7 min); Flow rate: 25 mL/min; Detector: UV 254 nm; Rt: 6.5 min). The product fractions were concentrated under vacuum. The two enantiomers were further separated by Chiral Prep-HPLC (Column: CHIRALPAK IE, 5 µm, 20 x 250 mm; Mobile Phase, A: MTBE (containing 0.2% IPA) and B: MeOH (keep 50% B over 30 min); Flow rate: 13 mL/min; Detector: UV 254/220 nm; M1, 16.249 min; M2, 23.328 min). From M1: Column: CHIRAL ART Amylose-SA S-5um, 250 x 20mm; Mobile Phase A: CO2: 65, Mobile Phase B: MeOH:DCM=1:1(2nM NH3-MEOH): 35; Flow rate: 50 mL/min; 220 nm; 0A:RT:14.53 min; 0B: RT :16.5 min. From M2: Column: Chiralpak IA, 20 x 250 mm, 5um; Mobile Phase A: MTBE(containing 0.2% IPA), Mobile Phase B: EtOH; Flow rate: 12 mL/min; Gradient: 50 B to 50 B in 40 min; 220/254 nm; 0C: RT: 24.603 min; 0D: RT: 32.591 min. The product fractions were concentrated and lyophilized to afford (2S)- 2-{3-[(3aR,6aR)-3a-fluoro-5-methyl-octahydropyrrolo[3,4-c]py rrol-2-yl]phenyl}-1-[5-(2,3- dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrro lo[3,4-c]pyrrol-2-yl]-2- hydroxyethan-1-one as a white solid (1.3 mg, 0.38%). (2R)-2-{3-[(3aR,6aR)-3a-fluoro-5-methyl- octahydropyrrolo[3,4-c]pyrrol-2-yl]phenyl}-1-[5-(2,3-dihydro -1,4-benzodioxine-6-sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2-hydroxyethan- 1-one as a white solid (2.0 mg, 0.58%). (2S)-2-{3-[(3aS,6aS)-3a-fluoro-5-methyl-octahydropyrrolo[3,4 -c]pyrrol-2-yl]phenyl}-1- [5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H,4H,5H, 6H-pyrrolo[3,4-c]pyrrol-2-yl]- 2-hydroxyethan-1-one as a white solid (5.7mg, 1.6%). (2R)-2-{3-[(3aS,6aS)-3a-fluoro-5-methyl- octahydropyrrolo[3,4-c]pyrrol-2-yl]phenyl}-1-[5-(2,3-dihydro -1,4-benzodioxine-6-sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]-2-hydroxyethan- 1-one as a white solid (5.3 mg, 1.5%). [00325] (2S)-2-{3-[(3aR,6aR)-3a-fluoro-5-methyl-octahydropyrrolo[3,4 -c]pyrrol-2- yl]phenyl}-1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H ,2H,3H,4H,5H,6H-pyrrolo[3,4- c]pyrrol-2-yl]-2-hydroxyethan-1-one (first eluting isomer): 1 H NMR (400 MHz, DMSO-d6) d :7.28-7.23 (m, 2H), 7.17-7.13 (m, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.70-6.68 (m, 2H), 6.63-6.61 (m, 1H), 5.52 (d, J = 6.8 Hz, 1H), 5.07 (d, J = 6.4 Hz, 1H), 4.33-4.29 (m, 4H), 4.26-4.22 (m, 1H), 4.14- 4.08 (m, 1H), 4.05-3.96 (m, 5H), 3.95-3.82 (m, 1H), 3.65-3.40 (m, 3H), 3.02-2.96 (m, 1H), 2.95- 2.71 (m, 4H), 2.38-2.31 (m, 1H), 2.24 (s, 3H). LCMS (ES, m/z) 585 [M+H] + . [00326] (2R)-2-{3-[(3aR,6aR)-3a-fluoro-5-methyl-octahydropyrrolo[3,4 -c]pyrrol-2- yl]phenyl}-1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H ,2H,3H,4H,5H,6H-pyrrolo[3,4- c]pyrrol-2-yl]-2-hydroxyethan-1-one (second eluting isomer): 1 H NMR (400 MHz, DMSO-d6) d :7.28-7.23 (m, 2H), 7.17-7.13 (m, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.70-6.68 (m, 2H), 6.63-6.61 (m, 1H), 5.52 (d, J = 6.8 Hz, 1H), 5.07 (d, J = 6.4 Hz, 1H), 4.33-4.29 (m, 4H), 4.26-4.22 (m, 1H), 4.14- 4.08 (m, 1H), 4.05-3.96 (m, 5H), 3.95-3.82 (m, 1H), 3.65-3.40 (m, 3H), 3.02-2.96 (m, 1H), 2.95- 2.71 (m, 4H), 2.38-2.31 (m, 1H), 2.26 (s, 3H). LCMS (ES, m/z) 585 [M+H] + . [00327] (2S)-2-{3-[(3aS,6aS)-3a-fluoro-5-methyl-octahydropyrrolo[3,4 -c]pyrrol-2- yl]phenyl}-1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H ,2H,3H,4H,5H,6H-pyrrolo[3,4- c]pyrrol-2-yl]-2-hydroxyethan-1-one (third eluting isomer): 1 H NMR (400 MHz, DMSO-d6) d :7.28-7.23 (m, 2H), 7.17-7.13 (m, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.70-6.68 (m, 2H), 6.63-6.61 (m, 1H), 5.52 (d, J = 6.8 Hz, 1H), 5.07 (d, J = 6.4 Hz, 1H), 4.33-4.29 (m, 4H), 4.26-4.22 (m, 1H), 4.14- 4.08 (m, 1H), 4.05-3.96 (m, 5H), 3.95-3.82 (m, 1H), 3.65-3.40 (m, 3H), 3.02-2.96 (m, 1H), 2.95- 2.71 (m, 4H), 2.38-2.31 (m, 1H), 2.26 (s, 3H). LCMS (ES, m/z) 585 [M+H] + . LCMS (ES, m/z) 585 [M+H] + [00328] (2R)-2-{3-[(3aS,6aS)-3a-fluoro-5-methyl-octahydropyrrolo[3,4 -c]pyrrol-2- yl]phenyl}-1-[5-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H ,2H,3H,4H,5H,6H-pyrrolo[3,4- c]pyrrol-2-yl]-2-hydroxyethan-1-one (fourth eluting isomer): 1 H NMR (400 MHz, DMSO-d 6 ) d:7.28-7.23 (m, 2H), 7.17-7.13 (m, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.70-6.68 (m, 2H), 6.63-6.61 (m, 1H), 5.52 (d, J = 6.8 Hz, 1H), 5.07 (d, J = 6.4 Hz, 1H), 4.33-4.29 (m, 4H), 4.26-4.22 (m, 1H), 4.14- 4.08 (m, 1H), 4.05-3.96 (m, 5H), 3.95-3.82 (m, 1H), 3.65-3.40 (m, 3H), 3.02-2.96 (m, 1H), 2.95- 2.71 (m, 4H), 2.38-2.31 (m, 1H), 2.26 (s, 3H). LCMS (ES, m/z) 585 [M+H] + . LCMS (ES, m/z) 585 [M+H] + Table 9. [00329] As set forth in Table 10, IC50 values are defined as follows: £ 25 µM and > 2 µM (+); £ 2 µM and > 0.2 µM (++); £ 0.2 µM and > 0.05 µM (+++); £ 0.05 µM and > 0.001 µM (++++); and not tested (--), based upon the Biochemical Assay of Example A. [00330] In Tables 1 and 10, absolute stereochemistry has not been determined for some Examples. Accordingly, assignment of any Examples as the “R” or “S” stereoisomer is arbitrary, unless otherwise noted. In some cases, Examples are labeled with “1 st eluting isomer”, “2 nd eluting isomer”, etc. based on the purification method used to separate the stereoisomers (see Table 9). Table 10.
Synthesis of Compounds of Formula II [00331] In some embodiments, the USP9X inhibitor may be a compound of Table 11: Table 11.
Intermediates for Compounds of Table 11 Intermediate 2’-1. (3-bromophenyl)([2-[3-fluoro-4-(1,3-oxazol-2-yl)benzenesulfo nyl]- 1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl])methanol B Step 1. 3-fluoro-4-(1,3-oxazol-2-yl)aniline [00332] To a solution of 4-bromo-3-fluoroaniline (474 mg, 2.51 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl 2 (183 mg, 0.25 mmol) and 2-(tributylstannyl)-1,3-oxazole (900 mg, 2.52 mmol). The resulting mixture was stirred for 48 h at 100 °C and then cooled to room temperature. The reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 50:50 ethyl acetate/petroleum ether) to afford 3-fluoro-4- (1,3-oxazol-2-yl)aniline (180 mg, 41%). LCMS (ES, m/z) 179 [M+H] + . Step 2. 3-fluoro-4-(1,3-oxazol-2-yl)benzene-1-sulfonyl chloride [00333] Into glacial acetic acid (10 mL) was bubbled in SO2 gas for 1 h at room temperature. Then CuCl2 (34 mg, 0.25 mmol) was added and SO2 gas was bubbled in for additional 2 h to afford solution A. To a pre-cooled solution of 3-fluoro-4-(1,3-oxazol-2-yl)aniline (180 mg, 1.01 mmol) in acetic acid (2 mL) and concentrated hydrochloric acid (6 mL) was added a solution of sodium nitrite (77 mg, 1.11 mmol) in distilled water (0.5 mL) dropwise with stirring at -10 °C. After stirring for 15 min, solution A was added to this diazonium salt solution at -10 °C. The resulting solution was allowed to warm to room temperature naturally and stirred for 16 h. The reaction mixture was treated with water (10 mL) and then extracted with EA (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 12:88 ethyl acetate/petroleum ether) to afford 3-fluoro-4-(1,3-oxazol-2-yl)benzene- 1-sulfonyl chloride (120 mg, 45%). LCMS (ES, m/z) 262, 264 [M+H] + . [00334] The Intermediate in Table 12 was synthesized according to the procedure described for Intermediate 2’-1 above. Table 12. Intermediate 3’-1. 1-tert-butyl-6-(3-[[2-(2,3-dihydro-1,4-benzodioxine-6-sulfon yl)- 1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl]carbonyl]phenyl)-1lambda 3,3,6-oxadiazocan-2-one [00335] To a solution of 6-[(3-chlorophenyl)carbonyl]-2-(2,3-dihydro-1,4-benzodioxine -6- sulfonyl)-1H,2H,3H-pyrrolo[3,4-c]pyridine (80 mg, 0.16 mmol) in toluene (8 mL) was added 1- tert-butyl-1lambda3,3,6-oxadiazocan-2-one (42 mg, 0.22 mmol), XPhos (19 mg, 0.04 mmol), Cs2CO3 (171 mg, 0.52 mmol) and Pd2(dba)3 . CHCl3 (18 mg, 0.02 mmol). The resulting mixture was stirred for 16 h at 100 °C and then cooled to room temperature. The reaction mixture was filtered and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 1:10 EA/PE) to afford 1-tert-butyl-6-(3-[[2-(2,3-dihydro-1,4- benzodioxine-6-sulfonyl)-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl ]carbonyl]phenyl)-1lambda3,3,6- oxadiazocan-2-one as a yellow solid (80 mg, 84%). LCMS (ES, m/z) 607 [M+H] + . [00336] The Intermediate in Table 13 was synthesized according to the procedure described for Intermediate 3’-1 above. Table 13. a Ruphos 3G, Ruphos, K 3 PO 4 , dioxane, 100 °C, 16 h; *Absolute stereochemistry not determined. Intermediate 4’-1. 1-(3-[[2-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H- pyrrolo[3,4-c]pyridin-6-yl]carbonyl]phenyl) piperazine [00337] To a solution of tert-butyl 4-(3-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carbonyl)phenyl)pipe razine-1-carboxylate (80 mg, 0.12 mmol) in DCM (3 mL) was added TFA (1 mL). The resulting solution was stirred for 1 h at rt and then concentrated under vacuum. The resulting mixture was then basified to pH 8 with saturated aqueous potassium carbonate solution. The resulting mixture was extracted with DCM (3 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 1-(3-[[2-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)- 1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl]carbonyl]phenyl)piperazi ne as a yellow solid (50 mg, 83%). LCMS (ES, m/z) 507 [M+H]+. [00338] The Intermediates in Table 14 were synthesized according to the procedure described for Intermediate 4’-1 above. Table 14. Intermediate 8’-1. 1-[4-({6-benzoyl-1H,2H,3H-pyrrolo[3,4-c]pyridinyl}sulfonyl)p henyl]-1H- imidazole [00339] To a solution of 4-(1H-imidazol-1-yl)benzene-1-sulfonyl chloride (200 mg, 0.82 mmol) in DCM (2 mL) was added 6-benzoyl-1H,2H,3H-pyrrolo[3,4-c]pyridine (124 mg, 0.55 mmol) and TEA (0.22 mL, 1.60 mmol). The resulting solution was stirred for 2 h at 25 °C. The reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 10:90 ethyl acetate/petroleum ether) to afford 1-[4-([6- benzoyl-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]sulfonyl)phenyl] -1H-imidazole as a white solid (95 mg, 22%). LCMS (ES, m/z) 431 [M+H] + . [00340] The Intermediates in Table 15 were synthesized according to the procedure described for Intermediate 8’-1 above. Table 15.
Intermediate 10’-1.6-[(3-chlorophenyl)carbonyl]-1H,2H,3H-pyrrolo[3,4-c] pyridine (TFA salt) Step 1. 2-tert-butyl 6-methyl 1H,2H,3H-pyrrolo[3,4-c]pyridine-2,6-dicarboxylate [00341] Into a high pressure tank was placed a solution of tert-butyl 6-chloro-1H,2H,3H- pyrrolo[3,4-c]pyridine-2-carboxylate (2 g, 6.99 mmol) in MeOH (30 mL), Pd(dppf)Cl 2 ·CH 2 Cl 2 (640 mg, 0.78 mmol) and TEA (3.28 mL, 23.7 mmol). Then CO (30 atm) was introduced. The resulting mixture was stirred for 16 h at 120 °C and cooled to room temperature. The reaction mixture was filtered and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 1:5 EA/PE) to afford 2-tert-butyl 6-methyl 1H,2H,3H-pyrrolo[3,4-c]pyridine-2,6-dicarboxylate as a yellow solid (1.2 g, 56%). LCMS (ES, m/z) 279 [M+H]+. Step 2. 2-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin e-6-carboxylic acid [00342] To a solution of 2-tert-butyl 6-methyl 1H,2H,3H-pyrrolo[3,4-c]pyridine-2,6- dicarboxylate (2 g, 6.47 mmol) in THF (20 mL) was added water (15 mL) and LiOH (863 mg, 36.0 mmol). The resulting solution was stirred for 16 h at rt. The resulting mixture was washed with Et2O (1 x 10 mL) and then acidified to pH 5 with hydrochloric acid solution (2 N). The resulting mixture was extracted with EA (3 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting crude product was purified by reversed phase chromatography (eluting with 1:1 water/MeCN). The collected fractions were combined and concentrated under vacuum to afford 2-(tert- butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carb oxylic acid as yellow oil (1.0 g, 53%). LCMS (ES, m/z) 265 [M+H]+. Step 3. Tert-butyl 6-[methoxy(methyl)carbamoyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine -2- carboxylate [00343] To a solution of 2-[(tert-butoxy)carbonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine-6- carboxylic acid (1 g, 3.41 mmol) in DMF (15 mL) was added methoxy(methyl)amine hydrochloride (441 mg, 4.52 mmol), HATU (2.88 g, 7.57 mmol) and DIEA (1.98 mL, 11.37 mmol). The resulting solution was stirred for 1 h at rt. The reaction mixture was poured into water (15 mL) and then extracted with EA (3 x 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrate under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 1:10 EA/PE) to afford tert-butyl 6-[methoxy(methyl)carbamoyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine -2-carboxylate as light yellow oil (700 mg, 67%). LCMS (ES, m/z) 308 [M+H]+. Step 4. Tert-butyl 6-[(3-chlorophenyl)carbonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine -2- carboxylate [00344] To a solution of tert-butyl 6-[methoxy(methyl)carbamoyl]-1H,2H,3H-pyrrolo[3,4- c]pyridine-2-carboxylate (100 mg, 0.29 mmol) in THF (1 mL) was added a solution of bromo(3- chlorophenyl)magnesium (0.78 mL, 0.5 M in THF) dropwise with stirring at 0 °C. The resulting solution was stirred for 1 h at rt and then poured into saturated ammonium chloride solution (5 mL). The resulting mixture was extracted with EA (3 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 1:3 EA/PE) to afford tert- butyl 6-[(3-chlorophenyl)carbonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine -2-carboxylate as yellow oil (80 mg, 76%). LCMS (ES, m/z) 359, 361 [M+H]+. Step 5. 6-[(3-chlorophenyl)carbonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine TFA salt [00345] To a solution of tert-butyl 6-[(3-chlorophenyl)carbonyl]-1H,2H,3H-pyrrolo[3,4- c]pyridine-2-carboxylate (500 mg, 1.25 mmol) in dichloromethane (8 mL) was added TFA (2 mL). The resulting solution was stirred for 1 h at rt. The resulting mixture was concentrated under vacuum to afford 6-[(3-chlorophenyl)carbonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine (TFA salt) as brown oil (500 mg, crude). LCMS (ES, m/z) 259, 261 [M+H]+. Intermediate 20’-1. Phenyl({5H,6H,7H-pyrrolo[3,4-d]pyrimidin-2-yl})methanol Step 1. tert-Butyl 2-chloro-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate [00346] To a solution of tert-butyl 2,4-dichloro-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6- carboxylate (6.00 g, 17.6 mmol) in methanol (48 mL) was added zinc powder (1.80 g, 26.4 mmol) and acetic acid (10.6 mL, 176 mmol). The resulting mixture was stirred for 16 h at 50 °C and cooled to room temperature. The resulting mixture was concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/petroleum ether) to afford tert-butyl 2-chloro-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6- carboxylate as a white solid (2.90 g, 54%). LCMS (ES, m/z): 256, 258 [M+H] + . Step 2. tert-Butyl 2-cyano-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate [00347] To a solution of tert-butyl 2-chloro-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6- carboxylate (1.50 g, 4.99 mmol) in DMF (15 mL ) was added Zn(CN) 2 (868 mg, 7.48 mmol) and Pd(dppf)Cl2 (364 mg, 0.50 mmol). The resulting mixture was irradiated with microwave for 3 h at 140 °C. After cooling to rt, the reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/petroleum ether) to afford tert-butyl 2-cyano-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate as a yellow oil (500 mg, 34%). LCMS (ES, m/z): 247 [M+H] + . Step 3. tert-Butyl 2-benzoyl-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate [00348] To a solution of tert-butyl 2-cyano-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6- carboxylate (200 mg, 0.69 mmol) in THF (2 mL) was added bromo(phenyl)magnesium (1.38 mL, 1 M in THF) dropwise at 0 °C. The resulting mixture was stirred for 1 h at rt. Then 1 N hydrochloric acid (2 mL) was added. The resulting mixture was stirred for 30 min at rt and then extracted with EA (3 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 4:5 ethyl acetate/petroleum ether) to afford tert-butyl 2- benzoyl-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate as a yellow oil (90 mg, 34%). LCMS (ES, m/z): 326 [M+H] + . Step 4. tert-Butyl 2-[hydroxy(phenyl)methyl]-5H,6H,7H-pyrrolo[3,4-d]pyrimidine- 6- carboxylate [00349] To a solution of tert-butyl 2-benzoyl-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6- carboxylate (90 mg, 0.24 mmol) in methanol (1 mL) was added sodium borohydride (18.7 mg, 0.47 mmol). The resulting mixture stirred for 1 h at rt. The reaction mixture was poured into water (5 mL) and then extracted with EA (3 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by Prep-TLC (eluting with 2:5 ethyl acetate/petroleum ether) to afford tert-butyl 2-[hydroxy(phenyl)methyl]-5H,6H,7H-pyrrolo[3,4-d]pyrimidine- 6- carboxylate as a yellow solid (60 mg, 77%) . LCMS (ES, m/z): 328 [M+H] + . Step 5. Phenyl({5H,6H,7H-pyrrolo[3,4-d]pyrimidin-2-yl})methanol [00350] To a solution of tert-butyl 2-[hydroxy(phenyl)methyl]-5H,6H,7H-pyrrolo[3,4- d]pyrimidine-6-carboxylate (60 mg, 0.18 mmol) in DCM (6 mL) was added trifluoroacetic acid (2 mL). The resulting mixture was stirred for 1 h at rt and concentrated under vacuum. The resulting mixture was basified to pH 8 with saturated potassium carbonate solution and extracted with DCM (3 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford phenyl({5H,6H,7H-pyrrolo[3,4-d]pyrimidin-2- yl})methanol as a yellow solid (35 mg, 85%). LCMS (ES, m/z): 228 [M+H] + . [00351] The Intermediate in Table 16 was synthesized according to the procedure described for Intermediate 20’-1 above. Table 16. Intermediate 21’-1. Benzyl 4-[1H,2H,3H-pyrrolo[3,4-c]pyridine-6-carbonyl]-2,3-dihydro- 1H-isoindole-2-carboxylate Step 1. Benzyl 4-bromo-2,3-dihydro-1H-isoindole-2-carboxylate [00352] To a solution of 4-bromo-2,3-dihydro-1H-isoindole hydrochloride (3.00 g, 12.2 mmol) and TEA (5.10 mL, 36.5 mmol) in dichloromethane (50 mL) was added CbzCl (4.10 g, 24.3 mmol) in portions at 0 °C. The resulting solution was stirred for 5 h at room temperature. The reaction mixture was poured into water (50 mL) and then extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 20:80 ethyl acetate/petroleum ether) to afford benzyl 4- bromo-2,3-dihydro-1H-isoindole-2-carboxylate as a pink solid (3.50 g, 87%). LCMS (ES, m/z): 332, 334[M+H] + . Step 2. tert-Butyl 4-(cyanomethyl)-2,3-dihydro-1H-isoindole-2-carboxylate [00353] To a solution of tert-butyl 4-bromo-2,3-dihydro-1H-isoindole-2-carboxylate (1.50 g, 4.78 mmol) in mesitylene (20 mL) was added Pd(allyl)2Cl2 (46 mg, 0.10 mmol), SPhos (118 mg, 0.29 mmol) and sodium 2-cyanoacetate (808 mg, 7.17 mmol). The resulting mixture was stirred for 5 h at 140 °C. After cooling to room temperature, the reaction mixture was filtered and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 50:50 ethyl acetate/petroleum ether) to afford tert-butyl 4- (cyanomethyl)-2,3-dihydro-1H-isoindole-2-carboxylate as a brown solid (1.00 g, 81%). LCMS (ES, m/z): 293[M+H] + . Step 3. Benzyl 4-([2-[(tert-butoxy)carbonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridin -6- yl](cyano)methyl)-2,3-dihydro-1H-isoindole-2-carboxylate [00354] To a solution of tert-butyl 6-chloro-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxylate (500 mg, 1.86 mmo) in THF (10 mL) was added benzyl 4-(cyanomethyl)-2,3-dihydro-1H- isoindole-2-carboxylate (861 mg, 2.80 mmol) and sodium amide (146 mg, 3.74 mmol). The resulting solution was stirred for 4 h at 50 °C. After cooling to room temperature, the reaction mixture was poured into water (20 mL) and then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 30:60 ethyl acetate/petroleum ether) to afford benzyl 4-([2-[(tert-butoxy)carbonyl]- 1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl](cyano)methyl)-2,3-dihyd ro-1H-isoindole-2-carboxylate as yellow oil (300 mg, 32%). LCMS (ES, m/z): 511[M+H] + . Step 4. Benzyl 4-([2-[(tert-butoxy)carbonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridin -6- yl](cyano)methyl)-2,3-dihydro-1H-isoindole-2-carboxylate [00355] To a solution of benzyl 4-([2-[(tert-butoxy)carbonyl]-1H,2H,3H-pyrrolo[3,4- c]pyridin-6-yl](cyano)methyl)-2,3-dihydro-1H-isoindole-2-car boxylate (300 mg, 0.56 mmol) in DMSO (5 mL) was added benzyltriethylammonium chloride (6 mg, 0.03 mmol) and sodium hydroxide (0.2 mL, 4 N in water). Then oxygen was bubbled in. The resulting mixture was stirred for 2 h at room temperature. The reaction mixture was poured into water (20 mL) and then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 50:50 ethyl acetate/petroleum ether) to afford benzyl 4-[2-[(tert-butoxy)carbonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine -6- carbonyl]-2,3-dihydro-1H-isoindole-2-carboxylate as yellow oil (200 mg, 72%). LCMS (ES, m/z): 500 [M+H] + . Step 5. Benzyl 4-[1H,2H,3H-pyrrolo[3,4-c]pyridine-6-carbonyl]-2,3-dihydro-1 H-isoindole-2- carboxylate (TFA salt) [00356] To a solution of benzyl 4-[2-[(tert-butoxy)carbonyl]-1H,2H,3H-pyrrolo[3,4- c]pyridine-6-carbonyl]-2,3-dihydro-1H-isoindole-2-carboxylat e (200 mg, 0.38 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The resulting solution was stirred for 5 h at room temperature. The resulting mixture was concentrated under vacuum to afford benzyl 4-[1H,2H,3H-pyrrolo[3,4-c]pyridine-6-carbonyl]-2,3-dihydro-1 H-isoindole-2-carboxylate (TFA salt) as yellow oil (180 mg, crude). LCMS (ES, m/z): 400[M+H] + . Intermediate 25’-1. Tert-butyl 6-[hydroxy[2-(4-methylpiperazin-1-yl)phenyl]methyl]-1H, 2H, 3H-pyrrolo [3,4-c] pyridine-2-carboxylate [00357] To a solution of tert-butyl 6-[2-(4-methylpiperazin-1-yl)benzoyl]-1H, 2H, 3H-pyrrolo [3,4-c] pyridine-2-carboxylate (200 mg, 0.43 mmol) in MeOH (10 mL) was added sodium borohydride (8 mg, 0.21 mmol). The resulting mixture was stirred for 1 h at 25 °C. The reaction mixture was concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 1:10 MeOH/DCM) to afford tert-butyl 6-[hydroxy[2-(4- methylpiperazin-1-yl)phenyl]methyl]-1H,2H,3H-pyrrolo[3,4-c]p yridine-2-carboxylate as yellow oil (170 mg, 85%). LCMS (ES, m/z): 425 [M+H] + . [00358] The Intermediate in Table 17 was synthesized according to the procedure described for Intermediate 25’-1 above. Table 17. *Absolute stereochemistry not determined. Intermediate 27’-1. Tert-butyl 2-(3-bromobenzoyl)-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6- carboxylate Step 1. Tert-butyl (3E)-3-[(dimethylamino)methylidene]-4-oxopyrrolidine-1-carbo xylate [00359] To tert-butyl 3-oxopyrrolidine-1-carboxylate (20 g, 102 mmol) was added dimethylformamide dimethyl acetal (200 mL). The resulting solution was stirred for 12 h at 140 °C. After cooling to room temperature, the resulting mixture was concentrated. The residue was dissolved with a minimum amount of DCM and then treated with hexane (100 mL). The resulting solids were collected by filtration and dried under vacuum to afford tert-butyl (3E)-3- [(dimethylamino)methylidene]-4-oxopyrrolidine-1-carboxylate as a yellow solid (15 g, 58%). LCMS (ES, m/z): 241 [M+H] + . Step 2. Tert-butyl 2-(methylsulfanyl)-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carbo xylate [00360] To a solution of (methylsulfanyl)methanimidamide (17 g, 183 mmol) in EtOH (200 mL) was added sodium ethoxide (13 g, 183 mmol) at 0 °C. After stirring for 10 min, to the above solution was added tert-butyl (3E)-3-[(dimethylamino)methylidene]-4-oxopyrrolidine-1- carboxylate (15 g, 61.2 mmol). The resulting mixture was stirred for 4 h at 80 °C. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was dissolved with water (100 mL) and then extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 1:2 ethyl acetate/petroleum ether) to afford tert-butyl 2-(methylsulfanyl)-5H,6H,7H-pyrrolo[3,4- d]pyrimidine-6-carboxylate as a yellow solid (4 g, 41%). LCMS (ES, m/z): 268 [M+H] + . Step 3. Tert-butyl 2-methanesulfonyl-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carbox ylate [00361] To a solution of tert-butyl 2-(methylsulfanyl)-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6- carboxylate (4 g, 14.1 mmol) in DCM (80 mL) was added m-CPBA (7.5 g, 42.6 mmol). The resulting mixture was stirred for 5 h at 0 °C. The resulting mixture was washed with saturated sodium bicarbonate solution (5 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by silica gel chromatography (eluting with 2:1 ethyl acetate/petroleum ether) to afford tert-butyl 2-methanesulfonyl-5H,6H,7H-pyrrolo[3,4- d]pyrimidine-6-carboxylate as a yellow solid (4 g, 89%). LCMS (ES, m/z): 300 [M+H] + . Intermediate 32’-1.4-({6-[hydroxy(phenyl)methyl]-1H,2H,3H-pyrrolo[3,4-c ]pyridin-2- yl}sulfonyl)benzonitrile Step 1. Tert-butyl 6-[hydroxy(phenyl)methyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine-2- carboxylate [00362] To a solution of tert-butyl 6-benzoyl-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxylate (340 mg, 1.05 mmol) in MeOH (10 mL), was added sodium borohydride (12 mg, 0.32 mmol). The resulting mixture was stirred for 1 h at 25 °C. The reaction mixture was poured into water (15 mL) and then extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 10:90 ethyl acetate/petroleum ether) to afford tert-butyl 6-[hydroxy(phenyl)methyl]-1H,2H,3H-pyrrolo[3,4- c]pyridine-2-carboxylate as a yellow solid (300 mg, 88%). LCMS (ES, m/z): 327 [M+H] + . Step 2. Phenyl({1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl})methanol (TFA salt) [00363] To a solution of tert-butyl 6-[hydroxy(phenyl)methyl]-1H,2H,3H-pyrrolo[3,4- c]pyridine-2-carboxylate (280 mg, 0.86 mmol) in dichloromethane (4 mL) was added TFA (1 mL). The resulting mixture was stirred for 1 h at 25 °C. The reaction mixture was concentrated under vacuum to afford phenyl({1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl})methanol (TFA salt) as light yellow oil (200 mg, crude). LCMS (ES, m/z): 227 [M+H] + . Step 3. 4-({6-[hydroxy(phenyl)methyl]-1H,2H,3H-pyrrolo[3,4-c]pyridin -2- yl}sulfonyl)benzonitrile [00364] To a solution of phenyl({1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl})methanol (TFA salt) (225 mg, 0.99 mmol) in dichloromethane (7 mL) was added TEA (0.55 mL, 3.98 mmol) and 4- cyanobenzene-1-sulfonyl chloride (200 mg, 0.99 mmol). The resulting mixture was stirred for 2 h at 25 °C and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 10:90 ethyl acetate/petroleum ether) to afford 4-({6- [hydroxy(phenyl)methyl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl} sulfonyl)benzonitrile as a white solid (200 mg, 51%). LCMS (ES, m/z): 392 [M+H] + . [00365] The Intermediate in Table 18 was synthesized according to the procedure described for Intermediate 32’-1 above. Table 18. Intermediate 33’-1. Tert-butyl 2-(3-bromobenzoyl)-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6- carboxylate [00366] To a solution of 2-(3-bromophenyl)acetonitrile (1.96 g, 9.52 mmol) in THF (50 mL) was added tert-butyl 2-methanesulfonyl-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carbox ylate (2 g, 6.35 mmol) and potassium bis(trimethylsilyl)amide solution (10 mL, 1 M in THF). The resulting mixture was stirred for 12 h at room temperature while oxygen was kept bubbling in. The reaction mixture was poured into water (50 mL) and then extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 30:70 ethyl acetate/petroleum ether) to afford tert-butyl 2- (3-bromobenzoyl)-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxy late as a yellow solid (1.20 g, 44%). LCMS (ES, m/z): 404, 406 [M+H] + . [00367] The Intermediate in Table 19 was synthesized according to the procedure described for Intermediate 33’-1 above. Table 19. Methods for Preparing Final Compounds Method A’[(2S)-2-[2-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H, 2H,3H-pyrrolo[3,4- c]pyridin-6-yl]-2-phenylethyl] (methyl)amine; [(2R)-2-[2-(2,3-dihydro-1,4-benzodioxine-6- sulfonyl)-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl]-2-phenylethyl ](methyl) amine [00368] To a solution of (3-[2-[2-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H- pyrrolo[3,4-c]pyridin-6-yl]-2-phenylethyl]phenyl)methyl N-methylcarbamate (100 mg, 0.17 mmol) in methanol (2 mL) was added palladium carbon (10 mg, 10 wt% palladium on charcoal). Then hydrogen was introduced with hydrogen balloon. The resulting mixture was stirred for 16 h at room temperature. The reaction mixture was filtered and concentrated under vacuum. The resulting crude product was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5 µm, 19 x 150 mm; Mobile Phase, A: water (containing 10 mmol/L NH 4 HCO 3 ) and B: CH3CN (5% to 30% over 25 min); Flow rate: 20 mL/min; Detector: UV 254 nm). The two enantiomers were further separated by Chiral-Pre-HPLC (Column: CHIRALPAK IG, 5 µm, 20 x 250 mm; Mobile Phase, A: methanol (containing 0.1% DEA) and B: DCM (hold 50% B over 10 min); Detector: UV 254/220 nm; Retention time: 1 st eluting isomer, 3.965 min; 2 nd eluting isomer, 5.955 min). The product fractions of 1 st eluting isomer were concentrated and lyophilized to afford a white solid (10.1 mg, 26%). 1 H-NMR (Methanol-d4, 400 MHz,) d (ppm): 8.40 (s, 1H), 7.36-7.16 (m, 7H), 7.17 (s, 1H), 6.99-6.92 (m, 1H), 4.60 (s, 2H), 4.54 (s, 2H), 4.35-4.33 (m, 1H), 4.26-4.22 (m, 4H), 3.53-3.50 (m, 1H), 3.19-3.14 (m, 1H), 2.44 (s, 3H). LCMS (ES, m/z) 452 [M+H] + . The product fractions of 2 nd eluting isomer were concentrated and lyophilized to a white solid (11.5 mg, 30%). 1 H-NMR (Methanol-d4, 400 MHz,) d (ppm): 8.40 (s, 1H), 7.36-7.16 (m, 7H), 7.17 (s, 1H), 6.99-6.92 (m, 1H), 4.61 (s, 2H), 4.56 (s, 2H), 4.42-4.39 (m, 1H), 4.26-4.22 (m, 4H), 3.66-3.59 (m, 1H), 3.19-3.14 (m, 1H), 2.55 (s, 3H). LCMS (ES, m/z) 452 [M+H] + . Method B’ [2-[3-fluoro-4-(1,3-oxazol-2-yl)benzenesulfonyl]-1H,2H,3H-py rrolo[3,4-c]pyridin-6-yl][3- (piperazin-1-yl)phenyl]methanol Step 1. Tert-butyl 4-[3-[[2-[3-fluoro-4-(1,3-oxazol-2-yl)benzenesulfonyl]-1H,2H ,3H- pyrrolo[3,4-c]pyridin-6-yl](hydroxy)methyl]phenyl]piperazine -1-carboxylate [00369] To a solution of (3-bromophenyl)([2-[3-fluoro-4-(1,3-oxazol-2-yl)benzenesulfo nyl]- 1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl])methanol (50 mg, 0.09 mmol) in 1,4-dioxane (2 mL) was added K 3 PO 4 (61 mg, 0.29 mmol), tert-butyl piperazine-1-carboxylate (88 mg, 0.47 mmol), RuPhos 3G (16 mg, 0.02 mmol), and RuPhos (9 mg, 0.02 mmol). The resulting mixture was stirred for 2 h at 100 °C and then cooled to room temperature. The reaction mixture was poured into water (3 mL) and then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by prep-TLC (eluting with 1:1 ethyl acetate/petroleum ether) to afford tert-butyl 4-[3-[ [2-[3-fluoro-4-(1,3-oxazol-2-yl)benzenesulfonyl]-1H,2H,3H- pyrrolo[3,4-c]pyridin-6-yl](hydroxy)methyl]phenyl}piperazine -1-carboxylate (40 mg, 67%). LCMS (ES, m/z) 636 [M+H] + . Step 2. [2-[3-fluoro-4-(1,3-oxazol-2-yl)benzenesulfonyl]-1H,2H,3H-py rrolo[3,4-c]pyridin-6- yl][3-(piperazin-1-yl)phenyl]methanol [00370] To a solution of tert-butyl 4-[3-[ [2-[3-fluoro-4-(1,3-oxazol-2-yl)benzenesulfonyl]- 1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl](hydroxy)methyl]phenyl}p iperazine-1-carboxylate (40 mg, 0.06 mmol) in dichloromethane (4 mL) was added TFA (1 mL). The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum. The resulting mixture was basified to pH 8 with saturated potassium carbonate solution and then extracted with dichloromethane (2 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5 µm, 19 x 150 mm; Mobile Phase, A: water (containing 10 mmol/L NH4HCO3) and B: CH3CN (25% to 45% over 7 min); Flow rate: 20 mL/min; Detector: UV 254 nm). The product fractions were concentrated and lyophilized to afford [2-[3-fluoro-4-(1,3-oxazol-2-yl)benzenesulfonyl]-1H,2H,3H-py rrolo[3,4- c]pyridin-6-yl][3-(piperazin-1-yl)phenyl]methanol (13.1 mg, 37%). 1 H-NMR (DMSO-d6, 400 MHz) d (ppm) 8.35 (d, J = 16.8 Hz, 2H), 8.24-8.22 (m, 1H), 7.90-7.83 (m, 2H), 7.52 (s, 1H), 7.47 (s, 1H), 7.06-7.02 (m, 1H), 6.95 (s, 1H), 6.76-6.67 (m, 2H), 5.98 (d, J = 4.0 Hz, 1H), 5.60 (d, J = 4.0 Hz, 1H), 4.73-4.62 (m, 4H), 2.98-2.81 (m, 4H), 2.80-2.70 (m, 4H), 2.57-2.54 (m, 1H). LCMS (ES, m/z) 536 [M+H] + . Method C’ [2-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H-pyrrol o[3,4-c]pyridin-6-yl][3- (piperazin-1-yl)phenyl]methanol [00371] To a solution of 1-(3-[[2-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1H,2H,3H- pyrrolo[3,4-c]pyridin-6-yl]carbonyl]phenyl)piperazine (30 mg, 0.05 mmol) in THF (0.5 mL) was added NaBH4 (2 mg, 0.05 mmol) at 0 °C. The resulting solution was stirred for 30 min at 0 °C. The reaction mixture was poured into water (3 mL) and then extracted with DCM (3 x 3 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 1:10 MeOH/DCM), and further purified by Prep-HPLC (Column: XBridge Shield C 1 8 OBD Column, 5 µm, 19 x 150 mm; Mobile Phase, A: water (containing 10 mmol/L NH4HCO3) and B: CH3CN (20% to 42% over 7 min); Flow rate: 20 mL/min; Detector: UV 254/220 nm). The product fractions were concentrated and lyophilized to afford [2-(2,3-dihydro-1,4-benzodioxine-6- sulfonyl)-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl][3-(piperazin- 1-yl)phenyl]methanol as a white solid (3.6 mg, 13%). 1 H-NMR (Methanol-d4, 400 MHz) d (ppm): 8.30 (s, 1H), 7.49 (s, 1H), 7.40- 7.27 (m, 2H), 7.21-7.10 (m, 1H), 7.08-7.01 (m, 1H), 6.99-6.94 (m, 1H), 6.88-6.79 (m, 2H), 5.71 (s, 1H), 4.59 (s, 4H), 4.36-4.20 (m, 4H), 3.16-3.07 (m, 4H), 3.01-2.91 (m, 4H). LCMS (ES, m/z) 509 [M+H] + . Method F’ [2-[4-(5-fluoro-1H-pyrazol-1-yl) benzenesulfonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine-6- yl](phenyl) methanol [00372] To a solution of phenyl([1H,2H,3H-pyrrolo[3,4-c]pyridine-6-yl])methanol (TFA salt) (100 mg, 0.29 mmol) in dichloromethane (10 mL) and N,N-dimethylformamide (2 mL) was added potassium carbonate (122 mg, 0.88 mmol). The resulting mixture was stirred for 30 min at room temperature. To this was added 4-(5-fluoro-1H-pyrazol-1-yl) benzene-1-sulfonyl chloride (77 mg, 0.30 mmol). The resulting solution was stirred for 1 h at room temperature. The reaction mixture was poured into water (3 mL) and then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by prep-TLC (eluting with 99:1 ethyl acetate/petroleum ether), and further purified by prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5 µm, 19 x 150 mm; Mobile Phase, A: water (containing 10 mmol/L NH4HCO3) and B: CH 3 CN (30% B to 62% B over 7 min); Flow rate: 20 mL/min; Detector: UV 254 nm). The product fractions were concentrated and lyophilized to afford [2-[4-(5-fluoro-1H-pyrazol-1- yl)benzenesulfonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine-6-yl](ph enyl)methanol (13.6 mg, 10%). 1 H-NMR (DMSO-d6, 400 MHz) d (ppm): 8.33 (s, 1H), 8.07-7.98 (m, 2H), 7.88-7.85 (m, 2H), 7.74-7.73 (m, 1H), 7.49 (s, 1H), 7.31 (d, J = 6.8 Hz, 2H), 7.24-7.21 (m, 2H), 7.17-7.14 (m, 1H). 6.30-6.29 (m, 1H), 6.08-6.06 (m, 1H), 5.64 (d, J = 4.0 Hz, 1H), 4.69-4.57 (m, 4H). LCMS (ES, m/z) 451 [M+H] + . Method J’ Phenyl(2-{[1-(1,3-thiazol-2-yl)piperidin-4-yl]sulfonyl}-1H,2 H,3H-pyrrolo[3,4-c]pyridine-6- yl)methanol [00373] To a solution of phenyl[2-(piperidine-4-sulfonyl)-1H,2H,3H-pyrrolo[3,4-c]pyri din-6- yl]methanol (40 mg, 0.11 mmol) in 1,4-dioxane (1 mL), was added 2-bromo-1,3-thiazole (18 mg, 0.11 mmol), Cs2CO3 (105 mg, 0.32 mmol) and RuPhos 3G (10 mg, 0.01 mmol). The resulting mixture was stirred for 16 h at 100 °C and then cooled to room temperature. The reaction mixture was poured into water (2 mL) and then extracted with ethyl acetate (2 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 0:100 to 10:90 methanol/dichloromethane) and further purified by Prep-HPLC (Column: XBridge Shield C18 OBD Column, 5 µm, 19 x 150 mm; Mobile Phase, A: water (containing 10 mmol/L NH4HCO3) and B: CH3CN (30% to 65% over 7 min); Flow rate: 20 mL/min; Detector: UV 254/220 nm). The product fractions were concentrated and lyophilized to afford phenyl(2-[[1-(1,3-thiazol-2-yl)piperidin-4-yl]sulfonyl]-1H,2 H,3H-pyrrolo[3,4- c]pyridin-6-yl)methanol as a white solid (2.0 mg, 4%). 1H-NMR (CDCl3, 400 MHz,) d (ppm): 8.51 (s, 1H), 7.47-7.35 (m, 4H), 7.32-7.31 (m, 1H), 7.19 (s, 1H), 7.10 (s, 1H), 6.62-6.60 (s, 1H), 5.79 (s, 1H), 4.98 (s, 1H), 4.87-4.83 (m, 2H), 4.79-4.69 (m, 2H), 4.19- 4.16 (m, 2H), 3.29-3.22 (m, 1H), 3.07-3.01 (m, 2H), 2.23-2.20 (m, 2H), 2.06-1.96 (m, 2H). LCMS (ES, m/z) 457 [M+H]+ Method L’ (S)-[2-[3-fluoro-4-(1,3-oxazol-2-yl)benzenesulfonyl]-1H,2H,3 H-pyrrolo[3,4-c]pyridin-6- yl]([3-[(1-methylazetidin-3-yl)oxy]phenyl])methanol; (R)-[2-[3-fluoro-4-(1,3-oxazol-2- yl)benzenesulfonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl]([3- [(1-methylazetidin-3- yl)oxy]phenyl])methanol [00374] To a solution of [3-(azetidin-3-yloxy)phenyl]([2-[3-fluoro-4-(1,3-oxazol-2- yl)benzenesulfonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl])met hanol (TFA salt) (80 mg, 0.14 mmol) in MeOH (2 mL) was added formaldehyde (1 mL, 30% in water). The resulting solution was stirred for 30 min at room temperature. This was followed by the addition of STAB (92 mg, 0.41 mmol). The resulting solution was stirred for 12 h at room temperature. The reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5 µm, 30 x 150 mm; Mobile Phase, A: water (containing 10 mmol/L NH 4 HCO 3 ) and B: CH 3 CN (25% to 50% in 7 min); Flow rate: 60 mL/min; Detector: UV 220 nm). The product fractions were concentrated under vacuum. The two enantiomers were further separated by Chiral Prep-HPLC (Column: CHIRALPAK IC, 5 µm, 20 x 250 mm; Mobile Phase, A: MeOH (containing 0.1% DEA) and B: DCM (keep 40% B in 15 min); Flow rate: 20 mL/min; Detector: UV 254/220 nm; Retention time: 1 st eluting isomer, 10.772 min; 2 nd eluting isomer, 13.314 min). The product fractions were concentrated and lyophilized to afford 1 st eluting isomer as a white solid (12.4 mg, 16%). 1 H-NMR (DMSO-d 6 , 400 MHz) d (ppm): 8.38 (s, 1H), 8.34 (s, 1H), 8.24-8.20 (m, 1H), 7.90-7.83 (m, 2H), 7.53 (s, 1H), 7.47 (s, 1H), 7.14-7.10 (m, 1H), 6.88 (d, J= 7.6 Hz, 1H), 6.81 (s, 1H), 6.60-6.57 (m, 1H), 6.10 (d, J= 4.0 Hz, 1H), 5.63 (d, J= 4.4 Hz, 1H), 4.70-4.63 (m, 5H), 3.71-3.68 (m, 2H), 2.92-2.89 (m, 2H), 2.27 (s, 3H). LCMS (ES, m/z): 537 [M+H] + . The product fractions were concentrated and lyophilized to afford 2 nd eluting isomer as a white solid (13.3 mg, 18%). 1 H-NMR (DMSO-d6, 400 MHz) d (ppm): 8.38 (s, 1H), 8.34 (s, 1H), 8.24-8.20 (m, 1H), 7.90-7.83 (m, 2H), 7.53 (s, 1H), 7.47 (s, 1H), 7.14-7.10 (m, 1H), 6.88 (d, J= 7.6 Hz, 1H), 6.81 (s, 1H), 6.60-6.58 (m, 1H), 6.10 (d, J= 4.4 Hz, 1H), 5.63 (d, J= 4.0 Hz, 1H), 4.69-4.65 (m, 5H), 3.74-3.71 (m, 2H), 2.92-2.89 (m, 2H), 2.29 (s, 3H). LCMS (ES, m/z): 537 [M+H] + . Method M’ (S)-[4-methyl-3-(4-methylpiperazin-1-yl)phenyl]({2-[4-(1,3-o xazol-2-yl)benzenesulfonyl]- 1H,2H,3H-pyrrolo[3,4-c]pyridine-6-yl})methanol (first eluting isomer); (R)-[4-methyl-3-(4- methylpiperazin-1-yl)phenyl]({2-[4-(1,3-oxazol-2-yl)benzenes ulfonyl]-1H,2H,3H- pyrrolo[3,4-c]pyridine-6-yl})methanol (second eluting isomer) Step 1. 4-(1,3-oxazol-2-yl)benzenesulfonyl chloride [00375] To a stirred mixture of 4-(1,3-oxazol-2-yl)aniline (1.00 g, 6.24 mmol) in conc. HCl (12 mL) and acetic acid (4 mL) was added NaNO 2 (517 mg, 7.49 mmol) in water (0.5 mL) dropwise at -10 °C. The mixture was stirred for 1 h at 0 °C to afford the fresh prepared diazonium salt (mixture A). In a separated 3-necked round-bottom flask, SO2 was pumped into the stirred mixture of CuCl2 (235 mg, 1.75 mmol) in acetic acid (20 mL) for 2 h at 20 °C to afford mixture B. The mixture A was then added into the mixture B at 20 °C. The resulting mixture was stirred for additional overnight at 25 °C. The reaction mixture was diluted with water (40 mL), the precipitated solids were collected by filtration, washed with water (2 x 20 mL) and dried under vacuum to afford 4-(1,3-oxazol-2-yl)benzenesulfonyl chloride (1.20 g, 67%) as an off-white solid. LCMS (ES, m/z): 244, 246 [M+H] + . Step 2. tert-butyl N,N-bis(prop-2-yn-1-yl)carbamate [00376] To a stirred mixture of tert-butyl N-(prop-2-yn-1-yl)carbamate (5.00 g, 30.6 mmol) in DMF (50 mL) was added NaH (1.35 g, 33.7 mmol, 60%) in portions at 0 °C. The resulting mixture was stirred for 30 min at 0 °C under nitrogen atmosphere. This was followed by the additional of 3-bromoprop-1-yne (4.60 g, 36.7 mmol). The resulting mixture was stirred for 3 h at 26 °C under nitrogen atmosphere. The reaction mixture was poured into water/ice (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford tert-butyl N,N- bis(prop-2-yn-1-yl)carbamate (2.60 g, 42%) as a yellow oil. LCMS (ES, m/z): 194 [M+H] + . Step 3. 3-bromo-4-methylbenzoyl cyanide [00377] A mixture of 3-bromo-4-methylbenzoic acid (80 g, 316 mmol, 85%) in SOCl2 (70 mL) was stirred for 2 h at 80 °C. The mixture was cooled to room temperature and concentrated under vacuum. The fresh prepared acyl chloride was dissolved in DCM (900 mL), to the above mixture was added SnCl4 (43.4 g, 158 mmol) and TMSCN (34.6 g, 332 mmol). The resulting mixture was stirred for 2 h at 25 °C. The reaction mixture was poured into water (200 mL) and extracted with DCM (3 x 500 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether (1/10)) to afford 3-bromo-4-methylbenzoyl cyanide as yellow oil (35.2 g, 49%). LCMS (ES, m/z): 224, 226 [M+H] + . Step 4. Tert-butyl 6-(3-bromo-4-methylbenzoyl)-1H,2H,3H-pyrrolo[3,4-c]pyridine- 2-carboxylate [00378] To a solution of 3-bromo-4-methylbenzoyl cyanide (2.50 g, 0.01 mol) in DCE (250 mL) was added tert-butyl N,N-bis(prop-2-yn-1-yl)carbamate (1.21 g, 0.01 mol), chloro(1,5- cyclooctadiene)(pentamethylcyclopentadienyl)ruthenium(II) (0.35 g, 0.92 mmol). The resulting mixture was stirred for 1 h at 60 °C. The mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether (1/9)) to afford tert-butyl 6-(3-bromo-4-methylbenzoyl)-1H,2H,3H- pyrrolo[3,4-c]pyridine-2-carboxylate as yellow solid (2.50 g, 53%). LCMS (ES, m/z): 417, 419 [M+H] + . Step 5. 6-(3-bromo-4-methylbenzoyl)-1H,2H,3H-pyrrolo[3,4-c]pyridine hydrochloride [00379] To a solution of tert-butyl 6-(3-bromo-4-methylbenzoyl)-1H,2H,3H-pyrrolo[3,4- c]pyridine-2-carboxylate (2.50 g, 6.01 mmol) in DCM (30 mL) was added HCl in dioxane (10 mL, 4 M). The resulting solution was stirred for 2 h at room temperature. The mixture was concentrated under vacuum to afford 6-(3-bromo-4-methylbenzoyl)-1H,2H,3H-pyrrolo[3,4-c]pyridine hydrochloride as yellow solid (1.90 g, 90%). LCMS (ES, m/z): 317, 319 [M-HCl+H] + . Step 6. 2-(4-{[6-(3-bromo-4-methylbenzoyl)-1H,2H,3H-pyrrolo[3,4-c]py ridine-2- yl]sulfonyl}phenyl)-1,3-oxazole [00380] To a mixture of 6-(3-bromo-4-methylbenzoyl)-1H,2H,3H-pyrrolo[3,4-c]pyridine hydrochloride (800 mg, 2.27 mmol) in DCM (30 mL) was added triethylamine (0.87 mL, 6.73 mmol) and 4-(1,3-oxazol-2-yl)benzene-1-sulfonyl chloride (660 mg, 2.71 mmol) dropwise at 0 °C. The resulting mixture was stirred for 2 h at 25 °C. The mixture was concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether (1/10)) to afford 2-(4-{[6-(3-bromo-4-methylbenzoyl)-1H,2H,3H-pyrrolo[3,4-c]py ridine-2- yl]sulfonyl}phenyl)-1,3-oxazole as a white solid (750 mg, 63%). LCMS (ES, m/z): 524,526 [M+H] + . Step 7. 1-methyl-4-(2-methyl-5-{2-[4-(1,3-oxazol-2-yl)benzenesulfony l]-1H,2H,3H-pyrrolo[3,4- c]pyridine-6-carbonyl}phenyl)piperazine [00381] To a mixture of 2-(4-{[6-(3-bromo-4-methylbenzoyl)-1H,2H,3H-pyrrolo[3,4- c]pyridine-2-yl]sulfonyl}phenyl)-1,3-oxazole (600 mg, 1.15 mmol) in 1,4-dioxane (70 mL) was added 1-methylpiperazine (1.20 g, 12.0 mmol), RuPhos-Pd 3G (100 mg, 0.12 mmol), RuPhos (600 mg, 1.28 mmol) and Cs 2 CO 3 (1.10 g, 3.34 mmol). The resulting mixture was stirred for 5 h at 100 °C. The mixture was cooled to room temperature, poured into water (50 mL) and extracted with ethyl acetate (3 x 120 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with methanol/dichloromethane (1/10)) to afford 1-methyl-4-(2-methyl- 5-{2-[4-(1,3-oxazol-2-yl)benzenesulfonyl]-1H,2H,3H-pyrrolo[3 ,4-c]pyridine-6- carbonyl}phenyl)piperazine as a white solid (400 mg, 64%). LCMS (ES, m/z): 544 [M+H] + . Step 8. (S)-[4-methyl-3-(4-methylpiperazin-1-yl)phenyl]({2-[4-(1,3-o xazol-2-yl)benzenesulfonyl]- 1H,2H,3H-pyrrolo[3,4-c]pyridine-6-yl})methanol (PH-FMA-PJ00135-640-0A, first eluting isomer) and (R)-[4-methyl-3-(4-methylpiperazin-1-yl)phenyl]({2-[4-(1,3-o xazol-2- yl)benzenesulfonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine-6-yl})me thanol (PH-FMA-PJ00135-640- 0B, second eluting isomer) [00382] To a mixture of 1-methyl-4-(2-methyl-5-{2-[4-(1,3-oxazol-2-yl)benzenesulfony l]- 1H,2H,3H-pyrrolo[3,4-c]pyridine-6-carbonyl}phenyl)piperazine (250 mg, 0.46 mmol) in methanol (3 mL) was added NaBH4 (16 mg, 0.42 mmol) in portions at 0 °C. The resulting mixture was stirred for 1 h at 25 °C. The mixture was poured into water (25 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with methanol/dichloromethane (1/9)) to afford the racemic product. The racemate was separated by Chiral Prep-HPLC with the following conditions: Column: Chiralpak IC 2 x 25 cm, 5um; mobile phase A: MTBE (0.2% IPA), B: MeOH (50B to 50B in 18 min); Flow rate 20 mL/min, 220/254nm, RT1: 15.54, RT2: 19.22. The product fractions were concentrated and lyophilized to afford (S)-[4-methyl-3-(4-methylpiperazin-1-yl)phenyl]({2-[4-(1,3-o xazol-2- yl)benzenesulfonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine-6-yl})me thanol (first eluting isomer, RT1: 15.54) (34.4 mg, 15.97%) as a white solid. And (R)-[4-methyl-3-(4-methylpiperazin-1- yl)phenyl]({2-[4-(1,3-oxazol-2-yl)benzenesulfonyl]-1H,2H,3H- pyrrolo[3,4-c]pyridine-6- yl})methanol (second eluting isomer, RT2: 19.22) (32.6 mg, 15.13%) as a white solid. [00383] First eluting isomer: 1H-NMR (DMSO, 400 MHz) d (ppm): 8.32 (s, 2H), 8.16 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.4 Hz, 2H),7.46 (d, J = 8.4 Hz, 2H), 7.05 (s, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 5.99 (d, J = 4.0 Hz, 1H), 5.60 (d, J = 4.0 Hz, 1H), 4.65-4.59 (m, 4H), 2.76 (br s, 4H), 2.43 (br s, 4H), 2.21 (s, 3H), 2.13 (s, 3H). LCMS (ES, m/z): 546 [M+H] + . [00384] Second eluting isomer: 1H-NMR (DMSO, 400 MHz) d (ppm): 8.32 (s, 2H), 8.16 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.4 Hz, 2H), 7.47-7.45 (m, 2H), 7.04 (s, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.79-6.77 (m, 1H), 5.99 (d, J = 4.4 Hz, 1H), 5.60 (d, J = 4.0 Hz, 1H), 4.69-4.59 (m, 4H), 2.76 (br s, 4H), 2.45 (br s, 4H), 2.23 (s, 3H), 2.13 (s, 3H). LCMS (ES, m/z): 546 [M+H] + .
Method N’ (S)-(3-[6-methyl-2,6-diazaspiro[3.3]heptan-2-yl]phenyl)([2-[ 4-(1,3-oxazol-2- yl)benzenesulfonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl])met hanol (first eluting isomer); R)-(3-[6-methyl-2,6-diazaspiro[3.3]heptan-2-yl]phenyl)([2-[4 -(1,3-oxazol-2- yl)benzenesulfonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl])met hanol (second eluting isomer) Step 1. 4-(1,3-oxazol-2-yl)benzenesulfonyl chloride [00385] To a stirred mixture of 4-(1,3-oxazol-2-yl)aniline (1.00 g, 6.24 mmol) in conc. HCl (12 mL) and acetic acid (4 mL) was added NaNO 2 (517 mg, 7.49 mmol) in water (0.5 mL) dropwise at -10 °C. The mixture was stirred for 1 h at 0 °C to afford the fresh prepared diazonium salt (mixture A). In a separated 3-necked round-bottom flask, SO2 was pumped into the stirred mixture of CuCl 2 (235 mg, 1.75 mmol) in acetic acid (20 mL) for 2 h at 20 °C to afford mixture B. The mixture A was then added into the mixture B at 20 °C. The resulting mixture was stirred for additional overnight at 25 °C. The reaction mixture was diluted with water (40 mL), the precipitated solids were collected by filtration, washed with water (2 x 20 mL) and dried under vacuum to afford 4-(1,3-oxazol-2-yl)benzenesulfonyl chloride (1.20 g, 67%) as an off-white solid. LCMS (ES, m/z): 244, 246 [M+H] + . Step 2. tert-butyl N,N-bis(prop-2-yn-1-yl)carbamate [00386] To a stirred mixture of tert-butyl N-(prop-2-yn-1-yl)carbamate (5.00 g, 30.6 mmol) in DMF (50 mL) was added NaH (1.35 g, 33.7 mmol, 60%) in portions at 0 °C. The resulting mixture was stirred for 30 min at 0 °C under nitrogen atmosphere. This was followed by the additional of 3-bromoprop-1-yne (4.60 g, 36.7 mmol). The resulting mixture was stirred for 3 h at 26 °C under nitrogen atmosphere. The reaction mixture was poured into water/ice (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford tert-butyl N,N- bis(prop-2-yn-1-yl)carbamate (2.60 g, 42%) as a yellow oil. LCMS (ES, m/z): 194 [M+H] + . Step 3. tert-butyl 6-(3-bromobenzoyl)-1H,3H-pyrrolo[3,4-c]pyridine-2-carboxylat e [00387] To a stirred mixture of tert-butyl N,N-bis(prop-2-yn-1-yl)carbamate(1.50 g, 7.76 mmol) and 3-bromobenzoyl cyanide (1.63 g, 7.76 mmol) in DCE (20 mL) was added chloro(1,5- cyclooctadiene)(pentamethylcyclopentadienyl)ruthenium(II) (236 mg, 0.62 mmol). The resulting mixture was stirred for 1 h at 60 °C under nitrogen atmosphere. The mixture was cooled to room temperature, poured into water/ice (40 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford tert-butyl 6-(3-bromobenzoyl)-1H,3H-pyrrolo[3,4- c]pyridine-2-carboxylate (1.80 g, 55%) as a brown solid. LCMS (ES, m/z): 403, 405 [M+H] + . Step 4. Tert-butyl 6-[(3-bromophenyl)(hydroxy)methyl]-1H,2H,3H-pyrrolo[3,4-c]py ridine-2- carboxylate [00388] To a solution of tert-butyl 6-(3-bromobenzoyl)-1H,3H-pyrrolo[3,4-c]pyridine-2- carboxylate (2.40 g, 5.95 mmol) in methanol (15 mL) and dichloromethane (15 mL) was added NaBH 4 (450 mg, 11.9 mmol) in portions at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The mixture was concentrated and diluted with water (10 mL). The resulting mixture was extracted with dichloromethane (3 x 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether (1/1)) to afford tert-butyl 6-[(3- bromophenyl)(hydroxy)methyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine -2-carboxylate as a yellow oil (2.20 g, 91%). LCMS (ES, m/z): 405, 407 [M+H] + . Step 5. (3-bromophenyl)({1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl})methan ol hydrochloride [00389] To a solution of tert-butyl 6-[(3-bromophenyl)(hydroxy)methyl]-1H,2H,3H- pyrrolo[3,4-c]pyridine-2-carboxylate (2.20 g, 5.43 mmol) in dichloromethane (20 mL) was added HCl (5 mL, 4 M in dioxane). The resulting solution was stirred for 3 h at room temperature. The mixture was concentrated under vacuum to afford (3-bromophenyl)({1H,2H,3H-pyrrolo[3,4- c]pyridin-6-yl})methanol hydrochloride as yellow solid (1.70 g, 91%). LCMS (ES, m/z): 305, 307 [M-HCl+H] + . Step 6. (3-bromophenyl)({2-[4-(1,3-oxazol-2-yl)benzenesulfonyl]-1H,2 H,3H-pyrrolo[3,4- c]pyridin-6-yl})methanol [00390] To a stirred mixture of (3-bromophenyl)({1H,2H,3H-pyrrolo[3,4-c]pyridin-6- yl})methanol hydrochloride (1.68 g, 4.92 mmol) in dichloromethane (20 mL) was added TEA (6.85 mL, 67.7 mmol) and 4-(1,3-oxazol-2-yl)benzene-1-sulfonyl chloride (1.20 g, 4.93 mmol) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The mixture was concentrated under vacuum and the residue was diluted with of methanol (30 mL). The solids were collected by filtration and dried under vacuum to afford (3-bromophenyl)({2-[4-(1,3-oxazol-2- yl)benzenesulfonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl})met hanol as pink solid (2.00 g, 79%). LCMS (ES, m/z): 512, 514 [M+H] + . Step 7. (S)-(3-[6-methyl-2,6-diazaspiro[3.3]heptan-2-yl]phenyl)([2-[ 4-(1,3-oxazol-2- yl)benzenesulfonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl])met hanol (first eluting isomer) and (R)-(3-[6-methyl-2,6-diazaspiro[3.3]heptan-2-yl]phenyl)([2-[ 4-(1,3-oxazol-2- yl)benzenesulfonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl])met hanol (second eluting isomer) [00391] To a solution of (3-bromophenyl)([2-[4-(1,3-oxazol-2-yl)benzenesulfonyl]-1H,2 H,3H- pyrrolo[3,4-c]pyridin-6-yl])methanol (100 mg, 0.19 mmol) in dioxane (5 mL) was added RuPhos 3 G (16 mg, 0.02 mmol), RuPhos (9 mg, 0.02 mmol), Cs2CO3 (191 mg, 0.56 mmol) and bis(2- methyl-2,6-diazaspiro[3.3]heptane); oxalic acid (66 mg, 0.21 mmol). The resulting mixture was stirred for 4 h at 110 °C. The reaction mixture was cooled to room temperature, poured into water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate concentrated under vacuum. The crude product was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5 µm, 30 x 150 mm; Mobile Phase, A: water (containing 10 mmol/L NH4HCO3) and B: CH3CN (10% to 40% in 7 min); Flow rate: 60 mL/min; Detector: UV 254 nm). The product fractions were concentrated under vacuum to afford the racemic product. The racemate was separated by Chiral Prep-HPLC with the following condition: Column: CHIRALPAK IC, 5 µm, 20 x 250 mm; Mobile Phase, A: methanol (containing 0.1% DEA) and B: DCM (keep 50% B in 18 min); Flow rate: 20 mL/min; Detector: UV 254/220 nm; RT1: 10.692 min; RT2: 14.71 min. The product fractions were concentrated and lyophilized to afford (S)-(3-[6-methyl-2,6-diazaspiro[3.3]heptan-2-yl]phenyl)([2-[ 4-(1,3-oxazol-2- yl)benzenesulfonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl])met hanol (first eluting isomer, RT1: 10.692 min) as a white solid (16.9 mg, 16%). And (R)-(3-[6-methyl-2,6-diazaspiro[3.3]heptan-2- yl]phenyl)([2-[4-(1,3-oxazol-2-yl)benzenesulfonyl]-1H,2H,3H- pyrrolo[3,4-c]pyridin-6- yl])methanol (second eluting isomer, RT2: 14.71 min) as a white solid (15.2 mg, 15%). [00392] First eluting isomer: 1 H-NMR (DMSO-d6, 400 MHz) d (ppm): 8.32 (s, 2H), 8.16 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.4 Hz, 2H), 7.47-7.44 (m, 2H), 7.00-6.96 (m, 1H), 6.58 (d, J = 8.0 Hz, 1H), 6.44 (s, 1H), 6.20 (d, J = 8.4 Hz, 1H), 5.96 (d, J = 4.0 Hz, 1H), 5.56 (d, J = 3.6 Hz, 1H), 4.64-4.58 (m, 4H), 3.78 (s, 4H), 3.33-3.27 (m, 4H), 2.20 (s, 3H). LCMS (ES, m/z): 544 [M+H] + . [00393] Second eluting isomer: 1H-NMR (DMSO-d6, 400 MHz) d (ppm): 8.32 (s, 2H), 8.16 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.4 Hz, 2H), 7.47-7.44 (m, 2H), 7.00-6.96 (m, 1H), 6.58 (d, J = 7.6 Hz, 1H), 6.44 (s, 1H), 6.20 (d, J = 7.6 Hz, 1H), 5.96 (d, J = 4.0 Hz, 1H), 5.56 (d, J = 4.0 Hz, 1H), 4.65-4.58 (m, 4H), 3.79-3.75 (m, 4H), 3.25 (s, 4H), 2.19 (s, 3H). LCMS (ES, m/z): 544 [M+H] + . Table 20.
[00394] As set forth in Table 21, IC50 values are defined as follows: £ 25 µM and > 10 µM (+); £ 10 µM and > 1 µM (++); £ 1 µM and > 0.1 µM (+++); £ 0.1 µM and > 0.001 µM (++++); based upon the Biochemical Assay of Example A. [00395] In Tables 11 and 21, absolute stereochemistry has not been determined for some Examples. Accordingly, assignment of any Examples as the “R” or “S” stereoisomer is arbitrary, unless otherwise noted. In some cases, Examples are labeled with “1 st eluting isomer”, “2 nd eluting isomer”, etc. based on the purification method used to separate the stereoisomers (see Table 20). Table 21. Example A. Biochemical Assay for USP9X Inhibitory Activity [00396] The assay was performed in a final volume of 6 µL assay buffer containing 20 mM Tris-HCl (pH 8.0, (1M Tris-HCl, pH 8.0 solution; Corning 46-031-CM)), L-Glutathione (GSH) reducing agent (1 mM, Sigma-Aldrich, G4251-100G), 0.03% Bovine Gamma Globulin (BGG) (0.22 µM filtered, Sigma, G7516-25G), and 0.01% Triton X-100 (Sigma, T9284-10L). DMSO solutions of the compounds in nanoliter quantities (10-point, 3-fold serial dilutions) were dispensed into 1536 assay plates (Corning, #3724BC) for final test concentrations of 25 µM to 1.3 nM, top to lowest dose, respectively. Concentration and incubation times were optimized for the maximal signal-to-background while maintaining initial velocity conditions at a fixed substrate concentration (<< Km). The final concentration of USP9X (Enzyme, E) was 0.025 nM, and the final concentration of Ubiquitin-Rhodamine 110 (Ub-Rh110, UbiQ-126) (Substrate, S) was 25 nM. To assay plates (pre-stamped with compound) was added 3 µL 2x Enzyme. The enzyme was preincubated for 30 minutes and then treated with 3 µL of 2x Substrate. Plates were incubated for 11 min (continuous kinetic read) at room temperature before the fluorescence was read on the Envision plate reader (Perkin Elmer) or PheraSTAR plate reader (BMG), with excitation at 485 nm and emission at 535 nm. The slope (best fit linear regression) of the five reads was used to normalize for inhibition. For all assays, data are reported as percent inhibition compared with control wells based on the following equation: %inh = 100*((FLU - AveLow) / (AveHigh -- AveLow)), wherein FLU is measured Fluorescence, AveLow is average Fluorescence of no enzyme control (n=64), and AveHigh is average Fluorescence of DMSO control (n=64). IC50 values are determined by curve fitting of the standard 4 parameter logistic fitting algorithm included in the Activity Base software package: IDBS XE Designer Model205. Data are fitted using the Levenburg Marquardt algorithm. Equivalents [00397] The present disclosure enables one of skill in the relevant art to make and use the inventions provided herein in accordance with multiple and varied embodiments. Various alterations, modifications, and improvements of the present disclosure that readily occur to those skilled in the art, including certain alterations, modifications, substitutions, and improvements are also part of this disclosure. Accordingly, the foregoing description and drawings are by way of example to illustrate the discoveries provided herein. [00398] 1. A method of treating cancer in a patient in need thereof, comprising administering to the patient a USP9X Inhibitor. [00399] 2. A method of treating cancer in a patient in need thereof, comprising administering to the patient an antineoplastic therapy consisting of the administration of a USP9X Inhibitor. [00400] 3. A method of treating cancer in a patient in need thereof, comprising administering to the patient a USP9X Inhibitor, wherein the patient is receiving or has received an immune checkpoint pathway inhibitor. [00401] 4. A method of treating cancer in a patient in need thereof, comprising administering to the patient an immune checkpoint pathway inhibitor, wherein the patient is receiving or has received a USP9X Inhibitor. [00402] 5. A method of treating cancer in a patient in need thereof, comprising administering to the patient an antineoplastic therapy consisting of the administration of a USP9X Inhibitor and the administration of an immune checkpoint pathway inhibitor. [00403] 6. A method of treating a patient diagnosed with a cancer, comprising administering a USP9X Inhibitor to the patient, wherein the patient is already being treated for the cancer with an immune checkpoint pathway inhibitor. [00404] 7. A method of treating a patient diagnosed with a cancer, comprising administering a USP9X Inhibitor to the patient, wherein the cancer has progressed while receiving an immune checkpoint pathway inhibitor. [00405] 8. A method of treating a patient diagnosed with a cancer, wherein the patient i) has been diagnosed with cancer that has progressed, or ii) has relapsed after previously being administered an immune checkpoint pathway inhibitor for the cancer. [00406] 9. A method of treating a patient diagnosed with a cancer, wherein the method comprises administering a USP9X Inhibitor to the patient while the patient continues to receive an immune checkpoint pathway inhibitor after being diagnosed with a cancer that is refractory to an immune checkpoint pathway inhibitor. [00407] 10. The method of any one of the preceding embodiments, wherein the cancer comprises a tumor that expresses PD-L1. [00408] 11. The method of any one of the preceding embodiments, wherein the cancer comprises a tumor that expresses PD-L1 and the PD-L1 can be detected using PD-L1 IHC 22C 3 pharmDx. [00409] 12. The method of any one of embodiments 1-9, wherein the cancer comprises a tumor that expresses CTLA-4. [00410] 13. The method of any one of the preceding embodiments, wherein the cancer is selected from unresectable or metastatic melanoma, cutaneous melanoma, advanced renal cell carcinoma, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, metastatic squamous non-small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, cervical cancer, hepatocellular carcinoma, or Merkel cell carcinoma. [00411] 14. The method of any one of the preceding embodiments, wherein the patient has received one or more prior lines of chemotherapy. [00412] 15. The method of any one of the preceding embodiments, wherein the patient has received two or more prior lines of chemotherapy. [00413] 16. The method of any one of the preceding embodiments, wherein the patient has received three or more prior lines of chemotherapy. [00414] 17. The method of any one of the preceding embodiments, wherein the patient has not responded to a prior line of chemotherapy. [00415] 18. The method of any one of the preceding embodiments, wherein the patient has relapsed after receiving a prior line of chemotherapy. [00416] 19. The method of any one of embodiments 14-18, wherein the prior line of chemotherapy is selected from platinum-based chemotherapy, fluoropyrimidine therapy, irinotecan therapy, paclitaxel therapy, nab-paclitaxel therapy, HER 2 /neu-targeted therapy, or sorafenib therapy. [00417] 20. The method of any one of the preceding embodiments, wherein the patient has not responded to prior therapy with an immune checkpoint pathway inhibitor. [00418] 21. The method of any one of the preceding embodiments, wherein the cancer is refractory or resistant to treatment with an immune checkpoint pathway inhibitor. [00419] 22. The method of any one of the preceding embodiments, wherein the cancer is unresectable or metastatic melanoma. [00420] 23. The method of any one of the preceding embodiments, wherein the cancer is cutaneous melanoma with pathologic involvement of regional lymph nodes. [00421] 24. The method of claim 23, wherein the patient has undergone complete resection and/or a total lymphadenectomy. [00422] 25. The method of any one of the preceding embodiments, wherein the cancer is previously untreated advanced renal cell carcinoma. [00423] 26. The method of any one of the preceding embodiments, wherein the cancer is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer. [00424] 27. The method of claim 26, wherein the cancer has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. [00425] 28. The method of any one of the preceding embodiments, wherein the cancer is unresectable or metastatic melanoma that has progressed following treatment with ipilimumab. [00426] 29. The method of any one of the preceding embodiments, wherein the cancer is metastatic squamous non-small cell lung cancer. [00427] 30. The method of claim 29, wherein the cancer has progressed on or after platinum- based chemotherapy. [00428] 31. The method of any one of the preceding embodiments, wherein the cancer is melanoma with involvement of lymph node(s) following complete resection. [00429] 32. The method of any one of the preceding embodiments, wherein the cancer is metastatic nonsquamous non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations. [00430] 33. The method of any one of the preceding embodiments, wherein the cancer is metastatic non-small cell lung cancer, wherein the cancer comprises a tumor with high PD-L1 expression with no EGFR or ALK genomic tumor aberrations. [00431] 34. The method of claim 33, wherein high PD-L1 expression is a Tumor Proportion Score (TPS) ³50% as determined by an FDA-approved test. [00432] 35. The method of any one of the preceding embodiments, wherein the cancer is metastatic non-small cell lung cancer, wherein the cancer comprises a tumor with PD-L1 expression of TPS ³1% as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. [00433] 36. The method of any one of the preceding embodiments, wherein the cancer is recurrent or metastatic head and neck squamous cell cancer (HNSCC) with disease progression on or after platinum-containing chemotherapy. [00434] 37. The method of any one of the preceding embodiments, wherein the cancer is refractory classical Hodgkin lymphoma. [00435] 38. The method of any one of the preceding embodiments, wherein the cancer is refractory primary mediastinal large B-cell lymphoma. [00436] 39. The method of any one of the preceding embodiments, wherein the cancer is locally advanced or metastatic urothelial carcinoma, wherein the cancer comprises a tumor with PD-L1 expression of Combined Positive Score (CPS) ³10 as determined by an FDA-approved test. [00437] 40. The method of any one of the preceding embodiments, wherein the cancer is locally advanced or metastatic urothelial carcinoma, and wherein the patient is not eligible for platinum- containing chemotherapy. [00438] 41. The method of any one of the preceding embodiments, wherein the cancer is locally advanced or metastatic urothelial carcinoma. [00439] 42. The method of any one of the preceding embodiments, wherein the cancer is unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumors that have progressed following prior treatment. [00440] 43. The method of any one of the preceding embodiments, wherein the cancer is locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, wherein the cancer comprises a tumor with PD-L1 expression of Combined Positive Score (CPS) ³1 as determined by an FDA-approved test. [00441] 44. The method of claim 43, wherein the cancer has progressed on or after prior lines of therapy. [00442] 45. The method of any one of the preceding embodiments, wherein the cancer is recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ³1) as determined by an FDA-approved test. [00443] 46. The method of any one of the preceding embodiments, wherein the cancer is hepatocellular carcinoma (HCC), and wherein the patient has previously been treated with sorafenib. [00444] 47. The method of any one of the preceding embodiments, wherein the cancer is recurrent locally advanced or metastatic Merkel cell carcinoma. [00445] 48. The method of any one of the preceding embodiments, wherein the immune checkpoint pathway inhibitor is selected from ipilimumab, nivolumab, or pembrolizumab. [00446] 49. The method of any one of the preceding embodiments, comprising administering two or more immune checkpoint pathway inhibitors. [00447] 50. The method of any one of the preceding embodiments, wherein the immune checkpoint pathway inhibitor is ipilimumab. [00448] 51. The method of any one of the preceding embodiments, wherein the patient is receiving or has received ipilimumab in a dose of any one of the following: (i) 3 mg/kg over 90 minutes every 3 weeks for a total of 4 doses; and/or (ii) 10 mg/kg over 90 minutes every 3 weeks for a total of 4 doses; and/ or (iii) 10 mg/kg every 12 weeks for up to 3 years; and/or (iv) 1 mg/kg over 30 minutes every 3 weeks for a total of 4 doses. [00449] 52. The method of any one of the preceding embodiments, comprising administering to the patient ipilimumab in a dose of any one of the following: (i) 3 mg/kg over 90 minutes every 3 weeks for a total of 4 doses; and/or (ii) 10 mg/kg over 90 minutes every 3 weeks for a total of 4 doses; and/ or (iii) 10 mg/kg every 12 weeks for up to 3 years; and/or (iv) 1 mg/kg over 30 minutes every 3 weeks for a total of 4 doses. [00450] 53. The method of any one of the preceding embodiments, wherein the immune checkpoint pathway inhibitor is nivolumab. [00451] 54. The method of any one of the preceding embodiments, wherein the patient is receiving or has received nivolumab in a dose of any one of the following: (i) 3 mg/kg over 60 minutes every 2 weeks; and/or (ii) 3 mg/kg over 30 minutes. [00452] 55. The method of any one of the preceding embodiments, comprising administering to the patient nivolumab in a dose of any one of the following: (i) 3 mg/kg over 60 minutes every 2 weeks; and/or (ii) 3 mg/kg over 30 minutes. [00453] 56. The method of any one of the preceding embodiments, wherein the immune checkpoint pathway inhibitor is ipilimumab and nivolumab. [00454] 57. The method of any one of the preceding embodiments, wherein the patient is receiving or has received the immune checkpoint pathway inhibitor in a dose of any one of the following: (i) 3 mg/kg nivolumab over 30 minutes followed 1 mg/kg ipilimumab over 30 minutes on the same day, every 3 weeks for a total of 4 doses; and/or (ii) 3 mg/kg nivolumab over 30 minutes, followed by 1 mg/kg ipilimumab over 30 minutes on the same day, every 3 weeks for a total of 4 doses, followed by 240 mg nivolumab every 2 weeks over 30 minutes; and/or (iii) 3 mg/kg nivolumab over 30 minutes, followed by 1 mg/kg ipilimumab over 30 minutes on the same day, every 3 weeks for a total of 4 doses, followed by 480 mg nivolumab every 2 weeks over 30 minutes. [00455] 58. The method of any one of the preceding embodiments, comprising administering to the patient the immune checkpoint pathway inhibitor in a dose of any one of the following: (i) 3 mg/kg nivolumab over 30 minutes followed 1 mg/kg ipilimumab over 30 minutes on the same day, every 3 weeks for a total of 4 doses; and/or (ii) 3 mg/kg nivolumab over 30 minutes, followed by 1 mg/kg ipilimumab over 30 minutes on the same day, every 3 weeks for a total of 4 doses, followed by 240 mg nivolumab every 2 weeks over 30 minutes; and/or (iii) 3 mg/kg nivolumab over 30 minutes, followed by 1 mg/kg ipilimumab over 30 minutes on the same day, every 3 weeks for a total of 4 doses, followed by 480 mg nivolumab every 2 weeks over 30 minutes. [00456] 59. The method of any one of the preceding embodiments, wherein the immune checkpoint pathway inhibitor is pembrolizumab. [00457] 60. The method of any one of the preceding embodiments, wherein the patient is receiving or has received pembrolizumab in a dose of any one of the following: (i) 200 mg every 3 weeks; and/or (ii) 2 mg/kg over 30 minutes every 3 weeks. [00458] 61. The method of any one of the preceding embodiments, comprising administering to the patient pembrolizumab in a dose of any one of the following: (i) 200 mg every 3 weeks; and/or (ii) 2 mg/kg over 30 minutes every 3 weeks. [00459] 62. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor has an IC 50 value of £ 10 µM in the Biochemical Assay of Example A. [00460] 63. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor has an IC50 value of £ 2 µM in the Biochemical Assay of Example A. [00461] 64. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor has an IC 50 value of £ 1 µM in the Biochemical Assay of Example A. [00462] 65. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor has an IC50 value of £ 0.2 µM in the Biochemical Assay of Example A. [00463] 66. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor has an IC50 value of £ 0.1 µM in the Biochemical Assay of Example A. [00464] 67. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor has an IC 50 value of £ 0.05 µM in the Biochemical Assay of Example A. [00465] 68. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor is a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: X is CR 5 R 6 , CR 5 , NR 5 , or N, as valency permits; dashed bonds are each independently a single or a double bond, as valency permits; Y 1 , Y 2 , and Y 3 are each independently N or CR a ; each R a is independently -H, halogen, or -CN; Ring A is a 5- to 6-membered aryl, 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, 5- to 7-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, or 5- to 7-membered cycloalkyl, wherein each aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally substituted with one or more halogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, oxo, or -C(O)R’; Z 1 is O, S, or NR; Z 2 is O or NR; W is CR 1’ R 2’ , O, S, or NR; m is 0 or 1; R 1 and R 2 are each independently -H, halogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -(CR b R c ) n C 3 -C 12 cycloalkyl, -(CR b R c ) n C 4 -C 12 cycloalkenyl, -(CR b R c ) n heterocyclyl, -(CR b R c )nC 6 -C 1 4aryl, -(CR b R c )nheteroaryl, -OR, -OC(O)R’, -OS(O)2R’, -OS(O)2NR 2 , -OC(O)NR 2 , -OC(O)OR, -(CR b R c )nNR 2 , -(CR b R c )nNRC(O)R’, -(CR b R c )nNRS(O)2R’, -(CR b R c ) n NRC(O)NR 2 , -(CR b R c ) n NRC(O)OR, -(CR b R c ) n CN, -(CR b R c ) n NO 2 , -(CR b R c ) n SR, -(CR b R c )nC(O)R’, -(CR b R c )nC(O)OR, -(CR b R c )nC(O)NR 2 , -(CR b R c )nSO2R’, -(CR b R c )nSO2NR 2 , or -(CR b R c )nSO2OR, wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R e , wherein each alkyl, alkenyl, or alkynyl is optionally substituted with one or more halogen, wherein each heterocyclyl is 3- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z 1 ), and wherein each heteroaryl is 5- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S; or R 1 and R 2 combine with the carbon to which they are attached to form oxo, a C 3 -C8cycloalkyl, or a 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z 1 ), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more R e ; R 1’ and R 2’ are each independently -H, halogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -(CR b R c ) n C 3 -C 12 cycloalkyl, -(CR b R c ) n C 4 -C 12 cycloalkenyl, -(CR b R c ) n heterocyclyl, -(CR b R c )nC 6 -C 1 4aryl, -(CR b R c )nheteroaryl, -(CR b R c )nNR 2 , -(CR b R c )nNRC(O)R’, -(CR b R c )nNRS(O)2R’, -(CR b R c )nNRC(O)NR 2 , -(CR b R c )nNRC(O)OR, -(CR b R c )nCN, -(CR b R c )nNO2, -(CR b R c )nSR, -(CR b R c )nC(O)R’, -(CR b R c )nC(O)OR, -(CR b R c )nC(O)NR 2 , -(CR b R c ) n SO 2 R’, -(CR b R c ) n SO 2 NR 2 , or -(CR b R c ) n SO 2 OR, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R e , wherein each heterocyclyl is 3- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein each heteroaryl is 5- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S; or R 1’ and R 2’ combine with the carbon to which they are attached to form oxo, a C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S, wherein each heterocyclyl does not contain an O in the g-position relative to C(=Z 1 ), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more R e ; or R 1 and R 1’ combine with the carbons to which they are attached to form a C 3 -C8cycloalkyl or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S, wherein each heterocyclyl does not contain an O in the g-position relative to C(=Z 1 ), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more R e ; R b and R c are each independently selected from the group consisting of -H, halogen, and -C 1 -C 6 alkyl; each n is independently 0, 1, 2, 3, or 4; each R e is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O)2NR 2 , -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 12 cycloalkyl, -C 4 -C 12 cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C 6 -C 14 aryl, and 5- to 14- membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein -OR of R e does not result in an O in the g-position relative to C(=Z 1 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -C 1 -C 6 alkyl optionally substituted with one or more halogen, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -OR, -C 3 -C 12 cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; B is a monocyclic or bicyclic 3- to 14-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein the ring is optionally substituted with one or more R d , and when m is 0 and the ring is saturated or partially unsaturated, then the ring does not contain an O in the g-position relative to C(=Z 1 ); each R d is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O) 2 NR 2 , -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 12 cycloalkyl, -C 4 -C 12 cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C 6 -C 1 4aryl, and 5- to 14- membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -C 1 -C 6 alkyl optionally substituted with one or more halogen, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -OR, -C 3 -C 12 cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; each R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is independently -H, -C 1 -C 6 alkyl, -C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more halogen, oxo, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O)2NR 2 ,-C 3 -C8cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein R 3 , R 7 , and R 9 are each independently present or absent, as valency permits; or R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , or combinations thereof, combine with the carbon to which they are attached to form an oxo, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; each R is independently selected from the group consisting of -H, -OH, -O(C 1 -C 6 alkyl), -NH2, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)2, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 12 cycloalkyl, -C 4 -C 12 cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C 6 -C 1 4aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, oxo, -O-C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -C 1 -C 6 alkyl optionally substituted with one or more oxo or -OH, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 12 cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; and each R’ is independently selected from the group consisting of -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 12 cycloalkyl, -C 4 -C 12 cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, oxo, -C 1 -C 6 alkyl optionally substituted with one or more oxo or -OH, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -O-C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl)2. [00466] 69. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor is a compound of Formula I-a:
or a pharmaceutically acceptable salt thereof wherein Y 2 is CH or N. [00467] 70. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor is a compound of Formula I-b: or a pharmaceutically acceptable salt thereof, wherein: Y 2 is CH or N; R 1 is -OH or -(CH 2 )NHMe; B is a phenyl ring or a bicyclic ring, wherein at least one of the rings in the bicyclic ring is a phenyl ring, wherein the phenyl ring or bicyclic ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the phenyl ring or bicyclic ring is optionally substituted with one or more R d ; each R d is independently selected from the group consisting of halogen, -C 1 -C 6 alkyl, and -OR; and each R is independently -H, -C 1 -C 6 alkyl, or 3- to 8-membered heterocyclyl optionally substituted with -C 1 -C 6 alkyl. [00468] 71. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor is a compound Formula I-c:
or a pharmaceutically acceptable salt thereof. [00469] 72. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor is a compound of Formula I-d: or a pharmaceutically acceptable salt thereof. [00470] 73. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor is a compound of Formula I-e: or a pharmaceutically acceptable salt thereof. [00471] 74. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor is a compound of Formula I-f: (I-f) or a pharmaceutically acceptable salt thereof. [00472] 75. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor is a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein: X 1 is NR or O; Y 1 is CR 7 or N; Y 2 is CR 8 or N; Y 3 is CR 9 or N; wherein the heteroaryl formed when at least one of Y 1 , Y 2 , or Y 3 is N may comprise an N- oxide; Ring A is a monocyclic or bicyclic 3- to 12-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of N, O, and S, and wherein Ring A is optionally substituted with one or more R a ; each R a is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O) 2 R’, -S(O) 2 NR 2 , optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R a group may be substituted with one or more substituents selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O)2NR 2 , and C 1 -C 6 aliphatic; Ring B is a monocyclic or bicyclic 3- to 12-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of N, O, and S, and wherein Ring B is optionally substituted with one or more R b ; each R b is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O) 2 NR 2 , optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R b group may be substituted with one or more substituents selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O) 2 R’, -S(O) 2 NR 2 , and C 1 -C 6 aliphatic; R 1 and R 2 are each independently selected from the group consisting of -H, halogen, -OR, -OC(O)R’, -OS(O) 2 R’, -OS(O) 2 NR 2 , -OC(O)NR 2 , -OC(O)OR, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -NRC(O)NR 2 , -NRC(O)OR, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -SO2NR 2 , -S(O)2OR, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, or R 1 and R 2 combine with the carbon to which they are attached to form an optionally substituted C 3 -C8cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S, wherein an optionally substituted R 1 and R 2 group may be substituted with one or more of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O) 2 R’, -S(O) 2 NR 2 , and C 1 -C 6 aliphatic; R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of -H, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C8cycloalkyl, and optionally substituted 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S, or R 3 and R 4 , or R 5 and R 6 , or a combination thereof, combine with the carbon to which they are attached to form an optionally substituted C 3 -C8cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S, wherein an optionally substituted R 3 , R 4 , R 5 , and R 6 group may be substituted with one or more of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O)2NR 2 , and C 1 -C 6 aliphatic; R 7 , R 8 , and R 9 are each independently selected from the group consisting of -H, halogen, -OR, -OC(O)R’, -OS(O) 2 R’, -OS(O) 2 NR 2 , -OC(O)NR 2 , -OC(O)OR, -NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -NRC(O)NR 2 , -NRC(O)OR, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -SO2NR 2 , -S(O)2OR, and optionally substituted C 1 -C 6 aliphatic, wherein an optionally substituted R 7 , R 8 , and R 9 group may be substituted with one or more of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O)2NR 2 , and C 1 -C 6 aliphatic; each R is independently selected from the group consisting of -H, optionally substituted C 1 - C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10- membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R group may be optionally substituted with one or more of halogen, oxo, -OH, -O(C 1 -C 6 aliphatic), -NH2, -NH(C 1 -C 6 aliphatic), -N(C 1 -C 6 aliphatic)2, -CN, and C 1 -C 6 aliphatic; each R’ is independently selected from the group consisting of optionally substituted C 1 - C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10- membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R’ group may be substituted with one or more of halogen, oxo, -OH, -O(C 1 -C 6 aliphatic), -NH2, -NH(C 1 -C 6 aliphatic), -N(C 1 -C 6 aliphatic)2, -CN, and C 1 -C 6 aliphatic; m is 0, 1, or 2; and n is 0, 1, or 2. [00473] 76. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor is a compound of Formula II-a: or a pharmaceutically acceptable salt thereof. [00474] 77. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor is a compound of Formula II-b: or a pharmaceutically acceptable salt thereof. [00475] 78. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor is a compound of Formula II-c: or a pharmaceutically acceptable salt thereof. [00476] 79. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor is a compound of Formula II-d: or a pharmaceutically acceptable salt thereof. [00477] 80. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor is a compound of Formula II-e: or a pharmaceutically acceptable salt thereof. [00478] 81. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor is a compound of Formula II-f: or a pharmaceutically acceptable salt thereof. [00479] 82. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor is selected from: or a pharmaceutically acceptable salt thereof. [00480] 83. The method of any one of the preceding embodiments, wherein the USP9X Inhibitor is administered in a therapeutically effective amount. [00481] 1A. A method of treating cancer in a patient in need thereof, comprising administering to the patient a USP9X Inhibitor, wherein the patient is receiving or has received an immune checkpoint pathway inhibitor. [00482] 2A. A method of treating cancer in a patient in need thereof, comprising administering to the patient an immune checkpoint pathway inhibitor, wherein the patient is receiving or has received a USP9X Inhibitor. [00483] 3A. The method of any one of embodiments 1A-2A, comprising administering the USP9X Inhibitor to the patient, wherein the cancer has progressed while receiving the immune checkpoint pathway inhibitor. [00484] 4A. The method of any one of embodiments 1A-3A, wherein the patient has relapsed after previously being administered the immune checkpoint pathway inhibitor for the cancer. [00485] [00486] 5A. The method of any one of embodiments 1A-4A, wherein the method comprises administering the USP9X Inhibitor to the patient while the patient continues to receive the immune checkpoint pathway inhibitor after being diagnosed with a cancer that is refractory to the immune checkpoint pathway inhibitor. [00487] 6A. The method of any one of embodiments 1A-5A, wherein the cancer comprises a tumor that expresses PD-L1. [00488] 7A. The method of any one of embodiments 1A-6A, wherein the cancer comprises a tumor that expresses PD-L1 and the PD-L1 can be detected using PD-L1 IHC 22C 3 pharmDx. [00489] 8A. The method of any one of embodiments 1A-5A, wherein the cancer comprises a tumor that expresses CTLA-4. [00490] 9A. The method of of any one of embodiments 1A-8A, wherein the cancer is selected from unresectable or metastatic melanoma, cutaneous melanoma, advanced renal cell carcinoma, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, metastatic squamous non-small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, cervical cancer, hepatocellular carcinoma, or Merkel cell carcinoma. [00491] 10A. The method of any one of embodiments 1A-9A, wherein the patient has received one or more prior lines of chemotherapy. [00492] 11A. The method of any one of embodiments 1A-10A, wherein the immune checkpoint pathway inhibitor is selected from ipilimumab, nivolumab, and pembrolizumab. [00493] 12A. The method of any one of embodiments 1A-10A, wherein the immune checkpoint pathway inhibitor is selected from atezolizumab, durvalumab, avelumab, and cemiplimab. [00494] 13A. The method of any one of embodiments 1A-12A, wherein the USP9X Inhibitor is a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: X is CR 5 R 6 , CR 5 , NR 5 , or N, as valency permits; dashed bonds are each independently a single or a double bond, as valency permits; Y 1 , Y 2 , and Y 3 are each independently N or CR a ; each R a is independently –H, halogen, or –CN; Ring A is a 5- to 6-membered aryl, 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, 5- to 7-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, or 5- to 7-membered cycloalkyl, wherein each aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally substituted with one or more halogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, oxo, or –C(O)R’; Z 1 is O, S, or NR; Z 2 is O or NR; W is CR 1’ R 2’ , O, S, or NR; m is 0 or 1; R 1 and R 2 are each independently –H, halogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, - (CR b R c )nC 3 -C 12 cycloalkyl, -(CR b R c )nC 4 -C 12 cycloalkenyl, -(CR b R c )nheterocyclyl, - (CR b R c ) n C 6 -C 14 aryl, -(CR b R c ) n heteroaryl, -OR, -OC(O)R’, -OS(O) 2 R’, -OS(O) 2 NR 2 , - OC(O)NR 2 , -OC(O)OR, -(CR b R c ) n NR 2 , -(CR b R c ) n NRC(O)R’, -(CR b R c ) n NRS(O) 2 R’, - (CR b R c )nNRC(O)NR 2 , -(CR b R c )nNRC(O)OR, -(CR b R c )nCN, -(CR b R c )nNO2, -(CR b R c )nSR, - (CR b R c )nC(O)R’, -(CR b R c )nC(O)OR, -(CR b R c )nC(O)NR 2 , -(CR b R c )nSO2R’, - (CR b R c ) n SO 2 NR 2 , or -(CR b R c ) n SO 2 OR, wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R e , wherein each alkyl, alkenyl, or alkynyl is optionally substituted with one or more halogen, wherein each heterocyclyl is 3- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z 1 ), and wherein each heteroaryl is 5- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S; or R 1 and R 2 combine with the carbon to which they are attached to form oxo, a C 3 -C8cycloalkyl, or a 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z 1 ), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more R e ; R 1’ and R 2’ are each independently –H, halogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, - (CR b R c )nC 3 -C 12 cycloalkyl, -(CR b R c )nC 4 -C 12 cycloalkenyl, -(CR b R c )nheterocyclyl, - (CR b R c ) n C 6 -C 14 aryl, -(CR b R c ) n heteroaryl, -(CR b R c ) n NR 2 , -(CR b R c ) n NRC(O)R’, - (CR b R c ) n NRS(O) 2 R’, -(CR b R c ) n NRC(O)NR 2 , -(CR b R c ) n NRC(O)OR, -(CR b R c ) n CN, - (CR b R c )nNO2, -(CR b R c )nSR, -(CR b R c )nC(O)R’, -(CR b R c )nC(O)OR, -(CR b R c )nC(O)NR 2 , - (CR b R c )nSO2R’, -(CR b R c )nSO2NR 2 , or -(CR b R c )nSO2OR, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R e , wherein each heterocyclyl is 3- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein each heteroaryl is 5- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S; or R 1’ and R 2’ combine with the carbon to which they are attached to form oxo, a C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S, wherein each heterocyclyl does not contain an O in the g-position relative to C(=Z 1 ), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more R e ; or R 1 and R 1’ combine with the carbons to which they are attached to form a C 3 -C8cycloalkyl or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S, wherein each heterocyclyl does not contain an O in the g-position relative to C(=Z 1 ), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more R e ; R b and R c are each independently selected from the group consisting of –H, halogen, and -C 1 - C 6 alkyl; each n is independently 0, 1, 2, 3, or 4; each R e is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, - NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O) 2 R’, - S(O)2NR 2 , -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 12 cycloalkyl, -C 4 - C 12 cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C 6 -C 1 4aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein –OR of R e does not result in an O in the g-position relative to C(=Z 1 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -C 1 -C 6 alkyl optionally substituted with one or more halogen, -C 2 - C 6 alkenyl, -C 2 -C 6 alkynyl, -OR, –C 3 -C 12 cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; B is a monocyclic or bicyclic 3- to 14-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein the ring is optionally substituted with one or more R d , and when m is 0 and the ring is saturated or partially unsaturated, then the ring does not contain an O in the g-position relative to C(=Z 1 ); each R d is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, - NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, - S(O) 2 NR 2 , -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 12 cycloalkyl, -C 4 - C 12 cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C 6 -C 1 4aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -C 1 -C 6 alkyl optionally substituted with one or more halogen, -C 2 - C 6 alkenyl, -C 2 -C 6 alkynyl, -OR, –C 3 -C 12 cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; each R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is independently –H, -C 1 -C 6 alkyl, -C 3 -C8cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more halogen, oxo, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -OR, -OC(O)R’, -NR 2 , - NRC(O)R’, -NRS(O) 2 R’, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O) 2 R’, - S(O) 2 NR 2 ,-C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein R 3 , R 7 , and R 9 are each independently present or absent, as valency permits; or R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , or combinations thereof, combine with the carbon to which they are attached to form an oxo, C 3 -C8cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; each R is independently selected from the group consisting of –H, -OH, -O(C 1 -C 6 alkyl), -NH 2 , - NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)2, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 - C 12 cycloalkyl, -C 4 -C 12 cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C 6 -C 14 aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, oxo, -O-C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)2, -C 1 -C 6 alkyl optionally substituted with one or more oxo or –OH, -C 2 - C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 12 cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; and each R’ is independently selected from the group consisting of -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 - C 6 alkynyl, -C 3 -C 12 cycloalkyl, -C 4 -C 12 cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, oxo, -C 1 -C 6 alkyl optionally substituted with one or more oxo or -OH, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -O-C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl), or -N(C 1 - C 6 alkyl)2. [00495] 14A. The method of any one of embodiments 1A-12A, wherein the USP9X Inhibitor is a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein: X 1 is NR or O; Y 1 is CR 7 or N; Y 2 is CR 8 or N; Y 3 is CR 9 or N; wherein the heteroaryl formed when at least one of Y 1 , Y 2 , or Y 3 is N may comprise an N- oxide; Ring A is a monocyclic or bicyclic 3- to 12-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of N, O, and S, and wherein Ring A is optionally substituted with one or more R a ; each R a is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, - NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O) 2 R’, - S(O) 2 NR 2 , optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R a group may be substituted with one or more substituents selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, - NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O)2NR 2 , and C 1 -C 6 aliphatic; Ring B is a monocyclic or bicyclic 3- to 12-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of N, O, and S, and wherein Ring B is optionally substituted with one or more R b ; each R b is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, - NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, - S(O) 2 NR 2 , optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R b group may be substituted with one or more substituents selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, - NRS(O) 2 R’, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O) 2 R’, -S(O) 2 NR 2 , and C 1 -C 6 aliphatic; R 1 and R 2 are each independently selected from the group consisting of –H, halogen, -OR, - OC(O)R’, -OS(O) 2 R’, -OS(O) 2 NR 2 , -OC(O)NR 2 , -OC(O)OR, -NR 2 , -NRC(O)R’, - NRS(O)2R’, -NRC(O)NR 2 , -NRC(O)OR, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , - S(O)2R’, -SO2NR 2 , -S(O)2OR, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, or R 1 and R 2 combine with the carbon to which they are attached to form an optionally substituted C 3 -C8cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S, wherein an optionally substituted R 1 and R 2 group may be substituted with one or more of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, - C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O) 2 R’, -S(O) 2 NR 2 , and C 1 -C 6 aliphatic; R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of –H, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C8cycloalkyl, and optionally substituted 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S, or R 3 and R 4 , or R 5 and R 6 , or a combination thereof, combine with the carbon to which they are attached to form an optionally substituted C 3 -C8cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S, wherein an optionally substituted R 3 , R 4 , R 5 , and R 6 group may be substituted with one or more of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O)2NR 2 , and C 1 -C 6 aliphatic; R 7 , R 8 , and R 9 are each independently selected from the group consisting of –H, halogen, -OR, - OC(O)R’, -OS(O) 2 R’, -OS(O) 2 NR 2 , -OC(O)NR 2 , -OC(O)OR, -NR 2 , -NRC(O)R’, - NRS(O) 2 R’, -NRC(O)NR 2 , -NRC(O)OR, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , - S(O)2R’, -SO2NR 2 , -S(O)2OR, and optionally substituted C 1 -C 6 aliphatic, wherein an optionally substituted R 7 , R 8 , and R 9 group may be substituted with one or more of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -CN, -NO 2 , -SR, - C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O)2NR 2 , and C 1 -C 6 aliphatic; each R is independently selected from the group consisting of –H, optionally substituted C 1 - C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10- membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R group may be optionally substituted with one or more of halogen, oxo, -OH, -O(C 1 -C 6 aliphatic), -NH2, -NH(C 1 -C 6 aliphatic), -N(C 1 -C 6 aliphatic)2, - CN, and C 1 -C 6 aliphatic; each R’ is independently selected from the group consisting of optionally substituted C 1 - C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10- membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R’ group may be substituted with one or more of halogen, oxo, -OH, -O(C 1 -C 6 aliphatic), -NH2, -NH(C 1 -C 6 aliphatic), -N(C 1 -C 6 aliphatic)2, -CN, and C 1 -C 6 aliphatic; m is 0, 1, or 2; and n is 0, 1, or 2. [00496] 15A. The method of any one of embodiments 1A-14A, wherein the USP9X Inhibitor is a compound selected from Table 1 or Table 11, or a pharmaceutically acceptable salt thereof. [00497] 1B. A method of treating cancer in a patient in need thereof, comprising administering to the patient a USP9X Inhibitor, wherein the patient is receiving or has received an immune checkpoint pathway inhibitor, wherein the USP9X Inhibitor is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof. [00498] 2B. A method of treating cancer in a patient in need thereof, comprising administering to the patient an immune checkpoint pathway inhibitor, wherein the patient is receiving or has received a USP9X Inhibitor, wherein the USP9X Inhibitor is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof. [00499] 3B. The method of Embodiment 1B, comprising administering the USP9X Inhibitor to the patient, wherein the cancer has progressed while receiving the immune checkpoint pathway inhibitor. [00500] 4B. The method of Embodiment 1B, wherein the patient has relapsed after previously being administered the immune checkpoint pathway inhibitor for the cancer. [00501] 5B. The method of claim Embodiment 1B, wherein the method comprises administering the USP9X Inhibitor to the patient while the patient continues to receive the immune checkpoint pathway inhibitor after being diagnosed with a cancer that is refractory to the immune checkpoint pathway inhibitor. [00502] 6B. The method of Embodiment 1B or Embodiment 2B, wherein the cancer comprises a tumor that expresses PD-L1. [00503] 7B. The method of Embodiment 6B, wherein the cancer comprises a tumor that expresses PD-L1 and the PD-L1 can be detected using PD-L1 IHC 22C 3 pharmDx. [00504] 8B. The method of Embodiment 1B or Embodiment 2B, wherein the cancer comprises a tumor that expresses CTLA-4. [00505] 9B. The method of Embodiment 1B or Embodiment 2B, wherein the cancer is selected from unresectable or metastatic melanoma, cutaneous melanoma, advanced renal cell carcinoma, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, metastatic squamous non-small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, cervical cancer, hepatocellular carcinoma, or Merkel cell carcinoma. [00506] 10B. The method of Embodiment 1B or Embodiment 2B, wherein the patient has received one or more prior lines of chemotherapy. [00507] 11B. The method of Embodiment 1B or Embodiment 2B, wherein the cancer comprises a tumor that expresses PD-1. [00508] 12B. The method of Embodiment 1B or Embodiment 2B, wherein the patient has not responded to prior therapy with an immune checkpoint pathway inhibitor. [00509] 13B. The method of Embodiment 1B or Embodiment 2B, comprising administering two or more immune checkpoint pathway inhibitors. [00510] 14B. The method of Embodiment 1B or Embodiment 2B, wherein the USP9X Inhibitor is selected from the group consisting of:
[00511] 15B. The method of Embodiment 1B or Embodiment 2B, wherein the USP9X Inhibitor is selected from the group consisting of:
[00512] 16B. A method of treating cancer in a patient in need thereof, comprising administering to the patient a USP9X Inhibitor of Formula I: (I) or a pharmaceutically acceptable salt thereof, wherein: X is CR 5 R 6 , CR 5 , NR 5 , or N, as valency permits; dashed bonds are each independently a single or a double bond, as valency permits; Y 1 , Y 2 , and Y 3 are each independently N or CR a ; each R a is independently -H, halogen, or -CN; Ring A is a 5- to 6-membered aryl, 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, 5- to 7-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, or 5- to 7-membered cycloalkyl, wherein each aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally substituted with one or more halogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, oxo, or -C(O)R’; Z 1 is O, S, or NR; Z 2 is O or NR; W is CR 1’ R 2’ , O, S, or NR; m is 0 or 1; R 1 and R 2 are each independently -H, halogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -(CR b R c )nC 3 -C 12 cycloalkyl, -(CR b R c )nC 4 -C 12 cycloalkenyl, -(CR b R c )nheterocyclyl, -(CR b R c )nC 6 -C 1 4aryl, -(CR b R c )nheteroaryl, -OR, -OC(O)R’, -OS(O)2R’, -OS(O)2NR 2 , -OC(O)NR 2 , -OC(O)OR, -(CR b R c ) n NR 2 , -(CR b R c ) n NRC(O)R’, -(CR b R c ) n NRS(O) 2 R’, -(CR b R c )nNRC(O)NR 2 , -(CR b R c )nNRC(O)OR, -(CR b R c )nCN, -(CR b R c )nNO2, -(CR b R c )nSR, -(CR b R c )nC(O)R’, -(CR b R c )nC(O)OR, -(CR b R c )nC(O)NR 2 , -(CR b R c )nSO2R’, -(CR b R c ) n SO 2 NR 2 , or -(CR b R c ) n SO 2 OR, wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R e , wherein each alkyl, alkenyl, or alkynyl is optionally substituted with one or more halogen, wherein each heterocyclyl is 3- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z 1 ), and wherein each heteroaryl is 5- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S; or R 1 and R 2 combine with the carbon to which they are attached to form oxo, a C 3 -C8cycloalkyl, or a 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z 1 ), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more R e ; R 1’ and R 2’ are each independently -H, halogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -(CR b R c ) n C 3 -C 12 cycloalkyl, -(CR b R c ) n C 4 -C 12 cycloalkenyl, -(CR b R c ) n heterocyclyl, -(CR b R c )nC 6 -C 1 4aryl, -(CR b R c )nheteroaryl, -(CR b R c )nNR 2 , -(CR b R c )nNRC(O)R’, -(CR b R c )nNRS(O)2R’, -(CR b R c )nNRC(O)NR 2 , -(CR b R c )nNRC(O)OR, -(CR b R c )nCN, -(CR b R c ) n NO 2 , -(CR b R c ) n SR, -(CR b R c ) n C(O)R’, -(CR b R c ) n C(O)OR, -(CR b R c ) n C(O)NR 2 , -(CR b R c )nSO2R’, -(CR b R c )nSO2NR 2 , or -(CR b R c )nSO2OR, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R e , wherein each heterocyclyl is 3- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein each heteroaryl is 5- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S; or R 1’ and R 2’ combine with the carbon to which they are attached to form oxo, a C 3 -C8cycloalkyl, or a 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S, wherein each heterocyclyl does not contain an O in the g-position relative to C(=Z 1 ), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more R e ; or R 1 and R 1’ combine with the carbons to which they are attached to form a C 3 -C 8 cycloalkyl or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S, wherein each heterocyclyl does not contain an O in the g-position relative to C(=Z 1 ), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more R e ; R b and R c are each independently selected from the group consisting of -H, halogen, and -C 1 -C 6 alkyl; each n is independently 0, 1, 2, 3, or 4; each R e is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O) 2 NR 2 , -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 12 cycloalkyl, -C 4 -C 12 cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C 6 -C 1 4aryl, and 5- to 14- membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein -OR of R e does not result in an O in the g-position relative to C(=Z 1 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -C 1 -C 6 alkyl optionally substituted with one or more halogen, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -OR, -C 3 -C 12 cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; B is a monocyclic or bicyclic 3- to 14-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein the ring is optionally substituted with one or more R d , and when m is 0 and the ring is saturated or partially unsaturated, then the ring does not contain an O in the g-position relative to C(=Z 1 ); each R d is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O) 2 R’, -S(O)2NR 2 , -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 12 cycloalkyl, -C 4 -C 12 cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C 6 -C 14 aryl, and 5- to 14- membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -C 1 -C 6 alkyl optionally substituted with one or more halogen, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -OR, -C 3 -C 12 cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; each R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is independently -H, -C 1 -C 6 alkyl, -C 3 -C8cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more halogen, oxo, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O) 2 NR 2 ,-C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein R 3 , R 7 , and R 9 are each independently present or absent, as valency permits; or R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , or combinations thereof, combine with the carbon to which they are attached to form an oxo, C 3 -C8cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; each R is independently selected from the group consisting of -H, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 12 cycloalkyl, -C 4 -C 12 cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C 6 -C 1 4aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, oxo, -O-C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)2, -C 1 -C 6 alkyl optionally substituted with one or more oxo or -OH, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 12 cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; and each R’ is independently selected from the group consisting of -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 12 cycloalkyl, -C 4 -C 12 cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, oxo, -C 1 -C 6 alkyl optionally substituted with one or more oxo or -OH, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -O-C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 ; wherein the patient is receiving or has received an immune checkpoint pathway inhibitor selected from the group consisting of cemiplimab, atezolizumab, durvalumab, and avelumab. [00513] 17B. A method of treating cancer in a patient in need thereof, comprising administering to the patient an immune checkpoint pathway inhibitor, wherein the patient is receiving or has received an USP9X Inhibitor of Formula I: or a pharmaceutically acceptable salt thereof, wherein: X is CR 5 R 6 , CR 5 , NR 5 , or N, as valency permits; dashed bonds are each independently a single or a double bond, as valency permits; Y 1 , Y 2 , and Y 3 are each independently N or CR a ; each R a is independently -H, halogen, or -CN; Ring A is a 5- to 6-membered aryl, 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, 5- to 7-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, or 5- to 7-membered cycloalkyl, wherein each aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally substituted with one or more halogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, oxo, or -C(O)R’; Z 1 is O, S, or NR; Z 2 is O or NR; W is CR 1’ R 2’ , O, S, or NR; m is 0 or 1; R 1 and R 2 are each independently -H, halogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -(CR b R c )nC 3 -C 12 cycloalkyl, -(CR b R c )nC 4 -C 12 cycloalkenyl, -(CR b R c )nheterocyclyl, -(CR b R c )nC 6 -C 1 4aryl, -(CR b R c )nheteroaryl, -OR, -OC(O)R’, -OS(O)2R’, -OS(O)2NR 2 , -OC(O)NR 2 , -OC(O)OR, -(CR b R c ) n NR 2 , -(CR b R c ) n NRC(O)R’, -(CR b R c ) n NRS(O) 2 R’, -(CR b R c ) n NRC(O)NR 2 , -(CR b R c ) n NRC(O)OR, -(CR b R c ) n CN, -(CR b R c ) n NO 2 , -(CR b R c ) n SR, -(CR b R c )nC(O)R’, -(CR b R c )nC(O)OR, -(CR b R c )nC(O)NR 2 , -(CR b R c )nSO2R’, -(CR b R c )nSO2NR 2 , or -(CR b R c )nSO2OR, wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R e , wherein each alkyl, alkenyl, or alkynyl is optionally substituted with one or more halogen, wherein each heterocyclyl is 3- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z 1 ), and wherein each heteroaryl is 5- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S; or R 1 and R 2 combine with the carbon to which they are attached to form oxo, a C 3 -C8cycloalkyl, or a 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z 1 ), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more R e ; R 1’ and R 2’ are each independently -H, halogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -(CR b R c )nC 3 -C 12 cycloalkyl, -(CR b R c )nC 4 -C 12 cycloalkenyl, -(CR b R c )nheterocyclyl, -(CR b R c )nC 6 -C 1 4aryl, -(CR b R c )nheteroaryl, -(CR b R c )nNR 2 , -(CR b R c )nNRC(O)R’, -(CR b R c ) n NRS(O) 2 R’, -(CR b R c ) n NRC(O)NR 2 , -(CR b R c ) n NRC(O)OR, -(CR b R c ) n CN, -(CR b R c ) n NO 2 , -(CR b R c ) n SR, -(CR b R c ) n C(O)R’, -(CR b R c ) n C(O)OR, -(CR b R c ) n C(O)NR 2 , -(CR b R c )nSO2R’, -(CR b R c )nSO2NR 2 , or -(CR b R c )nSO2OR, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R e , wherein each heterocyclyl is 3- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein each heteroaryl is 5- to 14-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S; or R 1’ and R 2’ combine with the carbon to which they are attached to form oxo, a C 3 -C8cycloalkyl, or a 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S, wherein each heterocyclyl does not contain an O in the g-position relative to C(=Z 1 ), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more R e ; or R 1 and R 1’ combine with the carbons to which they are attached to form a C 3 -C 8 cycloalkyl or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S, wherein each heterocyclyl does not contain an O in the g-position relative to C(=Z 1 ), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more R e ; R b and R c are each independently selected from the group consisting of -H, halogen, and -C 1 -C 6 alkyl; each n is independently 0, 1, 2, 3, or 4; each R e is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O) 2 NR 2 , -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 12 cycloalkyl, -C 4 -C 12 cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C 6 -C 1 4aryl, and 5- to 14- membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein -OR of R e does not result in an O in the g-position relative to C(=Z 1 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -C 1 -C 6 alkyl optionally substituted with one or more halogen, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -OR, -C 3 -C 12 cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; B is a monocyclic or bicyclic 3- to 14-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein the ring is optionally substituted with one or more R d , and when m is 0 and the ring is saturated or partially unsaturated, then the ring does not contain an O in the g-position relative to C(=Z 1 ); each R d is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O) 2 NR 2 , -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 12 cycloalkyl, -C 4 -C 12 cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C 6 -C 1 4aryl, and 5- to 14- membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -C 1 -C 6 alkyl optionally substituted with one or more halogen, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -OR, -C 3 -C 12 cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; each R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is independently -H, -C 1 -C 6 alkyl, -C 3 -C8cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more halogen, oxo, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O) 2 R’, -S(O) 2 NR 2 ,-C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein R 3 , R 7 , and R 9 are each independently present or absent, as valency permits; or R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , or combinations thereof, combine with the carbon to which they are attached to form an oxo, C 3 -C8cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; each R is independently selected from the group consisting of -H, -OH, -O(C 1 -C 6 alkyl), -NH2, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)2, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 12 cycloalkyl, -C 4 -C 12 cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C 6 -C 14 aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, oxo, -O-C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)2, -C 1 -C 6 alkyl optionally substituted with one or more oxo or -OH, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 12 cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; and each R’ is independently selected from the group consisting of -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 12 cycloalkyl, -C 4 -C 12 cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, oxo, -C 1 -C 6 alkyl optionally substituted with one or more oxo or -OH, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -O-C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl)2; and wherein the immune checkpoint pathway inhibitor selected from the group consisting of cemiplimab, atezolizumab, durvalumab, and avelumab. [00514] 18B. The method of Embodiment 16B or Embodiment 17B, with the proviso that the USP9X Inhibitor is not a compound of Figure 14. [00515] 19B. A method of treating cancer in a patient in need thereof, comprising administering to the patient a USP9X Inhibitor of Formula II:
or a pharmaceutically acceptable salt thereof, wherein: X 1 is NR or O; Y 1 is CR 7 or N; Y 2 is CR 8 or N; Y 3 is CR 9 or N; wherein the heteroaryl formed when at least one of Y 1 , Y 2 , or Y 3 is N may comprise an N- oxide; Ring A is a monocyclic or bicyclic 3- to 12-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of N, O, and S, and wherein Ring A is optionally substituted with one or more R a ; each R a is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O) 2 NR 2 , optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R a group may be substituted with one or more substituents selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O) 2 R’, -S(O) 2 NR 2 , and C 1 -C 6 aliphatic; Ring B is a monocyclic or bicyclic 3- to 12-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of N, O, and S, and wherein Ring B is optionally substituted with one or more R b ; each R b is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O) 2 NR 2 , optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R b group may be substituted with one or more substituents selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O) 2 R’, -S(O) 2 NR 2 , and C 1 -C 6 aliphatic; R 1 and R 2 are each independently selected from the group consisting of -H, halogen, -OR, -OC(O)R’, -OS(O) 2 R’, -OS(O) 2 NR 2 , -OC(O)NR 2 , -OC(O)OR, -NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -NRC(O)NR 2 , -NRC(O)OR, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -SO2NR 2 , -S(O)2OR, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, or R 1 and R 2 combine with the carbon to which they are attached to form an optionally substituted C 3 -C8cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S, wherein an optionally substituted R 1 and R 2 group may be substituted with one or more of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O)2NR 2 , and C 1 -C 6 aliphatic; R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of -H, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 8 cycloalkyl, and optionally substituted 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S, or R 3 and R 4 , or R 5 and R 6 , or a combination thereof, combine with the carbon to which they are attached to form an optionally substituted C 3 -C8cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S, wherein an optionally substituted R 3 , R 4 , R 5 , and R 6 group may be substituted with one or more of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O)2NR 2 , and C 1 -C 6 aliphatic; R 7 , R 8 , and R 9 are each independently selected from the group consisting of -H, halogen, -OR, -OC(O)R’, -OS(O)2R’, -OS(O)2NR 2 , -OC(O)NR 2 , -OC(O)OR, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -NRC(O)NR 2 , -NRC(O)OR, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O) 2 R’, -SO 2 NR 2 , -S(O) 2 OR, and optionally substituted C 1 -C 6 aliphatic, wherein an optionally substituted R 7 , R 8 , and R 9 group may be substituted with one or more of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O) 2 R’, -S(O) 2 NR 2 , and C 1 -C 6 aliphatic; each R is independently selected from the group consisting of -H, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10- membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R group may be optionally substituted with one or more of halogen, oxo, -OH, -O(C 1 -C 6 aliphatic), -NH 2 , -NH(C 1 -C 6 aliphatic), -N(C 1 -C 6 aliphatic) 2 , -CN, and C 1 -C 6 aliphatic; each R’ is independently selected from the group consisting of optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10- membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R’ group may be substituted with one or more of halogen, oxo, -OH, -O(C 1 -C 6 aliphatic), -NH2, -NH(C 1 -C 6 aliphatic), -N(C 1 -C 6 aliphatic)2, -CN, and C 1 -C 6 aliphatic; m is 0, 1, or 2; and n is 0, 1, or 2; wherein the patient is receiving or has received an immune checkpoint pathway inhibitor selected from the group consisting of cemiplimab, atezolizumab, durvalumab, and avelumab. [00516] 20B. A method of treating cancer in a patient in need thereof, comprising administering to the patient an immune checkpoint pathway inhibitor, wherein the patient is receiving or has received an USP9X Inhibitor of Formula II: or a pharmaceutically acceptable salt thereof, wherein: X 1 is NR or O; Y 1 is CR 7 or N; Y 2 is CR 8 or N; Y 3 is CR 9 or N; wherein the heteroaryl formed when at least one of Y 1 , Y 2 , or Y 3 is N may comprise an N- oxide; Ring A is a monocyclic or bicyclic 3- to 12-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of N, O, and S, and wherein Ring A is optionally substituted with one or more R a ; each R a is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O) 2 NR 2 , optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R a group may be substituted with one or more substituents selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O) 2 R’, -S(O) 2 NR 2 , and C 1 -C 6 aliphatic; Ring B is a monocyclic or bicyclic 3- to 12-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of N, O, and S, and wherein Ring B is optionally substituted with one or more R b ; each R b is independently selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O) 2 NR 2 , optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R b group may be substituted with one or more substituents selected from the group consisting of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O) 2 R’, -S(O) 2 NR 2 , and C 1 -C 6 aliphatic; R 1 and R 2 are each independently selected from the group consisting of -H, halogen, -OR, -OC(O)R’, -OS(O) 2 R’, -OS(O) 2 NR 2 , -OC(O)NR 2 , -OC(O)OR, -NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -NRC(O)NR 2 , -NRC(O)OR, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -SO2NR 2 , -S(O)2OR, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, or R 1 and R 2 combine with the carbon to which they are attached to form an optionally substituted C 3 -C8cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S, wherein an optionally substituted R 1 and R 2 group may be substituted with one or more of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O) 2 R’, -CN, -NO 2 , -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O)2NR 2 , and C 1 -C 6 aliphatic; R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of -H, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 8 cycloalkyl, and optionally substituted 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S, or R 3 and R 4 , or R 5 and R 6 , or a combination thereof, combine with the carbon to which they are attached to form an optionally substituted C 3 -C8cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S, wherein an optionally substituted R 3 , R 4 , R 5 , and R 6 group may be substituted with one or more of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O)2R’, -S(O)2NR 2 , and C 1 -C 6 aliphatic; R 7 , R 8 , and R 9 are each independently selected from the group consisting of -H, halogen, -OR, -OC(O)R’, -OS(O)2R’, -OS(O)2NR 2 , -OC(O)NR 2 , -OC(O)OR, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -NRC(O)NR 2 , -NRC(O)OR, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O) 2 R’, -SO 2 NR 2 , -S(O) 2 OR, and optionally substituted C 1 -C 6 aliphatic, wherein an optionally substituted R 7 , R 8 , and R 9 group may be substituted with one or more of halogen, oxo, -OR, -OC(O)R’, -NR 2 , -NRC(O)R’, -NRS(O)2R’, -CN, -NO2, -SR, -C(O)R’, -C(O)OR, -C(O)NR 2 , -S(O) 2 R’, -S(O) 2 NR 2 , and C 1 -C 6 aliphatic; each R is independently selected from the group consisting of -H, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10- membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R group may be optionally substituted with one or more of halogen, oxo, -OH, -O(C 1 -C 6 aliphatic), -NH2, -NH(C 1 -C 6 aliphatic), -N(C 1 -C 6 aliphatic)2, -CN, and C 1 -C 6 aliphatic; each R’ is independently selected from the group consisting of optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10- membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, optionally substituted phenyl, and optionally substituted 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, wherein an optionally substituted R’ group may be substituted with one or more of halogen, oxo, -OH, -O(C 1 -C 6 aliphatic), -NH 2 , -NH(C 1 -C 6 aliphatic), -N(C 1 -C 6 aliphatic) 2 , -CN, and C 1 -C 6 aliphatic; m is 0, 1, or 2; and n is 0, 1, or 2; and wherein the immune checkpoint pathway inhibitor selected from the group consisting of cemiplimab, atezolizumab, durvalumab, and avelumab. [00517] 21B. The method of Embodiment 19B or Embodiment 20B, with the proviso that the USP9X Inhibitor is not a compound of Figure 15.
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