P53 modulators

Abstract

Disclosed are p53 modulators represented by the following structural formula (I): The variables in structural formula I are described herein. Also disclosed are methods of treating cancer in a subject with the disclosed p53 modulators, particularly cancers with dysfunctional p53.

Description

[0001]136867-00720 P53 MODULATORS RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application Serial No. 63 / 643,203, filed May 6, 2024. The entire teachings of the aforementioned application are incorporated herein by reference. BACKGROUND OF THE INVENTION The p53 protein is a tetrameric transcription factor that prevents mutation to the genome by regulating the expression of a subgroup of target genes. Activation of p53 initiates pathways involved in apoptosis, DNA repair, cell cycle arrest, anti-angiogenesis, and senescence in order to avoid propagation of damaged cells. Tumor suppressor protein p53 is also a transcription factor that plays an important role in human cancers. Tumor initiation and maintenance depend upon inactivation of p53 pathways, which otherwise would deter uncontrolled cell growth. Consequently, p53 is the most frequently mutated gene in human cancers. It was estimated that more than half of all human tumors have mutant p53. The majority of those tumors that harbor mutant p53 are found to express full-length p53 protein with a single residue missense mutation in the p53 DNA-binding core domain (DBD). However, structural mutations remote from the DBD are also common. The Y220C mutation, which occurs in approximately 1.5% all human cancers, is such a structurally destabilizing mutation at codon 220, resulting in structural instability and loss of DNA binding at body temperature due to loss of beneficial lipophilic contacts of the tyrosine-220 residue as seen in wt-p53. The p53 Y220C mutation is associated with many cancers, including breast cancer, non-small cell lung cancer, colorectal cancer, pancreatic cancer, and ovarian cancer. The frequency and aggressive nature of cancers exhibiting p53 malfunction coupled with the potential benefits of restoring wild type p53 function has driven a widespread effort to identify compounds that restore normal p53 expression and activity. Nonetheless, there is still a critical need in the art for the development of new small molecule reactivators targeting p53 mutants (e.g., Y220C mutant) with high specificity and activity as well as low toxicity. 1 ME153015591v.1 136867-00720 SUMMARY Provided herein are compounds, or pharmaceutically acceptable salts thereof, and compositions which bind to the Y220C pocket, stabilize the mutant protein and restore ability of the mutant protein to bind to DNA at physiologically relevant temperatures. For example, Biological Example 1 provides data showing that the disclosed compounds can bind to the Y220C pocket, stabilize the mutant protein and restore ability of the mutant protein to bind to DNA at physiologically relevant temperatures. Also disclosed are methods of using the compounds and compositions described herein for treating cancer. A first embodiment of the disclosure is a compound represented by the following structural formula I: , or a pharmaceutically acceptable salt thereof, wherein: A is a phenylene, 5- or 6-membered heteroarylene or 5- or 6-membered heterocyclylene; Z is S, or O; U, V, W and X are independently CR5or N, provided that one of U, V, W and X is C-Y-R1; Y is a bond, O, NH, N(C1-4alkyl), NHCH2^, OCH2^, S or CH2,wherein “^” indicates the point of attachment to R1; R1is (CH2)nOR11, (CH2)nN(R11)2, (CH2)nCN, (CH2)nC(O)R11, (CH2)nC(O)OR11, (CH2)nC(S)R11, (CH2)nC(S)OR11, (CH2)nC(O)N(R11)2,(CH2)nNHC(O)R11, (CH2)nNHC(O)OR11, (CH2)nOC(O)N(R11)2, (CH2)nC(S)N(R11)2, (CH ) NHC(S)11 11n1111 2 n R , (CH2)nNHC(S)OR , (CH2) OC(S)N(R )2, (CH2)nNHS(O)iR , (CH2)nS(O)iN(R11)2, C1-6alkyl, C3-8cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted by one or more R21; 2 ME153015591v.1 136867-00720 R2is (CH2)mOR12, (CH2)mN(R12)2, (CH2)mCN, (CH2)mC(O)R12, (CH2)mC(O)OR12, (CH2)mC(S)R12, (CH2)mC(S)OR12, (CH2)mC(O)N(R12)2, (CH2)mNHC(O)R12, (CH2)mNRaNRbC(O)R12, (CH2)mNHC(O)OR12, (CH2)mOC(O)N(R12)2, (CH2)mC(S)N(R12)2, (CH2)mNHC(S)R12, (CH2)mNHC(S)OR12, (CH2)mOC(S)N(R12)2, (CH2)mNHS(O) 12 iR , (CH2)mS(O)iN(R12)2, C1-6 alkyl, C3-8 cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, (C1-4alkyl)[5-10 membered heteroaryl], or 4-13 membered heterocyclyl, wherein said C1-6alkyl, C1-4 alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and heteroaryl are each optionally and independently substituted by one or more R22and wherein said cycloalkyl and heterocyclyl are each optionally substituted by one or more R22a; R3is –S[halo(C1-C4)alkyl], –SO2[halo(C1-C4)alkyl], or halo(C1-C4)alkoxy; each R5is independently H, halo, (CH2)pOR15, (CH2)pN(R15)2, (CH2)pCN, (CH2)oC(O)R15, (CH2)pC(O)OR15, (CH2)pC(S)R15, (CH2)pC(S)OR15, (CH2)pC(O)N(R15)2, (CH2)pNHC(O)R15, (CH2)pNHC(O)OR15, (CH2)pOC(O)N(R15)2, (CH2)pC(S)N(R15)2, (CH2)pNHC(S)R15, (CH2)pNHC(S)OR15, (CH2)pOC(S)N(R15)2, (CH2)pNHS(O)iR15,(CH2)pS(O)iN(R15)2,C1-6alkyl, C3-8cycloalkyl, C2-6alkenyl or C2-6alkynyl, C6-10aryl, 5- to 10-membered membered heteroaryl or 4- to 10-membered heterocyclyl; wherein said alkyl, alkenyl, alkoxy, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally and independently substituted by one or more R25; R11, R12, and R15are each independently H, C1-6alkyl, (CH2)nC3-8cycloalkyl, (CH2)nC6-10 aryl, (CH2)n(5-10 membered heteroaryl) or (CH2)n(4-10 membered heterocyclyl); wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally and independently substituted by one or more R30; or N(R11)2and N(R12)2are independently a 4-10 membered heterocyclyl, wherein the heterocyclyl represented by N(R11) is optionally substituted with one or more R21and the heterocyclyl represented by N(R12) is optionally substituted with one or more R22; R21, R22, and R25are each independently H, halo, OH, NH2, CN, NO2, (CH2)nORa, (CH2)nNRbRc, S(O)iRb, (=NRa)NRbRc, NRbS(O)iRc, S(O)iNRbRc, alkyl, OC(=O)ORb, C(=S)ORb, O(C=S)Rb, C(=O)NRbRc, NRbC(=O)Rc, C(=S)NRbRc, NRbC(=S)Rc, NRb(C=O)ORc, O(C=O)NRbRc, NRb(C=S)ORc, O(C=S)NRbRc, NRb(C=O)NRbRc, NRb(C=S)NRbRc, C(=S)Rb, C(=O)Rb, halo(C1-C5)alkyl, (C1-C5)alkyl, (C2-C5)alkenyl, 4-7 membered heterocyclyl, 6-10 membered spiroheterocyclyl, or (C2-C5)alkynyl, wherein said alkyl is optionally 3 ME153015591v.1 136867-00720 substituted with one or more groups selected from halo, methoxy, halomethoxy, and phenyl; or two R21groups on the same ring atom taken together with their intervening atom are an oxo; each R22ais independently halo, OH, NHC(O)R12, CN, NO2, (CH2)nORa, (CH2)nNRbRc, S(O)iRb, (=NRa)NRbRc, NRbS(O)iRc, S(O)iNRbRc, C(=O)ORb, OC(=O)ORb, C(=S)ORb, O(C=S)Rb, C(=O)NRbRc, NRbC(=O)Rc, C(=S)NRbRc, NRbC(=S)Rc, NRb(C=O)ORc, O(C=O)NRbRc, NRb(C=S)ORc, O(C=S)NRbRc, NRb(C=O)NRbRc, NRb(C=S)NRbRc, C(=S)Rb, C(=O)Rb, halo(C1-C5)alkyl, (C1- C5)alkyl, (C1-C4)alkoxy, (C3-C6)cycloalkoxy, (C6-C10)aryl, (CH2)n(5-10 membered heteroaryl), (C2-C5)alkenyl or (C2-C5)alkynyl, or two R22agroups on the same ring atom taken together with their intervening atom are a (C3-C6)spirocycloalkyl, 4-6 membered spiroheterocyclyl, (=NRd), thio, or oxo, or two R22aon adjacent ring atoms, taken together with their intervening atoms form a (C3-C6)cycloalkyl, phenyl, or a 5-6 membered heteroaryl, wherein said phenyl or heteroaryl is optionally substituted with one or more groups selected from halo, methyl, halomethyl, methoxy and halomethoxy; each R30is independently halo, CN, 4-6 membered heterocyclyl, (C1-C4)alkyl, (C1-C4)fluororalkyl, O(C1-C4)fluororalkyl, O(C1-C4)hydroxyalkyl, hydroxy[halo(C1- C4)alkyl], (C3-C5)cycloalkyl, (C1-C4)alkoxy, (CH2)nORaor (CH2)nNRaRb; each Ra, Rband Rcis independently –H, D, T, (C1-C4)alkyl, C3-8cycloalkyl, hydroxy(C1-C4)alkyl, or (C1-C4)alkylO(C1-C4)alkyl, wherein said cycloalkyl is optionally substituted with one or more groups selected from (C1-C4)alkyl, halo(C1- C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, and OH; and each n, m, o, p and i are independently 0, 1 or 2. Another embodiment of the disclosure is a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, or diluent, and a compound disclosed herein or a pharmaceutically acceptable salt thereof. Another embodiment of the disclosure is a method of re-activating p53 Y220C mutant in a subject in need thereof, comprising contacting p53 Y220C mutant with an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof. 4 ME153015591v.1 136867-00720 Another embodiment of the disclosure is the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for re-activating p53 Y220C mutant in a subject in need thereof. Another embodiment of the disclosure is a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof for re-activating p53 Y220C mutant in a subject in need thereof. Another embodiment of the disclosure is a method of treating a p53 Y220C mutant- dependent disorder or disease (e.g., treating a cancer) in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound(s). Another embodiment of the disclosure is the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound(s), for the preparation of a medicament for treating a p53 Y220C mutant- dependent disorder or disease (e.g., treating a cancer) in a subject in need thereof. Another embodiment of the disclosure is a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound(s), for use in treating a p53 Y220C mutant-dependent disorder or disease (e.g., treating a cancer) in a subject in need thereof. DETAILED DESCRIPTION The present invention provides compounds, compositions and methods for restoring wild-type function of mutant p53. The compounds of the present invention can bind to mutant p53 and restore the ability of the p53 mutant to bind DNA. The restoration of activity of the p53 mutant can allow for the activation of downstream effectors of p53 leading to inhibition of cancer progression. The present invention further provides a method for treating a disease or condition related to p53 mutant protein. Example embodiments include: First embodiment: a compound represented by Formula I: 5 ME153015591v.1 136867-00720 or a pharmaceutically acceptable salt thereof. The variables in Formula I are described in the summary above. Alternatively, as part of a first embodiment, R21, R22, and R25are each independently H, halo, OH, NH2, CN, NO2, (CH2)nORa, (CH2)nNRbRc, S(O)iRb, (=NRa)NRbRc, NRbS(O)iRc, S(O)iNRbRc, C(=O)ORb, OC(=O)ORb, C(=S)ORb, O(C=S)Rb, C(=O)NRbRc, NRbC(=O)Rc, C(=S)NRbRc, NRbC(=S)Rc, NRb(C=O)ORc, O(C=O)NRbRc, NRb(C=S)ORc, O(C=S)NRbRc, NRb(C=O)NRbRc, NRb(C=S)NRbRc, C(=S)Rb, C(=O)Rb, halo(C1-C5)alkyl, (C1- C5)alkyl, (C2-C5)alkenyl, 4-7 membered heterocyclyl, 6-10 membered spiroheterocyclyl, or (C2-C5)alkynyl, wherein said alkyl is optionally substituted with one or more groups selected from halo, methoxy, halomethoxy, and phenyl; or two R21groups on the same ring atom taken together with their intervening atom are an oxo; each R22ais independently halo, OH, NHC(O)R12, CN, NO2, (CH2)nORa, (CH2)nNRbRc, S(O)iRb, (=NRa)NRbRc, NRbS(O)iRc, S(O)iNRbRc, C(=O)ORb, OC(=O)ORb, C(=S)ORb, O(C=S)Rb, C(=O)NRbRc, NRbC(=O)Rc, C(=S)NRbRc, NRbC(=S)Rc, NRb(C=O)ORc, O(C=O)NRbRc, NRb(C=S)ORc, O(C=S)NRbRc, NRb(C=O)NRbRc, NRb(C=S)NRbRc, C(=S)Rb, C(=O)Rb, halo(C1-C5)alkyl, (C1- C5)alkyl, (C6-C10)aryl, (CH2)n(5-10 membered heteroaryl), (C2-C5)alkenyl or (C2- C5)alkynyl, or two R22agroups on the same ring atom taken together with their intervening atom are a (C3-C6)spirocycloalkyl, 4-6 membered spiroheterocyclyl, (=NRd), thio, or oxo, or two R22aon adjacent ring atoms, taken together with their intervening atoms form a (C3-C6)cycloalkyl, phenyl, or a 5-6 membered heteroaryl, wherein said phenyl or heteroaryl is optionally substituted with one or more groups selected from halo, methyl, halomethyl, methoxy and halomethoxy; and each R30is independently halo, CN, 4-6 membered heterocyclyl, (C1-C4)alkyl, (C1-C4)fluororalkyl, O(C1-C4)fluororalkyl, O(C1-C4)hydroxyalkyl, hydroxy[halo(C1-C4)alkyl], (C3-C5)cycloalkyl, (CH2)nORaor (CH2)nNRaRb. 6 ME153015591v.1 136867-00720 Second embodiment: a compound represented by Formula II: or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables in Formula II are as defined in the first embodiment. Third embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein R3is –S[halo(C1-C4)alkyl] or – SO2[halo(C1-C4)alkyl], wherein the definitions for the other variables in Formulae I and II are as defined in the first or second embodiments. Fourth embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein R3is –S[halo(C1-C4)alkyl], wherein the definitions for the other variables in Formulae I and II are as defined in the first or second embodiments. Fifth embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein R3is SCF3, wherein the definitions for the other variables in Formulae I and II are as defined in the first or second embodiments. Sixth embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein W is CR5, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, or fifth embodiments. Seventh embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen or halo, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth or sixth embodiments. Eighth embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen, wherein the definitions for 7 ME153015591v.1 136867-00720 the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, or sixth embodiments. Ninth embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein Y is O or NH, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiments. Tenth embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein Y is NH, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiments. Eleventh embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein A is a 5- or 6-membered heteroarylene, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiments. Twelfth embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroarylene, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiments. Thirteenth embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein A is 1,2,4-oxadiazolylene, furanylene, isoxazolylene, or oxazolylene, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiments. Fourteenth embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein A is represented by 8 ME153015591v.1 136867-00720 wherein indicates the point of attachment to R2, and wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiments. Fifteenth embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein R2is (CH2)mNHC(O)R12, (CH2)mC(O)N(R12)2, or a 5- or 6-membered heterocyclyl optionally substituted by one or more R22a, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiments. Sixteenth embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein R2is (CH2)mNHC(O)R12, (CH2)mC(O)N(R12)2, or pyrrolidinyl, piperidinyl, morpholinyl, imidazolidinyl, or oxazolidinyl, each optionally substituted by one or more R22a, each R12is independently H, C3-6 cycloalkyl, or 5-6 membered heteroaryl, wherein said cycloalkyl and heteroaryl are optionally and independently substituted with one or more R30; and each R30is independently a group selected from C1-4 alkyl, (C1-C4)alkox, C1-4 hydroxyalkyl, C1-4 fluoroalkyl, fluoro, oxetanyl, and (CH2)nORa, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, 9 ME153015591v.1 136867-00720 eleventh, twelfth, thirteenth, or fourteenth embodiments. Alternatively, as part of a sixteenth embodiment, a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein R2is (CH2)mNHC(O)R12, (CH2)mC(O)N(R12)2, or pyrrolidinyl, piperidinyl, morpholinyl, imidazolidinyl, or oxazolidinyl, each optionally substituted by one or more R22a; each R12is independently H, C3-6cycloalkyl, or 5-6 membered heteroaryl, wherein said cycloalkyl and heteroaryl are optionally and independently substituted with one or more R30; and each R30is independently a group selected from C1-4alkyl, C1-4hydroxyalkyl, C1-4 fluoroalkyl, fluoro, oxetanyl, and (CH2)nORa, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiments. Seventeenth embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein each R22ais independently OH, (C1- C5)alkyl, (C1-C4)alkoxy, (C3-C6)cycloalkoxy, (CH2)nORa, (C2-C5)alkenyl, or 5-6 membered heteroaryl; or two R22agroups on the same carbon ring atom are taken together to form a C3-6 cycloalkyl, thio, oxo, or imino, wherein said imino nitrogen is optionally substituted with CN or –S(O)2(C1-C5)alkyl, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiments. Alternatively, as part of a seventeenth embodiment, a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein each R22ais independently OH, (C1-C5)alkyl, (CH2)nORa, (C2-C5)alkenyl, or 5-6 membered heteroaryl; or two R22agroups on the same carbon ring atom are taken together to form a C3-6cycloalkyl, thio, oxo, or imino, wherein said imino nitrogen is optionally substituted with CN or –S(O)2(C1-C5)alkyl, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiments. Eighteenth embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein each R22ais independently OH, CH3, OCH3, , OCD3, OCT3, =C(CH3)2, (CH2)2OCH3, or pyrimidinyl; or two R22agroups 10 ME153015591v.1 136867-00720 on the same carbon ring atom are taken together to form cyclopropyl, thio, oxo, =N(SO2)CH3 or =NCN, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiments. Alternatively, as part of an eighteenth embodiment, a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein each R22ais independently OH, CH3, OCH3, OCD3, OCT3, =C(CH3)2, (CH2)2OCH3, or pyrimidinyl; or two R22agroups on the same carbon ring atom are taken together to form cyclopropyl, thio, oxo, =N(SO2)CH3 or =NCN, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiments. Nineteenth embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein R2is (CH2)mNHC(O)R12, (CH2)mC(O)N(R12)2, or is represented by: , and each R12is independently H, or is represented by: 11 ME153015591v.1 136867-00720 HN N 12 ME153015591v.1 136867-00720 , wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiments. Alternatively, as part of a nineteenth embodiment, a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein R2is (CH2)mNHC(O)R12, (CH2)mC(O)N(R12)2, or is represented by: 13 ME153015591v.1 136867-00720 and each R12is independently H, or is represented by: 14 ME153015591v.1 136867-00720 wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiments. 15 ME153015591v.1 136867-00720 Twentieth embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein R1is C1-6 alkyl, 5- to 10-membered heteroaryl, C3-8cycloalkyl, or 4- to 10-membered heterocyclyl, wherein said alkyl, heteroaryl, cycloalkyl, and heterocyclyl are optionally substituted by one or more R21, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, or nineteenth embodiments. Twenty-first embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein R1is C1-4 alkyl, C4-7 cycloalkyl, 5- or 6- membered heteroaryl or 4- to 9-membered heterocyclyl, wherein said alkyl, heteroaryl, cycloalkyl, and heterocyclyl are optionally substituted by one or more R21, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, or nineteenth embodiments. Twenty-second embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein R1is C1-4alkyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, oxabicyclo[3.2.1]octanyl, tetrahydrothiopyranyl, cyclohexyl, cyclopentyl, oxa- azabicyclo[3.3.1]nonanyl, or pyridinyl, each of which are optionally substituted by one or more R21, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, or nineteenth embodiments. Twenty-third embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein R21is halo, OH, (CH2)nORa, C(=O)ORb, C(=O)Rb, halo(C1-C5)alkyl, hydroxy(C1-C5)alkyl, (C1-C5)alkyl, NH(C1-C5)alkyl, (C1- C5)alkyl[5- to 6-membered heteroaryl], 6-8 membered spiroheterocyclyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, or S(O)2(C1-C5)alkyl; or two R21groups on the same atom are taken together to form oxo, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second embodiments. Alternatively, as part of a twenty-third embodiment, a compound represented by Formulae I or II, or a 16 ME153015591v.1 136867-00720 pharmaceutically acceptable salt thereof, wherein R21is halo, OH, (CH2)nORa, C(=O)ORb, C(=O)Rb, halo(C1-C5)alkyl, hydroxy(C1-C5)alkyl, (C1-C5)alkyl, (C1-C5)alkyl[5- to 6- membered heteroaryl], 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, or S(O)2(C1-C5)alkyl; or two R21groups on the same atom are taken together to form oxo, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second embodiments. Twenty-fourth embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein R21is fluoro, CH3, CD3, CH(CH3)2, oxetanyl, CH2CH3, C(O)CH2OCH3, S(O)2CH3, CH2CHF2, COCH3, (CH2)2OCH3, (CH2)2OH, CH2OH, CH2(pyrimidinyl), C(O)CH2OH, C(O)[cyclopropyl], CH2(C)(CH3)2OH, C(O)CH2CH3, 2-oxa-6-azaspiro[3.3]heptanyl, C(O)[cyclopropylOH], NH[isopropyl], pyrimidinyl, C(O)O(cyclopropyl), C(O)OCH2CH3, C(O)OC(CH3)3, OH, or tetrahydropyranyl; or two R21on the same atom are taken together to form oxo, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty- second embodiments. Alternatively, as part of a twenty-fourth embodiment, a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein R21is fluoro, CH3, CD3, CH(CH3)2, oxetanyl, CH2CH3, C(O)CH2OCH3, S(O)2CH3, CH2CHF2, COCH3, (CH2)2OCH3, (CH2)2OH, CH2OH, CH2(pyrimidinyl), C(O)CH2OH, C(O)[cyclopropyl], CH2(C)(CH3)2OH, C(O)CH2CH3, C(O)[cyclopropylOH], pyrimidinyl, C(O)O(cyclopropyl), C(O)OCH2CH3, C(O)OC(CH3)3, OH, or tetrahydropyranyl; or two R21on the same atom are taken together to form oxo, wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second embodiments. Twenty-fifth embodiment: a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein R1is represented by: 17 ME153015591v.1 136867-00720 18 ME153015591v.1 136867-00720 19 ME153015591v.1 136867-00720 and when Y is a bond, R1is represented by: , wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiments. Alternatively, as part of a twenty-fifth embodiment, a compound represented by Formulae I or II, or a pharmaceutically acceptable salt thereof, wherein R1is represented by: 20 ME153015591v.1 136867-00720 21 ME153015591v.1 136867-00720 and when Y is a bond, R1is represented by: wherein the definitions for the other variables in Formulae I and II are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiments. The disclosure also includes the compounds prepared in the Exemplification, in both the neutral form and pharmaceutically acceptable salts thereof. The synthetic protocol used to prepare the disclosed compounds is described in the Exemplification. Another embodiment of the disclosure is a compound disclosed herein, including a compound of Formulae I or II, or as disclosed in the Exemplification, or a pharmaceutically acceptable salt of any of the foregoing, in which one or more hydrogen atoms is replaced with deuterium. The deuterium enrichment at any one of the sites where hydrogen has been replaced by deuterium is at least 50%, 75%, 85%, 90%, 95%, 98% or 99%. Deuterium enrichment is a mole percent and is obtained by dividing the number of compounds with deuterium enrichment at the site of enrichment with the number of compounds having hydrogen or deuterium at the site of enrichment. The number of carbon atoms in a group is specified herein by the prefix “Cx-xx”, wherein x and xx are integers. For example, "C1-3 alkyl" is an alkyl group which has from 1 to 3 carbon atoms. 22 ME153015591v.1 136867-00720 The suffix “yl” added to the end of a chemical name indicates that the named moiety is bonded to the molecule at one point, i.e., monovalent. The suffix “ylene” added to the end of a chemical name indicates that the named moiety is bonded to the molecule at two points, i.e., bivalent. In the event that a chemical name conflicts with the depicted structure for that name, the depicted structure takes priority. "Alkyl", when used alone or part of a larger moiety, refers to a fully saturated branched or unbranched hydrocarbon moiety. Unless otherwise specified, an alkyl comprises 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, or n-hexyl. "Alkenyl" refers to a branched or unbranched hydrocarbon moiety containing at least one double bond. Unless otherwise specified, an alkenyl group comprises 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkenyl include, but are not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-methypropenyl, 2-methypropenyl, 3- methypropenyl and the like. "Alkynyl" refers to a branched or unbranched hydrocarbon moiety containing at least one triple bond. Unless otherwise specified, an alkynyl group comprises 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-methypropynyl, 2-methypropynyl, 3- methypropynyl and the like. "Alkoxy" refers to OR, where oxygen is singularly bonded to R, and R is an alkyl group. Examples of alkoxy include methoxy, ethoxy, isopropoxy, and the like. “Aryl”, when used alone or as part of another moiety such as aralkyl, refers to an aromatic hydrocarbon of six to 10 ring atoms, such as phenyl or naphthyl. “Phenylene” refers to a bivalent phenyl group. "Halogen" or "halo" is fluoro, chloro, bromo or iodo. The term “haloalkyl” includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine. A “hydroxyalkyl” is an alkyl group substituted by one or more hydroxyl groups. “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g, –OCHF2 or –OCF3. “Cycloalkyl” refers to completely saturated monocyclic or bicyclic hydrocarbon group. Unless otherwise specified, a cycloalkyl has 3-10 ring carbon atoms, alternatively 3-8 23 ME153015591v.1 136867-00720 ring carbon atoms. A cycloalkyl can be monocyclic, fused bicyclic and bridged bicyclic. A monocyclic cycloalkyl has 3-8 ring carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclopheptyl and cyclooctyl. A fused bicyclic cycloalkyl has 8-10 ring carbon atoms and two rings which share two adjacent ring atoms, e.g., a 4 to 7 membered cycloalkyl fused to a 3 to 6 membered cycloalkyl. Examples include decahydronapthalene, octahydro-1H-indene, octahydropentalene, decahydroazulene, decahydro-1H-annulene, bicycle[4.2.0]octane, bicycle[3.2.0]heptane, and the like. A bridged bicyclic cycloalkyl has 5 to 8 ring carbon atoms and two monocyclic cycloalkyl groups which share three adjacent ring atoms. Examples include includes bicyclo[1.1.1]pentanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, and the like. “Cycloalkoxy” refers to OR, where oxygen is singularly bonded to R, and R is a cycloalkyl group. Examples of alkoxy include cyclopropoxy, cyclobutoxy, cyclopentoxy, and the like. "Heteroaryl" refers to an aromatic 5- to 10-membered mono or bicyclic cyclic ring system, having 1 to 4 heteroatoms independently selected from O, N and S, and wherein N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone. A monocyclic heteroaryl has 5 or 6 ring atoms, i.e., is 5 to 6 membered. Examples of 5- to 6-membered monocyclic heteroaryls include, but are not limited to, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, tetrazinyl, and the like. A bicyclic heteroaryl has 8 to 10 ring atoms, i.e., is 8 to 10 membered. Examples of 8- to 10-membered bicyclic heteroaryls include, but are not limited to indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothiofuranyl, quinolinyl, isoquinolinyl and the like. “Heteroarylene” refers to a bivalent aromatic 5- to 10-membered heteroaryl group, i.e., a heteroaryl group connect to the remainder of the molecule at two points. Examples include 1,3,4-oxadiazolylene, 1,2,4-oxadiazolylene, 1,2,4-thiadiazoylene, 1,3,4- thiadiazolylene, imidazolylene, pyrazolylene, 1,2,3-triazolylene, 1,2,4-triazolylene, isoxazolylene, tetrazolylene, oxazolylene, thiazolylene, furylene, thienylene, pyridinylene, pyrimidinylene, pyridazinlylene, pyrazinlylene, ot triazinylene. 24 ME153015591v.1 136867-00720 "Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or bicyclic (e.g., fused or bridged) ring system which has from 4 to 13 ring members, e.g., 4-10 ring members, at least one of which is a heteroatom, and up to 4 (e.g., 1, 2, 3, or 4) of which may be heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and wherein N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone. An “oxygen-containing heterocyclyl” is a heterocyclyl comprising a ring oxygen atom. An oxygen-containing heterocyclyl can have more than one ring heteroatom. A “nitrogen-containing heterocyclyl” is a heterocyclyl comprising a ring nitrogen atom. A nitrogen-containing heterocyclyl can have more than one ring heteroatom. Examples of 4-7 membered monocyclic heterocyclyl include, but are not limited to, oxetanyl, thietanyl, azetedinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl. A fused bicyclic heterocyclyl has a 4-7 membered heterocyclyl which shares two adjacent ring atoms with a 4-7 membered heterocyclyl or a 3-7 membered cycloalkyl, i.e., a 4 to 7 membered heterocyclyl fused to a 4 to 7 membered heterocyclyl or a 3 to 7 membered carbocyclyl. Examples include cyclopropylpyrrolidinyl, cyclopentapyrrolidinyl, cyclopentapiperidinyl, cyclopentaazapanyl, cyclohexapyrrolidinyl, cyclohexapiperidinyl, cyclohexaazapanyl, cycloheptapyrrolidinyl, cycloheptapiperidinyl, cycloheptaazapanyl, pyranopyrrolidinyl, pyranopiperidinyl, pyranoazapanyl, and the like. A “bridged bicyclic heterocyclyl” has 7-10 members and comprises a 5 to 7 membered heterocyclyl which shares three ring atoms with a 5 to 7 membered heterocyclyl or a 5 to 7 membered non-aromatic cycloalkyl. Examples of nitrogen containing bridged bicyclics include azabicyclo[2.2.1]hepantyl, azabicyclo[3.2.1]octanyl, azabicyclo [3.3.1]nonanyl, diazabicyclo[2.2.1]hepantyl, diazabicyclo[3.2.1]octanyl and diazabicyclo [3.3.1]nonanyl. Examples of oxygen containing bridged bicyclics include oxobicyclo[2.2.1]hepantyl, oxobicyclo[3.2.1]octanyl, oxobicyclo [3.3.1]nonanyl, oxa- azabicyclo[2.2.1]hepantyl, oxa-azabicyclo[3.2.1]octanyl and oxa-azabicyclo [3.3.1]nonanyl. “Heterocyclylene” refers to a bivalent heterocyclyl, i.e., a heterocyclyl that is connected to the remainder of the molecule at two points. 25 ME153015591v.1 136867-00720 ”N-Substituted” means that a heterocyclyl group is substituted at a ring nitrogen atom with a group other than hydrogen. ”C-Substituted” means that a cycloalkyl or heterocyclyl group is substituted at a ring carbon atom, i.e., that hydrogen on a ring carbon atom is replaced with another group. The term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of a hydrogen substituent in a given structure with a non-hydrogen substituent. Thus, for example, a substituted alkyl is an alkyl wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl group. To illustrate, monofluoroalkyl is an alkyl substituted with a fluoro substituent, and difluoroalkyl is an alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent can be identical or different (unless otherwise stated). If a group is described as “optionally substituted”, the group can be either (1) not substituted or (2) substituted. If a group is described as optionally substituted with up to a particular number of non-hydrogen substituents, that group can be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a group is described as a cycloalkyl optionally substituted with up to 3 non- hydrogen substituents, then any cycloalkyl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the cycloalkyl has substitutable positions. Spirocycloalkyl or spiroheterocyclyl refers to a cycloalkyl or heterocyclyl that shares one ring atom with another cyclic group, such as another cycloalkyl or heterocyclyl. The described compounds include all tautomeric forms. Compounds having one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other. When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is 26 ME153015591v.1 136867-00720 indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9% “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture. When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers. When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that, unless otherwise indicated, one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers. In cases where a compound provided herein is sufficiently basic or acidic to form stable nontoxic acid or base salts, preparation and administration of the compounds as pharmaceutically acceptable salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α ketoglutarate, or α-glycerophosphate. Inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made. 27 ME153015591v.1 136867-00720 Pharmaceutically-acceptable base addition salts can be prepared from inorganic and organic bases. Salts from inorganic bases, can include but are not limited to, sodium, potassium, lithium, ammonium, calcium or magnesium salts. Salts derived from organic bases can include, but are not limited to, salts of primary, secondary or tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocycloalkyl amines, diheterocycloalkyl amines, triheterocycloalkyl amines, or mixed di- and tri-amines where at least two of the substituents on the amine can be different and can be alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocycloalkyl or heteroaryl group. Non-limiting examples of amines can include, isopropylamine, trimethyl amine, diethyl amine, tri(iso- propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethyl¬aminoethanol, trimethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, or N-ethylpiperidine, and the like. Other carboxylic acid derivatives can be useful, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, or dialkyl carboxamides, and the like. As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some aspects, treatment may be administered after one or more symptoms have developed, i.e, therapeutic treatment. In other aspects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g, in light of a history of symptoms and / or in light of exposure to a particular organism, or other 28 ME153015591v.1 136867-00720 susceptibility factors), i.e, prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence. The compounds disclosed herein or pharmaceutically acceptable salts thereof can be used for reactivating mutated p53 in a subject in need thereof. The method comprises administering to the subject an effective amount of a compound disclosed herein or pharmaceutically acceptable salts thereof or a pharmaceutical composition disclosed herein. “Reactivating mutated p53” refers to increasing the ability of a mutated p53 protein to bind to DNA at physiologically relevant temperatures, where that mutated p53 protein has decreased ability to to DNA at physiologically relevant temperatures compared with wild type p53 protein. A subject in need of inhibition of p53 includes, for example, a subject with a cancer characterized by dysfunctional p53. A dysfunctional p53 includes, for example, p53 with an inactivating mutation and / or mutated p53 with decreased ability to bind to DNA at physiologically relevant temperatures compared with wild type p53 protein. Inactivating p53 mutations included Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, Arg282, and / or a combination thereof. Alternatively, the p53 mutation is V157F, R175H, Y220C, G245S, R248Q, R248W, R249S, R273H, R273C, R282W, and / or a combination thereof. In another alternative, the p53 mutation is Y220C. Cancers which can be treated with the disclosed compounds or pharmaceutically acceptable salts thereof or pharmaceutically acceptable salts thereof or the disclosed pharmaceutical compositions include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, bladder cancer, bone cancers, brain tumors, such as cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, colon cancer, gallbladder cancer, gastric cancer, head and neck cancer, heart cancer, hepatocellular (liver) cancer, kidney cancer, liver cancer, lung cancers, such as non-small cell and small cell lung cancer, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, pancreatic cancer, pancreatic cancer islet cell, prostate cancer, rectal cancer, renal cell carcinoma, skin cancers, skin carcinoma merkel cell, small intestine cancer or throat cancer. In one aspect, the disclosed compounds or pharmaceutically acceptable salts thereof or disclosed pharmaceutical compositions can be part of a combination therapies with one or more other therapeutic agents. 29 ME153015591v.1 136867-00720 In some embodiments, one or more other therapeutic agents can be an immune checkpoint inhibitor. In some embodiments, the checkpoint inhibitors include but are not limited to anti programed cell death receptor-1 (aPD-1) monoclonal antibodies such as pembrolizumab, nivolumab, cemiplimab, or anti programed cell death receptor-1 ligand (aPD-L1) monoclonal antibodies such as atezolizumab, dostarlimab, durvalumab and avelumab, or anti cytotoxic T lymphocyte-associated antigen (anti-CTLA4) monoclonal antibodies such as ipilimumab and tremelimumab, or anti lymphocyte activated gene-3 (LAG-3) monoclonal antibodies such as relatlimab. In some embodiments, one or more other therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2. Inhibitors of p53 suppression proteins being studied which may be used in the present invention include ALRN-6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL). In some embodiments, one or more other therapeutic agent is an inhibitor of interaction between p53 and MDM2. Said MDM2 inhibitors include but are not limited to navtemadlin (AMG-232, KRG 232, Amgen), idasanutlin (RG7388, Hoffman‐La Roche), milademetan (RAIN-32), MK-8242 (Merck), SAR405838, NVP-CGM097, RG7112, and DS- 3032b. In some embodiments, one or more other therapeutic agent is an MDM2 targeted protein degrader such as MD-224. In some embodiments, one or more other therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor. In some embodiments, a PARP inhibitor is selected from olaparib (LYNPARZA®, AstraZeneca); rucaparib (RUBRACA®, Clovis Oncology); niraparib (ZEJULA®, Tesaro); talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, Abb Vie); and BGB-290 (BeiGene, Inc.). In some embodiments, one or more other therapeutic agent is a CDK inhibitor such as a CDK4 / CDK6 inhibitor. In some embodiments, a CDK 4 / 6 inhibitor is selected from Palbociclib (IBRANCE®, Pfizer); ribociclib (KISQALI®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, Gl Therapeutics). In some embodiments, a CDK inhibitor is a CDK9 selective inhibitor selected from dinaciclib, AT-7519, P276-00, 30 ME153015591v.1 136867-00720 AZD-4573, alvocidib / flavopiridol, CYC065, atuveciclib, BAY-1251152, voruciclib or GFH009. In some embodiments, one or more other therapeutic agent is an inhibitor of antiapoptotic proteins, such as BCL-2. Approved anti-apoptotics which may be used in the present invention include venetoclax (VENCLEXTA®, AbbVie / Genentech); and blinatumomab (BLINCYTO®, Amgen). Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott). Other therapeutic agents targeting BCL family proteins via E3 ligase-mediated target protein degradation may be used in the present invention. In some embodiments, one or more other therapeutic agent is a platinum-based therapeutic, also referred to as platins. Platins cause cross-linking of DNA, such that they inhibit DNA repair and / or DNA synthesis, mostly in rapidly reproducing cells, such as cancer cells. In some embodiments, a platinum-based therapeutic is selected from cisplatin (PLATINOL®, Bristol-Myers Squibb); carboplatin (PARAPLATIN®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (ELOXITIN® Sanofi-Aventis); nedaplatin (AQUPLA®, Shionogi), picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix). In some embodiments, one or more other therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division. In some embodiments, a taxane compound is selected from paclitaxel (TAXOL®, Bristol-Myers Squibb), docetaxel (TAXOTERE®, Sanofi-Aventis; DOCEFREZ®, Sun Pharmaceutical), albumin-bound paclitaxel (ABRAXANE®; Abraxis / Celgene), cabazitaxel (JEVTANA®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.). In some embodiments, one or more other therapeutic agent is a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells. In some embodiments, a nucleoside inhibitor is selected from trabectedin (guanidine alkylating agent, YONDELIS®, Janssen Oncology), mechlorethamine (alkylating agent, VALCHLOR®, Aktelion Pharmaceuticals); vincristine (ONCOVIN®, Eli Lilly; VINCASAR®, Teva Pharmaceuticals; MARQIBO®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-l-yl)-imidazole-4-carboxamide (MTIC) TEMODAR®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CEENU®, Bristol-Myers Squibb; GLEOSTINE®, NextSource 31 ME153015591v.1 136867-00720 Biotechnology); azacytidine (pyrimidine nucleoside analog of cytidine, VIDAZA®, Celgene); omacetaxine mepesuccinate. (cephalotaxine ester) (protein synthesis inhibitor, SYNRIBO®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (enzyme for depletion of asparagine, ELSPAR®, Lundbeck; ERWINAZE®, EElSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic, HALAVEN®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic, JEVTANA®, Sanofi-Aventis); capacetrine (thymidylate synthase inhibitor, XELODA®, Genentech); bendamustine (bifunctional mechlorethamine derivative, believed to form interstrand DNA cross-links, TREANDA®, Cephalon / Teva); ixabepilone (semi-synthetic analog of epothilone B, microtubule inhibitor, tubulin-based antimitotic, IXEMPRA®, Bristol-Myers Squibb); nelarabine (prodrug of deoxyguanosine analog, nucleoside metabolic inhibitor, ARRANON®, Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor, competitive inhibitor of deoxycytidine, CLOLAR®, Sanofi-Aventis); and trifluridine and tipiracil (thymidinebased nucleoside analog and thymidine phosphorylase inhibitor, LONSEIRF®, Taiho Oncology). In some embodiments, one or more other therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor. In some embodiments, a PBK inhibitor is selected from idelalisib (ZYDELIG®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202(formerly RP5230, TG Therapeutics). In some embodiments, one or more other therapeutic agent is a kinase inhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (AVASTIN®, Genentech / Roche) an anti-VEGF monoclonal antibody; ramucirumab (CYRAMZA®, Eli Lilly), an anti-VEGFR-2 antibody and ziv- aflibercept, also known as VEGF Trap (ZALTRAP®; Regeneron / Sanofi). VEGFR inhibitors, such as regorafenib (STIVARGA®, Bayer); vandetanib (CAPRELSA®, AstraZeneca); axitinib (INLYTA®, Pfizer); and lenvatinib (LENVIMA®, Eisai); Raf inhibitors, such as sorafenib (NEXAVAR®, Bayer AG and Onyx); dabrafenib (TAFINLAR®, Novartis); and vemurafenib (ZELBORAF®, Genentech / Roche); MEK inhibitors, such as cobimetanib (COTELLIC®, Exelexis / Genentech / Roche); trametinib (MEKINIST®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (GLEEVEC®, Novartis); nilotinib (TASIGNA®, Novartis); dasatinib (SPRYCEL®, BristolMyersSquibb); bosutinib (BOSULIF®, Pfizer); and ponatinib (INCLUSIG®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as 32 ME153015591v.1 136867-00720 gefitinib (IRESSA®, AstraZeneca); erlotinib (TARCEEVA®, Genentech / Roche / Astellas); lapatinib (TYKERB®, Novartis); afatinib (GILOTRIF®, Boehringer Ingelheim); osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca); and brigatinib (ALUNBRIG®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib (COMETRIQ®, Exelexis); and multikinase inhibitors, such as sunitinib (SUTENT®, Pfizer); pazopanib (VOTRIENT®, Novartis); ALK inhibitors, such as crizotinib (XALKORI®, Pfizer); ceritinib (ZYKADIA®, Novartis); and alectinib (ALECENZa®, Genentech / Roche); Bruton’s tyrosine kinase inhibitors, such as ibrutinib (IMBRErVICA®, Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin (RYE)APT®, Novartis). Other kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer / Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (SUPECT®, IY5511, Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (JAKAFI®, Incyte Corporation); PTC299 (PTC Therapeutics); CP- 547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen / T akeda). In some embodiments, one or more other therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake. In some embodiments, an mTOR inhibitor is everolimus (AFINITOR®, Novartis); temsirolimus (TORISEL®, Pfizer); and sirolimus (RAPAMUNE®, Pfizer). In some embodiments, one or more other therapeutic agent is a proteasome inhibitor. Approved proteasome inhibitors useful in the present invention include bortezomib (VELCADE®, Takeda); carfilzomib (KYPROLIS®, Amgen); and ixazomib (NINLARO®, Takeda). In some embodiments, one or more other therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists which may be used in the present invention include olaratumab (LARTRUVO®; Eli Lilly). Approved EGFR antagonists which may be used in the present invention include cetuximab (ERBITUX®, Eli Lilly); necitumumab (PORTRAZZA®, Eli Lilly), panitumumab (VECTIBIX®, Amgen); and Osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca). 33 ME153015591v.1 136867-00720 In some embodiments, one or more other therapeutic agent is an aromatase inhibitor. In some embodiments, an aromatase inhibitor is selected from exemestane (AROMASIN®, Pfizer); anastazole (ARIMIDEX®, AstraZeneca) and letrozole (FEMARA®, Novartis). In some embodiments, one or more other therapeutic agent is a folic acid inhibitor. Approved folic acid inhibitors useful in the present invention include pemetrexed (ALIMTA®, Eli Lilly). In some embodiments, one or more other therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors useful in the present invention include irinotecan (ONIVYDE®, Merrimack Pharmaceuticals); topotecan (HYCAMTIN®, GlaxoSmithKline). Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (PIXUVRI®, CTI Biopharma). Pharmaceutical compositions are disclosed that include one or more compounds provided herein or a pharmaceutically acceptable salt thereof, and typically at least one additional substance, such as an excipient, a known therapeutic other than those of the disclosure, and combinations thereof. In some embodiments, the disclosed compounds or pharmaceutically acceptable salts thereof can be used in combination with other agents known to have beneficial activity targeting diseases or disorders listed above. For example, disclosed compounds or pharmaceutically acceptable salts thereof can be administered alone or in combination with one or more anti-cancer or antiviral agent. The terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. 34 ME153015591v.1 136867-00720 A “subject” is a mammal in need of medical treatment, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). The precise amount of compound or pharmaceutically acceptable salt thereof administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease or condition, and on the characteristics of the subject, such as general health, age, sex, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, e.g., when administered in combination with an anti-cancer or antiviral agent, an “effective amount” of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof being used by following, for example, dosages reported in the literature and recommended in the Physician’s Desk Reference (57th ed., 2003). The term “effective amount” means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control. For example, a therapeutically effective amount can be given in unit dosage form (e.g., 0.1 mg to about 50 g per day). The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g. the subject, the disease, the disease state involved, the particular treatment, and whether the treatment is prophylactic). Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly etc.) doses over a period of a few days to months, or even years. The pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. In an embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings. In preferred embodiments, the pharmaceutical composition is formulated for intravenous administration. 35 ME153015591v.1 136867-00720 “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the formulation and / or administration of an active agent to and / or absorption by a subject and can be included in the compositions of the disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds. The following examples are intended to be illustrative and are not meant in any way to be limiting. EXEMPLIFICATION The abbreviations used in the entire specification may be summarized herein below with their meaning: AcOH - acetic acid AgSbF6 – Silver hexafluoroantimonate AgBF4– Silver tetrafluoroborate Aq. - Aqueous ACN – Acetonitrile BF3.Et2O – Boron trifluoride diethyl etherate BnNH2 - Benzylamine BOC – tert-Butyloxycarbonyl Boc2O –Di- tert-butyl dicarbonate B2Pin2- Bis(pinacolato)diboron 36 ME153015591v.1 136867-00720 br s – Broad singlet nBuLi – n-butyllithium n-BuOH – n-butanol t-BuOK – Potassium t-butoxide °C – degree Celsius CBz – benzyloxycarbonyl CDCl3– Deuterated chloroform CD3CN – Deuterated acetonitrile CDI – N,N’-carbonyl diimidazole CHCl3– Chloroform Cs2CO3 - Cesium carbonate CsF – Cesium fluoride CuCN – Copper(I) cyanide d – Doublet dd – Doublet of doublet δ – Delta DCC – N,N’-Dicyclohexyl carbodiimide DCE – 1,2-Dichloroethane DCM – Dichloromethane (DHQD)2PHAL - Hydroquinidine 1,4-phthalazinediyl diether DIAD - Disopropyl azodicarboxylate DIBAL - Diisobutylaluminium hydride DIEA - Diisopropylethylamine DIPA – N,N-diisopropylamine DIPEA - Diisopropylethylamine DMAc or DMA – N, N-Dimethylacetamide DMAP – 4-Dimethylaminopyridine DMF – N, N-Dimethylformamide DMSO – Dimethyl sulfoxide DMSO–d6 – Deuterated dimethyl sulfoxide EDCI - 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI – Electrospray ionization Et3N - triethylamine 37 ME153015591v.1 136867-00720 Et2O – diethyl ether EtOH – ethanol EA – Ethyl acetate FA – Formic acid19F NMR – Fluorine-19 nuclear magnetic resonance FeCl3–Iron(III) chloride g – Gram GCMS – Gas chromatography-mass spectrometry h or hr – Hour1H – Proton1H NMR – Proton nuclear magnetic resonance HATU - Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium H2O – Water HBr – Hydrobromic acid HCHO - Formaldehyde HCl – Hydrochloric acid HOBt – 1-Hydroxybenzotriazole HPLC – High performance liquid chromatography Hz – Hertz H2SO4- Sulfuric acid J – Coupling constant K2CO3 – Potassium carbonate KOAc – Potassium acetate KOH – Potassium hydroxide K2OsO2(OH)4 - Potassium osmate(VI) dihydrate LCMS – Liquid chromatography mass spectrometry LDA – Lithium diisopropylamide LiCl – Lithium chloride LiHMDS – Lithium hexamethyldisilazide M+ – Molecular ion m – Multiplet MeI – Methyl iodide Me3OBF4- Trimethyloxonium tetrafluoroborate 38 ME153015591v.1 136867-00720 MeOH – Methanol MeOD – Deuterated methanol MsCl – Methanesulfonyl chloride MTBE – Methyl t-butyl ether mg – Milligrams min – Minutes MHz – Mega Hertz (frequency) mL – Milliliters mm – Millimeters mmol – Millimoles MsCl – methanesulfonyl chloride MTBE – methyl t-butyl ether MS – Mass spectroscopy NaBH3CN – Sodium cyanoborohydride NaBH2O3 – Sodium dihydrogen borate NaBH(OAc)3- Sodium triacetoxyborohydride NaH – Sodium hydride Sat.NaHCO3 - Saturated sodium hydrogencarbonate NaIO4 – Sodium periodate Na2SO4- Sodium sulfate Na2S2O3 – Sodium thiosulfate NH3 - Ammonia NH4HCO3- Ammonium bicarbonate NH4Cl – Ammonium chloride NH2OH - Hydroxylamine NBS – N-Bromosuccinimide Pd / C – Palladium on activated carbon Pd2(dba)3 - Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2 – [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(OAc)2– Palladium acetate PE – Petroleum ether % – Percentage pH – potential of Hydrogen 39 ME153015591v.1 136867-00720 ppm – Parts per million iPrMgCl – Isopropyl magnesium chloride iPrOH – 2-propanol i-Pr2NH - diisopropylamine Py – Pyridine q – Quartet Rt – Retention time RuO2 – Ruthenium oxide rt – room temperature s – Singlet t – Triplet TBDPSCl - tert-Butyldiphenylchlorosilane TBSCl - tert-Butyldimethylchlorosilane TBSOTf - tert-Butyldimethylsilyl triflate TEA – Triethylamine TFA – Trifluoroacetic acid THF – Tetrahydrofuran TLC – Thin layer chromatography Prep TLC – Preparative thin layer chromatography TMSN3– Trimethylsilyl azide μL – Microliters μm – Millimeters μmol – Micromoles UV - ultraviolet Xphos - dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′-biphenyl]-2-yl]phosphane ZnCl2– Zinc chloride The following Examples, while representing preferred embodiments of the invention, serve to illustrate the invention without limiting its scope. 40 ME153015591v.1 136867-00720 Intermediate 1 Step 1. 7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophene A mixture of 7-bromobenzo[b]thiophene (1 g, 4.7 mmol), 2- ((trifluoromethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (1.5 g, 5.2 mmol), AgSbF6(483.8 mg, 1.4 mmol) and FeCl3 (76.2 mg, 0.5 mmol) in dry DCE (10 mL) was stirred for 3.5 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford the title compound (1.1 g) as an oil. GCMS (M)+m / z: 311.9. Step 2. 7-bromo-2-iodo-3-((trifluoromethyl)thio)benzo[b]thiophene To a stirred mixture of 7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophene (1 g, 3.2 mmol) in dry THF (10 mL) was added LDA (1.0 M in THF , 4.8 mL, 4.8 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at -78 °C under nitrogen atmosphere. To the above mixture was added iodine (891.6 mg, 3.6 mmol) in dry THF (3 mL) dropwise at -78 °C. The resulting mixture was stirred for additional 1 h at rt. The reaction was quenched by the addition of sat. NH4Cl (aq.) (20 mL) at 0 °C. The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with water (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford the title compound (680 mg) as a solid. GCMS (M)+m / z: 437.8. Step 3. 7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophene-2-carbonitrile A mixture of 7-bromo-2-iodo-3-((trifluoromethyl)thio)benzo[b]thiophene (620 mg, 1.4 mmol) and CuCN (252.9 mg, 2.8 mmol) in dry DMF (12 mL) was stirred for 7 h at 110 °C under nitrogen atmosphere. The resulting mixture was diluted with EA (60 mL) and water (60 mL). The resulting mixture was extracted with EA (3 × 60 mL). The combined organic layers were washed with water (60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% NH3.H2O+10 mmol / L NH4HCO3), 75% to 90% gradient in 20 41 ME153015591v.1 136867-00720 min; detector, UV 254 nm. The title compound was isolated as a solid. GCMS (M)+m / z: 336.8. Step 4. 7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophene-2-carbonitrile To a stirred mixture of 7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophene-2-carbonitrile (150 mg, 0.5 mmol), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (136.5 mg, 0.7 mmol) and Cs2CO3(578.1 mg, 1.8 mmol) in dioxane (2 mL) was added Pd-PEPPSI- IHeptCl (CAS: 1814936-54-3) (46.6 mg, 0.1 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 90 °C under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford the title compound (65 mg) as a solid. LCMS [M + H]+m / z: 390.0. Intermediate 2 Step 1. 2-bromo-4-fluorobenzenethiol To a stirred mixture of CuSO4.5H2O (1.2 g, 4.9 mmol) in DMSO (180 mL) and H2O (18 mL) were added 2-bromo-4-fluoro-1-iodobenzene (30 g, 99.7 mmol) at rt under nitrogen atmosphere. To the above mixture was added KOH (27.9 g, 498.5 mmol) in portions at 0 °C. The resulting mixture was stirred for 10 min at 0 °C. To the above mixture was added ethane- 1,2-dithiol (18.7 g, 199.4 mmol) at 0 °C. The resulting mixture was stirred for additional 2 h at 80 °C. The mixture was allowed to cool down to rt. The reaction mixture was acidified to pH 5 with HCl (1 M, aq.), and then extracted with EA (3×1 L). The combined organic layers were washed with brine (3 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA(10:1) to afford 2-bromo-4-fluorobenzenethiol (6 g) as an oil. GCMS (M)+m / z: 205.8. 42 ME153015591v.1 136867-00720 Step 2. (2-bromo-4-fluorophenyl)(2,2-diethoxyethyl)sulfane To a stirred mixture of 2-bromo-4-fluorobenzenethiol (34 g, 164.2 mmol) and K2CO3 (22.6 g, 164.2 mmol) in acetone (150 mL) was added 2-bromo-1,1-diethoxyethane (64.7 g, 328.4 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred for 3 h at rt under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EA (3×50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (15:1) to afford the title compound (43 g) as an oil. GCMS (M)+m / z: 322.0. Step 3. 7-bromo-5-fluorobenzo[b]thiophene To a stirred mixture of polyphosphoric acid (86 g, 877.5 mmol) in chlorobenzene (160 mL) was added (2-bromo-4-fluorophenyl)(2,2-diethoxyethyl)sulfane (43 g, 133 mmol) at rt. The resulting mixture was stirred for 3 h at 130 °C under nitrogen atmosphere. The mixture was allowed to cool down to rt. The supernatant of the reaction mixture was separated and the residue was washed with toluene (3×100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford the title compound (7 g) as an oil. GCMS (M)+m / z: 229.9. Step 4. 7-bromo-5-fluoro-3-((trifluoromethyl)thio)benzo[b]thiophene To a stirred mixture of 2-((trifluoromethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (1.3 g, 4.5 mmol), AgSbF6(423.8 mg, 1.2 mmol) and ferric chloride (66.7 mg, 0.4 mmol) were added 7-bromo-5-fluorobenzo[b]thiophene (950 mg, 4.1 mmol) in dry DCE (10 mL) at rt under nitrogen atmosphere. The resulting mixture was stirred for 3.5 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford the title compound (1.2 g) as an oil. GCMS (M)+m / z: 329.8. Step 5. 7-bromo-5-fluoro-2-iodo-3-((trifluoromethyl)thio)benzo[b]thiophene To a stirred mixture of 7-bromo-5-fluoro-3-((trifluoromethyl)thio)benzo[b]thiophene (1.2 g, 3.6 mmol) in dry THF (24 mL) was added LDA (1.0 M in THF, 4.4 mL, 4.4 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at -78 °C under nitrogen atmosphere. To the above mixture was added iodine (1.0 g, 4.0 mmol) in dry THF (12 mL) dropwise at -78 °C. The resulting mixture was stirred for additional 30 min at - 78 °C. The reaction was quenched by the addition of sat. NH4Cl (aq.) (20 mL) at 0 °C. The resulting mixture was extracted with EA (3 × 60 mL). The combined organic layers were 43 ME153015591v.1 136867-00720 dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford the title compound (910 mg) as a solid. GCMS (M)+m / z: 455.8. Step 6. 7-bromo-5-fluoro-3-((trifluoromethyl)thio)benzo[b]thiophene-2-carbonitrile A mixture of 7-bromo-5-fluoro-2-iodo-3-((trifluoromethyl)thio)benzo[b]thiophene (200 mg, 0.4 mmol) and cuprous cyanide (78.4 mg, 0.8 mmol) in dry DMF (2 mL) was stirred for 5 h at 110°C under nitrogen atmosphere. The resulting mixture was diluted with EA (20 mL) and water (20 mL). The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford the title compound (80 mg) as a solid. GCMS (M)+m / z: 354.9. Intermediate 3 Step 1. 2,7-dibromo-3-(bromodifluoromethoxy)benzo[b]thiophene To a stirred solution of 7-bromobenzo[b]thiophen-3-ol (5.5 g, 24.0 mmol) in DMAc (160 mL) was added NaH (60 wt%, 1.9 g, 48.0 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 °C under nitrogen atmosphere. To the above mixture was added dibromodifluoromethane (10.0 g, 48.0 mmol) dropwise at 0 °C. The resulting mixture was stirred for additional 30 min at 0 °C. The reaction mixture was quenched by the addition of sat. NH4Cl (aq, 500 mL) at 0 °C. The resulting mixture was extracted with EA (3 × 500 mL). The combined organic layers were washed with brine (1.5 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford the crude product, which was further purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 70% to 95% gradient in 20 min; detector, UV 254 nm. The title compound was isolated (1.3 g) as an oil. GCMS [M]+m / z: 433.8. Step 2. 2,7-dibromo-3-(trifluoromethoxy)benzo[b]thiophene To a stirred solution of 2,7-dibromo-3-(bromodifluoromethoxy)benzo[b]thiophene (1.2 g, 2.7 mmol) in DCM (20 mL) was added AgBF4 (1.0 g, 5.4 mmol) under nitrogen atmosphere at rt. 44 ME153015591v.1 136867-00720 The resulting mixture was stirred for 24 h at 40 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford the title compound (900 mg) as a solid. GCMS [M]+m / z: 373.8. Step 3. 7-bromo-2-iodo-3-(trifluoromethoxy)benzo[b]thiophene To a stirred solution of 2,7-dibromo-3-(trifluoromethoxy)benzo[b]thiophene (1.1 g, 2.9 mmol) in dry THF (30 mL) was added nBuLi (2.5 M in hexane, 1.3 mL, 3.2 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 5 min at -78 °C under nitrogen atmosphere. To the above mixture was added the solution of I2 (0.8 g, 3.2 mmol) in dry THF (5 mL) dropwise at -78 °C. The resulting mixture was stirred for additional 30 min at -78 °C. The reaction was quenched by the addition of sat. NH4Cl (aq.) (60 mL) at 0 °C. The resulting mixture was extracted with EA (3 × 60 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford the title compound (650 mg) as a solid. GCMS [M]+m / z: 421.8. Step 4. 7-bromo-3-(trifluoromethoxy)benzo[b]thiophene-2-carbonitrile A solution of 7-bromo-2-iodo-3-(trifluoromethoxy)benzo[b]thiophene (645 mg, 1.5 mmol) and CuCN (273 mg, 3.0 mmol) in DMSO (2 mL) and pyridine (2 mL) was stirred for 16 h at 90 °C under nitrogen atmosphere. The reaction mixture was allowed to cool to rt and 100 mL water was added to the above mixture. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (5 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-10%) to afford the title compound (345 mg) as a solid. GCMS m / z: 320.9. Intermediate 4 Step 1. 7-bromo-3-(difluoromethoxy)benzo[b]thiophene To a stirred solution of 7-bromobenzo[b]thiophen-3-ol (2 g, 8.7 mmol) in ACN (40 mL) was added a solution of KOH (4.5 g, 79.9 mmol) in H2O (40 mL) dropwise at 0 °C. Then diethyl (bromodifluoromethyl)phosphonate (4.7 g, 17.5 mmol) was added the above mixture at 0 °C. 45 ME153015591v.1 136867-00720 The resulting mixture was stirred for 30 min at 0 °C. The reaction mixture was diluted with water (20 mL). The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-10%) to afford 7-bromo-3- (difluoromethoxy)benzo[b]thiophene (1.5 g) as an oil. GCMS [M]+m / z: 277.9. Step 2. 7-bromo-3-(difluoromethoxy)-2-iodobenzo[b]thiophene To a stirred solution of 7-bromo-3-(difluoromethoxy)benzo[b]thiophene (1.4 g, 4.8 mmol) and I2 (1.4 g, 5.3 mmol) in dry THF (27 mL) was added LiHMDS (1.3 M in THF, 7.8 mL, 10.2 mmol) dropwise at -40 °C under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at -40 °C under nitrogen atmosphere. To the above mixture was added a solution of I2 (1.4 g, 5.3 mmol) in THF (13.5 mL) at -40 °C. The resulting mixture was stirred for additional 1 h at rt. The reaction was quenched by the addition of sat. NH4Cl (aq, 50 mL) and sat. Na2S2O3 (aq, 50 mL) at 0 °C. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The title compound was isolated (1.7 g) as a solid. GCMS [M]+m / z: 403.8. Step 3. 7-bromo-3-(difluoromethoxy)benzo[b]thiophene-2-carbonitrile To a stirred mixture of 7-bromo-3-(difluoromethoxy)-2-iodobenzo[b]thiophene (1 g, 2.5 mmol) and CuCN (442.3 mg, 5.0 mmol) in DMSO (6 mL) was added pyridine (6 mL) at rt under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 80 °C under nitrogen atmosphere. The reaction mixture was diluted with water (12 mL). The precipitated solids were collected by filtration and washed with water (3 × 10 mL). The collected solids was further purified by silica gel column chromatography, eluted with EA in PE (0%-20%) to afford the title compound (660 mg) as a solid. GCMS [M]+m / z: 302.9. Intermediate 5 Step 1. 7-hydroxy-3-((trifluoromethyl)thio)benzo[b]thiophene-2-carbonitrile A mixture of 7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophene-2-carbonitrile (2 g, 5.9 mmol), B2Pin2 (1.8 g, 7.1 mmol), Pd2(dba)3.CHCl3 (600 mg, 0.6 mmol), 3-tert-butyl-4-(2,6- 46 ME153015591v.1 136867-00720 dimethoxyphenyl)-2,3-dihydro-1,3-benzoxaphosphole (0.2 g, 0.6 mmol) and AcOK (1.7 g, 17.7 mmol) in 1,4-dioxane (40 mL) was stirred for 16 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in THF (50 mL) and H2O (50 mL). Then NaBH2O3 (1.5 g, 17.7 mmol) was added at rt. The resulting mixture was stirred for another 4 h at rt. The reaction mixture was filtered, the filter cake was washed with EA (3 × 100 mL). The resulting mixture was extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%- 20%) to afford the title compound (176 mg) as a solid. LCMS [M - H]- m / z: 273.9. Step 2. Tert-butyl (3S,4R)-4-((2-cyano-3-((trifluoromethyl)thio)benzo[b]thiophen-7- yl)oxy)-3-fluoropiperidine-1-carboxylate To a stirred mixture of PPh3(486 mg, 1.8 mmol) in THF (20 mL) was added DIAD (312 mg, 1.5 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 10 min. Then 7-hydroxy-3-((trifluoromethyl)thio)benzo[b]thiophene-2-carbonitrile (170 mg, 0.6 mmol) and tert-butyl (3S,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (149 mg, 0.7 mmol) was added to above mixture at rt. The resulting mixture was stirred for another 2 h at rt. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-75%) to afford the title compound (260 mg) as a solid. LCMS [M + H]+m / z: 477.1. Intermediate 6 Step 1. Di-tert-butyl (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate To a stirred solution of (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (50 g, 0.21 mol, 1 equiv)^in^dry THF (750 mL)^was added^tert-butyl (E)-N, N'- diisopropylcarbamimidate (65 g, 0.32 mol, 1.5 equiv)^dropwise at^rt^under^nitrogen^atmosphere. The resulting mixture was stirred for 2.5^h^at 60^°C. Then additional^(E)-N,N'-diisopropylcarbamimidate (43.3 g, 0.21 mol, 1 equiv)^was added, The resulting mixture was stirred for 16^h^at 60^°C. The resulting mixture was allowed to cool down to rt. The resulting mixture was filtered, the filter cake was washed with^EA^(3 × 500^mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with^MTBE in PE^(0% - 50%) to afford^di-tert- 47 ME153015591v.1 136867-00720 butyl (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (162 g)^as a solid. LCMS [M + H]+m / z: 288.20. Step 2. Di-tert-butyl (2R,4S)-4-methoxypyrrolidine-1,2-dicarboxylate To a stirred solution of di-tert-butyl (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (90 g, 0.31 mol, 1 equiv) in dry DCM (900 mL) were added N1, N1, N8, N8-tetramethylnaphthalene- 1,8-diamine (201.3 g, 0.93 mol, 3 equiv) and Me3OBF4(92.8 g, 0.62 mol, 2 equiv) at rt under nitrogen atmosphere. The resulting mixture was stirred for 3 h at rt and then 64 mL MeOH was added. The resulting mixture was stirred for another 10 min, 5 L 0.5 M HCl (aq.) was added. The reaction mixture was filtered, the filter cake was washed with EA (500 mL). The resulting mixture was extracted with EA (3 × 2 L). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MTBE in PE^(0% - 50%) to afford di-tert-butyl (2R,4S)-4-methoxypyrrolidine-1,2-dicarboxylate (80 g) as a solid. LCMS [M + H]+m / z: 302.10. Step 3. Di-tert-butyl (2R,4S)-4-methoxy-5-oxopyrrolidine-1,2-dicarboxylate To a stirred mixture of^di-tert-butyl (2R,4S)-4-methoxypyrrolidine-1,2-dicarboxylate (40 g, 0.13 mol, 1 equiv)^in^EA (800 mL) was added NaIO4(140.3 g, 0.65 mol, 5 equiv)^in^H2O (600 mL)^dropwise at 0^°C^under^nitrogen^atmosphere. Then^RuO2.H2O (3.9 g, 0.026 mol, 0.2 equiv)^was added. The resulting mixture was stirred for 24^h^at^rt^under^nitrogen^atmosphere. ~ 44% SM remained based on LCMS (200 nm). Additional NaIO4(28.1 g, 1 equiv.) and RuO2.H2O (0.8 g, 0.04 eq.) was added. The resulting reaction was stirred for another 24 h at rt. ~26% SM remained based on LCMS (200 nm). Additional NaIO4 (56.1 g, 2 eq.) and RuO2.H2O (1.6 g, 0.08 eq.) was added, the resulting reaction was stirred for another 24 h at rt. ~ 5% SM remained based on LCMS (200 nm). The resulting mixture was extracted with EA (3 × 2 L). The combined organic layers were added iPrOH (320 mL) and then stirred for 30 min. The resulting mixture was washed with H2O (1.2 L). The combined organic layers were dried over Na2SO4and concentrated under reduce pressure. The residue (75 g crude) was purified by trituration with hexane (225 mL). The title compound was isolated (58 g) as a solid. LCMS [2M + Na + H]+m / z: 653.40. Step 4. (2R,4S)-4-methoxy-5-oxopyrrolidine-2-carboxylic acid To a stirred solution of di-tert-butyl (2R,4S)-4-methoxy-5-oxopyrrolidine-1,2-dicarboxylate (23 g) in DCM (240 mL) was added TFA (60 mL) dropwise at 0 °C. The resulting mixture was stirred for 8 h at 30 °C. The reaction mixture was concentrated under reduce pressure. 48 ME153015591v.1 136867-00720 The residue was dissolve in 75 mL DCM and extracted with H2O (75 mL), the aq. layer was washed with DCM (50 mL), then the aq. layer was concentrated under vacuum. The title compound was isolated (9.6 g) as a solid. LCMS [M + H]+m / z: 159.95. Intermediate 7 Step 1. Di-tert-butyl (2R,4S)-4-((tert-butoxycarbonyl)oxy)pyrrolidine-1,2-dicarboxylate To a stirred solution of di-tert-butyl (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (1 g, 3.5 mmol) and DMAP (42.5 mg, 0.4 mmol) in THF (10 mL) were added (Boc)2O (1.5 mL, 7.0 mmol) and TEA (1.5 mL, 10.4 mmol) dropwise at rt. The resulting mixture was stirred for 2 h at rt. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MTBE in PE (0% to 20%) to afford di-tert-butyl (2R,4S)-4-((tert- butoxycarbonyl)oxy)pyrrolidine-1,2-dicarboxylate (1.1 g, 82%) as a solid. LCMS [M + H]+m / z: 388.2. Step 2. Di-tert-butyl (2R,4S)-4-((tert-butoxycarbonyl)oxy)-5-oxopyrrolidine-1,2- dicarboxylate To a stirred solution of di-tert-butyl (2R,4S)-4-((tert-butoxycarbonyl)oxy)pyrrolidine-1,2- dicarboxylate (1.1 g, 2.8 mmol) in ACN (5 mL) and H2O (15 mL) were added NaIO4(1.7 g, 11.4 mmol) and RuCl3.H2O (128 mg, 0.6 mmol) in portions at rt under nitrogen atmosphere. The resulting mixture was stirred for 24 h at rt under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with sat. Na2S2O3 (aq, 2 × 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MTBE in PE (0% to 20%) to afford the title compound (790 mg, 69%) as an oil. LCMS [M + H]+m / z: 402.2. Step 3. (2R,4S)-4-hydroxy-5-oxopyrrolidine-2-carboxylic acid To a stirred solution of di-tert-butyl (2R,4S)-4-((tert-butoxycarbonyl)oxy)-5-oxopyrrolidine- 1,2-dicarboxylate (750 mg, 1.9 mmol) in DCM (8 mL) was added TFA (2 mL) dropwise at 0oC. The resulting mixture was stirred for 16 h at rt. The reaction was monitored by LCMS, and LCMS showed some intermediate A remained. Additional DCM (12 mL) and TFA (3 mL) was added to above reaction mixture. The resulting mixture was stirred for additional 8 h at rt. LCMS showed the completion of the reaction. The reaction mixture was concentrated 49 ME153015591v.1 136867-00720 under reduced pressure. The residue was dissolved in water (40 mL). The aq. layer was washed with DCM (2 × 30 mL) and EA (2 × 30 mL), the aq. layer was concentrated under vacuum. The title compound was isolated (380 mg, crude) as an oil. LCMS [M - H]- m / z: 144.2. Intermediate 8 Step 1. 2-benzyl 1-(tert-butyl) (2R,4R)-4-methoxy-5-oxopyrrolidine-1,2-dicarboxylate To a stirred solution of 2-benzyl 1-(tert-butyl) (2R,4R)-4-hydroxy-5-oxopyrrolidine-1,2- dicarboxylate (2.1 g, 6.3 mmol) and N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (4.0 g, 18.8 mmol) in DCM (50 mL) was added trimethyloxonium tetrafluoroborate (1.9 g, 12.5 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred for 2 h at rt under nitrogen atmosphere. The reaction was quenched by the addition of MeOH (1.3 mL) at rt. The resulting mixture was stirred for 5 min at rt under nitrogen atmosphere. To the above mixture was added 0.5 M HCl (aq, 336 mL) dropwise at rt. The resulting mixture was extracted with EA (400 mL×3). The combined organic layers were dried over anhydrous Na2SO4, concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 40% to 60% gradient in 30 min; detector, UV 254 nm. The title compound was isolated (1.1 g, 50%) as a solid. LCMS [M + H]+m / z: 350.05. Step 2. (2R,4R)-1-(tert-butoxycarbonyl)-4-methoxy-5-oxopyrrolidine-2-carboxylic acid To a solution of 2-benzyl 1-(tert-butyl) (2R,4R)-4-methoxy-5-oxopyrrolidine-1,2- dicarboxylate (717 mg, 2 mmol) in EA (30 mL) was added dry Pd / C (70 mg, 10%) under nitrogen atmosphere. The mixture was hydrogenated at rt for 2 h under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure. The title compound was isolated (800 mg, crude) as an oil. The crude product was used in the next step directly without further purification. LCMS [M + H]+m / z: 260.25. Step 3. (2R,4R)-4-methoxy-5-oxopyrrolidine-2-carboxylic acid A mixture of (2R,4R)-1-(tert-butoxycarbonyl)-4-methoxy-5-oxopyrrolidine-2-carboxylic acid (800 mg, crude) and HCl (4 M in 1,4-dioxane, 8 mL) was stirred for 2 h at rt under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by trituration with ethyl acetate (20 mL). The title compound was isolated (360 mg) as a solid. LCMS [M + H]+m / z: 160.25. 50 ME153015591v.1 136867-00720 Intermediate 9 Step 1. Tert-butyl (2S,3R)-3-(((benzyloxy)carbonyl)amino)-2-hydroxybutanoate A solution of NaOH (2.5 g, 61 mmol) in H2O (150 mL) was prepared in a single-necked, round-bottom flask (500 mL) equipped with a magnetic stir bar. Approximately 20 mL of this solution was transferred into a flask (50 mL) with a Pasteur pipet, and K2OsO2(OH)4(591 mg, 1.6 mmol) was solubilized by gentle swirling. Benzyl carbamate (18.2 g, 120 mmol) was added into 160 mL dry ACN and was stirred vigorously until 90% of the carbamate was in solution (20 min). The reaction flask was immersed in an ice water bath and tert-butyl hypochlorite (13.8 mL, 0.1 mmol) was added dropwise with stirring over a period of 20 min. In a single-necked, round-bottom flask (250 mL), (DHQD)2PHAL (1.6 g, 2.0 mmol) and tert- butyl (E)-but-2-enoate (5.7 g, 40 mmol) were added to dry ACN (140 mL) with stirring. This solution was transferred to the reaction mixture with a Pasteur pipet. The pink K2[OsO2(OH)4] solution was added to the reaction flask and stirred at rt. After 1 h, to the reaction mixture was added Na2SO3 (40 g, 160 mmol) and this reaction mixture was stirred for 45 min. The reaction mixture was concentrated and diluted with water and extracted with EA (4×500 mL). The combined organic layers were dried over Na2SO4, and concentrated to dryness to afford the crude product contaminated by some excess benzyl carbamate. The crude product was further purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford the title compound (1.9 g) as a solid. LCMS [M + H]+m / z: 310.1. Step 2. Tert-butyl (2S,3R)-3-(((benzyloxy)carbonyl)amino)-2- ((methylsulfonyl)oxy)butanoate To a stirred mixture of MsCl (1.8 g, 15.5 mmol) in DCM (70 mL) was added TEA (1.6 g, 15.5 mmol) and tert-butyl (2S,3R)-3-(((benzyloxy)carbonyl)amino)-2-hydroxybutanoate (3.2 g, 10 mmol) in DCM (80 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at rt under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford the title compound (3.6 g) as an oil. LCMS [M + H]+m / z: 388.1. 51 ME153015591v.1 136867-00720 Step 3. 1-benzyl 2-(tert-butyl) (2R,3R)-3-methylaziridine-1,2-dicarboxylate To a stirred mixture of tert-butyl (2S,3R)-3-(((benzyloxy)carbonyl)amino)-2- ((methylsulfonyl)oxy)butanoate (3.6 g, 9.3 mmol) in THF (60 mL) was added t-BuOK (1.6 g, 14 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at rt under nitrogen atmosphere. The reaction was quenched by the addition of water / ice (50 mL) at 0 °C. The resulting mixture was extracted with EA (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford the title compound (1.5 g) as a solid. LCMS [M + H]+m / z: 292.1. Step 4. Tert-butyl (2R,3S)-3-azido-2-(((benzyloxy)carbonyl)amino)butanoate A mixture of 1-benzyl 2-(tert-butyl) (2R,3R)-3-methylaziridine-1,2-dicarboxylate (1.5 g, 5 mmol) and TMSN3(10 mL) in MeOH (10 mL) was stirred for 5 h at 70 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford tert-butyl (2R,3S)-3-azido-2-(((benzyloxy)carbonyl)amino)butanoate (1.2 g) as a solid. LCMS [M + H]+m / z: 335.2. Step 5. Tert-butyl (2R,3S)-2,3-diaminobutanoate To a stirred mixture of tert-butyl (2R,3S)-3-azido-2-(((benzyloxy)carbonyl)amino)butanoate (1.2 g, 3.6 mmol) in MeOH (20 mL) was added Pd / C (10 wt%, 764 mg) at rt under nitrogen atmosphere. The resulting mixture was stirred for 4 h at rt under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with EA (3×10 mL). The filtrate was concentrated under reduced pressure. The title compound was isolated (500 mg) as an oil. LCMS [M + H]+m / z: 175.0. Step 6. Tert-butyl (4R,5S)-5-methyl-2-oxoimidazolidine-4-carboxylate To a stirred mixture of tert-butyl (2R,3S)-2,3-diaminobutanoate (300 mg, 1.7 mmol) and 1 M NaOH (aq, 5.2 mL, 5.2 mmol) in dioxane (5 mL) was added bis(trichloromethyl) carbonate (511 mg, 1.7 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 80 °C under nitrogen atmosphere. The reaction was quenched with water at rt. The resulting mixture was extracted with EA (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The title compound was isolated (290 mg) as an oil. LCMS [M + H]+m / z: 201.1. 52 ME153015591v.1 136867-00720 Step 7. (4R,5S)-5-methyl-2-oxoimidazolidine-4-carboxylic acid To a stirred mixture of tert-butyl (4R,5S)-5-methyl-2-oxoimidazolidine-4-carboxylate (260 mg, 1.3 mmol) in DCM (2 mL) was added TFA (2 mL) dropwise at 0 °C under air atmosphere. The resulting mixture was stirred for 5 h at 70 °C under air atmosphere. The reaction mixture was concentrated under reduced pressure to afford the title compound (150 mg) as an oil. LCMS [M+H]+m / z: 144.9. Intermediate 10 Step 1. Di-tert-butyl (2R)-4-(2-hydroxypropan-2-yl)-5-oxopyrrolidine-1,2-dicarboxylate To a stirred solution of di-tert-butyl (R)-5-oxopyrrolidine-1,2-dicarboxylate in dry THF (15 mL) were added LiHMDS (1.3 M in THF, 6.5 mL, 8.4 mmol) dropwise at -78 ℃ under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 ℃ under nitrogen atmosphere. To the above mixture was added propan-2-one (0.5 g, 7.7 mmol) and BF3.Et2O (1.1 g, 7.7 mmol) in dry THF (15 mL) dropwise at -78 ℃. The resulting mixture was stirred for additional 2.5 h at -78 ℃. The reaction was quenched with sat. NH4Cl (aq.) at -78 ℃. The resulting mixture was extracted with Et2O (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The title compound was isolated (3 g) as an oil. The crude product was used in the next step directly without further purification. LCMS [M + H]+m / z: 344.3. Step 2. Di-tert-butyl (R)-5-oxo-4-(propan-2-ylidene)pyrrolidine-1,2-dicarboxylate To a stirred solution of di-tert-butyl (2R)-4-(2-hydroxypropan-2-yl)-5-oxopyrrolidine-1,2- dicarboxylate (3 g, 8.7 mmol) and Et3N (1.8 g, 17.5 mmol) in dry DCM (30 mL) were added MsCl (1.1 g, 9.6 mmol) dropwise at 0 ℃ under nitrogen atmosphere. The resulting mixture was stirred for 48 h at rt under nitrogen atmosphere. The reaction was quenched with sat. NaHCO3 (aq.) at 0 ℃. The resulting mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 40% to 70% gradient in 30 min; detector, UV 254 nm. The title compound was isolated (150 mg) as an oil. LCMS [M + H]+m / z: 326.0. 53 ME153015591v.1 136867-00720 Step 3. (R)-5-oxo-4-(propan-2-ylidene)pyrrolidine-2-carboxylic acid A mixture of di-tert-butyl (R)-5-oxo-4-(propan-2-ylidene)pyrrolidine-1,2-dicarboxylate (50 mg, 0.2 mmol) and 4 M HCl in 1,4-dioxane (2 mL) was stirred for 8 h at rt. The resulting mixture was concentrated under reduced pressure. The title compound was isolated (25 mg) as an oil. The crude product was used in the next step directly without further purification. LCMS [M + H]+m / z: 170.1. Intermediate 11 The title compound was prepared from di-tert-butyl (S)-5-oxopyrrolidine-1,2-dicarboxylate using an identical sequence to Intermediate 10. Intermediate 12 Step 1. Tert-butyl (1R,2R,5S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-oxo-3- azabicyclo[3.1.0]hexane-3-carboxylate To a stirred mixture of 1-methyl-1-nitrosourea (4.0 g, 39.1 mmol) in Et2O (100 mL) was added KOH (15.4 g, 275 mmol) in H2O (60 mL) dropwise at -10 ℃ under nitrogen atmosphere. The resulting mixture was stirred for 30 min at -10 ℃ and then the organic solution was separated. To a stirred mixture of tert-butyl (R)-2-(((tert- butyldimethylsilyl)oxy)methyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (1000 mg, 3.1 mmol) and Pd(OAc)2 (69 mg, 0.3 mmol) in Et2O (10 mL) was added above organic solution dropwise at -10 ℃ under nitrogen atmosphere. The resulting mixture was stirred for 1 h at - 10 ℃ under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford the title compound (600 mg) as an oil. LCMS [M + H]+m / z: 342.1. Step 2. (1R,2R,5S)-3-(tert-butoxycarbonyl)-4-oxo-3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a stirred solution of tert-butyl (1R,2R,5S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-oxo- 3-azabicyclo[3.1.0]hexane-3-carboxylate (500 mg, 1.5 mmol) in acetone (10 mL) were added Jones reagent (1.5 mL, 2.9 mmol) dropwise at 0 ℃ under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 0 ℃ under nitrogen atmosphere. The reaction was quenched by 54 ME153015591v.1 136867-00720 addition of isopropyl (50 mL) and sat. NaHCO3 (aq.) (20 mL) at 0 ℃. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in H2O (50 mL) and EA (10 mL). The resulting mixture was washed with Et2O (3×50 mL). The aq. layer was collected and acidified to pH 3 with HCl (0.1 M, aq.). The aq. layer was extracted with EA (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The title compound was isolated (300 mg) as a solid. LCMS [M + H]+m / z: 242.2. Step 3. (1R,2R,5S)-4-oxo-3-azabicyclo[3.1.0]hexane-2-carboxylic acid A mixture of (1R,2R,5S)-3-(tert-butoxycarbonyl)-4-oxo-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (150 mg, 0.6 mmol) and HCl (4 M in 1,4-dioxane, 5 mL) was stirred for 2 h at rt. The resulting mixture was concentrated under reduced pressure. The title compound was isolated (150 mg) as an oil. LCMS [M + H]+m / z: 141.9. Intermediate 13 Step 1. (S)-2-oxothiazolidine-4-carboxylic acid To a stirred solution of D-Cysteine hydrochloride hydrate (500 mg, 2.8 mmol) and NaOH (569.3 mg, 14.2 mmol) in H2O (2.8 mL) was added phenyl carbonochloridate (0.8 mL, 6.2 mmol) in toluene (1.2 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at rt. The reaction mixture was quenched with toluene (1.2 mL) and H2O (1.2 mL) at rt. The aq. layer was washed with toluene (3×5 mL). The aq. layer was acidified to pH 1 with 1 N HCl (aq.). The resulting mixture was extracted with EA (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The title compound was isolated (293 mg) as a solid. LCMS [M + H]+m / z: 148.1. Intermediate 14 Step 1. (R)-2-((tert-butoxycarbonyl)amino)-3-(pyrimidin-2-ylamino)propanoic acid To a stirred mixture of (R)-3-amino-2-((tert-butoxycarbonyl)amino)propanoic acid (2 g, 9.8 mmol) and 2-chloropyrimidine (1.1 g, 9.8 mmol) in n-BuOH (30 mL) was added TEA (4.1 mL, 29.4 mmol) dropwise at rt under nitrogen atmosphere. The resulting mixture was stirred 55 ME153015591v.1 136867-00720 for 2 h at 110 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The title compound was isolated (1.5 g) as a solid. LCMS [M + H]+m / z: 283.2. Step 2. (R)-2-amino-3-(pyrimidin-2-ylamino)propanoic acid hydrochloride To a stirred solution of (R)-2-((tert-butoxycarbonyl)amino)-3-(pyrimidin-2- ylamino)propanoic acid (778 mg, 2.8 mmol) in DCM (5 mL) was added HCl (4 M in EA, 5 mL) dropwise at rt. The resulting mixture was stirred for 1 h at rt. The reaction mixture was concentrated under reduced pressure. The title compound was isolated (680 mg) as a solid. LCMS [M + H]+m / z: 183.2. Step 3. (R)-2-oxo-1-(pyrimidin-2-yl)imidazolidine-4-carboxylic acid To a stirred solution of (R)-2-amino-3-(pyrimidin-2-ylamino)propanoic acid hydrochloride (500 mg, 2.3 mmol) in ACN (8 mL) was added TEA (1.6 mL, 11.4 mmol) dropwise at 0 °C. The resulting mixture was stirred for 10 min at 0 °C. To the above mixture was added CDI (556.2 mg, 3.4 mmol) at 0 °C. The resulting mixture was stirred for additional 3 h at rt. The reaction mixture was acidified to pH 5 with formic acid and concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in Water (0.1% FA), 5% to 30% gradient in 20 min; detector, UV 254 nm. The title compound was isolated (110 mg) as a solid. LCMS [M + H]+m / z: 209.1. Intermediate 14 Step 1. 2-((benzyloxy)methyl)-2,3-dihydro-4H-pyran-4-one To a stirred solution of 2-(benzyloxy)acetaldehyde (34 g, 226.4 mmol) in toluene (310 mL) was added (E)-((4-methoxybuta-1,3-dien-2-yl)oxy)trimethylsilane (39 g, 226.4 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred for 15 min at rt under nitrogen atmosphere. To the above mixture was added ZnCl2 (0.5 M in THF, 226.4 mL, 113.2 mmol) dropwise at 0 °C. The resulting mixture was stirred for additional 16 h at rt. The reaction mixture was concentrated under reduced pressure. The resulting mixture was dissolved in EA (400 mL). The resulting mixture was washed with 1 N HCl (aq, 3 × 200 mL), sat. NaHCO3 56 ME153015591v.1 136867-00720 (aq, 3 × 200 mL) and brine (3 × 200 mL). The organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-50%) to afford 2- ((benzyloxy)methyl)-2,3-dihydro-4H-pyran-4-one (37 g) as an oil. LCMS [M + H]+m / z: 219.2. Step 2. 2-((benzyloxy)methyl)tetrahydro-4H-pyran-4-one To a stirred solution of 2-((benzyloxy)methyl)-2,3-dihydro-4H-pyran-4-one (40.8 g, 186.9 mmol) and TEA (26 mL, 186.9 mmol) in EA (450 mL) was added Pd / C (10% wt, 4 g, 3.7 mmol) under nitrogen. The resulting mixture was hydrogenated at rt for 4 h under hydrogen atmosphere. The reaction was monitored by TLC (PE / EA = 2:1). The resulting mixture was filtered, and the filter cake was washed with EA (3 × 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MTBE in PE (0-10%) to afford 2-((benzyloxy)methyl)tetrahydro-4H-pyran-4-one (39 g) as an oil. LCMS [M + H]+m / z: 221.2. Step 3. ((2-((benzyloxy)methyl)-3,6-dihydro-2H-pyran-4-yl)oxy)(tert- butyl)dimethylsilane To a stirred solution of 2-((benzyloxy)methyl)tetrahydro-4H-pyran-4-one (37 g, 168 mmol) and TEA (46.7 mL, 336 mmol) in DCM (370 mL) was added a solution of TBSOTf (66.6 g, 252 mmol) in DCM (180 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at rt under nitrogen atmosphere. The reaction mixture was diluted with water (400 mL). The resulting mixture was extracted with DCM (3 × 400 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MTBE in PE (0%-15%) to afford the title compound (54.8 g) as an oil. LCMS [M + H]+m / z: 335.2. Step 4. Rac-(2R,5S)-2-((benzyloxy)methyl)-5-fluorotetrahydro-4H-pyran-4-one To a stirred solution of ((2-((benzyloxy)methyl)-3,6-dihydro-2H-pyran-4-yl)oxy)(tert- butyl)dimethylsilane (49 g, 146.5 mmol) in DMF (500 mL) was added Selectfluor (77.8 g, 219.7 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at rt under nitrogen atmosphere. The reaction was monitored by TLC (PE / EA = 2:1). The reaction mixture was diluted with water (500 mL). The resulting mixture was extracted with EA (3 × 350 mL). The combined organic layers were washed with brine (3 × 600 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. 57 ME153015591v.1 136867-00720 The residue was purified by silica gel column chromatography, eluted with MTBE in PE (0%-30%) to afford the title compound (12 g) as an oil. LCMS [M + H]+m / z: 239.2. Step 5. Rac-(2R,4R,5R)-N-benzyl-2-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran- 4-amine To a stirred solution of rac-(2R,5S)-2-((benzyloxy)methyl)-5-fluorotetrahydro-4H-pyran-4- one (2 g, 8.4 mmol) and BnNH2(944.5 mg, 8.8 mmol) in MeOH (20 mL) was added AcOH (0.5 mL, 8.4 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred for 30 min at rt under nitrogen atmosphere. To the above mixture was added NaBH3CN (791.2 mg, 12.6 mmol) in portions at 0 °C. The resulting mixture was stirred for additional 1 h at rt. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 45% to 60% gradient in 20 min; detector, UV 220 nm. The title compound was isolated as an oil. LCMS [M + H]+m / z: 330.0. Step 6. Rac-((2R,4R,5R)-4-(benzylamino)-5-fluorotetrahydro-2H-pyran-2-yl)methanol To a stirred solution of rac-(2R,4R,5R)-N-benzyl-2-((benzyloxy)methyl)-5-fluorotetrahydro- 2H-pyran-4-amine (190 mg, 0.6 mmol) in DCM (6 mL) was added BCl3(1 M in DCM, 1.2 mL, 1.2 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0 °C under nitrogen atmosphere. The reaction was quenched by the addition of MeOH (2 mL) at 0 °C. The resulting mixture was diluted with sat. NaHCO3 (aq, 10 mL) and then extracted with DCM (3 × 15 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 5% to 50% gradient in 20 min; detector, UV 254 nm. The title compound was isolated (120 mg) as an oil. LCMS [M + H]+m / z: 240.0. Step 7. Rac-(2R,4R,5R)-N-benzyl-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5- fluorotetrahydro-2H-pyran-4-amine To a stirred solution of rac-((2R,4R,5R)-4-(benzylamino)-5-fluorotetrahydro-2H-pyran-2- yl)methanol (120 mg, 0.5 mmol) and TEA (0.2 mL, 1.5 mmol) in DCM (3 mL) was added DMAP (12.3 mg, 0.1 mmol) and TBDPSCl (344.6 mg, 1.3 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred for 1 h at rt under nitrogen atmosphere. The reaction mixture was quenched with sat. NaHCO3 (aq, 10 mL). The resulting mixture was extracted with DCM (3 × 15 mL). The combined organic layers were dried over anhydrous 58 ME153015591v.1 136867-00720 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 5% to 95% gradient in 20 min; detector, UV 254 nm. The title compound was isolated as an oil. LCMS [M + H]+m / z: 478.4. Step 8. Rac-(2R,4R,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-fluorotetrahydro-2H- pyran-4-amine To a solution of rac-(2R,4R,5R)-N-benzyl-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5- fluorotetrahydro-2H-pyran-4-amine (240 mg, 0.5 mmol) in iPrOH (3 mL) was added Pd / C (10% wt, 106.9 mg, 0.1 mmol) under nitrogen atmosphere in a 10 mL 2-necked round- bottom flask. The mixture was hydrogenated at rt for 16 h under hydrogen atmosphere using a hydrogen balloon. The reaction mixture was filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 60% to 90% gradient in 20 min; detector, UV 254 nm. The title compound was isolated (50 mg) as an oil. LCMS [M + H]+m / z: 388.2. Intermediate 15 Step 1. (((1S, 5R)-8-oxabicyclo[3.2.1]oct-2-en-3-yl)oxy)trimethylsilane To a stirred solution of (S)-bis((S)-1-phenylethyl)amine (5.3 g, 23.7 mmol) in THF (160 mL) was added n-BuLi (2.5 M in hexane, 9.5 mL, 23.7 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at rt under nitrogen atmosphere. To the above mixture was added TMSCl (10.1 mL, 79.2 mmol) dropwise at -78 °C. The resulting mixture was stirred for additional 2 min at -78 °C. To the above mixture was added the solution of 8-oxabicyclo[3.2.1]octan-3-one (2 g, 15.8 mmol) in THF (16 mL) dropwise at -78 °C. The resulting mixture was stirred for additional 6 h at -78 °C. The resulting mixture was poured into sat. NaHCO3 (aq, 400 mL) at 0 °C. The resulting mixture was extracted with PE (3 × 400 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MTBE in PE (0%-20%) to afford the title compound (1.2 g) as an oil. LCMS [M + H]+m / z: 199.0. 59 ME153015591v.1 136867-00720 Step 2. (1S, 5R)-2-fluoro-8-oxabicyclo[3.2.1]octan-3-one To a stirred solution of (((1S,5R)-8-oxabicyclo[3.2.1]oct-2-en-3-yl)oxy)trimethylsilane (5.3 g, 26.7 mmol) in DMF (40 mL) was added Selectfluor (14.2 g, 40.0 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0 °C under nitrogen atmosphere. The reaction mixture was diluted with water (120 mL). The resulting mixture was extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (600 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MTBE in PE (0%-80%) to afford the title compound (2 g) as an oil. LCMS [M + H]+m / z: 145.0. Step 3. (1S,2S,3S,5R)-N-benzyl-2-fluoro-8-oxabicyclo[3.2.1]octan-3-amine. To a stirred solution of (1S,5R)-2-fluoro-8-oxabicyclo[3.2.1]octan-3-one (1.8 g, 12.4 mmol) in DCE (20 mL) was added benzylamine (1.4 g, 13.1 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 10 min at 0 °C under nitrogen atmosphere. To the above mixture was added NaBH(OAc)3 (3.7 g, 17.4 mmol) and AcOH (0.7 g, 12.4 mmol) at 0 °C. The resulting mixture was stirred for additional 2 h at rt. The reaction mixture was poured into 1 N NaOH (aq, 60 mL). The aq. layer was extracted with DCM (3 × 60 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 25% to 70% gradient in 40 min; detector, UV 254 nm. The title compound was isolated (200 mg) as an oil. LCMS [M + H]+m / z: 236.0. Step 4. (1S,2S,3S,5R)-2-fluoro-8-oxabicyclo[3.2.1]octan-3-amine To a solution of (1S,2S,3S,5R)-N-benzyl-2-fluoro-8-oxabicyclo[3.2.1]octan-3-amine (300 mg, 1.3 mmol) in EtOH (5 mL) was added Pd / C (10 wt %, 27.1 mg, 0.03 mmol) under nitrogen atmosphere in a 10 mL 2-necked round-bottom flask. The mixture was hydrogenated at rt for 3 h under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure. The filter cake was washed with ACN (3 × 3 mL). The filtrate was concentrated under reduced pressure. The title compound was isolated (100 mg) as a solid. LCMS [M + H]+m / z: 146.3. 60 ME153015591v.1 136867-00720 Intermediate 16 Step 1. Tert-butyl ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)carbamate To a stirred solution of (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (2.5 g, 12.2 mmol) in DCM (25 mL) were added TEA (6.8 mL, 48.8 mmol) and Boc2O (3.13 mL, 14.6 mmol) in portions at 0 °C. The resulting mixture was stirred for 3 h at rt. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (5%-15%) to afford tert-butyl ((3S,4R)- 3-fluoro-1-methylpiperidin-4-yl)carbamate (2.4 g) as a solid. LCMS [M + H]+m / z: 233.2. Step 2. Tert-butyl ((4R,5S)-5-fluoro-1-methyl-2-oxopiperidin-4-yl)carbamate To a stirred solution of tert-butyl ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)carbamate (2.4 g, 10.3 mmol) in EA (60 mL) was added RuCl3(642.9 mg, 3.1 mmol) at rt under nitrogen atmosphere. To the above mixture was added a solution of NaIO4 (11.1 g, 51.7 mmol) in water (60 mL) dropwise at 0 °C. The resulting mixture was stirred for additional 1 h at rt. The reaction was quenched by the addition of sat. Na2S2O3(aq, 5 mL) at 0 °C. The resulting mixture was diluted with water (20 mL) and then extracted with EA (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 40% gradient in 10 min; detector, UV 220 nm. The title compound was isolated (620 mg) as an oil. LCMS [M + H]+m / z: 247.2. Step 3. (4R,5S)-4-amino-5-fluoro-1-methylpiperidin-2-one hydrochloride A mixture of tert-butyl ((4R,5S)-5-fluoro-1-methyl-2-oxopiperidin-4-yl)carbamate (620 mg, 2.5 mmol) and HCl (4 M in 1,4-dioxane, 8 mL) was stirred for 2 h at rt. The resulting mixture was concentrated under reduced pressure. The title compound was isolated (500 mg) as a solid. The crude product was used in the next step directly without further purification. LCMS [M + H]+m / z: 147.0. Intermediate 17 Step 1. Tert-butyl (R)-2-carbamoyl-5-oxopyrrolidine-1-carboxylate To a stirred solution of (R)-1-(tert-butoxycarbonyl)-5-oxopyrrolidine-2-carboxylic acid (400 mg, 1.7 mmol) in ACN (10 mL) were added HOBt (282.9 mg, 2.1 mmol) and EDCI (401.4 61 ME153015591v.1 136867-00720 mg, 2.1 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 6 h at rt under nitrogen atmosphere. To the above mixture was added NH3 (28 wt% in H2O, 2 mL, 14.3 mmol) dropwise at 0 °C. The resulting mixture was stirred for additional 16 h at rt. The reaction mixture was filtered, the filter cake was washed with ACN (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in Water (10 mmol / L NH4HCO3), 0% to 25% gradient in 30 min; detector, UV 220 nm. The title compound was isolated (130 mg) as a solid. LCMS [M + H]+m / z: 229.0. Intermediate 18 Step 1. Methyl (3-methoxy-1-methyl-1H-pyrazole-4-carbonyl)glycinate To a stirred mixture of 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid (5 g, 32 mmol) and methyl glycinate hydrochloride (4.82 g, 38.4 mmol) in DMF (50 mL) were added EDCI (12.3 g, 64 mmol), HOBT (8.7 g, 64 mmol), and DIEA (41.4 g, 320 mmol) dropwise at rt under nitrogen atmosphere. The resulting mixture was stirred at 30 ℃ for 2 h. The reaction mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 5% to 30% gradient in 30 min; detector, UV 254 nm. The title compound was isolated (6 g, 82%) as a solid. LCMS [M + H]+m / z: 228.0. Step 2. (3-hydroxy-1-methyl-1H-pyrazole-4-carbonyl)glycine A mixture of methyl (3-methoxy-1-methyl-1H-pyrazole-4-carbonyl)glycinate (880 mg, 3.9 mmol) in AcOH (8 mL) and HBr (48 wt% in water, 2 mL) was stirred at 90 ℃ for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The title compound was isolated (1.2 g, crude) as a solid. The crude was used in the next step directly without further purification. LCMS [M + H]+m / z: 200.0. Step 3. Methyl-d3 (3-(methoxy-d3)-1-methyl-1H-pyrazole-4-carbonyl)glycinate To a stirred mixture of (3-hydroxy-1-methyl-1H-pyrazole-4-carbonyl)glycine (1.1 g, 3.9 mmol) and K2CO3 (2.7 g, 19.6 mmol) in DMF (20 mL) was added CD3I (1.1 g, 7.9 mmol) dropwise at 0 °C. The resulting mixture was stirred at rt for 2 h. The reaction mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 5% to 40% gradient in 20 min; detector, 62 ME153015591v.1 136867-00720 UV 254 nm. The title compound was isolated (120 mg) as a solid. LCMS [M + H]+m / z: 234.3. In Step 1. Dibenzyl (R)-2-oxoimidazolidine-1,5-dicarboxylate To a stirred mixture of (R)-3-((benzyloxy)carbonyl)-2-oxoimidazolidine-4-carboxylic acid (1 g, 3.8 mmol) and PTSA (0.1 g, 0.8 mmol) in toluene (10 mL) was added phenylmethanol (1.0 g, 9.5 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred for 48 h at 110 °C. To the above reaction mixture was added 10 mL NaHCO3(2 M, aq.). Then the resulting mixture was extracted with EA (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford dibenzyl (R)-2-oxoimidazolidine- 1,5-dicarboxylate (200 mg) as an oil. LCMS [M + H]+m / z: 355.0. Step 2. Dibenzyl (R)-3-methyl-2-oxoimidazolidine-1,5-dicarboxylate To a stirred mixture of (R)-2-oxoimidazolidine-1,5-dicarboxylate (200 mg, 0.6 mmol) and K2CO3 (234 mg, 1.7 mmol) in acetone (4 mL) was added MeI (401 mg, 2.8 mmol) dropwise at rt under nitrogen atmosphere. The resulting mixture was stirred for 48 h at 60 °C. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford dibenzyl (R)-3-methyl-2- oxoimidazolidine-1,5-dicarboxylate (80 mg) as an oil. LCMS [M + H]+m / z: 369.1. Step 3. (R)-1-methyl-2-oxoimidazolidine-4-carboxylic acid To a stirred mixture of dibenzyl (R)-3-methyl-2-oxoimidazolidine-1,5-dicarboxylate (80 mg, 0.2 mmol) in MeOH (3 mL) was added dry Pd / C (10 wt%, 18 mg, 0.02 mmol) at rt under N2. The resulting mixture was stirred for 1 h at rt under hydrogen atmosphere. The reaction mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The title compound was isolated as a solid (40 mg) and was used directly in the next step without further purification. LCMS [M + H]+m / z: 145.1. 63 ME153015591v.1 136867-00720 Intermediate 20-1 Step 1. 7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophene-2-carbonitrile To a stirred mixture of 7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophene-2-carbonitrile (150 mg, 0.5 mmol), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (136.5 mg, 0.7 mmol) and Cs2CO3(578.1 mg, 1.8 mmol) in dioxane (2 mL) was added Pd-PEPPSI- IHeptCl (CAS: 1814936-54-3) (46.6 mg, 0.1 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 90 °C under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford the title compound (65 mg) as a solid. The following compounds were prepared from the appropriate intermediates by similar methods as described for Intermediate 20-1 above: 64 ME153015591v.1 136867-00720 65 ME153015591v.1 136867-00720 66 ME153015591v.1 136867-00720 67 ME153015591v.1 136867-00720 68 ME153015591v.1 136867-00720 69 ME153015591v.1 136867-00720 Example 1-1 Step 1. 7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophene-2-carbonitrile To a stirred mixture of 7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophene-2-carbonitrile (150 mg, 0.5 mmol), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (136.5 mg, 0.7 mmol) and Cs2CO3(578.1 mg, 1.8 mmol) in dioxane (2 mL) was added Pd-PEPPSI- IHeptCl (CAS: 1814936-54-3) (46.6 mg, 0.1 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 90 °C under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford the title compound (65 mg) as a solid. LCMS [M + H]+m / z: 390.0. Step 2. (Z)-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-N'-hydroxy-3- ((trifluoromethyl)thio)benzo[b]thiophene-2-carboximidamide To a stirred mixture of 7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophene-2-carbonitrile (65 mg, 0.2 mmol) in EtOH (2 mL) was added NH2OH (50 wt% in water, 2 mL) dropwise at rt. The resulting mixture was stirred for 3 h at rt. The resulting mixture was concentrated under reduced pressure. The 70 ME153015591v.1 136867-00720 residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 40% to 60% gradient in 20 min; detector, UV 254 nm. The title compound was isolated (50 mg) as a solid. LCMS [M + H]+m / z: 423.2. Step 3. (R)-4-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)imidazolidin-2-one To a stirred mixture of (Z)-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-N'-hydroxy- 3-((trifluoromethyl)thio)benzo[b]thiophene-2-carboximidamide (45 mg, 0.1 mmol), (R)-2- oxoimidazolidine-4-carboxylic acid (20.8 mg, 0.2 mmol), EDCI (30.6 mg, 0.2 mmol) and HOBt (17.3 mg, 0.1 mmol) in dioxane (3 mL) was added i-Pr2NH (21.6 mg, 0.2 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred for 4 h at at 80 °C under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile Phase B: MeOH; 55% to 70% gradient in 20 min; detector, UV 254 nm. The title compound was isolated (7.7 mg) as a solid. LCMS [M + H]+m / z: 517.1. The compounds in the table below were synthesized as described in Example 1-1 from appropriate intermediates. 71 ME153015591v.1 136867-00720 72 ME153015591v.1 136867-00720 73 ME153015591v.1 136867-00720 74 ME153015591v.1 136867-00720 75 ME153015591v.1 136867-00720 76 ME153015591v.1 136867-00720 77 ME153015591v.1 136867-00720 78 ME153015591v.1 136867-00720 79 ME153015591v.1 136867-00720 80 ME153015591v.1 136867-00720 81 ME153015591v.1 136867-00720 82 ME153015591v.1 136867-00720 83 ME153015591v.1 136867-00720 84 ME153015591v.1 136867-00720 85 ME153015591v.1 136867-00720 86 ME153015591v.1 136867-00720 87 ME153015591v.1 136867-00720 88 ME153015591v.1 136867-00720 89 ME153015591v.1 136867-00720 90 ME153015591v.1 136867-00720 91 ME153015591v.1 136867-00720 92 ME153015591v.1 136867-00720 93 ME153015591v.1 136867-00720 94 ME153015591v.1 136867-00720 95 ME153015591v.1 136867-00720 96 ME153015591v.1 136867-00720 97 ME153015591v.1 136867-00720 98 ME153015591v.1 136867-00720 99 ME153015591v.1 136867-00720 100 ME153015591v.1 136867-00720 101 ME153015591v.1 136867-00720 102 ME153015591v.1 136867-00720 103 ME153015591v.1 136867-00720 104 ME153015591v.1 136867-00720 105 ME153015591v.1 136867-00720 Example 2 106 ME153015591v.1 136867-00720 Step 1. (R)-5-(3-(7-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-2-one To a stirred solution of tert-butyl (3S,4R)-3-fluoro-4-((2-(5-((R)-5-oxopyrrolidin-2-yl)-1,2,4- oxadiazol-3-yl)-3-((trifluoromethyl)thio)benzo[b]thiophen-7-yl)amino)pyrrolidine-1- carboxylate (200 mg, 0.3 mmol) in DCM (4 mL) was added TFA (1 mL) dropwise at 0 °C under air atmosphere. The resulting mixture was stirred for 1 h at rt. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 5% to 60% gradient in 30 min; detector, UV 254 nm. The title compound was isolated (150 mg) as a solid. LCMS [M + H]+m / z: 488.1. Step 2. (R)-5-(3-(7-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-2-one To a stirred solution of (R)-5-(3-(7-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-2-one (60 mg, 0.1 mmol) in MeOH (5 mL) was added 2 drops of AcOH (cat.). The above mixture was stirred for 10 min at rt, and then HCHO (37 wt% aq, 9 mg, 0.1 mmol) in MeOH (0.5 mL) was added. The resulting mixture was stirred for 30 min at rt. Then NaBH3CN (15 mg, 0.2 mmol) was added at 0 °C. The resulting mixture was stirred for additional 30 min at rt. The reaction mixture was quenched with water at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 30% to 50% gradient in 30 min; detector, UV 254 nm. The title compound was isolated (40 mg) as a solid. LCMS [M + H]+m / z: 502.10. The compounds in the table below were synthesized as described in Example 2 from appropriate intermediates. 107 ME153015591v.1 136867-00720 108 ME153015591v.1 136867-00720 109 ME153015591v.1 136867-00720 110 ME153015591v.1 136867-00720 111 ME153015591v.1 136867-00720 112 ME153015591v.1 136867-00720 113 ME153015591v.1 136867-00720 114 ME153015591v.1 136867-00720 115 ME153015591v.1 136867-00720 116 ME153015591v.1 136867-00720 117 ME153015591v.1 136867-00720 118 ME153015591v.1 136867-00720 119 ME153015591v.1 136867-00720 120 ME153015591v.1 136867-00720 121 ME153015591v.1 136867-00720 122 ME153015591v.1 136867-00720 123 ME153015591v.1 136867-00720 124 ME153015591v.1 136867-00720 125 ME153015591v.1 136867-00720 126 ME153015591v.1 136867-00720 Example 3 Step 1. cyclopropyl (3S,4R)-3-fluoro-4-((2-(5-((R)-2-oxoimidazolidin-4-yl)-1,2,4- oxadiazol-3-yl)-3-((trifluoromethyl)thio)benzo[b]thiophen-7-yl)amino)piperidine-1- carboxylate To a stirred solution of (R)-4-(3-(7-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)imidazolidin-2-one (20 mg, 0.04 mmol) in pyridine (0.5 mL) was added the crude DCE solution of cyclopropyl carbonochloridate (10 mg / mL in DCE, 0.96 mL, 0.08 mmol) dropwise at 0 ℃ under nitrogen atmosphere. The resulting mixture was stirred for 2 h at rt under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 50% to 70% gradient in 20 min; detector, UV 254 127 ME153015591v.1 136867-00720 nm. This resulted in 20 mg crude product. The crude product was further purified by prep- HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column 30*150 mm, 5 µm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 49% B to 69% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 11.63. The title compound was isolated (9.9 mg) as a solid. The compounds in the table below were synthesized as described in Example 3 from appropriate intermediates. 128 ME153015591v.1 136867-00720 129 ME153015591v.1 136867-00720 130 ME153015591v.1 136867-00720 131 ME153015591v.1 136867-00720 132 ME153015591v.1 136867-00720 Example 4 Step 1. (3S,5R)-5-(3-(7-(((1S,2R,3R,5R)-2-fluoro-8-(2-hydroxy-2-methylpropyl)-8- azabicyclo[3.2.1]octan-3-yl)amino)-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)- 1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidin-2-one A solution of (3R,5R)-5-(3-(7-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl)amino)-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)-3- hydroxypyrrolidin-2-one (40 mg, 0.1 mmol) in 2,2-dimethyloxirane (3 mL) was stirred for 16 h at 50 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC with the following conditions: Column: 133 ME153015591v.1 136867-00720 XBridge Prep Phenyl OBD Column 19*250 mm, 5 µm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 35% B to 50% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 12.23. The title compound was isolated (25.3 mg) as a solid. The compounds in the table below were synthesized as described in Example 4 from appropriate intermediates. 134 ME153015591v.1 136867-00720 Example 5 135 ME153015591v.1 136867-00720 Step 1. tert-butyl ((R)-1-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)-2- hydroxyethyl)carbamate To a stirred mixture of (Z)-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-N'-hydroxy- 3-((trifluoromethyl)thio)benzo[b]thiophene-2-carboximidamide (200 mg, 0.5 mmol) and (tert-butoxycarbonyl)-D-serine (146 mg, 0.7 mmol) in dioxane (5 mL) were added EDCI (136 mg, 0.7 mmol), HOBt (77 mg, 0.6 mmol) and diisopropylamine (96 mg, 1.0 mmol) at rt. The resulting mixture was stirred for 1 h at 50 °C, then additional 16 h at 80 °C. The reaction mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 50% to 70% gradient in 20 min; detector, UV 254 nm. The title compound was isolated (130 mg, 47%) as a solid. LCMS [M + H]+m / z: 592.20. Step 2. tert-butyl ((R)-1-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)-2- (methylamino)ethyl)carbamate To a stirred solution of tert-butyl ((R)-1-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)-2- hydroxyethyl)carbamate (130 mg, 0.2 mmol) in dry DCM (2 mL) were added TEA (67 mg, 0.7 mmol) and MsCl (38 mg, 0.3 mmol) at 0 °C. The resulting mixture was stirred for 2 h at rt. To the above mixture was added methylamine (2 M in THF, 5 mL) at rt. The resulting mixture was stirred for additional 1 h at rt. The reaction mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 15 min; detector, UV 254 nm. The title compound was isolated (80 mg, 60%) as a solid. LCMS [M + H]+m / z: 605.20. 136 ME153015591v.1 136867-00720 Step 3. (R)-1-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)-N2-methylethane- 1,2-diamine To a stirred solution of tert-butyl ((R)-1-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)-2- (methylamino)ethyl)carbamate (80 mg, 0.1 mmol) in DCM (4 mL) were added TFA (1 mL) at 0 °C. The resulting mixture was stirred for 2 h at rt. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The title compound was isolated (40 mg, 60%) as a solid. LCMS [M + H]+m / z: 505.25. Step 4. N-((E)-4-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)-1- methylimidazolidin-2-ylidene)cyanamide To a stirred solution of (R)-1-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)-N2-methylethane-1,2- diamine (50 mg, 0.1 mmol) in EtOH (3 mL) was added diphenyl cyanocarbonimidate (35 mg, 0.2 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C. The reaction mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 40% to 60% gradient in 30 min; detector, UV 254 nm. The title compound was isolated (6 mg, 11%) as a solid. The compounds in the table below were synthesized as described in Example 5 from appropriate intermediates. 137 ME153015591v.1 136867-00720 Example 6 Step 6. (R)-5-(3-(7-(((3R,4S)-4-fluoro-1-methylpiperidin-3-yl)amino)-3- ((trifluoromethyl)sulfonyl)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-2-one To a stirred solution of (R)-5-(3-(7-(((3R,4S)-4-fluoro-1-methylpiperidin-3-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-2-one (100 mg, 0.2 mmol) in EA (2.4 mL) was added a solution of NaIO4(207.4 mg, 1.0 mmol) in H2O (1.8 mL) at 0 °C under nitrogen atmosphere. To the above mixture was added RuO2.H2O (4.4 mg, 0.03 mmol) in portions at 0 °C. The resulting mixture was stirred for additional 6 h at rt. The reaction mixture was extracted with EA (3 × 2 mL).The combined organic layers were dried over anhydrous Na2SO4, then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 40% to 60% gradient in 20 min; detector, UV 254 / 220 nm. The title compound was isolated (2.3 mg) as a solid. LCMS [M + H]+m / z: 548.151H NMR (400 MHz, Methanol-d4) δ 7.76 (d, J = 8.2 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H), 5.22 (dd, J = 8.6, 3.3 Hz, 1H), 5.05 – 4.70 (m, 1H), 3.96 (dd, J = 26.4, 10.1 Hz, 1H), 2.91 (dd, J = 11.8, 4.4 Hz, 1H), 2.81 – 2.66 (m, 2H), 2.64 – 2.52 (m, 1H), 2.51 – 2.35 (m, 7H), 2.20 – 2.05 (m, 1H), 2.03 – 1.86 (m, 1H).19F NMR (377 MHz, Methanol- d4) δ -79.06, -204.63. 138 ME153015591v.1 136867-00720 Example 7 Step 1. 7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophene-2-carboxylic acid. To a stirred mixture of KOH (3.9 g, 69.3 mmol) in H2O (18 mL) was added a solution of 7- (((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophene-2-carbonitrile (900 mg, 2.3 mmol) in MeOH (18 mL) dropwise at 0 °C. The resulting mixture was stirred for 1.5 h at 80 °C. The reaction mixture was allowed to cool down to rt. The above mixture was acidified to pH 3 with conc. HCl (aq.). The resulting mixture was concentrated under reduced pressure. The title compound was isolated (6 g, crude) as a solid. The crude product was used in the next step directly without further purification. LCMS [M + H]+m / z: 409.1. Step 2. Methyl 7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophene-2-carboxylate. To a stirred mixture of 7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophene-2-carboxylic acid (6 g, crude) in MeOH (30 mL, 740.9 mmol) was added conc. H2SO4 (3 mL, 56.3 mmol) dropwise at 0 °C. The resulting mixture was stirred for 4 h at 80 °C. The reaction mixture was allowed to cool down to rt. The reaction was quenched by the addition of water / ice (50 mL) at 0 °C. The resulting mixture was basified to pH 7 with sat. NaHCO3 (aq.). The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with water (2 × 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. The title compound was isolated (650 mg) as a solid. LCMS [M + H]+m / z: 423.0. 139 ME153015591v.1 136867-00720 Step 3. 7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophene-2-carbohydrazide. A solution of methyl 7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophene-2-carboxylate (650 mg, 1.5 mmol) and N2H4 (80 wt% in H2O, 4 mL) in EtOH (4.0 mL) was stirred for 1 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The title compound was isolated (600 mg) as a solid. LCMS [M + H]+m / z: 423.1. Step 4. (R)-N'-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophene-2-carbonyl)-5-oxopyrrolidine-2- carbohydrazide. To a stirred mixture of 7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophene-2-carbohydrazide (300 mg, 0.7 mmol) and (R)-5- oxopyrrolidine-2-carboxylic acid (110.1 mg, 0.9 mmol) in DCM (5 mL) were added HATU (297.1 mg, 0.8 mmol) and DIEA (275.4 mg, 2.1 mmol) at rt. The resulting mixture was stirred for 1 h at rt. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. The title compound was isolated (90 mg) as a solid. LCMS [M + H]+m / z: 534.1. Step 5. (R)-5-(5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one. To a stirred mixture of (R)-N'-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophene-2-carbonyl)-5-oxopyrrolidine-2-carbohydrazide (50 mg, 0.1mmol) and TEA (18.9 mg, 0.2 mmol) in DCM (6 mL) was added TsCl (26.8 mg, 0.1 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at rt under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. The title compound was isolated (22.2 mg) as a solid.. LCMS [M + H]+m / z: 516.0. 140 ME153015591v.1 136867-00720 The compounds in the table below were synthesized as described in Example 7 from appropriate intermediates. Examp Step 1. (3R,5R)-5-(3-(6-chloro-7-(((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)-3- hydroxypyrrolidin-2-one and (3R,5R)-5-(3-(4,6-dichloro-7-(((3R,4R)-3-fluorotetrahydro- 2H-pyran-4-yl)amino)-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol- 5-yl)-3-hydroxypyrrolidin-2-one 141 ME153015591v.1 136867-00720 A mixture of (3R,5R)-5-(3-(7-(((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidin-2- one (40.8 mg, 0.08 mmol) and NCS (10.5 mg, 0.08 mmol) in AcOH (1 mL) was stirred for 16 h at 60 °C under nitrogen atmosphere. The reaction mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 20% to 80% gradient in 25 min; detector, UV 254 nm. This resulted in (3R,5R)-5-(3-(6-chloro-7-(((3R,4R)-3-fluorotetrahydro-2H-pyran-4- yl)amino)-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)-3- hydroxypyrrolidin-2-one (14.7 mg) as a solid and (3R,5R)-5-(3-(4,6-dichloro-7-(((3R,4R)-3- fluorotetrahydro-2H-pyran-4-yl)amino)-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)- 1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidin-2-one (8.2 mg) as a solid. (3R,5R)-5-(3-(6-chloro-7-(((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidin-2- one LCMS [M + H]+m / z: 552.9.1H NMR (300 MHz, Methanol-d4) δ 7.72 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 5.12 (t, J = 7.5 Hz, 1H), 4.67 (d, J = 48.8 Hz, 1H), 4.44 (t, J = 8.2 Hz, 1H), 4.13 (t, J = 12.8 Hz, 1H), 3.97 (d, J = 11.5 Hz, 2H), 3.71 – 3.44 (m, 2H), 3.06 (dt, J = 13.1, 7.7 Hz, 1H), 2.27 (dt, J = 12.7, 8.0 Hz, 1H), 1.99 (d, J = 5.1 Hz, 1H), 1.81 (d, J = 10.6 Hz, 1H).19F NMR (377 MHz, Methanol-d4) δ -43.00, -207.75. (3R,5R)-5-(3-(4,6-dichloro-7-(((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidin-2- one LCMS [M + H]+m / z: 586.9.1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.82 (s, 1H), 5.76 (d, J = 5.7 Hz, 1H), 5.12 – 5.00 (m, 2H), 4.62 (d, J = 49.2 Hz, 1H), 4.21 (q, J = 7.3 Hz, 1H), 4.05 – 3.78 (m, 3H), 3.62 – 3.39 (m, 2H), 2.90 (dt, J = 12.5, 7.7 Hz, 1H), 2.04 (dt, J = 14.2, 7.5 Hz, 1H), 1.98 – 1.86 (m, 1H), 1.75 (d, J = 13.1 Hz, 1H).19F NMR (377 MHz, DMSO-d6) δ -41.86, -204.09. Example 9 142 ME153015591v.1 136867-00720 Step 1. (3S,4R)-3-fluoro-1-methyl-4-((2-(5-((R)-2-oxoimidazolidin-4-yl)-1,2,4-oxadiazol- 3-yl)-3-((trifluoromethyl)thio)benzo[b]thiophen-7-yl)amino)piperidine 1-oxide To a stirred mixture of (R)-4-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)imidazolidin-2-one (20 mg, 0.04 mmol) in ACN (0.9 mL) was added H2O2(30 wt% in H2O, 0.1 mL) at rt. The resulting mixture was stirred for 24 h at rt under nitrogen atmosphere. The reaction mixture was filtered and the filtrate was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase A: Water (10 mmol / L NH4HCO3); mobile phase B: ACN; 10% to 50% gradient in 10 min; detector, UV 254 nm. The title compound was isolated (4.6 mg) as a solid. The compounds in the table below were synthesized as described in Example 9 from appropriate intermediates. 143 ME153015591v.1 136867-00720 144 ME153015591v.1 136867-00720 Step 1. 1-(7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)ethan-1-one To a stirred solution of 7-bromo-2-iodo-3-((trifluoromethyl)thio)benzo[b]thiophene (2 g, 4.5 mmol) in dry THF (15 mL) was added iPrMgCl.LiCl (1.3 M in THF, 4.2 mL, 5.4 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 15 min at -78 °C under nitrogen atmosphere. To the above mixture was added a solution of N- methoxy-N-methylacetamide (560 mg, 5.4 mmol) in dry THF (5 mL) dropwise at -78 °C. The resulting mixture was stirred for additional 2 h at rt. The reaction was quenched by the addition of sat. NH4Cl (aq, 20 mL) at 0 °C. The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-10%) to afford the crude product, which was further purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 70% to 95% gradient in 20 min; detector, UV 254 nm. The title compound was isolated (700 mg) as a solid. GCMS [M]+m / z: 353.9. Step 2. 2-bromo-1-(7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)ethan-1-one To a stirred solution of 1-(7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)ethan-1- one (620 mg, 1.7 mmol) in AcOH (10 mL) was added the solution of Br2 (306.8 mg, 1.9 mmol) in AcOH (5 mL) dropwise at rt. The resulting mixture was stirred for 3 h at 40 °C. The reaction was monitored by LCMS. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase 145 ME153015591v.1 136867-00720 flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 70% to 95% gradient in 20 min; detector, UV 254 nm. The title compound was isolated (220 mg) as a solid. LCMS [M + H]+m / z: 433.0. Step 3. (R)-5-(4-(7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)oxazol-2- yl)pyrrolidin-2-one A mixture of 2-bromo-1-(7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)ethan-1- one (150 mg, 0.3 mmol), tert-butyl (R)-2-carbamoyl-5-oxopyrrolidine-1-carboxylate (98.5 mg, 0.4 mmol) and AgOTf (177.5 mg, 0.7 mmol) in EA (15 mL) was stirred for 16 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to afford the crude product, which was further purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 40% to 70% gradient in 25 min; detector, UV 254 nm. The title compound was isolated (12 mg) as a solid. LCMS [M + H]+m / z: 462.9. Step 4. (R)-5-(4-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)oxazol-2-yl)pyrrolidin-2-one A mixture of (R)-5-(4-(7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)oxazol-2- yl)pyrrolidin-2-one (8 mg, 0.02 mmol), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (7.0 mg, 0.03 mmol), Pd-PEPPSI-IHeptCl (CAS: 1814936-54-3, 2.7 mg, 0.003 mmol, 0.2 equiv) and Cs2CO3(33.7 mg, 0.1 mmol) in 1,4-dioxane (1 mL) was stirred for 16 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH 10:1) to afford a crude product, which was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 30% to 60% gradient in 30 min; detector, UV 254 nm. The title compound was isolated (2 mg) as a solid. LCMS [M + H]+m / z: 515.1.1H NMR (400 MHz, Methanol-d4) δ 8.74 (s, 1H), 7.46 – 7.35 (m, 2H), 6.82 (dd, J = 7.5, 1.2 Hz, 1H), 5.00 (m, 2H), 3.78 (m, 1H), 3.24 (t, J = 6.5 Hz, 1H), 2.96 (d, J = 11.6 Hz, 1H), 2.71 –2.52 (m, 2H), 2.49 – 2.34 (m, 3H), 2.33 (m, 4H), 2.01 (m, 2H).19F NMR (377 MHz, Methanol-d4) δ -43.14, -202.82. The compounds in the table below were synthesized as described in Example 10 from appropriate intermediates. 146 ME153015591v.1 136867-00720 Example 11 147 ME153015591v.1 136867-00720 Step 1. (R)-4-(3-(7-(((3S,4R)-3-fluoro-1-(pyrimidin-2-yl)piperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)imidazolidin-2-one A mixture of (R)-4-(3-(7-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)imidazolidin-2-one (60 mg, 0.2 mmol) and 2-chloropyrimidine (16.4 mg, 0.2 mmol) in EtOH (3 mL) was stirred for 24 h at 50 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. The title compound was isolated (5.5 mg) as a solid. The compounds in the table below were synthesized as described in Example 11-1 from appropriate intermediates. 148 ME153015591v.1 136867-00720 Example 12 Step 1. 5-(5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,3,4-thiadiazol-2-yl)pyrrolidin-2-one To a stirred mixture of (R)-N'-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophene-2-carbonyl)-5-oxopyrrolidine-2-carbohydrazide (20 mg, 0.1 mmol) in THF (1 mL) was added Lawesson's reagent (360 mg, 0.6 mmol) in portions at rt under nitrogen atmosphere. The resulting mixture was stirred for 7 days at 100 °C. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 30% to 50% gradient in 20 min; detector, UV 254 nm. The title compound was isolated (3 mg) as a solid. LCMS [M + H]+m / z: 532.1.1H NMR (400 MHz, Methanol-d4) δ 7.53 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 6.97 – 6.87 (m, 1H), 5.39 (dd, J = 8.4, 4.9 Hz, 1H), 4.98 (s, 1H), 3.89 – 3.72 (m, 1H), 3.30 – 3.19 (m, 1H), 3.04 – 2.93 (m, 1H), 2.90 – 2.76 (m, 1H), 2.66 – 2.25 (m, 8H), 2.16 – 1.95 (m, 2H).19F NMR (377 MHz, Methanol-d4) δ -42.96, -202.54. Example 13 Step 1. (3R,5R)-5-(3-(4-chloro-7-(((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)-3- hydroxypyrrolidin-2-one A mixture of (3R,5R)-5-(3-(7-(((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidin-2- one (40 mg, 0.08 mmol) and NCS (9.3 mg, 0.07 mmol) in AcOH (1 mL) was stirred for 10 h 149 ME153015591v.1 136867-00720 at 60 °C under nitrogen atmosphere. The reaction mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 20% to 80% gradient in 25 min; detector, UV 254 nm. The title compound was isolated (6.5 mg) as a solid. LCMS [M + H]+m / z: 553.0.1H NMR (400 MHz, Methanol-d4) δ 7.41 (dd, J = 8.5, 3.6 Hz, 1H), 6.89 (dd, J = 8.7, 3.3 Hz, 1H), 5.11 (t, J = 7.5 Hz, 1H), 4.71 (s, 1H), 4.43 (t, J = 8.2 Hz, 1H), 4.13 (t, J = 12.8 Hz, 1H), 4.07 – 3.86 (m, 2H), 3.76 – 3.58 (m, 2H), 3.06 (dt, J = 13.0, 7.7 Hz, 1H), 2.26 (dt, J = 12.9, 8.1 Hz, 1H), 2.16 – 2.01 (m, 1H), 1.91 (d, J = 13.2 Hz, 1H).19F NMR (377 MHz, Methanol-d4) δ -44.49, -207.50. Example 14 Step 1. 7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophene-2-carbaldehyde To a stirred solution of 7-bromo-2-iodo-3-((trifluoromethyl)thio)benzo[b]thiophene (2 g, 4.6 mmol) in THF (20 mL) was added iPrMgCl.LiCl (1.3 M in THF, 4.2 mL, 5.5 mmol) dropwise at -78°C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at -78 °C under nitrogen atmosphere. Then a solution of DMF (402 mg, 5.5 mmol) in THF (5 mL) was added to above solution dropwise over 2 min at -78 °C. The resulting mixture was stirred for additional 2 h at rt. The reaction was quenched by sat. NH4Cl (aq, 60 mL) at 0 °C. The resulting mixture was extracted with EA (3 × 60 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-10%) to afford the title compound (1.2 g) as a solid. GCMS [M]+m / z: 339.9. Step 2. (E)-7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophene-2-carbaldehyde oxime A mixture of NH2OH.HCl (236.3 mg, 3.4 mmol) and TEA (516.1 mg, 5.1 mmol) in EtOH (6 mL) was stirred for 30 min at rt. Then 7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophene- 2-carbaldehyde (580 mg, 1.7 mmol) was added to above mixture at rt. The resulting mixture was stirred for 2 h at rt. The reaction mixture was concentrated under reduced pressure. The 150 ME153015591v.1 136867-00720 residue was purified by silica gel column chromatography, eluted with EA in PE (0%-10%) to afford the title compound (500 mg) as a solid. LCMS [M + H]+m / z: 355.9. Step 3. (Z)-7-bromo-N-hydroxy-3-((trifluoromethyl)thio)benzo[b]thiophene-2- carbimidoyl chloride A mixture of (E)-7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophene-2-carbaldehyde oxime (200 mg, 0.6 mmol) and NCS (98.3 mg, 0.6 mmol) in ACN (10 mL) was stirred for 1 h at 60 °C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ACN (3 × 10 mL). The filtrate was concentrated under reduced pressure to afford the title compound (160 mg) as a solid. GCMS [M]+m / z: 389.1. Step 4. (R)-5-(3-(7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)isoxazol-5- yl)pyrrolidin-2-one To a stirred solution of (Z)-7-bromo-N-hydroxy-3-((trifluoromethyl)thio)benzo[b]thiophene- 2-carbimidoyl chloride (160 mg, 0.4 mmol) and (R)-5-ethynylpyrrolidin-2-one (89.4 mg, 0.8 mmol) in toluene (4 mL) was added a solution of K2CO3 (62.3 mg, 0.5 mmol) in H2O (0.4 mL) dropwise at rt under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 100 °C. The reaction mixture was diluted with H2O (10 mL). The resulting mixture was extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to afford the crude product, which was further purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 50% to 95% gradient in 20 min; detector, UV 254 nm. The title compound was isolated (55 mg) as a solid. LCMS [M + H]+m / z: 462.9. Step 5. (R)-5-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)isoxazol-5-yl)pyrrolidin-2-one A mixture of (R)-5-(3-(7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)isoxazol-5- yl)pyrrolidin-2-one (20 mg, 0.04 mmol), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (8 mg, 0.06 mmol), Cs2CO3 (70 mg, 0.2 mmol) and Pd-PEPPSI-IPentCl (CAS: 1814936-54-3, 4 mg, 0.004 mmol) in 1,4-dioxane (1 mL) was stirred for 16 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to afford the crude product, which was further purified by reversed-phase 151 ME153015591v.1 136867-00720 flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 30% to 50% gradient in 30 min; detector, UV 254 nm. The title compound was isolated (6.5 mg) as a solid. LCMS [M + H]+m / z: 515.2.1H NMR (400 MHz, Methanol-d4) δ 7.50 (d, J = 8.0 Hz, 1H), 7.45 – 7.39 (m, 1H), 7.22 (s, 1H), 6.89 (d, J = 7.7 Hz, 1H), 5.15 – 5.05 (m, 1H), 4.98 – 4.77 (m, 1H), 3.87 – 3.70 (m, 1H), 3.27 – 3.16 (m, 1H), 3.01 –2.89 (m, 1H), 2.75 – 2.63 (m, 1H), 2.61 – 2.38 (m, 3H), 2.37 – 2.22 (m, 5H), 2.11 – 1.92 (m, 2H).19F NMR (377 MHz, Methanol-d4) δ -43.38, -202.63. Examp Step 1. 7-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophene-2-carbonitrile To a stirred solution of tert-butyl (1S,2R,3R,5R)-3-((2-cyano-3- ((trifluoromethyl)thio)benzo[b]thiophen-7-yl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8- carboxylate (1.5 g, 2.6 mmol) in DCM (12 mL) was added TFA (3 mL) at 0 °C. The resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 25 min; detector, UV 254 nm. The title compound was isolated (1 g) as a solid. LCMS [M + H]+m / z: 401.9. Step 2. 7-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophene-2-carbonitrile To a stirred solution of 7-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)amino)-3- ((trifluoromethyl)thio)benzo[b]thiophene-2-carbonitrile (1 g, 2.5 mmol) in MeOH (12 mL) was added HCHO (37 wt% in water, 202.2 mg, 2.5 mmol) dropwise at rt. The mixture was acidified to pH 3 with AcOH (0.3 mL). The resulting mixture was stirred at rt for 20 min. 152 ME153015591v.1 136867-00720 Then to the above mixture was added NaBH3CN (310 mg, 5.0 mmol) in portions over 5 min at 0 °C. The resulting mixture was stirred at rt for additional 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 25 min; detector, UV 254 nm. The title compound was isolated (900 mg) as a solid. LCMS [M + H]+m / z: 416.0. Step 3. (Z)-7-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)amino)- N'-hydroxy-3-((trifluoromethyl)thio)benzo[b]thiophene-2-carboximidamide To a stirred mixture of 7-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octan-3- yl)amino)-3-((trifluoromethyl)thio)benzo[b]thiophene-2-carbonitrile (900 mg, 2.2 mmol) in EtOH (30 mL) was added NH2OH (50 wt% in water, 3 mL) dropwise at rt. The resulting mixture was stirred for 30 min at rt. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 30% to 60% gradient in 30 min; detector, UV 254 nm. The title compound was isolated (900 mg) as a solid. LCMS [M + H]+m / z: 449.1. Step 4. Tert-butyl ((3-(7-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octan-3- yl)amino)-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5- yl)methyl)carbamate (method 1) A mixture of (Z)-7-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)amino)- N'-hydroxy-3-((trifluoromethyl)thio)benzo[b]thiophene-2-carboximidamide (850 mg, 1.9 mmol), methyl (tert-butoxycarbonyl)glycinate (609.6 mg, 3.2 mmol) and Cs2CO3 (1.8 g, 5.7 mmol) in toluene (12 mL) was stirred at 100 °C for 1 h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EA (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 254 nm. The title compound was isolated (370 mg) as a solid. LCMS [M + H]+m / z: 588.1. Step 4. Tert-butyl ((3-(7-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octan-3- yl)amino)-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5- yl)methyl)carbamate (method 2) A mixture of (Z)-7-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)amino)- N'-hydroxy-3-((trifluoromethyl)thio)benzo[b]thiophene-2-carboximidamide (240 mg, 0.5 153 ME153015591v.1 136867-00720 mmol), DCC (220.8 mg, 1 mmol) and (tert-butoxycarbonyl)glycine (140.6 mg, 0.8 mmol) in 1,4-dioxane (4 mL) was stirred at 100 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-15%) to afford the title compound (200 mg) as a solid. LCMS [M + H]+m / z: 588.1. Step 5. (1S,2R,3R,5R)-N-(2-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)-3- ((trifluoromethyl)thio)benzo[b]thiophen-7-yl)-2-fluoro-8-methyl-8- azabicyclo[3.2.1]octan-3-amine To a stirred solution of tert-butyl ((3-(7-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)amino)-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4- oxadiazol-5-yl)methyl)carbamate (360 mg, 0.6 mmol) in DCM (8 mL) was added TFA (2 mL) at 0 °C. The resulting mixture was stirred at rt for 30 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 254 nm. The title compound was isolated (250 mg) as a solid. LCMS [M + H]+m / z: 488.1. Step 6. N-((3-(7-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)amino)- 3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1-methyl- 1H-imidazole-4-carboxamide To a stirred mixture of (1S,2R,3R,5R)-N-(2-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)-3- ((trifluoromethyl)thio)benzo[b]thiophen-7-yl)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octan-3- amine (80 mg, 0.2 mmol) and EDCI (38.2 mg, 0.2 mmol) in pyridine (3 mL) was added 1- methyl-1H-imidazole-4-carboxylic acid (31 mg, 0.2 mmol) at rt. The reaction mixture was stirred at 50 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 254 nm. The title compound was isolated (51.7 mg) as a solid. LCMS [M + H]+m / z: 596.2. The compounds in the table below were synthesized as described in Example 15 from appropriate intermediates. 154 ME153015591v.1 136867-00720 155 ME153015591v.1 136867-00720 156 ME153015591v.1 136867-00720 157 ME153015591v.1 136867-00720 Example 16 158 ME153015591v.1 136867-00720 Biological assays to measure the activities of p53-Y220C reactivators Biological Example 1. Biochemical p53-Y220C and DNA binding assay. 159 ME153015591v.1 136867-00720 The compounds of this invention can bind to p53-Y220C and increase the ability of the mutant p53 to bind to DNA at higher temperatures. His-tagged p53-Y220C DNA binding domain containing amino acid 94-312 is used to measure DNA binding activities in vitro with the sequence described below. (SEQ ID NO: 1: MHHHHHHENLYFQGSSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTYSPALNKMFC QLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHERCSDSDGLAPP QHLIRVEGNLRVEYLDDRNTFRHSVVVPCEPPEVGSDCTTIHYNYMCNSSCMGGMN RRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPHHELPPGSTKR ALPNNT. Biotin labeled double strand DNA (dsDNA) containing consensus p53 binding sequence (SEQ ID NO: 2: Forward: 5’-(biotin)-ATTAGGCATGTCTAGGCATGTCTAGG- 3’; Reverse: 5’-(biotin)-CCTAGACATGCCTAGACATGCCTAAT-3’) is used to measure protein-DNA binding activities. Compounds, His-tagged p53-Y220C DBD proteins (100 nM), and biotinylated dsDNA (200 nM) were mixed in ice-cold assay buffer containing DPBS, 20 mM NaCl, and 0.5% BAS, and incubated at 4oC overnight in 384-well plate. Plates were transferred to incubator at 27 to 29oC with constant shaking for 60 minutes. Equal volume of Homogeneous Time-Resolved Fluorescence (HTRF) dyes containing mAb anti-6HIS Tb cryptate gold and d2 labeled streptavidin in the assay buffer was added to each well and incubated at 27 to 29oC with constant shaking for 60 minutes. The plate was read using Envision multimode plate reader. Reference compound 1 was used as high control and DMSO was used as low control. The percentage activation (A%) of protein-DNA binding by compounds was normalized by setting up high control (reference compound) as 500% and low control (DMSO) as 0% (A%=(HTRF ratio of compound -HTRF ratio of low control) / (HTRF ratio of high control – HTRF ratio of low control)*500). 10 points dose titration curves for each compound were analyzed by 4 parameter curve fit and inflection point (IP) was reported. Reference compound 1 is shown below Table 1. Compounds of the invention are active in the HTRF assay. Data in Table 1 collected using Biological Example 1. Table 1 160 ME153015591v.1 136867-00720 161 ME153015591v.1 136867-00720 162 ME153015591v.1 136867-00720 163 ME153015591v.1 136867-00720 164 ME153015591v.1 136867-00720 165 ME153015591v.1 136867-00720 Reference compound 1 (HTRF = A; IP < 100 nM) 166 ME153015591v.1

Claims

1. 136867-00720 CLAIMS What is claimed is:

1. A compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof, wherein: A is a phenylene, 5- or 6-membered heteroarylene or 5- or 6-membered heterocyclylene; Z is S, or O; U, V, W and X are independently CR5or N, provided that one of U, V, W and X is C-Y-R1; Y is a bond, O, NH, N(C1-4alkyl), NHCH2^, OCH2^, S or CH2, wherein “^” indicates the point of attachment to R1; R1is (CH2)nOR11, (CH2)nN(R11)2, (CH2)nCN, (CH2)nC(O)R11, (CH2)nC(O)OR11, (CH2)nC(S)R11, (CH2)nC(S)OR11, (CH2)nC(O)N(R11)2, (CH2)nNHC(O)R11, (CH2)nNHC(O)OR11, (CH2)nOC(O)N(R11)2, (CH2)nC(S)N(R11)2, (CH2)nNHC(S)R11, (CH2)nNHC(S)OR11, (CH2)nOC(S)N(R11)2, (CH2)nNHS(O)iR11 , (CH2)nS(O)iN(R11)2, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted by one or more R21; R2is (CH2)mOR12, (CH2)mN(R12)2, (CH2)mCN, (CH2)mC(O)R12, (CH2)mC(O)OR12, (CH2)mC(S)R12, (CH2)mC(S)OR12, (CH2)mC(O)N(R12)2,(CH2)mNHC(O)R12, (CH2)mNRaNRbC(O)R12, (CH2)mNHC(O)OR12, (CH2)mOC(O)N(R12)2, (CH2)mC(S)N(R12)2, (CH2)mNHC(S)R12, (CH2)mNHC(S)OR12, (CH2)mOC(S)N(R12)2, (CH2)mNHS(O)iR12,(CH2)mS(O)iN(R12)2, C1-6alkyl, C3-8cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, (C1-4alkyl)[5-10 membered heteroaryl], or 4-13 membered heterocyclyl, wherein said C1-6 alkyl, C1-4 alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and heteroaryl are each 167 ME153015591v.1 136867-00720 optionally and independently substituted by one or more R22and wherein said cycloalkyl and heterocyclyl are each optionally substituted by one or more R22a; R3is –S[halo(C1-C4)alkyl], –SO2[halo(C1-C4)alkyl], or halo(C1-C4)alkoxy; each R5is independently H, halo, (CH2)pOR15, (CH2)pN(R15)2, (CH2)pCN, (CH2)oC(O)R15, (CH2)pC(O)OR15, (CH2)pC(S)R15, (CH2)pC(S)OR15, (CH2)pC(O)N(R15)2,(CH2)pNHC(O)R15, (CH2)pNHC(O)OR15, (CH2)pOC(O)N(R15)2, (CH2)pC(S)N(R15)2,(CH2)pNHC(S)R15, (CH2)pNHC(S)OR15, (CH2)pOC(S)N(R15)2, (CH2)pNHS(O)iR15 , (CH2)pS(O)iN(R15)2,C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl or C2-6 alkynyl, C6-10 aryl, 5- to 10-membered membered heteroaryl or 4- to 10-membered heterocyclyl; wherein said alkyl, alkenyl, alkoxy, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally and independently substituted by one or more R25; R11, R12, and R15are each independently H, C1-6 alkyl, (CH2)nC3-8 cycloalkyl, (CH2)nC6-10aryl, (CH2)n(5-10 membered heteroaryl) or (CH2)n(4-10 membered heterocyclyl); wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally and independently substituted by one or more R30; or N(R11)2 and N(R12)2 are independently a 4-10 membered heterocyclyl, wherein the heterocyclyl represented by N(R11) is optionally substituted with one or more R21and the heterocyclyl represented by N(R12) is optionally substituted with one or more R22; R21, R22, and R25are each independently H, halo, OH, NH2, CN, NO2, (CH2)nORa, (CH2)nNRbRc, S(O)iRb, (=NRa)NRbRc, NRbS(O)iRc, S(O)iNRbRc, alkyl, OC(=O)ORb, C(=S)ORb, O(C=S)Rb, C(=O)NRbRc, NRbC(=O)Rc, C(=S)NRbRc, NRbC(=S)Rc, NRb(C=O)ORc, O(C=O)NRbRc, NRb(C=S)ORc, O(C=S)NRbRc, NRb(C=O)NRbRc, NRb(C=S)NRbRc, C(=S)Rb, C(=O)Rb, halo(C1-C5)alkyl, (C1-C5)alkyl, (C2-C5)alkenyl, 4-7 membered heterocyclyl, 6-10 membered spiroheterocyclyl, or (C2-C5)alkynyl, wherein said alkyl is optionally substituted with one or more groups selected from halo, methoxy, halomethoxy, and phenyl; or two R21groups on the same ring atom taken together with their intervening atom are an oxo; each R22ais independently halo, OH, NHC(O)R12, CN, NO2, (CH2)nORa, (CH2)nNRbRc, S(O)iRb, (=NRa)NRbRc, NRbS(O)iRc, S(O)iNRbRc, C(=O)ORb, OC(=O)ORb, C(=S)ORb, O(C=S)Rb, C(=O)NRbRc, NRbC(=O)Rc, C(=S)NRbRc, NRbC(=S)Rc, NRb(C=O)ORc, O(C=O)NRbRc, NRb(C=S)ORc, O(C=S)NRbRc, NRb(C=O)NRbRc, NRb(C=S)NRbRc, C(=S)Rb, C(=O)Rb, halo(C1-C5)alkyl, (C1- 168 ME153015591v.1 136867-00720 C5)alkyl, (C1-C4)alkoxy, (C3-C6)cycloalkoxy, (C6-C10)aryl, (CH2)n(5-10 membered heteroaryl), (C2-C5)alkenyl or (C2-C5)alkynyl, or two R22agroups on the same ring atom taken together with their intervening atom are a (C3-C6)spirocycloalkyl, 4-6 membered spiroheterocyclyl, (=NRd), thio, or oxo, or two R22aon adjacent ring atoms, taken together with their intervening atoms form a (C3-C6)cycloalkyl, phenyl, or a 5-6 membered heteroaryl, wherein said phenyl or heteroaryl is optionally substituted with one or more groups selected from halo, methyl, halomethyl, methoxy and halomethoxy; each R30is independently halo, CN, 4-6 membered heterocyclyl, (C1-C4)alkyl, (C1-C4)fluororalkyl, O(C1-C4)fluororalkyl, O(C1-C4)hydroxyalkyl, hydroxy[halo(C1- C4)alkyl], (C3-C5)cycloalkyl, (C1-C4)alkoxy, (CH2)nORaor (CH2)nNRaRb; each Ra, Rband Rcis independently –H, D, T, (C1-C4)alkyl, C3-8 cycloalkyl, hydroxy(C1-C4)alkyl, or (C1-C4)alkylO(C1-C4)alkyl, wherein said cycloalkyl is optionally substituted with one or more groups selected from (C1-C4)alkyl, halo(C1- C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, and OH; and each n, m, o, p and i are independently 0, 1 or 2.

2. The compound of claim 1, wherein R21, R22, and R25are each independently H, halo, OH, NH2, CN, NO2, (CH2)nORa, (CH2)nNRbRc, S(O)iRb, (=NRa)NRbRc, NRbS(O)iRc, S(O)iNRbRc, C(=O)ORb, OC(=O)ORb, C(=S)ORb, O(C=S)Rb, C(=O)NRbRc, NRbC(=O)Rc, C(=S)NRbRc, NRbC(=S)Rc, NRb(C=O)ORc, O(C=O)NRbRc, NRb(C=S)ORc, O(C=S)NRbRc, NRb(C=O)NRbRc, NRb(C=S)NRbRc, C(=S)Rb, C(=O)Rb, halo(C1- C5)alkyl, (C1-C5)alkyl, (C2-C5)alkenyl, 4-7 membered heterocyclyl, 6-10 membered spiroheterocyclyl, or (C2-C5)alkynyl, wherein said alkyl is optionally substituted with one or more groups selected from halo, methoxy, halomethoxy, and phenyl; or two R21groups on the same ring atom taken together with their intervening atom are an oxo; each R22ais independently halo, OH, NHC(O)R12, CN, NO2, (CH2)nORa, (CH2)nNRbRc, S(O)iRb, (=NRa)NRbRc, NRbS(O)iRc, S(O)iNRbRc, C(=O)ORb, OC(=O)ORb, C(=S)ORb, O(C=S)Rb, C(=O)NRbRc, NRbC(=O)Rc, C(=S)NRbRc, NRbC(=S)Rc, NRb(C=O)ORc, O(C=O)NRbRc, NRb(C=S)ORc, O(C=S)NRbRc, NRb(C=O)NRbRc, NRb(C=S)NRbRc, C(=S)Rb, C(=O)Rb, halo(C1-C5)alkyl, (C1- 169 ME153015591v.1 136867-00720 C5)alkyl, (C6-C10)aryl, (CH2)n(5-10 membered heteroaryl), (C2-C5)alkenyl or (C2- C5)alkynyl, or two R22agroups on the same ring atom taken together with their intervening atom are a (C3-C6)spirocycloalkyl, 4-6 membered spiroheterocyclyl, (=NRd), thio, or oxo, or two R22aon adjacent ring atoms, taken together with their intervening atoms form a (C3-C6)cycloalkyl, phenyl, or a 5-6 membered heteroaryl, wherein said phenyl or heteroaryl is optionally substituted with one or more groups selected from halo, methyl, halomethyl, methoxy and halomethoxy; and each R30is independently halo, CN, 4-6 membered heterocyclyl, (C1-C4)alkyl, (C1-C4)fluororalkyl, O(C1-C4)fluororalkyl, O(C1-C4)hydroxyalkyl, hydroxy[halo(C1- C4)alkyl], (C3-C5)cycloalkyl, (CH2)nORaor (CH2)nNRaRb.

3. The compound of claim 1 or 2, wherein the compound is represented by the following structural formula: or pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R3is –S[halo(C1-C4)alkyl] or –SO2[halo(C1-C4)alkyl].

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R3is –S[halo(C1-C4)alkyl].

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R3is SCF3.

7. The compound of any one of claims 1 to 6, wherein W is CR5. 170 ME153015591v.1 136867-00720 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen or halo.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein Y is O or NH.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Y is NH.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein A is a 5- or 6-membered heteroarylene.

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroarylene.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein A is 1,2,4-oxadiazolylene, furanylene, isoxazolylene, or oxazolylene.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein A is represented by 171 ME153015591v.1 136867-00720 wherein indicates the point of attachment to R2.

16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R2is (CH2)mNHC(O)R12, (CH2)mC(O)N(R12)2, or a 5- or 6-membered heterocyclyl optionally substituted by one or more R22a.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R2is (CH2)mNHC(O)R12, (CH2)mC(O)N(R12)2, or pyrrolidinyl, piperidinyl, morpholinyl, imidazolidinyl, or oxazolidinyl, each optionally substituted by one or more R22a; each R12is independently H, C3-6 cycloalkyl, or 5-6 membered heteroaryl, wherein said cycloalkyl and heteroaryl are optionally and independently substituted with one or more R30; and each R30is independently a group selected from C1-4 alkyl, (C1-C4)alkoxy, C1-4 hydroxyalkyl, C1-4fluoroalkyl, fluoro, oxetanyl, and (CH2)nORa.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein 172 ME153015591v.1 136867-00720 R2is (CH2)mNHC(O)R12, (CH2)mC(O)N(R12)2, or pyrrolidinyl, piperidinyl, morpholinyl, imidazolidinyl, or oxazolidinyl, each optionally substituted by one or more R22a; each R12is independently H, C3-6 cycloalkyl, or 5-6 membered heteroaryl, wherein said cycloalkyl and heteroaryl are optionally and independently substituted with one or more R30; and each R30is independently a group selected from C1-4alkyl, C1-4hydroxyalkyl, C1-4 fluoroalkyl, fluoro, oxetanyl, and (CH2)nORa.

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein each R22ais independently OH, (C1-C5)alkyl, (C1-C4)alkoxy, (C3- C6)cycloalkoxy, (CH2)nORa, (C2-C5)alkenyl, or 5-6 membered heteroaryl; or two R22agroups on the same carbon ring atom are taken together to form a C3-6cycloalkyl, thio, oxo, or imino, wherein said imino nitrogen is optionally substituted with CN or – S(O)2(C1-C5)alkyl.

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein each R22ais independently OH, (C1-C5)alkyl, (CH2)nORa, (C2- C5)alkenyl, or 5-6 membered heteroaryl; or two R22agroups on the same carbon ring atom are taken together to form a C3-6cycloalkyl, thio, oxo, or imino, wherein said imino nitrogen is optionally substituted with CN or –S(O)2(C1-C5)alkyl.

21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each R22ais independently OH, CH3, OCH3, , OCD3, OCT3, =C(CH3)2, (CH2)2OCH3, or pyrimidinyl; or two R22agroups on the same carbon ring atom are taken together to form cyclopropyl, thio, oxo, =N(SO2)CH3 or =NCN.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein each R22ais independently OH, CH3, OCH3, OCD3, OCT3, =C(CH3)2, (CH2)2OCH3, or pyrimidinyl; or two R22agroups on the same carbon ring atom are taken together to form cyclopropyl, thio, oxo, =N(SO2)CH3or =NCN. 173 ME153015591v.1 136867-00720 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R2is (CH2)mNHC(O)R12, (CH2)mC(O)N(R12)2, or is represented by: o and each R12is independently H, or is represented by: 174 ME153015591v.1 136867-00720 175 ME153015591v.1 136867-00720 24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R2is (CH2)mNHC(O)R12, (CH2)mC(O)N(R12)2, or is represented by: and each R12is independently H, or is represented by: 176 ME153015591v.1 136867-00720 177 ME153015591v.1 136867-00720 25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R1is C1-6 alkyl, 5- to 10-membered heteroaryl, C3-8 cycloalkyl, or 4- to 10-membered heterocyclyl, wherein said alkyl, heteroaryl, cycloalkyl, and heterocyclyl are optionally substituted by one or more R21.

26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R1is C1-4alkyl, C4-7cycloalkyl, 5- or 6-membered heteroaryl or 4- to 9-membered heterocyclyl, wherein said alkyl, heteroaryl, cycloalkyl, and heterocyclyl are optionally substituted by one or more R21.

27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R1is C1-4 alkyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, 178 ME153015591v.1 136867-00720 tetrahydrothiofuranyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, oxabicyclo[3.2.1]octanyl, tetrahydrothiopyranyl, cyclohexyl, cyclopentyl, oxa- azabicyclo[3.3.1]nonanyl, or pyridinyl, each of which are optionally substituted by one or more R21.

28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R21is halo, OH, (CH2)nORa, C(=O)ORb, C(=O)Rb, halo(C1-C5)alkyl, hydroxy(C1-C5)alkyl, (C1-C5)alkyl, NH(C1-C5)alkyl, (C1-C5)alkyl[5- to 6-membered heteroaryl], 6-8 membered spiroheterocyclyl, 5- to 6-membered heteroaryl, 4- to 6- membered heterocyclyl, or S(O)2(C1-C5)alkyl; or two R21groups on the same atom are taken together to form oxo.

29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R21is halo, OH, (CH2)nORa, C(=O)ORb, C(=O)Rb, halo(C1-C5)alkyl, hydroxy(C1-C5)alkyl, (C1-C5)alkyl, (C1-C5)alkyl[5- to 6-membered heteroaryl], 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, or S(O)2(C1-C5)alkyl; or two R21groups on the same atom are taken together to form oxo.

30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein R21is fluoro, CH3, CD3, CH(CH3)2, oxetanyl, CH2CH3, C(O)CH2OCH3, S(O)2CH3, CH2CHF2, COCH3, (CH2)2OCH3, (CH2)2OH, CH2OH, CH2(pyrimidinyl), C(O)CH2OH, C(O)[cyclopropyl], CH2(C)(CH3)2OH, C(O)CH2CH3, 2-oxa-6-azaspiro[3.3]heptanyl, C(O)[cyclopropylOH], NH[isopropyl], pyrimidinyl, C(O)O(cyclopropyl), C(O)OCH2CH3, C(O)OC(CH3)3, OH, or tetrahydropyranyl; or two R21on the same atom are taken together to form oxo.

31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R21is fluoro, CH3, CD3, CH(CH3)2, oxetanyl, CH2CH3, C(O)CH2OCH3, S(O)2CH3, CH2CHF2, COCH3, (CH2)2OCH3, (CH2)2OH, CH2OH, CH2(pyrimidinyl), C(O)CH2OH, C(O)[cyclopropyl], CH2(C)(CH3)2OH, C(O)CH2CH3, C(O)[cyclopropylOH], pyrimidinyl, C(O)O(cyclopropyl), C(O)OCH2CH3, C(O)OC(CH3)3, OH, or tetrahydropyranyl; or two R21on the same atom are taken together to form oxo. 179 ME153015591v.1 136867-00720 32. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R1is represented by: 180 ME153015591v.1 136867-00720 181 ME153015591v.1 136867-00720 and when Y is a bond, R1is represented by: .

33. The compound of any one of claims 1 to 22 or 32, or a pharmaceutically acceptable salt thereof, wherein R1is represented by: 182 ME153015591v.1 136867-00720 183 ME153015591v.1 136867-00720 and when Y is a bond, R1is represented by: .

34. The compound of Claim 1, wherein the compound is selected from any one of Compounds 1 to 258, or a pharmaceutically acceptable salt thereof.

35. The compound of Claim 1 or 34, wherein the compound is selected from any one of Compounds 1 to 251, or a pharmaceutically acceptable salt thereof.

36. A pharmaceutical composition comprising: i) the compound of any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof; and ii) a pharmaceutically acceptable carrier, excipient or diluent. 184 ME153015591v.1 136867-00720 37. A method of treating a subject with cancer, comprising administering to the subject an effective amount of the compound of claims 1 to 35 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 36.

38. The method of claim 37, wherein the cancer is characterized by dysfunctional p53.

39. The method of claim 37, wherein the cancer is characterized by an inactivating p53 mutation.

40. The method of claim 39, wherein the p53 mutation is Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, Arg282, and / or a combination thereof.

41. The method according to claim 39, wherein the p53 mutation is V157F, R175H, Y220C, G245S, R248Q, R248W, R249S, R273H, R273C, R282W, and / or a combination thereof.

42. The method of claim 39, wherein the p53 mutation is Y220C.

43. The method of any one of claims 37 to 41, wherein the cancer is acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, bladder cancer, bone cancers, brain tumors, such as cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, colon cancer, gallbladder cancer, gastric cancer, head and neck cancer, heart cancer, hepatocellular (liver) cancer, kidney cancer, liver cancer, lung cancers, such as non-small cell and small cell lung cancer, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, pancreatic cancer, pancreatic cancer islet cell, prostate cancer, rectal cancer, renal cell carcinoma, skin cancers, skin carcinoma merkel cell, small intestine cancer or throat cancer. 185 ME153015591v.1 136867-00720 44. A method for re-activating p53 Y220C mutant in a subject in need thereof, comprising administering to the subject an effective amount of the compound of claims 1 to 35 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 36. 186 ME153015591v.1

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