Pyridazinones as PARP7 inhibitors

Abstract

The present invention relates to pyridazinones and related compounds that are PARP7 inhibitors and are useful in the treatment of cancer.

Description

[Technical field]

[0001] The present invention relates to pyridazinones and related compounds that are PARP7 inhibitors and are useful in the treatment of cancer. [Background technology]

[0002] Poly(ADP-ribose) polymerases (PARPs) are members of a family of 17 enzymes that regulate fundamental cellular processes, including gene expression, protein degradation, and multiple cellular stress responses (MS Cohen, P. Chang, Insights into the biogenesis, function, and regulation of ADP-ribosylation. Nat Chem Biol 14, 236-243 (2018)). The ability of cancer cells to survive under stress is a fundamental cancer mechanism and a new approach for novel therapeutics. One member of the PARP family, PARP1, has already been shown to be a valid cancer target in the context of cellular stress induced by DNA damage caused by either genetic mutations or cytotoxic chemotherapy, with four drugs approved in the clinic and several others in late stages of development (A. Ohmoto, S. Yachida, Current status of poly(ADP-ribose) polymerase inhibitors and future directions. Onco Targets Ther 10, 5195-5208 (2017)).

[0003] Seventeen members of the PARP family have been identified in the human genome based on homology within their catalytic domains (S. Vyas, M. Chesarone-Cataldo, T. Todorova, YH Huang, P. Chang, A systematic analysis of the PARPprotein family identifies new functions critical for cell physiology. Nat Commun 4, 2240 (2013)). However, their catalytic activities fall into three distinct categories (S. Vyas et al., Family-wide analysis of poly(ADP-ribose) polymerase activity. Nat Commun 5, 4426 (2014)). The majority of PARP family members catalyze the transfer of mono-ADP-ribose units (mono-PARPs) to their substrates, while the other members (PARP1, PARP2, TNKS, TNKS2) catalyze the transfer of poly-ADP-ribose units (poly-PARPs) to their substrates. Finally, PARP13 is the only PARP among them that failed to exhibit catalytic activity either in vitro or in vivo.

[0004] The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in regulating multiple cellular functions, including proinflammatory responses and xenobiotic metabolism (S. Feng, Z. Cao, X. Wang, Role of aryl hydrocarbon receptor in cancer. Biochim Biophys Acta 1836, 197-210 (2013), and B. Stockinger, P. Di Meglio, M. Gialitakis, JH Duarte, The aryl hydrocarbon receptor: multitasking in the immune system. Annu Rev Immunol 32, 403-432 (2014)). The AHR can be activated by a broad number of ligands, including endogenous tryptophan metabolites such as kynurenine (CAOpitz et al., An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197-203 (2011)), and certain polycyclic aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (KW Bock, Toward elucidation of dioxin-mediated chloracne and Ah receptor functions. Biochem Pharmacol 112, 1-5 (2016)). Activation of the AHR induces target gene expression, including genes involved in metabolism such as cytochromes P4501A1 and P4501B1.Activation of the AHR also leads to an increase in TCDD-inducible poly(ADP-ribose)polymerase (TIPARP, also called PARP7), an AHR target gene that functions as a negative regulator of certain AHR transcriptional targets (L. MacPherson et al., Aryl hydrocarbon receptor repressor and TIPARP (ARTD14) use similar, but also distinct mechanisms to repress aryl hydrocarbon receptor signaling. Int J Mol Sci 15, 7939-7957 (2014), and L. MacPherson et al., 2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose)polymerase (TIPARP, ARTD14) is a mono-ADP-ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation. Nucleic Acids Res 41, 1604-1621 (2013)).

[0005] PARP7 can also be regulated by other transcription factors and signaling pathways, including the androgen receptor (E. C. Bolton et al., Cell-and gene-specific regulation of primary target genes by the androgen receptor. Genes Dev 21, 2005-2017 (2007)), platelet-derived growth factor (J. Schmahl, C. S. Raymond, P. Soriano, PDGF signaling specificity is mediated through multiple immediate early genes. Nat Genet 39, 52-60 (2007)), and hypoxia-inducible factor 1 (N. Hao et al., Xenobiotics and loss of cell adhesion drive distinct transcriptional outcomes by aryl hydrocarbon receptor signaling. Mol Pharmacol 82, 1082-1093 (2012)). The PARP7 gene is located on chromosome 3 (3q25) within a region frequently amplified in squamous cell carcinoma histology (http: / / www.cbioportal.org / index.do?session_id=5ae1bcde498eb8b3d565d8b2). A genome-wide association study identified 3q25 as a susceptibility loci for ovarian cancer and suggested a role for PARP7 in this cancer type (ELGoode et al.,A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24.Nat Genet 42,874-879(2010)). PARP7 has multiple cellular functions.In the context of AHR signaling, PARP7 functions as a negative feedback mechanism to regulate the expression of P4501A1 and P4501B1 (L. MacPherson et al., Aryl hydrocarbon receptor repressor and TIPARP (ARTD14) use similar, but also distinct mechanisms to repress aryl hydrocarbon receptor signaling. Int J Mol Sci 15, 7939-7957 (2014), and L. MacPherson et al., 2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose)polymerase (TIPARP, ARTD14) is a mono-ADP-ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation. Nucleic Acids Res 41, 1604-1621 (2013)). PARP7 has also been described as an ADP-ribosylate liver X receptor, which results in the regulation of transcriptional activity (C. Bindesboll et al., TCDD-inducible poly-ADP-ribose polymerase (TIPARP / PARP7) mono-ADP-ribosylates and co-activates liver X receptors. Biochem J 473, 899-910 (2016). During viral infection, PARP7 can bind to Sindbis virus (SINV) and promote viral RNA degradation (T. Kozaki et al., Mitochondrial damage elicits a TCDD-inducible poly(ADP-ribose) polymerase-mediated antiviral response. Proc Natl Acad Sci USA 114, 2681-2686 (2017)).Also, in the context of viral infection, AHR-induced PARP7 can interact with TBK1, a key kinase activated during the onset of the pathogen-associated molecular pattern pathway leading to the activation of type I interferon responses and antiviral immunity (T. Yamada et al., Constitutive aryl hydrocarbon receptor signaling constrains Type I interferon-mediated antiviral innate defense. Nat Immunol 17, 687-694 (2016)). It was shown that PARP7 ADP-ribosylates TBK1, preventing its activation and thereby suppressing type I interferon responses.

[0006] Based on these results from viral infection, it could be hypothesized that cancer cells could use aberrantly expressed and / or activated PARP7 as a mechanism to evade the host immune system by suppressing type I interferon and thereby T cell-mediated antitumor immunity. Indeed, in a recent genetic screen to identify tumor factors that suppress T cell activation, PARP7 was identified as a hit (D. Pan et al., A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science 359, 770-775 (2018)). It was shown that PARP7 knockout in a mouse melanoma cell line increased the proliferation and activation of co-cultured T cells, suggesting that PARP7 inhibition could be a viable strategy to activate T cell-mediated tumor killing. Thus, there is a continuing need for the development of PARP7 inhibitors. Summary of the Invention

[0007] The present invention relates to a compound of formula I, [ka] The present invention relates to a compound as defined above, or a pharma- ceutically acceptable salt thereof, wherein the members are as defined below.

[0008] The present invention further relates to pharmaceutical compositions comprising a compound of formula I, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier.

[0009] The present invention further relates to a method of inhibiting the activity of PARP7, comprising contacting PARP7 with a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0010] The present invention further relates to a method of treating a disease or disorder in a patient in need of treatment, wherein the disease or disorder is characterized by overexpression or increased activity of PARP7, comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof.

[0011] The present invention further relates to a method for treating cancer in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of an agent that inhibits PARP7 activity, such as a compound of formula I or a pharma- ceutically acceptable salt thereof.The present disclosure also provides the use of the compounds described herein in the manufacture of a medicament for use in therapy.The present disclosure also provides the compounds described herein for use in therapy. [Brief description of the drawings]

[0012] [Figure 1] 1 shows the effect of compounds of the invention on mean tumor volume in the animal model described in Example B. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present invention relates to a compound of formula I, [ka] During the ceremony, X is Cl, Br, F, or CH 3 , C.F.3 , C.F. 2 H, CN, OCH 3 , ethyl, cyclopropyl, SCH 3 or isopropyl, A is a group having the formula (A-1), [ka] Y 1 , Y 2 , and Y 3 are each independently O, S, or NR Y , C(=O), C(=O)O, C(=O)NR Y , S(=O), S(=O) 2 , S(=O)NR Y , S(=O) 2 NR Y , or N.R. Y C(=O)NR Y wherein each R Y are independent, H, C 1-4 Alkyl, or C 1-4 is haloalkyl, L is C 1-3 Alkylene, O, S, NR Y , C(=O), C(=O)O, C(=O)NR Y , S(=O), S(=O)NR Y , or N.R. Y C(=O)NR Y and Z is H, Cy Z , Haro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , N.R. c R d , N.R. c C(O)Rb , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d where Z is the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 Each haloalkyl is Cy Z , Haro, CN, NO 2 , OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R.c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy Z But, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, wherein the alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl is halo, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1, S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Ring D is halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2is a monocyclic or polycyclic 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 groups independently selected from 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl is halo, CN, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 and optionally substituted with 1, 2, or 3 groups independently selected from R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R8 , R 9 , R 10 , R 11 , and R 12 are each independently H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3, S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 The relevant C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Each of the alkyl groups is halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R.c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 or R 1 and Y 1 R Y The groups, together with the atoms to which they are attached, and Y 1 Together with the atoms that form halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 or forming a 4-10 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from R 7 and Y 3 R Y The groups, together with the atoms to which they are attached, and Y 3 When present, together with the atoms forming R 9 , R 10 , R 11 , and R 12 Together with the carbon atom substituted by halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 Rd3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 or forming a 4-10 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from R 1 and R 3 together with the carbon atom to which they are attached, form halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3, N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 each optionally substituted with 1, 2, or 3 substituents independently selected from 5-10 forming a cycloalkyl ring or a 5- to 10-membered heterocycloalkyl ring; or R 3 and R 5 together with the carbon atom to which they are attached, form halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 each optionally substituted with 1, 2, or 3 substituents independently selected from 5-10 forming a cycloalkyl ring or a 5- to 10-membered heterocycloalkyl ring; or R 7 and R 9 together with the carbon atom to which they are attached, form halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)ORa3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 each optionally substituted with 1, 2, or 3 substituents independently selected from 5-10 forming a cycloalkyl ring or a 5- to 10-membered heterocycloalkyl ring; or R 9 and R 11 together with the carbon atom to which they are attached, form halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R.c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 each optionally substituted with 1, 2, or 3 substituents independently selected from 5-10 forming a cycloalkyl ring or a 5- to 10-membered heterocycloalkyl ring; or R 5 and R 7 together with the carbon atoms to which they are attached, and Y 2 Together, Hello, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)ORa3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 or forming a 5-10 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from R 1 and R 3 together form a double bond between the carbon atoms to which they are attached, or R 3 and R 5 together form a double bond between the carbon atoms to which they are attached, or R 7 and R 9 together form a double bond between the carbon atoms to which they are attached, or R 9 and R 11 together form a double bond between the carbon atoms to which they are attached, or R 9 and R 10 and R 11 and R 12 together form a triple bond between the carbon atoms to which they are attached, Each R a , Rb , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 The relevant C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a7 , S.R. a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , O.C.(O)R b7 , O-C(O)NR c7 R d7 , N.R. c7 R d7 , N.R. c7 C(O)R b7 , N.R. c7 C(O)NR c7 R d7 , N.R. c7 C(O)OR a7 , C(=NR e7 )NR c7 R d7 , N.R. c7 C(=NR e7 )NR c3 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O) 2 R b7 , N.R. c7 S(O) 2 R b7 , N.R. c7 S(O) 2 NR c7 R d7 , and S(O) 2 NR c7 R d7 or R c and R d However, together with the N atom to which they are attached, they form CN, halo, and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a7 , S.R. a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , O.C.(O)R b7 , O-C(O)NR c7 R d7 , N.R. c7 R d7 , N.R. c7 C(O)R b7 , N.R. c7 C(O)NR c7 R d7 , N.R. c7 C(O)OR a7 , C(=NR e7 )NR c7 R d7 , N.R. c7 C(=NR e7 )NR c3 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O) 2 R b7 , N.R. c7 S(O) 2 R b7 , N.R. c7 S(O) 2 NR c7 R d7 , and S(O) 2 NR c7 R d7 or forming a 4- to 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R c1 and R d2 However, together with the N atom to which they are attached, they form CN, halo, and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a7 , S.R. a7 , C(O)R b7 , C(O)NRc7 R d7 , C(O)OR a7 , O.C.(O)R b7 , O-C(O)NR c7 R d7 , N.R. c7 R d7 , N.R. c7 C(O)R b7 , N.R. c7 C(O)NR c7 R d7 , N.R. c7 C(O)OR a7 , C(=NR e7 )NR c7 R d7 , N.R. c7 C(=NR e7 )NR c3 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O) 2 R b7 , N.R. c7 S(O) 2 R b7 , N.R. c7 S(O) 2 NR c7 R d7 , and S(O) 2 NR c7 R d7 or forming a 4- to 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R c2 and R d2 However, together with the N atom to which they are attached, they form CN, halo, and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a7 , S.R. a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , O.C.(O)R b7 , O-C(O)NR c7 R d7 , N.R.c7 R d7 , N.R. c7 C(O)R b7 , N.R. c7 C(O)NR c7 R d7 , N.R. c7 C(O)OR a7 , C(=NR e7 )NR c7 R d7 , N.R. c7 C(=NR e7 )NR c3 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O) 2 R b7 , N.R. c7 S(O) 2 R b7 , N.R. c7 S(O) 2 NR c7 R d7 , and S(O) 2 NR c7 R d7 or forming a 4- to 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R c3 and R d3 However, together with the N atom to which they are attached, they form CN, halo, and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a7 , S.R. a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , O.C.(O)R b7 , O-C(O)NR c7 R d7 , N.R. c7 R d7 , N.R. c7 C(O)R b7 , N.R. c7 C(O)NR c7 Rd7 , N.R. c7 C(O)OR a7 , C(=NR e7 )NR c7 R d7 , N.R. c7 C(=NR e7 )NR c3 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O) 2 R b7 , N.R. c7 S(O) 2 R b7 , N.R. c7 S(O) 2 NR c7 R d7 , and S(O) 2 NR c7 R d7 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R a7 , R b7 , R c7 , and R d7 are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Each R e , R e1 , R e2 , R e3 , and R e7 are independent, H, C 1-4 alkyl, and CN; a is 0 or 1, m is 0 or 1; n is 0 or 1; p is 0 or 1; q is 0 or 1; r is 0 or 1; Any of the foregoing heteroaryl or heterocycloalkyl groups contain 1, 2, 3, or 4 ring-forming heteroatoms independently selected from O, N, and S; The present invention relates to compounds, or pharma- ceutically acceptable salts thereof, wherein one or more ring-forming C or N atoms of any of the aforementioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups.

[0014] In some embodiments, X is CF 3 , Br, or Cl. In some embodiments, X is CF 3 In some embodiments, X is Br or Cl. In some embodiments, X is Br. In some embodiments, X is Cl.

[0015] In some embodiments, Y 1 is NRY or O. In some embodiments, Y 1 is NR Y In some embodiments, Y 1 is NH. In some embodiments, Y 1 is O. In some embodiments, Y 1 is NH or O.

[0016] In some embodiments, Y 2 , O, NR Y , or C(=O)NR Y In some embodiments, Y 2 are O, NH, and NCH. 3 or C(=O)NH. In some embodiments, Y 2 is O or NR Y In some embodiments, Y 2 is O. In some embodiments, Y 2 is NR Y In some embodiments, Y 2 is O, NH, or NCH 3 In some embodiments, Y 2 NH or NCH 3 In some embodiments, Y 2 is NH. In some embodiments, Y 2 NCH 3 It is.

[0017] In some embodiments, Y 3 is C(=O)NR Y In some embodiments, Y 3 is C(=O)NH. In some embodiments, Y 3 is C(=O)NCH 3 In some embodiments, Y 3 is C(=O)NCH 2 In some embodiments, Y 3 is C(=O)NH or C(=O)NCH 3 It is.

[0018] In some embodiments, Y 1 R Y is H.

[0019] In some embodiments, Y 2 R Y is H or C 1-4 In some embodiments, Y is alkyl. 2 R Y is H or methyl. In some embodiments, Y 2 R Y is H. In some embodiments, Y 2 R Y is methyl.

[0020] In some embodiments, Y 3 R Y is H or C 1-4 In some embodiments, Y is alkyl. 3 R Y is H, methyl, or ethyl. In some embodiments, Y 3 R Y is H. In some embodiments, Y 3 R Y is methyl. In some embodiments, Y 3 R Y is ethyl. In some embodiments, Y 3 R Y is CH 2 It is.

[0021] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently H, halo, or C 1-6 Alkyl, C 1-6 Haloalkyl, CN, NO 2, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 wherein said C 1-6 Alkyl, halo, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O) 2 R b3, and S(O) 2 NR c3 R d3 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0022] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently H, halo, or C 1-6 Alkyl, and C 1-6 haloalkyl, wherein the C 1-6 Alkyl, halo, CN, NO 2 , OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 is optionally substituted with 1 or 2 substituents independently selected from

[0023] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently H, halo, or C 1-6 Alkyl, and C 1-6 haloalkyl, wherein the C1-6 Alkyl is OR a3 is optionally replaced by

[0024] In some embodiments, R 1 , R 2 , R 5 , R 6 , R 7 , and R 8 are each independently H, halo, or C 1-6 Alkyl, C 1-6 Haloalkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 wherein said C 1-6 Alkyl, halo, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R.c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0025] In some embodiments, R 1 , R 2 , R 5 , R 6 , R 7 , and R 8 are each independently H, halo, or C 1-6 Alkyl, and C 1-6 haloalkyl, wherein the C 1-6 Alkyl, halo, CN, NO 2 , OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 is optionally substituted with 1 or 2 substituents independently selected from

[0026] In some embodiments, R 1 , R 2 , R 5 , R 6 , R 7 , and R 8are each independently H, halo, or C 1-6 Alkyl, and C 1-6 haloalkyl, wherein the C 1-6 Alkyl is OR a3 is optionally replaced by

[0027] In some embodiments, R 1 is H or C 1-6 alkyl, wherein 1-6 Alkyl is OR a3 , N.R. c3 R d3 , and N.R. c3 C(O)R b3 In some embodiments, R 1 is H or C 1-6 alkyl, wherein 1-6 Alkyl is OR a3 In some embodiments, R 1 is H or C 1-6 alkyl, wherein 1-6 Alkyl is optionally substituted with methoxy. In some embodiments, R 1 is H or methyl, where the methyl is optionally substituted with methoxy. In some embodiments, R 1 is H, methyl, methoxymethyl, CH 2 OH, CH(OH)CH 3 , C.H. 2 NHCH 2 CF 3 , or C.H. 2 NHC(O)CH 3 In some embodiments, R 1 is H, methyl, or methoxymethyl.

[0028] In some embodiments, R 1 OR a3 C optionally substituted with 1-6 In some embodiments, R 1 is optionally substituted with methoxy 1-6 In some embodiments, R1 is methyl optionally substituted with methoxy. In some embodiments, R 1 is methyl. In some embodiments, R 1 is methoxymethyl.

[0029] In some embodiments, R 1 is H.

[0030] In some embodiments, R 2 is H.

[0031] In some embodiments, R 5 is H or C 1-6 It is an alkyl.

[0032] In some embodiments, R 5 is methyl.

[0033] In some embodiments, R 5 is H.

[0034] In some embodiments, R 6 is H.

[0035] In some embodiments, R 7 is H or C 1-6 It is an alkyl.

[0036] In some embodiments, R 7 is CH 2 It is.

[0037] In some embodiments, R 7 is H.

[0038] In some embodiments, R 8 is H.

[0039] In some embodiments, R 1 and Y 1 R YThe groups, together with the atoms to which they are attached, and Y 1 Together with the atoms that form halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 Forms a 4-10 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from:

[0040] In some embodiments, R1 and Y 1 R Y The groups, together with the atoms to which they are attached, and Y 1 Together with the atoms that form halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 and forming an azetidine ring optionally substituted with 1, 2, or 3 substituents independently selected from:

[0041] In some embodiments, R 1 and Y 1 R Y The groups, together with the atoms to which they are attached, and Y 1 Together with the atoms forming, form an azetidine ring.

[0042] In some embodiments, R 7 and Y 3 R Y The groups, together with the atoms to which they are attached, and Y 3 When present, together with the atoms forming R 9 , R 10 , R 11 , and R 12 Together with the carbon atom substituted by halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 Rb3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 Forms a 4-10 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from:

[0043] In some embodiments, R 7 and Y 3 R Y The groups, together with the atoms to which they are attached, and Y 3 When present, together with the atoms forming R 9 , R 10 , R 11 , and R 12 Together with the carbon atom substituted by halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R.c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 and forming an oxopyrrolidine or pyrrolidine ring optionally substituted with 1, 2, or 3 substituents independently selected from:

[0044] In some embodiments, R 7 and Y 3 R Y The groups, together with the atoms to which they are attached, and Y 3 When present, together with the atoms forming R 9 , R 10 , R 11 , and R 12 Together with the carbon atom substituted by - forms a pyrrolidine ring or an oxopyrrolidine ring.

[0045] In some embodiments, R 7 and Y 3 R Y The groups, together with the atoms to which they are attached, and Y 3 When present, together with the atoms forming R 9 , R 10 , R 11 , and R 12 Together with the carbon atom substituted by - forms an oxopyrrolidine ring.

[0046] In some embodiments, R 7 and Y 3 RY The groups, together with the atoms to which they are attached, and Y 3 When present, together with the atoms forming R 9 , R 10 , R 11 , and R 12 Together with the carbon atom substituted by, form an oxopiperidine ring.

[0047] In some embodiments, ring D is halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NRc2 R d2 is a monocyclic or polycyclic 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 groups independently selected from 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl is halo, CN, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 and optionally substituted with 1, 2, or 3 groups independently selected from:

[0048] In some embodiments, Ring D is halo, CN, OR a2 , C(O)NR c2R d2 , C 1-6 Alkyl, and C 1-6 and a monocyclic or polycyclic 4-6 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl.

[0049] In some embodiments, Ring D is halo, OR a2 , C 1-6 Alkyl, and C 1-6 and a monocyclic or polycyclic 4-6 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl.

[0050] In some embodiments, Ring D is 3-azabicyclo[3.1.0]hexane.

[0051] In some embodiments, Ring D is halo, OR a2 , C 1-6 Alkyl, and C 1-6 In some embodiments, Ring D is a monocyclic 4-6 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, OR a2 , C 1-6 Alkyl, and C 1-6 In some embodiments, ring D is an azetidine ring or a piperidine ring, each of which is selected from halo, OR, aryl ... a2 , C 1-6 Alkyl, and C 1-6 In some embodiments, ring D is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, OR a2 , C 1-6 Alkyl, and C 1-6 A piperidine ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl. In some embodiments, Ring D is OH, F, C(O)NH 2In some embodiments, ring D is a piperidine ring optionally substituted with 1 or 2 substituents independently selected from halo, OR, a2 , C 1-6 Alkyl, and C 1-6 The azetidine ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl.

[0052] In some embodiments, ring D is a monocyclic 4-6 membered heterocycloalkyl group. In some embodiments, ring D is a polycyclic 10 membered heterocycloalkyl group. In some embodiments, ring D is an azetidine ring or a piperidine ring. In some embodiments, ring D is a piperidine ring. In some embodiments, ring D is an azetidine ring.

[0053] In some embodiments, Ring D is halo, OR a2 , C 1-6 Alkyl, and C 1-6 and a monocyclic 4-6 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl.

[0054] In some embodiments, ring D is OR a2 is an azetidine or piperidine ring optionally substituted with

[0055] In some embodiments, ring D is a piperidine ring optionally substituted with OH.

[0056] In some embodiments, ring D is a piperidine ring.

[0057] In some embodiments, Z is H, Cy. Z , Haro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a , S.R. a , C(O)R b, C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d where Z is the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 Each haloalkyl is Cy Z , Haro, CN, NO 2 , OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , C(=NR e )NRc R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0058] In some embodiments, Z is Cy. Z , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, NO 2 , OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R.c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O) 2 R b , and S(O) 2 NR c R d where Z is the C 1-6 Alkyl is Cy Z , Haro, CN, NO 2 , OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O) 2 R b , and S(O) 2 NR c R d and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0059] In some embodiments, Z is Cy. Z , Haro, C 1-6 Alkyl, C 1-6 haloalkyl, or CN.

[0060] In some embodiments, Z is Cy. Z It is.

[0061] In some embodiments, Cy Z Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 wherein the alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl is halo, CN, NO 2 , OR a1 , S.R.a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from:

[0062] In some embodiments, Cy Z is halo, CN, methyl, or C 1-3 It is a 5- or 6-membered heteroaryl group substituted with haloalkyl.

[0063] In some embodiments, Cy Z is halo, CN, or C 1-3 In some embodiments, Cy is a 5-membered heteroaryl group substituted with haloalkyl. Z is halo, CN, methyl, or C1-3 In some embodiments, Cy is a 6-membered heteroaryl group substituted with haloalkyl. Z is halo, CN, or C 1-3 It is a 6-membered heteroaryl group substituted with haloalkyl.

[0064] In some embodiments, Cy Z is halo, CN or C 1-3 A pyrimidinyl, pyrazinyl, pyridinyl, or thiazolyl group substituted with haloalkyl. Z is halo, CN or C 1-3 In some embodiments, Cy is a pyrimidinyl, pyrazinyl, or pyridinyl group substituted with haloalkyl. Z is halo, CN or C 1-3 In some embodiments, Cy is a pyrimidinyl or pyrazinyl group substituted with haloalkyl. Z CF 3 In some embodiments, Cy is substituted with Z is halo, CN or C 1-3 It is a thiazolyl group substituted with haloalkyl.

[0065] In some embodiments, Cy Z is selected from 5-(trifluoromethyl)pyrimidin-2-yl, 5-(trifluoromethyl)thiazol-2-yl, 5-(trifluoromethyl)pyrazin-2-yl, 5-(difluoromethyl)pyrimidin-2-yl, 5-(difluoromethyl)pyrazin-2-yl, 5-fluoropyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5-chloropyrazin-2-yl, 5-bromopyrimidin-2-yl, 5-cyanopyridin-2-yl, 5-cyanothiazol-2-yl, 5-cyanopyrazin-2-yl, 5-methylpyrimidin-2-yl.

[0066] In some embodiments, Cy Zis selected from 5-(trifluoromethyl)pyrimidin-2-yl, 5-(trifluoromethyl)thiazol-2-yl, 5-(trifluoromethyl)pyrazin-2-yl, 5-cyanopyridin-2-yl, 5-(difluoromethyl)pyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5-(difluoromethyl)pyrazin-2-yl, and 5-bromopyrimidin-2-yl.

[0067] In some embodiments, Cy Z is 5-(trifluoromethyl)pyrimidin-2-yl.

[0068] In some embodiments, m is 1.

[0069] In some embodiments, n is 0.

[0070] In some embodiments, p is 0.

[0071] In some embodiments, q is 0.

[0072] In some embodiments, r is 1. In some embodiments, r is 0.

[0073] In some embodiments, a is 0.

[0074] In some embodiments, X is CF 3 and Y 1 is NR Y and Y 2 is O and Y 3 is C(=O)NR Y and R 1 is methyl, R 2 is H and R 5 is H and R 6 is H and R 7 CH 2 and R 8 is H, ring D is piperidine substituted with OH, and Z is Cy Z where CyZ CF 3 is pyrimidinyl substituted with

[0075] In some embodiments, the compound has formula IIa: [ka] or a pharma- ceutically acceptable salt thereof is provided herein.

[0076] In some embodiments, the compound has the formula IIb: [ka] or a pharma- ceutically acceptable salt thereof is provided herein.

[0077] In some embodiments, the compound has formula IIc: [ka] In the formula, Z 1 and Z 2 are each independently selected from N and CH; R Z But halo, CN, or C 1-3 Provided herein are compounds, or pharma- ceutically acceptable salts thereof, in which R is haloalkyl. Z CF 3 , C.N., C.F. 2 H, and Cl.

[0078] In some embodiments, the compounds of the invention have formula IId: [ka] or a pharma- ceutically acceptable salt thereof.

[0079] In some embodiments, the compounds of the invention have formula IIe: [ka] or a pharma- ceutically acceptable salt thereof.

[0080] In some embodiments, the compound of formula I, wherein: X is Cl, Br, or CF 3 and A is a group having the formula (A-1a), [ka] Y 1 , Y 2 , and Y 3 each independently represents O, NR Y , C(=O), and C(=O)NR Y wherein each R Y are independently H or C 1-4 is alkyl, Z is Cy Z and Cy Z But, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)Rb1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 wherein the alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl is halo, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1, S(O) 2 R b1 , and S(O) 2 NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from Ring D is halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 is a monocyclic or polycyclic 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 groups independently selected from1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl is halo, CN, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 and optionally substituted with 1, 2, or 3 groups independently selected from R 1 , R 2 , R 5 , R 6 , R 7 , and R 8 are each independently H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Ants ー Ru-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 wherein R1 , R 2 , R 5 , R 6 , R 7 , and R 8 The relevant C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Each of the alkyl groups is halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 or R 1 and Y 1 R Y The groups, together with the atoms to which they are attached, and Y 1 Together with the atoms that form halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 or forming a 4-10 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from R 7 and Y 3 R Y The groups, together with the atoms to which they are attached, and Y 3 Together with the atoms that form halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 forming a 4-10 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from Each R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2, R d2 , R a3 , R b3 , R c3 , and R d3 The relevant C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a7 , S.R. a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , O.C.(O)R b7 , O-C(O)NR c7 R d7 , N.R. c7 R d7 , N.R. c7 C(O)R b7 , N.R. c7 C(O)NR c7 R d7 , N.R. c7 C(O)OR a7 , C(=NR e7 )NR c7 R d7 , N.R. c7 C(=NR e7 )NR c3 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O) 2 R b7 , N.R. c7 S(O) 2 R b7 , N.R.c7 S(O) 2 NR c7 R d7 , and S(O) 2 NR c7 R d7 or R a7 , R b7 , R c7 , and R d7 are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Each R e , Re1 , R e2 , R e3 , and R e7 are independent, H, C 1-4 alkyl, and CN; Any of the foregoing heteroaryl or heterocycloalkyl groups contain 1, 2, 3, or 4 ring-forming heteroatoms independently selected from O, N, and S; Provided herein are compounds, or pharma- ceutically acceptable salts thereof, wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups.

[0081] In some embodiments, (S)-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide, (S)—N-methyl-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide, (S)—N-methyl-2-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-N-(1-(5-(trifluoromethyl)thiazol-2-yl)piperidin-4-yl)acetamide, (S)-N-methyl-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)acetamide, ((S)-N-methyl-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)acetamide, (S)—N-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)-N-methyl-2-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetamide, (S)-N-ethyl-2-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide, (S)—N-methyl-2-((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)azetidin-2-yl)methoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide, (S)-2-(3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide, 5-((S)-1-((S)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-((S)-1-((R)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 4-chloro-5-((S)-1-(2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yloxy)propan-2-ylamino)pyridazin-3(2H)-one, 4-bromo-5-(((2S)-1-((2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)pyridazin-3(2H)-one, 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 6-(4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 6-(4-((S)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 5-(((S)-1-(((S)-1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 6-(4-((S)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 6-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, (S)-N-methyl-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)acetamide, 5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-methoxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 4-(trifluoromethyl)-5-(((2S)-1-((1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)pyridazin-3(2H)-one, 5-(((S)-1-(((S)-1-(1-(5-(difluoromethyl)pyrazin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-(1-(5-(difluoromethyl)pyrazin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 4-bromo-5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, (S)—N-methyl-2-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide, 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((R)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((R)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((2S)-1-((1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, (S)-2-(2-((5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)propoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide, 5-(((2S)-1-(methyl(2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 6-(4-(2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 4-bromo-5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)pyridazin-3(2H)-one, N-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetamide, and A compound selected from N-((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetamide, or a pharma- ceutically acceptable salt of any of the foregoing is provided herein.

[0082] In some embodiments, (S)-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-1'-(5-(trifluoromethyl)pyrimidin-2-yl)-[1,4'-bipiperidin]-2-one, (R)-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-1'-(5-(trifluoromethyl)pyrimidin-2-yl)-[1,4'-bipiperidin]-2-one, 5-(((S)-1-(((S)-4,4-dimethyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-4,4-dimethyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, (R)-6-(4-(2-oxo-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)ethoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, (S)-6-(4-(2-oxo-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)ethoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 5-(((S)-1-(((3S,4R)-4-methyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((3R,4S)-4-methyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-((3R,4R)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-((3S,4S)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-((3S,4R)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-((3R,4S)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 6-((R)-3,3-difluoro-4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 6-((S)-3,3-difluoro-4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 5-(((S)-1-(((R)-1-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-2-oxo-1-((1R,5S,6s)-3-(5-(trifluoromethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile, 4-bromo-5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)pyridazin-3(2H)-one, 4-bromo-5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)pyridazin-3(2H)-one, 4-chloro-5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)pyridazin-3(2H)-one, 4-chloro-5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)pyridazin-3(2H)-one, 6-(4-((R)-3-((S)-2-((5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 6-(4-((S)-3-((S)-2-((5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 5-(((S)-1-(((S)-1-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 6-(4-((S)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 6-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-methoxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-methoxy-3-(((S)-1-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-methoxy-3-(((R)-1-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-methoxy-3-(((R)-1-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 2-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)thiazole-5-carbonitrile, 6-(4-((S)-3-((S)-2-((5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 6-(4-((R)-3-((S)-2-((5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 4-bromo-5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)pyridazin-3(2H)-one, 4-bromo-5-(((S)-1-methoxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, (S)—N-((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propanamide, 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)-3-((2,2,2-trifluoroethyl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-hydroxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((S)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((2S)-1-((1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, N-((S)-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)acetamide, 5-(((2R,3R)-3-hydroxy-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)butan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxamide, and A compound selected from 4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carbonitrile, or a pharma- ceutically acceptable salt of any of the foregoing is provided herein.

[0083] It will be further understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0084] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that this description include any and all individual subcombinations of the members of such groups and ranges. For example, "C 1-6 The term "alkyl" includes methyl, ethyl, C 3 Alkyl, C4 Alkyl, C 5 Alkyl, and C 6 It is specifically intended to disclose alkyl individually.

[0085] Various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described in various places herein. Unless otherwise specified, these rings can be attached to the remainder of the molecule at any ring member allowed by valence. For example, the term "pyridinyl," "pyridyl," or "pyridine ring" can refer to a pyridin-2-yl ring, a pyridin-3-yl ring, or a pyridin-4-yl ring.

[0086] The term "n-membered," where "n" is an integer, typically refers to the number of ring-forming atoms in the moiety where the number of ring-forming atoms is "n." For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0087] For compounds of the invention in which a variable occurs multiple times, each variable can be a different moiety independently selected from the group defining the variable. For example, when a structure is described having two R groups simultaneously present on the same compound, those two R groups can represent different moieties independently selected from the groups defined for R.

[0088] As used herein, the phrase "optionally substituted" means unsubstituted or substituted.

[0089] As used herein, the term "substituted" means that a hydrogen atom is replaced with a non-hydrogen group. It is understood that substitution at a given atom is limited by valence.

[0090] As used herein, i and j are integers and are used in conjunction with chemical groups to refer to "Ci-j The term "ij" specifies a range of the number of carbon atoms in a chemical group, where ij defines the range. For example, C 1-6 Alkyl refers to alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0091] As used herein, the term "alkyl", used alone or in combination with other terms, refers to a saturated hydrocarbon group that may be linear or branched. In some embodiments, the alkyl group has 1-7, 1-6, 1-4, or 1-3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and n-heptyl. In some embodiments, the alkyl group is methyl, ethyl, or propyl.

[0092] As used herein, "halo" or "halogen," employed alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, halo is F or Cl.

[0093] As used herein, the term "haloalkyl," used alone or in combination with other terms, refers to an alkyl group having a maximum valence of halogen atom substituents, which may be the same or different. In some embodiments, the halogen atom is a fluoro atom. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 etc.

[0094] As used herein, the term "alkoxy," employed alone or in combination with other terms, refers to a group of formula -O-alkyl. Exemplary alkoxy groups include methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0095] As used herein, "haloalkoxy," employed alone or in combination with other terms, refers to a group of formula -O-(haloalkyl). In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkoxy groups include -OCF 3 It is.

[0096] As used herein, "amino", used alone or in combination with other terms, means NH 2 Refers to...

[0097] As used herein, "alkylamino," employed alone or in combination with other terms, refers to a group of formula -NH(alkyl). In some embodiments, alkylamino groups have 1 to 6 or 1 to 4 carbon atoms. Exemplary alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0098] As used herein, "dialkylamino", used alone or in combination with other terms, refers to an aryl group having the formula -N(alkyl) 2 Exemplary dialkylamino groups include dimethylamino, diethylamino, dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and the like. In some embodiments, the alkyl groups each independently have 1 to 6 or 1 to 4 carbon atoms.

[0099] As used herein, the term "heterocycloalkyl", used alone or in combination with other terms, refers to a non-aromatic ring or ring system that may optionally have one or more alkenylene or alkynylene groups as part of the ring structure having at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus. Heterocycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. In some embodiments, heterocycloalkyl groups are monocyclic or bicyclic groups having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Moieties having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused to (i.e., having a bond in common with) non-aromatic heterocycloalkyl rings, such as 1,2,3,4-tetrahydro-quinoline, are also included in the definition of heterocycloalkyl. Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups (e.g., heterocycloalkyl moieties having at least one bridgehead atom, such as azaadmantan-1-yl) and spiroheterocycloalkyl groups (e.g., heterocycloalkyl moieties having at least two rings fused at a single atom, such as [1,4-dioxa-8-aza-spiro[4.5]decane-N-yl). In some embodiments, heterocycloalkyl groups have 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, or about 3 to 8 ring-forming atoms. In some embodiments, heterocycloalkyl groups have 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8 carbon atoms. In some embodiments, heterocycloalkyl groups have 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. Carbon atoms or heteroatoms in the ring of a heterocycloalkyl group can be oxidized to form a carbonyl, N-oxide, or sulfonyl group (or other oxidized bond), or a nitrogen atom can be quaternized. In some embodiments, the heterocycloalkyl moiety is 2-7Monocyclic heterocycloalkyl groups. In some embodiments, the heterocycloalkyl group is a morpholine ring, a pyrrolidine ring, a piperazine ring, a piperidine ring, a tetrahydropyran ring, a tetrahydropyridine ring, an azetidine ring, or a tetrahydrofuran ring.

[0100] As used herein, the term "heterocycloalkylalkyl," used alone or in combination with other terms, refers to a group of formula heterocycloalkyl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkyl portion is methylene. In some embodiments, the heterocycloalkyl portion has 3 to 10 ring members, 4 to 10 ring members, or about 3 to 7 ring members. In some embodiments, the heterocycloalkyl group is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl portion is monocyclic. In some embodiments, the heterocycloalkyl portion is C 2-7 It is a monocyclic heterocycloalkyl group.

[0101] As used herein, the term "aryl", used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., fused ring system) aromatic hydrocarbon moiety, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, etc. In some embodiments, an aryl group has 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments, an aryl group is a monocyclic or bicyclic group. In some embodiments, an aryl group is phenyl or naphthyl.

[0102] As used herein, the term "arylalkyl," employed alone or in combination with other terms, refers to a group of formula aryl-alkyl-. In some embodiments, the alkyl portion has 1-4, 1-3, 1-2, or 1 carbon atoms. In some embodiments, the alkyl portion is methylene. In some embodiments, the aryl portion is phenyl. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the arylalkyl group is benzyl.

[0103] As used herein, the term "heteroaryl," used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., fused ring system) aromatic hydrocarbon moiety having one or more heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, etc. Carbon atoms or heteroatoms in the rings of a heteroaryl group can be oxidized to form carbonyl, N-oxide, or sulfonyl groups (or other oxidized bonds), or nitrogen atoms can be quaternized, provided that the aromatic character of the ring is preserved. In some embodiments, the heteroaryl group has 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 5 carbon atoms, 1 to 5 carbon atoms, or about 5 to 10 carbon atoms. In some embodiments, the heteroaryl group has 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

[0104] As used herein, the term "heteroarylalkyl," used alone or in combination with other terms, refers to a group of formula heteroaryl-alkyl-. In some embodiments, the alkyl moiety has 1-4, 1-3, 1-2, or 1 carbon atoms. In some embodiments, the alkyl moiety is methylene. In some embodiments, the heteroaryl moiety is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl moiety has 5-10 carbon atoms.

[0105] The compounds described herein can be asymmetric (e.g., have one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention having asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials, such as resolution of racemic compounds or stereoselective synthesis, are known in the art. Geometric isomers of olefins, geometric isomers of C=N double bonds, and the like, can also be present in the compounds described herein, and all such stable isomers are contemplated by the present invention. Cis and trans geometric isomers of the compounds of the present invention can be isolated as a mixture of isomers or as separated isomeric forms.

[0106] The compounds of the present invention also include tautomeric forms. Tautomeric forms arise by swapping a single bond with an adjacent double bond with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers that are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms (wherein a proton can occupy more than one position of a heterocyclic ring system, e.g., 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole). Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. Examples of tautomeric forms, pyridazin-3(2H)-one and pyridazin-3-ol, are shown below. [ka]

[0107] The compounds of the present invention also include all isotopes of atoms occurring in intermediates or final compounds.Isotopes include atoms with the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.In some embodiments, the compounds of the present invention include at least one deuterium atom.

[0108] The term "compound," as used herein, unless otherwise specified, is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.

[0109] All compounds and their pharma- ceutically acceptable salts may be found together with or isolated from other substances such as water and solvents (eg, in the form of hydrates and solvates).

[0110] In some embodiments, the compounds of the present invention or their salts are substantially isolated. "Substantially isolated" means that the compounds are at least partially or substantially separated from the environment in which they are formed or detected. Partial separation can include, for example, compositions enriched in the compounds of the present invention. Substantial separation can include compositions that contain at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds of the present invention or their salts. Methods for isolating compounds and their salts are conventional in the art.

[0111] The phrase "pharmacologically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0112] The present invention also includes pharma- ceutically acceptable salts of the compounds described herein. As used herein, "pharma- ceutically acceptable salts" refers to derivatives of the disclosed compounds, in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharma- ceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharma- ceutically acceptable salts of the present invention include non-toxic salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. The pharma- ceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0113] synthesis The compounds of the present invention (including their salts) may be prepared using known organic synthesis techniques, and may be synthesised according to any of a number of possible synthetic routes.

[0114] The reaction for preparing the compound of the present invention can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be one that does not substantially react with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, which can range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or in a mixture of two or more solvents. Depending on the particular reaction step, a suitable solvent for that particular reaction step can be selected by those skilled in the art.

[0115] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The necessity of protection and deprotection, and the selection of suitable protecting groups, can be easily determined by those skilled in the art. The chemical nature of protecting groups can be found, for example, in TW Greene and PG M Huts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0116] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), by spectroscopic means such as infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0117] As used herein, the terms "ambient temperature," "room temperature," and "RT" are understood in the art and generally refer to a temperature, e.g., a reaction temperature, i.e., the temperature within a room where a reaction is carried out, e.g., a temperature of about 20° C. to about 30° C.

[0118] Compounds of formula I can be prepared according to a number of preparation routes known in the literature.The following scheme provides examples of synthetic methods for preparing compounds of the present invention.Unless otherwise indicated, all substituents are as defined herein.

[0119] In the process depicted in Scheme 1, an appropriately substituted halogen-containing compound of formula (1-1) (i.e., X ais Cl or Br) is protected as the p-methoxybenzyl ether ("PMB") compound of formula (1-2) by treatment with p-methoxybenzyl chloride ("PMB-Cl") in the presence of sodium hydride (NaH). [ka]

[0120] As shown in Schemes 2-4, compounds of formula (1-2) can be reacted with various nucleophiles to give compounds of formula (I) after deprotection of the PMB protecting group.

[0121] In the process depicted in Scheme 2, a compound of formula (1-3), a But, O, NR Y , or S) is a base (e.g., triethylamine, Cs 2 CO 3 or potassium tert-butoxide) to give a compound of formula (1-4). Deprotection with an acid (e.g., trifluoroacetic acid or trifluoromethanesulfonic acid in hydrochloric acid) gives a compound of formula (IA). [ka]

[0122] Usage The compounds of the present invention can inhibit the activity of PARP7. For example, the compounds of the present invention can be used to inhibit the activity of PARP7 in a cell or an individual or a patient in need of enzyme inhibition by administering an inhibitory amount of the compounds of the present invention to the cell, individual, or patient.

[0123] As PARP7 inhibitors, the compounds of the present invention are useful for treating various diseases related to the abnormal expression or activity of PARP7.For example, the compounds of the present invention are useful for treating cancer.In some embodiments, the cancers treatable by the present invention include breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colon cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck (upper aerodigestive tract) cancer, urinary tract cancer, colon cancer, and other cancers.

[0124] In some embodiments, cancers treatable by the present invention include hematopoietic malignancies such as leukemias and lymphomas. Examples of lymphomas include Hodgkin's or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, hairy cell lymphoma, and Burkett's lymphoma. Examples of leukemias include acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

[0125] Other cancers treatable by administration of the compounds of the invention include liver cancer (e.g., hepatocellular carcinoma), bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, colon cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, gastrointestinal tumors, head and neck cancer (upper aerodigestive tract cancer), intestinal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.

[0126] In some embodiments, cancers treatable by administration of the compounds of the invention are multiple myeloma, DLBCL, hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer (upper aerodigestive tract cancer), kidney cancer, prostate cancer, rectal cancer, gastric cancer, thyroid cancer, uterine cancer, and breast cancer.

[0127] The PARP7 inhibitors of the present invention may also have therapeutic utility in PARP7-associated disorders in disease areas such as cardiology, virology, neurodegeneration, inflammation, and pain, particularly where the disease is characterized by overexpression or increased activity of PARP7.

[0128] As used herein, the term "cell" is intended to refer to an in vitro cell, an ex vivo cell, or an in vivo cell. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism, such as a mammal. In some embodiments, an in vitro cell can be a cell in cell culture. In some embodiments, an in vivo cell is a living cell in an organism, such as a mammal.

[0129] As used herein, the term "contacting" refers to joining the indicated moiety in an in vitro system or in vivo system. For example, "contacting" PARP7 with the compound of the present invention or "contacting" a cell with the compound of the present invention includes administering the compound of the present invention to an individual or patient, such as a human, having PARP7, and also includes introducing the compound of the present invention into a sample containing a cell preparation or purified preparation that contains PARP7.

[0130] As used herein, the terms "individual" or "patient" are used interchangeably and refer to a mammal, specifically, a human.

[0131] As used herein, the phrase "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits the biological or drug response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other clinician.

[0132] As used herein, the term "treating" or "treatment" refers to 1) inhibiting a disease in an individual experiencing or exhibiting a lesion or symptom of the disease (i.e., halting further development of the lesion and / or symptom), or 2) ameliorating a disease in an individual experiencing or exhibiting a lesion or symptom of the disease (i.e., reversing the lesion and / or symptom).

[0133] As used herein, the terms "preventing" or "prevention" refer to preventing a disease in an individual who may be susceptible to the disease, but who has not yet experienced or exhibited the lesions or symptoms of the disease.

[0134] Combination therapy One or more additional pharmaceutical agents or therapies can be used in combination with the compounds of the invention, such as chemotherapeutic or other anti-cancer agents, immune enhancers, immunosuppressants, immunotherapy, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.), and / or kinase (tyrosine or serine / threonine), epigenetic or signal transduction inhibitors, etc. These agents can be combined with the compounds of the invention in a single dosage form or can be administered simultaneously or sequentially as separate dosage forms.

[0135] Suitable drugs for use in combination with the compounds of the present invention for the treatment of cancer include chemotherapy, targeted cancer therapy, immunotherapy, or radiation therapy.The compounds of the present invention may be effective in combination with antihormonal drugs for the treatment of breast cancer and other tumors.Suitable examples are antiestrogens including but not limited to tamoxifen and toremifene, aromatase inhibitors including but not limited to letrozole, anastrozole, and exemestane, corticosteroids (e.g., prednisone), progestins (e.g., megastrol acetate), and estrogen receptor antagonists (e.g., fulvestrant).Suitable antihormonal drugs used in the treatment of prostate cancer and other cancers may also be combined with the compounds of the present invention. These include antiandrogens, including but not limited to flutamide, bicalutamide, and nilutamide, luteinizing hormone-releasing hormone (LHRH) analogs, including leuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists (e.g., degarelix), androgen receptor blockers (e.g., enzalutamide), and agents that inhibit androgen production (e.g., biraterone).

[0136] Angiogenesis inhibitors can be effective in some tumors in combination with FGFR inhibitors.These include antibodies against VEGF or VEGFR, or kinase inhibitors of VEGFR.Antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept.VEGFR kinase inhibitors and other antiangiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0137] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including but not limited to nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0138] Other anti-cancer agents include antibody therapeutics against checkpoint or costimulatory molecules, such as CTLA-4, PD-1, PD-L1, or 4-1BB, respectively, or antibodies against cytokines (IL-10, TGF-β, etc.). Exemplary cancer immunotherapy antibodies include pembrolizumab, ipilimumab, nivolumab, atezolizumab, and durvalumab. Additional anti-cancer agents include antibody therapeutics directed against surface molecules of hematological cancers, such as ofatumumab, rituximab, and alemtuzumab.

[0139] Methods for safely and effectively administering many of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in standard texts. For example, the administration of many of the chemotherapeutic agents is described in the Physicians' Desk Reference (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0140] Pharmaceutical Preparations and Dosage Forms When used as a pharmaceutical, the compound of the present invention can be administered in the form of a pharmaceutical composition. A pharmaceutical composition refers to a combination of the compound of the present invention or its pharmaceutically acceptable salt with at least one pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by various routes depending on whether local or systemic treatment is desired and the area to be treated. Administration can be oral, local (e.g., for administration to the eye, mucous membrane, e.g., intranasal, vaginal, and rectal delivery), pulmonary (e.g., inhalation or insufflation of powder or aerosol (e.g., by nebulizer), intratracheal, intranasal, epidermal, and transdermal), intraocular, or parenteral.

[0141] The present disclosure also includes pharmaceutical compositions that contain one or more of the compounds of the present invention as active ingredients in combination with one or more pharma- ceutically acceptable carriers.When preparing the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper, or other container.When an excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient.Thus, the present compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders.

[0142] The compositions can be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, together with a suitable pharmaceutical excipient.

[0143] The active compound can be effective over a wide dosage range and is generally administered in a medicamentously effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by the physician according to the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0144] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogenous mixture of the compound of the present invention. When these preformulation compositions are referred to as homogenous, the active ingredient is typically uniformly dispersed throughout the composition, which allows the composition to be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, for example, containing about 0.1 to about 500 mg of the active ingredient of the present invention.

[0145] The tablet or pill of the present invention can be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action.For example, the tablet or pill can comprise an inner dosage component and an outer dosage component, the latter being in the form of a coating over the former.These two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allows the inner component to pass intact through the duodenum or be delayed in release.Various materials can be used for such enteric layers or coatings, including some polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0146] Liquid forms into which the compounds and compositions of the present invention may be incorporated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0147] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route to produce a local or systemic effect. Compositions may be nebulized by use of an inert gas. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0148] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of administration, such as prophylaxis or treatment, the condition of the patient, the mode of administration, etc. In therapeutic applications, the compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the disease state being treated and will also be dependent on the judgment of the attending clinician depending on such factors as the severity of the disease, the age, weight, and general condition of the patient.

[0149] The composition administered to patient can be in the form of the above-mentioned pharmaceutical composition.These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered.Aqueous solution can be packaged for direct use or lyophilized, and lyophilized preparation is combined with sterile aqueous carrier before administration.

[0150] The therapeutic dosage of the compounds of the invention may vary depending on the particular application for which the treatment is made, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound of the invention in a pharmaceutical composition may vary depending on several factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compounds of the invention may be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dose ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dose range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage may depend on such variables as the type of disease or disorder and its progression, the general health of the particular patient, the relative biological efficiency of the compound selected, the formulation of excipients, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0151] The compounds of the invention may also be formulated in combination with one or more additional active ingredients, which may include any pharmaceutical agent, such as an antiviral agent, an anticancer agent, a vaccine, an antibody, an immune enhancer, an immunosuppressant, an anti-inflammatory agent, etc. EXAMPLES

[0152] device: 1 H NMR spectra were recorded at 300 MHz or 400 MHz using a Bruker AVANCE 300 MHz / 400 MHz spectrometer. NMR interpretation was performed using Bruker Topspin software to assign chemical shifts and multiplicities. If two adjacent peaks of equal or unequal height are observed, these two peaks can be labeled as either a multiplet or a doublet. In the case of a doublet, coupling constants can be assigned using this software. In any given example, one or more protons may not be observed because they are obscured by water and / or solvent peaks. LCMS equipment and conditions are as follows: 1.LC (basic conditions): Shimadzu LC-20AD, binary pump, diode array detector. Column: Kinetex 2.6 μm EVO C18 100A, 50 × 3.0 mm, 2.6 μm. Mobile phase: A: water / 5 mM NH 4 HCO 3 , B: acetonitrile. Flow rate: 1.2 mL / min at 40°C. Detectors: 254 nm, 220 nm. Gradient stop time: 2.9 min. Timetable: [Table 1] 2.LC (basic conditions): Shimadzu LC-20ADXR, binary pump, diode array detector. Column: Poroshell HPH-C18, 50×3.0 mm, 2.7 μm. Mobile phase A: 0.04% ammonium hydroxide, mobile phase B: acetonitrile. Flow rate: 1.2 mL / min at 40° C. Detectors: 254 nm, 220 nm. Gradient stop time: 3.0 min. Timetable: [Table 2] 3.LC (acidic conditions): Shimadzu LC-20AD, binary pump, diode array detector. Column: Ascentis Express C18, 50×3.0 mm, 2.7 μm. Mobile phase: A: water / 0.05% TFA, B: acetonitrile / 0.05% TFA. Flow rate: 1.5 mL / min at 40° C. Detectors: 254 nm, 220 nm. Gradient stop time: 2.9 min. Timetable: [Table 3] 4.LC (acidic conditions): Shimadzu LC-30AD, binary pump, diode array detector. Column: Accucore C18, 50×2.1 mm, 2.6 μm. Mobile phase A: water / 0.1% FA, mobile phase B: acetonitrile / 0.1% FA. Flow rate: 1.0 mL / min at 40° C. Detectors: 254 nm, 220 nm. Gradient stop time: 3.0 min. Timetable: [Table 4] 1.S: LCMS-2020, quadrupole LC / MS, ion source: ES-API, TIC: 90-900 m / z, fragmentor: 60, drying gas flow rate: 15 L / min, nebulizer gas flow rate: 1.5 L / min, drying gas temperature: 250 °C, Vcap: 1100 V. 2. Sample preparation: Samples were dissolved in ACN or methanol at 1-10 mg / mL, then filtered through a 0.22 μm filter membrane. Injection volume: 1-10 μL.

[0153] Definition: ACN (acetonitrile), CH 3 CN (acetonitrile), CDCl 3 (deuterated chloroform), CD 3 OD (deuterated methanol), DCM (dichloromethane), DEA (diethylamine), DIEA (diisopropylethylamine), DMF (N,N-dimethylformamide), DMAP (4-dimethyl aminopyridine), DMSO (dimethyl sulfoxide), DMSO-d 6 (deuterated dimethylsulfoxide), equiv (equivalent), ESI (electrospray ionization), EtOAc (ethyl acetate), EtOH (ethanol), g (grams), h (hours), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), 1 H NMR (proton nuclear magnetic resonance), HCl (hydrochloric acid), Hz (hertz), H 2 O (water), Hex (hexane), i-prOH (isopropyl alcohol), K 2 CO 3 (potassium carbonate), L (liters), LCMS (liquid chromatography mass spectrometry), M (moles), MeCN (acetonitrile), MeOH (methanol), mg (milligrams), MHz (megahertz), min (minutes), MtBE (methyl tert-butyl ether), mL (milliliters), mmol (millimoles), N (normalized concentration), NaBH(AcO) 3 (sodium triacetoxyborohydride), NaCl (sodium chloride), NaH (sodium hydride), NaHCO 3(sodium bicarbonate), n-BuOH (n-butyl alcohol), NH 4 Cl (ammonium chloride), NMP (N-methyl-2-pyrrolidone), PE (petroleum ether), PMB (paramethoxybenzyl), prep-HPLC (preparative high performance liquid chromatography), RT (room temperature), TEA (triethylamine), TFA (trifluoroacetic acid), tR (retention time), triflic (trifluoromethanesulfonic acid), AcOH (acetic acid), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), Na 2 CO 3 (Sodium Carbonate), NaBH 3 CN (sodium cyanoborohydride), NaOH (sodium hydroxide), NH 3 (ammonia), Pd / C (palladium on carbon), PMB (p-methoxybenzyl), STAB (sodium triacetoxyborohydride), t-BuOK (potassium tert-butoxide), TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl), Tf 2 O(trifluoromethanesulfonic anhydride), TfOH(trifluoromethanesulfonic acid), THF(tetrahydrofuran), Ti(Oi-Pr) 4 (Titanium Isopropoxide).

[0154] Intermediate I-1: Synthesis of 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0155] Step A To a solution of 4,5-dibromo-2,3-dihydropyridazin-3-one (250 g, 984.71 mmol, 1 equiv) in DMF (2.5 L) was added NaH (59.1 g, 1477.07 mmol, 1.50 equiv, 60%) in portions at 0-10 °C, followed by 1-(chloromethyl)-4-methoxybenzene (230.3 g, 1470.53 mmol, 1.49 equiv) at 0 °C. The resulting solution was stirred at room temperature for 3 h. The reaction was then quenched by the addition of 5 L of water / ice and extracted twice with 2.5 L of DCM. The organic layers were combined and concentrated. The solid was washed with MeOH (500 mL x 2) to give 290 g (79% yield) of 4,5-dibromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydropyridazin-3-one as a solid. LCMS [M+H] + 378.00.

[0156] Step B A solution of 4,5-dibromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydropyridazin-3-one (290 g, 775.33 mmol, 1 equiv.) and potassium hydroxide (130.5 g, 2326.00 mmol, 3.00 equiv.) in MeOH (2.5 L) was stirred at room temperature for 2 h. The resulting mixture was concentrated to 500 mL and the solid was collected by filtration. The resulting cake was slurried in water (1 L) for 1 h to give 232 g (92% yield) of 4-bromo-5-methoxy-2-[(4-methoxyphenyl)methyl]-2,3-dihydropyridazin-3-one as a solid. LCMS [M+H] + 326.90.

[0157] Step C A solution of 4-bromo-5-methoxy-2-[(4-methoxyphenyl)methyl]-2,3-dihydropyridazin-3-one (232 g, 713.49 mmol, 1 equiv.), 2,2-difluoro-2-methylsulfoacetate (411.2 g, 2140.44 mmol, 3.00 equiv.), and CuI (67.9 g, 356.52 mmol, 0.50 equiv.) in NMP (1.2 L) was stirred at 100° C. for 3 h. Then, 1.5 L of water was added to quench the reaction. The resulting solution was extracted three times with 1 L of DCM. The organic layers were combined and concentrated. The residue was applied to a silica gel column with EtOAc / petroleum ether (1 / 1). The collected fractions were combined and concentrated to give a crude oil, to which 1 L of water was added. The solid was collected by filtration and washed with 100 mL of MeOH to give 170 g (76% yield) of 5-methoxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one as a solid. LCMS [M+H] + 315.10.

[0158] Step D To a solution of 5-methoxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (170 g, 540.95 mmol, 1 equiv.) in DMF (850 mL) was added TMSI (140 g, 699.67 mmol, 1.29 equiv.) dropwise at 20° C. The resulting solution was stirred at 85° C. for 20 h. Then, 850 mL of water was added to quench the reaction mixture, and the resulting solution was extracted three times with 850 mL of DCM, and the organic layers were combined and dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum and the crude product was purified by silica gel column chromatography and then recrystallized with MtBE to give 120 g (74% yield) of 5-hydroxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one as a white solid. LCMS [M+H] + 301.07.

[0159] Step E To a solution of 5-hydroxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (110 g, 366.38 mmol, 1 equiv.) in DMF (550 mL) was added oxalic acid dichloride (93 g, 732.75 mmol, 2.00 equiv.) dropwise at 0-5°C. The resulting solution was stirred at room temperature for 8 h. The reaction was then quenched by adding 550 mL of water. The solid was collected by filtration to give 108 g (93%) of 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one as a white solid. LCMS [M+H] + 319.04[M+H] + , 1 H NMR (30 MHz, DMSO-d 6 )δ 8.22(d,J=0.8Hz,1H),7.33-7.22(m,2H),6.94-6.84(m,2H),5.18(s,2H),3.71(s,3H).

[0160] Intermediate I-2: Synthesis of (S)-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetic acid [ka]

[0161] Step A To a solution of (S)-tert-butyl(1-hydroxypropan-2-yl)carbamate (5.00 g, 28.5 mmol, 1.0 equiv.) in DMF (80 mL) was added NaH (60% dispersion in oil, 3.4 g, 85.6 mmol, 3.0 equiv.) in portions at 0° C. The mixture was stirred at that temperature for 20 min, and to this suspension was added tert-butyl 2-bromoacetate (7.30 g, 57 mmol, 2.00 equiv.). The resulting solution was stirred at 0° C. for 30 min, after which water (60 mL) was added. The solution was extracted three times with 100 mL of ethyl acetate. The organic layers were combined and washed three times with 50 mL of brine. The organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (3:7) to give 2.8 g (34% yield) of (S)-tert-butyl 2-(2-((tert-butoxycarbonyl)amino)propoxy)acetate as a colorless oil. LCMS (ESI, m / z): 290.20 [M+H] + .

[0162] Step B A solution of tert-butyl 2-[(2S)-2-[(tert-butoxycarbonyl)amino]propoxy]acetate (2.80 g, 9.7 mmol, 1.0 equiv) in 4N HCl (30 mL) in dioxane was stirred at room temperature for 14 h. The mixture was concentrated to give 2.5 g of crude (S)-2-(2-aminopropoxy)acetic acid hydrochloride as a red oil. LCMS (ESI, m / z): 133.15 [M+H] + .

[0163] Step C A solution of 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (3.00 g, 9.4 mmol, 1.00 equiv., intermediate I-1), TEA (2.86 g, 28.2 mmol, 3.0 equiv.), and (S)-2-(2-aminopropoxy)acetic acid hydrochloride (2.50 g, 14.7 mmol, 1.6 equiv.) in i-PrOH (100 mL) was stirred for 2 h at 60° C. The mixture was concentrated and the crude product was applied to a silica gel column eluted with dichloromethane / methanol (10:1) to give 1.9 g (49% yield) of (S)-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetic acid as a yellow oil. LCMS(ESI,m / z):415.2[M+H] + .

[0164] Intermediate I-3: Synthesis of 3-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride [ka]

[0165] Step A A solution of 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (6.00 g, 37.9 mmol, 1.0 eq.), acetic acid (2.73 g, 45.5 mmol, 1.2 eq.), and tert-butyl 4-aminopiperidine-1-carboxylate (15.2 g, 75.9 mmol, 2.0 eq.) in DCE (100 mL) was stirred for 1 hour, after which STAB (24.0 grams, 114 mmol, 3.0 eq.) was added. The resulting solution was stirred at room temperature for 14 hours. The pH value of the solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate. The resulting solution was extracted three times with 100 mL of dichloromethane. The organic layers were combined and washed with 50 mL of 10% aqueous citric acid and 50 mL of brine. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (8:2) to give 5.1 g (47% yield) of tert-butyl 4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate as a yellow solid. LCMS (ESI, m / z): 285.2 [M+H] + .

[0166] Step B A solution of tert-butyl 4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2.0 g, 1.0 equiv.) in 4N HCl (30 mL) in dioxane was stirred at room temperature for 1 h. The resulting mixture was concentrated to give 1.8 g of crude 3-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride as a white solid, which was carried forward without further purification. LCMS (ESI, m / z): 185.1 [M+H] + .

[0167] Intermediate I-4: Synthesis of N-methyl-1-(5-(trifluoromethyl)thiazol-2-yl)piperidin-4-amine [ka]

[0168] Step A tert-Butyl methyl(piperidin-4-yl)carbamate (214 mg, 0.99 mmol, 1.0 equiv.), 2-bromo-5-(trifluoromethyl)thiazole (232 mg, 0.99 mmol, 1.0 equiv.), and K 2 CO 3 A solution of (207 mg, 1.49 mmol, 1.5 equiv) in NMP (5 mL) was stirred at 80° C. for 2 h. Water (20 mL) was added and the resulting solution was extracted three times with 15 mL of ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (2 / 3) to give 343 mg (94% yield) of tert-butyl methyl(1-(5-(trifluoromethyl)thiazol-2-yl)piperidin-4-yl)carbamate as a white solid. LCMS (ESI, m / z): 366.1 [M+H] + .

[0169] Step B A solution of tert-butyl methyl(1-(5-(trifluoromethyl)thiazol-2-yl)piperidin-4-yl)carbamate (343 mg, 0.94 mmol, 1.00 equiv) in 4N HCl (5 mL) in dioxane was stirred for 1 h, then the mixture was concentrated to give 275 mg (97% yield) of N-methyl-1-(5-(trifluoromethyl)thiazol-2-yl)piperidin-4-amine hydrochloride as a white solid. LCMS (ESI, m / z): 266.00 [M+H] + .

[0170] Intermediates I-5 to I-6 were synthesized following the procedure described for the synthesis of N-methyl-1-(5-(trifluoromethyl)thiazol-2-yl)piperidin-4-amine (Intermediate I-4), using the appropriate building blocks and modified reaction conditions (such as reagent ratios, temperatures, coupling conditions, and reaction times) as necessary. [Table 5]

[0171] Example 1: Synthesis of (S)-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide [ka]

[0172] Step A tert-Butyl piperidin-4-ylcarbamate (2.00 g, 9.98 mmol, 1.0 equiv.), 2-chloro-5-(trifluoromethyl)pyrimidine (1.82 g, 9.99 mmol, 1.0 equiv.), and K 2 CO 3 A solution of (1.38 g, 9.99 mmol, 1.0 equiv) in NMP (50 mL) was stirred at 80° C. for 2 h. Water (200 mL) was added and the solid was collected by filtration to give tert-butyl 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-ylcarbamate (3.7 g, 96% yield, 90% purity) as a white solid. LCMS (ESI, m / z): 347.15 [M+H] + .

[0173] Step B A solution of tert-butyl 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-ylcarbamate (2.31 g, 6.0 mmol, 1.0 equiv, 90% purity) in 4N HCl (20 mL) in 1,4-dioxane was stirred at room temperature for 1 h. The solid was collected by filtration to give 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine hydrochloride (1.27 g, 82% yield) as a white solid. LCMS (ESI, m / z): 247.20 [M+H] + .

[0174] Step C A solution of (S)-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetic acid (200 mg, 0.48 mmol, 1.0 equiv, 50% purity, intermediate I-2), DIEA (187 mg, 1.44 mmol, 3.0 equiv), HATU (183 mg, 0.48 mmol, 1.0 equiv), and 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine hydrochloride (119 mg, 0.48 mmol, 1.0 equiv) in DMF (2.0 mL) was stirred at room temperature for 1 h. After concentration, the residue was purified by H 2 O / CH 3 Application to a reverse phase column eluting with CN (31 / 69) gave (S)-2-(2-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide (51 mg, 15% yield) as a yellow oil. LCMS (ESI, m / z): 644.20 [M+H] + .

[0175] Step D To a solution of (S)-2-(2-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide (49 mg, 0.076 mmol, 1.0 equiv) in TFA (1.00 mL) was added trifluoromethanesulfonic acid (0.10 mL) at 0° C. and the solution was maintained at that temperature for 1 h. Ice water (30 mL) was added and the pH value of the solution was adjusted to 0.05 with saturated NaHCO 3 The pH was adjusted to 7 with aqueous solution. The resulting solution was extracted three times with 60 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by HCl distillation. 2 O / CH 3Applying to a reverse phase column eluting with CN (50 / 50) gave (S)-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide (14 mg, 35% yield) as a white solid. LCMS (ESI, m / z): 524.2 [M+H] + ; 1 H NMR (300MHz, DMSO-d 6 )δ 12.48(s,1H),8.74(s,2H),7.97(s,1H),7.58(d,J=8.1Hz,1H),6.46-6.39(m,1H),4.62(d,J=13.5Hz,2H),4.22-4.15(m,1H),4.01-3. 90(m,2H),3.89(s,2H),3.52(d,J=5.4Hz,2H),3.16(t,J=12.2Hz,2H),1.80(d,J=9.3Hz,2H),1.42-1.30(m,2H),1.18(d,J=6.6Hz,3H).

[0176] Example 2: Synthesis of (S)-N-methyl-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide [ka]

[0177] Step A A solution of tert-butyl 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-ylcarbamate (2.31 g, 6.67 mmol, 1.00 equiv., Example 1, Step A) in DMF was treated with NaH (800 mg, 20.0 mmol, 3.0 equiv., 60% dispersion in mineral oil) at 0° C. After 15 min, iodomethane (0.95 g, 6.67 mmol, 1.0 equiv.) was added and the solution was stirred at room temperature for 1 h. 50 mL of water was added and the solid was collected by filtration to give tert-butyl methyl(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)carbamate (1.65 g, 63% yield) as a white solid. LCMS (ESI, m / z): 361.20 [M+H] + .

[0178] Step B A solution of tert-butyl methyl(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)carbamate (1.65 g, 4.578 mmol, 1.00 equiv) in 4N HCl (16 mL) in 1,4-dioxane was stirred at room temperature for 1 h. The solid was collected by filtration to give N-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine hydrochloride (1.21 g, 96% yield) as a white solid. LCMS (ESI, m / z): 261.20 [M+H] + .

[0179] Step C A solution of (S)-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetic acid (200 mg, 0.48 mmol, 1.0 equiv., intermediate I-2), N-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine hydrochloride (125 mg, 0.48 mmol, 1.0 equiv.), DIEA (187 mg, 1.44 mmol, 3.0 equiv.), and HATU (183 mg, 0.48 mmol, 1.0 equiv.) in DMF (2 mL) was stirred at room temperature for 1 h. After concentration, the residue was purified by H 2 O / CH 3Application to a reverse phase column eluting with CN (26 / 74) gave (S)-2-(2-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide (117 mg, 29% yield) as a yellow oil. LCMS (ESI, m / z): 658.25 [M+H] + .

[0180] Step D A solution of (S)-2-(2-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide (115 mg, 0.18 mmol, 1.0 equiv) in TFA (2.00 mL) was treated with trifluoromethanesulfonic acid (0.20 mL) at 0° C. and maintained at that temperature for 20 min. Ice water (30 mL) was added and the pH value of the solution was adjusted to 0.01 g with saturated NaHCO 3 The pH was adjusted to 7 with aqueous solution. The resulting solution was extracted three times with 100 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by HCl distillation. 2 O / CH 3 Applying to a reverse phase column eluting with CN (42 / 58) gave (S)-N-methyl-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide (18 mg, 19% yield) as a white solid. LCMS (ESI, m / z): 538.2 [M+H] + ; 1 H NMR (300MHz, DMSO-d 6)δ 12.22(s,1H),8.65(s,2H),7.89(s,1H),6.75-6.50(br,1H),4.86(d,J=12.6Hz,2H),4.60-4.40(rotamer A,m,1H),4.30(s,1H),4.22-4.1 2(m,3H),3.85-3.79(rotamer B,m,1H).3.52-3.48(m,2H),3.10-2.89(m,2H),2.65-2.72(m,3H),1.80-1.50(m,4H),1.23(d,J=6.6Hz,3H).

[0181] Examples 3-5 were synthesized according to the procedure described for the synthesis of (S)-N-methyl-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide (see Example 2), using the appropriate building blocks and modified reaction conditions (such as reagent ratios, temperatures, coupling conditions, and reaction times) as necessary. [Table 6-1] [Table 6-2]

[0182] Example 6: Synthesis of (S)—N-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)-N-methyl-2-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetamide [ka]

[0183] Step A tert-Butyl methyl(piperidin-4-yl)carbamate (1.00 g, 4.666 mmol, 1.00 equiv.), 6-chloronicotinonitrile (0.52 g, 3.733 mmol, 0.80 equiv.), and K 2 CO3 A solution of (0.64 g, 4.666 mmol, 1.0 equiv) in NMP (50 mL) was stirred at 80° C. for 2 h. 150 mL of water was added and the solid was collected by filtration to give tert-butyl (1-(5-cyanopyridin-2-yl)piperidin-4-yl)(methyl)carbamate (970 mg, 59% yield) as a white solid. LCMS: [M+H] + 317.10.

[0184] Step B A solution of tert-butyl (1-(5-cyanopyridin-2-yl)piperidin-4-yl)(methyl)carbamate (960 mg, 3.034 mmol, 1.00 equiv) in 4N HCl (20 mL) in 1,4-dioxane was stirred at room temperature for 1 h. The solution was concentrated to give 6-(4-(methylamino)piperidin-1-yl)nicotinonitrile hydrochloride (810 mg, 99% yield) as a yellow oil. LCMS: [M+H] + 217.20.

[0185] Step C A solution of (S)-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetic acid (77 mg, 0.185 mmol, 1.00 equiv, intermediate I-2), 6-(4-(methylamino)piperidin-1-yl)nicotinonitrile hydrochloride (26 mg, 0.120 mmol, 0.65 equiv), DIEA (23 mg, 0.185 mmol, 1 equiv), and HATU (46 mg, 0.120 mmol, 0.65 equiv) in DMF (2 mL) was stirred for 1 h. After concentration, the residue was purified by H 2 O / CH 3 Application to a reverse phase column eluting with CN (37 / 63) gave (S)-N-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-N-methylacetamide (51 mg, 43% yield) as a yellow oil. LCMS: [M+H] + 614.25.

[0186] Step D To a solution of (S)-N-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-N-methylacetamide (50 mg, 0.081 mmol, 1.00 equiv.) in TFA (1.00 mL) was added trifluoromethanesulfonic acid (0.10 mL) at 0° C., and the mixture was stirred at that temperature for 1 h. Ice water (30 mL) was added and the pH value of the solution was adjusted to 0.05 with saturated NaHCO 3 The acid was adjusted to 7 with aqueous solution. The resulting solution was extracted three times with 60 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by H 2 O / CH 3 Application to a reverse phase column eluting with CN (51 / 49) gave (S)-N-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)-N-methyl-2-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetamide (15 mg, 36% yield) as a white solid. LCMS: [M+H] + 494.20. 1 H NMR (300MHz, DMSO-d 6 )δ 12.48(s,1H),8.48(d,J=3.0Hz,1H),7.95(s,1H),7.83(dd,J=9.3,2.4H z,1H),6.97(d,J=9.1Hz,1H),6.73-6.65(m,1H),4.71-4.50(m,2H),4.3 3(s,1H),4.15(s,2H),3.80-3.75(m,1H),3.60-3.50(m,2H),3.01-2.88 (m,2H),2.67(d,J=9.6Hz,3H),1.78-1.52(m,4H),1.18(d,J=6.4Hz,3H).

[0187] Example 7: Synthesis of (S)-N-ethyl-2-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide [ka]

[0188] Step A A solution of (S)-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetic acid (414 mg, 1.0 mmol, 1.0 equiv., intermediate I-2), HATU (380 mg, 1.0 mmol, 1.0 equiv.), DIEA (260 mg, 2 mmol, 2.00 equiv.), and tert-butyl 4-(ethylamino)piperidine-1-carboxylate (230 mg, 1.0 mmol, 1.0 equiv.) in DMF (4 mL) was stirred at room temperature for 1 h. The residue was purified by H 2 O / CH 3 Purification by reverse phase chromatography eluting with CN afforded 200 mg (32% yield) of (S)-tert-butyl 4-(N-ethyl-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetamido)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m / z): 626.25 [M+H] + .

[0189] Step B A solution of (S)-4-(N-ethyl-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetamide)piperidine-1-carboxylate tert-butyl (200 mg, 0.32 mmol, 1.0 equiv) in 4N HCl (5 mL) in dioxane was stirred at room temperature for 2 h. The solution was concentrated under vacuum to give 130 mg (78% yield) of (S)-N-ethyl-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-N-(piperidin-4-yl)acetamide hydrochloride as a yellow oil, which was carried forward without further purification. LCMS (ESI, m / z): 526.25 [M+H] + .

[0190] Step C (S)-N-Ethyl-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-N-(piperidin-4-yl)acetamide (130 mg, 0.25 mmol, 1.0 equiv.), K 2 CO 3 A solution of 2-chloro-5-(trifluoromethyl)pyrimidine hydrochloride (104 mg, 0.75 mmol, 3.0 equiv.) and 2-chloro-5-(trifluoromethyl)pyrimidine hydrochloride (46 mg, 0.25 mmol, 1.0 equiv.) in DMF (5 mL) was stirred at room temperature for 2 h. Water was added and the resulting solution was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by HPLC using H 2 O / CH 3 Purification by reverse phase chromatography eluting with CN afforded 140 mg (83% yield) of (S)-N-ethyl-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide as a yellow solid. LCMS (ESI, m / z): 672.25 [M+H] + .

[0191] Step D A solution of (S)-N-ethyl-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide (140 mg, 0.21 mmol, 1.00 equiv) in trifluoroacetic acid (3 mL) was treated with trifluoromethanesulfonic acid (0.3 mL) at 0° C. and maintained at that temperature for 1 h. Water was added and the pH was adjusted to 0.1 mg / mL with saturated NaCl. 2 CO 3 The acid was adjusted to 6 with aqueous solution. The resulting solution was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude residue was purified by HCl distillation. 2 O / CH 3 Purification by reverse phase chromatography eluting with CN afforded 80 mg (69% yield) of (S)-N-ethyl-2-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide as a white solid. LCMS (ESI, m / z): 552.20 [M+H] + ; 1 HNMR (DMSO-d 6 ,300MHz)δ 12.47(s,1H),8.69(s,2H),7.93(s,1H),6.75-6.68(m,1H),4.82(d,J=13.1Hz,2H),4.27(s,1H),4.18(d,J=3.5Hz,2H),3.80-3.71( m,1H),3.56(d,J=5.6Hz,2H),3.15(d,J=7.3Hz,2H),3.01-2.89(m,2H),1.78-1.62(m,4H),1.18(t,J=5.8Hz,3H),1.12-0.93(m,3H).

[0192] Example 8: Synthesis of (S)-N-methyl-2-((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)azetidin-2-yl)methoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide [ka]

[0193] Step A A solution of (S)-azetidin-2-ylmethanol hydrochloride (1.20 g, 9.71 mmol, 1.0 equiv), TEA (2.80 mL), and 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (3.20 g, 10.0 mmol, 1.03 equiv, intermediate I-1) in ethanol (20 mL) was stirred at 60° C. for 1 h. After cooling to room temperature, the solution was concentrated in vacuo. The crude product was purified by HPLC using H 2 O / CH 3 Purification by reverse phase chromatography eluting with CN gave 2.0 g (55% yield) of (S)-5-(2-(hydroxymethyl)azetidin-1-yl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as a white solid. LCMS (ESI, m / z): 370.15 [M+H] + .

[0194] Step B A solution of (S)-5-(2-(hydroxymethyl)azetidin-1-yl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (738 mg, 1.99 mmol, 1.0 equiv), tert-butyl 2-chloroacetate (604 mg, 4.01 mmol, 2.01 equiv), and NaH (60% dispersion in oil, 240 mg, 6.0 mmol, 3.0 equiv) in DMF (10 mL) was stirred at 0° C. for 2 h. After concentration, the residue was purified by HCl distillation. 2 O / CH 3Purification by C18 reverse phase chromatography eluting with CN afforded 430 mg (44% yield) of (S)-tert-butyl 2-((1-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)azetidin-2-yl)methoxy)acetate as a yellow oil. LCMS (ESI, m / z): 483.15 [M+H] + .

[0195] Step C A solution of (S)-2-((1-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)azetidin-2-yl)methoxy)acetate tert-butyl (420 mg, 0.87 mmol, 1.0 equiv) in TFA (5 mL) and DCM (5 mL) was stirred at room temperature for 2 h and the solution was concentrated to give 490 mg (92% yield) of (S)-2-((1-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)azetidin-2-yl)methoxy)acetic acid as a brown oil. LCMS (ESI, m / z): 428.10 [M+H] + .

[0196] Step D A solution of (S)-2-((1-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)azetidin-2-yl)methoxy)acetic acid (274 mg, 1.05 mmol, 1.0 equiv.), DIEA (408 mg, 3.16 mmol, 3.0 equiv.), and HATU (600 mg, 1.58 mmol, 1.5 equiv.) in DMF (5 mL) was stirred at room temperature for 1 h. The residue was purified by H 2 O / CH 3Direct purification by reverse phase chromatography eluting with CN afforded 533 mg of (S)-2-((1-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)azetidin-2-yl)methoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide (76% yield) as a colorless oil. LCMS (ESI, m / z): 670.20 [M+H] + .

[0197] Step E A solution of (S)-2-((1-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)azetidin-2-yl)methoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide (520 mg, 0.76 mmol, 1.0 equiv.) and trifluoromethanesulfonic acid (0.33 mL) in trifluoroacetic acid (3.3 mL) was stirred at room temperature for 1 h. 20 mL of water was added and the pH value of the solution was adjusted to 0.1 mL by addition of saturated NaCl. 2 CO 3 The acid was adjusted to 8 with aqueous solution. The resulting solution was extracted three times with 15 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by H 2 O / CH 3 Purification by C18 reverse phase chromatography eluting with CN afforded 65 mg of (S)-N-methyl-2-((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)azetidin-2-yl)methoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide (15%) as a white solid. LCMS (ESI, m / z): 550.15 [M+H] + ; 1 H NMR (400MHz, DMSO-d 6)δ 12.36(d,J=10.6Hz,1H),8.69(d,J=0.9Hz,2H),7.75(s,1H),4.89-4.78(m,3H),4.57-4.52(m,1H),4.42-4.27(m,2H),4.24(s,1H),3.88( dr.

[0198] Example 9: Synthesis of (S)-2-(3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide [ka]

[0199] Step A A solution of methyl (R)-2-amino-3-methoxypropan-1-ol hydrochloride (4.00 g, 28.3 mmol, 1.0 equiv.), TEA (8.58 g, 84.8 mmol, 3.0 equiv.), and 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (9.00 g, 28.24 mmol, 1.0 equiv., intermediate I-1) in i-PrOH (40 mL) was stirred for 2 h at 60° C. The resulting mixture was concentrated under vacuum and the crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (7:3) to give 10.5 g (96% yield) of (R)-5-((1-hydroxy-3-methoxypropan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as a white solid. LCMS(ESI,m / z):388.10[M+H] + .

[0200] Step B To a solution of (R)-5-((1-hydroxy-3-methoxypropan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (2.0 g, 5.16 mmol, 1.0 equiv.) in DMF (40 mL) was added NaH (60% dispersion in mineral oil, 207 mg, 5.16 mmol, 1.0 equiv.) in small portions at 0° C. The solution was stirred for 15 min, after which tert-butyl 2-bromoacetate (2.01 g, 10.33 mmol, 2.0 equiv.) was added to the resulting solution. The mixture was stirred at room temperature for 1 h. 30 mL of water was added and the resulting solution was extracted three times with 50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:1) to give 300 mg (12% yield) of (S)-2-(3-methoxy-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)tert-butyl acetate as a yellow solid. LCMS (ESI, m / z): 502.20 [M+H] + .

[0201] Step C A solution of (S)-2-(3-methoxy-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)tert-butyl acetate (240 mg, 0.48 mmol, 1.0 equiv.) in trifluoroacetic acid / trifluoromethanesulfonic acid (5:1, 2.4 mL) was stirred at room temperature for 3 h. Water (20 mL) was added and the pH value of the solution was adjusted to 0.05 with saturated NaHCO 3 The acid was adjusted to 8 with aqueous solution. The resulting solution was extracted three times with 50 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by HCl. 2 O / CH 3Application to a C18 reverse phase column eluted with CN (7:3) gave 60 mg (39% yield) of (S)-2-(3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetic acid as a yellow solid. LCMS (ESI, m / z): 326.10 [M+H] + .

[0202] Step D A solution of (S)-2-(3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetic acid (55 mg, 0.17 mmol, 1.0 equiv.), N-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine (48 mg, 0.19 mmol, 1.10 equiv.), HATU (71 mg, 0.19 mmol, 1.10 equiv.), and DIEA (44 mg, 0.34 mmol, 2.0 equiv.) in DMF (1 mL) was stirred at room temperature for 2 h. 10 mL of water was added and the resulting solution was extracted twice with 50 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After concentration, the crude product was purified by HPLC using H 2 O / CH 3 Purification by reverse phase chromatography eluting with CN (45:55) afforded 16 mg (17% yield) of (S)-2-(3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide as a white solid. LCMS (ESI, m / z): 568.30 [M+H] + ; 1 H NMR (DMSO-d 6,300MHz)δ 12.48(s,1H),8.68(s,2H),7.94(s,1H),6.70-6.55(m,1H),4.82(d,J=13.2Hz,2H),4.53-4.41(m,1H),4.48-4.29(m,2H),4.18 (s,1H),3.58(d,J=5.8Hz,2H),3.47(d,J=5.6Hz,2H),3.27(s,3H),3.10-2.90(m,2H),2.65(d,J=8.9Hz,3H),1.80-1.61(m,4H).

[0203] Example 10: Synthesis of 5-((S)-1-((S)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(2H)-one (10A) and 5-((S)-1-((R)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(2H)-one (10B) [ka]

[0204] Step A 3-Hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (600 mg, 2.72 mmol, 1.0 equiv., intermediate I-3), 2-chloro-5-(trifluoromethyl)pyrimidine (496 mg, 2.72 mmol, 1.0 equiv.), and K 2 CO 3 A solution of (751 mg, 5.44 mmol, 2.0 equiv) in DMF (40 mL) was stirred at 60° C. for 2 h. Water (30 mL) was added and the solid was collected by filtration and dried in an oven under reduced pressure to give 550 mg (61% yield) of 1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one as a white solid. LCMS (ESI, m / z): 331.1 [M+H] + .

[0205] Step B A solution of 1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one (550 mg, 1.67 mmol, 1.00 equiv) in DMF (60 mL) was treated with NaH (60% dispersion in oil, 200 mg, 4.99 mmol, 3.0 equiv) in small portions at 0° C. The mixture was stirred at 0° C. for 15 min. Then, (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate tert-butyl 2,2-dioxide (593 mg, 2.5 mmol, 1.5 equiv) was added in small portions. After stirring at that temperature for 1 h, 30 mL of water was added. The resulting solution was extracted three times with 50 mL of ethyl acetate. The organic layers were combined and washed three times with 30 mL of brine. The organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product was applied to a silica gel column eluted with ethyl acetate / hexane (9:1) to give 480 mg (59% yield) of (S)-1-(1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-ylcarbamate tert-butyl as a yellow solid. LCMS (ESI, m / z): 488.2 [M+H] + .

[0206] Step C A solution of tert-butyl (S)-1-(1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-ylcarbamate (480 mg, 1.00 equiv.) in 4N HCl (30 mL) in dioxane was stirred at room temperature for 1 h. The mixture was concentrated to give 420 mg of 3-((S)-2-aminopropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride as a yellow solid. LCMS (ESI, m / z): 388.2 [M+H] + .

[0207] Step D A solution of 3-((S)-2-aminopropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride (220 mg, 0.52 mmol, 1.0 equiv), triethylamine (157 mg, 1.56 mmol, 3.0 equiv), and 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridazin-3-one (165 mg, 0.52 mmol, 1.00 equiv) in EtOH (40 mL) was stirred at 60° C. for 2 h. After concentration, the crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (9:1) to give 280 mg (81% yield) of 5-((S)-1-(1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-ylamino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as a yellow oil. LCMS (ESI, m / z): 670.2 [M+H] + .

[0208] Step E A solution of 5-((S)-1-(1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-ylamino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (280 mg, 0.42 mmol, 1.0 equiv.) in TFA (15 mL) was treated with trifluoromethanesulfonic acid (1.50 mL) at 0° C. After stirring for 1 h at 0° C., the pH value of the solution was adjusted to 8 with saturated aqueous sodium bicarbonate solution. The resulting solution was extracted three times with 70 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by reverse phase chromatography and chiral preparative HPLC (column: CHIRALPAK IA, 2 × 25 cm, 5 um, mobile phase A: hexane:DCM=3:1 (10 mM NH 3-MeOH), mobile phase B: EtOH, flow rate: 20 mL / min, 10% B over 14 min, 220 / 254 nm) to give the separated compounds. The stereochemistry was assigned based on the X-ray crystal structure of Example 10 Isomer B (10B).

[0209] Example 10 Isomer A (10A): 5-((S)-1-((S)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(2H)-one (59 mg, 35%, white solid). LC-MS: (ESI, m / z): 550.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d 6 )δ 12.47(s,1H),8.70(s,2H),7.95(s,1H),6.39-6.30(m,1H),4.85-4.82(m,2H),4.1 8-4.11(m,1H),4.10-4.04(dt,J=12.7,6.8Hz,2H),3.83(dd,J=10.0,6.5Hz,1H),3. 61(dd,J=10.1,4.7Hz,1H),3.25-3.14(m,1H),3.19-3.09(m,1H),3.13-3.01(m,2H ),2.31-2.19(m,1H),1.79-1.55(m,5H),1.18(d,J=6.5Hz,3H).Chiral HPLC: CHIRALPAK IA-3, 4.6 x 50 mm, 3 μm, detection at 254 nm, mobile phase A: hexane: DCM = 3:1 (contains 0.1% DEA), mobile phase B: EtOH, 15% mobile phase B, flow rate: 1 mL / min, retention time = 1.472 minutes

[0210] Example 10 Isomer B (10B): 5-((S)-1-((R)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(2H)-one (92 mg, 54%, white solid). LC-MS: (ESI, m / z): 550.2 [M+H] + ; 1H NMR (400MHz, DMSO-d 6 )δ 12.47(s,1H),8.70(s,2H),7.95(s,1H),6.39-6.30(m,1H),4.84-4.81(m, 2H),4.18-4.08(m,3H),3.83(dd,J=10.0,6.5Hz,1H),3.61(dd,J=10.1,4. 7Hz,1H),3.25-3.24(m,1H),3.18-3.11(m,1H),3.10-2.98(m,2H),2.31-2.19(m,1H),1.79-1.45(m,5H),1.18(d,J=6.5Hz,3H).Chiral HPLC: CHIRALPAK IA-3, 4.6×50 mm, 3 μm, detection at 254 nm, mobile phase A: hexane:DCM=3:1 (containing 0.1% DEA), mobile phase B: EtOH, 15% mobile phase B, flow rate: 1 mL / min, retention time=2.209 min

[0211] Example 11: Synthesis of 4-chloro-5-((S)-1-(2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yloxy)propan-2-ylamino)pyridazin-3(2H)-one [ka]

[0212] A solution of 3-((S)-2-aminopropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (60 mg, 0.16 mmol, 1.0 equiv., see Example 10, Step C), 4,5-dichloropyridazin-3(2H)-one (38 mg, 0.23 mmol, 1.5 equiv.), and TEA (83 mg, 0.82 mmol, 5.3 equiv.) in n-BuOH (3 mL) was stirred at 100° C. for 15 h. The residue was purified by H 2 O / CH 3Purified by reverse phase column eluted with CN (60 / 40). The product was further purified by preparative HPLC to give 6 mg (8% yield) of 4-chloro-5-((S)-1-(2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yloxy)propan-2-ylamino)pyridazin-3(2H)-one as a white solid. LCMS (ESI, m / z): 516.20 [M+H] + ; 1 H NMR (400MHz, methanol-d 4 )δ 8.55(s,2H),7.96(d,J=9.9Hz,1H),5.01-4.91(m,2H),4.24-4.06(m,3H),4.00-3.86(m,1H),3.72(dd,J=9.7,4.6Hz,1H),3.41-3 .33(m,1H),3.31-3.23(m,1H),3.10-2.97(m,2H),2.42-2.27(m,1H),1.89-1.87(m,1H),1.85-1.63(m,4H),1.31(d,J=6.6Hz,3H).

[0213] Example 12: Synthesis of 4-bromo-5-(((2S)-1-((2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)pyridazin-3(2H)-one [ka]

[0214] 3-((S)-2-aminopropoxy)-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride (90 mg, 0.212 mmol, 1.00 equiv., see Example 13, Step C), 4,5-dibromopyridazin-3(2H)-one (54 mg, 0.213 mmol, 1.00 equiv.), and Et 3 A solution of N (65 mg, 0.637 mmol, 3.00 equiv) in n-butyl alcohol (2 mL) was stirred at 100° C. for 3 days. The resulting solution was concentrated and2 O / CH 3 Purification by reverse phase chromatography eluting with CN (53 / 47) afforded impure desired product. The product was further purified by preparative HPLC to afford 11 mg (9% yield) of 4-bromo-5-(((2S)-1-((2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)pyridazin-3(2H)-one as a white solid. LCMS (ESI, m / z): 560.10 [M+H] + ; 1 H NMR (300MHz, DMSO-d 6 )δ 12.53(s,1H),8.47(s,2H),7.82(s,1H),5.90-5.79(m,1H),4.65-4.45(m,2H),4.20-4.00(m,3H),3.90-3.7 8(m,1H),3.62-3.48(m,1H),3.30-2.90(m,4H),2.30-2.11(m,1H),1.79-1.51(m,5H),1.15(d,J=6.5Hz,3H).

[0215] Example 13: 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (13A) and 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (13B) [ka]

[0216] Step A 3-Hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (717 mg, 3.26 mmol, 1.0 equiv., intermediate I-3), 2-chloro-5-(trifluoromethyl)pyrazine (654 mg, 3.58 mmol, 1.1 equiv.), and K 2 CO 3( A solution of 3-hydroxy-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-2-one (900 mg, 6.51 mmol, 2.0 equiv) in DMF (8 mL) was stirred at 60° C. for 2 h. Water was added and the resulting solution was extracted three times with 10 mL of ethyl acetate. The organic layer was washed three times with 50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was applied to a silica gel column and eluted with dichloromethane / methanol (97:3) to give 702 mg (65% yield) of 3-hydroxy-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-2-one as a yellow solid. LCMS (ES, m / z): 331.15 [M+H] + .

[0217] Step B To a solution of methyl 3-hydroxy-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-2-one (680 mg, 2.06 mmol, 1.0 equiv.) in DMF (6 mL) was added NaH (60% dispersion in oil, 82 mg, 2.06 mmol, 1.0 equiv.) in small portions at 0° C. The resulting solution was stirred at that temperature for 15 min, after which (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate tert-butyl 2,2-dioxide (537 mg, 2.27 mmol, 1.1 equiv.) was added to the resulting solution. After stirring at 0° C. for 2 h, 5 mL of water was added and the mixture was concentrated under vacuum. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (39:61) to give 500 mg (50% yield) of tert-butyl ((2S)-1-((2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)carbamate as a yellow oil. LCMS (ES, m / z): 488.25 [M+H] + .

[0218] Step C A solution of tert-butyl ((2S)-1-((2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)carbamate (300 mg, 0.62 mmol, 1.0 equiv) in 4N HCl (5 mL) in dioxane was stirred at room temperature for 1 h and then concentrated in vacuo to give 200 mg (84% yield) of 3-((S)-2-aminopropoxy)-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride as a yellow solid. LCMS (ES, m / z): 388.20 [M+H] + .

[0219] Step D A solution of 3-((S)-2-aminopropoxy)-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride (150 mg, 0.39 mmol, 1.0 equiv.), triethylamine (78 mg, 0.77 mmol, 2.0 equiv.), and 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (136 mg, 0.43 mmol, 1.1 equiv., intermediate I-1) in EtOH (5.00 mL) was stirred at 60° C. for 1 h. The resulting mixture was concentrated and applied to a silica gel column eluted with ethyl acetate / petroleum ether (85:15) to give 160 mg (62% yield) of 2-(4-methoxybenzyl)-5-(((2S)-1-((2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one as a white solid. (ES,m / z):670.20[M+H] + .

[0220] Step E A solution of 2-(4-methoxybenzyl)-5-(((2S)-1-((2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (150 mg, 0.22 mmol, 1.0 equiv) in TFA (3.00 mL) was treated with trifluoromethanesulfonic acid (0.3 mL) at −10° C. and stirred at −10° C. for 1 h. 5 mL of ice water was added and the pH value was adjusted to 0.1 with saturated NaCl. 2 CO 3 The acid was adjusted to 8 with aqueous solution. The resulting solution was extracted three times with 10 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by reverse phase chromatography to give an isomeric mixture. The mixture was purified by chiral preparative HPLC: (CHIRALPAK IG, 2.0×25 cm, 5 um, mobile phase A: hexane:DCM=3:1 (10 mM NH 3 -MeOH), mobile phase B: EtOH, flow rate: 16 mL / min, 50% B over 19 min, 220 / 254 nm) to give the desired isomer. The relative stereochemistry of the compound was assigned by analogy to Example 10, based on the PARP7 potency of the more active diastereomer, and by analogy to the X-ray crystal structure of Example 10B.

[0221] Example 13 Isomer A (13A): 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (23 mg, 27% yield) as a white solid. LCMS (ESI, m / z): 550.20 [M+H] + ; 1 H NMR (300MHz, DMSO-d 6)δ 12.45(s,1H),8.47(d,J=3.1Hz,2H),7.92(s,1H),6.45-6.32(m,1H),4.5 9(d,J=13.6Hz,2H),4.18-4.07(m,3H),3.84(dd,J=10.0,4.2Hz,1H),3.6 0(dd,J=10.0,6.9Hz,1H),3.25-3.19(m,1H),3.18-3.04(m,3H),2.25-2.17(m,1H),1.80-1.55(m,5H),1.18(d,J=6.0Hz,3H).Chiral HPLC:(CHIRALPAK IG-3, 4.6×50mm, 3um, Hexane:DCM=3:1 (containing 0.1% DEA):EtOH=80:20, 1.0mL / min, retention time=2.423min)

[0222] Example 13 Isomer B (13B): 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (45 mg, 53% yield) as a white solid. LCMS (ESI, m / z): 550.20 [M+H] + ;1H NMR (300MHz, DMSO-d 6 )δ 12.48(s,1H),8.47(d,J=3.9Hz,2H),7.95(s,1H),6.46-6.32(m,1H),4.5 9(d,J=13.4Hz,2H),4.18-4.07(m,3H),3.83(dd,J=10.0,6.6Hz,1H),3.6 0(dd,J=10.0,6.9Hz,1H),3.25-3.19(m,1H),3.16-2.99(m,3H),2.25-2.17(m,1H),1.81-1.56(m,5H),1.17(d,J=6.4Hz,3H).Chiral HPLC:(CHIRALPAK IG-3, 4.6×50mm, 3um, Hexane:DCM=3:1 (containing 0.1% DEA):EtOH=80:20, 1.0mL / min, retention time=3.085min)

[0223] Example 14: Synthesis of 6-(4-((S)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (14A) and 6-(4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (14B) [ka]

[0224] Step A 3-Hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (700 mg, 3.17 mmol, 1.0 equiv., intermediate I-3), 6-chloronicotinonitrile (440 mg, 3.18 mmol, 1.0 equiv.), and K 2 CO 3 A solution of (1.30 g, 9.41 mmol, 2.97 equiv) in DMF (5 mL) was stirred at 50° C. for 2 h. The resulting solution was diluted with 10 mL of water. The solid was collected by filtration to give 530 mg (58% yield) of 6-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile as a brown solid. LCMS (ESI, m / z): 287.20 [M+H] + .

[0225] Step B To a solution of 6-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (286 mg, 0.99 mmol, 1.0 equiv) in DMF (5 mL) was added NaH (60% suspension in mineral oil, 133 mg, 3.33 mmol, 3.3 equiv) at 0° C. and the solution was stirred for 15 min. (S)-4-Methyl-1,2,3-oxathiazolidine-3-carboxylate tert-butyl 2,2-dioxide (261 mg, 1.10 mmol, 1.10 equiv) was added and the solution was stirred at 0° C. for 2 h. Water was added and the resulting mixture was concentrated under vacuum. The crude product was purified by HPLC using H 2 O / CH 3 Purification by reverse phase chromatography eluting with CN (40 / 60) afforded 200 mg (45% yield) of tert-butyl ((2S)-1-((1-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate as a yellow oil. LCMS (ESI, m / z): 444.30 [M+H] + .

[0226] Step C A solution of tert-butyl ((2S)-1-((1-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate (180 mg, 1.0 equiv.) in 4N HCl (5 mL) in dioxane was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum to give 120 mg (78% yield) of 6-(4-(3-((S)-2-aminopropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile hydrochloride as a white solid. LCMS (ESI, m / z): 344.15 [M+H] + .

[0227] Step D A solution of 6-(4-(3-((S)-2-aminopropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile hydrochloride (110 mg, 0.32 mmol, 1.0 equiv.), 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (101 mg, 0.32 mmol, 1.0 equiv., Intermediate I-1), and N-methylmorpholine (97 mg, 0.96 mmol, 3.0 equiv.) in MeCN (2 mL) was stirred at 60° C. for 12 h. The mixture was concentrated under vacuum and the residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (9 / 1) to give 70 mg (23% yield) of 6-(4-(3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile as a white solid. LCMS (ESI, m / z): 626.25 [M+H] + .

[0228] Step E A solution of 6-(4-(3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (40 mg, 0.064 mmol, 1.0 equiv.) in TFA (3 mL) was treated with trifluoromethanesulfonic acid (0.3 mL) at 0° C. and stirred at that temperature for 1 h. 10 mL of ice water was added and the pH value of the solution was adjusted to 0.1 mg with saturated NaCl. 2 CO 3 The resulting solution was extracted three times with 10 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by HCl. 2 O / CH 3 The product was purified by reverse phase chromatography eluting with CN (60 / 40) to give a mixture of isomers. The product was purified by chiral preparative HPLC with the following conditions: (CHIRALPAK IA, 2×25 cm, 5 um, mobile phase A: Hexane:EtOH=1:1 (8 mmol / L NH 3-MeOH), mobile phase B: EtOH, flow rate: 16 mL / min, 50% B over 18 min, 220 / 254 nm) to give separated isomers. The relative stereochemistry of the compounds was assigned by analogy to Example 10, based on the PARP7 potency of the more active diastereomer, and by analogy to the X-ray crystal structure of Example 10B.

[0229] Example 14 Isomer A (14A): 6-(4-((S)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (11 mg, 33% yield) as a white solid. LCMS (ESI, m / z): 506.20 [M+H] + ; 1 H-NMR (methanol-d 4 ,400MHz)δ 8.40(s,1H),7.98(s,1H),7.72(dd,J=9.1,2.4Hz,1H),6.90(dd,J=9.2,0.8Hz,1H),4.64(m, J=13.5Hz,2H),4.19-4.10(m,3H),3.99(dd,J=9.8,3.8Hz,1H),3.63(dd,J=9.8,6.8Hz,1H),3 .38(dd,J=9.7,3.6Hz,1H),3.29-3.21(m,2H),3.10-2.98(m,2H),2.42-2.29(m,1H),2.42-2. 29(m,1H),1.92-1.79(m,1H),1.78-1.65(m,4H),1.30(d,J=6.6Hz,3H).Chiral HPLC:(CHIRALPAK IA-3, 4.6×50mm, 3um, hexane (contains 0.1% DEA):EtOH=50:50, flow rate: 1mL / min, retention time=2.167min)

[0230] Example 14 Isomer B (14B): 6-(4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (14 mg, 43% yield) as a white solid. LCMS (ESI, m / z): 506.20 [M+H] + ; 1 H NMR (400MHz, methanol-d 4 )δ 8.40(dd,J=2.4,0.7Hz,1H),8.00(s,1H),7.72(dd,J=9.1,2.4Hz,1H),6.90(dd,J=9.2,0.8H z,1H),4.64(m,J=13.5Hz,2H),4.19-4.10(m,3H),3.99(dd,J=9.8,3.8Hz,1H),3.63(dd,J=9 .8,6.8Hz,1H),3.38(dd,J=9.7,3.6Hz,1H),3.29-3.21(m,2H),3.10-2.98(m,2H),2.42-2.2 9(m,1H),1.92-1.79(m,1H),1.78-1.65(m,4H),1.30(d,J=6.6Hz,3H).Chiral HPLC:(CHIRALPAK IA-3, 4.6×50mm, 3um, hexane (contains 0.1% DEA):EtOH=50:50, flow rate: 1mL / min, retention time=3.159min)

[0231] Example 15: Synthesis of 5-(((S)-1-(((S)-1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (15A) and 5-(((S)-1-(((R)-1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (15B) [ka]

[0232] Step A 3-Hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (1.20 g, 5.437 mmol, 1.99 equiv., intermediate I-3), 2-chloro-5-(difluoromethyl)pyrimidine (450 mg, 2.735 mmol, 1.00 equiv.), and K 2 CO 3 A solution of (2.27 g, 16.43 mmol, 6.01 equiv) in DMF (15 mL) was stirred at 80° C. for 15 h. After filtration, the filtrate was concentrated in vacuo and the crude product was purified by hydrochloric acid HCl. 2 O / CH 3 Application to a reverse phase column eluted with CN (1:1) gave 450 mg (46% yield) of 1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one as a yellow solid. LCMS (ESI, m / z): 313.20 [M+H] + .

[0233] Step B To a solution of 1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one (150 mg, 0.480 mmol, 1.00 equiv.) in DMF (10 mL) was added NaH (120 mg, 3.00 mmol, 6.25 equiv., 60% dispersion in mineral oil) at 0° C. and stirred for 10 min. To the solution was added (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate tert-butyl 2,2-dioxide (177 mg, 0.746 mmol, 1.55 equiv.) at 0° C. The resulting solution was stirred at room temperature for 2 h. The reaction was then quenched by the addition of 0.2 mL of 20% aqueous sodium carbonate. The solution was concentrated and the crude product was purified by HCl distillation. 2 O / CH 3Applying to a reverse phase column eluted with OH (40 / 60) gave 224 mg (50% yield) of tert-butyl ((2S)-1-((1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate as an orange solid. LCMS (ESI, m / z): 470.15 [M+H] + .

[0234] Step C A solution of tert-butyl ((2S)-1-((1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate (250 mg, 0.532 mmol, 1.00 equiv) in 4N HCl (5 mL) in dioxane was stirred at room temperature for 2 h. The resulting mixture was concentrated to give 220 mg (71% yield) of 3-((S)-2-aminopropoxy)-1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride as an orange solid. LCMS (ESI, m / z): 370.15 [M+H] + .

[0235] Step D A solution of 3-[(2S)-2-aminopropoxy]-1-[1-[5-(difluoromethyl)pyrimidin-2-yl]piperidin-4-yl]pyrrolidin-2-one hydrochloride (220 mg, 0.542 mmol, 1.00 equiv), 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridazin-3-one (189 mg, 0.593 mmol, 1.09 equiv), and TEA (180 mg, 1.779 mmol, 3.28 equiv) in EtOH (5 mL) was stirred at 60° C. for 3 h. The mixture was concentrated, diluted with 100 mL of ethyl acetate, and washed twice with 20 mL of saturated aqueous ammonium chloride. The aqueous layers were combined and extracted twice with 50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column eluted with 100% ethyl acetate to give 107 mg (30% yield) of 5-(((2S)-1-((1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as a yellow solid. LCMS (ESI, m / z): 652.50 [M+H] + .

[0236] Step E A solution of 5-(((2S)-1-((1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (100 mg, 0.153 mmol, 1.00 equiv) in trifluoromethanesulfonic acid / TFA=1:10 (1.5 mL) was stirred at room temperature for 2 h. The resulting solution was diluted with 15 mL of H 2 The mixture was diluted with 20 mL of ethyl acetate. The pH value of the solution was adjusted to 7-8 with 20% aqueous sodium carbonate. The resulting solution was extracted twice with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by HCl distillation. 2 O / CH 3The product was purified by reverse phase chromatography eluting with CN. The product was purified by chiral preparative HPLC (CHIRAL ART Cellulose-SB, 2×25 cm, 5 um, mobile phase A: hexane (8 mmol / L NH 3 -MeOH), mobile phase B: EtOH, flow rate: 20 mL / min, gradient: 50% B over 16 min, 220 / 254 nm). The relative stereochemistry of the compound was assigned by analogy to Example 10, based on the PARP7 potency of the more active diastereomer, and by analogy to the X-ray crystal structure of Example 10B.

[0237] Example 15 Isomer A (15A): 5-(((S)-1-(((S)-1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (16 mg, 32% yield, off-white solid). LCMS (ESI, m / z): 532.25 [M+H] + ; 1 H NMR (400MHz, DMSO-d 6 )δ 12.44(s,1H),8.54(s,2H),7.91(s,1H),6.96(t,J=55.5Hz,1H),6.41-6.32(m,1H), 4.86-4.75(m,2H),4.21-4.14(m,1H),4.08-4.04(m,2H),3.83(dd,J=10.0,4.3Hz,1 H),3.59(dd,J=10.1,7.0Hz,1H),3.25-3.19(m,1H),3.15-3.08(m,1H),3.02-2.95( m,2H),2.25-2.16(m,1H),1.73-1.48(m,5H),1.16(d,J=6.5Hz,3H).Chiral HPLC: CHIRAL Cellulose-SB, 0.46×10cm, 3um, Hexane (contains 0.1% DEA):EtOH=50:50, Flow rate: 1.0mL / min, Retention time=2.642min

[0238] Example 15 Isomer B (15B): 5-(((S)-1-(((R)-1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (25 mg, 50% yield, off-white solid). LCMS (ESI, m / z): 532.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d 6 )δ 12.46(s,1H),8.54(s,2H),7.94(s,1H),6.96(t,J=55.5Hz,1H),6.41-6.32(m,1H),4.86 -4.75(m,2H),4.21-4.14(m,1H),4.08-4.03(m,2H),3.83(dd,J=10.0,4.3Hz,1H),3.59( dd,J=10.1,7.0Hz,1H),3.25-3.20(m,1H),3.15-3.09(m,1H),3.03-2.95(m,2H),2.25-2 .17(m,1H),1.73-1.66(m,1H),1.61-1.48(m,4H),1.17(d,J=6.5Hz,3H).Chiral HPLC:CHIRAL Cellulose-SB, 0.46×10cm, 3um, Hexane (contains 0.1% DEA):EtOH=50:50, Flow rate: 1.0mL / min, Retention time=4.415min

[0239] Example 16: Synthesis of 5-(((S)-1-(((R)-1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0240] Step A A solution of (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (3.47 g, 21.941 mmol, 1.00 equiv.), tert-butyl 4-aminopiperidine-1-carboxylate (6.40 g, 31.955 mmol, 1.46 equiv.), and acetic acid (2.64 g, 43.962 mmol, 2.00 equiv.) in DCM (200 mL) was stirred for 15 min. NaBH(AcO) 3 (14.00 g, 66.042 mmol, 3.01 equiv) was added and the solution was stirred at room temperature for an additional 2 h. 300 mL of saturated NaHCO 3 Aqueous solution was added. The layers were separated and the aqueous layer was extracted three times with 200 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (75 / 25) to give 2.9 g (46% yield) of (R)-tert-butyl 4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate as a yellow solid. LCMS (ESI, m / z): 285.15 [M+H] + .

[0241] Step B A solution of (R)-tert-butyl 4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2.90 g, 10.2 mmol, 1.00 equiv) in 1,4-dioxane (10 mL) and 4N HCl in dioxane (30 mL) was stirred at room temperature for 15 h. The solution was concentrated to give 2.2 g (98% yield) of (R)-3-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride as a yellow solid. LCMS (ESI, m / z): 185.15 [M+H] + .

[0242] Step C (R)-3-Hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (700 mg, 3.172 mmol, 1.00 equiv.), K 2 CO 3A solution of (1310 mg, 9.479 mmol, 2.99 equiv) and 2,5-dichloropyrimidine (492 mg, 3.303 mmol, 1.04 equiv) in DMF (5 mL) was stirred at 80° C. for 4 h. 25 mL of water was added and the resulting solution was extracted three times with 20 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was applied to a silica gel column eluted with dichloromethane / MeOH (10:1) to give 750 mg (80% yield) of (R)-1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one as a light yellow solid. LCMS (ESI, m / z): 297.05 [M+H] + .

[0243] Step D To a solution of (R)-1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one (350 mg, 1.179 mmol, 1.00 equiv) in DMF (6 mL) was added NaH (60% dispersion in mineral oil, 236 mg, 5.901 mmol, 5 equiv) in small portions at 0° C. To the solution was added (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate tert-butyl 2,2-dioxide (420 mg, 1.770 mmol, 1.50 equiv). The resulting solution was allowed to warm to room temperature. 0.5 mL of water was added and the solvent was removed in vacuo. The crude product was purified by HPLC using H 2 O / CH 3 Purification by reverse phase chromatography eluting with OH (7 / 3) afforded 490 mg (82% yield) of tert-butyl ((S)-1-(((R)-1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate as a light yellow solid. LCMS (ESI, m / z): 454.15 [M+H] + .

[0244] Step E A solution of tert-butyl ((S)-1-(((R)-1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate (490 mg, 1.079 mmol, 1.00 equiv) in 1,4-dioxane (10.00 mL) and 4N HCl in dioxane (5.00 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated to give 420 mg (90% yield) of (R)-3-((S)-2-aminopropoxy)-1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride as a light yellow solid. LCMS (ESI, m / z): 354.15 [M+H] + .

[0245] Step F A solution of (R)-3-((S)-2-aminopropoxy)-1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride (210 mg, 0.538 mmol, 1.00 equiv), TEA (190 mg, 1.878 mmol, 3.49 equiv), and 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridazin-3-one (205 mg, 0.643 mmol, 1.20 equiv) in EtOH (5 mL) was stirred at 50° C. for 4 h. The mixture was concentrated, diluted with 60 mL of ethyl acetate, and diluted with 20 mL of saturated NH 4 The mixture was washed twice with aqueous Cl. The layers were separated and the aqueous layer was extracted twice with 50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (3 / 1) to give 240 mg (70% yield) of 5-(((S)-1-(((R)-1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as a white solid. LCMS (ESI, m / z): 652.50 [M+H] + .

[0246] Step G A solution of 5-(((S)-1-(((R)-1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (230 mg, 0.362 mmol, 1.00 equiv.) in trifluoromethanesulfonic acid / TFA=1:10 (2.50 mL) was stirred at room temperature for 2 h. 15 mL of water was added and the pH value of the solution was adjusted to 7-8 with 20% aqueous sodium bicarbonate. The solution was extracted three times with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by HPLC using H 2 O / CH 3 Purification by reverse phase chromatography eluting with CN gave 99 mg of 5-(((S)-1-(((R)-1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one. LCMS (ESI, m / z): 516.15 [M+H] + ; 1 H NMR (400MHz, DMSO-d 6 )δ 12.47(s,1H),8.42(s,2H),7.95(s,1H),6.36-6.33(m,1H),4.70-4.67(m ,2H),4.18-4.02(m,3H),3.83(dd,J=10.0,6.6Hz,1H),3.61(dd,J=10.0,4 .7Hz,1H),3.34-3.21(m,1H),3.14-3.11(m,1H),2.98-2.92(m,2H),2.25- 2.23(m,1H),1.74-1.69(m,1H),1.60-1.51(m,4H),1.17(d,J=6.5Hz,3H).

[0247] Example 17: Synthesis of 6-(4-((S)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (17A) and 6-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (17B) [ka]

[0248] Step A To a solution of 6-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (300 mg, 1.048 mmol, 1.00 equiv., Example 14, Step A) in DMF (5 mL) was added NaH (126 mg, 5.239 mmol, 5 equiv.) at 0° C. The solution was stirred at 0° C. for 10 min, after which (S)-4-(methoxymethyl)-1,2,3-oxathiazolidine-3-carboxylate tert-butyl 2,2-dioxide (336 mg, 1.26 mmol, 1.2 equiv.) was added. The solution was stirred at 0° C. for an additional 1 h. 20 mL of methanol was added and the solution was concentrated. The crude product was purified by C18 reverse phase chromatography eluting with water / ACN (30 / 70) to give 121 mg (24% yield) of tert-butyl ((2S)-1-((1-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)-3-methoxypropan-2-yl)carbamate as a yellow solid. LCMS (ESI, m / z): 474.25 [M+H] + .

[0249] Step B A solution of tert-butyl ((2S)-1-((1-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)-3-methoxypropan-2-yl)carbamate (121 mg, 0.256 mmol, 1.00 equiv) in 4N HCl (8 mL) in dioxane was stirred at room temperature for 1.5 h. The mixture was concentrated under vacuum to give 89 mg (93% yield) of 6-(4-(3-((S)-2-amino-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile hydrochloride as a yellow oil. LCMS (ESI, m / z): 374.10 [M+H] + .

[0250] Step C A solution of 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (61 mg, 0.191 mmol, 1.00 equiv., intermediate I-1), 6-(4-(3-((S)-2-amino-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile hydrochloride (71 mg, 0.191 mmol, 1.0 equiv.), and TEA (58 mg, 0.574 mmol, 3.0 equiv.) in ethanol (4.00 mL) was stirred at 70° C. in an oil bath for 4 hours. The mixture was concentrated under vacuum and the crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (10:1) to give 60 mg (48% yield) of 6-(4-(3-((S)-3-methoxy-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile as a yellow oil. LCMS (ESI, m / z): 656.20 [M+H] + .

[0251] Step D A solution of 6-(4-(3-((S)-3-methoxy-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (54 mg, 0.082 mmol, 1.00 equiv.) in TFA (2 mL) was treated with trifluoromethanesulfonic acid (0.2 mL) at 0° C. and stirred at the same temperature for 30 min. 10 mL of ice water was added and the pH value of the solution was adjusted to 8 with 40% aqueous sodium hydroxide solution. The resulting solution was extracted three times with 20 mL of ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product was purified by reverse phase chromatography eluting with water / ACN (60 / 40) to give an isomeric mixture. The diastereomers were separated by chiral preparative HPLC under the following conditions: CHIRALPAK IF, 2×25 cm, 5 um, mobile phase A: hexane (8 mM NH 3 -MeOH), mobile phase B: EtOH, flow rate: 20 mL / min, gradient: 50% B over 22 min, 220 / 254 nm). The relative stereochemistry of the compounds was assigned by analogy to Example 10, based on the PARP7 potency of the more active diastereomer, and by analogy to the X-ray crystal structure of Example 10B.

[0252] Example 17 Isomer A (17A): 6-(4-((S)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (5.3 mg, 12% yield, white solid). LCMS (ESI, m / z): 536.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d 6)δ 12.48(s,1H),8.47(s,1H),7.93(s,1H),7.83(d,J=9.1Hz,1H),6.96(d,J=9.2Hz,1H),6.3 3-6.28(m,1H),4.58-4.50(m,2H),4.33-4.26(m,1H),4.09-4.01(m,2H),3.92-3.87(m,1H) ),3.69-3.63(m,1H),3.48(d,J=5.7Hz,2H),3.28-3.27(m,3H),3.23-3.19(m,1H),3.15-3 .08(m,1H),3.03-2.95(m,2H),2.27-2.19(m,1H),1.73-1.48(m,5H).Chiral HPLC: CHIRALPAK IF-3, 4.6×50mm, 3μm, hexane (contains 0.1% DEA):EtOH=50:50, flow rate: 1mL / min, retention time=2.405min

[0253] Example 17 Isomer B (17B): 6-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (9 mg, 20% yield, white solid). LCMS (ESI, m / z): 536.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d 6)δ 12.50(s,1H),8.47(s,1H),7.96(s,1H),7.83(d,J=9.1Hz,1H),6.96(d,J=9.0Hz,1H),6.3 3-6.28(m,1H),4.58-4.50(m,2H),4.33-4.26(m,1H),4.11-4.01(m,2H),3.92-3.87(m,1H) ),3.69-3.63(m,1H),3.49(d,J=5.3Hz,2H),3.29-3.26(m,3H),3.23-3.19(m,1H),3.15-3 .08(m,1H),3.03-2.94(m,2H),2.27-2.18(m,1H),1.73-1.48(m,5H).Chiral HPLC: CHIRALPAK IF-3, 4.6×50mm, 3μm, hexane (contains 0.1% DEA):EtOH=50:50, flow rate: 1mL / min, retention time=3.678min

[0254] Example 18 was synthesized according to the procedure described for the synthesis of 6-(4-((S)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile and 6-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (see Example 17), using the appropriate building blocks and modified reaction conditions (such as reagent ratios, temperatures, coupling conditions, and reaction times) as necessary. The relative stereochemistry of the compounds was assigned based on the PARP7 potency of the more active diastereomer by analogy to Example 10 and by analogy to the X-ray crystal structure of Example 10B. [Table 7-1] [Table 7-2]

[0255] Example 19: Synthesis of 5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (19A) and 5-(((S)-1-methoxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (19B) [ka]

[0256] Step A To a solution of 3-hydroxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (500 mg, 1.51 mmol, 1.00 equiv.) in DMF (5 mL) was added NaH (60% dispersion in mineral oil, 121 mg, 3.02 mmol, 2.0 equiv.) at 0° C. After stirring at that temperature for 15 min, a solution of (S)-4-(methoxymethyl)-1,2,3-oxathiazolidine-3-carboxylate tert-butyl 2,2-dioxide (605 mg 2.26 mmol, 1.50 equiv.) in DMF (3 mL) was added dropwise at 0° C. The resulting solution was stirred at 0° C. for 2 h. 50 mL of water was added and the solution was extracted three times with 50 mL of EtOAc. The organic layers were combined, washed with 50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was applied to a silica gel column eluted with EtOAc / petroleum ether (11:9) to give 500 mg (64% yield) of tert-butyl ((2S)-1-methoxy-3-((2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)carbamate as a brown oil. LCMS (ESI, m / z): 518.20 [M+H] +

[0257] Step B A solution of tert-butyl ((2S)-1-methoxy-3-((2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)carbamate (500 mg, 0.97 mmol, 1.00 equiv) in 4N HCl (4 mL) in 1,4-dioxane was stirred at room temperature for 1 h. After concentration, the crude product was purified by HPLC using H 2 O / CH 3 Purification by C18 reverse phase chromatography eluting with CN (1:1) afforded 260 mg (65% yield) of 3-((S)-2-amino-3-methoxypropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one as a yellow solid. LCMS (ESI, m / z): 418.20 [M+H] + .

[0258] Step C CH of 3-((S)-2-amino-3-methoxypropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (250 mg, 0.60 mmol, 1.00 equiv.), 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (286 mg, 0.90 mmol, 1.50 equiv., intermediate I-1), and N-methylmorpholine (91 mg, 0.90 mmol, 1.50 equiv.). 3 The CN (4 mL) solution was stirred at 60° C. for 1 h. The solution was diluted with 50 mL of water and extracted three times with 50 mL of EtOAc. The organic layers were combined, washed with 50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (7:13) to give 100 mg (24% yield) of 5-(((2S)-1-methoxy-3-((2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as a yellow solid. LCMS (ESI, m / z): 700.20 [M+H] +

[0259] Step D A solution of 5-(((2S)-1-methoxy-3-((2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (90 mg, 0.13 mmol, 1.00 equiv) in TFA (1.00 mL) and trifluoromethanesulfonic acid (0.20 mL) was stirred at room temperature for 1 h. The residue was diluted with 20 mL of water and the pH was adjusted to 0.1 with saturated NaCl. 2 CO 3The acid was adjusted to 7-8 with aqueous solution. The resulting solution was extracted three times with 20 mL of EtOAc. The organic layers were combined, washed with 20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by HCl distillation. 2 O / CH 3 The product was purified by a C18 reversed-phase column eluted with CN (16:29). The product was purified by chiral preparative HPLC (CHIRALPAK IA, 2×25 cm, 5 um, mobile phase A: hexane (8 mmol / L NH 3 -MeOH), mobile phase B: EtOH, flow rate: 18 mL / min, 50% B over 20 min, 220 / 254 nm). The relative stereochemistry of the compound was assigned by analogy to Example 10 based on the PARP7 potency of the more active diastereomer, and by analogy to the X-ray crystal structure of Example 10B.

[0260] Example 19 Isomer A (19A): 5-(((S)-1-Methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (20.8 mg, 28% yield, white solid). LCMS (ESI, m / z): 580.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d 6 )δ 12.48(s,1H),8.69(s,2H),7.93(s,1H),6.37-6.30(m,1H),4.88-4.74(m,2 H),4.35-4.24(m,1H),4.14-4.03(m,2H),3.90(dd,J=10.0Hz,3.6Hz,1H),3. 70-3.61(m,1H),3.51-3.44(m,2H),3.29-3.25(m,3H),3.23-3.17(m,1H),3 .17-2.97(m,3H),2.26-2.18(m,1H),1.78-1.49(m,5H);Chiral HPLC:CHIRALPAK IA-3, 4.6×50mm, 3μm, hexane:EtOH=50:50, flow rate=1.3mL / min, retention time=1.33min

[0261] Example 19 Isomer B (19B): 5-(((S)-1-Methoxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (25.0 mg, 34% yield, white solid). LCMS (ESI, m / z): 580.20 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ 12.49(s,1H),8.69(s,2H),7.96(s,1H),6.32-6.24(m,1H),4.86-4.77(m,2 H),4.35-4.24(m,1H),4.15-4.00(m,2H),3.90(dd,J=10.0Hz,3.6Hz,1H),3 .71-3.63(m,1H),3.52-3.45(m,2H),3.28-3.27(m,3H)3.24-3.21(m,1H),3 .18-2.97(m,3H),2.31-2.19(m,1H),1.77-1.49(m,5H).Chiral HPLC: CHIRALPAK IA-3, 4.6×50mm, 3μm, hexane:EtOH=50:50, flow rate=1.3mL / min, retention time=2.91min

[0262] Example 20: Synthesis of 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one (20A) and 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one (20B) [ka]

[0263] Step A A solution of 3-hydroxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (500 mg, 1.51 mmol, 1.00 equiv), 4-methylbenzenesulfonyl chloride (864 mg, 4.53 mmol, 2.99 equiv), and TEA (612 mg, 6.06 mmol, 4.00 equiv) in DCM (15 mL) was stirred at 25° C. for 4 h. The resulting solution was diluted with 50 mL of water. The layers were separated and the aqueous layer was extracted three times with 50 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 500 mg (68% yield) of 2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl 4-methylbenzenesulfonate as a brown solid. LCMS (ESI, m / z): 485.20 [M+H] + .

[0264] Step B A solution of (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (264 mg, 1.65 mmol, 2.00 equiv.) in DMF (4 mL) was treated with NaH (60% dispersion in mineral oil, 67 mg, 1.65 mmol, 2.00 equiv.) in DMF (4 mL) at 0° C. and stirred at that temperature for 15 min. 2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl 4-methylbenzenesulfonate (400 mg, 0.83 mmol, 1.00 equiv.) was added and the solution was stirred at room temperature for 2 h. 20 mL of saturated NH 4Aqueous Cl and ethyl acetate were added. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 50 mL). The organic layers were combined, washed with 5 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 450 mg of 3-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one as a brown oil which was carried forward without further purification. LCMS (ESI, m / z): 473.0 [M+H] + .

[0265] Step C A solution of 3-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (900 mg, 1.91 mmol, 1.00 equiv) in 4N HCl (6 mL) in dioxane was stirred at room temperature for 1 h. The resulting mixture was concentrated and the residue was purified by HCl distillation. 2 O / CH 3 Application to a reverse phase column eluted with CN (1:2) gave 250 mg (34% yield) of 3-((S)-2-hydroxypropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one as a yellow solid. LCMS (ESI, m / z): 389.10 [M+H] + .

[0266] Step D A solution of 3-((S)-2-hydroxypropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (75 mg, 0.16 mmol, 1.00 equiv.), 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (184 mg, 0.58 mmol, 3.64 equiv., intermediate I-1), and potassium tert-butoxide (65 mg, 0.58 mmol, 3.65 equiv.) in DCM (3.00 mL) was stirred at room temperature for 15 h. The resulting solution was diluted with 50 mL of DCM and diluted with 50 mL of H 2 2H)-1-((2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one as a colorless oil. LCMS (ESI, m / z): 671.20 [M+H] + .

[0267] Step E A solution of 2-(4-methoxybenzyl)-5-(((2S)-1-((2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one (65 mg, 0.10 mmol, 1.00 equiv) in TFA (1 mL) and trifluoromethanesulfonic acid (0.20 mL) was stirred at room temperature for 1 h. The solution was diluted with water and added saturated Na 2 CO 3 The pH was adjusted to 7-8 with aqueous solution. After concentration, the crude product was 2 O / CH 3The product was purified by C18 reverse phase chromatography eluting with CN (52:48). The product was purified by chiral preparative HPLC with the following conditions: (CHIRALPAK IA, 2×25 cm, 5 μm, mobile phase A: hexane (8 mM NH 3 -MeOH), mobile phase B: EtOH, flow rate: 20 mL / min, 50% B over 15 min, 220 / 254 nm). The relative stereochemistry of the compound was assigned by analogy to Example 10, based on the PARP7 potency of the more active diastereomer, and by analogy to the X-ray crystal structure of Example 10A.

[0268] Example 20 Isomer A (20A): 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one (13 mg, 24% yield, white solid). LCMS (ESI, m / z): 551.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d 6 )δ 13.22(s,1H),8.69(s,2H),8.28(s,1H),5.22-5.12(m,1H),4.86-4.76(m,2H),4.11-3.94(m,3H),3.65-3.58(m,1H),3.24-3.16 (m,1H),3.15-3.09(m,1H),3.08-2.97(m,2H),2.24-2.13(m,1H),1.68-1.47(m,5H),1.27(d,J=6.2Hz,3H).Chiral HPLC: CHIRALPAK IA-3, 4.6 x 50 mm, 3 μm, hexane (containing 0.1% DEA):EtOH = 50:50, flow rate = 1.0 mL / min, retention time = 1.981 min

[0269] Example 20 Isomer B (20B): 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one (17.5 mg, 33% yield, white solid). LCMS (ESI, m / z): 551.20 [M+H] + .1H NMR (400MHz, DMSO-d 6 )δ:13.22(s,1H),8.69(s,2H),8.30(s,1H),5.22-5.12(m,1H),4.86-4.77(m,2H),4.11-3.99(m,2H),3.89-3.82(m,1H),3.77-3.70(m,1H) ,3.25-3.17(m,1H),3.16-3.08(m,1H),3.07-2.98(m,2H),2.28-2.17(m,1H),1.75-1.47(m,5H),1.27(d,J=6.2Hz,3H).Chiral HPLC: CHIRALPAK IA-3, 4.6 x 50 mm, 3 μm, hexane (containing 0.1% DEA):EtOH = 50:50, flow rate = 1.0 mL / min, retention time = 2.695 min

[0270] The compounds of Examples 21-33B were synthesized similarly to the compounds described in Examples 1-20. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9] [Table 8-10]

[0271] Intermediate I-7: Synthesis of 3-hydroxy-[1,4'-bipiperidin]-2-one hydrochloride [ka]

[0272] Step A A solution of 1-benzylpiperidin-4-amine (1.91 g, 10.0 mmol, 1.0 equiv) in water (5 mL) and ethyl acetate (10 mL) was added to K 2 CO 3(N-(1-benzylpiperidin-4-yl)-5-bromopentanamide (2.08 g, 15.0 mmol, 1.5 equiv.) and 5-bromopentanoyl chloride (2.00 g, 10.0 mmol, 1.0 equiv.) were added. The reaction mixture was stirred for 1 h, diluted with water (20 mL) and extracted three times with 20 mL of ethyl acetate. The combined organic extracts were washed with water (10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give 3.5 g (99% yield) of N-(1-benzylpiperidin-4-yl)-5-bromopentanamide as a white solid. LCMS (ESI, m / z): 355.00 [M+H] + .

[0273] Step B To a solution of N-(1-benzylpiperidin-4-yl)-5-bromopentanamide (3.40 g, 9.60 mmol, 1.0 equiv) in THF (20 mL) was added t-BuOK (1.62 g, 14.4 mmol, 1.5 equiv). The reaction mixture was stirred for 1 h and then quenched by the addition of water (20 mL). The resulting solution was extracted three times with 50 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give 2.5 g (95% yield) of 1'-benzyl-[1,4'-bipiperidin]-2-one as a white solid. LCMS (ESI, m / z): 273.10 [M+H] + .

[0274] Step C A solution of 1'-benzyl-[1,4'-bipiperidin]-2-one (2.00 g, 7.30 mmol, 1.0 equiv) in DCM (20 mL) was added with TEMPO (2.50 g, 16.0 mmol, 2.2 equiv), 3 Å molecular sieves (2 g), and Tf 20 (2.28 g, 8.08 mmol, 1.1 equiv) was added at 0° C. The resulting solution was stirred for 2 h and then diluted with water (20 mL). The solution was extracted three times with 50 mL of DCM and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (4 / 1) to give 1.5 g (48% yield) of 1′-benzyl-3-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)-[1,4′-bipiperidin]-2-one as a yellow oil. LCMS (ESI, m / z): 428.20 [M+H] + .

[0275] Step D To a solution of 1'-benzyl-3-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)-[1,4'-bipiperidin]-2-one (800 mg, 1.87 mmol, 1.0 equiv.) in a mixture of AcOH / THF / water (20 mL, 3:1:1) was added zinc powder (2.00 g, 30.6 mmol, 16 equiv.). The resulting solution was stirred at 70° C. for 1 h. The solution was diluted with water (20 mL). The pH of the solution was adjusted to 12 with saturated aqueous NaOH. After filtration, the filtrate was extracted three times with 50 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was applied to a silica gel column eluted with DCM / MeOH to give 300 mg (56% yield) of 1'-benzyl-3-hydroxy-[1,4'-bipiperidin]-2-one as a yellow oil. LCMS(ESI,m / z):289.05[M+H] + .

[0276] Step E To a solution of 1'-benzyl-3-hydroxy-[1,4'-bipiperidine]-2-one (400 mg, 1.4 mmol, 1.0 equiv) in EtOH (10 mL) was added Pd / C (20 mg, 0.19 mmol, 0.1 equiv) and di-tert-butyl dicarbonate (605 mg, 2.77 mmol, 2.0 equiv). The resulting solution was stirred under a hydrogen atmosphere for 1 h. The solids were filtered and the filtrate was concentrated in vacuo to give 380 mg (92% yield) of tert-butyl 3-hydroxy-2-oxo-[1,4'-bipiperidine]-1'-carboxylate as a colorless oil. LCMS (ESI, m / z): 299.15 [M+H] + .

[0277] Step F A solution of tert-butyl 3-hydroxy-2-oxo-[1,4'-bipiperidine]-1'-carboxylate (370 mg, 1.24 mmol, 1.0 equiv) in 4 M HCl (10 mL) in dioxane was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo to give 280 mg (96% yield) of 3-hydroxy-[1,4'-bipiperidine]-2-one hydrochloride as a colorless oil. LCMS (ESI, m / z): 199.00 [M+H] + .

[0278] Intermediate I-8: Synthesis of 3-hydroxy-4,4-dimethyl-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride [ka]

[0279] Step A To a solution of 1-benzylpiperidin-4-amine (1.90 g, 9.99 mmol, 1.0 equiv.) in 1-methoxy-2-(2-methoxyethoxy)ethane (1 mL) was added TsOH (0.28 g, 1.6 mmol, 0.2 equiv.) and 3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (1.56 g, 12.0 mmol, 1.2 equiv.). The reaction mixture was irradiated with microwave radiation at 150° C. for 1 h. The resulting solution was stirred at 200° C. for an additional 2 h and then diluted with ethyl acetate (2 mL). The crude product was applied to a silica gel column eluted with dichloromethane / methanol (9 / 1) to give 840 mg (28% yield) of 1-(1-benzylpiperidin-4-yl)-3-hydroxy-4,4-dimethylpyrrolidin-2-one as a brown solid. LC-MS(ES,m / z):303.00[M+H] + .

[0280] Step B To a solution of 1-(1-benzylpiperidin-4-yl)-3-hydroxy-4,4-dimethylpyrrolidin-2-one (837 mg, 2.77 mmol, 1.0 equiv.) in EtOH (20 mL) was added Pd / C (80 mg, 0.75 mmol, 0.3 equiv.) and di-tert-butyl dicarbonate (1.2 g, 5.5 mmol, 1.2 equiv.). The resulting solution was stirred under hydrogen atmosphere for 2 h. After filtration, the filtrate was concentrated in vacuo and the crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (9 / 1) to give 660 mg (76% yield) of tert-butyl 4-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate as a white solid. LC-MS (ES, m / z): 313.10 [M+H] +

[0281] Step C To a solution of tert-butyl 4-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (660 mg, 2.11 mmol, 1.0 equiv.) in dioxane (5 mL) was added 4M HCl in 1,4-dioxane (5 mL). The resulting solution was stirred for 2 h and then concentrated in vacuo to give 680 mg (91% yield) of 3-hydroxy-4,4-dimethyl-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride as a yellow solid. LCMS (ESI, m / z): 213.15 [M+H] + .

[0282] Intermediate I-9: Synthesis of (S)-3-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride [ka]

[0283] Step A To a solution of (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (10.0 g, 57.4 mmol, 1.0 equiv) in DCM (150 mL) was added DCC (17.8 g, 86.3 mmol, 1.5 equiv), DMAP (701 mg, 5.74 mmol, 0.1 equiv), and ethanethiol (7.14 g, 115 mmol, 2 equiv) at 0° C. The resulting solution was stirred at 0° C. for 10 min and then at room temperature for 10 h. The solids were filtered and the filtrate was concentrated in vacuo. The crude product was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (6 / 94) to give 5.8 g (47% yield) of (S)-S-ethyl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)ethanethiolate as a colorless oil.

[0284] Step B To a solution of (S)-S-ethyl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)ethanethiolate (5.80 g, 26.6 mmol, 1.0 equiv) in DCM (100 mL) was added triethylsilane (4.60 g, 39.5 mmol, 1.5 equiv) and Pd / C (2.00 g, 18.8 mmol, 0.7 equiv). The resulting solution was stirred at 25° C. for 3 h. The solid was filtered and the filtrate was concentrated in vacuo. The crude product was cooled and the isolated solid was collected to give 5 g of crude (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde as a colorless solid.

[0285] Step C To a solution of (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (4.90 g, 30.9 mmol, 1.0 equiv) in DCM (100 mL) was added tert-butyl 4-aminopiperidine-1-carboxylate (9.31 g, 46.5 mmol, 1.5 equiv) and AcOH (3.72 g, 0.1 mmol, 2.0 equiv). The resulting solution was stirred for 1 h, after which STAB (19.7 g, 93.0 mmol, 3.0 equiv) was added and the reaction mixture was stirred for an additional 3 h. Saturated NaHCO 3 Aqueous solution was added and the aqueous layer was extracted twice with 50 mL of DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (30 / 70) to give 6 g (68% yield) of (S)-tert-butyl 4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate as a yellow solid. LCMS (ESI, m / z): 285.20 [M+H] + .

[0286] Step D A solution of (S)-tert-butyl 4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (6.00 g, 0.02 mmol, 1.0 equiv) in 4 M HCl (15 mL) in dioxane was stirred for 1 h and then concentrated to give 4.5 g (96% yield) of (S)-3-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride as a yellow solid. LCMS (ESI, m / z): 185.10 [M+H] + .

[0287] Intermediate I-11: Synthesis of (R)-1-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)-3-hydroxypyrrolidin-2-one hydrochloride [ka]

[0288] Step A To a solution of (1R,5S,6s)-tert-butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.00 g, 10.1 mmol, 1.0 equiv) in DCM (40 mL) was added 2-[(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetaldehyde (5.00 g, 31.6 mmol, 3.1 equiv) and AcOH (0.20 g, 3.33 mmol, 0.3 equiv). The reaction mixture was stirred for 1 h, after which STAB (4.10 g, 19.4 mmol, 1.9 equiv) was added and the reaction was stirred for an additional 1.5 h. The solution was diluted with 50 mL of NaHCO 3 After washing twice with aqueous solution, the organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was applied to a silica gel column eluted with ethyl acetate / MeOH (4 / 1) to give 600 mg (21% yield) of tert-butyl (1R,5S,6s)-6-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate as a yellow solid. LCMS (ESI, m / z): 283.15 [M+H] + .

[0289] Step B A solution of tert-butyl (1R,5S,6s)-6-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (600 mg, 2.13 mmol, 1.0 equiv) in 4M HCl (5 mL) in dioxane was stirred for 1 h. The mixture was concentrated to give 400 mg (crude) of (R)-1-((1R,5S,6s)-3-azabicyclo[3.1.0]hexane-6-yl)-3-hydroxypyrrolidin-2-one hydrochloride as a yellow solid. LCMS (ES, m / z): 183.20 [M+H] + .

[0290] Intermediate I-12: Synthesis of (3R,4S)-3-hydroxy-4-methyl-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride and (3S,4R)-3-hydroxy-4-methyl-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride [ka]

[0291] Step A To a solution of 4-methyldihydrofuran-2(3H)-one (5.30 g, 52.9 mmol, 1.0 equiv.) in diethylene glycol dimethyl ether (4 mL) was added 1-benzylpiperidin-4-amine (15.1 g, 79.4 mmol, 1.5 equiv.) and 4-methylbenzenesulfonic acid (1.37 g, 7.94 mmol, 0.2 equiv.). The resulting solution was stirred at 180° C. for 16 h, then diluted with 6 mL of ethyl acetate and applied to a silica gel column eluted with dichloromethane / methanol (87 / 13) to give 2.49 g (17% yield) of 1-(1-benzylpiperidin-4-yl)-4-methylpyrrolidin-2-one as a yellow oil. LCMS (ESI, m / z): 273.05 [M+H] + .

[0292] Step B A solution of 1-(1-benzylpiperidin-4-yl)-4-methylpyrrolidin-2-one (3.10 g, 11.4 mmol, 1.0 equiv) in DCM (20 mL) was added under a nitrogen atmosphere with 3 Å molecular sieves (2 g), TEMPO (3.91 g, 25.0 mmol, 2.2 equiv), and Tf 2 0 (6.42 g, 22.8 mmol, 2.0 equiv) was added at 0° C. The resulting solution was stirred for 30 min and then at room temperature for another 2 h. The solid was filtered and then the filtrate was concentrated and applied to a silica gel column eluted with dichloromethane / methanol (97 / 3) to give 1.3 g (20% yield) of (3R,4S)-1-(1-benzylpiperidin-4-yl)-4-methyl-3-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)pyrrolidin-2-one and (3S,4R)-1-(1-benzylpiperidin-4-yl)-4-methyl-3-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)pyrrolidin-2-one as yellow solids. LCMS (ESI, m / z): 428.30 [M+H]+.

[0293] Step C To (3R,4S)-1-(1-benzylpiperidin-4-yl)-4-methyl-3-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)pyrrolidin-2-one and (3S,4R)-1-(1-benzylpiperidin-4-yl)-4-methyl-3-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)pyrrolidin-2-one (1.30 g, 3.04 mmol, 1.0 equiv.) in a mixture of AcOH / THF / water (15 mL, 3:1:1) was added Zn (3.98 g, 60.8 mmol, 20 equiv.). The resulting solution was stirred at 70° C. for 2 h and then diluted with water (15 mL). The pH was adjusted to 12 with aqueous NaOH and extracted three times with 30 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with dichloromethane / methanol (93 / 7) to give 180 mg (21% yield) of (3R,4S)-1-(1-benzylpiperidin-4-yl)-3-hydroxy-4-methylpyrrolidin-2-one and (3S,4R)-1-(1-benzylpiperidin-4-yl)-3-hydroxy-4-methylpyrrolidin-2-one as a yellow oil. LCMS (ESI, m / z): 289.20 [M+H] + .

[0294] Step D To a solution of (3R,4S)-1-(1-benzylpiperidin-4-yl)-3-hydroxy-4-methylpyrrolidin-2-one and (3S,4R)-1-(1-benzylpiperidin-4-yl)-3-hydroxy-4-methylpyrrolidin-2-one in MeOH (4 mL) was added di-tert-butyl dicarbonate (272 mg, 1.25 mmol, 2.0 equiv.) and Pd / C (7 mg, 0.06 mmol, 0.1 equiv.). The resulting solution was stirred under a hydrogen atmosphere for 1 h. The solids were filtered and the filtrate was concentrated to give 226 mg of crude tert-butyl (3R,4S)-4-(3-hydroxy-4-methyl-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate and tert-butyl (3S,4R)-4-(3-hydroxy-4-methyl-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m / z): 299.05 [M+H] + .

[0295] Step E A solution of crude (3R,4S)-tert-butyl 4-(3-hydroxy-4-methyl-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate and (3S,4R)-tert-butyl 4-(3-hydroxy-4-methyl-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (226 mg, 0.76 mmol, 1.0 equiv.) in HCl / dioxane (10 mL, 4M) was stirred for 1 h and then concentrated to give 168 mg of crude (3R,4S)-3-hydroxy-4-methyl-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride and (3S,4R)-3-hydroxy-4-methyl-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride as a white solid. LCMS (ESI, m / z): 199.05 [M+H] + .

[0296] Intermediate I-13: Synthesis of (R)-1-((3R,4R)-3-fluoropiperidin-4-yl)-3-hydroxypyrrolidin-2-one-TFA salt and (R)-1-((3S,4S)-3-fluoropiperidin-4-yl)-3-hydroxypyrrolidin-2-one-TFA salt [ka]

[0297] Step A To a solution of (3R,4R)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate and (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (1.00 g, 4.51 mmol, 1.0 equiv.) in DCM (20 mL) was added (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (1.10 g, 6.96 mmol, 1.5 equiv.) and AcOH (1.70 g, 0.03 mmol, 0.01 equiv.). The resulting solution was stirred for 1 h, after which STAB (2.90 g, 0.01 mmol, 3.0 equiv.) was added and the reaction mixture was stirred for an additional 3 h. Saturated NaHCO 3 The reaction was quenched by the addition of aqueous solution. The aqueous layer was extracted twice with 50 mL of DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluted with MeOH / DCM (5 / 95) to give 700 mg (51% yield) of tert-butyl (3R,4R)-3-fluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate and tert-butyl (3S,4S)-3-fluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate as an off-white oil.

[0298] Step B To a solution of (3R,4R)-3-fluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate tert-butyl and (3S,4S)-3-fluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate tert-butyl (700 mg, 2.32 mmol, 1.0 equiv.) in DCM (5 mL) was added TFA (0.5 mL). The resulting solution was stirred for 1 hour and then concentrated to give 600 mg of crude (R)-1-((3R,4R)-3-fluoropiperidin-4-yl)-3-hydroxypyrrolidin-2-one-TFA salt and (R)-1-((3S,4S)-3-fluoropiperidin-4-yl)-3-hydroxypyrrolidin-2-one-TFA salt as a brown oil.

[0299] Intermediate I-14: Synthesis of (R)-1-((3R,4S)-3-fluoropiperidin-4-yl)-3-hydroxypyrrolidin-2-one hydrochloride and (R)-1-((3S,4R)-3-fluoropiperidin-4-yl)-3-hydroxypyrrolidin-2-one hydrochloride [ka]

[0300] Step A To a solution of (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (2.90 g, 18.34 mmol, 4.0 equiv) in DCM (20 mL) was added AcOH (550 mg, 9.16 mmol, 2.0 equiv) and a mixture of tert-butyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate and tert-butyl (3R,4S)-4-amino-3-fluoropiperidine-1-carboxylate (1.00 g, 4.51 mmol, 1.0 equiv). The resulting solution was stirred for 0.5 h, after which STAB (2.91 g, 13.74 mmol, 3.0 equiv) was added and the reaction was stirred for an additional 3 h. Then, 20 mL of NaHCO 3The reaction was quenched by the addition of aqueous solution. The resulting solution was extracted three times with 50 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was applied to a silica gel column eluted with dichloromethane / methanol (2 / 3) to give 0.66 g (48% yield) of tert-butyl (3S,4R)-3-fluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate and tert-butyl (3R,4S)-3-fluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m / z): 303.15 [M+H] + .

[0301] Step B A solution of (3S,4R)-3-fluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate and (3R,4S)-3-fluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (660 mg, 2.18 mmol, 1.0 equiv.) in HCl / dioxane (15 mL, 4M) was stirred for 15 hours. The resulting mixture was concentrated to give 510 mg (98% yield) of (R)-1-((3R,4S)-3-fluoropiperidin-4-yl)-3-hydroxypyrrolidin-2-one hydrochloride and (R)-1-((3S,4R)-3-fluoropiperidin-4-yl)-3-hydroxypyrrolidin-2-one hydrochloride as a yellow oil. LCMS(ESI,m / z):203.15[M+H] + .

[0302] Intermediate I-15: Synthesis of (R)-1-((R)-3,3-difluoropiperidin-4-yl)-3-hydroxypyrrolidin-2-one hydrochloride and (R)-1-((S)-3,3-difluoropiperidin-4-yl)-3-hydroxypyrrolidin-2-one hydrochloride [ka]

[0303] Step A To a solution of tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate (1.00 g, 4.23 mmol, 1.0 equiv) in DCM (50 mL) was added (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (1004 mg, 6.35 mmol, 1.5 equiv), STAB (3.59 g, 16.9 mmol, 4.0 equiv), and AcOH (250 mg, 4.2 mmol, 1.0 equiv). The resulting solution was stirred for 12 h and concentrated in vacuo. The crude product was applied to a silica gel column eluted with DCM / methanol (9 / 1) to give 1.5 g (crude) of tert-butyl 3,3-difluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate as a yellow solid. LCMS (ESI, m / z): 321.30 [M+H] + .

[0304] Step B A solution of tert-butyl 3,3-difluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.50 g, 4.68 mmol, 1.0 equiv) in 4 M HCl (10 mL) in dioxane was stirred for 6 h and then concentrated in vacuo to give 1.5 g (crude) of (R)-1-((R)-3,3-difluoropiperidin-4-yl)-3-hydroxypyrrolidin-2-one hydrochloride and (R)-1-((S)-3,3-difluoropiperidin-4-yl)-3-hydroxypyrrolidin-2-one hydrochloride as a yellow oil. LCMS (ESI, m / z): 221.10 [M+H] + .

[0305] Intermediate I-16: Synthesis of (1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)-L-alanine [ka]

[0306] A solution of 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (2.00 g, 6.28 mmol, 1.0 equiv) in DMF (15 mL) was treated with L-alanine (725 mg, 8.14 mmol, 1.3 equiv) and K 2 CO 3 (2.60 g, 18.8 mmol, 3.0 equiv.) was added. The resulting solution was stirred at 60° C. for 2 h and then quenched by adding 100 mL of water. The pH was adjusted to 2-3 with 1N aqueous HCl. The solution was extracted three times with 150 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by filtration using water / CH 3 Application to a reverse phase column eluted with CN (1 / 1) gave 1.4 g (60% yield) of (1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)-L-alanine as a light yellow solid. LCMS (ES, m / z): 372.11 [M+H] + .

[0307] Examples 34 to 37 Examples 34-37 were synthesized according to the procedure described for the synthesis of 5-((S)-1-((S)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(2H)-one and 5-((S)-1-((R)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(2H)-one (see Example 10), using the appropriate building blocks and modified reaction conditions (such as reagent ratios, temperatures, coupling conditions, and reaction times) as necessary. The relative stereochemistry of the compounds was assigned based on the PARP7 potency of the more active diastereomer by analogy to Example 10 and by analogy to the X-ray crystal structure of Example 10B. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6]

[0308] Examples 38 to 40 Examples 38-40 were synthesized according to the procedure described for the synthesis of 5-((S)-1-((S)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(2H)-one and 5-((S)-1-((R)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(2H)-one (see Example 10), using the appropriate building blocks and modified reaction conditions (such as reagent ratios, temperatures, coupling conditions, and reaction times) as necessary. The absolute stereochemistry of the substituted piperidine moiety has been arbitrarily assigned. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5]

[0309] Examples 41 to 45 Examples 41-45 were synthesized according to the procedure described for the synthesis of 5-(((S)-1-(((R)-1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (see Example 16), using the appropriate building blocks and modified reaction conditions (such as reagent ratios, temperatures, coupling conditions, and reaction times) as necessary. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4]

[0310] Examples 46 to 49 Examples 46-49 were synthesized according to the procedures described for the synthesis of 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one and 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one (see Examples 20A and 20B), using the appropriate building blocks and modified reaction conditions (such as reagent ratios, temperatures, coupling conditions, and reaction times) as necessary. The relative stereochemistry of the compounds was assigned based on the PARP7 potency of the more active diastereomer by analogy to Example 10 and by analogy to the X-ray crystal structure of Example 10B. [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5] [Table 12-6]

[0311] Example 50: Synthesis of 6-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile and 6-(4-((S)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile [ka]

[0312] Step A A solution of 3-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (2.00 g, 9.06 mmol, 1.0 equiv.) in DMF (8 mL) was treated with 6-chloronicotinonitrile (1.26 g, 9.09 mmol, 1.0 equiv.) and K 2CO 3 (2.50 g, 18.1 mmol, 2.0 equiv.) was added. The resulting solution was stirred at 80° C. for 2 h and then quenched by the addition of water (20 mL). The solution was extracted twice with 50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (60 / 40) to give 1.8 g (69% yield) of 6-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile as a white solid. (ES, m / z): 287.15 [M+H] + .

[0313] Step B To a solution of 6-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (600 mg, 2.10 mmol, 1.0 equiv) in DMF (5 mL) was added NaH (334 mg, 8.35 mmol, 4.0 equiv, 60% dispersion in mineral oil) at 0° C. The solution was stirred at 0° C. for 10 min, after which (S)-oxiran-2-yl methyl-3-nitrobenzenesulfonate (650 mg, 2.51 mmol, 1.2 equiv) was added. The solution was stirred at 50° C. for 25 h. MeOH (5 mL) was added and the reaction was stirred at 50° C. for an additional 2 h. After concentration, the crude product was dissolved in water / CH 3 Purification by reverse phase chromatography eluting with CN (45 / 55) afforded 300 mg (39% yield) of 6-(4-(3-((S)-2-hydroxy-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile as a white solid. (ES, m / z): 375.25 [M+H] + .

[0314] Step C To a solution of 6-(4-(3-((S)-2-hydroxy-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (120 mg, 0.32 mmol, 1.0 equiv.) in DCM (4 mL) was added 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (120 mg, 0.38 mmol, 1.2 equiv.) and t-BuOK (72 mg, 0.64 mmol, 2.0 equiv.). The resulting solution was stirred for 2 h and then concentrated in vacuo. The crude product was applied to a silica gel column eluted with MeOH / DCM (8 / 92) to give 160 mg (68% yield) of 6-(4-(3-((S)-3-methoxy-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile as a white solid. LCMS (ESI, m / z): 657.25 [M+H] + .

[0315] Step D A solution of 6-(4-(3-((S)-3-methoxy-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (160 mg, 0.244 mmol, 1.00 equiv) in TFA / trifluoromethanesulfonic acid (1.2 mL, 5 / 1) was stirred at 0° C. for 10 min. The reaction was then quenched by the addition of water / ice (10 mL). The pH of the solution was adjusted to 0.2 mg with saturated NaCl. 2 CO 3 The pH was adjusted to about 7-8 with aqueous hexanes. The resulting solution was extracted three times with 50 mL of DCM. The organic layers were combined and concentrated in vacuo. The crude product was purified by reverse phase chromatography to obtain a mixture of isomers. Chiral preparative HPLC: CHIRALPAK IA, 2 × 25 cm, 5 μm, mobile phase A: MTBE (10 mM NH 3-MEOH), mobile phase B: EtOH, flow rate: 16 mL / min, gradient: 30% B over 15 min, 220 / 254 nm to give the separated compounds. The relative stereochemistry of the compounds was assigned by analogy to Example 10 based on the PARP7 potency of the more active diastereomer, and by analogy to the X-ray crystal structure of Example 10B.

[0316] Example 50 Isomer A (50A): 6-(4-((S)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (46 mg, 35% yield, white solid). LCMS (ESI, m / z): 537.15 [M+H] + ; 1 HNMR(300MHz,DMSO-d6)δ 13.21(s,1H),8.45(d,J=2.3Hz,1H),8.27(s,1H),7.80(dd,J=9.1,2.4Hz, 1H),6.94(d,J=9.1Hz,1H),5.21(br,1H),4.52(d,J=13.4Hz,2H),4.09-3. 96(m,3H),3.77-3.64(m,1H),3.62-3.47(m,2H),3.26(s,3H),3.23-3.04( m,2H),3.02-2.89(m,2H),2.25-2.11(m,1H),1.69-1.46(m,5H).CHIRALPAK IA-3, 4.6×100 mm, 3 μm, Mobile phase A: MtBE (0.1% diethylamine):EtOH=75:25, Flow rate: 1 mL / min, Retention time: 1.589 min (earlier peak)

[0317] Example 50 Isomer A (50B): 6-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (54 mg, 41% yield, white solid). LCMS (ESI, m / z): 537.15 [M+H] + , 1H NMR(300MHz,DMSO-d6)δ 13.21(s,1H),8.45(d,J=2.4Hz,1H),8.29(s,1H),7.80(dd,J=9.1,2.4Hz,1H),6.94(d,J=9.1Hz,1H),5.21(br,1H),4.52(d,J=13.3Hz,2H) ,4.11-3.87(m,3H),3.85-3.75(m,1H),3.64-3.47(m,2H),3.25(s,3H),3.24-2.87(m,4H),2.27-2.13(m,1H),1.76-1.47(m,5H).CHIRALPAK IA-3, 4.6×100 mm, 3 μm, Mobile phase A: MtBE (0.1% diethylamine):EtOH=75:25, Flow rate: 1 mL / min, Retention time: 1.992 min (slower peak)

[0318] Examples 51 and 52 Examples 51 and 52 were synthesized according to the procedure described for the synthesis of 6-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile and 6-(4-((S)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (see Example 50), using the appropriate building blocks and modified reaction conditions (such as reagent ratios, temperatures, coupling conditions, and reaction times) as necessary. The relative stereochemistry of the compounds was assigned based on the PARP7 potency of the more active diastereomer by analogy to Example 10 and by analogy to the X-ray crystal structure of Example 10B. [Table 13-1] [Table 13-2]

[0319] Examples 53 and 54 Examples 53 and 54 were synthesized according to the procedures described for the synthesis of 6-(4-((S)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile and 6-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (see Examples 17A and 17B), using the appropriate building blocks and modified reaction conditions (such as reagent ratios, temperatures, coupling conditions, and reaction times) as necessary. [Table 14]

[0320] Example 55: Synthesis of 6-(4-((R)-3-((S)-2-((5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile and 6-(4-((S)-3-((S)-2-((5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile [ka]

[0321] Step A To a solution of 6-(4-(3-((S)-2-hydroxy-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (280 mg, 0.75 mmol, 1.0 equiv) in DMF (3 mL) was added NaH (60 mg, 1.50 mmol, 2.01 equiv, 60% dispersion in mineral oil) at 0° C. The mixture was stirred at 0° C. for 10 min, after which 4,5-dibromo-2-(4-methoxybenzyl)pyridazin-3(2H)-one (330 mg, 0.88 mmol, 1.2 equiv) was added and the resulting solution was stirred at room temperature for 1 h. The reaction was then diluted with saturated NH 4 It was quenched with aqueous Cl (0.5 mL) and the resulting mixture was concentrated. The crude product was purified by distillation with water / CH 3 Purification by reverse phase column eluting with CN (65 / 45) afforded 150 mg (30% yield) of 6-(4-(3-((S)-2-((5-bromo-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazin-4-yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile as a yellow solid. (ES,m / z):669.30[M+H] + .

[0322] Step B A solution of 6-(4-(3-((S)-2-((5-bromo-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazin-4-yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (150 mg, 0.23 mmol, 1.0 equiv) in TfOH / TFA (1.5 mL, 1:5) was stirred at room temperature for 15 min. The resulting solution was diluted with water (15 mL) and the pH was adjusted to 7-8 with sodium bicarbonate solution. The solution was extracted three times with 50 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by elution with water / CH 3 The isomeric mixture was purified by reversed-phase chromatography eluting with CN and then purified by chiral preparative HPLC: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm, mobile phase A: MTBE (10 mM NH 3 -MEOH), mobile phase B: EtOH, flow rate: 20 mL / min, gradient: 20% B over 15 min, 220 / 254 nm. The relative stereochemistry of the compounds was assigned by analogy to Example 10, based on the PARP7 potency of the more active diastereomer, and by analogy to the X-ray crystal structure of Example 10B.

[0323] Example 55 Isomer A (55A): 6-(4-((S)-3-((S)-2-((5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (31 mg, 25% yield, white solid). LCMS (ESI, m / z): 549.10 [M+H] + ;1H NMR (400MHz, DMSO-d 6)δ 13.13(s,1H),8.47(s,1H),8.11(s,1H),7.83(d,J=9.1Hz,1H),6.96(d, J=9.1Hz,1H),5.08(br,1H),4.59-4.48(m,2H),4.12-3.95(m,3H),3.79 -3.70(m,1H),3.65-3.54(m,2H),3.29(s,3H),3.25-3.06(m,2H),3.04-2.91(m,2H),2.27-2.15(m,1H),1.72-1.46(m,5H).Chiral HPLC: Column: CHIRAL ART Cellulose-SB, 4.6 x 100 mm, 3 um, mobile phase: MtBE (0.1% diethylamine):EtOH = 80:20, flow rate: 1 mL / min, retention time: 3.928 min (earlier peak)

[0324] Example 55 Isomer A (55B): 6-(4-((R)-3-((S)-2-((5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (42 mg, 35% yield, white solid). LCMS (ESI, m / z): 549.15 [M+H] + ;1H NMR(400MHz,DMSO-d6)δ 13.14(s,1H),8.47(s,1H),8.13(s,1H),7.85(d,J=9.2Hz,1H),6.96(d, J=9.2Hz,1H),5.08(br,1H),4.57-4.49(m,2H),4.14-3.91(m,3H),3.86 -3.79(m,1H),3.65-3.53(m,2H),3.29(s,3H),3.25-3.07(m,2H),3.05-2.92(m,2H),2.34-2.19(m,1H),1.78-1.46(m,5H).Chiral HPLC: Column: CHIRAL ART Cellulose-SB, 4.6 x 100 mm, 3 μm, mobile phase: MtBE (0.1% diethylamine):EtOH = 80:20, flow rate: 1 mL / min, retention time: 4.384 min (slower peak)

[0325] Example 56 Example 56 was synthesized according to the procedure described for the synthesis of 6-(4-((R)-3-((S)-2-((5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile and 6-(4-((S)-3-((S)-2-((5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (see Example 55), using the appropriate building blocks and modified reaction conditions (such as reagent ratios, temperatures, coupling conditions, and reaction times) as necessary. The relative stereochemistry of the compounds was assigned based on the PARP7 potency of the more active diastereomer by analogy to Example 10 and by analogy to the X-ray crystal structure of Example 10B. [Table 15]

[0326] Example 57: Synthesis of 5-(((S)-1-(((R)-1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0327] Step A A solution of tert-butyl ((3R,4R)-3-hydroxypiperidin-4-yl)carbamate (980 mg, 4.53 mmol, 1.0 equiv.) in DMF (5 mL) was added to 2-chloro-5-(trifluoromethyl)pyrimidine (825 mg, 4.52 mmol, 1.0 equiv.) and K 2 CO 3(940 mg, 6.80 mmol, 1.5 equiv.) was added. The resulting solution was stirred at 50° C. for 1 h and then quenched by the addition of water (15 mL). The solid was collected by filtration to give 1.6 g (97% yield) of tert-butyl ((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)carbamate as a white solid. (ESI, m / z): 363.10 [M+H] + .

[0328] Step B A solution of tert-butyl ((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)carbamate (1.60 g, 4.42 mmol, 1.0 equiv) in 4 M HCl (30 mL) in 1,4-dioxane was stirred at 40° C. for 1 h. The resulting mixture was concentrated in vacuo to give 1.1 g (95% yield) of (3R,4R)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol hydrochloride as a white solid. (ESI, m / z): 263.05 [M+H] + .

[0329] Step C (3R,4R)-4-Amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol hydrochloride (980 mg, 3.74 mmol, 1.0 equiv.) 3 To the CN (30 mL) solution was added imidazole (1.27 g, 18.7 mmol, 5.0 equiv.) and tert-butylchlorodimethylsilane (1.69 g, 11.2 mmol, 3.0 equiv.). The resulting solution was stirred at 60° C. for 30 h. After filtration, the filtrate was concentrated in vacuo and the crude product was applied to a silica gel column eluted with MeOH / DCM (3:97) to give 1.3 g (92% yield) of (3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine as a yellow oil. (ESI, m / z): 377.4 [M+H] + .

[0330] Step D To a solution of (3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine (1.28 g, 3.40 mmol, 1.0 equiv) in DCM (20 mL) was added (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (1.88 g, 11.9 mmol, 3.5 equiv) and AcOH (408 mg, 6.79 mmol, 2.0 equiv). The resulting solution was stirred for 1 h. STAB (2.16 g, 10.2 mmol, 3.0 equiv) was added and the solution was stirred for an additional 4 h. Saturated NaHCO 3 The reaction was quenched by the addition of aqueous solution. The aqueous layer was extracted twice with 50 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (35 / 65) to give 680 mg (43% yield) of (R)-1-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one as a white solid. (ESI,m / z):461.20[M+H] + .

[0331] Step E To a solution of (R)-1-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one (670 mg, 1.46 mmol, 1.00 equiv.) in DMF (7 mL) was added NaH (117 mg, 2.93 mmol, 2.01 equiv., 60% dispersion in mineral oil) at 0° C. The resulting solution was stirred for 10 min, after which (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate tert-butyl 2,2-dioxide (518 mg, 2.18 mmol, 1.5 equiv.) was added and the solution was maintained at the same temperature for 4 h. Then, saturated NH 4The reaction was quenched by the addition of aqueous Cl. The solution was extracted twice with 50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (3 / 2) to give 300 mg (33% yield) of tert-butyl ((S)-1-(((R)-1-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate as a yellow solid. (ESI, m / z): 618.30 [M+H] + .

[0332] Step F A solution of tert-butyl ((S)-1-(((R)-1-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate (290 mg, 0.47 mmol, 1.0 equiv) in 4N HCl (20 mL) in 1,4-dioxane was stirred for 15 hours. The resulting mixture was concentrated to give 240 mg of (R)-3-((S)-2-aminopropoxy)-1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride as a white solid, which was carried forward without further purification. (ESI, m / z): 404.15 [M+H] + .

[0333] Step G To a solution of (R)-3-((S)-2-aminopropoxy)-1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride (230 mg, 0.57 mmol, 1.0 equiv) in EtOH (4 mL) was added 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (181 mg, 0.57 mmol, 1.0 equiv) and triethylamine (173 mg, 1.71 mmol, 3.0 equiv). The resulting solution was stirred at 60° C. for 1 h. After completion, the crude product was dissolved in water / CH 3 Application to a reverse phase column eluting with CN (45 / 55) gave 185 mg (47% yield) of 5-(((S)-1-(((R)-1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as a white solid. (ESI, m / z): 686.25 [M+H] + .

[0334] Step H A solution of 5-(((S)-1-(((R)-1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (185 mg, 0.270 mmol, 1.0 equiv) in TFA (1.5 mL) and TfOH (0.3 mL) was stirred for 1 h. The reaction was quenched by the addition of ice water (2 mL). The pH was adjusted to 0.05 with saturated NaCl. 2 CO 3 The pH was adjusted to about 7-8 with aqueous solution. The resulting solution was extracted twice with 50 mL of DCM. The organic layers were combined and concentrated. The crude product was purified by elution with water / CH 3Purification by reverse phase chromatography eluting with CN (45 / 55) afforded 89 mg (59% yield) of 5-(((S)-1-(((R)-1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one as a white solid. (ESI, m / z): 566.15 [M+H] + ;1H NMR(300MHz,DMSO-d6)δ 12.46(s,1H),8.69(d,J=0.9Hz,2H),7.94(s,1H),6.39-6.29(m,1H),5.28(d,J=5.3Hz, 1H),4.91-4.80(m,1H),4.72(d,J=13.4Hz,1H),4.21-4.07(m,2H),3.84-3.73(m,2H),3 .63-3.49(m,2H),3.29-3.22(m,1H),3.17-3.07(m,1H),3.02-2.89(m,1H),2.84-2.70( m,1H),2.31-2.16(m,1H),1.83-1.68(m,1H),1.65-1.48(m,2H),1.16(d,J=6.4Hz,3H).

[0335] Example 58: Synthesis of 5-(((S)-1-(((R)-1-((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0336] Step A A solution of tert-butyl ((3S,4S)-3-hydroxypiperidin-4-yl)carbamate (1.00 g, 4.62 mmol, 1.0 equiv) in DMF (5 mL) was 2 CO 3(0.96 g, 6.95 mmol, 1.5 equiv.) and 2-chloro-5-(trifluoromethyl)pyrimidine (0.85 g, 4.66 mmol, 1.0 equiv.) were added. The resulting solution was stirred at 50° C. for 1 h. The reaction mixture was quenched by adding 10 mL of water and the solid was collected by filtration to give 1.45 g (87% yield) of tert-butyl ((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)carbamate as a white solid. LCMS (ESI, m / z): 363.10 [M+H] + .

[0337] Step B A solution of tert-butyl ((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)carbamate (1.45 g, 4.00 mmol, 1.0 equiv) in 4N HCl (30 mL) in 1,4-dioxane was stirred at 40° C. for 2 h. The resulting mixture was concentrated to give 1.0 g (95% yield) of (3S,4S)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol hydrochloride as a yellow solid. LCMS (ESI, m / z): 263.05 [M+H] + .

[0338] Step C (3S,4S)-4-Amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol hydrochloride (1.19 g, 3.98 mmol, 1.0 equiv.) 3To the CN (40 mL) solution was added tert-butyldimethylsilyl chloride (2.36 g, 15.7 mmol, 3.93 equiv) and imidazole (1.77 g, 26.0 mmol, 6.5 equiv). The resulting solution was stirred at 60° C. overnight. After filtration, the filtrate was concentrated in vacuo and the crude product was applied to a silica gel column eluted with chloroform / methanol (10 / 1) to give 1.20 g (80% yield) of (3S,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(5-methylpyrimidin-2-yl)piperidin-4-amine as a white solid. LCMS (ESI, m / z): 377.10 [M+H] +

[0339] Step D To a solution of (3S,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(5-methylpyrimidin-2-yl)piperidin-4-amine (1.40 g, 3.72 mmol, 1.0 equiv) in DCM (20 mL) was added (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (1.88 g, 11.9 mmol, 3.2 equiv) and AcOH (446 mg, 7.44 mmol, 2.0 equiv). After stirring for 15 min, STAB (2.36 g, 11.2 mmol, 3.0 equiv) was added and the solution was stirred for an additional 5 h. 20 mL of saturated NaHCO 3 The reaction was quenched by addition of aqueous solution and extracted with 3 x 50 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (3 / 2) to give 470 mg (27% yield) of (R)-1-((3S,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one as a yellow solid. LCMS (ESI, m / z): 461.20 [M+H] + .

[0340] Step E To a solution of (R)-1-((3S,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one (465 mg, 1.01 mmol, 1.0 equiv) in DMF (5 mL) was added NaH (121 mg, 3.03 mmol, 3.0 equiv, 60%) at 0° C. The reaction mixture was stirred for 10 min, after which a solution of (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl 2,2-dioxide (287 mg, 1.21 mmol, 1.2 equiv) in DMF (2 mL) was added. The resulting solution was stirred at 0° C. for 2 h. The reaction was quenched by the addition of water (10 mL). The resulting solution was extracted twice with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (3 / 2) to give 480 mg (77% yield) of tert-butyl ((S)-1-(((R)-1-((3S,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate as a yellow solid. LCMS (ESI, m / z): 618.35 [M+H] + .

[0341] Step F A solution of tert-butyl ((S)-1-(((R)-1-((3S,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate (480 mg, 0.78 mmol, 1.0 equiv.) in 4M HCl (10 mL, 4M) in 1,4-dioxane was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo to give 278 mg (81% yield) of (R)-3-((S)-2-aminopropoxy)-1-((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride as a white solid. (ESI, m / z): 461.25 [M+H] + .

[0342] Step G To a solution of (R)-3-((S)-2-aminopropoxy)-1-((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride (270 mg, 0.61 mmol, 1.0 equiv.) in EtOH (8 mL) was added 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (293 mg, 0.92 mmol, 1.5 equiv.) and triethylamine (621 mg, 6.14 mmol, 10.0 equiv.). The resulting solution was stirred at 60° C. for 3 h and then concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (7 / 3) to give 280 mg (67% yield) of 5-(((S)-1-(((R)-1-((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as a yellow solid. LCMS (ESI, m / z): 686.20 [M+H] + .

[0343] Step H A solution of 5-(((S)-1-(((R)-1-((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (270 mg, 0.39 mmol, 1.0 equiv) in TfOH / TFA (3 mL, 1:10) was stirred at 0 °C for 2 h. The reaction was quenched by the addition of water (5 mL) and the pH was adjusted to 7-8 with aqueous sodium bicarbonate. The resulting solution was extracted three times with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by elution with water / CH 3 Purification by reverse phase chromatography eluting with CN (1 / 1) afforded 120 mg (54% yield) of 5-(((S)-1-(((R)-1-((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one as an off-white solid. LCMS (ESI, m / z): 566.20 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ 12.46(s,1H),8.70(s,2H),7.95(s,1H),6.35-6.34(m,1H),5.26(d,J=5.0Hz,1H),4.91- 4.83(m,1H),4.80-4.75(m,1H),4.28-4.10(m,2H),3.80-3.91(m,2H),3.63-3.58(m,1H) ,3.55-3.40(m,1H),3.31-3.25(m,1H),3.22-3.12(m,1H),3.06-2.95(m,1H),2.81-2.76 (m,1H),2.33-2.20(m,1H),1.78-1.66(m,1H),1.64-1.51(m,2H),1.17(d,J=6.4Hz,3H).

[0344] Example 59: Synthesis of 5-(((S)-1-(((R)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0345] Step A A solution of tert-butyl ((3S,4R)-3-hydroxypiperidin-4-yl)carbamate (2.00 g, 9.2 mmol, 1.0 equiv.) in DMF (10 mL) was added to 2-chloro-5-(trifluoromethyl)pyrimidine (1.68 g, 9.2 mmol, 1.00 equiv.) and K 2 CO 3 (2.56 g, 18.5 mmol, 2.0 equiv) was added. The resulting solution was stirred at 50° C. for 1 h and then diluted with water (10 mL). The solid was collected by filtration to give 1.37 g (39% yield) of tert-butyl ((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)carbamate as a white solid. LCMS (ESI, m / z): 363.10 [M+H] + .

[0346] Step B A solution of tert-butyl ((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)carbamate (1.28 g, 3.53 mmol, 1.0 equiv) in 4 M HCl (6 mL) in dioxane was stirred for 2 h. The resulting mixture was concentrated in vacuo to give 1.0 g (95% yield) of (3S,4R)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol hydrochloride as a yellow solid. LCMS (ESI, m / z): 263.05 [M+H] + .

[0347] Step C (3S,4R)-4-Amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol hydrochloride (2.60 g, 9.92 mmol, 1.0 equiv.) 3 To the CN (20 mL) solution was added tert-butyldimethylsilyl chloride (11.95 g, 79.35 mmol, 8.0 equiv.) and imidazole (5.40 g, 79.4 mmol, 8.0 equiv.). The resulting solution was stirred at 60° C. for 4 h and then concentrated in vacuo. The crude product was applied to a silica gel column eluted with chloroform / methanol (9 / 1) to give 3.40 g (88% yield) of (3S,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine as a yellow solid. LCMS (ESI, m / z): 377.10 [M+H] + .

[0348] Step D To a solution of (3S,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine (3.20 g, 8.50 mmol, 1.0 equiv) in DCM (30 mL) was added (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (1.24 g, 7.82 mmol, 0.9 equiv) and AcOH (1.53 g, 25.5 mmol, 3.0 equiv). The resulting solution was stirred for 15 min, after which STAB (14.0 g, 66.0 mmol, 3.0 equiv) was added. After 2 h, 20 mL of saturated NaHCO 3The reaction was quenched by the addition of aqueous solution. The solution was extracted three times with 100 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (3 / 1) to give 0.93 g (24% yield) of (R)-1-((3S,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one as a yellow solid. LCMS (ESI, m / z): 461.20 [M+H] + .

[0349] Step E To a solution of (R)-1-((3S,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one (920 mg, 2.0 mmol, 1.0 equiv.) in DMF (8 mL) was added NaH (239 mg, 5.99 mmol, 3.0 equiv., 60% dispersion in mineral oil) slowly over 10 min at 0° C. Then (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate tert-butyl 2,2-dioxide (568 mg, 2.40 mmol, 1.2 equiv.) was added and the resulting solution was stirred at 0° C. for 2 h. The reaction was quenched by the addition of water (10 mL) and extracted twice with 30 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (3 / 2) to give 767 mg (62% yield) of tert-butyl ((S)-1-(((R)-1-((3S,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate as a yellow solid. LCMS (ESI, m / z): 618.35 [M+H] + .

[0350] Step F A solution of tert-butyl ((S)-1-(((R)-1-((3S,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate (790 mg, 1.28 mmol, 1.0 equiv) in 4M HCl (10 mL) in dioxane was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to give 600 mg (96% yield) of (R)-3-((S)-2-aminopropoxy)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride as a white solid. (ESI, m / z): 461.25 [M+H] + .

[0351] Step G To a solution of (R)-3-((S)-2-aminopropoxy)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride (650 mg, 1.6 mmol, 1.0 equiv.) in ethanol (8 mL) was added 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (616 mg, 1.93 mmol, 1.2 equiv.) and triethylamine (1.04 g mg, 8.06 mmol, 5.0 equiv.). The resulting solution was stirred at 60° C. for 4 hours and then concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (10 / 1) to give 550 mg (50% yield) of 5-(((S)-1-(((R)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as a yellow solid. LCMS (ESI, m / z): 686.20 [M+H] + .

[0352] Step H A solution of 5-(((S)-1-(((R)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (550 mg, 0.80 mmol, 1.0 equiv) in TfOH / TFA (3 mL, 1:10) was stirred at room temperature for 2 h and then quenched by the addition of water (5 mL). The pH was adjusted to 7-8 with sodium bicarbonate. The resulting solution was extracted three times with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by elution with water / CH 3 Purification by reverse phase chromatography eluting with CN (3 / 2) afforded 189 mg (42% yield) of 5-(((S)-1-(((R)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one as an off-white solid. LCMS (ESI, m / z): 566.25 [M+H] + ; 1 H NMR (400MHz, DMSO-d 6 )δ 12.47(s,1H),8.65(s,2H),7.96(s,1H),6.38(br,1H),5.06(d,J=5.1Hz,1H),4. 93-4.78(m,2H),4.21-4.09(m,2H),4.02-3.94(m,1H),3.92-3.81(m,2H),3.62- 3.56(m,2H),3.26-3.10(m,2H),3.04(t,J=12.6Hz,1H),2.29-2.18(m,1H),2.12 -1.99(m,1H),1.83-1.69(m,1H),1.53(d,J=12.3Hz,1H),1.18(d,J=6.4Hz,3H).

[0353] Example 60: Synthesis of 5-(((S)-1-(((R)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0354] Step A A solution of tert-butyl ((3R,4S)-3-hydroxypiperidin-4-yl)carbamate (1.02 g, 4.71 mmol, 1.0 equiv.) in DMF (6 mL) was 2 CO 3 (980 mg, 7.2 mmol, 1.5 equiv) and 2-chloro-5-(trifluoromethyl)pyrimidine (863 mg, 4.73 mmol, 1.0 equiv) were added. The resulting solution was stirred at 60° C. for 2 h and then quenched by the addition of water (20 mL). The solid was collected by filtration to give 1.59 g (93% yield) of tert-butyl ((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)carbamate as an off-white solid. LCMS (ESI, m / z): 363.10 [M+H] + .

[0355] Step B To a solution of tert-butyl ((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)carbamate (1.59 g, 4.39 mmol, 1.0 equiv) in dioxane (50 mL) was added 4N HCl in dioxane (30 mL). The resulting solution was stirred for 5 h and then concentrated to give 1.43 g (97% yield) of (3R,4S)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol hydrochloride as a yellow solid, which was carried forward without further purification. LCMS (ESI, m / z): 263.10 [M+H] + .

[0356] Step C (3R,4S)-4-Amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol hydrochloride (1.43 g, 4.26 mmol, 1.0 equiv.) 3 To the CN (30 mL) solution was added imidazole (2.20 g, 32.3 mmol, 7.6 equiv) and tert-butylchlorodimethylsilane (4.05 g, 26.9 mmol, 6.3 equiv). The resulting solution was stirred at 60° C. for 15 h and then concentrated in vacuo. The crude product was applied to a silica gel column eluted with dichloromethane / methanol (19 / 1) to give 1.74 g (98% yield) of (3R,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine as an orange oil. LCMS (ESI, m / z): 377.20 [M+H] + .

[0357] Step D To a solution of (3R,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine (1.74 g, 4.16 mmol, 1.0 equiv) in DCM (50 mL) was added (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (3.71 g, 23.5 mmol, 5.6 equiv) and AcOH (0.57 g, 9.6 mmol, 2.3 equiv). The resulting solution was stirred for 1 h, after which STAB (3.04 g, 14.3 mmol, 3.5 equiv) was added and the mixture was stirred for an additional 3 h. The reaction was quenched by the addition of 50 mL of saturated aqueous sodium bicarbonate. The resulting solution was extracted three times with 60 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (2 / 1) to give 1.16 g (56% yield) of (R)-1-((3R,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one as an off-white solid. LCMS (ESI, m / z): 461.20 [M+H] + .

[0358] Step E To a solution of (R)-1-((3R,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one (1.12 g, 2.43 mmol, 1.0 equiv) in DMF (10 mL) was added NaH (437 mg, 11.0 mmol, 4.5 equiv, 60% dispersion in mineral oil) at 0° C. The resulting solution was stirred for 30 min, after which a solution of (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate tert-butyl 2,2-dioxide (700 mg, 3 mmol, 1.2 equiv) in DMF (2 mL) was added. The reaction mixture was stirred for 13 h and then quenched by the addition of ice water (10 mL). The pH was adjusted to approximately 6-7 with 2N HCl. The resulting solution was extracted three times with 60 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1 / 2) to give 790 mg (52% yield) of tert-butyl ((S)-1-(((R)-1-((3R,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate as a light yellow solid. LCMS (ESI, m / z): 618.35 [M+H] + .

[0359] Step F A solution of tert-butyl ((S)-1-(((R)-1-((3R,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate (790 mg, 1.28 mmol, 1.0 equiv) in 4N HCl (20 mL) in dioxane was stirred at room temperature for 1.5 days. The resulting mixture was concentrated in vacuo to give 600 mg of (R)-3-((S)-2-aminopropoxy)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride as a yellow solid, which was carried forward without further purification. LCMS(ESI,m / z):404.20[M+H] + .

[0360] Step G (R)-3-((S)-2-aminopropoxy)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride (593 mg, 1.35 mmol, 1.0 equiv.) 3 To a solution of CN (15 mL) was added diisopropylethylamine (750 mg, 5.8 mmol, 4.3 equiv) and 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (452 ​​mg, 1.42 mmol, 1.1 equiv). The resulting solution was stirred at 60° C. for 7 h and then quenched by the addition of water (20 mL). The resulting solution was extracted twice with 30 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by filtration using a water / CH 3Application to a reverse phase column eluted with CN (1 / 3) gave 706 mg (64% yield) of 5-(((S)-1-(((R)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as an off-white solid. LCMS (ESI, m / z): 686.10 [M+H] + .

[0361] Step H A solution of 5-(((S)-1-(((R)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (706 mg, 1.03 mmol, 1.0 equiv) in TFA / TfOH (4.5 mL, 10:1) was stirred at 0° C. for 1 h and then quenched by the addition of ice water (10 mL). The pH was adjusted to 0.2 with saturated NaHCO 3 The acid was adjusted to 7 with aqueous solution. The resulting solution was extracted three times with 30 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was diluted with water / CH 3 Purification by reverse phase chromatography eluting with CN (2 / 1) afforded 254 mg (43% yield) of 5-(((S)-1-(((R)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one as a light green solid. LCMS (ESI, m / z): 566.15 [M+H] + ; 1 H NMR (400MHz, DMSO-d 6)δ 12.45(s,1H),8.65(s,2H),7.95(s,1H),6.39-6.27(m,1H),5.02(d,J=5.1Hz,1H),4.89-4.75(m,2H),4. 22-4.15(m,1H),4.11(t,J=7.6Hz,1H),4.08-3.96(m,1H),3.91(br,1H),3.83(dd,J=10.0,6.5Hz,1H),3 .61(dd,J=10.0,4.7Hz,1H),3.44-3.36(m,1H),3.35-3.26(m,1H),3.13(d,J=13.5Hz,1H),3.09-2.99(m ,1H),2.30-2.18(m,1H),2.12-1.99(m,1H),1.77-1.65(m,1H),1.52-1.42(m,1H),1.18(d,J=6.5Hz,3H).

[0362] Example 61: Synthesis of (S)-N-((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propanamide [ka]

[0363] Step A To a solution of (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid (2.65 g, 10.6 mmol, 1.0 equiv.) in DMF (20 mL) was added 1-[5-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-amine hydrochloride (3.00 g, 10.6 mmol, 1.00 equiv.), HATU (4.44 g, 11.7 mmol, 1.1 equiv.) and diisopropylethylamine (4.11 g, 31.8 mmol, 3.0 equiv.). The resulting solution was stirred for 1 h, then quenched by the addition of water (20 mL) and extracted three times with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 1) to give 3.9 g (77% yield) of tert-butyl (R)-(4-(methylthio)-1-oxo-1-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)amino)butan-2-yl)carbamate as a yellow oil. LCMS (ESI, m / z): 478.20 [M+H] + .

[0364] Step B To a solution of (R)-(4-(methylthio)-1-oxo-1-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)amino)butan-2-yl)tert-butyl carbamate (3.87 g, 8.10 mmol, 1.0 equiv.) in DMF (50 mL) was added methyl iodide (1.73 g, 12.2 mmol, 1.5 equiv.). The resulting solution was stirred at 30° C. overnight and then concentrated in vacuo to give 4.7 g (94% yield) of (R)-(3-((tert-butoxycarbonyl)amino)-4-oxo-4-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)amino)butyl)dimethylsulfonium iodide as a yellow oil. LCMS(ESI,m / z):492.23[M] + .

[0365] Step C To a solution of (R)-(3-((tert-butoxycarbonyl)amino)-4-oxo-4-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)amino)butyl)dimethylsulfonium iodide (4.7 g, 7.6 mmol, 1.0 equiv.) in DMF (100 mL) was added sodium hydride (970 mg, 40.4 mmol, 5.3 equiv., 60% dispersion in mineral oil). The resulting solution was stirred at 30° C. overnight, then quenched by the addition of 100 mL of water and extracted three times with 100 mL of DCM. The organic layers were combined, washed with water, dried and concentrated in vacuo. The crude product was recrystallized from PE:EtOAc (10:1) to give 2 g (61% yield) of tert-butyl (R)-(2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)carbamate as a white solid. LCMS (ESI, m / z): 430.20 [M+H] + .

[0366] Step D A solution of (R)-(2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)carbamate tert-butyl (2.00 g, 4.66 mmol, 1.00 equiv) in 4N HCl (10 mL) in dioxane was stirred for 2 h and then concentrated in vacuo to give 1.5 g (98% yield) of (R)-3-amino-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride as a light yellow solid. LCMS (ESI, m / z): 330.15 [M+H] + .

[0367] Step E To a solution of (1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)-L-alanine (1.4 g, 8 equiv.) in DMF (20 mL) was added (R)-3-amino-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride (155 mg, 1.0 equiv.), HATU (179 mg, 1 equiv.), and diisopropylethylamine (243 mg). After 2 h, the reaction was quenched by the addition of 100 mL of water and extracted three times with 100 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by elution with water / CH 3 Purification by reverse phase chromatography eluting with CN (2 / 3) afforded 220 mg (66% yield) of (S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)-N-((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)propanamide as a white solid. LC-MS (ESI, m / z): 683.25 [M+H] + .

[0368] Step F To a solution of (S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)-N-((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)propanamide (210 mg, 0.31 mmol, 1.0 equiv) in TFA (2.7 mL) was added TfOH (0.3 mL). The mixture was stirred for 2 h, after which 50 mL of water was added. The pH was adjusted to 100 with saturated NaCl. 2 CO 3 The acid was adjusted to 7 with aqueous solution. The resulting solution was extracted three times with 100 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was extracted with water / CH 3Purification by reverse phase chromatography eluting with CN (1 / 1) afforded 81 mg (46% yield) of (S)-N-((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propanamide as a white solid. LCMS (ESI, m / z): 563.10 [M+H] + .1H NMR(300MHz,DMSO-d6)δ 12.61(s,1H),8.70(s,2H),8.59(d,J=8.0Hz,1H),7.65(s,1H),6.71(br,1H),4.93-4.69(m,2H),4.53-4.31(m,2H),4.09(br ,1H),3.30-3.24(m,1H),3.24-3.11(m,1H),3.11-2.94(m,2H),2.36-2.18(m,1H),1.82-1.47(m,5H),1.37(d,J=6.7Hz,3H).

[0369] Example 62: Synthesis of 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)-3-((2,2,2-trifluoroethyl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0370] Step A To a solution of (R)-3-hydroxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (1.30 g, 3.94 mmol, 1.0 equiv.) in DMF (40 mL) was added NaH (0.47 g, 11.8 mmol, 3 equiv., 60% dispersion in mineral oil) and (S)-tert-butyl 2,2-dimethyl-4-((tosyloxy)methyl)oxazolidine-3-carboxylate (6.07 g, 15.7 mmol, 4 equiv.). The mixture was stirred at 40° C. for 7 h. The reaction was quenched by the addition of 40 mL of water. After extraction with ethyl acetate, drying of the organic layer over sodium sulfate and filtration, the resulting mixture was concentrated and applied to a silica gel column eluted with ethyl acetate / petroleum ether (34 / 66) to give tert-butyl (R)-2,2-dimethyl-4-((((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)methyl)oxazolidine-3-carboxylate (1.12 g, 47% yield) as a white solid. LCMS (ESI, m / z): 544.30 [M+H] + .

[0371] Step B A solution of (R)-2,2-dimethyl-4-((((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)methyl)oxazolidine-3-carboxylate tert-butyl (1.12 g, 2.06 mmol, 1.0 equiv) in 1,4-dioxane (10 mL) was treated with 4N HCl in dioxane (5 mL). The resulting solution was stirred for 3 h and concentrated to give (R)-3-((S)-2-amino-3-hydroxypropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride (600 mg, 65% yield) as a yellow oil. LCMS (ESI, m / z): 404.20 [M+H] + .

[0372] Step C To a solution of (R)-3-((S)-2-amino-3-hydroxypropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride (420 mg, 0.96 mmol, 1.0 equiv.) in i-PrOH (45 mL) was added 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (304 mg, 0.96 mmol, 1 equiv.) and diisopropylethylamine (987 mg, 7.64 mmol, 8 equiv.). The resulting solution was stirred at 80° C. for 3 h and then diluted with 150 mL of ethyl acetate. The mixture was washed three times with 50 mL of water, then dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluted with ethyl acetate to give 5-(((S)-1-hydroxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (440 mg, 60% yield) as a yellow oil. LCMS (ESI, m / z): 686.25 [M+H] + .

[0373] Step D To a solution of 5-(((S)-1-hydroxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (775 mg, 1.13 mmol, 1.0 equiv) in DCM (30 mL) was added DMAP (27 mg, 0.23 mmol, 0.2 equiv), triethylamine (343 mg, 3.39 mmol, 3.0 equiv), and 4-methylbenzenesulfonyl chloride (430 mg, 2.3 mmol, 2 equiv). The resulting solution was stirred overnight, then concentrated and applied to a silica gel column eluting with ethyl acetate / petroleum ether (71 / 29) to give (R)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propyl 4-methylbenzenesulfonate (330 mg, 30% yield) as a yellow oil. LCMS (ESI, m / z): 840.25 [M+H] + .

[0374] Step E To a solution of (R)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propyl 4-methylbenzenesulfonate (330 mg, 0.39 mmol, 1.0 equiv.) in DMF (5 mL) was added sodium azide (38 mg, 0.59 mmol, 1.5 equiv.). The solution was stirred at 80° C. for 1 h and then quenched by the addition of 25 mL of water. The mixture was extracted three times with 50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 5-(((2S)-1-azido-3-((2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (330 mg, 71% yield) as a yellow oil. LCMS (ESI, m / z): 711.20 [M+H] + .

[0375] Step F To a solution of 5-(((2S)-1-azido-3-((2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (330 mg, 0.46 mmol, 1.0 equiv, 60%) in THF (5 mL) was added triphenylphosphine (182 mg, 0.70 mmol, 1.5 equiv) and water (0.5 mL). The solution was stirred at 60° C. for 1.5 h, concentrated and applied to a silica gel column eluting with DCM / methanol (87 / 13) to give 5-(((2S)-1-amino-3-((2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (186 mg, 92% yield) as a white solid. LCMS (ESI, m / z): 685.30 [M+H] + .

[0376] Step G A solution of 5-(((2S)-1-amino-3-((2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (100 mg, 0.15 mmol, 1.00 equiv.) in dichloroethane (8 mL) was added with 2,2,2-trifluoroacetaldehyde (57 mg, 0.44 mmol, 3 equiv.), Ti(Oi-Pr) 4 (41 mg, 0.15 mmol, 1.0 equiv.), AcOH (8 mg, 0.15 mmol, 1 equiv.), and NaBH 3CN (18 mg, 0.29 mmol, 2 equiv.) was added. The resulting solution was stirred at 70° C. for 1.5 h, then diluted with 50 mL of ethyl acetate and washed three times with 20 mL of water. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (91 / 9) to give 2-(4-methoxybenzyl)-5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)-3-((2,2,2-trifluoroethyl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (67 mg, 56% yield) as a white solid. LCMS (ESI, m / z): 767.25 [M+H] + .

[0377] Step H To a solution of 2-(4-methoxybenzyl)-5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)-3-((2,2,2-trifluoroethyl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (60 mg, 0.08 mmol, 1.0 equiv.) in TFA (1 mL) was added TfOH (0.1 mL) and the mixture was stirred for 1 h. 8 mL of water was added and the pH was adjusted to 1.0 with solid NaCl. 2 CO 3 The acid was adjusted to 9 with 50 mL of ethyl acetate. The resulting solution was extracted twice with 30 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was diluted with water / CH 3Application to a reverse phase column eluting with CN (37 / 63) gave 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)-3-((2,2,2-trifluoroethyl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (20 mg, 39% yield) as a white solid. LCMS (ESI, m / z): 647.20 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 12.45(s,1H),8.69(s,2H),7.96(s,1H),6.60-6.60(m,1H),4.82(d,J=13.2Hz,2H),4.20-4.01(m,4H),3.95-3.82(m,1 H),3.72-3.58(m,1H),3.18-2.96(m,4H),2.92-2.89(m,1H),2.85-2.78(m,1H),2.30-2.15(m,1H),1.81-1.50(m,6H).

[0378] Example 63: Synthesis of 5-(((S)-1-hydroxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0379] Step A (R)-3-((S)-2-amino-3-hydroxypropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride (130 mg, 0.29 mmol, 1.0 equiv.) 3 To a solution of CN (5 mL) was added 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (106 mg, 0.33 mmol, 1.1 equiv) and triethylamine (101 mg, 1.00 mmol, 3.4 equiv). The resulting solution was stirred at 60° C. for 1.5 days and then concentrated in vacuo. The crude product was extracted with water / CH 3 Application to a reverse phase column eluted with CN (1 / 1) gave 150 mg (62% yield) of 5-(((S)-1-hydroxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as a yellow solid. LCMS (ES, m / z): 686.20 [M+H] + .

[0380] Step B A solution of 5-(((S)-1-hydroxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (150 mg, 0.22 mmol, 1.0 equiv) in TFA / TfOH (1.5 mL, 10:1) was stirred at room temperature for 1 h and then quenched by the addition of ice water (10 mL). The pH was adjusted to 0.1 with saturated NaHCO 3The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was diluted with water / CH 3 Purification by reverse phase chromatography eluting with CN (3 / 2) afforded 15 mg (12% yield) of 5-(((S)-1-hydroxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one as an off-white solid. LCMS (ESI, m / z): 566.25 [M+H] + ; 1 H NMR (400MHz, DMSO-d 6 )δ 12.45(br,1H),8.69(s,1H),7.95(s,1H),6.29-6.31(m,1H),5.10(t,J=5.2H z,1H),4.82(d,J=12.8Hz,1H),4.13-4.07(m,3H),3.88(dd,J=10.1,6.4Hz,1H ),3.68(dd,J=10.2,5.4Hz,1H),3.54(t,J=5.4Hz,2H),3.28-3.22(m,1H),3.1 6-3.10(m,1H),3.04(t,J=11.6Hz,2H),2.29-2.21(m,1H),1.77-1.50(m,5H).

[0381] Example 64: Synthesis of syn-5-(((2S)-1-(((3S)-1-(3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one and syn-5-(((2S)-1-(((3R)-1-(3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0382] Step A To a solution of racemic syn-(3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)tert-butyl carbamate (2.22 g, 6.13 mmol, 1.0 equiv) in dioxane (10 mL) was added 4N HCl in dioxane (10 mL, 4M). The solution was stirred at 50° C. for 1.5 h and then concentrated in vacuo to give 2.28 g (99% yield) of syn-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol hydrochloride as an off-white solid. LCMS (ESI, m / z): 263.05 [M+H] + .

[0383] Step B syn-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol hydrochloride (2.28 g, 7.63 mmol, 1.0 equiv.) 3 To the CN (20 mL) solution was added imidazole (3.15 g, 46.3 mmol, 6.1 equiv) and tert-butylchlorodimethylsilane (5.80 g, 38.5 mmol, 5.0 equiv). The solution was stirred at 60° C. for 15 h and then concentrated in vacuo. The crude product was applied to a silica gel column eluted with DCM / methanol (24 / 1) to give 2.27 g (78% yield) of syn-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine as a light yellow solid. LCMS (ESI, m / z): 377.10 [M+H] + .

[0384] Step C To a solution of syn-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine (2.27 g, 6.03 mmol, 1.0 equiv) in DCM (50 mL) was added (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (5.70 g, 36.0 mmol, 5.98 equiv) and AcOH (1.08 g, 17.9 mmol, 3.0 equiv). The resulting solution was stirred for 1 h, after which STAB (3.84 g, 18.1 mmol, 3.0 equiv) was added and the mixture was stirred for an additional 3 h. After completion, the reaction was quenched by the addition of 50 mL of saturated aqueous sodium bicarbonate and extracted three times with 60 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with DCM / methanol (24 / 1) to give 2.55 g (81% yield) of syn-(3S)-1-(3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one as an off-white solid. LCMS (ESI, m / z): 461.15 [M+H] + .

[0385] Step D To a solution of syn-(3S)-1-(3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one (2.40 g, 5.21 mmol, 1.0 equiv.) in DCM (30 mL) was added triethylamine (2.19 g, 21.6 mmol, 4.2 equiv.), 4-methylbenzenesulfonyl chloride (2.04 g, 10.7 mmol, 2.1 equiv.), and DMAP (0.13 g, 1.07 mmol, 0.2 equiv.). The resulting solution was stirred at room temperature overnight and then quenched by the addition of 50 mL of ice water. The solution was extracted twice with 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:2 to 10:1) to give 3.4 g (99% yield) of syn-(3S)-1-(3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl 4-methylbenzenesulfonate as a light yellow solid. LCMS (ESI, m / z): 615.20 [M+H] + .

[0386] Step E To a solution of (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (1.09 g, 6.80 mmol, 2.0 equiv.) in DMF (20 mL) was added NaH (0.27 g, 6.85 mmol, 2.0 equiv., 60% dispersion in mineral oil) at 0° C. The reaction mixture was stirred for 15 min, after which syn-(3S)-1-(3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl 4-methylbenzenesulfonate (2.10 g, 3.42 mmol, 1.0 equiv.) was added and the solution was stirred at room temperature for 1 h. The reaction was treated with MeOH (5 mL), concentrated in vacuo, and applied to a silica gel column eluted with ethyl acetate / petroleum ether (1 / 2) to give 775 mg (38% yield) of syn-1-(3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyrrolidin-2-one as an off-white solid. LCMS (ESI, m / z): 603.20 [M+H] + .

[0387] Step F To a solution of syn-1-(3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyrrolidin-2-one (500 mg, 0.8 mmol, 1 equiv) in MeOH (30 mL) was added pyridinium p-toluenesulfonate (210 mg, 0.83 mmol, 1.0 equiv). The resulting solution was stirred at room temperature for 15 h and then cooled to rt with solid NaCl. 2 CO 3(200 mg) was added to quench. The resulting mixture was concentrated and applied to a silica gel column eluted with ethyl acetate to give 350 mg (79% yield) of 1-syn-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-((S)-2-hydroxypropoxy)pyrrolidin-2-one as a light yellow solid. LCMS (ESI, m / z): 519.20 [M+H] + .

[0388] Step G To a solution of syn-1-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-((S)-2-hydroxypropoxy)pyrrolidin-2-one (360 mg, 0.70 mmol, 1.0 equiv) in DCM (5 mL) was added 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridazin-3-one (301 mg, 0.95 mmol, 1.4 equiv) and t-BuOK (290 mg, 2.6 mmol, 3.8 equiv) at 0° C. The resulting solution was stirred for 1.5 h, then concentrated and applied to a silica gel column eluted with ethyl acetate / petroleum ether (1 / 1) to give 471 mg (85% yield) of syn-5-(((2S)-1-((1-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as a white solid. LCMS (ESI, m / z): 801.3 [M+H] + .

[0389] Step H A solution of syn-5-(((2S)-1-((1-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (471 mg, 0.59 mmol, 1.0 equiv) in TFA / TfOH (3 mL, 10:1) was stirred at room temperature for 2 h. The reaction was quenched by the addition of ice water (20 mL) and the pH was adjusted to saturated Na 2 CO 3 The pH was adjusted to 7 with aqueous solution. The solution was extracted three times with 60 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was diluted with water / CH 3 The mixture was subjected to reverse phase chromatography eluting with CN (1 / 1) and the following conditions for chiral preparative HPLC: CHIRAL ART Cellulose-SB, 2×25 cm, 5 μm, mobile phase A: hexane:DCM=3:1 (10 mM NH 3 -MeOH), mobile phase B: IPA, flow rate: 20 mL / min, gradient: 30% B over 7 min, 220 / 254 nm. The absolute stereochemistry of the pyrrolidone stereocenter was assigned by analogy to Example 10, based on the PARP7 potency of the more active diastereomer, and by analogy to the X-ray crystal structure of Example 10B. The absolute stereochemistry of the piperidine stereocenter was not determined.

[0390] Example 64 Isomer A (64A): Syn-5-(((2S)-1-(((3S)-1-(3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one (61 mg, 25% yield, off-white solid). LCMS (ESI, m / z): 567.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d 6)δ 13.22(s,1H),8.65(s,2H),8.28(s,1H),5.22-5.15(m,1H),5.00(br,1H),4. 90-4.72(m,2H),4.06-3.95(m,3H),3.90(s,1H),3.63(dd,J=11.1,8.0Hz,1H) ,3.30-3.24(m,2H),3.14-2.98(m,2H),2.20-2.16(m,1H),2.07-2.02(m,1H), 1.61-1.58(m,1H),1.49-1.41(m,1H),1.28(d,J=6.2Hz,3H).Chiral HPLC: CHIRAL Cellulose-SB, 0.46 x 10 cm, 3 μm (Hexane:DCM=3:1 (containing 0.1% diethylamine:IPA=90:10), flow rate: 1 mL / min), retention time: 3.726 min (earlier peak)

[0391] Example 64 Isomer B (64B): Syn-5-(((2S)-1-(((3R)-1-(3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one (144 mg, 59% yield, off-white solid). LCMS (ESI, m / z): 567.10 [M+H] + 1 H NMR (400MHz, DMSO-d 6)δ 13.21(s,1H),8.65(s,2H),8.31(s,1H),5.19-5.15(m,1H),5.00(br,1H),4.88-4.76 (m,2H),4.07(t,J=7.4Hz,1H),4.04-3.98(m,1H),3.93-3.83(m,2H),3.74(dd,J=11.1 , 3.3Hz, 1H), 3.30-3.24(m, 2H), 3.17-2.98(m, 2H), 2.28-2.17(m, 1H), 2.11-1.97(m, 1H), 1.71-1.62(m, 1H), 1.47(d, J=12.2Hz, 1H), 1.28(d, J=6.2Hz, 3H).Chiral HPLC: CHIRAL Cellulose-SB, 0.46×10cm, 3μm (Hexane:DCM=3:1 (containing 0.1% diethylamine:IPA=90:10), flow rate: 1mL / min), retention time: 5.703min (later peak)

[0392] Example 65: Synthesis of 5-(((2S)-1-((1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0393] Step A A solution of tert-butyl ((3R,4R)-3-hydroxypiperidin-4-yl)carbamate (2.00 g, 9.25 mmol, 1.00 equiv.) and 2-chloro-5-(trifluoromethyl)pyrimidine (1.69 g, 9.25 mmol, 1.00 equiv.) in DMF (20 mL) was 2 CO 3(2.56 g, 18.5 mmol, 2.00 equiv.) was added. The resulting solution was stirred at 50° C. for 2 h and quenched by adding 50 mL of ice water. The solid was then collected by filtration to give 2.8 g (84% yield) of tert-butyl ((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)carbamate as a white solid. LCMS (ESI, m / z): 363.10 [M+H] + .

[0394] Step B A solution of tert-butyl ((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)carbamate (2.80 g, 7.73 mmol, 1.00 equiv) in 4N HCl (20 mL) in dioxane was stirred for 1 h. The mixture was concentrated to give 2.6 g of crude (3R,4R)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol as a clear oil, which was carried forward without further purification. LCMS (ESI, m / z): 263.05 [M+H] + .

[0395] Step C (3R,4R)-4-Amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol (2.60 g, 9.92 mmol, 1.00 equiv.) 3 To the CN (15 mL) solution was added tert-butyldimethylsilyl chloride (5.98 g, 39.7 mmol, 4.00 equiv) and imidazole (5.40 g, 79.3 mmol, 8.00 equiv). The resulting solution was stirred at 60° C. for 4 h, then concentrated in vacuo and applied to a silica gel column eluted with DCM / methanol (99 / 1) to give 2.5 g (67% yield) of (3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine as a yellow oil. LCMS (ESI, m / z): 377.15 [M+H] + .

[0396] Step D To a solution of (3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine (3.20 g, 8.50 mmol, 1.0 equiv) in DCM and DMF (1:1, 90 mL) was added (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (2.69 g, 17.0 mmol, 2.0 equiv), STAB (7.21 g, 34.0 mmol, 4.0 equiv), and AcOH (0.51 g, 8.5 mmol, 1.0 equiv). The solution was stirred for 6 h and then quenched by the addition of 90 mL of water. The solution was extracted three times with 180 mL of DCM and the combined organic layers were concentrated in vacuo. The crude residue was applied to a silica gel column with DCM / methanol (95 / 5) to give 1.9 g (49% yield) of (S)-1-((3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one as a white solid. LCMS (ESI, m / z): 461.20 [M+H] + .

[0397] Step E To a solution of (S)-1-((3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one (1.00 g, 2.17 mmol, 1.0 equiv.) and TsCl (496 mg, 2.61 mmol, 1.2 equiv.) in DCM (10 mL) was added DMAP (265 mg, 2.17 mmol, 1.0 equiv.) and triethylamine (439 mg, 4.34 mmol, 2.0 equiv.). The solution was stirred for 2 h and then saturated NaHCO 3 Aqueous solution was added. The layers were separated and the aqueous layer was extracted 3 times with 10 mL of DCM. The combined organic layers were washed with 30 mL of saturated NaHCO 3The mixture was washed three times with aqueous solution, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1 / 1) to give 1.0 g (75% yield) of (S)-1-((3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl 4-methylbenzenesulfonate as a white solid. LCMS (ESI, m / z): 615.30 [M+H] + .

[0398] Step F To a solution of (S)-1-((3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl 4-methylbenzenesulfonate (540 mg, 0.88 mmol, 1.0 equiv) in DMF (5 mL) was added NaH (42 mg, 1.8 mmol, 2.0 equiv, 60% dispersion in mineral oil) at 0° C. and the mixture was stirred at 0° C. for 15 min. (2S)-2-(oxan-2-yloxy)propan-1-ol (281 mg, 1.76 mmol, 2.0 equiv) was added and the mixture was stirred for an additional 30 min, after which the reaction was quenched by addition of 10 mL of MeOH, concentrated in vacuo, and applied to a silica gel column eluted with ethyl acetate / petroleum ether (1 / 1) to give 181 mg (34% yield) of 1-((3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-((S)-2-(tetrahydro-2H-pyran-2-yloxy)propoxy)pyrrolidin-2-one as a white solid. LCMS (ESI, m / z): 519.25 [M+H] + .

[0399] Step G To a solution of 1-((3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-((S)-2-(tetrahydro-2H-pyran-2-yloxy)propoxy)pyrrolidin-2-one (180 mg, 0.30 mmol, 1.0 equiv) in MeOH (5 mL) was added pyridinium p-toluenesulfonate (75 mg, 0.30 mmol, 1.0 equiv). The resulting solution was stirred at 40° C. for 1 h, then concentrated and applied to a silica gel column eluted with ethyl acetate / petroleum ether (4 / 1) to give 127 mg (82% yield) of 1-((3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-((S)-2-hydroxypropoxy)pyrrolidin-2-one as a white solid. LCMS (ESI, m / z): 519.20 [M+H] + .

[0400] Step H To a solution of 1-((3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-3-((S)-2-hydroxypropoxy)pyrrolidin-2-one (120 mg, 0.2 mmol, 1 equiv.) in DCM (5 mL) was added t-BuOK (50 mg, 0.5 mmol, 2 equiv.) at 0° C. The resulting solution was stirred for 15 min, after which 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (86 mg, 0.27 mmol, 1.2 equiv.) was added and the mixture was stirred at 0° C. for 1.5 h. The mixture was concentrated and the residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (4 / 1) to give 62 mg (34% yield) of 5-((S)-1-(1-((3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-yloxy)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as a white solid. LCMS (ESI, m / z): 801.35 [M+H] + .

[0401] Step I A solution of 5-[[(2S)-1-([1-[(3R,4R)-3-[(tert-butyldimethylsilyl)oxy]-1-[5-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl]-2-oxopyrrolidin-3-yl]oxy)propan-2-yl]oxy]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridazin-3-one (60 mg, 0.08 mmol, 1 equiv) in TFA and TfOH (3 mL, 10:1) was stirred at 0° C. for 4 h and then diluted with 10 mL of ice water. 3 The pH was adjusted to 7 by adding aqueous solution. The resulting solution was extracted three times with 20 mL of ethyl acetate and the combined organic layers were concentrated in vacuo. The crude product was purified by elution with water / CH 3Purification by C18 reverse phase chromatography eluting with CN (1 / 1) afforded 7 mg (14% yield) of 5-(((2S)-1-((1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one. LCMS (ESI, m / z): 567.40 [M+H] + ; 1 H NMR (300MHz, DMSO-d 6 )δ 13.21(s,1H),8.69(s,2H),8.31-8.27(m,1H),5.31-5.20(m,1H),5.19 -5.12(m,1H),4.89-4.81(m,1H),4.73(d,J=13.2Hz,1H),4.14-3.69(m, 4H),3.64-3.39(m,2H),3.17-3.09(m,2H),3.05-2.91(m,1H),2.80-2. 69(m,1H),2.27-2.18(m,1H),1.62-1.50(m,3H),1.26(d,J=6.3Hz,3H).

[0402] Example 66: Synthesis of N-((S)-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)acetamide [ka]

[0403] Step A To a solution of 5-(((2S)-1-amino-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (70 mg, 0.1 mmol, 1 equiv.) in DCM (3 mL) was added DMAP (1 mg, 0.01 mmol, 0.1 equiv.), acetic anhydride (15 mg, 0.15 mmol, 1.5 equiv.), and triethylamine (31 mg, 0.31 mmol, 3 equiv.). The resulting solution was stirred for 1 h and then diluted with 60 mL of ethyl acetate. The mixture was washed three times with 20 mL of water, then dried over anhydrous sodium sulfate and concentrated to give N-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propyl)acetamide (66 mg, 71% yield) as a white solid. LCMS (ESI, m / z): 727.25 [M+H] + .

[0404] Step B To a solution of N-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propyl)acetamide (66 mg, 0.090 mmol, 1.0 equiv) in TFA (1 mL) was added TfOH (0.1 mL) and the mixture was stirred for 1 h. The reaction was quenched by the addition of 8 mL of water and the pH was adjusted to saturated NaCl. 2 CO 3 The acid was adjusted to 9 with aqueous solution. The resulting solution was extracted twice with 30 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was diluted with water / CH 3Application to a C18 reverse phase column eluted with CN (47 / 53) gave N-((S)-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)acetamide (13 mg, 22% yield) as a white solid. LCMS (ESI, m / z): 607.30 [M+H] + . 1 H NMR (300MHz, DMSO-d 6 )δ 12.49(s,1H),8.69(s,2H),8.14(t,J=5.9Hz,1H),7.98(s,1H),6.55-6.44(m,1H),4.82(d,J=13.2Hz,2H),4.21-4.02 (m,3H),3.90-3.81(m,1H),3.70-3.61(m,1H),3.30-2.96(m,6H),2.31-2.15(m,1H),1.81(s,3H),1.81-1.45(m,5H).

[0405] Example 67: Synthesis of 5-(((2R,3R)-3-hydroxy-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)butan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0406] Step A To a solution of tert-butyl (4R,5R)-4-(hydroxymethyl)-2,2,5-trimethyloxazolidine-3-carboxylate (4.0 g, 16 mmol, 1.0 equiv.) in DCM (10 mL) was added 4-toluenesulfonyl chloride (3.7 g, 20 mmol, 1.2 equiv.), DMAP (1.9 g, 16 mmol, 1.0 equiv.), and triethylamine (3.3 g, 32.6 mmol, 2.0 equiv.). The resulting solution was stirred for 4 h and then washed with 25 mL of saturated NaHCO.3 The organic layer was concentrated and applied to a silica gel column eluted with ethyl acetate / petroleum ether (9 / 1) to give 5.8 g (89% yield) of tert-butyl (4R,5R)-2,2,5-trimethyl-4-((tosyloxy)methyl)oxazolidine-3-carboxylate as a yellow oil. LCMS (ESI, m / z): 344.05 [M+H] + .

[0407] Step B To a solution of (R)-3-hydroxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (500 mg, 1.51 mmol, 1.0 equiv) in DMF (5 mL) was added NaH (72 mg, 3.0 mmol, 2.0 equiv, 60% dispersion in oil) at 0° C. The mixture was stirred for 10 min, after which (4R,5R)-tert-butyl 2,2,5-trimethyl-4-((tosyloxy)methyl)oxazolidine-3-carboxylate (1.8 g, 4.5 mmol, 3.0 equiv) was added at 0° C. The reaction mixture was stirred at 40° C. for a further 6 h, then concentrated and purified by silica gel chromatography eluting with ethyl acetate / petroleum ether (15 / 85) to give 900 mg of tert-butyl (4R,5R)-2,2,5-trimethyl-4-((((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)methyl)oxazolidine-3-carboxylate as a yellow oil. LCMS (ESI, m / z): 558.25 [M+H] + .

[0408] Step C A solution of tert-butyl (4R,5R)-2,2,5-trimethyl-4-((((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)methyl)oxazolidine-3-carboxylate (900 mg, 1.6 mmol, 1.0 equiv) in 4 M HCl (10 mL) in dioxane was stirred for 6 h and then concentrated to give 850 mg of (R)-3-((2R,3R)-2-amino-3-hydroxybutoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride as a colorless oil, which was carried forward without further purification. LCMS (ESI, m / z): 418.10 [M+H] + .

[0409] Step D To a solution of (R)-3-((2R,3R)-2-amino-3-hydroxybutoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrogen chloride (400 mg, 0.96 mmol, 1.0 equiv) in isopropanol (5 mL) was added 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (366 mg, 1.15 mmol, 1.2 equiv) and N,N-diisopropylethylamine (620 mg, 4.8 mmol, 5.0 equiv). The solution was stirred at 80° C. for 6 h, then concentrated and applied to a silica gel column eluted with ethyl acetate / petroleum ether (95 / 5) to give 170 mg (25% yield) of 5-(((2R,3R)-3-hydroxy-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)butan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as a yellow solid. LCMS (ESI, m / z): 700.20 [M+H] + .

[0410] Step E A solution of 5-(((2R,3R)-3-hydroxy-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)butan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (120 mg, 0.17 mmol, 1.0 equiv) in TFA / TfOH (3 mL, 3:1) was stirred at -10°C for 40 min. The pH was adjusted to saturation with Na 2 CO 3 The pH was adjusted to about 6-7 with aqueous solution, and the resulting solution was extracted three times with 25 mL of ethyl acetate. The organic layers were combined and washed with Na 2 SO 4 The crude product was purified by evaporation to dryness and concentrated in CH 3 Purification by C18 reverse phase chromatography eluting with CN / water afforded 55 mg (55% yield) of 5-(((2R,3R)-3-hydroxy-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)butan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one as a white solid. LCMS (ESI, m / z): 580.20 [M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 )δ 12.45(s,1H),8.67(s,2H),7.93(s,1H),6.25-6.12(m,1H),5.29(d,J=4.1Hz,1H),4.80(d,J=13.2Hz,2H),4.15-4.07(m,2 H),3.96-3.82(m,3H),3.69-3.61(m,1H),3.28-2.94(m,4H),2.25-2.16(m,1H),1.79-1.53(m,5H),1.07(d,J=6.2Hz,3H).

[0411] Example 68: Synthesis of 4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxamide [ka]

[0412] Step A To a solution of 1-(tert-butyl)3-ethyl 4-aminopiperidine-1,3-dicarboxylate (16.0 g, 58.7 mmol, 1.00 equiv) in DCM (200 mL) was added AcOH (5.29 g, 88.1 mmol, 1.50 equiv) and (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (10.2 g, 64.6 mmol, 1.1 equiv). The resulting solution was stirred at room temperature for 5 h, after which STAB (24.9 g, 117 mmol, 2.0 equiv) was added and the reaction mixture was stirred for an additional 45 h. The solution was quenched by adding 100 mL of ice water and the pH was adjusted to 8 with 1% aqueous NaOH. The solution was extracted with 300 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1 / 9) to give 5.7 g (27% yield) of 1-(tert-butyl)3-ethyl 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1,3-dicarboxylate as a brown oil.

[0413] Step B A solution of 1-(tert-butyl)3-ethyl 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1,3-dicarboxylate (5.70 g, 16.0 mmol, 1.0 equiv) in 4N HCl (40 mL) in dioxane was stirred for 20 h. The resulting mixture was concentrated in vacuo to give 5 g of ethyl 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-3-carboxylate hydrochloride as a brown solid, which was carried forward without further purification.

[0414] Step C A solution of ethyl 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-3-carboxylate hydrochloride (5.00 g, 17.1 mmol, 1.0 equiv.) in DMF (40 mL) was treated with 2-chloro-5-(trifluoromethyl)pyrimidine (3.12 g, 17.1 mmol, 1.0 equiv.) and K 2 CO 3 (7.08 g, 51.2 mmol, 3.0 equiv) was added. The resulting solution was stirred at 60° C. for 1 h, concentrated in vacuo, and diluted with water / CH 3 Purification by reverse phase chromatography eluting with CN (9 / 11) afforded 1.2 g (17% yield) of ethyl 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxylate as a yellow solid. LCMS (ESI, m / z): 403.2 [M+H] + .

[0415] Step D To a solution of ethyl 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxylate (558 mg, 1.39 mmol, 1.0 equiv.) in EtOH (5 mL) and water (1 mL) was added NaOH (111 mg, 2.78 mmol, 2.0 equiv.). The resulting solution was stirred for 15 h. The pH was adjusted to 5 with HCl (2M) and concentrated in vacuo. The residue was dissolved in water / CH 3Application to a silica gel column eluted with CN (5:1) gave 420 mg (81% yield) of 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxylic acid as a yellow solid. LCMS (ESI, m / z): 375.10 [M+H] + .

[0416] Step E A solution of 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxylic acid (420 mg, 1.1 mmol, 1.0 equiv.) in DMF (5 mL) was added with N,N-diisopropylethylamine (290 mg, 2.2 mmol, 2.0 equiv.), NH 4 Cl (90 mg, 1.7 mmol, 1.5 equiv.) and HATU (640 mg, 1.7 mmol, 1.5 equiv.) were added. The resulting solution was stirred for 1.5 h and then diluted with water / CH 3 Application to a reversed-phase C18 column eluted with CN (5:1) gave 400 mg (95% yield) of 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxamide as a yellow solid. LCMS (ESI, m / z): 374.10 [M+H] + .

[0417] Step F To a solution of 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxamide (400 mg, 1.1 mmol, 1.0 equiv.) in DMF (20 mL) was added NaH (86 mg, 2.2 mmol, 2.0 equiv., 60% dispersion in oil) at 0° C. After 15 min, a solution of (4S)-tert-butyl 4-methyl-2,2-dioxo-1,2 lambda 6,3-oxathiazolidine-3-carboxylate (265 mg, 1.12 mmol, 1.0 equiv.) in DMF (2 mL) was added and the mixture was stirred for 1 h. The reaction was quenched by the addition of 2 mL of saturated aqueous sodium bicarbonate. The resulting mixture was concentrated and diluted with water / CH 3 Applying to a reverse phase column eluting with OH (11:9) gave 330 mg (48% yield) of tert-butyl ((2S)-1-(((3R)-1-(3-carbamoyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate as a yellow solid. LCMS (ESI, m / z): 531.30 [M+H] + .

[0418] Step G A solution of tert-butyl ((2S)-1-(((3R)-1-(3-carbamoyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate (330 mg, 0.62 mmol, 1.0 equiv) in 4N HCl (5 mL) in dioxane was stirred for 1 h and then concentrated in vacuo to give 305 mg (66% yield) of 4-((R)-3-((S)-2-aminopropoxy)-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxamide hydrochloride as a light yellow solid. LCMS (ESI, m / z): 431.20 [M+H] + .

[0419] Step H CH of 4-((R)-3-((S)-2-aminopropoxy)-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxamide hydrochloride (280 mg, 0.60 mmol, 1.0 equiv.) 3 To a solution of CN (5 mL) was added N,N-diisopropylethylamine (280 mg, 2.2 mmol, 3.6 equiv) and 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridazin-3-one (201 mg, 0.63 mmol, 1.1 equiv). The solution was stirred at 80° C. for 1 h and then concentrated in vacuo. The crude product was extracted with water / CH 3 Application to a reversed-phase C18 column eluted with CN (1 / 1) gave 290 mg (63% yield) of 4-((R)-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxamide as a yellow solid. LCMS (ESI, m / z): 713.25 [M+H] + .

[0420] Step I A solution of 4-((R)-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxamide (570 mg, 0.80 mmol, 1.0 equiv) in TFA / TfOH (5 mL, 10:1) was stirred for 1 h. The reaction was quenched by the addition of 15 mL of ice water and the pH was adjusted to saturated NaCl. 2 CO 3 The pH was adjusted to about 7-8 with aqueous solution. The solution was extracted three times with 60 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by aqueous water / CH 3Purification by reverse phase chromatography eluting with CN (3 / 2) afforded 314 mg (66% yield) of 4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxamide as a yellow solid. LCMS (ESI, m / z): 593.15 [M+H] + ; 1 H NMR (400MHz, DMSO-d 6 )δ 12.46(s,1H),8.74(s,2H),7.95(d,J=7.9Hz,1H),7.53-7.48(m,1H),6.9 9(s,1H),6.37-6.29(m,1H),4.89-4.76(m,2H),4.33-4.01(m,3H),3.86- 3.73(m,1H),3.63-3.53(m,1H),3.29-3.20(m,1H),3.15-3.00(m,3H),2. 68-2.53(m,1H),2.31-2.12(m,1H),1.82-1.56(m,3H),1.19-1.13(m,3H).

[0421] Example 69: Synthesis of 4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carbonitrile [ka]

[0422] 4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxamide (320 mg, 0.54 mmol, 1.0 equiv) in water (22 mL) and CH 3Palladium chloride (133 mg, 0.75 mmol, 1.4 equiv) was added to a solution of CN (27 mL). The resulting solution was stirred at 80° C. overnight and then extracted four times with 30 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in water / CH 3 Application to a C18 reverse phase column eluted with CN (1 / 1) gave 15 mg (5% yield) of 4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carbonitrile as a white solid. LCMS (ESI, m / z): 575.25 [M+H] + ; 1 H NMR (400MHz, DMSO-d 6 )δ 12.46(s,1H),8.85(s,2H),7.95(d,J=3.6Hz,1H),6.32(br,1H),5.13-5.01(m,1H),4.93-4.76(m,1H),4.46-4.34(m,1...

Claims

1. A compound of formula IIa, 【Chemistry 1】 During the ceremony, X is CF 3 , Br, or Cl; Y １ , Y ２ , and Y ３ each independently represents O, S, or NR Ｙ , C(=O), C(=O)O, C(=O)NR Ｙ , S(=O), S(=O) ２ , S(=O)NR Ｙ , S(=O) ２ N.R. Ｙ , or N.R. Ｙ C(=O)NR Ｙ wherein each R Ｙ are independent, H, C １－４ Alkyl, or C １－４ is haloalkyl, Z is CyZ; Cy Ｚ is a pyrimidinyl, pyrazinyl, pyridinyl or thiazolyl group substituted by halo, C1-3 haloalkyl or CN; Ring D is an azetidine or piperidine ring optionally substituted with one or two groups selected from OH, F, C(O)NH 2 , and CN; R １ , R ２ , R ５ , R ６ , R ７ and R8 are each independently H, halo, C １－６ Alkyl, and C １－６ haloalkyl, wherein said C １－６ Alkyl is CN, NO ２ , OR ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ or R １ and Y １ R Ｙ The groups, together with the atoms to which they are attached, and Y １ Together with the atoms that form halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) R ｂ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ or forming a 4-10 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from R ７ and Y ３ R Ｙ The groups, together with the atoms to which they are attached, and Y ３ Together with the atoms that form halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) R ｂ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ or forming a 4-10 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from R ５ and R ７ together with the carbon atom to which they are attached, and Y ２ Together, Hello, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) R ｂ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ forming a 5-10 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from Each R ａ３ , R ｂ３ , R ｃ３ , and R ｄ３ are independent, H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ alkyl, wherein R ａ３ , the R ｂ３ , the R ｃ３ and the R ｄ３ The above C １－６ Alkyl, the C ２－６ Alkenyl, the above C ２－６ Alkynyl, the above C ６－１０ Aryl, the C ３－７ cycloalkyl, the 5- to 10-membered heteroaryl, the 4- to 10-membered heterocycloalkyl, the C ６－１０ Aryl-C １－４ Alkyl, the C ３－７ Cycloalkyl-C １－４ alkyl, the 5- to 10-membered heteroaryl-C １－４ alkyl, and the 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, halo, C １－４ Alkyl, C １－４ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, CN, OR ａ７ , S.R. ａ７ , C(O)R ｂ７ , C(O)NR ｃ７ R ｄ７ , C(O)OR ａ７ , O.C.(O)R ｂ７ , O.C.(O)NR ｃ７ R ｄ７ , N.R. ｃ７ R ｄ７ , N.R. ｃ７ C(O)R ｂ７ , N.R. ｃ７ C(O)NR ｃ７ R ｄ７ , N.R. ｃ７ C(O)OR ａ７ , C(=NR ｅ７ ) N.R. ｃ７ R ｄ７ , N.R. ｃ７ C (=NR ｅ７ ) N.R. ｃ３ R ｄ７ , S(O)R ｂ７ , S(O)NR ｃ７ R ｄ７ , S(O) ２ R ｂ７ , N.R. ｃ７ S (O) ２ R ｂ７ , N.R. ｃ７ S (O) ２ N.R. ｃ７ R ｄ７ , and S(O) ２ N.R. ｃ７ R ｄ７ or R ｃ３ and R ｄ３ together with the N atom to which they are attached, they form CN, halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, CN, OR ａ７ , S.R. ａ７ , C(O)R ｂ７ , C(O)NR ｃ７ R ｄ７ , C(O)OR ａ７ , O.C.(O)R ｂ７ , O.C.(O)NR ｃ７ R ｄ７ , N.R. ｃ７ R ｄ７ , N.R. ｃ７ C(O)R ｂ７ , N.R. ｃ７ C(O)NR ｃ７ R ｄ７ , N.R. ｃ７ C(O)OR ａ７ , C(=NR ｅ７ ) N.R. ｃ７ R ｄ７ , N.R. ｃ７ C (=NR ｅ７ ) N.R. ｃ３ R ｄ７ , S(O)R ｂ７ , S(O)NR ｃ７ R ｄ７ , S(O) ２ R ｂ７ , N.R. ｃ７ S (O) ２ R ｂ７ , N.R. ｃ７ S (O) ２ N.R. ｃ７ R ｄ７ , and S(O) ２ N.R. ｃ７ R ｄ７ forming a 4- to 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R ａ７ , R ｂ７ , R ｃ７ , and R ｄ７ are independent, H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ alkyl, wherein said C １－６ Alkyl, the C １－６ Haloalkyl, the C ２－６ Alkenyl, the above C ２－６ Alkynyl, the above C ６－１０ Aryl, the C ３－７ cycloalkyl, the 5- to 10-membered heteroaryl, the 4- to 10-membered heterocycloalkyl, the C ６－１０ Aryl-C １－４ Alkyl, the C ３－７ Cycloalkyl-C １－４ alkyl, the 5- to 10-membered heteroaryl-C １－４ alkyl, and the 4- to 10-membered heterocycloalkyl-C １－４ Each of the alkyl groups is selected from OH, CN, amino, halo, and C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl and C １－６ optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Each R e3 and R ｅ７ are independent, H, C １－４ alkyl, and CN; Any of the foregoing heteroaryl or heterocycloalkyl groups contain 1, 2, 3, or 4 ring-forming heteroatoms independently selected from O, N, and S; The above compounds, or pharma- ceutically acceptable salts thereof, wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups.

2. X is CF ３ 2. The compound of claim 1, wherein:

3. Y １ But, N.R. Ｙ or O, or a pharma- ceutically acceptable salt thereof.

4. Y １ But, N.R. Ｙ 3. The compound of claim 1 or 2, which is: or a pharma- ceutically acceptable salt thereof.

5. Y １ 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein:

6. Y １ is O, or a pharma- ceutically acceptable salt thereof.

7. Y ２ But, O, NR Ｙ or C(=O)NR Ｙ 7. The compound according to any one of claims 1 to 6, which is: or a pharma- ceutically acceptable salt thereof.

8. Y ２ But, O, NH, NCH ３ or C(═O)NH, or a pharma- ceutically acceptable salt thereof.

9. Y ２ is O or NR Ｙ 7. The compound according to any one of claims 1 to 6, which is: or a pharma- ceutically acceptable salt thereof.

10. Y ２ is O, NH, or NCH ３ 7. The compound according to any one of claims 1 to 6, which is: or a pharma- ceutically acceptable salt thereof.

11. Y ２ The compound according to any one of claims 1 to 6, wherein is O, or a pharma- ceutically acceptable salt thereof.

12. Y ３ C(=O)NR Ｙ 12. The compound according to any one of claims 1 to 11, which is: or a pharma- ceutically acceptable salt thereof.

13. Y ３ The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein is C(=O)NCH3.

14. R １ is H or C １－６ alkyl, wherein said C １－６ The alkyl is OR ａ３ , N.R. ｃ３ R ｄ３ , and N.R. ｃ３ C(O)R ｂ３ 14. The compound of any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

15. R １ is H or C １－６ alkyl, wherein said C １－６ The alkyl is OR ａ３ 14. The compound of any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

16. R １ is H, methyl, methoxymethyl, CH ２ OH, CH(OH)CH ３ , C.H. ２ N.H.C.H. ２ CF ３ , or C.H. ２ NHC(O)CH ３ 14. The compound according to any one of claims 1 to 13, which is: or a pharma- ceutically acceptable salt thereof.

17. R １ The compound of any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein is H, methyl, or methoxymethyl.

18. R １ The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

19. R １ The compound according to any one of claims 1 to 13, wherein is H, or a pharma- ceutically acceptable salt thereof.

20. R １ and Y １ R Ｙ The groups, together with the atoms to which they are attached, and Y １ Together with the atoms that form halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) R ｂ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ 14. The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, which forms a 4-10 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from:

21. R １ and Y １ R Ｙ The groups, together with the atoms to which they are attached, and Y １ Together with the atoms that form halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) R ｂ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ 14. The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, which forms an azetidine ring optionally substituted with 1, 2, or 3 substituents independently selected from:

22. R １ and Y １ R Ｙ The groups, together with the atoms to which they are attached, and Y １ The compound according to any one of claims 1 to 13, which, together with the atoms forming:

23. R ２ The compound according to any one of claims 1 to 22, wherein is H, or a pharma- ceutically acceptable salt thereof.

24. R ５ is H or C １－６ 24. The compound of any one of claims 1 to 23, or a pharma- ceutically acceptable salt thereof, which is alkyl.

25. R ５ The compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

26. R ５ The compound according to any one of claims 1 to 23, wherein is H, or a pharma- ceutically acceptable salt thereof.

27. R ６ The compound according to any one of claims 1 to 26, wherein is H, or a pharma- ceutically acceptable salt thereof.

28. R ７ is H or C １－６ 28. The compound of any one of claims 1 to 27, or a pharma- ceutically acceptable salt thereof, which is alkyl.

29. R ７ The compound according to any one of claims 1 to 27, or a pharma- ceutically acceptable salt thereof, wherein is CH3.

30. R ７ The compound according to any one of claims 1 to 27, wherein is H, or a pharma- ceutically acceptable salt thereof.

31. R ８ The compound according to any one of claims 1 to 30, wherein is H, or a pharma- ceutically acceptable salt thereof.

32. Y １ R Ｙ The compound according to any one of claims 1 to 31, wherein is H, or a pharma- ceutically acceptable salt thereof.

33. Y ２ R Ｙ is H or C １－４ 33. The compound of any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof, which is alkyl.

34. Y ２ R Ｙ The compound of any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof, wherein is H or methyl.

35. Y ３ R Ｙ is H or C １－４ 35. The compound of any one of claims 1 to 34, or a pharma- ceutically acceptable salt thereof, which is alkyl.

36. Y ３ R Ｙ The compound of any one of claims 1 to 34, or a pharma- ceutically acceptable salt thereof, wherein is H, methyl, or ethyl.

37. Y ３ R Ｙ The compound according to any one of claims 1 to 34, or a pharma- ceutically acceptable salt thereof, wherein is CH3.

38. R ７ and Y ３ R Ｙ The groups, together with the atoms to which they are attached, and Y ３ Together with the atoms that form halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) R ｂ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ 38. The compound according to any one of claims 1 to 37, or a pharma- ceutically acceptable salt thereof, which forms a 4-10 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from:

39. R ７ and Y ３ R Ｙ The groups, together with the atoms to which they are attached, and Y ３ Together with the atoms that form halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) R ｂ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ 38. The compound according to any one of claims 1 to 37, or a pharma- ceutically acceptable salt thereof, which forms an oxopyrrolidine or pyrrolidine ring, each optionally substituted with 1, 2, or 3 substituents independently selected from:

40. R ７ and Y ３ R Ｙ The groups, together with the atoms to which they are attached, and Y ３ 38. The compound according to any one of claims 1 to 37, which, together with the atoms forming:

41. R ７ and Y ３ R Ｙ The groups, together with the atoms to which they are attached, and Y ３ 38. The compound according to any one of claims 1 to 37, which, together with the atoms forming:

42. 42. The compound according to any one of claims 1 to 41, or a pharma- ceutically acceptable salt thereof, wherein Ring D is an azetidine or piperidine ring optionally substituted with OH.

43. Ring D is OH, F, C(O)NH ２ or CN, or a pharma- ceutically acceptable salt thereof.

44. 42. The compound of any one of claims 1 to 41, or a pharma- ceutically acceptable salt thereof, wherein Ring D is a piperidine ring optionally substituted with OH.

45. The compound according to any one of claims 1 to 41, or a pharma- ceutically acceptable salt thereof, wherein ring D is a piperidine ring.

46. Cy Ｚ But, CF ３ 46. ​​The compound of any one of claims 1 to 45, which is pyrimidinyl substituted with: or a pharma- ceutically acceptable salt thereof.

47. Cy Ｚ is selected from 5-(trifluoromethyl)pyrimidin-2-yl, 5-(trifluoromethyl)thiazol-2-yl, 5-(trifluoromethyl)pyrazin-2-yl, 5-(difluoromethyl)pyrimidin-2-yl, 5-(difluoromethyl)pyrazin-2-yl, 5-fluoropyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5-chloropyrazin-2-yl, 5-bromopyrimidin-2-yl, 5-cyanopyridin-2-yl, 5-cyanothiazol-2-yl, 5-cyanopyrazin-2-yl, and 5-methylpyrimidin-2-yl. The compound according to any one of claims 1 to 45, or a pharma- ceutically acceptable salt thereof.

48. Cy Ｚ is selected from 5-(trifluoromethyl)pyrimidin-2-yl, 5-(trifluoromethyl)thiazol-2-yl, 5-(trifluoromethyl)pyrazin-2-yl, 5-cyanopyridin-2-yl, 5-(difluoromethyl)pyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5-(difluoromethyl)pyrazin-2-yl, and 5-bromopyrimidin-2-yl, or a pharma- ceutically acceptable salt thereof.

49. Cy Ｚ The compound according to any one of claims 1 to 45, wherein is 5-(trifluoromethyl)pyrimidin-2-yl, or a pharma- ceutically acceptable salt thereof.

50. X is CF ３ And Y １ is NR Ｙ And Y ２ is O and Y ３ C(=O)NR Ｙ and R １ is methyl, R ２ is H, and R ５ is H, and R ６ is H, and R ７ is CH3, R ８ is H, Ring D is piperidine substituted with OH, Cy Ｚ is CF ３ 50. The compound of any one of claims 1 to 49, which is pyrimidinyl substituted with: or a pharma- ceutically acceptable salt thereof.

51. A compound according to any one of claims 1 to 41 and 46 to 49 having the formula IIb, 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof.

52. having the formula IIc, 【Chemistry 3】 During the ceremony, Z １ and Z ２ are each independently selected from N and CH; R Ｚ Halo, CN, or C １－３ 42. The compound of any one of claims 1 to 41, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

53. A compound according to any one of claims 1 to 27 and 42 to 49, having the formula IId, 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof.

54. A compound according to any one of claims 1 to 27 and 42 to 49 having the formula IIe, 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof.

55. (S)-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide, (S)—N-methyl-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide, (S)—N-methyl-2-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-N-(1-(5-(trifluoromethyl)thiazol-2-yl)piperidin-4-yl)acetamide, (S)—N-methyl-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)acetamide, ((S)—N-methyl-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)acetamide, (S)—N-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)-N-methyl-2-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetamide, (S)—N-ethyl-2-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide, (S)—N-methyl-2-((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)azetidin-2-yl)methoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide, (S)-2-(3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide, 5-((S)-1-((S)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-((S)-1-((R)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 4-chloro-5-((S)-1-(2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yloxy)propan-2-ylamino)pyridazin-3(2H)-one, 4-bromo-5-(((2S)-1-((2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)pyridazin-3(2H)-one, 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 6-(4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 6-(4-((S)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 5-(((S)-1-(((S)-1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 6-(4-((S)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 6-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, (S)—N-methyl-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)acetamide, 5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-methoxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 4-(trifluoromethyl)-5-(((2S)-1-((1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)pyridazin-3(2H)-one, 5-(((S)-1-(((S)-1-(1-(5-(difluoromethyl)pyrazin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-(1-(5-(difluoromethyl)pyrazin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 4-bromo-5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, (S)—N-methyl-2-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide, 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((R)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((R)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((2S)-1-((1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, (S)-2-(2-((5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)propoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide, 5-(((2S)-1-(methyl(2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 6-(4-(2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 4-bromo-5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)pyridazin-3(2H)-one, N-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetamide, and The compound according to claim 1 selected from N-((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetamide, or a pharma- ceutically acceptable salt of any of the foregoing.

56. (S)-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-1'-(5-(trifluoromethyl)pyrimidin-2-yl)-[1,4'-bipiperidin]-2-one, (R)-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-1'-(5-(trifluoromethyl)pyrimidin-2-yl)-[1,4'-bipiperidin]-2-one, 5-(((S)-1-(((S)-4,4-dimethyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-4,4-dimethyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, (R)-6-(4-(2-oxo-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)ethoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, (S)-6-(4-(2-oxo-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)ethoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 5-(((S)-1-(((3S,4R)-4-methyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((3R,4S)-4-methyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-((3R,4R)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-((3S,4S)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-((3S,4R)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-((3R,4S)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 6-((R)-3,3-difluoro-4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 6-((S)-3,3-difluoro-4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 5-(((S)-1-(((R)-1-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile, 4-bromo-5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)pyridazin-3(2H)-one, 4-bromo-5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)pyridazin-3(2H)-one, 4-chloro-5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)pyridazin-3(2H)-one, 4-chloro-5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)pyridazin-3(2H)-one, 6-(4-((R)-3-((S)-2-((5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 6-(4-((S)-3-((S)-2-((5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 5-(((S)-1-(((S)-1-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 6-(4-((S)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 6-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-methoxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-methoxy-3-(((S)-1-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-methoxy-3-(((R)-1-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-methoxy-3-(((R)-1-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 2-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)thiazole-5-carbonitrile, 6-(4-((S)-3-((S)-2-((5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 6-(4-((R)-3-((S)-2-((5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile, 4-bromo-5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)pyridazin-3(2H)-one, 4-bromo-5-(((S)-1-methoxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, (S)—N-((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propanamide, 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)-3-((2,2,2-trifluoroethyl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-hydroxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((S)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((S)-1-(((R)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5-(((2S)-1-((1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one, N-((S)-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)acetamide, 5-(((2R,3R)-3-hydroxy-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)butan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one, 4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxamide, and The compound of claim 1 selected from 4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carbonitrile, or a pharma- ceutically acceptable salt of any of the foregoing.

57. 57. A pharmaceutical composition comprising a compound according to any one of claims 1 to 56, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier.

58. A pharmaceutical for inhibiting the activity of PARP7, comprising a compound according to any one of claims 1 to 56 or a pharma- ceutically acceptable salt thereof.

59. 57. A medicament for treating cancer in a patient in need of such treatment, comprising a compound according to any one of claims 1 to 56, or a pharma- ceutically acceptable salt thereof.

60. 60. The pharmaceutical composition of claim 59, wherein the cancer is breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colon cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck cancer (upper aerodigestive tract cancer), urinary tract cancer, or colon cancer.

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