Pyridazinone as a PARP7 inhibitor

Abstract

The present invention relates to pyridazinones and related compounds that are inhibitors of PARP7 and can be used for the treatment of cancer.

Description

Technical Field

[0001] The present invention relates to pyridazinones and related compounds that are inhibitors of PARP7 and can be used for the treatment of cancer. Background of the Invention

[0003] Poly(ADP-ribose) polymerase (PARP) is a member of a family of seventeen enzymes that regulate fundamental cellular processes, including gene expression, protein degradation, and a variety of cellular stress responses (M.S. 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 an emerging approach to novel therapeutic agents. One member of the PARP family, PARP1, has been shown to be an effective cancer target associated with DNA damage-induced cellular stress, which is induced by gene mutations or cytotoxic chemotherapy. Four approved drugs are in clinical use and several other drugs are in advanced development (A. Ohmoto, S. Yachida, Current status of poly(ADP-ribose) polymerase inhibitors and future directions. Onco Targets Ther 10, 5195-5208 (2017)).

[0004] Based on homology within their catalytic domains, 17 members of the PARP family have been identified in the human genome (S. Vyas, M. Chesarone-Cataldo, T. Todorova, Y. H. Huang, P. Chang, A systematic analysis of the PARP protein family identifies new functions critical for cell physiology. Nat Commun 4, 2240 (2013)). However, their catalytic activities fall into 3 distinct classes (S. Vyas et al., Family-wide analysis of poly(ADP-ribose) polymerase activity. Nat Commun 5, 4426 (2014)). Most PARP family members catalyze the transfer of single ADP-ribose units to their substrates (mono-PARPs), while other PARP family members (PARP1, PARP2, TNKS, TNKS2) catalyze the transfer of poly-ADP-ribose units to substrates (poly-PARPs). Finally, PARP13 is the only PARP that has yet to demonstrate catalytic activity in vitro or in vivo.

[0005] The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in the regulation of multiple cellular functions, including pro-inflammatory 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, J. H. Duarte, The aryl hydrocarbon receptor: multitasking in the immune system. Annu Rev Immunol 32, 403-432 (2014)). AHR can be activated by a variety of ligands, including endogenous tryptophan metabolites such as kynurenine (C. A. Opitz 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) (K. W. Bock, Toward elucidation of dioxin-mediated chloracne and Ah receptor functions. Biochem Pharmacol 112, 1-5 (2016)). Activation of AHR induces the expression of target genes, including genes involved in metabolism such as cytochrome P450 1A1 and P450 1B1.Activation of the AHR also leads to an increase in the AHR target gene, the TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, also known as PARP7), which acts 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)).

[0006] 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) in a region that is frequently amplified in cancers with squamous histology (http: / / www.cbioportal.org / index.do?session_id=5ae1bcde498eb8b3d565d8b2). Genome-wide association studies have identified 3q25 as a susceptibility locus for ovarian cancer, suggesting a role for PARP7 in this cancer type (E.L. Goode 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 regulates the expression of P4501A1 and P4501B1 as a negative feedback mechanism (L. MacPherson et al., Aryl hydrocarbon receptor repressor and TIPARP(ARTD14) uses 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)). It has also been described that PARP7 can ADP - ribosylate liver X receptors, which results in the regulation of their 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) to 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 U S A 114, 2681 - 2686(2017)).Also in the context of viral infection, AHR-induced PARP7 can interact with TBK1, a major kinase that is activated during the initiation 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)). PARP7 has been shown to ADP-ribosylate TBK1, which prevents its activation and thus inhibits type I interferon responses.

[0007] Based on these results in viral infection, it can be hypothesized that cancer cells can use aberrantly expressed and / or activated PARP7 as a mechanism to evade the host immune system by suppressing type I interferon and thereby suppressing T cell-mediated anti-tumor 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)). PARP7 knockout in a murine melanoma cell line showed increased proliferation and activation of co-cultured T cells, indicating that PARP7 inhibition could be a viable strategy to activate T cell-mediated tumor killing. Thus, there is a continuing need to develop PARP7 inhibitors. SUMMARY OF THE INVENTION

[0008] The present invention relates to a compound of formula I:

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein the members are defined as follows.

[0011] The present invention also relates to a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0012] The present invention also relates to a method of inhibiting the activity of PARP7, the method comprising contacting a compound of formula I or a pharmaceutically acceptable salt thereof with PARP7.

[0013] The present invention also 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, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0014] The present invention also relates to a method of treating cancer in a subject in need thereof, the method 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 pharmaceutically 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

[0015] Figure 1 Shows the effect of the compounds of the present invention on the average tumor volume in the animal model described in Example B. DETAILED DESCRIPTION

[0016] The present invention relates to a compound of formula I:

[0017]

[0018] or a pharmaceutically acceptable salt thereof, wherein:

[0019] X is Cl, Br, F, CH3, CF3, CF2H, CN, OCH3, ethyl, cyclopropyl, SCH3 or isopropyl;

[0020] A is a group of the formula having (A-1):

[0021]

[0022] Y 1 、Y 2 and Y 3 each independently selected from O, S, NR Y 、C(=O), C(=O)O, C(=O)NR Y 、S(=O), S(=O)2, S(=O)NR Y 、S(=O)2NR Y or NR Y C(=O)NR Y wherein each R Y is independently H, C 1-4 alkyl or C 1-4 haloalkyl;

[0023] L is C 1-3 alkylene, O, S, NR Y 、C(=O), C(=O)O, C(=O)NRY 、 S(=O), S(=O)NR Y or NR Y C(=O)NR Y ;

[0024] Z is H, Cy Z , a halogen group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , NR c C(=NR e )NR c R d , NR c S(O)R b , NR c S(O)2R b , NR c S(O)2NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)2NR c R d ; wherein said C of Z 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the following: Cy Z, halo, CN, NO2, OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , NR c C(=NR e )NR c R d , NR c R d , NR c , C(O)R b , NR c , C(O)OR a , NR c , C(O)NR c R d , NR c , S(O)R b , NR c , S(O)2R b , NR c , S(O)2NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)2NR c R d ;

[0025] Cy Z is selected from C 6-10 aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NRc1 R d1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 wherein the alkyl group, C 2-6 Alkenyl and C 2-6 The alkynyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, CN, NO2, OR a1 , SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 Rd1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NR c1 R d1 ;

[0026] Ring D is a monocyclic or polycyclic 4- to 10-membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 groups independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , NR c2 , C(=NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 , C(O)R b2 , NR c2 , C(O)OR a2 , NR c2 , C(O)NR c2 R d2 , NR c2 , S(O)R b2 , NR c2 , S(O)2R b2 , NR c2 , S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2and S(O)2NR c2 R d2 , wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted by 1, 2 or 3 groups independently selected from the following: halo, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 ;

[0027] 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 selected from H, halo, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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, 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 , S(O)R b3 , NR c3 , S(O)2R b3 , NR c3 , S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 ; wherein said R 1 , R 2 , R 3 , R 4 , R5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 of the 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 alkyl are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NRc3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ;

[0028] or R 1 and Y 1 R Y The group together with the atom to which it is attached and with the atoms forming Y 1 The atoms are taken together to form a 4-10 membered heterocycloalkyl ring, which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 Rd3 , S(O)2R b3 and S(O)2NR c3 R d3 ;

[0029] or R 7 and Y 3 of R Y group together with the atom to which it is attached and with the atoms that form Y 3 and with the atoms that are R 9 , R 10 , R 11 and R 12 substituted carbon atoms (if any) together form a 4 - 10 membered heteroalkyl ring, which is optionally substituted by 1, 2 or 3 substituents independently selected from: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2Rb3 and S(O)2NR c3 R d3 ;

[0030] or R 1 and R 3 together with the carbon atom to which it is attached form a C 5-10 cycloalkyl ring or a 5- to 10-membered heterocycloalkyl ring, each of which is optionally substituted by 1, 2 or 3 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 ;

[0031] or R 3 and R 5forms a C together with the carbon atom to which it is attached 5-10 cycloalkyl ring or 5- to 10-membered heterocycloalkyl ring, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 、SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、NR c3 R d3 、NR c3 C(O)R b3 、NR c3 C(O)OR a3 、NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 、NR c3 C(=NR e3 )NR c3 R d3 、NR c3 S(O)R b3 、NR c3 S(O)2R b3 、NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ;

[0032] or R 7 and R 9 forms a C together with the carbon atom to which it is attached 5-10 cycloalkyl ring or 5- to 10-membered heterocycloalkyl ring, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 ;

[0033] Or R 9 and R 11 Together with the carbon atom to which it is attached form a C 5-10 Cycloalkyl ring or a 5 - 10 membered heteroalkyl ring, each of which is optionally substituted by 1, 2 or 3 substituents independently selected from: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 Rd3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 ;

[0034] or R 5 and R 7 together with the carbon atom to which it is attached and with Y 2 together form a 5- to 10-membered heteroalkyl ring, which is optionally substituted by 1, 2 or 3 substituents independently selected from: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3, NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 ;

[0035] or R 1 and R 3 together form a double bond between the carbon atoms to which they are attached;

[0036] or R 3 and R 5 together form a double bond between the carbon atoms to which they are attached;

[0037] or R 7 and R 9 together form a double bond between the carbon atoms to which they are attached;

[0038] or R 9 and R 11 together form a double bond between the carbon atoms to which they are attached;

[0039] or R 9 , R 10 , R 11 and R 12 together form a triple bond between the carbon atoms to which they are attached;

[0040] Each R a , R b , R c , R d , R a1 , Rb1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 and R d3 are independently selected from 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 said 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 of said 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 is optionally substituted with 1, 2 or 3 substituents independently selected from: halo, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR a7, SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 C(O)OR a7 , C(=NR e7 )NR c7 R d7 , NR c7 C(=NR e7 )NR c3 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O)2R b7 , NR c7 S(O)2R b7 , NR c7 S(O)2NR c7 R d7 and S(O)2NR c7 R d7 ;

[0041] or R c and R d together with the N atom to which it is attached form a 4- to 7-membered heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 substituents independently selected from: 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 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NRc7 C(O)R b7 NR c7 C(O)NR c7 R d7 NR c7 C(O)OR a7 、C(=NR e7 )NR c7 R d7 NR c7 C(=NR e7 )NR c3 R d7 、S(O)R b7 、S(O)NR c7 R d7 、S(O)2R b7 NR c7 S(O)2R b7 NR c7 S(O)2NR c7 R d7 and S(O)2NR c7 R d7 ;

[0042] or R c1 and R d2 Together with the N atom to which it is attached, it forms a 4-7 membered heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of CN, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a7 , SR a7 、C(O)R b7 、C(O)NR c7 R d7 、C(O)OR a7 、OC(O)R b7 、OC(O)NR c7 R d7 NR c7 R d7 NR c7 C(O)R b7 NR c7 C(O)NR c7 R d7 NR c7 C(O)OR a7 、C(=NR e7 )NR c7 R d7 NR c7 C(=NRe7 )NR c3 R d7 、S(O)R b7 、S(O)NR c7 R d7 、S(O)2R b7 NR c7 S(O)2R b7 NR c7 S(O)2NR c7 R d7 and S(O)2NR c7 R d7 ;

[0043] or R c2 and R d2 Together with the N atom to which it is attached, it forms a 4-7 membered heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of CN, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a7 , SR a7 、C(O)R b7 、C(O)NR c7 R d7 、C(O)OR a7 、OC(O)R b7 、OC(O)NR c7 R d7 NR c7 R d7 NR c7 C(O)R b7 NR c7 C(O)NR c7 R d7 NR c7 C(O)OR a7 、C(=NR e7 )NR c7 R d7 NR c7 C(=NR e7 )NR c3 R d7 、S(O)R b7 、S(O)NR c7 R d7 、S(O)2R b7 NR c7 S(O)2R b7 NR c7 S(O)2NR c7 Rd7 and S(O)2NR c7 R d7 ;

[0044] or R c3 and R d3 together with the N atom to which it is attached form a 4- to 7-membered heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 substituents independently selected from the following: 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 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 C(O)OR a7 , C(=NR e7 )NR c7 R d7 , NR c7 C(=NR e7 )NR c3 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O)2R b7 , NR c7 S(O)2R b7 , NR c7 S(O)2NR c7 R d7 and S(O)2NR c7 R d7 ;

[0045] R a7 、R b7 、R c7 and R d7 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6Alkenyl, 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 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- 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 Alkyls are each optionally substituted with 1, 2 or 3 substituents independently selected from: OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy;

[0046] Each R e 、R e1 、R e2 、R e3 and R e7 is independently selected from H, C 1-4 Alkyl and CN;

[0047] a is 0 or 1;

[0048] m is 0 or 1;

[0049] n is 0 or 1;

[0050] p is 0 or 1;

[0051] q is 0 or 1;

[0052] r is 0 or 1;

[0053] wherein any of the above heteroaryl or heterocycloalkyl contains 1, 2, 3 or 4 ring-forming heteroatoms independently selected from O, N and S; and

[0054] One or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted with one or two oxo (=O) groups.

[0055] In some embodiments, X is CF3, Br, or Cl. In some embodiments, X is CF3. In some embodiments, X is Br or Cl. In some embodiments, X is Br. In some embodiments, X is Cl.

[0056] In some embodiments, Y 1 is NR Y 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.

[0057] In some embodiments, Y 2 is O, NR Y or C(=O)NR Y . In some embodiments, Y 2 is O, NH, NCH3, 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 NCH3. In some embodiments, Y 2 is NH or NCH3. In some embodiments, Y 2 is NH. In certain embodiments, Y 2 is NCH3.

[0058] 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)NCH3. In some embodiments, Y 3 is C(=O)NCH2. In some embodiments, Y 3 is C(=O)NH or C(=O)NCH3.

[0059] In some embodiments, Y 1 's R Y is H.

[0060] In some embodiments, Y 2 's R Y is H or C 1-4 alkyl. In some embodiments, Y 2 's R Y is H or methyl. In some embodiments, Y 2 's R Y is H. In some embodiments, Y 2 's R Y is methyl.

[0061] In some embodiments, Y 3 's R Y is H or C 1-4 alkyl. In some embodiments, Y 3 's R Y is H, methyl or ethyl. In some embodiments, Y 3 's R Y is H. In some embodiments, Y 3 's R Y is methyl. In some embodiments, Y 3 's R Y is ethyl. In some embodiments, Y 3 's R Y is CH2.

[0062] 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 each independently selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 wherein said C 1-6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halo, CN, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 .

[0063] 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 selected from H, halogen, C 1-6 Alkyl and C 1-6 haloalkyl, wherein the C 1-6The alkyl group is optionally substituted by 1 or 2 substituents independently selected from the following: halo, CN, NO2, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , NR c3 R d3 , NR c3 C(O)R b3 , S(O)2R b3 and S(O)2NR c3 R d3 .

[0064] 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 selected from H, halo, C 1-6 alkyl, and C 1-6 haloalkyl, wherein the C 1-6 alkyl is optionally substituted by OR a3 .

[0065] In some embodiments, R 1 , R 2 , R 5 , R 6 , R 7 and R 8 are each independently selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3C(O)NR c3 R d3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 wherein said C 1-6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halo, CN, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 .

[0066] In some embodiments, R 1 , R 2 , R 5 , R 6 , R 7 and R 8 are each independently selected from H, halogen, C 1-6 Alkyl and C 1-6 haloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, CN, NO2, OR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 NRc3 R d3 NR c3 C(O)R b3 、S(O)2R b3 and S(O)2NR c3 R d3 .

[0067] In some embodiments, R 1 , R 2 , R 5 , R 6 , R 7 and R 8 are each independently selected from H, halogen, C 1-6 Alkyl and C 1-6 haloalkyl, wherein the C 1-6 The alkyl group is optionally replaced by OR a3 replace.

[0068] In some embodiments, R 1 Is H or C 1-6 Alkyl; wherein the C 1-6 The alkyl group is optionally replaced by OR a3 NR c3 R d3 and NR c3 C(O)R b3 In some embodiments, R 1 Is H or C 1-6 Alkyl; wherein the C 1-6 The alkyl group is optionally replaced by OR a3 In some embodiments, R 1 Is H or C 1-6 Alkyl; wherein the C 1-6 Alkyl is optionally substituted with methoxy. 1 is H or methyl; wherein the methyl is optionally substituted with methoxy. 1 is H, methyl, methoxymethyl, CH2OH, CH(OH)CH3, CH2NHCH2CF3 or CH2NHC(O)CH3. In some embodiments, R 1 It is H, methyl or methoxymethyl.

[0069] In some embodiments, R 1 is optionally OR a3 Substituted C 1-6 In some embodiments, R 1 is C optionally substituted by methoxy 1-6 In some embodiments, R 1is a methyl group optionally substituted by methoxy. In some embodiments, R 1 is methyl. In some embodiments, R 1 is methoxymethyl.

[0070] In some embodiments, R 1 is H.

[0071] In some embodiments, R 2 is H.

[0072] In some embodiments, R 5 is H or C 1-6 alkyl.

[0073] In some embodiments, R 5 is methyl.

[0074] In some embodiments, R 5 is H.

[0075] In some embodiments, R 6 is H.

[0076] In some embodiments, R 7 is H or C 1-6 alkyl.

[0077] In some embodiments, R 7 is CH2.

[0078] In some embodiments, R 7 is H.

[0079] In some embodiments, R 8 is H.

[0080] In some embodiments, R 1 and the R 1 group of Y Y together with the atoms to which it is attached and together with the atoms forming Y 1 form a 4- to 10-membered heterocycloalkyl ring, which is optionally substituted by 1, 2, or 3 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NRc3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 .

[0081] In some embodiments, R 1 and Y 1 R Y The group together with the atom to which it is attached and with the atoms forming Y 1 The atoms are taken together to form an azetidine ring, which is optionally substituted by 1, 2 or 3 substituents independently selected from the following: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 .

[0082] In some embodiments, R 1 and Y 1 R Y The group together with the atom to which it is attached and with the atoms forming Y 1 The atoms of azetidine come together to form an azetidine ring.

[0083] In some embodiments, R 7 and Y 3 R Y The group together with the atom to which it is attached and with the atoms forming Y 3 The atoms together with R 9 , R 10 , R 11 and R 12 The substituted carbon atoms (if present) together form a 4-10 membered heterocycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3, OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 , C(O)R b3 , NR c3 , C(O)OR a3 , NR c3 , C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , NR c3 , C(=NR e3 )NR c3 R d3 , NR c3 , S(O)R b3 , NR c3 , S(O)2R b3 , NR c3 , S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 .

[0084] In some embodiments, R 7 and Y 3 's R Y group, together with the atom to which it is attached, and together with the atoms that form Y 3 , and together with the carbon atom (if present) substituted by R 9 , R 10 , R 11 and R 12 form an oxopyrrolidine ring or a pyrrolidine ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)Rb3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 。

[0085] In some embodiments, the R 7 and Y 3 R Y group, together with the atoms to which it is attached and together with the atoms forming Y 3 and together with the carbon atoms (if any) substituted by R 9 , R 10 , R 11 and R 12 form a pyrrolidine ring or an oxopyrrolidine ring.

[0086] In some embodiments, the R 7 and Y 3 R Y group, together with the atoms to which it is attached and together with the atoms forming Y 3 and together with the carbon atoms (if any) substituted by R 9 , R 10 , R 11 and R 12 form an oxopyrrolidine ring.

[0087] In some embodiments, R 7 and Y 3 of the R Y group, together with the atom to which it is attached and with the atoms that form Y 3 and with the atoms that are R 9 、R 10 、R 11 and R 12 substituted carbon atoms (if any) together form an oxopiperidine ring.

[0088] In some embodiments, ring D is a monocyclic or polycyclic 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a2 、SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 、NR c2 C(=NR e2 )NR c2 R d2 、NR c2 R d2 、NR c2 C(O)R b2 、NR c2 C(O)OR a2 、NR c2 C(O)NR c2 R d2 、NR c2 S(O)R b2 、NR c2 S(O)2R b2 、NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 , where the C 1-6 alkyl, C2-6 The alkenyl and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 groups independently selected from the following: halo, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 , C(O)R b2 , NR c2 , C(O)OR a2 , NR c2 , C(O)NR c2 R d2 , NR c2 , S(O)R b2 , NR c2 , S(O)2R b2 , NR c2 , S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 .

[0089] In some embodiments, ring D is a monocyclic or polycyclic 4-6 membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the following: halo, CN, OR a2 , C(O)NR c2 R d2 , C 1-6 alkyl and C 1-6 haloalkyl.

[0090] In some embodiments, ring D is a monocyclic or polycyclic 4-6 membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the following: halo, OR a2 , C 1-6 alkyl and C1-6 Halogenated alkyl group.

[0091] In some embodiments, Ring D is 3-azabicyclo[3.1.0]hexane.

[0092] In some embodiments, Ring D is a monocyclic 4- to 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: halogen, OR a2 , C 1-6 alkyl, and C 1-6 halogenated alkyl. In some embodiments, Ring D is a polycyclic 10-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: halogen, OR a2 , C 1-6 alkyl, and C 1-6 halogenated alkyl. In some embodiments, Ring D is an azetidine ring or a piperidine ring; each optionally substituted with 1, 2, 3, or 4 substituents independently selected from: halogen, OR a2 , C 1-6 alkyl, and C 1-6 halogenated alkyl. In some embodiments, Ring D is a piperidine ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from: halogen, OR a2 , C 1-6 alkyl, and C 1-6 halogenated alkyl. In some embodiments, Ring D is a piperidine ring optionally substituted with 1 or 2 substituents independently selected from: OH, F, C(O)NH2, or CN. In some embodiments, Ring D is an azetidine ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from: halogen, OR a2 , C 1-6 alkyl, and C 1-6 halogenated alkyl.

[0093] In some embodiments, Ring D is a monocyclic 4- to 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.

[0094] In some embodiments, Ring D is a monocyclic 4- to 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: halogen, OR a2 , C 1-6 alkyl, and C 1-6 halogenated alkyl.

[0095] In some embodiments, Ring D is an azetidine ring or a piperidine ring optionally substituted with OR a2 .

[0096] In some embodiments, ring D is a piperidine ring optionally substituted with OH.

[0097] In some embodiments, ring D is a piperidine ring.

[0098] In some embodiments, Z is Cy Z , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , NR c C(=NR e )NR c R d , NR c S(O)R b , NR c S(O)2R b , NR c S(O)2NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)2NR c R d ; wherein said C of Z 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6The haloalkyl groups are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the following: Cy Z , halo, CN, NO2, OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , NR c C(=NR e )NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O)R b , NR c S(O)2R b , NR c S(O)2NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)2NR c R d .

[0099] In some embodiments, Z is Cy Z , halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO2, OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NRc C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)2R b NR c S(O)2NR c R d 、S(O)2R b and S(O)2NR c R d ; wherein the C of Z 1-6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy Z 、halogen、CN、NO2、OR a , SR a 、C(O)R b 、C(O)NR c R d 、C(O)OR a 、OC(O)R b 、OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)2R b NR c S(O)2NR c R d 、S(O)2R b and S(O)2NR c R d .

[0100] In some embodiments, Z is Cy Z , halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or CN.

[0101] In some embodiments, Z is Cy Z .

[0102] In some embodiments, Cy Za 5- to 6-membered heteroaryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NR c1 R d1 , wherein said alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, CN, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1, C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NR c1 R d1 。

[0103] In some embodiments, Cy Z is a 5- or 6-membered heteroaryl substituted with a halogen group, CN, methyl, or C 1-3 haloalkyl.

[0104] In some embodiments, Cy Z is a 5-membered heteroaryl substituted with a halogen group, CN, or C 1-3 haloalkyl. In some embodiments, Cy Z is a 6-membered heteroaryl substituted with a halogen group, CN, methyl, or C 1-3 haloalkyl. In some embodiments, Cy Z is a 6-membered heteroaryl substituted with a halogen group, CN, or C 1-3 haloalkyl.

[0105] In some embodiments, Cy Z is a pyrimidinyl, pyrazinyl, pyridinyl, or thiazolyl substituted with a halogen group, CN, or C 1-3 haloalkyl. In some embodiments, Cy Z is a pyrimidinyl, pyrazinyl, or pyridinyl substituted with a halogen group, CN, or C 1-3 haloalkyl. In some embodiments, Cy Z is a pyrimidinyl, pyrazinyl, or pyridinyl substituted with a halogen group, CN, or C 1-3Halogenoalkyl-substituted pyrimidinyl or pyrazinyl. In some embodiments, Cy Z is a pyrimidinyl substituted with CF3. In some embodiments, Cy Z is a halogen, CN or C 1-3 halogenoalkyl-substituted thiazolyl.

[0106] 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.

[0107] In some embodiments, 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.

[0108] In some embodiments, Cy Z is 5-(trifluoromethyl)pyrimidin-2-yl.

[0109] In some embodiments, m is 1.

[0110] In some embodiments, n is 0.

[0111] In some embodiments, p is 0.

[0112] In some embodiments, q is 0.

[0113] In some embodiments, r is 1. In some embodiments, r is 0.

[0114] In some embodiments, a is 0.

[0115] In some embodiments, X is CF3, Y 1 is NR Y and Y 2 is O, Y 3 is C(=O)NR Y and R 1 is methyl, R 2 is H, R 5 is H, R 6 is H, R 7is CH2, R 8 is H, ring D is piperidine substituted by OH and Z is Cy Z , where Cy Z is pyrimidinyl substituted by CF3.

[0116] In some embodiments, provided herein is a compound having Formula IIa:

[0117]

[0118] or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, provided herein is a compound having Formula IIb:

[0120]

[0121] or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, provided herein is a compound having Formula IIc:

[0123]

[0124] or a pharmaceutically acceptable salt thereof, where Z 1 and Z 2 are each independently selected from N and CH, and where R Z is halo, CN or C 1-3 haloalkyl. In some embodiments, R Z is selected from CF3, CN, CF2H and Cl.

[0125] In some embodiments, the compounds of the invention have Formula IId:

[0126]

[0127] or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the compounds of the invention have Formula IIe:

[0129]

[0130] or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments, provided herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, where:

[0132] X is Cl, Br or CF3;

[0133] A is a group having the formula (A-1a):

[0134]

[0135] Y 1 , Y 2 and Y 3 Each independently selected from O, NR Y , C(=O) and C(=O)NR Y , where each R Y independently H or C 1-4 alkyl;

[0136] Z is Cy Z ;

[0137] Cy Z is selected from 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1and S(O)2NR c1 R d1 , wherein the alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted with 1, 2 or 3 substituents independently selected from: halo, CN, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NR c1 R d1 ;

[0138] Ring D is a monocyclic or polycyclic 4- to 10-membered heterocycloalkyl, which is optionally substituted with 1, 2 or 3 groups independently selected from: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)ORa2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , NR c2 , C(=NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 , C(O)R b2 , NR c2 , C(O)OR a2 , NR c2 , C(O)NR c2 R d2 , NR c2 , S(O)R b2 , NR c2 , S(O)2R b2 , NR c2 , S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 , wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted by 1, 2 or 3 groups independently selected from the following: halo, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , NR c2 , C(=NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 , C(O)R b2 , NR c2C(O)OR a2 、NR c2 C(O)NR c2 R d2 、NR c2 S(O)R b2 、NR c2 S(O)2R b2 、NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ;

[0139] R 1 、R 2 、R 5 、R 6 、R 7 and R 8 each independently selected from 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, NO2, OR a3 、SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、NR c3 R d3 、NR c3 C(O)R b3 、NR c3 C(O)OR a3 、NR c3 C(O)NR c3 R d3 、C(=NR e3)R b3 、C(=NR e3 )NR c3 R d3 、NR c3 C(=NR e3 )NR c3 R d3 、NR c3 S(O)R b3 、NR c3 S(O)2R b3 、NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; wherein said R 1 、R 2 、R 5 、R 6 、R 7 and R 8 of said 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 alkyl are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 、SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、NR c3 R d3 、NRc3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ;

[0140] or R 1 and Y 1 R Y The group together with the atom to which it is attached and with the atoms forming Y 1 The atoms are taken together to form a 4-10 membered heterocycloalkyl ring, which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NRc3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ;

[0141] or R 7 and Y 3 R Y The group together with the atom to which it is attached and with the atoms forming Y 3 The atoms are taken together to form a 4-10 membered heterocycloalkyl ring, which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 Rd3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ;

[0142] 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 Independently selected from 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 , Rd2 , R a3 , R b3 , R c3 and R d3 of said 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 is optionally substituted by 1, 2 or 3 substituents independently selected from: halo, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 , C(O)OR a7 , C(=NR e7 )NR c7 R d7 , NR c7 C(=NR e7 )NR c3 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O)2R b7 , NR c7 S(O)2R b7 , NR c7 , S(O)2NR c7 R d7 and S(O)2NR c7 Rd7 ;

[0143] R a7 , R b7 , R c7 and R d7 Independently selected from 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 Each alkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy; and

[0144] Each R e , R e1 , R e2 , R e3 and R e7 Independently selected from H, C 1-4 Alkyl and CN;

[0145] wherein any of the above heteroaryl or heterocycloalkyl contains 1, 2, 3 or 4 ring-forming heteroatoms independently selected from O, N and S; and

[0146] wherein one or more ring-forming C or N atoms of any of the above heterocycloalkyl groups are optionally substituted by 1 or 2 oxo (=O) groups.

[0147] In some embodiments, provided herein are compounds selected from the following:

[0148] (S)-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide;

[0149] (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;

[0150] (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;

[0151] (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;

[0152] ((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;

[0153] (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;

[0154] (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;

[0155] (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;

[0156] (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;

[0157] 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;

[0158] 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;

[0159] 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;

[0160] 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;

[0161] 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;

[0162] 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;

[0163] 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;

[0164] 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;

[0165] 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;

[0166] 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;

[0167] 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;

[0168] 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;

[0169] 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;

[0170] 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;

[0171] (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;

[0172] 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;

[0173] 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;

[0174] 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;

[0175] 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;

[0176] 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;

[0177] 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;

[0178] 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;

[0179] 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;

[0180] 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;

[0181] (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;

[0182] 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;

[0183] 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;

[0184] 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;

[0185] 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;

[0186] 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;

[0187] (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;

[0188] 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;

[0189] 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;

[0190] 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;

[0191] 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;

[0192] 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;

[0193] 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

[0194] 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;

[0195] or a pharmaceutically acceptable salt of any of the foregoing.

[0196] In some embodiments, provided herein are compounds selected from:

[0197] (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;

[0198] (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;

[0199] 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;

[0200] 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;

[0201] (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;

[0202] (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;

[0203] 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;

[0204] 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;

[0205] 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;

[0206] 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;

[0207] 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;

[0208] 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;

[0209] 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;

[0210] 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;

[0211] 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;

[0212] 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;

[0213] 5-(((S)-1-(((R)-2-oxo-1-((1R,5S,6s)-3-(5-(trifluoromethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one;

[0214] 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;

[0215] 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;

[0216] 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;

[0217] 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;

[0218] 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;

[0219] 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;

[0220] 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;

[0221] 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;

[0222] 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;

[0223] 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;

[0224] 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;

[0225] 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;

[0226] 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;

[0227] 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;

[0228] 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;

[0229] 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;

[0230] 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;

[0231] 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;

[0232] 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;

[0233] 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;

[0234] 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;

[0235] 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;

[0236] 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;

[0237] 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;

[0238] 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;

[0239] 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;

[0240] (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;

[0241] 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;

[0242] 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;

[0243] 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;

[0244] 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;

[0245] 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;

[0246] 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;

[0247] 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;

[0248] 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

[0249] 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;

[0250] or a pharmaceutically acceptable salt of any of the foregoing.

[0251] It should be further understood that certain features of the invention that are described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, the various features of the invention that are described in the context of a single embodiment for clarity may also be provided separately or in any suitable sub-combination.

[0252] At various places in this specification, substituents of the compounds of the invention are disclosed in groups or ranges. The invention is specifically intended to include each and every individual sub-combination of the members of such groups and ranges. For example, the term "C 1-6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0253] At various places in this specification, various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings may be attached to the remainder of the molecule at any ring member where the valence allows. For example, the term "pyridinyl", "pyridyl", or "pyridine ring" may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[0254] The term "n-membered" (where "n" is an integer) generally describes the number of ring-forming atoms in a 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, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl.

[0255] For compounds of the invention in which a variable occurs more than once, each variable may independently be a different moiety selected from the group defining the variable. For example, if a structure is described having two R groups that are present simultaneously on the same compound, the two R groups may represent different moieties independently selected from the groups defined for R.

[0256] As used herein, the phrase "optionally substituted" means unsubstituted or substituted.

[0257] As used herein, the term "substituted" means that a hydrogen atom is replaced by a non-hydrogen group. It should be understood that substitution at a given atom is limited by valence.

[0258] As used herein, the term "C" when used in combination with a chemical group i-j " (wherein i and j are integers) names the range of the number of carbon atoms in the chemical group, where i - j defines the range. For example, C 1-6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0259] As used herein, the term "alkyl", whether used alone or in combination with other terms, refers to a saturated hydrocarbon group that can be straight-chain or branched-chain. In some embodiments, the alkyl group contains 1 to 7, 1 to 6, 1 to 4, or 1 to 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, n-heptyl, and the like. In some embodiments, the alkyl group is methyl, ethyl, or propyl.

[0260] As used herein, the term "halo" or "halogen", whether used alone or in combination with other terms, includes fluorine, chlorine, bromine, and iodine. In some embodiments, the halo group is F or Cl.

[0261] As used herein, the term "haloalkyl", whether used alone or in combination with other terms, refers to an alkyl group having a halogen atom substituent with up to full valence, and the halogen atom substituents can be the same or different. In some embodiments, the halogen atom is a fluorine atom. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkyls include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, and the like.

[0262] As used herein, the term "alkoxy", whether used alone or in combination with other terms, refers to a group of the formula -O-alkyl. Exemplary alkoxys include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0263] As used herein, the term "haloalkoxy", whether used alone or in combination with other terms, refers to a group of the formula -O-(haloalkyl). In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. An exemplary haloalkoxy is -OCF3.

[0264] As used herein, the term "amino", whether used alone or in combination with other terms, refers to NH2.

[0265] As used herein, the term "alkylamino", used alone or in combination with other terms, refers to a group of the formula -NH(alkyl). In some embodiments, the alkylamino has 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.

[0266] As used herein, the term "dialkylamino", used alone or in combination with other terms, refers to a group of 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, each alkyl independently has 1 to 6 or 1 to 4 carbon atoms.

[0267] As used herein, the term "heterocycloalkyl", used alone or in combination with other terms, refers to a non-aromatic ring or ring system that optionally contains one or more alkenylene or alkynylene groups as part of the ring structure, the ring structure having at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus. Heterocycloalkyl can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. In some embodiments, heterocycloalkyl is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The definition of heterocycloalkyl also includes moieties having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a common bond) to the non-aromatic heterocycloalkyl ring, such as 1,2,3,4-tetrahydro-quinoline, and the like. Heterocycloalkyl can also include bridged heterocycloalkyl (e.g., a heterocycloalkyl moiety containing at least one bridging atom, such as 1-azatricyclo[3.3.1.13,7]dec-1-yl, and the like) and spiroheterocycloalkyl (e.g., a heterocycloalkyl moiety containing at least two rings fused at a single atom, such as [1,4-dioxo-8-aza-spiro[4.5]dec-N-yl], and the like). In some embodiments, heterocycloalkyl has 3 to 10 ring atoms, 4 to 10 ring atoms, or about 3 to 8 ring atoms. In some embodiments, heterocycloalkyl has 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 has 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. The carbon atoms or heteroatoms in the ring of heterocycloalkyl can be oxidized to form a carbonyl, N-oxide, or sulfonyl (or other oxidized linkages), or the nitrogen atom can be quaternized. In some embodiments, the heterocycloalkyl moiety is a C 2-7 monocyclic heterocycloalkyl. In some embodiments, heterocycloalkyl is a morpholine ring, pyrrolidine ring, piperazine ring, piperidine ring, tetrahydropyran ring, tetrahydropyridine, azetidine ring, or tetrahydrofuran ring.

[0268] As used herein, the term "heterocycloalkyl", alone or in combination with other terms, refers to a group of the formula heterocycloalkyl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom. In some embodiments, the alkyl moiety is methylene. In some embodiments, the heterocycloalkyl moiety has 3 to 10 ring members, 4 to 10 ring members, or 3 to 7 ring members. In some embodiments, the heterocycloalkyl is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl moiety is monocyclic. In some embodiments, the heterocycloalkyl moiety is C 2-7 monocyclic heterocycloalkyl.

[0269] As used herein, the term "aryl", 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, the aryl has 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments, the aryl is a monocyclic or bicyclic group. In some embodiments, the aryl is phenyl or naphthyl.

[0270] As used herein, the term "arylalkyl", alone or in combination with other terms, refers to a group of the formula aryl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom. In some embodiments, the alkyl moiety is methylene. In some embodiments, the aryl moiety is phenyl. In some embodiments, the aryl is a monocyclic or bicyclic group. In some embodiments, the arylalkyl is benzyl.

[0271] As used herein, the term "heteroaryl", 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 ring members that are independently selected from the group consisting of nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, oxazolyl, quinolinyl, isoquinolinyl, benzoisoxazolyl, imidazo[1,2-b]thiazolyl, and the like. The carbon atoms or heteroatoms in the ring of the heteroaryl may be oxidized to form a carbonyl, N-oxide, or sulfonyl (or other oxidized linkage), or the nitrogen atom may be quaternized, provided that the aromatic nature of the ring is maintained. In some embodiments, the heteroaryl has 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 5 carbon atoms, 1 to 5 carbon atoms, or 5 to 10 carbon atoms. In some embodiments, the heteroaryl contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

[0272] As used herein, the term "heteroarylalkyl", alone or in combination with other terms, refers to a group of the formula heteroaryl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom. 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 to 10 carbon atoms.

[0273] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise specified, all stereoisomers (e.g., enantiomers and diastereomers) are contemplated. The compounds of the present invention containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic form. Methods for how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of a racemic mixture or by stereoselective synthesis. Geometric isomers of alkenes, C=N double bonds, etc. may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. The cis and trans geometric isomers of the compounds of the present invention may be isolated as a mixture of isomers or as separated isomer forms.

[0274] The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond along with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers that are isomeric protonation states having the same empirical formula and total charge. Exemplary prototropic tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms where a proton can occupy two or more positions in a heterocyclic 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 spatially locked into one form by appropriate substitution. Illustrated below are examples of tautomeric forms, pyridazin-3(2H)-one and pyridazin-3-ol:

[0275]

[0276] The compounds of the present invention also include all isotopes of atoms that occur in the intermediates or final compounds. Isotopes include those atoms having 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.

[0277] Unless otherwise indicated, the term "compound" as used herein is intended to include all stereoisomers, geometric isomers, tautomeric forms, and isotopes of the depicted structures.

[0278] All compounds and their pharmaceutically acceptable salts can exist with other substances such as water and solvents (e.g., in the form of hydrates and solvates) or can be isolated.

[0279] In some embodiments, the compounds of the present invention or their salts are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation can include, for example, a composition enriched in the compound of the present invention. Substantial isolation can include a composition containing at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt% of the compound of the present invention or its salt. Methods for isolating compounds and their salts are conventional in the art.

[0280] The phrase "pharmaceutically acceptable" as used herein is employed to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications and are commensurate with a reasonable benefit / risk ratio.

[0281] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include (but are not limited to) inorganic or organic acid salts of basic residues (such as amines); base salts or organic salts of acidic residues (such as carboxylic acids); and the like. Pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of the parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both. A list of suitable salts is found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985, page 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), the entire contents of each of which are incorporated herein by reference.

[0282] Synthesis

[0283] The compounds of the present invention (including their salts) can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0284] The reactions for preparing the compounds of the present invention can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents are substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out (e.g., a temperature within the range from the freezing temperature to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, those skilled in the art can select a solvent suitable for the particular reaction step.

[0285] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. Those skilled in the art can readily determine the need for protection and deprotection and the selection of appropriate protecting groups. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Ed., Wiley & Sons, Inc., New York (1999), the entire text of which is incorporated herein by reference.

[0286] The reaction can be monitored according to any suitable method known in the art. For example, it can be monitored spectroscopically (e.g., nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible light), or mass spectrometry) or by chromatography (e.g., high performance liquid chromatography (HPLC) or thin layer chromatography) to monitor product formation.

[0287] As used herein, the expressions “ambient temperature,” “room temperature,” and “RT” are understood in the art and generally refer to the temperature that is approximately the indoor temperature at which the reaction is carried out (e.g., the reaction temperature), e.g., a temperature of about 20 °C to about 30 °C.

[0288] The compounds of formula I can be prepared according to many preparative routes known in the literature. Exemplary synthetic methods for preparing the compounds of the present invention are provided in the following schemes. Unless otherwise specified, all substituents are as defined herein.

[0289] In the method depicted in Scheme 1, an appropriately substituted halogen-containing compound of formula (1-1) (i.e., X a = Cl or Br) is protected as a p-methoxybenzyl ether (“PMB”) compound of formula (1-2) by treatment with p-methoxybenzyl chloride (“PMB-Cl”) in the presence of sodium hydride (NaH).

[0290] Scheme 1

[0291]

[0292] As shown in Schemes 2-4, after deprotection of the PMB protecting group, the compound of formula (1-2) can react with various nucleophiles to provide the compound of formula (I).

[0293] In the method depicted in Scheme 2, a compound of formula (1-3) (where Y a is O, NR Y or S) reacts with a compound of formula (1-2) in the presence of a base (e.g., triethylamine, Cs2CO3, or potassium tert-butoxide) to provide a compound of formula (1-4). Deprotection with an acid (e.g., trifluoroacetic acid or trifluoromethanesulfonic acid in hydrochloric acid) provides the compound of formula (IA).

[0294] Scheme 2

[0295]

[0296] Usage

[0297] The compounds of the present invention can inhibit the activity of PARP7. For example, by administering an inhibitory amount of the compounds of the present invention to a cell, an individual or a patient, the compounds of the present invention can be used to inhibit the activity of PARP7 in a cell, an individual or a patient in need of inhibiting the enzyme.

[0298] As a PARP7 inhibitor, the compounds of the present invention can be used to treat various diseases associated with abnormal expression or activity of PARP7. For example, the compounds of the present invention can be used to treat cancer. In some embodiments, cancers that can be treated according to the present invention include breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck (upper respiratory and digestive tract) cancer, urinary tract cancer, colon cancer and other cancers.

[0299] In some embodiments, cancers that can be treated according to the present invention include hematopoietic malignancies such as leukemia and lymphoma. Exemplary lymphomas include Hodgkin's or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (such as diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, hairy cell lymphoma and Burkett's lymphoma. Exemplary leukemias include acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML).

[0300] Other cancers that can be treated by administering the compounds of the present invention include liver cancer (such as 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 respiratory and digestive tract cancer), intestinal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer (such as hepatocellular carcinoma), lung cancer, prostate cancer, rectal cancer, skin cancer, gastric cancer, testicular cancer, thyroid cancer and uterine cancer.

[0301] In some embodiments, the cancers that can be treated by administering the compounds of the present invention are multiple myeloma, DLBCL, hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer (upper respiratory and digestive tract cancer), kidney cancer, prostate cancer, rectal cancer, gastric cancer, thyroid cancer, uterine cancer and breast cancer.

[0302] The PARP7 inhibitors of the present invention may also have therapeutic utility in PARP7-related disorders in disease areas such as cardiology, virology, neurodegeneration, inflammation and pain, particularly in cases where the disease is characterized by overexpression or increased activity of PARP7.

[0303] As used herein, the term "cell" is intended to mean a cell in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be a part of a tissue sample excised from an organism (e.g., a mammal). In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell that is viable in an organism (e.g., a mammal).

[0304] As used herein, the term "contact" means bringing together the indicated components in an in vitro system or an in vivo system. For example, "contacting" PARP7 with a compound of the invention or "contacting" a cell with a compound of the invention includes administering a compound of the invention to an individual or patient (e.g., a human) having PARP7, and, for example, introducing a compound of the invention into a sample containing a cell or a purified preparation containing PARP7.

[0305] As used herein, the terms "individual" or "patient" are used interchangeably and refer to a mammal, and particularly a human.

[0306] As used herein, the phrase "therapeutically effective amount" means the amount of an active compound or pharmaceutical agent that a researcher, veterinarian, physician, or other clinician seeks to elicit a biological or medical response in a tissue, system, animal, individual, or human.

[0307] As used herein, the term "treating" or "treatment" means 1) inhibiting a disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., arresting the further development of the pathology and / or symptomatology), or 2) ameliorating a disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., reversing the pathology and / or symptomatology).

[0308] As used herein, the term "preventing" means preventing a disease in an individual who may be susceptible to the disease but has not yet experienced or displayed the pathology or symptomatology of the disease.

[0309] Combination therapy

[0310] One or more additional pharmaceutical agents or treatment methods (e.g., chemotherapeutic agents or other anti-cancer agents, immunopotentiators, immunosuppressants, immunotherapies, radiation, anti-tumor and anti-viral vaccines, cytokine therapies (e.g., IL2, GM-CSF, etc.) and / or kinases (tyrosine or serine / threonine), epigenetic or signal transduction inhibitors) can be used in combination with a compound of the invention. The agents can be combined with a compound of the invention in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0311] Agents suitable for combination with the compounds of the present invention for the treatment of cancer include chemotherapeutic agents, targeted cancer therapies, immunotherapies, or radiation therapies. The compounds of the present invention can be effectively used in combination with antihormonal agents for the treatment of breast cancer and other tumors. Suitable examples are antiestrogen agents, including (but not limited to) tamoxifen and toremifene; aromatase inhibitors, including (but not limited to) letrozole, anastrozole, and exemestane; adrenocortical steroids (such as prednisone); progestins (such as megastrol acetate); and estrogen receptor antagonists (such as fulvestrant). Suitable antihormonal agents for the treatment of prostate cancer and other cancers can also be combined with the compounds of the present invention. These antihormonal agents 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 (such as degarelix); androgen receptor blockers (such as enzalutamide); and agents that inhibit androgen production (such as abiraterone).

[0312] The combination of angiogenesis inhibitors with FGFR inhibitors can be effective in some tumors. These angiogenesis inhibitors include antibodies against VEGF or VEGFR or kinase inhibitors of VEGFR. Antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept. Inhibitors of VEGFR kinase and other antiangiogenesis inhibitors include (but not limited to) sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0313] Suitable chemotherapeutic agents or other anti-cancer agents include, for example, alkylating agents (including but not limited to nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan TM ), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, thiotepa, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0314] Other anti-cancer agents include, respectively, antibody therapeutics directed against checkpoint or co-stimulatory molecules (such as CTLA-4, PD-1, PD-L1, or 4-1BB) 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 blood cancers, such as ofatumumab, rituximab, and alemtuzumab.

[0315] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those of skill in the art. Additionally, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., the 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in full.

[0316] Pharmaceutical preparations and dosage forms

[0317] When used as a medicine, the compounds of the present invention can be administered in the form of pharmaceutical compositions. A pharmaceutical composition refers to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and 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, topical (including ophthalmic administration and administration to mucous membranes, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ophthalmic or parenteral.

[0318] The present invention also includes pharmaceutical compositions containing a combination of one or more of the above-described compounds of the present invention as active ingredients and one or more pharmaceutically acceptable carriers. In preparing the compositions of the present invention, the active ingredient is usually admixed with an excipient, diluted by the excipient or enclosed within a carrier in the form of, for example, a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid or liquid material which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments (containing, for example, up to 10% by weight of the active compound), soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

[0319] The compositions can be formulated into unit dosage forms. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect, together with the appropriate pharmaceutical excipient.

[0320] The active compounds are effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. However, it will be understood that the actual amount of the compound administered will usually be determined by the physician in accordance with relevant circumstances including: the disorder to be treated, the selected route of administration, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0321] To prepare solid compositions such as tablets, the principal active ingredient is admixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compound of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is usually uniformly dispersed throughout the composition so that the composition can be readily re-divided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then re-divided into unit dosage forms of the above type which contain, for example, from 0.1 mg to about 500 mg of the active ingredient of the present invention.

[0322] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form with the advantage of a sustained action. For example, the tablets or pills can contain an internal dosage component and an external dosage component, the latter being in the form of a coating for the former. The two components can be separated by an enteric layer, which is used to resist disintegration in the stomach and allow the internal component to enter the duodenum intact or be released in a delayed manner. Such enteric layers or coatings can use a variety of materials, including a large number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0323] The liquid forms of the compounds and compositions that can be incorporated into the present invention for oral or parenteral 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.

[0324] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. The liquid or solid compositions can contain suitable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route to obtain local or systemic effects. The compositions can be atomized by using an inert gas. The atomized solution can be inhaled directly from the atomizing device or the atomizing device can be attached to a face mask canopy or an intermittent positive pressure breathing machine. The solution, suspension, or powder composition can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0325] The amount of the compound or composition administered to a patient will vary depending on the substance administered, the purpose of administration (e.g., prophylaxis or treatment), the condition of the patient, the mode of administration, etc. In therapeutic applications, the composition can be administered to a patient 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 condition being treated and the judgment of the attending clinician based on factors such as the severity of the disease, the age, weight, and general condition of the patient.

[0326] The composition administered to a patient can be in the form of the above-described pharmaceutical compositions. These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered. The aqueous solution can be packaged for use as is or can be lyophilized, and the lyophilized preparation is combined with a sterile aqueous carrier before administration.

[0327] The therapeutic dosage of the compounds of the present invention can be varied according to, for example, the particular use for which the treatment is carried out, the manner of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the present invention in the pharmaceutical composition can vary depending on a variety of factors, including the dosage, chemical characteristics (such as hydrophobicity), and route of administration. For example, the compounds of the present invention can be provided in the form of an aqueous physiological buffer solution containing from about 0.1% w / v to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg body weight per day. The dosage may depend on variables such as the type and progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. The effective dosage can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0328] The compounds of the present invention can also be formulated in combination with one or more additional active ingredients, which may include any pharmaceutical agent, such as antiviral agents, anticancer agents, vaccines, antibodies, immunostimulants, immunosuppressants, anti-inflammatory agents, etc.

[0329] Examples

[0330] Equipment : Recorded at 300 or 400 MHz using a Bruker AVANCE 300 MHz / 400 MHz spectrometer 1 1H NMR spectra. NMR interpretation was performed using Bruker Topsin software to assign chemical shifts and multiplicities. In cases where two adjacent peaks of equal or unequal height were observed, the two peaks could be labeled as a multiplet or a doublet. In the case of a doublet, the coupling constant could be assigned using this software. In any given instance, one or more protons may not be observable due to the ambiguity of water and / or solvent peaks. LCMS equipment and conditions are as follows:

[0331] 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 NH4HCO3, B: acetonitrile. Flow rate: 1.2 mL / min at 40 °C. Detector: 254 nm, 220 nm. Gradient end time, 2.9 min. Schedule:

[0332] T (min) A(％) B(％) 0.01 90 10 2.10 5 95 2.70 5 95 2.90 90 10

[0333] 2.LC (under alkaline conditions): Shimadzu LC-20ADXR, binary pump, diode array detector, column: Poroshell HPH-C18 50*3.0mm, 2.7μm. Mobile phase A: 0.04% ammonium hydroxide, mobile phase B: acetonitrile. Flow rate: 1.2 ml / min at 40°C. Detector: 254nm, 220nm. Gradient termination time 3.0min Schedule:

[0334] T (min) A(％) B(％) 0.01 90 10 2.0 5 95 2.7 5 95 2.8 90 10

[0335] 3. LC (under acidic conditions): Shimadzu LC-20AD, binary pump, diode array detector. Column: AscentisExpress C18, 50*3.0mm, 2.7μm. Mobile phase: A: water / 0.05% TFA, B: acetonitrile / 0.05% TFA. Flow rate: 1.5 mL / min at 40°C. Detector: 254nm, 220nm. Gradient termination time, 2.9min. Schedule:

[0336]

[0337]

[0338] 4. LC (under acidic conditions): Shimadzu LC-30AD, binary pump, diode array detector. Column: AccucoreC18 50*2.1mm, 2.6μm. Mobile phase A: water / 0.1% FA, mobile phase B: acetonitrile / 0.1% FA. Flow rate: 1.0 ml / min at 40°C. Detector: 254nm, 220nm. Gradient termination time 3.0min. Schedule:

[0339] T (min) A(％) B(％) 0.01 95 5 2.0 5 95 2.7 5 95 2.8 95 5

[0340] 1. S: LCMS-2020, quadrupole LC / MS, ion source: ES-API, TIC: 90~900m / z, fragmenter: 60, drying gas flow: 15L / min, nebulizing gas flow: 1.5L / min, drying gas temperature: 250°C, Vcap: 1100V.

[0341] 2. Sample preparation: Dissolve the sample at 1~10mg / mL in ACN or methanol, then filter through a 0.22μm filter membrane. Injection volume: 1~10μL.

[0342] Definition:ACN (acetonitrile); CH3CN (acetonitrile); CDCl3 (chloroform-d); CD3OD (methanol-d); DCM (dichloromethane); DEA (diethylamine); DIEA (diisopropylethylamine); DMF (N,N-dimethylformamide); DMAP (4-dimethylaminopyridine); DMSO (dimethyl sulfoxide); DMSO-d6 (dimethyl sulfoxide-d6); equiv (equivalent); ESI (electrospray ionization); EtOAc (ethyl acetate); EtOH (ethanol); g (gram); h (hour); 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); H2O (water); Hex (hexane); i-prOH (isopropanol); K2CO3 (potassium carbonate); L (liter); LCMS (liquid chromatography - mass spectrometry); M (molarity); MeCN (acetonitrile); MeOH (methanol); mg (milligram); MHz (megahertz); min (minute); MtBE (methyl tert-butyl ether); mL (milliliter), mmol (millimole); N (nominal); NaBH(AcO)3 (sodium triacetoxyborohydride); NaCl (sodium chloride); NaH (sodium hydride); NaHCO3 (sodium bicarbonate); n-BuOH (n-butyl alcohol); NH4Cl (ammonium chloride); NMP (N-methyl-2-pyrrolidone); PE (petroleum ether); PMB (p-methoxybenzyl); prep-HPLC (preparative high performance liquid chromatography); RT (room temperature); TEA (triethylamine); TFA (trifluoroacetic acid); tR (retention time); triflic (trifluoromethanesulfonic); AcOH (acetic acid); HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); Na2CO3 (sodium carbonate); NaBH3CN (sodium cyanoborohydride); NaOH (sodium hydroxide); NH3 (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)oxy); Tf2O (trifluoromethanesulfonic anhydride); TfOH (trifluoromethanesulfonic acid); THF (tetrahydrofuran); Ti(Oi-Pr)4 (titanium(IV) isopropoxide).

[0343] Intermediate I-1: Synthesis of 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0344]

[0345] Step A

[0346] To a solution of 4,5-dibromo-2,3-dihydropyridazin-3-one (250 g, 984.71 mmol, 1 equiv) in DMF (2.5 L) at 0 - 10 °C was added NaH (59.1 g, 1477.07 mmol, 1.50 equiv, 60%) in several portions, followed by the addition of 1-(chloromethyl)-4-methoxybenzene (230.3 g, 1470.53 mmol, 1.49 equiv) at 0 °C. The resulting solution was stirred at RT for 3 h. The reaction was then quenched by the addition of 5 L of ice / water and extracted with 2 × 2.5 L of DCM. The organic layers were combined and concentrated. The solid was washed with MeOH (500 mL × 2) to afford 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.

[0347] Step B

[0348] 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 RT 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 afford 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.

[0349] Step C

[0350] A solution of 4-bromo-5-methoxy-2-[(4-methoxyphenyl)methyl]-2,3-dihydropyridazin-3-one (232 g, 713.49 mmol, 1 equiv), methyl 2,2-difluoro-2-sulfoacetate (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. The reaction was then quenched by the addition of 1.5 L of water. The resulting solution was extracted with 3 × 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。

[0351] Step D

[0352] 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) at 20 °C was added dropwise TMSI (140 g, 699.67 mmol, 1.29 equiv). The resulting solution was stirred at 85 °C for 20 h. The reaction mixture was then quenched by the addition of 850 mL of water and the resulting solution was extracted with 3 × 850 mL of DCM and the organic layers were combined and dried over anhydrous sodium sulfate. The organic layer was concentrated in vacuo and the crude product was purified by silica gel column chromatography and then recrystallized from 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。

[0353] Step E

[0354] To a solution of 5-hydroxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (110 g, 366.38 mmol, 1 equivalent) in DMF (550 mL) was added dropwise oxalyl dichloride (93 g, 732.75 mmol, 2.00 equivalents) at 0 - 5 °C. The resulting solution was stirred at RT for 8 h. Then the reaction was 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-d6) δ 8.22 (d, J = 0.8 Hz, 1H), 7.33–7.22 (m, 2H), 6.94–6.84 (m, 2H), 5.18 (s, 2H), 3.71 (s, 3H).

[0355] Intermediate I-2: Synthesis of (S)-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetic acid

[0356]

[0357] Step A

[0358] To a solution of (S)-(1-hydroxypropan-2-yl)carbamic acid tert-butyl ester (5.00 g, 28.5 mmol, 1.0 equivalent) in DMF (80 mL) was added portionwise NaH (60% dispersion in oil, 3.4 g, 85.6 mmol, 3.0 equivalents) at 0 °C. The mixture was stirred at this temperature for 20 min and 2-bromoethyl tert-butyl carbonate (7.30 g, 57 mmol, 2.00 equivalents) was added to this suspension. The resulting solution was stirred at 0 °C for 30 min and then water (60 mL) was added. The solution was extracted with 3 × 100 mL of ethyl acetate. The organic layers were combined and washed with 3 × 50 mL of brine. The organic layer was 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)-2-(2-((tert-butoxycarbonyl)amino)propoxy)acetic acid tert-butyl ester as a colorless oil. LCMS (ESI, m / z): 290.20 [M+H] + 。

[0359] Step B

[0360] A solution of tert-butyl 2-[(2S)-2-[(tert-butoxycarbonyl)amino]propoxy]acetate (2.80 g, 9.7 mmol, 1.0 eq) 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] + 。

[0361] Step C

[0362] A solution of 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (3.00 g, 9.4 mmol, 1.00 eq; Intermediate I-1), TEA (2.86 g, 28.2 mmol, 3.0 eq), and (S)-2-(2-aminopropoxy)acetic acid hydrochloride (2.50 g, 14.7 mmol, 1.6 eq) in i-PrOH (100 mL) was stirred at 60 °C for 2 h. The mixture was concentrated and the crude product was applied to a silica gel column eluting 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] + 。

[0363] Intermediate I-3: Synthesis of 3-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride

[0364]

[0365] Step A

[0366] 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 h and then STAB (24.0 g, 114 mmol, 3.0 eq) was added. The resulting solution was stirred at room temperature for 14 h. The pH of the solution was adjusted to 8 with saturated aqueous sodium bicarbonate. The resulting solution was extracted with 3 × 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 layer was 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 afford 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] + 。

[0367] Step B

[0368] A solution of tert-butyl 4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2.0 g, 1.0 eq) 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 used without further purification. LCMS (ESI, m / z): 185.1 [M+H] + 。

[0369] Intermediate I-4: Synthesis of N-methyl-1-(5-(trifluoromethyl)thiazol-2-yl)piperidin-4-amine

[0370]

[0371] Step A

[0372] A solution of 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 K2CO3 (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 with 3 × 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 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] + 。

[0373] Step B

[0374] 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 and 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] + 。

[0375] Intermediates I-5–I-6 are synthesized as required using appropriate structural units and modified reaction conditions (e.g., reagent ratios, temperature, coupling conditions and reaction time) according to the procedure described for the synthesis of N-methyl-1-(5-(trifluoromethyl)thiazol-2-yl)piperidin-4-amine (Intermediate I-4).

[0376]

[0377] 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

[0378]

[0379] Step A

[0380] A solution of tert-butyl piperidin-4-ylcarbamate (2.00 g, 9.98 mmol, 1.0 eq), 2-chloro-5-(trifluoromethyl)pyrimidine (1.82 g, 9.99 mmol, 1.0 eq) and K2CO3 (1.38 g, 9.99 mmol, 1.0 eq) 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 as a white solid (3.7 g, 96% yield, 90% purity). LCMS (ESI, m / z): 347.15 [M+H] + .

[0381] Step B

[0382] A solution of tert-butyl 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-ylcarbamate (2.31 g, 6.0 mmol, 1.0 eq, 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 as a white solid (1.27 g, 82% yield). LCMS (ESI, m / z): 247.20 [M+H] + .

[0383] Step C

[0384] 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 eq, 50% purity; Intermediate I-2), DIEA (187 mg, 1.44 mmol, 3.0 eq), HATU (183 mg, 0.48 mmol, 1.0 eq) and 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine hydrochloride (119 mg, 0.48 mmol, 1.0 eq) in DMF (2.0 mL) was stirred at room temperature for 1 h. After concentration, the residue was applied to a reverse phase column eluted with H2O / CH3CN (31 / 69) to give (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 as a yellow oil (51 mg, 15% yield). LCMS (ESI, m / z): 644.20 [M+H] + .

[0385] Step D

[0386] At 0 °C, trifluoromethanesulfonic acid (0.10 mL) was added 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) and the solution was maintained at that temperature for 1 h. Ice water (30 mL) was added and the pH of the solution was adjusted to pH 7 with saturated aqueous NaHCO3. The resulting solution was extracted with 3 × 60 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a reverse-phase column eluting with H2O / CH3CN (50 / 50) to give (S)-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide as a white solid (14 mg, 35% yield). LCMS (ESI, m / z): 524.2 [M+H] + ; 1 H NMR (300 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.74 (s, 2H), 7.97 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 6.46–6.39 (m, 1H), 4.62 (d, J = 13.5 Hz, 2H), 4.22–4.15 (m, 1H), 4.01 - 3.90 (m, 2H), 3.89 (s, 2H), 3.52 (d, J = 5.4 Hz, 2H), 3.16 (t, J = 12.2 Hz, 2H), 1.80 (d, J = 9.3 Hz, 2H), 1.42–1.30 (m, 2H), 1.18 (d, J = 6.6 Hz, 3H).

[0387] 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

[0388]

[0389] Step A

[0390] 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). After 15 minutes, methyl iodide (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 as a white solid (1.65 g, 63% yield). LCMS (ESI, m / z): 361.20 [M+H] + .

[0391] Step B

[0392] 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 as a white solid (1.21 g, 96% yield). LCMS (ESI, m / z): 261.20 [M+H] + .

[0393] Step C

[0394] 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 applied to a reverse phase column eluting with H2O / CH3CN (26 / 74) to give (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 as a yellow oil (117 mg, 29% yield). LCMS (ESI, m / z): 658.25 [M+H] + .

[0395] Step D

[0396] 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) and maintained at said temperature for 20 min. Ice water (30 mL) was added and the pH of the solution was adjusted to pH 7 with saturated aqueous NaHCO3. The resulting solution was extracted with 3 × 100 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a reverse-phase column eluted with H2O / CH3CN (42 / 58) to give (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 as a white solid (18 mg, 19% yield). LCMS (ESI, m / z): 538.2 [M+H] + ; 1 H NMR (300 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.65 (s, 2H), 7.89 (s, 1H), 6.75–6.50 (br, 1H), 4.86 (d, J = 12.6 Hz, 2H), 4.60–4.40 (rotamer A, m, 1H), 4.30 (s, 1H), 4.22–4.12 (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 = 6.6 Hz, 3H).

[0397] 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 appropriate structural units and modified reaction conditions (e.g., reagent ratios, temperature, coupling conditions, and reaction time) as needed.

[0398]

[0399]

[0400] 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

[0401]

[0402] Step A

[0403] A solution of tert-butyl (piperidin-4-yl)methylcarbamate (1.00 g, 4.666 mmol, 1.00 equiv), 6-chloronicotinonitrile (0.52 g, 3.733 mmol, 0.80 equiv) and K2CO3 (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 as a white solid (970 mg, 59% yield). LCMS: (M+H) + : 317.10.

[0404] Step B

[0405] 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 as a yellow oil (810 mg, 99% yield). LCMS: (M+H) + : 217.20.

[0406] Step C

[0407] (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 a solution of DMF (2 mL) was stirred for 1 h. After concentration, the residue was applied to a reverse-phase column eluted with H2O / CH3CN (37 / 63) to afford (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.

[0408] Step D

[0409] 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) at 0 °C was added trifluoromethanesulfonic acid (0.10 mL) and the mixture was stirred at that temperature for 1 h. Ice water (30 mL) was added and the pH of the solution was adjusted to 7 with saturated aqueous NaHCO3. The resulting solution was extracted with 3 × 60 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a reverse-phase column eluted with H2O / CH3CN (51 / 49) to afford (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. 11H NMR (300 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.48 (d, J = 3.0 Hz, 1H), 7.95 (s, 1H), 7.83 (dd, J = 9.3, 2.4 Hz, 1H), 6.97 (d, J = 9.1 Hz, 1H), 6.73–6.65 (m, 1H), 4.71–4.50 (m, 2H), 4.33 (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 = 9.6 Hz, 3H), 1.78–1.52 (m, 4H), 1.18 (d, J = 6.4 Hz, 3H).

[0410] 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

[0411]

[0412] Step A

[0413] 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 reverse-phase chromatography eluting with H2O / CH3CN to give 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] + .

[0414] Step B

[0415] A solution of tert-butyl (S)-4-(N-ethyl-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetamido)piperidine-1-carboxylate (200 mg, 0.32 mmol, 1.0 eq) in 4N HCl (5 mL) in dioxane was stirred at room temperature for 2 h. The solution was concentrated in vacuo 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 used without further purification. LCMS (ESI, m / z): 526.25 [M+H] + 。

[0416] Step C

[0417] A solution 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 (130 mg, 0.25 mmol, 1.0 eq), K2CO3 (104 mg, 0.75 mmol, 3.0 eq) and 2-chloro-5-(trifluoromethyl)pyrimidine hydrochloride (46 mg, 0.25 mmol, 1.0 eq) 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 in vacuo. The residue was purified by reverse phase chromatography eluting with H2O / CH3CN to give 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] + 。

[0418] Step D

[0419] 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 eq) in trifluoroacetic acid (3 mL) was treated with trifluoromethanesulfonic acid (0.3 mL) and maintained at said temperature for 1 h. Water was added and the pH was adjusted to 6 with saturated aqueous Na2CO3. The resulting solution was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude residue was purified by reverse-phase chromatography eluting with H2O / CH3CN to afford 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 1H NMR (DMSO-d6, 300 MHz) δ 12.47 (s, 1H), 8.69 (s, 2H), 7.93 (s, 1H), 6.75–6.68 (m, 1H), 4.82 (d, J = 13.1 Hz, 2H), 4.27 (s, 1H), 4.18 (d, J = 3.5 Hz, 2H), 3.80–3.71 (m, 1H), 3.56 (d, J = 5.6 Hz, 2H), 3.15 (d, J = 7.3 Hz, 2H), 3.01–2.89 (m, 2H), 1.78–1.62 (m, 4H), 1.18 (t, J = 5.8 Hz, 3H), 1.12–0.93 (m, 3H).

[0420] 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

[0421]

[0422] Step A

[0423] 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 removed in vacuo. The crude product was purified by reverse-phase chromatography eluting with H2O / CH3CN to afford 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] + .

[0424] Step B

[0425] 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 C18 reverse-phase chromatography eluting with H2O / CH3CN to afford 430 mg (44% yield) of tert-butyl (S)-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] + .

[0426] Step C

[0427] A solution of tert-butyl (S)-2-((1-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)azetidin-2-yl)methoxy)acetate (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 afford 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] + .

[0428] Step D

[0429] 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 directly by reverse-phase chromatography eluting with H2O / CH3CN to afford 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 as a colorless oil (76% yield). LCMS (ESI, m / z): 670.20 [M+H] + 。

[0430] Step E

[0431] 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 of the solution was adjusted to 8 with saturated aqueous Na2CO3. The resulting solution was extracted with 3 × 15 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN to afford 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 as a white solid (15%). LCMS (ESI, m / z): 550.15 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 12.36 (d, J = 10.6 Hz, 1H), 8.69 (d, J = 0.9 Hz, 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, 1H), 3.77 (dd, J = 10.2, 4.5 Hz, 2H), 3.04–2.92 (m, 2H), 2.67 (d, J = 16.7 Hz, 3H), 2.49 - 2.41 (m, 1H), 2.11 - 2.01 (m, 1H), 1.71–1.46 (m, 4H).

[0432] 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

[0433]

[0434] Step A

[0435] A solution of (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 at 60 °C for 2 h. The resulting mixture was concentrated in vacuo and the crude product was applied to a silica gel column eluting with ethyl acetate / petroleum ether (7:3) to afford 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] + .

[0436] Step B

[0437] 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 portionwise NaH (60% dispersion in mineral oil, 207 mg, 5.16 mmol, 1.0 equiv) at 0 °C. The solution was stirred for 15 minutes and then 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 with 3 × 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 (1:1) to afford 300 mg (12% yield) of (S)-tert-butyl 2-(3-methoxy-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetate as a yellow solid. LCMS (ESI, m / z): 502.20 [M+H] + 。

[0438] Step C

[0439] A solution of (S)-tert-butyl 2-(3-methoxy-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)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. 20 mL of water was added and the pH of the solution was adjusted to 8 with saturated aqueous NaHCO3. The resulting solution was extracted with 3 × 50 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was applied to a C18 reverse phase column eluted with H2O / CH3CN (7:3) to afford 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] + 。

[0440] Step D

[0441] (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 a solution of DMF (1 mL) were stirred at room temperature for 2 h. 10 mL of water was added and the resulting solution was extracted with 2 × 50 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After concentration, the crude product was purified by reverse-phase chromatography eluting with H2O / CH3CN (45:55) to give 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 1H NMR (DMSO-d6, 300 MHz) δ 12.48 (s, 1H), 8.68 (s, 2H), 7.94 (s, 1H), 6.70–6.55 (m, 1H), 4.82 (d, J = 13.2 Hz, 2H), 4.53–4.41 (m, 1H), 4.48–4.29 (m, 2H), 4.18 (s, 1H), 3.58 (d, J = 5.8 Hz, 2H), 3.47 (d, J = 5.6 Hz, 2H), 3.27 (s, 3H), 3.10–2.90 (m, 2H), 2.65 (d, J = 8.9 Hz, 3H), 1.80–1.61 (m, 4H).

[0442] 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)

[0443]

[0444] Step A

[0445] A solution of 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 K2CO3 (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 afford 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] + .

[0446] Step B

[0447] 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 portionwise with NaH (60% dispersion in oil, 200 mg, 4.99 mmol, 3.0 equiv.) at 0 °C. The mixture was stirred at 0 °C for 15 min. Then (S)-tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (593 mg, 2.5 mmol, 1.5 equiv.) was added portionwise. After stirring for 1 h at the temperature, 30 mL of water was added. The resulting solution was extracted with 3 × 50 mL of ethyl acetate. The organic layers were combined and washed with 3 × 30 ml of brine. The organic matter was 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 afford 480 mg (59% yield) of (S)-tert-butyl 1-(1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-ylcarbamate as a yellow solid. LCMS (ESI, m / z): 488.2 [M+H] + .

[0448] Step C

[0449] 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 eq) 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] + 。

[0450] Step D

[0451] 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 eq), triethylamine (157 mg, 1.56 mmol, 3.0 eq) and 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridazin-3(2H)-one (165 mg, 0.52 mmol, 1.00 eq) in EtOH (40 mL) was stirred at 60 °C for 2 h. After concentration, the crude product was applied to a silica gel column eluting 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] + 。

[0452] Step E

[0453] 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 eq) in TFA (15 mL) was treated with trifluoromethanesulfonic acid (1.50 mL). After stirring for 1 h at 0 °C, the pH of the solution was adjusted to 8 with saturated aqueous sodium bicarbonate. The resulting solution was extracted with 3 × 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 further purified by chiral preparative HPLC (column: CHIRALPAK IA, 2*25 cm, 5 μm; mobile phase A: Hex:DCM = 3:1, containing 10 mM NH3-MeOH, mobile phase B: EtOH; flow rate: 20 mL / min; 10% B for 14 min; 220 / 254 nm) to give the isolated compound. The stereochemistry was assigned based on the x-ray crystal structure of Example 10 isomer B (10B).

[0454] 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 1H NMR (400 MHz, DMSO-d6) 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), 4.18–4.11 (m, 1H), 4.10–4.04 (dt, J = 12.7, 6.8 Hz, 2H), 3.83 (dd, J = 10.0, 6.5 Hz, 1H), 3.61 (dd, J = 10.1, 4.7 Hz, 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 = 6.5 Hz, 3H). Chiral HPLC: CHIRALPAK IA-3, 4.6*50 mm, 3 μm; detected at 254 nm; mobile phase A: Hex:DCM = 3:1, containing 0.1% DEA, mobile phase B: EtOH, 15% mobile phase B; flow rate: 1 mL / min; tR = 1.472 min.

[0455] 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] + ; 1 1H NMR (400 MHz, DMSO-d6) 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, 6.5 Hz, 1H), 3.61 (dd, J = 10.1, 4.7 Hz, 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 = 6.5 Hz, 3H). Chiral HPLC: CHIRALPAK IA-3, 4.6*50 mm, 3 μm; detected at 254 nm; mobile phase A: Hex:DCM = 3:1, containing 0.1% DEA, mobile phase B: EtOH, 15% mobile phase B; flow rate: 1 mL / min; tR = 2.209 min.

[0456] 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

[0457]

[0458] 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 for 15 h. The residue was purified by a reverse-phase column eluted with H2O / CH3CN (60 / 40). The product was further purified by preparative HPLC to afford 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 (400 MHz, methanol-d4) δ 8.55 (s, 2H), 7.96 (d, J = 9.9 Hz, 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, 4.6 Hz, 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 = 6.6 Hz, 3H).

[0459] 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

[0460]

[0461] At 100 °C, a solution of 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 Et3N (65 mg, 0.637 mmol, 3.00 equiv.) in n-butyl alcohol (2 mL) was stirred for 3 days. The resulting solution was concentrated and purified by reverse-phase chromatography eluting with H2O / CH3CN (53 / 47) to give the impure desired product. The product was further purified by preparative HPLC to give 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 (300 MHz, DMSO-d6) 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), 3.90–3.78 (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 = 6.5 Hz, 3H).

[0462] 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)

[0463]

[0464] Step A

[0465] A solution of 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 K2CO3 (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 with 3 × 10 mL of ethyl acetate. The organic layer was washed with 3 × 50 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. 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] + 。

[0466] Step B

[0467] 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) at 0 °C was added portionwise NaH (60% dispersion in oil, 82 mg, 2.06 mmol, 1.0 equiv.). The resulting solution was stirred at that temperature for 15 min and then (S)-tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 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 in vacuo. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (39:61) to give 500 mg (50% yield) of ((2S)-1-((2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)carbamic acid tert-butyl ester as a yellow oil. LCMS (ES, m / z): 488.25 [M+H] + 。

[0468] Step C

[0469] 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 afford 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] + .

[0470] Step D

[0471] 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 eluting with ethyl acetate / petroleum ether (85:15) to afford 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] + .

[0472] Step E

[0473] 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 eq) in TFA (3.00 mL) was treated with trifluoromethanesulfonic acid (0.3 mL) and stirred at -10 °C for 1 h. 5 mL of ice water was added and the pH was adjusted to 8 with saturated aqueous Na2CO3. The resulting solution was extracted with 3 × 10 mL of ethyl acetate and the organics were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase chromatography to give a mixture of isomers. The mixture was further purified by chiral preparative HPLC: (CHIRALPAK IG, 2.0*25 cm, 5 um; mobile phase A: Hex:DCM = 3:1, containing 10 mM NH3-MeOH, mobile phase B: EtOH; flow rate: 16 mL / min; 50% B for 19 min; 220 / 254 nm) to give the desired isomer. The relative stereochemistry of the compound was assigned based on the PARP7 potency of the more active diastereomer and the X-ray crystal structure similar to Example 10B, similar to Example 10.

[0474] 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 as a white solid (23 mg, 27% yield). LCMS (ESI, m / z): 550.20 [M+H] + ; 1 H NMR (300 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.47 (d, J = 3.1 Hz, 2H), 7.92 (s, 1H), 6.45–6.32 (m, 1H), 4.59 (d, J = 13.6 Hz, 2H), 4.18-4.07 (m, 3H), 3.84 (dd, J = 10.0, 4.2 Hz, 1H), 3.60 (dd, J = 10.0, 6.9 Hz, 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 = 6.0 Hz, 3H). Chiral HPLC: (CHIRALPAK IG-3, 4.6*50 mm, 3 um; Hex:DCM = 3:1, containing 0.1% DEA:EtOH = 80:20; 1.0 mL / min, tR = 2.423 min.)

[0475] 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 as a white solid (45 mg, 53% yield). LCMS (ESI, m / z): 550.20 [M+H] + ; 1H NMR (300 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.47 (d, J = 3.9 Hz, 2H), 7.95 (s, 1H), 6.46–6.32 (m, 1H), 4.59 (d, J = 13.4 Hz, 2H), 4.18 - 4.07 (m, 3H), 3.83 (dd, J = 10.0, 6.6 Hz, 1H), 3.60 (dd, J = 10.0, 6.9 Hz, 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 = 6.4 Hz, 3H). Chiral HPLC: (CHIRALPAK IG-3, 4.6*50 mm, 3um; Hex:DCM = 3:1, containing 0.1% DEA:EtOH = 80:20; 1.0 mL / min, tR = 3.085 min.)

[0476] 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)

[0477]

[0478] Step A

[0479] A solution of 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 K2CO3 (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] + .

[0480] Step B

[0481] 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) at 0 °C was added NaH (60% suspension in mineral oil, 133 mg, 3.33 mmol, 3.3 equiv.) and the solution was stirred for 15 min. (S)-tert-Butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 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 in vacuo. The crude product was purified by reverse phase chromatography eluting with H2O / CH3CN (40 / 60) to give 200 mg (45% yield) of ((2S)-1-((1-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamic acid tert-butyl ester as a yellow oil. LCMS (ESI, m / z): 444.30 [M+H] + .

[0482] Step C

[0483] A solution of ((2S)-1-((1-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamic acid tert-butyl ester (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 in vacuo 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] + .

[0484] Step D

[0485] 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 in vacuo 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] + 。

[0486] Step E

[0487] 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 of the solution was adjusted to 5 - 6 with saturated aqueous Na2CO3 solution. The resulting solution was extracted with 3 × 10 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by reverse-phase chromatography eluted with H2O / CH3CN (60 / 40) to give a mixture of isomers. The product was further purified by chiral preparative HPLC with the following conditions: (CHIRALPAK IA, 2*25 cm, 5um; mobile phase A: Hex:EtOH = 1:1, containing 8 mmol / L NH3-MeOH, mobile phase B: EtOH; flow rate: 16 mL / min; 50% B: for 18 min; 220 / 254 nm), to give the separated isomers. The relative stereochemistry of the compound was assigned based on the PARP7 potency of the more active diastereomer and the X-ray crystal structure similar to Example 10B, similar to Example 10.

[0488] 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 as a white solid (11 mg, 33% yield). LCMS (ESI, m / z): 506.20 [M+H] + ; 1 1H-NMR (methanol-d4, 400 MHz) δ 8.40 (s, 1H), 7.98 (s, 1H), 7.72 (dd, J = 9.1, 2.4 Hz, 1H), 6.90 (dd, J = 9.2, 0.8 Hz, 1H), 4.64 (m, J = 13.5 Hz, 2H), 4.19 - 4.10 (m, 3H), 3.99 (dd, J = 9.8, 3.8 Hz, 1H), 3.63 (dd, J = 9.8, 6.8 Hz, 1H), 3.38 (dd, J = 9.7, 3.6 Hz, 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 = 6.6 Hz, 3H). Chiral HPLC: (CHIRALPAK IA-3, 4.6*50 mm, 3um; Hex, containing 0.1% DEA:EtOH = 50:50; flow rate: 1 mL / min; tR = 2.167 min).

[0489] 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 as a white solid (14 mg, 43% yield). LCMS (ESI, m / z): 506.20 [M+H] + ; 11H NMR (400 MHz, methanol-d4) δ 8.40 (dd, J = 2.4, 0.7 Hz, 1H), 8.00 (s, 1H), 7.72 (dd, J = 9.1, 2.4 Hz, 1H), 6.90 (dd, J = 9.2, 0.8 Hz, 1H), 4.64 (m, J = 13.5 Hz, 2H), 4.19 - 4.10 (m, 3H), 3.99 (dd, J = 9.8, 3.8 Hz, 1H), 3.63 (dd, J = 9.8, 6.8 Hz, 1H), 3.38 (dd, J = 9.7, 3.6 Hz, 1H), 3.29 – 3.21 (m, 2H), 3.10 – 2.98 (m, 2H), 2.42 – 2.29 (m, 1H), 1.92 – 1.79 (m, 1H), 1.78 – 1.65 (m, 4H), 1.30 (d, J = 6.6 Hz, 3H). Chiral HPLC: (CHIRALPAK IA-3, 4.6 * 50 mm, 3 um; Hex, containing 0.1% DEA:EtOH = 50:50; flow rate: 1 mL / min; tR = 3.159 min).

[0490] 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)

[0491]

[0492] Step A

[0493] A solution of 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 K2CO3 (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 applied to a reverse-phase column eluted with H2O / CH3CN (1:1) to afford 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]+ .

[0494] Step B

[0495] 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 the mixture was stirred for 10 min. To the solution was added tert-butyl (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 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. Then the reaction was quenched by adding 0.2 mL of 20% aqueous sodium carbonate solution. The solution was concentrated and the crude product was applied to a reverse-phase column eluted with H2O / CH3OH (40 / 60) to give 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] + .

[0496] Step C

[0497] 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] + .

[0498] Step D

[0499] 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(2H)-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 and diluted with 100 mL of ethyl acetate and washed with 2×20 mL of saturated aqueous ammonium chloride. The aqueous layers were combined and extracted with 2×50 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] + 。

[0500] Step E

[0501] 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 H2O. The pH of the solution was adjusted to 7 - 8 with 20% aqueous sodium carbonate. The resulting solution was extracted with 2×20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by reverse phase chromatography eluted with H2O / CH3CN. The product was further purified by chiral preparative HPLC (CHIRAL ART Cellulose-SB, 2*25 cm, 5um; mobile phase A: Hex, containing 8 mmol / L NH3-MeOH, mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 50% B for 16 min; 220 / 254 nm). The relative stereochemistry of the compound was assigned based on the PARP7 potency of the more active diastereomer and the X-ray crystal structure similar to Example 10B, similar to Example 10.

[0502] 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 (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.54 (s, 2H), 7.91 (s, 1H), 6.96 (t, J = 55.5 Hz, 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, 4.3 Hz, 1H), 3.59 (dd, J = 10.1, 7.0 Hz, 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 = 6.5 Hz, 3H). Chiral HPLC: CHIRAL Cellulose-SB, 0.46*10 cm, 3 um; Hex, containing 0.1% DEA:EtOH = 50:50; flow rate: 1.0 mL / min; rT = 2.642 min.

[0503] 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] + ; 11H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.54 (s, 2H), 7.94 (s, 1H), 6.96 (t, J = 55.5 Hz, 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, 4.3 Hz, 1H), 3.59 (dd, J = 10.1, 7.0 Hz, 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 = 6.5 Hz, 3H). Chiral HPLC: Chiral Cellulose-SB, 0.46 * 10 cm, 3 um; Hex, containing 0.1% DEA:EtOH = 50:50; flow rate: 1.0 mL / min; rT = 4.415 min.

[0504] 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

[0505]

[0506] Step A

[0507] A solution of (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (3.47 g, 21.941 mmol, 1.00 equivalent), tert-butyl 4-aminopiperidine-1-carboxylate (6.40 g, 31.955 mmol, 1.46 equivalents), and acetic acid (2.64 g, 43.962 mmol, 2.00 equivalents) in DCM (200 mL) was stirred for 15 minutes. NaBH(AcO)3 (14.00 g, 66.042 mmol, 3.01 equivalents) was added and the solution was stirred for an additional 2 hours at room temperature. 300 mL of saturated aqueous NaHCO3 was added. The layers were separated and the aqueous layer was extracted with 3 × 200 mL of dichloromethane. 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 (75 / 25) to afford 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] + 。

[0508] Step B

[0509] A solution of tert-butyl (R)-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] + 。

[0510] Step C

[0511] A solution of (R)-3-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (700 mg, 3.172 mmol, 1.00 equiv), K2CO3 (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 with 3 × 20 mL of dichloromethane. 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 eluting 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 pale yellow solid. LCMS (ESI, m / z): 297.05 [M+H] + 。

[0512] Step D

[0513] 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 portionwise NaH (60% dispersion in mineral oil, 236 mg, 5.901 mmol, 5 equiv) at 0 °C. (S)-tert-Butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (420 mg, 1.770 mmol, 1.50 equiv) was added to the solution. The resulting solution was warmed to room temperature. 0.5 mL of water was added and the solvent was removed in vacuo. The crude product was purified by reverse phase chromatography eluting with H2O / CH3OH (7 / 3) to afford 490 mg (82% yield) of ((S)-1-(((R)-1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamic acid tert-butyl ester as a pale yellow solid. LCMS (ESI, m / z): 454.15 [M+H] + 。

[0514] Step E

[0515] A solution of ((S)-1-(((R)-1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamic acid tert-butyl ester (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 h. The resulting mixture was concentrated to afford 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 pale yellow solid. LCMS (ESI, m / z): 354.15 [M+H] + 。

[0516] Step F

[0517] 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(2H)-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 washed with 2 × 20 mL of saturated aqueous NH4Cl. The layers were separated and the aqueous layer was extracted with 2 × 50 mL of ethyl acetate. The combined organic layers were 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 afford 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] + 。

[0518] Step G

[0519] 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 of the solution was adjusted to 7 - 8 with 20% aqueous sodium bicarbonate. The solution was extracted with 3 × 20 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by reverse phase chromatography eluted with H2O / CH3CN to afford 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] + ; 11H NMR (400 MHz, DMSO-d6) 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, 6.6 Hz, 1H), 3.61 (dd, J = 10.0, 4.7 Hz, 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 = 6.5 Hz, 3H).

[0520] 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)

[0521]

[0522] Step A

[0523] 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 and then (S)-tert-butyl 4-(methoxymethyl)-1,2,3-oxathiazolidine-3-carboxylate 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 ((2S)-1-((1-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)-3-methoxypropan-2-yl)carbamic acid tert-butyl ester as a yellow solid. LCMS (ESI, m / z): 474.25 [M+H] + .

[0524] Step B

[0525] 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 in vacuo to afford 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] + 。

[0526] Step C

[0527] 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 in an oil bath at 70 °C for 4 h. The mixture was concentrated in vacuo and the crude product was applied to a silica gel column eluting with ethyl acetate / petroleum ether (10:1) to afford 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] + 。

[0528] Step D

[0529] 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) and stirred at the same temperature for 30 min. 10 mL of ice water was added and the pH of the solution was adjusted to 8 with 40% aqueous sodium hydroxide. The resulting solution was extracted with 3 × 20 mL of ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse-phase chromatography eluting with water / ACN (60 / 40) to give a mixture of isomers. The diastereoisomers were separated by chiral preparative HPLC with the following conditions: CHIRALPAK IF, 2*25 cm, 5 µm; mobile phase A: Hex, containing 8 mM NH3-MeOH, mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 50% B for 22 min; 220 / 254 nm.) The relative stereochemistry of the compound was assigned based on the PARP7 potency of the more active diastereoisomer and the X-ray crystal structure similar to Example 10B, similar to Example 10.

[0530] 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] + ; 11H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.47 (s, 1H), 7.93 (s, 1H), 7.83 (d, J = 9.1 Hz, 1H), 6.96 (d, J = 9.2 Hz, 1H), 6.33–6.28 (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 = 5.7 Hz, 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 * 50 mm, 3 μm; Hex, containing 0.1% DEA:EtOH = 50:50; flow rate: 1 mL / min; rT = 2.405 min.

[0531] 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 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 8.47 (s, 1H), 7.96 (s, 1H), 7.83 (d, J = 9.1 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 6.33–6.28 (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 = 5.3 Hz, 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 * 50 mm, 3 μm; Hex, containing 0.1% DEA:EtOH = 50:50; flow rate: 1 mL / min; rT = 3.678 min.

[0532] 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 appropriate structural units and modified reaction conditions (e.g., reagent ratios, temperature, coupling conditions, and reaction time) as needed. The relative stereochemistry of the compounds was assigned based on the PARP7 potency of the more active diastereoisomer and the X-ray crystal structure, similar to Example 10.

[0533]

[0534] 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)

[0535]

[0536] Step A

[0537] 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 for 15 minutes at said temperature, a solution of tert-butyl (S)-4-(methoxymethyl)-1,2,3-oxathiazolidine-3-carboxylate 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 with 3 × 50 mL of EtOAc. The organic layers were combined, washed with 50 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was applied to a silica gel column eluting with EtOAc / petroleum ether (11:9) to afford 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] +

[0538] Step B

[0539] 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 C18 reverse phase chromatography eluting with H2O / CH3CN (1:1) to afford 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] + 。

[0540] Step C

[0541] Dissolve 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) in CH3CN (4 mL). Stir the solution at 60 °C for 1 h. Dilute the solution with 50 ml of water and extract with 3 × 50 mL of EtOAc. Combine the organic layers, wash with 50 mL of brine, dry over anhydrous sodium sulfate, and concentrate in vacuo. Apply the residue 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] +

[0542] Step D

[0543] Stir 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) at room temperature for 1 h. Dilute the residue with 20 ml of water and adjust the pH to 7 - 8 with saturated aqueous Na2CO3. Extract the resulting solution with 3 × 20 mL of EtOAc. Combine the organic layers, wash with 20 mL of brine, dry over anhydrous sodium sulfate, and concentrate in vacuo. Purify the crude product by a C18 reverse-phase column eluted with H2O / CH3CN (16:29). Further purify the product by chiral preparative HPLC (CHIRALPAK IA, 2*25 cm, 5um; mobile phase A: Hex(8 mmol / L NH3-MeOH), mobile phase B: EtOH; flow rate: 18 mL / min; 50% B for 20 min; 220 / 254 nm). Assign the relative stereochemistry of the compound based on the PARP7 potency of the more active diastereomer and the X-ray crystal structure similar to Example 10B, similar to Example 10.

[0544] 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 (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.69 (s, 2H), 7.93 (s, 1H), 6.37 - 6.30 (m, 1H), 4.88 - 4.74 (m, 2H), 4.35 - 4.24 (m, 1H), 4.14–4.03 (m, 2H), 3.90 (dd, J = 10.0 Hz, 3.6 Hz, 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*50 mm, 3 μm; Hex:EtOH = 50:50; Flow rate = 1.3 mL / min; rT = 1.33 min.

[0545] 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] + 。 11H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.69 (s, 2H), 7.96 (s, 1H), 6.32–6.24 (m, 1H), 4.86 - 4.77 (m, 2H), 4.35 - 4.24 (m, 1H), 4.15–4.00 (m, 2H), 3.90 (dd, J=10.0 Hz, 3.6 Hz, 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*50 mm, 3 μm; Hex:EtOH = 50:50; flow rate = 1.3 mL / min; rT = 2.91 min

[0546] 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)

[0547]

[0548] Step A

[0549] 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-toluenesulfonyl 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 with 3 × 50 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 500 mg (68% yield) of 2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl 4-toluenesulfonate as a brown solid. LCMS (ESI, m / z): 485.20 [M+H] + .

[0550] Step B

[0551] 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) and stirred at that temperature for 15 minutes. 4-Toluenesulfonic acid 2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl ester (400 mg, 0.83 mmol, 1.00 equiv) was added and the solution was stirred at room temperature for 2 hours. 20 mL of saturated aqueous NH4Cl and ethyl acetate were added. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with 5 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo 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 used without further purification. LCMS (ESI, m / z): 473.0 [M+H] + 。

[0552] Step C

[0553] 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 hour. The resulting mixture was concentrated and the residue was applied to a reverse-phase column eluting with H2O / CH3CN (1:2) to give 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] + 。

[0554] Step D

[0555] 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 washed with 50 mL of H2O and 50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The crude product was applied to a silica gel column eluted with EtOAc / petroleum ether (7 / 3) to afford 70 mg (66% yield) 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 as a colorless oil. LCMS (ESI, m / z): 671.20 [M+H] + .

[0556] Step E

[0557] 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 adjusted to pH 7 - 8 with saturated aqueous Na2CO3. After concentration, the crude product was purified by C18 reverse-phase chromatography eluted with H2O / CH3CN (52:48). The product was further purified by chiral-preparative HPLC under the following conditions: (CHIRALPAK IA, 2*25 cm, 5 μm; mobile phase A: Hex, containing 8 mM NH3-MeOH, mobile phase B: EtOH; flow rate: 20 mL / min; 50% B for 15 min; 220 / 254 nm.) The relative stereochemistry of the compound was assigned based on the PARP7 potency of the more active diastereomer and the X-ray crystal structure similar to Example 10, similar to Example 10A.

[0558] 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 1H NMR (400 MHz, DMSO-d6) 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 = 6.2 Hz, 3H). Chiral HPLC: CHIRALPAK IA-3, 4.6*50 mm, 3 μm; Hex, containing 0.1% DEA:EtOH = 50:50; flow rate = 1.0 mL / min; rT = 1.981 min.

[0559] 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 (400 MHz, DMSO-d6) 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 = 6.2 Hz, 3H). Chiral HPLC: CHIRALPAK IA-3, 4.6*50 mm, 3 μm; Hex, containing 0.1% DEA:EtOH = 50:50; flow rate = 1.0 mL / min; rT = 2.695 min.

[0560] The compounds of Examples 21 - 33B were synthesized analogously to the compounds described in Examples 1 - 20.

[0561]

[0562]

[0563]

[0564]

[0565] *Based on the PARP7 potency of the more active diastereoisomer and analogous to the X - ray crystal structure of Example 10B, the stereochemistry of the compound was assigned analogously to Example 10.

[0566] ± The stereochemistry of the compound was optionally assigned.

[0567] Intermediate I - 7: Synthesis of 3 - hydroxy - [1,4'-bipiperidin]-2 - one hydrochloride

[0568]

[0569] Step A

[0570] To 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 K2CO3 (2.08 g, 15.0 mmol, 1.5 equiv) and 5 - bromovaleryl chloride (2.00 g, 10.0 mmol, 1.0 equiv). The reaction mixture was stirred for 1 h and diluted with water (20 mL) and extracted with 3×20 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 - bromovaleramide as a white solid. LCMS (ESI, m / z): 355.00 [M + H] + .

[0571] Step B

[0572] To a solution of N-(1-benzylpiperidin-4-yl)-5-bromopentanamide (3.40 g, 9.60 mmol, 1.0 eq) in THF (20 mL) was added t-BuOK (1.62 g, 14.4 mmol, 1.5 eq). The reaction mixture was stirred for 1 h and then quenched by the addition of water (20 mL). The resulting solution was extracted with 3×50 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] + .

[0573] Step C

[0574] To a solution of 1'-benzyl-[1,4'-bipiperidin]-2-one (2.00 g, 7.30 mmol, 1.0 eq) in DCM (20 mL) at 0 °C was added TEMPO (2.50 g, 16.0 mmol, 2.2 eq), molecular sieves (2 g) and Tf2O (2.28 g, 8.08 mmol, 1.1 eq). The resulting solution was stirred for 2 h and then diluted with water (20 mL). The solution was extracted with 3×50 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 eluting 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] + .

[0575] Step D

[0576] 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 and 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 with 3 × 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] + 。

[0577] Step E

[0578] To a solution of 1'-benzyl-3-hydroxy-[1,4'-bipiperidin]-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 solid was filtered off and the filtrate was concentrated in vacuo to give 380 mg (92% yield) of tert-butyl 3-hydroxy-2-oxo-[1,4'-bipiperidin]-1'-carboxylate as a colorless oil. LCMS (ESI, m / z): 299.15 [M+H] + 。

[0579] Step F

[0580] A solution of tert-butyl 3-hydroxy-2-oxo-[1,4'-bipiperidin]-1'-carboxylate (370 mg, 1.24 mmol, 1.0 equiv) in 4M 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'-bipiperidin]-2-one hydrochloride as a colorless oil. LCMS (ESI, m / z): 199.00 [M+H] + 。

[0581] Intermediate I-8: Synthesis of 3-hydroxy-4,4-dimethyl-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride

[0582]

[0583] Step A

[0584] To a solution of 1-benzylpiperidin-4-amine (1.90 g, 9.99 mmol, 1.0 eq) in 1-methoxy-2-(2-methoxyethoxy)ethane (1 mL) was added TsOH (0.28 g, 1.6 mmol, 0.2 eq) and 3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (1.56 g, 12.0 mmol, 1.2 eq). 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 afford 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] + 。

[0585] Step B

[0586] To a solution of 1-(1-benzylpiperidin-4-yl)-3-hydroxy-4,4-dimethylpyrrolidin-2-one (837 mg, 2.77 mmol, 1.0 eq) in EtOH (20 mL) was added Pd / C (80 mg, 0.75 mmol, 0.3 eq) and di-tert-butyl dicarbonate (1.2 g, 5.5 mmol, 1.2 eq). The resulting solution was stirred under a 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 afford 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] +

[0587] Step C

[0588] 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 eq) in dioxane (5 mL) was added 4 M HCl in 1,4-dioxane (5 mL). The resulting solution was stirred for 2 h and then concentrated in vacuo to afford 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] + 。

[0589] Synthesis of Intermediate I-9: (S)-3-Hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one Hydrochloride

[0590]

[0591] Step A

[0592] 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) at 0 °C 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). The resulting solution was stirred at 0 °C for 10 min and then at room temperature for 10 h. The solid was filtered off 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)-ethyl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)thioacetate as a colorless oil.

[0593] Step B

[0594] To a solution of (S)-ethyl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)thioacetate (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 off and the filtrate was concentrated in vacuo. The crude product was cooled and the separated 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.

[0595] Step C

[0596] 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, then STAB (19.7 g, 93.0 mmol, 3.0 equiv) was added and the reaction mixture was stirred for an additional 3 h. Saturated aqueous NaHCO3 was added and the aqueous layer was extracted with 2 × 50 mL DCM. The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate / petroleum ether (30 / 70) to afford 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] + 。

[0597] Step D

[0598] 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 afford 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] + 。

[0599] Intermediate I-11: Synthesis of (R)-1-((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)-3-hydroxypyrrolidin-2-one hydrochloride

[0600]

[0601] Step A

[0602] To a solution of tert-butyl (1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.00 g, 10.1 mmol, 1.0 eq) 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 eq) and AcOH (0.20 g, 3.33 mmol, 0.3 eq). The reaction mixture was stirred for 1 h, then STAB (4.10 g, 19.4 mmol, 1.9 eq) was added and the reaction was stirred for an additional 1.5 h. The solution was washed with 2 × 50 mL aqueous NaHCO3 and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was applied to a silica gel column eluting with ethyl acetate / MeOH (4 / 1) to afford 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] + 。

[0603] Step B

[0604] 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 eq) in 4 M HCl in dioxane (5 mL) was stirred for 1 h. The mixture was concentrated to afford 400 mg of (R)-1-((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)-3-hydroxypyrrolidin-2-one hydrochloride as a yellow solid (crude). LCMS (ES, m / z): 183.20 [M+H] + 。

[0605] 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

[0606]

[0607] Step A

[0608] 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-toluenesulfonic acid (1.37 g, 7.94 mmol, 0.2 equiv). The resulting solution was stirred at 180 °C for 16 h and then diluted with 6 mL of ethyl acetate and applied to a silica gel column eluting 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] + .

[0609] Step B

[0610] To 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) at 0 °C under a nitrogen atmosphere was added molecular sieves (2 g), TEMPO (3.91 g, 25.0 mmol, 2.2 equiv) and Tf2O (6.42 g, 22.8 mmol, 2.0 equiv). The resulting solution was stirred for 30 min and then stirred at room temperature for an additional 2 h. The solid was filtered off, then the filtrate was concentrated and applied to a silica gel column eluting 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]+.

[0611] Step C

[0612] To a mixture 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 (1.30 g, 3.04 mmol, 1.0 equiv) in 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 with 3 × 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 eluting with dichloromethane / methanol (93 / 7) to afford 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] + 。

[0613] Step D

[0614] 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 solid was filtered off and the filtrate was concentrated to afford 226 mg 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 as a yellow oil. LCMS (ESI, m / z): 299.05 [M+H] + 。

[0615] Step E

[0616] The 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 a solution of HCl / dioxane (10 mL, 4 M) 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] + 。

[0617] 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

[0618]

[0619] Step A

[0620] 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, then STAB (2.90 g, 0.01 mmol, 3.0 equiv) was added, and the reaction mixture was stirred for an additional 3 h. The reaction was quenched by the addition of saturated aqueous NaHCO3. The aqueous layer was extracted with 2 × 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 (3R,4R)-3-fluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate and (3S,4S)-3-fluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate as an off-white oil.

[0621] Step B

[0622] To a solution 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 (700 mg, 2.32 mmol, 1.0 eq) in DCM (5 mL) was added TFA (0.5 mL). The resulting solution was stirred for 1 h 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.

[0623] 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

[0624]

[0625] Step A

[0626] 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 eq) in DCM (20 mL) was added AcOH (550 mg, 9.16 mmol, 2.0 eq) 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 eq). The resulting solution was stirred for 0.5 h, then STAB (2.91 g, 13.74 mmol, 3.0 eq) was added, and the reaction was stirred for an additional 3 h. The reaction was then quenched by the addition of 20 mL of aqueous NaHCO3. The resulting solution was extracted with 3 × 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 eluting 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] + 。

[0627] Step B

[0628] A solution 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 (660 mg, 2.18 mmol, 1.0 equiv) in HCl / dioxane (15 mL, 4 M) was stirred for 15 h. The resulting mixture was concentrated to afford 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] + 。

[0629] 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

[0630]

[0631] Step A

[0632] 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 eluting with DCM / MeOH (9 / 1) to afford 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] + 。

[0633] Step B

[0634] 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 afford 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] + 。

[0635] Intermediate I-16: Synthesis of (1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)-L-alanine

[0636]

[0637] To 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 added L-alanine (725 mg, 8.14 mmol, 1.3 equiv) and K2CO3 (2.60 g, 18.8 mmol, 3.0 equiv). The resulting solution was stirred at 60 °C for 2 h and then quenched by the addition of 100 mL of water. The pH was adjusted to 2-3 with 1 N HCl. The solution was extracted with 3 × 150 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a reverse-phase column eluting with water / CH3CN (1 / 1) to afford 1.4 g (60% yield) of (1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)-L-alanine as a pale yellow solid. LCMS (ES, m / z): 372.11 [M+H] + 。

[0638] Examples 34 - 37

[0639] Examples 34 - 37 are prepared according to the procedures 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 - yl)amino)-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 - yl)amino)-4-(trifluoromethyl)pyridazin - 3(2H)-one (see Example 10), using appropriate building blocks and modified reaction conditions (e.g., reagent ratios, temperature, coupling conditions, and reaction time) as needed for synthesis. The relative stereochemistry of the compounds is assigned based on the PARP7 potency of the more active diastereoisomer and the X - ray crystal structure, similar to Example 10.

[0640]

[0641]

[0642]

[0643] Examples 38 - 40

[0644] Examples 38 - 40 are prepared according to the procedures 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 - yl)amino)-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 - yl)amino)-4-(trifluoromethyl)pyridazin - 3(2H)-one (see Example 10), using appropriate building blocks and modified reaction conditions (e.g., reagent ratios, temperature, coupling conditions, and reaction time) as needed for synthesis. The absolute stereochemistry of the substituted piperidine moiety is arbitrarily assigned.

[0645]

[0646]

[0647]

[0648] Examples 41 - 45

[0649] Examples 41 - 45 were synthesized according to the procedures 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 appropriate structural units and modified reaction conditions (e.g., reagent ratios, temperature, coupling conditions, and reaction time) as needed.

[0650]

[0651]

[0652]

[0653] Examples 46 - 49

[0654] 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 appropriate structural units and modified reaction conditions (e.g., reagent ratios, temperature, coupling conditions, and reaction time) as needed. The relative stereochemistry of the compounds was assigned by analogy to Example 10, based on the PARP7 potency of the more active diastereoisomer and by analogy to the X - ray crystal structure of Example 10B.

[0655]

[0656]

[0657]

[0658] 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

[0659] Step A

[0660] To 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 added 6-chloronicotinonitrile (1.26 g, 9.09 mmol, 1.0 equiv) and K2CO3 (2.50 g, 18.1 mmol, 2.0 equiv). 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 with 2 × 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 afford 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] + 。

[0661] Step B

[0662] 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) at 0 °C was added NaH (334 mg, 8.35 mmol, 4.0 equiv, 60% dispersion in mineral oil). The solution was stirred at 0 °C for 10 min and then (S)-oxirane-2-ylmethyl 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 purified by reverse phase chromatography eluted with water / CH3CN (45 / 55) to afford 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] + 。

[0663] Step C

[0664] 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 afford 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] + .

[0665] Step D

[0666] 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 1.2 ml of TFA and trifluoromethanesulfonic acid (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 ~7 - 8 with saturated aqueous Na2CO3. The resulting solution was extracted with 3 x 50 mL of DCM. The organic layers were combined and concentrated in vacuo. The crude product was purified by reverse phase chromatography and the mixture of isomers was separated by chiral preparative HPLC: CHIRALPAK IA, 2*25 cm, 5 μm; mobile phase A: MTBE (10 mM NH3 - MEOH), mobile phase B: EtOH; flow rate: 16 mL / min; gradient: 30% B for 15 min; 220 / 254 nm to afford the separated compound. The relative stereochemistry of the compound was assigned by analogy to Example 10 based on the PARP7 potency of the more active diastereomer and the X-ray crystal structure of Example 10B.

[0667] 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 1H NMR (300 MHz, DMSO-d6) δ 13.21 (s, 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.27 (s, 1H), 7.80 (dd, J = 9.1, 2.4 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H), 5.21 (br, 1H), 4.52 (d, J = 13.4 Hz, 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 (faster peak).

[0668] 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] + , 11H NMR (300 MHz, DMSO-d6) δ 13.21 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.29 (s, 1H), 7.80 (dd, J = 9.1, 2.4 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H), 5.21 (br, 1H), 4.52 (d, J = 13.3 Hz, 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).

[0669] Examples 51 - 52

[0670] Examples 51 - 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 appropriate structural units and modified reaction conditions (e.g., reagent ratios, temperature, coupling conditions, and reaction time) as needed. The relative stereochemistry of the compounds was assigned by analogy to Example 10, based on the PARP7 potency of the more active diastereoisomer and similar to the X-ray crystal structure of Example 10B.

[0671]

[0672]

[0673] Examples 53 and 54

[0674] Examples 53 and 54 were prepared 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 appropriate building blocks and modified reaction conditions (e.g., reagent ratios, temperature, coupling conditions, and reaction times) as needed for the synthesis.

[0675]

[0676]

[0677] 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

[0678]

[0679] Step A

[0680] 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) at 0 °C was added NaH (60 mg, 1.50 mmol, 2.01 equiv, 60% dispersion in mineral oil). The mixture was stirred at 0 °C for 10 min and then 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 quenched with saturated aqueous NH4Cl (0.5 mL), and the resulting mixture was concentrated. The crude product was purified by reverse-phase column eluting with water / CH3CN (65 / 45) to give 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] + 。

[0681] Step B

[0682] 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 1:5 TfOH / TFA (1.5 mL) 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 with 3 × 50 mL DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by reverse-phase chromatography eluting with water / CH3CN, and the mixture of isomers was separated by chiral preparative HPLC: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: MTBE (10 mM NH3 - MEOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 20% B for 15 min; 220 / 254 nm. The relative stereochemistry of the compound was assigned based on the PARP7 potency of the more active diastereomer and the X-ray crystal structure similar to Example 10B, similar to Example 10.

[0683] 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 (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.47 (s, 1H), 8.11 (s, 1H), 7.83 (d, J = 9.1 Hz, 1H), 6.96 (d, J = 9.1 Hz, 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 ARTCellulose-SB, 4.6*100 mm, 3 um; Mobile phase: MtBE (0.1% diethylamine):EtOH = 80:20; Flow rate: 1 mL / min. Retention time: 3.928 min (faster peak).

[0684] Example 55 Isomer B (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 (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.47 (s, 1H), 8.13 (s, 1H), 7.85 (d, J = 9.2 Hz, 1H), 6.96 (d, J = 9.2 Hz, 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 ARTCellulose - SB, 4.6 * 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).

[0685] Example 56

[0686] 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 appropriate structural units and modified reaction conditions (e.g., reagent ratios, temperature, coupling conditions, and reaction time) as needed. The relative stereochemistry of the compound was assigned based on the PARP7 potency of the more active diastereoisomer and the X-ray crystal structure similar to Example 10B, similar to Example 10.

[0687]

[0688]

[0689] 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

[0690]

[0691] Step A

[0692] To 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 2-chloro-5-(trifluoromethyl)pyrimidine (825 mg, 4.52 mmol, 1.0 equiv) and K2CO3 (940 mg, 6.80 mmol, 1.5 equiv). 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] + 。

[0693] Step B

[0694] 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] + 。

[0695] Step C

[0696] To a solution of (3R,4R)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol hydrochloride (980 mg, 3.74 mmol, 1.0 equiv) in CH3CN (30 mL) was added imidazole (1.27 g, 18.7 mmol, 5.0 equiv) and tert-butyldimethylsilyl chloride (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] + 。

[0697] Step D

[0698] 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. The reaction was quenched by addition of saturated aqueous NaHCO3. The aqueous layer was extracted with 2 × 50 mL of DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluting with ethyl acetate / petroleum ether (35 / 65) to afford 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] + 。

[0699] Step E

[0700] 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) at 0 °C was added NaH (117 mg, 2.93 mmol, 2.01 equiv, 60% dispersion in mineral oil). The resulting solution was stirred for 10 min, then (S)-tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 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. The reaction was then quenched by addition of saturated aqueous NH4Cl. The solution was extracted with 2 × 50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product was applied to a silica gel column eluting with ethyl acetate / petroleum ether (3 / 2) to afford 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] + 。

[0701] Step F

[0702] 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 4 N HCl (20 mL) in 1,4-dioxane was stirred for 15 h. The resulting mixture was concentrated to afford 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 used without further purification. (ESI, m / z): 404.15 [M+H] + 。

[0703] Step G

[0704] 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. Upon completion, the crude product was applied to a reverse-phase column eluting with water / CH3CN (45 / 55) to afford 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] + 。

[0705] Step H

[0706] 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 eq) 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 ~7 - 8 with saturated aqueous Na2CO3. The resulting solution was extracted with 2 × 50 mL DCM. The organic layers were combined and concentrated. The crude product was purified by reverse-phase chromatography eluting with water / CH3CN (45 / 55) to afford 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 (300 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.69 (d, J = 0.9 Hz, 2H), 7.94 (s, 1H), 6.39 - 6.29 (m, 1H), 5.28 (d, J = 5.3 Hz, 1H), 4.91 - 4.80 (m, 1H), 4.72 (d, J = 13.4 Hz, 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 = 6.4 Hz, 3H).

[0707] 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

[0708]

[0709] Step A

[0710] To 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 added K2CO3 (0.96 g, 6.95 mmol, 1.5 equiv) and 2-chloro-5-(trifluoromethyl)pyrimidine (0.85 g, 4.66 mmol, 1.0 equiv). The resulting solution was stirred at 50 °C for 1 h. The reaction mixture was quenched by addition of 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] + 。

[0711] Step B

[0712] 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] + 。

[0713] Step C

[0714] To a solution of (3S,4S)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol hydrochloride (1.19 g, 3.98 mmol, 1.0 equiv) in CH3CN (40 mL) 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 eluting 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] +

[0715] Step D

[0716] 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 eq) 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 eq) and AcOH (446 mg, 7.44 mmol, 2.0 eq). After stirring for 15 min, STAB (2.36 g, 11.2 mmol, 3.0 eq) was added and the solution was stirred for an additional 5 h. The reaction was quenched by addition of 20 mL of saturated aqueous NaHCO3 and extracted with 3 × 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 eluting with ethyl acetate / petroleum ether (3 / 2) to afford 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] + 。

[0717] Step E

[0718] 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 eq) in DMF (5 mL) at 0 °C was added NaH (121 mg, 3.03 mmol, 3.0 eq, 60%). The reaction mixture was stirred for 10 min and then a solution of tert-butyl (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (287 mg, 1.21 mmol, 1.2 eq) in DMF (2 mL) was added. The resulting solution was stirred at 0 °C for 2 h. The reaction was quenched by addition of water (10 mL). The resulting solution was extracted with 2 × 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 eluting with ethyl acetate / petroleum ether (3 / 2) to afford 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] + 。

[0719] Step F

[0720] 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 eq) in 4 M HCl (10 mL, 4 M) in 1,4-dioxane was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo to afford 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] + 。

[0721] Step G

[0722] 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 eq) in EtOH (8 mL) was added 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (293 mg, 0.92 mmol, 1.5 eq) and triethylamine (621 mg, 6.14 mmol, 10.0 eq). 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 afford 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] + 。

[0723] Step H

[0724] 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 = 1:10 (3 mL) 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 with 3 × 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by reverse-phase chromatography eluting with water / CH3CN (1 / 1) to give 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 (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.70 (s, 2H), 7.95 (s, 1H), 6.35 - 6.34 (m, 1H), 5.26 (d, J = 5.0 Hz, 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 = 6.4 Hz, 3H).

[0725] 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

[0726]

[0727] Step A

[0728] To 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 2-chloro-5-(trifluoromethyl)pyrimidine (1.68 g, 9.2 mmol, 1.00 equiv) and K2CO3 (2.56 g, 18.5 mmol, 2.0 equiv). 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] + 。

[0729] Step B

[0730] 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 4M 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] + 。

[0731] Step C

[0732] To a solution of (3S,4R)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol hydrochloride (2.60 g, 9.92 mmol, 1.0 equiv) in CH3CN (20 mL) 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 eluting with chloroform / methanol (9 / 1) to afford 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] + 。

[0733] Step D

[0734] 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 and then STAB (14.0 g, 66.0 mmol, 3.0 equiv) was added. After 2 h, the reaction was quenched by addition of 20 mL of saturated aqueous NaHCO3. The solution was extracted with 3 × 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 eluting with ethyl acetate / petroleum ether (3 / 1) to afford 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] + 。

[0735] Step E

[0736] 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 slowly added NaH (239 mg, 5.99 mmol, 3.0 equiv, 60% dispersion in mineral oil) over a 10 min period at 0 °C. Then (S)-tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 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 addition of water (10 mL) and extracted with 2 × 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 eluting with ethyl acetate / petroleum ether (3 / 2) to afford 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] + 。

[0737] Step F

[0738] 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 4 M HCl (10 mL) in dioxane was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to afford 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] + 。

[0739] Step G

[0740] 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 h and then concentrated in vacuo. The crude product was applied to a silica gel column eluting with ethyl acetate / petroleum ether (10 / 1) to afford 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] + 。

[0741] Step H

[0742] 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 eq) 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 with 3 × 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by reverse-phase chromatography eluting with water / CH3CN (3 / 2) to give 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 (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.65 (s, 2H), 7.96 (s, 1H), 6.38 (br, 1H), 5.06 (d, J = 5.1 Hz, 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 = 12.6 Hz, 1H), 2.29–2.18 (m, 1H), 2.12–1.99 (m, 1H), 1.83–1.69 (m, 1H), 1.53 (d, J = 12.3 Hz, 1H), 1.18 (d, J = 6.4 Hz, 3H).

[0743] 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

[0744]

[0745] Step A

[0746] To 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 added K2CO3 (980 mg, 7.2 mmol, 1.5 equiv) and 2-chloro-5-(trifluoromethyl)pyrimidine (863 mg, 4.73 mmol, 1.0 equiv). 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] + 。

[0747] Step B

[0748] 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 used without further purification. LCMS (ESI, m / z): 263.10 [M+H] + 。

[0749] Step C

[0750] To a solution of (3R,4S)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol hydrochloride (1.43 g, 4.26 mmol, 1.0 equiv) in CH3CN (30 mL) was added imidazole (2.20 g, 32.3 mmol, 7.6 equiv) and tert-butyldimethylsilyl chloride (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] + 。

[0751] Step D

[0752] 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, then 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 with 3 × 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 eluting with ethyl acetate / petroleum ether (2 / 1) to afford 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] + .

[0753] Step E

[0754] At 0 °C, NaH (437 mg, 11.0 mmol, 4.5 equiv., 60% dispersion in mineral oil) was added 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). The resulting solution was stirred for 30 min and then a solution of tert-butyl (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 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 addition of ice water (10 mL). The pH was adjusted to ~6 - 7 with 2N HCl. The resulting solution was extracted with 3 × 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 eluting with ethyl acetate / petroleum ether (1 / 2) to afford 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 pale yellow solid. LCMS (ESI, m / z): 618.35 [M+H] + 。

[0755] Step F

[0756] 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 afford 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 used without further purification. LCMS (ESI, m / z): 404.20 [M+H] + 。

[0757] Step G

[0758] To a solution of (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) in CH3CN (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 with 2 × 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 reverse-phase column eluting with water / CH3CN (1 / 3) to afford 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] + 。

[0759] Step H

[0760] 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 7 with saturated aqueous NaHCO3. The resulting solution was extracted with 3 × 30 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by reverse-phase chromatography eluting with water / CH3CN (2 / 1) to afford 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 pale green solid. LCMS (ESI, m / z): 566.15 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.65 (s, 2H), 7.95 (s, 1H), 6.39–6.27 (m, 1H), 5.02 (d, J = 5.1 Hz, 1H), 4.89–4.75 (m, 2H), 4.22–4.15 (m, 1H), 4.11 (t, J = 7.6 Hz, 1H), 4.08–3.96 (m, 1H), 3.91 (br, 1H), 3.83 (dd, J = 10.0, 6.5 Hz, 1H), 3.61 (dd, J = 10.0, 4.7 Hz, 1H), 3.44–3.36 (m, 1H), 3.35–3.26 (m, 1H), 3.13 (d, J = 13.5 Hz, 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 = 6.5 Hz, 3H).

[0761] 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.

[0762]

[0763] Step A

[0764] To a solution of (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylthio)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 and then quenched by addition of water (20 mL) and extracted with 3 × 20 mL of ethyl acetate. The combined organic layers were 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 afford 3.9 g (77% yield) of (R)-(4-(methylthio)-1-oxo-1-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)amino)butan-2-yl)carbamic acid tert-butyl ester. LCMS (ESI, m / z): 478.20 [M+H] + .

[0765] Step B

[0766] To a solution of tert-butyl (R)-(4-(methylthio)-1-oxo-1-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)amino)butan-2-yl)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 overnight at 30 °C and then concentrated in vacuo to afford 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] + 。

[0767] Step C

[0768] 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 overnight at 30 °C and then quenched by the addition of 100 mL of water and extracted with 3 × 100 mL of DCM. The combined organic layers were washed with water, dried, and concentrated in vacuo. The crude product was recrystallized from PE:EtOAc (10:1) to afford 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] + 。

[0769] Step D

[0770] A solution of tert-butyl (R)-(2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)carbamate (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 afford 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 pale yellow solid. LCMS (ESI, m / z): 330.15 [M+H] + 。

[0771] Step E

[0772] 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 adding 100 mL of water and extracted with 3 × 100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by reverse-phase chromatography eluting with water / CH3CN (2 / 3) to give 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] + 。

[0773] Step F

[0774] 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 and then 50 mL of water was added. The pH was adjusted to 7 with saturated aqueous Na2CO3. The resulting solution was extracted with 3 × 100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by reverse-phase chromatography eluting with water / CH3CN (1 / 1) to give 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 (300 MHz, DMSO-d6) δ 12.61 (s, 1H), 8.70 (s, 2H), 8.59 (d, J = 8.0 Hz, 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 = 6.7 Hz, 3H).

[0775] 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.

[0776]

[0777] Step A

[0778] 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 tert-butyl (S)-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 adding 40 mL of water. After extraction with ethyl acetate, drying the organic matter 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 (R)-tert-butyl 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 as a white solid (1.12 g, 47% yield). LCMS (ESI, m / z): 544.30 [M+H] + 。

[0779] Step B

[0780] A solution of 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, 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 afford (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] + 。

[0781] Step C

[0782] 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 with 3 × 50 mL of water and then dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluted with ethyl acetate to afford 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] + 。

[0783] Step D

[0784] 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-toluenesulfonyl chloride (430 mg, 2.3 mmol, 2 equiv). The resulting solution was stirred overnight and then concentrated and applied to a silica gel column eluting with ethyl acetate / petroleum ether (71 / 29) to give (R)-4-toluenesulfonic acid 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 ester (330 mg, 30% yield). LCMS (ESI, m / z): 840.25 [M+H] + 。

[0785] Step E

[0786] To a solution of (R)-4-toluenesulfonic acid 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 ester (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 with 3 × 50 mL of ethyl acetate. The combined organics 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). LCMS (ESI, m / z): 711.20 [M+H] + 。

[0787] Step F

[0788] 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 eq, 60%) in THF (5 mL) was added triphenylphosphine (182 mg, 0.70 mmol, 1.5 eq) 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 afford 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 as a white solid (186 mg, 92% yield). LCMS (ESI, m / z): 685.30 [M+H] + 。

[0789] Step G

[0790] To 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 eq) in dichloroethane (8 mL) was added 2,2,2-trifluoroacetaldehyde (57 mg, 0.44 mmol, 3 eq), Ti(Oi-Pr)4 (41 mg, 0.15 mmol, 1.0 eq), AcOH (8 mg, 0.15 mmol, 1 eq) and NaBH3CN (18 mg, 0.29 mmol, 2 eq). The resulting solution was stirred at 70 °C for 1.5 h and then diluted with 50 mL of ethyl acetate and washed with 3 × 20 ml of water. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column eluting with ethyl acetate / petroleum ether (91 / 9) to afford 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 as a white solid (67 mg, 56% yield). LCMS (ESI, m / z): 767.25 [M+H] + 。

[0791] Step H

[0792] 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 eq) 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 9 with solid Na2CO3. The resulting solution was extracted with 2 × 30 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a reverse-phase column eluting with water / CH3CN (37 / 63) to give 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 as a white solid (20 mg, 39% yield). LCMS (ESI, m / z): 647.20 [M+H] + ; 1 1H NMR (300 MHz, 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 = 13.2 Hz, 2H), 4.20–4.01 (m, 4H), 3.95–3.82 (m, 1H), 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).

[0793] 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.

[0794]

[0795] Step A

[0796] 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 (130 mg, 0.29 mmol, 1.0 equiv) in CH3CN (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 applied to a reverse-phase column eluted with water / CH3CN (1 / 1) to afford 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] + 。

[0797] Step B

[0798] 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 neutralized with saturated aqueous NaHCO3 and the resulting solution was extracted with 3 × 30 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by reverse-phase chromatography eluted with water / CH3CN (3 / 2) to afford 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] + ; 11H NMR (400 MHz, DMSO-d6) δ 12.45 (br, 1H), 8.69 (s, 1H), 7.95 (s, 1H), 6.29–6.31 (m, 1H), 5.10 (t, J = 5.2 Hz, 1H), 4.82 (d, J = 12.8 Hz, 1H), 4.13–4.07 (m, 3H), 3.88 (dd, J = 10.1, 6.4 Hz, 1H), 3.68 (dd, J = 10.2, 5.4 Hz, 1H), 3.54 (t, J = 5.4 Hz, 2H), 3.28–3.22 (m, 1H), 3.16–3.10 (m, 1H), 3.04 (t, J = 11.6 Hz, 2H), 2.29–2.21 (m, 1H), 1.77–1.50 (m, 5H).

[0799] Example 64: Synthesis of cis-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 cis-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.

[0800]

[0801] Step A

[0802] To a solution of tert-butyl (rac)-cis-(3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)carbamate (2.22 g, 6.13 mmol, 1.0 equiv) in dioxane (10 mL) was added 4N HCl in dioxane (10 mL, 4 M). The solution was stirred at 50 °C for 1.5 h and then concentrated in vacuo to afford 2.28 g (99% yield) of cis-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] + .

[0803] Step B

[0804] To a solution of cis-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol hydrochloride (2.28 g, 7.63 mmol, 1.0 equiv) in CH3CN (20 mL) was added imidazole (3.15 g, 46.3 mmol, 6.1 equiv) and tert-butyldimethylsilyl chloride (5.80 g, 38.5 mmol, 5.0 equiv). The mixture 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 afford 2.27 g (78% yield) of cis-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine as a pale yellow solid. LCMS (ESI, m / z): 377.10 [M+H] + .

[0805] Step C

[0806] To a solution of cis-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, then STAB (3.84 g, 18.1 mmol, 3.0 equiv) was added, and the mixture was stirred for an additional 3 h. Upon completion, the reaction was quenched by adding 50 mL of saturated aqueous sodium bicarbonate and extracted with 3 × 60 mL of DCM. 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 DCM / methanol (24 / 1) to afford 2.55 g (81% yield) of cis-(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] + .

[0807] Step D

[0808] To a solution of cis-(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-toluenesulfonyl 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 overnight at room temperature and then the reaction was quenched by the addition of 50 mL of ice water. The solution was extracted with 2 × 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 cis-(3S)-4-toluenesulfonic acid 1-(3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl ester as a pale yellow solid. LCMS (ESI, m / z): 615.20 [M+H] + 。

[0809] Step E

[0810] 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) at 0 °C was added NaH (0.27 g, 6.85 mmol, 2.0 equiv, 60% dispersion in mineral oil). The reaction mixture was stirred for 15 min and then cis-(3S)-4-toluenesulfonic acid 1-(3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl ester (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 cis-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] + 。

[0811] Step F

[0812] To a solution of cis-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 quenched by the addition of solid Na2CO3 (200 mg). The resulting mixture was concentrated and applied to a silica gel column eluted with ethyl acetate to afford 350 mg (79% yield) of cis-1-(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] + 。

[0813] Step G

[0814] To a solution of cis-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) at 0 °C was added 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridazin-3(2H)-one (301 mg, 0.95 mmol, 1.4 equiv) and t-BuOK (290 mg, 2.6 mmol, 3.8 equiv). The resulting solution was stirred for 1.5 h and then concentrated and applied to a silica gel column eluted with ethyl acetate / petroleum ether (1 / 1) to afford 471 mg (85% yield) of cis-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] + 。

[0815] Step H

[0816] A solution of cis-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 eq) 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 7 with saturated aqueous Na2CO3. The solution was extracted with 3 × 60 mL of ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to reverse phase chromatography eluting with water / CH3CN (1 / 1) and further purified by chiral preparative HPLC with the following conditions: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: Hex:DCM = 3:1 (10 mM NH3-MeOH); mobile phase B: IPA; flow rate: 20 mL / min; gradient: 30% B for 7 min; 220 / 254 nm. The absolute stereochemistry of the pyrrolidone stereocenter was assigned based on the PARP7 potency of the more active diastereomer and the X-ray crystal structure similar to Example 10. The absolute stereochemistry of the piperidine stereocenter was not determined, similar to Example 10B.

[0817] Example 64 Isomer A (64A): cis-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] + ; 11H NMR (400 MHz, DMSO-d6) 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, 8.0 Hz, 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 = 6.2 Hz, 3H). Chiral HPLC: CHIRAL Cellulose-SB, 0.46 * 10 cm; 3 μm; (Hex:DCM = 3:1, containing 0.1% diethylamine:IPA = 90:10; flow rate: 1 mL / min); retention time: 3.726 min. (faster peak).

[0818] Example 64 Isomer B (64B): cis-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 1H NMR (400 MHz, DMSO-d6) 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 = 7.4 Hz, 1H), 4.04–3.98 (m, 1H), 3.93–3.83 (m, 2H), 3.74 (dd, J = 11.1, 3.3 Hz, 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 = 12.2 Hz, 1H), 1.28 (d, J = 6.2 Hz, 3H). Chiral HPLC: CHIRALCellulose-SB, 0.46 * 10 cm; 3 μm; (Hex:DCM = 3:1, containing 0.1% diethylamine:IPA = 90:10; flow rate: 1 mL / min); retention time: 5.703 min. (slower peak).

[0819] 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

[0820]

[0821] Step A

[0822] To a solution of tert-butyl ((3R,4R)-3-hydroxypiperidin-4-yl)carbamate (2.00 g, 9.25 mmol, 1.00 equiv), 2-chloro-5-(trifluoromethyl)pyrimidine (1.69 g, 9.25 mmol, 1.00 equiv) in DMF (20 mL) was added K2CO3 (2.56 g, 18.5 mmol, 2.00 equiv). The resulting solution was stirred at 50 °C for 2 h and quenched by adding 50 mL of ice water. The solid was 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] + .

[0823] Step B

[0824] 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 used without further purification. LCMS (ESI, m / z): 263.05 [M+H] + .

[0825] Step C

[0826] To a solution of (3R,4R)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol (2.60 g, 9.92 mmol, 1.00 equiv) in CH3CN (15 mL) 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 and then concentrated in vacuo and applied to a silica gel column eluting with DCM / methanol (99 / 1) to afford 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] + 。

[0827] Step D

[0828] 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 with 3 × 180 mL of DCM and the combined organics were concentrated in vacuo. The crude residue was applied to a silica gel column with DCM / methanol (95 / 5) to afford 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] + 。

[0829] Step E

[0830] 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 aqueous NaHCO3 was added. The layers were separated and the aqueous layer was extracted with 3 x 10 mL of DCM. The combined organic layers were washed with 3 x 30 mL of saturated aqueous NaHCO3, dried over anhydrous sodium sulfate, and concentrated in vacuo. 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)-4-toluenesulfonic acid 1-((3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl ester as a white solid. LCMS (ESI, m / z): 615.30 [M+H] + 。

[0831] Step F

[0832] To a solution of (S)-4-toluenesulfonic acid 1-((3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yl ester (540 mg, 0.88 mmol, 1.0 equiv) in DMF (5 mL) at 0 °C was added NaH (42 mg, 1.8 mmol, 2.0 equiv, 60% dispersion in mineral oil), and the mixture was stirred at 0 °C for 15 min. (2S)-2-(oxiran-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. The reaction was then quenched by the 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] + 。

[0833] Step G

[0834] 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 and 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] + 。

[0835] Step H

[0836] 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) at 0 °C was added t-BuOK (50 mg, 0.5 mmol, 2 equiv). The resulting solution was stirred for 15 min, then 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)prop-2-yloxy)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as a white solid. LCMS (ESI, m / z): 801.35 [M+H] + 。

[0837] Step I

[0838] 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(2H)-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. The pH was adjusted to 7 by addition of saturated aqueous NaHCO3. The resulting solution was extracted with 3 × 20 mL of ethyl acetate and the combined organic layers were concentrated in vacuo. The crude product was purified by C18 reverse-phase chromatography eluting with water / CH3CN (1 / 1) to afford 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 (300 MHz, DMSO-d6) 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 = 13.2 Hz, 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 = 6.3 Hz, 3H).

[0839] 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.

[0840]

[0841] Step A

[0842] 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 eq) in DCM (3 mL) was added DMAP (1 mg, 0.01 mmol, 0.1 eq), acetic anhydride (15 mg, 0.15 mmol, 1.5 eq) and triethylamine (31 mg, 0.31 mmol, 3 eq). The resulting solution was stirred for 1 h and then diluted with 60 mL of ethyl acetate. The mixture was washed with 3 × 20 mL of water and 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 as a white solid (66 mg, 71% yield). LCMS (ESI, m / z): 727.25 [M+H] + 。

[0843] Step B

[0844] 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 eq) in TFA (1 mL) was added TfOH (0.1 mL), and the mixture was stirred for 1 h. The reaction was quenched by adding 8 mL of water and the pH was adjusted to 9 with saturated aqueous Na2CO3. The resulting solution was extracted with 2 × 30 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a C18 reverse-phase column eluting with water / CH3CN (47 / 53) to give 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 as a white solid (13 mg, 22% yield). LCMS (ESI, m / z): 607.30 [M+H] + 。 11H NMR (300 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.69 (s, 2H), 8.14 (t, J = 5.9 Hz, 1H), 7.98 (s, 1H), 6.55–6.44 (m, 1H), 4.82 (d, J = 13.2 Hz, 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).

[0845] 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

[0846]

[0847] Step A

[0848] 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 2 × 25 mL saturated aqueous NaHCO3. The organic layer was concentrated and applied to a silica gel column eluting 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] + .

[0849] Step B

[0850] 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) at 0 °C was added NaH (72 mg, 3.0 mmol, 2.0 equiv, 60% dispersion in oil). The mixture was stirred for 10 minutes and then (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 an additional 6 hours and then concentrated and purified by silica gel chromatography eluting with ethyl acetate / petroleum ether (15 / 85) to afford 900 mg of (4R,5R)-tert-butyl 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] + .

[0851] Step C

[0852] A solution of (4R,5R)-tert-butyl 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 hours and then concentrated to afford 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 used without further purification. LCMS (ESI, m / z): 418.10 [M+H] + .

[0853] Step D

[0854] 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 hydrochloride (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 and 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] + 。

[0855] Step E

[0856] 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 ~6 - 7 with saturated aqueous Na2CO3 and the resulting solution was extracted with 3 x 25 mL of ethyl acetate. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was purified by C18 reverse phase chromatography eluted with CH3CN / H2O to give 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] + ; 1H-NMR (300 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.67 (s, 2H), 7.93 (s, 1H), 6.25 - 6.12 (m, 1H), 5.29 (d, J = 4.1 Hz, 1H), 4.80 (d, J = 13.2 Hz, 2H), 4.15 - 4.07 (m, 2H), 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 = 6.2 Hz, 3H).

[0857] 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

[0858]

[0859] Step A

[0860] To a solution of 4 - aminopiperidine - 1,3 - dicarboxylic acid 1 - (tert - butyl) ester 3 - ethyl ester (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, then 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 the addition of 100 mL of ice - cold 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 4 - ((R)-3 - hydroxy - 2 - oxopyrrolidin - 1 - yl)piperidine - 1,3 - dicarboxylic acid 1 - (tert - butyl) ester 3 - ethyl ester as a brown oil.

[0861] Step B

[0862] 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 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)ethyl piperidine-3-carboxylate hydrochloride as a brown solid, which was used without further purification.

[0863] Step C

[0864] To a solution of 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)ethyl piperidine-3-carboxylate hydrochloride (5.00 g, 17.1 mmol, 1.0 equiv) in DMF (40 mL) was added 2-chloro-5-(trifluoromethyl)pyrimidine (3.12 g, 17.1 mmol, 1.0 equiv) and K2CO3 (7.08 g, 51.2 mmol, 3.0 equiv). The resulting solution was stirred at 60 °C for 1 h and concentrated in vacuo and purified by reverse phase chromatography eluting with water / CH3CN (9 / 11) to give 1.2 g (17% yield) of 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)ethyl piperidine-3-carboxylate as a yellow solid. LCMS (ESI, m / z): 403.2 [M+H] + 。

[0865] Step D

[0866] To a solution of 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)ethyl 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 applied to a silica gel column eluting with water / CH3CN (5:1) to give 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] + 。

[0867] Step E

[0868] To 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 N,N-diisopropylethylamine (290 mg, 2.2 mmol, 2.0 equiv), NH4Cl (90 mg, 1.7 mmol, 1.5 equiv), and HATU (640 mg, 1.7 mmol, 1.5 equiv). The resulting solution was stirred for 1.5 h and then applied to a reverse-phase C18 column eluting with water / CH3CN (5:1) to give 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] + .

[0869] Step F

[0870] 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) at 0 °C was added NaH (86 mg, 2.2 mmol, 2.0 equiv, 60% dispersion in oil). After 15 min, a solution of tert-butyl (4S)-4-methyl-2,2-dioxido-1,2λ6,3-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 addition of 2 mL of saturated aqueous sodium bicarbonate. The resulting mixture was concentrated and applied to a reverse-phase column eluting with water / CH3OH (11:9) to give 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] + .

[0871] Step G

[0872] The 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 pale yellow solid. LCMS (ESI, m / z): 431.20 [M+H] + 。

[0873] Step H

[0874] To a solution 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) in CH3CN (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 applied to a reverse-phase C18 column eluting with water / CH3CN (1 / 1) to give 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] + 。

[0875] Step I

[0876] 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 eq) in TFA / TfOH (5 mL, 10:1) was stirred for 1 h. The reaction was quenched by addition of 15 mL of ice water and the pH was adjusted to ~7 - 8 with saturated aqueous Na2CO3. The solution was extracted with 3 × 60 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase chromatography eluting with water / CH3CN (3 / 2) to afford 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 (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.74 (s, 2H), 7.95 (d, J = 7.9 Hz, 1H), 7.53 - 7.48 (m, 1H), 6.99 (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).

[0877] 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.

[0878]

[0879] To a solution 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 (320 mg, 0.54 mmol, 1.0 eq) in water (22 mL) and CH3CN (27 mL) was added palladium(II) chloride (133 mg, 0.75 mmol, 1.4 eq). The resulting solution was stirred overnight at 80 °C and then extracted with 4 × 30 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was applied to a C18 reverse phase column eluting with water / CH3CN (1 / 1) to give 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 (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.85 (s, 2H), 7.95 (d, J = 3.6 Hz, 1H), 6.32 (br, 1H), 5.13–5.01 (m, 1H), 4.93–4.76 (m, 1H), 4.46–4.34 (m, 1H), 4.28–4.12 (m, 2H), 3.86–3.75 (m, 1H), 3.68–3.58 (m, 1H), 3.49–3.39 (m, 1H), 3.26–3.08 (m, 3H), 2.32–2.24 (m, 1H), 1.99–1.58 (m, 3H), 1.28–1.13 (m, 4H).

[0880] Example A. Enzymatic assay for PARP7 inhibition

[0881] Time-resolved fluorescence energy transfer (TR-FRET) assays were used to measure the displacement of probe A (a biotinylated probe that binds to the active site of TIPARP). Dose-response curve points of 20 nL of each test compound were spotted onto black 384-well polystyrene proxiplates (Perkin Elmer) using a Mosquito (TTP Labtech). The test compounds were incubated with 6 μL of TIPARP and probe A in assay buffer (20 mM HEPES pH = 8, 100 mM NaCl, 0.1% bovine serum albumin, 2 mM DTT, and 0.002% Tween 20) at 25 °C for 30 min, and then 2 μL of ULight-anti-6xHis and LANCE Eu-W1024-labeled streptavidin (Perkin Elmer) were added to effect the reaction in an 8 μL volume. The final concentrations of TIPARP and probe A were 6 nM and 2 nM, respectively. The final concentrations of ULight-anti-6xHis and LANCE Eu-W1024-labeled streptavidin were 4 nM and 0.25 nM, respectively. The reaction mixture was incubated at 25 °C for an additional 30 min and then read on an Envision plate reader equipped with a LANCE / DELFIA top reader (Perkin Elmer) using excitation at 320 nm and emission readings at 615 nm and 665 nM, with a 90 μs delay. The ratio of 665 / 615 nm emission was calculated for each well to determine the amount of the complex of TIPARP and probe A in each well. Control wells containing a negative control with 0.25% DMSO vehicle or a positive control of 100 μM 5-(5-(piperidin-4-yloxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one were used to calculate the percent inhibition as follows:

[0882]

[0883] where TRF cmpd is the TR-FRET ratio from the wells treated with the compound, TRF min is the TR-FRET ratio from the positive control wells treated with 5-(5-(piperidin-4-yloxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one and TRF max is the TR-FRET ratio from the DMSO-treated negative control wells.

[0884] The percent inhibition values were plotted as a function of compound concentration and the following 4-parameter fit was applied to derive the IC 50 value:

[0885]

[0886] The top and bottom values are usually allowed to float, but can be fixed ...

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: X is Cl, Br, F, CH3, CF3, CF2H, CN, OCH3, ethyl, cyclopropyl, SCH3 or isopropyl; A is a group of the formula having (A-1): Y 1 、 Y 2 and Y 3 each independently selected from O, S, NR Y , C(=O), C(=O)O, C(=O)NR Y , S(=O), S(=O)2, S(=O)NR Y , S(=O)2NR Y or NR Y C(=O)NR Y , wherein each R Y is independently H, C 1-4 alkyl or C 1-4 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 NR Y C(=O)NR Y ; Z is H, Cy Z , a halogen group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , NR c C(=NR e )NR c R d , NR c S(O)R b , NR c S(O)2R b , NR c S(O)2NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)2NR c R d ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl of Z are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: Cy Z , a halogen group, CN, NO2, OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , NR c C(=NR e )NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O)R b , NR c S(O)2R b , NR c S(O)2NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)2NR c R d ; Cy Z Selected from C 6-10 aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a1 、SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 、NR c1 C(=NR e1 )NR c1 R d1 、NR c1 R d1 、NR c1 C(O)R b1 、NR c1 C(O)OR a1 、NR c1 C(O)NR c1 R d1 、NR c1 S(O)R b1 、NR c1 S(O)2R b1 、NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 , wherein said alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are optionally substituted with 1, 2, or 3 substituents independently selected from the following: halo, CN, NO2, OR a1 、SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、 OC(O)R b1 、 OC(O)NR c1 R d1 、 C(=NR e1 )NR c1 R d1 、 NR c1 C(=NR e1 )NR c1 R d1 、NR c1 R d1 、NR c1 C(O)R b1 、NR c1 C(O)OR a1 、NR c1 C(O)NR c1 R d1 、NR c1 S(O)R b1 、NR c1 S(O)₂R b1 、 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 和S(O)2NR c1 R d1 ; Ring D is an azetidine ring or a piperidine ring, optionally substituted by 1, 2 or 3 groups independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 , wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted by 1, 2 or 3 groups independently selected from the following: halo, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 、NR c2 C(=NR e2 )NR c2 R d2 、NR c2 R d2 、NR c2 C(O)R b2 、NR c2 C(O)OR a2 、NR c2 C(O)NR c2 R d2 、NR c2 S(O)R b2 、NR c2 S(O)2R b2 、NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 和S(O)2NR c2 R d2 ; 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 selected from H, halogen, 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, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; wherein said 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 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 alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 、NR c3 C(=NR e3 )NR c3 R d3 、NR c3 S(O)R b3 、NR c3 S(O)2R b3 、NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 和S(O)2NR c3 R d3 ; or R 1 and Y 1 the R Y group, together with the atom to which it is attached and the atom forming Y 1 form a 4- to 10-membered heterocycloalkyl ring which is optionally substituted by 1, 2 or 3 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 ; or R 7 and Y 3 the R Y group together with the atoms to which it is attached and with the atoms that form Y 3 and with the atoms that form Y and with, if present, the R 9 's, R 10 's, R 11 's and R 12 substituted carbon atoms together form a 4- to 10-membered heterocycloalkyl ring which is optionally substituted by 1, 2 or 3 substituents independently selected from: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 ', SR a3 ', C(O)R b3 ', C(O)NR c3 R d3 ', C(O)OR a3 ', OC(O)R b3 ', OC(O)NR c3 R d3 ', NR c3 R d3 ', NR c3 C(O)R b3 ', NR c3 C(O)OR a3 ', NR c3 C(O)NR c3 R d3 ', C(=NR e3 )R b3 ', C(=NR e3 )NR c3 R d3 ', NR c3 C(=NR e3 )NR c3 R d3 ', NR c3 S(O)R b3 ', NR c3 S(O)2R b3 ', NR c3 S(O)2NR c3 R d3 ', S(O)R b3 ', S(O)NR c3 R d3 ', S(O)2R b3 and S(O)2NR c3 R d3 ; or R 1 and R 3 together with the carbon atom to which it is attached forms a C 5-10 cycloalkyl ring or a 5- to 10-membered heterocycloalkyl ring, each optionally substituted with 1, 2 or 3 substituents independently selected from: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 、SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、NR c3 R d3 、NR c3 C(O)R b3 、NR c3 C(O)OR a3 、NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 、NR c3 C(=NR e3 )NR c3 R d3 、NR c3 S(O)R b3 、NR c3 S(O)2R b3 、NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; or R 3 and R 5 together with the carbon atom to which it is attached forms a C 5-10 cycloalkyl ring or a 5- to 10-membered heterocycloalkyl ring, each optionally substituted with 1, 2 or 3 substituents independently selected from: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 、SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、NR c3 R d3 、NR c3 C(O)R b3 、NR c3 C(O)OR a3 、NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 、NR c3 C(=NR e3 )NR c3 R d3 、NR c3 S(O)R b3 、NR c3 S(O)2R b3 、NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; or R 7 and R 9 together with the carbon atom to which it is attached forms a C 5-10 cycloalkyl ring or a 5- to 10-membered heteroalkyl ring, each optionally substituted with 1, 2 or 3 substituents independently selected from: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 、SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、NR c3 R d3 、NR c3 C(O)R b3 、NR c3 C(O)OR a3 、NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 、NR c3 C(=NR e3 )NR c3 R d3 、NR c3 S(O)R b3 、NR c3 S(O)2R b3 、NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; or R 9 and R 11 together with the carbon atom to which it is attached forms a C 5-10 cycloalkyl ring or a 5- to 10-membered heterocycloalkyl ring, each optionally substituted with 1, 2 or 3 substituents independently selected from: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 、SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、NR c3 R d3 、NR c3 C(O)R b3 、NR c3 C(O)OR a3 、NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 、NR c3 C(=NR e3 )NR c3 R d3 、NR c3 S(O)R b3 、NR c3 S(O)2R b3 、NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; or R 5 and R 7 together with the carbon atom to which it is attached and with Y 2 together form a 5- to 10-membered heteroalkyl ring, which is optionally substituted by 1, 2 or 3 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 、SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、NR c3 R d3 、NR c3 C(O)R b3 、NR c3 C(O)OR a3 、NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 、NR c3 C(=NR e3 )NR c3 R d3 、NR c3 S(O)R b3 、NR c3 S(O)2R b3 、NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; or 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 、R 10 、R 11 and R 12 together form a triple bond between the carbon atoms to which they are attached; 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 independently selected from 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 said 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 of said 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 is optionally substituted with 1, 2 or 3 substituents independently selected from: halo, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 C(O)OR a7 , C(=NR e7 )NR c7 R d7 , NR c7 C(=NR e7 )NR c3 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O)2R b7 , NR c7 S(O)2R b7 , NR c7 S(O)2NR c7 R d7 and S(O)2NR c7 R d7 ; or R c and R d together with the N atom to which it is attached form a 4- to 7-membered heterocycloalkyl group, optionally substituted with 1, 2 or 3 substituents independently selected from: 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 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 C(O)OR a7 , C(=NR e7 )NR c7 R d7 , NR c7 C(=NR e7 )NR c3 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O)2R b7 , NR c7 S(O)2R b7 , NR c7 S(O)2NR c7 R d7 and S(O)2NR c7 R d7 ; or R c1 and R d2 together with the N atom to which it is attached forms a 4- to 7-membered heterocycloalkyl group, optionally substituted by 1, 2 or 3 substituents independently selected from: CN, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR a7 、SR a7 、C(O)R b7 、C(O)NR c7 R d7 、C(O)OR a7 、OC(O)R b7 、OC(O)NR c7 R d7 、NR c7 R d7 、NR c7 C(O)R b7 、NR c7 C(O)NR c7 R d7 、NR c7 C(O)OR a7 、C(=NR e7 )NR c7 R d7 、NR c7 C(=NR e7 )NR c3 R d7 、S(O)R b7 、S(O)NR c7 R d7 、S(O)2R b7 、NR c7 S(O)2R b7 、NR c7 S(O)2NR c7 R d7 and S(O)2NR c7 R d7 ; or R c2 and R d2 Together with the N atom to which it is attached, form a 4- to 7-membered heteroalkyl ring, optionally substituted with 1, 2 or 3 substituents independently selected from: 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 、SR a7 、C(O)R b7 、C(O)NR c7 R d7 、C(O)OR a7 、OC(O)R b7 、OC(O)NR c7 R d7 、NR c7 R d7 、NR c7 C(O)R b7 、NR c7 C(O)NR c7 R d7 、NR c7 C(O)OR a7 、C(=NR e7 )NR c7 R d7 、NR c7 C(=NR e7 )NR c3 R d7 、S(O)R b7 、S(O)NR c7 R d7 、S(O)2R b7 、NR c7 S(O)2R b7 、NR c7 S(O)2NR c7 R d7 and S(O)2NR c7 R d7 ; or R c3 and R d3 together with the N atom to which it is attached form a 4- to 7-membered heterocycloalkyl group, optionally substituted by 1, 2 or 3 substituents independently selected from: 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 、SR a7 、C(O)R b7 、C(O)NR c7 R d7 、C(O)OR a7 、OC(O)R b7 、OC(O)NR c7 R d7 、NR c7 R d7 、NR c7 C(O)R b7 、NR c7 C(O)NR c7 R d7 、NR c7 C(O)OR a7 、C(=NR e7 )NR c7 R d7 、NR c7 C(=NR e7 )NR c3 R d7 、S(O)R b7 、S(O)NR c7 R d7 、S(O)2R b7 、NR c7 S(O)2R b7 、NR c7 S(O)2NR c7 R d7 and S(O)2NR c7 R d7 ; R a7 、R b7 、R c7 and R d7 are independently selected from 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 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- 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 are each optionally substituted with 1, 2 or 3 substituents independently selected from: OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; Each R e 、R e1 、R e2 、R e3 and R e7 is independently selected from 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; wherein any of the above-mentioned heteroaryl or heterocycloalkyl contains 1, 2, 3 or 4 ring-forming heteroatoms independently selected from O, N and S; and wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl are optionally substituted by 1 or 2 oxo (=O) groups.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is CF3, Br or Cl.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is CF3.

4. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein Y 1 is NR Y or O.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein Y 1 is NR Y .

6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein Y 1 is NH.

7. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein Y 1 is O.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein Y 2 is O, NR Y or C(=O)NR Y .

9. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein Y 2 is O, NH, NCH3 or C(=O)NH.

10. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein Y 2 is O or NR Y .

11. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein Y 2 is O, NH or NCH3.

12. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein Y 2 is O.

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

14. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein Y 3 is C(=O)NCH2.

15. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 5 , R 6 , R 7 and R 8 are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 ; wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , NR c3 S(O)2R b3 、NR c3 S(O)2NR c3 R d3 、S(O)2R b3 和S(O)2NR c3 R d3 。 16. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 5 , R 6 , R 7 and R 8 are each independently selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl, wherein said C 1-6 alkyl is optionally substituted with one or two substituents independently selected from: CN, NO2, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , NR c3 R d3 , NR c3 C(O)R b3 , S(O)2R b3 and S(O)2NR c3 R d3 .

17. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R 1 is H or C 1-6 alkyl; wherein said C 1-6 alkyl is optionally substituted by OR a3 , NR c3 R d3 and NR c3 C(O)R b3 .

18. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R 1 is H or C 1-6 alkyl; wherein the C 1-6 alkyl is optionally substituted by OR a3 .

19. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R 1 is H, methyl, methoxymethyl, CH2OH, CH(OH)CH3, CH2NHCH2CF3 or CH2NHC(O)CH3.

20. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R 1 is H, methyl or methoxymethyl.

21. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein R 1 is H.

23. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R 1 and Y 1 of R Y group together with the atoms to which it is attached and together with the atoms forming Y 1 form a 4- to 10-membered heterocycloalkyl ring, which is optionally substituted by 1, 2 or 3 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 .

24. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R 1 and Y 1 of R Y group together with the atoms to which it is attached and together with the atoms forming Y 1 form an azetidine ring, which is optionally substituted by 1, 2 or 3 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 .

25. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R 1 and Y 1 The R Y group together with the atoms to which it is attached and together with the atoms forming Y 1 form an azetidine ring.

26. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R 2 is H.

27. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein R 5 is H or C 1-6 alkyl.

28. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl.

29. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein R 5 is H.

30. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R 6 is H.

31. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R 7 is H or C 1-6 alkyl.

32. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein R 7 is CH2.

33. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R 7 is H.

34. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein R 8 is H.

35. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein Y 1 of R Y is H.

36. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein Y 2 of R Y is H or C 1-4 alkyl.

37. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein Y 2 for R Y is H or methyl.

38. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein Y 3 of R Y is H or C 1-4 alkyl.

39. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein Y 3 R of Y is H, methyl or ethyl.

40. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein Y 3 of R Y is CH3.

41. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein R 7 and Y 3 the R Y group together with the atoms to which it is attached and together with the atoms forming Y 3 and together with the atoms, if any, substituted by R 9 、R 10 、R 11 and R 12 form a 4- to 10-membered heterocycloalkyl ring, which is optionally substituted by 1, 2 or 3 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 、SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、NR c3 R d3 、NR c3 C(O)R b3 、NR c3 C(O)OR a3 、NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 、NR c3 C(=NR e3 )NR c3 R d3 、NR c3 S(O)R b3 、NR c3 S(O)2R b3 、NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 .

42. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 - 3, wherein R 7 and Y 3 's R Y group, together with the atoms to which it is attached, and together with the atoms forming Y 3 , and together with the carbon atoms substituted by R 9 , R 10 , R 11 and R 12 if present, form an oxopyrrolidine ring or a pyrrolidine ring, each optionally substituted by 1, 2, or 3 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 .

43. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R 7 and Y 3 the R Y group together with the atom to which it is attached and together with the atoms forming Y 3 and together with the atoms, if present, substituted by R 9 、R 10 、R 11 and R 12 form an oxopyrrolidine ring together with the substituted carbon atoms.

44. A compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R 7 and Y 3 the R Y group together with the atom to which it is attached and together with the atoms forming Y 3 and together with the atoms, if present, of R 9 R 10 R 11 and R 12 substituted carbon atoms together form an oxopiperidine ring.

45. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein ring D is a piperidine ring, which is optionally substituted by 1 or 2 substituents independently selected from OH, F, C(O)NH2 or CN.

46. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein ring D is a piperidine ring optionally substituted by OH.

47. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein ring D is a piperidine ring.

48. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein Z is Cy Z .

49. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein Cy Z is a 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a1 、SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 、NR c1 C(=NR e1 )NR c1 R d1 、NR c1 R d1 、NR c1 C(O)R b1 、NR c1 C(O)OR a1 、NR c1 C(O)NR c1 R d1 、NR c1 S(O)R b1 、NR c1 S(O)2R b1 、NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ,wherein the alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, CN, NO2, OR a1 、SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NR c1 R d1 .

50. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein Cy Z is a 5- or 6-membered heteroaryl group substituted by a halogen group, CN, methyl or C 1-3 haloalkyl.

51. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein Cy Z is a 6-membered heteroaryl substituted by a halogen group, CN, methyl or C 1-3 haloalkyl.

52. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein Cy Z is a 6-membered heteroaryl substituted by a halogen group, CN or C 1-3 haloalkyl.

53. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein Cy Z is a pyrimidinyl, pyrazinyl, pyridinyl or thiazolyl group substituted with a halogen group, CN or C 1-3 haloalkyl.

54. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein Cy Z is a pyrimidinyl group substituted by CF3.

55. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein 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.

56. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein 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.

57. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein Cy Z is 5-(trifluoromethyl)pyrimidin-2-yl.

58. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein m is 1.

59. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein n is 0.

60. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein p is 0.

61. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein q is 0.

62. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein r is 1.

63. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein a is 0.

64. The compound according to any one of claims 1-3, said compound having formula IIa: or a pharmaceutically acceptable salt thereof.

65. The compound according to any one of claims 1-3, said compound having formula IIb: or a pharmaceutically acceptable salt thereof.

66. The compound according to any one of claims 1-3, said compound having formula IIc: or a pharmaceutically acceptable salt thereof, wherein Z 1 and Z 2 each independently selected from N and CH, and wherein R Z is a halogen group, CN or C 1-3 haloalkyl.

67. The compound according to any one of claims 1-3, said compound having formula IId: or a pharmaceutically acceptable salt thereof.

68. The compound according to any one of claims 1-3, said compound having formula IIe: or a pharmaceutically acceptable salt thereof.

69. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: X is Cl, Br or CF3; A is a group of the formula having (A-1a): Y 1 、 Y 2 and Y 3 each independently selected from O, NR Y , C(=O) and C(=O)NR Y , where each R Y is independently H or C 1-4 alkyl; Z is Cy Z ; Cy Z selected from 5- to 10-membered heteroaryl, optionally substituted with 1, 2, 3 or 4 substituents independently selected from: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a1 、SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 、NR c1 C(=NR e1 )NR c1 R d1 、NR c1 R d1 、NR c1 C(O)R b1 、NR c1 C(O)OR a1 、NR c1 C(O)NR c1 R d1 、NR c1 S(O)R b1 、NR c1 S(O)2R b1 、NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ,wherein said alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted with 1, 2 or 3 substituents independently selected from: halo, CN, NO2, OR a1 、SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 、NR c1 C(=NR e1 )NR c1 R d1 、NR c1 R d1 、NR c1 C(O)R b1 、NR c1 C(O)OR a1 、NR c1 C(O)NR c1 R d1 、NR c1 S(O)R b1 、NR c1 S(O)2R b1 、NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 和S(O)2NR c1 R d1 ; Ring D is an azetidine ring or a piperidine ring, which is unsubstituted or substituted by 1, 2 or 3 groups independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a2 、SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 、NR c2 C(=NR e2 )NR c2 R d2 、NR c2 R d2 、NR c2 C(O)R b2 、NR c2 C(O)OR a2 、NR c2 C(O)NR c2 R d2 、NR c2 S(O)R b2 、NR c2 S(O)2R b2 、NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ,wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted by 1, 2 or 3 groups independently selected from the following: halo, CN, NO2, OR a2 、SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 、NR c2 C(=NR e2 )NR c2 R d2 、NR c2 R d2 、NR c2 C(O)R b2 、NR c2 C(O)OR a2 、NR c2 C(O)NR c2 R d2 、NR c2 S(O)R b2 、NR c2 S(O)2R b2 、NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 和S(O)2NR c2 R d2 ; R 1 、R 2 、R 5 、R 6 、R 7 and R 8 each independently selected from 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, NO2, OR a3 、SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、NR c3 R d3 、NR c3 C(O)R b3 、NR c3 C(O)OR a3 、NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 、NR c3 C(=NR e3 )NR c3 R d3 、NR c3 S(O)R b3 、NR c3 S(O)2R b3 、NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; wherein said R 1 ,R 2 ,R 5 ,R 6 ,R 7 and R 8 of said 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 alkyl are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 ,SR a3 ,C(O)R b3 ,C(O)NR c3 R d3 ,C(O)OR a3 ,OC(O)R b3 ,OC(O)NR c3 R d3 ,NR c3 R d3 ,NR c3 C(O)R b3 ,NR c3 C(O)OR a3 ,NR c3 C(O)NR c3 R d3 ,C(=NR e3 )R b3 ,C(=NR e3 )NR c3 R d3 ,NR c3 C(=NR e3 )NR c3 R d3 ,NR c3 S(O)R b3 ,NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 ; or R 1 and Y 1 of R Y group together with the atom to which it is attached and with the atoms forming Y 1 form a 4 - 10 membered heteroalkyl ring, which is optionally substituted by 1, 2 or 3 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 、SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、NR c3 R d3 、NR c3 C(O)R b3 、NR c3 C(O)OR a3 、NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 、NR c3 C(=NR e3 )NR c3 R d3 、NR c3 S(O)R b3 、NR c3 S(O)2R b3 、NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; or R 7 and Y 3 the R Y group, together with the atom to which it is attached and with the atoms forming Y 3 form a 4- to 10-membered heteroalkyl ring, which is optionally substituted by 1, 2 or 3 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 ; 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 independently selected from 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 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 of said C 1-6 alkyl, 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 are optionally substituted by 1, 2 or 3 substituents independently selected from the following: halo, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 C(O)OR a7 , C(=NR e7 )NR c7 R d7 , NR c7 C(=NR e7 )NR c3 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O)2R b7 , NR c7 S(O)2R b7 , NR c7 S(O)2NR c7 R d7 and S(O)2NR c7 R d7 ; R a7 、R b7 、R c7 and R d7 are independently selected from 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 are each optionally substituted with 1, 2 or 3 substituents independently selected from: OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; and Each R e 、R e1 、R e2 、R e3 and R e7 is independently selected from H, C 1-4 alkyl, and CN; wherein any of the above-mentioned heteroaryl or heterocycloalkyl contains 1, 2, 3 or 4 ring-forming heteroatoms independently selected from O, N and S; and One or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted with one or two oxo (=O) groups.

70. The compound according to claim 1, wherein the compound is selected from: (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 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 pharmaceutically acceptable salt of any of the foregoing.

71. The compound according to claim 1, wherein the compound is selected from: (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 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 pharmaceutically acceptable salt of any of the foregoing.

72. A pharmaceutical composition comprising the compound of any one of claims 1-71 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

73. Use of the compound of any one of claims 1-71 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting the activity of PARP7.

74. Use of the compound of any one of claims 1-71 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer, wherein the cancer is characterized by overexpression or increased activity of PARP7.

75. The use according to claim 74, wherein the cancer is breast cancer, central nervous system cancer, endometrial cancer, renal cancer, colorectal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck cancer, urinary tract cancer or colon cancer.

76. The use according to claim 74, wherein the cancer is upper respiratory and digestive tract cancer.

Images