Pyridazinone as a PARP7 inhibitor

Abstract

The present invention relates to pyridazinone and compounds of formula I, which are inhibitors of PARP7 and can be used for treating cancer.

Description

Technical Field

[0001] The present invention relates to pyridazinone and related compounds, which are inhibitors of PARP7 and can be used for treating 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 the multi-cellular stress response (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 avenue for novel therapeutic agents. One member of the PARP family, PARP1, has been shown to be an effective cancer target associated with cellular stress induced by DNA damage (induced by gene mutations or cytotoxic chemotherapy), where three drugs have been approved for clinical use and several others are in late-stage development (A. Ohmoto, S. Yachida, Current status of poly(ADP-ribose) polymerase inhibitors and future directions. Onco Targets Ther 10, 5195-5208 (2017)).

[0004] Seventeen members of the PARP family were identified in the human genome based on homology within their catalytic domains (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 three different 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 onto their substrates (monoPARP), while other members (PARP1, PARP2, TNKS, TNKS2) catalyze the transfer of polyADP-ribose units onto acceptors (polyPARP). Finally, PARP13 is thus the only PARP to date that cannot demonstrate catalytic activity either 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, Towards 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 results in 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 squamous histological cancers (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 acts as a negative feedback mechanism to regulate the expression of P4501A1 and P4501B1 (L. MacPherson et al., Aryl hydrocarbon receptor repressor and TIPARP(ARTD14) use similar, but also distinct mechanisms to repress aryl hydrocarbon receptor signaling. Int J Mol Sci 15, 7939 - 7957(2014), and L. MacPherson et al., 2,3,7,8 - Tetrachlorodibenzo - p - dioxin poly(ADP - ribose) polymerase(TIPARP, ARTD14) is a mono - ADP - ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation. Nucleic Acids Res 41, 1604 - 1621(2013)). PARP7 has also been described to 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)).In addition, in the case of viral infection, AHR-induced PARP7 can interact with TBK1, a major kinase activated during the initiation of the pathogen-associated molecular pattern pathway, leading to the activation of the type I interferon response and antiviral immunity (T. Yamada et al., Constitutive arylhydrocarbon receptor signaling constrains Type I interferon-mediated antiviral innate defense. Nat Immunol 17, 687-694 (2016)). PARP7 is shown to ADP-ribosylate TBK1, which prevents TBK1 activation and thus inhibits the type I interferon response.

[0007] Based on these results from 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 inhibiting type I interferon and thus suppressing T cell-mediated anti-tumor immunity. Indeed, in a recent genetic screen for tumor factors that robustly inhibit 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)). Knockout of the PARP7 gene in a mouse melanoma cell line is shown to enhance the proliferation and activation of co-cultured T cells, indicating that PARP7 inhibition could be a viable strategy for activating T cell-mediated tumor killing. 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 constituent members are defined below.

[0011] The present invention further 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 further relates to a method of inhibiting PARP7 activity, the method comprising contacting a compound of formula I or a pharmaceutically acceptable salt thereof with PARP7.

[0013] The present invention further relates to a method of treating a disease or disorder in a patient in need of treatment, wherein the disease or disorder is characterized by overexpression or increased activity of PARP7, 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 further 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 for the manufacture of an agent 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 illustrates (A) PARP7 amplification across TCGA primary tumor samples; and (B) PARP7 copy number amplification corresponding to increased PARP7 mRNA expression levels in TCGA (The Cancer Genome Atlas) lung squamous tumor samples.

[0016] Figure 2 Demonstration of the inhibition of cancer cell growth by PARP7 inhibitors (compounds of Examples 18B, 39, 98, and 93A), showing a dose-dependent decrease in the growth of NCI-H1373 lung cancer cells.

[0017] Figure 3 Demonstration of the induction of interferon-β (IFN-β) levels by PARP7 inhibitors (compounds of Examples 18B and 98) in CT26 murine colon cancer cells and RAW264.7 murine macrophages in the presence of the STING agonist DMXAA (also known as Vadimezan or ASA404).

[0018] Figure 4 Demonstration of the induction of STAT1 phosphorylation by PARP7 inhibitors in CT26 murine colon cancer cells and RAW264.7 murine macrophages.

[0019] Figure 5 Demonstration of the in vitro proliferation of CT26 cells in the presence of a PARP7 inhibitor (compound of Example 18B).

[0020] Figure 6A Demonstration of tumor growth in the murine syngeneic model CT26 and in the presence of PARP7 inhibitors (compounds of Examples 98 and 93A).

[0021] Figure 6BDescribe tumor growth in the syngeneic murine model 4T1 and in the presence of PARP7 inhibitors (compounds of Examples 98 and 93A).

[0022] Figure 7A Describe that administration of the PARP7 inhibitor of Example 561 once daily significantly reduces tumor growth in human NCI-H1373 lung cancer xenografts.

[0023] Figure 7B Describe that administration of the PARP7 inhibitor of Example 561 once or twice daily significantly reduces tumor growth in the syngeneic murine CT26 colon cancer model.

[0024] Figure 8 Show the X-ray powder diffraction (XRPD) pattern of the compound of Form A of Example 561.

[0025] Figure 9 Show the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermal analysis patterns of the compound of Form A of Example 561.

[0026] Figure 10 Show the dynamic vapor sorption (DVS) isotherm of the compound of Form A of Example 561. Detailed Description

[0027] The present invention relates to compounds of formula I:

[0028]

[0029] or a pharmaceutically acceptable salt thereof, wherein:

[0030] X is Cl, Br, CH3, CF3, CN, OCH3, ethyl, cyclopropyl, SCH3 or isopropyl;

[0031] A is a group having a formula selected from (A-1), (A-2) and (A-3):

[0032]

[0033]

[0034] Y 1 、Y 2 and Y 3 are 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)NRY , wherein each R Y is independently H or C 1-4 alkyl;

[0035] 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 ;

[0036] Z is H, Cy Z , halogen, 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)2NRc 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 by 1, 2, 3, 4 or 5 substituents independently selected from: 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 ;

[0037] Cy Z is selected from C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of said groups being optionally substituted by 1, 2, 3 or 4 substituents independently selected from: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6Halogenated 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 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: halogen, 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 Rd1 , 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 ;

[0038] Ring D is a monocyclic or polycyclic 4- to 10-membered heterocycloalkyl group, 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 , NRc2 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 the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted with 1, 2 or 3 groups independently selected from the group consisting of 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 ;

[0039] R 1 , R 2 , R 3 , R4 , 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, 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)NRc3 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 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 ;

[0040] 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 said rings being 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 ;

[0041] or R 3 and R 5 together with the carbon atom to which it is attached form a C 5-10 cycloalkyl ring or a 5 - 10 membered heterocycloalkyl ring, each of said rings being 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 ;

[0042] or R 7 and R 9 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 said rings being 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 ;

[0043] 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 of said rings being 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 ;

[0044] or R 5 and R 7 together with the carbon atom to which it is attached and together with Y 2Together form a 5- to 10-membered heteroalkyl ring, which ring 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 ;

[0045] or R 1 and R 3 together form a double bond between the carbon atoms to which they are attached;

[0046] or R 3 and R 5 together form a double bond between the carbon atoms to which they are attached;

[0047] or R 7 and R9 together form a double bond between the carbon atoms to which they are attached;

[0048] or R 9 and R 11 together form a double bond between the carbon atoms to which they are attached;

[0049] or R 9 、R 10 、R 11 and R 12 together form a triple bond between the carbon atoms to which they are attached;

[0050] R 13 、R 14 and R 15 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 a4 、SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 、NR c4 R d4 、NR c4 C(O)R b4 、NR c4 C(O)OR a4 、NR c4 C(O)NR c4 R d4 、C(=NR e4 )R b4 、C(=NR e4 )NR c4 R d4 、NR c4 C(=NR e4 )NR c4 R d4 、NRc4 S(O)R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 and S(O)2NR c4 R d4 ; wherein said R 13 , R 14 and R 15 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 a4 , SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)OR a4 NR c4 C(O)NR c4 R d4 、C(=NR e4 )R b4 、C(=NR e4 )NRc4 R d4 NR c4 C(=NR e4 )NR c4 R d4 NR c4 S(O)R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 and S(O)2NR c4 R d4 ;

[0051] Ring E is selected from C 6-10 Aryl, C 3-7 a monocyclic or polycyclic ring of a cycloalkyl group, a 5- to 10-membered heteroaryl group, or a 4- to 10-membered heterocycloalkyl group;

[0052] Q 1 , Q 2 and Q 3 Each is a group of formula (B-1):

[0053]

[0054] Y 4 , Y 5 and Y 6 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 ;

[0055] G 1 -C(R G )(R H )- or a group of formula (C-1), (C-2) or (C-3):

[0056]

[0057] G 2 -C(R I )(R J )- or a group of formula (C-1), (C-2) or (C-3);

[0058] R A 、R B 、R C 、R D 、R E 、R F 、R G 、R H 、R I 、R J 、R K 、R L 、R M and R N 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- 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 a5 、SR a5 、C(O)R b5 、C(O)NR c5 R d5 、C(O)OR a5 、OC(O)R b5 、OC(O)NR c5 R d5 、C(=NR e5 )NR c5 R d5 、NR c5 C(=NR e5 )NR c5 R d5 、NR c5 R d5 、NR c5 C(O)R b5 、NR c5 C(O)OR a5 、NR c5 C(O)NR c5 R d5 、NR c5 S(O)R b5 、NR c5 S(O)2R b5 、NR c5 S(O)2NRc5 R d5 、S(O)R b5 、S(O)NR c5 R d5 、S(O)2R b5 and S(O)2NR c5 R d5 ; wherein said R A , R B , R C , R D , R E , R F , R G , R H , R I , R J , R K , R L , R M and R N 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 a5 , SR a5 、C(O)R b5 、C(O)NR c5 R d5 、C(O)OR a5 、OC(O)R b5 、OC(O)NR c5 R d5 、C(=NR e5 )NR c5 R d5 NR c5 C(=NR e5 )NR c5 R d5 NR c5 Rd5 , NR c5 C(O)R b5 , NR c5 C(O)OR a5 , NR c5 C(O)NR c5 R d5 , NR c5 S(O)R b5 , NR c5 S(O)2R b5 , NR c5 S(O)2NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O)2R b5 and S(O)2NR c5 R d5 ;

[0059] or R G and R I together with the carbon atom to which it is attached and together with Y 5 form a 5 - 10 membered heteroalkyl ring, said ring being 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 c3R 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 ;

[0060] or R C and R E Together they form a double bond between the carbon atoms to which they are attached;

[0061] or R E and R G Together they form a double bond between the carbon atoms to which they are attached;

[0062] or R I and R K Together they form a double bond between the carbon atoms to which they are attached;

[0063] or R K and R M Together they form a double bond between the carbon atoms to which they are attached;

[0064] or R K , R L , R M and R N Together they form a triple bond between the carbon atoms to which they are attached;

[0065] D 1 and D 2 are each independently selected from N and CH;

[0066] D 3 , D 4 , D 5 , D 6 , D 7 , D 8 and D 9 Each independently selected from N and CR X , where R X are each independently selected from H, halogen and C 1-4 alkyl;

[0067] D 10 O, S, NH or CH2;

[0068] Ring F is selected from C6-10 Aryl, C 3-7 monocyclic or polycyclic of cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl, each of said groups being 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 a6 , SR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , OC(O)R b6 , OC(O)NR c6 R d6 , C(=NR e6 )NR c6 R d6 , NR c6 C(=NR e6 )NR c6 R d6 , NR c6 R d6 , NR c6 C(O)R b6 , NR c6 C(O)OR a6 , NR c6 C(O)NR c6 R d6 , NR c6 S(O)R b6 , NR c6 S(O)2R b6 , NR c6 S(O)2NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O)2R b6 and S(O)2NR c6 R d6 , 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 a6 , SR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6, OC(O)R b6 , OC(O)NR c6 R d6 , C(=NR e6 )NR c6 R d6 , NR c6 , C(=NR e6 )NR c6 R d6 , NR c6 R d6 , NR c6 , C(O)R b6 , NR c6 , C(O)OR a6 , NR c6 , C(O)NR c6 R d6 , NR c6 , S(O)R b6 , NR c6 , S(O)2R b6 , NR c6 , S(O)2NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O)2R b6 and S(O)2NR c6 R d6 ;

[0069] 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 , R d3 , R a4 , R b4 , R c4 , R d4 , R a5 , R b5 , R c5 , R d5 , R a6 , R b6 , R c6 and R d6 is independently selected from H, C1-6 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 , R d3 , R a4 , R b4 , R c4 , R d4 , R a5 , R b5 , R c5 , R d5 , R a6 , R b6 , R c6 and R d6 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 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, ORa7 , 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 ;

[0070] 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 group 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 Rd7 , 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 ;

[0071] or R c1 and R d2 together with the N atom to which it is attached form a 4- to 7-membered heterocycloalkyl group, which group 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 , 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 , NRc7 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 ;

[0072] or R c2 and R d2 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which group 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 c7S(O)2NR c7 R d7 and S(O)2NR c7 R d7 ;

[0073] or R c3 and R d3 together with the N atom to which it is attached form a 4- to 7-membered heteroalkyl group, which group 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 , 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 ;

[0074] or R c4 and R d4Together with the attached N atom, 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 ;

[0075] or R c5 and R d5 Together with the attached N atom, 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 ;

[0076] or R c6 and R d6 together with the N atom to which it is attached form a 4- to 7-membered heterocycloalkyl group, which group 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 , NR c7 C(O)Rb7 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 ;

[0077] 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 1-4Each alkyl group is optionally substituted by 1, 2 or 3 substituents independently selected from the following: OH, CN, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy;

[0078] Each R e , R e1 , R e2 , R e3 , R e4 , R e5 , R e6 and R e7 is independently selected from H, C 1-4 alkyl and CN;

[0079] a is 0 or 1;

[0080] b is 0, 1, 2 or 3;

[0081] c is 0, 1 or 2;

[0082] d is 0, 1 or 2;

[0083] m is 0 or 1;

[0084] n is 0 or 1;

[0085] p is 0 or 1;

[0086] q is 0 or 1;

[0087] r is 0 or 1;

[0088] s1 is 0, 1 or 2;

[0089] s2 is 0, 1, 2 or 3;

[0090] t1 is 0 or 1;

[0091] t2 is 0 or 1;

[0092] t3 is 0 or 1;

[0093] u is 0, 1, 2 or 3;

[0094] v is 0 or 1; and

[0095] w is 0 or 1;

[0096] wherein any of the foregoing heteroaryl or heterocycloalkyl groups contains 1, 2, 3 or 4 ring-forming heteroatoms independently selected from O, N and S; and

[0097] one or more ring-forming C or N atoms of any of the foregoing heterocycloalkyl groups are optionally substituted by an oxo (═O) group.

[0098] In some embodiments, A is a group having formula A-1.

[0099] In some embodiments, provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein:

[0100] X is Cl, Br, CH3, CF3, CN, OCH3, ethyl, cyclopropyl, SCH3, or isopropyl;

[0101] A is a group having formula (A-1):

[0102]

[0103] 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 or C 1-4 alkyl;

[0104] 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 ;

[0105] Z is H, Cy Z 、halogen, 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 cC(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 the C of Z 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Each haloalkyl 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 、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)NRc 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 ;

[0106] Cy Z Selected from C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3 or 4 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 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 by 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 ;

[0107] Ring D is a monocyclic or polycyclic 4 - 10 membered heterocycloalkyl group, which is optionally substituted by 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 , SRa2 , 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 , NR b2 , C(O)R 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 independently optionally substituted with 1, 2 or 3 groups selected from the group consisting of: 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 , NRc2 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 ;

[0108] 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 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 1-6Alkyl, 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 ;

[0109] 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 said rings being 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)Rb3 , 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 ;

[0110] or R 3 and R 5 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 said rings being 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 Rd3 , 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 ;

[0111] 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 heterocycloalkyl ring, each of said rings being 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 ;

[0112] 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- to 10-membered heterocycloalkyl ring, each of said rings being 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 , OC(O)R a3 , NR c3 , C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NRc3 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 ;

[0113] or R 5 and R 7 together with the carbon atom to which it is attached and together with Y 2 Together they form a 5-10 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)Rb3 , 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 ;

[0114] or R 1 and R 3 together form a double bond between the carbon atoms to which they are attached;

[0115] or R 3 and R 5 together form a double bond between the carbon atoms to which they are attached;

[0116] or R 7 and R 9 together form a double bond between the carbon atoms to which they are attached;

[0117] or R 9 and R 11 together form a double bond between the carbon atoms to which they are attached;

[0118] or R 9 , R 10 , R 11 and R 12 together form a triple bond between the carbon atoms to which they are attached;

[0119] 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 is 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 3-7Cycloalkyl, 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 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 , NRc7 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 ;

[0120] or R c and R d Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which group 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 c7R 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 ;

[0121] or R c1 and R d2 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which group 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 R d7 and S(O)2NR c7 R d7 ;

[0122] or R c2 and R d2 together with the attached N atom form a 4- to 7-membered heterocycloalkyl group, which group is 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 ;

[0123] or R c3 and R d3 together with the attached N atom form a 4- to 7-membered heterocycloalkyl group, which group is 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, ORa7 , 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 ;

[0124] 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 2-6Alkenyl, 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;

[0125] Each R e , R e1 , R e2 , R e3 and R e7 Independently selected from H, C 1-4 Alkyl and CN;

[0126] a is 0 or 1;

[0127] m is 0 or 1;

[0128] n is 0 or 1;

[0129] p is 0 or 1;

[0130] q is 0 or 1;

[0131] r is 0 or 1;

[0132] wherein any of the aforementioned heteroaryl or heterocycloalkyl contains 1, 2, 3 or 4 ring-forming heteroatoms independently selected from O, N and S; and

[0133] wherein one or more ring-forming C or N atoms of any of the aforementioned heterocycloalkyl groups are optionally substituted with an oxo (=O) group.

[0134] In some embodiments, A is a group having formula (A-1a):

[0135]

[0136] In some embodiments, A is a group having formula (A-1b):

[0137]

[0138] In some embodiments, A is a group having formula (A-1c):

[0139]

[0140] wherein Z 1 and Z 2 are each independently selected from N and CH, and wherein R is CN, Cl or CF3.

[0141] In some embodiments, A is a group having formula (A-1d):

[0142]

[0143] wherein Z 1 and Z 2 are each independently selected from N and CH, and wherein R is CN, Cl or CF3.

[0144] In some embodiments, L is NR Y or O. In some embodiments, L is NH2 or O. In some embodiments, L is NR Y . In some embodiments, L is O. In some embodiments, L is NH2.

[0145] In some embodiments, X is CF3, CH3, CN, Cl or Br.

[0146] In some embodiments, Y 1 is NR Y or O. In some embodiments, Y 1 is NR Y . In some embodiments, Y 1 is O. In some embodiments, Y 1 is NR Y , O or S. In some embodiments, Y 1 is S.

[0147] In some embodiments, Y 2 is NR Y or O. In some embodiments, Y 2 is O. In some embodiments, Y 2 is NR Y , O or S. In some embodiments, Y 2 is NR Y . In some embodiments, Y 2 is S.

[0148] In some embodiments, Y 3 is C(=O). In some embodiments, Y 3 is C(=O) or S(=O)2. In some embodiments, Y 3 is S(=O)2.

[0149] In some embodiments, R Y is H or C 1-4 alkyl. In some embodiments, R Y is methyl. In some embodiments, R Y is H.

[0150] In some embodiments, Z is H, Cy Z , halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO2, OR a , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d and NR c C(O)R b ; wherein said C 1-6 alkyl and C 1-6 haloalkyl of Z are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: 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 , NR c R d and NR c C(O)R b . In some embodiments, Z is Cy Z .

[0151] In some embodiments, Cy Z is selected from 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl, each of said groups being 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)ORa1 , 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 by 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 .

[0152] In some embodiments, Cy Z is a 5- to 10-membered heteroaryl optionally substituted with CN, CF3 or Cl. In some embodiments, Cy Z is a pyridyl or pyrimidinyl each optionally substituted with CN, CF3 or Cl. In some embodiments, Cy Z is a 5- to 10-membered heteroaryl optionally substituted with CN, C 1-6 alkyl, C 1-6 haloalkyl, halo or NR c1 R d1 , wherein C 1-6 alkyl is optionally substituted with CN or NR c1 R d1 . In some embodiments, Cy Z is a pyridyl, pyrimidinyl or pyrazinyl each optionally substituted with CN, C 1-6 alkyl, C 1-6 haloalkyl, halo or NR c1 R d1 , wherein C 1-6 alkyl is optionally substituted with CN or NR c1 R d1 . In some embodiments, Cy Z is a pyridyl, pyrimidinyl, pyrazinyl or thiazolyl each optionally substituted with CN, C 1-6 alkyl, C 1-6 haloalkyl, halo or NR c1 R d1 , wherein C 1-6 alkyl is optionally substituted with CN or NR c1 R d1 .

[0153] In some embodiments, ring D is a monocyclic or polycyclic 4-10 membered heteroalkyl group, optionally substituted with 1, 2, or 3 groups independently selected from the following: halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO2, OR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、NR c2 R d2 、NR c2 C(O)R b2 ,wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 groups independently selected from the following: halo, CN, NO2, OR a2 、C(O)R b2 、NR c2 R d2 and NR c2 C(O)R b2 。

[0154] In some embodiments, ring D is a monocyclic 4-10 membered heteroalkyl group. In some embodiments, ring D is a piperazinyl group. In some embodiments, ring D is a piperazinyl group, a dihydropyridazinyl group, a diazepanyl group, a pyrrolidinyl group, or a hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl group. In some embodiments, ring D is a piperazinyl group, a dihydropyridazinyl group, a diazepanyl group, a pyrrolidinyl group, or a hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl group, each optionally substituted with 1, 2, or 3 groups independently selected from the following: halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO2, OR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、NR c2 R d2 、NR c2 C(O)R b2 ,wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 groups independently selected from the following: halo, CN, NO2, OR a2 、C(O)R b2 、NR c2 R d2 and NR c2 C(O)R b2 。In some embodiments, ring D is optionally substituted with C 1-6An alkyl-substituted piperazinyl. In some embodiments, ring D is a piperazinyl optionally substituted with 1 to 8 deuterium atoms. In some embodiments, ring D is piperazin-1-yl-2,2,3,3,5,5,6,6-d8.

[0155] In some embodiments, R 1 is H, halogen, OR a3 , C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a3 or NR c3 R d3 substituted. In some embodiments, R 1 is H, halogen, OR a3 , C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl or 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 6-10 aryl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl or 4- to 10-membered heterocycloalkyl-C 1-4 alkyl is optionally substituted with OR a3 or NR c3 R d3 substituted.

[0156] In some embodiments, R 1 is C 1-6 alkyl. In some embodiments, R 1 is C a3 alkyl optionally substituted with OR 1-6 In some embodiments, R 1 is H. In some embodiments, R 1 is methyl, ethyl or isopropyl. In some embodiments, R 1 is methoxymethyl or hydroxymethyl. In some embodiments, R 1 is phenyl, phenylmethyl or pyridyl. In some embodiments, R1 is a 5- to 10-membered heteroaryl-C 1-4 alkyl or a 4- to 10-membered heterocycloalkyl-C 1-4 alkyl. In some embodiments, R 1 is pyridinylmethyl, piperidinylmethyl or morpholinylmethyl. In some embodiments, R 1 is tetrahydrofuranyl or piperidinyl. In some embodiments, R 1 is phenyl, pyridinyl, tetrahydrofuranyl or piperidinyl.

[0157] In some embodiments, R 2 is H, halo, OR a3 , C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a3 or NR c3 R d3 Substituted. In some embodiments, R 2 is H, halo, OR a3 , C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl or 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 6-10 aryl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl or 4- to 10-membered heterocycloalkyl-C 1-4 alkyl is optionally substituted by OR a3 or NR c3 R d3 Substituted.

[0158] In some embodiments, R 2 is OR a3 . In some embodiments, R 2 is H.

[0159] In some embodiments, R 3 is H, halo, OR a3 , C1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a3 or NR c3 R d3 substituted.

[0160] In some embodiments, R 3 is H. In some embodiments, R 3 is methyl, ethyl or isopropyl. In some embodiments, R 3 is methoxymethyl or hydroxymethyl. In some embodiments, R 3 is phenyl, phenylmethyl or pyridyl.

[0161] In some embodiments, R 4 is H, halo, OR a3 , C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a3 or NR c3 R d3 substituted.

[0162] In some embodiments, R 4 is H.

[0163] In some embodiments, R 5 is H, halo, OR a3 , C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a3 or NR c3 R d3 substituted.

[0164] In some embodiments, R 5 is H. In some embodiments, R 5 is methyl, ethyl or isopropyl. In some embodiments, R 5 is methoxymethyl or hydroxymethyl. In some embodiments, R 5 is phenyl, phenylmethyl or pyridyl.

[0165] In some embodiments, R 6 is H, a halogen group, OR a3 , C 1-6 alkyl, C 6-10 aryl, a 5-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a3 or NR c3 R d3 .

[0166] In some embodiments, R 6 is H.

[0167] In some embodiments, R 7 is H, a halogen group, OR a3 , C 1-6 alkyl, C 6-10 aryl, a 5-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a3 or NR c3 R d3 .

[0168] In some embodiments, R 7 is C 1-6 alkyl. In some embodiments, R 7 is methyl.

[0169] In some embodiments, R 8 is H, a halogen group, OR a3 , C 1-6 alkyl, C 6-10 aryl, a 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6Alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a3 or NR c3 R d3 Substituted.

[0170] In some embodiments, R 8 is H.

[0171] In some embodiments, R 9 is H, halo, OR a3 , C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a3 or NR c3 R d3 Substituted.

[0172] In some embodiments, R 9 is H.

[0173] In some embodiments, R 10 is H, halo, OR a3 , C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a3 or NR c3 R d3 Substituted.

[0174] In some embodiments, R 10 is H.

[0175] In some embodiments, R 11 is H, halo, OR a3 , C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C6-10 An aryl, 5- to 10-membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a3 or NR c3 R d3 substituted.

[0176] In some embodiments, R 11 is H.

[0177] In some embodiments, R 12 is H, a halogen, OR a3 , C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a3 or NR c3 R d3 substituted.

[0178] In some embodiments, R 12 is H.

[0179] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each H.

[0180] In some embodiments, R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each H.

[0181] In some embodiments, R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each H.

[0182] In some embodiments, R 2 , R 5, R 6 , R 7 , R 8 , R 9 and R 10 are each H.

[0183] In some embodiments, R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each H.

[0184] In some embodiments, R 3 and R 5 together with the carbon atom to which they are attached form a C 5-10 cycloalkyl ring or a 5- to 10-membered heterocycloalkyl ring, each of said rings being 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 .

[0185] In some embodiments, R 3 and R 5 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.

[0186] In some embodiments, R 3 and R 5 together with the carbon atom to which it is attached form a tetrahydrofuranyl ring.

[0187] In some embodiments, R 3 and R 5 together with the carbon atom to which it is attached form a cyclobutyl or cyclopentyl ring.

[0188] In some embodiments, R 5 and R 7 together with the carbon atom to which it is attached and together with Y 2 form a 5- to 10-membered heterocycloalkyl ring, which ring 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)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 , NRc3 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 .

[0189] In some embodiments, R 5 and R 7 together with the carbon atom to which it is attached and together with Y 2 Together they form a 5-10 membered heterocycloalkyl ring.

[0190] In some embodiments, R 5 and R 7 together with the carbon atom to which it is attached and together with Y 2 Together they form a tetrahydrofuranyl ring or a tetrahydropyranyl ring. 5 and R 7 together with the carbon atom to which it is attached and together with Y 2 Together they form a tetrahydrofuranyl ring, a tetrahydropyranyl ring, or a pyrrolidinyl ring. 5 and R 7 together with the carbon atom to which it is attached and together with Y 2 Together they form a pyrrolidinyl ring.

[0191] In some embodiments, R a3 C 1-6 In some embodiments, R a3 In some embodiments, R a3 For H.

[0192] In some embodiments, R c3 and R d3 Each independently selected from C 1-6 In some embodiments, R c3 C 1-6 In some embodiments, R d3 C 1-6 In some embodiments, R c3 and Rd3 Each is methyl. In some embodiments, R c3 and R d3 Each is H.

[0193] In some embodiments, m is 1.

[0194] In some embodiments, n is 0. In some embodiments, n is 1.

[0195] In some embodiments, p is 0. In some embodiments, p is 1.

[0196] In some embodiments, q is 0. In some embodiments, q is 1.

[0197] In some embodiments, r is 0.

[0198] In some embodiments, a is 0.

[0199] In some embodiments, provided herein are compounds of formula (I) having formula IIa or a pharmaceutically acceptable salt thereof:

[0200]

[0201] In some embodiments, provided herein are compounds of formula (I) having formula IIb or a pharmaceutically acceptable salt thereof:

[0202]

[0203] In some embodiments, provided herein are compounds of formula (I) having formula IIc or a pharmaceutically acceptable salt thereof:

[0204]

[0205] wherein Z 1 and Z 2 are each independently selected from N and CH, and wherein R is CN, Cl, or CF3.

[0206] In some embodiments, provided herein are compounds of formula (I) having formula IId or a pharmaceutically acceptable salt thereof:

[0207]

[0208] wherein Z 1 and Z 2 are each independently selected from N and CH, and wherein R is CN, Cl, or CF3.

[0209] In some embodiments, A is a group having formula A-2.

[0210] In some embodiments, provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein:

[0211] X is Cl, Br, CH3, CF3, CN, OCH3, cyclopropyl, SCH3, or isopropyl;

[0212] A is a group having formula (A-2):

[0213]

[0214] 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 ;

[0215] Z is H, 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 , NRc 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 the C of Z 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Each haloalkyl 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 、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 ;

[0216] Cy Z Selected from C 6-10 Aryl, C3-7 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which groups 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 , where 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)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 ;

[0217] R 13 , R 14 and R 15 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 a4 , SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 Rd4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , C(=NR e4 )R b4 , C(=NR e4 )NR c4 R d4 , NR c4 C(=NR e4 )NR c4 R d4 , NR c4 S(O)R b4 , NR c4 S(O)2R b4 , NR c4 S(O)2NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 and S(O)2NR c4 R d4 ; wherein said R 13 , R 14 and R 15 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: halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a4 , SR a4 , C(O)R b4 , C(O)NRc4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)OR a4 NR c4 C(O)NR c4 R d4 、C(=NR e4 )R b4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 NR c4 S(O)R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 and S(O)2NR c4 R d4 ;

[0218] Q 1 , Q 2 and Q 3 Each is a group of formula (B-1):

[0219]

[0220] Y 4 , Y 5 and Y 6 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 ;

[0221] G1 is -C(R G )(R H )- or a group of formula (C-1), (C-2) or (C-3):

[0222]

[0223] G 2 is -C(R I )(R J )- or a group of formula (C-1), (C-2) or (C-3);

[0224] R A , R B , R C , R D , R E , R F , R G , R H , R I , R J , R K , R L , R M and R N 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 a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , C(=NR e5 )NR c5 R d5 , NR c5 C(=NR e5 )NR c5 R d5 , NR c5 Rd5 , NR c5 C(O)R b5 , NR c5 C(O)OR a5 , NR c5 C(O)NR c5 R d5 , NR c5 S(O)R b5 , NR c5 S(O)2R b5 , NR c5 S(O)2NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O)2R b5 and S(O)2NR c5 R d5 ; wherein said R A , R B , R C , R D , R E , R F , R G , R H , R I , R J , R K , R L , R M and R N 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 is 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 a5 , SR a5 , C(O)R b5 , C(O)NR c5 Rd5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , C(=NR e5 )NR c5 R d5 , NR c5 C(=NR e5 )NR c5 R d5 , NR c5 R d5 , NR c5 , C(O)R b5 , NR c5 , C(O)OR a5 , NR c5 , C(O)NR c5 R d5 , NR c5 , S(O)R b5 , NR c5 , S(O)2R b5 , NR c5 , S(O)2NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O)2R b5 and S(O)2NR c5 R d5 ;

[0225] or R G and R I together with the carbon atom to which it is attached and together with Y 5 form a 5- to 10-membered heteroalkyl ring, which ring 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)Rb3 , 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 ;

[0226] or R C and R E together form a double bond between the carbon atoms to which they are attached;

[0227] or R E and R G together form a double bond between the carbon atoms to which they are attached;

[0228] or R I and R K together form a double bond between the carbon atoms to which they are attached;

[0229] or R K and R M together form a double bond between the carbon atoms to which they are attached;

[0230] or R K , R L , R M and R N together form a triple bond between the carbon atoms to which they are attached;

[0231] D 1 and D 2 each independently selected from N and CH;

[0232] D 3 , D 4 , D5 , D 6 , D 7 , D 8 and D 9 are each independently selected from N and CR X , where R X is each independently selected from H, halo, and C 1-4 alkyl;

[0233] D 10 is O, S, NH, or CH2;

[0234] Ring F is a monocyclic or polycyclic ring selected from C 6-10 aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of said groups being 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 a6 , SR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , OC(O)R b6 , OC(O)NR c6 R d6 , C(=NR e6 )NR c6 R d6 , NR c6 C(=NR e6 )NR c6 R d6 , NR c6 R d6 , NR c6 C(O)R b6 , NR c6 C(O)OR a6 , NR c6 C(O)NR c6 R d6 , NR c6 S(O)R b6 , NR c6 S(O)2R b6 , NR c6 S(O)2NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O)2Rb6 and S(O)2NR c6 R d6 wherein the alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are optionally substituted by 1, 2, or 3 substituents independently selected from the following: halo, CN, NO2, OR a6 , SR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , OC(O)R b6 , OC(O)NR c6 R d6 , C(=NR e6 )NR c6 R d6 , NR c6 C(=NR e6 )NR c6 R d6 , NR c6 R d6 , NR c6 C(O)R b6 , NR c6 C(O)OR a6 , NR c6 C(O)NR c6 R d6 , NR c6 S(O)R b6 , NR c6 S(O)2R b6 , NR c6 S(O)2NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O)2R b6 and S(O)2NR c6 R d6 ;

[0235] Each R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a3 , R b3 , R c3 , R d3 , R a4 , Rb4 , R c4 , R d4 , R a5 , R b5 , R c5 , R d5 , R a6 , R b6 , R c6 and R d6 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 , R d3 , R a4 , R b4 , R c4 , R d4 , R a5 , R b5 , R c5 , R d5 , R a6 , R b6 , R c6 and R d6 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-C1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl and 4-10 membered heterocycloalkyl-C 1-4 The 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 ;

[0236] or R c and R d together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, the group being 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 ;

[0237] or R c3 and R d3 together with the N atom to which it is attached form a 4- to 7-membered heteroalkyl ring, which group 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 ;

[0238] or R c4 and R d4 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which group 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 c7C(=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 ;

[0239] or R c5 and R d5 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which group 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)2NRc7 R d7 and S(O)2NR c7 R d7 ;

[0240] or R c6 and R d6 together with the N atom to which it is attached form a 4- to 7-membered heterocycloalkyl group, which group 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 , 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 ;

[0241] R a7 , R b7 , R c7 and R d7 are independently selected from H, C 1-6 alkyl, C 1-6haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5 - 10 - membered heteroaryl, 4 - 10 - membered heterocycloalkyl, C 6-10 aryl - C 1-4 alkyl, C 3-7 cycloalkyl - C 1-4 alkyl, 5 - 10 - membered heteroaryl - C 1-4 alkyl and 4 - 10 - membered heterocycloalkyl - C 1-4 alkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5 - 10 - membered heteroaryl, 4 - 10 - membered heterocycloalkyl, C 6-10 aryl - C 1-4 alkyl, C 3-7 cycloalkyl - C 1-4 alkyl, 5 - 10 - membered heteroaryl - C 1-4 alkyl and 4 - 10 - membered heterocycloalkyl - C 1-4 alkyl is each independently optionally substituted with 1, 2, or 3 substituents selected from: OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy;

[0242] each R e , R e1 , R e3 , R e4 , R e5 , R e6 and R e7 is independently selected from H, C 1-4 alkyl, and CN;

[0243] a is 0 or 1;

[0244] b is 0, 1, 2, or 3;

[0245] c is 0, 1, or 2;

[0246] d is 0, 1, or 2;

[0247] m is 0 or 1;

[0248] n is 0 or 1;

[0249] p is 0 or 1;

[0250] q is 0 or 1;

[0251] r is 0 or 1;

[0252] s1 is 0, 1 or 2;

[0253] s2 is 0, 1, 2 or 3;

[0254] v is 0 or 1; and

[0255] w is 0 or 1;

[0256] wherein any of the foregoing heteroaryl or heterocycloalkyl contains 1, 2, 3 or 4 ring heteroatoms independently selected from O, N and S; and

[0257] wherein one or more ring C or N atoms of any of the foregoing heterocycloalkyl are optionally substituted with an oxo(=O) group.

[0258] In some embodiments, Q 1 is a group of formula (B-1a):

[0259]

[0260] In some embodiments, Q 1 is a group of formula (B-1b):

[0261]

[0262] In some embodiments, Q 1 is a group of formula (B-1c):

[0263]

[0264] wherein Z 1 and Z 2 are each independently selected from N and CH, and wherein R is CN, Cl or CF3.

[0265] In some embodiments, X is CF3, CH3, CN, Cl or Br.

[0266] In some embodiments, ring F is a 4- to 10-membered heterocycloalkyl or C 1-6 cycloalkyl optionally substituted with C 3-7 alkyl, wherein the C 1-6 alkyl is optionally substituted with OR a6 In some embodiments, ring F is a 4- to 10-membered heterocycloalkyl or C 3-7 cycloalkyl each optionally substituted with methyl.

[0267] In some embodiments, ring F is piperazinyl, piperidinyl, pyrrolidinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 2,8-diazaspiro[4.5]decyl, 2,5-diazabicyclo[2.2.2]octyl, 1,4-diazepanyl, azetidinyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, octahydropyrrolo[3,2-b]pyrrolyl, 2,7-diazaspiro[4.4]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, octahydropyrrolo[3,4-c]pyrrolyl or 2,7-diazaspiro[3.5]nonyl.

[0268] In some embodiments, ring F is piperazinyl.

[0269] In some embodiments, ring F is cyclohexyl.

[0270] In some embodiments, ring F is a 4- to 10-membered heterocycloalkyl optionally substituted with an oxo (=O) group.

[0271] In some embodiments, Z is Cy Z , C 1-6 alkyl or C(O)R b , wherein said C 1-6 alkyl is optionally substituted with a halogen group. In some embodiments, Z is CF3.

[0272] In some embodiments, Cy Z is selected from 5- to 10-membered heteroaryl and C 1-6 aryl optionally substituted with C 6-10 alkyl, CN or CF3, wherein said C 1-6 alkyl is optionally substituted with CN.

[0273] In some embodiments, Cy Z is a pyridinyl, pyrimidinyl or pyrazinyl optionally substituted with C 1-6 alkyl, CN, Cl, S(O)2R b1 or CF3.

[0274] In some embodiments, Cy Z is a pyridinyl, pyrimidinyl or pyrazinyl optionally substituted with methyl, CN, Cl, CF3 or S(O)2CH3.

[0275] In some embodiments, Cy Z is a phenyl optionally substituted with cyanomethyl or CN.

[0276] In some embodiments, R b is C 1-6 alkyl. In some embodiments, Rb is methyl.

[0277] In some embodiments, Y 4 is O or NR Y . In some embodiments, Y 4 is O. In some embodiments, Y 4 is NR Y .

[0278] In some embodiments, Y 5 is O, NR Y or C(=O)NR Y .

[0279] In some embodiments, Y 6 is C(=O) or C(=O)NR Y .

[0280] In some embodiments, R Y is H or C 1-4 alkyl. In some embodiments, R Y is H. In some embodiments, R Y is methyl.

[0281] In some embodiments, L is O or NR Y .

[0282] In some embodiments, G 1 is -C(R G )(R H ).

[0283] In some embodiments, G 2 is C-1. In some embodiments, D 1 and D 2 are each CH and D 10 is CH2. In some embodiments, D 1 is CH, D 2 is N, and D 10 is CH2. In some embodiments, D 3 is CH, D 4 is N, D 5 is CH. In some embodiments, D 10 is CH2.

[0284] In some embodiments, b is 0, c is 1, and d is 1. In some embodiments, b is 0, c is 2, and d is 0. In some embodiments, b is 0, c is 0, and d is 0. In some embodiments, b is 0, c is 1, and d is 0.

[0285] In some embodiments, G 2 is C-2. In some embodiments, D 3 , D 4 and D 5 are each CR X , where each R X is independently selected from H, halogen, and C 1-4 alkyl.

[0286] In some embodiments, G 2 is C-3. In some embodiments, D 6 , D 7 and D 9 are CR X , and D 8 is N. In some embodiments, D 6 and D 7 are each N, and D 8 and D 9 are each CR X . In some embodiments, D 6 , D 7 , D 8 and D 9 are each CR X . In some embodiments, D 6 , D 8 and D 9 are each CR X , and D 7 is N. In some embodiments, D 6 , D 7 and D 8 are each CR X and D 9 is N. In some embodiments, D 6 and D 8 are each N, and D 7 and D 9 are each CR X .

[0287] In some embodiments, each R X is H or halogen. In some embodiments, R X is H or F. In some embodiments, R X is H.

[0288] In some embodiments, G 2 is -C(R I )(R J )-.

[0289] In some embodiments, R 13 is C 1-6alkyl, OR a4 , CN or NR c4 R d4 , wherein said C 1-6 alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halo and OR a4 and NR c4 R d4 .

[0290] In some embodiments, R 13 is methyl. In some embodiments, R 13 is CN. In some embodiments, R 13 is CF3. In some embodiments, R 13 is amino. In some embodiments, R 13 is aminomethyl.

[0291] In some embodiments, R A is H, halo, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5 or NR c5 R d5 .

[0292] In some embodiments, R A is C 1-6 alkyl or H. In some embodiments, R A is methyl. In some embodiments, R A is H.

[0293] In some embodiments, R B is H, halo, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5 or NR c5 R d5 .

[0294] In some embodiments, R B is C 1-6 alkyl or H. In some embodiments, R B is methyl. In some embodiments, R B is H.

[0295] In some embodiments, R C is H, a halogen, OR a5 , C 1-6 alkyl, C 6-10 aryl, a 5- to 10-membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 substituted.

[0296] In some embodiments, R C is C 1-6 alkyl or H. In some embodiments, R C is methyl. In some embodiments, R C is H.

[0297] In some embodiments, R D is H, a halogen, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 substituted.

[0298] In some embodiments, R D is C 1-6 alkyl or H. In some embodiments, R D is methyl. In some embodiments, R D is H.

[0299] In some embodiments, R E is H, a halogen, OR a5 , C 1-6 alkyl, C6-10 Aryl, 5- to 10-membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 Substituted.

[0300] In some embodiments, R E is C 1-6 alkyl or H. In some embodiments, R E is methyl. In some embodiments, R E is H.

[0301] In some embodiments, R F is H, halo, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 Substituted.

[0302] In some embodiments, R F is C 1-6 alkyl or H. In some embodiments, R F is methyl. In some embodiments, R F is H.

[0303] In some embodiments, R G is H, halo, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 Substituted.

[0304] In some embodiments, R G is C 1-6 alkyl or H. In some embodiments, R G is methyl. In some embodiments, R G is H.

[0305] In some embodiments, R H is H, a halogen, OR a5 , C 1-6 alkyl, C 6-10 aryl, a 5- to 10-membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, a 5- to 10-membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5 or NR c5 R d5 .

[0306] In some embodiments, R H is C 1-6 alkyl or H. In some embodiments, R H is methyl. In some embodiments, R H is H.

[0307] In some embodiments, R I is H, a halogen, OR a5 , C 1-6 alkyl, C 6-10 aryl, a 5- to 10-membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, a 5- to 10-membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5 or NR c5 R d5 .

[0308] In some embodiments, R I is C 1-6 alkyl or H. In some embodiments, R I is methyl. In some embodiments, R I is H.

[0309] In some embodiments, R J is H, a halogen, OR a5 , C1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 substituted.

[0310] In some embodiments, R J is C 1-6 alkyl or H. In some embodiments, R J is methyl. In some embodiments, R J is H.

[0311] In some embodiments, R K is H, halo, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 substituted.

[0312] In some embodiments, R K is C 1-6 alkyl or H. In some embodiments, R K is methyl. In some embodiments, R K is H.

[0313] In some embodiments, R L is H, halo, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 Rd5 Substituted.

[0314] In some embodiments, R L is C 1-6 alkyl or H. In some embodiments, R L is methyl. In some embodiments, R L is H.

[0315] In some embodiments, R M is H, halo, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 Substituted.

[0316] In some embodiments, R M is C 1-6 alkyl or H. In some embodiments, R M is methyl. In some embodiments, R M is H.

[0317] In some embodiments, R N is H, halo, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 Substituted.

[0318] In some embodiments, R N is C 1-6 alkyl or H. In some embodiments, R N is methyl. In some embodiments, R N is H.

[0319] In some embodiments, R I and RK Together form a double bond between the carbon atoms to which they are attached.

[0320] In some embodiments, R K and R M Together form a double bond between the carbon atoms to which they are attached.

[0321] In some embodiments, R K , R L , R M and R N Together form a triple bond between the carbon atoms to which they are attached.

[0322] In some embodiments, R G and R I Together with the carbon atoms to which they are attached and together with Y 5 form a 5- to 10-membered heterocycloalkyl ring, which ring 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)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 , C(O)R b3 , NR c3 , OC(O)R 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 Rd3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)₂R b3 and S(O)₂NR c3 R d3 .

[0323] In some embodiments, R G and R I together with the carbon atom to which they are attached and together with Y 5 form a tetrahydrofuranyl ring.

[0324] In some embodiments, R a6 is H.

[0325] In some embodiments, R b1 is C 1-6 alkyl. In some embodiments, R b1 is methyl.

[0326] In some embodiments, R a4 is H or C 1-6 alkyl. In some embodiments, R a4 is methyl.

[0327] In some embodiments, R c4 and R d4 are each H.

[0328] In some embodiments, R c5 and R d5 are each H.

[0329] In some embodiments, R Y is H.

[0330] In some embodiments, a is 0. In some embodiments, a is 1.

[0331] In some embodiments, s1 is 0. In some embodiments, s1 is 1. In some embodiments, s1 is 2.

[0332] In some embodiments, s2 is 0. In some embodiments, s2 is 1. In some embodiments, s2 is 2.

[0333] In some embodiments, v is 0. In some embodiments, v is 1.

[0334] In some embodiments, w is 0. In some embodiments, w is 1.

[0335] In some embodiments, m is 0. In some embodiments, m is 1.

[0336] In some embodiments, n is 0. In some embodiments, n is 1.

[0337] In some embodiments, p is 0. In some embodiments, p is 1.

[0338] In some embodiments, q is 0. In some embodiments, q is 1.

[0339] In some embodiments, r is 0. In some embodiments, r is 1.

[0340] In some embodiments, provided herein is a compound of formula (I) having formula IIIa or a pharmaceutically acceptable salt thereof:

[0341]

[0342] In some embodiments, provided herein is a compound of formula (I) having formula IIIb or a pharmaceutically acceptable salt thereof:

[0343]

[0344] In some embodiments, A is a group having formula A-3.

[0345] In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0346] X is Cl, Br, CH3, CF3, CN, OCH3, ethyl, cyclopropyl, SCH3, or isopropyl;

[0347] A is a group having formula (A-3):

[0348]

[0349] 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 R Y each independently is H or C 1-4 alkyl;

[0350] 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 ;

[0351] Z is H, 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 ; where the C of Z 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6Each haloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: 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 ;

[0352] Cy Z is selected from C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of said groups being 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 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)ORa1 , 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 ;

[0353] R 13 , R 14 and R 15 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 a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 , C(O)OR a4 , NR c4 , C(O)NR c4 R d4 , C(=NR e4 )R b4 , C(=NR e4 )NR c4 Rd4 , NR c4 C(=NR e4 )NR c4 R d4 , NR c4 S(O)R b4 , NR c4 S(O)₂R b4 , NR c4 S(O)₂NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)₂R b4 and S(O)₂NR c4 R d4 ; wherein said R 13 , R 14 and R 15 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 a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4R d4 、C(=NR e4 )R b4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 NR c4 S(O)R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 and S(O)2NR c4 R d4 ;

[0354] Ring E is selected from C 6-10 Aryl, C 3-7 a monocyclic or polycyclic ring of a cycloalkyl group, a 5- to 10-membered heteroaryl group, or a 4- to 10-membered heterocycloalkyl group;

[0355] Q 2 and Q 3 Each is a group of formula (B-1):

[0356]

[0357] Y 4 , Y 5 and Y 6 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 ;

[0358] G 1 -C(R G )(R H )- or a group of formula (C-1), (C-2) or (C-3):

[0359]

[0360] G 2 -C(RI )(R J ) - or a group of formula (C-1), (C-2) or (C-3);

[0361] R A 、R B 、R C 、R D 、R E 、R F 、R G 、R H 、R I 、R J 、R K 、R L 、R M and R N are 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 a5 、SR a5 、C(O)R b5 、C(O)NR c5 R d5 、C(O)OR a5 、OC(O)R b5 、OC(O)NR c5 R d5 、C(=NR e5 )NR c5 R d5 、NR c5 C(=NR e5 )NR c5 R d5 、NR c5 R d5 、NR c5 C(O)R b5 、NR c5 C(O)OR a5 、NR c5 C(O)NR c5 R d5 、NR c5 S(O)Rb5 , NR c5 S(O)2R b5 , NR c5 S(O)2NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O)2R b5 and S(O)2NR c5 R d5 ; wherein said R A , R B , R C , R D , R E , R F , R G , R H , R I , R J , R K , R L , R M and R N 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 a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , C(=NR e5 )NR c5 R d5 , NR c5C(=NR e5 )NR c5 R d5 、NR c5 R d5 、NR c5 C(O)R b5 、NR c5 C(O)OR a5 、NR c5 C(O)NR c5 R d5 、NR c5 S(O)R b5 、NR c5 S(O)2R b5 、NR c5 S(O)2NR c5 R d5 、S(O)R b5 、S(O)NR c5 R d5 、S(O)2R b5 and S(O)2NR c5 R d5 ;

[0362] or R G and R I together with the carbon atom to which it is attached and together with Y 5 form a 5- to 10-membered heteroalkyl ring, said ring being 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 )NRc3 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 ;

[0363] or R C and R E Together they form a double bond between the carbon atoms to which they are attached;

[0364] or R E and R G Together they form a double bond between the carbon atoms to which they are attached;

[0365] or R I and R K Together they form a double bond between the carbon atoms to which they are attached;

[0366] or R K and R M Together they form a double bond between the carbon atoms to which they are attached;

[0367] or R K , R L , R M and R N Together they form a triple bond between the carbon atoms to which they are attached;

[0368] D 1 and D 2 are each independently selected from N and CH;

[0369] D 3 , D 4 , D 5 , D 6 , D 7 , D 8 and D 9 Each independently selected from N and CR X , where each R X are independently selected from H, halo and C 1-4 alkyl;

[0370] D 10 is O, S, NH or CH2;

[0371] Ring F is a monocyclic or polycyclic ring selected from C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of said groups being 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 a6 、SR a6 、C(O)R b6 、C(O)NR c6 R d6 、C(O)OR a6 、OC(O)R b6 、OC(O)NR c6 R d6 、C(=NR e6 )NR c6 R d6 、NR c6 C(=NR e6 )NR c6 R d6 、NR c6 R d6 、NR c6 C(O)R b6 、NR c6 C(O)OR a6 、NR c6 C(O)NR c6 R d6 、NR c6 S(O)R b6 、NR c6 S(O)2R b6 、NR c6 S(O)2NR c6 R d6 、S(O)R b6 、S(O)NR c6 R d6 、S(O)2R b6 and S(O)2NR c6 R d6 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 a6 、SR a6 、C(O)Rb6 , C(O)NR c6 R d6 , C(O)OR a6 , OC(O)R b6 , OC(O)NR c6 R d6 , C(=NR e6 )NR c6 R d6 , NR c6 C(=NR e6 )NR c6 R d6 , NR c6 R d6 , NR c6 , C(O)R b6 , NR c6 , C(O)OR a6 , NR c6 , C(O)NR c6 R d6 , NR c6 , S(O)R b6 , NR c6 , S(O)2R b6 , NR c6 , S(O)2NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O)2R b6 and S(O)2NR c6 R d6 ;

[0372] Each R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a3 , R b3 , R c3 , R d3 , R a4 , R b4 , R c4 , R d4 , R a5 , R b5 , R c5 , R d5 , R a6 , R b6 , R c6 and R d6Independently 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 , R d3 , R a4 , R b4 , R c4 , R d4 , R a5 , R b5 , R c5 , R d5 , R a6 , R b6 , R c6 and R d6 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 2-6Alkynyl, 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 ;

[0373] or R c and R d together with the N atom to which it is attached form a 4- to 7-membered heteroalkyl ring, which group 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 Rd7 , 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 ;

[0374] or R c1 and R d1 together with the N atom to which it is attached form a 4- to 7-membered heterocycloalkyl group, which group 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 , 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 , NRc7 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 ;

[0375] or R c3 and R d3 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which group 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 c7S(O)2NR c7 R d7 and S(O)2NR c7 R d7 ;

[0376] or R c4 and R d4 together with the N atom to which it is attached form a 4- to 7-membered heterocycloalkyl group, which group 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 , 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 ;

[0377] or R c5 and R d5Together with the attached N atom, form a 4- to 7-membered heterocycloalkyl group, which is optionally substituted with 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 , NR c7 S(O)2NR d7 and S(O)2NR c7 R d7 ;

[0378] or R c6 and R d6 Together with the attached N atom, form a 4- to 7-membered heterocycloalkyl group, which is optionally substituted with 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 ;

[0379] 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, C6-10 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 is 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;

[0380] Each R e , R e1 , R e3 , R e4 , R e5 , R e6 and R e7 is independently selected from H, C 1-4 Alkyl and CN;

[0381] a is 0 or 1;

[0382] b is 0, 1, 2 or 3;

[0383] c is 0, 1 or 2;

[0384] d is 0, 1 or 2;

[0385] m is 0 or 1;

[0386] n is 0 or 1;

[0387] p is 0 or 1;

[0388] q is 0 or 1;

[0389] r is 0 or 1;

[0390] t1 is 0 or 1;

[0391] t2 is 0 or 1;

[0392] t3 is 0 or 1;

[0393] u is 0, 1, 2 or 3;

[0394] v is 0 or 1; and

[0395] w is 0 or 1;

[0396] Any of the foregoing heteroaryl or heterocycloalkyl groups contains 1, 2, 3, or 4 ring heteroatoms independently selected from O, N, and S; and

[0397] One or more ring C or N atoms of any of the foregoing heterocycloalkyl groups are optionally substituted with an oxo (═O) group.

[0398] In some embodiments, Q 2 is a compound having formula B-2a:

[0399]

[0400] In some embodiments, Q 2 is a compound having formula B-2a:

[0401]

[0402] wherein Z 1 and Z 2 are each independently selected from N and CH, and wherein R is CN, Cl, or CF3.

[0403] In some embodiments, Q 3 is a compound having formula B-3a:

[0404]

[0405] In some embodiments, Q 3 is a compound having formula B-3b:

[0406]

[0407] wherein Z 1 and Z 2 are each independently selected from N and CH, and wherein R is CN, Cl, or CF3.

[0408] In some embodiments, X is Cl, Br, CH3, CF3, CN, OCH3, ethyl, cyclopropyl, SCH3, or isopropyl.

[0409] In some embodiments, ring E is a monocyclic or polycyclic ring selected from C 6-10 aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl. In some embodiments, ring E is a monocyclic or polycyclic ring selected from C 6-10 aryl. In some embodiments, ring E is a monocyclic or polycyclic ring selected from 5- to 10-membered heteroaryl. In some embodiments, ring E is a monocyclic or polycyclic ring selected from C 3-7 cycloalkyl. In some embodiments, ring E is a monocyclic or polycyclic ring selected from 4- to 10-membered heterocycloalkyl.

[0410] In some embodiments, ring E is phenyl. In some embodiments, ring E is pyridyl. In some embodiments, ring E is cyclohexyl. In some embodiments, ring E is pyridin-4(1H)-one, 4-pyridone or piperidyl.

[0411] In some embodiments, each R 14 is independently selected from H, halo, OR a4 and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with CN, OR a7 , NR c4 R d4 or NR c4 C(O)R b4 .

[0412] In some embodiments, each R 14 is independently selected from halo, methyl, ethyl and cyanomethyl, each of said groups being optionally substituted with CN, OR a7 , NR c4 R d4 or NR c4 C(O)R b4 .

[0413] In some embodiments, each R 15 is independently selected from H, halo, CN, NR c4 R d4 , OR a4 , C(O)R b4 , NRc4C(O)R b4 , C(O)NR c4 R d4 and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with CN, OR a7 , NR c4 R d4 or NR c4 C(O)R b4 .

[0414] In some embodiments, R 15 is F or Cl. In some embodiments, each R 15 is independently selected from halo and OR a4 . In some embodiments, each R 15 is independently selected from halo and NR c4 R d4 . In some embodiments, each R 15 is independently selected from halo, NR c4 C(O)Rb4 , C(O)Rb4 and C(O)NR c4 R d4 . In some embodiments, R 15 is CN. In some embodiments, R 15 is a halogen group. In some embodiments, R 15 is optionally substituted by C 1-6 alkyl, NR c4 R d4 or C(O)R b4 substituted 4-10 membered heterocycloalkyl. In some embodiments, R 15 is optionally substituted by OR a4 , NR c4 R d4 or C(O)R b4 substituted morpholinyl, piperidinyl, pyrrolidinyl.

[0415] In some embodiments, R a4 is selected from C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, each of said groups being optionally substituted by C 1-4 alkyl, OR a7 , NR c7 R d7 , C(O)NR c7 R d7 , C(O)R b7 , C(O)OR a7 or NR c7 C(O)R b7 substituted.

[0416] In some embodiments, R a4 is H or C 1-6 alkyl. In some embodiments, R a4 is pyridyl. In some embodiments, R a4 is phenyl. In some embodiments, R a4 is pyridylmethyl, pyridylethyl, tetrahydropyranylmethyl, tetrahydrofuranylmethyl, piperidinylmethyl, piperidylethyl, morpholinoethyl, piperazinoethyl, pyrrolidinylmethyl. In some embodiments, R a4 is methyl, ethyl or isopropyl. In some embodiments, R a4is piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and each of said groups is optionally substituted by an oxo(=O) group, C 1-4 alkyl, OR a7 、NR c7 R d7 、C(O)NR c7 R d7 、C(O)R b7 or NR c7 C(O)R b7 Substituted. In some embodiments, R a4 is pyrimidinyl.

[0417] In some embodiments, R b4 is C 1-6 alkyl. In some embodiments, R b4 is methyl.

[0418] In some embodiments, R c4 is H or C 1-6 alkyl. In some embodiments, R c4 is methyl.

[0419] In some embodiments, R d4 is H, C 1-6 alkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and said groups are optionally substituted by 1, 2, 3 or 4 substituents independently selected from C 1-6 alkyl, C(O)R b7 and C(O)OR a7 Substituted. In some embodiments, R d4 is methyl. In some embodiments, R d4 is tetrahydrofuranylmethyl, pyridylmethyl, pyridylethyl, morpholinyl, piperidinyl, tetrahydropyranyl or pyridyl.

[0420] In some embodiments, R a7 is H or C 1-6 alkyl. In some embodiments, R a7 is methyl.

[0421] In some embodiments, R b7 is H or C 1-6 alkyl.

[0422] In some embodiments, R c7 is H or C 1-6 alkyl.

[0423] In some embodiments, R d7 is H or C 1-6 alkyl.

[0424] In some embodiments, R b7 is H or methyl.

[0425] In some embodiments, R c7 is H or methyl.

[0426] In some embodiments, R d7 is H or methyl.

[0427] In some embodiments, Y 4 is O.

[0428] In some embodiments, Y 5 is O, NR Y , C(=O) or C(=O)NR Y .

[0429] In some embodiments, G 1 is -C(R G )(R H )-. In some embodiments, G 1 is C-2.

[0430] In some embodiments, D 3 , D 4 and D 5 are each CR X , where each R X is independently selected from H, halo, and C 1-4 alkyl.

[0431] In some embodiments, R X is H.

[0432] In some embodiments, G 2 is -C(R I )(R J )-. In some embodiments, G 2 is C-3.

[0433] In some embodiments, D 6 , D 7 and D 9 are each CR X , and D 8 is N. In some embodiments, D 6 and D 7 are each N, and D 8 and D 9 are each CR XIn some embodiments, D 6 , D 7 , D 8 and D 9 Each is CR X In some embodiments, D 6 , D 8 and D 9 Each is CR X , and D 7 is N. In some embodiments, D 6 , D 7 and D 8 Each is CR X And D 9 is N. In some embodiments, D 6 and D 8 Each is N, and D 7 and D 9 Each is CR X In some embodiments, D 6 and D 9 Each is N, and D 7 and D 8 Each is CR X .

[0434] In some embodiments, G 2 It is C-1.

[0435] In some embodiments, D 1 and D 2 Each is N and D 10 For CH2.

[0436] In some embodiments, b is 0, c is 1, and d is 1.

[0437] In some embodiments, ring F is 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, or C 3-7 Cycloalkyl, each of which is optionally substituted by C 1-6 Alkyl substituted, wherein the C 1-6 The alkyl group is optionally replaced by OR a6 In some embodiments, ring F is a 4-10 membered heterocycloalkyl or a C 3-7 Cycloalkyl, each of which is optionally substituted by methyl.

[0438] In some embodiments, ring F is piperazinyl, piperidinyl, pyrrolidinyl, pyridyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 2,8-diazaspiro[4.5]decyl, 2,5-diazabicyclo[2.2.2]octyl, 1,4-diazepanyl, azetidinyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, octahydropyrrolo[3,2-b]pyrrolyl, 2,7-diazaspiro[4.4]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, octahydropyrrolo[3,4-c]pyrrolyl, 2,7-diazaspiro[3.5]nonyl, or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine.

[0439] In some embodiments, ring F is piperazinyl. In some embodiments, ring F is cyclohexyl. In some embodiments, ring F is a 4- to 10-membered heterocycloalkyl optionally substituted with an oxo (═O) group.

[0440] In some embodiments, Z is Cy Z , CN, C 1-6 alkyl or C(O)R b , wherein said C 1-6 alkyl is optionally substituted with a halogen group. In some embodiments, Z is CF3, CH3, or CN. In some embodiments, Z is H.

[0441] In some embodiments, R b is C 1-6 alkyl optionally substituted with CN. In some embodiments, R b is methyl.

[0442] In some embodiments, Cy Z is selected from 5- to 10-membered heteroaryl and C 1-6 aryl, each optionally substituted with C 6-10 alkyl, halogen, CN, or CF3, wherein said C 1-6 alkyl is optionally substituted with CN. In some embodiments, Cy Z is pyridyl, pyrimidinyl, or pyrazinyl, each optionally substituted with C 1-6 alkyl, CN, Cl, F, S(O)2R b1 or CF3. In some embodiments, Cy Z is pyridyl, pyrimidinyl, pyrazinyl, each optionally substituted with methyl, CN, Cl, F, CF3, or S(O)2CH3. In some embodiments, Cy Z is phenyl optionally substituted with cyanomethyl or CN.

[0443] In some embodiments, Rb1 is C 1-6 alkyl. In some embodiments, R b1 is methyl.

[0444] In some embodiments, R A is H, halogen, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 substituted.

[0445] In some embodiments, R A is C 1-6 alkyl or H. In some embodiments, R A is methyl. In some embodiments, R A is H.

[0446] In some embodiments, R B is H, halogen, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 substituted.

[0447] In some embodiments, R B is C 1-6 alkyl or H. In some embodiments, R B is methyl. In some embodiments, R B is H.

[0448] In some embodiments, R C is H, halogen, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 substituted.

[0449] In some embodiments, R C is C 1-6 alkyl or H. In some embodiments, R C is methyl. In some embodiments, R C is H.

[0450] In some embodiments, R D is H, halogen, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 substituted.

[0451] In some embodiments, R D is C 1-6 alkyl or H. In some embodiments, R D is methyl. In some embodiments, R D is H.

[0452] In some embodiments, R E is H, halogen, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 substituted.

[0453] In some embodiments, R E is C1-6 alkyl or H. In some embodiments, R E is methyl. In some embodiments, R E is H.

[0454] In some embodiments, R F is H, halo, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 substituted.

[0455] In some embodiments, R F is C 1-6 alkyl or H. In some embodiments, R F is methyl. In some embodiments, R F is H.

[0456] In some embodiments, R G is H, halo, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 substituted.

[0457] In some embodiments, R G is C 1-6 alkyl or H. In some embodiments, R G is methyl. In some embodiments, R G is H.

[0458] In some embodiments, R H is H, halo, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10Aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5 or NR c5 R d5 Substituted.

[0459] In some embodiments, R H is C 1-6 alkyl or H. In some embodiments, R H is methyl. In some embodiments, R H is H.

[0460] In some embodiments, R I is H, halo, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5 or NR c5 R d5 Substituted.

[0461] In some embodiments, R I is C 1-6 alkyl or H. In some embodiments, R I is methyl. In some embodiments, R I is H.

[0462] In some embodiments, R J is H, halo, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5 or NR c5 R d5 Substituted.

[0463] In some embodiments, RJ is C 1-6 alkyl or H. In some embodiments, R J is methyl. In some embodiments, R J is H.

[0464] In some embodiments, R K is H, halogen, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 substituted.

[0465] In some embodiments, R K is C 1-6 alkyl or H. In some embodiments, R K is methyl. In some embodiments, R K is H.

[0466] In some embodiments, R L is H, halogen, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 substituted.

[0467] In some embodiments, R L is C 1-6 alkyl or H. In some embodiments, R L is methyl. In some embodiments, R L is H.

[0468] In some embodiments, R M is H, halogen, OR a5 , C 1-6 alkyl, C 6-10Aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 Substituted.

[0469] In some embodiments, R M is C 1-6 alkyl or H. In some embodiments, R M is methyl. In some embodiments, R M is H.

[0470] In some embodiments, R N is H, halogen, OR a5 , C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 6-10 aryl-C 1-4 alkyl is optionally substituted by OR a5 or NR c5 R d5 Substituted.

[0471] In some embodiments, R N is C 1-6 alkyl or H. In some embodiments, R N is methyl. In some embodiments, R N is H.

[0472] In some embodiments, R K and R M together form a double bond between the carbon atoms to which they are attached.

[0473] In some embodiments, R I and R K together form a double bond between the carbon atoms to which they are attached.

[0474] In some embodiments, each R X is H or halogen. In some embodiments, R X is H. In some embodiments, R X is F.

[0475] In some embodiments, Y 6 is C(=O), NR Y or C(=O)NR Y .

[0476] In some embodiments, R Y is H or C 1-4 alkyl. In some embodiments, R Y is H. In some embodiments, R Y is methyl.

[0477] In some embodiments, t1 is 0. In some embodiments, t1 is 1.

[0478] In some embodiments, t2 is 0. In some embodiments, t2 is 1.

[0479] In some embodiments, t3 is 0. In some embodiments, t3 is 1.

[0480] In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2.

[0481] In some embodiments, a is 0.

[0482] In some embodiments, v is 0. In some embodiments, v is 1.

[0483] In some embodiments, w is 0.

[0484] In some embodiments, w is 1.

[0485] In some embodiments, m is 0. In some embodiments, m is 1.

[0486] In some embodiments, n is 0. In some embodiments, n is 1.

[0487] In some embodiments, p is 0. In some embodiments, p is 1.

[0488] In some embodiments, q is 0. In some embodiments, q is 1.

[0489] In some embodiments, r is 1.

[0490] In other embodiments, the present disclosure provides a compound of formula I having formula IVa or a pharmaceutically acceptable salt thereof:

[0491]

[0492] In other embodiments, the present disclosure provides a compound of formula I having formula IVb or a pharmaceutically acceptable salt thereof:

[0493]

[0494] In other embodiments, provided herein are compounds of Formula I having Formula IVc or a pharmaceutically acceptable salt thereof:

[0495]

[0496] In other embodiments, provided herein are compounds of Formula I having Formula IVd or a pharmaceutically acceptable salt thereof:

[0497]

[0498] In other embodiments, provided herein are compounds of Formula I having Formula IVe or a pharmaceutically acceptable salt thereof:

[0499]

[0500] Crystalline 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0501] In some embodiments, the compound of Formula I is 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (see Example 561). The compound 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one of Example 561 may also be referred to as:

[0502] (S)-5-((1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; or

[0503] (S)-5-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0504] In some embodiments, 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one is crystalline and has the characteristics of Form A below. The synthesis and characterization of 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (including Form A) are described, for example, in Example 561.

[0505] In some embodiments, Form A has characteristic XRPD peaks selected from about 5.8, about 10.8, about 11.9, and about 17.2° 2θ. In some embodiments, Form A has at least one characteristic XRPD peak selected from about 5.8, about 10.8, about 11.9, and about 17.2° 2θ. In some embodiments, Form A has at least two characteristic XRPD peaks selected from about 5.8, about 10.8, about 11.9, and about 17.2° 2θ. In some embodiments, Form A has a characteristic XRPD peak at about 5.8° 2θ. In some embodiments, Form A has a characteristic XRPD peak at about 10.8° 2θ. In some embodiments, Form A has a characteristic XRPD peak at about 11.9° 2θ. In some embodiments, Form A has a characteristic XRPD peak at about 17.2° 2θ.

[0506] In some embodiments, Form A has at least one characteristic XRPD peak selected from about 5.8, about 10.8, about 11.9, about 13.3, about 13.5, about 15.5, and about 17.2° 2θ. In some embodiments, Form A has at least one characteristic XRPD peak selected from about 5.8, about 10.8, about 11.2, about 11.9, about 12.3, about 13.3, about 13.5, about 15.5, about 17.2, about 17.7, about 18.0, about 18.4, about 19.5, about 21.0, and about 21.6° 2θ.

[0507] In some embodiments, Form A has at least two characteristic XRPD peaks selected from about 5.8, about 10.8, about 11.9, about 13.3, about 13.5, about 15.5, and about 17.2° 2θ. In some embodiments, Form A has at least two characteristic XRPD peaks selected from about 5.8, about 10.8, about 11.2, about 11.9, about 12.3, about 13.3, about 13.5, about 15.5, about 17.2, about 17.7, about 18.0, about 18.4, about 19.5, about 21.0, and about 21.6° 2θ.

[0508] In some embodiments, Form A has at least three characteristic XRPD peaks selected from about 5.8, about 10.8, about 11.9, about 13.3, about 13.5, about 15.5, and about 17.2° 2θ. In some embodiments, Form A has at least three characteristic XRPD peaks selected from about 5.8, about 10.8, about 11.2, about 11.9, about 12.3, about 13.3, about 13.5, about 15.5, about 17.2, about 17.7, about 18.0, about 18.4, about 19.5, about 21.0, and about 21.6° 2θ.

[0509] In some embodiments, Form A has at least four characteristic XRPD peaks selected from about 5.8, about 10.8, about 11.9, about 13.3, about 13.5, about 15.5, and about 17.2° 2θ. In some embodiments, Form A has at least four characteristic XRPD peaks selected from about 5.8, about 10.8, about 11.2, about 11.9, about 12.3, about 13.3, about 13.5, about 15.5, about 17.2, about 17.7, about 18.0, about 18.4, about 19.5, about 21.0, and about 21.6° 2θ.

[0510] In some embodiments, the XRPD pattern of Form A has characteristic peaks substantially as Figure 8 shown.

[0511] In some embodiments, Form A has an endothermic peak at a temperature of about 174 °C. In some embodiments, Form A shows a weight loss of about 0.5% when heated to about 150 °C. In some embodiments, Form A has a DSC thermogram substantially as Figure 9 depicted. In some embodiments, Form A has a TGA thermogram substantially as Figure 9 depicted. In some embodiments, Form A has a DVS isotherm substantially as Figure 10 depicted.

[0512] In some embodiments, Form A has at least one characteristic XRPD peak selected from about 5.8, about 10.8, about 11.9, and about 17.2° 2θ; and has an endothermic peak at a temperature of about 174 °C. In some embodiments, Form A has at least one characteristic XRPD peak selected from about 5.8, about 10.8, about 11.9, and about 17.2° 2θ; and a DSC thermogram substantially as Figure 9 depicted. In some embodiments, Form A has at least one characteristic XRPD peak selected from about 5.8, about 10.8, about 11.9, and about 17.2° 2θ; and a DVS isotherm substantially as Figure 10 depicted.

[0513] In some embodiments, Form A can be isolated with a crystalline purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form A can be isolated with a crystalline purity greater than about 99%. In some embodiments, Form A can be isolated with a crystalline purity greater than about 99.9%. In some embodiments, Form A is substantially free of other crystalline forms. In some embodiments, Form A is substantially free of the amorphous form.

[0514] In some embodiments, Form A is provided by precipitating 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one from a solution comprising the compound and S1, where S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is selected from one of the following solvents: ethanol, methyl isobutyl ketone, isopropyl acetate, methyl tert-butyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, acetone, dichloromethane, and water. In some embodiments, S1 is a mixture of organic solvents. In some embodiments, S1 is a mixture of acetonitrile and heptane. In some embodiments, S1 is a mixture of isopropanol and ethyl acetate. In some embodiments, S1 is a mixture of chloroform and ethyl acetate. In some embodiments, S1 is a mixture of 1,4-dioxane and methanol. In some embodiments, S1 is a mixture of NMP and toluene. In some embodiments, S1 is a mixture of petroleum ether and hexane. In some embodiments, the precipitation is carried out by concentrating the solution, evaporating the solvent, lowering the temperature of the solution, adding an antisolvent, or a combination thereof.

[0515] Furthermore, it should be understood that certain features of the invention that are described in the context of individual embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention that are described in the context of a single embodiment for brevity may also be provided individually or in any suitable sub-combination.

[0516] At various places in this specification, substituents of the compounds of the invention are disclosed in groups or ranges. It is particularly contemplated that the invention includes each and every individual sub-combination of the members of such groups and ranges. By way of example, the term "C 1-6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0517] At various places in this specification, various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by the valence. For example, the term "pyridinyl / pyridyl" or "pyridine ring" can refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[0518] The term "n-membered" (where "n" is an integer) generally describes the number of ring-forming atoms in a moiety, and the number of ring-forming atoms in the moiety 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.

[0519] For compounds of the present invention in which a variable appears more than once, each variable can independently be a different moiety selected from the group defining the variable. For example, when describing a structure having two R groups present simultaneously on the same compound, the two R groups can represent different moieties independently selected from the group defined for R.

[0520] As used herein, the phrase "optionally substituted" means unsubstituted or substituted.

[0521] 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 the valence.

[0522] As used herein, the term "C" used in combination with a chemical group i-j "(where i and j are integers) represents 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 having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0523] As used herein, the term "alkyl", used alone or in combination with other terms, refers to a saturated hydrocarbon group, which can be straight-chain or branched-chain. In some embodiments, the alkyl 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) the following 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, etc. In some embodiments, the alkyl is methyl, ethyl, or propyl.

[0524] As used herein, "alkenyl", used alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon double bonds. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Exemplary alkenyls include, but are not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0525] As used herein, "alkynyl", used alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon triple bonds. Exemplary alkynyls include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.

[0526] As used herein, "halo" or "halogen", used alone or in combination with other terms, includes fluorine, chlorine, bromine, and iodine. In some embodiments, the halo group is F or Cl.

[0527] As used herein, the term "haloalkyl", used alone or in combination with other terms, refers to an alkyl group having the full valence of up to halogen atom substituents, which substituents may 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.

[0528] As used herein, the term "alkoxy", 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.

[0529] As used herein, "haloalkoxy", 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.

[0530] As used herein, "amino", used alone or in combination with other terms, refers to NH2.

[0531] 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 alkylaminos include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0532] As used herein, the term "dialkylamino", 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 carbon atoms or 1 to 4 carbon atoms.

[0533] As used herein, the term "cycloalkyl", alone or in combination with other terms, refers to a non-aromatic cycloalkane hydrocarbon including cycloalkyl and alkenyl groups. The cycloalkyl may include a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring system. The definition of cycloalkyl also includes moieties having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a common bond) to the cycloalkyl ring, such as benzo derivatives of cyclopentane, cyclohexene, cyclohexane, etc., or pyrido derivatives of cyclopentane or cyclohexane. The ring-forming carbon atoms of the cycloalkyl may optionally be substituted with oxo groups. Cycloalkyl also includes cycloalkylidene. The term "cycloalkyl" also includes bridged cycloalkyl (e.g., a non-aromatic cycloalkane hydrocarbon moiety containing at least one bridgehead carbon, such as adamantan-1-yl) and spirocycloalkyl (e.g., a non-aromatic hydrocarbon moiety containing at least two rings fused at a single carbon atom, such as spiro[2.5]octane, etc.). In some embodiments, the cycloalkyl has 3 to 10 ring members, or 3 to 7 ring members. In some embodiments, the cycloalkyl is monocyclic or bicyclic. In some embodiments, the cycloalkyl is monocyclic. In some embodiments, the cycloalkyl is C 3-7 monocyclic cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaranyl, tetrahydronaphthyl, octahydronaphthyl, indanyl, and the like. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0534] As used herein, the term "cycloalkylalkyl", alone or in combination with other terms, refers to a group of the formula cycloalkyl-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 cycloalkyl moiety has 3 to 10 ring members or 3 to 7 ring members. In some embodiments, the cycloalkyl is monocyclic or bicyclic. In some embodiments, the cycloalkyl moiety is monocyclic. In some embodiments, the cycloalkyl moiety is C 3-7 monocyclic cycloalkyl.

[0535] As used herein, the term "heterocycloalkyl", used alone or in combination with other terms, refers to a non-aromatic ring or ring system which may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure, said ring structure having at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen and phosphorus. Heterocycloalkyl may 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. Also included in the definition of heterocycloalkyl are 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 may also include bridged heterocycloalkyl (e.g., a heterocycloalkyl moiety containing at least one bridgehead atom, such as 1-azatricyclo[3.3.1.13,7]dec-1-yl and the like) and spiro heterocycloalkyl (e.g., a heterocycloalkyl moiety containing at least two rings fused at a single atom, such as [1,4-dioxa-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 may be oxidized to form a carbonyl, N-oxide or sulfonyl (or other oxidized bond) or a nitrogen atom may be quaternized. In some embodiments, the heterocycloalkyl moiety is 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.

[0536] As used herein, the term "heterocycloalkylalkyl", used 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, 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.

[0537] As used herein, the term "aryl", used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., fused ring system) aromatic hydrocarbon moiety, such as but not limited to phenyl, 1-naphthyl, 2-naphthyl, etc. In some embodiments, aryl has 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments, aryl is a monocyclic or bicyclic group. In some embodiments, aryl is phenyl or naphthyl.

[0538] As used herein, the term "aralkyl", used 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, aryl is a monocyclic or bicyclic group. In some embodiments, aralkyl is benzyl.

[0539] As used herein, the term "heteroaryl", used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., fused ring system) aromatic hydrocarbon moiety having one or more heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, 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, benzisoxazolyl, imidazo[1,2-b]thiazolyl, etc. The carbon atoms or heteroatoms in the ring of heteroaryl may be oxidized to form a carbonyl, N-oxide, or sulfonyl (or other oxidized bond) or the nitrogen atom may be quaternized, provided that the aromatic nature of the ring is retained. In some embodiments, 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, heteroaryl contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring-forming atoms. In some embodiments, heteroaryl has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

[0540] 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 atoms. In some embodiments, the alkyl moiety is methylene. In some embodiments, the heteroaryl moiety is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl moiety has 5 to 10 carbon atoms.

[0541] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are contemplated. Compounds of the invention containing an asymmetrically substituted carbon atom may be isolated in optically active or racemic form. Methods for preparing optically active forms from optically inactive starting materials are known in the art, e.g., by resolution of racemic mixtures or by stereoselective synthesis. Geometric isomers of olefins, C=N double bonds, etc. may also be present in the compounds described herein, and all such stable isomers are encompassed by the present invention. The cis and trans geometric isomers of the compounds of the invention may be isolated as mixtures of isomers or in separate isomer forms.

[0542] The compounds of the invention also include tautomeric forms. Tautomeric forms are generated by the exchange of a single bond with an adjacent double bond and the accompanying migration of a proton. Tautomeric forms include prototropic tautomers in isomeric protonated states having the same empirical formula and total charge. Exemplary prototropic tautomers include keto-enol pairs, amide-imino pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which the proton may occupy two or more positions of a heterocyclic system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or locked in one form spatially by appropriate substitution. Examples of tautomeric forms, pyridazin-3(2H)-one and pyridazin-3-ol, are depicted below:

[0543]

[0544] The compounds of the 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. By way of example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the compounds of the invention include at least one deuterium atom.

[0545] Unless otherwise specified, the term "compound" as used herein is intended to include all stereoisomers, geometric isomers, tautomeric forms, and isotopes of the depicted structure.

[0546] All compounds and their pharmaceutically acceptable salts may be found together with other substances such as, for example, water and solvents (e.g., in the form of hydrates and solvates) or may be isolated.

[0547] In some embodiments, the compounds or salts of the invention are substantially isolated. “Substantially isolated” means that the compound is at least partially or substantially separated from its formation or detection environment. Partial separation may include, for example, a composition enriched in the compound of the invention. Substantial separation may 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 or salt of the invention. Methods for separating compounds and their salts are conventional in the art.

[0548] As used herein, the term “crystalline” or “crystalline form” refers to the crystalline solid form of a compound, including but not limited to single-component or multi-component crystal forms, such as including solvates, hydrates, clathrates and co-crystals. As used herein, “crystalline form” is intended to refer to a specific lattice configuration of a crystalline substance. Different crystalline forms of the same substance typically have different crystal lattices (e.g., unit cells), which contribute to different physical properties characteristic of each crystalline form. In some cases, different lattice configurations have different water or solvent contents. Different crystal lattices can be identified by solid-state characterization methods such as, for example, X-ray powder diffraction (XRPD). Other characterization methods such as, for example, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), solid-state NMR, etc. further assist in the identification of crystalline forms and in determining stability and solvent / water content.

[0549] The crystalline forms of a substance include solvated (e.g., hydrated) and non-solvated (e.g., anhydrous) forms. Hydrated forms are crystalline forms that include water in the lattice. Hydrated forms may be stoichiometric hydrates, where water is present in the lattice in a specific water / molecule ratio, e.g., for hemihydrates, monohydrates, dihydrates, etc. Hydrated forms may also be non-stoichiometric, where the water content is variable and depends on external conditions such as, for example, humidity.

[0550] As used herein, the term "substantially crystalline" means that most of the weight of a sample or preparation of a salt (or its hydrate or solvate) of the invention is crystalline and the remainder of the sample is in an amorphous form (e.g., an amorphous form) of the same compound. In some embodiments, a substantially crystalline sample has at least about 95% crystallinity (e.g., about 5% of the amorphous form of the same compound), preferably at least about 96% crystallinity (e.g., about 4% of the amorphous form of the same compound), more preferably at least about 97% crystallinity (e.g., about 3% of the amorphous form of the same compound), even more preferably at least about 98% crystallinity (e.g., about 2% of the amorphous form of the same compound), still more preferably at least about 99% crystallinity (e.g., about 1% of the amorphous form of the same compound) and most preferably about 100% crystallinity (e.g., about 0% of the amorphous form of the same compound). In some embodiments, the term "fully crystalline" means at least about 99% or about 100% crystallinity.

[0551] Crystalline forms are most often characterized by XRPD. The XRPD pattern of the reflections (peaks) is generally regarded as a fingerprint of a particular crystalline form. It is well known that the relative intensities of XRPD peaks can vary widely depending especially on the sample preparation technique, crystal size distribution, filter, sample mounting procedure and the particular instrument used. In some cases, depending on the type or setting of the instrument (e.g., whether a Ni filter is used), new peaks may be observed or existing peaks may disappear. As used herein, the term "peak" refers to a reflection having a relative height / intensity of at least about 4% of the maximum peak height / intensity. In addition, instrument variations and other factors can affect the 2θ values. Thus, peak assignments (e.g., the assignments reported herein) can vary by ± about 0.2° (2θ), and as used herein in the context of XRPD, the term "substantially" is intended to cover the variations mentioned above.

[0552] In the same manner, temperature readings associated with DSC, TGA or other thermal experiments can vary by about ±3 °C depending on the instrument, particular settings, sample preparation, etc. For example, in the case of DSC, it is known that the observed temperature will depend on the rate of temperature change as well as the sample preparation technique and particular instrument used. Thus, as noted above, the values reported herein in connection with DSC thermograms can vary by ±3 °C. Accordingly, a crystalline form reported herein having a DSC thermogram "substantially" as shown in any of the figures should be understood to accommodate such variations.

[0553] As used herein and unless otherwise specified, the term "about" when used in connection with a value provided to describe a particular solid form (e.g., a particular temperature or temperature range, e.g., describing melting, dehydration or glass transition; mass change, e.g., mass change as a function of temperature or humidity; solvent or water content in terms of, e.g., mass or percentage; or peak position, e.g., in the case of 13When combined with the values or ranges of values in the analysis of 13C NMR, DSC, TGA, and XRPD), it is indicated that the said values or ranges of values may deviate to the extent considered reasonable by those of ordinary skill in the art while still describing a particular solid form.

[0554] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, substances, compositions, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for 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.

[0555] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, the term "pharmaceutically acceptable salt" 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); alkali metal salts or organic salts of acidic residues (such as carboxylic acids); and the like. The 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. The 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 an organic solvent or in a mixture of both. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985, page 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), which are hereby incorporated by reference in their entirety.

[0556] Synthesis

[0557] 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 numerous possible synthetic routes.

[0558] The reactions for preparing the compounds of the present invention can be carried out in a suitable solvent, which can be readily selected by those skilled in the art of organic synthesis. A suitable solvent is substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, for example, at 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, the solvent suitable for a particular reaction step can be selected by a skilled person.

[0559] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemical properties of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0560] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means (such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible) or mass spectrometry) or by chromatography (such as high performance liquid chromatography (HPLC) or thin layer chromatography).

[0561] As used herein, the expressions "ambient temperature", "room temperature" and "RT" are understood in the art and generally refer to the temperature of the room in which the reaction is carried out, for example, a temperature in the range of about 20 °C to about 30 °C, such as the reaction temperature.

[0562] 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 indicated, all substituents are as defined herein.

[0563] In the process depicted in Scheme 1, the appropriately substituted halogen-containing compound of formula (1-1) (i.e., X a = Cl or Br) is protected in the form of the 2-(trimethylsilyl)ethoxymethyl ether ("SEM") of the compound of formula (1-2) by treatment with 2-(trimethylsilyl)ethoxymethyl chloride ("SEM-Cl") in the presence of sodium hydride (NaH).

[0564] Scheme 1

[0565]

[0566] The compound of formula (1-2) can react with a variety of nucleophiles to give the compound of formula (I) after removal of the SEM protecting group, as shown in Schemes 2-4.

[0567] In the process depicted in Scheme 2, the compound of formula (1-2) (where Y a is O, NR YCompound (1-2) or (1-3) reacts with a compound of formula (1-5) in the presence of a base (e.g., triethylamine or Cs2CO3) to give a compound of formula (1-6). Deprotection with an acid (e.g., trifluoroacetic acid or hydrochloric acid) gives a compound of formula (IB).

[0568] Scheme 2

[0569]

[0570] In the process depicted in Scheme 3, compound (1-2) reacts with a compound of formula (1-5) in the presence of a base (e.g., triethylamine or Cs2CO3) to give a compound of formula (1-6). Deprotection with an acid (e.g., trifluoroacetic acid or hydrochloric acid) gives a compound of formula (IB).

[0571] Scheme 3

[0572]

[0573] In the process depicted in Scheme 4, compound (1-2) reacts with a compound of formula (1-7) in the presence of a base (e.g., triethylamine or Cs2CO3) to give a compound of formula (1-8). Deprotection with an acid (e.g., trifluoroacetic acid or hydrochloric acid) gives a compound of formula (IC).

[0574] Scheme 4

[0575]

[0576] Usage method

[0577] The compounds of the present invention can inhibit the activity of PARP7. For example, the compounds of the present invention can be used to inhibit PARP7 activity in cells or in an individual or patient in need of enzyme inhibition by administering an inhibitory amount of the compounds of the present invention to the cells, individual or patient.

[0578] As PARP7 inhibitors, 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 treatable according to the present invention include 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 (upper respiratory and digestive tract cancer), urethral cancer, colon cancer and other cancers.

[0579] In some embodiments, cancers treatable according to the 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 leukemia (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).

[0580] Other cancers treatable by administration of a compound of the 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), bowel 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.

[0581] In some embodiments, cancers treatable by administration of a compound of the 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.

[0582] The PARP7 inhibitors of the invention may also have therapeutic utility in PARP7-related disorders in, for example, the fields of cardiology, virology, neurodegeneration, inflammation, and pain, particularly diseases characterized by overexpression or increased activity of PARP7.

[0583] 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 may be a part of a tissue sample excised from an organism (such as a mammal). In some embodiments, an in vitro cell may be a cell in a cell culture. In some embodiments, an in vivo cell is a cell that resides in an organism (such as a mammal).

[0584] As used herein, the term "contact" means bringing the indicated moieties together in an in vitro system or an in vivo system. By way of example, "contacting" PARP7 or a cell with a compound of the invention includes administering the compound of the invention to an individual or patient having PARP7, such as a human, and, for example, introducing the compound of the invention into a sample containing a cell or a purified preparation containing PARP7.

[0585] As used herein, the terms "individual" or "patient" are used interchangeably and refer to a mammal, and particularly a human.

[0586] As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits a biological or pharmaceutical response sought by a researcher, veterinarian, medical doctor, or other clinician in a tissue, system, animal, individual, or human.

[0587] As used herein, the term "treating / treatment" means 1) inhibiting a disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., arresting 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).

[0588] As used herein, the term "preventing / prevention" means preventing a disease in an individual who may be predisposed to the disease but has not yet experienced or displayed the pathology or symptomatology of the disease.

[0589] Combination therapy

[0590] One or more additional pharmaceutical agents or treatment methods, such as chemotherapeutic agents or other anti-cancer agents, immunostimulants, immunosuppressants, immunotherapies, radiation, anti-tumor and anti-viral vaccines, cytokine therapies (such as IL2, GM-CSF, etc.) and / or kinases (tyrosine or serine / threonine), epigenetic or signal transduction inhibitors can be used in combination with the compounds of the present invention. The agents can be combined with the compounds of the present invention in the form of a single dosage form, or the agents can be administered simultaneously or sequentially in separate dosage forms.

[0591] 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 combined 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 megestrol acetate); and estrogen receptor antagonists (such as fulvestrant). Antihormonal agents suitable for the treatment of prostate cancer and other cancers can also be combined with the compounds of the present invention. These include antiandrogens, including but not limited to flutamide, bicalutamide and nilutamide; luteinizing hormone-releasing hormone (LHRH) analogs, including leuprolide, goserelin, triptorelin and histrelin; LHRH antagonists (such as degarelix); androgen receptor blockers (such as enzalutamide); and agents that inhibit androgen production (such as abiraterone).

[0592] Combinations of angiogenesis inhibitors and FGFR inhibitors can be effective in some tumors. These include antibodies against VEGF or VEGFR or kinase inhibitors of VEGFR. Antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept. VEGFR kinase inhibitors and other antiangiogenic inhibitors include but are not limited to sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib and vandetanib.

[0593] Suitable chemotherapeutic agents or other anticancer agents include, for example, alkylating agents (including but not limited to nitrogen mustard, 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.

[0594] Other anti-cancer agents include antibody therapeutics directed against checkpoint or costimulatory molecules such as CTLA-4, PD-1, PD-L1, or 4-1BB, or antibodies directed 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.

[0595] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled 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., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0596] Pharmaceutical preparations and dosage forms

[0597] The compounds of the present invention, when used as medicaments, 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 a variety of routes, depending on whether local or systemic treatment is required and the area being treated. Administration can be oral, topical (including ophthalmic and 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.

[0598] The present invention also includes a pharmaceutical composition, which contains a combination of one or more of the compounds of the present invention and one or more pharmaceutically acceptable carriers as an active ingredient. When preparing the composition of the present invention, the active ingredient is usually mixed with an excipient, diluted by the excipient or encapsulated in such a carrier in the form of, for example, a capsule, sachet, paper or other container. When the excipient acts 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. Therefore, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form 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.

[0599] The composition can be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable for use in unit dose form for human subjects and other mammals, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0600] The active compound can be effective within a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it should be understood that the amount of the compound actually administered will usually be determined by the physician according to the relevant circumstances, including the disorder to be treated, the route of administration selected, the actual compound to be administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0601] To prepare solid compositions (such as tablets), the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present invention. When these preformulation compositions are referred to as homogeneous compositions, the active ingredient is usually uniformly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills and capsules. This solid preparation is then subdivided into unit dosage forms of the type described above containing, for example, from 0.1 to about 500 mg of the active ingredient of the present invention.

[0602] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form with the advantage of extended action. For example, the tablet or pill can contain an internal dose and an external dose component, the latter in the form of a coating enclosing the former. The two components can be separated by an enteric layer, which is used to prevent disintegration in the stomach and allow the internal component to enter the duodenum intact or with a delayed release. A variety of materials can be used for such enteric layers or enteric coatings, and such materials include a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

[0603] The compounds and compositions of the present invention can be combined and used in liquid forms for oral or parenteral administration, including aqueous solutions; properly flavored syrups, aqueous or oily suspensions; and flavored emulsions with edible oils (such as cottonseed oil, sesame oil, coconut oil, or peanut oil); as well as elixirs and similar pharmaceutical vehicles.

[0604] Compositions for inhalation or insufflation include solutions and suspensions and powders in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effects. The compositions can be atomized using an inert gas. The atomized solution can be inhaled directly from the atomizing device or the atomizing device can be connected to a face mask holder 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.

[0605] The amount of the compound or composition administered to a patient will vary depending on the substance being administered, the purpose of administration (e.g., prophylaxis or treatment), the patient's condition, 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 will be determined by the attending clinician based on factors such as the severity of the disease, the age, weight, and general condition of the patient, etc.

[0606] The compositions administered to a patient can be in the form of the pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered. The aqueous solution can be encapsulated for use as is or lyophilized, and the lyophilized preparation is combined with a sterile aqueous carrier before administration.

[0607] The therapeutic dose of the compounds of the present invention can vary depending on, for example, the specific use for which treatment is being carried out, the mode of administration of the compound, the health and condition of the patient, and the judgment of the attending 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 dose, 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 to about 10% w / v of the compound for parenteral administration. Some typical dose ranges are from about 1 μg to about 1 g per kilogram of body weight per day. In some embodiments, the dose range is from about 0.01 mg to about 100 mg per kilogram of body weight per day. The dose may depend on variables such as, for example: the type and degree of progression of the disease or disorder, the overall health of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. The effective dose can be extrapolated from the dose-response curve derived from in vitro or animal model test systems.

[0608] The compounds of the present invention can also be formulated in combination with one or more additional active ingredients, and the one or more additional active ingredients may include any pharmaceutical agent, such as antiviral agents, anticancer agents, vaccines, antibodies, immunostimulants, immunosuppressants, anti-inflammatory agents, etc.

[0609] Examples

[0610] Equipment : 1 1H NMR spectra were recorded at 300 or 400 MHz using a Bruker AVANCE 300 MHz / 400 MHz spectrometer. NMR interpretation was performed using Bruker Topspin software to assign chemical shifts and multiplicities. In cases where two adjacent peaks of equal or unequal height were observed, the two peaks could be labeled as a multiplet or doublet. In the case of a doublet, the coupling constant could be assigned using this software. In any given example, one or more protons may not be observable due to being obscured by water and / or solvent peaks. The LCMS equipment and conditions are as follows:

[0611] 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 um. Mobile phase: A: water / 5 mM NH4HCO3, B: acetonitrile. Flow rate: 1.2 mL / min, at 40 °C. Detector: 254 nm, 220 nm. Gradient stop time, 2.9 minutes. Schedule:

[0612] T (minutes) A(％) B(％) 0.01 90 10 2.10 5 95 2.70 5 95 2.90 90 10

[0613] 2. LC (acidic conditions): Shimadzu LC-20AD, binary pump, diode array detector. Column: AscentisExpress C18, 50 × 3.0 mm, 2.7 um. Mobile phase: A: water / 0.05% TFA, B: acetonitrile / 0.05% TFA. Flow rate: 1.5 mL / min, at 40 °C. Detector: 254 nm, 220 nm. Gradient stop time, 2.9 minutes. Schedule:

[0614] T (minutes) A(％) B(％) 0.01 90 5 2.10 5 95 2.70 5 95 2.90 90 5

[0615] 1.S: LCMS-2020, Quadrupole LC / MS, ion source: ES-API, TIC: 90~900 m / z, fragmenter: 60, drying gas flow: 15 L / min, nebulizing gas flow: 1.5 L / min, drying gas temperature: 250 °C, Vcap: 1100 V.

[0616] 2. Sample preparation: Dissolve the sample at 1 - 10 mg / mL in ACN or methanol, and then filter through a 0.22 μm filter membrane. Injection volume: 1 - 10 μL.

[0617] XRPD analysis: For XRPD analysis, a PANalytical Empyrean / X'Pert3 X-ray powder diffractometer is used. The XRPD parameters used are listed below:

[0618] XRPD parameters

[0619]

[0620] The term "2Th" refers to 2θ. The term "FWIM" refers to full width at half maximum. The term "rel.int." refers to relative intensity.

[0621] DSC / TGA analysis: TGA data is collected using a TA Q5000 / Q5500 TGA obtained from TA Instruments. DSC is performed using a TA Q2000 / Q2500 DSC from TA Instruments. The detailed parameters used are listed below:

[0622] Parameters for TGA and DSC

[0623] Parameters TGA DSC Method Uniform change Uniform change Sample pan Aluminum, open Aluminum, tightened Temperature RT - Desired temperature 25°C - Desired temperature Heating rate 10°C / min 10°C / min Purge gas <![CDATA[N2]]> <![CDATA[N2]]>

[0624] DVS analysis: DVS is measured via an SMS (Surface Measurement Systems) DVS Intrinsic. The relative humidity at 25 °C is calibrated against the deliquescence points of LiCl, Mg(NO3)2, and KCl. The parameters used for the DVS test are listed below:

[0625] Parameters for DVS test

[0626]

[0627] RH = relative humidity. dm / dt = rate of change of moisture content over time.

[0628] Definition:ACN (acetonitrile); Ac2O (acetic anhydride); AIBN (2,2'-azobis(2-methylpropionitrile)); BHMPO (N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide); Boc (tert-butoxycarbonyl); Boc2O (di-tert-butyl dicarbonate); CAN (ammonium cerium(IV) nitrate); CsF (cesium fluoride); CuI (copper(I) iodide); CCl4 (carbon tetrachloride); CH3CN (acetonitrile); CDCl3 (deuterochloroform); CD3OD (deuteromethanol); Cu(acac)2 (copper(II) acetylacetonate); Dess Martin (1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DEA (diethylamine); DEAD (diethyl azodicarboxylate); DIAD (diisopropyl azodicarboxylate); DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); DMAP (4-dimethylaminopyridine); DMSO (dimethyl sulfoxide); DMSO-d6 (deuterated dimethyl sulfoxide); DPPA (diphenylphosphoryl azide); eq (equivalent); EDCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); EtOAc (ethyl acetate); EtOH (ethanol); g (gram); h (hour); Grubbs 2nd generation catalyst (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium; (HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridin-3-ium 3-oxide hexafluorophosphate); HOBT (hydroxybenzotriazole); 11H NMR (Proton Nuclear Magnetic Resonance); HCl (Hydrochloric Acid); Hz (Hertz); IPA (Isopropyl Alcohol); K2CO3 (Potassium Carbonate); L (Liter); LiCl (Lithium Chloride); LCMS (Liquid Chromatography-Mass Spectrometry); M (Mole); MeOH (Methanol); mg (Milligram); MHz (Megahertz); min (Minute); MtBE (Methyl tert-Butyl Ether); mL (Milliliter); mmol (Millimole); Ms2O (Methanesulfonic Anhydride); NaCl (Sodium Chloride); NaH (Sodium Hydride); NaHMDS (Sodium Bis(trimethylsilyl)amide); NH4Cl (Ammonium Chloride); NaN3 (Sodium Azide); NBS (N-Bromosuccinimide); NMP (N-Methyl-2-pyrrolidone); Pd(allyl)Cl2 (Bis(η3-allyl)di(μ-chloro)dipalladium(II)); Pd(dppf)Cl2 ([1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)); Preparative HPLC (Preparative High Performance Liquid Chromatography); ppm (Parts Per Million); PMB (4-Methoxybenzyl); Rockphos (2-Di(tert-butyl)phosphino-2,4,6'-triisopropyl-3-methoxy-6-methylbiphenyl)); RT (Room Temperature); SEM (2-(Trimethylsilyl)ethoxymethyl); SEMCl (2-(Trimethylsilyl)ethoxymethyl Chloride); TBAF (Tetrabutylammonium Fluoride); TEA (Triethylamine); THF (Tetrahydrofuran); TsCl (Toluenesulfonyl Chloride); tR (Retention Time); T3P (1-Propane Phosphonic Anhydride); TfOH (Trifluoromethanesulfonic Acid); TFA (Trifluoroacetic Acid); TLC (Thin Layer Chromatography); TMSI (Iodotrimethylsilane); v / v (Volume / Volume).

[0629] Synthesis of Intermediate

[0630] Int-A1: 2-(Piperazin-1-yl)pyrimidine-5-carbonitrile Dihydrochloride

[0631]

[0632] Step 1: tert-Butyl 4-(5-cyanopyrimidin-2-yl)piperazine-1-carboxylate

[0633] A solution of 2-chloropyrimidine-5-carbonitrile (5 g, 35.83 mmol, 1 equivalent), tert-butyl piperazine-1-carboxylate (6.7 g, 35.97 mmol, 1.00 equivalent) and K2CO3 (9.9 g, 71.63 mmol, 2.00 equivalents) in NMP (80 mL) was stirred at 80 °C for 1 hour. The resulting mixture was diluted with 1 L of water, and the solid was collected by filtration and dried in an oven to give 8.4 g of the title compound as a white solid. LCMS: [M+H] + 290.15.

[0634] Step 2: 2-(Piperazin-1-yl)pyrimidine-5-carbonitrile dihydrochloride

[0635] A solution of tert-butyl 4-(5-cyanopyrimidin-2-yl)piperazine-1-carboxylate (8.4 g, 29.03 mmol, 1 eq) in HCl / dioxane (40 mL, 4 M) was stirred at room temperature for 1 h, then the resulting solution was concentrated in vacuo to afford 6.4 g (76%) of the title compound as a white solid. LCMS: [M+H] + 190.10

[0636] Int-A2: 2-(Piperazin-1-yl)-5-(trifluoromethyl)pyrimidine dihydrochloride

[0637]

[0638] Step 1: tert-Butyl 4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxylate

[0639] A solution of 2-chloro-5-(trifluoromethyl)pyrimidine (100 g, 550 mmol, 1.05 eq), tert-butyl piperazine-1-carboxylate (96.7 g, 520 mmol, 1 eq) and K2CO3 (151.8 g, 1100 mmol, 2 eq) in NMP (800 mL) was stirred at 80 °C for 1 h, then 2.5 L of H2O was added. The solid was collected by filtration to afford 190 g (94%) of the title compound as a white solid. LCMS: [M+H] + 333.16

[0640] Step 2: 2-(Piperazin-1-yl)-5-(trifluoromethyl)pyrimidine

[0641] A solution of tert-butyl 4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxylate (190 g, 571.73 mmol, 1 eq) in HCl / dioxane (800 mL / 4 M) was stirred at room temperature for 1 h. The solid was collected by filtration to afford 154 g (99%) of the title compound as a white solid. LCMS: [M+H] + 199.08

[0642] Int-A3: 5-Chloro-2-(piperazin-1-yl)pyrimidine dihydrochloride

[0643]

[0644] Step 1: tert-Butyl 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate

[0645] A solution of 2,5-dichloropyrimidine (19.4 g, 13.00 mmol, 1.05 equiv), tert-butyl piperazine-1-carboxylate (23 g, 12.40 mmol, 1 equiv) and K2CO3 (34 g, 25.00 mmol, 2 equiv) in NMP (500 mL) was stirred at 80 °C for 1 h, then 600 mL of H2O was added to the resulting solution. The solid was collected by filtration to give 41 g of the crude title compound as a white solid. LCMS: [M+H] + 299.13.

[0646] Step 2: 5-chloro-2-(piperazin-1-yl)pyrimidine dihydrochloride

[0647] A solution of tert-butyl 4-(5-chloropyrimidin-2-yl)piperazine-1-carboxylate (41 g, 14.00 mmol, 1 equiv) in HCl / dioxane (500 mL / 4 M) was stirred at room temperature for 1 h. The solid was collected by filtration to give 26.7 g of the title compound as a white solid. LCMS: [M+H] + 199.08.

[0648] Int-A4: 6-(piperazin-1-yl)pyridine-3-carbonitrile dihydrochloride

[0649]

[0650] Step 1: tert-butyl 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate

[0651] A solution of 6-chloropyridine-3-carbonitrile (90 g, 650 mmol, 1.05 equiv), tert-butyl piperazine-1-carboxylate (114.3 g, 620 mmol, 1 equiv) and K2CO3 (171.1 g, 124 mmol, 2 equiv) in NMP (500 mL) was stirred at 80 °C for 1 h, then 1.5 L of H2O was added to the resulting solution. The solid was collected by filtration to give 195 g of the title compound as a white solid. LCMS: [M+H] + 289.17.

[0652] Step 2: 6-(piperazin-1-yl)pyridine-3-carbonitrile dihydrochloride

[0653] tert-butyl 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate (195 g, 680 mmol, 1 equiv) and HCl / dioxane (800 mL / 4 M) were stirred at room temperature for 1 h. The solid was collected by filtration to give 160 g of the title compound as a white solid. LCMS: [M+H] + 189.12.

[0654] Int-A5: 1-(5-chloropyridin-2-yl)piperazine dihydrochloride

[0655]

[0656] Step 1: tert-Butyl 4-(5-chloropyridin-2-yl)piperazine-1-carboxylate

[0657] A solution of tert-butyl piperazine-1-carboxylate (10 g, 53.69 mmol, 1.00 eq), NMP (30 mL), potassium carbonate (13.4 g, 96.95 mmol, 1.80 eq) and 2,5-dichloropyridine (8.7 g, 58.79 mmol, 1.10 eq) was stirred at 110 °C for 20 h. Then 500 mL of H2O was added to the reaction mixture. The solid was collected by filtration to give 10.2 g (64%) of the title compound as a pale yellow solid. LCMS: [M+H] + 298.12

[0658] Step 2: 1-(5-chloropyridin-2-yl)piperazine dihydrochloride

[0659] A solution of tert-butyl 4-(5-chloropyridin-2-yl)piperazine-1-carboxylate (10.2 g, 34.25 mmol, 1.00 eq) and HCl / dioxane (50 mL / 4 M) was stirred at room temperature for 1 h. The solid was collected by filtration to give 7.4 g (80%) of the title compound as a pale yellow solid. LCMS: [M+H] + 198.07

[0660] Int-A6: 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one

[0661]

[0662] Step 1: 4,5-Dibromo-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0663] To a solution of 4,5-dibromo-2,3-dihydropyridazin-3-one (3500 g, 13.78 mol, 1.00 equiv) in DMF (30 L) was added sodium hydride (400 g, 16.56 mol, 1.20 equiv) portionwise at 0 °C under nitrogen. The resulting solution was stirred at room temperature for 1 h, followed by dropwise addition of [2-(chloromethoxy)ethyl]trimethylsilane (2500 g, 15.2 mol, 1.10 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Then the reaction was quenched by addition of 30 L of water. The resulting solution was extracted with 3 × 50 L of EtOAc and the organic layers were combined. The organic layer was washed with 3 × 30 L of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4.2 kg of the title compound. LCMS: [M+H] + 384.70。

[0664] Step 2: 4-Bromo-5-chloro-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0665] To a solution of 4,5-dibromo-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (2200 g, 5.73 mol, 1.00 equiv) in NMP (6 L) was added lithium chloride (231 g, 5.73 mol, 1.00 equiv) and the resulting solution was stirred at 95 °C for 4 h. This reaction was repeated again in 2000 g scale batches. After completion, the two batches of reactants were combined and then diluted by addition of 10 L of water, extracted with 3 × 20 L of EtOAc and the organic layers were combined. The organic layer was washed with 3 × 20 L of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc: petroleum ether, 1:50, v / v). In total, 2.2 kg (59% yield) of the title compound was obtained from 4.2 kg of 4,5-dibromo-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one starting material. LCMS: [M+H] + 340.90。

[0666] Step 3: 5-Chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0667] At room temperature, CuI (56 g, 0.64 mol, 0.20 eq) was added to a solution of 4-bromo-5-chloro-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1100 g, 3.23 mol, 1.00 eq) in NMP (6 L), and then methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1865 g, 9.7 mol, 3.00 eq) was added dropwise. The resulting solution was stirred at 80 °C for 2 h. Then the reaction mixture was quenched by adding 10 L of water and extracted with 3 × 10 L of EtOAc. The organic layers were combined, washed with 3 × 10 L of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc / petroleum ether, 1 / 100, v / v) to give 1030 g (76%) of the title compound. LCMS: [M+H] + 329.00。 1 H NMR (300 MHz, CDCl3) δ 7.82 (s, 1H), 5.50 (d, J = 27.3 Hz, 2H), 3.74 (dt, J = 12.9, 8.2 Hz, 2H), 0.97 (td, J = 8.3, 5.0 Hz, 2H), 0.01 (d, J = 2.1 Hz, 9H).

[0668] Int-A7: 4,5-dichloro-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0669]

[0670] A solution of 4,5-dichloro-2,3-dihydropyridazin-3-one (10 g, 60.62 mmol, 1 eq) in DMF (40 mL) was stirred at 0 °C and NaH (2.9 g, 121.23 mmol, 2 eq) was added in several portions at 0 °C. The mixture was stirred at 0 °C for 30 min, and then [2-(chloromethoxy)ethyl]trimethylsilane (13 g, 78.80 mmol, 1.3 eq) was added slowly at 0 °C. The resulting solution was stirred at 0 °C for an additional 10 min. Then the reaction mixture was quenched by adding 100 mL of water. The resulting solution was extracted with 2 × 80 mL of EtOAc and the organic layers were combined. The resulting solution was extracted with 3 × 60 mL of NaCl (aqueous solution) and the organic layers were combined and concentrated in vacuo. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (4 / 96) to give 9 g (50%) of the title compound as a yellow oil. LCMS: [M-Cl] + 295.04。

[0671] Int-A8: 4,5-Dibromo-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0672]

[0673] Under nitrogen at 0 °C, NaH (400 g, 16.56 mol, 1.20 eq) was added portionwise to a solution of 4,5-dibromo-2,3-dihydropyridazin-3-one (3500 g, 13.78 mol, 1.00 eq) in DMF (30 L). The resulting solution was stirred at room temperature for 1 h, then 2-[(chloromethoxy)ethyl]trimethylsilane (2500 g, 15.2 mol, 1.10 eq) was added dropwise at 0 °C and the mixture was stirred at room temperature for 2 h. The reaction was then quenched by the addition of 30 L of water. The resulting solution was extracted with 3 x 50 L of EtOAc and the organic layers were combined. The organic layer was washed with 3 x 30 L of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 4.2 kg of the title compound. LCMS: [M+H] + 384.70

[0674] Int-A9: 3-[2-[(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic acid

[0675]

[0676] Step 1: tert-Butyl 3-[2-[(5-chloro-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate

[0677] A solution of tert-butyl 3-(2-hydroxyethoxy)propanoate (778.8 mg, 4.09 mmol, 1.00 eq), S2 K2CO3 (2.66 g, 8.16 mmol, 2.00 eq) and 4,5-dichloro-2-[2-(trimethylsilyl)ethoxy]methyl-2,3-dihydropyridazin-3-one (1.2 g, 4.06 mmol, 1.00 eq) in ACN (15 mL) was stirred at 80 °C for 3 h. The solid was filtered off and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using EtOAc / petroleum ether (1:1) to give 200 mg (11%) of the title compound as a white solid. LCMS: [M+H] + 449.01

[0678] Step 2: 3-[2-[(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic acid

[0679] A solution of tert-butyl 3-[2-[(5-chloro-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propionate (10 mg, 0.02 mmol, 1.00 equiv) in TFA (2 mL) and DCM (10 mL) was stirred at room temperature for 0.5 h. After completion, the crude product was directly concentrated under reduced pressure to afford 776 mg of the title compound as a white solid. LCMS: [M+H] + 263.01.

[0680] Int-A10: 3-[2-[(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]ethoxy]propionic acid

[0681]

[0682] Step 1: Methyl 3-(2-(tert-butoxycarbonylamino)ethoxy)propionate

[0683] A solution of N-(2-hydroxyethyl)carbamic acid tert-butyl ester (6 g, 37.2 mmol, 1.00 equiv), sodium hydride (2 g, 83.3 mmol, 1.50 equiv), and methyl 3-bromopropionate (6.18 g, 37.0 mmol, 1.00 equiv) in THF (40 mL) was stirred at 25 °C overnight. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (1:3, v:v) to afford 1.6 g (17%) of the title compound as a colorless oil. LCMS: [M+H] + 248.14.

[0684] Step 2: Methyl 3-(2-aminoethoxy)propionate hydrochloride

[0685] A solution of methyl 3-(2-[[(tert-butoxy)carbonyl]amino]ethoxy)propionate (1.6 g, 6.47 mmol, 1.00 equiv) in HCl / dioxane (20 mL / 4 M) was stirred at 25 °C for 1 h. The resulting mixture was concentrated in vacuo to afford 900 mg (95%) of the title compound as a colorless oil. LCMS: [M+H] + 148.09.

[0686] Step 3: Methyl 3-[2-[(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]ethoxy]propionate

[0687] A solution of methyl 3-(2-aminoethoxy)propionate (955 mg, 6.5 mmol, 1.00 equiv), 4,5-dichloro-2,3-dihydropyridazin-3-one (1.06 g, 6.43 mmol, 1.00 equiv) and TEA (1.95 g, 19.3 mmol, 3.00 equiv) in EtOH (20 mL) was stirred overnight at 80 °C. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with EtOAc / petroleum ether (3:1) to give 1.2 g (67%) of the title compound as a yellow oil. LCMS: [M+H] + 276.07.

[0688] Step 4: 3-[2-[(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]ethoxy]propanoic acid

[0689] A solution of methyl 3-[2-[(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]ethoxy]propionate (1.2 g, 4.35 mmol, 1.00 equiv) and LiOH·H2O (488 mg, 11.6 mmol, 2.00 equiv) in water (50 mL) and MeOH (50 mL) was stirred overnight at 50 °C. The resulting mixture was concentrated under reduced pressure to give 800 mg (70%) of the title compound as a yellow oil. LCMS: [M+H] + 262.05.

[0690] Int-A11: 3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)propanoic acid

[0691]

[0692] Step 1: tert-Butyl 3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]ethoxy)propionate

[0693] A solution of Int-A6 (1.1 g, 3.4 mmol, 1 equiv), Cs2CO3 (2.2 g, 6.8 mmol, 2 equiv), tert-butyl 3-(2-hydroxyethoxy)propionate (649.2 mg, 3.41 mmol, 1 equiv) in MeCN (20 mL) was stirred at room temperature for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (16 / 84) to give 1 g (61%) of the title compound as a yellow oil. LCMS: [M+H] + 483.21.

[0694] Step 2: 3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)propanoic acid

[0695] A solution of tert-butyl 3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]ethoxy)propanoate (450 mg, 0.93 mmol, 1 equiv) and TFA (1 mL) in DCM (10 mL) was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN to afford 110 mg (40%) of the title compound as a white oil. LCMS: [M+H] + 297.06.

[0696] Int-A12: 3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoic acid

[0697]

[0698] Step 1: Methyl 3-(2-aminoethoxy)propanoate

[0699] A solution of methyl 3-(2-[[(tert-butoxy)carbonyl]amino]ethoxy)propanoate (800 mg, 3.24 mmol, 1 equiv) in HCl / dioxane (10 mL) was stirred at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure to afford 476 mg of the title compound as a yellow crude oil. LCMS: [M+H] + 148.09.

[0700] Step 2: Methyl 3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoate

[0701] A solution of methyl 3-(2-aminoethoxy)propanoate (476 mg, 3.23 mmol, 1 equiv), TEA (981.8 mg, 9.70 mmol, 3 equiv) and Int-A6 (1.06 g, 3.23 mmol, 1 equiv) in EtOH (10 mL) was stirred at room temperature for 60 min. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (28 / 72, v / v) to afford 259 mg (18%) of the title compound as a yellow oil. LCMS: [M+H] + 440.18.

[0702] Step 3: Methyl 3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propionate

[0703] A solution of methyl 3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)propionate (259 mg, 0.59 mmol, 1 equiv) in HCl / dioxane (10 mL / 4 M) was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure to afford 182 mg of the title compound as a yellow oil. LCMS: [M+H] + 310.09.

[0704] Step 4: 3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propionic acid

[0705] A solution of methyl 3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propionate (182 mg, 0.59 mmol, 1 equiv) and LiOH·H2O (123.5 mg, 2.94 mmol, 5 equiv) in MeOH (5 mL) and H2O (1 mL) was stirred at room temperature for 3 h. The pH of the solution was adjusted to 7 with aqueous HCl. The resulting solution was extracted with 3 × 3 mL DCM and the aqueous layers were combined and concentrated in vacuo. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H2O / ACN to afford 100 mg (58%) of the title compound as a white solid. LCMS: [M+H] + 296.08.

[0706] Int-A13: 3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propionic acid

[0707]

[0708] Step 1: 5-[[(2S)-1-hydroxypropan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0709] A solution of Int-A6 (8 g, 24 mmol, 1 equiv), TEA (2.463 g, 24 mmol, 1 equiv) and (2S)-2-aminopropan-1-ol (1.829 g, 24 mmol, 1 equiv) in EtOH (60 mL) was stirred at 60 °C for 1 h. The solvent was concentrated in vacuo and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (1 / 1) to afford 5.39 g (58%) of the title compound as a yellow oil. LCMS [M+H] + 367.44

[0710] Step 2: Methyl 3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy]propionate

[0711] A solution of 5-[[(2S)-1-hydroxypropan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (5.39 g, 15 mmol, 1 equiv), methyl acrylate (13.24 g, 147 mmol, 10 equiv) and Cs2CO3 (4.773 g, 15 mmol, 1 equiv) in MeCN (50 mL) was stirred at 25 °C for 4 h. The solvent was concentrated in vacuo and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (1 / 1) to afford 3.12 g (42%) of the title compound as a white solid. LCMS [M+H] + 454.53

[0712] Step 3: Methyl 3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propionate

[0713] A solution of methyl 3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy]propionate (3.12 g, 1 equiv) and TFA (10 mL) in DCM (40 mL) was stirred at 25 °C for 0.5 h. The resulting mixture was concentrated in vacuo to afford 2.1 g (93%) of the title compound as a white solid.

[0714] Step 4: 3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propionic acid

[0715] Methyl 3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propionate (2.12 g, 7 mmol, 1 equiv), LiOH·H2O (1.378 g, 33 mmol, 5 equiv) in a solution of MeOH (15 mL) and H2O (15 mL) was stirred at 25 °C for 0.5 h. The pH of the solution was adjusted to 6 with TFA. The resulting mixture was concentrated in vacuo and the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN (6:1) to give 2.1 g (90%) of the title compound as a yellow oil. LCMS [M+H] + 310.25。

[0716] Int-A14: 3-[2-[(5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic acid

[0717]

[0718] Step 1: tert-Butyl 3-[2-[(5-bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propionate

[0719] A solution of Int-A8 (4 g, 10.4 mmol, 1.0 equiv), tert-butyl 3-(2-hydroxyethoxy)propionate (1.99 g, 10.4 mmol, 1.0 equiv) and Cs2CO3 (6.82 g, 20.9 mmol, 2 equiv) in MeCN (30 mL) was stirred at 60 °C for 2 h, then the solid was filtered off and the resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether to give 2.2 g (43%) of the title compound as a pale yellow oil. LCMS [M+H] + 493.13,495.13

[0720] Step 2: 3-[2-[(5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic acid

[0721] A solution of tert-butyl 3-[2-[(5-bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propionate (1.66 g, 1 equiv) and TFA (2 mL) in DCM (10 mL) was stirred at room temperature for 2 h, then the resulting solution was concentrated under reduced pressure to give 380 mg (37%) of the title compound as a yellow oil. LCMS [M+H] + 307.10。

[0722] Int-A15: 3-[2-[(5-methyl-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic acid

[0723]

[0724] Step 1: tert-Butyl 3-(2-((5-methyl-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)oxy)ethoxy)propanoate

[0725] A solution of tert-butyl 3-[2-[(5-bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate (2 g, 4.05 mmol, 1 equiv), methylboronic acid (485.2 mg, 8.11 mmol, 2 equiv), Pd(dppf)Cl2 (296.6 mg, 0.41 mmol, 0.1 equiv) and CsF (1847.0 mg, 12.16 mmol, 3 equiv) in dioxane (15 mL) and H2O (3 mL) was stirred at 80 °C for 2 h. The solvent was concentrated in vacuo and the residue was applied to a silica gel column eluting with EtOAc / petroleum ether to give 1.5 g (86%) of the title compound as a yellow oil. LCMS [M+H] + 429.23.

[0726] Step 2: 3-[2-[(5-methyl-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic acid

[0727] A solution of tert-butyl 3-[2-[(5-methyl-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate (1.5 g, 1 equiv) in HCl / dioxane (30 mL / 4 M) was stirred at 25 °C overnight. The resulting mixture was concentrated under reduced pressure to give 800 mg (94%) of the title compound as a yellow crude oil. LCMS [M+H] + 243.09.

[0728] Int-A16: 3-[2-[(5-cyano-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic acid

[0729]

[0730] Step 1: 3-[2-[(5-bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate

[0731] A solution of Int-A8 (4 g, 10.41 mmol, 1 equiv), Cs2CO3 (10.14 g, 31.12 mmol, 2.99 equiv) and tert-butyl 3-(2-hydroxyethoxy)propionate (3.97 g, 20.87 mmol, 2.00 equiv) in DMF (40 mL) was stirred at room temperature for 18 h. The reaction was then quenched by the addition of 40 mL of water. The resulting solution was extracted with 3 × 50 mL of EtOAc and the organic layers were combined and dried over anhydrous sodium sulfate. The organic layer was concentrated in vacuo and the residue was applied to a silica gel column eluting with EtOAc / petroleum ether (1 / 9) to afford 2.2 g (43%) of the title compound as a yellow oil. LCMS [M+H] + 493.13, 495.13. 2 g of 4-bromo-5-(2-hydroxyethoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one was isolated as a reaction by-product during purification and used as a starting material for the synthesis of Int-A19, step 1. LCMS [M+H] + : 365.05, 367.05.

[0732] Step 2: tert-butyl 3-[2-[(5-cyano-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propionate

[0733] A solution of tert-butyl 3-[2-[(5-bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propionate (2.2 g, 4.46 mmol, 1 equiv) and CuCN (800 mg, 8.93 mmol, 2.00 equiv) in NMP (20 mL) was stirred at 120 °C for 23 h. The reaction was then quenched by the addition of 20 mL of water and the resulting solution was extracted with 3 × 30 mL of EtOAc, and the organic layers were combined and dried over anhydrous calcium chloride. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using EtOAc / petroleum ether (3 / 7) to afford 800 mg (41%) of the title compound as a yellow oil. LCMS [M+H] + 254.07.

[0734] Step 3: 3-[2-[(5-cyano-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propionic acid

[0735] A solution of tert-butyl 3-[2-[(5-cyano-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propionate (800 mg, 1.82 mmol, 1 equiv) in HCl / dioxane (10 mL / 4 M) was stirred at room temperature for 18 h. The resulting mixture was concentrated under reduced pressure to afford 350 mg (76%) of the title compound as a yellow crude oil. LCMS [M+H] + 254.07

[0736] Int-A17: 2-[5-(hydroxymethyl)oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethan-1-one

[0737]

[0738] Step 1: 1-(Benzyloxy)hex-5-en-2-ol

[0739] To a solution of bromo(prop-2-en-1-yl)magnesium (27.4 mL, 1.50 equiv) in THF (20 mL) at -40 °C under nitrogen was added dropwise 2-[(benzyloxy)methyl]oxirane (3 g, 18.27 mmol, 1.00 equiv). The resulting solution was stirred at -40 °C for 1 h and the resulting solution was quenched with 100 mL of aqueous NH4Cl and extracted with 3 × 100 mL of EtOAc. The organic layers were combined, washed with 1 × 100 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with EtOAc / petroleum ether (1:5) to afford 2.16 g (57%) of the title compound as a yellow oil. LCMS [M+H] + 207.13

[0740] Step 2: Methyl (2Z)-7-(benzyloxy)-6-hydroxyhept-2-enoate

[0741] Under nitrogen, a solution of 1-(benzyloxy)hex-5-en-2-ol (2 g, 9.70 mmol, 1.00 equiv), methyl prop-2-enoate (4.17 g, 48.44 mmol, 5.00 equiv) and Grubbs 2nd generation catalyst (82 mg, 0.01 equiv) in DCM (25 mL) was stirred at 40 °C for 4 h. The resulting solution was concentrated in vacuo and the residue was purified by C18 reverse phase chromatography eluting with H2O / ACN to afford 1.4 g (55%) of the title compound as a yellow oil. LCMS [M+H] + 265.14

[0742] Step 3: Methyl 2-[5-[(benzyloxy)methyl]oxolan-2-yl]acetate

[0743] A solution of methyl (2Z)-7-(benzyloxy)-6-hydroxyhept-2-enoate (46 g, 1 equiv) and NaH (0.7 g, 0.1 equiv) in THF (200 mL) was stirred at 25 °C for 12 h. The resulting solution was quenched with 200 mL of water, extracted with 3 × 200 mL of DCM, and the organic layers were combined and washed with 1 × 100 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 46 g of the title compound as a brown oil. LCMS [M+H] + 265.14

[0744] Step 4: 2-[5-[(benzyloxy)methyl]oxolan-2-yl]acetic acid

[0745] A solution of methyl 2-[5-[(benzyloxy)methyl]oxolan-2-yl]acetate (46 g, 174.03 mmol, 1 equiv) and LiOH·H2O (14.6 g, 350 mmol, 2 equiv) in THF (200 mL) and H2O (200 mL) was stirred at 25 °C for 2 h. The resulting solution was washed with 1 × 200 mL of DCM, the aqueous layers were combined and the pH of the aqueous layer was adjusted to 4 with HCl (1 M). After concentration, the residue was dissolved in 100 mL of EtOH and the solid was filtered off. The resulting solution was concentrated in vacuo to give 40 g (92%) of the title compound as a pale yellow oil. LCMS [M+H] + 251.12

[0746] Step 5: 2-[5-[(benzyloxy)methyl]oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethan-1-one

[0747] A solution of 2-[5-[(benzyloxy)methyl]oxolan-2-yl]acetic acid (3 g, 11.99 mmol, 1 equiv), 1-[5-(trifluoromethyl)pyridin-2-yl]piperazine (1.7 g, 7.35 mmol, 0.61 equiv), HATU (4.6 g, 11.99 mmol, 1 equiv) and DIPEA (4.6 g, 35.96 mmol, 3 equiv) in DMF (50 mL) was stirred at room temperature for 4 h. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3 × 60 mL of EtOAc and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (3 / 2) to give 3.2 g (58%) of the title compound as a yellow oil. LCMS [M+H] + 464.15

[0748] Step 6: 2-[5-(Hydroxymethyl)oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethan-1-one

[0749] Under an H2 (gas) atmosphere, a solution of 2-[5-[(benzyloxy)methyl]oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethan-1-one (3.2 g, 6.90 mmol, 1 eq), palladium 10% / carbon (1 g, 9.40 mmol, 1.36 eq) in MeOH (50 mL) was stirred at 50 °C overnight. The solid was filtered off and the resulting mixture was concentrated under reduced pressure to give 1.7 g (66%) of the title compound as a colorless oil. LCMS [M+H] + 374.10

[0750] Int-A18: 1-[5-(Trifluoromethyl)pyridin-2-yl]piperazine

[0751]

[0752] This compound was purchased from a commercial source: CAS [132834-58-3].

[0753] Int-A19: 6-[4-(3-[2-[(5-Bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

[0754]

[0755] Step 1: 6-[4-(3-[2-[(5-Bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

[0756] A solution of 4-bromo-5-(2-hydroxyethoxy)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1.0 g, 2.74 mmol, 1 equiv), Cs2CO3 (2.652 g, 8.14 mmol, 2.97 equiv) and Int-A25 (0.99 g, 4.09 mmol, 1.49 equiv) in DMF (20 mL) was stirred at room temperature for 24 h. The reaction was quenched by the addition of 20 mL of water and the resulting solution was extracted with 3×30 mL of EtOAc, and the organic layers were combined and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (9 / 1) to give 350 mg (21%) of the title compound as a yellow oil. LCMS [M+H] + 609.16。

[0757] Int-A20: 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0758]

[0759] Step 1: 4,5-dibromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydropyridazin-3-one

[0760] NaH (59.1 g, 1477.07 mmol, 1.50 equiv, 60%) was added in several portions 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, 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 room temperature for 3 h. The reaction was quenched by the addition of 5 L of water / ice 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 give 290 g (79%) of the title compound as a solid. LCMS [M+H] + 378.00。

[0761] Step 2: 5-methoxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0762] A solution of 4,5-dibromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydropyridazin-3-one (290 g, 775.33 mmol, 1 equiv), potassium hydroxide (130.5 g, 2326.00 mmol, 3.00 equiv) in MeOH (2.5 L) was stirred at room temperature for 2 h. The resulting mixture was concentrated to 500 mL and the solid was collected by filtration. The resulting filter cake was slurried in water (1 L) for 1 h to give 232 g (92%) of the title compound as a solid. LCMS [M+H] + 326.90.

[0763] Step 3: 5-Methoxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0764] 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. Then the reaction was quenched by adding 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 using EtOAc / petroleum ether (1 / 1). The collected eluates 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%) of the title compound as a solid. LCMS [M+H] + 315.10.

[0765] Step 4: 5-Hydroxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0766] TMSI (140 g, 699.67 mmol, 1.29 equiv) was added dropwise 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. The resulting solution was stirred at 85 °C for 20 h. Then the reaction mixture was quenched by adding 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%) of the title compound as a white solid. LCMS [M+H]+ 301.07

[0767] Step 5: 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0768] At 0 - 5 °C, oxalyl chloride (93 g, 732.75 mmol, 2.00 equivalents) was added dropwise 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). The resulting solution was stirred at room temperature for 8 hours. Then the reaction was quenched by adding 550 mL of water. The solid was collected by filtration to give 108 g (93%) of the title compound 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).

[0769] Int-A21: 1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]prop-2-en-1-one

[0770]

[0771] A solution of Int-A2 (2.2 g, 7 mmol, 1 equivalent), TEA (2.924 g, 29 mmol, 4 equivalents) and prop-2-enoyl chloride (1.954 g, 11 mmol, 10.00 equivalents) in MeOH (20 mL) was stirred at 0 °C for 4.5 hours. The solid was filtered off and washed with EtOAc (30 mL × 2). Then the organic layers were combined, concentrated and applied to a silica gel column using chloroform / methanol (11 / 1) to give 1.83 g (58%) of the title compound as a yellow solid. LCMS [M+H] + 287.25

[0772] Int-A22: 1-[4-(5-chloropyridin-2-yl)piperazin-1-yl]prop-2-en-1-one

[0773]

[0774] A solution of Int-A5 (2.4 g, 8.92 mmol, 1.00 equiv), TEA (4 g, 39.5 mmol, 4.00 equiv), and allyl acrylate (3.64 g, 28.9 mmol, 3.00 equiv) in DCM (20 mL) was stirred at room temperature for 1.5 h. The solvent was concentrated in vacuo and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (1:1) to afford 1280 mg (57%) of the title compound as a yellow oil. LCMS [M+H]+ 252.09.

[0775] Int-A23: 1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]prop-2-en-1-one

[0776]

[0777] A solution of Int-A3 (1 g, 3.70 mmol, 1.00 equiv), TEA (1.5 g, 14.82 mmol, 4.00 equiv), and allyl acrylate (700 mg, 5.55 mmol, 1.50 equiv) in DCM (20 mL) was stirred at room temperature for 1 h. The solvent was concentrated in vacuo and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (2:3) to afford 720 mg (77%) of the title compound as a white solid. LCMS [M+H]+ 253.07.

[0778] Int-A24: 2-[4-(prop-2-enoyl)piperazin-1-yl]pyrimidine-5-carbonitrile

[0779]

[0780] A solution of Int-A1 (6.4 g, 33.82 mmol, 1 equiv), allyl acrylate (5.1 g, 40.44 mmol, 1.20 equiv), and TEA (6.8 g, 67.20 mmol, 1.99 equiv) in DCM (40 mL) was stirred at room temperature for 1 h, then the resulting solution was concentrated in vacuo, and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (7:3) to afford 3.6 g (43.75%) of the title compound as a white solid. LCMS [M+H]+: 244.12.

[0781] Int-A25: 6-[4-(prop-2-enoyl)piperazin-1-yl]pyridine-3-carbonitrile

[0782]

[0783] At -40 °C, prop-2-enyl prop-2-enoate (17.42 g, 138.132 mmol, 1.30 equiv) was added to a solution of Int-A4 (20 g, 106.251 mmol, 1 equiv) and TEA (32.25 g, 318.752 mmol, 3 equiv) in DCM (500 mL). The resulting solution was stirred for an additional 1 h at -40 °C. The reaction was quenched with 500 mL of water and extracted with 2 x 500 mL of DCM. After concentration, the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (70:30) to give 16.4 g (64%) of the title compound as a yellow solid. LCMS [M+H]+ 243.13.

[0784] Int-A26: 5-(trifluoromethyl)-2-(4-(vinylsulfonyl)piperazin-1-yl)pyrimidine

[0785]

[0786] A solution of Int-A2, 2-chloroethane-1-sulfonyl chloride and TEA (305.0 mg, 3.02 mmol, 3.50 equiv) in DCM (6 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure and the residue was eluted onto a silica gel column using EtOAc / petroleum ether (1:5) to give 210 mg (75.7%) of the title compound as a white solid. LCMS [M+H]+ 323.07.

[0787] Int-A27: 1-[5-(trifluoromethyl)-1,3-thiazol-2-yl]piperazine hydrochloride

[0788]

[0789] Step 1: tert-Butyl 4-(5-(trifluoromethyl)thiazol-2-yl)piperazine-1-carboxylate

[0790] A solution of 2-bromo-5-(trifluoromethyl)thiazole (3.00 g, 12.9 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (2.41 g, 12.9 mmol, 1.00 equiv) and Cs2CO3 (8.43 g, 25.9 mmol, 2.00 equiv) in NMP (20.0 mL) was stirred at 110 °C for 1 h. The reaction was then quenched by the addition of 50 mL of water and extracted with 3 x 50 mL of EtOAc. After concentration under reduced pressure, the residue was purified by silica gel column chromatography using EtOAc / petroleum ether (15 / 85) to give 2.56 g (95%) of the title compound as a yellow solid. LCMS [M+H]+ 338.11.

[0791] Step 2: 1-[5-(Trifluoromethyl)-1,3-thiazol-2-yl]piperazine hydrochloride

[0792] A solution of tert-butyl 4-(5-(trifluoromethyl)thiazol-2-yl)piperazine-1-carboxylate (2.50 g, 7.41 mmol, 1.00 equiv) and HCl (gas) in 1,4-dioxane (20.0 mL) was stirred at room temperature for 30 minutes. The resulting mixture was concentrated in vacuo to afford 2.26 g (95%) of the title compound as a white solid. LCMS [M+H]+ 274.03.

[0793] Int-A28: 5-(Trifluoromethyl)-2-(4-(vinylsulfonyl)piperazin-1-yl)thiazole

[0794]

[0795] A solution of Int-A27 (2.25 g, 9.48 mmol, 1.00 equiv), TEA (4.80 g, 0.047 mmol, 5 equiv) and 2-chloroethane-1-sulfonyl chloride (1.86 g, 0.011 mmol, 1.20 equiv) in DCM (30.0 mL) was stirred at 0 °C in a water / ice bath for 1 hour. The reaction mixture was quenched by the addition of MeOH and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using EtOAc / petroleum ether (18 / 82) to afford 1.74 g (54.9%) of the title compound as a white solid. LCMS [M+H]+ 328.03.

[0796] Int-A29: 5-Mercapto-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0797]

[0798] A solution of Int-A20 (2 g, 6.3 mmol, 1 equiv), NaHS (1.4 g, 25.1 mmol, 4 equiv) and TEA (1.9 g, 18.9 mmol, 3 equiv) in EtOH (10 mL) was stirred at 70 °C for 40 minutes. After concentration under reduced pressure, the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN to afford 1.8 g (90.7%) of the title compound as a yellow solid. LCMS [M+H]+ 317.06.

[0799] Synthesis of the Example Compounds

[0800] Example 1: 5-[5-[(1-Acetylpiperidin-4-yl)oxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0801]

[0802] Step 1: Synthesis of 1-bromo-4,5-bis(bromomethyl)-2-fluorobenzene

[0803] A solution of 1-bromo-2-fluoro-4,5-dimethylbenzene (5 g, 24.62 mmol, 1 equiv), NBS (10.85 g, 60.96 mmol, 2.476 equiv), and AIBN (1.98 g, 12.06 mmol, 0.490 equiv) in CCl4 (50 mL) was stirred at 80 °C for 12 h. After concentration, the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN to give 5.4 g (61%) of the title compound as a yellow solid. LCMS (ESI, m / z): 360.80 [M+H] + 。

[0804] Step 2: Synthesis of 5-bromo-6-fluoro-2,3-dihydro-1H-isoindole

[0805] A solution of 1-bromo-4,5-bis(bromomethyl)-2-fluorobenzene (3 g, 8.31 mmol, 1 equiv) in NH3 / MeOH (300 mL, 1 M) was stirred at 5 °C for 2 h. The resulting mixture was concentrated in vacuo to give 2.8 g (crude) of the title compound as a yellow solid. LCMS (ESI, m / z): 215.97 [M+H] + 。

[0806] Step 3: Synthesis of 5-(5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0807] A solution of 5-bromo-6-fluoro-2,3-dihydro-1H-isoindole (1.2 g, 5.55 mmol, 1 equiv), Int-A6 (2.17 g, 6.60 mmol, 1.188 equiv), and TEA (1.7 g, 16.80 mmol, 3.025 equiv) in EtOH (40 mL) was stirred at 80 °C for 2 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluting with EtOAc / petroleum ether (15 / 85) to give 870 mg (30.81%) of the title compound as a brown solid. LCMS (ESI, m / z): 510.06 [M+H] + 。

[0808] Step 4: Synthesis of 5-(5-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0809] A solution of 5-(5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (850 mg, 1.67 mmol, 1 equiv), LiOH·H2O (154.6 mg, 3.68 mmol, 2.203 equiv), BHMPO (287 mg, 0.84 mmol, 0.5 equiv), and Cu(acac)2 (220 mg, 0.84 mmol, 0.5 equiv) in DMSO (16 mL) and H2O (4 mL) was stirred at 80 °C for 2 h. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3 × 30 mL of EtOAc and the organic layers were combined and dried over anhydrous sodium sulfate. After concentration, the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (25 / 75) to afford 260 mg (35%) of the title compound as a yellow solid. LCMS (ESI, m / z): 446.14 [M+H] + 。

[0810] Step 5: Synthesis of tert-butyl 4-([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate

[0811] A solution of 5-(5-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (260 mg, 0.58 mmol, 1 equiv), tert-butyl 4-iodopiperidine-1-carboxylate (362.6 mg, 1.17 mmol, 1.997 equiv), and K2CO3 (126 mg, 0.91 mmol, 1.562 equiv) in DMF (20 mL) was stirred at 80 °C for 12 h. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3 × 30 mL of EtOAc and the organic layers were combined and dried over anhydrous sodium sulfate. After concentration, the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (20 / 80) to afford 500 mg (crude) of the title compound as a brown oil. LCMS (ESI, m / z): 629.25 [M+H] + 。

[0812] Step 6: Synthesis of 5-[5-Fluoro-6-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0813] A solution of tert-butyl 4-([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate (500 mg, 0.80 mmol, 1 equiv) in HCl / dioxane (5 mL) was stirred at room temperature for 12 h. After concentration, the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN to give 330 mg (crude) of the title compound as a yellow oil. LCMS (ESI, m / z): 399.25 [M+H] + 。

[0814] Step 7: Synthesis of 5-[5-[(1-Acetylpiperidin-4-yl)oxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0815] A solution of 5-[5-Fluoro-6-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (330 mg, 0.83 mmol, 1 equiv), Ac2O (85.2 mg, 0.83 mmol, 1.007 equiv), and TEA (372 mg, 3.68 mmol, 4.438 equiv) in DCM (5 mL) was stirred at room temperature for 1 h. After concentration, the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN. The residue was then further purified by preparative HPLC to give the title compound as a white solid (44 mg, 12%). LCMS (ESI, m / z): 441.39 [M+H] + , 1 1H NMR (DMSO-d6, 300 MHz) δ: 12.52 (s, 1H), 7.96 (s, 1H), 7.29 (dd, J = 11.8, 9.4 Hz, 2H), 4.90 (br, 4H), 4.59 (dt, J = 8.0, 4.2 Hz, 1H), 3.83 (dd, J = 13.3, 6.4 Hz, 1H), 3.73 - 3.61 (m, 1H), 3.59 - 3.47 (m, 1H), 3.39 - 3.13 (m, 1H), 2.01 - 1.81 (m, 5H), 1.88 - 1.42 (m, 2H).

[0816] Example 2: 5-[4-[(1-acetylpiperidin-4-yl)oxy]-7-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0817]

[0818] Step 1: Synthesis of 2-benzyl-4-bromo-7-fluoro-2,3-dihydro-1H-isoindole

[0819] A solution of 1-bromo-2,3-bis(bromomethyl)-4-fluorobenzene (2.2 g, 6.10 mmol, 1 eq), phenylmethanamine (0.66 g, 6.16 mmol, 1.010 eq), and KHCO3 (1.5 g, 14.98 mmol, 2.457 eq) in ACN (200 mL) was stirred in an oil bath at 75 °C for 3 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (5 / 95) to give 660 mg (35%) of the title compound as a yellow solid. LCMS (ESI, m / z): 306.02 [M+H] + 。

[0820] Step 2: Synthesis of 2-benzyl-4-fluoro-7-methoxy-2,3-dihydro-1H-isoindole

[0821] A solution of MeOH (5 mL), 2-benzyl-4-bromo-7-fluoro-2,3-dihydro-1H-isoindole (700 mg, 2.29 mmol, 1 eq), Pd2(allyl)2Cl2 (56.0 mg, 0.15 mmol, 0.067 eq), RockPhos (107.2 mg, 0.23 mmol, 0.100 eq), and Cs2CO3 (1492.1 mg, 4.58 mmol, 2.003 eq) in toluene (12 mL) was stirred in an oil bath at 80 °C under a nitrogen atmosphere for 3 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (5 / 95) to give 500 mg (85%) of the title compound as a yellow oil. LCMS (ESI, m / z): 258.12 [M+H] + 。

[0822] Step 3: Synthesis of 2-benzyl-7-fluoro-2,3-dihydro-1H-isoindol-4-ol

[0823] Stir a solution of 2-benzyl-4-fluoro-7-methoxy-2,3-dihydro-1H-isoindole (500 mg, 1.94 mmol, 1 equiv) in DCM (5 mL) at 0 °C. Dropwise add BBr3 (5 mL, 52.89 mmol, 27.217 equiv) to this solution with stirring at 0 °C. Stir the resulting solution at room temperature for 12 h. Then quench the reaction by adding 10 mL of methanol. Concentrate the resulting mixture in vacuo. Apply the residue to a silica gel column eluted with EtOAc / petroleum ether (15 / 85) to afford 456 mg (96.5%) of the title compound as a white solid. LCMS (ESI, m / z): 244.11 [M+H] + 。

[0824] Step 4: Synthesis of 7-fluoro-2,3-dihydro-1H-isoindol-4-ol hydrochloride

[0825] A solution of 2-benzyl-7-fluoro-2,3-dihydro-1H-isoindol-4-ol (400 mg, 1.64 mmol, 1 equiv), Pd / C (40.1 mg), and HCl (1 M, 3 mL). Stir the resulting solution at room temperature for 1 h. Filter off the solid. Concentrate the filtrate in vacuo. This gives 210 mg (67%) of the title compound as a yellow solid. LCMS (ESI, m / z): 154.06 [M+H] + 。

[0826] Step 5: Synthesis of 5-(4-fluoro-7-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0827] A solution of 7-fluoro-2,3-dihydro-1H-isoindol-4-ol hydrochloride (100 mg, 0.53 mmol, 1 equiv), Int-A6 (214 mg, 0.65 mmol, 1.234 equiv), and TEA (194.7 mg, 1.92 mmol, 3.648 equiv) in EtOH (3 mL) is stirred in an oil bath at 80 °C for 2 h. Concentrate the resulting mixture in vacuo. Apply the residue to a silica gel column eluted with EtOAc / petroleum ether to afford 140 mg (60%) of the title compound as a yellow oil. LCMS (ESI, m / z): 446.14 [M+H] + 。

[0828] Step 6: Synthesis of tert-butyl 4-([7-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)piperidine-1-carboxylate

[0829] A solution of 5-(4-fluoro-7-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (400 mg, 0.90 mmol, 1 equiv), tert-butyl 4-iodopiperidine-1-carboxylate (558 mg, 1.79 mmol, 1.997 equiv), and K2CO3 (193.8 mg, 1.40 mmol, 1.562 equiv) in DMF (5 mL) was stirred at 80 °C for 4 days. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3 × 30 mL of EtOAc and the organic layers were combined and dried over anhydrous sodium sulfate. The organic layer was concentrated in vacuo. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (50 / 50) to afford 130 mg (23%) of the title compound as a yellow solid. LCMS (ESI, m / z): 629.27 [M+H] + 。

[0830] Step 7: Synthesis of 5-[4-fluoro-7-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0831] A solution of tert-butyl 4-([7-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)piperidine-1-carboxylate (130 mg, 0.21 mmol, 1.00 equiv) in hydrogen chloride / dioxane (10 mL) was stirred at room temperature for 16 h. After concentration, the residue was purified by C18 reverse phase chromatography eluted with H2O / CH3CN to afford 80 mg (96%) of the title compound as a white solid. LCMS (ESI, m / z): 399.14 [M+H] + 。

[0832] Step 8: Synthesis of 5-[4-[(1-acetylpiperidin-4-yl)oxy]-7-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0833] A solution of TEA (90 mg, 0.89 mmol, 3.00 equiv), 5-[4-fluoro-7-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (80 mg, 0.20 mmol, 1.00 equiv), and Ac2O (20.65 mg, 0.20 mmol, 1.00 equiv) in DCM (5 mL) was stirred at room temperature for 2 h. After concentration, the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN. The residue was then further purified by preparative HPLC to give the title compound as a white solid (18.5 mg, 21%). LCMS (ESI, m / z): 441.39 [M+H] + , 1 1H NMR (DMSO-d6, 300 MHz) δ 12.56 (s, 1H), 8.11 (s, 1H), 7.15 - 7.07 (m, 2H), 5.02 (s, 2H), 4.92 (s, 2H), 4.68 (dt, J = 6.6, 3.4 Hz, 1H), 3.74 - 3.57 (m, 2H), 3.45 - 3.32 (m, 2H), 2.02 (s, 3H), 2.00 - 1.84 (m, 2H), 1.72 - 1.51 (m, 2H).

[0834] Example 3: 5-[4-Fluoro-6-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one; formic acid

[0835]

[0836] Step 1: Synthesis of methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate

[0837] A solution of methyl 4-bromo-6-fluoro-2-methylbenzoate (10 g, 40.48 mmol, 1.00 equiv), NBS (7.23 g, 40.62 mmol, 1.10 equiv), and AIBN (3.33 g, 20.28 mmol, 0.50 equiv) in CCl4 (150 mL) was stirred at 80 °C for 12 h. The resulting solution was then concentrated in vacuo and the crude product was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN to give 10 g (76%) of the title compound as a yellow oil. LCMS (ESI, m / z): 324.88 [M+H] + 。

[0838] Step 2: Synthesis of 5-bromo-7-fluoro-2,3-dihydro-1H-isoindol-1-one

[0839] A solution of 4-bromo-2-(bromomethyl)-6-fluorobenzoate (10 g, 30.68 mmol, 1.00 equiv) in NH3 (gas) / MeOH (40 mL, 7 M) was stirred at 40 °C for 40 minutes, and then the resulting solution was concentrated in vacuo to give 9.1 g (crude) of the title compound as an off-white solid. LCMS (ESI, m / z): 230.04 [M+H] + 。

[0840] Step 3: Synthesis of tert-butyl 5-bromo-7-fluoro-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate To a solution of 5-bromo-7-fluoro-2,3-dihydro-1H-isoindol-1-one (9.1 g, 39.56 mmol, 1.00 equiv) and DMAP (977 mg, 8.00 mmol, 0.20 equiv) in THF (70 mL) was added (Boc)2O (12.99 g, 59.52 mmol, 1.50 equiv), and the resulting solution was stirred at room temperature for 2 hours, and then the resulting solution was concentrated in vacuo. The crude product was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN to give 5.7 g (44%) of the title compound as a white solid. LCMS (ESI, m / z): 330.15 [M+H] + 。

[0841] Step 4: Synthesis of 6-bromo-4-fluoro-2,3-dihydro-1H-isoindole

[0842] Under nitrogen, BF3 / Et2O (36.9 g, 15.00 equiv, 1 M) was added dropwise to a solution of tert-butyl 5-bromo-7-fluoro-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate (5.7 g, 17.26 mmol, 1.00 equiv) and NaBH4 (7.9 g, 208.83 mmol, 12.00 equiv) in THF (60 mL), and then the resulting solution was stirred at 70 °C for 3 hours. The resulting solution was quenched by the addition of 200 mL of water, extracted with 3 × 200 mL of EtOAc, and the organic layers were combined, washed with 1 × 200 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo, and then the residue was applied to a silica gel column eluting with DCM / methanol (2:3) to give 2.05 g (55%) of the title compound as an off-white solid. LCMS (ESI, m / z): 216.05 [M+H] + 。

[0843] Step 5: Synthesis of 5-(6-bromo-4-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0844] A solution of 6-bromo-4-fluoro-2,3-dihydro-1H-isoindole (2.05 g, 9.49 mmol, 1.00 equiv), 5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (3.12 g, 9.49 mmol, 1.00 equiv) and TEA (2.88 g, 28.46 mmol, 3.00 equiv) in ethanol (20 mL) was stirred at 60 °C for 2 h, then the resulting solution was concentrated in vacuo, and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (1:5) to give 2.1 g (44%) of the title compound as a light brown solid. LCMS (ESI, m / z): 508.39 [M+H] + 。

[0845] Step 6: Synthesis of 5-(4-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0846] A solution of 5-(6-bromo-4-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (2 g, 3.93 mmol, 1.00 equiv), BHMPO (135 mg, 0.41 mmol, 0.10 equiv), Cu(acac)2 (103 mg, 0.39 mmol, 0.10 equiv) and LiOH·H2O (363 mg, 8.64 mmol, 2.20 equiv), DMSO (20 mL) and water (5 mL) was stirred at 80 °C for 12 h, then the solid was filtered off, and the resulting solution was diluted with 100 mL of H2O, extracted with 3×100 mL of EtOAc and the organic layers were combined, washed with 1×100 mL of brine and concentrated in vacuo, and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (3:1) to give 680 mg (39%) of the title compound as a green solid. LCMS (ESI, m / z): 446.14 [M+H] + 。

[0847] Step 7: Synthesis of tert-butyl 4-([7-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate

[0848] A solution of 5-(4-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (300 mg, 0.67 mmol, 1.00 equiv), tert-butyl 4-iodopiperidine-1-carboxylate (629 mg, 2.02 mmol, 3.00 equiv) and potassium carbonate (279 mg, 2.02 mmol, 3.00 equiv) in DMF (5 mL) was stirred at 80 °C for 12 h. The resulting solution was then diluted with 50 mL of H2O, extracted with 3 × 50 mL of EtOAc and the organic layers were combined, washed with 1 × 50 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was then applied to a silica gel column eluting with EtOAc / petroleum ether (3:1) to afford 153 mg (36%) of the title compound as a yellow oil. LCMS (ESI, m / z): 629.27 [M+H] + 。

[0849] Step 8: Synthesis of 5-[4-fluoro-6-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one; formic acid

[0850] A solution of tert-butyl 4-([7-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate (135 mg, 0.21 mmol, 1.00 equiv) in HCl (gas) / dioxane (6 mL, 4 M) was stirred at room temperature for 2 h. The resulting solution was then concentrated in vacuo and the crude product was further purified by preparative HPLC to afford the title compound as a white solid (34.2 mg, 36%). LCMS (ESI, m / z): 399.05 [M+H] + 。 1 1H NMR (DMSO-d6, 300 MHz): δ 12.54 (s, 1H), 8.32 (s, 1H), 8.02 (s, 1H), 6.91 (s, 1H), 6.87 (d, J = 11.4 Hz, 1H), 4.96 (d, J = 12.2 Hz, 4H), 4.53 (dr, 1H), 3.05 (dr, 2H), 2.79 (dr, 2H), 2.01 - 1.97 (m, 2H), 1.62 - 1.60 (m, 2H).

[0851] Example 4: 5-[6-[(1-Acetylpiperidin-4-yl)oxy]-4-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0852]

[0853] A solution of 5-[4-Fluoro-6-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one; formic acid (110 mg, 0.28 mmol, 1.00 equiv), TEA (90 mg, 0.89 mmol, 3.00 equiv) and Ac2O (150 mg, 1.47 mmol, 5.00 equiv) in DCM (20 mL) was stirred at room temperature for 4 h, then the resulting solution was concentrated in vacuo, and the residue was purified by preparative HPLC to give the title compound as a white solid (18.3 mg, 15%). LCMS (ESI, m / z): 441.05 [M+H] + 。 1 1H NMR (DMSO-d6, 300 MHz): δ 12.56 (s, 1H), 8.03 (s, 1H), 6.92 (d, J = 2.0 Hz, 1H), 6.86 (dd, J = 11.2, 2.0 Hz, 1H), 4.96 (d, J = 12.2 Hz, 4H), 4.63 (dt, J = 8.1, 4.3 Hz, 1H), 3.88 - 3.84 (m, 1H), 3.69 - 3.64 (m, 1H), 3.32 - 3.30 (m, 1H), 3.22 - 3.14 (m, 1H), 2.01 (s, 3H), 1.94 - 1.88 (m, 2H), 1.67 - 1.56 (m, 1H), 1.53 - 1.39 (m, 1H).

[0854] Example 5: 5-[6-[(1-Acetylpiperidin-4-yl)oxy]-5-fluoro-1-methyl-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0855]

[0856] Step 1: Synthesis of 4-Bromo-2-(bromomethyl)-5-fluorobenzoate

[0857] A solution of methyl 4-bromo-5-fluoro-2-methylbenzoate (9.5 g, 38.45 mmol, 1.00 eq), AIBN (3.15 g, 19.18 mmol, 0.50 eq), and NBS (10.31 g, 57.93 mmol, 1.50 eq) in CCl4 (100 mL) was stirred at 80 °C overnight. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (1 / 50) to afford 12.5 g of the title compound as a yellow crude oil. LCMS (ESI, m / z): 324.88 [M+H] + 。

[0858] Step 2: Synthesis of 5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-1-one

[0859] A solution of methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate (12.5 g, 38.35 mmol, 1.00 eq) in NH3 / MeOH (150 mL, 7 M) was stirred at 40 °C for 3 h. The solid was collected by filtration after the resulting solution was cooled to room temperature. This gave 7.1 g (80%) of the title compound as a white solid. LCMS (ESI, m / z): 229.95 [M+H] + 。

[0860] Step 3: Synthesis of tert-butyl 5-bromo-6-fluoro-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate

[0861] A solution of 5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-1-one (7.1 g, 30.87 mmol, 1.00 eq), 4-dimethylaminopyridine (759 mg, 6.21 mmol, 0.20 eq), and (Boc)2O (8 g, 36.66 mmol, 1.20 eq) in THF (100 mL) was stirred at room temperature for 2 h. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 2 × 100 mL of EtOAc and the organic layers were combined and concentrated in vacuo. This gave 9.8 g (96%) of the title compound as a white solid. LCMS (ESI, m / z): 330.01 [M+H] + 。

[0862] Step 4: Synthesis of tert-butyl 5-bromo-6-fluoro-3-methyl-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate

[0863] Stir a solution of tert-butyl 5-bromo-6-fluoro-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate (500 mg, 1.51 mmol, 1.00 equiv) in THF (5 mL) at -70 °C. Subsequently, add THF solution containing NaHMDS (1.8 mL, 1.20 equiv, 1 M) dropwise with stirring at -70 °C. Stir the resulting solution at -70 °C for 30 minutes. Add methyl iodide (213.7 mg, 1.51 mmol, 1.00 equiv) thereto. Stir the resulting solution at room temperature for 2 hours. Then quench the reaction by adding 10 mL of water. Extract the resulting solution with 3 × 10 mL of EtOAc and combine the organic layers and concentrate in vacuo. Apply the residue to a silica gel column eluted with EtOAc / petroleum ether (1 / 15) to give 210 mg (40%) of the title compound as a brown solid. LCMS (ESI, m / z): 344.02 [M+H] + 。

[0864] Step 5: Synthesis of tert-butyl 6-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-isoindole-2-carboxylate

[0865] Stir a solution of tert-butyl 5-bromo-6-fluoro-3-methyl-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate (210 mg, 0.61 mmol, 1.00 equiv), NaBH4 (220 mg, 5.97 mmol, 10.00 equiv), and BH3·Et2O (0.86 mL, 12.00 equiv) in THF (5 mL) at 70 °C for 3 hours. Then quench the reaction by adding 10 mL of water. Extract the resulting solution with 3 × 10 mL of EtOAc and combine the organic layers. Wash the resulting mixture with 2 × 10 mL of brine. Concentrate the resulting mixture in vacuo. This gives 180 mg (89%) of the title compound as a yellow oil. LCMS (ESI, m / z): 330.04 [M+H] + 。

[0866] Step 6: Synthesis of 6-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-isoindole hydrochloride

[0867] Stir a solution of tert-butyl 6-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-isoindole-2-carboxylate (180 mg, 0.55 mmol, 1.00 equiv) in HCl / dioxane (5 mL, 4 M) at room temperature for 2 hours. Collect the solid by filtration to give 130 mg (89%) of the title compound as a yellow crude oil. LCMS (ESI, m / z): 229.99 [M+H] + 。

[0868] Step 7: Synthesis of 5-(6-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0869] A solution of 5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (161 mg, 0.49 mmol, 1.00 equiv), TEA (100 mg, 0.99 mmol, 2.00 equiv), and 6-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-isoindole hydrochloride (130 mg, 0.49 mmol, 1.00 equiv) in ethanol (5 mL) was stirred at 40 °C for 3 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (1 / 6) to afford 114 mg (45%) of the title compound as a yellow oil. LCMS (ESI, m / z): 522.08 [M+H] + 。

[0870] Step 8: Synthesis of 5-(5-fluoro-6-hydroxy-1-methyl-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0871] A solution of 5-(6-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1.5 g, 2.87 mmol, 1.00 equiv), BHMPO (472 mg, 1.43 mmol, 0.50 equiv), Cu(acac)2 (376 mg, 1.44 mmol, 0.50 equiv), and LiOH·H2O (241 mg, 5.74 mmol, 2.00 equiv) in DMSO (20 mL) and water (5 mL) was stirred at 80 °C for 2 h. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3 × 20 mL of EtOAc and the organic layers were combined and concentrated in vacuo. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (1 / 3) to afford 136 mg (10%) of the title compound as a brown solid. LCMS (ESI, m / z): 460.19 [M+H] + 。

[0872] Step 9: Synthesis of tert-butyl 4-([6-fluoro-3-methyl-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate

[0873] A solution of 5-(5-fluoro-6-hydroxy-1-methyl-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (136 mg, 0.30 mmol, 1.00 equiv), potassium carbonate (81.6 mg, 0.59 mmol, 2.00 equiv), and tert-butyl 4-iodopiperidine-1-carboxylate (276 mg, 0.89 mmol, 3.00 equiv) in DMF (10 mL) was stirred at 80 °C for 3 days. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3 × 10 mL of EtOAc and the organic layers were combined and concentrated in vacuo. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (1 / 4) to give 190 mg of the title compound as a yellow crude oil. LCMS (ESI, m / z): 643.29 [M+H] + 。

[0874] Step 10: Synthesis of 5-[5-fluoro-1-methyl-6-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0875] A solution of tert-butyl 4-([6-fluoro-3-methyl-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate (180 mg, 0.28 mmol, 1 equiv) in HCl / dioxane (5 mL) was stirred at room temperature for 12 h. The resulting mixture was concentrated in vacuo to give 200 mg (crude) of the title compound as a yellow oil.

[0876] Step 11: Synthesis of 5-[6-[(1-acetylpiperidin-4-yl)oxy]-5-fluoro-1-methyl-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0877] A solution of 5-[5-fluoro-1-methyl-6-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (120 mg, 0.29 mmol, 1 equiv), acetic anhydride (30 mg, 0.29 mmol, 1.010 equiv), and TEA (131 mg, 1.29 mmol, 4.449 equiv) in DCM (5 mL) was stirred at room temperature for 2 h. After concentration, the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN. The residue was then further purified by preparative HPLC to give the title compound as a white solid (9.9 mg, 7.5%). LCMS (ESI, m / z): 455.42 [M+H] + , 1 1H NMR (DMSO-d6, 300 MHz) δ: 12.60 (s, 1H), 8.12 (s, 1H), 7.30 (s, 1H), 7.27 (s, 1H), 5.64 (d, J = 6.9 Hz, 1H), 5.05 (d, J = 14.8 Hz, 1H), 4.80 - 4.65 (br, 1H), 4.50 (d, J = 14.8 Hz, 1H), 3.90 - 4.75 (m, 1H), 3.73 - 3.56 (m, 1H), 3.40 - 3.20 (m, 2H), 2.03 (s, 3H), 1.95 - 1.80 (m, 2H), 1.72 - 1.80 (m, 2H), 1.49 - 1.43 (m, 3H).

[0878] Example 6: 5-[2-[(1-methylpiperidin-4-yl)oxy]-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0879]

[0880] Step 1: Synthesis of 5-[2-chloro-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0881] A solution of 2-chloro-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl hydrochloride (5 g, 26.31 mmol, 1.00 equiv), TEA (8 g, 79.06 mmol, 3.00 equiv), and 5-chloro-4-(trifluoromethyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydropyridazin-3-one (14.3 g, 43.49 mmol, 1.00 equiv) in EtOH (30 mL) was stirred at 80 °C for 2 h. The solvent was concentrated in vacuo and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (1 / 4) to give 9.3 g (79%) of the title compound as a yellow oil. LCMS (ESI, m / z): 447.12 [M+H] + 。

[0882] Step 2: Synthesis of 5-[2-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydropyridazin-3-one

[0883] A solution of 5-[2-chloro-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydropyridazin-3-one (1.2 g, 2.69 mmol, 1.00 equiv), t-BuBrettphos (196 mg, 0.15 equiv), K3PO4 (1.711 g, 8.06 mmol, 3.00 equiv), and Pd(OAc)2 (61 mg, 0.27 mmol, 0.10 equiv) in dioxane (15 mL) and water (5 mL) was stirred at 100 °C for 2 h under a nitrogen atmosphere. The solvent was concentrated in vacuo and the residue was applied to a silica gel column eluted with DCM / methanol (9 / 1) to give 700 mg (61%) of the title compound as a yellow solid. LCMS (ESI, m / z): 429.15 [M+H] + 。

[0884] Step 3: Synthesis of tert-butyl 4-([6-[6-oxo-5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-2-yl]oxy)piperidine-1-carboxylate

[0885] A solution of 5-[2-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (500 mg, 1.17 mmol, 1.00 equiv), Ag2CO3 (640 mg, 2.00 equiv), and tert-butyl 4-iodopiperidine-1-carboxylate (1 g, 3.21 mmol, 3.00 equiv) in DMF (15 mL) was stirred at 80 °C for 4 h. The resulting solution was diluted with 15 mL of water and extracted with 3 × 15 mL of EtOAc. The organic layers were combined. The resulting solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (1 / 4) to give 500 mg (73%) of the title compound as a yellow oil. LCMS (ESI, m / z): 612.28 [M+H] + 。

[0886] Step 4: Synthesis of 5-[2-(piperidin-4-yloxy)-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0887] A solution of tert-butyl 4-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-2-yl]oxy)piperidine-1-carboxylate (500 mg, 0.82 mmol, 1.00 equiv) in HCl / dioxane (20 mL, 4 M) was stirred at 25 °C overnight. The resulting solution was concentrated in vacuo to give 200 mg (64%) of the title compound as a yellow crude oil. LCMS (ESI, m / z): 382.14 [M+H] + 。

[0888] Step 5: Synthesis of 5-[2-[(1-methylpiperidin-4-yl)oxy]-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0889] 5-(2-(Piperidin-4-yloxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (200 mg, 0.52 mmol, 1.00 equiv), (HCHO) n(45 mg, 3.00 eq), acetic acid (60 mg, 1.00 mmol, 2.00 eq), and NaBH3CN (95 mg, 1.51 mmol, 3.00 eq) in MeOH (5 mL) were stirred overnight at 25 °C. After concentration, the residue was purified by preparative HPLC to give the title compound (27.8 mg, 13%) as a white solid. LCMS (ESI, m / z): 396.16 [M+H] + , 1 1H NMR (300 MHz, methanol-d4) δ: 8.08 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 5.12 (dq, J = 8.1, 4.1 Hz, 1H), 5.02 (s, 2H), 4.92 (s, 2H), 2.78 (m, 2H), 2.35 (m, 5H), 2.09 (dd, J = 11.9, 7.5 Hz, 2H), 1.86 (qd, J = 11.8, 10.1, 3.5 Hz, 2H).

[0890] Example 7: 5-[3-(Piperidin-4-yloxy)-5H, 6H, 7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0891]

[0892] Step 1: Synthesis of 5-[3-bromo-5H, 6H, 7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0893] A solution of 3-bromo-5H, 6H, 7H-pyrrolo[3,4-b]pyridine hydrochloride (1 g, 4.25 mmol, 1.00 eq) in ethanol (5 mL), 5-chloro-4-(trifluoromethyl)-2-[2-(trimethylsilyl)ethoxy]methyl-2,3-dihydropyridazin-3-one (1.6 g, 4.87 mmol, 1.15 eq), and TEA (1.2 mL) was stirred at 80 °C for 1 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column using EtOAc / petroleum ether (1:2). This gave 1.5 g (72%) of the title compound as a solid. LCMS (ESI, m / z): 491.07 [M+H] + 。

[0894] Step 2: Synthesis of 5-[3-Hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0895] A solution of 5-[3-Bromo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1 g, 2.04 mmol, 1.00 equiv), Pd(OAc)2 (92 mg, 0.41 mmol, 0.20 equiv), t-BuBrettphos (200 mg), and K3PO4 (1.3 g, 6.12 mmol, 3.01 equiv) in dioxane / H2O (12.5 mL) was stirred at 80 °C for 4 h under a nitrogen inert atmosphere. The resulting solution was extracted with 250 mL of EtOAc. The resulting mixture was washed with 2 × 50 mL of water and 1 × 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column using DCM / methanol (9:1). This gave 680 mg (78%) of the title compound as a solid. LCMS (ESI, m / z): 429.16 [M+H] + 。

[0896] Step 3: Synthesis of tert-Butyl 4-([6-[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-3-yl]oxy)piperidine-1-carboxylate as an oil

[0897] A solution of 5-[3-Hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (190 mg, 0.44 mmol, 1.00 equiv), Ag2CO3 (370 mg), and tert-Butyl 4-iodopiperidine-1-carboxylate (450 mg, 1.45 mmol, 3.26 equiv) in DMF (5 mL) was stirred at 80 °C for 2 h. The solid was filtered off. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column using DCM / methanol (95:5). This gave 60 mg (22%) of the title compound as an oil. LCMS (ESI, m / z): 612.28 [M+H] + 。

[0898] Step 4: Synthesis of 5-[3-(Piperidin-4-yloxy)-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0899] To a stirred solution of tert-butyl 4-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-3-yl]oxy)piperidine-1-carboxylate (60 mg, 0.10 mmol, 1.00 equiv) in DCM (5 mL) was added trifluoroacetic acid (2 mL). The resulting solution was stirred at room temperature for 1 h. After concentration, the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN. The residue was then further purified by preparative HPLC to give the title compound as an off-white solid (13.1 mg, 35%). LCMS (ESI, m / z): 382.15 [M+H] + 。 1 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 2.7 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J = 2.6 Hz, 1H), 4.93 (s, 2H), 4.86 (s, 2H), 4.49 (tt, J = 8.6, 3.9 Hz, 1H), 3.05 - 2.95 (m, 2H), 2.71 - 2.60 (m, 2H), 2.00 - 1.90 (m, 2H), 1.58 - 1.44 (m, 2H).

[0900] Example 8: 5-[3-[(1-Acetylpiperidin-4-yl)oxy]-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0901]

[0902] To a stirred solution of 5-[3-(piperidin-4-yloxy)-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (150 mg, 0.39 mmol, 1.00 equiv) in pyridine (5 mL) was added Ac2O (0.5 mL). The resulting solution was stirred at room temperature for 2 h. After concentration, the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN. The residue was then further purified by preparative HPLC to give the title compound as a white solid (50.4 mg, 30%). LCMS (ESI, m / z): 424.05 [M+H] + 。1 1H NMR (300 MHz, methanol-d4) δ 8.22 (d, J = 2.6 Hz, 1H), 8.08 (s, 1H), 7.53 (d, J = 2.6 Hz, 1H), 5.09 (s, 2H), 4.97 (s, 2H), 4.78 - 4.67 (m, 1H), 3.94 - 3.73 (m, 2H), 3.61 - 3.44 (m, 2H), 2.14 (s, 3H), 2.11 - 1.93 (m, 2H), 1.88 - 1.67 (m, 2H).

[0903] Example 9: 5-[4-(Piperidin-4-yloxy)-5H, 6H, 7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0904]

[0905] Step 1: Synthesis of 5-[4-bromo-5H, 6H, 7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0906] A solution of 5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (2.3 g, 7.00 mmol, 1.00 equivalent), 4-bromo-5H, 6H, 7H-pyrrolo[3,4-b]pyridine hydrobromide (1.95 g, 6.97 mmol, 1.00 equivalent), and TEA (3.6 g, 35.58 mmol, 5.00 equivalents) in EtOH (30 mL) was stirred at 80 °C for 2 h. The solvent was concentrated in vacuo and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (1 / 4) to give 1.1 g (32%) of the title compound as a yellow solid. LCMS (ESI, m / z): 491.06 [M+H] + .

[0907] Step 2: Synthesis of 5-[4-hydroxy-5H, 6H, 7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0908] A solution of 5-[4-bromo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (400 mg, 0.81 mmol, 1.00 equiv), Pd(OAc)2 (19 mg, 0.08 mmol, 0.10 equiv), K3PO4 (520 mg, 2.45 mmol, 3.00 equiv), and t-BuBrettphos (60 mg, 0.15 equiv) in dioxane (10 mL) and water (3 mL) was stirred at 100 °C for 2 h under a nitrogen atmosphere. The solvent was concentrated in vacuo and the residue was applied to a silica gel column eluted with DCM / methanol (19 / 1) to afford 215 mg (62%) of the title compound as a yellow solid. LCMS (ESI, m / z): 429.15 [M+H] + 。

[0909] Step 3: Synthesis of tert-butyl 4-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-4-yl]oxy)piperidine-1-carboxylate

[0910] A solution of 5-[4-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (250 mg, 0.58 mmol, 1.00 equiv), Ag2CO3 (322 mg, 2.00 equiv), and tert-butyl 4-iodopiperidine-1-carboxylate (545 mg, 1.75 mmol, 3.00 equiv) in DMF (15 mL) was stirred at 80 °C for 4 h. The resulting solution was diluted with 15 mL of water and extracted with 3 × 15 mL of EtOAc. The organic layers were combined. The resulting solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluted with DCM / methanol (19 / 1) to afford 240 mg (67%) of the title compound as a yellow solid. LCMS (ESI, m / z): 612.28 [M+H] + 。

[0911] Step 4: Synthesis of 5-[4-(piperidin-4-yloxy)-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0912] A solution of tert-butyl 4-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-4-yl]oxy)piperidine-1-carboxylate (240 mg, 0.39 mmol, 1.00 eq) in dioxane / HCl (15 mL, 4 M) was stirred at 25 °C overnight. After concentration, the residue was purified by preparative HPLC to give the title compound as a white solid (31.5 mg, 21%). LCMS (ESI, m / z): 382.14 [M+H] + , 1 1H NMR (400 MHz, methanol-d4) δ: 8.36 (d, J = 6.0 Hz, 1H), 8.11 (s, 1H), 7.07 (d, J = 6.1 Hz, 1H), 5.03 (d, J = 11.7 Hz, 4H), 4.78 (dq, J = 8.3, 4.1 Hz, 1H), 3.11 (dt, J = 12.9, 4.6 Hz, 2H), 2.79 (ddd, J = 12.7, 9.2, 3.2 Hz, 2H), 2.39 - 1.85 (m, 2H), 1.75 (dtd, J = 13.0, 8.9, 3.8 Hz, 2H).

[0913] Example 10: 5-[4-[2-(morpholin-4-yl)ethoxy]-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0914]

[0915] Step 1: Synthesis of 5-[4-[2-(morpholin-4-yl)ethoxy]-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0916] A solution of 5-[4-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (200 mg, 0.47 mmol, 1.00 equiv), Ag2CO3 (387 mg, 3.00 equiv), NaI (140 mg, 2.00 equiv), and 4-(2-chloroethyl)morpholine (280 mg, 1.87 mmol, 4.00 equiv) in DMF (15 mL) was stirred at 80 °C for 2 h. The resulting solution was diluted with 15 mL of water and extracted with 3 × 15 mL of EtOAc. The organic layers were combined. The resulting solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluted with DCM / methanol (9 / 1) to give 200 mg (79%) of the title compound as a yellow oil. LCMS (ESI, m / z): 542.23 [M+H] + 。

[0917] Step 2: Synthesis of 5-[4-[2-(morpholin-4-yl)ethoxy]-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0918] A solution of 5-[4-[2-(morpholin-4-yl)ethoxy]-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (80 mg, 0.15 mmol, 1.00 equiv) in dioxane / HCl (15 mL, 4 M) was stirred at 25 °C overnight. After concentration, the residue was purified by preparative HPLC to give the title compound as a white solid (22.6 mg, 37%). LCMS (ESI, m / z): 412.15 [M+H]+, 1H NMR (300 MHz, methanol-d4) δ: 8.40 (d, J = 5.9 Hz, 1H), 8.11 (s, 1H), 7.06 (d, J = 6.0 Hz, 1H), 5.04 (d, J = 11.1 Hz, 4H), 4.38 (t, J = 5.5 Hz, 2H), 3.91 - 3.56 (m, 4H), 2.89 (t, J = 5.4 Hz, 2H), 2.77 - 2.51 (m, 4H).

[0919] Example 11: 5-[6-methoxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0920]

[0921] Step 1: Synthesis of 5-[6-chloro-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0922] A solution of 5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (6 g, 18.25 mmol, 1.00 equiv), TEA (5.5 g, 54.35 mmol, 3.00 equiv), 6-chloro-1H,2H,3H-pyrrolo[3,4-c]pyridine hydrochloride (3.5 g, 18.32 mmol, 1.00 equiv) in ethanol (70 mL) was stirred at 80 °C for 3 h. The reaction mixture was concentrated in vacuo and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (4 / 6) to give 4.9 g (60%) of the title compound as a yellow solid. LCMS (ESI, m / z): 447.12 [M+H] + 。

[0923] Step 2: Synthesis of 5-[6-methoxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0924] A solution of 5-[6-chloro-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (500 mg, 1.12 mmol, 1.00 equiv), [Pd(allyl)Cl]2 (41 mg, 0.11 mmol, 0.10 equiv), Rockphos (53 mg, 0.11 mmol, 0.10 equiv), Cs2CO3 (730 mg, 2.24 mmol, 2.00 equiv), methanol (76 mg, 2.37 mmol, 2.12 equiv) in toluene (10 mL) was stirred at 80 °C for 3 h under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (3 / 7) to give 336 mg (68%) of the title compound as a yellow oil. LCMS (ESI, m / z): 443.16 [M+H] + 。

[0925] Step 3: Synthesis of 5-[6-methoxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0926] A solution of 5-[6-methoxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (336 mg, 0.76 mmol, 1.00 equiv) in HCl / dioxane (10 mL) was stirred at room temperature for 12 h. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H2O / CH3CN. The residue was then further purified by preparative HPLC to give the title compound as a white solid (44.3 mg, 19%). LCMS (ESI, m / z): 313.25 [M+H] + , 1 1H NMR (400 MHz, DMSO-d 6) δ: 12.56 (s, 1H), 8.19 (d, J = 1.1 Hz, 1H), 8.00 (s, 1H), 6.88 - 6.83 (m, 1H), 4.98 - 4.93 (m, 4H), 3.86 (s, 3H).

[0927] Example 12: 5-[6-(Piperidin-4-yloxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one.

[0928]

[0929] Step 1: Synthesis of 5-[6-hydroxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0930] A solution of 5-[6-chloro-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (2.5 g, 5.59 mmol, 1.00 equiv), Pd(OAc)2 (125 mg, 0.56 mmol, 0.10 equiv), t-Bubrettphos (407 mg, 0.84 mmol, 0.15 equiv), K3PO4 (2.4 g, 11.31 mmol, 2.00 equiv) in dioxane (40 mL) and water (4 mL) was stirred at 100 °C for 3 h. The reaction mixture was concentrated in vacuo. The residue was applied to a silica gel column eluting with DCM / methanol (9 / 1) to give 890 mg (37%) of the title compound as a brown solid. LCMS (ESI, m / z): 429.15 [M+H].[[]END]]

[0931] Step 2: Synthesis of tert-butyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl]oxy)piperidine-1-carboxylate

[0932] A solution of 5-[6-hydroxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (870 mg, 2.03 mmol, 1.00 equiv), Ag2CO3 (1.13 g, 2.00 equiv), and tert-butyl 4-iodopiperidine-1-carboxylate (1.27 g, 4.08 mmol, 2.00 equiv) in DMF (25 mL) was stirred at 80 °C for 10 h. The resulting solution was diluted with 20 mL of water and extracted with 3 × 100 mL of EtOAc. The organic layers were combined, washed with 3 × 100 mL of brine, dried over Na2SO4. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (3 / 7) to give 1.21 g (97%) of the title compound as a yellow oil. LCMS (ESI, m / z): 612.28 [M+H].

[0933] Step 3: Synthesis of 5-[6-(piperidin-4-yloxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0934] A solution of tert-butyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl]oxy)piperidine-1-carboxylate (1.21 g, 1.98 mmol, 1.00 equiv) in hydrogen chloride / dioxane (20 mL) was stirred at room temperature for 2.5 h. After concentration, the residue was purified by C18 reverse-phase chromatography eluted with H2O / CH3CN. The residue was then further purified by preparative HPLC to give the title compound as a white solid (17.3 mg, 2%). LCMS (ESI, m / z): 382.35 [M+H] + , 1HNMR(400MHz, methanol-d4) δ: 8.17 - 8.11 (m, 1H), 8.07 (s, 1H), 6.81 (d, J = 1.1 Hz, 1H), 5.14 (dt, J = 8.6, 4.5 Hz, 1H), 5.02 (m, 4H), 3.16 - 3.07 (m, 2H), 2.79 (ddd, J = 12.7, 9.4, 3.2 Hz, 2H), 2.13 - 2.01 (m, 2H), 1.72 (dtd, J = 13.0, 9.0, 3.8 Hz, 2H).

[0935] Example 13: 5-[6-(Piperidin-4-yloxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0936]

[0937] A solution of 5-[6-(piperidin-4-yloxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (290 mg, 0.76 mmol, 1.00 equivalent), TEA (154 mg, 1.52 mmol, 2.00 equivalents), and Ac2O (93 mg, 0.91 mmol, 1.20 equivalents) in DCM (10 mL) was stirred at room temperature for 2 hours. After concentration, the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN. The residue was then further purified by preparative HPLC to give the title compound as a white solid (100.1 mg, 31%). LCMS (ESI, m / z): 424.39 [M + H] + , 1 H NMR(300MHz, methanol-d4) δ: 8.18 - 8.11 (m, 1H), 8.06 (s, 1H), 6.82 (d, J = 1.0 Hz, 1H), 5.28 (dq, J = 7.5, 3.7 Hz, 1H), 4.89 (m, 4H), 3.98 - 3.83 (m, 1H), 3.79 (ddd, J = 11.5, 7.3, 3.8 Hz, 1H), 3.48 (dd, J = 15.3, 6.4 Hz, 2H), 2.13 (s, 3H), 2.11 - 1.94 (m, 2H), 1.89 - 1.65 (m, 2H).

[0938] Example 14: 5-[5-[2-(Dimethylamino)ethoxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one; formic acid

[0939]

[0940] Step 1: Synthesize 5-(5-fluoro-6-hydroxyisoindolin-2-yl)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one.

[0941] A solution of 5-(5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (508 mg, 1.00 mmol, 1.00 equiv), Cu(acac)2 (27 mg, 0.10 equiv), BHMPO (35 mg, 0.10 equiv), LiOH·H2O (89 mg, 3.72 mmol, 2.10 equiv), and water (1 mL) in DMSO (4 mL) was stirred at 80 °C for 3 h. The solution was quenched with 20 mL of water and then extracted with EtOAc (3 × 30 mL), and the organic layers were combined. After concentration in vacuo, the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (7:3) to give 180 mg (40%) of the title compound as a brown oil. LCMS (ESI, m / z): 446.15 [M+H] + 。

[0942] Step 2: Synthesize 5-[5-[2-(dimethylamino)ethoxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0943] A solution of 5-(5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (254 mg, 0.50 mmol, 1.00 equiv), 2-(dimethylamino)ethan-1-ol (222.5 mg, 2.50 mmol, 5.00 equiv), [Pd(allyl)Cl]2 (18.3 mg, 0.05 mmol, 0.10 equiv), Rockphos (23.4 mg, 0.05 mmol, 0.10 equiv), and Cs2CO3 (326 mg, 1.00 mmol, 2.00 equiv) in toluene (20 mL) was stirred at 80 °C for 3 h. The resulting mixture was concentrated, and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (5 / 95) to give 97 mg (38%) of the title compound as a brown oil. LCMS (ESI, m / z): 517.00 [M+H] + 。

[0944] Step 3: Synthesis of 5-[5-[2-(dimethylamino)ethoxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one; formic acid

[0945] A solution of 5-[5-[2-(dimethylamino)ethoxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (88 mg, 0.17 mmol, 1.00 equiv) in HCl / dioxane (15 mL) was stirred at room temperature for 2 h. After concentration, the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN. The residue was then further purified by preparative HPLC to give the title compound as a white solid (19.5 mg, 26%). LCMS (ESI, m / z): 387.10 [M+H] + , 1 1H NMR (300 MHz, methanol-d4) δ 8.46 (s, 1H), 8.05 (s, 1H), 7.24 - 7.21 (m, 2H), 5.04 - 5.01 (m, 4H), 4.39 (t, J = 5.1 Hz, 2H), 3.52 - 3.40 (m, 2H), 2.87 (s, 6H).

[0946] Example 15: 5-[4-(pyridin-3-ylmethoxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0947]

[0948] Step 1: Synthesis of 2-bromo-3,4-bis(bromomethyl)pyridine

[0949] A solution of 2-bromo-3,4-dimethylpyridine (5 g, 26.87 mmol, 1.00 equiv), NBS (10 g, 56.19 mmol, 2.00 equiv) and AIBN (2.22 g, 13.52 mmol, 0.50 equiv) in CCl4 (40 mL) was stirred at 80 °C for 2 h, then the resulting solution was concentrated in vacuo, and the residue was applied to a silica gel column eluting with EtOAc / petroleum ether (2:98) to give 5.7 g (62%) of the title compound as a red oil. LCMS (ESI, m / z): 341.81 [M+H]+.

[0950] Step 2: Synthesis of 4-bromo-2-[(4-methylphenyl)sulfonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine

[0951] To a solution of 2-bromo-3,4-bis(bromomethyl)pyridine (2.7 g, 7.85 mmol, 1.00 eq) and sodium hydride (380 mg, 15.83 mmol, 1.20 eq) in DMF (20 mL) was added TosNH2 (1.485 g, 1.10 eq). The resulting solution was then stirred at 0 °C for 0.5 h and then at 25 °C for 1 h. The resulting solution was then quenched by the addition of 50 mL of water, extracted with 3 × 15 mL of EtOAc, and the organic layers were combined and concentrated in vacuo. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (3:7) to give 2 g (72%) of the title compound as a pale yellow solid. LCMS (ESI, m / z): 353.23 [M+H] + 。

[0952] Step 3: Synthesis of 4-bromo-1H,2H,3H-pyrrolo[3,4-c]pyridine hydrobromide

[0953] A solution of 4-bromo-2-[(4-methylphenyl)sulfonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine (2 g, 5.66 mmol, 1.00 eq) and phenol (3.2 g, 6.00 eq) in 48% HBr / HOAc (5 mL) and acetic acid (10 mL) was stirred overnight at 90 °C. The resulting solution was then concentrated in vacuo, and the crude product was purified by recrystallization from EtOAc to give 1.4 g (88%) of the title compound as a yellow solid. LCMS (ESI, m / z): 199.05 [M+H] + 。

[0954] Step 4: Synthesis of (5-[4-bromo-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0955] A solution of 4-bromo-1H,2H,3H-pyrrolo[3,4-c]pyridine hydrobromide (1.4 g, 5.00 mmol, 1.00 equiv), 5-chloro-4-(trifluoromethyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydropyridazin-3-one (2.55 g, 7.76 mmol, 1.10 equiv) and TEA (2.15 g, 21.25 mmol, 3.00 equiv) in ethanol (15 mL) was stirred at 60 °C for 2 h, then the resulting solution was concentrated in vacuo, and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (4:6) to afford 400 mg (16%) of the title compound as a dark green solid. LCMS (ESI, m / z): 491.38 [M+H] + 。

[0956] Step 5: Synthesis of 5-[4-(pyridin-3-ylmethoxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0957] A solution of 5-[4-bromo-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (150 mg, 0.31 mmol, 1.00 equiv), (Pd(allyl)Cl)2 (14 mg, 0.10 equiv), Rockphos (11 mg, 0.10 equiv), pyridin-3-ylmethanol (134 mg, 1.23 mmol, 4.00 equiv) and Cs2CO3 (200 mg, 0.61 mmol, 2.00 equiv) in toluene (5 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere, then the resulting solution was concentrated in vacuo, and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (6:4) to afford 80 mg (50%) of the title compound as a yellow oil. LCMS (ESI, m / z): 520.19 [M+H] + 。

[0958] Step 6: Synthesis of 5-[4-(pyridin-3-ylmethoxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0959] A solution of 5-[4-(pyridin-3-ylmethoxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (200 mg, 0.38 mmol, 1.00 equiv) in HCl / dioxane (5 mL, 4 M) was stirred overnight at room temperature, then the resulting solution was concentrated in vacuo, and the residue was purified by preparative HPLC to give the title compound as a white solid (2.7 mg, 2.0%). LCMS (ESI, m / z): 390.15 [M+H]+, 1 1H NMR (DMSO-d6, 400 MHz) δ 8.71 (d, J = 1.6 Hz, 1H), 8.54 (dd, J = 4.8, 1.6 Hz, 1H), 8.16 (d, J = 5.6 Hz, 1H), 8.07 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.43 (dd, J = 8.4, 4.8 Hz, 1H), 7.13 (d, J = 5.2 Hz, 1H), 5.51 (s, 2H), 4.97 (d, J = 11.6 Hz, 4H).

[0960] Example 16: 5-[4-(Piperidin-4-yloxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0961]

[0962] Step 1: Synthesis of 5-[4-bromo-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0963] A solution of (4-bromo-1H,2H,3H-pyrrolo[3,4-c]pyridine hydrobromide (700 mg, 2.50 mmol, 1.00 equiv), TEA (1.07 g, 10.57 mmol, 3.00 equiv), 5-chloro-4-(trifluoromethyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydropyridazin-3-one (1.25 g, 3.80 mmol, 1.10 equiv) in ethanol (20 mL, 1.00 equiv) was stirred at 60 °C for 2 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (4 / 6) to give 300 mg (24%) of the title compound as a dark green solid. LCMS (ESI, m / z): 493.06 [M+H] + 。

[0964] Step 2: Synthesis of 5-[4-Hydroxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0965] A solution of 5-[4-Bromo-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (440 mg, 0.90 mmol, 1.00 equiv), t-BuBrettphos (65 mg, 0.15 equiv), K3PO4 (571 mg, 2.69 mmol, 3.00 equiv), Pd(OAc)2 (20 mg, 0.09 mmol, 0.10 equiv) in dioxane (5 mL) and water (1 mL) was stirred at 100 °C for 1 h. The reaction mixture was concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl DCM / methanol (95 / 5) to afford 125 mg (33%) of the title compound as a yellow solid. LCMS (ESI, m / z): 429.15 [M+H].

[0966] Step 3: Synthesis of tert-Butyl 4-([2-[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-4-yl]oxy)piperidine-1-carboxylate

[0967] A solution of 5-[4-Hydroxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (115 mg, 0.27 mmol, 1.00 equiv), Ag2CO3 (149 mg, 0.54 mmol, 20.00 equiv), tert-Butyl 4-iodopiperidine-1-carboxylate (168 mg, 0.54 mmol, 2.00 equiv) in DMF (10 mL) was stirred at 80 °C for 48 h. The resulting solution was diluted with 20 mL of water and extracted with 3 × 20 ml EtOAc. The organic layers were combined, washed with 3 × 40 mL of brine, dried over Na2SO4. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluting with EtOAc / petroleum ether (1 / 1) to afford 146 mg (89%) of the title compound as a yellow oil. LCMS (ESI, m / z): 612.28 [M+H].

[0968] Step 4: Synthesis of 5-[4-(Piperidin-4-yloxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0969] A solution of tert-butyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-4-yl]oxy)piperidine-1-carboxylate (146 mg, 0.24 mmol, 1.00 eq) in methanol (2 mL) and hydrogen chloride / Et2O (10 mL) was stirred at room temperature for 4 h. After concentration, the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN. The residue was then further purified by preparative HPLC to give the title compound as a brown solid (6 mg, 7%). LCMS (ESI, m / z): 382.35 [M+H] + , 1 1H NMR (400 MHz, DMSO-d6) δ: 12.56 (s, 1H), 8.14 - 8.03 (m, 2H), 7.04 (d, J = 5.3 Hz, 1H), 5.18 (dt, J = 9.0, 4.8 Hz, 1H), 4.97 - 4.94 (m, 2H), 4.88 - 4.83 (m, 2H), 2.97 (dd, J = 11.0, 6.4 Hz, 2H), 2.62 (t, J = 10.0 Hz, 2H), 1.94 (dd, J = 12.5, 8.1 Hz, 2H), 1.60 - 1.47 (m, 2H).

[0970] Example 17: 5-(5-[[(Pyridin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0971]

[0972] Step 1: Synthesis of 5-(5-bromo-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0973] A solution of 5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (3.29 g, 10.01 mmol, 1.00 equiv), 5-bromo-2,3-dihydro-1H-isoindole hydrochloride (2.35 g, 10.02 mmol, 1.00 equiv), and TEA (2.02 g, 19.96 mmol, 2.00 equiv) in ethanol (50 mL) was stirred at 40 °C for 3 h. The solvent was concentrated in vacuo and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (1 / 5) to afford 3.65 g (74%) of the title compound as a yellow solid. LCMS (ESI, m / z): 490.07 [M+H] + 。

[0974] Step 2: Synthesis of 2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindole-5-carbonitrile

[0975] A solution of 5-(5-bromo-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1.3 g, 2.65 mmol, 1 equiv), Pd(PPh3)4 (0.6 g, 0.52 mmol, 0.196 equiv), and Zn(CN)2 (0.62 g, 5.28 mmol, 1.991 equiv) in NMP (15 mL) was stirred in an oil bath at 120 °C for 2 h. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3 × 30 mL of EtOAc, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (25 / 75) to afford 1.8 g of the title compound as a yellow oil. LCMS (ESI, m / z): 437.15 [M+H] + 。

[0976] Step 3: Synthesis of 5-[5-(aminomethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0977] A solution of 2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydro-pyridazin-4-yl]-2,3-dihydro-1H-isoindole-5-carbonitrile (1 g, 2.29 mmol, 1.00 equiv), palladium on carbon (500 mg), and hydrogen chloride (0.2 mL) in ethanol (20 mL) was stirred at 30 °C under a hydrogen atmosphere at a pressure of 30 atm for 2 days. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was applied to a silica gel column eluted with DCM / methanol (96:4) to give 700 mg (69%) of the title compound as a yellow oil. LCMS (ESI, m / z): 441.19 [M+H] + 。

[0978] Step 4: Synthesis of 5-(5-[[(pyridin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0979] A solution of 5-[5-(aminomethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (200 mg, 0.45 mmol, 1.00 equiv), Pd2(dba)3·CHCl3 (50 mg, 0.05 mmol, 0.10 equiv), Xantphos (28 mg, 0.05 mmol, 0.10 equiv), 4-bromopyridine (152 mg, 0.96 mmol, 2.00 equiv), and Cs2CO3 (315 mg, 2.00 equiv) in dioxane (15 mL) was stirred in a nitrogen atmosphere in an oil bath at 100 °C for 2 h. After concentration, the residue was applied to a silica gel column eluted with DCM / methanol (9:1) to give 130 mg (55%) of the title compound as a yellow solid. LCMS (ESI, m / z): 518.21 [M+H] + 。

[0980] Step 5: Synthesis of 5-(5-[[(pyridin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0981] A solution of 5-(5-[[(pyridin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (130 mg, 0.25 mmol, 1.00 eq) in hydrogen chloride / dioxane (20 mL) was stirred at room temperature for 14 h. The resulting mixture was concentrated in vacuo. The pH of the solution was adjusted to 9 with saturated aqueous sodium bicarbonate. The resulting solution was extracted with DCM and the organic layers were combined and dried over anhydrous sodium sulfate. After concentration, the residue was applied to a silica gel column eluting with DCM / methanol (9:1). The residue was then further purified by preparative HPLC to give the title compound as a white solid (35.7 mg, 37%). LCMS (ESI, m / z): 388.13 [M+H] + , 1 HNMR (DMSO-d6, 400 MHz) δ: 12.52 (s, 1H), 8.00 (d, J = 5.2 Hz, 3H), 7.38 - 7.27 (m, 3H), 7.25 (t, J = 6.1 Hz, 1H), 6.54 - 6.48 (m, 2H), 4.95 (d, J = 9.1 Hz, 4H), 4.36 (d, J = 6.1 Hz, 2H).

[0982] Example 18 Isomer A: 6-[4-[(3-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile and

[0983] Example 18 Isomer B: 6-[4-[(3-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

[0984]

[0985] Step 1: 5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0986] A solution of 5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (Int-A6, 4.8 g, 14.60 mmol, 1.00 equiv), 2,3-dihydro-1H-isoindol-1-ylmethanol hydrochloride (2.7 g, 14.54 mmol, 1.00 equiv) and TEA (4.4 g, 43.48 mmol, 2.99 equiv) in ethanol (100 mL) was stirred at 60 °C for 1 h. The resulting solution was then concentrated in vacuo and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether (45:55) to afford 2.9 g (45%) of the title compound as a brown solid. LCMS: [M+H] + 442.17。

[0987] Step 2: Methyl 3-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoate

[0988] Under nitrogen, a solution of 5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (2.93 g, 6.64 mmol, 1.00 equiv), methyl 3-bromobenzoate (2.84 g, 13.21 mmol, 1.99 equiv), Pd(allyl)Cl2 (243 mg), Rockphos (311 mg) and Cs2CO3 (4.3 g, 13.20 mmol, 1.99 equiv) in toluene (100 mL) was stirred at 80 °C for 18 h. The resulting solution was concentrated in vacuo and the residue was then applied to a silica gel column eluted with EtOAc / petroleum ether (1:3) to afford 3 g (79%) of the title compound as a brown solid. LCMS: [M+H] + 576.21。

[0989] Step 3: 3-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoic acid

[0990] Methyl 3-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoate (1.15 g, 2.00 mmol, 1.00 equiv) and LiOH (240 mg, 10.02 mmol, 5.02 equiv) in a solution of THF (12 mL) and water (3 mL) were stirred at 60 °C for 3 h. The resulting solution was concentrated in vacuo and the residue was diluted with 10 mL of H2O, and then the pH of the solution was adjusted to 5 with HCl (36.5%). The solid was collected by filtration to give 1.1 g (98%) of the title compound as a pale yellow solid. LCMS: [M+H] + 562.19。

[0991] Step 4: 3-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoic acid

[0992] A solution of 3-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoic acid (1.1 g, 1.96 mmol, 1.00 equiv) in HCl / dioxane (20 mL, 4 M) was stirred at room temperature for 3 h, and then the resulting solution was concentrated in vacuo to give 1 g of the title compound as a crude brown solid. LCMS: [M+H] + 432.11。

[0993] Step 5: 6-[4-[(3-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile and 6-[4-[(3-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

[0994] A solution of 3-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoic acid (500 mg, 1.16 mmol, 1.00 equiv), HATU (528 mg, 1.39 mmol, 1.20 equiv), DIPEA (449 mg, 3.47 mmol, 3.00 equiv) and Int-A4 (240 mg, 1.27 mmol, 1.1 equiv) in DMF (5 mL) was stirred at room temperature for 2 h. After concentration under reduced pressure, the resulting solution was purified by C18 reverse phase chromatography eluting with H2O / ACN. The residue was further purified by preparative HPLC and chiral preparative HPLC (CHIRAL Repaired IA, 5 μm, 0.46×10 cm column, eluting with a gradient of (hexane:DCM = 3:1)(0.1% DEA):EtOH = 50:50 at a flow rate of 1 mL / min) to afford the title compound as a white solid. The absolute stereochemistry was assigned based on the protein X-ray crystal structure obtained for Example 18 Isomer B, which confirmed the (S)-absolute stereochemistry and was observed to be the more potent enantiomer.

[0995] Example 18 Isomer A: 153.2 mg, 22%, LCMS: [M+H] + 602.05, 1 1H NMR (300 MHz, methanol-d4) δ 8.43 (d, J = 1.8 Hz, 1H), 8.42 (s, 1H), 7.79 (dd, J = 9.0, 2.4 Hz, 1H), 7.53 - 7.50 (m, 1H), 7.41 - 7.35 (m, 4H), 7.05 - 6.99 (m, 2H), 6.94 - 6.87 (m, 2H), 6.20 (s, 1H), 5.33 (d, J = 14.8 Hz, 1H), 4.68 (d, J = 14.7 Hz, 1H), 4.53 (dd, J = 10.2, 3.3 Hz, 1H), 4.29 (dd, J = 10.2, 6.6 Hz, 1H), 3.91 - 3.44 (m, 8H). tR = 4.369 min.

[0996] Example 18 Isomer B: 153.3 mg, 22%, 11H NMR (300 MHz, methanol-d4) δ 8.43 (d, J = 1.8 Hz, 1H), 8.38 (s, 1H), 7.79 (dd, J = 9.0, 2.4 Hz, 1H), 7.52 - 7.50 (m, 1H), 7.41 - 7.35 (m, 4H), 7.04 - 6.99 (m, 2H), 6.94 - 6.87 (m, 2H), 6.19 (s, 1H), 5.32 (d, J = 14.7 Hz, 1H), 4.67 (d, J = 14.7 Hz, 1H), 4.53 (dd, J = 10.2, 3.6 Hz, 1H), 4.26 (dd, J = 10.2, 6.6 Hz, 1H), 3.92 - 3.41 (m, 8H). LCMS: [M+H] + 602.05. tR = 5.955 min.

[0997] Example 19: 5-[5-Fluoro-6-[2-(morpholin-4-yl)ethoxy]-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0998]

[0999] Step 1: Synthesis of 5-[5-Fluoro-6-[2-(morpholin-4-yl)ethoxy]-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[1000] A solution of 5-(5-Fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (200 mg, 0.45 mmol, 1 equiv), 4-(2-Chloroethyl)morpholine hydrochloride (99.6 mg, 0.54 mmol, 1.192 equiv), and K2CO3 (123.6 mg, 0.89 mmol, 1.992 equiv) in DMF (10 mL) was stirred at 80 °C for 12 h. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3 × 15 mL of EtOAc and the organic layers were combined and dried over anhydrous sodium sulfate. The organic layer was concentrated in vacuo. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (90 / 10) to give 180 mg (72%) of the title compound as a yellow oil. LCMS (ESI, m / z): 559.23 [M+H] + .

[1001] Step 2: Synthesis of 5-[5-fluoro-6-[2-(morpholin-4-yl)ethoxy]-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[1002] A solution of 5-[5-fluoro-6-[2-(morpholin-4-yl)ethoxy]-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (180 mg, 0.32 mmol, 1 equiv) in HCl / dioxane (10 mL) was stirred at room temperature for 12 h. After concentration, the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN. The residue was then further purified by preparative HPLC to give the title compound as a white solid (52.1 mg, 37.8%). LCMS (ESI, m / z): 429.38 [M+H] + , 1 1H NMR (DMSO-d6, 300 MHz) δ: 12.55 (s, 1H), 7.98 (s, 1H), 7.27 (m, 2H), 4.91 (m, 4H), 4.18 (t, J = 5.7 Hz, 2H), 3.64 - 3.54 (m, 4H), 3.31 (m, 2H), 2.73 (t, J = 5.7 Hz, 2H), 2.48 (m, 2H).

[1003] Example 20: 5-[5-Fluoro-6-(piperidin-4-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[1004]

[1005] Step 1: Synthesis of tert-butyl 4-[([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)methyl]piperidine-1-carboxylate

[1006] A solution of 5-(5-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1 g, 2.24 mmol, 1.00 equiv), potassium carbonate (3.1 g, 22.43 mmol, 10.00 equiv), and tert-butyl 4-(iodomethyl)piperidine-1-carboxylate (4.4 g, 13.53 mmol, 6.00 equiv) in DMF (15 mL) was stirred at 80 °C for 1.5 h. The solution was quenched with 50 mL of water, and the resulting solution was extracted with EtOAc (3 × 60 mL), and the organic layers were combined. The solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (5 / 95) to give 1 g (69%) of the title compound as a white solid. LCMS (ESI, m / z): 643.30 [M+H] + 。

[1007] Step 2: Synthesis of 5-[5-fluoro-6-(piperidin-4-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[1008] A solution of tert-butyl 4-[([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)methyl]piperidine-1-carboxylate (200 mg, 0.31 mmol, 1.00 equiv) and trifluoroacetic acid (2 mL) in DCM (10 mL) was stirred at room temperature for 3 h. After concentration, the residue was purified by C18 reverse-phase chromatography eluted with H2O / CH3CN. The residue was then further purified by preparative HPLC to give the title compound as a white solid (24.2 mg, 19%). LCMS (ESI, m / z): 413.10 [M+H] + , 1 1H NMR (DMSO-d6, 300 MHz) δ 7.98 (d, J = 13.8 Hz, 1H), 7.28 - 7.18 (m, 2H), 4.90 - 4.88 (m, 4H), 3.87 (dd, J = 6.4, 3.9 Hz, 2H), 3.01 - 2.95 (m, 2H), 2.45 - 2.44 (m, 2H), 1.84 (d, J = 4.2 Hz, 1H), 1.75 - 1.58 (m, 2H), 1.22 - 1.13 (m, 2H).

[1009] Example 21: 5-[5-[(1-acetylpiperidin-4-yl)methoxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[1010]

[1011] A solution of 5-[5-fluoro-6-(piperidin-4-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (325.35 mg, 0.79 mmol, 1.00 equiv), TEA (227.25 mg, 2.25 mmol, 4.00 equiv), and Ac2O (45.9 mg, 0.45 mmol, 1.00 equiv) in DCM (15 mL) was stirred at room temperature for 2 h. After concentration, the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN. The residue was then further purified by preparative HPLC to give the title compound as a white solid (68.2 mg, 19%). LCMS (ESI, m / z): 455.05 [M+H] + , 1 1H NMR (methanol-d4, 300 MHz) δ 8.04 (s, 1H), 7.14 (dd, J = 9.2, 4.7 Hz, 2H), 5.00 - 4.99 (s, 4H), 4.59 (d, J = 12.9 Hz, 1H), 4.06 - 3.84 (m, 3H), 3.25 - 3.13 (m, 1H), 2.80 - 2.56 (m, 1H), 2.13 (s, 3H), 2.12 - 2.11 (m, 1H), 2.04 - 1.84 (m, 2H), 1.50 - 1.22 (m, 2H).

[1012] Example 22: 5-[5-fluoro-6-[(1-methylpiperidin-4-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[1013]

[1014] A solution of 5-[5-fluoro-6-(piperidin-4-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (150 mg, 0.36 mmol, 1.00 equiv), (HCHO)n (62.1 mg, 3.00 equiv), acetic acid (0.5 mL), and NaBH3CN (43.47 mg, 0.69 mmol, 3.00 equiv) in methanol (15 mL) was stirred at room temperature for 15 h. After concentration, the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN. The residue was then further purified by preparative HPLC to afford the title compound as a white solid (57.9 mg, 37%). LCMS (ESI, m / z): 427.10 [M+H] + , 1 1H NMR (methanol-d4, 300 MHz) δ 8.04 (s, 1H), 7.12 (dd, J = 9.2, 4.5 Hz, 2H), 4.96 (s, 4H) 3.93 (d, J = 5.7 Hz, 2H), 2.95 (d, J = 11.5 Hz, 2H), 2.31 (s, 3H), 2.11 (t, J = 6.3 Hz, 2H), 1.98 - 1.81 (m, 3H), 1.65 - 1.26 (m, 2H).

[1015] Example 23: 5-(5-Fluoro-6-[[(piperidin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[1016]

[1017] Step 1: Synthesis of 6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindole-5-carbonitrile

[1018] A solution of 6-fluoro-2,3-dihydro-1H-isoindole-5-carbonitrile (600 mg, 3.70 mmol, 1 equiv), 5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1.45 g, 4.41 mmol, 1.192 equiv), and TEA (1.12 g, 11.07 mmol, 2.991 equiv) in EtOH (15 mL) was stirred at 80 °C for 2 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (15 / 85) to afford 1.2 g (71%) of the title compound as a yellow solid. LCMS (ESI, m / z): 455.14 [M+H] + 。

[1019] Step 2: Synthesis of 5-[5-(aminomethyl)-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[1020] A solution of 6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindole-5-carbonitrile (3 g, 6.60 mmol, 1 equiv) and Pd / C (300 mg, 2.82 mmol, 0.427 equiv) in EtOH (30 mL) was stirred at room temperature under a hydrogen atmosphere for 7 days. The solid was filtered off. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluted with DCM / methanol (93 / 7) to afford 1.58 g (52.2%) of the title compound as a yellow solid. LCMS (ESI, m / z): 459.18 [M+H] + 。

[1021] Step 3: Synthesis of tert-butyl 4-[([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]methyl)amino]piperidine-1-carboxylate

[1022] A solution of 5-[5-(aminomethyl)-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (200 mg, 0.44 mmol, 1 equiv), tert-butyl 4-oxopiperidine-1-carboxylate (104.6 mg, 0.52 mmol, 1.204 equiv), and NaBH3CN (137.34 mg, 2.19 mmol, 5.010 equiv) in MeOH (10 mL) was stirred at room temperature for 2 h. After concentration, the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN to give 100 mg (35.7%) of the title compound as a yellow oil. LCMS (ESI, m / z): 642.30 [M+H] + 。

[1023] Step 4: Synthesis of 5-(5-fluoro-6-[[(piperidin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[1024] A solution of tert-butyl 4-[([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]methyl)amino]piperidine-1-carboxylate (100 mg, 0.16 mmol, 1 equiv) in HCl / dioxane (12 mL) was stirred at room temperature for 12 h. After concentration, the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN. The residue was then further purified by preparative HPLC to give the title compound as a white solid (20.4 mg, 31.8%). LCMS (ESI, m / z): 412.40 [M+H] + , 1 1H NMR (300 MHz, DMSO-d6) δ: 8.01 (s, 1H), 7.48 (d, J = 6.7 Hz, 1H), 7.21 (d, J = 10.0 Hz, 1H), 4.95 (s, 4H), 3.77 (s, 2H), 2.91 (d, J = 12.0 Hz, 2H), 2.47 - 2.33 (m, 3H), 1.77 (d, J = 11.9 Hz, 2H), 1.13 (m, 2H).

[1025] Example 24: 5-(5-[[(1-acetylpiperidin-4-yl)amino]methyl]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[1026]

[1027] Step 1: Synthesis of 5-(5-[[(1-acetylpiperidin-4-yl)amino]methyl]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[1028] A solution of 5-[5-(aminomethyl)-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (300 mg, 0.65 mmol, 1 equiv), 1-acetylpiperidin-4-one (110.6 mg, 0.78 mmol, 1.197 equiv), and NaBH3CN (206 mg, 3.28 mmol, 5.01 equiv) in MeOH (10 mL) was stirred at room temperature for 2 h. After concentration, the residue was purified by C18 reverse-phase chromatography eluting with H2O / CH3CN to give 250 mg (65.5%) of the title compound as a yellow oil. LCMS (ESI, m / z): 584.26 [M+H] + 。

[1029] Step 2: Synthesis of 5-(5-[[(1-acetylpiperidin-4-yl)amino]methyl]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[1030] A solution of 5-(5-[[(1-acetylpiperidin-4-yl)amino]methyl]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (250 mg, 0.43 mmol, 1 equiv) in HCl / dio...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: X is Cl, Br, CH3, CF3, CN, OCH3, ethyl, cyclopropyl, SCH3 or isopropyl; A is a group having formula (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 or NR Y C(=O)NR Y , where each R Y is independently H or C 1-4 alkyl; L is C 1-3 alkylene, O, S, NR Y , C(=O), C(=O)O, C(=O)NR Y or S(=O); Z is Cy Z ; Cy Z is a pyridyl or pyrimidinyl group, each optionally substituted by CN, CF3 or Cl; Ring D is piperazinyl, dihydropyridazinyl, azepanyl, pyrrolidinyl or hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl; 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, a halogen group, OR a3 、C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl and C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl and C 6-10 aryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from OR a3 and NR c3 R d3 ; Each R a3 、R c3 and R d3 are independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; 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; and r is 0 or 1; wherein any of the foregoing heteroaryl groups contains 1, 2, 3 or 4 ring-forming heteroatoms independently selected from O, N and S.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is a group having formula (A-1a):

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is a group having formula (A-1b):

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is a group having formula (A-1c): wherein Z 1 and Z 2 are each independently selected from N and CH, wherein at least one of Z 1 and Z 2 is N, and wherein R is CN, Cl or CF3.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is a group having formula (A-1d): Wherein Z 1 and Z 2 are each independently selected from N and CH, wherein at least one of Z 1 and Z 2 is N, and wherein R is CN, Cl or CF3.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L is NR Y or O.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein X is CF3, CH3, CN, Cl or Br.

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

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

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

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

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

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

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

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

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-14, wherein Y 3 is C(=O) or S(=O)2.

17. The compound according to any one of claims 1-16 or a pharmaceutically acceptable salt thereof, wherein R Y is C 1-4 alkyl.

18. The compound according to any one of claims 1-16 or a pharmaceutically acceptable salt thereof, wherein R Y is methyl.

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein R Y is H.

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-19, wherein ring D is piperazinyl.

21. The compound according to any one of claims 1-20 or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-6 alkyl.

22. The compound according to any one of claims 1-20 or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally C a3 alkyl substituted by OR 1-6 .

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

24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-20, wherein R 1 is methyl, ethyl or isopropyl.

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

26. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-20, wherein R 1 is phenyl, phenylmethyl or pyridyl.

27. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-26, wherein R 2 is OR a3 .

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

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

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

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

32. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-28, wherein R 3 is phenyl, phenylmethyl or pyridyl.

33. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-32, wherein R 4 is H.

34. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-33, wherein R 5 is H.

35. The compound according to any one of claims 1-33 or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl, ethyl or isopropyl.

36. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-33, wherein R 5 is methoxymethyl or hydroxymethyl.

37. The compound according to any one of claims 1-33 or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl, phenylmethyl or pyridyl.

38. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-37, wherein R 6 is H.

39. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-38, wherein R 7 is C 1-6 alkyl.

40. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-38, wherein R 7 is methyl.

41. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-40, wherein R 8 is H.

42. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-40, wherein R 9 is H.

43. The compound according to any one of claims 1-40 or a pharmaceutically acceptable salt thereof, wherein R 10 is H.

44. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-43, wherein R 11 is H.

45. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-44, wherein R 12 is H.

46. The compound or a pharmaceutically acceptable salt thereof according to claim 1 and any one of claims 6-45, wherein m is 1.

47. The compound or a pharmaceutically acceptable salt thereof according to claim 1 and any one of claims 6-46, wherein n is 0.

48. The compound or a pharmaceutically acceptable salt thereof according to claim 1 and any one of claims 6-47, wherein p is 1.

49. The compound or a pharmaceutically acceptable salt thereof according to claim 1 and any one of claims 6-48, wherein q is 0.

50. The compound or a pharmaceutically acceptable salt thereof according to claim 1 and any one of claims 6-49, wherein r is 1.

51. The compound or a pharmaceutically acceptable salt thereof according to claim 1 and any one of claims 6-50, wherein a is 0.

52. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which has formula IIa:

53. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which has formula IIb:

54. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which has formula IIc: Wherein Z 1 and Z 2 are each independently selected from N and CH, wherein at least one of Z 1 and Z 2 is N, and wherein R is CN, Cl or CF3.

55. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which has formula IId: Wherein Z 1 and Z 2 are each independently selected from N and CH, wherein at least one of Z 1 and Z 2 is N, and wherein R is CN, Cl or CF3.

56. The compound according to claim 1, wherein the compound is 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one, or a pharmaceutically acceptable salt thereof.

57. The compound according to claim 56, wherein the compound is crystalline and has characteristic XRPD peaks at about 5.8, about 10.8, about 11.9, about 13.3, about 13.5, about 15.5 and about 17.2° 2θ.

58. The compound according to claim 56 or 57, wherein the XRPD pattern of the compound has characteristic peaks substantially as shown in Figure 8.

59. The compound according to any one of claims 56 - 58, wherein the DSC thermogram of the compound is characterized by an endothermic peak at a temperature of about 174 °C.

60. The compound according to any one of claims 56 - 58, wherein the compound has a DSC thermogram substantially as depicted in Figure 9.

61. A pharmaceutical composition comprising the compound according to any one of claims 1 to 60 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

62. Use of the compound according to any one of claims 1 to 60 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting the activity of PARP7.

63. Use of the compound according to any one of claims 1 to 60 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a patient in need thereof, wherein the cancer is characterized by overexpression or increased activity of PARP7.

64. The use according to claim 63, wherein the cancer is 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 cancer or urinary tract cancer.

65. The use according to claim 63, wherein the cancer is colon cancer.

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