CYCLOPROPYLAMINES AS LSD1 INHIBITORS

Abstract

The present invention is directed to cyclopropylamine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.

Description

FIELD OF THE INVENTION

The present invention relates to enzyme inhibitors, which selectively modulate demethylase, and uses therefor. Particular embodiments contemplate compounds and disease indications amenable to treatment by modulation of lysine specific demethylase-1 (LSD1).

BACKGROUND OF THE INVENTION

Epigenetic modifications can impact genetic variation but, when dysregulated, can also contribute to the development of various diseases (Portela, A. and M. Esteller, Epigenetic modifications and human disease. Nat Biotechnol, 2010. 28(10): p. 1057-68; Lund, A. H. and M. van Lohuizen, Epigenetics and cancer. Genes Dev, 2004. 18(19): p. 2315-35). Recently, in depth cancer genomics studies have discovered many epigenetic regulatory genes are often mutated or their own expression is abnormal in a variety of cancers (Dawson, M. A. and T. Kouzarides, Cancer epigenetics: from mechanism to therapy. Cell, 2012. 150(1): p. 12-27; Waldmann, T. and R. Schneider, Targeting histone modifications—epigenetics in cancer. Curr Opin Cell Biol, 2013. 25(2): p. 184-9; Shen, H. and P. W. Laird, Interplay between the cancer genome and epigenome. Cell, 2013. 153(1): p. 38-55). This implies epigenetic regulators function as cancer drivers or are permissive for tumorigenesis or disease progression. Therefore, deregulated epigenetic regulators are attractive therapeutic targets.

One particular enzyme which is associated with human diseases is lysine specific demethylase-1 (LSD1), the first discovered histone demethylase (Shi, Y., et al., Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell, 2004. 119(7): p. 941-53). It consists of three major domains: the N-terminal SWIRM which functions in nucleosome targeting, the tower domain which is involved in protein-protein interaction, such as transcriptional co-repressor, co-repressor of RE1-silencing transcription factor (CoREST), and lastly the C terminal catalytic domain whose sequence and structure share homology with the flavin adenine dinucleotide (FAD)-dependent monoamine oxidases (i.e., MAO-A and MAO-B) (Forneris, F., et al., Structural basis of LSD1-CoREST selectivity in histone H3 recognition. J Biol Chem, 2007. 282(28): p. 20070-4; Anand, R. and R. Marmorstein, Structure and mechanism of lysine-specific demethylase enzymes. J Biol Chem, 2007. 282(49): p. 35425-9; Stavropoulos, P., G. Blobel, and A. Hoelz, Crystal structure and mechanism of human lysine-specific demethylase-1. Nat Struct Mol Biol, 2006. 13(7): p. 626-32; Chen, Y., et al., Crystal structure of human histone lysine-specific demethylase 1 (LSD1). Proc Natl Acad Sci USA, 2006. 103(38): p. 13956-61). LSD1 also shares a fair degree of homology with another lysine specific demethylase (LSD2) (Karytinos, A., et al., A novel mammalian flavin-dependent histone demethylase. J Biol Chem, 2009. 284(26): p. 17775-82). Although the biochemical mechanism of action is conserved in two isoforms, the substrate specificities are thought to be distinct with relatively small overlap. The enzymatic reactions of LSD1 and LSD2 are dependent on the redox process of FAD and the requirement of a protonated nitrogen in the methylated lysine is thought to limit the activity of LSD1/2 to mono- and di-methylated at the position of 4 or 9 of histone 3 (H3K4 or H3K9). These mechanisms make LSD1/2 distinct from other histone demethylase families (i.e. Jumonji domain containing family) that can demethylate mono-, di-, and tri-methylated lysines through alpha-ketoglutarate dependent reactions (Kooistra, S. M. and K. Helin, Molecular mechanisms and potential functions of histone demethylases. Nat Rev Mol Cell Biol, 2012. 13(5): p. 297-311; Mosammaparast, N. and Y. Shi, Reversal of histone methylation: biochemical and molecular mechanisms of histone demethylases. Annu Rev Biochem, 2010. 79: p. 155-79).

Methylated histone marks on K3K4 and H3K9 are generally coupled with transcriptional activation and repression, respectively. As part of corepressor complexes (e.g., CoREST), LSD1 has been reported to demethylate H3K4 and repress transcription, whereas LSD1, in nuclear hormone receptor complex (e.g., androgen receptor), may demethylate H3K9 to activate gene expression (Metzger, E., et al., LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature, 2005. 437(7057): p. 436-9; Kahl, P., et al., Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence. Cancer Res, 2006. 66(23): p. 11341-7). This suggests the substrate specificity of LSD1 can be determined by associated factors, thereby regulating alternative gene expressions in a context dependent manner. In addition to histone proteins, LSD1 may demethylate non-histone proteins. These include p53 (Huang, J., et al., p53 is regulated by the lysine demethylase LSD1. Nature, 2007. 449(7158): p. 105-8.), E2F (Kontaki, H. and I. Talianidis, Lysine methylation regulates E2F1-induced cell death. Mol Cell, 2010. 39(1): p. 152-60), STAT3 (Yang, J., et al., Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes. Proc Natl Acad Sci USA, 2010. 107(50): p. 21499-504), Tat (Sakane, N., et al., Activation of HIV transcription by the viral Tat protein requires a demethylation step mediated by lysine-specific demethylase 1 (LSD1/KDM1). PLoS Pathog, 2011. 7(8): p. e1002184), and myosin phosphatase target subunit 1 (MYPT1) (Cho, H. S., et al., Demethylation of RB regulator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells. Cancer Res, 2011. 71(3): p. 655-60). The lists of non-histone substrates are growing with technical advances in functional proteomics studies. These suggest additional oncogenic roles of LSD1 beyond in regulating chromatin remodeling. LSD1 also associates with other epigenetic regulators, such as DNA methyltransferase 1 (DNMT1) (Wang, J., et al., The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat Genet, 2009. 41(1): p. 125-9) and histone deacetylases (HDACs) complexes (Hakimi, M. A., et al., A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc Natl Acad Sci USA, 2002. 99(11): p. 7420-5; Lee, M. G., et al., Functional interplay between histone demethylase and deacetylase enzymes. Mol Cell Biol, 2006. 26(17): p. 6395-402; You, A., et al., CoREST is an integral component of the CoREST-human histone deacetylase complex. Proc Natl Acad Sci USA, 2001. 98(4): p. 1454-8). These associations augment the activities of DNMT or HDACs. LSD1 inhibitors may therefore potentiate the effects of HDAC or DNMT inhibitors. Indeed, preclinical studies have shown such potential already (Singh, M. M., et al., Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors. Neuro Oncol, 2011. 13(8): p. 894-903; Han, H., et al., Synergistic re-activation of epigenetically silenced genes by combinatorial inhibition of DNMTs and LSD1 in cancer cells. PLoS One, 2013. 8(9): p. e75136).

LSD1 has been reported to contribute to a variety of biological processes, including cell proliferation, epithelial-mesenchymal transition (EMT), and stem cell biology (both embryonic stem cells and cancer stem cells) or self-renewal and cellular transformation of somatic cells (Chen, Y., et al., Lysine-specific histone demethylase 1 (LSD1): A potential molecular target for tumor therapy. Crit Rev Eukaryot Gene Expr, 2012. 22(1): p. 53-9; Sun, G., et al., Histone demethylase LSD1 regulates neural stem cell proliferation. Mol Cell Biol, 2010. 30(8): p. 1997-2005; Adamo, A., M. J. Barrero, and J. C. Izpisua Belmonte, LSD1 and pluripotency: a new player in the network. Cell Cycle, 2011. 10(19): p. 3215-6; Adamo, A., et al., LSD1 regulates the balance between self-renewal and differentiation in human embryonic stem cells. Nat Cell Biol, 2011. 13(6): p. 652-9). In particular, cancer stem cells or cancer initiating cells have some pluripotent stem cell properties that contribute the heterogeneity of cancer cells. This feature may render cancer cells more resistant to conventional therapies, such as chemotherapy or radiotherapy, and then develop recurrence after treatment (Clevers, H., The cancer stem cell: premises, promises and challenges. Nat Med, 2011. 17(3): p. 313-9; Beck, B. and C. Blanpain, Unravelling cancer stem cell potential. Nat Rev Cancer, 2013. 13(10): p. 727-38). LSD1 was reported to maintain an undifferentiated tumor initiating or cancer stem cell phenotype in a spectrum of cancers (Zhang, X., et al., Pluripotent Stem Cell Protein Sox2 Confers Sensitivity to LSD1 Inhibition in Cancer Cells. Cell Rep, 2013. 5(2): p. 445-57; Wang, J., et al., Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties. Cancer Res, 2011. 71(23): p. 7238-49). Acute myeloid leukemias (AMLs) are an example of neoplastic cells that retain some of their less differentiated stem cell like phenotype or leukemia stem cell (LSC) potential. Analysis of AML cells including gene expression arrays and chromatin immunoprecipitation with next generation sequencing (ChIP-Seq) revealed that LSD1 may regulate a subset of genes involved in multiple oncogenic programs to maintain LSC (Harris, W. J., et al., The histone demethylase KDMJA sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell, 2012. 21(4): p. 473-87; Schenk, T., et al., Inhibition of the LSD1 (KDMJA) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med, 2012. 18(4): p. 605-11). These findings suggest potential therapeutic benefit of LSD1 inhibitors targeting cancers having stem cell properties, such as AMLs.

Overexpression of LSD1 is frequently observed in many types of cancers, including bladder cancer, NSCLC, breast carcinomas, ovary cancer, glioma, colorectal cancer, sarcoma including chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma, neuroblastoma, prostate cancer, esophageal squamous cell carcinoma, and papillary thyroid carcinoma. Notably, studies found over-expression of LSD1 was significantly associated with clinically aggressive cancers, for example, recurrent prostate cancer, NSCLC, glioma, breast, colon cancer, ovary cancer, esophageal squamous cell carcinoma, and neuroblastoma. In these studies, either knockdown of LSD1 expression or treatment with small molecular inhibitors of LSD1 resulted in decreased cancer cell proliferation and/or induction of apoptosis. See, e.g., Hayami, S., et al., Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers. Int J Cancer, 2011. 128(3): p. 574-86; Lv, T., et al., Over-expression of LSD1 promotes proliferation, migration and invasion in non-small cell lung cancer. PLoS One, 2012. 7(4): p. e35065; Serce, N., et al., Elevated expression of LSD1 (Lysine-specific demethylase 1) during tumour progression from pre-invasive to invasive ductal carcinoma of the breast. BMC Clin Pathol, 2012. 12: p. 13; Lim, S., et al., Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology. Carcinogenesis, 2010. 31(3): p. 512-20; Konovalov, S. and I. Garcia-Bassets, Analysis of the levels of lysine-specific demethylase 1 (LSD1) mRNA in human ovarian tumors and the effects of chemical LSD1 inhibitors in ovarian cancer cell lines. J Ovarian Res, 2013. 6(1): p. 75; Sareddy, G. R., et al., KDM1 is a novel therapeutic target for the treatment of gliomas. Oncotarget, 2013. 4(1): p. 18-28; Ding, J., et al., LSD1-mediated epigenetic modification contributes to proliferation and metastasis of colon cancer. Br J Cancer, 2013. 109(4): p. 994-1003; Bennani-Baiti, I. M., et al., Lysine-specific demethylase 1 (LSD1/KDM1A/A0F2/BHC110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. Hum Pathol, 2012. 43(8): p. 1300-7; Schulte, J. H., et al., Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer Res, 2009. 69(5): p. 2065-71; Crea, F., et al., The emerging role of histone lysine demethylases in prostate cancer. Mol Cancer, 2012. 11: p. 52; Suikki, H. E., et al., Genetic alterations and changes in expression of histone demethylases in prostate cancer. Prostate, 2010. 70(8): p. 889-98; Yu, Y., et al., High expression of lysine-specific demethylase 1 correlates with poor prognosis of patients with esophageal squamous cell carcinoma. Biochem Biophys Res Commun, 2013. 437(2): p. 192-8; Kong, L., et al., Immunohistochemical expression of RBP2 and LSD1 in papillary thyroid carcinoma. Rom J Morphol Embryol, 2013. 54(3): p. 499-503.

Recently, the induction of CD86 expression by inhibiting LSD1 activity was reported (Lynch, J. T., et al., CD86 expression as a surrogate cellular biomarker for pharmacological inhibition of the histone demethylase lysine-specific demethylase 1. Anal Biochem, 2013. 442(1): p. 104-6). CD86 expression is a marker of maturation of dendritic cells (DCs) which are involved in antitumor immune response. Notably, CD86 functions as a co-stimulatory factor to activate T cell proliferation (Greaves, P. and J. G. Gribben, The role of B7 family molecules in hematologic malignancy. Blood, 2013. 121(5): p. 734-44; Chen, L. and D. B. Flies, Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol, 2013. 13(4): p. 227-42).

In addition to playing a role in cancer, LSD1 activity has also been associated with viral pathogenesis. Particularly, LSD1 activity appears to be linked with viral replications and expressions of viral genes. For example, LSD1 functions as a co-activator to induce gene expression from the viral immediate early genes of various type of herpes virus including herpes simplex virus (HSV), varicella zoster virus (VZV), and β-herpesvirus human cytomegalovirus (Liang, Y., et al., Targeting the JMJD2 histone demethylases to epigenetically control herpesvirus infection and reactivation from latency. Sci Transl Med, 2013. 5(167): p. 167ra5; Liang, Y., et al., Inhibition of the histone demethylase LSD1 blocks alpha-herpesvirus lytic replication and reactivation from latency. Nat Med, 2009. 15(11): p. 1312-7). In this setting, a LSD1 inhibitor showed antiviral activity by blocking viral replication and altering virus associated gene expression.

Recent studies have also shown that the inhibition of LSD1 by either genetic depletion or pharmacological intervention increased fetal globin gene expression in erythroid cells (Shi, L., et al., Lysine-specific demethylase 1 is a therapeutic target for fetal hemoglobin induction. Nat Med, 2013. 19(3): p. 291-4; Xu, J., et al., Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A. Proc Natl Acad Sci USA, 2013. 110(16): p. 6518-23). Inducing fetal globin gene would be potentially therapeutically beneficial for the disease of β-globinopathies, including β-thalassemia and sickle cell disease where the production of normal β-globin, a component of adult hemoglobin, is impaired (Sankaran, V. G. and S. H. Orkin, The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med, 2013. 3(1): p. a011643; Bauer, D. E., S. C. Kamran, and S. H. Orkin, Reawakening fetal hemoglobin: prospects for new therapies for the beta-globin disorders. Blood, 2012. 120(15): p. 2945-53). Moreover, LSD1 inhibition may potentiate other clinically used therapies, such as hydroxyurea or azacitidine. These agents may act, at least in part, by increasing γ-globin gene expression through different mechanisms.

In summary, LSD1 contributes to tumor development by altering epigenetic marks on histones and non-histone proteins. Accumulating data have validated that either genetic depletion or pharmacological intervention of LSD1 normalizes altered gene expressions, thereby inducing differentiation programs into mature cell types, decreasing cell proliferation, and promoting apoptosis in cancer cells. Therefore, LSD1 inhibitors alone or in combination with established therapeutic drugs would be effective to treat the diseases associated with LSD1 activity.

SUMMARY OF THE INVENTION

The present invention is directed to, inter alia, a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein constituent variables are defined herein.

The present invention is further directed to a pharmaceutical composition comprising a compound of Formula I and at least one pharmaceutically acceptable carrier.

The present invention is further directed to a method of inhibiting LSD1 comprising contacting the LSD1 with a compound of Formula I.

The present invention is further directed to a method of treating an LSD1-mediated disease in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula I.

DETAILED DESCRIPTION

The present invention provides, inter alia, LSD1-inhibiting compounds such as a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is C_6-10 aryl or 5-10 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;

ring B is 4-10 membered heterocycloalkyl having carbon and 1, 2, or 3 heteroatoms selected from N, O, and S;

ring C is (1) phenyl, (2) monocyclic 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (3) a fused bicyclic moiety having Formula (A):

wherein:

• • ring C1 is phenyl or 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;
  • ring C2 is (1) phenyl, (2) C_5-6 cycloalkyl, (3) 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (4) 5-6 membered heterocycloalkyl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;

wherein said fused bicyclic moiety of Formula A is bonded to ring B via ring C1, and wherein Ring C substituents R³ and R⁴ are substituted on either or both of C1 and C2;

wherein ring C is substituted on any ring-forming atom of ring B except the ring-forming atom of ring B to which R^Z is bonded;

each R¹ is independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C14 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^c)R^b, C(═NR^c)NR^cR^d, NR^cC(═NR^c)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, C(═NR^c)NR^cR^d, NR^cC(═NR^c)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d;

each R² is independently selected from halo, C_1-6 alkyl, CN, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1, wherein said C_1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═NR^c1)NR^c1R^d1, NR^c1C(═NR^c1)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

wherein each R² is substituted on any ring-forming atom of ring B except the ring-forming atom of ring B to which R^Z is bonded;

each R³ is independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, C(═NR^c2)R^b2, C(═NR^c2)NR^c2R^d2, NR^c2C(═NR^c2)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, C(═NR^c2)NR^c2R^d2, NR^c2C(═NR^c2)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2;

R⁴ is halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3 NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, C(═NR^c3)R^b3, C(═NR^e3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3, NR^c3 S(O)R^b3, NR^c3 S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3OC(O)NR^c3R^d3, C(═NR^e3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3 NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3;

R⁵ and R⁶ are each independently selected from H, halo, CN, C_1-4 alkyl, C_1-4 cyanoalkyl, C_1-4 haloalkyl, and —(C_1-4 alkyl)-OR^a;

R^Z is H, halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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^c4R^d4, C(O)OR^a4 OC(O)R^b4, OC(O)NR^c4R^d4, NR^c4R^d4, NR^c4C(O)R^b4, NR^c4C(O)OR^a4, NR^c4C(O)NR^c4R^d4, C(═NR^e4)R^b4, C(═NR^e4)NR^c4R^d4, NR^c4C(═NR^e4)NR^c4R^d4 NR^c4S(O)R^b4, NR^c4S(O)₂R^b4, NR^c4S(O)₂NR^c4R^d4, S(O)R^b4, S(O)NR^c4R^d4, S(O)₂R^b4, and S(O)₂NR^c4R^d4, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a4, SR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, OC(O)R^b4, OC(O)NR^c4R^d4, C(═NR^e4)NR^c4R^d4, NR^c4C(═NR^e4)NR^c4R^d4 NR^c4R^d4, NR^c4C(O)R^b4, NR^c4C(O)OR^a4, NR^c4C(O)NR^c4R^d4 NR^c4S(O)R^b4, NR^c4S(O)₂R^b4, NR^c4S(O)₂NR^c4R^d4, S(O)R^b4, S(O)NR^c4R^d4, S(O)₂R^b4, and S(O)₂NR^c4R^d4;

each R^a, R^b, R^c, R^d, R^a2, R^b2, R^c2, R^d2, R^a3, R^b3, R^c3, R^d3, R^a4, R^b4, R^c4, and R^d4 is independently selected from H, C_1-6 alkyl, C_1-4 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C₃-cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cycanoalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

or any R^c and R^d together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, 5-6 membered heteroaryl, C_1-6 haloalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

or any R^c2 and R^d2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl, C_1-6 haloalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

or any R^c3 and R^d3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, 5-6 membered heteroaryl, C_1-6 haloalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

• • or any R^c4 and R^d4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, 5-6 membered heteroaryl, C_1-6 haloalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NRSC(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C₁-4 cyanoalkyl, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

each R^a1, R^b1, R^c1, R^d1 is independently selected from H and C_1-6 alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

each R^a5, R^b5, R^c5, and R^d5 is independently selected from H, C_1-4 alkyl, C_1-4 haloalkyl, C_2-4 alkenyl, and C_2-4 alkynyl, wherein said C_1-4 alkyl, C_2-4 alkenyl, and C_2-4 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, C_1-4 alkylamino, di(C_1-4 alkyl)amino, C_1-4 haloalkyl, and C_1-4 haloalkoxy; and

each R^e, R^e1, R^e2, R^e3, R^e4, and R^e5 is independently selected from H, C_1-4 alkyl, and CN;

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

p is 0, 1, 2, or 3; and

q is 0 or 1.

In some embodiments, ring B is monocyclic 4-7 membered heterocycloalkyl having carbon and 1, 2, or 3 heteroatoms selected from N, O, and S.

In some embodiments, ring B is a 4-10 membered heterocycloalkyl having carbon and 1, 2, or 3 heteroatoms selected from N, O, and S wherein said ring B comprises at least one ring-forming N atom.

In some embodiments, ring B is a 4-7 membered heterocycloalkyl having carbon and 1, 2, or 3 heteroatoms selected from N, O, and S wherein said ring B comprises at least one ring-forming N atom.

In some embodiments, ring B is a 6-membered heterocycloalkyl ring having carbon and 1 or 2 heteroatoms selected from N, O, and S wherein said ring B comprises at least one ring-forming N atom.

In some embodiments, ring B is azetidine or piperidine.

In some embodiments, ring B is azetidine.

In some embodiments, ring B is piperidine.

In some embodiments, ring C is bound to a ring-forming N atom of ring B.

In some embodiments, ring A is C_6-10 aryl or 5-10 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

In some embodiments, ring B is 4-10 membered heterocycloalkyl having carbon and 1, 2, or 3 heteroatoms selected from N, O, and S.

In some embodiments, ring C is (1) phenyl, (2) monocyclic 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (3) a fused bicyclic moiety having Formula (A):

wherein:

• • ring C1 is phenyl or 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;
  • ring C2 is (1) phenyl, (2) C_5-6 cycloalkyl, (3) 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (4) 5-6 membered heterocycloalkyl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

In some embodiments, the compounds of the invention include a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is C_6-10 aryl or 5-10 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;

ring C is (1) phenyl, (2) monocyclic 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (3) a fused bicyclic moiety having Formula (A):

wherein:

• • ring C1 is phenyl or 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;
  • ring C2 is (1) phenyl, (2) C_5-6 cycloalkyl, (3) 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (4) 5-6 membered heterocycloalkyl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;

wherein said fused bicyclic moiety of Formula A is bonded to ring B via ring C1, and wherein Ring C substituents R³ and R⁴ are substituted on either or both of C1 and C2;

X is —CH₂— or —CH₂—CH₂—;

Y is —CH₂— or —CH₂—CH₂—;

each R¹ is independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C₆-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d;

each R² is independently selected from halo, C_1-6 alkyl, CN, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1, wherein said C_1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═NR^e1)NR^c1R^d1, NR^c1C(═NR^e1)NRlRdl, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

wherein each R² is substituted any ring-forming carbon atom of the ring in Formula II containing X and Y except the ring-forming carbon atom to which R^Z is bonded;

each R³ is independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, C(═NR^e2)R^b2, C(═NR^e2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, C(═NR^e2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2;

R⁴ is C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, C(═NR^e3)R^b3, C(═NR^e3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3, NR^c3 S(O)R^b3, NR^c3 S(O)₂R^b3, NR^c3 S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, C(═NR^e3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3;

R⁵ and R⁶ are each independently selected from H, halo, CN, C_1-4 alkyl, C_1-4 cyanoalkyl, C_1-4 haloalkyl, and —(C_1-4 alkyl)-OR^a5;

R^Z is H, halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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^c4R^d4, C(O)OR^a4, OC(O)R^b4, OC(O)NR^c4R^d4, NR^c4R^d4, NR^c4C(O)R^b4, NR^c4C(O)OR^a4, NR^c4C(O)NR^c4R^d4, C(═NR^e4)R^b4, C(═NR^e4)NR^c4R^d4, NR^c4C(═NR^e4)NR^c4R^d4, NR^c4S(O)R^b4, NR^c4S(O)₂R^b4, NR^c4S(O)₂NR^c4R^d4, S(O)R^b4, S(O)NR^c4R^d4, S(O)₂R^b4, and S(O)₂NR^c4R^d4, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a4, SR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, OC(O)R^b4, OC(O)NR^c4R^d4, C(═NR^e4)NR^c4R^d4, NR^c4C(═NR^e4)NR^c4R^d4 NR^c4R^d4, NR^c4C(O)R^b4, NR^c4C(O)OR^a4, NR^c4C(O)NR^c4R^d4 NR^c4S(O)R^b4, NR^c4S(O)₂R^b4, NR^c4S(O)₂NR^c4R^d4, S(O)R^b4, S(O)NR^c4R^d4, S(O)₂R^b4, and S(O)₂NR^c4R^d4;

• • each R^a, R^b, R^c, R^d, R^a2, R^b2, R^c2, R^d2, R^a3, R^b3, R^c3, R^d3, R^a4, R^b4, R^c4, and R^d4 is independently selected from H, C_1-6 alkyl, C_1-4 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cycanoalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

or any R^c and R^d together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, 5-6 membered heteroaryl, C_1-6 haloalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

or any R^c2 and R^d2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl, C_1-6 haloalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

or any R^c3 and R^d3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, 5-6 membered heteroaryl, C_1-6 haloalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NRSC(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

or any R^c4 and R^d4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, 5-6 membered heteroaryl, C_1-6 haloalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

• • each R^a1, R^b1, R^c1, R^d1 is independently selected from H and C_1-6 alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^cC(═NR^e)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

each R^a5, R^b5, R^c5, and R^d5 is independently selected from H, C_1-4 alkyl, C_1-4 haloalkyl, C_2-4 alkenyl, and C_2-4 alkynyl, wherein said C_1-4 alkyl, C_2-4 alkenyl, and C_2-4 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, C_1-4 alkylamino, di(C_1-4 alkyl)amino, C_1-4 haloalkyl, and C_1-4 haloalkoxy; and

each R^e, R^e1, R^e2, R^e3, R^e4, and R^e5 is independently selected from H, C_1-4 alkyl, and CN;

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

p is 0, 1, 2, or 3; and

q is 0 or 1.

In some embodiments, the compounds of the invention include a compound of Formula IIIa or IIIb:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is C_6-10 aryl or 5-10 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;

ring C is (1) phenyl, (2) monocyclic 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (3) a fused bicyclic moiety having Formula (A):

wherein:

• • ring C1 is phenyl or 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;
  • ring C2 is (1) phenyl, (2) C_5-6 cycloalkyl, (3) 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (4) 5-6 membered heterocycloalkyl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;

wherein said fused bicyclic moiety of Formula A is bonded to ring B via ring C1, and wherein Ring C substituents R³ and R⁴ are substituted on either or both of C1 and C2;

each R¹ is independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d;

each R² is independently selected from halo, C_1-6 alkyl, CN, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1, wherein said C_1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═NR^e1)NR^c1R^d1, NR^c1C(═NR^e1)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

wherein each R² is substituted on any ring-forming carbon atom of the azetidine ring depicted in in Formula IIIa or the piperidine ring depicted in Formula IIIb except the ring-forming carbon atom to which R^Z is bonded;

each R³ is independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, C(═NR^e2)R^b2, C(═NR^e2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a2, SR^a, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, C(═NR^e2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2;

R⁴ is C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, C(═NR^e3)R^b3, C(═NR^e3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3, NR^c3 S(O)R^b3, NR^c3 S(O)₂R^b3, NR^c3 S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, C(═NR^e3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3;

R⁵ and R⁶ are each independently selected from H, halo, CN, C_1-4 alkyl, C_1-4 cyanoalkyl, C_1-4 haloalkyl, and —(C_1-4 alkyl)-OR^a5;

R^Z is H, halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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^c4R^d4, C(O)OR^a4, OC(O)R^b4, OC(O)NR^c4R^d4, NR^c4R^d4, NR^c4C(O)R^b4, NR^c4C(O)OR^a4, NR^c4C(O)NR^c4R^d4, C(═NR^e4)R^b4, C(═NR^e4)NR^c4R^d4, NR^c4C(═NR^e4)NR^c4R^d4, NR^c4S(O)R^b4, NR^c4S(O)₂R^b4, NR^c4S(O)₂NR^c4R^d4, S(O)R^b4, S(O)NR^c4R^d4, S(O)₂R^b4, and S(O)₂NR^c4R^d4, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a4, SR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, OC(O)R^b4, OC(O)NR^c4R^d4, C(═NR^e4)NR^c4R^d4, NR^c4C(═NR^e4)NR^c4R^d4 NR^c4R^d4, NR^c4C(O)R^b4, NR^c4C(O)OR^a4, NR^c4C(O)NR^c4R^d4 NR^c4S(O)R^b4, NR^c4S(O)₂R^b4, NR^c4S(O)₂NR^c4R^d4, S(O)R^b4, S(O)NR^c4R^d4, S(O)₂R^b4, and S(O)₂NR^c4R^d4;

• • each R^a, R^b, R^c, R^d, R^a2, R^b2, R^c2, R^d2, R^a3, R^b3, R^c3, R^d3, R^a4, R^b4, R^c4, and R^d4 is independently selected from H, C_1-6 alkyl, C_1-4 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cycanoalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

or any R^c and R^d together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, 5-6 membered heteroaryl, C_1-6 haloalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

or any R^c2 and R^d2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl, C_1-6 haloalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

or any R^c3 and R^d3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, 5-6 membered heteroaryl, C_1-6 haloalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NRSC(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

• • or any R^c4 and R^d4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, 5-6 membered heteroaryl, C_1-6 haloalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

each R^a1, R^b1, R^c1, R^d1 is independently selected from H and C_1-6 alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^cC(═NR^e)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

each R^a5, R^b5, R^c5, and R^d5 is independently selected from H, C_1-4 alkyl, C_1-4 haloalkyl, C_2-4 alkenyl, and C_2-4 alkynyl, wherein said C_1-4 alkyl, C_2-4 alkenyl, and C_2-4 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, C_1-4 alkylamino, di(C_1-4 alkyl)amino, C_1-4 haloalkyl, and C_1-4 haloalkoxy; and

each R^e, R^e1, R^e2, R^e3, R^e4, and R^e5 is independently selected from H, C_1-4 alkyl, and CN;

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

p is 0, 1, 2, or 3; and

q is 0 or 1.

In some embodiments, the compounds of the invention include a compound of Formula IVa or IVb:

In some embodiments, the compounds of the invention include a compound of Formula Va or Vb:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is C_6-10 aryl or 5-10 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;

ring C is (1) phenyl, (2) monocyclic 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (3) a fused bicyclic moiety having Formula (A):

wherein:

• • ring C1 is phenyl or 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;
  • ring C2 is (1) phenyl, (2) C_5-6 cycloalkyl, (3) 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (4) 5-6 membered heterocycloalkyl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;
  • wherein said fused bicyclic moiety of Formula A is bonded to ring B via ring C1, and wherein ring C substituents R³ and R⁴ are substituted on either or both of C1 and C2;

each R¹ is independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d;

each R³ is independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, C(═NR^e2)R^b2, C(═NR^e2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2 NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a2, SR^a, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, C(═NR^e2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2 NR^c2R^d2 NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2;

R⁴ is halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3 NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, C(═NR^e3)R^b3, C(═NR^e3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3, NR^c3 S(O)R^b3, NR^c3 S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 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, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3OC(O)NR^c3R^d3, C(═NR^e3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3;

each R^a, R^b, R^c, R^d, 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_1-4 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cycanoalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

or any R^c and R^d together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, 5-6 membered heteroaryl, C_1-6 haloalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5 S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

or any R^c2 and R^d2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl, C_1-6 haloalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

or any R^c3 and R^d3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, 5-6 membered heteroaryl, C_1-6 haloalkyl, halo, CN, OR^as, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5;

• • each R^a5, R^b5, R^c5, and R^d5 is independently selected from H, C_1-4 alkyl, C_1-4 haloalkyl, C_2-4 alkenyl, and C_2-4 alkynyl, wherein said C_1-4 alkyl, C_2-4 alkenyl, and C_2-4 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, C_1-4 alkylamino, di(C_1-4 alkyl)amino, C_1-4 haloalkyl, and C_1-4 haloalkoxy; and

each R^e, R^e2, R^e3, and R^e5 is independently selected from H, C_1-4 alkyl, and CN;

n is 0, 1, 2, or 3;

p is 0, 1, 2, 3; and

q is 0 or 1.

In some embodiments, q is 0.

In some embodiments, q is 1.

In some embodiments, ring A is phenyl.

In some embodiments, n is 0.

In some embodiments, both R⁵ and R⁶ are H.

In some embodiments, ring C is phenyl.

In some embodiments, ring C is monocyclic 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

In some embodiments, ring C is phenyl, pyridyl, piperazinyl, pyrazinyl, pyrimidinyl, or pyrazolyl.

In some embodiments, ring C is phenyl, pyridyl, piperazinyl, pyrazinyl, or pyrazolyl.

In some embodiments, R⁴ is C_1-6 alkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, 4-10 membered heterocycloalkyl, CN, NR^c3R^d3, C(O)OR^a3, or C(O)NR^c3R^d3, wherein said C_1-6 alkyl, C_3-10 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, C(═NR^e3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3 NR^c3R^d3 NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

In some embodiments, R⁴ is C_1-6 alkyl, C_1-6 haloalkyl, 4-10 membered heterocycloalkyl, CN, or C(O)NR^c3R^d3, wherein said C_1-6 alkyl and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, C(═NR^e3)NR^c3R^d3 NR^c3C(═NR^e3)NR^c3R^d3 NR^c3R^d3 NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3 S(O)R^b3, NR^c3 S(O)₂R^b3, NR^c3 S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

In some embodiments, R⁴ is methyl, F, Cl, CN, —C(O)OH, —C(O)NH₂, —C(O)NH(methyl), —C(O)N(CH₃)₂, —C(O)NH(2-propyl), —C(O)NH(ethyl), methoxy, 4-methylpiperazinyl, —CH₂—CN, CF₃, or a moiety of formula:

In some embodiments, R⁴ is methyl, F, Cl, CN, —C(O)NH(2-propyl), —C(O)NH(ethyl), methoxy, 4-methylpiperazinyl, —CH₂—CN, CF₃, or a moiety of formula:

In some embodiments, R⁴ is —CH₂—CN.

In some embodiments, each R³ is independently selected from halo, C_1-6 alkyl, C_1-6 haloalkyl, CN, OR^a2, and C(O)NR^c2R^d2, wherein said C_1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, C(═NR^e2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2.

In some embodiments, each R³ is independently selected from halo, C_1-6 alkyl, C_1-6 haloalkyl, CN, OR^a2, and C(O)NR^c2R^d2.

In some embodiments, each R³ is independently selected from F, Cl, CF₃, and methyl.

In some embodiments, p is 0.

In some embodiments, p is 1.

In some embodiments, p is 2.

In some embodiments, m is 0.

In some embodiments, m is 1.

In some embodiments, R^Z is C_1-4 alkyl or C_6-10 aryl-C_1-4 alkyl-, wherein said C_1-4 alkyl and C_6-10 aryl-C_1-4 alkyl- are each optionally substituted by halo, CN, or OR^a4.

In some embodiments, R^Z is C_1-4 alkyl.

In some embodiments, R^Z is C_1-4 alkyl substituted by CN or methoxy.

In some embodiments, R^Z is C_6-10 aryl-C_1-4 alkyl- substituted by fluoro.

In some embodiments, R^Z is methyl, cyanomethyl, methoxymethyl, or 4-fluorophenylmethyl.

In some embodiments, R^Z is C_1-4 alkyl substituted by CN.

In some embodiments, R^Z is cyanomethyl.

In some embodiments, R^Z is H.

In some embodiments, each R^a, R^b, R^c, and R^d is independently selected from H, C_1-6 alkyl, C_1-4 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_1-4 alkyl, C₁i 4 haloalkyl, C₁-4 cycanoalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^cC(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5 and S(O)₂NR^c5R^d5.

In some embodiments, each R^a2, R^b2, R^c2, and R^d2 is independently selected from H, C_1-6 alkyl, C_1-4 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_1-4 alkyl, C_1-4 haloalkyl, C₁-4 cycanoalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b, NR^c5 S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5.

In some embodiments, each R^a3, R^b3, R^c3, and R^d3 is independently selected from H, C_1-6 alkyl, C_1-4 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_1-4 alkyl, C₁i 4 haloalkyl, C₁-4 cycanoalkyl, halo, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)NR^c5R^d5, NR^c5C(O)OR^a5, C(═NR^e)NR^c5R^d5, NR^cC(═NR^e5)NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, and S(O)₂NR^c5R^d5.

In some embodiments, each R^a, R^b, R^c, and R^d is independently selected from H, C_1-6 alkyl, C_1-4 haloalkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, wherein said C_1-6 alkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl- is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, C_1-4 alkylamino, di(C₁-4 alkyl)amino, C_1-4 haloalkyl, and C_1-4 haloalkoxy.

In some embodiments, each R^a2, R^b2, R^c2, and R^d2 is independently selected from H, C_1-6 alkyl, C_1-4 haloalkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, wherein said C_1-6 alkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl- is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, C_1-4 alkylamino, di(C_1-4 alkyl)amino, C_1-4 haloalkyl, and C_1-4 haloalkoxy.

In some embodiments, each R^a3, R^b3, R^c3, and R^d3 is independently selected from H, C_1-6 alkyl, C_1-4 haloalkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, wherein said C_1-6 alkyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4 alkyl- is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, C_1-4 alkylamino, di(C_1-4 alkyl)amino, C_1-4 haloalkyl, and C_1-4 haloalkoxy.

In some embodiments, each R^a, R^b, R^c, and R^d is independently selected from H and C_1-6 alkyl.

In some embodiments, each R^a2, R^b2, R^c2, and R^d2 is independently selected from H and C_1-6 alkyl.

In some embodiments, each R^a3, R^b3, R^c3, and R^d3 is independently selected from H and C_1-6 alkyl.

In some embodiments, the compound has a trans configuration with respect to the di-substituted cyclopropyl group depicted in Formula I (or any of Formulas II, IIIa, IIIb, IVa, IVb, Va, and Vb).

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

A floating bond crossing a ring moiety in any structure or formula depicted herein is intended to show, unless otherwise indicated, that the bond can connect to any ring-forming atom of the ring moiety. For example, where ring A in Formula I is a naphthyl group, an R¹ substituent, if present, can be substituted on either of the two rings forming the naphthyl group.

In embodiments when ring C is a fused bicyclic moiety of Formula (A), the phrase “wherein said fused bicyclic moiety of Formula (A) is bonded to ring B via ring Cl, and wherein Ring C substituents R³ and R⁴ are substituted on either or both of C1 and C2” is intended to denote that (1) ring B of Formula I is connected to ring C1 and not to ring C2, (2) R⁴ is substituted on either ring C1 or ring C2, and (3) any R³ that is present is substituted on either ring C1 or ring C2. The floating bond over ring C1 in Formula (A) is intended to show that ring C1 (not ring C2) connects to ring B.

As used herein, the phrase “optionally substituted” means unsubstituted or substituted. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. It is to be understood that substitution at a given atom is limited by valency. Throughout the definitions, the term “C_i-j” indicates a range which includes the endpoints, wherein i and j are integers and indicate the number of carbons. Examples include C_1-4, C_1-6, and the like.

The term “z-membered” (where z is an integer) typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is z. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1, 2, 3, 4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

The term “carbon” refers to one or more carbon atoms.

As used herein, the term “C_i-j alkyl,” employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having i to j carbons. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms or from 1 to 4 carbon atoms, or from 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl.

As used herein, the term “C_i-j alkoxy,” employed alone or in combination with other terms, refers to a group of formula —O-alkyl, wherein the alkyl group has i to j carbons. Example alkoxy groups include methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy). In some embodiments, the alkyl group has 1 to 3 carbon atoms.

As used herein, “C_i-j alkenyl,” employed alone or in combination with other terms, refers to an unsaturated hydrocarbon group having one or more double carbon-carbon bonds and having i to j carbons. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “C_i-j alkynyl,” employed alone or in combination with other terms, refers to an unsaturated hydrocarbon group having one or more triple carbon-carbon bonds and having i to j carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.

As used herein, the term “C_i-j alkylamino,” employed alone or in combination with other terms, refers to a group of formula —NH(alkyl), wherein the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary alkylamino groups include methylamino, ethylamino, and the like.

As used herein, the term “di-C_i-j-alkylamino,” employed alone or in combination with other terms, refers to a group of formula —N(alkyl)₂, wherein each of the two alkyl groups has, independently, i to j carbon atoms. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms. In some embodiments, the dialkylamino group is —N(C_1-4 alkyl)₂ such as, for example, dimethylamino or diethylamino.

As used herein, the term “C_i-j alkylthio,” employed alone or in combination with other terms, refers to a group of formula —S-alkyl, wherein the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments, the alkylthio group is C_1-4 alkylthio such as, for example, methylthio or ethylthio.

As used herein, the term “amino,” employed alone or in combination with other terms, refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl is C_6-10 aryl. In some embodiments, the aryl group is a naphthalene ring or phenyl ring. In some embodiments, the aryl group is phenyl.

As used herein, the term “carbonyl”, employed alone or in combination with other terms, refers to a —C(O)— group.

As used herein, the term “C_i-j cyanoalkyl,” employed alone or in combination with other terms, refers to an alkyl group substituted by a CN group.

As used herein, the term “C_i-j cycloalkyl,” employed alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon moiety having i to j ring-forming carbon atoms, which may optionally contain one or more alkenylene groups as part of the ring structure.

Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane, cyclopentene, cyclohexane, and the like. One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized to form carbonyl linkages. In some embodiments, cycloalkyl is C_3-10 cycloalkyl, C_3-7 cycloalkyl, or C_5-6 cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and the like. Further exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, “C_i-j haloalkoxy,” employed alone or in combination with other terms, refers to a group of formula —O-haloalkyl having i to j carbon atoms. An example haloalkoxy group is OCF₃. An additional example haloalkoxy group is OCHF₂. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments, the haloalkoxy group is C_1-4 haloalkoxy.

As used herein, the term “halo,” employed alone or in combination with other terms, refers to a halogen atom selected from F, Cl, I or Br. In some embodiments, “halo” refers to a halogen atom selected from F, Cl, or Br. In some embodiments, the halo substituent is F.

As used herein, the term “C_i-j haloalkyl,” employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has i to j carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the haloalkyl group is fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, the haloalkyl group is trifluoromethyl. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “heteroaryl,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic heterocylic moiety, having one or more heteroatom ring members selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group has 1, 2, 3, or 4 heteroatom ring members. In some embodiments, the heteroaryl group has 1, 2, or 3 heteroatom ring members. In some embodiments, the heteroaryl group has 1 or 2 heteroatom ring members. In some embodiments, the heteroaryl group has 1 heteroatom ring member. In some embodiments, the heteroaryl group is 5- to 10-membered or 5- to 6-membered. In some embodiments, the heteroaryl group is 5-membered. In some embodiments, the heteroaryl group is 6-membered. In some embodiments, the heteroaryl ring has or comprises carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides. Example heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, furanyl, thiophenyl, triazolyl, tetrazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1, 2-b]thiazolyl, purinyl, triazinyl, and the like.

A 5-membered heteroaryl is a heteroaryl group having five ring-forming atoms wherein one or more of the ring-forming atoms are independently selected from N, O, and S. In some embodiments, the 5-membered heteroaryl group has 1, 2, or 3 heteroatom ring members. In some embodiments, the 5-membered heteroaryl group has 1 or 2 heteroatom ring members. In some embodiments, the 5-membered heteroaryl group has 1 heteroatom ring member. Example ring-forming members include CH, N, NH, 0, and S. Example five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1, 2, 3-triazolyl, tetrazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-triazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-triazolyl, 1, 3, 4-thiadiazolyl, and 1, 3, 4-oxadiazolyl.

A 6-membered heteroaryl is a heteroaryl group having six ring-forming atoms wherein one or more of the ring-forming atoms is N. In some embodiments, the 6-membered heteroaryl group has 1, 2, or 3 heteroatom ring members. In some embodiments, the 6-membered heteroaryl group has 1 or 2 heteroatom ring members. In some embodiments, the 6-membered heteroaryl group has 1 heteroatom ring member. Example ring-forming members include CH and N. Example six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

As used herein, the term “heterocycloalkyl,” employed alone or in combination with other terms, refers to non-aromatic heterocyclic ring system, which may optionally contain one or more unsaturations as part of the ring structure, and which has at least one heteroatom ring member independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heterocycloalkyl group has 1, 2, 3, or 4 heteroatom ring members. In some embodiments, the heterocycloalkyl group has 1, 2, or 3 heteroatom ring members. In some embodiments, the heterocycloalkyl group has 1 or 2 heteroatom ring members. In some embodiments, the heterocycloalkyl group has 1 heteroatom ring member. In some embodiments, the heterocycloalkyl group has or comprises carbon and 1, 2, or 3 heteroatoms selected from N, O, and S. When the heterocycloalkyl group contains more than one heteroatom in the ring, the heteroatoms may be the same or different. Example ring-forming members include CH, CH₂, C(O), N, NH, O, S, S(O), and S(O)₂. Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spiro systems. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non-aromatic ring, for example, 1, 2, 3, 4-tetrahydro-quinoline, dihydrobenzofuran and the like. The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized to form a carbonyl, sulfinyl, or sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized. In some embodiments, the heterocycloalkyl is 5- to 10-membered, 4- to 10-membered, or 4- to 7-membered. Examples of heterocycloalkyl groups include 1, 2, 3, 4-tetrahydro-quinolinyl, dihydrobenzofuranyl, azetidinyl, azepanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and pyranyl.

The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereoisomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

When the compounds of the invention contain a chiral center, the compounds can be any of the possible stereoisomers. In compounds with a single chiral center, the stereochemistry of the chiral center can be (R) or (S). In compounds with two chiral centers, the stereochemistry of the chiral centers can each be independently (R) or (S) so the configuration of the chiral centers can be (R) and (R), (R) and (S); (S) and (R), or (S) and (S). In compounds with three chiral centers, the stereochemistry each of the three chiral centers can each be independently (R) or (S) so the configuration of the chiral centers can be (R), (R) and (R); (R), (R) and (S); (R), (S) and (R); (R), (S) and (S); (S), (R) and (R); (S), (R) and (S); (S), (S) and (R); or (S), (S) and (S).

Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1, 2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone—enol pairs, amide—imidic acid pairs, lactam—lactim pairs, amide—imidic acid pairs, enamine—imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1, 2, 4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers.

The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified (e.g., in the case of purine rings, unless otherwise indicated, when the compound name or structure has the 9H tautomer, it is understood that the 7H tautomer is also encompassed).

All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in a compound of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20° C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17^th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002).

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O (acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc (t-butoxycarbonyl); BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc. (calculated); d (doublet); dd (doublet of doublets); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DIAD (N, N′-diisopropyl azidodicarboxylate); DIEA (N,N-diisopropylethylamine); DIPEA (N, N-diisopropylethylamine); DMF (N, N-dimethylformamide); Et (ethyl); EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HATU (N, N, N′, N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate); HCl (hydrochloric acid); HPLC (high performance liquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquid chromatography-mass spectrometry); m (multiplet); M (molar); mCPBA (3-chloroperoxybenzoic acid); MS (Mass spectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg (milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol (millimole(s)); N (normal); nM (nanomolar); NMP (N-methylpyrrolidinone); NMR (nuclear magnetic resonance spectroscopy); OTf (trifluoromethanesulfonate); Ph (phenyl); pM (picomolar); RP-HPLC (reverse phase high performance liquid chromatography); s (singlet); t (triplet or tertiary); TBS (tert-butyldimethylsilyl); tert (tertiary); tt (triplet of triplets); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg (microgram(s)); μL (microliter(s)); μM (micromolar); wt % (weight percent).

Synthesis

Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.

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

Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in P. G. M. Wuts and T. W. Greene, Protective Groups in Organic Synthesis, 4^th Ed., Wiley & Sons, Inc., New York (2006), which is incorporated herein by reference in its entirety. Protecting groups in the synthetic schemes are typically represented by “PG.”

Reactions 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., ¹H or ¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6(6), 874-883, which is incorporated herein by reference in its entirety) and normal phase silica chromatography.

Compounds of formula 3 can be prepared following the synthetic route as outlined in Scheme 1. The union of cyclopropylamine derivatives of formula 1 with aldehydes of formula 2 can be accomplished through reductive amination under standard conditions employing borohydride reducing reagents such as, but not limited to, sodium triacetoxyborohydride. If any functional groups in compound 1 or 2 are protected to avoid any side reactions, a subsequent deprotection step can be performed to obtain the final product of formula 3. The deprotection conditions can be found in the literature or detailed in the specific examples described below. The starting materials of formula 1 or 2 are either commercially available, or can be prepared as described herein, or prepared following methods disclosed in the literature.

Compounds of formula 3a can be alternatively synthesized by the methods outlined in Scheme 2. Reductive amination of cyclopropylamine derivatives of formula 1 with aldehydes of formula 4 using similar conditions as described in Scheme 1 can give compounds of formula 5. The free amine group in compound 5 can then be protected with a suitable protecting group (PG) such as but not limited to CF₃CO and Cbz, followed by selective removal of the Boc protecting group by acid to give compound 6. Coupling of compound 6 with a (hetero)aryl-halide 7 can be achieved via direct displacement of the halide such as fluoride in compound 7 by the piperidine in compound 6 in the presence of a suitable base (such as K₂CO₃ or NaH, etc) in a polar solvent such as DMF. The union of piperidine derivatives of formula 6 with (hetero)aryl-halie 7 can also be achieved via palladium catalyzed amination reactions to give compounds of formula 8, which can be deprotected to give compounds of formula 3a.

Compounds of formula 3b can be prepared by the methods outlined in Scheme 3 starting from compounds of formula 1 and ketones of formula 9 by reductive amination in a suitable solvent such as DCM or THF using a reducing agent such as, but not limited to, sodium triacetoxyborohydride, optionally in the presence of an acid such as acetic acid. If any functional groups in compound 1 or 9 are protected to avoid any side reactions, a subsequent deprotection step can be performed to obtain the final product of formula 3b.

To synthesize cyclopropylamine derivatives of formula 1, cyclopropanation reactions can be initially carried out on α,β-unsaturated esters of formula 10 (R is, e.g., alkyl such as ethyl) under commonly applied conditions (e.g., Corey-Chaykovsky Cyclopropanation, or Pd(OAc)₂ and diazomethane). The ester functional group can then be converted to a primary amine via a three-step sequence, namely saponification (e.g. LiOH in H₂O/EtOH) to elaborate carboxylic acid 11, followed by Curtius rearrangement (e.g. (PhO)₂P(═O)N₃, Et₃N, t-BuOH), and deprotection of the amine moiety (e.g. HCl in H₂O/1,4-dioxane), to give the desired cyclopropylamine derivatives of formula 1 (See Scheme 4).

Methods of Use

Compounds of the invention are LSD1 inhibitors and, thus, are useful in treating diseases and disorders associated with activity of LSD1. For the uses described herein, any of the compounds of the invention, including any of the embodiments thereof, may be used.

In some embodiments, the compounds of the invention are selective for LSD1 over LSD2, meaning that the compounds bind to or inhibit LSD1 with greater affinity or potency, compared to LSD2. In general, selectivity can be at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 200-fold, at least about 500-fold or at least about 1000-fold.

As inhibitors of LSD1, the compounds of the invention are useful in treating LSD1-mediated diseases and disorders. The term “LSD1-mediated disease” or “LSD1-mediated disorder” refers to any disease or condition in which LSD1 plays a role, or where the disease or condition is associated with expression or activity of LSD1. The compounds of the invention can therefore be used to treat or lessen the severity of diseases and conditions where LSD1 is known to play a role.

Diseases and conditions treatable using the compounds of the invention include generally cancers, inflammation, autoimmune diseases, viral induced pathogenesis, beta-globinopathies, and other diseases linked to LSD1 activity.

Cancers treatable using compounds according to the present invention include, for example, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

Example hematological cancers include, for example, lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), and multiple myeloma.

Example sarcomas include, for example, chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, harmatoma, and teratoma.

Example lung cancers include, for example, non-small cell lung cancer (NSCLC), bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.

Example gastrointestinal cancers include, for example, cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

Example genitourinary tract cancers include, for example, cancers of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).

Example liver cancers include, for example, hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

Example bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors

Example nervous system cancers include, for example, cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

Example gynecological cancers include, for example, cancers of the uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).

Example skin cancers include, for example, melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids.

The compounds of the invention can further be used to treat cancer types where LSD1 may be overexpressed including, for example, breast, prostate, head and neck, laryngeal, oral, and thyroid cancers (e.g., papillary thyroid carcinoma).

The compounds of the invention can further be used to treat genetic disorders such as Cowden syndrome and Bannayan-Zonana syndrome.

The compounds of the invention can further be used to treat viral diseases such as herpes simplex virus (HSV), varicella zoster virus (VZV), human cytomegalovirus, hepatitis B virus (HBV), and adenovirus.

The compounds of the invention can further be used to treat beta-globinopathies including, for example, beta-thalassemia and sickle cell anemia.

As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” a LSD1 protein with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having a LSD1 protein, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the LSD1 protein.

As used herein, the term “individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.

As used herein, the term “treating” or “treatment” refers to inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology) or ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.

As used herein, the term “preventing” or “prevention” refers to preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.

Combination Therapies

The compounds of the invention can be used in combination treatments where the compound of the invention is administered in conjunction with other treatments such as the administration of one or more additional therapeutic agents. The additional therapeutic agents are typically those which are normally used to treat the particular condition to be treated. The additional therapeutic agents can include, e.g., chemotherapeutics, anti-inflammatory agents, steroids, immunosuppressants, as well as Bcr-Abl, Flt-3, RAF, FAK, JAK, PIM, PI3K inhibitors for treatment of LSD1-mediated diseases, disorders or conditions. The one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.

In some embodiments, the compounds of the invention can be used in combination with a therapeutic agent that targets an epigenetic regulator. Examples of epigenetic regulators include the histone lysine methyltransferases, histone arginine methyl transferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases. Histone deacetylase inhibitors include, e.g., vorinostat.

For treating cancer and other proliferative diseases, the compounds of the invention can be used in combination with chemotherapeutic agents, or other anti-proliferative agents. The compounds of the invention can also be used in combination with medical therapy such as surgery or radiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes. Examples of suitable chemotherapeutic agents include any of: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, panobinostat, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

For treating cancer and other proliferative diseases, the compounds of the invention can be used in combination with ruxolitinib.

For treating cancer and other proliferative diseases, the compounds of the invention can be used in combination with targeted therapies, including JAK kinase inhibitors (Ruxolitinib, JAK1-selective), Pim kinase inhibitors, PI3 kinase inhibitors including PI3K-delta selective and broad spectrum PI3K inhibitors, MEK inhibitors, Cyclin Dependent kinase inhibitors, b-RAF inhibitors, mTOR inhibitors, Proteasome inhibitors (Bortezomib, Carfilzomib), HDAC-inhibitors (Panobinostat, Vorinostat), DNA methyl transferase inhibitors, dexamethasone, bromo and extra terminal family members inhibitors and indoleamine 2,3-dioxygenase inhibitors.

For treating autoimmune or inflammatory conditions, the compound of the invention can be administered in combination with a corticosteroid such as triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone.

For treating autoimmune or inflammatory conditions, the compound of the invention can be administered in combination with an immune suppressant such as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol, Alcon), or cyclosporine (Restasis®).

For treating autoimmune or inflammatory conditions, the compound of the invention can be administered in combination with one or more additional agents selected from Dehydrex™ (Holles Labs), Civamide (Opko), sodium hyaluronate (Vismed, Lantibio/TRB Chemedia), cyclosporine (ST-603, Sirion Therapeutics), ARG101(T) (testosterone, Argentis), AGR1012(P) (Argentis), ecabet sodium (Senju-Ista), gefarnate (Santen), 15-(s)-hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine, doxycycline (ALTY-0501, Alacrity), minocycline, iDestrin™ (NP50301, Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali), oxytetracycline (Duramycin, MOLI1901, Lantibio), CF101 (2S, 3S, 4R, 5R)-3, 4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyl-oxolane-2-carbamyl, Can-Fite Biopharma), voclosporin (LX212 or LX214, Lux Biosciences), ARG103 (Agentis), RX-10045 (synthetic resolvin analog, Resolvyx), DYN15 (Dyanmis Therapeutics), rivoglitazone (DE011, Daiichi Sanko), TB4 (RegeneRx), OPH-01 (Ophtalmis Monaco), PCS101 (Pericor Science), REV1-31 (Evolutec), Lacritin (Senju), rebamipide (Otsuka-Novartis), OT-551 (Othera), PAI-2 (University of Pennsylvania and Temple University), pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednol etabonate, rituximab, diquafosol tetrasodium (INS365, Inspire), KLS-0611 (Kissei Pharmaceuticals), dehydroepiandrosterone, anakinra, efalizumab, mycophenolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267 (TorreyPines Therapeutics), or thalidomide.

In some embodiments, the compound of the invention can be administered in combination with one or more agents selected from an antibiotic, antiviral, antifungal, anesthetic, anti-inflammatory agents including steroidal and non-steroidal anti-inflammatories, and anti-allergic agents. Examples of suitable medicaments include aminoglycosides such as amikacin, gentamycin, tobramycin, streptomycin, netilmycin, and kanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin; naphthyridine; sulfonamides; polymyxin; chloramphenicol; neomycin; paramomycin; colistimethate; bacitracin; vancomycin; tetracyclines; rifampin and its derivatives (“rifampins”); cycloserine; beta-lactams; cephalosporins; amphotericins; fluconazole; flucytosine; natamycin; miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen; ketorolac; suprofen; cromolyn; lodoxamide; levocabastin; naphazoline; antazoline; pheniramine; or azalide antibiotic.

Other examples of agents, one or more of which a provided compound may also be combined with include: a treatment for Alzheimer's Disease such as donepezil and rivastigmine; a treatment for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine; an agent for treating multiple sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), glatiramer acetate, and mitoxantrone; a treatment for asthma such as albuterol and montelukast; an agent for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; an anti-inflammatory agent such as a corticosteroid, such as dexamethasone or prednisone, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; an immunomodulatory agent, including immunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, an interferon, a corticosteroid, cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factor such as an acetylcholinesterase inhibitor, an MAO inhibitor, an interferon, an anti-convulsant, an ion channel blocker, riluzole, or an anti-Parkinson's agent; an agent for treating cardiovascular disease such as a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, a calcium channel blocker, or a statin; an agent for treating liver disease such as a corticosteroid, cholestyramine, an interferon, and an anti-viral agent; an agent for treating blood disorders such as a corticosteroid, an anti-leukemic agent, or a growth factor; or an agent for treating immunodeficiency disorders such as gamma globulin.

Biological drugs, such as antibodies and cytokines, used as anticancer angents, can be combined with the compounds of the invention. In addition, drugs modulating microenvironment or immune responses can be combined with the compounds of the invention. Examples of such drugs are anti-Her2 antibodies, anti-CD20 antibodies, anti-CTLA1, anti-PD-1, anti-PDL1, and other immunotherapeutic drugs.

Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the invention can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, 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 or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain, as the active ingredient, the compound of the invention or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical administration. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by processes known in the art, e.g., see International App. No. WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

The active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil 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.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. In some embodiments, ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white vaseline, and the like. Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, e.g., glycerinemonostearate, PEG-glycerinemonostearate and cetylstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as, for example, glycerol, hydroxyethyl cellulose, and the like. In some embodiments, topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5 wt % of the compound of the invention. The topical formulations can be suitably packaged in tubes of, for example, 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.

The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

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

The compositions of the invention can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.

The compounds of the invention can be provided with or used in combination with a companion diagnostic. As used herein, the term “companion diagnostic” refers to a diagnostic device useful for determining the safe and effective use of a therapeutic agent. For example, a companion diagnostic may be used to customize dosage of a therapeutic agent for a given subject, identify appropriate subpopulations for treatment, or identify populations who should not receive a particular treatment because of an increased risk of a serious side effect.

In some embodiments, the companion diagnostic is used to monitor treatment response in a patient. In some embodiments, the companion diagnostic is used to identify a subject that is likely to benefit from a given compound or therapeutic agent. In some embodiments, the companion diagnostic is used to identify a subject having an increased risk of adverse side effects from administration of a therapeutic agent, compared to a reference standard. In some embodiments, the companion diagnostic is an in vitro diagnostic or imaging tool selected from the list of FDA cleared or approved companion diagnostic devices. In some embodiments, the companion diagnostic is selected from the list of tests that have been cleared or approved by the Center for Devices and Radiological Health.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds of the invention (radio-labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating LSD1 in tissue samples, including human, and for identifying LSD1 ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes LSD1 assays that contain such labeled compounds.

The present invention further includes isotopically-labeled compounds of the invention. An “isotopically” or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound.

It is to be understood that a “radio-labeled” or “labeled compound” is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group consisting of ³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. In some embodiments, the compound incorporates 1, 2, or 3 deuterium atoms.

The present invention can further include synthetic methods for incorporating radio-isotopes into compounds of the invention. Synthetic methods for incorporating radio-isotopes into organic compounds are well known in the art, and an ordinary skill in the art will readily recognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay to identify/evaluate compounds. For example, a newly synthesized or identified compound (i.e., test compound) which is labeled can be evaluated for its ability to bind LSD1 by monitoring its concentration variation when contacting with LSD1, through tracking of the labeling. For example, a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to LSD1 (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to LSD1 directly correlates to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.

The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. The compounds of the Examples were found to be inhibitors of LSD1 as described below.

EXAMPLES

Experimental procedures for compounds of the invention are provided below. Preparatory LC-MS purifications of some of the compounds prepared were performed on Waters mass directed fractionation systems. The basic equipment setup, protocols, and control software for the operation of these systems have been described in detail in the literature. See e.g. “Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K. Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification”, K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and “Preparative LC-MS Purification: Improved Compound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity check under the following conditions: Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5 μm particle size, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA in water and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3 minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparative scale by reverse-phase high performance liquid chromatography (RP-HPLC) with MS detector or flash chromatography (silica gel) as indicated in the Examples. Typical preparative reverse-phase high performance liquid chromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 m particle size, 19×100 mm column, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile; the flow rate was 30 mL/minute, the separating gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature [see “Preparative LCMS Purification: Improved Compound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used with the 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 m particle size, 19×100 mm column, eluting with mobile phase A: 0.15% NH₄OH in water and mobile phase B: acetonitrile; the flow rate was 30 mL/minute, the separating gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature [See “Preparative LCMS Purification: Improved Compound Specific Method Optimization”, K.

Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used with 30×100 mm column was 60 mL/minute.

Example 1

3-Fluoro-4-[3-({[trans-2-phenylcyclopropyl]amino}methyl)azetidin-1-yl]benzonitrile

Step 1: tert-butyl 3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxylate

To the solution of tert-butyl 3-formylazetidine-1-carboxylate (556 mg, 3.00 mmol, Alfa Aesar: Cat # H52794) and 2-phenylcyclopropanamine hydrochloride (600. mg, 3.54 mmol, trans, racemic, J&W PharmLab: Cat #20-0073 S, Lot: JW152-128A) in DCM (10 mL) was added acetic acid (510 μL, 9.0 mmol). The resulting yellow solution was stirred at room temperature overnight then Na(OAc)₃BH (1.9 g, 9.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then diluted with DCM, washed with saturated Na₂CO₃, water and brine. The organic layer was dried over Na₂SO₄ then concentrated. The residue was purified on silica gel column eluting with 0 to 100% EtOAc/Hexanes to give the desired product (513 mg, 57%) as a light yellow oil. LC-MS calculated for C₁₄H₁₉N₂O₂ (M-^tBu+2H)⁺: m/z=247.1; found 247.2.

Step 2: tert-butyl 3-{[(trans-2-phenylcyclopropyl) (trifluoroacetyl)amino]methyl}azetidine-1-carboxylate

To a solution of tert-butyl 3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxylate (187 mg, 0.618 mmol) in DCM (5 mL) at 0° C. was added triethylamine (0.431 mL, 3.09 mmol), followed by dropwise addition of trifluoroacetic anhydride (114 μL, 0.804 mmol). The resulting yellow solution was stirred at 0° C. for 1 h then quenched with saturated NaHCO₃ solution and extracted with DCM. The combined extracts were dried over Na₂SO₄ then concentrated. The residue was purified on silica gel column eluting with 0 to 60% EtOAc/Hexanes to give the desired product (228 mg, 93%) as a yellow oil. LC-MS calculated for C₁₆H₁₈F₃N₂O₃(M-^tBu+2H)⁺: m/z=343.1; found 343.2.

Step 3: N-(azetidin-3-ylmethyl)-2, 2, 2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide

To the solution of tert-butyl 3-{[(trans-2-phenylcyclopropyl)-(trifluoroacetyl)amino]methyl}azetidine-1-carboxylate (228 mg, 0.572 mmol) in DCM (3 mL) was added TFA (3 mL). The resulting light yellow solution was stirred at room temperature for 1 h then concentrated. The residue (TFA salt) was used in the next step without further purification. LC-MS calculated for C₁₅H₁₈F₃N₂O (M+H)⁺: m/z=299.1; found 299.2.

Step 4: N-{[1-(4-cyano-2-fluorophenyl)azetidin-3-yl]methyl}-2, 2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide

A mixture of N-(azetidin-3-ylmethyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide (20 mg, 0.048 mmol), 3,4-difluorobenzonitrile (6.7 mg, 0.048 mmol) and potassium carbonate (16 mg, 0.12 mmol) in DMF (0.5 mL) was stirred at 120° C. for 2 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc, filtered and concentrated under reduced pressure to afford the crude product which was used in the next step without further purification. LC-MS calculated for C₂₂H₂₀F₄N₃O (M+H)⁺: m/z=418.2; found 418.1.

Step 5:. 3-Fluoro-4-[3-({[trans-2-phenylcyclopropyl]amino}methyl)azetidin-1-yl]benzonitrile

The crude product from Step 4 was dissolved in THF (0.5 mL) and MeOH (0.5 mL) then 1 N sodium hydroxide in water (0.5 mL) was added. The reaction mixture was stirred at 40° C. for 1 h then cooled to room temperature, filtered and purified by prep. HPLC (pH=10, acetonitrile/water+NH₄OH) to afford the desired product. LC-MS calculated for C₂₀H₂₁FN₃ (M+H)⁺: m/z=322.2; found 322.1.

Example 2

3,5-Difluoro-4-[3-({[trans-2-phenylcyclopropyl]amino}methyl)azetidin-1-yl]benzonitrile

This compound was prepared using procedures analogous to those described for the synthesis of Example 1 with 3,4,5-trifluorobenzonitrile replacing 3,4-difluorobenzonitrile in Step 4. LC-MS calculated for C₂₀H₂₀F₂N₃ (M+H)⁺: m/z=340.2; found 340.1.

Example 3

2,5-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

This compound was prepared using procedures analogous to those described for the synthesis of Example 1 with 2,4,5-trifluoro-N-isopropylbenzamide (prepared using similar methods as disclosed in the literature such as WO 2012/177606) replacing 3,4-difluorobenzonitrile in Step 4. LC-MS calculated for C₂₃H₂₈F₂N₃O (M+H)⁺: m/z=400.2; found 400.2.

Example 4

2-Methyl-6-[3-({[trans-2-phenylcyclopropyl]amino}methyl)azetidin-1-yl]nicotinonitrile

This compound was prepared using procedures analogous to those described for the synthesis of Example 1 with 6-fluoro-2-methylnicotinonitrile replacing 3,4-difluorobenzonitrile in Step 4. LC-MS calculated for C₂₀H₂₃N₄ (M+H)⁺: m/z=319.2; found 319.1.

Example 5

N-Ethyl-5-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)pyrazine-2-carboxamide

This compound was prepared using procedures analogous to those described for the synthesis of Example 1 with 5-chloro-N-ethylpyrazine-2-carboxamide (prepared using similar methods as disclosed in the literature such as WO 2012/177606) replacing 3,4-difluorobenzonitrile in Step 4. LC-MS calculated for C₂₀H₂₆N₅O (M+H)⁺: m/z=352.2; found 352.2.

Example 6

3,5-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

This compound was prepared using procedures analogous to those described for the synthesis of Example 1 with 3,4,5-trifluoro-N-isopropylbenzamide (prepared using similar methods as disclosed in the literature such as WO 2012/177606) replacing 3,4-difluorobenzonitrile in Step 4. LC-MS calculated for C₂₃H₂₈F₂N₃O (M+H)⁺: m/z=400.2; found 400.2.

Example 7

2,6-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

This compound was prepared using procedures analogous to those described for the synthesis of Example 1 with 2,4,6-trifluoro-N-isopropylbenzamide (prepared using similar methods as disclosed in the literature such as WO 2012/177606) replacing 3,4-difluorobenzonitrile in Step 4. LC-MS calculated for C₂₃H₂₈F₂N₃O (M+H)⁺: m/z=400.2; found 400.2.

Example 8

2,3-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

A container with a mixture of N-(azetidin-3-ylmethyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide (23 mg, 0.056 mmol, prepared as described in Example 1, Step 3), 4-bromo-2,3-difluoro-N-isopropylbenzamide (24 mg, 0.084 mmol, prepared using similar methods as disclosed in the literature such as WO 2012/177606), palladium acetate (1 mg, 0.006 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4 mg, 0.006 mmol), and cesium carbonate (55 mg, 0.17 mmol) in 1,4-dioxane (1 mL) was evacuated then refilled with nitrogen. After stirring at 125° C. overnight, the reaction mixture was cooled to room temperature, then 1N NaOH (0.5 mL) and MeOH (1 mL) were added. The resulting mixture was stirred at 40° C. for 1 h then cooled to room temperature, filtered and purified by prep HPLC (pH=10, acetonitrile/water+NH₄OH) to afford the desired product. LC-MS calculated for C₂₃H₂₈F₂N₃O (M+H)⁺: m/z=400.2; found 400.1.

Example 9

2-Chloro-5-fluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

This compound was prepared using procedures analogous to those described for the synthesis of Example 8 with 4-bromo-2-chloro-5-fluoro-N-isopropylbenzamide (prepared using similar methods as disclosed in the literature such as WO 2012/177606) replacing 4-bromo-2,3-difluoro-N-isopropylbenzamide. LC-MS calculated for C₂₃H₂₈ClFN₃O (M+H)⁺: m/z=416.2; found 416.1.

Example 10

3-Fluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

This compound was prepared using procedures analogous to those described for the synthesis of Example 8 with 4-bromo-3-fluoro-N-isopropylbenzamide (prepared using similar methods as disclosed in the literature such as WO 2012/177606) replacing 4-bromo-2,3-difluoro-N-isopropylbenzamide. LC-MS calculated for C₂₃H₂₉FN₃O (M+H)⁺: m/z=382.2; found 382.2.

Example 11

2-Fluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

This compound was prepared using procedures analogous to those described for the synthesis of Example 8 with 4-bromo-2-fluoro-N-isopropylbenzamide (prepared using similar methods as disclosed in the literature such as WO 2012/177606) replacing 4-bromo-2,3-difluoro-N-isopropylbenzamide. LC-MS calculated for C₂₃H₂₉FN₃O (M+H): m/z=382.2; found 382.2.

Example 12

2-Fluoro-N-isopropyl-5-methyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

This compound was prepared using procedures analogous to those described for the synthesis of Example 8 with 4-bromo-2-fluoro-N-isopropyl-5-methylbenzamide (prepared using similar methods as disclosed in the literature such as WO 2012/177606) replacing 4-bromo-2,3-difluoro-N-isopropylbenzamide. LC-MS calculated for C₂₄H₃₁FN₃O (M+H)⁺: m/z=396.2; found 396.4.

Example 13

N-Isopropyl-2-methoxy-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

This compound was prepared using procedures analogous to those described for the synthesis of Example 8 with 4-bromo-N-isopropyl-2-methoxybenzamide (prepared using similar methods as disclosed in the literature such as WO 2012/177606) replacing 4-bromo-2,3-difluoro-N-isopropylbenzamide. LC-MS calculated for C₂₄H₃₂N₃O₂ (M+H)⁺: m/z=394.2; found 394.4.

Example 14

3-Chloro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

This compound was prepared using procedures analogous to those described for the synthesis of Example 8 with 4-bromo-3-chloro-N-isopropylbenzamide (prepared using similar methods as disclosed in the literature such as WO 2012/177606) replacing 4-bromo-2,3-difluoro-N-isopropylbenzamide. LC-MS calculated for C₂₃H₂₉C1N₃O (M+H)⁺: m/z=398.2; found 398.2.

Example 15

5-(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide

This compound was prepared using procedures analogous to those described for the synthesis of Example 8 with 5-bromo-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide (prepared using similar methods as disclosed in the literature such as WO 2012/177606) replacing 4-bromo-2,3-difluoro-N-isopropylbenzamide. LC-MS calculated for C₂₃H₂₆F₃N₄O (M+H)⁺: m/z=431.2; found 431.2.

Example 16

N-({1-[6-(4-Methylpiperazin-1-yl)pyrimidin-4-yl]azetidin-3-yl}methyl)-trans-2-phenylcyclopropanamine

This compound was prepared using procedures analogous to those described for the synthesis of Example 8 with 4-chloro-6-(4-methylpiperazin-1-yl)pyrimidine (Combi-Blocks, cat # QA-3632) replacing 4-bromo-2,3-difluoro-N-isopropylbenzamide. LC-MS calculated for C₂₂H₃₁N₆(M+H)⁺: m/z=379.3; found 379.4.

Example 17

trans-N-{[1-(1-Methyl-1H-pyrazol-4-yl)azetidin-3-yl]methyl}-2-phenylcyclopropanamine

This compound was prepared using procedures analogous to those described for the synthesis of Example 8 with 4-bromo-1-methyl-1H-pyrazole replacing 4-bromo-2,3-difluoro-N-isopropylbenzamide. LC-MS calculated for C₁₇H₂₃N₄(M+H)⁺: m/z=283.2; found 283.2.

Example 18

2-Chloro-6-(4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)benzonitrile

Step 1: 1-tert-butyl 4-methyl 4-(cyanomethyl)piperidine-1,4-dicarboxylate

To a solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (0.97 g, 4.0 mmol) in THF (20 mL) at −40° C. was added 2.0 M LDA in THF (2.8 mL, 5.6 mmol) dropwise. The resulting mixture was stirred at −40° C. for 30 min then bromoacetonitrile (0.44 mL, 6.4 mmol) was added. The reaction mixture was stirred at −40° C. for 2 h then quenched with water. The mixture was warmed to room temperature then diluted with EtOAc, washed with water and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc in hexane (0-30%) to give the desired product. LC-MS calculated for C₁₀H₁₅N₂O₄ (M-^tBu+2H)⁺: m/z=227.1; found 227.2.

Step 2:. 1-(tert-Butoxycarbonyl)-4-(cyanomethyl)piperidine-4-carboxylic Acid

To the solution of 1-tert-butyl 4-methyl 4-(cyanomethyl)piperidine-1,4-dicarboxylate (0.60 g, 2.1 mmol) in THF (4.0 mL)/MeOH (4.0 mL)/water (1.0 mL) was added lithium hydroxide (monohydrate, 0.44 g, 11 mmol). The reaction mixture was stirred at room temperature for 2 h then acidified with cold 1 N HCl and extracted with EtOAc. The extract was washed with water, brine, dried over Na₂SO₄, filtered and concentrated. The residue was used in the next step without further purification. LC-MS calculated for C₉H₁₃N₂O₄ (M-^tBu+2H)⁺: m/z=213.1; found 213.1.

Step 3: tert-Butyl 4-(cyanomethyl)-4-(hydroxymethyl)piperidine-1-carboxylate

To a solution of 1-(tert-butoxycarbonyl)-4-(cyanomethyl)piperidine-4-carboxylic acid (0.50 g, 1.9 mmol) and triethylamine (0.52 mL, 3.7 mmol) in THF (6 mL) at 0° C. was added ethyl chloroformate (0.21 mL, 2.2 mmol). The resulting mixture was stirred for 30 min then filtered and washed with THF (2 mL). The filtrate was cooled to 0° C. and then sodium tetrahydroborate (0.14 g, 3.7 mmol) in methanol (1 mL)/water (1 mL) was added. The mixture was warmed to room temperature then stirred for 30 min. The mixture was diluted with EtOAc, washed with saturated NaHCO₃, water and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was used in the next step without further purification. LC-MS calculated for C₉H₁₅N₂O₃ (M-^tBu+2H)⁺: m/z=199.1; found 199.1.

Step 4: tert-Butyl 4-(cyanomethyl)-4-formylpiperidine-1-carboxylate

To a solution of tert-butyl 4-(cyanomethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (400.0 mg, 1.573 mmol) in DCM (8 mL) was added Dess-Martin periodinane (1.0 g, 2.4 mmol). The resulting mixture was stirred at room temperature for 3 h then saturated Na₂S₂O₃ aqueous solution was added and stirred for 10 min. The mixture was diluted with DCM, washed with 1N NaOH, water and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc in hexane (0-30%) to give the desired product. LC-MS calculated for C₉H₁₃N₂O₃ (M-^tBu+2H)⁺: m/z=197.1; found 197.1.

Step 5: tert-Butyl 4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidine-1-carboxylate

To the solution of tert-butyl 4-(cyanomethyl)-4-formylpiperidine-1-carboxylate (180.0 mg, 0.7134 mmol) and 2-phenylcyclopropanamine (114 mg, 0.856 mmol, trans, racemic, J&W PharmLab: Cat #20-0073S) in DCM (3.0 mL) was added acetic acid (0.061 mL, 1.1 mmol). The mixture was stirred at r.t. for 2 h then sodium triacetoxyborohydride (300 mg, 1.4 mmol) was added. The resulting mixture was stirred at r.t. for 2 h then diluted with DCM, washed with saturated NaHCO₃, water and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with methanol in methylene chloride (0-8%) to give the desired product. LC-MS calculated for C₂₂H₃₂N₃O₂ (M+H)⁺: m/z=370.2; found 370.3.

Step 6: tert-Butyl 4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl) (trifluoroacetyl)amino]methyl}piperidine-1-carboxylate

To a solution of tert-butyl 4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidine-1-carboxylate (0.18 g, 0.49 mmol) and DIEA (0.17 mL, 0.97 mmol) in DCM (2.4 mL) at 0° C. was added dropwise trifluoroacetic anhydride (0.08 mL, 0.58 mmol). The mixture was warmed to room temperature and stirred for 1 h then diluted with DCM, washed with saturated NaHCO₃, water and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc in hexane (0-20%) to give the desired product. LC-MS calculated for C₂₀H₂₃F₃N₃O₃(M-^tBu+2H)⁺: m/z=410.2; found 410.1.

Step 7: N-{[4-(Cyanomethyl)piperidin-4-yl]methyl}-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide

To a solution of tert-butyl 4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl)(trifluoroacetyl)amino]methyl}piperidine-1-carboxylate (0.16 g, 0.34 mmol) in DCM (0.2 mL) was added 4.0 M hydrogen chloride in dioxane (0.8 mL, 3.2 mmol). The resulting mixture was stirred at room temperature for 30 min then concentrated. The residue was used in the next step without further purification. LC-MS calculated for C₁₉H₂₃F₃N₃O (M+H)⁺: m/z=366.2; found 366.1.

Step 8: 2-Chloro-6-(4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl) benzonitrile

To a solution of N-{[4-(cyanomethyl)piperidin-4-yl]methyl}-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide (15.0 mg, 0.0410 mmol) and 2-chloro-6-fluorobenzonitrile (13 mg, 0.082 mmol) in NMP (0.4 mL) was added DIEA (29 μL, 0.16 mmol). The resulting mixture was stirred at 140° C. for 3 h then cooled to room temperature and 1 N NaOH (1.0 mL) was added. The mixture was stirred at 40° C. for 2 h then cooled to room temperature and purified by prep HPLC (pH=2, acetonitrile/water+TFA) to afford the desired product as TFA salt. LC-MS calculated for C₂₄H₂₆C1N₄ (M+H)⁺: m/z=405.2; found 405.1.

Example 19

{4-{[(trans-2-Phenylcyclopropyl)amino]methyl}-1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}acetonitrile

This compound was prepared using procedures analogous to those described for the synthesis of Example 18 with 2-chloro-3-(trifluoromethyl)pyridine replacing 2-chloro-6-fluorobenzonitrile. LC-MS calculated for C₂₃H₂₆F₃N₄ (M+H): m/z=415.2; found 415.3.

Example 20

6-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic Acid

Step 1: 1-tert-butyl 4-methyl 4-(4-fluorobenzyl)piperidine-1,4-dicarboxylate

To a solution of N,N-diisopropylamine (4.9 mL, 35 mmol) in tetrahydrofuran (80 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 14 mL, 35 mmol). The resulting mixture was warmed to −20° C. and stirred for 10 min then cooled to −78° C. and a solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (AstaTech, cat # B56857: 6.08 g, 25.0 mmol) in THF (10 mL) was slowly added. The reaction mixture was slowly warmed to −40° C. and stirred for 1 h. The mixture was then cooled to −78° C. and α-bromo-4-fluorotoluene (4.9 mL, 40. mmol) was added. The reaction mixture was stirred at −78° C. for 1 h then quenched with saturated NH₄Cl, warmed to room temperature and diluted with ethyl ether. The mixture was then washed with water, brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc in hexane (0-20%) to give the desired product (6.5 g, 74%). LC-MS calculated for C₁₅H₁₉FNO₄ (M-^tBu+2H)⁺: m/z=296.1; found 296.1.

Step 2: tert-butyl 4-(4-fluorobenzyl)-4-(hydroxymethyl)piperidine-1-carboxylate

To a solution of 1-tert-butyl 4-methyl 4-(4-fluorobenzyl)piperidine-1,4-dicarboxylate (6.5 g, 18 mmol) in tetrahydrofuran (90 mL) at 0° C. was added LiAlH₄ (1 M in THF, 24 mL, 24 mmol) slowly. The resulting mixture was stirred at 0° C. for 30 min then water (0.9 mL) was added, followed by NaOH (15 wt % in water, 0.9 mL) and water (0.9 mL). The mixture was stirred for 20 min then filtered and washed with THF. The filtrate was concentrated and the residue (5.8 g, 97%) was used in the next step without further purification. LC-MS calculated for C₁₄H₁₉FNO₃ (M-^tBu+2H)⁺: m/z=268.1; found 268.1.

Step 3: tert-butyl 4-(4-fluorobenzyl)-4-formylpiperidine-1-carboxylate

A solution of dimethyl sulfoxide (4.3 mL, 60. mmol) in methylene chloride (6 mL) was added to a solution of oxalyl chloride (2.6 mL, 30 mmol) in methylene chloride at −78° C. over 10 min and then the resulting mixture was warmed to −60° C. over 25 min. A solution of tert-butyl 4-(4-fluorobenzyl)-4-(hydroxymethyl)piperidine-1-carboxylate (5.2 g, 16 mmol) in methylene chloride (6 mL) was slowly added and then warmed to −45° C. over 30 mins. N,N-Diisopropylethylamine (21 mL, 120 mmol) was then added and the mixture was warmed to 0° C. over 15 min. The mixture was poured into a cold 1 N HCl aqueous solution and then extracted with ethyl ether. The combined extracts were dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc in hexane (0-20%) to give the desired product (4.3 g, 83%). LC-MS calculated for C₁₄H₁₇FNO₃ (M-^tBu+2H)⁺: m/z=266.1; found 266.1.

Step 4:. tert-butyl 4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(4-fluorobenzyl)-4-formylpiperidine-1-carboxylate (4.2 g, 13 mmol) and (1R, 2S)-2-phenylcyclopropanamine (1.96 g, 14.7 mmol) (prepared using procedures as described in Bioorg. Med. Chem. Lett., 2011, 21, 4429) in 1,2-dichloroethane (50 mL) was added acetic acid (1.1 mL, 20. mmol). The resulting mixture was stirred at room temperature for 2 h then sodium triacetoxyborohydride (5.7 g, 27 mmol) was added. The reaction mixture was stirred at room temperature for 5 h then diluted with methylene chloride, washed with 1 N NaOH aqueous solution, water and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with MeOH in DCM (0-6%) to give the desired product (5.0 g, 87%). LC-MS calculated for C₂₇H₃₆FN₂O₂(M+H)⁺: m/z=439.3; found 439.2.

Step 5: tert-butyl 4-(4-fluorobenzyl)-4-{[(JR, 2S)-2-phenylcyclopropyl-(trifluoroacetyl)amino]-methyl}piperidine-1-carboxylate

Trifluoroacetic anhydride (2.08 mL, 14.7 mmol) was added to a solution of tert-butyl 4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate (4.3 g, 9.8 mmol) and N,N-diisopropylethylamine (4.3 mL, 24 mmol) in methylene chloride (40 mL) at 0° C. The resulting mixture was stirred at 0° C. for 1 h then diluted with ether and washed with 1 N HCl, water and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc in hexanes (0-30%) to give the desired product (4.6 g, 88%). LC-MS calculated for C₂₅H₂₇F₄N₂O₃ (M-^tBu+2H)⁺: m/z=479.2; found 479.2.

Step 6: 2,2,2-trifluoro-N-{[4-(4-fluorobenzyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide

Hydrogen chloride (4 M in 1,4-dioxane, 20 mL, 80 mmol) was added to a solution of tert-butyl 4-(4-fluorobenzyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}-piperidine-1-carboxylate (4.6 g, 8.6 mmol) in methylene chloride (6 mL). The resulting mixture was stirred at room temperature for 30 min then concentrated. The residue was used in the next step without further purification. LC-MS calculated for C₂₄H₂₇F₄N₂O (M+H)⁺: m/z=435.2; found 435.2.

Step 7: 6-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic Acid

N,N-Diisopropylethylamine (0.040 mL, 0.23 mmol) was added to a mixture of 2,2,2-trifluoro-N-{[4-(4-fluorobenzyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide (25.0 mg, 0.0575 mmol) and methyl 6-fluoropyridine-2-carboxylate (Aldirch, cat #697842: 0.018 g, 0.12 mmol) in dimethyl sulfoxide (0.3 mL). The resulting mixture was stirred at 140° C. for 1.5 h then cooled to room temperature and NaOH (15 wt % in water, 0.5 mL) was added. The mixture was stirred at room temperature for 2 h then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C₂₈H₃₁FN₃O₂(M+H)⁺: m/z=460.2; found 460.2.

Example 21

5-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic Acid

This compound was prepared using similar procedures as described for Example 20 with methyl 5-fluoropyridine-2-carboxylate (Combi-Blocks, cat # PY-1211) replacing methyl 6-fluoropyridine-2-carboxylate. The mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C₂₈H₃₁FN₃O₂(M+H)⁺: m/z=460.2; found 460.2.

Example 22

1-{4-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]phenyl}cyclopropanecarboxylic Acid

To a mixture of 2,2,2-trifluoro-N-{[4-(4-fluorobenzyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide (Example 20, Step 6: 25 mg, 0.058 mmol), palladium acetate (0.6 mg, 0.003 mmol), (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (35 mg, 0.056 mmol), and cesium carbonate (56 mg, 0.17 mmol) in 1,4-dioxane (0.29 mL, 3.8 mmol) was added methyl 1-(4-bromophenyl)cyclopropanecarboxylate (Combi-Blocks, cat # HC-3048: 22 mg, 0.086 mmol). The resulting mixture was purged with nitrogen then stirred at 130° C. for overnight. The mixture was cooled to room temperature, diluted with acetonitrile and then filtered. The filtrate was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired intermediate. The intermediate was dissolved in MeOH/THF (0.2/0.2 mL) and then NaOH (15 wt % in water, 1.0 mL) was added. The resulting mixture was stirred at room temperature for 6 h then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C₃₂H₃₆FN₂O₂(M+H)⁺: m/z=499.3; found 499.2.

Example 23

4-[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic Acid

Step 1: 1-tert-butyl 4-methyl 4-(methoxymethyl)piperidine-1,4-dicarboxylate

To a solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (AstaTech, cat # B56857: 2.43 g, 10.0 mmol) in tetrahydrofuran (30 mL) at −40° C. was added lithium diisopropylamide (2 M in THF, 5.8 mL, 12 mmol). The resulting mixture was stirred at −40° C. for 30 min then chloromethyl methyl ether (1.2 mL, 16 mmol) was added. The reaction mixture was stirred at −40° C. for 1 h then quenched with saturated NH₄Cl aqueous solution and warmed to room temperature. The mixture was diluted with ethyl acetate, washed with saturated NaHCO₃ aqueous solution, water and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The crude material was purified via flash chromatography on a silica gel column (0 to 20% EtOAc in hexanes) to give the desired product (2.6 g, 90%). LC-MS calculated for C₉H₁₈NO₃ (M-Boc+2H)⁺: m/z=188.1; found 188.1.

Step 2: tert-butyl 4-(hydroxymethyl)-4-(methoxymethyl)piperidine-1-carboxylate

To a solution of 1-tert-butyl 4-methyl 4-(methoxymethyl)piperidine-1,4-dicarboxylate (2.3 g, 8.0 mmol) in tetrahydrofuran (40 mL) at 0° C. was added LiAlH₄ (1 M in THF, 10. mL, 10. mmol) slowly. The resulting mixture was stirred at 0° C. for 30 min then quenched with addition of water (0.1 mL), NaOH (15 wt % in water, 0.1 mL) and water (0.1 mL). The mixture was stirred for 10 min then filtered and washed with THF. The filtrate was concentrated and the residue was used in the next step without further purification. LC-MS calculated for C₉H₁₈NO₄ (M-^tBu+2H)⁺: m/z=204.1; found 204.1.

Step 3: tert-butyl 4-formyl-4-(methoxymethyl)piperidine-1-carboxylate

Dimethyl sulfoxide (1.7 mL, 24 mmol) in methylene chloride (2 mL) was added to a solution of oxalyl chloride (1.0 mL, 12 mmol) in methylene chloride (3 mL) at −78° C. over 10 min. The resulting mixture was warmed to −60 OC over 25 min then a solution of tert-butyl 4-(hydroxymethyl)-4-(methoxymethyl)piperidine-1-carboxylate (1.6 g, 6.0 mmol) in methylene chloride (5 mL) was slowly added. The mixture was warmed to −45° C. over 30 min then triethylamine (6.7 mL, 48 mmol) was added. The mixture was warmed to 0° C. over 15 min. The reaction mixture was then poured into a cold 1 N HCl aqueous solution and extracted with diethyl ether. The combined extracts were dried over Na₂SO₄, filtered and concentrated. The residue was purified via flash chromatography on a silica gel column eluting with 0 to 20% EtOAc in hexanes to give the desired product (1.3 g, 84%). LC-MS calculated for C₈H₁₆NO₂ (M-Boc+2H)⁺: m/z=158.1; found 158.1.

Step 4: tert-butyl 4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate

A mixture of tert-butyl 4-formyl-4-(methoxymethyl)piperidine-1-carboxylate (1.3 g, 5.0 mmol), acetic acid (0.43 mL, 7.5 mmol) and (1R,2S)-2-phenylcyclopropanamine (699 mg, 5.25 mmol) in 1,2-dichloroethane (20 mL) was stirred at room temperature for 1 h then sodium triacetoxyborohydride (2.1 g, 10. mmol) was added. The resulting mixture was stirred at room temperature for 2 h then diluted with methylene chloride, washed with saturated NaHCO₃ aqueous solution, water and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified via flash chromatography on a silica gel column eluting with 0 to 8% methanol in DCM to give the desired product (1.7 g, 91%). LC-MS calculated for C₂₂H₃₅N₂O₃ (M+H)⁺: m/z=375.3; found 375.2.

Step 5: tert-butyl 4-(methoxymethyl)-4-{[[(1R,2S)-2-phenylcyclopropyl]-(trifluoroacetyl)amino]methyl}piperidine-1-carboxylate

Trifluoroacetic anhydride (0.96 mL, 6.8 mmol) was added to a solution of tert-butyl 4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate (1.7 g, 4.5 mmol) and N,N-diisopropylethylamine (1.6 mL, 9.1 mmol) in methylene chloride (25 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 h then diluted with methylene chloride, washed with sat. NaHCO₃ aqueous solution, water, and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified via flash chromatography on a silica gel column eluting with 0 to 20% EtOAc in hexanes to give the desired product (1.8 g, 84%). LC-MS calculated for C₁₉H₂₆F₃N₂O₂(M-Boc+2H)⁺: m/z=371.2; found 371.1.

Step 6: 2,2,2-trifluoro-N-{[4-(methoxymethyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide

4.0 M Hydrogen chloride in dioxane (7 mL, 28 mmol) was added to a solution of tert-butyl 4-(methoxymethyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl})-piperidine-1-carboxylate (1.8 g, 3.8 mmol) in methylene chloride (4 mL). The resulting mixture was stirred at room temperature for 30 min then concentrated. The residue was used in the next step without further purification. LC-MS calculated for C₁₉H₂₆F₃N₂O₂(M+H)⁺: m/z=371.2; found 371.2.

Step 7: 4-[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic Acid

To a solution of 2,2,2-trifluoro-N-{[4-(methoxymethyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide (90. mg, 0.24 mmol) and methyl 4-fluoropyridine-2-carboxylate (0.075 g, 0.48 mmol) in dimethyl sulfoxide (0.5 mL) was added N,N-diisopropylethylamine (0.17 mL, 0.97 mmol). The resulting mixture was stirred at 140° C. for 1.5 h then cooled to room temperature and NaOH (15 wt % in water, 0.5 mL) was added. The reaction mixture was stirred at room temperature for 5 h then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C₂₃H₃₀N₃O₃ (M+H)⁺: m/z=396.2; found 396.2.

Example 24

6-[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic Acid

This compound was prepared using procedures analogous to those described for Example 23 with methyl 6-fluoropyridine-2-carboxylate replacing methyl 4-fluoropyridine-2-carboxylate. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C₂₃H₃₀N₃O₃ (M+H)⁺: m/z=396.2; found 396.2.

Example 25

5-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic Acid

Step 1: tert-butyl 4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate

A mixture of tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate (Synnovator, cat # PBN2011767: 2.50 g, 11.0 mmol), acetic acid (0.94 mL, 16 mmol) and (1R,2S)-2-phenylcyclopropanamine (1.54 g, 11.5 mmol) in 1,2-dichloroethane (40 mL) was stirred at room temperature for 1 h then sodium triacetoxyborohydride (4.7 g, 22 mmol) was added. The mixture was stirred at room temperature for 2 h then diluted with methylene chloride, washed with saturated NaHCO₃, water and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified via flash chromatography on a silica gel column eluting with 0 to 8% MeOH in DCM to give the desired product (3.4 g, 90%). LC-MS calculated for C₂₁H₃₃N₂O₂ (M+H): m/z=345.3; found 345.2.

Step 2:. tert-butyl 4-methyl-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}-piperidine-1-carboxylate

Trifluoroacetic anhydride (0.96 mL, 6.8 mmol) was added to a solution of tert-butyl 4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate (1.6 g, 4.5 mmol) and N,N-diisopropylethylamine (1.6 mL, 9.1 mmol) in methylene chloride (25 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 h then diluted with methylene chloride, washed with saturated NaHCO₃, water and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified via flash chromatography on a silica gel column eluting with 0 to 20% EtOAc in hexanes to give the desired product (1.8 g, 90%). LC-MS calculated for C₁₉H₂₄F3N₂O₃(M-^tBu+2H)⁺: m/z=385.2; found 385.2.

Step 3: 2,2,2-trifluoro-N-[(4-methylpiperidin-4-yl)methyl]-N-[(1R,2S)-2-phenylcyclopropyl]-acetamide

To a solution of tert-butyl 4-methyl-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)-amino]methyl}piperidine-1-carboxylate (1.5 g, 3.4 mmol) in methylene chloride (3 mL) was added hydrogen chloride (4 M in 1,4-dioxane, 6 mL, 24 mmol). The resulting mixture was stirred at room temperature for 1 h then concentrated. The residue was used in the next step without further purification. LC-MS calculated for C₁₈H₂₄F₃N₂O (M+H)⁺: m/z=341.2; found 341.2.

Step 4: 5-[4-methyl-4-({[(R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic Acid

N,N-Diisopropylethylamine (61 μL, 0.35 mmol) was added to a solution of 2,2,2-trifluoro-N-[(4-methylpiperidin-4-yl)methyl]-N-[(1R,2S)-2-phenylcyclopropyl]acetamide (30. mg, 0.088 mmol) and methyl 5-fluoropyridine-2-carboxylate (27 mg, 0.18 mmol) in N-methylpyrrolidinone (0.5 mL). The resulting mixture was stirred at 130° C. for overnight then cooled to room temperature and concentrated. The residue was dissolved in THF (1.0 mL) then 1 N NaOH (1.0 mL) was added. The mixture was stirred at room temperature for 5 h then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C₂₂H₂₈N₃O₂ (M+H)⁺: m/z=366.2; found 366.2. ¹H NMR (500 MHz, DMSO) δ 8.35 (d, J=2.9 Hz, 1H), 7.88 (d, J=8.9 Hz, 1H), 7.41 (dd, J=9.0, 2.9 Hz, 1H), 7.35-7.26 (m, 2H), 7.26-7.12 (m, 3H), 3.70-3.53 (m, 2H), 3.36-3.21 (m, 2H), 3.18-3.08 (m, 2H), 3.06-2.93 (m, 1H), 2.57-2.50 (m, 1H), 1.68-1.57 (m, 2H), 1.57-1.44 (m, 3H), 1.34-1.24 (m, 1H), 1.11 (s, 3H).

Example 26

6-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic Acid

N,N-Diisopropylethylamine (0.15 mL, 0.86 mmol) was added to a mixture of 2,2,2-trifluoro-N-[(4-methylpiperidin-4-yl)methyl]-N-[(1R,2S)-2-phenylcyclopropyl]acetamide (Example 25, Step 3: 74 mg, 0.22 mmol) and methyl 6-fluoropyridine-2-carboxylate (67 mg, 0.43 mmol) in dimethyl sulfoxide (0.5 mL). The resulting mixture was stirred at 140° C. for 1.5 h then cooled to room temperature and NaOH (15 wt % in water, 0.5 mL) was added. The reaction mixture was stirred at room temperature for 5 h then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C₂₂H₂₈N₃O₂ (M+H)⁺: m/z=366.2; found 366.2. ¹H NMR (500 MHz, DMSO) δ 8.58 (br, 2H), 7.65 (dd, J=8.6, 7.3 Hz, 1H), 7.35-7.24 (m, 3H), 7.25-7.14 (m, 3H), 7.07 (d, J=8.5 Hz, 1H), 4.00-3.81 (m, 2H), 3.43-3.29 (m, 2H), 3.16-3.07 (m, 2H), 3.07-2.97 (m, 1H), 2.56-2.49 (m, 1H), 1.63-1.49 (m, 3H), 1.48-1.37 (m, 2H), 1.35-1.22 (m, 1H), 1.11 (s, 3H).

Example 27

4-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic Acid

This compound was prepared using procedures analogous to those described for Example 26. The mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C₂₂H₂₈N₃O₂ (M+H)⁺: m/z=366.2; found 366.2.

Example 28

N,N-dimethyl-5-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxamide

To a solution of 5-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic acid (Example 25: 9.2 mg, 0.025 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (21.0 mg, 0.0403 mmol) in N,N-dimethylformamide (0.6 mL) was added dimethylamine (2 M in THF, 0.2 mL, 0.5 mmol), followed by triethylamine (24 μL, 0.17 mmol). The resulting mixture was stirred at room temperature for 1 h then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C₂₄H₃₃N₄O (M+H)⁺: m/z=393.3; found 393.3. ¹H NMR (500 MHz, DMSO) δ 8.60 (br, 2H), 8.26 (d, J=2.8 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.40 (dd, J=8.8, 2.9 Hz, 1H), 7.35-7.26 (m, 2H), 7.26-7.15 (m, 3H), 3.57-3.47 (m, 2H), 3.25-3.16 (m, 2H), 3.15-3.09 (m, 2H), 3.08-2.91 (m, 7H), 2.54-2.50 (m, 1H), 1.68-1.58 (m, 2H), 1.57-1.45 (m, 3H), 1.34-1.25 (m, 1H), 1.10 (s, 3H).

Example 29

N-methyl-5-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxamide

This compound was prepared using procedures analogous to those described for Example 28. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C₂₃H₃₁N₄O (M+H)⁺: m/z=379.2; found 379.2.

Example 30

2-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)pyrimidin-4-amine

Step 1: 1-(4-aminopyrimidin-2-yl)piperidin-4-one

To the mixture of 2-chloropyrimidin-4-amine (130 mg, 1.00 mmol) and piperidin-4-one hydrochloride hydrate (169 mg, 1.10 mmol) in isopropyl alcohol (5 mL) was added N,N-diisopropylethylamine (435 μL, 2.50 mmol). The resulting suspension was heated to 100° C. and stirred for overnight. The reaction mixture was cooled to room temperature then diluted with EtOAc and washed with water and brine. The organic layer was dried over Na₂SO₄ then concentrated to give the desired product as a yellow solid, which was used in the next step without further purification. LC-MS calculated for C₉H₁₃N₄O (M+H)⁺: m/z=193.1; found 193.2.

Step 2: 2-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)pyrimidin-4-amine

To the solution of (1R,2S)-2-phenylcyclopropanamine (24. mg, 0.18 mmol) and 1-(4-aminopyrimidin-2-yl)piperidin-4-one (34 mg, 0.18 mmol) in methylene chloride (1 mL) was added acetic acid (30 μL, 0.53 mmol). The resulting mixture was stirred at room temperature for overnight then sodium triacetoxyborohydride (75 mg, 0.35 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then diluted with DCM and washed with saturated NaHCO₃ aqueous solution, water and brine. The organic layer was dried over Na₂SO₄ then concentrated. The residue was dissolved in acetonitrile then purified by prep HPLC (pH=10, acetonitrile/water+NH₄OH) to give the desire product as a white solid. LC-MS calculated for C₁₈H₂₄N₅(M+H)⁺: m/z=310.2; found 310.1.

Example 31

2-(4-{[(1 S,2R)-2-phenylcyclopropyl]amino}piperidin-1-yl)pyrimidin-4-amine

This compound was prepared using procedures analogous to those described for Example 30 with (1S,2R)-2-phenylcyclopropanamine (prepared using procedures as described in Bioorg. Med. Chem. Lett., 2011, 21, 4429) replacing (1R,2S)-2-phenylcyclopropanamine. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH₄OH) to give the desired product as a white solid. LC-MS calculated for C₁₈H₂₄N₅(M+H)⁺: m/z=310.2; found 310.1.

Example A: LSD1 Histone Demethylase Biochemical Assay

LANCE LSD1/KDM1A demethylase assay-10 μL of 1 nM LSD-1 enzyme (ENZO BML-SE544-0050) in the assay buffer (50 mM Tris, pH 7.5, 0.01% Tween-20, 25 mM NaCl, 5 mM DTT) were preincubated for 1 hour at 25° C. with 0.8 μL compound/DMSO dotted in black 384 well polystyrene plates. Reactions were started by addition of 10 μL of assay buffer containing 0.4 μM Biotin-labeled Histone H3 peptide substrate: ART-K(Me1)-QTARKSTGGKAPRKQLA-GGK(Biotin) SEQ ID NO: 1 (AnaSpec 64355) and incubated for 1 hour at 25° C. Reactions were stopped by addition of 10 μL 1× LANCE Detection Buffer (PerkinElmer CR97-100) supplemented with 1.5 nM Eu-anti-unmodified H3K4 Antibody (PerkinElmer TRF0404), and 225 nM LANCE Ultra Streptavidin (PerkinElmer TRF 102) along with 0.9 mM Tranylcypromine-HCl (Millipore 616431). After stopping the reactions plates were incubated for 30 minutes and read on a PHERAstar FS plate reader (BMG Labtech). Compounds having an IC₅₀ of 1 μM or less were considered active. IC₅₀ data for the example compounds is provided in Table 1 (+ refers to IC₅₀≤100 nM; ++ refers to IC₅₀>100 nM and ≤500 nM).

TABLE 1
Example No. IC50 (nM)
1           +
2           +
3           +
4           +
5           +
6           +
7           +
8           +
9           +
10          +
11          +
12          +
13          +
14          +
15          +
16          +
17          +
18          +
19          +
20          +
21          +
22          +
23          +
24          +
25          +
26          +
27          +
28          +
29          +
30          +
31          ++

Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims

1. A compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein: except the ring-forming atom of ring to which RZ is bonded;

X is —CH2—;

Y is —CH2— or —CH2—CH2—;

wherein each R2 is substituted on any ring-forming carbon atom of the ring in Formula II containing X and Y except the ring-forming carbon atom to which RZ is bonded;

ring A is phenyl;

ring C is (1) phenyl, (2) monocyclic 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (3) a fused bicyclic moiety having Formula (A):

wherein: ring C1 is phenyl or 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S; ring C2 is (1) phenyl, (2) C5-6 cycloalkyl, (3) 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (4) 5-6 membered heterocycloalkyl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;

wherein said fused bicyclic moiety of Formula A is bonded to ring B via ring Cl, and wherein Ring C substituents R3 and R4 are substituted on either or both of C1 and C2;

wherein ring C is substituted on any ring-forming atom of ring

each R1 is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRdd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(═NRe)Rb, C(═NRe)NRcRd, NRcC(═NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(═NRe)NRcRd, NRcC(═NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd;

each R2 is independently selected from halo, C1-6 alkyl, CN, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRclRd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(═NRe1)NRc1Rd1, NRc1C(═NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1;

wherein each R2 is substituted on any ring-forming atom of ring B except the ring-forming atom of ring B to which RZ is bonded;

each R3 is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa2, SR, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(═NRe2)Rb2, C(═NRe2)NRc2Rd2 NRc2C(═NRe2)NRc2Rd2 NRc2S(O)Rb2, NRc2S(O)2Rb2 NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(═NRe2)NRc2Rd2 NRc2C(═NRe2)NRc2Rd2 NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2;

R4 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, C(═NRe3)Rb3, C(═NRe3)NRc3Rd3 NRc3C(═NRe3)NRc3Rd3 NRc3 S(O)Rb3, NRc3 S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3OC(O)NRc3Rd3, C(═NRe3)NRc3Rd3 NRc3C(═NRe3)NRc3Rd3 NRc3Rd3 NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3 S(O)Rb3, NRc3 S(O)2Rb3, NRc3 S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3;

R5 and R6 are each H;

RZ is H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, C(═NRe4)Rb4, C(═NRe4)NRc4Rd4 NRc4C(═NRe4)NRc4Rd4 NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(═NRe4)NRc4Rd4 NRc4C(═NRe4)NRc4Rd4 NRc4Rd4 NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4;

each Ra, Rb, Rc, Rd, Ra2, Rb2, Rc2, Rd2, Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)NRc5Rd5, NRc5C(O)ORa5, C(═NRe5)NRc5Rd5, NRc5C(═NRe5)NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, and S(O)2NRc5Rd5;

or any Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)NRc5Rd5, NRc5C(O)ORa5, C(═NRe5)NRc5Rd5, NRc5C(═NRe5)NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, and S(O)2NRc5Rd5, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)NRc5Rd5, NRc5C(O)ORa5, C(═NRe5)NRc5Rd5, NRc5C(═NRe5)NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, and S(O)2NRc5Rd5;

or any Rc2 and Rd2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)NRc5Rd5, NRc5C(O)ORa5, C(═NRe5)NRc5Rd5, NRc5C(═NRe)NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, and S(O)2NRc5Rd5, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)NRc5Rd5, NRc5C(O)ORa5, C(═NRe5)NRc5Rd5, NRc5C(═NRe)NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, and S(O)2NRc5Rd5;

or any Rc3 and Rd3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)NRc5Rd5, NRc5C(O)ORa5, C(═NRe5)NRc5Rd5, NRc5C(═NRe5)NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, and S(O)2NRc5Rd5, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)NRc5Rd5, NRc5C(O)ORa5, C(═NRe5)NRc5Rd5, NRc5C(═NRe5)NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, and S(O)2NRc5Rd5;

or any Rc4 and Rd4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)NRc5Rd5, NRc5C(O)ORa5, C(═NRe5)NRc5Rd5, NRc5C(═NRe5)NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, and S(O)2NRc5Rd5, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)NRc5Rd5, NRc5C(O)ORa5, C(═NRe5)NRc5Rd5, NRc5C(═NRe)NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, and S(O)2NRc5Rd5;

each Ra1, Rb1, Rc1, Rd1 is independently selected from H and C1-6 alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)NRc5Rd5, NRc5C(O)ORa5, C(═NRe5)NRc5Rd5, NRc5C(═NRe5)NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, and S(O)2NRc5Rd5;

each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, and C2-4 alkynyl, wherein said C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-4 haloalkyl, and C1-4 haloalkoxy; and

each Re, Re1, Re2, Re3, Re4, and Re5 is independently selected from H, C1-4 alkyl, and CN;

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

p is 0, 1, 2, or 3; and

q is 0 or 1.

2-3. (canceled)

4. The compound of claim 1 having Formula IIIa: or a pharmaceutically acceptable salt thereof, wherein:

wherein each R2 is substituted on any ring-forming carbon atom of the azetidine ring depicted in Formula IIIa except the ring-forming carbon atom to which RZ is bonded.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, having Formula IVa:

6. The compound of claim 1 having Formula Va: or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein q is 0.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein q is 1.

9. (canceled)

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0.

11. (canceled)

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring C is phenyl.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring C is monocyclic 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring C is phenyl, pyridyl, piperazinyl, pyrazinyl, pyrimidinyl, or pyrazolyl.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring C is phenyl, pyridyl, piperazinyl, pyrazinyl, or pyrazolyl.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, CN, NRc3Rd3, C(O)ORa3, or C(O)NRc3Rd3, wherein said C1-6 alkyl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(═NRe3)NRc3Rd3, NRc3C(═NRe3)NRc3Rd3 NRc3Rd3, NRc3C(O)Rb3 NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3.

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is C1-6 alkyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, CN, or C(O)NRc3Rd3, wherein said C1-6 alkyl and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(═NRe3)NRc3Rd3 NRc3C(═NRe3)NRc3Rd3 NRc3Rd3 NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3 S(O)Rb3, NRc3 S(O)2Rb3, NRc3 S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3.

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R3 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, ORa2, and C(O)NRc2Rd2, wherein said C1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(═NRe2)NRc2Rd2, NRc2C(═NRe2)NRc2Rd2 NRc2Rd2 NRc2C(O)Rb2 NRc2C(O)ORa2 NRc2C(O)NRc2Rd2, NRc2S(O)Rb2 NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2.

19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R3 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, ORa2, and C(O)NRc2Rd2.

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 0.

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 1.

22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 2.

23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 0.

24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1.

25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is C1-4 alkyl or C6-10 aryl-C1-4 alkyl-, wherein said C1-4 alkyl and C6-10 aryl-C1-4 alkyl- are each optionally substituted by halo, CN, or ORa4.

26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is C1-4 alkyl.

27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is C1-4 alkyl substituted by CN or methoxy.

28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is C6-10 aryl-C1-4 alkyl-substituted by fluoro.

29. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is methyl, cyanomethyl, methoxymethyl, or 4-fluorophenylmethyl.

30. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is C1-4 alkyl substituted by CN.

31. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is cyanomethyl.

32. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is H.

33. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a trans configuration with respect to the di-substituted cyclopropyl group depicted in Formula II.

34. The compound of claim 1, wherein the compound is selected from:

3-Fluoro-4-[3-({[trans-2-phenylcyclopropyl]amino}methyl)azetidin-1-yl]benzonitrile;

3,5-Difluoro-4-[3-({[trans-2-phenylcyclopropyl]amino}methyl)azetidin-1-yl]benzonitrile;

2,5-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;

2-Methyl-6-[3-({[trans-2-phenylcyclopropyl]amino}methyl)azetidin-1-yl]nicotinonitrile;

N-Ethyl-5-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)pyrazine-2-carboxamide;

3,5-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;

2,6-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;

2,3-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;

2-Chloro-5-fluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}-azetidin-1-yl)benzamide;

3-Fluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;

2-Fluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;

2-Fluoro-N-isopropyl-5-methyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl})-azetidin-1-yl)benzamide;

N-Isopropyl-2-methoxy-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;

3-Chloro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;

5-(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide;

N-({1-[6-(4-Methylpiperazin-1-yl)pyrimidin-4-yl]azetidin-3-yl}methyl)-trans-2-phenylcyclopropanamine; and

trans-N-{[1-(1-Methyl-1H-pyrazol-4-yl)azetidin-3-yl]methyl}-2-phenylcyclopropanamine;

or a pharmaceutically acceptable salt of any of the aforementioned.

35. (canceled)

36. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

37. A method of inhibiting LSD1 comprising contacting a compound of claim 1, or a pharmaceutically acceptable salt thereof, with said LSD1.

38. A method of treating a disease comprising administering to a patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said disease is cancer.

39. The method of claim 38 wherein said cancer is a hematological cancer.

40. The method of claim 39 wherein said hematological cancer is selected from acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma, Hodgkin lymphoma, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), or multiple myeloma.

41. The method of claim 38 wherein said cancer is a sarcoma, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, or skin cancer.

42. A method of treating a disease comprising administering to a patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said disease is a viral disease or a beta-globinopathy.

43. The method of claim 40, wherein said hematological cancer is myelodysplasia syndrome.

44. The method of claim 40, wherein said hematological cancer is acute myelogenous leukemia.

45. The method of claim 40, wherein said hematological cancer is primary myelofibrosis.

46. The method of claim 41, wherein said lung cancer is undifferentiated small cell lung cancer.

47. The method of claim 38, wherein said cancer is Ewing's sarcoma.