NZ723817B2 - Cyclopropylamines as lsd1 inhibitors - Google Patents

Cyclopropylamines as lsd1 inhibitors Download PDF

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Publication number
NZ723817B2
NZ723817B2 NZ723817A NZ72381715A NZ723817B2 NZ 723817 B2 NZ723817 B2 NZ 723817B2 NZ 723817 A NZ723817 A NZ 723817A NZ 72381715 A NZ72381715 A NZ 72381715A NZ 723817 B2 NZ723817 B2 NZ 723817B2
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New Zealand
Prior art keywords
methyl
alkyl
amino
nrc4
aryl
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NZ723817A
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NZ723817A (en
Inventor
Joel R Courter
Chunhong He
Dingquan Qian
Bo Shen
xiaozhao Wang
Liangxing Wu
Wenqing Yao
Fenglei Zhang
Ding Quan Qian
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Incyte Corporation
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Priority claimed from PCT/US2015/015706 external-priority patent/WO2015123465A1/en
Publication of NZ723817A publication Critical patent/NZ723817A/en
Publication of NZ723817B2 publication Critical patent/NZ723817B2/en

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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/4965—Non-condensed pyrazines
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • C—CHEMISTRY; METALLURGY
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D471/10—Spiro-condensed systems

Abstract

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

Description

CYCLOPROPYLAMINES AS LSDl INHIBITORS FIELD OF THE INVENTION The present invention relates to enzyme tors, which selectively modulate demethylase, and uses therefor. Particular embodiments contemplate compounds and disease indications amenable to treatement by modulation of lysine specific demethylase-1 (LSDl).
BACKGROUND OF THE INVENTION Epigenetic ations 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. : p. 1057—68; Lund, AH. and M. van Lohuizen, Epigenetics and cancer. Genes Dev, 2004. 18(19): p. 5). 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, MA. and T. Kouzarides, Cancer epigenetics: from mechanism to therapy. Cell, 2012. : 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 n the cancer genome and epigenome. Cell, 2013. 153(1): p. 38—55). This s etic 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 (LSDl), the first discovered histone demethylase (Shi, Y., et al., Histone demethylation mediated by the nuclear amine oxidase homolog LSD] . 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 riptional co-repressor, co-repressor of REl-silencing transcription factor (CoREST), and lastly the C terminal catalytic domain whose sequence and structure share homology with the flaVin e dinucleotide (FAD)-dependent monoamine oxidases (i.e., MAO—A and MAO-B) (Forneris, F., et al., Structural basis -CoREST selectivity in histone H3 recognition. J Biol Chem, 2007. ): p. 20070-4; Anand, R. and R. stein, ure and mechanism oflysine-specific demethylase enzymes. J Biol Chem, 2007. 2015/015706 282(49): p. 35425—9; Stavropoulos, P., G. Blobel, and A. Hoelz, Crystal structure and mechanism n lysine-specific demethylase-I . Nat Struct Mol Biol, 2006. 13(7): p. 626— 32; Chen, Y., et al., Crystal ure ofhuman histone lysine-specific demethylase I (LSD1).
Proc Natl Acad Sci U S A, 2006. 103(38): p. 13956—61). LSD1 also shares a fair degree of homology with another lysine c demethylase (LSD2) (Karytinos, A., et al., A novel mammalianflavin-dependent histone ylase. 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 ct 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 e 3 (H3K4 or H3K9). These mechanisms make LSD 1/2 distinct from other histone demethylase es (i.e. Jumonji domain containing family) that can demethylate mono-, di-, and thylated s through alpha-ketoglutarate dependent ons (Kooistra, S.M. and K. Helin, Molecular mechanisms andpotentialfunctions ofhistone demethylases. Nat Rev Mol Cell Biol, 2012. 13(5): p. 297-31 1; Mosammaparast, N. and Y. Shi, Reversal ofhistone methylation: biochemical and molecular mechanisms ofhistone demethylases. Annu Rev Biochem, 2010. 79: p. 155—79).
Methylated histone marks on K3K4 and H3K9 are generally coupled with transcriptional activation and sion, respectively. As part of corepressor complexes (e. g., CoREST), LSD1 has been reported to demethylate H3K4 and repress transcription, whereas LSD 1, in nuclear hormone receptor complex (e.g., androgen or), 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. 43 6—9; Kahl, P., et al., Androgen receptor coactivators lysine-specific histone demethylase I andfour and a halfLIM domain protein 2 predict risk ofprostate cancer recurrence. Cancer Res, 2006. : 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 , J et al., p53 is regulated by the lysine ylase LSD1. Nature, 2007. 449(7158): p. 105-8.), E2F (Kontaki, H. and I.
Talianidis, Lysine methylation regulates EZFI-induced cell death. Mol Cell, 2010. 39(1): p. 152—60), STAT3 (Yang, J., et al., Reversible methylation ofpromoter-bound STAT3 by histone-modzfying enzymes. Proc Natl Acad Sci U S A, 2010. 107(50): p. 21499—504), Tat (Sakane, N., et al., Activation ofH]V transcription by the viral Tat protein requires a demethylation step mediated by lysine-specific demethylase ] KDMI). PLoS Pathog, 2011. 7(8): p. 84), and myosin phosphatase target t 1 (MYPTl) (Cho, H.S., et al., Demethylation ofRB tor MYPT] by histone demethylase LSD] 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 LSDl beyond in regulating chromatin remodeling.
LSDl also associates with other epigenetic regulators, such as DNA methyltransferase 1 (DNMTl) (Wang, J., et al., The lysine demethylase LSD] (KDMI) is requiredfor maintenance ofglobal DNA methylation. Nat Genet, 2009. 41(1): p. 125-9) and histone deacetylases (HDACs) complexes (Hakimi, M.A., et al., A core-BRAF35 complex ning histone deacetylase mediates repression ofneuronal-specific genes. Proc Natl Acad Sci U S A, 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 ofthe CoREST- human histone deacetylase complex.
Proc Natl Acad Sci U S A, 2001. 98(4): p. 1454—8). These associations augment the activities ofDNMT or HDACs. LSDl tors may therefore potentiate the effects of HDAC or DNMT inhibitors. Indeed, preclinical studies have shown such potential already (Singh, M.M., et al., Inhibition ofLSD] 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 s and LSD] in cancer cells. PLoS One, 2013. 8(9): p. e75136).
LSDl has been reported to contribute to a variety of biological processes, including cell proliferation, epithelial-mesenchymal tion (EMT), and stem cell y (both embryonic stem cells and cancer stem cells) or self—renewal and ar ormation of somatic cells (Chen, Y., et al., Lysine-specific histone demethylase ] (LSDI): A potential molecular targetfor tumor therapy. Crit Rev Eukaryot Gene Expr, 2012. 22(1): p. 53-9; Sun, G., et al., Histone demethylase LSD] regulates neural stem cell proliferation. Mol Cell Biol, 2010. 30(8): p. 1997—2005; Adamo, A., M.J. Barrero, and J.C. a Belmonte, LSD] and pluripotency: a new player in the network. Cell Cycle, 2011. 10(19): p. ; Adamo, A., et al., LSD] 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 ting cells have some pluripotent stem cell properties that contribute the heterogeneity of cancer cells. This feature may render cancer cells more resistant to conventional ies, 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 , 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 tors ively target cancer cells with pluripotent stem cell properties. Cancer Res, 2011. 71(23): p. 723 8—49). Acute d leukemias (AMLs) are an example of neoplastic cells that retain some of their less differentiated stem cell like phenotype or ia stem cell (LSC) potential. Analysis ofAML cells including gene expression arrays and chromatin immunoprecipitation with next tion sequencing (ChIP—Seq) revealed that LSD1 may regulate a subset of genes involved in le oncogenic programs to maintain LSC (Harris, W.J., et al., The histone demethylase KDMIA sustains the oncogenic potential ofMLL-AF9 leukemia stem cells. Cancer Cell, 2012. 21(4): p. 473—87; Schenk, T., et al., Inhibition ofthe LSD1 (KDMIA) demethylase vates 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 ties, such as AMLs.
Overexpression of LSD1 is frequently ed in many types of cancers, including bladder cancer, NSCLC, breast carcinomas, ovary cancer, , colorectal cancer, sarcoma including osarcoma, Ewing’s sarcoma, osteosarcoma, and rhabdomyosarcoma, neuroblastoma, prostate cancer, esophageal squamous cell carcinoma, and papillary thyroid carcinoma. Notably, studies found xpression of LSD1 was significantly associated with clinically aggressive cancers, for example, recurrent te cancer, NSCLC, glioma, breast, colon cancer, ovary cancer, esophageal squamous cell carcinoma, and neuroblastoma.
In these studies, either knockdown of LSDlexpression or treatment with small molecular inhibitors of LSD1 resulted in sed cancer cell proliferation and/or induction of apoptosis. See, e.g., Hayami, S., et al., Overexpression ofLSD] 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 ofLSD] promotes proliferation, migration and invasion in non-small cell lung cancer. PLoS One, 2012. 7(4): p. ; Serce, N., et al., Elevated expression ofLSD] (Lysine-specific demethylase 1) during tumour progression from pre-invasive to ve ductal carcinoma ofthe breast. BMC Clin Pathol, 2012. 12: p. 13; Lim, S., et al., Lysine-specific ylase I (LSD1) is highly expressed in ER-negative breast cancers and a ker predicting aggressive biology. Carcinogenesis, 2010. 31(3): p. 512—20; lov, S. and I. Garcia—Bassets, Analysis ofthe levels oflysine-specific demethylase I (LSD1) mRNA in human ovarian tumors and the effects ofchemical LSD1 inhibitors in ovarian cancer cell lines. J Ovarian Res, 2013. 6(1): p. 75; Sareddy, G.R., et al., KDMI is a novel therapeutic targetfor the treatment ofgliomas. rget, 2013. 4(1): p. 18—28; Ding, J., et al., LSD1-mediated epigenetic modification contributes to proliferation and metastasis ofcolon . Br J Cancer, 2013. 109(4): p. 03; i-Baiti, I.M., et al., Lysine-specific ylase I (LSD1/KDMIA/AOF2/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; e, J.H., et a1., -specific demethylase I is strongly expressed in poorly entiated neuroblastoma: implicationsfor therapy. Cancer Res, 2009. 69(5): p. 2065—71; Crea, F., et al., The emerging role ofhistone lysine demethylases in prostate cancer. M01 , 2012. 11: p. 52; Suikki, H.E., et al., Genetic alterations and changes in expression ofhistone demethylases in prostate cancer.
Prostate, 2010. 70(8): p. 889—98; Yu, Y., et al., High expression oflysine-specific demethylase I correlates with poor prognosis ofpatients with esophageal squamous cell carcinoma. Biochem Biophys Res Commun, 2013. 437(2): p. 192-8; Kong, L., et a1., Immunohistochemical expression ofRBP2 and LSD] in papillary thyroid carcinoma. Rom J Morphol Embryol, 2013. 54(3): p. 499—503.
Recently, the induction of CD86 expression by ting LSD1 activity was reported (Lynch, J.T., et al., CD86 sion as a surrogate cellular biomarkerforpharmacological inhibition ofthe histone demethylase lysine-specific demethylase I . Anal Biochem, 2013. 442(1): p. 104-6). CD86 expression is a marker of maturation of dendritic cells (DCs) which are ed in antitumor immune response. Notably, CD86 functions as a co—stimulatory factor to activate T cell proliferation (Greaves, P. and J.G. n, The role ofB 7family molecules in hematologic malignancy. Blood, 2013. 121(5): p. 734—44; Chen, L. and DB.
Flies, Molecular mechanisms ofT 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 B—herpesvirus human cytomegalovirus (Liang, Y., et al., Targeting the JMJDZ histone demethylases to epigenetically control herpesvirus infection and reactivation from latency. Sci Transl Med, 2013. 5(167): p. 167ra5; Liang, Y., et al., tion ofthe histone demethylase LSD1 blocks alpha-herpesvirus lytic replication and reactivationfrom 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 ention increased fetal globin gene expression in erythroid cells (Shi, L., et al., Lysine-specific demethylase I is a therapeutic targetforfetal hemoglobin induction. Nat Med, 2013. 19(3): p. 291—4; Xu, J., et al., Corepressor-dependent silencing of fetal hemoglobin sion by . Proc Natl Acad Sci U S A, 2013. 110(16): p. 6518- 23). Inducing fetal globin gene would be potentially therapeutically cial for the disease of B—globinopathies, including B-thalassemia and sickle cell disease where the production of normal B-globin, a component of adult hemoglobin, is impaired (Sankaran, V.G. and SH.
Orkin, The switchfromfetal to adult hemoglobin. Cold Spring Harb Perspect Med, 2013. 3(1): p. a011643; Bauer, D.E., S.C. Kamran, and SH. Orkin, eningfetal hemoglobin: prospectsfor new therapiesfor the beta-globin disorders. Blood, 2012. 120(15): p. 2945—53).
Moreover, LSD1 tion may potentiate other clinically used therapies, such as hydroxyurea or idine. These agents may act, at least in part, by increasing y-globin gene sion through different isms.
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 ng differentiation programs into mature cell types, decreasing cell eration, and promoting apoptosis in cancer cells. Therefore, LSD1 inhibitors alone or in combination with ished therapeutic drugs would be effective to treat the diseases associated with LSD1 activity.
SUMlVLARY OF THE INVENTION The present invention is directed to, inter alia, a compound of Formula I: WO 23465 (R3)p (R2)m L (R1 )n N R5 R6 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 ion is further directed to a method of inhibiting LSDl comprising contacting the LSDl with a compound of Formula I.
The present invention is r directed to a method of treating an LSDl-mediated disease in a patient comprising administering to the patient a eutically effective amount of a compound of Formula 1.
DETAILED DESCRIPTION The present invention provides, inter alia, LSDl—inhibiting compounds such as a compound of Formula I: (R3)p (R1) H n R2 R5 R6 or a pharmaceutically acceptable salt thereof, wherein: ring A is C6—10 aryl or 5—10 membered heteroaryl comprising carbon and l, 2, 3 or 4 heteroatoms ed from N, O, and S; ring B is 4-10 ed heterocycloalkyl comprising carbon and l, 2, or 3 heteroatoms selected from N, O, and S; ring C is (1) C640 aryl, (2) C340 cycloalkyl, (3) 5—10 membered heteroaryl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (4) 4—20 membered heterocycloalkyl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S; wherein L is substituted on any ring-forming atom of ring B except the ring-forming atom of ring B to which RZ is ; L is C1-4 alkylene, -C(=O)—, O—, —C(=O)NR7—, O, NR7, —S(O)2—, -S(O)—, or - S(O)2NR7-; each R1 is independently selected from halo, C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 haloalkyl, C640 aryl, cloalkyl, 5—10 membered heteroaryl, 4—10 membered cycloalkyl, C640 aryl—C1-4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl-, (4-10 membered heterocycloalkyl)-C1—4 alkyl—, CN, N02, ORa, SR3, C(O)Rb, C(O)NRcRd, C(O)ORa, b, OC(O)NRcRd, NRcRd, NRCC(O)Rb, )ORa, NRCC(O)NRcRd, C(=NR€)Rb, C(=NR€)NRCRd, NRCC(=NR€)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, C640 aryl, C340cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl—C1.4 alkyl—, C340 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 kyl, C1.4 cyanoalkyl, CN, N02, ORa, SR3, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRC)NRcRd, NRCC(=NRC)NRCRd, NRCRd, NRCC(O)Rb, NRCC(O)ORa, NRCC(O)NRcRd, )Rb, NRCS(O)2Rb, NRCS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; RZ is H, halo, C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 haloalkyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 ed heterocycloalkyl, C640 1—4 alkyl— C340 cycloalkyl—C1.4 alkyl—, (5—10 membered heteroaryl)—C1.4 alkyl—, (4—10 membered heterocycloalkyl)-C1_4 alkyl-, CN, N02, OR“, SR‘”, C(O)Rb1, C(O)NRCle1, C(O)ORal, b1, RCle1, NRClR‘“, NR°1C(O)Rb1, NRC1C(O)OR31, NRC1C(O)NR61R‘“, C(=NR€1)Rb1, C(=NR€1)NRC1R‘“, NRclc(=NRel)NRc1Rd1, NRc1S(0)Rb1, NRcls(0)sz1, NR“S(O)2NR¢1R‘“, S(O)Rb1, S(O)NRC1R‘“, b1, or S(O)2NR°1R‘“, wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl—C1.4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 ed aryl)—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, N02, ORal, SR“, 1, C(O)NRC1Rd1, C(O)OR31, OC(O)Rb1, OC(O)NRC1R‘“, C(=NR€1)NRcle1,NRc1C(=NRel)NRc1Rd1,NRclel, NR°1C(O)Rb1, O)OR31, NRC1C(O)NRC1R‘“, NR61S(O)Rb1, NRcls(O)2Rb1, NRcls(0)2NRcle1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRCle1; each R2 is independently ed from halo, C16 alkyl, CN, ORaS, C(O)Rb5, C(O)NRC5Rd5, C(O)ORa5, NRCSRdS, S(O)Rb5, S(O)NR05Rd5, S(O)2Rb5, and S(O)2NR°5Rd5, wherein said C1-6 alkyl is ally substituted with l, 2, or 3 substituents ndently selected from halo, CN, ORaS, SRaS, C(O)Rb5, C(O)NRC5Rd5, C(O)OR35, OC(O)Rb5, OC(O)NRC5Rd5, C(=NR€5)NRCSRd5, NRC5C(=NRC5)NRC5Rd5, NRCSRd5, NRC5C(O)Rb5, NRC5C(O)OR35, NR65C(O)NRCSRd5, NRCSS(O)Rb5, NRCSS(O)2Rb5, NRCSS(O)2NR°5Rd5, S(O)Rb5, S(O)NRc5Rd5, b5, and S(O)2NR65Rd5; 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 ndently selected from halo, C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 haloalkyl, C640 aryl, C340cycloalkyl, 5—10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 alkyl—, C340 lkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl-, (4-10 membered heterocycloalkyl)-C1—4 , CN, N02, ORaZ, SRaZ, C(O)Rb2, C(O)NRC2Rd2, C(O)OR32, OC(O)Rb2, OC(O)NRCZRd2, NRCZRdZ, NR°2C(O)Rb2, NRC2C(O)ORa2, NR02C(O)NRCZRd2, C(=NR€2)Rb2, C(=NR€2)NR°2Rd2, =NR62)NRCZRd2, O)Rb2, NRCZS(O)2Rb2, NRCZS(O)2NR02Rd2, S(O)Rb2, S(O)NRC2Rd2, S(O)2Rb2, and S(O)2NRCZRd2, wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 l, C640 aryl, C340 lkyl, —10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 alkyl—, C340 cycloalkyl—C1.4 alkyl—, (5—10 membered heteroaryl)—C1.4 alkyl—, and (4—10 membered heterocycloalkyl)—C1-4 alkyl— are each optionally tuted with l, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1.4 haloalkyl, C1-4 cyanoalkyl, CN, N02, ORaZ, SRaZ, C(O)Rb2, C(O)NRC2Rd2, C(O)OR32, OC(O)Rb2, OC(O)NRC2Rd2, C(=NR€2)NR°2Rd2, NR02C(=NR62)NRCZRd2, NRCZRdZ, NR°2C(O)Rb2, NR°2C(O)OR32, NR02C(O)NRCZRd2, NRCZS(O)Rb2, NRCZS(O)2Rb2, NRCZS(O)2NR02Rd2, S(O)Rb2, S(O)NRC2Rd2, S(O)2Rb2, and S(O)2NRCZRd2; R4 is halo, C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 kyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-C1—4 alkyl— C340 cycloalkyl—C1.4 alkyl—, (5—10 membered heteroaryl)—C1.4 alkyl—, (4—10 membered heterocycloalkyl)-C1_4 alkyl-, CN, N02, ORa3, SRa3, C(O)Rb3, C(O)NRC3Rd3, C(O)OR“3, OC(O)Rb3, OC(O)NRC3Rd3, NR°3Rd3, NR°3C(O)Rb3, NRC3C(O)ORa3, NRC3C(O)NRC3Rd3, C(=NR€3)Rb3, C(=NR€3)NRC3Rd3, NRC3C(=NRC3)NRC3Rd3, NR°3S(O)Rb3, NRC3S(O)2Rb3, NR°3S(O)2NRC3Rd3, S(O)Rb3, C3Rd3, b3, and S(O)2NRC3Rd3, wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 lkyl, 5-10 membered heteroaryl, 4-10 ed heterocycloalkyl, C640 aryl—C1.4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl—, and (4—10 membered heterocycloalkyl)—C1-4 alkyl— are each optionally substituted with l, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1_4 haloalkyl, C1-4 cyanoalkyl, CN, N02, ORa3, SR”, 3, C(O)NR°3Rd3, C(O)OR"3, OC(O)Rb3, OC(O)NRC3Rd3, C(=NR€3)NRC3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NR°3C(O)Rb3, NRc3C(O)ORa3, NRC3C(O)NRC3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(0)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRC3Rd3; R5 and R6 are each independently selected from H, halo, CN, C1-4 alkyl, C1.4 haloalkyl, C1-4 cyanoalkyl, and —(C1—4 alkyl)-ORa4; R7 is H C1-4 alkyl or C1-4 haloalkyl, each Ra, Rb, Rc, Rd, Ral) R“, R61, Rdl) Ra2, sz) R62, Rdz) Ra3, Rb3, R63, and Rd3 is independently selected from H, C1—6 alkyl, C1.4 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5—10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 alkyl-, C340 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, C640 aryl, C340 cycloalkyl, 5—10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl-C1—4 alkyl-, C340 cycloalkyl—C1.4 alkyl-, (5—10 ed heteroaryl)—C1.4 alkyl-, and (4- 10 membered heterocycloalkyl)—C1-4 alkyl— is ally substituted with l, 2, 3, 4, or 5 substituents independently selected from 04 alkyl, 04 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa“, SRa“, C(O)Rb4, C(O)NRC4Rd4, a4, OC(O)Rb4, R04Rd4, NR°4Rd4, NR°4C(O)Rb4, NRC4C(O)NRC4Rd4, NR°4C(O)OR34, 4)NRC4Rd4, NR°4C(=NRC4)NR°4Rd4, S(O)Rb4, S(O)NR°4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NR°4S(O)2NRC4Rd4, and S(O)2NRC4Rd4; or any Rc and Rd together with the N atom to which they are ed form a 4-, 5-, 6-, or 7—membered heterocycloalkyl group optionally substituted with l, 2, or 3 substituents independently selected from C1—6 alkyl, C3-7 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, 5-6 membered heteroaryl, C1.6 haloalkyl, halo, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NR°4Rd4, NR°4C(O)Rb4, NRC4C(O)NRC4Rd4, NRC4C(O)OR34, C(=NR€4)NR°4Rd4, NR°4C(=NRC4)NRC4Rd4, S(O)Rb4, C4Rd4, S(O)2Rb4, NR°4S(O)2Rb4, NR°4$(O)2NRC4Rd4, and S(O)2NRC4Rd4, wherein said C1—6 alkyl, C3_7 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, and 5—6 ed heteroaryl are optionally substituted by l, 2, or 3 substituents independently selected from halo, C14 alkyl, C1_4 kyl, C1-4 cyanoalkyl, CN, ORa“, SR“, C(O)Rb4, C4Rd4, C(O)ORa4, b4, OC(O)NR°4Rd4, NR°4Rd4, NR°4C(O)Rb4, NR°4C(O)NRC4Rd4, NRC4C(O)OR34, C(=NR64)NRC4Rd4, NRC4C(=NRC4)NR°4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NR°4$(O)2Rb4, NRC4S(O)2NRC4Rd4, and S(O)2NRC4Rd4; or any RC1 and Rdl together with the N atom to which they are attached form a 4-, 5-, 6—, or 7—membered heterocycloalkyl group optionally substituted with l, 2, or 3 substituents independently selected from C1—6 alkyl, C3-7 cycloalkyl, 3—7 membered heterocycloalkyl, C640 aryl, 5-6 membered aryl, C1.6 haloalkyl, halo, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, b4, OC(O)NRC4Rd4, NRC4Rd4, NR°4C(O)Rb4, NRC4C(O)NRC4Rd4, NRC4C(O)OR34, C(=NR€4)NR°4Rd4, NR°4C(=NRC4)NR°4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, O)2Rb4, NR°4$(O)2NRC4Rd4, and S(O)2NRC4Rd4, wherein said C1—6 alkyl, C3—7 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, and 5-6 membered heteroaryl are optionally substituted by l, 2, or 3 substituents ndently selected from halo, C1-4 alkyl, C1_4 haloalkyl, C1-4 cyanoalkyl, CN, ORa“, SR“, C(O)Rb4, C(O)NRC4Rd4, a4, OC(O)Rb4, OC(O)NR°4Rd4, NR°4Rd4, NR°4C(O)Rb4, NR°4C(O)NRC4Rd4, NRC4C(O)OR34, C(=NR64)NRC4Rd4, NRC4C(=NRC4)NR°4Rd4, S(O)Rb4, S(O)NRC4Rd4, b4, NR°4$(O)2Rb4, NRC4S(O)2NRC4Rd4, and S(O)2NRC4Rd4; or any R62 and Rdz together with the N atom to which they are ed form a 4-, 5-, 6—, or 7—membered heterocycloalkyl group optionally substituted with l, 2, or 3 substituents independently ed from C1—6 alkyl, C3-7 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, and 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa4, SRa4, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NR°4Rd4, NR°4Rd4, NR°4C(O)Rb4, NRC4C(O)NRC4Rd4, NRC4C(O)OR34, 4)NRC4Rd4, =NR64)NR°4Rd4, 4, S(O)NRC4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NR°4$(O)2NRC4Rd4, and S(O)2NRC4Rd4, wherein said C1—6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C640 aryl, and 5-6 membered heteroaryl are optionally substituted by l, 2, or 3 substituents independently selected from halo, C1—4 alkyl, 04 haloalkyl, C1-4 cyanoalkyl, CN, ORa4, SRa4, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, 4, NR°4C(O)Rb4, NRC4C(O)NRC4Rd4, NRC4C(O)OR34, C(=NR€4)NR°4Rd4, NR°4C(=NRC4)NR°4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NR°4$(O)2NRC4Rd4, and S(O)2NRC4Rd4; 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 l, 2, or 3 tuents independently selected from C1—6 alkyl, C3-7 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa4, SR“, C(O)Rb4, C(O)NRC4Rd4, 2015/015706 C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NRC4Rd4, NRC4C(O)Rb4, NRC4C(O)NRC4Rd4, NR°4C(O)OR34, C(=NR€4)NRC4Rd4, NR°4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NR°4S(O)2Rb4, NR°4$(O)2NR°4Rd4, and S(O)2NRC4Rd4, wherein said C1—6 alkyl, C3_7 cycloalkyl, 4—7 membered heterocycloalkyl, C6—10 aryl, and 5—6 membered heteroaryl are optionally substituted by l, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1_4 haloalkyl, C1-4 cyanoalkyl, CN, ORa“, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NR°4Rd4, NR°4Rd4, NRC4C(O)Rb4, NR°4C(O)NR°4Rd4, NR°4C(O)OR34, 4)NR°4Rd4, NRC4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NR°4$(O)2Rb4, NRC4S(O)2NR°4Rd4, and S(O)2NRC4Rd4; each R34, R“, RC4, and Rd4 is independently selected from H, 04 alkyl, 04 haloalkyl, C2—4 alkenyl, and C24 l, wherein said 04 alkyl, C2—4 alkenyl, and C24 l, is ally substituted with l, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1—4 alkyl, 04 alkoxy, C1—4 alkylthio, C1-4 alkylamino, 4 alkyl)amino, C1—4 haloalkyl, and C14 haloalkoxy; or any RC4 and Rd4 together with the N atom to which they are attached form a 3-, 4-, —, 6—, or 7—membered heterocycloalkyl group optionally substituted with l, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1—6 alkyl, 04 alkoxy, C1-4 alkylthio, C1-4 alkylamino, di(C1—4 alkyl)amino, C1—4 haloalkyl, and C14 koxy; each R6, R61, R62, R63, R64, and Res is independently selected from H, 04 alkyl, and CN; each R35, R“, RC5, Rds is independently selected from H and C1—6 alkyl optionally substituted with l, 2, 3, 4, or 5 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRC6Rd6, C(O)ORa6, b6, OC(O)NRC6Rd6, NR°6Rd6, NRC6C(O)Rb6, O)NR°6Rd6, O)OR36, 6)NR°6Rd6, NRC6C(=NRC6)NRC6Rd6, S(O)Rb6, S(O)NRC6Rd6, S(O)2Rb6, NRC6S(Osz6, NRC6S(O)2NR°6Rd6, and S(O)2NRC6Rd6; each R36, R“, RC6, and Rd6 is independently selected from H, 04 alkyl, 04 haloalkyl, C2—4 alkenyl, and C24 alkynyl, wherein said 04 alkyl, C2—4 l, and C24 alkynyl, is optionally substituted with l, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1—4 alkyl, 04 alkoxy, C1—4 alkylthio, C1-4 alkylamino, di(C1—4 alkyl)amino, C1—4 haloalkyl, and C14 koxy; each R66 is independently selected from H, C1-4 alkyl, and CN, m is 0, l, or 2; n is 0,1, 2, or 3; p is 0,1, 2, or 3; and q is 0, 1, or 2; wherein when ring B is 6-membered heterocycloalkyl, q is 0, and L is S(O)2, then ring C is other than thienyl.
In some embodiments, wherein when ring B is 5-6 membered heterocycloalkyl, A is phenyl, q is 1 or 2, and R4 is halo, C1—6 alkyl, substituted C1—6 alkyl, C1—6 haloalkyl, 5—10 membered heteroaryl, CN, OR”, C(O)NRC3Rd3, C(O)ORa3, NRC3C(O)Rb3, NRC3S(O)2Rb3, or S(O)2Rb3, then RZ is not H or C(O)ORal.
In some embodiments, ring B is monocyclic 4—7 membered heterocycloalkyl comprising carbon and 1, 2, or 3 heteroatoms ed from N, O, and S.
In some embodiments, ring B is a 4-10 membered heterocycloalkyl comprising 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 comprising 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 ered heterocycloalkyl ring comprising carbon and 1 or 2 heteroatoms ed from N, O, and S wherein said ring B comprises at least one ring-forming N atom.
In some embodiments, ring B is an azetidinyl or piperidinyl ring.
In some embodiments, ring B is an azetidinyl ring.
In some embodiments, ring B is a piperidine ring.
In some ments, ring C is bound to a ring-forming N atom of ring B.
In some embodiments, ring A is C6—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 ed heterocycloalkyl having carbon and 1, 2, or 3 heteroatoms selected from N, O, and S.
In some embodiments, ring C is (1) C6—10 aryl, (2) C340 cycloalkyl, (3) 5—10 ed aryl having carbon and 1, 2, 3 or 4 atoms selected from N, O, and S, or (4) 4—20 membered heterocycloalkyl having carbon and 1, 2, 3 or 4 heteroatoms ed 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 C640 aryl or 5—10 membered heteroaryl comprising carbon and l, 2, 3 or 4 heteroatoms selected from N, O, and S; ring C is (1) C640 aryl, (2) C340 cycloalkyl, (3) 5—10 ed heteroaryl comprising carbon and l, 2, 3 or 4 heteroatoms ed from N, O, and S, or (4) 4—20 membered heterocycloalkyl comprising carbon and l, 2, 3 or 4 heteroatoms selected from N, O, and S; X is —CH2— or —CH2-CH2—; Y is —CH2— or —CH2-CH2—; L is C1-4 ne, -C(=O)—, —C(=O)O—, —C(=O)NR7—, O, NR7, —S(O)2—, —S(O)—, or - S(O)2NR7-; each R1 is independently ed from halo, C1-6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 haloalkyl, C640 aryl, C340 cycloalkyl, 5—10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl-, (4-10 membered cycloalkyl)-C1—4 alkyl—, CN, N02, ORa, SR3, C(O)Rb, C(O)NR°Rd, C(O)ORa, OC(O)Rb, RcRd, NRcRd, NR°C(O)Rb, NRCC(O)ORa, NRCC(O)NRcRd, C(=NR€)Rb, C(=NRC)NRCRd, NRCC(=NR€)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, C640 aryl, C340 cycloalkyl, 5—10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1.4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 , and (4—10 membered heterocycloalkyl)—C1-4 alkyl— are each optionally substituted with l, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1_4 haloalkyl, C1-4 cyanoalkyl, CN, N02, ORa, SR3, C(O)Rb, C(O)NR°Rd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRC)NRcRd, NRCC(=NRC)NRCRd, NRcRd, NR°C(O)Rb, )ORa, NRCC(O)NRcRd, NRCS(O)Rb, )2Rb, NRCS(O)2NRcRd, S(O)Rb, cRd, S(O)2Rb, and S(O)2NRcRd; RZ is H, halo, C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 haloalkyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-C1—4 alkyl— C340 cycloalkyl—C1.4 alkyl—, (5—10 membered heteroaryl)—C1.4 alkyl—, (4—10 membered heterocycloalkyl)—C1_4 , CN, N02, OR“, SRal, C(O)Rb1, C(O)NRCle1, C(O)ORal, OC(O)Rb1, OC(O)NRC1R‘“, NRClR‘“, NR61C(O)Rb1, NRC1C(O)OR31, NR61C(O)NR61R‘“, C(=NR€1)Rb1, C(=NR€1)NRC1R‘“, NRclc(=NRel)NRc1Rd1, 0)Rb1, NRcls(0)sz1, NR“S(O)2NR°1R‘“, S(O)Rb1, 01R‘“, b1, or S(O)2NRC1R‘“, n said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl—C1.4 alkyl—, C340 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 lkyl, CN, N02, ORal, SR“, C(O)Rb1, C(O)NRC1Rd1, C(O)0Ra1, OC(O)Rb1, OC(O)NRcle1, C(=NR€1)NRcle1,NRc1C(=NRel)NRc1Rd1,NRclel, NR°1C(O)Rb1, O)OR31, NRC1C(O)NRC1R‘“, NRCls(O)Rb1, NRcls(O)2Rb1, NRcls(0)2NRcle1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRCle1; each R2 is independently selected from halo, C16 alkyl, CN, ORaS, C(O)Rb5, 65Rd5, 35, NRCSRdS, S(O)Rb5, S(O)NR65Rd5, S(O)2Rb5, and R65Rd5, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently ed from halo, CN, ORaS, SRaS, 5, C(O)NR65Rd5, C(O)OR35, OC(O)Rb5, R65Rd5, C(=NR€5)NR65Rd5, NRC5C(=NR65)NR05Rd5, NRCSRdS, NR05C(O)Rb5, NRC5C(O)OR35, NRC5C(O)NR65Rd5, NRCSS(O)Rb5, NRCSS(O)2Rb5, NRCSS(O)2NR°5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NR65Rd5; wherein each R2 is substituted any ring-forming carbon atom of the ring in Formula 11 containing X and Y except the ring-forming carbon atom to which RZ is bonded; each R3 is independently selected from halo, C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 haloalkyl, C640 aryl, C340cycloalkyl, 5—10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 alkyl—, C340 cycloalkyl—C1-4 , (5— 10 membered heteroaryl)—C1.4 alkyl-, (4-10 membered heterocycloalkyl)-C1—4 alkyl—, CN, N02, ORaZ, SRaZ, C(O)Rb2, CZRd2, C(O)ORa2, OC(O)Rb2, OC(O)NRC2Rd2, NRCZRdZ, NRCZC(O)Rb2, NRC2C(O)OR32, NRC2C(O)NRCZRd2, 2)Rb2, C(=NR€2)NR02Rd2, NRczc(=NR62)NRc2Rd2, NRCZS(O)Rb2, NRCZS(O)2Rb2, NRCZS(O)2NRCZRd2, S(O)Rb2, S(O)NR02Rd2, S(O)2Rb2, and S(O)2NRCZRd2, wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, —10 ed heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 alkyl—, C340 cycloalkyl-C1.4 alkyl-, (5-10 membered heteroaryl)-C1.4 alkyl-, and (4-10 membered heterocycloalkyl)—C1-4 alkyl— are each optionally substituted with l, 2, 3, or 4 substituents ndently selected from halo, C1-4 alkyl, C1.4 haloalkyl, C1-4 cyanoalkyl, CN, N02, ORaZ, SRaZ, C(O)Rb2, C(O)NRcsz2, C(O)OR32, OC(O)Rb2, OC(O)NRC2Rd2, C(=NR€2)NRcsz2, NRC2C(=NR62)NRCZRd2, NRCZRdZ, NRCZC(O)Rb2, NRCZC(O)OR32, NR02C(O)NRCZRd2, NRCZS(O)Rb2, NRCZS(O)2Rb2, NRCZS(O)2NR02Rd2, S(O)Rb2, S(O)NRcsz2, S(O)2Rb2, and S(O)2NRCZRd2; R4 is halo, C1—6 alkyl, C2—6 l, C2—6 alkynyl, C1—6 haloalkyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-C1—4 alkyl— C340 cycloalkyl—C1.4 alkyl—, (5—10 membered heteroaryl)—C1.4 alkyl—, (4—10 membered heterocycloalkyl)—C1_4 alkyl-, CN, N02, ORa3, SRa3, C(O)Rb3, C(O)NRC3Rd3, C(O)OR"3, OC(O)Rb3, OC(O)NRC3Rd3, NR°3Rd3, NRC3C(O)Rb3, NRC3C(O)ORa3, NRC3C(O)NRC3Rd3, C(=NR€3)Rb3, C(=NR€3)NRC3Rd3, NRC3C(=NRC3)NR°3Rd3, NRC3S(O)Rb3, NRC3S(O)2Rb3, NRC3S(O)2NR°3Rd3, S(O)Rb3, S(O)NRC3Rd3, S(O)2Rb3, and S(O)2NRC3Rd3, wherein said C1-6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered cycloalkyl, C640 1.4 , C340 lkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl—, and (4—10 membered heterocycloalkyl)—C1-4 alkyl— are each ally tuted with l, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1_4 haloalkyl, C1.4 cyanoalkyl, CN, N02, ORa3, SR”, C(O)Rb3, C(O)NR°3Rd3, C(O)OR"3, OC(O)Rb3, OC(O)NRC3Rd3, 3)NRC3Rd3, =NRC3)NR°3Rd3, 3, 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; R5 and R6 are each independently selected from H, halo, CN, C1-4 alkyl, C1.4 haloalkyl, C1-4 cyanoalkyl, and —(C14 alkyl)-ORa4; R7 is H or C14 alkyl, each Ra, Rb, R6, Rd, Ral, Rbl) R61, Rdl) RaZ, sz) R62, Rdz) Ra3, Rb3, R63, and Rd3 is independently ed from H, C1—6 alkyl, C1.4 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5—10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 alkyl-, C340 cycloalkyl—C1.4 , (5—10 membered aryl)—C1.4 alkyl-, and (4-10 membered heterocycloalkyl)—C1-4 alkyl—, wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5—10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl-C1—4 alkyl-, C340 cycloalkyl—C1.4 , (5—10 membered heteroaryl)—C1.4 alkyl-, and (4-10 membered heterocycloalkyl)—C1-4 alkyl— is optionally substituted with l, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa“, SRa“, C(O)Rb4, C4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NR°4Rd4, NR°4Rd4, NR°4C(O)Rb4, NR°4C(O)NR°4Rd4, NR°4C(O)OR34, 4)NRC4Rd4, NRC4C(=NRC4)NRC4Rd4, 4, °4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, O)2NRC4Rd4, and S(O)2NRC4Rd4; 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 l, 2, or 3 substituents independently selected from C1—6 alkyl, C3-7 cycloalkyl, 4—7 membered cycloalkyl, C640 aryl, 5-6 membered heteroaryl, C1.6 kyl, halo, CN, ORa4, SRa“, 4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NR°4Rd4, O)Rb4, NRC4C(O)NRC4Rd4, NR°4C(O)OR34, C(=NR€4)NRC4Rd4, NR°4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NR°4S(O)2Rb4, NR°4$(O)2NRC4Rd4, and S(O)2NRC4Rd4, wherein said C1—6 alkyl, C34 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, and 5—6 membered heteroaryl are optionally substituted by l, 2, or 3 substituents independently selected from halo, C14 alkyl, C1_4 haloalkyl, C1-4 cyanoalkyl, CN, ORa“, SR“, C(O)Rb4, C(O)NR°4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NR°4Rd4, NR°4C(O)Rb4, NR°4C(O)NRC4Rd4, NR°4C(O)OR34, C(=NR64)NR°4Rd4, NR°4C(=NRC4)NR°4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NR°4$(O)2Rb4, NRC4S(O)2NR°4Rd4, and S(O)2NRC4Rd4; or any RC1 and Rdl together with the N atom to which they are attached form a 4-, 5-, 6—, or 7—membered heterocycloalkyl group optionally substituted with l, 2, or 3 substituents independently selected from C1—6 alkyl, C3-7 cycloalkyl, 3—7 membered heterocycloalkyl, C640 aryl, 5-6 ed aryl, C1.6 haloalkyl, halo, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NR°4Rd4, NR°4C(O)Rb4, NRC4C(O)NRC4Rd4, NR°4C(O)OR34, C(=NR€4)NRC4Rd4, NR°4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NR°4S(O)2Rb4, NR°4$(O)2NRC4Rd4, and S(O)2NRC4Rd4, n said C1—6 alkyl, C34 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, and 5—6 membered heteroaryl are optionally substituted by l, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1_4 haloalkyl, C1-4 cyanoalkyl, CN, ORa“, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NR04Rd4, NRC4C(O)Rb4, O)NRC4Rd4, NRC4C(O)OR34, 4)NR°4Rd4, NR°4C(=NRC4)NR°4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, O)2Rb4, NRC4S(O)2NR°4Rd4, and S(O)2NRC4Rd4; or any R62 and Rdz together with the N atom to which they are attached form a 4-, 5-, 6—, or 7—membered heterocycloalkyl group optionally substituted with l, 2, or 3 substituents independently selected from C1—6 alkyl, C3-7 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, and 5-6 membered heteroaryl, C1—6 haloalkyl, halo, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NR°4Rd4, NR°4C(O)Rb4, NRC4C(O)NR°4Rd4, NRC4C(O)OR34, C(=NR€4)NRC4Rd4, NRC4C(=NR64)NRC4Rd4, S(O)Rb4, S(O)NR°4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NR°4$(O)2NRC4Rd4, and S(O)2NRC4Rd4, wherein said C1—6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6—10 aryl, and 5-6 membered heteroaryl are optionally substituted by l, 2, or 3 substituents ndently selected from halo, C14 alkyl, 04 kyl, C1-4 lkyl, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NRC4Rd4, NRC4C(O)Rb4, NR°4C(O)NRC4Rd4, NRC4C(O)OR34, C(=NRC4)NRC4Rd4, NR°4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, b4, NRC4S(O)2Rb4, NR°4$(O)2NRC4Rd4, and S(O)2NRC4Rd4; or any RC3 and Rd3 together with the N atom to which they are attached form a 4-, 5-, 6—, or 7—membered cycloalkyl group optionally substituted with l, 2, or 3 substituents independently selected from C1—6 alkyl, C3-7 cycloalkyl, 4—7 membered heterocycloalkyl, C6—10 aryl, 5-6 membered heteroaryl, C1—6 haloalkyl, halo, CN, ORa4, SR“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NRC4Rd4, NRC4C(O)Rb4, NR°4C(O)NRC4Rd4, NRC4C(O)OR34, 4)NRC4Rd4, NR°4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NR°4$(O)2NRC4Rd4, and RC4Rd4, wherein said C1—6 alkyl, C3_7 cycloalkyl, 4—7 membered heterocycloalkyl, C6—10 aryl, and 5—6 membered heteroaryl are optionally substituted by l, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1_4 haloalkyl, C1-4 lkyl, CN, ORa“, SRa“, C(O)Rb4, C4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NR04Rd4, NR°4Rd4, NRC4C(O)Rb4, NR°4C(O)NRC4Rd4, NRC4C(O)OR34, C(=NR64)NRC4Rd4, NRC4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NR°4$(O)2Rb4, O)2NRC4Rd4, and S(O)2NRC4Rd4; each R34, R“, RC4, and Rd4 is independently selected from H, 04 alkyl, 04 haloalkyl, C2—4 alkenyl, and C24 alkynyl, wherein said 04 alkyl, C2—4 alkenyl, and C24 alkynyl, is optionally substituted with l, 2, or 3 substituents ndently selected from OH, CN, amino, halo, C1—4 alkyl, 04 alkoxy, C1—4 alkylthio, C1-4 alkylamino, di(C1—4 alkyl)amino, C1—4 haloalkyl, and C14 haloalkoxy; or any RC4 and Rd4 together with the N atom to which they are attached form a 3-, 4-, —, 6—, or 7—membered heterocycloalkyl group optionally tuted with l, 2, or 3 substituents independently ed from OH, CN, amino, halo, C1—6 alkyl, 04 alkoxy, C1-4 alkylthio, C1-4 alkylamino, di(C1—4 alkyl)amino, C1—4 haloalkyl, and C14 haloalkoxy; and each R6, R61, R62, R63, R64, and Res is independently selected from H, 04 alkyl, and each R35, R”, RC5, Rds is independently selected from H and C1—6 alkyl optionally substituted with l, 2, 3, 4, or 5 substituents independently selected from halo, CN, OR”, SRa6, C(O)Rb6, C(O)NRC6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRC6Rd6, NRC6Rd6, NRC6C(O)Rb6, NRC6C(O)NRC6Rd6, NRC6C(O)OR36, C(=NR€6)NRC6Rd6, NRC6C(=NRC6)NRC6Rd6, S(O)Rb6, S(O)NRC6Rd6, S(O)2Rb6, NRC6S(Osz6, O)2NRC6Rd6, and S(O)2NRC6Rd6; each R36, R“, RC6, and Rd6 is independently selected from H, 04 alkyl, 04 haloalkyl, C2—4 alkenyl, and C24 alkynyl, wherein said 04 alkyl, C2—4 alkenyl, and C24 alkynyl, is optionally substituted with l, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1—4 alkyl, 04 alkoxy, C1—4 alkylthio, C1-4 alkylamino, di(C1—4 alkyl)amino, C1—4 haloalkyl, and C14 koxy; each R66 is independently selected from H, C1-4 alkyl, and CN; m is 0, l, or 2; n is 0,1, 2, or 3; p is 0,1, 2, or 3; and q is 0, l, or 2; wherein when X and Y are both —CH2—CH2—, q is 0, and L is S(O)2, then ring C is other than thienyl.
In some embodiments, wherein when one ofX and Y is H2— and the other of X and Y is —CH2—, A is phenyl, q is l or 2, and R4 is halo, C1—6 alkyl, substituted C1—6 alkyl, C1—6 kyl, 5-10 membered heteroaryl, CN, ORa3, C3Rd3, C(O)ORa3, NRC3C(O)Rb3, NR°3S(O)2Rb3, or S(O)2Rb3, then RZ is not H or C(O)OR31.
In some ments, the compounds of the invention include a compound of Formula Illa or IIIb: (R3)p (R1)n IIIa (R3)p (R2)m\KN <an N R5 R6 or a pharmaceutically acceptable salt f, wherein: ring A is C640 aryl or 5—10 membered heteroaryl comprising carbon and l, 2, 3 or 4 heteroatoms selected from N, O, and S; ring C is (1) C640 aryl, (2) C340 cycloalkyl, (3) 5—10 membered aryl comprising carbon and l, 2, 3 or 4 heteroatoms selected from N, O, and S, or (4) 4—20 membered heterocycloalkyl comprising carbon and l, 2, 3 or 4 heteroatoms selected from N, O, and S; L is C1-4 alkylene, —C(=O)-, -C(=O)O-, —C(=O)NR7—, O, NR7, -S(O)2-, —S(O)—, or — S(O)2NR7—; each R1 is ndently selected from halo, C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 haloalkyl, C640 aryl, C340 cycloalkyl, 5—10 membered heteroaryl, 4—10 ed heterocycloalkyl, C640 aryl—C1-4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl-, (4-10 membered heterocycloalkyl)-C1—4 alkyl—, CN, N02, ORa, SR3, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRCC(O)Rb, NRCC(O)ORa, NR°C(O)NRcRd, C(=NR€)Rb, C(=NR€)NRCRd, NRCC(=NR€)NRCRd, NRCS(O)Rb, NRCS(O)2Rb, NRCS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and RcRd, n said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl—C1.4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl—, and (4—10 membered heterocycloalkyl)—C1-4 alkyl— are each optionally tuted with l, 2, 3, or 4 tuents independently selected from halo, C1-4 alkyl, C1—4 haloalkyl, C1-4 cyanoalkyl, CN, N02, ORa, SR3, C(O)Rb, C(O)NRCRd, a, OC(O)Rb, OC(O)NRcRd, C(=NR€)NRCRd, NRCC(=NR€)NRCRd, NRcRd, )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; RZ is H, halo, C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 kyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-C1—4 alkyl— C340 lkyl—C1.4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl—, (4— 10 membered heterocycloalkyl)—C1.4 alkyl—, CN, N02, OR“, SRal, C(O)Rb1, C(O)NRC1R‘“, C(O)ORal, OC(O)Rb1, OC(O)NRCle1, NRClR‘“, NRC1C(O)Rb1, NRC1C(O)OR31, NRC1C(O)NR61R‘“, C(=NR€1)Rb1, C(=NR€1)NR61R‘“, NR01C(=NR61)NRC1R‘“, NR“S(O)Rb1, NR“S(O)2Rb1, )2NR°1R‘“, S(O)Rb1, 01R‘“, S(O)2Rb1, or S(O)2NR01R‘“, wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl—C1.4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl—, and (4—10 membered heterocycloalkyl)—C1-4 alkyl— are each optionally substituted with l, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1.4 haloalkyl, C1-4 cyanoalkyl, CN, N02, OR“, SR“, C(O)Rb1, C(O)NRC1R‘“, 31, OC(O)Rb1, OC(O)NRC1Rd1, C(=NR€1)NR61R‘“, NR01C(=NR61)NRC1R‘“, NRClR‘“, NRC1C(O)Rb1, NRC1C(O)OR31, NRC1C(O)NRC1R‘“, NRCls(O)Rb1, )2Rb1, NRcls(0)2NRcle1, S(O)Rb1, S(O)NRc1Rd1, b1, and S(O)2NRC1R‘“; each R2 is ndently selected from halo, C16 alkyl, CN, ORaS, C(O)Rb5, C(O)NRC5Rd5, C(O)OR35, NRCSRdS, S(O)Rb5, S(O)NR65Rd5, S(O)2Rb5, and S(O)2NRC5Rd5, wherein said C1-6 alkyl is optionally substituted with l, 2, or 3 substituents independently selected from halo, CN, ORaS, SRaS, C(O)Rb5, C(O)NRC5Rd5, C(O)OR35, OC(O)Rb5, OC(O)NRC5Rd5, C(=NR€5)NR65Rd5, =NR65)NRC5Rd5, NRC5Rd5, NRC5C(O)Rb5, NRC5C(O)OR35, NR65C(O)NR65Rd5, NRCSS(O)Rb5, NRCSS(O)2Rb5, NRCSS(O)2NR°5Rd5, 5, S(O)NR05Rd5, S(O)2Rb5, and S(O)2NRC5Rd5; wherein each R2 is substituted on any ring-forming carbon atom of the azetidine ring depicted in in Formula Illa or the piperidine ring depicted in Formula IIIb except the ring- forming carbon atom to which RZ is bonded; each R3 is independently selected from halo, C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 haloalkyl, C640 aryl, C340cycloalkyl, 5—10 membered aryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 ed heteroaryl)—C1.4 , (4-10 membered heterocycloalkyl)-C1—4 alkyl—, CN, N02, ORaZ, SRaZ, C(O)Rb2, C2Rd2, C(O)OR32, OC(O)Rb2, OC(O)NRCZRd2, Z, NRC2C(O)Rb2, NRC2C(O)OR32, NRC2C(O)NRCZRd2, C(=NR€2)Rb2, C(=NR€2)NR02Rd2, NRczc(=NR62)NRc2Rd2, NRCZS(O)Rb2, NRCZS(O)2Rb2, NRCZS(O)2NRCZRd2, S(O)Rb2, S(O)NR02Rd2, S(O)2Rb2, and S(O)2NRCZRd2, wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, —10 membered heteroaryl, 4—10 membered cycloalkyl, C640 aryl—C1-4 alkyl—, C340 cycloalkyl—C1.4 alkyl—, (5—10 membered heteroaryl)—C1.4 alkyl—, and (4—10 membered heterocycloalkyl)-C1.4 alkyl- are each optionally substituted with l, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1.4 haloalkyl, C1-4 cyanoalkyl, CN, N02, ORaZ, SRaZ, C(O)Rb2, C(O)NRCZRd2, C(O)OR32, OC(O)Rb2, OC(O)NRC2Rd2, C(=NR62)NRCZRd2, NRCZC(=NR62)NRCZRd2, NRCZRdZ, NRC2C(O)Rb2, NRCZC(O)OR32, O)NRCZRd2, NRCZS(O)Rb2, O)2Rb2, O)2NRC2Rd2, S(O)Rb2, 02Rd2, S(O)2Rb2, and S(O)2NRCZRd2; R4 is halo, C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 haloalkyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-C1—4 alkyl— C340 cycloalkyl—C1.4 alkyl—, (5—10 membered heteroaryl)—C1.4 , (4—10 membered heterocycloalkyl)—C1_4 alkyl-, CN, N02, ORa3, SRa3, C(O)Rb3, C(O)NRC3Rd3, "3, b3, OC(O)NRC3Rd3, NRC3Rd3, NRC3C(O)Rb3, NRC3C(O)ORa3, NRC3C(O)NRC3Rd3, C(=NR€3)Rb3, C(=NR€3)NRC3Rd3, NRC3C(=NRC3)NRC3Rd3, NRC3S(O)Rb3, NRC3S(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, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl—C1.4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl—, and (4—10 membered heterocycloalkyl)—C1-4 alkyl— are each optionally substituted with l, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1_4 haloalkyl, C1.4 cyanoalkyl, CN, N02, ORa3, SR”, C(O)Rb3, C(O)NRC3Rd3, C(O)ORa3, OC(O)Rb3, R°3Rd3, C(=NR€3)NRC3Rd3, NRC3C(=NRC3)NRC3Rd3, NRC3Rd3, NRC3C(O)Rb3, NRC3C(O)OR33, NRC3C(O)NRC3Rd3, NRC3S(O)Rb3, NRC3S(O)2Rb3, NRC3S(O)2NRC3Rd3, S(O)Rb3, C3Rd3, S(O)2Rb3, and S(O)2NRC3Rd3; R5 and R6 are each independently selected from H, halo, CN, C1—4 alkyl, C1—4 haloalkyl, C1-4 cyanoalkyl, and —(C1—4 alkyl)-ORa4; R7 is H or C14 alkyl, each Ra, Rb, R6, Rd, Ral, Rbl) R61, Rdl) RaZ, sz) R62, Rdz) Ra3, Rb3, R63, and Rd3 is independently selected from H, C1—6 alkyl, C1.4 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5—10 membered heteroaryl, 4—10 ed heterocycloalkyl, C640 aryl—C1-4 alkyl-, C340 lkyl—C1.4 alkyl-, (5—10 ed heteroaryl)—C1.4 alkyl-, and (4-10 membered heterocycloalkyl)—C1-4 alkyl—, wherein said C1—6 alkyl, C2—6 l, C2—6 alkynyl, C640 aryl, C340 lkyl, 5—10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl-C1—4 alkyl-, C340 cycloalkyl—C1.4 alkyl-, (5—10 membered heteroaryl)—C1.4 alkyl-, and (4-10 membered heterocycloalkyl)—C1-4 alkyl— is Optionally substituted with l, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa“, SRa“, C(O)Rb4, °4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NR04Rd4, NR°4Rd4, NRC4C(O)Rb4, O)NRC4Rd4, NR°4C(O)ORa4, C(=NR€4)NRC4Rd4, NRC4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NR°4S(O)2NR°4Rd4, and S(O)2NRC4Rd4; or any Rc and Rd together with the N atom to which they are ed form a 4-, 5-, 6-, or 7—membered heterocycloalkyl group optionally substituted with l, 2, or 3 tuents independently selected from C1—6 alkyl, C3-7 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, 5-6 membered heteroaryl, C1.6 haloalkyl, halo, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NRC4Rd4, NRC4C(O)Rb4, NRC4C(O)NRC4Rd4, NRC4C(O)OR34, C(=NR€4)NRC4Rd4, NR°4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NR°4$(O)2NRC4Rd4, and S(O)2NRC4Rd4, wherein said C1—6 alkyl, C34 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, and 5—6 membered heteroaryl are optionally substituted by l, 2, or 3 tuents independently selected from halo, C1-4 alkyl, C1.4 haloalkyl, C1.4 cyanoalkyl, CN, ORa“, SR“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NR°4Rd4, NRC4C(O)Rb4, O)NRC4Rd4, NRC4C(O)OR34, 4)NRC4Rd4, NRC4C(=NRC4)NRC4Rd4, 4, S(O)NRC4Rd4, S(O)2Rb4, O)2Rb4, O)2NRC4Rd4, and S(O)2NR°4Rd4; or any RC1 and Rdl together with the N atom to which they are ed form a 4-, 5-, 6—, or 7—membered cycloalkyl group optionally substituted with l, 2, or 3 substituents independently selected from C1—6 alkyl, C3-7 cycloalkyl, 3—7 membered heterocycloalkyl, C640 aryl, 5-6 membered heteroaryl, C1.6 kyl, halo, CN, ORa4, SRa“, 4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NRC4Rd4, NRC4C(O)Rb4, NRC4C(O)NRC4Rd4, O)OR34, C(=NR€4)NRC4Rd4, NR°4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NR°4$(O)2NRC4Rd4, and S(O)2NRC4Rd4, wherein said C1—6 alkyl, C34 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, and 5—6 membered heteroaryl are optionally substituted by l, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1_4 kyl, C1.4 cyanoalkyl, CN, ORa“, SR“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NR04Rd4, 4, NRC4C(O)Rb4, NR04C(O)NRC4Rd4, NRC4C(O)ORa4, C(=NR64)NRC4Rd4, NR°4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC“S(O)2Rb4, NR°4S(O)2NRC4Rd4, and S(O)2NR°4Rd4; or any R62 and Rdz together with the N atom to which they are attached form a 4-, 5-, 6—, or 7—membered heterocycloalkyl group optionally substituted with l, 2, or 3 substituents independently selected from C1—6 alkyl, C3-7 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, and 5-6 membered aryl, C1—6 haloalkyl, halo, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NR04Rd4, NR04Rd4, NRC4C(O)Rb4, NRC4C(O)NRC4Rd4, NRC4C(O)OR34, C(=NR€4)NRC4Rd4, NRC4C(=NR64)NRC4Rd4, S(O)Rb4, S(O)NR°4Rd4, S(O)2Rb4, NR°4S(O)2Rb4, NR°4$(O)2NRC4Rd4, and S(O)2NRC4Rd4, wherein said C1—6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6—10 aryl, and 5-6 membered heteroaryl are optionally substituted by l, 2, or 3 substituents independently selected from halo, C14 alkyl, 04 kyl, C1.4 cyanoalkyl, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NRC4Rd4, NRC4C(O)Rb4, O)NR°4Rd4, NRC4C(O)OR34, C(=NRC4)NRC4Rd4, NR°4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, b4, NR°4S(O)2Rb4, NR°4$(O)2NRC4Rd4, and S(O)2NRC4Rd4; or any RC3 and Rd3 together with the N atom to which they are attached form a 4-, 5-, 6—, or 7—membered heterocycloalkyl group optionally substituted with l, 2, or 3 substituents independently selected from C1—6 alkyl, C3-7 lkyl, 4—7 membered heterocycloalkyl, C6—10 aryl, 5-6 membered aryl, C1-6haloalkyl, halo, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NRC4Rd4, NRC4C(O)Rb4, NRC4C(O)NR°4Rd4, NRC4C(O)OR34, C(=NRC4)NRC4Rd4, NR°4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NR°4S(O)2Rb4, NR°4$(O)2NRC4Rd4, and S(O)2NR°4Rd4, wherein said C1—6 alkyl, C3_7 cycloalkyl, 4—7 membered heterocycloalkyl, C6—10 aryl, and 5—6 membered heteroaryl are optionally substituted by l, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1_4 haloalkyl, C1.4 cyanoalkyl, CN, ORa“, SR“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, b4, OC(O)NRC4Rd4, NR°4Rd4, NRC4C(O)Rb4, NR°4C(O)NR°4Rd4, NRC4C(O)OR34, 4)NRC4Rd4, NRC4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NR°4$(O)2Rb4, NRC4S(O)2NRC4Rd4, and S(O)2NRC4Rd4; each R34, R“, RC4, and Rd4 is independently selected from H, 04 alkyl, 04 haloalkyl, C2—4 alkenyl, and C24 alkynyl, wherein said 04 alkyl, C2—4 l, and C24 alkynyl, is optionally substituted with l, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1—4 alkyl, 04 alkoxy, C1—4 hio, C1-4 alkylamino, di(C1—4 alkyl)amino, C1—4 haloalkyl, and C14 haloalkoxy; or any RC4 and Rd4 together with the N atom to which they are attached form a 3-, 4-, —, 6—, or 7—membered heterocycloalkyl group optionally substituted with l, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1—6 alkyl, 04 alkoxy, C1-4 alkylthio, C1-4 mino, di(C1—4 amino, C1—4 haloalkyl, and C14 haloalkoxy; each R6, R61, R62, R63, R64, and Res is ndently selected from H, 04 alkyl, and each R35, R”, RC5, Rds is ndently selected from H and C1—6 alkyl optionally substituted with l, 2, 3, 4, or 5 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRC6Rd6, a6, OC(O)Rb6, OC(O)NRC6Rd6, NR°6Rd6, NRC6C(O)Rb6, NRC6C(O)NRC6Rd6, NR°6C(O)OR36, C(=NR€6)NRC6Rd6, NRC6C(=NRC6)NRC6Rd6, S(O)Rb6, C6Rd6, S(O)2Rb6, NRC6S(Osz6, NRC6S(O)2NR°6Rd6, and S(O)2NRC6Rd6; each R36, R“, RC6, and Rd6 is ndently selected from H, 04 alkyl, 04 kyl, C2—4 alkenyl, and C24 alkynyl, wherein said 04 alkyl, C2—4 alkenyl, and C24 alkynyl, is optionally substituted with l, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1—4 alkyl, 04 alkoxy, C1—4 alkylthio, C1-4 alkylamino, di(C1—4 alkyl)amino, C1—4 haloalkyl, and C14 haloalkoxy; each R66 is independently selected from H, C1-4 alkyl, and CN; m is 0, l, or 2; nisO, 1,2, or3; p is 0,1, 2, or 3; and q is 0, l, or 2; wherein in a IIIb when q is 0 and L is S(O)2, then ring C is other than thienyl.
In some embodiments, in Formula IIIb when A is phenyl, q is l or 2, and R4 is halo, C1—6 alkyl, substituted C1—6 alkyl, C1—6 haloalkyl, 5—10 membered heteroaryl, CN, OR”, C(O)NRC3Rd3, C(O)OR"3, NRC3C(O)Rb3, NRC3S(O)2Rb3, or S(O)2Rb3, then RZ is not H or C(O)OR31.
In some embodiments, the compounds of the invention have Formula IIIa: (R3)p (R1)n IIIa.
In some embodiments, the compounds of the invention have Formula IIIb: WO 23465 (R3)p (R1)n q RZ IIIb.
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 ments, n is 1.
In some embodiments, n is 2.
In some embodiments, each R1 is independently selected from halo and —O-(C1—6 alkyl).
In some embodiments, each R1 is independently ed from F and methoxy.
In some embodiments, both R5 and R6 are H.
In some embodiments, R5 and R6 are each independently selected from H and C14 alkyl.
In some embodiments, R5 is H and R6 is methyl.
In some embodiments, L is '(CH2)r—, —C(=O)—, O—, —C(=O)NR7—, or —S(O)2—, wherein r is l, 2, 3, or 4.
In some embodiments, L is —CH2—, —C(=O)—, —C(=O)O—, —C(=O)NH—, or —S(O)2—.
In some embodiments, L is -(CH2)r-, —C(=O)—, —C(=O)NR7—, or —S(O)2—, wherein r is l, 2, 3, or 4.
In some ments, L is —CH2—, —C(=O)—, —C(=O)NH—, or —S(O)2—.
In some embodiments, L is —CH2—.
In some embodiments, L is —C(=O)—.
In some embodiments, L is —S(O)2—.
In some embodiments, ring C is phenyl.
In some embodiments, ring C is monocyclic C3-7 cycloalkyl.
In some embodiments, ring C is cyclopentyl.
In some embodiments, ring C is cyclobutyl.
In some embodiments, ring C is cyclopropyl.
In some embodiments, ring C is monocyclic 5— or 6—membered heteroaryl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.
In some ments, ring C is monocyclic 6—membered heteroaryl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.
In some embodiments, ring C is 4-20 membered heterocycloalkyl comprising carbon and 1, 2, 3 or 4 heteroatoms ed from N, O, and S.
In some embodiments, ring C is 4-7 membered heterocycloalkyl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.
In some embodiments, ring C is 5—6 membered cycloalkyl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.
In some embodiments, ring C is ropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, pyridazinyl, pyrazolyl, pyrimidinyl, phenyl, pyridyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, ;\ N N 5;,\ O N NH HN or , , .
In some embodiments, ring C is ropyl, cyclobutyl, cyclopentyl, cyclohexyl, olyl, pyridazinyl, pyrazolyl, pyrimidinyl, phenyl, pyridyl, piperidinyl, tetrahydrofuranyl, fe\N N ;\N O HN or , , .
In some embodiments, ring C is phenyl, pyridyl, piperidinyl, tetrahydrofuranyl, E\ O ;\N N NH HN 01- In some embodiments, ring C is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, pyridazinyl, pyrazolyl, pyrimidinyl, phenyl, piperidinyl, pyrrolidinyl, azetidinyl, N \N HN or , .
In some embodiments, ring C is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, pyridazinyl, lyl, pyrimidinyl, phenyl, piperidinyl, N \N HN or , .
In some embodiments, R4 is C1—6 alkyl, halo, C1—6 kyl, C6—10 aryl, C3-1o cycloalkyl, CN, ORa3, NRC3Rd3, or C(O)OR“3, n said C1—6 alkyl, C6—10 aryl, and C340 cycloalkyl are each optionally substituted with l, 2, 3, or 4 substituents independently selected from halo, C14 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, N02, ORa3, SR”, C(O)Rb3, C(O)NRC3Rd3, C(O)OR“3, OC(O)Rb3, OC(O)NRC3Rd3, C(=NR€3)NRC3Rd3, NRC3C(=NRC3)NRC3R‘B, NRC3Rd3, NRC3C(O)Rb3, NRC3C(O)OR33, NRC3C(O)NRC3Rd3, O)Rb3, O)2Rb3, O)2NRc3Rd3, S(O)Rb3, S(O)NRC3Rd3, S(O)2Rb3, and S(O)2NRC3Rd3.
In some embodiments, R4 is halo, C1—6 haloalkyl, C6—10 aryl, C3.1o cycloalkyl, CN, OR”, or C(O)ORa3, wherein said C6—10 aryl and C340 cycloalkyl are each optionally substituted with l, 2, 3, or 4 substituents independently selected from halo, C14 alkyl, C1-4 haloalkyl, C1.4 lkyl, CN, N02, ORa3, SR”, C(O)Rb3, C(O)NRC3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRC3Rd3, C(=NR€3)NRC3Rd3, NRc3C(=NRe3)NRc3Rd3, NRC3Rd3, NR°3C(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.
In some embodiments, R4 is F, CF3, phenyl, cyclohexyl substituted by hydroxyl, CN, OCH3, OCF3, or COOH.
In some embodiments, R4 is C(O)ORa3.
In some embodiments, each R3 is ndently selected from halo, C1-6 kyl, C640 aryl, C340 cycloalkyl, CN, ORaz, and 32, n said C640 aryl and C340 cycloalkyl are each optionally substituted with l, 2, 3, or 4 substituents independently selected from halo, C1—4 alkyl, C1—4 haloalkyl, C1-4 cyanoalkyl, CN, N02, ORaz, SRaz, C(O)Rb2, C(O)NRC2Rd2, C(O)OR32, OC(O)Rb2, OC(O)NRC2Rd2, C(=NR€2)NRCZRd2, NRC2C(=NR62)NRCZRd2, NRcszz, O)Rb2, NRC2C(O)OR32, NRC2C(O)NRCZRd2, NRCZS(O)Rb2, NRCZS(O)2Rb2, NRCZS(O)2NRCZRd2, S(O)Rb2, S(O)NR02Rd2, S(O)2Rb2, and S(O)2NRCZRd2.
In some embodiments, p is 0.
In some embodiments, p is 1.
In some embodiments, RZ is H, C14 alkyl, or C640 aryl—C1-4 alkyl—, or (5—10 membered heteroaryl)—C1.4 alkyl—, wherein said C1-4 alkyl, C640 aryl—C1-4 alkyl— and (5—10 membered heteroaryl)—C1.4 alkyl— are each optionally substituted by CN, halo, OR‘”, C(O)ORal or C1.4 cyanoalkyl.
In some embodiments, RZ is H, C14 alkyl, or C640 aryl—C1-4 alkyl—, wherein said C14 alkyl and C640 aryl—C1-4 alkyl— are each optionally substituted by CN, halo, OR“, or C1-4 cyanoalkyl.
In some embodiments, RZ is C14 alkyl.
In some embodiments, RZ is C640 aryl—C1-4 alkyl— substituted by fluoro or cyanomethyl.
In some embodiments, RZ is C14 alkyl substituted by y or CN.
In some embodiments, RZ is (5—10 membered heteroaryl)—C1.4 alkyl— substituted by y or F.
In some embodiments, RZ is H, methyl, ethyl, methoxymethyl, 4- fluorophenylmethyl or 4-(cyanomethyl)phenylmethyl.
In some ments, RZ is H, methyl, cyanomethyl, methoxymethyl, ethoxymethyl, ophenylmethyl, 3-cyanophenylmethyl, 4-cyanophenylmethyl, 3-carboxyphenylmethyl, 6-methoxypyridinyl)methyl, 4-cyano-2—fluorobenzyl, (benzyloxy)methyl, (cyclobutylmethoxy)methyl, (cyclohexyloxy)methyl, (5-fluoropyridinyl)methyl, 4- methoxyphenylmethyl, (2-fluorophenoxy)methyl, (3-fluorophenoxy)methyl, (2- cyanophenoxy)methyl, (3-cyanophenoxy)methyl, (4-cyanophenoxy)methyl, (4-cyano-2— fluorophenoxy)methyl, (5-fluoropyridinyl)oxymethyl, (5-fluoropyrimidinyl)oxymethyl, (3 -fluoropyridinyl)oxymethyl, (6-(methylaminocarbonyl)pyridinyl)oxymethyl, (6- (methylaminocarbonyl)pyridinyl)oxymethyl, or 4-(cyanomethyl)phenylmethyl.
In some embodiments, RZ is H or C1-4 alkyl substituted by CN.
In some embodiments, RZ is cyanomethyl.
In some embodiments, RZ is methoxymethyl.
In some embodiments, RZ is H.
In some embodiments, RZ is halo, C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 haloalkyl, C640 aryl, C340 cycloalkyl, 5—10 ed heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl-C1—4 alkyl-, C340 cycloalkyl—C1.4 alkyl-, (5—10 membered heteroaryl)—C1—4 alkyl—, (4-10 ed heterocycloalkyl)—C1-4 alkyl—, CN, N02, ORal, SR“, C(O)Rb1, C(O)NRCle1, OC(O)Rb1, OC(O)NRC1R‘“, “, NRC1C(O)Rb1, NRC1C(O)OR31, NR61C(O)NR61R‘“, C(=NR€1)Rb1, 1)NRC1R‘“, NRclc(=NRel)NRc1Rd1, NRc1S(0)Rb1, NRcls(0)sz1, NR“S(O)2NR61R‘“, S(O)Rb1, Cle1, b1, or S(O)2NRCle1, wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered cycloalkyl, C640 aryl—C1.4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl—, and (4—10 membered heterocycloalkyl)—C1-4 alkyl— are each optionally substituted with l, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1_4 haloalkyl, C1-4 cyanoalkyl, CN, N02, ORal, SR“, C(O)Rb1, C(O)NRCle1, C(O)OR31, OC(O)Rb1, OC(O)NRCle1, 1)NRC1R‘“, NRC1C(=NR61)NR01R‘“, NRClR‘“, NRC1C(O)Rb1, O)OR31, NRClC(O)NRC1Rd1, NR“S(O)Rb1, )2Rb1, NR“S(O)2NR61R‘“, S(O)Rb1, S(O)NRCle1, S(O)2Rb1, and S(O)2NRCle1.
In some embodiments, m is 0.
In some embodiments, the compound of the invention is a compound Formula IIIa: (R3)p (R1)n IIIa or a pharmaceutically acceptable salt thereof, n: ring A is C640 aryl or 5—10 membered aryl comprising carbon and l, 2, 3 or 4 heteroatoms selected from N, O, and S; ring C is (1) C640 aryl, (2) C340 lkyl, (3) 5—10 membered heteroaryl comprising carbon and l, 2, 3 or 4 heteroatoms selected from N, O, and S, or (4) 4—20 membered heterocycloalkyl comprising carbon and l, 2, 3 or 4 heteroatoms selected from N, O, and S; L is C1-4 alkylene, -C(=O)—, —C(=O)O—, NR7—, O, NR7, —S(O)2—, —S(O)—, or - S(O)2NR7-; each R1 is independently selected from halo, C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 haloalkyl, C640 aryl, C340cycloalkyl, 5—10 ed heteroaryl, 4—10 membered heterocycloalkyl, C640 1-4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl—, (4—10 membered heterocycloalkyl)—C1-4 alkyl—, CN, N02, OR“, SR3, C(O)Rb, C(O)NR°Rd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NR°C(O)Rb, NRCC(O)ORa, NRCC(O)NRcRd, C(=NR€)Rb, C(=NRC)NRCRd, NRCC(=NR€)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, C640 aryl, C340cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl—C1.4 , C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 , and (4—10 membered heterocycloalkyl)—C1-4 alkyl— are each optionally substituted with l, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1—4 haloalkyl, C1-4 cyanoalkyl, CN, N02, ORa, SR3, , C(O)NRCRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NR€)NRCRd, NR€)NRCRd, NRcRd, )Rb, NRCC(O)ORa, NRCC(O)NR°Rd, NR°S(O)Rb, NRCS(O)2Rb, NRCS(O)2NR°Rd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; RZ is H, halo, C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 haloalkyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-C1—4 alkyl— C340 cycloalkyl—C1.4 alkyl—, (5—10 membered heteroaryl)—C1.4 alkyl—, (4—10 membered heterocycloalkyl)—C1_4 , CN, N02, OR‘“, SRal, C(O)Rb1, C(O)NR01R‘“, C(O)ORal, OC(O)Rb1, OC(O)NR°1R‘“, NRClR‘“, NR°1C(O)Rb1, NR°1C(O)OR“1, NRC1C(O)NRC1R‘“, C(=NR€1)Rb1, 1)NRC1R‘“, NRclc(=NRel)NRc1Rd1, NRC1S(O)Rb1, NRcls(0)sz1, NRC1S(O)2NR01R‘“, S(O)Rb1, S(O)NRC1R‘“, S(O)2Rb1, or S(O)2NR01R‘“, wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 ed heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl—C1.4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl—, and (4—10 membered heterocycloalkyl)—C1-4 alkyl— are each optionally substituted with l, 2, 3, or 4 tuents independently selected from halo, C14 alkyl, C1—4 haloalkyl, C1-4 cyanoalkyl, CN, N02, ORal, SR“, C(O)Rb1, C(O)NRCle1, C(O)OR31, OC(O)Rb1, RC1R‘“, C(=NR€1)NRcle1,NRc1C(=NRel)NRc1Rd1,NRclel, NR°1C(O)Rb1, NRC1C(O)OR31, NRC1C(O)NRC1R‘“, NR61S(O)Rb1, NRcls(O)2Rb1, NR“S(O)2NR¢1R‘“, S(O)Rb1, S(O)NR01R‘“, S(O)2Rb1, and S(O)2NR01R‘“; each R2 is independently ed from halo, C16 alkyl, CN, ORaS, C(O)Rb5, C(O)NRC5Rd5, C(O)OR35, NRCSRdS, 5, S(O)NR65Rd5, S(O)2Rb5, and S(O)2NRC5Rd5, wherein said C1-6 alkyl is optionally substituted with l, 2, or 3 substituents independently selected from halo, CN, ORaS, SRaS, C(O)Rb5, C(O)NRC5Rd5, C(O)OR35, OC(O)Rb5, OC(O)NRC5Rd5, C(=NR€5)NRCSRd5, NRC5C(=NRC5)NRC5Rd5, NRCSRd5, NRC5C(O)Rb5, NRC5C(O)OR35, NRC5C(O)NR65Rd5, NRCSS(O)Rb5, O)2Rb5, NRCSS(O)2NR65Rd5, S(O)Rb5, S(O)NR05Rd5, S(O)2Rb5, and S(O)2NRC5Rd5; wherein each R2 is tuted on any ring-forming carbon atom of the azetidine ring depicted in in Formula Illa or the piperidine ring depicted in Formula Illb except the ring- forming carbon atom to which RZ is bonded; each R3 is independently selected from halo, C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 haloalkyl, C640 aryl, C340cycloalkyl, 5—10 membered aryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl-, (4-10 membered heterocycloalkyl)-C1—4 alkyl—, CN, N02, ORaZ, SRaZ, C(O)Rb2, C(O)NRCZRd2, C(O)OR32, b2, OC(O)NRCZRd2, Z, NRC2C(O)Rb2, NRC2C(O)OR32, NRC2C(O)NRCZRd2, C(=NR€2)Rb2, 2)NRCZRd2, NRC2C(=NR62)NRCZRd2, NRCZS(O)Rb2, NRCZS(O)2Rb2, NRCZS(O)2NRCZRd2, S(O)Rb2, S(O)NRC2Rd2, S(O)2Rb2, and S(O)2NRCZRd2, wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, —10 membered heteroaryl, 4—10 ed heterocycloalkyl, C640 aryl—C1-4 alkyl—, C340 cycloalkyl—C1.4 alkyl—, (5—10 membered heteroaryl)—C1.4 alkyl—, and (4—10 membered heterocycloalkyl)—C1-4 alkyl— are each optionally substituted with l, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1.4 haloalkyl, C1-4 cyanoalkyl, CN, N02, ORaZ, SRaZ, C(O)Rb2, C(O)NRCZRd2, C(O)OR32, OC(O)Rb2, OC(O)NRC2Rd2, 2)NRCZRd2, NRC2C(=NR62)NRCZRd2, NRcszz, NRC2C(O)Rb2, O)OR32, NRC2C(O)NRCZRd2, NRCZS(O)Rb2, NRCZS(O)2Rb2, NRCZS(O)2NRCZRd2, S(O)Rb2, S(O)NR02Rd2, S(O)2Rb2, and S(O)2NRCZRd2; R4 is halo, C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 haloalkyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered cycloalkyl, C640 1—4 alkyl— C340 lkyl—C1.4 alkyl—, (5—10 membered heteroaryl)—C1.4 alkyl—, (4—10 membered heterocycloalkyl)—C1-4 , CN, N02, OR”, SRa3, C(O)Rb3, C(O)NRC3Rd3, C(O)OR“3, OC(O)Rb3, OC(O)NR°3Rd3, NRC3Rd3, NR°3C(O)Rb3, NR°3C(O)ORa3, NRC3C(O)NRC3Rd3, C(=NR€3)Rb3, 3)NRC3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3S(0)Rb3, 0)sz3, 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, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl—C1.4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl—, and (4—10 membered heterocycloalkyl)—C1-4 alkyl— are each optionally substituted with l, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1_4 haloalkyl, C1-4 lkyl, CN, N02, ORa3, SR”, C(O)Rb3, C(O)NR°3Rd3, C(O)OR"3, OC(O)Rb3, OC(O)NRC3Rd3, 3)NRC3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NR°3C(O)Rb3, NRc3C(O)ORa3, NRC3C(O)NRC3Rd3, O)Rb3, NRc3S(O)2Rb3, NRC3S(O)2NR°3Rd3, S(O)Rb3, C3Rd3, S(O)2Rb3, and S(O)2NRC3Rd3; R5 and R6 are each independently selected from H, halo, CN, C1—4 alkyl, C1—4 haloalkyl, C1-4 cyanoalkyl, and —(C1—4 alkyl)-ORa4; R7 is H or C14 alkyl, each Ra, Rb, Rc, Rd, Ral) R“, R61, Rdl) Ra2, sz) R62, Rdz) Ra3, Rb3, R63, and Rd3 is independently selected from H, C1—6 alkyl, C1.4 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5—10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 alkyl-, C340 cycloalkyl—C1.4 , (5—10 membered heteroaryl)—C1.4 alkyl-, and (4-10 membered heterocycloalkyl)—C1-4 , n said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5—10 ed heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1.4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5—10 membered heteroaryl)—C1.4 alkyl—, and (4— 10 membered heterocycloalkyl)—C1-4 alkyl— is optionally substituted with l, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa“, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NR04Rd4, 4, NR°4C(O)Rb4, NR°4C(O)NR°4Rd4, NR°4C(O)OR34, C(=NR€4)NRC4Rd4, NRC4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NRC4S(O)2NR°4Rd4, and S(O)2NRC4Rd4; or any Rc and Rd er with the N atom to which they are ed form a 4-, 5-, 6-, or 7—membered heterocycloalkyl group optionally tuted with l, 2, or 3 substituents independently selected from C1—6 alkyl, C3-7 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, 5-6 membered heteroaryl, C1.6 kyl, halo, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NR°4Rd4, NR°4C(O)Rb4, NRC4C(O)NRC4Rd4, NRC4C(O)OR34, C(=NR€4)NRC4Rd4, NR°4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NRC“S(O)2NRC4Rd4, and S(O)2NRC4Rd4, wherein said C1—6 alkyl, C34 2015/015706 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, and 5—6 membered heteroaryl are ally substituted by l, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1_4 kyl, C1.4 cyanoalkyl, CN, ORa“, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NR°4Rd4, NRC4C(O)Rb4, NRC4C(O)NR°4Rd4, NRC4C(O)OR34, C(=NR64)NRC4Rd4, NRC4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC“S(O)2Rb4, NRC4S(O)2NRC4Rd4, and S(O)2NR°4Rd4; or any RC1 and Rdl together with the N atom to which they are attached form a 4-, 5-, 6—, or 7—membered heterocycloalkyl group optionally substituted with l, 2, or 3 substituents ndently selected from C1—6 alkyl, C34 cycloalkyl, 3—7 ed heterocycloalkyl, C640 aryl, 5-6 membered aryl, C1.6 kyl, halo, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NRC4Rd4, NRC4C(O)Rb4, NRC4C(O)NRC4Rd4, NRC4C(O)OR34, C(=NRe4)NRC4Rd4, NR°4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NR°4$(O)2NRC4Rd4, and S(O)2NRC4Rd4, wherein said C1—6 alkyl, C3_7 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, and 5—6 membered heteroaryl are optionally substituted by l, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1_4 haloalkyl, C1.4 cyanoalkyl, CN, ORa“, SRa“, C(O)Rb4, C(O)NRC4Rd4, a4, OC(O)Rb4, OC(O)NRC4Rd4, NR°4Rd4, NRC4C(O)Rb4, NR04C(O)NRC4Rd4, NRC4C(O)OR34, C(=NR64)NRC4Rd4, NRC4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC“S(O)2Rb4, NRC4S(O)2NRC4Rd4, and RC4Rd4; or any R62 and Rdz together with the N atom to which they are attached form a 4-, 5-, 6—, or 7—membered heterocycloalkyl group ally substituted with l, 2, or 3 substituents independently selected from C1—6 alkyl, C34 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, and 5-6 membered heteroaryl, C1—6 haloalkyl, halo, CN, ORa4, SRa“, C(O)Rb4, C(O)NR°4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NR°4Rd4, NRC4C(O)Rb4, NRC4C(O)NRC4Rd4, NRC4C(O)OR34, 4)NRC4Rd4, NRC4C(=NR64)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NR°4$(O)2NR°4Rd4, and S(O)2NRC4Rd4, wherein said C1—6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C640 aryl, and 5-6 membered heteroaryl are optionally tuted by l, 2, or 3 substituents independently selected from halo, C14 alkyl, C1.4 kyl, C1.4 cyanoalkyl, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NRC4Rd4, NRC4C(O)Rb4, NRC4C(O)NR°4Rd4, NRC4C(O)OR34, C(=NRe4)NRC4Rd4, NR°4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NR°4$(O)2NRC4Rd4, and S(O)2NR°4Rd4; or any RC3 and Rd3 together with the N atom to which they are ed form a 4-, 5-, 6—, or 7—membered heterocycloalkyl group optionally substituted with l, 2, or 3 substituents independently selected from C1—6 alkyl, C3-7 cycloalkyl, 4—7 ed heterocycloalkyl, C6—10 aryl, 5-6 membered heteroaryl, C1—6 haloalkyl, halo, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NRC4Rd4, NRC4C(O)Rb4, NRC4C(O)NRC4Rd4, NRC4C(O)OR34, 4)NRC4Rd4, NRC4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NR°4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NR°4$(O)2NR°4Rd4, and S(O)2NRC4Rd4, n said C1—6 alkyl, C3.7 cycloalkyl, 4—7 membered heterocycloalkyl, C6—10 aryl, and 5—6 ed heteroaryl are optionally substituted by l, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1.4 cyanoalkyl, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NR°4Rd4, NR°4Rd4, NRC4C(O)Rb4, NRC4C(O)NRC4Rd4, NRC4C(O)ORa4, C(=NR64)NRC4Rd4, NRC4C(=NRC4)NRC4Rd4, 4, C4Rd4, S(O)2Rb4, NR°4$(O)2Rb4, NRC4S(O)2NRC4Rd4, and S(O)2NRC4Rd4; each R34, R“, RC4, and Rd4 is independently selected from H, 04 alkyl, 04 kyl, C2—4 alkenyl, and C24 alkynyl, wherein said 04 alkyl, C2—4 alkenyl, and C24 alkynyl, is ally substituted with l, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1—4 alkyl, 04 alkoxy, C1—4 alkylthio, C1-4 alkylamino, di(C1—4 alkyl)amino, C1—4 haloalkyl, and C14 koxy; or any RC4 and Rd4 together with the N atom to which they are attached form a 3-, 4-, —, 6—, or 7—membered heterocycloalkyl group optionally substituted with l, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1—6 alkyl, 04 alkoxy, C1-4 alkylthio, C1-4 alkylamino, di(C1—4 alkyl)amino, C1—4 haloalkyl, and C14 haloalkoxy; each R6, R61, R62, R63, R64, and Res is independently ed from H, 04 alkyl, and each R35, R”, RC5, Rds is independently ed from H and C1—6 alkyl optionally substituted with l, 2, 3, 4, or 5 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRC6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRC6Rd6, NRC6Rd6, NRC6C(O)Rb6, NRC6C(O)NRC6Rd6, NRC6C(O)OR36, C(=NR€6)NRC6Rd6, NRC6C(=NRC6)NRC6Rd6, S(O)Rb6, S(O)NR°6Rd6, S(O)2Rb6, NRC6S(Osz6, NRC6S(O)2NRC6Rd6, and S(O)2NRC6Rd6; each R36, R“, RC6, and Rd6 is independently selected from H, 04 alkyl, 04 haloalkyl, C2—4 alkenyl, and C24 alkynyl, wherein said 04 alkyl, C2—4 alkenyl, and C24 l, is optionally substituted with l, 2, or 3 substituents independently selected from OH, CN, amino, halo, C14 alkyl, 04 alkoxy, C1—4 alkylthio, C1-4 alkylamino, di(C1—4 amino, C1—4 haloalkyl, and C14 haloalkoxy; each R66 is ndently selected from H, C1-4 alkyl, and CN, mis 0, l, or2; nis0, 1,2, or3; p is 0,1, 2, or 3; and qis 0, l,or2.
In some embodiments, n the compounds have Formula IIIa, q is 1.
In some embodiments, wherein the compounds have Formula IIIa, ring A is phenyl.
In some ments, wherein the compounds have Formula IIIa, n is 0.
In some embodiments, wherein the compounds have Formula IIIa, both R5 and R6 are In some embodiments, wherein the compounds have Formula IIIa, L is —CH2—, — C(=O)-, NH—, or —S(O)2-.
In some ments, wherein the compounds have Formula IIIa, ring C is phenyl.
In some embodiments, wherein the compounds have Formula IIIa, ring C is 4—20 membered heterocycloalkyl comprising carbon and l, 2, 3 or 4 heteroatoms ed from N, O, and S.
In some embodiments, wherein the compounds have Formula IIIa, ring C is phenyl, piperidinyl, g: H HN 01' In some embodiments, wherein the compounds have Formula IIIa, ring C is phenyl.
In some embodiments, wherein the compounds have Formula IIIa, R4 is C1—6 alkyl, halo, C1—6 haloalkyl, C6—10 aryl, C3.1o cycloalkyl, CN, ORa3, NRC3Rd3, or C(O)ORa3, wherein said C1—6 alkyl, C6—10 aryl, and C340 cycloalkyl are each optionally substituted with l, 2, 3, or 4 substituents independently ed from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, N02, OR”, SRa3, C(O)Rb3, C(O)NRC3Rd3, C(O)OR"3, OC(O)Rb3, OC(O)NRC3Rd3, C(=NR€3)NRC3Rd3, NRC3C(=NRC3)NRC3R‘B, NRC3Rd3, NRC3C(O)Rb3, NRC3C(O)OR“3, 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.
In some ments, wherein the compounds have Formula IIIa, R4 is halo, C1—6 kyl, C6—10 aryl, C3-1ocycloalkyl, CN, OR”, or C(O)ORa3, wherein said C6—10 aryl and C3. cycloalkyl are each ally substituted with l, 2, 3, or 4 substituents independently selected from halo, C14 alkyl, C1-4 haloalkyl, C1-4 lkyl, CN, N02, ORa3, SR”, C(O)Rb3, C(O)NRC3Rd3, C(O)OR“3, OC(O)Rb3, OC(O)NRC3Rd3, 3)NRC3Rd3, NR°3C(=NRC3)NRC3Rd3, NR°3Rd3, NRC3C(O)Rb3, NRC3C(O)OR33, NR°3C(O)NR°3Rd3, NRC3S(O)Rb3, NRC3S(O)2Rb3, O)2NRC3Rd3, S(O)Rb3, S(O)NRC3Rd3, S(O)2Rb3, and S(O)2NRC3Rd3.
In some embodiments, wherein the compounds have Formula IIIa, p is 0.
In some embodiments, wherein the compounds have Formula IIIa, p is 1.
In some embodiments, wherein the compounds have Formula IIIa, RZ is H, 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 tuted by CN, halo, OR“, or C1-4 cyanoalkyl.
In some ments, wherein the compounds have Formula IIIa, RZ is H.
In some embodiments, n the compounds have Formula IIIa, m is 0.
In some embodiments, the compound of the invention is a compound of Formula IIIb: (R3)p (R2m ) \/ (R1) H n RZ R5 R6 IIIb or a pharmaceutically acceptable salt thereof, wherein: ring A is C6—10 aryl or 5—10 membered aryl comprising carbon and l, 2, 3 or 4 heteroatoms selected from N, O, and S; ring C is (l) C6—10 aryl, (2) C340 cycloalkyl, (3) 5—10 membered heteroaryl sing carbon and l, 2, 3 or 4 heteroatoms selected from N, O, and S, or (4) 4—20 membered heterocycloalkyl comprising carbon and l, 2, 3 or 4 heteroatoms selected from N, O, and S; L is C1.4 alkylene, —C(=O)—, —C(=O)O—, —C(=O)NR7—, O, NR7, —S(O)2—, —S(O)—, or - S(O)2NR7-; each R1 is independently selected from halo, C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 haloalkyl, C6—10 aryl, C3-1ocycloalkyl, 5—10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 , C340 cycloalkyl—C1-4 alkyl—, (5— 10 ed heteroaryl)—C1.4 alkyl-, (4-10 membered cycloalkyl)-C1—4 alkyl—, CN, N02, ORa, SR3, C(O)Rb, C(O)NRCRd, C(O)ORa, OC(O)Rb, OC(O)NRCRd, NRCRd, NRCC(O)Rb, NRCC(O)ORa, NR°C(O)NRcRd, C(=NR€)Rb, )NRCRd, NRCC(=NR€)NRCRd, NRCS(O)Rb, NRCS(O)2Rb, )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, C640 aryl, C340 cycloalkyl, 5-10 membered aryl, 4-10 membered heterocycloalkyl, C640 aryl—C1.4 alkyl—, C340 cycloalkyl—C1-4 , (5— 10 membered heteroaryl)—C1.4 alkyl—, and (4—10 membered heterocycloalkyl)—C1-4 alkyl— are each optionally tuted with l, 2, 3, or 4 substituents ndently selected from halo, C1-4 alkyl, C1.4 haloalkyl, C1-4 cyanoalkyl, CN, N02, ORa, SR3, C(O)Rb, C(O)NRCRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRC)NRcRd, NRCC(=NRC)NRCRd, NRcRd, NRCC(O)Rb, NRCC(O)ORa, NRCC(O)NRCRd, )Rb, NRCS(O)2Rb, NRCS(O)2NRCRd, S(O)Rb, S(O)NRCRd, S(O)2Rb, and S(O)2NRcRd; RZ is halo, C1—6 alkyl, C2—6 alkenyl, C2—6 l, C1—6 haloalkyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-C1—4 alkyl— C340 cycloalkyl—C1.4 alkyl—, (5—10 ed heteroaryl)—C1.4 alkyl—, (4—10 membered heterocycloalkyl)—C1.4 alkyl—, CN, N02, OR“, SRal, C(O)Rb1, C(O)NRC1R‘“, OC(O)Rb1, OC(O)NRCle1, NRClR‘“, NRC1C(O)Rb1, NRC1C(O)OR31, NRC1C(O)NRC1R‘“, C(=NR€1)Rb1, C(=NR€1)NR61R‘“, NRC1C(=NR61)NRC1R‘“, NRC18(O)Rb1, NR“S(O)2Rb1, NR“S(O)2NR01R‘“, S(O)Rb1, S(O)NRC1R‘“, S(O)2Rb1, or RC1R‘“, wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5—10 ed heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl-, and (4—10 membered heterocycloalkyl)—C1.4 alkyl- are each optionally substituted with l, 2, 3, or 4 substituents independently selected from halo, C14 alkyl, C1-4 haloalkyl, C1.4 cyanoalkyl, CN, N02, ORal, SR“, C(O)Rb1, C(O)NRCle1, C(O)ORal, OC(O)Rb1, OC(O)NRCle1, C(=NR€1)NR61R‘“, NR61C(=NR61)NR01R‘“, NRClR‘“, NRC1C(O)Rb1, NRC1C(O)OR31, NRC1C(O)NR61R‘“, O)Rb1, NR“S(O)2Rb1, NRcls(0)2NRcle1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRcle1; each R2 is independently selected from halo, C16 alkyl, CN, ORaS, C(O)Rb5, C5Rd5, C(O)OR35, NRCSRdS, S(O)Rb5, C5Rd5, S(O)2Rb5, and S(O)2NRC5Rd5, wherein said C1-6 alkyl is optionally substituted with l, 2, or 3 substituents independently selected from halo, CN, ORaS, SRaS, C(O)Rb5, C(O)NRC5Rd5, C(O)OR35, OC(O)Rb5, OC(O)NR65Rd5, C(=NR€5)NR65Rd5, NR65C(=NR65)NRC5Rd5, NRC5Rd5, NRC5C(O)Rb5, NR65C(O)OR35, NRC5C(O)NRCSRd5, NRCSS(O)Rb5, NRCSS(O)2Rb5, NRCSS(O)2NRC5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NR65Rd5; wherein each R2 is tuted on any ring-forming carbon atom of the azetidine ring depicted in in Formula Illa or the piperidine ring depicted in Formula IIIb except the ring- forming carbon atom to which RZ is bonded; each R3 is independently selected from halo, C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 kyl, C640 aryl, C340cycloalkyl, 5—10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 1-4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl-, (4-10 membered cycloalkyl)-C1—4 alkyl—, CN, N02, ORaZ, SRaZ, C(O)Rb2, C(O)NRC2Rd2, C(O)OR32, OC(O)Rb2, OC(O)NRCZRd2, NRcszz, NRCZC(O)Rb2, NRCZC(O)OR32, NRCZC(O)NRC2Rd2, C(=NR€2)Rb2, C(=NR62)NRCZRd2, NR02C(=NR62)NRCZRd2, NRCZS(O)Rb2, NRCZS(O)2Rb2, NRCZS(O)2NRCZRd2, S(O)Rb2, S(O)NRC2Rd2, S(O)2sz, and S(O)2NRCZRd2, wherein said C1—6 alkyl, C2—6 l, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, —10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 , C340 cycloalkyl—C1.4 alkyl—, (5—10 membered heteroaryl)—C1.4 alkyl—, and (4—10 membered cycloalkyl)—C1-4 alkyl— are each optionally substituted with l, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1.4 haloalkyl, C1-4 cyanoalkyl, CN, N02, ORaZ, SRaZ, C(O)Rb2, C(O)NRCZRd2, C(O)OR32, OC(O)Rb2, RC2Rd2, C(=NR62)NRCZRd2, NRCZC(=NR62)NRC2Rd2, NRCZRdZ, NRCZC(O)Rb2, NRC2C(O)OR32, NRCZC(O)NRC2Rd2, NRCZS(O)Rb2, NRCZS(O)2Rb2, NRCZS(O)2NRCZRd2, S(O)Rb2, S(O)NR02Rd2, S(O)2Rb2, and S(O)2NRCZRd2; R4 is halo, C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6 kyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-C1—4 alkyl— C340 cycloalkyl—C1.4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl—, (4— 10 membered heterocycloalkyl)—C1.4 alkyl—, CN, N02, ORa3, SRa3, 3, C(O)NRC3Rd3, “3, OC(O)Rb3, OC(O)NRC3Rd3, NRC3Rd3, NRC3C(O)Rb3, NRC3C(O)ORa3, O)NRC3Rd3, C(=NRC3)Rb3, C(=NR€3)NRC3Rd3, NRC3C(=NRC3)NRC3Rd3, NRC3S(O)Rb3, NRC3S(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, C640 aryl, C340 lkyl, 5-10 membered heteroaryl, 4-10 membered cycloalkyl, C640 1.4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl—, and (4—10 membered heterocycloalkyl)—C1-4 alkyl— are each optionally substituted with l, 2, 3, or 4 substituents independently ed from halo, C1-4 alkyl, C1.4 haloalkyl, C1-4 cyanoalkyl, CN, N02, ORa3, SR”, C(O)Rb3, C(O)NRC3Rd3, C(O)OR"3, OC(O)Rb3, OC(O)NRC3Rd3, C(=NR€3)NRC3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NR°3C(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; R5 and R6 are each independently ed from H, halo, CN, C1-4 alkyl, C1.4 haloalkyl, C1-4 cyanoalkyl, and —(C1—4 alkyl)-ORa4; R7 is H or C14 alkyl, each Ra, Rb, Re, Rd, Ral, R“, R61, Rdl) RaZ, sz) R62, Rdz) Ra3, Rb3, R63, and Rd3 is independently selected from H, C1—6 alkyl, C1.4 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5—10 membered aryl, 4—10 ed heterocycloalkyl, C640 aryl—C1-4 alkyl-, C340 cycloalkyl—C1.4 alkyl-, (5—10 ed aryl)—C1.4 alkyl-, and (4-10 membered heterocycloalkyl)—C1-4 alkyl—, wherein said C1—6 alkyl, C2—6 l, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5—10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1.4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5—10 membered heteroaryl)—C1.4 alkyl—, and (4— 10 membered heterocycloalkyl)—C1-4 alkyl— is optionally substituted with l, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa“, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NR°4Rd4, NRC4C(O)Rb4, NR°4C(O)NR°4Rd4, NR°4C(O)ORa4, C(=NR€4)NRC4Rd4, NR°4C(=NRC4)NR°4Rd4, S(O)Rb4, S(O)NR°4Rd4, b4, NR°4S(O)2Rb4, NRC4S(O)2NRC4Rd4, and S(O)2NRC4Rd4; or any Rc and Rd together with the N atom to which they are ed form a 4-, 5-, 6-, or 7—membered heterocycloalkyl group optionally substituted with l, 2, or 3 substituents independently selected from C1—6 alkyl, C3-7 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, 5-6 membered aryl, C1.6 haloalkyl, halo, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, R°4Rd4, NR°4Rd4, NRC4C(O)Rb4, NRC4C(O)NRC4Rd4, NRC4C(O)ORa4, C(=NR€4)NRC4Rd4, NR°4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NR°4$(O)2NRC4Rd4, and S(O)2NRC4Rd4, wherein said C1—6 alkyl, C3_7 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, and 5—6 membered heteroaryl are ally substituted by l, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1_4 haloalkyl, C1-4 cyanoalkyl, CN, ORa“, SR“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NR04Rd4, NR°4Rd4, NRC4C(O)Rb4, NR°4C(O)NRC4Rd4, NRC4C(O)ORa4, C(=NR64)NRC4Rd4, NRC4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NR°4$(O)2Rb4, NRC4S(O)2NR°4Rd4, and RC4Rd4; or any RC1 and Rdl together with the N atom to which they are attached form a 4-, 5-, 6—, or 7—membered heterocycloalkyl group optionally substituted with l, 2, or 3 substituents independently ed from C16 alkyl, C3-7 cycloalkyl, 3—7 membered heterocycloalkyl, C640 2015/015706 aryl, 5-6 membered heteroaryl, C1.6 kyl, halo, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NRC4Rd4, NRC4C(O)Rb4, O)NR°4Rd4, NRC4C(O)OR34, C(=NRe4)NRC4Rd4, NR°4C(=NRC4)NR°4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NR°4S(O)2Rb4, NR°48(O)2NRC4Rd4, and S(O)2NRC4Rd4, wherein said C1—6 alkyl, C3—7 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, and 5—6 membered aryl are optionally substituted by l, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1_4 haloalkyl, C1.4 lkyl, CN, ORa“, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NR°4Rd4, O)Rb4, NRC4C(O)NRC4Rd4, NRC4C(O)OR34, C(=NR64)NRC4Rd4, NRC4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC“S(O)2Rb4, NRC4S(O)2NRC4Rd4, and S(O)2NRC4Rd4; or any R62 and Rdz together with the N atom to which they are attached form a 4-, 5-, 6—, or ered heterocycloalkyl group optionally substituted with l, 2, or 3 substituents independently selected from C1—6 alkyl, C34 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, and 5-6 membered heteroaryl, C1—6 haloalkyl, halo, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NR°4Rd4, NRC4C(O)Rb4, NRC4C(O)NRC4Rd4, NRC4C(O)OR34, C(=NRC4)NRC4Rd4, NRC4C(=NR64)NR°4Rd4, S(O)Rb4, S(O)NRC4Rd4, b4, NRC4S(O)2Rb4, O)2NRC4Rd4, and S(O)2NRC4Rd4, wherein said C1—6 alkyl, C3-7 cycloalkyl, 4-7 ed heterocycloalkyl, C640 aryl, and 5-6 membered heteroaryl are optionally substituted by l, 2, or 3 substituents independently selected from halo, C14 alkyl, C1.4 haloalkyl, C1.4 cyanoalkyl, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, RC4Rd4, NRC4Rd4, NRC4C(O)Rb4, NRC4C(O)NR°4Rd4, NRC4C(O)OR34, C(=NRe4)NRC4Rd4, NR°4C(=NRC4)NR°4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NR°4$(O)2NRC4Rd4, and S(O)2NRC4Rd4; or any RC3 and Rd3 together with the N atom to which they are attached form a 4-, 5-, 6—, or 7—membered heterocycloalkyl group ally substituted with l, 2, or 3 substituents independently selected from C1—6 alkyl, C34 cycloalkyl, 4—7 membered cycloalkyl, C640 aryl, 5-6 membered heteroaryl, C1.6 haloalkyl, halo, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NRC4Rd4, NRC4C(O)Rb4, NRC4C(O)NR°4Rd4, NRC4C(O)OR34, C(=NRe4)NRC4Rd4, NR°4C(=NRC4)NR°4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NR°4$(O)2NRC4Rd4, and RC4Rd4, wherein said C1—6 alkyl, C3—7 cycloalkyl, 4—7 membered heterocycloalkyl, C640 aryl, and 5—6 membered aryl are optionally substituted by l, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1_4 haloalkyl, C1.4 cyanoalkyl, CN, ORa“, SRa4, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, NR°4Rd4, NRC4C(O)Rb4, NRC4C(O)NRC4Rd4, NRC4C(O)OR34, C(=NR64)NRC4Rd4, NRC4C(=NRC4)NRC4Rd4, 4, S(O)NR°4Rd4, b4, NR°4$(O)2Rb4, NR°4S(O)2NRC4Rd4, and RC4Rd4; each R34, R“, RC4, and Rd4 is independently selected from H, 04 alkyl, 04 haloalkyl, C2—4 alkenyl, and C24 alkynyl, wherein said 04 alkyl, C2—4 alkenyl, and C24 alkynyl, is optionally substituted with l, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1—4 alkyl, 04 alkoxy, C1—4 alkylthio, C1-4 alkylamino, di(C1—4 alkyl)amino, C1—4 haloalkyl, and C14 haloalkoxy; or any RC4 and Rd4 together with the N atom to which they are attached form a 3-, 4-, —, 6—, or 7—membered heterocycloalkyl group optionally substituted with l, 2, or 3 substituents independently ed from OH, CN, amino, halo, C1—6 alkyl, 04 alkoxy, C1-4 alkylthio, C1-4 alkylamino, di(C1—4 alkyl)amino, C1—4 haloalkyl, and C14 haloalkoxy; each R6, R61, R62, R63, R64, and Res is independently selected from H, 04 alkyl, and each R35, R”, RC5, Rds is independently selected from H and C1—6 alkyl ally substituted with l, 2, 3, 4, or 5 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRC6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRC6Rd6, NR°6Rd6, O)Rb6, NR°6C(O)NRC6Rd6, NRC6C(O)OR36, C(=NR€6)NRC6Rd6, NRC6C(=NRC6)NRC6Rd6, S(O)Rb6, S(O)NR°6Rd6, b6, NRC6S(Osz6, NRC6S(O)2NRC6Rd6, and S(O)2NRC6Rd6; each R36, R“, RC6, and Rd6 is independently selected from H, 04 alkyl, 04 haloalkyl, C2—4 alkenyl, and C24 alkynyl, wherein said 04 alkyl, C2—4 alkenyl, and C24 alkynyl, is optionally substituted with l, 2, or 3 tuents independently selected from OH, CN, amino, halo, C14 alkyl, 04 alkoxy, C1—4 alkylthio, C1-4 alkylamino, di(C1—4 alkyl)amino, C1—4 haloalkyl, and C14 haloalkoxy; each R66 is independently ed from H, C1-4 alkyl, and CN, m is 0, l, or 2; n is 0,1, 2, or 3; p is 0,1, 2, or 3; and q is 0, l, or 2; wherein in Formula IIIb when q is 0 and L is S(O)2, then ring C is other than l.
In some embodiments, wherein the compound has Formula IIIb, q is 1.
In some embodiments, wherein the compound has Formula IIIb, ring A is .
In some embodiments, wherein the compound has Formula IIIb, n is 0.
In some embodiments, wherein the compound has Formula IIIb, n is l.
In some embodiments, wherein the nd has Formula IIIb, n is 2.
In some embodiments, wherein the compound has Formula IIIb, each R1 is independently selected from halo and —O-(Cl—6 alkyl).
In some embodiments, wherein the compound has Formula IIIb, each R1 is independently selected from F and methoxy.
In some embodiments, wherein the compound has Formula IIIb, both R5 and R6 are In some ments, wherein the compound has Formula IIIb, R5 and R6 are each independently selected from H and C14 alkyl.
In some embodiments, wherein the compound has Formula IIIb, R5 is H and R6 is In some embodiments, wherein the compound has Formula IIIb, L is -CH2-.
In some embodiments, wherein the compound has Formula IIIb, L is -C(=O)—.
In some embodiments, wherein the compound has Formula IIIb, L is —.
In some ments, wherein the compound has a IIIb, ring C is phenyl.
In some embodiments, wherein the compound has Formula IIIb, ring C is monocyclic C3-7 cycloalkyl.
In some embodiments, wherein the compound has Formula IIIb, ring C is cyclopropyl, cyclobutyl, entyl, or cyclohexyl.
In some embodiments, wherein the compound has Formula IIIb, ring C is monocyclic — or 6—membered heteroaryl sing carbon and l, 2, 3 or 4 heteroatoms selected from N, O, and S.
In some embodiments, wherein the compound has Formula IIIb, ring C is pyrazolyl, imidazolyl, pyrimidinyl, or zinyl.
In some embodiments, wherein the compound has Formula IIIb, ring C is 4-6 membered heterocycloalkyl comprising carbon and l, 2, 3 or 4 heteroatoms selected from N, O, and S.
In some embodiments, wherein the nd has Formula IIIb, ring C is piperidinyl, pyrolidinyl, azetidinyl, or piperazinyl.
In some embodiments, wherein the compound has Formula IIIb, ring C is piperidinyl, pyrolidinyl, or piperazinyl.
In some embodiments, wherein the compound has a IIIb, R4 is C1—6 alkyl, halo, NRC3Rd3, C(O)ORa3, CN, —(C1-6 alkyl)—CN, —0Ra3, or —(C1-6 alkyl)—ORa3.
In some embodiments, n the compound has Formula IIIb, R4 is C1—6 alkyl, halo, NRc3Rd3, or C(O)0Ra3.
In some embodiments, wherein the compound has Formula IIIb, R4 is C(O)ORa3.
In some embodiments, n the compound has Formula IIIb, p is 0.
In some embodiments, wherein the compound has Formula IIIb, RZ is C14 alkyl, (5— membered heteroaryl)—C1.4 alkyl—, or C6—10 aryl—C1.4 alkyl—, wherein said 04 alkyl, (5—10 membered aryl)—C1.4 alkyl—, and C6—10 aryl—C1-4 alkyl— are each optionally substituted by CN, halo, ORal, C(O)ORal or 04 cyanoalkyl.
In some embodiments, wherein the compound has Formula IIIb, RZ is C14 alkyl or C6— 10 aryl—C1-4 alkyl-, wherein said 04 alkyl and C6—10 aryl—C1-4 alkyl- are each optionally tuted by CN, halo, OR“, or 04 cyanoalkyl.
In some embodiments, wherein the nd has Formula IIIb, RZ is Cl-4 alkyl.
In some ments, wherein the compound has a IIIb, RZ is C6—10 aryl—C1-4 alkyl- substituted by fluoro or cyanomethyl.
In some embodiments, wherein the compound has Formula IIIb, RZ is C14 alkyl substituted by methoxy or CN.
In some embodiments, wherein the compound has Formula IIIb, RZ is is (5—10 membered heteroaryl)—C1.4 alkyl— substituted by methoxy or F.
In some embodiments, wherein the compound has Formula IIIb, RZ is methyl, cyanomethyl, ymethyl, 4-fluorophenylmethyl or 4-(cyanomethyl)phenylmethyl.
In some embodiments, wherein the nd has Formula IIIb, RZ is methyl, cyanomethyl, methoxymethyl, ethoxymethyl, 4-fluorophenylmethyl, 3-cyanophenylmethyl, 4-cyanophenylmethyl, oxyphenylmethyl, 6-methoxypyridinyl)methyl, 4-cyano-2— fluorobenzyl, (benzyloxy)methyl, (cyclobutylmethoxy)methyl, (cyclohexyloxy)methyl, (5- fluoropyridinyl)methyl, 4-methoxyphenylmethyl, (2-fluorophenoxy)methyl, (3- fluorophenoxy)methyl, (2-cyanophenoxy)methyl, (3-cyanophenoxy)methyl, (4- cyanophenoxy)methyl, (4-cyanofluorophenoxy)methyl, (5-fluoropyridinyl)oxymethyl, (5-fluoropyrimidinyl)oxymethyl, (3-fluoropyridinyl)oxymethyl, (6- laminocarbonyl)pyridinyl)oxymethyl, (6-(methylaminocarbonyl)pyridin yl)oxymethyl, or nomethyl)phenylmethyl.
In some embodiments, wherein the compound has Formula IIIb, m is 0.
In some embodiments, the compound has a trans configuration with respect to the di— substituted cyclopropyl group depicted in FormulaI (or any of Formulas II, 111a, and IIIb).
In some embodiments of compounds of Formulas I, II, IIIa, or IIIb, the stereoconfiguration of the carbon atom on the cyclopropyl group connected to Ring A is R and the stereoconfiguration of the carbon atom on the cyclopropyl group connected to NH linkage is S.
In some embodiments of compounds of Formulas I, II, IIIa, or IIIb, the stereoconfiguration of the carbon atom on the cyclopropyl group connected to Ring A is S and the stereoconfiguration of the carbon atom on the cyclopropyl group connected to NH linkage is R.
In some embodiments of compounds of Formulas I, II, IIIa, or IIIb, the stereoconfiguration of the carbon atom on the cyclopropyl group connected to Ring A is R and the stereoconfiguration of the carbon atom on the cyclopropyl group connected to NH linkage is R.
In some embodiments of compounds of as I, II, IIIa, or IIIb, the stereoconfiguration of the carbon atom on the cyclopropyl group ted to Ring A is S and the stereoconfiguration of the carbon atom on the cyclopropyl group connected to NH linkage is S.
In some embodiments, each Ra, Rb, RC, and Rd is independently selected from H, C1-6 alkyl, C1.4 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 lkyl, 5—10 membered heteroaryl, 4— 10 membered heterocycloalkyl, C640 1-4 alkyl—, C340 cycloalkyl—C1.4 alkyl— membered heteroaryl)—C1.4 alkyl—, and (4—10 membered heterocycloalkyl)—C1-4 alkyl—, , (5—10 wherein said C16 alkyl, C2-6 alkenyl, C2—6 l, C640 aryl, C340 cycloalkyl, 5—10 membered heteroaryl, 4— 10 membered heterocycloalkyl, C640 aryl—C1-4 alkyl—, C340 cycloalkyl—C1.4 alkyl— membered heteroaryl)—C1.4 alkyl—, and (4—10 membered heterocycloalkyl)—C1-4 alkyl— is , (5—10 optionally substituted with l, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1_4 haloalkyl, C1.4 cyanoalkyl, halo, CN, ORa4, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRC4Rd4, 4, NR°4C(O)Rb4, NR°4C(O)NR°4Rd4, O)ORa4, C(=NR64)NRC4Rd4, NRC4C(=NRC4)NR°4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC“S(O)2Rb4, NRC4S(O)2NRC4Rd4, and S(O)2NRC4Rd4.
In some ments, each R31, R“, R“, and Rdl is ndently selected from H, 06 alkyl, 04 kyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, cloalkyl, 5—10 membered heteroaryl, 4—10 membered cycloalkyl, C640 aryl—C1-4 alkyl—, C340 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, C640 aryl, C3. cycloalkyl, 5—10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 alkyl-, C340 cycloalkyl—C1.4 alkyl-, (5—10 membered aryl)—C1.4 alkyl-, and (4-10 membered cycloalkyl)—C1-4 alkyl— is optionally substituted with l, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 lkyl, halo, CN, ORa“, SRa“, C(O)Rb4, C(O)NR04Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NR°4Rd4, NR°4Rd4, NRC4C(O)Rb4, NRC4C(O)NRC4Rd4, NR°4C(O)OR34, C(=NR€4)NRC4Rd4, NRC4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NRC4S(O)2NRC4Rd4, and S(O)2NRC4Rd4.
In some embodiments, each R33, R“, RC3, and Rd3 is independently selected from H, C1—6 alkyl, C1-4 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, cloalkyl, 5-10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 , C340 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, C640 aryl, C3— lkyl, 5—10 ed heteroaryl, 4—10 ed heterocycloalkyl, C640 aryl—C1-4 alkyl-, C340 cycloalkyl—C1.4 alkyl-, (5—10 membered heteroaryl)—C1.4 alkyl-, and (4-10 membered heterocycloalkyl)—C1-4 alkyl— is optionally substituted with l, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa“, SRa“, C(O)Rb4, C(O)NR°4Rd4, C(O)ORa4, b4, OC(O)NR°4Rd4, NR°4Rd4, NRC4C(O)Rb4, NRC4C(O)NRC4Rd4, NR°4C(O)OR34, C(=NR€4)NRC4Rd4, NRC4C(=NRC4)NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, NRC4S(O)2Rb4, NRC4S(O)2NRC4Rd4, and S(O)2NRC4Rd4.
In some ments, each Ra, Rb, RC, and Rd is ndently selected from H, C1—6 alkyl, C1.4 haloalkyl, C640 aryl, C340 cycloalkyl, 5—10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 ed heteroaryl)—C1.4 alkyl-, and (4—10 membered heterocycloalkyl)—C1.4 alkyl-, wherein said C1—6 alkyl, C640 aryl, C340cycloalkyl, 5—10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl-, and (4—10 membered heterocycloalkyl)—C1.4 alkyl- is optionally substituted with l, 2, or 3 tuents independently selected from OH, CN, amino, halo, C14 alkyl, C1-4 alkoxy, C1—4 alkylthio, C1-4 alkylamino, di(C1—4 alkyl)amino, C1—4 haloalkyl, and C14 haloalkoxy.
In some embodiments, each R31, R“, R“, and Rdl is independently selected from H, C1—6 alkyl, C1-4 haloalkyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl—C1.4 , C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered aryl)—C1.4 alkyl—, and (4—10 membered heterocycloalkyl)—C1-4 alkyl—, wherein 2015/015706 said C1—6 alkyl, C640 aryl, C340 cycloalkyl, 5—10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 alkyl—, C340 lkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl-, and (4—10 membered heterocycloalkyl)—C1.4 alkyl- is optionally substituted with l, 2, or 3 substituents independently selected from OH, CN, amino, halo, C14 alkyl, C1-4 alkoxy, C1—4 alkylthio, C1-4 alkylamino, di(C1—4 alkyl)amino, C1—4 haloalkyl, and C14 haloalkoxy.
In some embodiments, each R33, R“, RC3, and Rd3 is independently selected from H, C1—6 alkyl, C1-4 haloalkyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl—C1.4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered aryl)—C1.4 alkyl—, and (4—10 membered heterocycloalkyl)—C1-4 alkyl—, n said C1—6 alkyl, C640 aryl, C340 cycloalkyl, 5—10 membered heteroaryl, 4—10 membered heterocycloalkyl, C640 aryl—C1-4 alkyl—, C340 cycloalkyl—C1-4 alkyl—, (5— 10 membered heteroaryl)—C1.4 alkyl-, and (4—10 membered heterocycloalkyl)—C1.4 alkyl- is optionally substituted with l, 2, or 3 substituents ndently selected from OH, CN, amino, halo, C14 alkyl, C1-4 alkoxy, C1—4 alkylthio, C1-4 alkylamino, di(C1—4 alkyl)amino, C1—4 kyl, and C14 haloalkoxy.
In some embodiments, each Ra, Rb, RC, and Rd is independently selected from H and C1—6 alkyl.
In some embodiments, each R31, R“, RC1, and Rdl is ndently selected from H and C1—6 alkyl.
In some embodiments, each R33, R“, RC3, and Rd3 is independently selected from H and C1—6 alkyl.
It is appreciated that n 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, bed in the context of a single embodiment, can also be provided separately or in any le 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 tuent, if present, can be substituted on either of the two rings forming the naphthyl group.
In regard to linking group L, the groups listed as choices for L are not intended to have directionality. For example, when L is -C(=O)NR7-, it is meant to include both —C(=O)NR7— and —NR7C(=O)—.
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 tuent. It is to be tood that substitution at a given atom is limited by y.
Throughout the definitions, the term "CH" indicates a range which includes the endpoints, wherein i and j are integers and indicate the number of carbons. Examples include CM, CM, and the like.
The term "z-membered" (where z is an integer) lly describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is 2. For example, piperidinyl is an e of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a ered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and l, 2, 3, 4-tetrahydro—naphthalene is an example of a lO—membered cycloalkyl group.
The term “carbon” refers to one or more carbon atoms.
As used herein, the term "CH alkyl," employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having ito 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, yl, isopropyl, n-butyl, s- butyl, and t-butyl.
As used herein, the term "CH alkylene," employed alone or in combination with other terms, refers to a saturated linking (e.g., divalent) hydrocarbon group that may be straight- chain or branched, having i to j carbons. In some embodiments, the alkylene group contains from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or from 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as ene, ethylene, l,l-ethylene, hylene and , l,3-propylene, 1,2-propylene, l,l-propylene, isopropylene, the like.
As used herein, the term "CH 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 s.
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, "Ci.j l," employed alone or in combination with other terms, refers to an unsaturated hydrocarbon group having one or more double carbon—carbon bonds WO 23465 and having i to j carbons. In some embodiments, the l 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, "Ci.j alkynyl," ed 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-l-yl, 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 "CH alkylamino," ed alone or in ation with other terms, refers to a group of formula -NH(alkyl), wherein the alkyl group has ito 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—Ci.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(C1—4 alkyl)2 such as, for example, dimethylamino or diethylamino.
As used herein, the term "CH alkylthio," employed alone or in ation 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 04 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," ed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2 fused rings) aromatic hydrocarbon, such as, but not limited to, phenyl, l-naphthyl, thyl, and the like. In some embodiments, aryl is C6—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 "CH cyanoalkyl," employed alone or in combination with other terms, refers to an alkyl group substituted by a CN group.
As used herein, the term "CH 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 , 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 C340 cycloalkyl, C3-7 cycloalkyl, or C5—6 cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, eptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, yl, and the like. Further exemplary lkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
As used herein, "CH 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 OCHFz. 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 04 koxy.
As used , the term "halo," ed 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, C1, or Br. In some embodiments, the halo tuent is F.
As used herein, the term "CH kyl," employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+l 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 ments, 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 ed 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 ments, the heteroaryl group has 1 or 2 atom ring members.
In some embodiments, the heteroaryl group has 1 heteroatom ring member. In some embodiments, the heteroaryl group is 5— to lO—membered or 5— to 6—membered. In some embodiments, the heteroaryl group is 5—membered. In some embodiments, the heteroaryl group is 6—membered. 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, nyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, furanyl, thiophenyl, triazolyl, tetrazolyl, thiadiazolyl, inyl, isoquinolinyl, indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[l, 2-b]thiazolyl, purinyl, triazinyl, and the like.
A 5—membered heteroaryl is a heteroaryl group having five ring-forming atoms comprising wherein one or more of the ring-forming atoms are independently selected from N, O, and S. In some ments, the 5—membered aryl group has 1, 2, or 3 heteroatom ring s. In some embodiments, the 5-membered heteroaryl group has 1 or 2 heteroatom ring members. In some embodiments, the ered heteroaryl group has 1 heteroatom ring member. Example ring-forming s include CH, N, NH, O, and S.
Example f1ve-membered ring heteroaryls are thienyl, furyl, yl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, l, 2, zolyl, tetrazolyl, l, 2, 3-thiadiazolyl, l, 2, 3-oxadiazolyl, l, 2, zolyl, l, 2, 4-thiadiazolyl, l, 2, 4-oxadiazolyl, l, 3, 4-triazolyl, l, 3, 4-thiadiazolyl, and l, 3, 4-oxadiazolyl.
A 6—membered heteroaryl is a heteroaryl group having six orming atoms n 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 atom ring members. In some embodiments, the ered 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 , 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 . 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. 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 es 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, heterocycloalkyl is 5— to bered, 4— to lO—membered, 4— to 7—membered, 5—membered, or 6—membered. es of heterocycloalkyl groups include 1, 2, 3, 4-tetrahydro— quinolinyl, dihydrobenzofuranyl, azetidinyl, azepanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, rpholinyl, 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 ion that contain asymmetrically substituted carbon atoms can be isolated in lly 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 nds 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 ed as a mixture of isomers or as separated isomeric forms.
When the compounds of the ion 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 nds with two chiral s, 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).
WO 23465 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 B—camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of oc—methylbenzylamine (e. g., S and R forms, or diastereoisomerically pure forms), ylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, l, 2—diaminocyclohexane, and the like. tion of racemic es 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. eric forms result from the swapping of a single bond with an adjacent double bond er with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are ic 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 r forms where a proton can occupy two or more positions of a heterocyclic system, for example, lH- and 3H-imidazole, lH-, 2H- and 4H- 1, 2, 4-triazole, lH- and 2H- isoindole, and lH- and 2H-pyrazole.
Tautomeric forms can be in equilibrium or ally 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 s.
The term "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein fied by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless ise specified (e.g., in the case of purine rings, unless otherwise indicated, when the compound name or structure has the 9H tautomer, it is tood that the 7H tautomer is also encompassed).
All nds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., es and solvates) or can be isolated.
In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By "substantially ed" is meant that the compound is at least partially or substantially ted 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 e 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 ion, 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 ive 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 ature from about 20 0C to about 30 0C.
The present invention also es pharmaceutically acceptable salts of the compounds described . 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 ceutically acceptable salts include, but are not d 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 c 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, ueous media like ether, ethyl acetate, alcohols (e. g., ol, ethanol, iso-propanol, or butanol) or itrile (MeCN) are preferred. Lists of suitable salts are found in Remington ’s Pharmaceutical Sciences, 17th Ed., (Mack hing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1—19, and in Stahl et al., Handbook of ceutical Salts: Properties, Selection, and Use, , 2002).
The following abbreviations may be used : ACOH (acetic acid); A020 (acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc (t—butoxycarbonyl); BOP ((benzotriazolyloxy)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’—diisopropy1 icarboxylate); DIEA (N,N-diisopropylethylamine); DIPEA (N, N- diisopropylethylamine); DMF (N, N-dimethylformamide); EA (ethyl acetate); Et (ethyl); EtOAc (ethyl acetate); g (gram(s)); h s)); HATU (N, N, N’, ’-tetramethyl-O-(7- azabenzotriazolyl)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 nitrile); MeOH (methanol); mg (milligram(s)); min. (minutes(s)); mL liter(s)); mmol (millimole(s)); N (normal); nM (nanomolar); NMP (N-methylpyrrolidinone); NMR (nuclear magnetic resonance spectroscopy); OTf (trifluoromethanesulfonate); Ph l); 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); pg gram(s)); uL (microliter(s)); uM (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 atures at which the reactions are carried out, e.g., temperatures which can range from the solvent's ng temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one t. Depending on the particular reaction step, suitable solvents for a ular reaction step can be selected by the skilled artisan. ation of compounds of the invention can e 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 try of protecting groups can be found, for example, in P. G. M. Wuts and T. W.
Greene, Protective Groups in Organic Synthesis, 4th 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 mance liquid chromatography , liquid chromatography—mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified by those skilled in the art by a y 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 ty) and normal phase silica chromatography.
Compounds of formula 3 can be ed by the methods outlined in Scheme 1.
Reductive amination of compounds of a 1 and aldehydes of formula 2 in a suitable solvent such as DCM using a reducing agent such as, but not limited to, sodium triacetoxyborohydride, optionally in the presence of an acid such as acetic acid, can give compounds of formula 3. 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 a 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 s disclosed in the literature.
Scheme 1 (Rom (Rah) <an NH2 + R4 —> (1) (2) (Rom (Rah) GL R4 (R1) H n RZ Alternatively nds of formula 33 can be prepared using methods as outlined in Scheme 2 starting from aldehydes of formula 4, which are commercially available or can be prepared as described in the literature or herein. Reductive amination of ropylamine derivatives of formula 1 with aldehyde 4 using similar conditions as described in Scheme 1 can generate compounds of formula 5. The free amine group in compound 5 can then be protected with a suitable protecting group such as trifluoroacetyl (CF3CO), Cbz or allyloxycarbonyl (Alloc), followed by ive removal of the Boc protecting group With acid can give compounds of formula 6. Displacement of the leaving group Lv (Lv is Cl, OMs, etc) in compounds of formula 7 by piperidine in compound 6 in the presence of a suitable base such as DIEA can generate compounds of a 8, which can be deprotected to afford the nds of formula 33.
Scheme 2 Boo N (R1)n NH2 N + —> (R1)n NR (1) (4) (5) (R3)p N /L R4 FI’G R4 (7) I (R1) N n N i R2 “fig (6) (R1)n®/A/N nds of formula 3b can be prepared by the method outlined in Scheme 3 starting from compounds of a 1 and 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.
Scheme 3 (Ram (ng (R1)n NH2 (1) (9) (R2)m (R3)p (R1) H G L (3b) Cyclopropylamine derivatives of formula 1 can be prepared using methods as ed in Scheme 4, starting from the acrylate derivatives of formula 10 (R is alkyl such as ethyl) which are either commercially available or prepared using methods herein or in the literature.
Cyclopropanation of compound 10 under standard conditions such as the Corey—Chaykovsky reaction can give the cyclopropyl derivatives of formula 11. The ester can be saponifled to give acids of formula 12, which can be subjected to standard Curtius rearrangement conditions ed by deprotection to give cyclopropylamine tives of formula 1.
Scheme 4 (R1 )n 1 — 002R (R cyclopropanation )n CO2R —> _> (10) (11) (R1)n COZH (i) Cu rtius rearrangement (R1)n NH2 (ii) ection (12) (1) Methods of Use nds of the invention are LSDl inhibitors and, thus, are useful in ng diseases and disorders associated with activity of LSDl. For the uses described herein, any of the compounds of the invention, including any of the embodiments thereof, may be used.
In some ments, the compounds of the invention are selective for LSDl over LSD2, meaning that the compounds bind to or inhibit LSDl with greater affinity or potency, ed 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 lOO-fold, at least about ZOO-fold, at least about 500—fold or at least about lOOO—fold.
As inhibitors of LSD l, the compounds of the invention are useful in treating LSDl- mediated diseases and disorders. The term "LSDl—mediated disease” or “LSDl—mediated disorder" refers to any disease or condition in which LSDl plays a role, or where the disease or condition is associated with expression or activity of LSDl. The compounds of the invention can therefore be used to treat or lessen the severity of diseases and conditions where LSDl is known to play a role.
Diseases and conditions treatable using the compounds of the invention include lly cancers, inflammation, autoimmune diseases, viral induced pathogenesis, beta— opathies, and other diseases linked to LSDl activity.
Cancers treatable using nds ing 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), c myelogenous leukemia (CML), diffuse large B-cell lymphoma ), mantle cell lymphoma, Non- n lymphoma (including relapsed or refractory NHL and ent follicular), Hodgkin lymphoma, myeloproliferative es (e. g., primary myelof1brosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), and multiple myeloma.
Example sarcomas e, for example, chondrosarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, f1broma, lipoma, harmatoma, and teratoma.
Example lung cancers include, for example, non-small cell lung cancer (NSCLC), bronchogenic carcinoma (squamous cell, erentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar hiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and elioma.
Example gastrointestinal cancers include, for example, cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach noma, lymphoma, leiomyosarcoma), pancreas (ductal arcinoma, noma, glucagonoma, gastrinoma, carcinoid tumors, ), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous a, oma, 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), giocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.
Example bone cancers include, for e, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous cytoma, chondrosarcoma, 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 ans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, lastoma, glioma, moma, germinoma (pinealoma), glioblastoma multiform, endroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and tte—Duclos disease. e gynecological cancers include, for e, 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, f1brosarcoma, 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, us cell carcinoma, 's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatof1broma, and keloids.
The compounds of the invention can further be used to treat cancer types where LSDl may be overexpressed ing, for e, 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 es in an in vitro system or an in viva system. For e, "contacting" a LSDl protein with a compound of the invention includes the administration of a compound of the present invention to an dual or t, such as a human, having a LSDl protein, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the LSDl protein.
As used herein, the term "individual" or nt, " used interchangeably, refers to any , 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 peutically 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, , animal, individual or human by a researcher, narian, medical doctor or other clinician.
As used herein, the term "treating" or "treatment" refers to inhibiting the disease; for example, ting 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 e; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the e, condition or er (i. e.,, reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
As used herein, the term "preventing" or ntion" 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 er 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 stration of one or more onal 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 LSDl-mediated diseases, disorders or conditions. The one or more additional ceutical 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 e lysine methyltransferases, histone ne methyl transferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases. e deacetylase inhibitors include, e.g., stat.
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 nds 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, amine, anastrozole, arsenic trioxide, ginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan enous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin , dasatinib, daunorubicin, bine, denileukin, denileukin diftitox, dexrazoxane, xel, bicin, dromostanolone propionate, eculizumab, epirubicin, nib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, fllgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefltinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, lin acetate, ibritumomab an, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, lide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, lan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, momab, oxaliplatin, paclitaxel, pamidronate, mumab, panobinostat, pegaspargase, pegfllgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, omide, 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 ng cancer and other proliferative diseases, the compounds of the invention can be used in combination with targeted therapies, ing JAK kinase inhibitors itinib, JAKl-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, Carfllzomib), HDAC—inhibitors (Panobinostat, stat), DNA methyl transferase inhibitors, thasone, bromo and extra al family members inhibitors and indoleamine 2,3-dioxygenase inhibitors .
For treating mune or inflammatory ions, 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 ed from DehydrexTM (Holles Labs), Civamide (Opko), sodium hyaluronate (Vismed, Lantibio/TRB Chemedia), cyclosporine (ST—603, Sirion Therapeutics), ARG101(T) sterone, Argentis), AGR1012(P) (Argentis), ecabet sodium (Senju-Ista), gefamate (Santen), 15-(s)- hydroxyeicosatetraenoic acid (15(S)—HETE), cevilemine, doxycycline (ALTY-0501, Alacrity), minocycline, iDestrinTM (NP50301, t Pharmaceuticals), cyclosporine A (Nova22007, Novagali), oxytetracycline (Duramycin, MOL11901, Lantibio), CF101 (28, 3S, 4R, 5R)—3, 4-dihydroxy[6-[(3 -iodophenyl)methylamino]purinyl]-N-methyl-oxolane carbamyl, Can-Fite Biopharma), voclosporin (LX212 or LX214, Lux Biosciences), ARG103 is), RX-10045 (synthetic resolvin analog, yx), DYN15 (Dyanmis Therapeutics), rivoglitazone (DE011, Daiichi Sanko), TB4 (RegeneRx), OPH-Ol (Ophtalmis Monaco), PCSlOl or Science), REV1—31 (Evolutec), Lacritin (Senju), rebamipide (Otsuka— Novartis), OT-551 a), PAT-2 (University of Pennsylvania and Temple University), pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednol etabonate, rituximab, osol tetrasodium (INS3 65, Inspire), KLS-0611 (Kissei Pharmaceuticals), dehydroepiandrosterone, anakinra, efalizumab, enolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267 yPines 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- atories, and anti-allergic agents. es 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; in; paramomycin; colistimethate; acin; vancomycin; tetracyclines; rifampin and its tives ("rifampins"); cycloserine; beta-lactams; cephalosporins; amphotericins; fluconazole; flucytosine; natamycin; zole; ketoconazole; corticosteroids; diclofenac; flurbiprofen; ketorolac; suprofen; cromolyn; lodoxamide; levocabastin; oline; antazoline; pheniramine; or azalide antibiotic.
Other es 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 /carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and dine; 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 rol 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-l RA, azathioprine, cyclophosphamide, and sulfasalazine; an immunomodulatory agent, including immunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin, mycophenolate l, 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 l blocker, or a statin; an agent for treating liver disease such as a corticosteroid, cholestyramine, an eron, and an anti-viral agent; an agent for treating blood ers 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 ed 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 er2 dies, anti-CD20 antibodies, anti-CTLAl, anti-PD-l, anti-PDLl, and other immunotherapeutic drugs. ation, 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), ary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; racheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal uscular or injection or infusion; or ranial, e. g., hecal or intraventricular, administration. eral 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, nts, 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 n, as the active ingredient, the compound of the invention or a pharmaceutically acceptable salt f, in combination with one or more pharmaceutically acceptable rs (excipients). In some ments, the composition is le for topical administration. In making the compositions of the ion, 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 ient. Thus, the compositions can be in the form of s, pills, powders, lozenges, sachets, cachets, s, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for e, up to 10% by weight of the active compound, soft and hard gelatin es, 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 ed by milling to e 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. WC 2002/000 l 96.
Some examples of suitable excipients e 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; g agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening ; 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 (l 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 s, each unit containing a predetermined quantity of active al ated to e 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 stration, 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 ient is mixed with a pharmaceutical ent 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 ient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as s, pills and capsules. This solid preformulation is then ided 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 t 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 ent to pass intact into the um or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials ing a number of polymeric acids and es 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 ation 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 . Compositions can be nebulized by use of inert gases. Nebulized ons may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure ing machine. Solution, suspension, or powder compositions can be administered orally or y from devices which deliver the formulation in an appropriate manner.
Topical formulations can contain one or more conventional carriers. In some ments, ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene , white vaseline, and the like. r 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 l. Gels can be formulated using pyl 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 ated with instructions for the treatment of the select indication, e. g., psoriasis or other skin condition.
The amount of nd or composition administered to a t 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 ing 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 t can be in the form of pharmaceutical compositions bed above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous ons 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 ing 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 ition 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 ug/kg to about 1 g/kg of body weight per day. In some ments, 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 nd selected, formulation of the excipient, and its route of administration. ive 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 ceutical 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 nion 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 riate subpopulations for treatment, or identify populations who should not e a ular treatment because of an increased risk of a s side In some ments, the companion diagnostic is used to monitor ent 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 rd. 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 zing and quantitating LSDl in tissue samples, including human, and for identifying LSDl ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes LSDl assays that contain such labeled compounds.
The present invention further includes isotopically—labeled compounds of the ion. 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 lly 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, ”N, 15N, 150, 170, 180, 18F, 358, mg) 82Br, 7513f, 763B 77Br, 1231, 1241, 1251 and 1311‘ 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 nd incorporates l, 2, or 3 ium atoms.
The present invention can further include tic 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 sized or identified compound (i.e., test compound) which is labeled can be evaluated for its ability to bind LSDl by ring its concentration variation when ting with LSD l of the labeling. For , through tracking example, a test compound ed) can be evaluated for its y to reduce binding of another compound which is known to bind to LSDl (i.e., rd compound). Accordingly, the ability of a test compound to compete with the rd nd for binding to LSD tly correlates to its g affinity. Conversely, in some other screening assays, the standard compound is labeled and test compounds are unlabeled. Accordingly, the tration of the labeled standard compound is monitored in order to evaluate the competition n the standard compound and the test compound, and the relative binding ty of the test compound is thus ascertained.
The invention will be bed in greater detail by way of specific examples. The following es 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 y of non- critical parameters which can be changed or modified to yield ially the same results.
The compounds of the Examples were found to be inhibitors of LSDl 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 SunflreTM C18 5pm particle size, 2.1 x 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 s 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 tography (RP-HPLC) column conditions are as follows: pH = 2 ations: Waters SunfireTM C18 5 pm particle size, 19 x 100 mm column, eluting with mobile phase A: 0.1% TFA oroacetic acid) in water and mobile phase B: acetonitrile; the flow rate was 30 mL/minute, the separating gradient was optimized for each nd 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 x 100 mm column was 60 mL/minute. pH = 10 purifications: Waters XBridge C18 5 pm particle size, 19 x 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 ture [See "Preparative LCMS ation: Improved Compound Specific Method Optimization", K.
Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem, 6, 874—883 ]. Typically, the flow rate used with 30 x 100 mm column was 60 ute.
Example 1 4-[(3-{ s—Z-Phenylcyclopropyl)amino]methyl} azetidin-l-yl)methyl]benzoic acid H N COZH Step I: tert—bulyl 3-{[(tranSphenylcyclopropyl)amin0]methyl}azetidine-I—carboxylate H NBoc To a solution of tert-butyl 3-formylazetidinecarboxylate (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 uL, 9.0 mmol). The ing 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 NazCO3, water and brine. The organic layer was dried over NazSO4 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 C14H19N202 (M— tBu+2H)+: m/z = 247.1; found 247.2.
Step 2: tert-butyl rans-Z—phenylcyclopropyl) (trifluoroacetyl)amin0]methyl}azetidine-I- carboxylate QA/Tj/C/NF3C B0 c To a solution of tert-butyl 3 - { [(transphenylcyclopropyl)amino]methyl} azetidine carboxylate (187 mg, 0.618 mmol) in DCM (5 mL) at 0 0C was added triethylamine (0.431 mL, 3.09 mmol), followed by dropwise addition of trifluoroacetic ide (114 uL, 0.804 mmol). The resulting yellow solution was stirred at 0 0C for 1 h then quenched with saturated NaHCO3 solution and extracted with DCM. The combined extracts were dried over NazSO4 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 F3N203 (M—tBu+2H)+: m/z = 343.1; found 343.2.
Step 3: N-(azetidin-S-ylmethyD-Z, 2, 2-triflu0r0-N-(transphenylcyclopr0pyl)acetamide F3Cm To a on of tert—butyl rans—2—phenylcyclopropyl)— (trifluoroacetyl)amino]methyl}azetidinecarboxylate (228 mg, 0.572 mmol) in DCM (3 mL) was added TFA (3 mL). The resulting light yellow on 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 C15H18F3N20 (M+H)+: m/z = 299.1; found 299.2.
Step 4: methyl 4-[(3-{[(transphenylcyclopr0pyl)(trifluoroacetyl)amin0]methyl}azetidin-I- meethyUbenzoate (DA/Tova!“F3C /\©\C02Me To a solution of N—(azetidin—3—ylmethyl)—2,2,2—trifluoro—N—(trans—2— phenylcyclopropyl)acetamide (57 mg, 0.19 mmol) in acetonitrile (3 mL) was added K2CO3 (50 mg, 0.38 mmol), followed by methyl 4—bromomethylbenzoate (52 mg, 0.23 mmol). The resulting mixture was stirred at room ature for 2.5 h then diluted with water and extracted with DCM. The combined extracts were dried over NazSO4 then trated. The residue was purified on silica gel column eluting with 0 to 60 % EtOAc/Hexanes to give the desired product (27 mg, 32 %) as a clear oil. LC—MS calculated for C24H26F3N203 (M+H)+: m/z = 447.2; found 447.2.
Step 5 .‘ 4-[(3-{[(trans-Z—phenylcyclopropyl)amin0]methyl}azetidin-I—meethyUbenzoic acid To a solution of methyl 4-[(3- {[(transphenylcyclopropyl)— (trifluoroacetyl)amino]methyl}azetidinyl)methyl]benzoate (27 mg, 0.06 mmol) in THF (1 mL) and MeOH (1 mL) was added 0.5 M sodium hydroxide in water (1.2 mL, 0.6 mmol).
The resulting mixture was warmed to 50 0C and stirred for 1 h at which time LC-MS indicated the reaction was complete to give the desired product. The reaction mixture was cooled to room temperature then diluted with MeOH and purified by prep. HPLC (pH = 2, acetonitrile/water+TFA) to give the product in the form of TFA salt as a white solid. LC—MS calculated for C21H25N202 (M+H)+: m/z = 337.2; found 337.2. e 2 N—{ [1-(4-Flu0r0benzyl)azetidinyl]methyl}-trans—2-phenylcyclopropanamine HfiNWCL This compound was prepared using procedures analogous to those described for Example I with 1-(chloromethyl)fluoro-benzene replacing methyl omethylbenzoate in Step 4. The t was purified by prep. HPLC (pH = 2, itrile/water+TFA) to give the product in the form of TFA salt as a white solid. LC—MS calculated for C20H24FN2 (M+H)+: m/z = 311.2; found 311.1.
Example 3 4-({4-[(trans—Z-Phenylcyclopropyl)amino]piperidin-l-yl}methyl)benz0ic acid (DANG\/©/C02H Step I .‘ methyl 4-[(4-0x0piperidin-I—meethyUbenzoate oUpCOZMe A e of piperidinone hydrochloride hydrate (154 mg, 1.00 mmol, Aldrich, Cat#151769), methyl omethylbenzoate (230 mg, 1.00 mmol) and K2CO3 (346 mg, 2.51 mmol) in acetonitrile (2 mL) was stirred at room temperature overnight. The reaction mixture was d with water then extracted with DCM. The combined extracts were dried over NazSO4 then concentrated to give the desired product as a ess oil which was used in the next step without further purification. LC—MS calculated for C14H18NO3 (M+H)+: m/z = 248.1; found 248.1.
Step 2: methyl 4-({4-[(transphenylcyclopr0pyl)amin0]piperidin-I—yl}methyl)benzoate NUK?002MB To a solution of 2—phenylcyclopropanamine hydrochloride (30. mg, 0.17 mmol, trans, racemic, Acros, Cat#l30470050) and methyl 4-[(4-oxopiperidin-l-yl)methyl]benzoate (43 mg, 0.17 mmol) in DCM (2 mL) was added acetic acid (30. uL, 0.52 mmol). The resulting yellow solution was stirred at room temperature for 2 h then Na(OAc)3BH (110 mg, 0.52 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then diluted with DCM and washed with saturated NazCO3, water and brine. The organic layer was dried over NazSO4 then concentrated. The residue was used in the next step without r ation. LC-MS calculated for C23H29N202 (M+H)+: m/z = 365.2; found 365.1.
Step 3 .‘ 4-({4-[(transphenyleyclopropyl)amin0]pzperidin-I—yl}methyl)benzoic acid The crude product from Step 2 was dissolved in THF (1 mL) and MeOH (1 mL) then 2.0 M sodium hydroxide in water (0.43 mL, 0.87 mmol) was added. The resulting mixture was stirred at 50 0C for 1 h at which time LC—MS indicated the reaction was complete to give the desired product. The reaction mixture was cooled to room temperature then diluted with MeOH and purified by prep. HPLC (pH = 10, acetonitrile/water+NH4OH) to give the product in the form of ammonium salt as a white solid. LC-MS calculated for N202 (M+H)+: m/z = 351.2; found 351.3. 3-({4-[(trans—Z-Phenylcyclopropyl)amino]piperidin-l-yl}methyl)benzoic acid COZH This compound was prepared using procedures analogous to those described for Example 3 with methyl momethyl)benzoate replacing methyl 4-bromomethylbenzoate in Step I = 2, acetonitrile/water+TFA) to give . The product was purified by prep. HPLC (pH the desired product in the form of TFA salt as a white solid, LC-MS calculated for C22H27N202 (M+H)+: m/z = 351.2; found 351.2.
Example 5 1-(4-Fluorobenzyl)-N-(trans—2-phenylcyclopropyl)piperidinamine This compound was prepared using procedures analogous to those described for Example 3 with 1—(chloromethyl)fluoro-benzene replacing methyl 4-bromomethylbenzoate in Step I = 10, acetonitrile/water+NH4OH) to . The product was purified by prep. HPLC (pH give the product in the form of free base as a yellow oil. LC—MS ated for C21H26FN2 (M+H)+: m/z = 325.2; found 325.2.
Example 6 4-[(3-{ s—Z-Phenylcyclopropyl)amino]methyl} azetidin-l-yl)methyl]benzonitrile To a solution of N—(azetidin—3—ylmethyl)—2,2,2—trifluoro—N—(trans—2— phenylcyclopropyl)acetamide (20 mg, 0.07 mmol, prepared as described in Example I, Step 3) and 4-formylbenzonitrile (13 mg, 0.10 mmol) in THF (1.5 mL) was added acetic acid (17 uL, 0.30 mmol). The reaction mixture was stirred at room temperature overnight then sodium triacetoxyborohydride (64 mg, 0.30 mmol) was added. The mixture was stirred at room temperature for 1 h then 2N NaOH in water (1 mL) and MeOH (1 mL) were added. The resulting mixture was stirred at 40 0C for 1h then cooled to room temperature, filtered and purified by prep. HPLC (pH = 10, acetonitrile/water+NH4OH) to afford the desired product.
LC—MS ated for C21H24N3 (M+H)+: m/z = 318.2; found 318.2.
Example 7 3-[(3-{ [(trans—Z-Phenylcyclopropyl)amino]methyl} azetidin-l-yl)methyl]benzonitrile This nd was prepared using procedures analogous to those bed for Example 6 with 3—cyanobenzaldehyde replacing 4-formylbenzonitrile. LC—MS calculated for C21H24N3 : m/z = 318.2; found 318.3. (1-(3-Flu0r0benzoyl){ s-Z-phenylcyclopropyl)amino] methyl}piperidin yl)acet0nitrile Step I: I—tert-bulyl 4-methyl 4-(cyanomethybpiperidine-1,4-dicarb0xylate +0)fN o 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 0C was added 2.0 M LDA in THF (2.8 mL, 5.6 mmol) dropwise. The resulting mixture was stirred at -40 0C for 30 min then bromoacetonitrile (0.44 mL, 6.4 mmol) was added. The reaction mixture was stirred at -40 0C 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 NazSO4, filtered and concentrated.
The residue was purified by flash chromatography on a silica gel column eluting with EtOAc in hexane ) to give the desired product. LC—MS calculated for C10H15N204 (M— tBu+2H)+: m/z = 227.1; found 227.2.
Step 2: I-(tert—But0xycarb0nyl)(cyan0methyl)pzperidinecarb0xylic acid +0),»N o To a 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 ydrate, 0.44 g, 11 mmol). The reaction e was stirred at room ature for 2 h then acidified with cold 1 N HCl and extracted with EtOAc. The extract was washed with water, brine, dried over NazSO4, filtered and concentrated. The residue was used in the next step without further purification. LC—MS calculated for C9H13N204 (M— tBu+2H)+: m/z = 213.1; found 213.1.
Step 3 .‘ tert-Butyl nomethyl)(hydroxymethyl)piperidine-I—carboxylate JVOMQLOH\\ 0 To a solution of 1-(tert-butoxycarbonyl)(cyanomethyl)piperidinecarboxylic 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 ing mixture was stirred for 30 min then filtered and washed with THF (2 mL). The filtrate was cooled to 0 OC 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 NazSO4, filtered and concentrated. The residue was used in the next step without further purification. LC-MS calculated for C9H15N203 (M—tBu+2H)+: m/z = 199.1; found 199.1.
Step 4: tert-Butyl 4-(cyanomethyl)f0rmylpzperidine-I—carboxylate JVOMQLO To a on of tert-butyl 4-(cyanomethyl)(hydroxymethyl)piperidine 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 d at room temperature for 3 h then saturated 3 aqueous solution was added and stirred for 10 min. The mixture was diluted with DCM, then washed with 1N NaOH, water and brine. The organic layer was dried over NazSO4, d and then 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 ated for C9H13N203 (M—tBu+2H)+: m/z = 197.1; found 197.1.
Step 5 .‘ tert—Bulyl 4-(cyan0methyl){[(transphenylcyclopr0pyl)amin0]methyl}pzperidine- I—carboxylate N O UM \ \N To a on of tert-butyl 4-(cyanomethyl)formylpiperidinecarboxylate (180.0 mg, 0.7134 mmol) and 2-phenylcyclopropanamine (114 mg, 0.856 mmol, trans, racemic, J&W PharmLab: Cat#20—0073 S) 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, and washed with saturated NaHCO3, water and brine. The organic layer was dried over NazSO4, filtered and concentrated. The residue was purified by flash tography on a silica gel column eluting with methanol in methylene chloride (0—8%) to give the desired product. LC—MS ated for C22H32N3Oz (M+H)+: m/z = 370.2; found 370.3.
Step 6: tert—Butyl 4-(cyan0methyD{[(trans-Z— phenylcyclopropyl) (trzfluoroacelybamino]methyl}piperidine-I-carb0xylate o”FAY?JLOJ< \\N To a solution of tert—butyl 4—(cyanomethyl)—4— {[(trans—Z— phenylcyclopropyl)amino]methyl}piperidinecarboxylate (0.18 g, 0.49 mmol) and DIEA (0.17 mL, 0.97 mmol) in DCM (2.4 mL) at 0 0C was added dropwise trifluoroacetic anhydride (0.08 mL, 0.58 mmol). The mixture was warmed to room temperature and stirred for 1 h then d with DCM, washed with saturated NaHCO3, water and brine. The organic layer was dried over NazSO4, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column g 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-(Cyanomethybpz'peridinyl]methyl}-2,2,2-trzflu0r0-N-(trans phenylcyclopropyl)acetamide To a solution of tert-butyl nomethyl) {[(trans phenylcyclopropyl)(trifluoroacetyl)amino]methyl}piperidinecarboxylate (0.16 g, 0.34 mmol) in DCM (0.2 mL) was added 4.0 M hydrogen de 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 ated for C19H23F3N3O (M+H)+: m/z = 366.2; found 366.1.
Step 8: (I—(3-FZu0r0benzoyD{[(tranSphenylcyclopr0pyl)amin0]methyl}piperidin yl)acet0nitrile To a solution ofN— { [4-(cyanomethyl)piperidinyl]methyl} -2,2,2-trifluoro-N—(trans- 2-phenylcyclopropyl)acetamide (15.0 mg, 0.0410 mmol) and triethylamine (23 uL, 0.16 mmol) in DCM (0.4 mL) at 0 0C was added 3—fluorobenzoyl chloride (9.8 uL, 0.082 mmol).
The mixture was stirred for 30 min then concentrated. The residue was dissolved in methanol (1 mL) and THF (1 mL) then 1 N NaOH (1.0 mL) was added. The mixture was stirred at 40 0C for 2 h then cooled to room temperature and purified by prep. HPLC (pH = 2, acetonitrile/water+TFA) to afford the desired product as a TFA salt. LC—MS calculated for FN3O (M+H)+: m/z = 392.2; found 392.2.
Example 9 (1-(3-Flu0r0benzyl){ [(transphenylcyclopropyl)amino] methyl}piperidin yl)acet0nitrile To a solution of N-{[4-(cyanomethyl)piperidinyl]methyl}-2,2,2-trifluoro-N—(trans- 2—phenylcyclopropyl)acetamide (17.9 mg, 0.0490 mmol, prepared as described in Example 8, Step D in DCM (0.5 mL) was added 3—fluorobenzaldehyde (12 mg, 0.098 mmol). The mixture was stirred at room temperature for 1 h then sodium triacetoxyborohydride (21 mg, 0.098 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then d with DCM, and washed with ted NaHCO3, water and brine. The organic layer was dried over NazSO4, filtered and concentrated. The residue was dissolved in THF (1 mL) and methanol (1 mL) then 1 N NaOH (1 mL) was added. The resulting mixture was stirred at 40 0C for 4 h then cooled to room temperature and purified by prep. HPLC (pH = 2, itrile/water+TFA) to afford the desired product as a TFA salt. LC—MS calculated for C24H29FN3 (M+H)+: m/z = 378.2; found 378.2.
Example 10 (5R)—2-(cisHydroxycyclohexyl)—7-[(3-{[(trans—Z- phenylcyclopropyl)amino]methyl}azetidin-l-yl)carb0nyl]-2,7-diazaspir0[4.5]decan-l- 0116 To a mixture of phosgene in toluene (15 wt% in e, 60 uL, 0.1 mmol, Aldrich, cat#748684) was added a solution of —(cis—4—hydroxycyclohexyl)—2,7— diazaspiro[4.5]decanone (20 mg, 0.1 mmol, ed as disclosed in the ture such as WC 2008/157752) and triethylamine (30 uL, 0.2 mmol) in THF (2 mL). The resulting mixtures was stirred at room temperature for 1 h then concentrated under reduced pressure.
To the residue was added a solution of N—(azetidin-3 —ylmethyl)—2,2,2—trifluoro—N—(trans—2— 2015/015706 phenylcyclopropyl)acetamide (20 mg, 0.05 mmol, prepared as described in Example I, Step 3) and triethylamine (20 uL, 0.1 mmol) in acetonitrile (1 mL). The reaction mixture was stirred at room temperature for 30 min then 2N NaOH in water (1 mL) was added, ed by MeOH (1 mL). The resulting mixture was stirred at 30 0C for 1 h then cooled to room ature and purified by prep. HPLC (pH = 10, acetonitrile/water+NH4OH) to afford the desired product. LC—MS calculated for N403 (M+H)+: m/z = 481.3; found 481.3.
Example 11 (5S)—2-(cisHydroxycyclohexyl)—7—[(3-{[(trans—Z- phenylcyclopropyl)amino]methyl}azetidin-l-yl)carb0nyl]-2,7-diazaspir0[4.5]decan-l- 0116 This compound was prepared using procedures analogous to those described for the synthesis of Example 10 with (5 S)—2—(cis—4—hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan one(prepared using similar methods as sed in the literature such as WC 2008/ 157752) replacing (5R)(cishydroxycyclohexyl)—2,7-diazaspiro[4.5]decan—l—one. LC—MS calculated for C28H41N403 (M+H)+: m/z = 481.3; found 481.3.
Example 12 1-[(3-{ [(trans—Z-Phenylcyclopropyl)amino]methyl} azetidin-l-yl)carb0nyl]piperidine—4- carbonitrile H NAN This compound was prepared using ures analogous to those described for the synthesis of Example 10 with piperidinecarbonitrile replacing (5R)—2-(cis hydroxycyclohexyl)—2,7—diazaspiro[4.5]decan—l—one. LC—MS calculated for C20H27N4O : m/z = 3392; found 339.2.
Example 13 Trans—Z-phenyl—N- [(1-{ [4-(trifluoromethyl)piperidinyl] carbonyl} azetidin yl)methyl] cyclopropanamine This compound was ed using procedures analogous to those described for the synthesis of Example 10 with 4-(trifluoromethyl)piperidine replacing (5R)—2-(cis hydroxycyclohexyl)—2,7—diazaspiro[4.5]decan—l—one. LC—MS calculated for C20H27F3N3O (M+H)+: m/z = 3822; found 382.2.
Example 14 N—({1-[(3-Phenoxypiperidin-l-yl)carbonyl] azetidinyl}methyl)-trans—2- phenylcyclopropanamine This compound was ed using procedures analogous to those described for the synthesis of Example 10 with 3-phenoxypiperidine replacing (5R)(cis hydroxycyclohexyl)—2,7—diazaspiro[4.5]decan—l—one. LC—MS calculated for N3Oz (M+H)+: m/z = 4062; found 406.2.
Example 15 N—({1-[(3-Methoxypiperidinyl)carbonyl] inyl} methyl)-trans—2- phenylcyclopropanamine This compound was prepared using procedures analogous to those described for the synthesis of Example 10 with 3-methoxypiperidine replacing (5R)(cis hydroxycyclohexyl)—2,7—diazaspiro[4.5]decan—1—one. LC—MS calculated for C20H30N302 : m/z = 344.2; found 344.1.
Example 16 yl[(3-{[(trans—Z-phenylcyclopropyl)amin0] methyl} azetidin-lyl )carbonyl]piperidine—4-carbonitrile H NJKN This compound was prepared using procedures analogous to those described for the synthesis of Example 10 with 4-phenylpiperidinecarbonitrile hydrochloride replacing -(cishydroxycyclohexyl)-2,7-diazaspiro[4.5]decanone. LC-MS calculated for C26H31N4O (M+H)+: m/z = 415.2; found 415.2.
Example 17 4-Phenyl[(3-{[(trans—Z-phenylcyclopropyl)amin0] methyl} azetidin-lyl )carb0nyl]piperidinol LEAN 1 Q This nd was prepared using procedures analogous to those described for the synthesis of Example 10 with 4-phenylpiperidinol replacing (5R)(cis hydroxycyclohexyl)—2,7—diazaspiro[4.5]decan—1—one. LC—MS calculated for C25H32N3Oz : m/z = 406.2; found 406.2.
Example 18 N—({1-[(S-Fluoro-1,2-dihydr0-spiro[indole-3,4'-piperidin]-1'-yl)carbonyl] azetidin yl} )-trans—2-phenylcyclopropanamine HNfiN N To a mixture of phosgene in toluene (15wt% in toluene, 60 uL, 0.1 mmol, Aldrich, cat#748684) was added a solution of tert—butyl ospiro[indole—3,4'—piperidine]—1(2H)- carboxylate hydrochloride (30 mg, 0.1 mmol, prepared as disclosed in the literature such as WC 2008/157752) and triethylamine (30 uL, 0.2 mmol) in THF (2 mL). The ing mixtures was stirred at room ature for l h then concentrated under reduced pressure.
To the residue was added a solution of N—(azetidin-3 hyl)—2,2,2—trifluoro—N—(trans—2— phenylcyclopropyl)acetamide (20 mg, 0.05 mmol, prepared as described in Example I, Step 3) and triethylamine (20 uL, 0.1 mmol) in acetonitrile (1 mL). The on mixture was stirred at room temperature for 30 min then quenched with saturated aqueous NaHCO3, and extracted with EtOAc. The combined organic layers were washed with brine, dried over NazSO4, filtered and concentrated under reduced pressure. The residue was dissolved in acetonitrile (1 mL) then TFA (1 mL) was added. The resulting e was stirred at room temperature for l h then concentrated. The residue was dissolved in THF (1 mL) and MeOH (1 mL) then 2N aqueous NaOH (0.5 mL) was added. The reaction mixture was stirred at 30 0C for l h then cooled to room temperature and ed by prep. HPLC (pH = 10, acetonitrile/water+NH4OH) to afford the desired product. LC—MS calculated for C26H32FN4O (M+H)+: m/z = 435.3; found 435.3.
Example 19 N-(2-Flu0r0phenyl)—3-{[(trans—Z-phenylcyclopropyl)amin0]methyl} azetidine-l- carboxamide nfiWQO F To a solution of N—(azetidinylmethyl)-2,2,2—trifluoro-N—(trans phenylcyclopropyl)acetamide (20 mg, 0.05 mmol, prepared as described in Example I, Step 3) and triethylamine (30 uL, 0.2 mmol) in itrile (1 mL) was added ro—2— isocyanatobenzene (10 mg, 0.1 mmol). The reaction e was stirred at room temperature for 1 h then 2N aqueous NaOH (1 mL) was added, followed by MeOH (1mL). The reaction mixture was stirred at 30 0C for 1h 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 FN3O (M+H)+: m/z = 340.2; found 340.1.
Example 20 N-(3-Flu0r0phenyl)—3-{[(trans—Z-phenylcyclopropyl)amin0]methyl} azetidine-l- carboxamide This compound was prepared using procedures analogous to those described for the synthesis of e 19 with 1—fluoroisocyanatobenzene replacing 1-fluoro isocyanatobenzene. LC—MS calculated for C20H23FN3O (M+H)+: m/z = 340.2; found 340.1. e 21 N-(4-Flu0r0phenyl)—3-{[(trans—Z-phenylcyclopropyl)amin0]methyl} azetidine-l- carboxamide “whoF0 This compound was prepared using procedures analogous to those described for the synthesis of Example 19 with 1-fluoroisocyanatobenzene replacing 1-fluoro isocyanatobenzene. LC—MS calculated for C20H23FN3O (M+H)+: m/z = 340.2; found 340.1.
Example 22 N-(4-Methoxyphenyl)—3-{ [(trans—Z-phenylcyclopropyl)amin0] methyl}azetidine-l- carboxamide it 0 N N This compound was prepared using procedures analogous to those described for the synthesis of Example 19 with l-isocyanatomethoxybenzene ing l-fluoro isocyanatobenzene. LC—MS ated for N302 (M+H)+: m/z = 352.2; found 352.2.
Example 23 N-(3-Meth0xyphenyl)—3-{ [(trans—Z-phenylcyclopropyl)amin0] methyl}azetidine-l- carboxamide “VLNJLNQOMo e This compound was prepared using procedures analogous to those described for the synthesis of Example 19 with l-isocyanato-3 -methoxybenzene replacing l-fluoro isocyanatobenzene. LC—MS ated for C21H26N302 : m/z = 352.2; found 352.2.
Example 24 N-(2-Methoxyphenyl)—3-{ [(trans—Z-phenylcyclopropyl)amin0] }azetidine-l- carboxamide This compound was prepared using procedures analogous to those described for the synthesis of Example 19 with l-isocyanatomethoxybenzene replacing l-fluoro isocyanatobenzene. LC—MS calculated for C21H26N302 (M+H)+: m/z = 352.2; found 3521.
Example 25 4-[(3-{ [(trans—Z-Phenylcyclopropyl)amino]methyl} azetidin-l-yl)carb0nyl]benzonitrile To a solution of N—(azetidin—3—ylmethyl)—2,2;2—trifluoro—N—(trans—2— phenylcyclopropy1)acetamide (20 mg, 0.05 mmol, prepared as described in Example I, Step 3) and triethylamine (30 uL, 0.2 mmol) in acetonitrile (1 mL) was added 4-cyanobenzoyl chloride (20 mg, 0.1 mmol). The reaction mixture was stirred at room temperature for 1 h then 2N NaOH in water (1 mL) was added, ed by MeOH (1 mL). The resulting mixture was stirred at 30 0C for 1h then cooled to room ature, filtered and purified by prep.
HPLC (pH = 10, acetonitrile/water+NH4OH) to afford the desired product. LC—MS calculated for C21H22N3O (M+H)+: m/z = 332.2; found 332.1.
Example 26 3-[(3-{ s—Z-Phenylcyclopropyl)amino]methyl} azetidin-l-yl)carb0nyl]benzonitrile H N This compound was prepared using procedures analogous to those described for the synthesis of Example 25 with 3—cyanobenzoyl chloride replacing 4-cyanobenzoyl de.
LC—MS calculated for C21H22N3O (M+H)+: m/z = 332.2; found 332.1.
Example 27 N—{ [1-(3-Methoxybenzoyl)azetidinyl] methyl}-trans—2-phenylcyclopropanamine H N This compound was prepared using procedures analogous to those described for the synthesis of Example 25 with 3-methoxy-benzoyl chloride replacing 4-cyanobenzoyl chloride. LC—MS calculated for N202 (M+H)+: m/z = 337.2; found 337.1.
Example 28 N-{ [1-(4-Fluorobenzoyl)azetidinyl] methyl}-trans—2-phenylcyclopropanamine This compound was prepared using procedures analogous to those described for the synthesis of Example 25 with 4—fluoro—benzoyl de replacing 4-cyanobenzoyl chloride.
LC—MS ated for C20H22FN20 (M+H)+: m/z = 325.2; found 325.1.
Example 29 N-{ [1-(3-Fluorobenzoyl)azetidinyl] methyl}-trans—2-phenylcyclopropanamine H N This compound was prepared using procedures analogous to those described for the synthesis of e 25 with 3—fluoro—benzoyl chloride replacing 4—cyanobenzoyl chloride.
LC—MS calculated for C20H22FN20 (M+H)+: m/z = 325.2; found 325.1.
Example 30 Z-phenyl—N-[(1-{[4-(trifluor0methoxy)phenyl] sulfonyl}azetidin yl)methyl]cyclopropanamine O\\ ,,O WCH N 0 OCF3 This compound was prepared using procedures analogous to those described for the synthesis of e 25 with 4-(trifluoromethoxy)benzene sulfonyl chloride ing 4- cyanobenzoyl chloride. LC—MS calculated for C20H22F3N203$ (M+H)+: m/z = 427.1; found 427.0.
Example 31 1-{[4-(4-fluorobenzyl)—4—({[(1R,2S)—2-phenylcyclopropyl]amino}methyl)piperidin yl] methyl} cyclopropanecarboxylic acid Step I: I—tert-bulyl 4-methyl 4-(4-fluor0benzyl)pzperidine-I,4-dicarb0xylate \ O NBoc To a solution of N,N—diisopropylamine (4.9 mL, 35 mmol) in tetrahydrofuran (80 mL) at -78 0C was added n-butyllithium (2.5 M in hexanes, 14 mL, 35 mmol). The resulting mixture was warmed to -20 0C and stirred for 10 min then cooled to —78 0C and a solution of l—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 0C and stirred for l h. The mixture was then cooled to —78 0C and (x—bromo—4—fluorotoluene (4.9 mL, 40. mmol) was added. The reaction mixture was stirred at —78 0C for l h then quenched with saturated NH4C1, warmed to room temperature and diluted with ethyl ether.
The mixture was then washed with water, brine, dried over NazSO4, filtered and concentrated. The e 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—bulyl 4-(4-fluor0benzyl)(hydroxymethybpzperidine-I—carboxylate NBoc To a solution of l-tert-butyl 4-methyl 4-(4-fluorobenzyl)piperidine-l,4-dicarboxylate (6.5 g, 18 mmol) in ydrofuran (90 mL) at 0 0C was added LiAlH4 (1M in THF, 24 mL, 24 mmol) slowly. The resulting mixture was stirred at 0 0C 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 t further purification. LC—MS ated for FNO3 (M—tBu+2H)+: m/z = 268.1; found 268.1.
WO 23465 Step 3 .‘ tert—bulyl 4-(4-flu0r0benzyl)-4—f0rmylpiperidine-I—carboxylate NBoc A solution of dimethyl sulfoxide (4.3 mL, 60. mmol) in methylene de (6 mL) was added to a solution of oxalyl chloride (2.6 mL, 30 mmol) in methylene chloride at -78 0C over 10 min and then the resulting mixture was warmed to -60 0C over 25 min. A solution of tert-butyl 4-(4-fluorobenzyl)—4-(hydroxymethyl)piperidinecarboxylate (5.2 g, 16 mmol) in methylene chloride (6 mL) was slowly added and then warmed to —45 0C over 30 mins. isopropylethylamine (21 mL, 120 mmol) was then added and the mixture was warmed to 0 0C 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 NazSO4, filtered and concentrated. The residue was d by flash chromatography on a silica gel column eluting with EtOAc in hexane (0-20%) to give the d product (4.3 g, 83%). LC—MS calculated for C14H17FNO3 (M—tBu+2H)+: m/z = 266.1; found 266.1.
Step 4: tert—bulyl 4-(4-flu0r0benzyZ)({[(IR,2S) phenylcyclopropyl]amino}methyl)piperidine-I-carb0xylate N Boc : :: -‘\\ To a solution of tert-butyl 4-(4-fluorobenzyl)formylpiperidinecarboxylate (4.2 g, 13 mmol) and (IR, 2S)phenylcyclopropanamine (1.96 g, 14.7 mmol) (prepared using procedures as described in . Med. Chem. Lett., 2011, 2], 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 ene chloride, washed with 1 N NaOH aqueous solution, water and brine. The organic layer was dried over NazSO4, filtered and concentrated. The e 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 C27H36FN202 (M+H)+: m/z = 439.3; found 439.2.
Step 5 .‘ tert-butyl 4—(4—flu0r0benzyl){[(IR,2S)phenylcyclopr0pyl— (trifluoroacetyl)amin0]-methyl}pzperidine-I—carboxylate FSCYO N Boc Trifluoroacetic anhydride (2.08 mL, 14.7 mmol) was added to a solution of tert—butyl 4-(4-fluorobenzyl)( { [(1 2-phenylcyclopropyl]amino} methyl)piperidine- l - carboxylate (4.3 g, 9.8 mmol) and N,N—diisopropylethylamine (4.3 mL, 24 mmol) in methylene chloride (40 mL) at 0 0C. The resulting mixture was stirred at 0 0C for l h then diluted with ether and washed with l N HCl, water and brine. The organic layer was dried over NazSO4, filtered and trated. The residue was purified by flash chromatography on a silica gel column g with EtOAc in hexanes (0—30%) to give the desired product (4.6 g, 88 %). LC—MS calculated for C25H27F4N203 (M—tBu+2H)+: m/z = 479.2; found 479.2.
Step 6: triflu0r0-N-{[4-(4-flu0r0benzyl)pzperidin-4—yl]methyl}-N-[(IR,2S) phenylcyclopropracetamide “(A/N F Hydrogen chloride (4 M in 1,4-dioxane, 20 mL, 80 mmol) was added to a on of tert-butyl 4-(4-fluorobenzyl) {[[(lR,2S) phenylcyclopropyl](trifluoroacetyl)amino]methyl}-piperidine-l-carboxylate (4.6 g, 8.6 mmol) in methylene de (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 C24H27F4N20 (M+H)+: m/z = 435.2; found 435.2.
Step 7.‘ methyl I-(hydroxymethyl)cyclopropanecarboxylate Hofio/ Isobutyl chloroformate (0.61 mL, 4.7 mmol) was added to a solution of l- (methoxycarbonyl)cyclopropanecarboxylic acid (Alfa Aesar, cat#H25 828: 0.57 g, 3.9 mmol) and triethylamine (1.1 mL, 7.8 mmol) in tetrahydrofuran (10 mL) at 0 °C. The resulting mixture was stirred at 0 0C for 30 min then filtered and washed with THF (2 mL).
The filtrate was cooled to 0 °C and then a solution of sodium ydroborate (0.30 g, 7.9 mmol) in water (2 mL) was added. The reaction mixture was d for 30 min then diluted with ethyl acetate, washed with saturated NaHCO3 s solution, water and brine. The organic layer was dried over NazSO4, filtered and concentrated. The residue (0.46 g) was used in the next step without further purification.
Step 8: methyl Iformylcyclopropanecarboxylate Dimethyl sulfoxide (0.57 mL, 8.0 mmol) in methylene chloride (0.8 mL) was added to a solution of oxalyl chloride (0.34 mL, 4.0 mmol) in methylene chloride (5 mL) at -78 0C over 10 min. The resulting mixture was warmed to -60 0C over 25 min then a solution of methyl 1-(hydroxymethyl)cyclopropanecarboxylate (0.40 g, 3.1 mmol) in methylene chloride (5 mL) was slowly added. The mixture was warmed to —45 0C over 30 mins then N,N— diisopropylethylamine (2.8 mL, 16 mmol) was added and the e was warmed to 0 0C over 15 min. The reaction mixture was poured into a cold 1 N HCl aqueous solution and extracted with diethyl ether. The combined extracts were dried over , 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 (0.30 g, 76 %).
Step 9: methyl I—[(4-(4-flu0r0benzyl){[[(IR,2S) cyclopropyl] (trifluoroacetyl)amin0]-methyl}piperidin-I - yl)methyUcyclopropanecarboxylate FchO N/Xko/ ‘\\A»N F N,N—Diisopropylethylamine (0.19 mL, 1.1 mmol) was added to a mixture of 2,2,2- trifluoro-N— { [4-(4-fluorobenzyl)piperidinyl]methyl} -N-[(1R,2S)—2- phenylcyclopropyl]acetamide (Step 6: 400.0 mg, 0.92 mmol) in methylene chloride (4 mL). The resulting mixture was stirred for 5 min and then methyl 1- formylcyclopropanecarboxylate (153 mg, 1.20 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then sodium triacetoxyborohydride (0.58 g, 2.8 mmol) was added. The mixture was stirred at room temperature for 4 h then diluted with methylene chloride, washed with 1 N NaOH, water and brine. The c layer was dried over , filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with methanol in DCM (0—6%) to give the desired product (0.45 g, 89 %).
LC—MS calculated for C30H35F4N203 (M+H)+: m/z = 547.3; found 547.3.
Step 10: I-{[4-(4-fluor0benzyl)({[(IR,2S)phenylcyclopropramin0}methyl)pzperidin-I- yUmethyl}cyclopropanecarboxylic acid The product from Step 9 was dissolved in MeOH/THF (1 0/06 mL) and then NaOH (15 wt % in water, 3.0 mL) was added. The on mixture was stirred at 40 0C overnight then cooled to room temperature and purified by prep—HPLC (pH = 2, itrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C27H34FN202 (M+H)+: m/z = 437.3; found 437.2. 1H NMR (500 MHz, DMSO) 5 7.35 — 7.28 (m, 2H), 7.26 — 7.20 (m, 3H), 7.20 — 7.10 (m, 4H), 3.41 — 3.29 (m, 4H), 3.28 — 3.09 (m, 4H), 2.94 (br, 1H), 2.84 (s, 2H), 2.60 — 2.51 (m, 1H), 1.84 — 1.67 (m, 4H), 1.63 — 1.52 (m, 1H), 1.37 — 1.26 (m, 3H),1.17 — 1.09 (m, 2H).
Example 32 (4-fluorobenzyl)—4—({[(1R,2S)—2-phenylcyclopropyl]amino}methyl)piperidin yl] methyl}cyclobutanecarboxylic acid A,HN N/ZfikOH O‘\‘ ”503 Step I .‘ methyl Iformylcyclobutanecarboxylate 0/5 0/ To a solution of dimethyl cyclobutane-1,1-dicarboxylate (Alfa Aesar, cat#L12250: 1.0 g, 6.0 mmol) in methylene chloride (15 mL) at -78 0C was added 1.0 M utylaluminum hydride in toluene (12.0 mL, 12.0 mmol). The reaction mixture was stirred at -78 0C for 45 min, and quenched with slow addition of 1 M HCl. The resulting mixture was warmed to room temperature and stirred for r 30 min. The organic layer was separated, washed with brine, dried over NazSO4, and concentrated. The crude material was purified via column chromatography (0 to 20% EtOAc in hexanes) to give the product as a colorless oil (330 mg, 39 %). 1H NMR (400 MHz, CDCl3) 5 9.78 (s, 1H), 3.79 (s, 3H), 2.48 (t, J: 8.0 Hz, 4H), 2.13 — 1.87 (m, 2H).
Step 2: I-{[4-(4-flu0r0benzyl)({[(IR, 2S)phenylcyclopr0pyl]amino}methyl)piperidin-I - yUmethyl}cyclobutanecarboxylic acid A e of methyl 1-formylcyclobutanecarboxylate (20. mg, 0.14 mmol), acetic acid (6 ”L, 0.10 mmol) and 2,2,2-trifluoro-N—{[4-(4-fluorobenzyl)piperidinyl]methyl}-N- [(1R,2S)—2—phenylcyclopropyl]acetamide le 31, Step 6: 40.0 mg, 0.0921 mmol) in methylene chloride (2 mL) was stirred at room temperature for 2 h and then sodium triacetoxyborohydride (64 mg, 0.30 mmol) was added. The reaction mixture was stirred at room temperature overnight then diluted with methylene chloride, washed with 1 N NaOH, water and brine. The organic layer was dried over NazSO4, filtered and concentrated.
The e was dissolved in MeOH/THF (0.5/0.5 mL) and then 6 N NaOH (1.0 mL) was added. The resulting e was stirred at 40 °C overnight then cooled to room ature and purified by prep—HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C28H36FN202 (M+H)+: m/z = 451.3; found 451.3.
Example 33 4-{ [4-(4-flu0r0benzyl)—4-({ [(1R,2S)—2-phenylcyclopropyl]amino}methyl)piperidin- 1-yl]carb0nyl}cyclohexanamine N "(1 F Triethylamine (23 uL, 0.16 mmol) was added to a solution of trans[(tert- butoxycarbonyl)amino]cyclohexanecarboxylic acid (TCI America, cat#B3250: 10.0 mg, 0.0411 mmol), 2,2,2-trifluoro-N—{[4-(4-fluorobenzyl)piperidinyl]methyl}-N-[(1R,2S) phenylcyclopropyl]acetamide (Example 31, Step 6: 14 mg, 0.033 mmol) and benzotriazol—l— yloxytris(dimethylamino)phosphonium hexafluorophosphate (27 mg, 0.062 mmol) in N,N— dimethylformamide (0.6 mL). The resulting e was stirred at room temperature for l h then diluted with ethyl acetate, washed with saturated NaHCO3 aqueous solution, water and brine. The organic layer was dried over NazSO4, filtered and concentrated. The residue was dissolved in DCM (0.3 mL) and then TFA (0.3 mL) was added. The mixture was d at room temperature for l h then concentrated. The residue was ved in THF/MeOH (0.2 mL/0.2 mL) and then NaOH (15 wt % in water, 0.5 mL) was added and the mixture was stirred at 35 0C overnight. The mixture was purified by prep-HPLC (pH = 2, itrile/water+TFA) to give the d product as the TFA salt. LC—MS calculated for C29H39FN3O (M+H)+: m/z = 464.3; found 464.3.
Example 34 1-{[4-(4-fluorobenzyl)—4—({[(1R,2S)—2-phenylcyclopropyl]amino}methyl)piperidin yl]carbonyl}cyclobutanamine A’HN NJEENHZ o %.\\ This compound was prepared using procedures analogous to those described for Example 33 with l—[(tert—butoxycarbonyl)amino]cyclobutanecarboxylic acid (Aldrich, 0802) replacing trans[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid. 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 C27H35FN3O (M+H)+: m/z = 436.3; found 436.3.
Example 35 1-{[4-(meth0xymethyl)—4-({[(lR,ZS)phenylcyclopropyl]amino}methyl)piperidin yl] methyl} cyclopropanecarboxylic acid \A’l‘K/p COZH H “A © Step I: I—tert—bulyl 4-methyl 4-(methoxymethybpiperidine-I,4-dicarb0xylate 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 0C was added lithium ropylamide (2 M in THF, 5.8 mL, 12 mmol). The resulting mixture was stirred at -40 0C for 30 min then chloromethyl methyl ether (1.2 mL, 16 mmol) was added. The reaction mixture was stirred at —40 0C for 1 h then quenched with saturated NH4Cl aqueous solution and warmed to room temperature. The mixture was diluted with ethyl acetate, washed with ted NaHCO3 aqueous solution, water and brine. The organic layer was dried over NazSO4, filtered and concentrated. The crude material was d 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—bulyl 4-(hydroxymethyD(methoxymethpriperidine-I—carboxylate BocN 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 0C was added LiAlH4 (1 M in THF, 10. mL, 10. mmol) slowly. The resulting mixture was d at 0 0C for 30 min then ed with addition of water (0.1 mL), NaOH (15 wt % in water, 0.1 mL) and water (0.1 mL). The e was stirred for 10 min then filtered and washed with THF. The filtrate was trated 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—bulyl 4-f0rmyl(methoxymethybpiperidine-I—carboxylate BocN Dimethyl sulfoxide (1.7 mL, 24 mmol) in methylene chloride (2 mL) was added to a solution of oxalyl de (1.0 mL, 12 mmol) in methylene chloride (3 mL) at -78 0C over min. The resulting mixture was warmed to -60 0C over 25 min then a solution of tert-butyl 4-(hydroxymethyl)—4-(methoxymethyl)piperidinecarboxylate (1.6 g, 6.0 mmol) in methylene chloride (5 mL) was slowly added. The mixture was warmed to —45 0C over 30 min then triethylamine (6.7 mL, 48 mmol) was added. The mixture was warmed to 0 0C over min. The reaction mixture was then poured into a cold 1 N HCl aqueous on and extracted with diethyl ether. The combined extracts were dried over , d 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 C8H16N02 (M—Boc+2H)+: m/z = 158.1; found 158.1.
Step 4: tert—bulyl 4-(methoxymethyD({[(IR,2S)phenylcyclopropramin0}methyl)- piperidine-I-carb0xylate NBoc O OMe A mixture of tert-butyl 4-formyl(methoxymethyl)piperidinecarboxylate (1.3 g, .0 mmol), acetic acid (0.43 mL, 7.5 mmol) and (1R,2S)—2-phenylcyclopropanamine (prepared using procedures as described in Bioorg. Med. Chem. Lett., 2011, 21, 4429: 699 mg, 5.25 mmol) in 1,2-dichloroethane (20 mL) was stirred at room temperature for 1 h then sodium toxyborohydride (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 s solution, water and brine. The organic layer was dried over NazSO4, filtered and trated. 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 C22H35N203 (M+H)+: m/z = 375.3; found 375.2.
Step 5 .‘ tert—bulyl h0xymethyD{[[(IR,2S)phenylcyclopr0pyl]- (trifluoroacelyl)amino]methyl}piperidine-I-carb0xylate F30Y0 N Boc O OMe Trifluoroacetic anhydride (0.96 mL, 6.8 mmol) was added to a solution of utyl hoxymethyl)( { [( 1 R,2S)—2-phenylcyclopropyl]amino} methyl)piperidine carboxylate (1.7 g, 4.5 mmol) and N,N—diisopropylethylamine (1.6 mL, 9.1 mmol) in methylene chloride (25 mL) at 0 0C. The resulting mixture was stirred at room temperature for 1 h then diluted with methylene chloride, washed with sat'd NaHCO3 aqueous solution, water, and brine. The organic layer was dried over NazSO4, filtered and concentrated. The WO 23465 residue was purified Via flash chromatography on a silica gel column eluting with 0 to 20% EtOAc in s to give the desired product (1.8 g, 84 %). LC—MS calculated for C19H26F3N202 (M—Boc+2H)+: m/z = 371.2; found 371.1.
Step 6: 2,2,2-triflu0r0-N-{[4-(methoxymethprzperidinyl]methyl}-N-[(IR,2S) phenylcyclopropracetamide 4.0 M Hydrogen chloride in e (7 mL, 28 mmol) was added to a solution of tert- butyl 4-(methoxymethyl)—4- { [[(1R,2 S)phenylcyclopropyl](trifluoroacetyl)amino]methyl} - piperidinecarboxylate (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 F3N202 (M+H)+: m/z = 371.2; found 371.2. The crude product was neutralized to give the free base form of the product which was used to obtain the NMR data. 1H NMR (500 MHz, CD3OD) 5 7.31 — 7.26 (m, 2H), 7.22 — 7.17 (m, 1H), 7.12 — 7.07 (m, 2H), 3.79 — 3.58 (m, 2H), 3.35 — 3.32 (m, 2H), 3.28 — 3.22 (m, 1H), 3.19 — 2.98 (m, 7H), 2.44 — 2.34 (m, 1H), 1.84 — 1.54 (m, 5H), 1.48 — 1.37 (m, 1H); 13C NMR (126 MHz, CD3OD)5161.74, 141.21,129.63,127.51,126.73, 119.39, 76.75, 59.28, 53.29, 42.71, 41.54, 39.22, 30.06, 27.95, 20.10.
Step 7: methyl I—[(4-(meth0xymethyl)-4—{[[(IR,2S) phenylcyclopropyl] (trifluoroacetyl)amin0]-methyl}piperidin-I - yl)methyUcyclopropanecarboxylate FsCYO N/\Z :COZMe © OMe A mixture of methyl 1-formylcyclopropanecarboxylate (Example 31, Step 8: 53 mg, 0.41 mmol), acetic acid (17 ”L, 0.29 mmol) and 2,2,2-trifluoro-N—{[4- (methoxymethyl)piperidinyl]methyl} -N-[(1R,2S)phenylcyclopropyl]acetamide (100.0 mg, 0.2700 mmol) in methylene chloride (2 mL) was stirred at room ature for 2 h then sodium triacetoxyborohydride (190 mg, 0.88 mmol) was added. The mixture was stirred at room temperature for 2 h then diluted with methylene chloride, washed with 1 N NaOH, water and brine. The c layer was dried over NazSO4, filtered and concentrated. The residue was purified via flash chromatography on a silica gel column eluting with 0 to 6% MeOH in DCM to give the d product. LC—MS calculated for C25H34F3N204 (M+H)+: m/z = 483.2; found 483.3.
Step 8: (meth0xymethyl)({[(IR,2S)phenylcyclopropramin0}methyl)pzperidin-I- yl]methyl}cyclopropanecarboxylic acid The product from Step 7 was dissolved in MeOH/THF (0.5/0.5 mL) then NaOH (15 wt % in water, 1.0 mL) was added. The resulting mixture was stirred at 40 0C overnight then cooled to room temperature and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS ated for N203 (M+H)+: m/z = 373.2; found 373.3. 1H NMR (500 MHz, DMSO) 5 7.33 — 7.28 (m, 2H), 7.24 — 7.19 (m, 1H), 7.19 — 7.15 (m, 2H), 3.40 (s, 2H), 3.36 — 3.31 (m, 5H), 3.30 — 3.19 (m, 4H), 3.14 (s, 2H), 2.92 —2.83 (m, 1H), 2.47 —2.41(m,1H), 1.92 — 1.71 (m, 4H),1.54 — 1.41 (m, 1H), 1.37 — 1.30 (m, 2H), 1.29 — 1.20 (m, 1H), 1.16 — 1.09 (m, 2H).
Example 36 1-{[4-(meth0xymethyl)—4-({[(1R,2S)—2-phenylcyclopropyl]amino}methyl)piperidin yl] methyl}cyclobutanecarboxylic acid Azl‘K/p COZH H Q; ©.‘\\ OMe Step 1: methyl I—[(4-(meth0xymethyl)-4—{[[(IR,2S) phenylcyclopropyl] (triflaoroacetyl)amin0]-methyl}piperidin-I - yl)methyl]cycl0batanecarboxylate \A/va /23FchO COZMe ©‘ OMe A mixture of methyl 1-formylcyclobutanecarboxylate (Example 32, Step I : 200 mg, 1.4 mmol), acetic acid (60 ”L, 1.1 mmol) and 2,2,2-trifiuoro-N—{[4- (methoxymethyl)piperidinyl]methyl} -N-[(1R,2S)phenylcyclopropyl]acetamide (Example 35, Step 6: 350 mg, 0.95 mmol) in methylene chloride (7 mL) was stirred at room temperature for 2 h and then sodium triacetoxyborohydride (650 mg, 3.1 mmol) was added.
The resulting mixture was stirred at room temperature overnight then diluted with methylene de, washed with 1 N NaOH, water and brine. The organic layer was dried over NazSO4, filtered and trated. The residue was purified via flash chromatography on a silica gel column eluting with 0 to 6% MeOH in DCM to give the desired product. LC—MS calculated for C26H36F3N204 (M+H)+: m/z = 497.3; found 497.3.
Step 2: I-{[4-(meth0xymethyD({[(IR, 2S)phenylcyclopropramin0}methyl)pzperidin-I- yUmethyl}cyclobutanecarboxylic acid The product from Step I was ved in HF (2.0/2.0 mL) then 6 N NaOH (1.0 mL) was added. The resulting mixture was stirred at 40 0C for 36 h then cooled to room temperature and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C23H35N203 (M+H)+: m/z = 387.3; found 387.2. 1H NMR (500 MHz, CD3CN) 5 7.35 — 7.29 (m, 2H), 7.27 — 7.21 (m, 1H), 7.19 — 7.13 (m, 2H), 3.46 (s, 2H), 3.43 (s, 2H), 3.36 (s, 3H), 3.34 — 3.12 (m, 6H), 2.94 — 2.84 (m, 1H), 2.70 — 2.60 (m, 1H), 2.56 — 2.43 (m, 2H), 2.22 — 1.96 (m, 4H), 1.93 — 1.76 (m, 4H), 1.71 — 1.59 (m, 1H), 1.33 — 1.22 (m, 1H).
Example 37 1-{[4-(meth0xymethyl)—4-({[(1R,2S)—2-phenylcyclopropyl]amino}methyl)piperidin yl] methyl} cyclopentanecarboxylic acid \A/va COZH H /é © OMe Step I .‘ I—tert—butyl I—methyl cyclopentane—I, I—dicarboxylate O O 3980J< 1,4-Dibromobutane (2.4 mL, 20. mmol) was added to a mixture of tert-butyl methyl malonate (1.74 g, 10.0 mmol), cesium carbonate (9.8 g, 30. mmol) and 1-butylmethyl-1H- imidazolium uoroborate (0.4 g, 2 mmol) in acetonitrile (20 mL). The resulting mixture was stirred at room temperature overnight then diluted with diethyl ether and d.
The filtrate was concentrated and the residue was dissolved in diethyl ether then washed with water and brine. The organic layer was dried over NazSO4, filtered and concentrated. The residue was d via flash chromatography on a silica gel column eluting with 0 to 10% EtOAc in hexanes to give the desired product (1.7 g, 75%). LC—MS calculated for C8H1304 (M—tBu+2H)+: m/z = 173.1; found 173.1.
Step 2: I—(tert—butoxycarbonyl)cyclopentanecarboxylic acid To a solution of 1-tert-butyl 1-methyl cyclopentane-l,1-dicarboxylate (1.7 g, 7.4 mmol) in tetrahydrofuran(10 mL)/methanol(5 mL)/water(5 mL) was added lithium hydroxide, monohydrate (0.62 g, 15 mmol). The resulting mixture was stirred at room temperature for 5 h then concentrated to remove most of the solvents. The residue was dissolved in water and washed with ether. The aqueous layer was acidified using cold 1 N HCl on then extract with DCM. The ed DCM extracts were dried over NazSO4, filtered and concentrated under reduced pressure to afford the desired compound which was used in the next step without further purification. LC—MS calculated for 4 (M— tBu+2H)+: m/z = 159.1; found 159.1.
Step 3: utyl I-(hydroxymethyl)cyclopentanecarboxylate H060k lsobutyl chloroformate (1.1 mL, 8.2 mmol) was added to a solution of 1-(tert- butoxycarbonyl)cyclopentanecarboxylic acid (1.60 g, 7.47 mmol) and 4-methylmorpholine (0.9 mL, 8.2 mmol) in tetrahydrofuran (20 mL) at -20 °C. The resulting mixture was stirred for 30 min then filtered and washed with THF (4 mL). The filtrate was cooled to -20 OC and then sodium tetrahydroborate (0.56 g, 15 mmol) in water (4 mL) was added. The reaction e was stirred for 30 min then diluted with ethyl acetate, washed with saturated NaHCO3 aqueous solution, water and brine. The organic layer was dried over , filtered and concentrated. The residue was used in the next step without further purification.
LC—MS ated for C7H1303 (M—tBu+2H)+: m/z = 145.1; found 145.1.
Step 4: tert-butyl I—formylcyclopentanecarboxylate Dimethyl sulfoxide (1.9 mL, 26 mmol) in methylene chloride (3 mL) was added to a solution of oxalyl chloride (1.1 mL, 13 mmol) in methylene chloride (5 mL) at -78 0C over 10 min. The resulting mixture was warmed to -60 0C over 25 min then a solution of tert-butyl 1- (hydroxymethyl)cyclopentanecarboxylate (1.4 g, 7.0 mmol) in methylene chloride (5 mL) was slowly added. The mixture was warmed to —45 0C over 30 min then N,N— diisopropylethylamine (9.1 mL, 52 mmol) was added. The mixture was warmed to 0 0C over min then poured into a cold 1 N HCl aqueous solution and extracted with ethyl ether. The combined extracts were dried over NazSO4, filtered and concentrated. The residue was purified via flash tography on a silica gel column eluting with 0 to 20% EtOAc in hexanes to give the desired product (1.0 g, 72 %). LC—MS calculated for 3 (M— tBu+2H)+: m/z = 143.1; found 143.1.
Step 5 .‘ tert-butyl I—[(4-(meth0xymethyl){[[(IR,2S)phenylcyclopr0pyl](trzfluoroacetyl)- amino]methyl}piperidin-I-yl)methyl]cyclopentanecarboxylate \A/va/éFchO COZtBU ©l OMe To a solution of 2,2,2-trifluoro-N—{[4-(methoxymethyl)piperidinyl]methyl}-N- [(1R,2S)—2—pheny1cyclopropy1]acetamide (Example 35, Step 6: 400 mg, 1.00 mmol) and N,N— ropylethylamine (0.28 mL, 1.6 mmol) in methylene chloride (8 mL) was added tert— butyl 1-formylcyclopentanecarboxylate (280 mg, 1.4 mmol). The resulting mixture was stirred at room temperature for 2 h then sodium triacetoxyborohydride (690 mg, 3.2 mmol) was added. The reaction mixture was stirred at room temperature overnight then diluted with methylene de, washed with 1 N NaOH, water and brine. The organic layer was dried over NazSO4, filtered and concentrated. The residue was purified via flash chromatography on a silica gel column eluting with 0 to 6% MeOH in DCM to give the desired t (0.45 g, 75%). LC—MS calculated for F3N204 (M+H)+: m/z = 553.3; found 553.3.
Step 6: I-{[4-(meth0xymethyl)({[(IR,2S)phenylcyclopropramin0}methyl)pzperidin-I- yUmethyl}cyclopentanecarboxylic acid To a solution of tert-butyl 1-[(4-(methoxymethyl){[[(1R,2S) phenylcyclopropyl] uoroacetyl)amino]methyl}piperidin yl)methyl]cyclopentanecarboxylate (450 mg, 0.81 mmol) in methylene chloride (2 mL) was added trifluoroacetic acid (2.0 mL, 26 mmol). The resulting mixture was stirred at room ature for 4 h then concentrated. The residue was dissolved in THF/methanol (2 mL/2 mL) and then 6 N NaOH (3.0 mL) was added. The resulting mixture was stirred at room temperature overnight then purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C24H37N203 (M+H)+: m/z = 401.3; found 401.2.
Example 38 )-N-[(4-(methoxymethyl)—1-{[(2S)-l-methylpyrrolidin-Z-yl]carbonyl}piperidin-4— yl)methyl]phenylcyclopropanamine \A/vaN (>1 OMe To a on of (2S)methylpyrrolidinecarboxylic acid (Chem-Impex, cat#06356: 11 mg, 0.088 mmol), 2,2,2-trifluoro-N—{[4-(methoxymethyl)piperidin yl]methyl}-N—[(1R,2S)phenylcyclopropyl]acetamide (Example 35, Step 6: 16 mg, 0.044 mmol) and (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (46 mg, 0.088 mmol) in N,N—dimethylformamide (1 mL) was added triethylamine (31 uL, 0.22 mmol). The resulting mixture was stirred at room temperature for 4 h then NaOH (15 wt %, 0.5 mL) was added. The mixture was stirred at 40 °C overnight then cooled to room temperature and d by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS ated for C23H36N302 (M+H)+: m/z = 386.3; found 386.2.
Example 39 (1R,2S)—N-({4—(meth0xymethyl)—1-[(1-methyl—1H—imidazolyl)carbonyl]piperidin yl} methyl)phenylcyclopropanamine \MflofigNN \ ©l OMe This compound was prepared using similar ures as described for Example 38 with 1-methyl-1H-imidazolecarboxylic acid (Combi-Blocks, cat#HI—1090) replacing (2S)— 1-methylpyrrolidinecarboxylic acid. 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 C22H31N4Oz (M+H)+: m/z = 383.2; found 383.2.
Example 40 (meth0xymethyl)—4-({[(1R,2S)—2-phenylcyclopropyl]amino}methyl)piperidin yl] carb0nyl}pyridazinamine NA’N / © NH2 This compound was prepared using similar procedures as described for Example 38 with 6-aminopyridazinecarboxylic acid (Chem-Impex, cat#19168) replacing (2S) methylpyrrolidinecarboxylic acid. The reaction e was purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the d product as the TFA salt. LC—MS calculated for N502 (M+H)+: m/z = 396.2; found 396.2. 1H NMR (500 MHz, CD3CN) 5 7.75 (d, J= 9.5 Hz, 1H), 7.40 (d, J= 9.5 Hz, 1H), 7.35 — 7.28 (m, 2H), 7.27 — 7.20 (m, 1H), 7.19 — 7.13 (m, 2H), 3.80 — 3.47 (m, 6H), 3.37 (s, 3H), 3.36 — 3.23 (m, 2H), 2.98 — 2.82 (m, 1H), 2.73 — 2.60 (m, 1H), 1.72 — 1.54 (m, 5H), 1.35 — 1.20 (m, 1H).
Example 41 (1R,2S)—N-({4-(methoxymethyl)—1-[(1-methylpiperidinyl)carb0nyl]piperidin-4— yl} methyl)phenylcyclopropanamine A,“N “\ON\ E:n“ OMe This compound was prepared using similar procedures as described for Example 38 with ylpiperidinecarboxylic acid (AstaTech, cat#64217) replacing (2S) methylpyrrolidinecarboxylic acid. The reaction mixture was purified by prep-HPLC (pH = 2, itrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C24H38N302 (M+H)+: m/z = 400.3; found 400.3.
Example 42 (1R,2S)—N-({4—(meth0xymethyl)—1-[(l-methyl-1H-pyrazol—3-yl)carb0nyl]piperidin-4— yl} methyl)phenylcyclopropanamine (A’N \ © l-Methyl-1H-pyrazolecarbonyl chloride (Maybridge, cat#CC48302: 12 mg, 0.081 mmol) was added to a solution of 2,2,2-trifluoro-N— {[4-(methoxymethyl)piperidin yl]methyl}—N—[(1R,2S)—2—phenylcyclopropyl]acetamide (Example 35, Step 6: 15.0 mg, 0.040 mmol) and triethylamine (22 uL, 0.16 mmol) in methylene chloride (0.5 mL) at 0 0C. The resulting mixture was stirred at room temperature for 3 h then diluted with ethyl acetate, washed with 1 N NaOH, water and brine. The organic layer was dried over NazSO4, filtered and concentrated. The residue was dissolved in methanol/THF (1/1 mL) and then NaOH (15 wt % in water, 1.5 mL) was added. The mixture was stirred at 40 0C overnight then cooled to room temperature and purified by prep-HPLC (pH = 2, itrile/water+TFA) to give the desired t as the TFA salt. LC—MS calculated for C22H31N4Oz (M+H)+: m/z = 383.2; found 3 83 .2.
Example 43 )-N-({4—(methoxymethyl)—1-[(4—methylpiperazin-l-yl)carb0nyl]piperidin-4— yl} methyl)phenylcyclopropanamine 4-Methylpiperazinecarbonyl chloride ch, cat#563250: 99 uL, 0.73 mmol) was added to a on of 2,2,2-trifluoro—N—{[4-(methoxymethyl)piperidin—4—yl]methyl}-N— [(1R,2S)—2—phenylcyclopropyl]acetamide (Example 35, Step 6: 90.0 mg, 0.243 mmol) and N,N—diisopropylethylamine (0.13 mL, 0.73 mmol) in N,N—dimethylformamide (0.8 mL) at room temperature. The resulting mixture was stirred at 90 °C overnight then cooled to room temperature and concentrated. The residue was purified via flash chromatography on a silica gel column eluting with 0 to 6% MeOH in DCM to give the desired intermediate. To the solution of the intermediate in MeOH/THF (0.5 mL/0.5 mL) was added NaOH (15 wt % in water, 1 mL). The mixture was stirred at 40 0C overnight then cooled to room temperature and purified by prep—HPLC (pH = 2, itrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C23H37N4Oz (M+H)+: m/z = 401.3; found 401.3. e 44 1-{[4-methyl({ [(1R,2S)—2-phenylcyclopr0pyl]amino}methyl)piperidin yl] methyl} cyclopropanecarboxylic acid M433COZH Step I .‘ tert—bulyl 4-methyl—4-({[(IR, 2S)phenylcyclopr0pyl]amino}methyl)piperidine-I - carboxylate A mixture of utyl 4-formylmethylpiperidinecarboxylate (Synnovator, cat#PBN2011767: 2.50 g, 11.0 mmol), acetic acid (0.94 mL, 16 mmol) and (1R,2S) cyclopropanamine (1.54 g, 11.5 mmol) in chloroethane (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 NazSO4, 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 C21H33N202 (M+H)+: m/z = 345.3; found 345.2.
Step 2: tert-butyl yl—4-{[[(IR,2S)phenylcyclopr0pyl](trz'fluoroacetyDamin0]methyl}- pzperidine-I-carb0xylate F30Y0 N Boc -‘\\ : :: Trifluoroacetic anhydride (0.96 mL, 6.8 mmol) was added to a on of tert—butyl 4-methyl({[(1R,2 S)phenylcyclopropyl]amino}methyl)piperidinecarboxylate (1.6 g, 4.5 mmol) and N,N—diisopropylethylamine (1.6 mL, 9.1 mmol) in methylene chloride (25 mL) at 0 0C. The resulting mixture was stirred at room temperature for 1 h then diluted with ene chloride, washed with saturated NaHCO3, water and brine. The organic layer was dried over NazSO4, 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 C19H24F3N203 (M—tBu+2H)+: m/z = 385.2; found 385.2.
Step 3 : 2, 2,2-triflu0r0-N-[(4-methylpzperidiny0methyl]-N-[(IR, 2S)phenylcyclopr0pyl]- ide To a solution of tert-butyl 4-methyl {[[(1R,2S) phenylcyclopropyl](trifluoroacetyl)-amino]methyl}piperidinecarboxylate (1.5 g, 3.4 mmol) in methylene chloride (3 mL) was added hydrogen chloride (4M in 1,4-dioxane, 6 mL, 24 mmol). The resulting e 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 F3NZO (M+H)+: m/z = 341.2; found 341.2.
Step 4: I—{[4-methyl—4-({[(IR,2S)phenylcyclopr0pyl]amin0}methyl)piperidin-I- yUmethyl}cyclopropanecarboxylic acid A mixture of methyl 1-formylcyclopropanecarboxylate (Example 31, Step 8: 10. mg, 0.08 mmol), acetic acid (3.3 uL, 0.059 mmol) and 2,2,2—trifluoro—N—[(4-methylpiperidin—4— hyl]—N—[(1R,2S)phenylcyclopropyl]acetamide (20.0 mg, 0.0588 mmol) in methylene chloride (0.4 mL) was stirred at room temperature for 2 h then sodium triacetoxyborohydride (37 mg, 0.18 mmol) was added. The resulting mixture was stirred at room temperature for 2 h then diluted with methylene chloride, washed with 1 N NaOH, water and brine. The organic layer was dried over NazSO4, filtered and concentrated. The residue was dissolved in MeOH/THF (0.5/0.5 mL) and then NaOH (15 wt % in water, 1.0 mL) was added. The reaction e was stirred at 40 °C ght then cooled to room temperature and purified by prep—HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt.
LC—MS calculated for C21H31N202 (M+H)+: m/z = 343.2; found 343.2.
Example 45 1-{[4-methyl({ [(1R,2S)—2-phenylcyclopr0pyl]amino}methyl)piperidin yl] methyl}cyclobutanecarboxylic acid COZH A mixture of ethyl 1-formylcyclobutanecarboxylate (Example 32, Step I : 27.5 mg, 0.176 mmol), acetic acid (15 ”L, 0.26 mmol) and 2,2,2-trifluoro-N—[(4-methylpiperidin yl)methyl]—N—[(1R,2S)phenylcyclopropyl]acetamide (Example 44, Step 3: 90.0 mg, 0.264 mmol) in methylene de (2 mL) was stirred at room ature for 2 h then sodium triacetoxyborohydride (110 mg, 0.53 mmol) was added. The resulting mixture was stirred at room temperature for 2 h then diluted with methylene chloride, washed with 1 N NaOH, water and brine. The organic layer was dried over NazSO4, d and concentrated.
The residue was dissolved in MeOH/THF (0.5/0.5 mL) then NaOH (15 wt % in water, 1.0 mL) was added. The reaction mixture was stirred at 40 0C for 2 days then cooled to room temperature and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C22H33N202 (M+H)+: m/z = 357.3; found 357.2. 1H NMR (500 MHz, DMSO) 5 7.34 — 7.28 (m, 2H), 7.25 — 7.20 (m, 1H), 7.20 — 7.16 (m, 2H), 3.49 (s, 2H), 3.30 — 3.04 (m, 6H), 3.02 — 2.92 (m, 1H), 2.59 — 2.51 (m, 1H), 2.47 — 2.34 (m, 2H), 2.19 — 2.07 (m, 2H), 2.07 — 1.91 (m, 2H), 1.89 — 1.73 (m, 2H), 1.74 — 1.61 (m, 2H), 1.63 — 1.46 (m, 1H), 1.35 — 1.23 (m, 1H), 1.12 (s, 3H). e 46 (1R,2S)—N-({4—methyl—1-[(l-methyl-lH-pyrazol—3-yl)carb0nyl]piperidin-4—yl}methyl) phenylcyclopropanamine N NifiN/‘N/\ 1—Methyl—1H-pyrazole-3—carbonyl chloride (51 mg, 0.35 mmol) was added to a solution of 2,2,2-trifluoro-N—[(4-methylpiperidinyl)methyl]-N-[(1R,2S) cyclopropyl]acetamide (Example 44, Step 3: 60.0 mg, 0.176 mmol) and triethylamine (98 uL, 0.70 mmol) in methylene chloride (2 mL) at 0 0C. The resulting mixture was stirred for 30 min then concentrated. The residue was dissolved in methanol/THF (0.5 mL/0.5 mL) then 1 N NaOH (1.0 mL) was added. The mixture was d at 40 °C ght then cooled to room temperature and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS ated for C21H29N4O (M+H)+: m/z = 353.2; found 353.3. 1H NMR (500 MHz, DMSO) 5 8.76 (br, 2H), 7.73 (d, J= 2.2 Hz, 1H), 7.35 — 7.26 (m, 2H), 7.25 — 7.12 (m, 3H), 6.49 (d, J= 2.2 Hz, 1H), 4.26 — 4.10 (m, 1H), 4.03 — 3.88 (m, 1H), 3.86 (s, 3H), 3.67 — 3.51 (m, 1H), 3.38 — 3.21 (m, 1H), 3.15 — 3.06 (m, 2H), 3.04 — 2.94 (m, 1H), 2.56 — 2.50 (m, 1H), 1.59 — 1.48 (m, 3H), 1.46 — 1.34 (m, 2H), 1.32 — 1.24 (m, 1H), 1.11 (s, 3H).
Example 47 (1R,2S)—N-({4—methyl—1-[(l-methyl-lH-imidazol—4—yl)carbonyl]piperidin-4—yl}methyl) phenylcyclopropanamine AHVOkm (>9 N\ Triethylamine (31 uL, 0.22 mmol) was added to a solution of 1-methyl-1H-imidazole- 4-carboxylic acid (Combi-Blocks, cat#HI-1090: 11 mg, 0.088 mmol), 2,2,2-trifluoro-N—[(4- methylpiperidin—4—yl)methyl]—N—[(1R,2S)phenylcyclopropyl]acetamide (Example 44, Step 3: 15 mg, 0.044 mmol) and (benzotriazolyloxy)tripyrrolidinophosphonium hexafluorophosphate (46 mg, 0.088 mmol) in N,N—dimethylformamide (0.8 mL). The resulting mixture was stirred at room temperature for 4 h then NaOH (15 wt % in water, 0.5 mL) was added. The on mixture was stirred at 40 0C overnight then cooled to room temperature and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired WO 23465 product as the TFA salt. LC—MS calculated for N4O (M+H)+: m/z = 353.2; found 353.2. e 48 -{[4-methyl—4-({[(1R,2S)—2-phenylcyclopropyl]amino}methyl)piperidin yl] carbonyl}pyrimidin-Z-amine wow/i ©_.\\ N NH2 This compound was prepared using ures ous to those described for Example 47 with 2-aminopyrimidinecarboxylic acid (Ark Pharm, cat#AK-l7303) replacing l-methyl-lH-imidazolecarboxylic acid. 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 C21H28NSO (M+H)+: m/z = 366.2; found 366.2.
Example 49 6-{[4-methyl—4-({[(1R,2S)—2-phenylcyclopropyl]amino}methyl)piperidin yl] carb0nyl}pyridazinamine N ' N A,“ / ©_\\\ N H2 This compound was prepared using procedures analogous to those described for Example 47 with 6-aminopyridazinecarboxylic acid (Chem-Impex, cat#l9l68) replacing l-methyl-lH-imidazolecarboxylic acid. 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 C21H28NSO (M+H)+: m/z = 366.2; found 366.3.
Example 50 4-{[4-methyl—4-({[(1R,2S)—2-phenylcyclopropyl]amino}methyl)piperidinyl]carbonyl}- 1H-pyrazol—3-amine O NH2 ‘\\A»N NH This compound was prepared using procedures analogous to those described for e 47 with 3-amino-lH-pyrazolecarboxylic acid (Aldrich, cat#A77407) replacing l- methyl-lH-imidazolecarboxylic acid. 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 CZOHZSNSO (M+H)+: m/z = 354.2; found 354.2.
Example 51 1-{[4-methyl—4-({ [(1R,2S)—2-phenylcyclopr0pyl]amino}methyl)piperidin yl] carbonyl}cyclopentanamine Triethylamine (l20 uL, 0.88 mmol) was added to a solution of l—[(tert— butoxycarbonyl)amino]cyclopentanecarboxylic acid , cat#03583: 50. mg, 0.22 mmol), 2,2,2-trifluoro-N—[(4-methylpiperidinyl)methyl]-N-[(lR,2S) phenylcyclopropyl]acetamide (Example 44, Step 3: 60. mg, 0.17 mmol) and (benzotriazol—l— yloxy)tripyrrolidinophosphonium hexafluorophosphate (140 mg, 0.26 mmol) in N,N— dimethylformamide (2 mL). The resulting mixture was stirred at room temperature for l h then diluted with ethyl e, washed with saturated , water and brine. The organic layer was dried over NazSO4, filtered and concentrated. The residue was ved in CHzClz (0.3 mL) and then TFA (0.3 mL) was added. The e was stirred at room temperature for l h then concentrated and the residue was dissolved in THF/MeOH (0.2 mL/0.2 mL) and then NaOH (15 wt % in water, 0.5 mL) was added. The mixture was stirred at 35 °C overnight then cooled to room temperature and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS ated for C22H34N3O (M+H)+: m/z = 356.3; found 356.3. 1H NMR (500 MHz, DMSO) 5 8.83 (br, 2H), 8.09 (br, 3H), 7.34 — 7.27 (m, 2H), 7.26 — 7.19 (m, 1H), 7.19 — 7.14 (m, 2H), 3.82 — 3.45 (m, 2H), 3.38 — 3.23 (m, 2H), 3.17 — 3.05 (m, 2H), 3.04 — 2.93 (m, 1H), 2.57 — 2.50 (m, 1H), 2.20 WO 23465 — 2.03 (m, 2H), 2.01 — 1.80 (m, 6H), 1.62 — 1.46 (m, 3H), 1.45 — 1.35 (m, 2H), 1.34 — 1.25 (m, 1H), 1.10 (s, 3H).
Example 52 -{[4-methyl({[(1R,2S)—2-phenylcyclopropyl]amino}methyl)piperidin yl] methyl}pyrimidin-Z-amine QMfiY/im.
A mixture of 2,2,2-trifluoro-N—[(4-methy1piperidiny1)methyl]-N-[(1R,2S) phenylcyclopropyl]acetamide (Example 44, Step 3: 15.0 mg, 0.0441 mmol) and 2— yrimidinecarbaldehyde (Matrix Scientific, cat#008626: 11 mg, 0.092 mmol) in methylene chloride (0.5 mL) was d at room temperature for 1 h then sodium triacetoxyborohydride (28 mg, 0.13 mmol) was added. The resulting mixture was stirred at room temperature for 4 h then concentrated. The residue was dissolved in methanol/THF (0.4/0.4 mL) then NaOH (15 wt % in water, 1.5 mL) was added. The mixture was stirred at 40 °C overnight then cooled to room ature and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS ated for C21H30N5 (M+H)+: m/z = 352.2; found 352.3.
Example 53 1-{[4-[4-(cyan0methyl)benzyl]({[(1R,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] methyl}cyclopropanecarboxylic acid “ACOZH N Step I: I—tert—bulyl 4-methyl 4-[4-(cyanamethyDbenszpzperidine-I,4-dicarb0xylate \ O NC Boc To a solution of N,N—diisopropylamine (1.59 mL, 11.3 mmol) in tetrahydrofuran (55 mL) at -78 0C was added 2.5 M n-butyllithium in hexanes (4.35 mL, 10.9 mmol). This solution was warmed and stirred at 0 °C for 30 min then cooled to —78 OC, and added another solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (2.75 g, 11.3 mmol) in tetrahydrofuran (5.0 mL). The resulting solution was stirred at -45 0C for 1 h, and cooled back to —78 0C before another solution of [4-(chloromethyl)phenyl]acetonitrile (Enamine LTD, cat#EN300—1343 77: 1.50 g, 9.06 mmol) in tetrahydrofuran (5.0 mL) was added. The on mixture was stirred at —78 0C for 1.5 h, quenched with ted NaHCO3 solution, and diluted with EtOAc. The organic layer was separated, washed with brine, dried over NazSO4, and concentrated. The crude material was purified Via column chromatography (25% to 75% EtOAc in hexanes) to give the t (1.31 g, 39 %) as a colorless oil. LC—MS calculated for C17H21N204 (M—tBu+2H)+: m/z = 317.1; found 317.2.
Step 2: tert—bulyl 4-[4-(cyanomethybbensz—él-(hydroxymethybpzperidine-I-carboxylate NC 3 X NBoc To a solution of 1-tert-butyl 4-methyl 4-[4-(cyanomethyl)benzyl]piperidine-1,4- dicarboxylate (1.04 g, 2.79 mmol) in tetrahydrofuran (20 mL) at room temperature was added 2.0 M lithium tetrahydroborate in THF (2.8 mL, 5.6 mmol). The reaction mixture was then stirred at 65 0C for 2 days, cooled to room temperature, and quenched with a saturated NaHCO3 solution. This mixture was ted with EtOAc, and the combined organic layers were washed with brine, dried over NazSO4, and concentrated. The crude material was purified Via column chromatography (0% to 15% MeOH in DCM) to give the t (862 mg, 90%) as a ess oil. LC—MS calculated for C16H21N203 (M—tBu+2H)+: m/z = 289.2; found 289.1.
Step 3 .‘ tert—bulyl 4-[4-(cyanomethyl)bensz—4f0rmylpiperidine-I—carboxylate NC 3 X NBoc To a solution of oxalyl de (0.42 mL, 5.0 mmol) in methylene de (15 mL) at -78 0C was first added yl sulfoxide (0.71 mL, 10. mmol) dropwise. The resulting solution was stirred at -78 0C for 30 min, and then added another solution of tert- butyl 4-[4-(cyanomethyl)benzyl](hydroxymethyl)piperidinecarboxylate (862.8 mg, 2.505 mmol) in methylene chloride (5.0 mL). The reaction mixture was stirred, and warmed to -40 0C for over 1 h, and N,N—diisopropylethylamine (2.6 mL, 15 mmol) was added.
This mixture was further d and warmed to 0 0C over 1 h, and then diluted with DCM, and poured into 1 M HCl. The organic layer was separated, dried over NazSO4, and concentrated. The ing residue was purified via column chromatography (0% to 50% EtOAc in hexanes) to give the product (715 mg, 84%) as a colorless oil. LC—MS calculated for N203 (M—tBu+2H)+: m/z = 287.1; found 287.2.
Step 4: tert—bulyl 4-[4-(cyanomethyl)bensz—4-({[(IR,2S) phenylcyclopropyl]amino}methyl—)piperidine-I-carb0xylate NBoc n‘\\ : :: A mixture of tert-butyl 4-[4-(cyanomethyl)benzyl]formylpiperidine—1-carboxylate (715 mg, 2.087 mmol), acetic acid (178 uL, 3.13 mmol), and (1R,2S)—2— phenylcyclopropanamine (361 mg, 2.71 mmol) in 1,2-dichloroethane (12 mL) was stirred at room temperature for 2 h, and then sodium triacetoxyborohydride (880 mg, 4.2 mmol) was added. The reaction mixture was stirred at room ature overnight then quenched with saturated NaHCO3 on, and diluted with DCM. The organic layer was separated, washed with brine, dried over NazSO4, and concentrated. The crude material was purified via column chromatography (0% to 30% EtOAc in DCM) to give the product (659 mg, 69 %) as colorless oil. LC—MS calculated for C29H38N302 (M+H)+: m/z = 460.3; found 460.3.
Step 5 .‘ tert—bulyl 4-[4-(cyanomethyl)bensz—4-{[[(IR,2S)phenylcyclopr0pyl]- (trifluoroacelyl)amino]methyl}piperidine-I-carb0xylate FchO NBoc To a solution of tert-butyl 4-[4-(cyanomethyl)benzyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinecarboxylate (659 mg, 1.43 mmol) and N,N— diisopropylethylamine (0.75 mL, 4.3 mmol) in methylene chloride (13 mL) at 0 0C was added roacetic anhydride (0.31 mL, 2.2 mmol). The reaction mixture was stirred and slowly warmed to room temperature over 2 h. The resulting e was quenched with saturated NaHCO3 solution, and diluted with DCM. The organic layer was separated, dried over NazSO4, and concentrated. The crude al was purified Via column chromatography (25% to 75% EtOAc in hexanes) to give the product (760 mg, 95 %) as a slightly yellow oil.
LC—MS ated for C27H29F3N3O3 (M—tBu+2H)+: m/z = 500.2; found 500.2.
Step 6: N-({4-[4-(cyan0methyl)benzyl]piperidin-4—yl}methyl)-2, 2,2-triflu0r0-N-[(IR, 2S) phenylcyclopropracetamide hydrochloride F3c\]¢o NH “A’N To a solution of tert-butyl cyanomethyl)benzyl]{[[(1R,2S) phenylcyclopropyl](trifiuoroacetyl)amino]methyl}piperidinecarboxylate (760. mg, 1.37 mmol) in methylene chloride (10 mL) at 0 0C was added 4.0 M hydrogen chloride in 1,4— dioxane (1.7 mL, 6.8 mmol). The reaction mixture was then stirred at room temperature for 1.5 h then concentrated to give the crude product as a slightly yellow solid (HCl salt) which was used in the next step t further purification. LC—MS calculated for C26H29F3N3O : m/z = 456.2; found 456.2.
Step 7.‘ I—tert—butyl I—methyl cyclopropane—I, I—dicarboxylate O O J< To a solution of tert-butyl methyl malonate (7.6 g, 44 mmol) in N,N— dimethylformamide (70. mL) was added 1-bromochloro-ethane (7.2 mL, 87 mmol), potassium carbonate (15 g, 110 mmol) and 1-butyl-3 -methyl-1H-imidazolium tetrafiuoroborate (2 g, 9 mmol). The resulting mixture was stirred at room ature for 48 h then quenched with water and extracted with diethylether. The combined extracts were washed with water and brine. The organic layer was dried over NazSO4, filtered and concentrated. The residue was used in the next step without r purification.
Step 8: I-(tert—but0xycarb0nyl)cyclopropanecarboxylic acid HOJO%LSLOJ< To a solution of 1-tert-butyl 1-methyl cyclopropane-1,1-dicarboxylate (8.6 g, 43 mmol) in tetrahydrofuran (60 mL), methanol (30 mL) and water (30 mL) was added lithium hydroxide, monohydrate (3.6 g, 86 mmol). The mixture was stirred at room temperature for 2 h then concentrated to remove most of the solvents. The residue was dissolved in water and extracted with diethylether. The ether extracts were discarded. The aqueous layer was acidified to pH 2 with cold 6 N HCl aqueous solution, then extract with DCM. The combined extracts were dried over NazSO4, filtered and concentrated under reduced re to afford the desired compound (6.5 g, 81 %), which was used in the next step without further purification.
Step 9: tert—bulyl I-(hydr0xymethyl)cyclopropanecarboxylate HO/Xiok Isobutyl chloroformate (5.9 mL, 45 mmol) was added to a solution of 1-(tertbutoxycarbonyl propanecarboxylic acid (6.5 g, 35 mmol) and triethylamine (9.7 mL, 70. mmol) in tetrahydrofuran (80 mL) at 0 °C. The resulting mixture was stirred at 0 0C for 60 min then filtered and washed with THF (10 mL). The filtrate was cooled to 0 OC and then a on of sodium tetrahydroborate (2.6 g, 70. mmol) in N—methylpyrrolidinone (10 mL) was added. The reaction mixture was stirred at room temperature for 2 h then diluted with ether, washed with saturated NaHCO3 aqueous on, water and brine. The organic layer was dried over NazSO4, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc in hexane (0-15%) to give the d t (4.4 g, 73%). 1H NMR (300 MHz, CDC13) 5 3.56 (s, 2H), 2.39 (br, 1H), 1.44 (s, 9H), 1.23 — 1.14 (m, 2H), 0.84 — 0.75 (m, 2H).
Step 10: tert—butyl lcyclopropanecarboxylate 07XOKOJ< Dimethyl sulfoxide (7.2 mL, 100 mmol) was added to a solution of oxalyl chloride (4.32 mL, 51.1 mmol) in methylene chloride (100 mL) at -78 0C over 10 min. The resulting e was stirred for 10 min at —78 0C then a solution of tert-butyl 1- (hydroxymethyl)cyclopropane-carboxylate (4.4 g, 26 mmol) in methylene de (40 mL) was slowly added. The reaction mixture was stirred at -78 0C for 1 h then N,N— diisopropylethylamine (36 mL, 200 mmol) was added and the e was slowly warmed to room temperature. The on mixture was poured into saturated NaHCO3 aqueous solution and extracted with DCM. The combined extracts were washed with water and brine. The organic layer was dried over NazSO4, filtered and concentrated. The residue was d by flash chromatography on a silica gel column eluting with EtOAc in hexane (0-10%) to give the desired product (3.1 g, 71 %). 1H NMR (400 MHz, CDC13) 5 10.36 (s, 1H), 1.61 — 1.57 (m, 2H), 1.56 — 1.51 (m, 2H), 1.51 (s, 9H).
Step II: tert-butyl I-[(4-[4-(cyanomethyDbensz—4-{[[(IR,2S)phenylcyclopr0pyl]- (trzfluoroacetybamino]methyl}pzperidin-I-yl)methyl]cyclopropanecarboxylate Fch0 /: :COtB2 U \A/N A mixture ofN—( {4-[4-(cyanomethyl)benzyl]piperidinyl}methyl)-2,2,2-trifluoro- N—[(1R,2S)—2—phenylcyclopropyl]acetamide hydrochloride (Step 6: 400.0 mg, 0.8130 mmol), tert-butyl 1-formylcyclopropanecarboxylate (346 mg, 2.03 mmol), and acetic acid (139 uL, 2.44 mmol) in methylene chloride (7.5 mL) was stirred at room temperature for 1.5 h, and then sodium triacetoxyborohydride (431 mg, 2.03 mmol) was added. The on mixture was stirred at room ature overnight. The reaction mixture was quenched with saturated NaHCO3 aqueous solution, and extracted with EtOAc. The combined organic layers were dried over NazSO4 and concentrated. The residue was purified by flash tography on a silica gel column eluting with EtOAc in DCM (0—50%) to give the desired product as a yellow solid. LC—MS calculated for C35H43F3N3O3 (M+H)+: m/z = 610.3; found 610.3.
Step 12: [4-(cyanomethyl)benzyl]({[(IR,2S) phenylcyclopropyl]amin0}methyl)piperidin-I-yl]methyl}cyclopr0panecarb0xylic acid The product from Step II was dissolved in DCM (6 mL) then TFA (3 mL) was added.
The reaction mixture was stirred at room temperature for 1.5 h then concentrated. The residue was dissolved in THF/MeOH (1.0 mL/ 1.0 mL) then 1 M NaOH (1.5 mL) was added. This e was stirred at room temperature for 3.5 h then purified via prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C29H36N302 (M+H)+: m/z = 458.3; found 458.2.
Example 54 1-{[4-[4-(cyan0methyl)benzyl]({[(1R,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] methyl}cyclobutanecarboxylic acid COZH \AzN Q; A e ofN—( {4-[4-(cyanomethyl)benzyl]piperidinyl}methyl)-2,2,2-trifluoro- ,2S)—2-phenylcyclopropyl]acetamide le 53, Step 6: 105 mg, 0.230 mmol), methyl 1-formylcyclobutanecarboxylate (Example 32, Step I: 59.6 uL, 0.461 mmol), and acetic acid (39 uL, 0.69 mmol) in methylene chloride (3.5 mL) was stirred at room temperature for 1.5 h, and then sodium triacetoxyborohydride (122 mg, 0.576 mmol) was added to the reaction mixture. The resultant reaction mixture was stirred at room temperature overnight then quenched with saturated NaHCO3 solution, and extracted with DCM. The combined organic layers were dried over NazSO4, filtered and concentrated in vacuo. The crude material was purified via flash chromatography on a silica gel column (gradient elution, 0 to 5% MeOH in DCM) to give the crude intermediate methyl 1-((4-(4- (cyanomethyl)benzyl)((2,2,2-trifluoro-N—((1R,2S) phenylcyclopropyl)acetamido)methyl)piperidinyl)methyl)cyclobutanecarboxylate as a yellow oil. The intermediate was dissolved in MeOH/THF (1.5 mL/1.5 mL), and then 6 M NaOH (1.5 mL) was added to the reaction mixture. The resultant reaction mixture was d at room temperature for 5 h, then diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C30H38N302 (M+H)+: m/z = 472.3; found 472.3.
Example 55 1-{[4-(4-cyanobenzyl)—4—({[(1R,ZS)phenylcyclopropyl]amino}methyl)piperidin yl] methyl} cyclopropanecarboxylic acid COZH H ”X : N This compound was ed using r procedures as described for Example 53 with obenzyl bromide replacing [4-(chloromethyl)phenyl]acetonitrile. The reaction mixture was d by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C28H34N302 (M+H)+: m/z = 444.3; found 444.3.
Example 56 1-{[4-(3-cyan0benzyl)—4—({ [(1R,2S)—2-phenylcyclopr0pyl]amino}methyl)piperidin yl] methyl} cyclopropanecarboxylic acid H ”XCOZH \A’N 0 ON Step I: tert-butyl 4-(3-br0m0benzyD{[[(IR,2S) phenylcyclopropyl] (trzj’luoroaceZJ/Damino]methyl}piperidine-I-carb0xylate 1:3ch NBOC \A/N E 1'“ Br This compound was prepared using r ures as described for Example 53, Step [-5 with 1—bromo—3—(bromomethyl)benzene replacing [4- (chloromethyl)phenyl]acetonitrile in Step I. LC-MS calculated for BrF3N203 (M- tBu+2H)+: m/z = 539.1; found 539.1.
Step 2: tert-butyl 4-(3-cyan0benzyD{[[(IR,2S) phenylcyclopropyl] (trzj’luoroaceZJ/Damino]methyl}piperidine-I-carb0xylate FchO NBoc \A/N © ON A mixture of tert-butyl 4-(3 -bromobenzyl){[[(1R,2S) phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidine—1—carboxylate (3.57 g, 6.00 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(11) complexed with dichloromethane (1:1) (1.2 g, 1.44 mmol), zinc cyanide (2.25 g, 19.2 mmol), and zinc (392 mg, 6.00 mmol) in DMF (25 mL) was purged with nitrogen then stirred at 140 0C for 5 h.
The reaction e was cooled to room temperature, diluted with EtzO and washed with water. Layers were separated and the organic phase was dried over NazSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on a silica gel column eluting with 20—50% EtOAc/Hexanes to give the d product (2.24 g, 69% yield).
LC—MS calculated for C26H27F3N303 (M—tBu+2H)+: m/z = 486.2; found 486.2.
Step 3 .‘ N-{[4-(3-cyan0benzyl)piperidin-4—yl]methyl}-2,2,2-trzflu0r0-N-[(IR,2S) phenylcyclopropracetamide \JF30 0 G CN 4.0 M Hydrogen de in dioxane (3.97 mL, 15.9 mmol) was added to a solution of utyl 4-(3 -cyanobenzyl)—4- { [[(lR,2 S) phenylcyclopropyl](trifluoroacetyl)amino]methyl}- piperidine-l-carboxylate (1.23 g, 2.27 mmol) in MeOH (5 mL). The resulting solution was stirred at room temperature for l h then concentrated under reduced pressure. The residue was used in the next step without further purification. LC-MS calculated for C25H27F3N3O (M+H)+: m/z = 442.2; found 442.2.
Step 4: I-{[4-(3-cyan0benzyD({[(IR, 2S)phenylcyclopr0pyl]amin0}methyl)piperidin-I- yUmethyl}cyclopropanecarboxylic acid This compound was prepared using similar procedures as bed for Example 53, Step 11-12 starting from N-{[4-(3-cyan0benzy0piperidinyl]methyl}-2,2,2-triflu0r0-N- [(IR, 2S)phenylcyclopropracetamide. The reaction e was purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C28H34N302 : m/z = 444.3; found 444.3.
Example 57 1-{[4-(3-cyan0benzyl)—4—({ [(1R,2S)—2-phenylcyclopr0pyl]amino}methyl)piperidin yl] methyl}cyclobutanecarboxylic acid N/Z ScozH .\\A’ H G. CN 2015/015706 This compound was prepared using similar procedures as described for Example 54 starting from (3-cyan0benzyl)piperidinyl]methyl}-2, 2, u0r0-N-[(IR, 2S) phenylcyclopropyl]acetamide (Example 56, Step 3). The reaction e was purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt.
LC—MS calculated for C29H36N302 (M+H)+: m/z = 458.3; found 458.3.
Example 58 trans{[4-(3-cyan0benzyl)—4—({[(1R,2S)—2-phenylcyclopropyl]amino}methyl)piperidin- 1-yl] methyl} cyclohexanecarboxylic acid ///,l A,“ CL CN Acetic acid (3.6 uL, 0.063 mmol) was added to a on of N—{[4—(3— cyanobenzyl)piperidinyl]methyl}-2,2,2-trifluoro-N—[(lR,2S) phenylcyclopropyl]acetamide hydrochloride (Example 56, Step 3: 15.0 mg, 0.0314 mmol) and methyl transformylcyclohexanecarboxylate (Ark Pharm, cat#AK-50935 : 8.0 mg, 0.047 mmol) in DCM (0.5 mL). Then sodium triacetoxyborohydride (13 mg, 0.063 mmol) was added to the reaction mixture. The resultant reaction mixture was stirred at room temperature for 2 h, then diluted with DCM and washed with water and brine. Layers were ted and the organic phase was dried over , filtered and concentrated in vacuo.
The crude intermediate methyl trans((4-(3-cyanobenzyl)((2,2,2-trifluoro-N—((lR,2S)—2- phenylcyclopropyl)acetamido)methyl)piperidin- l -yl)methyl)cyclohexanecarboxylate was dissolved in MeOH (0.2 mL) and THF (0.2 mL) then 4.0 M sodium hydroxide in water (78. ”L, 0.31 mmol) was added to the reaction mixture. The resultant reaction mixture was stirred at room temperature overnight then diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C31H40N3Oz (M+H)+: m/z = 486.3; found 486.3.
Example 59 3-{[1-(3-methoxybenzyl)—4-({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin yl]methyl}benzoic acid : \©/ HO 0 Step I: tert-butyl 4-[3-(methoxycarbonyl)bensz—4-{[[(IR,2S) phenylcyclopropyl] (trzj’luoroaceZJ/Damino]methyl}piperidine-I-carb0xylate FchO NBoc \Afl‘l 0 O o/ A mixture of tert-butyl 4-(3 -bromobenzyl){[[(1R,2S) phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidinecarboxylate (Example 5 6, Step I: 399 mg, 0.67 mmol), [11- phenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1 :1) (82 mg, 0.10 mmol) and triethylamine (0.18 mL, 1.34 mmol) in methanol (2.50 mL) was refluxed under the positive pressure of carbon monoxide for 7 h. The resulting mixture was cooled to room temperature, diluted with DCM then filtered through a pad of . The filtrate was concentrated in vacuo, and the crude residue was purified by chromatography on silica gel eluting with 15—35% EtOAc/Hexanes to give the desired product 291 mg (75 % yield). LC—MS calculated for C26H30F3N203 [M—Boc+2H]+: m/z = 475.2; found 475.2.
Step 2: methyl 3-[(4-{[[(IR,2S) phenylcyclopropyl] (trzj’luoroaceZJ/Damino]methyl}piperidinyl)methyl]benzoate \A/N 0 © 0/ Hydrogen chloride (3M in MeOH, 1.35 mL, 4.05 mmol) was added to a on of tert-butyl 4- [3 -(methoxycarbonyl)benzyl] { [[(1R,2 S) phenylcyclopropyl](trifluoroacetyl)-amino]methyl}piperidine-l-carboxylate (291 mg, 0.51 mmol) in MeOH (5 mL). The resulting solution was stirred at room temperature for 1 h and then concentrated in vacuo. The crude residue was used in the next step without r purification. LC—MS calculated for C26H30F3N203 [M+H]+: m/z = 475.2; found 475.2.
Step 3 .‘ 3-{[I-(3-meth0xybenzyl)({[(IR, 2S)phenylcyclopropramin0}methyl)piperidin- 4-yl]methyl}benzoic acid Acetic acid (3.1 uL, 0.055 mmol) was added to a solution of methyl 3—[(4—{[[(1R,2S)— 2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidinyl)methyl]benzoate (14 mg, 0.027 mmol) and benzaldehyde, 3—methoxy— (5.01 uL, 0.0411 mmol) in methylene chloride (0.3 mL). Then sodium triacetoxyborohydride (12 mg, 0.055 mmol) was added to the reaction mixture. The resultant reaction mixture was stirred at room temperature for 2 h, then diluted with DCM and washed with water and brine. Layers were separated and the organic phase was dried over NazSO4, filtered and concentrated in vacuo. The ediate methyl 3— -methoxybenzyl)((2,2,2-trifluoro-N—((1R,2S) phenylcyclopropyl)acetamido)methyl)piperidinyl)methyl)benzoate was dissolved in MeOH (0.3 mL) and THF (0.3 mL) then 4.0 M Sodium hydroxide in water (68 uL, 0.27 mmol) was added to the on mixture. The resultant reaction mixture was stirred at room temperature overnight, then diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired t as the TFA salt. LC—MS calculated for C31H37N203 [M+H]+: m/z = 485.3; found 485.3.
Example 60 -{[4-(methoxymethyl)—4—({[(1R,2S)—2-phenylcyclopropyl]amino}methyl)piperidin- 1-yl] carbonyl}pyrrolidinol Afipkgm” ©M‘ OMe Step Irphenyl 4-(meth0xymethyD{[[(IR,2S) phenylcyclopropyl] (trzj’luoroaceZJ/Damino]methyl}piperidine-I-carb0xylate \A/vaFSCYO h ©| Carbonochloridic acid, phenyl ester (45.7 uL, 0.364 mmol) was added to a solution of 2,2,2-trifluoro-N— { [4-(methoxymethyl)piperidinyl]methyl} -N-[(1R,2S)—2- phenylcyclopropyl]acetamide (Example 35, Step 6: 90 mg, 0.24 mmol) and ylamine (0.10 mL, 0.73 mmol) in methylene de (1.0 mL) at 0 0C and the resultant reaction mixture was stirred for 1 h. The reaction mixture was diluted with ethyl acetate, washed with saturated solution of NaHCO3, water and brine. Layers were ted and the organic layer was dried over NazSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel column (gradient elution with 0 to 30 % EtOAc/Hexanes) to give the desired product. LC—MS calculated for C26H30F3N204 : m/z = 491.2; found 491.2.
Step 2: (3R)-I-{[4-(methoxymethyD({[(IR,2S) phenylcyclopropramino}methyl)piperidin-I-yl]carb0nyl}pyrrolidin0] (3R)-pyrrolidinol (16 mg, 0.18 mmol) was added to a solution of phenyl 4- (methoxymethyl)—4- { [[(1R,2S) phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidinecarboxylate (18 mg, 0.037 mmol) and triethylamine (15 uL, 0.11 mmol) in dimethyl sulfoxide (0.5 mL). The resulting mixture was stirred at 135 0C overnight, then cooled to room temperature and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired intermediate trifluoro- N—((1-((R)-3 -hydroxypyrrolidinecarbonyl)(methoxymethyl)piperidinyl)methyl)-N— ((1S,2R)phenylcyclopropyl)acetamide as the TFA salt. The intermediate was dissolved in MeOH/THF (0.2 mL/0.2 mL) and then 6 N NaOH (0.6 mL) was added. The ing mixture was stirred at 30 °C overnight, then cooled to room temperature and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C22H34N3O3 [M+H]+: m/z = 388.3; found 388.2.
Example 61 (3S){[4-(meth0xymethyl)—4-({[(1R,ZS)phenylcyclopropyl]amino}methyl)piperidin- 1-yl] carbonyl}pyrrolidinol AfipAD‘O” ©‘fl‘ OMe This compound was prepared using r procedures as bed for Example 60 with (3 S)-pyrrolidinol replacing (3R)-pyrrolidinol in Step 2. The reaction mixture was purified by prep—HPLC (pH = 2, acetonitrile/water+TFA) to give the desired t as the TFA salt. LC—MS calculated for C22H34N3O3 [M+H]+: m/z = 388.3; found 388.2.
Example 62 4-{[4-(methoxymethyl)—4-({[(1R,2S)—2-phenylcyclopropyl]amino}methyl)piperidin yl]methyl}benzoic acid /\©\ © COZH A mixture of 4-carbomethoxybenzaldehyde (20 mg, 0.12 mmol), acetic acid (5 ”L, 0.088 mmol) and 2,2,2-trifluoro-N—{[4-(methoxymethyl)piperidinyl]methyl}-N-[(1R,2S)— 2—pheny1cyclopropyl]acetamide (Example 35, Step 6: 30.0 mg, 0.0810 mmol) in methylene chloride (0.6 mL) was stirred at room temperature for 2 h and then sodium triacetoxyborohydride (56 mg, 0.26 mmol) was added to the reaction mixture. The resulting reaction mixture was stirred at room temperature overnight. The on mixture was d with methylene chloride, washed with 1N NaOH, water and brine. Layers were separated and the organic layer was dried over NazSO4, filtered and concentrated in vacuo. The crude methyl 4-((4-(methoxymethyl)((2,2,2-trifluoro-N—((1R,2S) phenylcyclopropyl)acetamido)methyl)piperidinyl)methyl)benzoate was ved in MeOH/THF (0.1 mL/0.1 mL) and then 6N NaOH (0.6 mL) was added. The reaction mixture was stirred at 40 0C overnight, then cooled to room temperature and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C25H33N203 [M+H]+: m/z = 409.2; found 409.3.
Example 63 1-{[4-({[(1R,2S)—2-(4-fluorophenyl)cyclopropyl] amino} methyl) (methoxymethyl)piperidin-l-yl] methyl}cyclobutanecarboxylic acid A/va COZH H Q; £2.‘\\ Step I: [4-(meth0xymethyl)pzperidinyl]methanOZ 4.0 M Hydrogen chloride in dioxane (4.0 mL, 16 mmol) was added to a solution of tert-butyl 4-(hydroxymethyl)(methoxymethyl)piperidine—1—carboxylate (Example 35, Step 2: 1.0 g, 3.8 mmol) in ene chloride (0.2 mL). The resulting reaction mixture was stirred at room temperature for 30 min and then concentrated in vacuo. The crude residue was used in the next step without further purification. LC—MS calculated for C8H18NOZ [M+H]+: m/z = 160.1; found 160.2.
Step 2: methyl I-{[4-(hydroxymethyD(methoxymethprzperidin-I- yl}cyclobutanecarboxylate Hope002MBN N,N—Diisopropylethylamine (0.82 mL, 4.71 mmol) was added to a mixture of [4- (methoxymethy1)piperidin—4—y1]methanol (0.50 g, 3.1 mmol) (HCl salt, crude product from Step I) in methylene chloride (20 mL) then methyl 1-formylcyclobutanecarboxylate (0.68 g, 4.8 mmol) was added. The resulting on mixture was stirred at room temperature for 1 h and then sodium triacetoxyborohydride (2.0 g, 9.4 mmol) was added. The reaction mixture mixture was stirred at room temperature overnight, then diluted with methylene chloride, washed with 1N NaOH, water and brine. Layers were separated and the organic layer was dried over NazSO4, filtered and concentrated in vacuo. The product was purified by flash chromtagraphy on a silica gel column (gradient elution with 0 to 10 % HzClz) to give the desired product. LC—MS ated for NO4 [M+H]+: m/z = 286.2; found 286.1.
Step 3 .‘ methyl I-{[4-f0rmyl—4-(methoxymethprzperidin-I-yl]methyl}cyclobutanecarboxylate Ovp 002MB N/Z§ OMe yl sulfoxide (0.28 mL, 4.0 mmol) in methylene chloride (0.4 mL) was added to a solution of oxalyl chloride (0.17 mL, 2.0 mmol) in methylene chloride (0.4 mL) at -78 0C over 10 min. The mixture was warmed to -60 0C over 25 min then a solution of methyl 1- {[4-(hydroxymethyl)(methoxymethyl)piperidinyl]methyl}cyclobutanecarboxylate (0.29 g, 1.0 mmol) in methylene de (0.4 mL) was slowly added and then warmed to —45 0C over 30 min. N,N—Diisopropylethylamine (1.4 mL, 7.9 mmol) was then added and the on mixture was warmed to 0 0C over 15 min. The reaction mixture was poured into cold water and extracted with methylene chloride. The ed extracts were dried over NazSO4, filtered and concentrated in vacuo. The product was purified by flash chromtagraphy on a silica gel column (dragient elution with 0 to 10 % MeOH/CHzClz) to give the desired product. LC—MS calculated for C15H26NO4 [M+H]+: m/z = 284.2; found 284.2.
Step 4: I—{[4-({[(IR,2S)(4-fluor0phenyl)cyclopropramin0}methyZ) (methoxymethybpzperidin-I-yl]methyl}cyclobutanecarb0xylic acid N,N—Diisopropylethylamine (35 uL, 0.20 mmol) was added to a mixture of (1R,2S)- 2-(4-fluorophenyl)cyclopropanamine hydrochloride (Enamine, cat#EN300-189082: 19 mg, 0.10 mmol) in methylene chloride (0.7 mL), followed by the addition of methyl 1-{[4- formyl(methoxymethyl)piperidinyl]methyl}cyclobutanecarboxylate (42 mg, 0.15 mmol). The resulting mixture was d at room temperature for 1 h, then sodium triacetoxyborohydride (69 mg, 0.33 mmol) was added. The mixture was stirred at room temperature overnight then diluted with methylene chloride, washed with 1N NaOH, water and brine. Layers were separated and the organic layer was dried over NazSO4, d and concentrated in vacuo. The intermediate methyl 1-((4—((((1R,2S)—2—(4— fluorophenyl)cyclopropyl)amino)methyl)(methoxymethyl)piperidin yl)methyl)cyclobutanecarboxylate was dissolved in MeOH/THF (0.1mL/0.2mL) then 6N NaOH (0.5 mL) was added. The mixture was stirred at 30 °C overnight, cooled to room temperature and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS ated for C23H34FN203 [M+H]+: m/z = 405.3; found 405.2.
Example 64 1-{[4-({[(1R,2S)—2-(2-fluorophenyl)cyclopropyl] amino} methyl) xymethyl)piperidin-l-yl] methyl}cyclobutanecarboxylic acid COZH F “$vaH Q; This compound was ed using similar procedures as bed for e 63 with (lR,2S)(2—fluorophenyl)cyclopropanamine hydrochloride (Enamine, cat#EN3 00- ) replacing (lR,2S)—2-(4-fluorophenyl)cyclopropanamine hydrochloride in Step 4. 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 C23H34FN203 [M+H]+: m/z = 405.3; found 405.3.
Example 65 1-{[4-({ [(1R,2S)—2-(3,4-difluorophenyl)cyclopropyl]amino}methyl)—4- (methoxymethyl)piperidin-l-yl] methyl}cyclobutanecarboxylic acid COZH H é F A’Nx/p D_\\\ OMe This compound was prepared using similar procedures as described for Example 63 with (lR,2S)(3,4-difluorophenyl)cyclopropanamine hydrochloride (AstaTech, 978) replacing (lR,2S)—2-(4-fluorophenyl)cyclopropanamine hydrochloride in Step 4. The reaction mixture was purified by PLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C23H33F2N203 [M+H]+: m/z = 423.2; found 423.2.
Example 66 1-{[4-(meth0xymethyl)—4-({[2-(2-methoxyphenyl)cyclopropyl]amino}methyl)piperidin yl] methyl}cyclobutanecarboxylic acid Me ZIJEJQECOZH This compound was prepared using similar procedures as described for Example 63 with 2-(2-methoxyphenyl)cyclopropanamine hydrochloride (Enamine, cat#EN3 00- 705 72) ing (lR,2S)—2-(4-fluorophenyl)cyclopropanamine hydrochloride in Step 4. The reaction mixture was purified by prep-HPLC (pH = 2, itrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C24H37N204 [M+H]+: m/z = 417.3; found 417.3.
Example 67 1-{[4—(meth0xymethyl)({[2-(4-methoxyphenyl)cyclopropyl]amino}methyl)piperidin yl] methyl}cyclobutanecarboxylic acid M0NH Q;COZH /©/& OMe This compound was prepared using similar procedures as described for Example 63 with 2-(4-methoxyphenyl)cyclopropanamine hydrochloride (Enamine, cat#EN300- 72215) replacing )—2-(4-fiuorophenyl)cyclopropanamine hydrochloride in Step 4. The reaction e was purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for N204 [M+H]+: m/z = 417.3; found 417.2.
Example 68 1-{[4—(methoxymethyl)(1-{[(1R,2S)—2-phenylcyclopropyl]amino} ethyl)piperidin yl] methyl}cyclobutanecarboxylic acid Mfg COZH H Q; © OMe Step I .‘ tert—bulyl 4—(meth0xymethyl)-4—{[methoxy(methyl)amin0]carb0nyl}pzperidine-I- carboxylate I NBoc O OMe 2.0 M Isopropylmagnesium chloride in THF (3.0 mL, 6.0 mmol) was added to a mixture of l-tert-butyl 4—methyl 4—(methoxymethyl)piperidine-1,4-dicarboxylate (Example , Step I : 0.86 g, 3.0 mmol) and N,O—Dimethylhydroxylamine hydrochloride (0.44 g, 4.5 mmol) in tetrahydrofuran (12 mL) at -30 0C. The resulting e was warmed to 0 0C and stirred at that temperature for 4 h. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3, water and brine. Layers were separated and the organic layer was dried over , filtered and concentrated in vacuo. The t was purified by flash chromtography on a silica gel column (gradient elution with 0 to 30 % EtOAc/CHzClz) to give the desired product (0.8 g, 84%). LC—MS calculated for C10H21N203 [M—Boc+2H]+: m/z = 217.2; found 217.2.
Step 2: tert—bulyl 4-acelyl—4-(methoxymethpriperidine-I—carboxylate YQBOC O OMe Methylmagnesium bromide (3.0 M in l ether, 2.0 mL, 6.0 mmol) was added to a solution of tert—butyl 4-(methoxymethyl){[methoxy(methyl)amino]carbonyl}piperidine carboxylate (0.95 g, 3.0 mmol) in tetrahydrofuran (10 mL) at 0 0C. The e was warmed to room temperature and stirred for 5 h. The e was quenched with saturated solution of NH4Cl, diluted with ethyl e, washed with water and brine. Layers were separated and the organic layer was dried over NazSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (gradient elution with 0 to 30 % EtOAc/Hexane) to give the desired product (0.65 g, 80 %). LC—MS calculated for C9H18N02 [M-Boc+2H]+: m/z = 172.1; found 172.1.
Step 3 .‘ tert—bulyl 4-(methoxymethyD(I-{[(IR,2S)-2— phenylcyclopropyl]amino}ethyl)piperidine-I-carb0xylate NBoc O OMe A mixture of tert-butyl 4-acetyl(methoxymethyl)piperidinecarboxylate (0.27 g, 1.0 mmol), acetic acid (85 uL, 1.5 mmol) and )phenylcyclopropanamine (0.173 g, 1.30 mmol) in methylene chloride (4 mL) was stirred at room temperature for 2 h, then sodium toxyborohydride (0.64 g, 3.0 mmol) was added to the reaction e. The resulting reaction mixture was stirred at room temperature overnight, then diluted with methylene chloride, washed with saturated solution ofNaHCO3, water and brine. Layers were separated and the organic layer was dried over NazSO4, filtered and concentrated in vacuo. The residue was ed by flash chromatography (gradient elution with 0 to 8 % MeOH/CHzClz) to give the desired product. LC—MS calculated for C23H37N203 [M+H]+: m/z = 389.3; found 389.3.
Step 4: tert-butyl 4-(meth0xymethyD{I-[[(IR,2S) phenylcyclopropyl] (trzfluoroacetybamino]ethyl}piperidine-I-carb0xylate FSCYO NBoc O OMe roacetic anhydride (0.065 mL, 0.46 mmol) was added to a solution of tert—butyl 4-(methoxymethyl)(1 - { [( 1 R,2S)phenylcyclopropyl]amino } ethyl)piperidine carboxylate (120 mg, 0.31 mmol) and N,N—diisopropylethylamine (0.16 mL, 0.93 mmol) in methylene chloride (3.0 mL) at 0 0C. The resulting reaction mixture was stirred at room ature for 1 h, then diluted with methylene chloride, washed with saturated solution of , water and brine. Layers were separated and the c layer was dried over NazSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel column (gradient elution with 0 to 20 % EtOAc/Hexane) to give the desired product. LC—MS calculated for C20H28F3N202 [M—Boc+2H]+: m/z = 385.2; found 3 85.1.
Step 5 .‘ 2, 2,2-triflu0r0-N-{I-[4-(methoxymethpriperidinyl]ethyl}-N-[(IR, 2S) phenylcyclopropracetamide 4.0 M Hydrogen chloride in dioxane (0.5 mL, 2 mmol) was added to a on of tert-butyl 4-(methoxymethyl)—4-{ 1 -[[(1R,2S)—2- phenylcyclopropyl](trifluoroacetyl)amino]ethyl}piperidinecarboxylate (80.0 mg, 0.165 mmol) in methylene chloride (0.4 mL). The resultant reaction mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure. The crude residue was used in the next step without further purification. LC—MS calculated for C20H28F3N202 [M+H]+: m/z = 385.2; found 385.1.
Step 6: I-{[4-(meth0xymethyD(I-{[(IR, 2S)phenylcyclopr0pyl]amino}ethyl)pzperidin-I - yl}cyclobutanecarboxylic acid Methyl ylcyclobutanecarboxylate (Example 32, Step I : 22 mg, 0.16 mmol) was added to a mixture of 2,2,2-trifluoro-N— {1-[4-(methoxymethyl)piperidinyl]ethyl}-N- [(1R,2S)phenylcyclopropyl]acetamide (40.0 mg, 0.104 mmol) and N,N— Diisopropylethylamine (27 uL, 0.16 mmol) in methylene chloride (0.8 mL). The ing mixture was stirred at room temperature for 2 h then sodium triacetoxyborohydride (72 mg, 0.34 mmol) was added. The mixture was stirred at room temperature overnight, then diluted with methylene chloride, washed with 1N NaOH, water and brine. Layers were ted and the organic layer was dried over NazSO4, filtered and concentrated in vacuo. The crude intermediate methyl (methoxymethyl)(1-(2,2,2-trifluoro-N-((1R,2 S) phenylcyclopropyl)acetamido)ethyl)-piperidinyl)methyl)cyclobutanecarboxylate was dissolved in MeOH/THF (0.2 mL/0.2 mL) and then 6N NaOH (0.6 mL) was added to the on mixture. The resultant reaction mixture was stirred at 40 0C for 2 days, then cooled to room temperature and purified by prep-HPLC (pH = 2, itrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C24H37N203 [M+H]+: m/z = 401.3; found 401.2.
Example 69 [(6-methoxypyridinyl)methyl] ({[(1R,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] methyl}cyclopropanecarboxylic acid C02H o“ \ N OMe Step I: tert-butyl 4-[(6—chloropyridinyl)methyl]({[(IR,2S) phenylcyclopropyl]amino}methyl)piperidine-I-carb0xylate N Boc ‘\\A»N O \ N CI This compound was prepared using similar procedures as bed for Example 31, Step [-4 with 2-chloro(chloromethyl)pyridine (Aldrich, cat#516910) replacing (x-bromo fluorotoluene in Step I. LC—MS calculated for C26H35C1N302 [M+H]+: m/z = 456.2; found 456.2.
Step 2: tert-butyl 4-({[(allyloxy)carb0nyl][(1R,2S)phenylcyclopr0pyl]amin0}methyZ) [(6-chloropyridinyl)methyl]piperidine-I—carboxylate o 0 Y NBoc \A/N E) \ N/ CI To a on of tert-butyl 4-[(6-chloropyridinyl)methyl]—4-({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinecarboxylate (1.1 g, 2.4 mmol) in methylene chloride (10 mL) was added allyl chloroformate (0.38 mL, 3.6 mmol) and N,N— diisopropylethylamine (0.84 mL, 4.8 mmol). The resulting solution was stirred at room temperature for 1 h and then concentrated in vacuo. The crude residue was ed by flash chromatography on a silica gel column (gradient elution with 0 to 30% EtOAc in hexanes) to afford the desired t. LC—MS calculated for C26H31ClN304 [M-tBu+2H]+: m/z = 484.2; found 484.2.
Step 3 .‘ allyl ({4-[(6—meth0xypyridinyl)methyUpiperidin-él-yl}methyl)[(1R,2S) phenylcyclopropyl]carbamate 0Y0 NH \A/N E) \ N OMe A mixture of tert-butyl 4-({[(allyloxy)carbonyl][(1R,2S)—2- phenylcyclopropyl]amino } methyl) [(6-chloropyridin-3 -yl)methyl]piperidinecarboxylate (350 mg, 0.65 mmol) and sodium methoxide (25 wt% in MeOH, 1.48 mL, 6.48 mmol) in methanol (0.5 mL) was stirred at 80 0C for 6 h. The reaction mixture was cooled to room temperature, then diluted with DCM, washed with water and brine. Layers were separated and the c layer was dried over NazSO4, filtered and concentrated in vacuo.
The residue was purified by flash chromatography on a silica gel column (gradient elution with 0 to 30% EtOAc in hexanes) to afford the desired ediate utyl 4- ((((allyloxy)carbonyl)((1R,2S)phenylcyclopropyl)amino)methyl)((6-methoxypyridin yl)methyl)piperidinecarboxylate. The intermediate was dissolved in DCM (2 mL) then TFA (2 mL) was added. The resulting reaction mixture was stirred at room temperature for 2 h, then concentrated and the crude title product was used in the next step without r purification. LC-MS calculated for C26H34N303 [M+H]+: m/z = 436.3; found 436.2.
Step 4: I-{[4-[(6—meth0xypyridin3/1)methyU—4-({[(IR,2S) phenylcyclopropyl]amin0}methyl)piperidin-I-yl]methyl}cyclopr0panecarb0xylic acid A mixture of tert—butyl l—formylcyclopropanecarboxylate le 53, Step 10: 18 mg, 0.10 mmol), triethylamine (l9 uL, 0.14 mmol) and allyl ({4-[(6-methoxypyridin yl)methyl]piperidinyl} methyl)[(lR,2S)—2—phenylcyclopropyl]carbamate (30 mg, 0.069 mmol) in methylene chloride (0.8 mL) was stirred at room temperature for l h then sodium triacetoxyborohydride (29 mg, 0.14 mmol) was added. The resulting mixture was stirred at room temperature overnight, then d with methylene chloride, washed with saturated solution of NaHCO3, water and brine. Layers were separated and the organic layer was dried over NazSO4, filtered and concentrated in vacuo. The residue was dissolved in THF (2 mL) then tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) and N—ethylethanamine (56 uL, 0.54 mmol) were added. The mixture was purged with nitrogen then stirred at 85 0C for 2 h. The reaction mixture was cooled to room temperature, filtered and trated in vacuo to yield intermediate tert-butyl l-((4-((6-methoxypyridinyl)methyl)((((lR,2S) phenylcyclopropyl)amino)methyl)piperidin- l -yl)methyl)cyclopropanecarboxylate, which was used futher t purification. The intermediate was dissolved in DCM (1 mL), then TFA (1 mL) was added. The mixture was stirred at room temperature for 3 h, then trated in vacuo and the residue was d by prep—HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C27H36N303 [M+H]+: m/z = 450.3; found 450.2.
Example 70 1-{[4-(ethoxymethyl)—4-({[(1R,2S)—2-phenylcyclopropyl]amino}methyl)piperidin yl] methyl} cyclopropanecarboxylic acid @vame This compound was prepared using similar procedures as described for e 35 with omethoxy)-ethane replacing chloromethyl methyl ether in Step I . The reaction mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS ated for C23H35N203 [M+H]+: m/z = 387.3; found 387.2.
Example 71 1-{[4-(ethoxymethyl)({[(1R,2S)—2-phenylcyclopropyl]amino}methyl)piperidin yl] methyl}cyclobutanecarboxylic acid or”?H N/ZECOZH This compound was prepared using similar procedures as described for e 36 with (chloromethoxy)-ethane replacing chloromethyl methyl ether. The reaction mixture was purified with prep—HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C24H37N203 [M+H]+: m/z = 401.3; found 401.2. e 72 1-{[4-[(benzyloxy)methyl]({ [(1R,2S)—2-phenylcyclopropyl] amino}methyl)piperidin yl] methyl} cyclopropanecarboxylic acid This compound was prepared using similar procedures as described for e 31 with benzyl chloromethyl ether replacing (x-bromofluorotoluene in Step I . The mixture was purified with prep—HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C28H37N203 [M+H]+: m/z = 449.3; found 449.3.
Example 73 [(benzyloxy)methyl]({ [(1R,2S)—2-phenylcyclopropyl] amino}methyl)piperidin yl] methyl}cyclobutanecarboxylic acid A,“ N/ZfiokOH This compound was prepared using similar procedures as described for Example 32 with benzyl chloromethyl ether replacing (x-bromofluorotoluene. The mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS ated for C29H39N203 [M+H]+: m/z = 463.3; found 463.3. e 74 1-{[4-(4-cyanoflu0r0benzyl)—4—({[(lR,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] methyl}cyclopropanecarboxylic acid This compound was prepared using similar ures as described for Example 53 with 4-(bromomethyl)-3 -fluorobenzonitrile (AstaTech, cat#54500) replacing [4- (chloromethyl)phenyl]acetonitrile in Step I . The reaction mixture was purified with prep- HPLC (pH = 2, acetonitrile/water+TFA) to give the desired t as the TFA salt. LC—MS calculated for C28H33FN3OZ [M+H]+: m/z = 462.3; found 462.3.
Example 75 [(2-fluorophenoxy)methyl]({ [(lR,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] methyl}cyclopropanecarboxylic acid Step I: I—tert—butyl 4-methyl 4-[(benzyloxy)methyUpzperidine-1,4-dicarb0xylate NBoc O OBn This compound was ed using similar procedures as bed for Example 31, Step I with benzyl chloromethyl ether replacing (x-bromofluorotoluene. LC—MS calculated for C15H22NO3 [M—Boc+2H]+: m/z = 264.2; found 264.2.
Step 2: I—tert-butyl 4-methyl 4-(hydroxymethprzperidine-I,4-dicarb0xylate NBoc O OH Palladium (10wt% on carbon, 880 mg, 0.83 mmol) was added to a solution of 1—tert— butyl 4-methyl 4-[(benzyloxy)methyl]piperidine-1,4-dicarboxylate (2.1 g, 5.8 mmol) in methanol (20 mL). The resulting on mixture was stirred under a ve preassure of hydrogen at room temperature overnight, then filtered through celite and washed with DCM.
The filtrate was concentrated in vacuo and the residue was used in the next step t further purification. LC—MS calculated for C8H16NO3 [M—Boc+2H]+: m/z = 174.1; found 174.2.
Step 3 .‘ I—tert-butyl 4-methyl 4-[(2-flu0r0phen0xy)methyUpiperidine—I,4-dicarb0xylate NBoc To a solution of 1-tert-butyl yl 4-(hydroxymethyl)piperidine-1,4-dicarboxylate (555 mg, 2.03 mmol), 2—f1uoro-phenol (Aldrich, cat#F12804) (0.16 mL, 1.8 mmol) and triphenylphosphine (530 mg, 2.0 mmol) in tetrahydrofuran (4 mL) was added diisopropyl azodicarboxylate (0.40 mL, 2.0 mmol). The resulting reaction mixture was heated to 65 0C and stirred overnight. The on mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography on a silica gel column (gradient elution with 0 to 25 % EtOAc/Hexanes) to give the desired product as a clear oil (524 mg, 77 %). LC—MS calculated for C14H19FNO3 [M—Boc+2H]+: m/z = 268.1; found 268.2.
Step 4: tert-butyl 4-[(2-flu0r0phen0xy)methyU—4-(hydroxymethybpzperidine-I—carboxylate NBoc To a solution of 1-tert-butyl 4-methyl 4-[(2-fluorophenoxy)methyl]piperidine-1,4- dicarboxylate (524 mg, 1.43 mmol) in tetrahydrofuran (1.5 mL) was added 2.0 M lithium tetrahydroborate in THF (1.4 mL, 2.8 mmol). The resulting reaction mixture was heated to 70 0C and d for 6 h. The reaction mixture was cooled to room temperature, quenched with water, diluted with EtOAc, and the organic phase was washed with water and brine. Layers were separated and the organic layer was dried over NazSO4, filtered and concentrated in vacuo. The residue was used in the next step without further purification. LC—MS calculated for C13H19FN02 [M—Boc+2H]+: m/z = 240.1; found 240.2.
Step 5 .‘ 2,2, 2-triflu0r0-N-({4-[(Z-fluorophenoxy)methyUpiperidinyl}methyl)-N-[(IR, 2S) phenylcyclopropracetamide This compound was prepared using similar procedures as described for Example 31, Step 3-6 with utyl 4-[(2-fluorophenoxy)methyl](hydroxymethyl)piperidine carboxylate (from Step 4) ing utyl 4-(4-fluorobenzyl) (hydroxymethyl)piperidine—1—carboxylate in Step 3. LC—MS calculated for C24H27F4N202 [M+H]+: m/z = 451.2; found 451.3.
Step 6: [(2-flu0r0phen0xy)methyU—4—({[(IR,2S) phenylcyclopropyl]amin0}methyl)piperidin-I-yl]methyl}cyclopr0panecarb0xylic acid To a solution of 2,2,2-trifluoro-N—( -fluorophenoxy)methyl]piperidin yl}methyl)-N—[(1R,2S)phenylcyclopropyl]acetamide (31 mg, 0.069 mmol) and tert—butyl 1—formylcyclopropanecarboxylate (Example 53, Step 10: 18 mg, 0.10 mmol) in methylene chloride (0.5 mL) was added acetic acid (4.3 uL, 0.075 mmol). The resultant solution was stirred at room temperature for 2 h, followed by the addition of sodium triacetoxyborohydride (48 mg, 0.23 mmol) to the reaction mixture. The reaction mixture was stirred at room temperature overnight, then diluted with DCM, washed with saturated NaHCO3 solution, water and brine. Layers were separated and the organic layer was dried over NazSO4, filtered and concentrated in vacuo. The crude tert—butyl l—((4-((2-fluorophenoxy)methyl)—4—((2,2,2— trifluoro-N—(( l R,2 S)phenylcyclopropyl)acetamido)methyl)piperidin- l - yl)methyl)cyclopropanecarboxylate was dissolved in DCM (2 mL), then trifluoroacetic acid (0.62 mL) was added. The reaction e was d at room temperature for 1.5 h and then concentrated in vacuo. The crude l—((4—((2—fluorophenoxy)methyl)—4—((2,2,2—trifluoro-N— (( l R,2 S)phenylcyclopropyl)acetamido)methyl)-piperidin- l - yl)methyl)cyclopropanecarboxylic acid was dissolved in MeOH/THF (0.5/0.5 mL) and then lN NaOH (0.75 mL) was added. The resulting reaction mixture was stirred at 50 0C for 4 h, then cooled to room temperature and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired t as the TFA salt. LC-MS calculated for C27H34FN203 [M+H]+: m/z = 453.3; found 453.2. e 76 1-{[4-[(2-flu0rophenoxy)methyl]({ [(lR,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] methyl}cyclobutanecarboxylic acid To a solution of 2,2,2-trifluoro-N—( {4-[(2-fluorophenoxy)methyl]piperidin yl}methyl)—N—[(lR,2S)—2—phenylcyclopropyl]acetamide (Example 75, Step 5: 35 mg, 0.077 mmol) and methyl l-formylcyclobutanecarboxylate (Example 32, Step I : 16 mg, 0. 12 mmol) in ene chloride (0.6 mL) was added acetic acid (4.7 uL, 0.083 mmol). The reaction mixture was stirred at room temperature for 2 h and then sodium toxyborohydride (53 mg, 0.25 mmol) was added. The resultant reaction mixture was stirred at room temperature overnight, then diluted with DCM, washed with saturated NaHCO3 solution, water and brine. Layers were ted and the organic layer was dried over NazSO4, filtered and concentrated in vacuo. The crude methyl l—((4-((2— fluorophenoxy)methyl)((2,2,2-trifluoro-N—((lR,2S) phenylcyclopropyl)acetamido)methyl)piperidin- l -yl)methyl)cyclobutanecarboxylate was dissolved in MeOH (0.5 mL) and THF (0.5 mL) then 6 N NaOH (0.5 mL) was added. The resulting reaction mixture was d at 40 °C ght, then cooled to room temperature and purified by prep—HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C28H36FN203 [M+H]+: m/z = 467.3; found 467.3.
Example 77 1-{[4-[(3-fluorophenoxy)methyl]({ [(lR,ZS) phenylcyclopropyl] methyl)piperidinyl] methyl}cyclopropanecarboxylic acid This compound was prepared using similar ures as described for Example 75 (using 3—fluoro—phenol (Aldrich, cat#Fl3002) to replace 2—fluoro—phenol in Step 3). The mixture was purified with PLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C27H34FN203 [M+H]+: m/z = 453.3; found 453.2.
Example 78 1-{[4-[(3-fluorophenoxy)methyl]({ [(lR,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] methyl}cyclobutanecarboxylic acid This compound was prepared using similar procedures as bed for Example 76 and e 75 (using 3—fluoro—phenol to replace 2—fluoro—phenol in step 3). The mixture was purified with prep—HPLC (pH = 2, acetonitrile/water+TFA) to give the desired t as the TFA salt. LC—MS calculated for C28H36FN203 [M+H]+: m/z = 467.3; found 467.3.
Example 79 1-{[4-[(2-cyanophen0xy)methyl]({[(lR,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] methyl}cyclopropanecarboxylic acid This compound was prepared using similar procedures as described for Example 75 using 2-hydroxybenzonitrile ch, cat#l4103 8) to replace 2-fluoro—phenol in Step 3. The mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C28H34N303 [M+H]+: m/z = 460.3; found 460.3. e 80 1-{[4-[(3-cyanophen0xy)methyl]({[(lR,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] }cyclopropanecarboxylic acid This compound was prepared using similar procedures as described for Example 75 using 3—hydroxybenzonitrile (Aldrich, cat#C93 800) to replace 2—fluoro—phenol in Step 3. The mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C28H34N303 [M+H]+: m/z = 460.3; found 460.3.
Example 81 1-{[4-[(4-cyanophen0xy)methyl]({[(1R,2S)—2- cyclopropyl] amino}methyl)piperidinyl] methyl}cyclopropanecarboxylic acid O“ 0 This compound was prepared using similar procedures as described for Example 75 using 4—hydroxybenzonitrile (Aldrich, cat#C94009) to replace 2—fluoro—phenol in Step 3. The mixture was d with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for N303 [M+H]+: m/z = 460.3; found 460.2. e 82 1-{[4-[(4-cyano-Z-fluor0phenoxy)methyl]({[(1R,2S)—2- phenylcyclopropyl] amino}methyl)piperidinyl] methyl}cyclopropanecarboxylic acid H ”$0” \A/N © 0 This compound was prepared using similar procedures as described for Example 75 using 3—fluoro—4—hydroxybenzonitrile (Oakwood, 3830) to replace 2—fluoro—phenol in Step 3. The mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C28H33FN303 [M+H]+: m/z = 478.3; found 478.2.
Example 83 1-{[4-[(2-cyanophen0xy)methyl]({[(1R,2S)—2- phenylcyclopropyl] amino}methyl)piperidinyl] methyl}cyclobutanecarboxylic acid This compound was prepared using similar procedures as described for Example 76 and Example 75 (using 2-cyanophenol (Aldrich, cat#l4103 8) to replace 2-fluoro-phenol in Step 3). The mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C29H36N303 [M+H]+: m/z = 474.3; found 474.3.
Example 84 1-{[4-[(3-cyanophen0xy)methyl]({[(lR,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] methyl}cyclobutanecarboxylic acid This compound was prepared using similar ures as described for Example 76 and Example 75 (using 3—cyanophenol (Aldrich, cat#C93 800) to replace 2—fluoro—phenol in Step 3). The mixture was d with PLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C29H36N303 : m/z = 474.3; found 474.3.
Example 85 1-{[4-[(4-cyanophen0xy)methyl]({[(lR,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] methyl}cyclobutanecarboxylic acid This compound was prepared using similar procedures as described for Example 76 and Example 75 (using 4—cyanophenol (Aldrich, cat#C94009) to replace 2-fluoro-phenol in Step 3).. The mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C29H36N303 [M+H]+: m/z = 474.3; found 474.3.
Example 86 1-{[4-[(4-cyano-Z-fluor0phenoxy)methyl]({[(1R,ZS) phenylcyclopropyl] methyl)piperidinyl] methyl}cyclobutanecarboxylic acid This compound was prepared using similar ures as described for Example 76 and Example 75 (using 3—fluoro—4—hydroxybenzonitrile (Oakwood, 3830) to replace 2— fluoro—phenol in Step 3). The mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the d product as the TFA salt. LC-MS calculated for C29H35FN3O3 [M+H]+: m/z = 492.3; found 492.3.
Example 87 {[(5-flu0r0pyridinyl)0xy]methyl}({[(1R,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] methyl}cyclopropanecarboxylic acid Step I .‘ I—tert—bulyl 4-methyl 4-f0rmylpzperidine-I,4-dicarb0xylate NBoc O O Dimethyl sulfoxide (2.5 mL, 35 mmol) in methylene chloride (17 mL) was added to a solution of oxalyl chloride (1.5 mL, 17 mmol) in methylene chloride (17 mL) at -78 0C over min and then the on e was warmed to -60 0C over 25 min. 1-tert-Butyl 4- methyl 4-(hydroxymethyl)piperidine-1,4-dicarboxylate (Example 75, Step 2: 2.39 g, 8.74 mmol) in DCM (30 mL) was slowly added and then the reaction mixture was warmed to — 45 0C and stirred at that temperature for 1h. Triethylamine (9.8 mL, 70. mmol) was added and then the reaction mixture was warmed to 0 0C over 1h. The on mixture was quenched with saturated aqueous NaHCO3, and extracted with DCM. The combined organic layers were washed with brine, dried over , filtered and concentrated under reduced pressure to afford the desired crude product which was used in the next step without further purification. LC-MS calculated for C8H14NO3 [M—Boc+2H]+: m/z = 172.1; found 172.2.
Step 2: I—tert—bulyl 4-methyl 4-({[(IR, 2S)phenylcyclopr0pyl]amin0}methyl)piperidine-I, 4- dicarboxylate N Boc (DO?|\\\ A mixture of (1R,2S)phenylcyclopropanamine (1.30 g, 9.79 mmol), -butyl 4— methyl 4-formylpiperidine-1,4-dicarboxylate (2.37 g, 8.74 mmol) and acetic acid (2.0 mL, 35 mmol) in methylene chloride (50 mL) was stirred at room temperature for 4 h, then cooled to room temperature and sodium triacetoxyborohydride (4.1 g, 19 mmol) was added to the reaction mixture. The reaction mixture was d at room temperature for 2h, then quenched with saturated aqueous NaHCO3, and extracted with DCM. The combined organic layers were washed with brine, dried over NazSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with (gradient elution with 0 to 5 % MeOH in DCM) to afford the d product. LC—MS calculated for C22H33N204 [M+H]+: m/z = 389.2; found 389.1.
Step 3 .‘ I—tert-butyl 4-methyl allyloxy)carbonyl][(IR,2S) phenylcyclopropyl]amino}methyl)piperidine-I, 4-dicarb0xylate O O \I// NBoc \A;N © 0 a? Allyl chloroformate (1.4 mL, 13 mmol) was added to a solution of the product from Step 2 and triethylamine (3.0 mL, 22 mmol) in tetrahydrofuran (30 mL) at 0 0C. The on mixture was warmed to room temperature and stirred at that temperature overnight. The reaction mixture was quenched with sat NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over NazSO4, ed and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column (gradient elution with ethyl acetate in hexanes (0—25%)) to afford the d product. LC—MS calculated for C21H29N204 [M—Boc+2H]+: m/z = 373.2; found 373.2.
Step 4: tert-butyl allyloxy)carb0nyl][(1R,2S)phenylcyclopr0pyl]amin0}methyl) (hydroxymethprzperidine-I—carboxylate .\\A’OYQBocN E).
Lithium tetrahydroaluminate (1M in THF, 4.5 mL, 4.5 mmol) was added to a solution of l-tert-butyl 4-methyl 4-({[(allyloxy)carbonyl][(lR,2S)—2- phenylcyclopropyl]amino}methyl)piperidine-l,4-dicarboxylate (2. 13 g, 4.51 mmol) in ydrofuran (40 mL) at -78 0C. The reaction mixture was warmed to -20 0C and stirred at that temperature for 0.5 h. The mixture was quenched with NaHCO3 (aq.), and extracted with ethyl e. The combined organic layers were washed with brine, dried over NazSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column (gradient elution with BA in hexanes (0-40%)) to afford the desired product (1.04 g, 52 %). LC—MS calculated for C20H29N203 [M—Boc+2H]+: m/z = 345.2; found 345.2.
Step 5 .‘ tert—bulyl 4-({[(allyloxy)carb0nyl][(1R,2S)phenylcyclopr0pyl]amin0}methyl) {[(5fluoropyridiny00xy]methyl}piperidine-I-carb0xylate To a solution of tert—butyl 4—({[(allyloxy)carbonyl][(lR,2S)—2— phenylcyclopropyl]amino}methyl)(hydroxymethyl)piperidine-l-carboxylate (208 mg, 0.468 mmol), 5—fluoropyridin—2—ol (Aldrich, cat#753l8l) (106 mg, 0.936 mmol), and triphenylphosphine (245 mg, 0.936 mmol) in toluene (5 mL) at room ature was added diisopropyl azodicarboxylate (0. 19 mL, 0.94 mmol) dropwise. The resulting on mixture was stirred at 50 °C overnight, then concentrated in vacuo. The crude e was purified by flash tography on a silica gel column (dragient elution with 0 to 35% EtOAc in hexanes) to afford the desired t (249 mg, 99 %). LC—MS calculated for C26H31FN305 [M—tBu+2H]+: m/z = 484.2; found 484.2.
Step 6: ally] [(4-{[(5-flu0r0pyridinyl)0xy]methyl}piperidinyl)methyl][(IR,2S) phenylcyclopropyl]carbamate WO 23465 The product from Step 5 was dissolved in ene chloride (2.0 mL) then trifluoroacetic acid (2.0 mL) was added. The resulting reaction mixture was stirred at room temperature for l h then concentrated under reduced pressure. The residue was dissolved in DCM, then neutralized with saturated aqueous NaHCO3 solution. The organic layer was washed with brine then dried over NazSO4, filtered and concentrated in vacuo. The residue was used in the next step without further purification. LC—MS ated for C25H31FN3O3 [M+H]+: m/z = 440.2; found 440.3.
Step 7: I—{[4-{[(5-flu0r0pyridinyl)0xy]methyl}({[(IR,2S) phenylcyclopropyl]amin0}methyl)piperidin-I-yl]methyl}cyclopr0panecarb0xylic acid To a solution of tert—butyl l—formylcyclopropanecarboxylate (Example 53, Step 10: 27 mg, 0.16 mmol), and allyl (5-fluoropyridinyl)oxy]methyl}piperidin yl)methyl][(lR,2S)phenylcyclopropyl]carbamate (47 mg, 0. 11 mmol) in methylene chloride (1 mL) was added acetic acid (6.6 ”L, 0. 12 mmol). The reaction mixture was d at room ature for l h then sodium triacetoxyborohydride (45 mg, 0.21 mmol) was added. The mixture was stirred at room temperature for 2 h, then diluted with methylene chloride, washed with saturated solution ofNaHCOs, water and brine. Layers were separated and the organic layer was dried over NazSO4, filtered and concentrated in vacuo. The crude tert-butyl l-((4-((((allyloxy)carbonyl)(( l R,2S)phenylcyclopropyl)amino)methyl)(((5- fluoropyridin—2—yl)oxy)methyl)piperidin— l —yl)methyl)cyclopropanecarboxylate was dissolved in tetrahydrofuran (2.0 mL), tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) and N—ethylethanamine (0.06 mL, 0.6 mmol) were added. The on mixture was purged with nitrogen, then stirred at 85 0C for 2 h. The reaction mixture was cooled to room temperature, then filtered and concentrated in vacuo. The crude tert—butyl l—((4—(((5— fluoropyridinyl)oxy)methyl)(((( l R,2 S)phenylcyclopropyl)amino)methyl)piperidin- l - yl)methyl)cyclopropanecarboxylate was dissolved in methylene de (1 .5 mL) and trifluoroacetic acid (1 .5 mL) was added. The reaction e was stirred at room ature for l h, then concentrated and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C26H33FN303 [M+H]+: m/z = 454.3; found 454.2.
Example 88 1-{[4-{ [(5-fluoropyrimidin-Z-yl)0xy]methyl}({[(1R,ZS) cyclopropyl] amino}methyl)piperidinyl] methyl}cyclopropanecarboxylic acid This compound was prepared using r procedures as described for Example 87 with 5-fluoropyrimidinol (Aldrich, 6445) ing 5-fluoropyridin—2—ol in Step 5.
The reaction mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C25H32FN4O3 [M+H]+: m/z = 455.2; found 455.3.
Example 89 1-{[4-{[(3-flu0r0pyridinyl)0xy]methyl}-4—({[(1R,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] methyl}cyclopropanecarboxylic acid “A’vaN/fiOH [>3 O F\©N\ I This compound was prepared using similar procedures as described for Example 87 with 3-fluoropyridinol (AstaTech, cat#224l7) replacing 5-fluoropyridinol in Step 5.
The reaction mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired t as the TFA salt. LC—MS calculated for C26H33FN303 [M+H]+: m/z = 454.3; found 454.2.
Example 90 1-{[4-[({6-[(methylamin0)carbonyl] pyridinyl}oxy)methyl] ({[(1R,ZS) phenylcyclopropyl] methyl)piperidinyl] methyl}cyclopropanecarboxylic acid This compound was prepared using similar procedures as described for Example 87 with 5-hydroxy-N—methylpicolinamide (AstaTech, cat#24328) replacing 5-fluoropyridinol in Step 5. The reaction mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C28H37N404 [M+H]+: m/z = 493.3; found 493.3.
Example 91 1-{[4-[({6-[(methylamin0)carbonyl]pyridin-Z-yl}0xy)methyl]({[(1R,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] methyl}cyclopropanecarboxylic acid Step I .‘ 6—hydr0xy-N-methylpicolinamide The mixture of methyl 6-hydroxypyridinecarboxylate (Aldrich, cat#ANV00114: 412 mg, 2.69 mmol) and methylamine (40 wt% in water, 4.0 mL, 36 mmol) was stirred at room temperature for 5 days then concentrated. The residue was used in the next step without further ation. LC—MS calculated for C7H9N202 [M+H]+: m/z = 153.1; found 153.1.
Step 2: I-{[4-[({6—[(methylamin0)carbonyUpyridinyl}0xy)methyU—4-({[(IR,2S) cyclopropyl]amin0}methyl)piperidin-I-yl]methyl}cyclopr0panecarb0xylic acid This compound was prepared ing to the procedures ofExample 87 with 6— hydroxy-N—methylpicolinamide (product from Step 1) ing 5-fluoropyridinol in Step . The reaction mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS ated for N404 [M+H]+: m/z = 493.3; found 493.3.
Example 92 1-{[4-[(cyclobutylmeth0xy)methyl]({[(lR,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] }cyclopropanecarboxylic acid H NXkOH f N Step I: tert-butyl 4—[(benzyloxy)methyU—4-(hydroxymethprzperidine-I—carboxylate NBoc OH Lithium tetrahydroaluminate (1M in THF, 28 mL, 28 mmol) was added to a solution of l-tert-butyl 4-methyl 4-[(benzyloxy)methyl]piperidine-l,4-dicarboxylate (Example 75, Step I : 10.0 g, 27.5 mmol) in tetrahydrofuran (200 mL) at —78 0C. The reaction mixture was warmed to -20 0C and stirred at that temperature for 0.5 h. The reaction mixture was quenched with NaHCO3 (aq.), and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over NazSO4, filtered and concentrated under reduced pressure. The residue was ed by flash chromatography on a silica gel column (gradient n with EtOAc in hexanes (0—40%)) to afford the desired product (4.3 g, 46 %). LC—MS calculated for C14H22N02 [M—Boc+2H]+: m/z = 236.2; found 236.1.
Step 2: tert-butyl 4-[(benzyloxy)methyl][(cyclobutylmeth0xy)methyUpzperidine-I- carboxylate NBoc To a solution of tert-butyl nzyloxy)methyl](hydroxymethyl)piperidine carboxylate (1.0 g, 3.0 mmol) in N,N—dimethylformamide (20 mL) was added NaH (60wt% in mineral oil, 180 mg, 4.5 mmol), the solution was stirred at room temperature for 30 min then (bromomethyl)cyclobutane (Aldrich, cat#441171) (670 uL, 6.0 mmol) was added. The resulting reaction mixture was stirred at 140 0C for 4 days, then cooled to room temperature and quenched with water and extracted with EtOAc. The combined extracts were washed with water and brine. The organic layer was dried over NazSO4, filtered and trated in vacuo. The residue was purified by chromatography on a silica gel column (gradient elution with EtOAc in hexanes (0—20%)) to afford the desired product (130 mg, 11 %). LC—MS calculated for N02 [M—Boc+2H]+: m/z = 304.2; found 304.2.
Step 3 .‘ ulyl 4-[(cyclobulylmeth0xy)methyU—4-(hydroxymethpriperidine-[-carboxylate NBoc To a solution of tert-butyl 4-[(benzyloxy)methyl]—4- [(cyclobutylmethoxy)methyl]piperidinecarboxylate (130 mg, 0.32 mmol) in methanol (4 mL) was added palladium on activated carbon (10 wt%, 30 mg). The on mixture was stirred at room temperature for 2 h under a positive re of hydrogen, then filtered through a pad of celite and concentrated in vacuo. The residue was used in the next step without further purification. LC—MS calculated for N02 [M-Boc+2H]+: m/z = 214.2; found 214.2.
Step 4: tert—bulyl 4-[(cyclobulylmethoxy)methyU—4f0rmylpiperidine-[-carboxylate NBoc Dimethyl sulfoxide (140 uL, 1.9 mmol) was added to a solution of oxalyl chloride (81 uL, 0.96 mmol) in methylene chloride (1 mL) at -78 0C over 5 min and the resulting reaction mixture was stirred for 10 min, then a solution of tert-butyl 4- [(cyclobutylmethoxy)methyl](hydroxymethyl)piperidinecarboxylate (100 mg, 0.32 mmol) in methylene chloride (0.8 mL) was slowly added. The reaction e was d at -75 0C for 60 min, then N,N—diisopropylethylamine (0.67 mL, 3.8 mmol) was added. The reaction mixture was slowly warmed to room temperature, then quenched with ted aqueous NaHCO3 solution and extracted with EtOAc. The combined extracts were washed with water and brine. The organic layer was dried over NazSO4, filtered and trated in vacuo. The residue was used in the next step without further purification. LC—MS calculated for C12H22N02 [M—Boc+2H]+: m/z = 212.2; found 212.1.
Step 5 .‘ tert-butyl 4-[(cyclobutylmeth0xy)methyU—4-({[(IR,2S) phenylcyclopropyl]amino}methyl)piperidine-I-carb0xylate NBoc O O A mixture of tert-butyl clobutylmethoxy)methyl]formylpiperidine-l- carboxylate (crude product from Step 4: 100 mg, 0.32 mmol), acetic acid (27 uL, 0.48 mmol) and (lR,2S)phenylcyclopropanamine (52 mg, 0.38 mmol) in methylene chloride (4 mL) was stirred at room temperature for 1 hour. Then sodium triacetoxyborohydride (140 mg, 0.64 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride, washed with saturated solution of NaHCO3, 1N NaOH, water and brine. The organic layer was dried over NazSO4, filtered and concentrated in vacuo. The residue was used in the next step without further ation. LC-MS calculated for C26H41N203 [M+H]+: m/z = 429.3; found 429.3.
Step 6: ally] ({4-[(cyclobutylmethoxy)methyl]piperidinyl}methyl)[(1R,2S) phenylcyclopropyl]carbamate WO 23465 To a solution of tert-butyl 4-[(cyclobutylmethoxy)methyl]({[(1R,2S)—2- phenylcyclopropyl]amino}methyl)piperidine-l-carboxylate (140 mg, 0.33 mmol) in ene chloride (2 mL) was added allyl chloroformate (69 uL, 0.65 mmol) and N,N— diisopropylethylamine (0.11 mL, 0.65 mmol). The resulting solution was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (gradient elution with EtOAc in hexanes (0- %)) to afford the desired intermediate (tert-butyl 4-((((allyloxy)carbonyl)((lR,2S) phenylcyclopropyl)amino)methyl)((cyclobutylmethoxy)methyl)piperidine- l -carboxylate, 150 mg). The intermediate was dissolved in DCM (1 mL) then TFA (1 mL) was added. The ing e was stirred at room temperature for l h and then concentrated. The residue was used in the next step without further purification. LC-MS calculated for C25H37N203 [M+H]+: m/z = 413.3; found 413.2.
Step 7: I-{[4-[(cyclobulylmeth0xy)methyU—4-({[(IR,2S) cyclopropyl]amin0}methyl)piperidin-I-yl]methyl}cyclopr0panecarb0xylic acid A mixture of tert-butyl l-formylcyclopropanecarboxylate (12 mg, 0.073 mmol), ylamine (l4 uL, 0.097 mmol) and allyl ({4-[(cyclobutylmethoxy)methyl]piperidin yl}methyl)[(lR,2S)—2-phenylcyclopropyl]carbamate (20.0 mg, 0.0485 mmol) in methylene chloride (0.6 mL) was stirred at room temperature for l h then sodium triacetoxyborohydride (20 mg, 0.097 mmol) was added. The reaction mixture was stirred at room temperature overnight, then diluted with methylene chloride, washed with saturated solution ofNaHCO3, water and brine. Layers were separated and the organic layer was dried over NazSO4, filtered and concentrated in vacuo. The crude tert—butyl 1—((4—((((allyloxy)carbonyl)((1R,2S)—2— phenylcyclopropyl)amino)methyl)((cyclobutylmethoxy)methyl)piperidin- l - yl)methyl)cyclopropanecarboxylate was dissolved in THF (2 mL) then tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) and lethanamine (56 uL, 0.54 mmol) were added. The resulting reaction mixture was purged with nitrogen then d at 85 0C for 2 h. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude tert—butyl 1-((4—((cyclobutylmethoxy)methyl)—4—((((1R,2S)— 2-phenylcyclopropyl)amino)methyl)piperidin- l thyl)cyclopropanecarboxylate was dissolved in DCM (1 mL) then TFA (lmL) was added. The mixture was d at room temperature for 3 h and then concentrated. The residue was purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C26H39N203 [M+H]+: m/z = 427.3; found 427.2.
Example 93 1-{[4-[(cyclobutylmethoxy)methyl]({[(lR,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] methyl}cyclobutanecarboxylic acid ©Mam? A mixture of methyl 1-formylcyclobutanecarboxylate (Example 32, Step I : 10 mg, 0.073 mmol), triethylamine (14 uL, 0.097 mmol) and allyl ({4- [(cyclobutylmethoxy)methyl]piperidinyl}methyl)[(1R,2 S)-2—phenylcyclopropyl]carbamate (Example 92, Step 6: 20 mg, 0.049 mmol) in methylene chloride (0.6 mL) was stirred at room temperature for 1 h, then sodium triacetoxyborohydride (20. mg, 0.097 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight, then diluted with methylene chloride, washed with saturated solution ofNaHCO3, water and brine.
Layers were separated and the organic layer was dried over NazSO4, filtered and concentrated in vacuo. The crude methyl 1—((4—((((allyloxy)carbony1)((1R,2S)—2— phenylcyclopropyl)amino)methyl)((cyclobutylmethoxy)methyl)piperidin yl)methyl)cyclobutanecarboxylate was dissolved in THF (2 mL) then tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) and N—ethylethanamine (56 uL, 0.54 mmol) were added. The ing reaction mixture was purged with nitrogen then stirred at 85 0C for 2 h. The mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude methyl 1—((4—((cyclobutylmethoxy)methy1)—4—((((1R,ZS) phenylcyclopropyl)amino)methyl)piperidinyl)methyl)cyclobutanecarboxylate was dissolved in THF (1 mL) and MeOH (1 mL) then lithium hydroxide, monohydrate (20 mg) in water (0.5 mL) was added to the ant solution. The resulting reaction e was stirred at 40 0C for 5 h, then cooled to room ature and d by prep—HPLC (pH = 2, acetonitrile/water+TFA) to give the desired t as the TFA salt. LC—MS calculated for N203 [M+H]+: m/z = 441.3; found 441.3.
Example 94 1-{[4-[(cyclohexyloxy)methyl]({[(1R,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] }cyclopropanecarboxylic acid \A/N : 6) Step I .‘ tert-butyl nzyloxy)methyU—4-(phenoxymethybpiperidine-I—carboxylate NBoc To a solution of tert-butyl 4-[(benzyloxy)methyl](hydroxymethyl)piperidine carboxylate (Example 53, Step I: 450 mg, 1.34 mmol), phenol (252 mg, 2.68 mmol), and triphenylphosphine (704 mg, 2.68 mmol) in toluene (10 mL) at room ature was added diisopropyl azodicarboxylate (560 uL, 2.7 mmol) dropwise. The reaction e was stirred at 65 °C overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (gradient elution with EtOAc in hexanes (0—20%)) to afford the d product (530 mg, 96 %). LC— MS calculated for C20H26N02 [M—Boc+2H]+: m/z = 312.2; found 312.1.
Step 2: tert-butyl 4-[(cyclohexyloxy)methyU—4—(hydroxymethybpzperidine-I—carboxylate NBoc i) To a solution of tert-butyl 4-[(benzyloxy)methyl](phenoxymethyl)piperidine carboxylate (530 mg, 1.3 mmol) in methanol (5 mL) was added palladium (10 wt% on activated carbon, 138 mg, 0.13 mmol). The on mixture was stirred at room temperature for 2h under a positive pressure of hydrogen, then filtered through a pad of celite and concentrated under reduced pressure. The crude tert—butyl 4—(hydroxymethyl)—4— (phenoxymethyl)piperidinecarboxylate was dissolved in MeOH (20 mL), then rhodium (5 wt% on activated carbon, 535 mg, 0.26 mmol) was added to the ant solution. The resulting reaction mixture was stirred at room temperature under 45 psi hydrogen for 3 days.
The mixture was filtered through a pad of celite and trated under reduced pressure.
The crude title product of Step 2 was used in the next step without further purification. LC- MS calculated for NO4 [M—tBu+2H]+: m/z = 272.2; found 272.1.
Step 3: I-{[4-[(cycl0hexyloxy)methyl]({[(IR,2S) phenylcyclopropyl]amin0}methyl)piperidin-I-yl]methyl}cycl0pr0panecarb0xylic acid This compound was prepared using similar procedures as described for Example 92, Step 4-7 starting from tert-batyl 4-[(cycl0hexyl0xy)methyl](hydroxymethprzperidine-I- carboxylate. The reaction mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C27H41N203 : m/z = 441.3; found 441.3.
Example 95 1-{[4-[(cyclohexyloxy)methyl]({[(1R,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] methyl}cyclobutanecarboxylic acid A,“ inOH O. p Step I: allyl cycl0hexyloxy)methyl]piperidinyl}methyl)[(lR,2S) phenylcyclopropyl]carbamate This compound was prepared using r procedures as described for Example 92, Step 4-6 ng from tert-butyl 4-[(cyclohexyloxy)methyl](hydroxymethyl)piperidine-l- carboxylate (Example 94, Step 2) instead of tert-butyl 4-[(cyclobutylmethoxy)methyl] (hydroxymethyl)piperidine-l-carboxylate. LC—MS calculated for C26H39N203 [M+H]+: m/z = 427.3; found 427.3.
WO 23465 Step 2: I-{[4-[(cyclohexyloxy)methyl]({[(IR,2S) phenylcyclopropramino}methpriperidin-I-yl]methyl}cyclobatanecarboxylic acid This compound was prepared using similar procedures as described for Example 93 starting from allyl cyclohexyloxy)methyl]piperidinyl}methyl)[(1R,2S) phenylcyclopropyl]carbamate d of allyl ({4-[(cyclobutylmethoxy)methyl]piperidin yl}methyl)[(1R,2S)—2-phenylcyclopropyl]carbamate. The reaction mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt.
LC—MS calculated for N203 [M+H]+: m/z = 455.3; found 455.3.
Example 96 1-{[4-[(S-fluor0pyridinyl)methyl]({ [(lR,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] methyl}cyclopropanecarboxylic acid (j |\ Step I .‘ (5-fla0r0pyridinyl)methyl methanesulfonate MSOLQF Methanesulfonyl chloride (0.91 mL, 12 mmol) was added to a mixture of (5— fluoropyridinyl)methanol (Pharmablock, cat#PB112906) (1.00 g, 7.87 mmol), and N,N— diisopropylethylamine (2.0 mL, 12 mmol) in ene chloride (20 mL) at 0 0C. The reaction mixture was stirred at room temperature overnight, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column (gradient n with ethyl acetate in hexanes (0—55%)) to afford the d product (0.63 g, 39 %).
LC—MS calculated for O3S [M+H]+: m/z = 206.0; found 206.1.
Step 2: I-{[4-[(5-fla0r0pyridinyl)methyU—4-({[(IR,2S) phenylcyclopropyl]amin0}methyl)piperidin-I-yl]methyl}cyclopr0panecarb0xylic acid This compound was prepared using similar procedures as described for Example 31, with (5-fluoropyridinyl)methyl methanesulfonate replacing a-bromofluorotoluene in Step I = 2, acetonitrile/water+TFA) . The reaction mixture was purified with prep-HPLC (pH WO 23465 to give the desired product as the TFA salt. LC—MS ated for C26H33FN302 [M+H]+: m/z = 438.3; found 438.2.
Example 97 1-{[4-[(S-fluoropyridin-Z-yl)methyl] ({[(1R,ZS) phenylcyclopropyl] methyl)piperidinyl] methyl}cyclobutanecarboxylic acid N OH A/N 6 H E) \ This nd was prepared using similar procedures as described for Example 32 and Example 3], with (5-fluoropyridinyl)methyl methanesulfonate replacing a-bromo fluorotoluene in Step I ofExample 31. The reaction mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C27H35FN302 [M+H]+: m/z = 452.3; found 452.2.
Example 98 1-{[4-(4-meth0xybenzyl)—4-({[(lR,ZS)phenylcyclopropyl]amino}methyl)piperidin yl] methyl} cyclopropanecarboxylic acid This compound was prepared using similar procedures as described for Example 31, with p-methoxybenzyl chloride replacing a-bromofluorotoluene in Step I . The reaction mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C28H37N203 [M+H]+: m/z = 449.3; found 449.2.
Example 99 (4-meth0xybenzyl)—4-({[(lR,ZS)phenylcyclopropyl]amino}methyl)piperidin yl] methyl}cyclobutanecarboxylic acid H : OH This compound was prepared using similar procedures as described for Example 32 and Example 3] with p-methoxybenzyl chloride replacing a-bromofluorotoluene in Step I of Example 31. The reaction mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the d product as the TFA salt. LC-MS calculated for C29H39N203 [M+H]+: m/z = 463.3; found 463.3.
Example 100 (trans{[4—(methoxymethyl)—4-({[(lR,ZS) phenylcyclopropyl] amino}methyl)piperidinyl] carbonyl}cyclohexyl)methanol \A/vaNH iO'W/OH r: ome Benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (33 mg, 0.075 mmol) was added to a mixture of 2,2,2-trifluoro-N—{[4-(methoxymethyl)piperidin yl]methyl}—N—[(lR,2S)—2—phenylcyclopropyl]acetamide (Example 35, Step 6: 20 mg, 0.06 mmol), trans(hydroxymethyl)cyclohexanecarboxylic acid (TCI America, cat#H1243: 13 mg, 0.080 mmol) in acetonitrile (10 mL), followed by the on of triethylamine (26 uL, 0.18 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with ted aqueous NaHCO3, and extracted with ethyl acetate. The ed organic layers were washed with brine, dried over NazSO4, filtered and concentrated under reduced pressure. The crude 2,2,2—trifluoro—N—((l—(4—(hydroxymethyl)— cyclohexanecarbonyl)(methoxymethyl)piperidinyl)methyl)-N—((lR,2S) phenylcyclopropyl)acetamide was dissolved in THF (1 mL) then 2N NaOH (1 mL) was added. The reaction mixture was stirred at 60 0C for 2 h. After cooling to room ature, the organic phase was separated, ied with TFA, and purified by prep- HPLC (pH = 2, acetonitrile/water+TFA) to afford the desired product as TFA salt. LC—MS ated for C25H39N203 [M+H]+: m/z = 415.3; found 415.3. e 101 (cis{[4-(meth0xymethyl)—4-({[(1R,2S)—2-phenylcyclopr0pyl]amin0}methyl)piperidin- l-yl]carbonyl}cyclohexyl)methanol Afivakw Q We This compound was prepared using similar procedures as described for Example 100 with cis(hydroxymethyl)cyclohexanecarboxylic acid (TCI America, cat#H1242) replacing trans(hydroxymethyl)cyclohexanecarboxylic acid. The reaction mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired t as the TFA salt.
LC—MS calculated for C25H39N203 [M+H]+: m/z = 415.3; found 415.3. e 102 1-{[4-(meth0xymethyl)—4-({[(lR,ZS)phenylcyclopropyl]amino}methyl)piperidin yl]carbonyl}cyclopropanecarbonitrile \A/va CN H NJX © OMe This compound was prepared using similar procedures as described for e 100 with ocyclopropanecarboxylic acid (Aldrich, cat#343390) replacing trans—4— (hydroxymethyl)cyclohexanecarboxylic acid. The reaction mixture was purified with prep- HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C22H30N302 [M+H]+: m/z = 368.2; found 368.1.
Example 103 2-(4-{[4-(meth0xymethyl)—4-({ [(lR,ZS)phenylcyclopropyl]amino}methyl)piperidin yl] carbonyl}-1H-pyrazol—1-yl)ethanol “A N \N, ’\’OH © OMe Step I .‘ 2,2, 2-triflu0r0-N-{[4-(meth0xymethyD-I-(IH-pyrazol—4-ylcarb0nyl)piperidin yl]methyl}-N-[(IR, 2S)phenylcyclopr0pyl]acetamide N,N—Diisopropylethylamine (0.59 mL, 3.4 mmol) was added to a mixture of 2,2,2- trifluoro-N— {[4-(methoxymethyl)piperidinyl]methyl} -N-[(1R,2 S) phenylcyclopropyl]acetamide (Example 35, Step 6: 0.50 g, 1.3 mmol), 1H—pyrazole—4— carboxylic acid (Ark Pharm, cat#AK-25877: 0.18 g, 1.6 mmol) and benzotriazol-l- yloxytris(dimethylamino)phosphonium uorophosphate (0.71 g, 1.6 mmol) in acetonitrile (5 mL). The on mixture was stirred at room temperature overnight, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column (gradient elution with 0 to 5 % MeOH in DCM) to afford the desired product. LC—MS calculated for C23H28F3N403 [M+H]+: m/z = 465.2; found 464.9.
Step 2: 2-(4-{[4-(methoxymethyD({[(IR,2S)phenylcyclopr0pyl]amin0}methyl)piperidin- rbonyl}-IH-pyrazol—I—yDethanol A mixture of 2,2,2-trifluoro-N— ethoxymethyl)(1H-pyrazol ylcarbonyl)piperidinyl]methyl}-N-[(1R,2S)phenylcyclopropyl]acetamide (50. mg, 0.11 mmol), 2-Bromoethanol (30 mg, 0.2 mmol), Cesium Carbonate (70. mg, 0.22 mmol) in N,N— dimethylformamide (1.5 mL) was heated at 100 °C overnight. The reaction e was cooled to room temperature then ed with saturated aqueous NaHCO3, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over NazSO4, filtered and concentrated under reduced pressure. The crude trifluoro—N—((1-(1-(2— hydroxyethyl)- 1H-pyrazolecarbonyl)(methoxymethyl)piperidinyl)methyl)-N- ((1R,2S)phenylcyclopropyl)acetamide was dissolved in THF (2 mL) then 2N NaOH (2mL) was added. The reaction mixture was stirred 80 0C for 2h. The reaction mixture was cooled to room temperature, then d with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over NazSO4, filtered and concentrated under reduced pressure. The residue was purified by prep—HPLC (pH = 2, acetonitrile/water+TFA) to give the d product as the TFA salt. LC—MS calculated for C23H33N4O3 [M+H]+: m/z = 413.3; found 413.0.
Example 104 (1R,ZS)-N-{[1-{[1-(2-methoxyethyl)—1H-pyrazol—4—yl]carbonyl} (methoxymethyl)piperidinyl]methyl}phenylcyclopropanamine A» m’ “We © OMe This compound was prepared using similar procedures as described for Example 103 with l-bromomethoxyethane replacing 2-bromoethanol in Step 2. The reaction mixture was purified with prep—HPLC (pH = 2, acetonitrile/water+TFA) to give the desired t as the TFA salt. LC—MS ated for C24H35N4O3 [M+H]+: m/z = 427.3; found 427.0.
Example 105 (1R,2S)—N-({4-(meth0xymethyl)—1-[(l-methyl-1H-pyrazol—4-yl)carb0nyl]piperidin-4— yl} methyl)phenylcyclopropanamine NJEN,/ “A/N \N G OMe This compound was prepared using similar procedures as described for Example 103 with methyl iodide replacing 2-bromoethanol in Step 2. The reaction mixture was purified with prep—HPLC (pH = 2, itrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C22H31N4Oz [M+H]+: m/z = 383.2; found 383.2.
Example 106 3-(4-{[4-(meth0xymethyl)—4-({ S)phenylcyclopropyl]amino}methyl)piperidin yl] carbonyl}-1H-pyrazol—1-yl)propanenitrile H 91fo “\A/N \N' CN © OMe The reaction mixture of 2,2,2-trifluoro-N—{[4-(methoxymethyl)(1H-pyrazol ylcarbonyl)piperidinyl]methyl} -N-[(1R,2 S)phenylcyclopropyl]acetamide (Example 103, Step I : 30. mg, 0.064 mmol) and 2—propenenitrile (4.5 mg, 0.084 mmol) in acetonitrile (1.0 mL) was stirred at 80 0C for 2 days. The on mixture was cooled to room temperature, diluted with water and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over NazSO4, filtered and concentrated under reduced pressure. The crude N—((1—(1—(2—cyanoethyl)—1H—pyrazole-4—carbonyl) (methoxymethyl)piperidinyl)methyl)-2,2,2-trifluoro-N—((1R,2S) phenylcyclopropyl)acetamide was dissolved in MeOH (1 mL) and THF (1 mL) then a on of m hydroxide, monohydrate (0.0083 g, 0.20 mmol) in water (1 mL) was added. The ant reaction e was stirred at 60 °C overnight then cooled to room temperature and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired t as the TFA salt. LC—MS calculated for C24H32N502 [M+H]+: m/z = 422.3; found 422.2.
Example 107 3-(3-{[4—(meth0xymethyl)—4-({ [(lR,ZS)phenylcyclopropyl]amino}methyl)piperidin yl] carbonyl}-1H-pyrazol—1-yl)propanenitrile fi“ \ ’\’CN ©| OMe This compound was prepared using similar procedures as described for Example 106 and Example 103, Step I with 1H-pyrazole-3 -carboxylic acid replacing 1H-pyrazole carboxylic acid in Step I ofExample 103. The reaction mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C24H32N502 [M+H]+: m/z = 422.3; found 422.2.
Example 108 [4—(meth0xymethyl)—4-({ [(lR,ZS)phenylcyclopropyl]amino}methyl)piperidin yl] carbonyl}-1H-pyrazol—1-yl)ethanol H \ XOH ©l OMe This compound was prepared using similar procedures as described for e 103 with 1H-pyrazolecarboxylic acid ing 1H-pyrazolecarboxylic acid. The reaction mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C23H33N4O3 [M+H]+: m/z = 413.3; found 413.2.
Example 109 (3R){[4-(meth0xymethyl)—4—({[(1R,ZS)phenylcyclopropyl]amin0}methyl)piperidin- 1-yl] carbonyl}piperidinol A»00% E)” OMe OH Phosgene (15wt% in toluene, 80 uL, 0.1 mmol) was added to a mixture of 2,2,2— trifluoro-N— {[4-(methoxymethyl)piperidinyl]methyl} -N-[(1R,2 S) phenylcyclopropyl]acetamide (Example 35, Step 6: 30 mg, 0.08 mmol) and ylamine (30 uL, 0.2 mmol) in acetonitrile (1.2 mL) at 0 0C. The resulting reaction mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure. The crude 4— (methoxymethyl)—4-((2,2,2-trifluoro-N—((1R,2S) phenylcyclopropyl)acetamido)methyl)piperidinecarbonyl chloride was dissolved in acetonitrile (1 mL) then (3R)-piperidinol (PharmaBlock, cat#PBOO798: 12 mg, 0.12 mmol) and triethylamine (20 uL, 0.2 mmol) were added. The reaction mixture was stirred at room temperature for 30 min then 2N NaOH (1mL) was added. The reaction mixture was d at 60 0C for 1 h then cooled to room temperature and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C23H36N303 [M+H]+: m/z = 402.3; found 402.3.
Example 110 (3S){[4—(meth0xymethyl)—4—({[(1R,ZS)phenylcyclopropyl]amino}methyl)piperidin- 1-yl] yl}piperidinol Made © OMe 5H This compound was prepared using similar procedures as described for Example 109 with (3 S)—piperidin—3—ol (PharmaBlock, OO799) replacing (3R)-piperidin—3—ol. The on mixture was purified with prep-HPLC (pH = 2, itrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C23H36N303 [M+H]+: m/z = 402.3; found 402.2.
Example 111 1-{[4-(meth0xymethyl)—4-({[(lR,ZS)phenylcyclopropyl]amino}methyl)piperidin yl] carbonyl}azetidinol This compound was prepared using similar procedures as bed for Example 109 with azetidin—3—ol hydrochloride (Oakwood, cat#013898) replacing (3R)—piperidin—3 —01. The reaction mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the d product as the TFA salt. LC—MS calculated for C21H32N3O3 [M+H]+: m/z = 374.2; found 374.2.
Example 112 1-{[4-(meth0xymethyl)—4-({[(lR,ZS)phenylcyclopropyl]amino}methyl)piperidin yl] carbonyl}piperidinol This compound was prepared using similar procedures as described for Example 109 with 4-hydroxypiperidine (Aldrich, cat#128 775) replacing (3R)-piperidinol. The reaction mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for C23H36N303 [M+H]+: m/z = 402.3; found 402.3.
Example 113 (1R,2S)—N-({4—(meth0xymethyl)—1-[(4-methoxypiperidin-l-yl)carb0nyl]piperidin yl} methyl)phenylcyclopropanamine ©.\“A’H\/E\)M: OOMe This compound was prepared using similar procedures as described for Example 109 with 4—methoxypiperidine (Acros Organics, cat#39339) replacing (3R)—piperidin—3—ol. The reaction mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for N303 [M+H]+: m/z = 416.3; found 416.3.
Example 114 )—N-({4—(methoxymethyl)—1-[(1-methyl—1H-pyrazol—4-yl)sulfonyl]piperidin-4— yl} methyl)phenylcyclopropanamine © OMe To a solution of 2,2,2-trifluoro-N—{[4-(methoxymethyl)piperidinyl]methyl}-N- S)—2—phenylcyclopropyl]acetamide (Example 35, Step 6: 30 mg, 0.08 mmol) and N,N— diisopropylethylamine (30 uL, 0.2 mmol) in acetonitrile (1.0 mL) was added l-methyl-lH- pyrazole—4—sulfonyl chloride (ChemBridge, cat#4035233: 18 mg, 0.097 mmol). The reaction mixture was stirred at room temperature for 30 min, then quenched with saturated s NaHCO3, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over NazSO4, filtered and concentrated under d pressure. The crude 2,2,2— trifluoro-N—((4-(methoxymethyl)- l -(( 1 -methyl- 1 H-pyrazolyl)sulfonyl)piperidin yl)methyl)—N—((lR,2S)phenylcyclopropyl)acetamide was dissolved in THF (1 mL) then 1.0 M Sodium hydroxide in water (1 mL, 1 mmol) was added. The reaction mixture was stirred at 80 0C for 1 h, then cooled to room temperature and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for N4O3S [M+H]+: m/z = 419.2; found 419.2.
Example 1 15 (1R,2S)—N-({4—(methoxymethyl)—1-[(1-methyl—1H-pyrazol—S-yl)sulfonyl]piperidin-4— yl} methyl)phenylcyclopropanamine © OMe This compound was prepared using similar procedures as described for Example 114 with 1-methyl-1H-pyrazolesulfonyl chloride (MayBridge, cat#CC62303) replacing 1— methyl-1H-pyrazolesulfonyl de. The on mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC—MS calculated for N4O3S [M+H]+: m/z = 419.2; found 419.2.
Example 1 16 (1R,2S)—N-({4—(methoxymethyl)—1-[(1-methyl—1H-pyrazol—3-yl)sulfonyl]piperidin-4— yl} )phenylcyclopropanamine E:A“ OMe This compound was ed using similar procedures as described for Example 114 with 1-methyl-1H-pyrazolesulfonyl chloride (MayBridge, cat#CC48303) replacing 1— methyl-1H-pyrazolesulfonyl chloride. The reaction mixture was purified with prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired t as the TFA salt. LC—MS calculated for C21H31N4O3S [M+H]+: m/z = 419.2; found 419.1.
Example A: LSDl histone demethylase biochemical assay LANCE LSDl/KDMlA demethylase assay- 10 uL of 1 nM LSD-l enzyme (ENZO BML—SE544—0050) in the assay buffer (50 mM Tris, pH 7.5, 0.01% Tween—20, 25 mM NaCl, mM DTT) were ubated for 1 hour at 25°C with 0.8 “L nd/DMSO dotted in black 384 well polystyrene plates. Reactions were started by addition of 10 “L of assay buffer containing 0.4 uM Biotin-labeled Histone H3 peptide substrate: ART-K(Mel)— QTARKSTGGKAPRKQLA-GGK(Biotin) SEQ ID NO:1 (AnaSpec 64355) and incubated for 1 hour at 25°C. Reactions were stopped by on of 10 uL 1X LANCE Detection Buffer (PerkinElmer CR97-100) supplemented with 1.5 nM Eu-anti-unmodif1ed H3K4 Antibody (PerkinElmer TRF0404), and 225 nM LANCE Ultra Streptavidin (PerkinElmer TRF102) along with 0.9 mM Tranylcypromine-HCl (Millipore 616431). After stopping the ons plates were incubated for 30 minutes and read on a PHERAstar FS plate reader (BMG Labtech). Compounds having an ICso of 1 HM or less were considered . ICso data for the example compounds is provided in Table l (+ refers to ICso S 100 nM; ++ refers to ICso > 100 nM and S 500 nM).
Table 1 Example N0. IC50 (nM) NNNNNNl—‘l—‘l—‘l—‘fi—‘fi—‘b—‘fi—‘t—tt—tU1#WNHoooouoUI—bmmHoooouommet—l || 2015/015706 Example N0. 2015/015706 Example N0.
Various ations 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 ations, cited in the present application is incorporated herein by reference in its entirety.

Claims (71)

The Claims ng the invention are as follows:
1. A compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein: X is -CH2- or -CH2-CH2-; Y is -CH2- or -CH2-CH2-; 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 C6-10 aryl or 5-10 membered heteroaryl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S; ring C is C3-7 cycloalkyl; L is C1-4 alkylene, -C(=O)-, O-, -C(=O)NR7-, O, NR7, -S(O)2-, -S(O)-, or -S(O)2NR7-; 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 ed heteroaryl, 4-10 ed heterocycloalkyl, C6-10 aryl-C1-4 , 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)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, 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 aryl, 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 ndently 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(=NR e)NR cRd, NRcC(=NR e)NR cRd, NRcRd, NRcC(O)R b, NRcC(O)OR a, NRcC(O)NR cRd, NR cS(O)R b, NRcS(O) b, NRcS(O) cRd, S(O)Rb, cRd, S(O) b, and S(O) cRd; 2R 2NR 2R 2NR RZ 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, ORa1 , SRa1 , 1 , C(O)NRc1 Rd1 , OC(O)Rb1 , OC(O)NR c1 Rd1 , NRc1 Rd1 , NRc1 C(O)R b1 , NRc1 C(O)OR a1 , NRc1 C(O)NR c1 Rd1 , C(=NRe1 )R b1 , C(=NR e1 )NR c1 Rd1 , NRc1 C(=NR e1 )NR c1 Rd1 , NRc1 S(O)R b1 , NRc1 S(O) b1 , NRc1 S(O) c1 Rd1 , 2R 2NR S(O)R b1 , S(O)NRc1 Rd1 , S(O) b1 , or S(O) c1 Rd1 , wherein said C 2R 2NR 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 ed heterocycloalkyl, C6-10 aryl-C1-4 , C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 , and (4- 10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, or 4 substituents ndently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, NO a1 , SRa1 , C(O)Rb1 , C(O)NRc1 Rd1 , C(O)ORa1 , OC(O)Rb1 , OC(O)NRc1 Rd1 , 2, OR C(=NR e1 )NR c1 Rd1 , NRc1 C(=NR e1 )NR c1 Rd1 , NRc1 Rd1 , NRc1 C(O)R b1 , NRc1 C(O)OR a1 , NR c1 C(O)NR c1 Rd1 , NRc1 S(O)R b1 , NRc1 S(O) b1 , NRc1 S(O) c1 Rd1 , S(O)Rb1 , S(O)NRc1 Rd1 , 2R 2NR S(O) 2Rb1 , and S(O)2NR c1 Rd1 ; each R2 is ndently selected from halo, C1-6 alkyl, CN, ORa5 , C(O)Rb5 , C(O)NR c5 Rd5 , C(O)ORa5 , NRc5 Rd5 , S(O)Rb5 , S(O)NRc5 Rd5 , S(O) b5 , and S(O) c5 Rd5 , 2R 2NR wherein said C1-6 alkyl is ally substituted with 1, 2, or 3 substituents independently selected from halo, CN, ORa5 , SRa5 , C(O)Rb5 , C(O)NRc5 Rd5 , a5 , OC(O)Rb5 , OC(O)NRc5 Rd5 , C(=NR e5 )NR c5 Rd5 , NRc5 C(=NR e5 )NR c5 Rd5 , NRc5 Rd5 , NRc5 C(O)R b5 , NRc5 C(O)OR a5 , NR c5 C(O)NR c5 Rd5 , NRc5 S(O)R b5 , NRc5 S(O) b5 , NRc5 S(O) c5 Rd5 , S(O)Rb5 , S(O)NRc5 Rd5 , 2R 2NR S(O) 2Rb5 , and S(O)2NR c5 Rd5 ; 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 , SRa2 , C(O)Rb2 , C(O)NR c2 Rd2 , C(O)ORa2 , b2 , OC(O)NRc2 Rd2 , NRc2 Rd2 , NRc2 C(O)R b2 , NRc2 C(O)OR a2 , NR c2 C(O)NR c2 Rd2 , C(=NRe2 )R b2 , C(=NRe2 )NR c2 Rd2 , NRc2 C(=NR e2 )NR c2 Rd2 , NRc2 S(O)R b2 , NR c2 S(O) b2 , NRc2 S(O) c2 Rd2 , S(O)Rb2 , S(O)NRc2 Rd2 , S(O) b2 , and S(O) c2 Rd2 , 2R 2NR 2R 2NR 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 ed aryl)-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)NRc2 Rd2 , C(O)ORa2 , OC(O)R b2 , Rc2 Rd2 , C(=NRe2 )NR c2 Rd2 , NRc2 C(=NR e2 )NR c2 Rd2 , NRc2 Rd2 , NRc2 C(O)R b2 , NR c2 C(O)OR a2 , NRc2 C(O)NR c2 Rd2 , NRc2 S(O)R b2 , NRc2 S(O) b2 , NRc2 S(O) c2 Rd2 , S(O)Rb2 , 2R 2NR S(O)NR c2 Rd2 , S(O) b2 , and S(O) c2 Rd2 ; 2R 2NR R4 is halo, C1-6 alkyl, C2-6 l, 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 , (4-10 membered heterocycloalkyl)-C1-4 , CN, NO2, ORa3 , SRa3 , C(O)Rb3 , C(O)NRc3 Rd3 , a3 , OC(O)R b3 , OC(O)NRc3 Rd3 , NRc3 Rd3 , NRc3 C(O)R b3 , NRc3 C(O)OR a3 , NRc3 C(O)NR c3 Rd3 , C(=NR e3 )R b3 , C(=NRe3 )NR c3 Rd3 , NRc3 C(=NR e3 )NR c3 Rd3 , NRc3 S(O)R b3 , NRc3 S(O) b3 , NR c3 S(O) c3 Rd3 , S(O)Rb3 , S(O)NRc3 Rd3 , S(O) b3 , and S(O) c3 Rd3 , 2NR 2R 2NR 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 ed heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, or 4 substituents ndently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, NO2, ORa3 , SRa3 , C(O)Rb3 , C(O)NRc3 Rd3 , C(O)ORa3 , OC(O)Rb3 , OC(O)NR c3 Rd3 , C(=NRe3 )NR c3 Rd3 , NRc3 C(=NR e3 )NR c3 Rd3 , NRc3 Rd3 , NRc3 C(O)R b3 , NR c3 C(O)OR a3 , NRc3 C(O)NR c3 Rd3 , NRc3 S(O)R b3 , NRc3 S(O) b3 , NRc3 S(O) c3 Rd3 , S(O)Rb3 , 2R 2NR S(O)NR c3 Rd3 , S(O) b3 , and S(O) c3 Rd3 ; 2R 2NR R5 is H; R6 is independently selected from H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, and –(C1-4 alkyl)-OR a4 ; R7 is H , C1-4 alkyl or C1-4 haloalkyl; each Ra, Rb, Rc, Rd, Ra1 , Rb1 , Rc1 , Rd1 , Ra2 , Rb2 , Rc2 , Rd2 , Ra3 , Rb3 , Rc3 , and Rd3 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 ed 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 aryl, 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, ORa4 , SRa4 , C(O)R b4 , C(O)NRc4 Rd4 , C(O)ORa4 , OC(O)Rb4 , OC(O)NRc4 Rd4 , NRc4 Rd4 , NRc4 C(O)R b4 , NR c4 C(O)NR c4 Rd4 , NRc4 C(O)OR a4 , C(=NRe4 )NR c4 Rd4 , NRc4 C(=NR e4 )NR c4 Rd4 , S(O)Rb4 , S(O)NR c4 Rd4 , S(O) b4 , NRc4 S(O) b4 , NRc4 S(O) c4 Rd4 , and S(O) c4 Rd4 ; 2R 2R 2NR 2NR 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 ndently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 kyl, halo, CN, ORa4 , SRa4 , C(O)Rb4 , C(O)NRc4 Rd4 , C(O)OR a4 , OC(O)Rb4 , OC(O)NRc4 Rd4 , NRc4 Rd4 , NRc4 C(O)R b4 , NRc4 C(O)NR c4 Rd4 , NR c4 C(O)OR a4 , C(=NRe4 )NR c4 Rd4 , NRc4 C(=NR e4 )NR c4 Rd4 , 4 , S(O)NRc4 Rd4 , S(O) b4 , NR c4 S(O) b4 , NRc4 S(O) c4 Rd4 , and S(O) c4 Rd4 , n said C 2R 2NR 2NR 1-6 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, ORa4 , SRa4 , C(O)Rb4 , C(O)NRc4 Rd4 , C(O)ORa4 , OC(O)Rb4 , OC(O)NRc4 Rd4 , NR c4 Rd4 , NRc4 C(O)R b4 , NRc4 C(O)NR c4 Rd4 , NRc4 C(O)OR a4 , C(=NRe4 )NR c4 Rd4 , NR c4 C(=NR e4 )NR c4 Rd4 , 4 , c4 Rd4 , S(O) b4 , NRc4 S(O) b4 , NRc4 S(O) c4 Rd4 , 2R 2R 2NR and S(O)2NR c4 Rd4 ; or any Rc1 and Rd1 er 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 ed from C1-6 alkyl, C3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C6-10 aryl, 5-6 ed heteroaryl, C1-6 haloalkyl, halo, CN, ORa4 , SRa4 , C(O)Rb4 , C(O)NRc4 Rd4 , C(O)OR a4 , OC(O)Rb4 , OC(O)NRc4 Rd4 , NRc4 Rd4 , NRc4 C(O)R b4 , NRc4 C(O)NR c4 Rd4 , NR c4 C(O)OR a4 , C(=NRe4 )NR c4 Rd4 , NRc4 C(=NR e4 )NR c4 Rd4 , S(O)Rb4 , S(O)NRc4 Rd4 , S(O) b4 , NR c4 S(O) b4 , NRc4 S(O) c4 Rd4 , and S(O) c4 Rd4 , wherein said C 2R 2NR 2NR 1-6 alkyl, C3-7 lkyl, 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, ORa4 , SRa4 , C(O)Rb4 , C(O)NRc4 Rd4 , C(O)ORa4 , OC(O)Rb4 , OC(O)NRc4 Rd4 , NR c4 Rd4 , NRc4 C(O)R b4 , NRc4 C(O)NR c4 Rd4 , NRc4 C(O)OR a4 , C(=NRe4 )NR c4 Rd4 , NR c4 C(=NR e4 )NR c4 Rd4 , S(O)Rb4 , S(O)NRc4 Rd4 , S(O) b4 , NRc4 S(O) b4 , NRc4 S(O) c4 Rd4 , 2R 2R 2NR and R c4 Rd4 ; 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 ndently 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, ORa4 , SRa4 , 4 , C(O)NRc4 Rd4 , C(O)OR a4 , OC(O)Rb4 , OC(O)NRc4 Rd4 , NRc4 Rd4 , NRc4 C(O)R b4 , NRc4 C(O)NR c4 Rd4 , NR c4 C(O)OR a4 , C(=NRe4 )NR c4 Rd4 , NRc4 C(=NR e4 )NR c4 Rd4 , S(O)Rb4 , S(O)NRc4 Rd4 , S(O) b4 , NR c4 S(O) b4 , NRc4 S(O) c4 Rd4 , and S(O) c4 Rd4 , wherein said C 2R 2NR 2NR 1-6 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, ORa4 , SRa4 , C(O)Rb4 , C(O)NRc4 Rd4 , C(O)ORa4 , OC(O)Rb4 , OC(O)NRc4 Rd4 , NR c4 Rd4 , NRc4 C(O)R b4 , NRc4 C(O)NR c4 Rd4 , NRc4 C(O)OR a4 , C(=NRe4 )NR c4 Rd4 , NR c4 C(=NR e4 )NR c4 Rd4 , 4 , S(O)NRc4 Rd4 , S(O) b4 , NRc4 S(O) b4 , NRc4 S(O) c4 Rd4 , 2R 2R 2NR and S(O)2NR c4 Rd4 ; 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 lkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered aryl, C1-6 haloalkyl, halo, CN, ORa4 , SRa4 , C(O)Rb4 , C(O)NRc4 Rd4 , C(O)OR a4 , OC(O)Rb4 , OC(O)NRc4 Rd4 , NRc4 Rd4 , NRc4 C(O)R b4 , NRc4 C(O)NR c4 Rd4 , NR c4 C(O)OR a4 , C(=NRe4 )NR c4 Rd4 , NRc4 C(=NR e4 )NR c4 Rd4 , S(O)Rb4 , S(O)NRc4 Rd4 , S(O) b4 , NR c4 S(O) b4 , NRc4 S(O) c4 Rd4 , and S(O) c4 Rd4 , wherein said C 2R 2NR 2NR 1-6 alkyl, C3-7 cycloalkyl, 4- 7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered aryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa4 , SRa4 , C(O)Rb4 , C(O)NRc4 Rd4 , C(O)ORa4 , OC(O)Rb4 , OC(O)NRc4 Rd4 , NR c4 Rd4 , NRc4 C(O)R b4 , NRc4 C(O)NR c4 Rd4 , NRc4 C(O)OR a4 , C(=NRe4 )NR c4 Rd4 , NR c4 C(=NR e4 )NR c4 Rd4 , S(O)Rb4 , c4 Rd4 , S(O) b4 , NRc4 S(O) b4 , NRc4 S(O) c4 Rd4 , 2R 2R 2NR and R c4 Rd4 ; each Ra4 , Rb4 , Rc4 , and Rd4 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 ally tuted 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; or any Rc4 and Rd4 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-4 haloalkyl, and C1-4 haloalkoxy; each Re, Re1 , Re2 , Re3 , Re4 , and Re5 is independently ed from H, C1-4 alkyl, and CN; each Ra5 , Rb5 , Rc5 , and Rd5 is independently selected from H and C1-6 alkyl ally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, ORa6 , SRa6 , C(O)R b6 , C(O)NRc6 Rd6 , C(O)ORa6 , OC(O)Rb6 , OC(O)NRc6 Rd6 , NRc6 Rd6 , NRc6 C(O)R b6 , NR c6 C(O)NR c6 Rd6 , NRc6 C(O)OR a6 , C(=NRe6 )NR c6 Rd6 , NRc6 C(=NR e6 )NR c6 Rd6 , S(O)Rb6 , S(O)NR c6 Rd6 , S(O) b6 , NRc6 S(O b6 , NRc6 S(O) c6 Rd6 , and S(O) c6 Rd6 ; 2R 2R 2NR 2NR each Ra6 , Rb6 , Rc6 , and Rd6 is independently selected from H, C1-4 alkyl, C1-4 haloalkyl, C2- 4 alkenyl, and C2-4 l, 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; each Re6 is ndently 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, 1, or 2.
2. The compound of claim 1 having Formula IIIa or IIIb: IIIa IIIb or a pharmaceutically acceptable salt thereof, wherein: each R2 is substituted on any ring-forming carbon atom of the azetidine ring depicted in Formula IIIa or the piperidine ring depicted in Formula IIIb except the ring-forming carbon atom to which RZ is .
3. The compound of claim 1 or claim 2, having Formula IIIa: IIIa or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 or claim 2, having Formula IIIb: IIIb or a pharmaceutically acceptable salt thereof.
5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein q is 0.
6. The nd of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein q is 1.
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt f, wherein ring A is phenyl.
8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein n is 0.
9. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein n is 1.
10. The compound of any one of claims 1 to 7, or a pharmaceutically able salt thereof, wherein n is 2.
11. The nd of any one of claims 1 to 10, or a ceutically acceptable salt thereof, wherein each R1 is independently selected from halo and -6 alkyl).
12. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein each R1 is independently selected from F and methoxy.
13. The nd of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R6 is H.
14. The nd of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R6 is independently selected from H and C1-4 alkyl.
15. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R6 is methyl.
16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein L is -(CH2)r-, -C(=O)-, -C(=O)NR7-, or -S(O)2-, wherein r is 1, 2, 3, or 4.
17. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein L is -CH2-, -C(=O)-, -C(=O)NH-, or -S(O)2-.
18. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein L is -CH2-.
19. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein L is -C(=O)-.
20. The compound of any one of claims 1 to 15, or a pharmaceutically able salt thereof, wherein L is -S(O)2-.
21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt f, wherein ring C is entyl.
22. The compound of any one of claims 1 to 20, or a ceutically acceptable salt thereof, wherein ring C is cyclobutyl.
23. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein ring C is ropyl.
24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R4 is C1-6 alkyl, halo, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, CN, ORa3 , NR c3 Rd3 , or C(O)ORa3 , wherein said C1-6 alkyl, C6-10 aryl, and C3-10 cycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1-4 kyl, C1-4 cyanoalkyl, CN, NO2, ORa3 , SRa3 , C(O)Rb3 , C(O)NRc3 Rd3 , C(O)ORa3 , OC(O)R b3 , OC(O)NRc3 Rd3 , C(=NRe3 )NR c3 Rd3 , NRc3 C(=NR e3 )NR c3 Rd3 , NRc3 Rd3 , NRc3 C(O)R b3 , NR c3 C(O)OR a3 , NRc3 C(O)NR c3 Rd3 , NRc3 S(O)R b3 , NRc3 S(O) b3 , NRc3 S(O) c3 Rd3 , S(O)Rb3 , 2R 2NR S(O)NR c3 Rd3 , S(O) b3 , and S(O) c3 Rd3 . 2R 2NR
25. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R4 is halo, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, CN, ORa3 , or C(O)ORa3 , wherein said C6-10 aryl and C3-10 cycloalkyl are each ally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, NO a3 , SRa3 , C(O)Rb3 , C(O)NRc3 Rd3 , C(O)ORa3 , OC(O)Rb3 , OC(O)NRc3 Rd3 , 2, OR C(=NR e3 )NR c3 Rd3 , NRc3 C(=NR e3 )NR c3 Rd3 , NRc3 Rd3 , NRc3 C(O)R b3 , NRc3 C(O)OR a3 , NR c3 C(O)NR c3 Rd3 , NRc3 S(O)R b3 , NRc3 S(O) b3 , NRc3 S(O) c3 Rd3 , S(O)Rb3 , S(O)NRc3 Rd3 , 2R 2NR S(O) 2Rb3 , and S(O)2NR c3 Rd3 .
26. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, n R4 is C(O)ORa3 .
27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein each R3 is independently selected from halo, C1-6 kyl, C6-10 aryl, C3-10 cycloalkyl, CN, ORa2 , and C(O)ORa2 , wherein said C6-10 aryl and C3-10 cycloalkyl 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)NRc2 Rd2 , C(O)ORa2 , OC(O)R b2 , OC(O)NRc2 Rd2 , C(=NRe2 )NR c2 Rd2 , NRc2 C(=NR e2 )NR c2 Rd2 , NRc2 Rd2 , NRc2 C(O)R b2 , NR c2 C(O)OR a2 , NRc2 C(O)NR c2 Rd2 , NRc2 S(O)R b2 , NRc2 S(O) b2 , NRc2 S(O) c2 Rd2 , S(O)Rb2 , 2R 2NR S(O)NR c2 Rd2 , S(O) b2 , and S(O) c2 Rd2 . 2R 2NR
28. The nd of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, n p is 0.
29. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein p is 1.
30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein RZ is C1-4 alkyl.
31. The nd of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein RZ is C6-10 aryl-C1-4 alkyl- substituted by fluoro or cyanomethyl.
32. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein RZ is C1-4 alkyl substituted by methoxy or CN.
33. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein RZ is (5-10 membered heteroaryl)-C1-4 alkyl- tuted by methoxy or F.
34. The compound of any one of claims 1 to 29, or a ceutically acceptable salt f, wherein RZ is cyanomethyl.
35. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein RZ is methoxymethyl.
36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein m is 0.
37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, having a trans configuration with respect to the di-substituted cyclopropyl group depicted in Formula II.
38. The compound of claim 1 selected from: 1-{[4-(4-fluorobenzyl)({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin hyl}cyclopropanecarboxylic acid; 1-{[4-(4-fluorobenzyl)({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin yl]methyl}cyclobutanecarboxylic acid; trans{[4-(4-fluorobenzyl)({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]carbonyl}cyclohexanamine; 1-{[4-(4-fluorobenzyl)({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin bonyl}cyclobutanamine; 1-{[4-(methoxymethyl)({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin yl]methyl}cyclopropanecarboxylic acid; (methoxymethyl)({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin yl]methyl}cyclobutanecarboxylic acid; 1-{[4-(methoxymethyl)({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin yl]methyl}cyclopentanecarboxylic acid; 1-{[4-methyl({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin yl]methyl}cyclopropanecarboxylic acid; 1-{[4-methyl({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin yl]methyl}cyclobutanecarboxylic acid; 1-{[4-methyl({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin yl]carbonyl}cyclopentanamine; and 1-{[4-[4-(cyanomethyl)benzyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid; or a pharmaceutically acceptable salt of any one of the aforementioned.
39. The compound of claim 1 selected from: (cis{[4-(methoxymethyl)({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin- arbonyl}cyclohexyl)methanol; {[4-(methoxymethyl)({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]carbonyl}cyclohexyl)methanol; 1-{[4-({[(1R,2S)(2-fluorophenyl)cyclopropyl]amino}methyl) (methoxymethyl)piperidinyl]methyl}cyclobutanecarboxylic acid; 1-{[4-({[(1R,2S)(3,4-difluorophenyl)cyclopropyl]amino}methyl) (methoxymethyl)piperidinyl]methyl}cyclobutanecarboxylic acid; 1-{[4-({[(1R,2S)(4-fluorophenyl)cyclopropyl]amino}methyl) (methoxymethyl)piperidinyl]methyl}cyclobutanecarboxylic acid; 1-{[4-(3-cyanobenzyl)({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin yl]methyl}cyclobutanecarboxylic acid; 1-{[4-(3-cyanobenzyl)({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin yl]methyl}cyclopropanecarboxylic acid; 1-{[4-(4-cyanofluorobenzyl)({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid; 1-{[4-(4-cyanobenzyl)({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin yl]methyl}cyclopropanecarboxylic acid; (4-methoxybenzyl)({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin yl]methyl}cyclobutanecarboxylic acid; 1-{[4-(4-methoxybenzyl)({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin yl]methyl}cyclopropanecarboxylic acid; 1-{[4-(ethoxymethyl)({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin yl]methyl}cyclobutanecarboxylic acid; 1-{[4-(ethoxymethyl)({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin yl]methyl}cyclopropanecarboxylic acid; 1-{[4-(methoxymethyl)({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin yl]carbonyl}cyclopropanecarbonitrile; 1-{[4-(methoxymethyl)({[2-(2-methoxyphenyl)cyclopropyl]amino}methyl)piperidin- 1-yl]methyl}cyclobutanecarboxylic acid; 1-{[4-(methoxymethyl)({[2-(4-methoxyphenyl)cyclopropyl]amino}methyl)piperidin- 1-yl]methyl}cyclobutanecarboxylic acid; 1-{[4-(methoxymethyl)(1-{[(1R,2S)phenylcyclopropyl]amino}ethyl)piperidin yl]methyl}cyclobutanecarboxylic acid; [({6-[(methylamino)carbonyl]pyridinyl}oxy)methyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid; 1-{[4-[({6-[(methylamino)carbonyl]pyridinyl}oxy)methyl]({[(1R,2S) cyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid; 1-{[4-[(2-cyanophenoxy)methyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclobutanecarboxylic acid; 1-{[4-[(2-cyanophenoxy)methyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid; 1-{[4-[(2-fluorophenoxy)methyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclobutanecarboxylic acid; 1-{[4-[(2-fluorophenoxy)methyl]({[(1R,2S) cyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid; 1-{[4-[(3-cyanophenoxy)methyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclobutanecarboxylic acid; 1-{[4-[(3-cyanophenoxy)methyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid; 1-{[4-[(3-fluorophenoxy)methyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclobutanecarboxylic acid; 1-{[4-[(3-fluorophenoxy)methyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid; 1-{[4-[(4-cyanofluorophenoxy)methyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclobutanecarboxylic acid; [(4-cyanofluorophenoxy)methyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid; [(4-cyanophenoxy)methyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclobutanecarboxylic acid; 1-{[4-[(4-cyanophenoxy)methyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid; 1-{[4-[(5-fluoropyridinyl)methyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclobutanecarboxylic acid; 1-{[4-[(5-fluoropyridinyl)methyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid; 1-{[4-[(6-methoxypyridinyl)methyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid; 1-{[4-[(benzyloxy)methyl]({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin yl]methyl}cyclobutanecarboxylic acid; 1-{[4-[(benzyloxy)methyl]({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin yl]methyl}cyclopropanecarboxylic acid; 1-{[4-[(cyclobutylmethoxy)methyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclobutanecarboxylic acid; 1-{[4-[(cyclobutylmethoxy)methyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid; 1-{[4-[(cyclohexyloxy)methyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclobutanecarboxylic acid; 1-{[4-[(cyclohexyloxy)methyl]({[(1R,2S) cyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid; 1-{[4-[4-(cyanomethyl)benzyl]({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclobutanecarboxylic acid; 1-{[4-{[(3-fluoropyridinyl)oxy]methyl}({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid; 1-{[4-{[(5-fluoropyridinyl)oxy]methyl}({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid; 1-{[4-{[(5-fluoropyrimidinyl)oxy]methyl}({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid; 4-{[4-(3-cyanobenzyl)({[(1R,2S)phenylcyclopropyl]amino}methyl)piperidin- 1-yl]methyl}cyclohexanecarboxylic acid; or a pharmaceutically acceptable salt of any of the aforementioned.
40. The compound of claim 1, which is 1-{[4-(methoxymethyl)({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclopentanecarboxylic acid, or a pharmaceutically acceptable salt f.
41. The compound of claim 1, which is 1-{[4-(methoxymethyl)({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclopentanecarboxylic acid.
42. The compound of claim 1, which is 1-{[4-(methoxymethyl)({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclobutanecarboxylic acid, or a pharmaceutically acceptable salt thereof.
43. The compound of claim 1, which is 1-{[4-(methoxymethyl)({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclobutanecarboxylic acid.
44. The compound of claim 1, which is 1-{[4-({[(1R,2S)(4- fluorophenyl)cyclopropyl]amino}methyl)(methoxymethyl)piperidin yl]methyl}cyclobutanecarboxylic acid, or a pharmaceutically acceptable salt thereof.
45. The nd of claim 1, which is 1-{[4-({[(1R,2S)(4- fluorophenyl)cyclopropyl]amino}methyl)(methoxymethyl)piperidin yl]methyl}cyclobutanecarboxylic acid.
46. The compound of claim 1, which is (ethoxymethyl)({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclobutanecarboxylic acid, or a pharmaceutically acceptable salt thereof.
47. The compound of claim 1, which is (ethoxymethyl)({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclobutanecarboxylic acid.
48. The compound of claim 1, which is 1-{[4-(methoxymethyl)({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid or a pharmaceutically acceptable salt thereof.
49. The compound of claim 1, which is 1-{[4-(methoxymethyl)({[(1R,2S) phenylcyclopropyl]amino}methyl)piperidinyl]methyl}cyclopropanecarboxylic acid.
50. A pharmaceutical composition comprising a compound of any one of claims 1 to 49, or a pharmaceutically able salt thereof, and at least one pharmaceutically acceptable carrier.
51. The pharmaceutical composition of claim 50, further comprising another therapeutic agent.
52. A method of inhibiting LSD1 comprising contacting a compound of any one of claims 1 to 40, 42, 44, 46 or 48, or a pharmaceutically acceptable salt thereof, or a compound of any one of claims 41, 43, 45, 47 or 49, in vitro, with said LSD1.
53. A method of inhibiting LSD1 comprising ting the pharmaceutical composition of claim 50 or claim 51 in vitro with said LSD1.
54. Use of a compound of any one of claims 1 to 40, 42, 44, 46, or 48, or a pharmaceutically acceptable salt thereof, or a compound of any one of claims 41, 43, 45, 47 or 49, in the manufacture of a medicament for ng a disease, wherein said disease is cancer.
55. The use of claim 54 n said cancer is a hematological cancer.
56. The use of claim 55 wherein said hematological cancer is selected from acute blastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic ia (CLL), chronic enous 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)), ysplasia me (MDS), or multiple myeloma.
57. The use of claim 55, wherein said hematological cancer is relapsed or refractory non- Hodgkin lymphoma, or recurrent follicular non-Hodgkin lymphoma.
58. The use of claim 55, wherein said hematological cancer is acute myelogenous leukemia.
59. The use of claim 55, wherein said hematological cancer is primary myelofibrosis (PMF).
60. The use of claim 55, wherein said hematological cancer is myelodysplasia syndrome (MDS).
61. The use of claim 54 wherein said cancer is a sarcoma, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, or skin .
62. The use of claim 54, wherein said cancer is breast cancer, ovarian cancer, or prostate cancer.
63. The use of claim 54, wherein said cancer is lung cancer.
64. The use of claim 54, wherein the cancer is ogenic carcinoma, alveolar carcinoma, bronchial adenoma, chondromatous hamartoma, or mesothelioma.
65. The use of claim 54, wherein said cancer is non-small cell lung cancer.
66. The use of claim 54, wherein said cancer is s sarcoma.
67. The use of claim 54, wherein said cancer is undifferentiated small cell lung cancer.
68. Use of a pharmaceutical ition of claim 50 or claim 51 in the manufacture of a medicament for treating a disease, n said disease is cancer.
69. Use of a compound of any one of claims 1 to 40, 42, 44, 46, or 48, or a pharmaceutically acceptable salt thereof, or a compound of any one of claims 41, 43, 45, 47 or 49, in the manufacture of a medicament for treating a disease, n said disease is a viral disease or a beta-globinopathy.
70. The use of claim 69, wherein the beta-globinopathy is sickle cell disease.
71. Use of the pharmaceutical composition of claim 50 or claim 51 in the manufacture of a medicament for treating a disease, n said disease is a viral disease or a beta-globinopathy.
NZ723817A 2014-02-13 2015-02-12 Cyclopropylamines as lsd1 inhibitors NZ723817B2 (en)

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US201461939488P 2014-02-13 2014-02-13
US61/939,488 2014-02-13
US201462061283P 2014-10-08 2014-10-08
US62/061,283 2014-10-08
PCT/US2015/015706 WO2015123465A1 (en) 2014-02-13 2015-02-12 Cyclopropylamines as lsd1 inhibitors

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