NZ621520B2 - Nuclear transport modulators and uses thereof - Google Patents

Nuclear transport modulators and uses thereof Download PDF

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NZ621520B2
NZ621520B2 NZ621520A NZ62152012A NZ621520B2 NZ 621520 B2 NZ621520 B2 NZ 621520B2 NZ 621520 A NZ621520 A NZ 621520A NZ 62152012 A NZ62152012 A NZ 62152012A NZ 621520 B2 NZ621520 B2 NZ 621520B2
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ring
nitrogen
oxygen
sulfur
optionally substituted
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NZ621520A
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NZ621520A (en
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Michael Kauffman
Yosef Landesman
Dilara Mccauley
Jeanrchard Saintmartin
Vincent P Sandanayaka
William Senapedis
Sharon Shacham
Sharon Shechter
Martin Jean Rchard Saint
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Karyopharm Therapeutics Inc
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Priority claimed from PCT/US2012/048368 external-priority patent/WO2013019561A1/en
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Publication of NZ621520B2 publication Critical patent/NZ621520B2/en

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    • C07D487/10—Spiro-condensed systems

Abstract

Disclosed herein are nuclear transport modulators, e.g CRM1 inhibitors, represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described herein. Also disclosed is the synthesis and use of a compound of structural formula (I), or a pharmaceutically acceptable salt or composition thereof, in the treatment, modulation and/or prevention of physiological conditions associated with CRM1 activity. Particular examples are when ring A is a triazole and ring B is di-triflurormethyl phenyl for example: (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(3-((dimethylamino)methyl)-3-fluoroazetidin-1-yl)prop-2-en-1-one; (Z)-1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-fluoroazetidine-3-carboxylic acid; and (Z)-1-(3-(aminomethyl)-3-fluoroazetidin-1-yl)-3-(3-(3,5-bis(trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl)prop-2-en-1-one. utically acceptable salt or composition thereof, in the treatment, modulation and/or prevention of physiological conditions associated with CRM1 activity. Particular examples are when ring A is a triazole and ring B is di-triflurormethyl phenyl for example: (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(3-((dimethylamino)methyl)-3-fluoroazetidin-1-yl)prop-2-en-1-one; (Z)-1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-fluoroazetidine-3-carboxylic acid; and (Z)-1-(3-(aminomethyl)-3-fluoroazetidin-1-yl)-3-(3-(3,5-bis(trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl)prop-2-en-1-one.

Description

NUCLEAR TRANSPORT MODULATORS AND USES THEREOF RELATED APPLICATIONS This application claims the benefit of US. Provisional Application No. 61/513,428, filed July 29, 2011, US. Provisional ation No. 61/513,432, filed July 29, 2011, and US. Provisional Application No. 61/653,588, filed May 31, 2012. The contents of the above applications are incorporated herein by reference in their entirety.
BACKGROUND OF THE INVENTION Cells from most major human solid and hematologic malignancies exhibit abnormal cellular zation of a variety of oncogenic proteins, tumor suppressor proteins, and cell cycle regulators (Cronshaw et al. 2004, Falini et a1 2006). For example, certain p53 ons lead to zation in the cytoplasm rather than in the nucleus. This s in the loss of normal growth regulation, despite intact tumor suppressor function. In other tumors, wild—type p53 is sequestered in the cytoplasm or rapidly degraded, again leading to loss of its ssor function. Restoration of appropriate nuclear zation of functional p53 protein can normalize some properties of neoplastic cells (Cai et al. 2008; Hoshino et al. 2008; Lain et al. 1999a; Lain et al. 1999b; Smart et al. 1999), can restore sensitivity of cancer cells to DNA damaging agents (Cai et al. 2008), and can lead to regression of established tumors (Sharpless & DePinho 2007, Xue et al. 2007). Similar data have been obtained for other tumor suppressor proteins such as ad (Turner and Sullivan 2008) and c-Abl (Vignari and Wang 2001). In addition, abnormal localization of several tumor suppressor and growth regulatory proteins may be involved in the pathogenesis of autoimmune es (Davis 2007, Nakahara 2009). CRMl inhibition may provide particularly interesting utility in familial cancer syndromes (e.g, Li-Fraumeni Syndrome due to loss of one p53 allele, BRCAl or 2 cancer syndromes), where specific tumor suppressor proteins (TSP) are d or dysfunctional and where increasing TSP levels by systemic (or local) administration of CRMl inhibitors could help restore normal tumor suppressor function.
Specific proteins and RNAs are carried into and out of the nucleus by specialized transport les, which are classified as importins if they transport molecules into the nucleus, and exportins if they transport molecules out of the s (Terry et al. 2007; Sorokin et al. 2007). Proteins that are transported into or out of the nucleus n nuclear import/localization (NLS) or export (NES) sequences that allow them to interact with the nt transporters. Chromosomal Region Maintenance 1 (Crml or CRMl), which is also called exportin-l or Xpol, is a major exportin.
Overexpression of Crml has been reported in several , including human ovarian cancer (Noske et al. 2008), al cancer (van der Watt et al. 2009), pancreatic cancer (Huang et al. 2009), hepatocellular carcinoma (Pascale et al. 2005) and osteosarcoma (Yao et al. 2009) and is independently correlated with poor clinical outcomes in these tumor types.
Inhibition of Crml blocks the exodus of tumor suppressor proteins and/0r growth regulators such as p53, c—Abl, p21, p27, pr, BRCAl, IkB, ICp27, E2F4, KLFS, YAPl, ZAP, KLFS, HDAC4, HDACS or forkhead proteins (e.g., FOXO3 a) from the nucleus that are associated with gene expression, cell proliferation, angiogenesis and epigenetics. Crml inhibitors have been shown to induce apoptosis in cancer cells even in the presence of activating oncogenic or growth stimulating signals, while sparing normal (untransformed) cells. Most studies of Crml tion have utilized the natural product Crml tor Leptomycin B (LMB). LMB itself is highly toxic to neoplastic cells, but poorly tolerated with marked gastrointestinal toxicity in animals (Roberts et al. 1986) and humans (Newlands et al. 1996). Derivatization of LMB to improve drug—like properties leads to compounds that retain antitumor activity and are better tolerated in animal tumor models (Yang et al. 2007, Yang et al. 2008, Mutka et al. 2009). Therefore, nuclear export inhibitors could have beneficial effects in stic and other proliferative disorders.
In addition to tumor suppressor proteins, Crml also exports several key proteins that are involved in many inflammatory processes. These include IkB, NF—kB, Cox—2, RXROL, Commdl, HIFl, HMGBl, FOXO, FOXP and others. The nuclear factor kappa B (NF-kB/rel) family of transcriptional tors, named for the discovery that it drives immunoglobulin kappa gene expression, regulate the mRNA expression of variety of genes involved in inflammation, proliferation, immunity and cell survival. Under basal conditions, a protein inhibitor of NF—kB, called IkB, binds to NF—kB in the nucleus and the complex IkB-NF-kB renders the NF—kB riptional function ve. In response to inflammatory stimuli, IkB dissociates from the IkB-NF—kB complex, which releases NF—kB and unmasks its potent transcriptional activity. Many s that activate NF-kB do so by ing IkB for proteolysis horylation of IkB renders it “marked” for ubiquitination and then lysis). The nuclear IkBa—NF—kB complex can be exported to the cytoplasm by Crml WO 19561 Where it dissociates and NF-kB can be reactivated. Ubiquitinated IkB may also dissociate from the NF—kB complex, restoring NF-kB transcriptional activity. tion of Crml induced export in human neutrophils and macrophage like cells (U937) by LMB not only results in accumulation of transcriptionally inactive, r IkBa-NF-kB complex but also prevents the initial activation of NF-kB even upon cell stimulation (Ghosh 2008, Huang 2000). In a different study, ent with LMB inhibited IL—lB induced NF-kB DNA binding (the first step in NF-kB transcriptional activation), IL-8 expression and ellular adhesion molecule expression in pulmonary ascular endothelial cells (Walsh 2008).
COMMDl is another r tor of both NF-kB and hypoxia-inducible factor 1 (HIFl) transcriptional activity. Blocking the nuclear export of COMMDl by inhibiting Crml s in increased inhibition of NF—kB and HIFl transcriptional activity (Muller 2009).
Crml also mediates retinoid X receptor or (RXROL) transport. RXRa is highly expressed in the liver and plays a central role in regulating bile acid, cholesterol, fatty acid, steroid and xenobiotic metabolism and homeostasis. During liver inflammation, nuclear RXROL levels are significantly reduced, mainly due to inflammation—mediated nuclear export of RXROL by Crml. LMB is able to prevent IL-lB induced cytoplasmic increase in RXROL levels in human liver derived cells (Zimmerman 2006).
The role of Crml-mediated nuclear export in NF-kB, HIF~l and RXROL signalling suggests that blocking nuclear export can be potentially beneficial in many inflammatory processes across multiple tissues and organs including the vasculature (vasculitis, arteritis, polymyalgia rheumatic, atherosclerosis), dermatologic (see below), tologic (rheumatoid and d arthritis, psoriatic arthritis, spondyloarthropathies, crystal arthropathies, systemic lupus erythematosus, mixed tive tissue disease, myositis syndromes, dermatomyositis, inclusion body myositis, undifferentiated connective tissue disease, Sjogren’s syndrome, scleroderma and overlap syndromes, etc.).
CRMl inhibition affects gene expression by ting/activating a series of transcription factors like ICp27, E2F4, KLFS, YAPl, and ZAP.
Crml inhibition has potential therapeutic effects across many dermatologic syndromes including inflammatory dermatoses (atopy, allergic dermatitis, chemical dermatitis, psoriasis), sun-damage (ultraviolet (UV) damage), and infections. CRMl inhibition, best studied With LMB, showed minimal effects on normal keratinocytes, and d anti—inflammatory activity on keratinocytes subjected to UV, TNFOL, or other inflammatory stimuli (Kobayashi & Shinkai 2005, Kannan & Jaiswal 2006). Crml inhibition also upregulates NRF2 (nuclear factor erythroid-related factor 2) ty, which protects keratinocytes (Schafer et al. 2010, Kannan & Jaiswal 2006) and other cell types (Wang et al. 2009) from oxidative damage. LMB induces sis in keratinocytes infected with oncogenic human papillomavirus (HPV) strains such as HPV16, but not in uninfected keratinocytes (Jolly et al. 2009).
Crml also es the transport of key neuroprotectant proteins that may be useful in neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS). For example, by (l) forcing nuclear ion of key neuroprotective regulators such as NRF2 (Wang 2009), FOXA2 ppa et al. 2007), parking in neuronal cells, and/or (2) inhibiting NFKB transcriptional activity by sequestering IKB to the s in glial cells, Crrnl inhibition could slow or prevent neuronal cell death found in these disorders. There is also evidence linking abnormal glial cell proliferation to abnormalities in CRMl levels or CRMl function (Shen 2008).
Intact nuclear export, primarily mediated through CRMl, is also required for the intact maturation of many Viruses. Viruses where r , and/or CRMl itself, has been implicated in their lifecycle include human immunodeficiency virus (HIV), adenovirus, simian retrovirus type 1, Borna disease virus, za (usual strains as well as HlNl and avian H5Nl strains), hepatitis B (HBV) and C (HCV) Viruses, human papillomavirus (HPV), respiratory syncytial virus (RSV), Dungee, Severe Acute Respiratory Syndrome coronavirus, yellow fever virus, West Nile Virus, herpes simplex virus (HSV), cytomegalovirus (CMV), and Merkel cell polyomavirus (MCV). (Bhuvanakantham 2010, Cohen 2010, Whittaker 1998). It is anticipated that additional viral infections t on intact nuclear export will be red in the future.
The HIV-1 Rev protein, which traffics through nucleolus and shuttles between the nucleus and cytoplasm, facilitates export of unspliced and singly spliced HIV transcripts containing Rev se Elements (RRE) RNA by the CRMl export pathway. Inhibition of diated RNA transport using CRMl inhibitors such as LMBor PKF050-638 can arrest the HIV-1 transcriptional process, inhibit the production of new HIV-1 virions, and thereby reduce HIV-l levels (Pollard 1998, Daelemans 2002).
Dengue virus (DENV) is the causative agent of the common arthropod-borne viral disease, Dengue fever (DF), and its more severe and potentially deadly Dengue hemorrhagic fever (DHF). DHF appears to be the result of an over exuberant inflammatory response to DENV. N85 is the largest and most ved protein of DENV. CRMl regulates the _ 5- transport ofNSS from the nucleus to the cytoplasm, where most of the NSS functions are mediated. Inhibition of CRMl—mediated export ofNSS results in altered kinetics of virus production and reduces induction of the atory chemokine interleukin-8 (IL-8), ting a new avenue for the ent of diseases caused by DENV and other medically ant flaviviruses including hepatitis C virus (Rawlinson 2009).
Other Virus-encoded RNA-binding proteins that use CRMl to exit the nucleus include the HSV type 1 tegument protein (VP13/14, or hUL47), human CMV protein pp65, the SARS Coronavirus ORF 3b Protein, and the RSV matrix (M) protein (Williams 2008, Sanchez 2007, Freundt 2009, al 2009).
Interestingly, many of these viruses are associated with specific types of human cancer including hepatocellular carcinoma (HCC) due to chronic HBV or HCV infection, cervical cancer due to HPV, and Merkel cell carcinoma associated with MCV. CRMl tors could therefore have beneficial effects on both the viral infectious process as well as on the process of stic ormation due to these viruses.
CRMl controls the nuclear localization and therefore activity of multiple DNA metabolizing enzymes including histone deacetylases (HDAC), histone acetyltransferases (HAT), and histone methyltransferases (HMT). Suppression of cardiomyocyte rophy with irreversible CRMl inhibitors has been demonstrated and is believed to be linked to r retention (and activation) ofHDAC 5, an enzyme known to suppress a hypertrophic genetic program (Monovich et al. 2009). Thus, CRMl inhibition may have beneficial effects in hypertrophic syndromes, including n forms of congestive heart failure and hypertrophic cardiomyopathies.
CRMl has also been linked to other ers. Leber’s er, a hereditary disorder characterized by degeneration of retinal ganglion cells and visual loss, is associated with inaction of the CRMl switch (Gupta N 2008). There is also ce linking neurodegenerative disorders to abnormalities in nuclear transport.
To date, however, small-molecule, drug—like Crml inhibitors for use in vitro and in vivo are uncommon.
SUMMARY OF THE INVENTION The present invention relates to compounds, or pharmaceutically acceptable salts thereof, useful as nuclear transport modulators. The invention also provides pharmaceutically acceptable compositions sing compounds of the present invention and methods of using said compounds and compositions in the treatment of various disorders, such as disorders or conditions associated with abnormal cellular responses triggered by improper nuclear transport.
In one embodiment of the invention, the compounds useful as nuclear transport modulators are ented by formula I: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.
According to first aspect of the present invention, there is provided a nd of formula I: (I), or a ceutically acceptable salt thereof, wherein: Ring A is a lyl ring; Ring B is represented by the following structural formula: X is O; Y is a covalent bond; R1 and R2 are taken together with their intervening atoms to form a saturated heterocyclic ring represented by the following structural formula: AH26(11270483_1):HJG each of m, and p is independently an integer selected from 0, 1, 2, 3 and 4; q is 0; each of R4, and R5 is independently n, –NO2, –CN, –N3, or -L-R6, or: two R4 groups on Ring A are taken together with their intervening atoms to form a fused 4-8 membered saturated, lly unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: two R5 groups on the ring formed by R1 and R2 are taken together with their intervening atoms to form a fused 4-8 membered ted, partially unsaturated, or aryl ring having 0-3 atoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent C1-6 hydrocarbon group, wherein one or two methylene units of L is optionally and independently replaced by –Cy–, –O–, –S–, -N(R6)–, –C(O)–, –C(S)–, –C(O)N(R6)–, –N(R6)C(O)N(R6)–, –N(R6)C(O)–, –N(R6)C(O)O–, -OC(O)N(R6)–, –S(O)–, –S(O)2–, N(R6)–, –N(R6)S(O)2–, –OC(O)– or –C(O)O–; –Cy– is a nt ring selected from a 3-7 membered saturated or partially unsaturated cycloalkylenylene ring, a 4membered saturated or partially unsaturated cycloalkylene ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenylene, a 5-6 membered monocyclic heteroarylene having 1-4 heteroatoms independently selected from en, oxygen, and sulfur, an 8-10 ed ic arylene, and an 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently ed from en, oxygen, and sulfur; and each R6 is independently hydrogen or a group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, a 4membered saturated or partially unsaturated heterocyclic ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 ed monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently ed from nitrogen, oxygen, and sulfur; or: two R6 on the same en are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or aromatic heterocyclic ring having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
AH26(11270483_1):HJG Another embodiment of the invention is a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Yet another embodiment of the invention is a method for treating a disorder associated with CRM1 activity, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention, or a pharmaceutically able salt thereof, or a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof.
Another embodiment of the invention is use of a compound of the invention for treating a disorder associated with CRM1 activity in a t.
Another embodiment of the invention is use of a nd of the invention for the manufacture of a medicament for ng a er associated with CRM1 activity in a subject.
The r transport modulators of the present invention, and pharmaceutically acceptable salts and/or compositions thereof, provide excellent in vivo exposure as ed by AUC in mouse, rat, dog and monkey, while exhibiting low levels of brain penetration. Therefore, nds of the present invention, and pharmaceutically able salts and/or compositions f, are useful for treating a y of diseases, disorders or conditions, associated with abnormal cellular responses triggered by improper nuclear transport, such as those diseases, disorders, or conditions described herein. Compounds provided by this invention are also useful for the study of nuclear transport modulation in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by kinases; and the comparative evaluation of nuclear transport modulators.
AH26(11270483_1):HJG BRIEF DESCRIPTION OF THE FIGURES is a graph of mean tumor volume as a on of time and shows the effect of (Z)-3 -(3 -(3 , 5 -bis(trifluoromethyl)phenyl)- 1 H— 1 ,2,4—triazol- 1 —yl)—l —(3 ,3 -difluoroazetidin—l — yl)prop—2—enone (Compound 1) on tumor volume in a mouse xenograft model of HCT— 1 16. is images of Western blots and shows the amount of p53, p21, full-length (FL) PARP and cleaved PARP, and lamin B in the cytoplasmic fraction of a n extract from HCT-l 16 cells at various times before and after ent with Compound 1. is images of Western blots and shows the amount of p53, p21, full-length (FL) PARP and cleaved PARP, and lamin B in the nuclear fraction of a protein extract from HCT-116 cells at various times before and after treatment with Compound 1. is images of Western blots and shows the amount ofpr, phosphorylated pRB (prphos), and lamin B in the cytoplasmic on of a protein extract from HCT—l 16 cells at various times before and after treatment with Compound 1. is images of Western blots and shows the amount ofpr, phosphorylated pRB S), and lamin B in the nuclear fraction of a protein extract from HCT-116 cells at various times before and after treatment with Compound 1. is a graph of EAE score a function of time and shows the effect of s s of Compound 1 on EAE score in the EAE model of le sclerosis. is a graph of body weight as a function of time and shows the effect of various amounts of Compound 1 on body weight in the EAE model of multiple sclerosis. shows the results of FACS sorting of lymphocytes for a subset of mice at day 26 of the EAE Model described herein.
DETAILED DESCRIPTION OF THE INVENTION The novel features of the present invention will become apparent to those of skill in the art upon examination of the following detailed description of the invention. It should be understood, however, that the detailed description of the invention and the specific es presented, while indicating certain embodiments of the present invention, are provided for illustration purposes only because various s and modifications within the spirit and scope of the invention will become apparent to those of skill in the art from the detailed description of the invention and claims that follow.
WO 19561 Definitions Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are fied in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and s, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, MB. and March, J ., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
Unless specified otherwise within this specification, the nomenclature used in this specification lly follows the examples and rules stated in lature of Organic try, ns A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated by nce herein for its exemplary chemical structure names and rules on naming chemical structures. Optionally, a name of a compound may be generated using a chemical naming program: ACD/ChemSketch, Version 509/September 2001, Advanced Chemistry Development, Inc., Toronto, .
Compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (e,g., as described in: E. L. Eliel and S. H. Wilen, Stereo-chemistry of Carbon nds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers or enantiomers, with all le isomers and mixtures thereof, including optical isomers, being included in the present ion.
The term “aliphatic” or “aliphatic group,” as used herein, denotes a monovalent hydrocarbon radical that is straight—chain (i.e., unbranched), ed, or cyclic (including fused, bridged, and Spiro—fused clic). An aliphatic group can be saturated or can contain one or more units of unsaturation, but is not aromatic. Unless ise specified, aliphatic groups contain 1—6 carbon atoms. However, in some embodiments, an aliphatic group contains 1—10 or 2-8 carbon atoms. In some embodiments, aliphatic groups contain 1— 4 carbon atoms and, in yet other embodiments, aliphatic groups contain 1—3 carbon atoms.
Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, W0 2013/019561 PCT/U82012/048368 and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
The term ,” as used herein, means a saturated, straight—chain or ed aliphatic group. In one aspect, an alkyl group ns 1—10 or 2-8 carbon atoms. Alkyl includes, but is not limited to, methyl, ethyl, , iso-propyl, n-butyl, sec—butyl, t-butyl, and the like.
The term “alkenyl,” as used herein, means a straight-chain or branched aliphatic group having one or more carbon—carbon double bonds (216., —CH=CH—). In one aspect, an l group has from two to eight carbon atoms, and includes, for example, and without being limited thereto, ethenyl, l—propenyl, l—butenyl and the like. The term “alkenyl” encompasses ls having carbon—carbon double bonds in the “cis” and “trans” or, alternatively, the “E” and “Z” configurations. If an alkenyl group includes more than one —carbon double bond, each carbon—carbon double bond is independently a cis or trans double bond, or a mixture thereof.
The term “alkynyl,” as used herein, means a straight—chain or ed aliphatic radical having one ore more carbon—carbond triple bonds (i.e., -CEC-). In one aspect, an alkyl group has from two to eight carbon atoms, and includes, for example, and without being limited thereto, l-propynyl (propargyl), l-butynyl and the like.
The terms “cycloaliphatic,” “carbocyclyl,” “carbocyclo,” and “carbocyclic,” used alone or as part of a larger moiety, refer to a saturated or partially unsaturated cyclic aliphatic monocyclic or bicyclic ring system, as described herein, having from 3 to 10 members, wherein the aliphatic ring system is optionally substituted as defined above and described herein. In some ments, a cycloaliphatic group has 3-6 carbon atoms. Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, exyl, cyclohexenyl, eptyl, cycloheptenyl, ctyl, cyclooctenyl, and cyclooctadienyl. The terms “cycloaliphatic,” “carbocyclyl,” “carbocyclo,” and “carbocyclic” also include aliphatic rings that are fused to one or more aromatic or matic rings, such as decahydronaphthyl, tetrahydronaphthyl, decalin, or bicyclo[2.2.2]octane.
The term “cycloalkyl,” as used herein, means a saturated cyclic aliphatic monocyclic or bicyclic ring system having from 3-10 members. A cycloalkyl can be optionally substituted as described herein. In some embodiments, a cycloalkyl has 3—6 carbons.
The term “heterocycloalkyl,” as used herein, means a saturated or unsaturated aliphatic ring system in which at least one carbon atom is replaced with a heteroatom selected from N, S and O. A heterocycloalkyl can contain one or more rings, which may be attached together in a pendent manner or may be fused. In one aspect, a heterocycloalkyl is a three- to seven—membered ring system and includes, for example, and without being limited thereto, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl and the like.
The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, and es any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; and a substitutable nitrogen of a heterocyclic ring, for example N (as in hydro—2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N- substituted pyrrolidinyl).
The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.
The term “alkoxy,” as used herein, means yl. “Alkoxy” can include a straight— chained or branched alkyl. In one aspect, y” has from one to eight carbon atoms and includes, for example, and without being limited thereto, methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
The term “halo” or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both ctive and non-radioactive forms.
The term “haloalkyl,” as used herein, means an alkyl group that is substituted with one or more n atoms. In some embodiments, kyl refers to a perhalogenated alkyl group. In some embodiments, haloalkyl refers to an alkyl group which is substituted with one or more halogen atoms. Exemplary haloalkyl groups include —CF3, -CC13, 3, -CH2CF3, -CH2(CF3)2, -CF2(CF3)2, and the like.
The term “alkylene,” as used herein, means a bivalent branched or unbranched ted hydrocarbon radical. In one aspect, “alkylene” has one to eight carbon atoms, and includes, for example, and without being limited thereto, ene, ne, n—propylene, lene and the like.
The term “alkenylene,” as used herein, means a nt branched or unbranched hydrocarbon radical having one or more carbon—carbon double bonds (i.e., -CH=CH—). In one aspect, “alkenylene” has two to eight carbon atoms, and includes, for example, and without being limited thereto, ethenylene, n—propenylene, n-butenylene and the like.
The term “alkynylene,” as used herein, means a bivalent branched or unbranched hydrocarbon radical having one ore more carbon-carbond triple bonds (1'. e., —CEC-). In one aspect, nylene” has two to eight carbon atoms, and includes, for example, and without being limited thereto, ethynylene, n—propynylene, n-biltynylene and the like.
The term “aryl,” alone or in combination, as used herein, means a carbocyclic aromatic system containing one or more rings, which may be attached together in a pendent manner or may be fused. In particular embodiments, aryl is one, two or three rings. In one aspect, the aryl has five to twelve ring atoms. The term “aryl” encompasses aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl and acenaphthyl. An “aryl” group can have 1 to 4 substituents, such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.
The term “heteroaryl,” alone or in combination, as used herein, means an aromatic system wherein at least one carbon atom is replaced by a heteroatom selected from N, S and O. A heteroaryl can contain one or more rings, which may be attached together in a pendent manner or may be fused. In particular embodiments, heteroaryl is one, two or three rings. In one , the heteroaryl has five to twelve ring atoms. The term “heteroaryl” encompasses heteroaromatic groups such as triazolyl, imidazolyl, pyrrolyl, lyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, furyl, benzofuryl, thienyl, benzothienyl, quinolyl, oxazolyl, zolyl, olyl, and the like. A “heteroaryl” group can have 1 to 4 substituents, such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.
It is understood that substituents and substitution patterns on the compounds of the invention can be ed by one of ordinary skill in the art to provide nds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more ens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted group” can have a le substituent at each substitutable position of the group and, when more than one position in any given ure may be substituted with more than one , substituent selected from a specified group, the substituent can be either the same or different at every position. Alternatively, an “optionally substituted group” can be unsubstitued.
Combinations of substituents envisioned by this invention are ably those that result in the formation of stable or chemically feasible nds. If a substituent is itself tuted with more than one group, it is understood that these le groups can be on the same carbon atom or on different carbon atoms, as long as a stable structure results. The WO 19561 —12- ' term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in n embodiments, their ry, purification, and use for one or more of the purposes disclosed herein.
Suitable monovalent substituents on a substitutable carbon atom of an nally substituted group” are independently halogen; MR°; —(CH2)MOR°; )0-4R°, —O—(CH2)04C(O)OR°; —(CH2)MCH(OR°)2; —(CH2)MSR°; —(CH2)MPh, which may be substituted with R0; —(CH2)04,O(CH2)0n1Ph which may be substituted with R°; —CH=CHPh, which may be substituted with R°; —(CH2)MO(CH2)0_1—pyridyl which may be substituted with R°; —N02; ~CN; ~N3; “(CH2)MN(R°)2; —(CH2)MN(R°)C(O)R°; —N(R°)C(S)R°; -(CH2)04N(R°)C(O)NR°2; -N(R°)C(S)NR°2; —(CH2)04N(R°)C(O)0R°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; —(CH2)04C(O)R°; -C(S)R°; o.4C(O)OR°; —(CH2)MC(O)SR°; '(CH2)0-4C(O)OSiRO3§ —(CH2)040C(0)R°; -OC(0)(CH2)04SR—, SC(S)SR°; —(CH2)MSC(O)R°; “(CH2)0—4C(O)NR°2; -C(S)NR°2; —C(S)SR°; ~SC(S)SR°, -(CH2)MOC(O)NR°2; -C(O)N(OR°)R°; —C(O)C(O)R°; H2C(0)R°; —C(NOR°)R°;-(CH2)MSSR°; —(CH2)04S(O)2R°; *(CH2)MS(O)2OR°; ‘(CH2)04OS(O)2R°; NR°2; -(CH2)o—4S(O)R°; -N(R°)S(O)2NR°2; —N(R°)S(O)2R°; -N(OR°)R°; —C(NH)NR°2; —P(0)2R°; °2; -0P(O)R°2; —OP(O)(OR°)2; SiR°3; —(C14 straight or branched a1kylene)O—N(R°)2; or —(C14 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1_6 aliphatic, —CH2Ph, —O(CH2)0-1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5—6—membered saturated, partially unsaturated, or aryl ring having 04 heteroatoms independently ed from nitrogen, oxygen, and , or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3—12—membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which may be substituted as defined below.
Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° er with their intervening atoms), are independently halogen, -(CH2)0_2R°, ~(haloR'), —(CH2)0.20H, —(CH2)HOR°, —(CH2)0_2CH(OR°)2; -O(haloR'), —CN, —N3, —(CH2)MC(O)R', —(CH2)0«2C(O)OH, —(CH2)HC(O)OR°, ~(CH2)HSR', —(CH2)0_28H, —(CH2)HNH2, —(CH2)0.2NHR°, —(CH2)0.2NR'2, —N02, ~SiR'3, 3, -C(O)SR', —(C1_4 straight or branched alkylene)C(O)OR°, or —S SR' wherein each R' is unsubstituted or where WO 19561 preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1_4 aliphatic, —CH2Ph, —O(CH2)(HPh, or a 5—6—membered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent tuents on a saturated carbon atom of R° include =0 and =S.
Suitable divalent tuents on a saturated carbon atom of an nally substituted group” include the following: =0, =s, =NNR*2, =NNHC(0)R*, =NNHC(O)OR*, =NNHS(0)2R*, =NR*, =N0R*, —0(C(R*2))2_30~, and —S(C(R*z))2"38—, wherein each independent occurrence of R* is selected from hydrogen, C1_6 aliphatic which may be ' substituted as defined below, or an unsubstituted 5—6—membered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally tuted” group include: —O(CR*2)2_3O—, wherein each independent occurrence of R* is selected from hydrogen, CH, aliphatic which may be substituted as defined below, or an unsubstituted 5—6—membered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms ndently selected from nitrogen, oxygen, and sulfur.
Suitable substituents on the aliphatic group of R* include halogen, —R°, ~(haloR'), —OH, “OR', —O(haloR°), —CN, -C(O)OH, —C(O)OR°, —NH2, —NHR°, ~NR°2, and —N02, wherein each R' is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is ndently C1_4 aliphatic, —CH2Ph, —O(CH2)0_1Ph, or a 5—6—~ membered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. le substituents on a substitutable nitrogen of an “optionally substituted group” e —Rl, —NRt2, —C(O)RT, —C(O)ORT, ~—C(O)C(O)RT, —C(O)CH2C(O)RT, —S(O)2RT, —S(O)2NRT2, —C(S)NRT2, -—C(NH)NRT2, and ~N(RT)S(O)2RT; wherein each RT is ndently hydrogen, C145 tic which may be substituted as defined below, unsubstituted —OPh, or an tituted 5—6—membered saturated, partially rated, or aryl ring having 0—4 heteroatoms ndently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent ences of RT, taken together with their intervening atom(s) form an unsubstituted 3—12—membered saturated, partially rated, or aryl monocyclic or bicyclic ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, and sulfiir.
Suitable substituents on the aliphatic group of RT are independently halogen, —R°, —(haloR°), —OH, wOR', —O(haloR'), ~CN, —C(O)OH, R', —NH2, —NHR°, —NR'2, or -N02, wherein each R' is tituted or where preceded by “halo” is tuted only with one or more halogens, and is independently CH aliphatic, —CH2Ph, )0_1Ph, or a 5—6— membered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
As used herein, the term “pharrnaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharrnaceutically acceptable salts in detail in J. ceutical Sciences, 1977, 66, 1—19, the relevant teachings of which are incorporated herein by reference in their entirety. Pharrnaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and bases that are compatible with the treatment of patients.
Examples of ceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharrnaceutically acceptable acid addition salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, e, cyclopentanepropionate, onate, lsulfate, sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2—hydroxy— ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2—naphthalenesulfonate, nate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, fate, 3—phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p—toluenesulfonate, noate, valerate salts, and the like.
In some embodiments, ary inorganic acids which form suitable salts include, but are not limited thereto, hydrochloric, romic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. rative organic acids which form suitable salts include the mono—, di— and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2—phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2—hydroxyethanesulfonic acid.
Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of these compounds are more e in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
In some embodiments, acid addition salts of the compounds of formula I are most suitably formed from pharmaceutically able acids, and e, for example, those formed with inorganic acids, e.g, hloric, sulfuric or phosphoric acids and c acids e.g. succinic, maleic, acetic or fumaric acid.
Other non-pharmaceutically acceptable salts, e. g., oxalates can be used, for e, in the isolation of compounds of formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. Also included Within the scope of the invention are base addition salts (such as sodium, potassium and ammonium salts), solvates and hydrates of compounds of the invention. The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, well known to one d in the art. 2O A “pharmaceutically acceptable basic addition salt” is any non-toxic organic or inorganic base on salt of the acid compounds represented by formula I, or any of its intermediates. Illustrative nic bases which form suitable salts include, but are not limited thereto, m, sodium, potassium, calcium, magnesium or barium hydroxides.
Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethyl amine and ne or ammonia. The selection of the appropriate salt may be ant so that an ester nality, if any, elsewhere in the molecule is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.
Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1w4alkyl)4 salts. Representative alkali or alkaline earth metal salts e sodium, lithium, ium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when riate, nontoxic ammonium, -l6- quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
Unless otherwise stated, ures depicted herein are also meant to include all isomeric (e. g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the ure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present nds are within the scope of the ion. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the ce of one or more ically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in ical assays, or as therapeutic agents in accordance with the t invention.
The term oisomers” is a general term for all isomers of an individual molecule that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
The term “pharmaceutically able carrier” means a non—toxic solvent, sant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of being administered to a patient. One example of such a carrier is ceutically acceptable oil typically used for parenteral administration. Pharmaceutically able carriers are well known in the art.
When introducing elements disclosed herein, the articles “a,” “an,” “the,” and “said” are intended to mean that there are one or more of the elements. The terms “comprising,” “having” and “including” are intended to be open—ended and mean that there may be additional elements other than the listed ts.
Compounds ofthe Invention One embodiment of the invention is a compound of formula I: _17_ wam, (R4)m R2 (1), or a pharmaceutically able salt thereof, n: Ring A is an optionally tuted ring selected from phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8—10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is an optionally substituted ring selected from a 3-8 ed saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aryl ring, a 3—8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic aryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently ed from en, oxygen, and sulfur; X is selected from O, S, N~CN, and NR; R is en or an optionally substituted group selected from CH, aliphatic, 3-8 membered saturated or partially unsaturated heterocyclic ring having 1—2 heteroatoms independently selected from nitrogen, , and sulfur, phenyl, and a 5-6 membered heteroaryl ring having 1—4 atoms independently selected from en, oxygen, and sulfur; 'Y is a covalent bond or an optionally substituted bivalent C1_4 hydrocarbon group, wherein one methylene unit of Y is optionally replaced by —O—, —S—, -N(R6)—, —C(O)— , ~c<s>—, -C<0>N<R6>—, ~N<R6>C<0>N<R6>—, ——N<R6>C<0>—, —N<R6)C(O>O—, -OC(O)N(R6)—, —S(O)—, -S(O)2~, ~—S(O)2N(R6)—, S(O)2—, «OC(O)— or - each of R1 and R2 is independently hydrogen or an optionally substituted group selected from C1_6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8—10 membered bicyclic aryl ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1—2 heteroatoms independently selected from nitrogen, , and sulfur, a 5~6 2012/048368 —18- membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and , and an 8-10 membered bicyclic heteroaryl ring having 1—4 heteroatoms independently selected from en, oxygen, and sulfur, or: R1 and R2 are taken together with their intervening atoms to form a 4-8 membered saturated, partially unsaturated, or aromatic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed thereby is substituted with ; each of n, m, and p is independently an integer selected from 0, 1, 2, 3 and 4; q is an integer selected from 0, l and 2; each of R3, R4, and R5 is independently halogen, —N02, —CN, ~N3, -L—R6, or an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially rated monocyclic oarbocyclic ring, phenyl, an 8-10 ed bicyclic aryl ring, a 3—8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1—2 heteroatoms independently selected from en, oxygen, and sulfur, a 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R3 groups on Ring B are taken together with their intervening atoms to form a fused 4-8 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently ed from nitrogen, oxygen, and sulfur; or: two R4 groups on Ring A are taken together with their intervening atoms to form a fused 4-8 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: two R5 groups on the ring formed by R1 and R2 are taken together with their intervening atoms to form a fused 4—8 membered saturated, lly unsaturated, or aryl ring having 0-3 heteroatoms independently ed from en, oxygen, and sulfur; L is a covalent bond or an optionally substituted nt C1_6 arbon group, wherein one or two ene units of L is optionally and independently replaced by —Cy—, —o—, —s—, —N(R6)-, —C(O)—, —C(S)-, —C(0)N(R6)-, —N(R6)C(O)N(R6)~, ~N<R6>C(O)—, —N(R6>C<0)O—, -0C<O>N<R6)—, —S<0>—; —s<0>2—, —s<0>2N(R6)—, —N(R6)S(O)2—, —OC(O)— or —C(O)O~—; ~Cy~ is an optionally substituted bivalent ring ed from a 3-7 membered saturated or partially unsaturated lkylenylene ring, a 4-7—membered saturated or partially unsaturated heterocycloalkylene ring having 14 heteroatoms independently selected from en, oxygen, and sulfur, phenylene, a 5-6 membered monocyclic heteroarylene having 1—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic arylene, and an 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from en, oxygen, and sulfur; and each R6 is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl yclic ring, a 4-7—membered saturated or partially rated heterocyclic ring having 1—4 heteroatoms independently selected from en, oxygen, and sulfur, a -6 membered monocyclic aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered ic heteroaryl ring having 1—4 heteroatoms ndently ed from nitrogen, oxygen, and sulfur; or: two R6 on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or aromatic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, , and sulfur.
As described genenerally above, Ring A‘is an optionally substituted ring selected from phenyl, an 8-10 membered bicyclic aryl ring, a 5—6 membered clic heteroaryl ring having 1-4 heteroatoms ndently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, Ring A is an optionally substituted phenyl'ring.
In some embodiments, Ring A is an optionally substituted 8—1 0 membered bicyclic aryl ring. In some embodiments, Ring A is an optionally substituted naphthyl ring.
In some embodiments, Ring A is an optionally substituted 5—6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally tuted 5-membered monocyclic aryl ring having 1—4 heteroatoms ndently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from en, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted S—membered heteroaryl ring having 1-2 heteroatoms independently selected from en, , and . In some embodiments, Ring A is an optionally substituted 5—membered heteroaryl ring having 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted S-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted S—membered heteroaryl ring having 1 heteroatom ed from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an ally substituted S-membered aryl ring having 1-3 en atoms. In some embodiments, Ring A is an optionally substituted group selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl.
In some embodiments, Ring A is selected from: N /N N /N N N U N \ EU},l/ £9 N \ ‘ ' I / b J\> 'N :3 N 31“ N andi‘t, N , , 3‘s N fikN H H H In some embodiments, Ring A is: “‘va In some embodiments, Ring A is an ally substituted 6-membered heteroaryl ring having l-4 nitrogen atoms. In some embodiments, Ring A is an optionally substituted 6- membered heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, Ring A is an optionally substituted 6—membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, Ring A is an optionally substituted 6—membered heteroaryl ring having 2 nitrogen atoms. In some embodiments, Ring A is an optionally substituted 6-membered heteroaryl ring having 1 nitrogen atom. In some embodiments, Ring A is an optionally substituted group selected from pyridinyl, pyrazinyl, pyridizinyl, pyrimidinyl, triazinyl and tetrazinyl.
In some embodiments, Ring A is an optionally tuted l ring. In some embodiments, Ring A is an optionally substituted 1,6-pyridyl ring. In some embodiments, Ring A is: -21_ As described generally above, Ring B is an optionally substituted ring selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8—10 membered bicyclic aryl ring, a 3-8 membered saturated or partially rated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from en, oxygen, and , a 5—6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, Ring B is an optionally substituted 3-8 membered saturated or IO partially unsaturated monocyclic yclic ring. In some embodiments, Ring B is an optionally substituted 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, Ring B is selected from an ally tuted cyclopropyl, cyclobutyl, cyclopentyl, exyl, cycloheptyl and cyclooctyl.
In some ments, Ring B is an optionally substituted 3-8 membered partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring B is selected from an optionally substituted cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, eptenyl, cyclooctenyl, cyclohexadienyl and cyclooctadienyl.
In some embodiments, Ring B is an optionally substituted phenyl ring.
In some embodiments, Ring B is a phenyl ring substituted with one or more groups independently selected from halogen, hydroxy or trifluoromethyl.
In some embodiments, Ring B is phenyl substituted with one or more optionally substituted methyl groups. In some embodiments, Ring B is phenyl substituted with one optionally substituted methyl group. In some embodiments, Ring B is phenyl substituted with two optionally substituted methyl groups.
In some embodiments, Ring B is phenyl substituted with one or more methyl groups substituted with at least one halogen. In some embodiments, Ring B is phenyl substituted with one or more methyl groups substituted with at least two halogens. In some embodiments, Ring B is phenyl substituted with one or more methyl groups tuted with three halogens.‘ In some ments, Ring B is phenyl substituted with one or more —CF3 groups.
In some embodiments, Ring B is phenyl substituted with two —CF3 groups.
In some embodiments, Ring B is: F30. ; i; In some embodiments, Ring B is an ally substituted 8-10 membered bicyclic aryl ring. In some embodiments, Ring B is an optionally substituted naphthyl.
In some embodiments, Ring B is an optionally tuted 3-8 membered saturated or lly unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from en, oxygen, and sulfur. In some ments, Ring B is an optionally substituted 3-8 membered saturated monocyclic heterocyclic ring having 1—2 heteroatoms independently selected from nitrogen, , and sulfur. In some embodiments, Ring B is an optionally substituted 3-8 membered saturated monocyclic heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an optionally substituted 3—8 membered saturated monocyclic heterocyclic ring having 1 atom ed from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is selected from an optionally substituted aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, oxolanyl, thiolanyl, imidazolidinyl, pyrazolidinyl, idinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, oxanyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl and homopiperazinyl.
In some embodiments, Ring B is an optionally substituted 3-8 membered partially unsaturated monocyclic heterocyclic ring having 1—2 heteroatoms independently selected from nitrogen, oxygen, and . In some embodiments, Ring B is selected from an optionally substituted azirinyl, oxirenyl, thiirenyl, diazirinyl, azetyl, , thietyl, dioxetyl, dithietyl, imidazolinyl, pyrazolinyl, oxazolinyl and thiazolinyl.
In some embodiments, Ring B is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and . In some embodiments, Ring B is an optionally substituted ered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, and . In some embodiments, Ring B is an optionally substituted 5-membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some ments, Ring B is an optionally substituted ered monocyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and a. sulfur. In some embodiments, Ring B is an optionally substituted 5—membered clic heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, and . In some embodiments, Ring B is an optionally substituted 5-membered monocyclic heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an optionally substituted pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl.
In some embodiments, Ring B is an optionally tuted ered monocyclic heteroaryl ring having 1-4 nitrogen atoms. In some embodiments, Ring B is an optionally substituted 6-membered monocyclic heteroaryl ring having 1-3 nitrogen atoms. In some ments, Ring B is an optionally substituted 6-membered monocyclic heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, Ring B is an optionally substituted 6- membered monocyclic heteroaryl ring having 2 nitrogen atoms. In some embodiments, Ring B is an optionally substituted 6-membered monocyclic heteroaryl ring having 1 nitrogen atom. In some embodiments, Ring B is an optionally tuted pyridinyl, pyrimidinyl, pyrizinyl, pyridizinyl, triazinyl or tetrazinyl.
In some embodiments, Ring B is an ally tuted pyridyl ring. In some embodiments, Ring B is a pyridyl ring substituted with one or more optionally substituted C1_6 aliphatic groups. In some embodiments, Ring B is a pyridyl ring substituted with one or more optionally substituted C1_4 tic groups. In some embodiments, Ring B is a l ring substituted with one or more optionally substituted C14 aliphatic groups. In some embodiments, Ring B is a pyridyl ring substituted with one or more optionally substituted methyl groups. In some embodiments, Ring B is a pyridyl ring substituted with one or more methyl groups which are r substituted with one or more halogens. In some embodiments, Ring B is a pyridyl ring substituted with one or more methyl groups tuted with one halogen. In some embodiments, Ring B is a pyridyl ring substituted with one or more methyl groups tuted with at least two halogens. In some embodiments, Ring B is a pyridyl ring substituted with one or more methyl groups substituted with three halogens. In some embodiments, Ring B is a pyridyl ring tuted with one or more —CF3 groups. In some embodiments, Ring B is a pyridyl ring substituted with two —CF3 groups. In some embodiments, Ring B is: W0 2013/019561 PCT/U82012/048368 In some embodiments, Ring B is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently ed from nitrogen, oxygen, and sulfur. In some ments, Ring B is an optionally substituted 8—10 membered ic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an optionally tuted 8-10 membered bicyclic aryl ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an optionally substituted benzofuranyl, benzothiophenyl, indolyl, indazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, riazolyl, azaindolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl or inyl.
As described generally above, X is selected from O, S, N-CN and NR, wherein R is hydrogen or an optionally substituted group selected from C1_6 tic, 3-8 membered saturated or partially unsaturated heterocyclic ring having 1—2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and a 5-6 membered heteroaryl ring having 1—4 heteroatoms independently ed from nitrogen, oxygen, and sulfur.
In some embodiments, X is O.
In some embodiments, X is S. 2O In some embodiments, X is N-CN.
In some embodiments, X is NR. More cally, X is NH. Alternatively, X is NCH3.
As described generally above, R is hydrogen or an optionally substituted group selected from CH; aliphatic, 3-8 membered saturated or partially unsaturated heterocyclic ring having 1—2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulphur.
In some embodiments, R is hydrogen.
In some embodiments, R is optionally substituted C1-6 aliphatic. In some embodiments, R is optionally substituted C1_5 aliphatic. In some embodiments, R is optionally substituted C1_4 aliphatic. In some embodiments, R is ally substituted C1_3 tic. In some embodiments, R is ally substituted C14 aliphatic. In some embodiments, R is selected from optionally substituted methyl, ethyl, propyl, isopropyl, butyl, yl, tert-butyl, pentyl, neopentyl, isopentyl, hexyl, ethenyl, propenyl, butenyl, yl, hexenyl and isobutenyl.
In some embodiments, R is optionally substituted 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted 3-8 ed saturated heterocyclic‘ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted 3-8 membered saturated heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted 3—8 membered saturated cyclic ring having 1 heteroatom selected from nitrogen, , and sulfur.
In some embodiments, R is optionally substituted aziridinyl, oxirany1,thiiranyl, idinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, oxolanyl, nyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, oxanyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl or homopiperazinyl.
In some embodiments, R is optionally tuted 3-8 membered partially unsaturated heterocyclic ring having 1-2 heteroatoms ndently ed from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally tuted 3-8 membered partially unsaturated heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted 3—8 membered partially unsaturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted azirinyl, oxirenyl, thiirenyl, diazirinyl, azetyl, oxetyl, l, yl, dithietyl, imidazolinyl, pyrazolinyl, oxazolinyl or thiazolinyl.
In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-4 atoms ndently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an ally substituted 5—membered aryl ring having 1-3 heteroatoms independently ed from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted S—membered heteroaryl ring having 1-2 -26— heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having 2 heteroatoms ndently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R is selected from optionally substituted pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, triazolyl and tetrazolyl.
In some embodiments, R is an optionally tuted 6-membered heteroaryl ring having 1-4 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1—2 nitrogen atoms. In some embodiments, R is an optionally tuted 6—membered aryl ring having 2 nitrogen atoms. In some embodiments, R is an ally substituted 6-membered heteroaryl ring having 1 nitrogen atom. In some embodiments, R is selected from optionally tuted pyridinyl, pyrimidinyl, pyrazinyl, zinyl, triazinyl and tetrazinyl.
In some ments, X is NH. In some embodiments, X is NCH3.
As described generally above, Y is a covalent bond or an optionally substituted bivalent C1_4 hydrocarbon chain, wherein one methylene unit ofY is optionally replaced by — 0—, -s—, —N(R6)—, —C(O)—, , -C(O)N(R6)—, —N(R6)C(O)N(R6)—, —N(R6)C(O)~, —N(R6)C(O)O—, -OC(O)N(R6)—, —S(O)—, —, N(R6)—, —N(R6)S(O)2—, —OC(O)— or ~C(O)O—.
In some embodiments, Y is a covalent bond.
In some embodiments, Y is an optionally substituted bivalent C1_4 hydrocarbon chain, wherein one methylene unit ofY is optionally ed by —O—, —S—, —N(R6)—, —C(O)—, -C(S)—, —C(O)N(R6)—, —N(R6)C(O)N(R6)—, C(O)—, —N(R6)C(O)O—, -OC(O)N(R6)—, —S(O)—, —S(O)2—, —S(O)2N(R6)—, —N(R6)S(O)2—, —OC(O)— or ——C(O)O—. In some embodiments, Y is an optionally substituted bivalent C1-3 hydrocarbon chain, wherein one methylene unit of Y is optionally replaced by —O—, —S—, -N(R6)—, —C(O)—, —, -C(O)N(R6)——, C(O)N(R6)—, -N(R6)C(O)—, —N(R6)C(O)O—, -OC(O)N(R6)—, —S(O)—, -S(O)2—, —S(O)2N(R6)—, —N(R6)S(O)2—, ~OC(O)— or —C(O)O—. In some embodiments, Y is an optionally tuted bivalent C1_2 hydrocarbon chain, wherein one methylene unit of Y is optionally replaced by —0—, -s—, ~N(R6)—, —C(O)—, —C(S)—, -C(O)N(R6)—, —N(R6)C(O)N(R6)— 2012/048368 ,—N(R6>C<0)—, C<O>O—, N(R6)—, —S<0)—, -s<0)2—, —S(O>2N<R6)—, —N(R6)S(O)2—, —OC(O)— or —C(O)O—.
In some embodiments, Y is —O—. In some embodiments, Y is —S—. In some embodiments, Y is —N(R6)-. In some embodiments, Y is —C(O)~. In some embodiments, Y is ~C(O)—. In some embodiments, Y is ~NH—. In some embodiments, Y is ~CH20—. In some embodiments, Y is —Cst—. In some embodiments, Y is ~CH2N(H)—.
As bed generally above, each of R1 and R2 is independently ed from hydrogen or an ally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8—10 membered ic aryl ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1—2 atoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, , and sulfur, and an 8-10 membered ic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, R1 and R2 are each hydrogen. In some embodiments, one of R1 and R2 is hydrogen.
In some embodiments, R1 is hydrogen. In some embodiments, R1 is optionally substituted C1_6 aliphatic. In some embodiments, R1 is optionally substituted C1_5 aliphatic.
In some embodiments, R1 is optionally tuted C1_4 aliphatic. In some embodiments, R1 is optionally substituted C1_3 aliphatic. In some ments, R1 is optionally substituted C1-2 aliphatic. In some embodiments, R1 is ed from optionally substituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, tyl, isopentyl, hexyl, ethenyl, propenyl, butenyl, pentenyl and hexenyl.
In some embodiments, R1 is an optionally substituted phenyl ring.
In some embodiments, R1 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R1 is an optionally substituted 3-8 membered saturated monocyclic carbocyclic ring. In some ments, R1 is an optionally substituted 3—8 membered partially unsaturated monocyclic carbocyclic ring.
In some embodiments, R1 is selected from optionally substituted cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, eptyl, cycloheptenyl, cyclohepadienyl, cyclooctyl, cyclooctenyl and cyclooctadienyl.
In some embodiments, R1 is an optionally substituted 8—10 membered bicyclic aryl ring. In some ments, R1 is an optionally substituted naphthyl ring.
In some embodiments, R1 is an optionally substituted 3—8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1—2 heteroatoms independently selected from en, oxygen, and sulfur. In some embodiments, R1 is an optionally substituted 3-8 ed saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some ments, R1 is an optionally substituted 3—8 membered saturated monocyclic heterocyclic ring having 2 heteroatoms ndently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1 is an ally substituted 3—8 membered saturated monocyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and . In some embodiments, R1 is an optionally tuted 3—8 membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1 is an optionally substituted 3-8 ed partially unsaturated monocyclic heterocyclic ring having 2 heteroatoms ndently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1 is an optionally substituted 3—8 membered partially unsaturated monocyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R1 is selected from optionally substituted aziridinyl, oxirany1,thiirany1, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, oxolanyl, thiolanyl, imidazolidinyl, lidinyl, oxazolidinyl, isoxazolidinyl, lidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, oxany1,thianyl, zinyl, morpholinyl, homopiperazinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl, azirinyl, oxirenyl, thiirenyl, diazirinyl, azetyl, , thietyl, dioxetyl, dithietyl, imidazolinyl, pyrazolinyl, oxazolinyl and linyl.
In some embodiments, R1 is an optionally substituted 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1 is an optionally substituted 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from en, oxygen, and sulfur. In some embodiments, R1 is an optionally substituted S-membered monocyclic heteroaryl ring having 1—3 atoms independently selected from nitrogen, oxygen, and sulfur. In some ments, R1 is an optionally substituted S-membered monocyclic heteroaryl ring having 1—2 heteroatoms ndently ed from nitrogen, oxygen, and sulfur. In some embodiments, R1 is an ally substituted 5-membered monocyclic heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1 is an ally substituted 5—membered monocyclic heteroaryl ring having 1 heteroatom selected from en, , and sulfur. In some embodiments, R1 is selected from optionally substituted pyrrolyl, furanyl, thiophenyl, imidazolyl, lyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl.
In some embodiments, R1 is an optionally substituted 6—membered monocyclic heteroaryl ring having 1—4 nitrogen atoms. In some embodiments, R1 is an optionally substituted 6-membered monocyclic heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, R1 is an optionally substituted 6~membered monocyclic heteroaryl ring having 1—2 nitrogen atoms. In some embodiments, R1 is an ally substituted 6-membered monocyclic aryl ring having 2 nitrogen atoms. In some embodiments, R1 is an optionally substituted 6-membered monocyclic aryl ring having 1 nitrogen atom. In some embodiments, R1 is ed from optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, nyl and tetrazinyl.
In some ments, R1 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1 is an optionally substituted 8—10 membered bicyclic heteroaryl ring having 1-3 heteroatoms ndently selected from en, oxygen, and sulfur. In some embodiments, R1 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1 is an optionally substituted 8—10 membered bicyclic heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen, and sulfiJr. In some embodiments, R1 is selected from optionally substituted indolyl, indazolyl, benzofuranyl, benzothiophenyl, hiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, azaindolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl and cinnolinyl.
In some embodiments, R2 is hydrogen. In some embodiments, R2 is optionally tuted C1-6 aliphatic. In some embodiments, R2 is optionally substituted C1-5 aliphatic.
In some ments, R2 is optionally substituted (31-4 aliphatic. In some embodiments, R2 is optionally substituted C1_3 aliphatic. In some embodiments, R2 is optionally substituted C1- 2 aliphatic. In some embodiments, R2 is selected from ally substituted methyl, ethyl, WO 19561 propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, tyl, tyl, hexyl, l, propenyl, butenyl, pentenyl and hexenyl.
In some embodiments, R2 is an optionally tuted phenyl ring.
In some embodiments, R2 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some ments, R2 is an ally substituted 3—8 membered saturated monocyclic carbocyclic ring. In some embodiments, R2 is an optionally substituted 3-8 membered partially unsaturated monocyclic carbocyclic ring.
In some embodiments, R2 is selected from optionally substituted cyclopropyl, cyclopropenyl, utyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, epadienyl, cyclooctyl, cyclooctenyl and cyclooctadienyl.
In some embodiments, R2 is an optionally substituted 8-10 ed bicyclic aryl ring. In some embodiments, R2 is an optionally substituted naphthyl ring.
In some embodiments, R2 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1—2 heteroatoms independently ed from nitrogen, oxygen, and sulfur. In some embodiments, R2 is an optionally substituted 3-8 membered saturated monocyclic heterocyclic ring having 1—2 heteroatoms ndently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is an optionally substituted 3-8 membered saturated monocyclic heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some ments, R2 is an optionally substituted 3-8 membered saturated monocyclic heterocyclic ring having 1 heteroatom ed from nitrogen, , and sulfur. In some embodiments, R2 is an ally substituted 3-8 membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is an optionally substituted 3-8 membered partially unsaturated clic heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is an optionally substituted 3-8 membered partially unsaturated monocyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is selected from optionally substituted aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, anyl, dithietanyl, pyrrolidinyl, oxolanyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, homopiperazinyl, oxanyl, thianyl, piperazinyl, . morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl, azirinyl, oxirenyl, thiirenyl, diazirinyl, azetyl, oxetyl, l, dioxetyl, tyl, imidazolinyl, pyrazolinyl, oxazolinyl and thiazolinyl.
In some embodiments, R2 is an optionally substituted 5-6 membered monocyclic aryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is an optionally substituted 5—membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is an optionally substituted 5—membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is an optionally substituted 5-membered clic aryl ring having 1—2 heteroatoms ndently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is an optionally substituted 5-membered monocyclic heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is an optionally substituted 5—membered monocyclic heteroaryl ring having 1 heteroatom ed from nitrogen, oxygen, and sulfur. In some embodiments, R2 is selected from optionally substituted pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, azolyl, zolyl, thiadiazolyl, triazolyl and tetrazolyl.
In some embodiments, R2 is an ally substituted 6-membered monocyclic heteroaryl ring having 1-4 nitrogen atoms. In some embodiments, R2 is an optionally substituted 6-membered monocyclic heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, R2 is an optionally substituted 6-membered clic heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, R2 is an optionally substituted 6-membered clic heteroaryl ring having 2 nitrogen atoms. In some embodiments, R2 is an optionally substituted 6—membered monocyclic heteroaryl ring having 1 nitrogen atom. some embodiments, R2 is selected from ally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl and tetrazinyl.
In some embodiments, R2 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from en, , and sulfur. In some ments, R2 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some ments, R2 is an optionally substituted 8-10 ed bicyclic heteroaryl ring having 1—2 heteroatoms independently selected from nitrogen, oxygen, and WO 19561 -3 2- sulfur. In some embodiments, R2 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1 heteroatom ed from nitrogen, oxygen, and sulfur. In some embodiments, R2 is selected from optionally substituted indolyl, indazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, azaindolyl, quinolinyl, isoquinolinyl, quinazolinyl, alinyl and cinnolinyl.
As described generally above, R1 and R2 are taken together with their intervening atoms to form a 4—8 membered saturated, partially unsaturated, or aromatic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1 and R2 are taken together with their intervening atoms to form a 4-8 membered saturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1 and R2 are taken together with their intervening atoms to form a 4-8 membered saturated cyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1 and R2 are taken er with their intervening atoms to form a 4-8 membered saturated cyclic ring having 2 heteroatoms independently ed from nitrogen, oxygen, and sulfur. In some embodiments, R1 and R2 are taken together With their intervening atoms to form a 4-8 membered saturated heterocyclic ring having 1 nitrogen atom. In some ments, R1 and R2 are taken together with their intervening atoms to form a ring selected from azepinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, and morpholinyl.
In some embodiments, the 4-8 membered saturated heterocyclic ring formed by R1, R2 and their intervening atoms is: ' (R5),o wherein R5 and p are as defined above and bed .
In some embodiments, the 4-8 membered saturated heterocyclic ring formed by R1, R2 and their intervening atoms is substituted with one or more halogens. In some such embodiments, the 4-8 membered ted heterocyclic ring formed by R1, R2 and their intervening atoms is: 2012/048368 In some embodiments, R‘1 and R2 are taken together with their intervening atoms to form a 4-8 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1 and R2 are taken together with their intervening atoms to form a 4-8 membered partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1 and R2 are taken together with their intervening atoms to form a 4-8 membered partially unsaturated heterocyclic ring having 2 heteroatoms independently selected from nitrogen, , and sulfur. In some embodiments, R1 and R2 are taken together with their intervening atoms to form a 4-8 membered partially unsaturated heterocyclic ring having 1 nitrogen atom. In some embodiments, R1 and R2 are taken er with their intervening atoms to form a ring ed from azetyl, imidazolidinyl, pyrazolinyl, oxazolinyl, thiazolinyl, oxazinyl, thiazinyl, azepinyl and diazepinyl.
In some embodiments, R1 and R2 are taken together with their intervening atoms to form a 4—8 ed aromatic heterocyclic ring having 1—3 heteroatoms independently selected from nitrogen, , and . In some embodiments, R1 and R2 are taken er with their intervening atoms to form a 4-8 membered aromatic heterocyclic ring having 1—2 heteroatoms independently ed from nitrogen, oxygen, and sulfur. In some embodiments, R1 and R2 are taken together with their intervening atoms to form a 4-8 membered aromatic heterocyclic ring having 2 heteroatoms independently selected from en, oxygen, and sulfiir. In some embodiments, R1 and R2 are taken together with their intervening atoms to form a 4—8 membered aromatic heterocyclic ring having 1 nitrogen atom. In some embodiments, R1 and R2 are taken together With their intervening atoms to form a ring selected from pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl.
As described generally above, the ring formed by R1 and R2, and their intervening atoms is substituted with —(R5)p, n p is 0-4. As defined above, R5 is halogen, ~N02, —CN, —N3, —L-R6, or an ally substituted group selected from C1_6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aryl ring, a 3—8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 atoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1—4 heteroatoms independently selected from en, oxygen, and sulfur, or two R5 groups on the ring formed by R1 and R2 are taken together with their intervening atoms to form a fused 4—8 membered ted, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, R5 is halogen. In some embodiments, R5 is fluorine. In some embodiments, R5 is chlorine. In some embodiments, R5 is bromine. In some embodiments, R5 is —N02. In some embodiments, R5 is —CN. In some embodiments, R5 is —N3. In some embodiments, R5 is —L-R6.
As defined lly above, each R6 is independently hydrogen or an optionally substituted group selected from C1_6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, a 4—7—membered saturated or lly unsaturated heterocyclic ring having 1—4 heteroatoms ndently selected from nitrogen, oxygen, and sulfur, a 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently ed from nitrogen, oxygen, and , and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, R6 is hydrogen. In some embodiments, R6 is optionally substituted phenyl. In some embodiments, R6 is an optionally substituted C1_6 aliphatic. In some embodiments, R6 is an optionally substituted C1-5 aliphatic. In some embodiments, R6 is an optionally substituted C1_4 aliphatic. In some embodiments, R6 is an optionally substituted C1_3 tic. In some embodiments, R6 is an optionally substituted Cm aliphatic.
In some embodiments, R6 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R6 is an optionally substituted 3-7 membered saturated carbocyclic ring. In some embodiments, R6 is an ally substituted 3-7 membered lly unsaturated carbocyclic ring. In some embodiments, R6 is ed from cyclopropyl, utyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl and cyclooctadienyl.
In some embodiments, R6 is an optionally substituted 8—1 0 membered bicyclic saturated, partially rated or aryl carbocyclic ring. In some embodiments, R6 is an optionally substituted 8-10 membered ic saturated carbocyclic ring. In some embodiments, R6 is an optionally substituted 8-10 ed ic partially unsaturated carbocyclic ring. In some embodiments, R6 is an ally substituted 8—10 membered bicyclic aryl carbocyclic ring. In some embodiments, R6 is naphthyl.
In some embodiments, R6 is an optionally substituted 4—7-membered saturated or partially unsaturated heterocyclic ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is optionally substituted 4—7— membered saturated heterocyclic ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is optionally substituted 4-7— ed ted cyclic ring having 1—3 heteroatoms independently selected from nitrogen, oxygen, and sulfiir. In some ments, R6 is optionally substituted 4-7— ed saturated heterocyclic ring having 1—2 atoms independently selected from nitrogen, oxygen, and . In some embodiments, R6 is optionally substituted 4-7— membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, inyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, oxolanyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, olidinyl, thiazolidinyl, isothiazolidinyl, anyl, dithiolanyl, piperidinyl, oxanyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, yl, dithianyl, azepanyl, oxepanyl, thiepanyl and homopiperazinyl.
In some embodiments, R6 is an optionally substituted 4-7—membered partially unsaturated heterocyclic ring having 1—4 heteroatoms independently selected from en, oxygen, and sulfur. In some embodiments, R6 is optionally substituted 4—7-membered partially unsaturated heterocyclic ring having 1—3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is optionally substituted 4 membered partially. unsaturated heterocyclic ring having 1—2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In s0rne embodiments, R6 is optionally substituted 4-7—membered partially unsaturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is selected from azirinyl, oxirenyl, thiirenyl, diazirinyl, azetyl, oxetyl, thietyl, dioxetyl, dithietyl, imidazolinyl, pyrazolinyl, oxazolinyl and thiazolinyl.
In some embodiments, R6 is an optionally substituted 5—6 ed clic heteroaryl ring having 1~4 heteroatoms independently ed from nitrogen, oxygen, and sulfur. In some embodiments, R6 is an optionally substituted S-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently ed from nitrogen, oxygen, and -3 6- sulfur. In some embodiments, R6 is an optionally substituted 5-membered monocyclic heteroaryl ring having 1-3 atoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is an optionally substituted 5-membered monocyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is an optionally tuted 5—membered monocyclic aryl ring having 2 heteroatoms ndently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is an optionally substituted 5-membered monocyclic heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is ed from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl.
In some embodiments, R6 is an ally substituted 6—membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some ments, R6 is an optionally substituted 6-membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some ments, R6 is an optionally substituted ered monocyclic heteroaryl ring having 1—2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is an optionally substituted 6—membered monocyclic heteroaryl ring having 2 heteroatoms independently selected from en, oxygen, and sulfur. In some embodiments, R6 is an optionally tuted 6-membered monocyclic heteroaryl ring having 1 heteroatom ed from nitrogen, oxygen, and sulfur. In some embodiments, R6 is selected from pyridinyl, pyrazinyl, pyridizinyl, pyrimidinyl, triazinyl and tetrazinyl.
In some ments, R6 is an optionally substituted 8—10 membered bicyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is an optionally substituted 8—10 membered bicyclic heteroaryl ring having 1-3 atoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is an optionally tuted 8—10 ed bicyclic heteroaryl ring having 1—2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is an ally substituted 8-10 membered bicyclic heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is selected from indolyl, lyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, azaindolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl and cinnolinyl.
In some embodiments, two R6 on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or aromatic heterocyclic ring having 1-2 heteroatoms independently ed from en, oxygen, and sulfur. In some embodiments, two R6 on the same nitrogen are taken together with their ening atoms to form a saturated heterocyclic ring having 1—2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R6 on the same nitrogen are taken together with their intervening atoms to form a partially rated heterocyclic ring having 1—2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some ments, two R6 on the same nitrogen are taken together with their intervening atoms to form an aromatic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is selected from inyl, azetyl, oxetyl, thietyl, dioxetyl, tyl, imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl, azetidinyl, yl, nyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, oxolanyl, thiolanyl, imidazolidinyl, pyrazolidinyl, idinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, oxanyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, yl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridizinyl and pyrimidinyl.
As defined lly above, each of n, m, and p is independently an integer selected from 0, l, 2, 3 and 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some ments, n is 3. In some embodiments, n is 4. In some embodiments, m is 0. In some embodiments, m is 1. In some‘embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, p is O. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.
As defined generally above, q is an integer selected from 0, 1 and 2. In some embodiments, q is 0. In some embodiments, q is I. In some embodiments, q is 2.
As defined lly above, each of R3 , R4, and R5 is independently halogen, —N02, — CN, —N3, -L-R6, or an optionally substituted group selected from C1_6 aliphatic, a 3—8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aryl ring, a 3—8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1—2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently 2012/048368 -3 8- selected from nitrogen, oxygen, and sulfur, and an 8—10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, , and .
In some embodiments, R3 is halogen. In some embodiments, R3 is —N02. In some embodiments, R3 is —CN. In some embodiments, R3 is —N3.
In some embodiments, R3 is optionally substituted C1-6 aliphatic. In some embodiments, R3 is optionally substituted C1-5 aliphatic. In some embodiments, R3 is optionally tuted C1_4 aliphatic. In some embodiments, R3 is optionally substituted (31-3 aliphatic. In some embodiments, R3 is optionally substituted C1-2 aliphatic. In some embodiments, R3 is selected from , ethyl, propyl, isopropyl, butyl, sec-butyl, tert—butyl, pentyl, neopentyl, isopentyl and hexyl.
In some embodiments, R3 is —L-R6.
In some embodiments, R3 is an optionally substituted phenyl.
In some embodiments, R3 is an optionally substituted 3-8 membered ted or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R3 is an optionally substituted 3-8 membered saturated monocyclic carbocyclic ring. In some ments, R3 is selected from cyclopropyl, utyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
In some embodiments, R3 is an optionally substituted 3—8 membered partially unsaturated monocyclic carbocyclic ring. In some embodiments, R3 is selected from cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl and ctadienyl.
In some embodiments, R3 is an optionally substituted an 8-10 membered bicyclic aryl ring. In some embodiments, R3 is naphthyl.
In some embodiments, R3 is an optionally substituted 3—8 membered saturated clic heterocyclic ring having 1—2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is an optionally substituted 3-8 membered saturated monocyclic cyclic ring having 2 heteroatoms independently ed from nitrogen, oxygen, and sulfur. In some embodiments, R3 is an optionally substituted 3-8 membered saturated monocyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and . In some embodiments, R3 is selected from aziridinyl, yl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, olidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, dithiolanyl, oxolanyl, thiolanyl, piperidinyl, piperazinyl, morpholinyl, oxanyl, thianyl, thiomorpholinyl, yl, dithianyl, yl, yl, thiepanyl and homopiperazinyl.
In some embodiments, R3 is an optionally substituted 3—8 membered lly unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is selected from azirinyl, oxirenyl, thiirenyl, diazirinyl, azetyl, oxetyl, thietyl, dioxetyl, dithietyl, imidazolinyl, pyrazolinyl, oxazolinyl and thiazolinyl.
In some ments, R3 is an optionally tuted 5-6 membered monocyclic heteroaryl ring having 1—4 atoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is an optionally substituted ered monocyclic heteroaryl ring having 1-4 heteroatoms independently ed from nitrogen, oxygen, and sulfur. In some embodiments, R3 is an optionally substituted 5-membered monocyclic heteroaryl ring having 1—3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is an optionally substituted 5-membered monocyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and . In some embodiments, R3 is an optionally substituted 5—membered monocyclic aryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is an optionally substituted 5-membered monocyclic heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is selected from pyrrolyl, l, enyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl.
In some embodiments, R3 is an optionally substituted 6-membered monocyclic aryl ring having 1—4 nitrogen atoms. In some ments, R3 is an optionally substituted 6-membered monocyclic heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, R3 is an optionally substituted 6-membered monocyclic heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, R3 is an optionally substituted 6-membered monocyclic heteroaryl ring having 2 nitrogen atoms. In some embodiments, R3 is an optionally substituted 6-membered monocyclic heteroaryl ring having 1 nitrogen atom. In some embodiments, R3 is selected from pyridinyl, nyl, pyridizinyl, pyrimidinyl, triazinyl and tetrazinyl.
In some embodiments, R3 is an optionally substituted 8—10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently ed from nitrogen, oxygen, and sulfur. In some embodiments, R3 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is an optionally substituted 8-10 ed bicyclic heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen, and . In some ments, R3 is selected from indolyl, indazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, riazolyl, azaindolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl and cinnolinyl.
In some ments, R4 is halogen. In some embodiments, R4 is —N02. In some embodiments, R4 is —CN. In some embodiments, R4 is —N3.
In some embodiments, R4 is optionally substituted C1_6 aliphatic. In some embodiments, R4 is optionally tuted C1_5 aliphatic. In some embodiments, R4 is optionally substituted C1_4 tic. In some embodiments, R4 is optionally substituted C1_3 aliphatic. In some embodiments, R4 is optionally substituted C1_2 aliphatic. In some ments, R4 is selected from , ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, neopentyl, isopentyl and hexyl.
In some embodiments, R4 is —L-R6.
In some embodiments, R4 is an optionally substituted phenyl.
In some embodiments, R4 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic yclic ring. In some embodiments, R4 is an optionally substituted 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, R4 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
In some embodiments, R4 is an optionally substituted 3-8 membered lly unsaturated monocyclic carbocyclic ring. In some embodiments, R4 is selected from cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, eptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl and cyclooctadienyl.
In some embodiments, R4 is an optionally substituted an 8—10 membered ic aryl ring. In some embodiments, R4 is naphthyl.
In some embodiments, R4 is an optionally substituted 3-8 ed saturated monocyclic heterocyclic ring having 1—2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some ments, R4 is an optionally substituted 3-8 membered saturated monocyclic heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R4 is an optionally substituted 3-8 membered saturated monocyclic heterocyclic ring having 1 heteroatom selected from en, oxygen, and sulfur. In some embodiments, R4 is selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, nyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, dithiolanyl, oxolanyl, thiolanyl, piperidinyl, piperazinyl, morpholinyl, oxanyl, thianyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl and homopiperazinyl.
In some embodiments, R4 is an optionally substituted 3-8 membered partially unsaturated clic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some ments, R4 is selected from azirinyl, yl, thiirenyl, diazirinyl, azetyl, , thietyl, dioxetyl, dithietyl, imidazolinyl, pyrazolinyl, oxazolinyl and thiazolinyl.
In some embodiments, R4 is an optionally substituted 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some ments, R4 is an optionally substituted S-membered monocyclic heteroaryl ring having l-4 heteroatoms independently ed from nitrogen, oxygen, and sulfur. In some embodiments, R4 is an optionally substituted 5—membered monocyclic heteroaryl ring having 1—3 heteroatoms independently ed from nitrogen, oxygen, and sulfur. In some embodiments, R4 is an optionally substituted S-membered monocyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R4 is an ally substituted ered monocyclic heteroaryl ring having 2 atoms independently selected from en, oxygen, and . In some embodiments, R4 is an optionally substituted S-membered monocyclic heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R4 is selected from pyrrolyl, l, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl.
In some embodiments, R4 is an optionally substituted ered monocyclic heteroaryl ring having l-4 nitrogen atoms. In some embodiments, R4 is an optionally tuted ered monocyclic heteroaryl ring having l-3 nitrogen atoms. In some embodiments, R4 is an optionally substituted 6-membered monocyclic heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, R4 is an optionally substituted 6-membered monocyclic heteroaryl ring having 2 nitrogen atoms. In some embodiments, R4 is an optionally tuted 6-membered monocyclic heteroaryl ring having 1 nitrogen atom. In some embodiments, R4 is selected from pyridinyl, pyrazinyl, zinyl, pyrimidinyl, triazinyl and tetrazinyl.
In some embodiments, R4 is an optionally substituted 8—10 membered bicyclic heteroaryl ring having 1—4 atoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R4 is an optionally substituted 8—10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R4 is an ally tuted 8—10 membered bicyclic heteroaryl ring having 1—2 heteroatoms independently selected from nitrogen, oxygen, and IO . In some embodiments, R4 is an optionally substituted 8—10 membered bicyclic heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R4 is selected from indolyl, indazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, azaindolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl and cinnolinyl.
In some embodiments, R5 is halogen. In some ments, R5 is —N02. In some embodiments, R5 is —CN. In some embodiments, R5 is —N3.
In some embodiments, R5 is ally substituted CM aliphatic. In some embodiments, R5 is optionally substituted C1_5 aliphatic. In some embodiments, R5 is optionally substituted C1-4 aliphatic. In some embodiments, R5 is optionally substituted C1_3 aliphatic. In some embodiments, R5 is optionally substituted C1_2 aliphatic. In some embodiments, R5 is selected from methyl, ethyl, propyl, isopropyl, butyl, tyl, utyl, pentyl, neopentyl, isopentyl and hexyl.
In some embodiments, R5 is ~L—R6.
In some ments, R5 is an optionally substituted phenyl.
In some embodiments, R5 is an optionally substituted 3—8 ed saturated or partially unsaturatedmonocyclic carbocyclic ring. In some embodiments, R5 is an optionally substituted 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, R5 is ed from cyclopropyl, cyclobutyl, entyl, cyclohexyl, cycloheptyl and cyclooctyl.
In some embodiments, R5 is an ally substituted 3-8 membered partially unsaturated monocyclic carbocyclic ring. In some embodiments, R5 is selected from cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, entadienyl, cyclohexadienyl, cycloheptadienyl and cyclooctadienyl.
In some ments, R5 is an optionally tuted an 8-10 membered bicyclic aryl ring. In some embodiments, R5 is yl.
In some embodiments, R5 is an optionally substituted 3-8 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently Selected from nitrogen, oxygen, and sulfur. In some embodiments, R5 is an optionally substituted 3-8 membered saturated clic heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R5 is an optionally substituted 3-8 membered ted monocyclic heterocyclic ring having 1 heteroatom selected from nitrogen, , and . In some embodiments, R5 is selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, imidazolidinyl, lidinyl, idinyl, isoxazolidinyl, dioxolanyl, dithiolanyl, oxolany1,thiolanyl, piperidinyl, piperazinyl, morpholinyl, oxanyl, thianyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl and homopiperazinyl.
In some embodiments, R5 is an optionally substituted 3-8 ed partially unsaturated clic heterocyclic ring having 1—2 heteroatoms independently selected from nitrogen, , and sulfur. In some embodiments, R5 is selected from azirinyl, oxirenyl, thiirenyl, diazirinyl, azetyl, oxetyl, thietyl, dioxety1,.dithiety1, imidazolinyl, pyrazolinyl, oxazolinyl and thiazolinyl.
In some embodiments, R5 is an optionally substituted 5-6 membered clic heteroaryl ring having 1-4 heteroatoms ndently ed from nitrogen, oxygen, and sulfur. In some embodiments, R5 is an optionally substituted 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R5 is an optionally substituted 5-membered clic heteroarylring having 1-3 atoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R5 is an optionally tuted S-membered monocyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfilr. In some embodiments, R5 is an optionally substituted 5-membered monocyclic heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R5 is an optionally substituted ered monocyclic heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R5 is selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl.
WO 19561 -44_ In some embodiments, R5 is an optionally substituted 6—membered monocyclic heteroaryl ring having 1-4 nitrogen atoms. In some embodiments, R5 is an optionally substituted 6—membered monocyclic heteroaryl ring having 1—3 nitrogen atoms. In some embodiments, R5 is an optionally tuted 6-membered monocyclic aryl ring having 1-2 nitrogen atoms. In some embodiments, R5 is an optionally substituted 6-membered monocyclic heteroaryl ring having 2 nitrogen atoms. In some embodiments, R5 is an optionally substituted 6-membered monocyclic heteroaryl ring having 1 nitrogen atom. In some embodiments, R5 is ed from pyridinyl, pyrazinyl, pyridizinyl, pyrimidinyl, triazinyl and inyl.
In some embodiments, R5 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, , and sulfur. In some embodiments, R5 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R5 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1—2 heteroatoms independently selected from nitrogen, , and sulfur. In some embodiments, R5 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R5 is selected from indolyl, indazolyl, uranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, idazolyl, benzotriazolyl, azaindolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl and inyl.
In some embodiments, two R3 groups on Ring B are taken together with their intervening atoms to form a fused 4—8 membered saturated, partially unsaturated, or aryl ring having 0—3 heteroatoms independently selected from nitrogen, oxygen, and . In some embodiments, two R3 groups on Ring B are taken together with their intervening atoms to form a fused 4—8 membered saturated, partially unsaturated, or aryl ring having 1-3 heteroatoms independently selected from en, oxygen, and sulfur. In some embodiments, two R3 groups on Ring B are taken together with their ening atoms to form a fused 4—8 membered saturated, partially unsaturated, or aryl ring having 1 heteroatom ed from nitrogen, oxygen, and sulfur. In some embodiments, two R3 groups on Ring B are taken together with their intervening atoms to form a fused 4-8 membered saturated, partially unsaturated, or aryl ring having 2—3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R3 groups on Ring B are taken together with their intervening atoms to form a fused 4-8 membered saturated, partially unsaturated, or aryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R3 groups on Ring B are taken together with their intervening atoms to form a phenyl ring. In some embodiments, two R3 groups on Ring B are taken together with their intervening atoms to form a ring selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, yl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, oxolanyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, lidinyl, isothiazolidinyl, dioxolanyl, lanyl, dinyl, , l, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, yl, oxepanyl, thiepanyl, homopiperazinyl, azirinyl, oxirenyl, thiirenyl, diazirinyl, azetyl, oxetyl, thietyl, dioxetyl, dithietyl, imidazolinyl, pyrazolinyl, inyl, thiazolinyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, yl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridizinyl, pyrimidinyl, triazinyl and tetrazinyl.
In some embodiments, two R4 groups on Ring A are taken together with their intervening atoms to form a fused 4-8 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R4 groups on Ring B are taken together with their intervening atoms to form a fused 4—8 membered saturated, partially unsaturated, or aryl ring having 1—3 atoms independently ed from nitrogen, oxygen, and sulfur. In some embodiments, two R4 groups on Ring B are taken together with their intervening atoms to form a fused 4-8 membered saturated, partially unsaturated, or aryl ring having 1 heteroatom selected from nitrogen, , and . In some embodiments, two R4 groups on Ring B are taken together with their intervening atoms to form a fused 4—8 membered saturated, partially unsaturated, or aryl ringhaving 2-3 heteroatoms ndently ed from nitrogen, oxygen, and sulfur. In some embodiments, two R4 groups on Ring B are taken together with their ening atoms to form a fused 4—8 membered saturated, partially unsaturated, or aryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R4 groups on Ring B are taken together with their intervening atoms to form a phenyl ring. In some embodiments, two R4 groups on Ring B are taken together with their ening atoms to form a ring selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl,thietany1, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, oxolanyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, oxanyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl, homopiperazinyl, azirinyl, oxirenyl, thiirenyl, inyl, azetyl, oxetyl, thietyl, yl, tyl, imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl, cyclobutyl, cyclopentyl, exyl, cycloheptyl, cyclooctyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, azolyl, oxadiazolyl, thiadiazolyl, triazoly1,tetrazolyl, pyridinyl, pyrazinyl, zinyl, pyrimidinyl, triazinyl and tetrazinyl.
In some embodiments, two R5 groups on the ring formed by R1 and R2 are taken together with their intervening atoms to form a fused 4-8 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R5 groups on Ring B are taken together with their intervening atoms to form a fused 4-8 ed saturated, partially unsaturated, or aryl ring having 1—3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R5 groups on Ring B are taken together with their intervening atoms to form a fused 4—8 membered ted, partially unsaturated, or aryl ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, two R5 groups on Ring B are taken together with their intervening atoms to form a fused 4-8 membered saturated, partially unsaturated, or aryl ring having 2—3 atoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R5 groups on Ring B are taken together with their intervening atoms to form a fiised 4-8 membered saturated, partially unsaturated, or aryl ring having 2 heteroatoms independently selected from nitrogen, , and sulfur. In some embodiments, two R5 groups on Ring B are taken together with their intervening atoms to form a phenyl ring. In some embodiments, two R5 groups on Ring B are taken together with their intervening atoms to form a ring selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, nyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, oxolanyl, nyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, oxanyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, yl, thiepanyl, homopiperazinyl, azirinyl, oxirenyl, thiirenyl, diazirinyl, azetyl, oxetyl, thietyl, dioxetyl, dithietyl, imidazolinyl, pyrazolinyl, inyl, thiazolinyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, ctyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, lyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridizinyl, pyrimidinyl,triaziny1 and tetrazinyl.
As defined generally above, L is a covalent bond or an optionally substituted bivalent C1_6 hydrocarbon chain, wherein one or two methylene units of L is optionally and independently ed by —C —, —0~, —s—, -N(R6)—, —C(O)—, —C(S)—, —C(O)N(R6)—, —N(R6>C<O>N<R6>~, —N(R6)C<O)—, —N<R6>C<O>O—, —OC<O>N<R6>~, —S<0>—, —s<0)2—, —S(O)2N(R6)—, —N(R6)S(O)2—, —OC(O)— or —. In some embodiments, L is a covalent bond. In some embodiments, L is an optionally substituted bivalent C1_6 arbon chain, wherein one or two ene units of L is optionally and ndently replaced by ~Cy—, -o—, —S—, -N(R6)—, —C(O)—, —C(S)—, (R6)—, C(O)N(R6)—, —N(R6)C(O)—, —N(R6)C(O)O—, -OC(O)N(R6)—, —S(O)—, —S(O)2—, —S(O)2N(R6)—, —N(R6)S(O)2—, —OC(O)— or -—. In some embodiments, L is an optionally substituted bivalent C1.5 arbon chain, wherein one or two methylene units of L is optionally and independently replaced by —Cy—, —o—, —s—, —N(R6)—, —C(O)—, —C(S)—, (R6)—, —N(R6)C(O)N(R6)—, —N(R6)C(O)—, C(O)O—, -OC(O)N(R6)-, —S(O)—, -S(O)2—, —S(O)2N(R6)-—, —N(R6)S(O)2—, —OC(O)— or —C(O)O—. In some embodiments, L is an optionally substituted bivalent CM hydrocarbon chain, wherein one or two methylene units of L is optionally and independently replaced by -Cy—, —o—, —s—, -N(R6)—, —C(O)—, —C(S)—, —C(O)N(R6)—, —N(R6)C(O)N(R6)—, —N(R6)C(O)—, C(O)O-—, -OC(O)N(R6)-, —S(O)—, —, —S(O)2N(R6)—, —N(R6)S(O)2—, ~OC(O)— or —C(O)O—. In some embodiments, L is an ally substituted bivalent C1_3 hydrocarbon chain, wherein one or two methylene units of L is optionally and independently replaced by —C e, —0—, es—, —, —C(O)—, —C(S)—, —C(O)N(R6)—, C(O)N(R6)—, —N(R6)C(O)—, —N(R6)C(O)O—, -OC(O)N(R6)—, —S(O)—,_ —S(O)2—, —S(O)2N(R6)—, —N(R6)S(O)2—, —OC(O)— or ~—C(O)O-. In some embodiments, L is an optionally substituted bivalent C1_2 hydrocarbon chain, wherein one or two methylene units of L is optionally and independently replaced by -C —, e0—, —S—, -N(R6)—, ——C(O)—, ~C(S)—, —C(O)N(R6)—, —N(R6)C(O)N(R6)—~, —N(R6)C(O)—, ~N(R6)C(O)O—, ~OC(O)N(R6)—, ~S(O)—, —S(O)2—, -S(O)2N(R6)—, —N(R6)S(O)2—, —OC(O)— or —C(O)O~—. In some embodiments, L is —Cy—. In some ments, L is -O—. In some embodiments, L is —S~. In some embodiments, L is —N(R6)—. In some embodiments, L is -C(O)—. In some embodiments, L is —C(S)-. In some embodiments, L is —C(O)N(R6)—. In some embodiments, L is —N(R6)C(O)N(R6)—. In some embodiments, L is —N(R6)C(O)—. In some embodiments, L is C(O)O—. In some embodiments, L is —OC(O)N(R6)—. In some embodiments, L is —S(O)—. In some embodiments, L is —S(O)2—. In some embodiments, L is —S(O)2N(R6)—. In some embodiments, L is —N(R6)S(O)2—. In some embodiments, L is —OC(O)—. In some embodiments, L is —C(O)O—.
In some embodiments, L is —CH2—Cy—. In some embodiments, L is —CH2—O—. In some embodiments, L is —. In some embodiments, L is —CH2-N(R6)—. In some embodiments, L is —CH2—C(O)—. In some embodiments, L is (S)—. In some embodiments, L is —CH2—C(O)N(R6)—. 'In some ments, L is —CH2—N(R6)C(O)N(R6)—.
In some embodiments, L is —CH2—N(R6)C(O)——. In some embodiments, L is ~CH2— N(R6)C(O)O—. In some embodiments, L is —CH2—OC(O)N(R6)—. In some embodiments, L is —CH2—S(O)—. In some embodiments, L is —CH2~S(O)2—. In some embodiments, L is —CH2~ S(O)2N(R6)—. In some embodiments, L is (R6)S(O)2—. In some embodiments, L is -CH2—OC(O)—. In some embodiments, L is —CH2—C(O)O—.
In some embodiments, L is ~Cy~CH2—. In some embodiments, L is ~O—CH2—. In some embodiments, L is —S—CH2—. In some ments, L is —N(R6)—CH2—. In some embodiments, L is —C(O)—CH2—. In some embodiments, L is —C(S)~CH2—. In some embodiments, L is -C(O)N(R6)—CH2~. In some embodiments, L is —N(R6)C(O)N(R6)—CH2~.
In some embodiments, L is —N(R6)C(O)—CH2—. In some embodiments, L is —N(R6)C(O)O~ CH2—. In some embodiments, L is -OC(O)N(R6)——CH2—. In some embodiments, L is —S(O)~CH2—. In some embodiments, L is —S(O)2~CH2—. In some embodiments, L is -S(O)2N(R6)—~CH2—. In some ments, L is —N(R6)S(O)2—CH2~. In some embodiments, L is —OC(O)-CH2—. In some embodiments, L is —C(O)O—CH2‘.
As defined generally above, —Cy* is an optionally substituted bivalent ring selected from a 3-7 ed saturated or partially unsaturated cycloalkylenylene ring, a 4-7— membered saturated or partially unsaturated cycloalkylene ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenylene, a 5-6 membered monocyclic heteroarylene having 1—4 heteroatoms ndently selected from en, oxygen, and sulfur, an 8-10 membered bieyclic arylene, or an 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some ments, the present invention provides a compound of formula I—a or I- (R3)n\G_Y_®\ME;fl®\(R4)m (I—a) or x N\R2 ()nR3)n‘Y N <R“>m (Lb), or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, X, Y, R1, R2, R3, R4, m, n and q is as defined above and described herein.
' In some embodiments of formulae La and I-b, q is 0. Thus, in some embodiments, the present invention es a nd of formula II-a or II-b: “noGo (R4)m (II-a) or Weox (R4)m (II—b), or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, X, Y, R1, R2, R3, R4, m and n is as defined above and described herein.
In some ments of formulae II—a and lI-b, Y is a covalent bond. Thus, in some embodiments, the present invention provides a compound of formula III—a or III-b: -———— R2 (R4)m (III-a) or _ R2 (Ran /—>-N/ ‘7®\ x \R1 (R )m4 (III—b), or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, X, R1, R2, R3, R4, m and n is as defined above and described herein.
In some embodiments of formulae III—a and III-b, X is 0. Accordingly, in some embodiments, the present ion provides a compound of formula IV-a or IV-b: __ \Rz ‘Rsl‘C/il (R4)m (IV-a) or _ R2 (R3)n ”N: to0 R1 (R4)m (IV-b), or a pharmaceutically acceptable salt‘thereof, wherein each of Ring A, Ring B, R1, R2, R3, R4, m and n is as defined above and described herein.
In some embodiments of ae IV-a and IV-b, Ring A is a 5—membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of formulae IV-a and IV-b, Ring A is a 5- membered monocyclic heteroaryl ring having 1-3 atoms independently selected from nitrogen, oxygen, and . In some embodiments of formulae IV—a and IV-b, Ring A is a —membered monocyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of formulae lV—a and IV-b, Ring A is a -membered monocyclic heteroaryl ring having 2 atoms ndently selected from nitrogen, oxygen, and . In some embodiments of formulae IV-a and IV—b, Ring A is a -membered monocyclic heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen, and . In some embodiments of formulae IV-a and IV—b, Ring A is selected from yl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, zolyl, thiadiazolyl, lyl and tetrazolyl.
In some embodiments of formulae lV-a and lV—b, Ring A is triazolyl. Accordingly, in some embodiments, the present ion provides compounds of formulae V-a, V—b, V-c and V-d: V R2 / N N/N N/Nq/ \R1 (R3)n 9 N/>—(R4)m I N)“(R4)m (R3)n a (V-a), ‘ (V-b), 0 N/ \R2 R2 / WM/ / R1 N N \ O l \N 1 N (R3)n a N: (R3)n a (Rom (we) and Wm (v-dx or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R1, R2, R3, R4 and n is as defined above and described herein and m is O or 1.
In some embodiments of formulae IV—a and IV-b, Ring A is imidazolyl. Accordingly, in some embodiments, the present invention provides compounds of formulae V-e, V-f, V-g, V-h, V—i and V-j: (R3)n a N (Rom (R3>n a N (Ram (V-e), (V-fl 2012/048368 (R4 Q>m m“ i3“: (Rm (k4)m (V-g), (kibm (V—h) HR If”:(R )m (Rena \ (R3)n G\ (R4)m (v-1) and 024),, (V-j), or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R1, R2, R3, R4, m and n is as defined above and described herein.
In some embodiments of ae lV-a and IV—b, Ring A is pyrazolyl. Accordingly, in some embodiments, the present invention provides compounds of formulae V-k, V—l, V-m, V'fla V*0, V-p, V-q, V—r, V-s and V-t: O N/R 2 WR2\R (R3)n\.L>(R4)m (R3L1)n\./|\:;Y(R4)m| (V--k), (V 1) 0 N/ \ R2 N N i N V (R3)n a X(R4)m (R3)n a (V-m), (V-n) 0 NR 2 \R2 5 / N N/ N/ O (R3)n\./N\//\(R4)m (V'OL (R3)n\./lll\//\(R4)m (V'P) (R3)'N\N’\(R4>m (V-s) and ./N\NX(R4)m (V4), R3 m and n or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R1, R2, , R4, is as defined above and described herein.
In some embodiments of formulae lV-a and lV-b, Ring A is pyrrolyl. Accordingly, in some embodiments, the present ion provides compounds of formulae V-u, V-v, V-W, V-X, V-y, V—z, V-aa, V-bb, V-cc and V—dd: \ R2 / W/ N N (R3)n\./£/(R4)m > O (R3)n e /\(R4)m (V41): (V-VL W0 2013/019561 PCT/U82012/048368 (R4)g N: (R3)na \(R4)m (R3)n)n\./‘\/\(R4)m (VWW) (V'X)> (V-bb), or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R1, R2, R3 , R4, m and n is as defined above and described herein.
In some embodiments of formula V—a, V-b, V-c, V—d, V-e, V-f, V-g, V—h, V—i, V-j, V- k, V-l, V-m, V—n, V-o, V-p, V—q, V-r, V—s, V-t, V-u, V—V, V-w, V—X, V-y, V-z, V—aa, V-bb, V— cc or V—dd, Ring B is optionally substituted phenyl. In some ments of a V—a, V—b, V-c, V-d, V-e, V-f, V-g, V-h, V—i, V—j, V-k, V—l, V-m, V—n, V-o, V—p, V-q, V—r, V—s, V— t, V—u, V-V, V-w, V-X, V-y, V—z, V—aa, V-bb, V—cc or V-dd, Ring B is phenyl substituted with one or more ally substituted methyl groups. In some embodiments of formula V—a, V— b, V-c, V-d, V—e, V-f, V—g, V-h, V—i, V-j, V-k, V-l, V—m, V-n, V-o, V—p, V-q, V—r, V-s, V—t,‘ V—u, V-V, V—w, V-X, V-y, V-z, V—aa, V-bb, V—cc or V—dd, Ring B is phenyl substituted with one optionally tuted methyl group. In some embodiments of formula V-a, V-b, V—c, V- d, V-e, V—f, V-g, V—h, V-i, V~j, V-k, V—l, V-m, V-n, V-o, V-p, V—q, V-r, V—s, V-t, V-u, V—V, V-w, V—X, V-y, V—z, V-aa, V—bb, V-cc or V-dd, Ring B is phenyl substituted with two optionally substituted methyl groups.
In some embodiments of formula V—a, V—b, V-c, V-d, V—e, V-f, V-g, V—h, V-i, V-j, V— k, V—l, V-m, V-n, V—o, V-p, V-q, V—r, V-s, V-t, V-u, V—V, V-w, V-X, V-y, V—z, V-aa, V-bb, V- with at cc or V-dd, Ring B is phenyl substituted with one or more methyl groups substituted least one halogen. In some embodiments of formula V-a, V~b, V—c, V-d, V—e, V-f, V-g, V—h, V-i, V—j, V—k, V-l, V-m, V—n, V-o, V-p, V-q, V—r, V—s, V-t, V-u, V—V, V-w, V-X, V-y, V-z, V— aa, V-bb, V-cc or V—dd, Ring B is phenyl substituted with one or more methyl groups substituted with at least two halogens. In some embodiments of formula V-a, V-b, V-c, V-d, V—e, V-f, V-g, V—h, V—i, V-j, V-k, V—l, V—m, V-n, V-o, V-p, V—q, V—r, V-s, V-t, V—u, V-V, V- substituted with one or more W, V-X, V-y, V-z, V-aa, V-bb, V—cc or V—dd, Ring B is phenyl methyl groups substituted with three halogens.
In some embodiments of formula V-a, V—b, V-c, V-d, V-e, V-f, V—g, V—h, V—i, V-j, V— k, V-l, V—m, V—n, V—o, V-p, V—q, V—r, V-s, V—t, V—u, V-V, V-w, V-X, V—y, V-z, V-aa, V-bb, V- cc or V-dd, Ring B is phenyl substituted with one or more —CF3 groups. In some embodiments of a V-a, V—b, V-c, V-d, V—e, V—f, V-g, V—h, V-i, V—j, V—k, V-I, V-m, V- V—cc or V-dd, n, V-o, V—p, V—q, V—r, V—s, V-t, V—u, V-V, V—w, V—X, V-y, V-z, V-aa, V-bb, Ring B is phenyl substituted with two —CF3 groups.
In some embodiments of formula V—a, V-b, V—c, V-d, V-e, V-f, V—g, V-h, V-i, V—j, V- k, V—l, V—m, V—n, V—o, V-p, V-q, V-r, V-s, V-t, V—u, V-V, V-w, V—X, V—y, V-z, V-aa, V-bb, V— cc or V—dd, Ring B is: F3C\ ; 2%: In some embodiments of formula V—a, V-b, V-c, V-d, V—e, V—f, V—g, V—h, V-i, V-j, V- k, V-l, V—m, V—n, V—o, V—p, V—q, V-r, V-s, V-t, V-u, V-v, V—w, V-X, V-y, V—z, V-aa, V-bb, V- cc or V-dd, R1 and R2 are taken together with their intervening atoms to form a 4—8 membered saturated, partially unsaturated, or ic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed thereby is substituted With —(R5)p.
In some embodiments of formula V—a, V-b, V-c, V—d, V—e, V—f, V-g, V-h, V-i, V—j, V— k, V-l, V—m, V-n, V—o, V—p, V-q, V-r, V-s, V—t, V—u, V-v, V-w, V—X, V-y, V—z, V-aa, V-bb, V- cc or V—dd, the 4-8 membered saturated heterocyclic ring formed by R1, R2 and their intervening atoms is: é‘N/\\ 5 V (R )9 ,wherein R5 and p are as defined above and described herein.
In some embodiments of formula V—a, V-b, V-c, V—d, V-e, V-f, V—g, V-h, V-i, V-j, V— k, V-l, V—m, V-n, V-o, V—p, V—q, V-r, V-s, V-t, V-u, V-V, V—W, V-X, V-y, V—z, V—aa, V—bb, V- cc or V—dd, the 4-8 membered saturated heterocyclic ring formed by R1, R2 and their intervening atoms is substituted with one or more halogens. In somesuch embodiments of formula V—a, V—b, V-c, V—d, V-e, V-f, V—g, V—h, V-i, V-j, V—k, V-l, V-m, V-n, V-o, V-p, V—q, V-r, V-s, V-t, V-u, V—V, V-w, V—X, V—y, V—z, V-aa, V—bb, V-cc or V—dd, the 4-8 ed saturated heterocyclic ring formed by R1, R2 and their intervening atoms is: — -N©<Fg 2O , In some embodiments of formula V-a, V-b, V—c, V-d, V-e, V—f, V—g, V-h, V-i, V-j, V— k, V-l, V-m, V—n, V-o, V-p, V—q, V-r, V-s, V-t, V-u, V-v, V-w, V—x, V—y, V-z, V-aa, V—bb, V- cc or V-dd, Ring B is optionally substituted phenyl and the 4-8 ed saturated heterocyclic ring formed by R], R2 and their intervening atoms is: I _N/\\ V R5 ( )9, n R5 and p are as defined above and described herein.
In some embodiments of formula V-a, V-b, V—c, V—d, V-e, V—f, V-g, V—h, V-i, V-j, V- k, V-l, V—m, V-n, V—o, V-p, V—q, V-r, V-s, V-t, V-u, V-v, V-w, V—X, V—y, V-z, V-aa, V—bb, V- cc or V-dd, Ring B is phenyl tuted with one or more ally substituted methyl groups and the 4-8 membered saturated heterocyclic ring formed by R1, R2 and their intervening atoms is: V —N/\>\ ( R5)P ,wherein R5 and p are as defined above and described herein.
In some embodiments of formula V-a, V—b, V—c, V—d, V-e, V—f, V-g, V-h, V—i, V—j, V— k, V-l, V—m, V-n, V-o, V-p, V-q, V-r, V—s, V-t, V-u, V-v, V-w, V-x, V—y, V—z, V—aa, V—bb, V- cc or V—dd, Ring B is phenyl substituted with two optionally tuted methyl groups and the 4-8 membered saturated heterocyclic ring formed by R‘, R2 and their intervening atoms ‘ -N/\\ V ( R5)9 ,wherein R5 and p are as defined above and described herein.
In some embodiments of formula V-a, V—b, V—c, V—d, V-e, V-f, V-g, V—h, V—i, V-j, V- k, V-l, V—m, V-n, V-o, V—p, V-q, V—r, V-s, V-t, V—u, V—v, V-w, V-X, V—y, V—z, V-aa, V-bb, V— cc or V-dd, Ring B is phenyl tuted with one or more methyl groups substituted with at least one halogen and the 4—8 membered saturated heterocyclic ring formed by R1, R2 and their ening atoms is: E‘N/\\ 5 (R )P ,Wherein R5 and p are as defined above and described herein.
In some embodiments of formula V—a, V-b, V-c, V—d, V—e, V-f, V—g, V-h, V-i, V—j, V- k, V—l, V-m, V—n, V—o, V-p, V—q, V-r, V—s, V—t, V-u, V-v, V—W, V—x, V—y, V—z, V-aa, V-bb, V- cc or V-dd, Ring B is phenyl substituted with one or more methyl groups substituted with three halogens and the 4-8 membered saturated heterocyclic ring formed by R1, R2 and their 2O intervening atoms is: _ _N/\ V\(R5)P in R5 and p are as defined above and bed herein.
In some embodiments of formula V—a, V-b, V-c, V—d, V-e, V-f, V-g, V—h, V-i, V—j, V- k, V-l, V-m, V-n, V—o, V-p, V—q, V-r, V—s, V-t, V-u, V-V, V-w, V—x, V-y, V-z, V-aa, V—bb, V— cc or V-dd, Ring B is phenyl substituted with one or more —CF3 groups and the 4—8 membered saturated heterocyclic ring formed by R1, R2 and their intervening atoms is: _ —N/\\ V ( R5)P ,wherein R5 and p are as defined above and described herein.
In some embodiments of formula V-a, V—b, V-c, V—d, V-e, V—f, V-g, V-h, V-i, V-j, V— k, V-l, V—m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-V, V-W, V-x, V-y, V—z, V-aa, V—bb, V- 2012/048368 -58~ cc or V—dd, Ring B is phenyl substituted With two —CF3 groups and the 4-8 membered saturated heterocyclic ring formed by R1, R2 and their intervening atoms is: ’ ’N<>\ ( R5)P ,wherein R5 and p are as defined above and described herein.
In some embodiments of formula V-a, V—b, V—c, V—d, V-e, V-f, V—g, V-h, V-i, V-j, V— k, V—l, V-m, V-n, V—o, V-p, V-q, V—r, V—s, V-t, V-u, V-v, V—W, V-X, V—y, V—z, V—aa, V-bb, V— cc or V—dd, Ring B is: F3C©LLL1/ CFS ,and the 4—8 membered saturated cyclic ring formed by R1, R2 and their intervening atoms is: gmV\(R5)P ,Wherein R5 and p are as defined above and described herein.
In some embodiments of formula V-a, V-b, V-c, V—d, V-e, V—f, V-g, V—h, V-i, V—j, V- k, V-l, V-m, V-n, V-o, V—p, V—q, V-r, V-s, V—t, V-u, V—V, V-w, V-x, V—y, V-z, V-aa, V—bb, V- cc or V—dd, Ring B is ally substituted phenyl and the 4—8 membered saturated heterocyclic ring formed by R1, R2 and their intervening atoms is: “E‘NyFF In some embodiments of formula V-a, V—b, V-c, V—d, V—e, V-f, V-g, V-h, V-i, V—j, V- k, V—l, V-m, V-n, V—o, V-p, V-q, V—r, V—s, V—t, V-u, V-V, V—W, V-x, V-y, V-z, V—aa, V-bb, V— cc or V—dd, Ring B is phenyl substituted with one or more optionally‘substituted methyl R2 and their groups and the 4-8 membered saturated heterocyclic ring formed by R1, intervening atoms is: E‘NyF In some embodiments of formula V-a, V—b, V-c, V—d, V—e, V—f, V-g, V—h, V-i, V—j, V- k, V—l, V-m, V—n, V-o, V—p, V-q, V-r, V-s, V—t, V-u, V-V, V—W, V-X, V-y, V—z, V—aa, V-bb, V— cc or V-dd, Ring B is phenyl substituted with two optionally substituted methyl groups and the 4-8 membered saturated cyclic ring formed by R1, R2 and their intervening atoms is: éNOfif In some embodiments of formula V-a, V-b, V-c, V-d, V—e, V-f, V—g, V-h, V—i, V-j, V- k, V—l, V-m, V—n, V-o, V—p, V—q, V-r, V-s, V—t, V-u, V-V, V—W, V-X, V—y, V—z, V-aa, V—bb, V- cc or V-dd, Ring B is phenyl substituted with one or more methyl groups substituted With at least one halogen and the 4—8 membered ted heterocyclic ring formed by R1, R2 and their intervening atoms is: “90$F In some embodiments of formula V-a, V—b, V—c, V-d, V—e, V-f, V-g, V—h, V-i, V-j, V- k, V-l, V—m, V—n, V—o, V-p, V-q, V-r, V-s, V—t, V—u, V-v, V-W, V-X, V-y, V—z, V—aa, V-bb, V— 00 or V-dd, Ring B is phenyl substituted With one or more methyl groups tuted with three halogens and the 4-8 membered saturated heterocyclic ring formed by R1, R2 and their intervening atoms is: g F - —NX: In some embodiments of formula V—a, V—b, V—c, V-d, V-e, V—f, V—g, V-h, V-i, V—j, V- k, V-l, V-m, V—n, V-o, V-p, V—q, V—r, V—s, V-t, V-u, V-v, V-W, V-X, V-y, V—z, V-aa, V-bb, V— cc or V—dd, Ring B is phenyl substituted with one or more —CF3 groups and the 4—8 membered saturated cyclic ring formed by R1, R2 and their ening atoms is: - -NE ©<F In some embodiments of formula V—a, V-b, V—c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V— k, V—l, V-m, V-n, V—o, V-p, V—q, V-r, V-s, V-t, V—u, V—v, V-W, V-X, V—y, V-z, V—aa, V—bb, V— membered cc or V-dd, Ring B is phenyl substituted with two ~CF3 groups and the 4—8 saturated heterocyclic ring formed by R1, R2 and their intervening atoms is: g N:><FF In some embodiments of formula V—a, V-b, V-c, V—d, V—e, V-f, V-g, V-h, V-i, V-j, V- k, V-l, V-m, V-n, V-o, V-p, V—q, V-r, V—s, V—t, V-u, V—v, V—W, V—X, V-y, V-z, V—aa, V-bb, V- cc or V—dd, Ring B is: F3C\©\1{ CF13 and the 4—8 membered saturated heterocyclic ring formed by R1, R2 and their intervening atoms is: ~60— One embodiment of the invention is a compound of formula I, or a pharmaceutically acceptable salt f, wherein: Ring A is an optionally substituted ring selected from phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently ed from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfiir; Ring B is an optionally substituted ring selected from a 3—8 membered saturated or partially unsaturated monocyclic carbocyclic ring, , an 8—10 membered bicyclic aryl ring, a 3-8 membered saturated or partially rated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered clic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8—10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently ed from nitrogen, oxygen, and sulfur; X is selected from O, S, N—CN, and NR; R is hydrogen or an optionally tuted group selected from C1-6 aliphatic, 3-8 ed saturated or partially unsaturated heterocyclic ring having 1—2 heteroatoms independently ed from nitrogen, oxygen, and sulfur, , and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently ed from nitrogen, oxygen, and sulfur; Y is a covalent bond or an optionally tuted bivalent C1_4 hydrocarbon group, n one methylene unit of Y is optionally replaced by —O—, —S—, -N(R6)—, —C(O)— , —C<S)—, -C(O>N(R6>—, wN(R6)C<O>N<R6>—, —N(R6)C(O>—, —N<R6>C(0>0—, -OC(O)N(R6)—, —S(O)—, -S(O)2—, N(R6)—, —N(R6)S(O)2—, —OC(O)— or — C(O)O~—; each of R1 and R2 is independently hydrogen or an optionally substituted group selected from C1_6 aliphatic, a 3—8 membered saturated or partially unsaturated monocyclic yclic ring, phenyl, an 8-10 membered bicyclic aryl ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, and sulfiir, and an 8-10 membered bicyclic heteroaryl ring having 1—4 atoms independently selected from nitrogen, oxygen, and sulfur, or: R1 and R2 are taken together with their intervening atoms to form a 4-8 membered saturated, partially unsaturated, or aromatic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed thereby is substituted with ; each of n, m, and p is independently an r selected from O, l, 2, 3 and 4; q is an integer selected from O, l and 2; each of R3, R4, and R5 is ndently halogen, —N02, —CN, ~N3, -L-R6, or an optionally substituted group selected from C1-6 aliphatic, a 3—8 membered saturated or partially unsaturated monocyclic yclic ring, phenyl, an 8—10 membered bicyclic aryl ring, a 3-8 ed saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms ndently selected from nitrogen, oxygen, and sulfur, a 5—6 membered clic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, , and sulfur, and an 8—10 membered bicyclic aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or: two R3 groups on Ring B are taken together with their intervening atoms to form a fused 4-8 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: two R4 groups on Ring A are taken together with their intervening atoms to form a fused 4-8 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: two R5 groups on the ring formed by R1 and R2 are taken together with their intervening atoms to form a fused 4-8 membered saturated, lly unsaturated, or aryl ring having 0-3 atoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or an optionally substituted bivalent C1-6 hydrocarbon group, wherein one or two methylene units of L is optionally and independently replaced by -Cy—, —o—, —s—, —N(R6)—, —C(O)—, —C(S)—, —C(O)N(R6)—, —N(R6)C(O)N(R6)—, —N<R6)C<0>—, —N<R6>C<O>O—, -OC<O>N<R6>—, ~s<0>—, —s<0>2—, —s<0>2N(R6>-, —N(R6)S(O)2—, — or —C(O)O—; WO 19561 ~Cy— is an optionally substituted bivalent ring selected from a 3-7 membered saturated or partially unsaturated cycloalkylenylene ring, a 4—7-membered ted or partially unsaturated heterocycloalkylene ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenylene, a 5-6 membered monocyclic heteroarylene having 1-4 heteroatoms independently ed from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic arylene, and an 8-10 ed bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R6 is independently en or an ally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, a 4membered saturated or lly unsaturated heterocyclic ring having 1—4 heteroatoms ndently selected from nitrogen, oxygen, and sulfur, a —6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and , and an 8—10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: two R6 on the same en are taken together with their intervening atoms to form a 4—7 membered saturated, partially unsaturated, or aromatic cyclic ring having 1—2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In one specific embodiment of a compound of formula I, the compound is not a compound listed in Table 1A.
Table 1A.
Compound ure ' Compound Name N’N_ N” (z)-3—(3-(3-ch1h1114'llorop eny )- H- ,2, -tr1azo ~ — / / O N yl)-N~cyclopentylacrylamide N’NWNO (Z)-l-(azetidin—l-yl)(3—(3-chlorophenyl)— CI / O N lH—l,2,4-triazol-1—yl)prop-2—en—1-one —63- nd Structure Compound Name (Z)-3—(3—(3 -chloropheny1)-1H—1,2,4—triazol-1— ’ O F CI / y1)—1—(3,3 -difluor0azetidin—1-y1)pr0p—2-en 0116 F (Z)-1—(3 ,3-difluoroazetidin—1—y1)(3 —(3 - ac / O N methoxy-S—(trifluoromethyl)phenyl)—1H- 1,2,4-triazol~1-y1)prop—2-en—1-0ne OCH3 N/Nf—T>-N:><—— F (Z)(3 ,3 -difluoroazetidiny1)—3 -(3 -(3 — isopropoxy-S -(trifluor0methy1)pheny1)—1H~ 1,2,4—triazoly1)propen0ne (5—(3-ch10ropheny1)-4H—1,2,4—triazol C' \ N N O y1)-N-phenylacrylamide (Z)(5—(3-ch10r0phenyl)—4H—1,2,4-triazol-3— y1)-N-methy1-N-phenylacry1amide (E)-tert-buty1 (4-(3 -(3 -(3 —ch10ropheny1)— 1 H— 1,2,4-triazol— 1 - y1)acry1amido)pheny1)carbamate Compound Structure Compound Name :49 (3-(3 -chlorophenyl)—1H-1,2,4-triazol—l- yl)-N-(4~methoxyphenyl)acrylamide ’ CIW/> (E)—N—(3-chlorophenyl)-3 -(3 —(3 - chlorophenyl)-1H-l ,2,4-triazol—1 — / ,N>/ yl)acrylamide $9 (E)-N~(4-aminophenyl)—3 —(3 -(3 — chlorophenyl)— l H— l ,2,4-triazol N’N yl)acrylamide CWed / /> N’N/:>*N N» (Z)-3 -(3 -(3 ophenyl)-lH-1,2,4—triazol-l- “o”/ o k yl)-N—isopropyl-N-methylacrylamide __ ’F egg (Z)-3 -(3-(3 —chlorophenyl)-1H-l ,2,4-triazol / 0 % yl)-N—fluoro-N—isopropylacrylamide In another specific embodiment of a compound of formula I, the compound is not a compound listed in Table 1B.
Table 1B.
Compound Structure Compound Name 2012/048368 Compound Structure nd Name (Z)-3 —(3 -(3 -chloropheny1)-1H-1,2,4—triazol y1)-N-cyclopentylacry1amide (Z)-1—(azetidin—1-yl)(3 -(3 -chloropheny1)- 1H-1 ,2,4-triazoly1)propen—1-one (Z)-3—(3-(3-chloropheny1)-1H-1,2,4-triazol—1— y1)(3 ,3 ~difluoroazetidiny1)prop-2—en-1— 0116 (Z)(3 ,3 -difluoroazetidin— 1 -y1)-3 -(3 -(3 - methoxy—S—(trifluoromethyl)pheny1)- 1 H- 1,2,4-triazol-1—y1)propen—1-one (Z)—1-(3 ,3 -difluoroazetidin— 1 -y1)—3 -(3 -(3 - isopropoxy-5—(trifluoromethy1)phenyl)- 1 H- 1,2,4-triazol—1-y1)prop-2—en—1-one (Z)—3-(5-(3-chloropheny1)—4H- 1 ,2,4—triazol y1)—N-pheny1acry1amide (Z)-3 —(5 -(3 —chlorophenyl)-4H-1,2,4-triazol-3 - yl)-N~methy1-N-pheny1acry1amide PCT/U82012/048368 -66— Compound Structure Compound Name ? (E)-tert~buty1 (4-(3 -(3 -(3 —ch10r0pheny1)- 1 H- 1,2,4—triazol yl)acrylamido)phenyl)carbamate CI /> O E r‘JLNH (E)~3 —(3 -(3 -ch10ropheny1)-1H—1,2,4—triazol-1~ N (4—methoxypheny1)acry1amide “W/ > N $90 (E)-N-(3 —ch10rophehyl)—3 —(3 —(3 — ch10r0pheny1)— 1 H— 1 ,2,4—triazol ”W//> y1)acrylamide 59 (E)—N—(4-amin0phenyl)—3 -(3 -(3 - chloropheny1)-1H~1 ,2,4-triazol-1— N,N y1)acry1amidé “W//> N WWI;_ / (Z)-3—(3 -(3 —ch10ropheny1)-1H—1,2,4-triazol OWN yl)-N—isopropyl-N-methylacrylamide WO 19561 Compound Structure Compound Name V IF N’N N (Z)(3-(3-chlorophenyl)-1H—1,2,4—triazol-1— ’ O W CI / N fluoro-N—isopropylacrylamide “f“: “”2 (3-(3—chloropheny1)-1H—1,2,4-triazol—l- N y1)acrylamide (E)-3—(3-(3 -chloropheny1)—1H-1,2,4—triazol-1 - yl)-N—phenylacrylamide (E)-3 -(3 ~(3 -chlorophenyl)— 1 H— 1 ,2,4—triazol— 1 — yl)-N-methyl-N-phenylacrylamide /_>\—NH2 (E)-3 -(3 —(3 -chlorophenyl)-1H-l ,2,4-triazol CI N/> y1)acrylamide N/N NH2 F30 N/ O (Z)—3-(3-(3 —isopropoxy-5— (trifluoromethyl)pheny1)— l H- 1 ,2,4—triazol yl)acry1amide In another specific embodiment of a compound of formula I, the compound is not a compound listed in Table 1C.
Table 1C.
Compound Structure Compound Name Compound Structure Compound Name fl»: NH2 0 (Z)—3-(3-(3 -chlorophenyl)-1H— 1 ,2,4-triazol N yl)acrylamide Q‘NH (E)—3-(3—(3 —chlorophenyl)-1H-1,2,4—triazol—l- N’N G / CI N/> yl)-N—phenylacrylamide 0 / JLN (E)-3—(3—(3 —chlorophenyl)-1H—l ,2,4-triazol-l - N , N G CI\©/flN/> yl)-N-methyl-N-phenylacrylamide /—_>‘NH2 (3-(3 -chlorophenyl)-1H—1,2,4—triazol ClUMN/> yl)acrylamide N a N N H2 F30 N/> O (Z)—3 -(3-(3 —isopropoxy—5- (trifluoromethyl)phenyl)— 1H— 1 ,2,4—triazol- l - yl)acrylamide Exemplary compounds of the invention are set forth in Table 2.
Table 2. Exemplary compounds ofthe ion.
Compoundj Structure Name —69— Compound Structure Name N, WNOQ: . / /> o (Z)(3-(3,5~bis(tr1fluor0methyl)pheny1)— F C3 1 1H—1,2,4-triazoly1)—1—(3,3- difluoroazetidin- 1 0pen— 1 -one N/NWNyF/ / /> O (Z)(3,3-difluoroazetidin—1-y1)—3—(3-(3— 2 N fluoro—S-(trifluoromethyl)phenyl)~1H- 1,2,4—triaz01y1)pr0p—2-en-1—one N’WNyF/ Zl33d‘fl - / /> 0 ( )- -( 1 uoroaze‘u'd' 113331n— , —y )~ -( -( 3 N hydroxy-S—(trifluoromethy1)phenyl)-1H- 1 ,2,4-triazoly1)pr0p—2~en0ne ijérF N/N F (3-(3,5 -bis(trifluoromethy1)pheny1)- / Nx) 4 F30 1H—1,2,4—triazolyl)—1-(3,3- difluoroazetidin— 1 -y1)pr0p—2-en— 1 -one F30 “@chng (Z)-3—(3-(3,5-bis(trifluoromethy1)pheny1)- (2%” F 1H—1,2,4-triazol-1~y1)-1—(3,3- CF3 difluoropiperidin—l-y1)prop—2—en-1 -0ne IN/ 0 F F30 (Z)—3~(3-(3,5—bis(trifluoromethy1)pheny1)— 1H-1 ,2,4-triazol—1-y1)—1—(4,4- opiperidin- 1 —y1)pr0p—2-en— 1 —one Compound ure Name N/N N F F30 IN)? (>— (3—(3,5-bis(trifluoromethyl)pheny1)- 7 1H-1,2,4—triazoly1)(3-fluoroazetidin— 1-y1)prop—2-enone — OH F30 5";ny (Z)—3—(3-(3,5-bis(triflu0r0methy1)pheny1)- 8 ,4—triazol—1-yl)(3~hydroxy CFS methylazetidiny1)prop—2-en— 1 -0ne N/NF>7N:><F \/ / o F (Z)3(3(26b'('fl- — — - 1s tr1 uoromet yhl)pyr1 m—'d' 4 9 3 , NI / yl)—1H—1,2,4—triazolyl)(3,3- difluoroazetidin- 1 —y1)pr0pen— 1 ~0ne — // Fgc [745—ng (Z)—3-(3-(3,5-bis(trifluoromethyl)pheny1)- Wig/AN / 1H-1,2,4-triazoly1)-N—ethy1—N-(1— \ r/q (pyridin—3—y1)ethy1)acry1amide F30 W?“ (Z)—3-(3—(3,5—bis(trifluoromethyl)pheny1)— 11 O \ lH—l,2,4-triazol—1—yl)-N—(oxazol CFE ylmethy1)acrylamide (Z)(5—(3,5—bis(trifluoromethyl)pheny1)— F c HNflNyF 3 U“ 12 4H—1,2,4-triazol—3-yl)(3,3— difluoroazetidin— 1 -y1)prop—2-en-1 —one N/N NH F3C IN) 0 (Z)-3~(3-(3,5-bis(trifluoromethyl)pheny1)- 13 / 1H-1,2,4-triazol—1—y1)—N—((2— N / methylpyrimidin-S—y1)methyl)acrylamide Compound Structure Name N’N NH F30 ’N/ o (Z)(3-(3,5—bis(trifluoromethyl)phenyl)- 14 / lH—l ,2,4-triazol-1—y1)-N-(pyrimidin-5 - N ylmethyl)acrylamide (E)—3 —(6-(3 ,5- 1 5 bis(trifluoromethyl)pheny1)pyridin—2~y1) (3 ,3 -difluorocyclobutyl)prop—2—en- 1 —0ne (Z)-3 -(4—(3 ,5 -bis(trifluoromethy1)phenyl)- 16 1H~imidazol— 1 —y1)-1 -(3 ,3 ~difluoroazetidin— ' 1-y1)prop—2—en0ne N/N N/ / N) F30 o (Z)-3 -(3 —(3 ,5 -bis(trifluoromethyl)phenyl)- 1 7 / 1H-1 riazol— 1-y1)—N-methy1-N— N (pyrimidin—S-y1methyl)acrylamide \\/ [G N’N N/ I N) F30 O (Z)—3-(3-(3,5-bis(trifluoromethyl)phenyl)- 18 / 1H-1,2,4-triazoly1)-N—methy1-N—((2— N / \ N methylpyrimidin-S-y1)methy1)acry1amide CF3 f '7] N),N NH F30 0 (Z)—3-(3~(3,5-bis(trifluoromethyl)phenyl)— 1 9 lH-l riaz01—1—y1)~N—(piperidin-3 — ”N ylmethy1)acry1amide Compound Structure Name N’N F F30 , 0 NE (Z)-3 -(3 -(3 ,5 -bis(triflu0romethy1)pheny1)- 1H—1,2,4-triazoly1)-1—(3,3- difluoropyrrolidiny1)propen-1 -0ne N’N NH / N) F30 O (Z)—3 -(3 -(3 ,5—bis(trifluoromethyl)pheny1)- 21 / ,4-triazol-1—y1)—N—(1-(2- [G methylpyrimidin-S—y1)ethy1)acry1amide N’N N/ F30 IN) 0 (Z)—3—(3-(3,5-bis(triflu0r0methy1)pheny1)- 22 1H—1,2,4-triazol—1-y1)-N—methy1-N—(oxazol— EN 5-y1methyl)acrylamide N/NF>—N / 9 F30 N/ O (Z)- 1 ~(azetidin-1 -y1)-3 -(3 -(3 ,5— 23 bis(trifluoromethy1)pheny1)-1H-1 ,2,4- triazol— 1 —y1)prop—2—en- 1 —0ne N’N N Fac / o (Z)—3 -(3 -(3 ,5 —bis(triflu0romethy1)phenyl)- 24 N’ \ 1H—1,2,4-triazol-1—y1)(3-(pyridin y1)azetidin-1—y1)prop-2—en~1-one 51’ng (Z)-3 -(3 —(3 ,5 —bis(trifluoromethy1)pheny1)- F30 N/ 0 1H-1,2,4-triazol—1-y1)-1—(3— /N\ thylamino)methyl)azetidin CF3 y1)propen—1-one ,N , N“ F30 ”N; o (Z)(3-(3,5—bis(triflu0r0methy1)pheny1)- 26 \Q/A gj 1H~1,2,4-triazoly1)—N—((1- methylpiperidin-4—y1)methy1)acry1amide Compound Structure Name F30 “FT?”— (3~(3,5-bis(triflu0romethy1)pheny1)- 27 1H—1,2,4—triazol—1—y1)-N—((1- / methylpiperidin—3-y1)methy1)acry1amide 1’51 “H C (Z)(3—(3,5-bis(trifluoromethy1)phenyl)~ 28 1H—1,2,4-triazol—1-y1)-N-(6,7-dihydro-5H— cps cyclopenta[b]pyridin—5-y1)acry1amide F30 W’TFCWH \Q/LN {'3 (Z)-3—(3-(3,5-bis(trifluoromethy1)phenyl)-‘ 29 1H-1,2,4-triaz01y1)-N—(1—(pyrazin—2— CF3 y1)acry1amide “1’3?“ (Z)-3—(3-(3,5-bis(trifluor0methy1)pheny1)- (B ,4—triaz01—1—y1)-N-((1- /N methylpyrrolidin—3—y1)methy1)acry1amide F C 117er (5% (Z)-3—(3—(3,5-bis(trifluoromethy1)pheny1)- N N 31 1H—1,2,4—triazol-1—y1)-N—((2,4- CF: dimethylpyrimidin—S-y1)methyl)acrylamide W’NWNOfi_ F (Z)—3-(3—(4-ch10r0-3,5- F36 N/ O bis(trifluoromethy1)pheny1)—lH-l,2,4- 32 triazol-l -y1)(3,3-diflu0r0azetidin— 1 - CF3 y1)pr0p—2—en0ne WWW— F / F F30 / o (Z)—1—(3 ,3 —d1fluoroazet1d1ny1)-3 —(3 —(4- 33 hydroxy-3 ,5-bis(trifluoromethyl)pheny1)- H0 1H—1,2,4-triazoly1)pr0p—2—enone Compound Structure Name ___T _ F / Nfi>iN9< F30 / o F (Z)(3—(3,5-bis(trifluoromethyl)pheny1)— 34 1H—pyrroly1)— 1 —(3 ,3 -difluoroazetidin y1)prop—2-en—1-0ne N/NWW__ F / .
F30 O F / (Z)~3 —(3 —(3 ,5 —b1s(tr1flu0romethy1)pheny1)—. lH-pyrazol-l-y1)-17(3,3-difluoroazetidin-1— y1)pr0p—2-en— 1 -one - F / \ N©< .
O F F30 (Z)—3-(5-(3,5—b1s(tr1flu0romethy1)pheny1)—. 36 H 1H—pyrr01—3 -y1)—1—(3,3-difluoroazetidin—1 - y1)prop-2—en— 1 -one Nflm-— F / (Z)—3 —(2-(3 , 5 ~b1s(tr1flu0romethy1)pheny1)-. .
F30 o F 37 H 1H—imidazol-4—y1)(3,3-diflu0roazetidin- 1—y1)pr0p—2-en— 1 —one / NO F30 N/ O (Z)-3 -(3 —(3 ,5-bis(trifluoromethy1)pheny1)- 1H-1 ,2,4—triazol-1 —y1)(pyrrolidin—1— y1)prop—2—enone [\ka N ’ (Z)-3 —(3 —(3 ,5 —bis(trifluoromethyl)pheny1)— F30 N/ O 1H—1,2,4—triazoly1)—1—(3- 39 NH ((methylamino)methy1)azetidin-1 op- 2—en—1—0ne WO 19561 -75 _ Compound 1 Structure Name 7 N)N#%N§VF D2-(Z)-3—(3-(3,5— F30 o F bis(triflu0romethyl)phenyl)-1H—1,2,4- K: 3 I triazol—1-yl)—1-(3,3-difluoroazetidin—1- yl)propen0ne Min D3-(Z)-3—(3-(3,5- F3 N/ D0 F bis(trifluoromethyl)phenyl)—1H—1,2,4- triazoly1)-1 —(3 ,3 —diflu0roazetidin yl)propenone WE}N:><F/ F30 / O F (E)—3 -(3 -(3 ,5 -bis(trifluoromethyl)phenyl)- 42 lH—l,2,4-triazoly1)-3—bromo—1-(3,3- difluoroazetidin-l -y1)propen-1 -0ne F #2/7 yF— 3-(3-(3,5— bis(trifluoromethyl)phenyl)pyrrolidin y1)-1 —(3 ,3 ~difluoroazetidin-1—yl)pr0pan CF3 one a“ wagi‘; V F r‘Nf (E)~4—(3,5—bis(trifluor0methyl)phenyl)-1— 44 ,3: F w. (3 -(3 ,3 -difluoroazetidiny1)-3 -0X0pr0p- > «Lka 1 -eny1)pyrrolidinone Compound Structure Name —- OH N’N , N (Z)(3-(3,5—bis(triflu0romethyl)pheny1)- F30 N/ O 1H—1,2,4—triazol—1-y1)—1-(3—hydroxy N// (pyridin—3-y1methyl)azetidin—1-y1)prop—2- CF3 en- 1 —0ne —- OH N’N N (Z)(3—(3 ,5-bis(trifluoromethy1)pheny1)- F30 N” O 1H—1,2,4-triazoly1)(3-hydroxy-3— 46 N/ /N (pyrazin-Z-ylmethyl)azetidiny1)pr0p—2- enone — F N’N N (Z)-3—(3—(3,5-bis(trifluoromethy1)pheny1)- F30 N/ O lH—l ,2,4-triaz01—1-y1)—1 —(3-flu0ro—3— 47 / N , (pyrimidin-5~y1methyl)azetidin-1—y1)pr0p— \\/N —0ne — F fill/N N (Z)(3-(3,5-bis(trifluoromethyl)phenyl)— F30 N’ 0 1H—1,2,4-triazol-1—y1)(3—fluor0—3— N// (pyridinylmethyl)azetidin—1-y1)pr0p—2— \ en—l-one —— F N’N N (Z)—3—(3-(3,5—bis(triflu0romethyl)pheny1)- F30 N” 0 lH-l,2,4-triazoly1)(3—flu0ro—3— 49 N/ /N (pyrazin—Z-y1methy1)azetidin— 1 op—2- V en—l—one ‘ OH 5w N (Z)—3 —(3 —(3 ,5 -bis(trifluoromethy1)pheny1)- F30 N) 0 “3 1H-1,2,4~triazolyl)(3—hydr0xy-3— 50 (2,2,2-trifluoroethyl)azetidin— 1 -y1)prop—2— CFa en—l-one — OH N’N NO<CF (Z)—3-(3 bis(tr1fluor0methy1)phenyl)-, my“ 0 3 1H—1,2,4-triazol—1-y1)-1—(3—hydr0xy—3— 51 (trifluoromethyl)azetidin—1 -y1)pr0pen-1 - 2012/048368 nd Structure Name FSCDXN‘ N’N/—>/*N:><:NHI / o (Z)-3 -(3 -(3 , 5 —bis(trifluoromethy1)pheny1)- 52 1H—1,2,4-triazoly1)—1—(2,6- diazaspiro [3 .3]heptany1)prop-2—en0ne WNWNO/OH (Z)(3 -(3—(3 ,5— (I N) 0 F30 bis(trifluor0methyl)pheny1)- 1 H— 1 ,2,4— triazol—l -y1)acry10y1)azetidine-3 — CF3 carboni’irile [/> O (Z)—1—(3 -(3 —(3 ,5— 54 bis(trifluoromethy1)pheny1)- 1 H— 1 ,2,4- CF3 triazoly1)acry10yl)azetidine-3 — carbonitrile (Z)(3 -(3 -(3 ,5 — F3C / O N bis(trifluoromethy1)pheny1)— 1 H— 1 ,2,4- 55 triazoly1)acryloy1)azetidine—3 —carboxylic CF3 acid I / (Z)-N-(3 -azabicyclo [3 .‘1 .0]hexan—6—y1)—3 - F30 0 56 bNHHm (3 —(3 ,5 -bis(trifluoromethy1)pheny1)-1H- 1 ,2,4-triazol—1-y1)acry1amide ’ N) (Z)—N—(3-aminobicyclo [3 . 1 .0]hexany1)- F30 0 57 3 -(3 —(3 ,5 rifluoromethy1)pheny1)—1H— CF3 1 ,2 ,4-triazoly1)acrylamide _ (Z)-N—(2,6—diazaspir0 [3 an—6- '7’“ F30 / O N NSCNH ylmethyl)—3 -(3 -(3 ,5 - 58 bis(trifluoromethy1)pheny1)— 1 H— 1 ,2,4- triazoly1)acry1amide nd Structure Name ,41 N:><F (Z)—3-(3-(4-ch10r0—3,5- F30 N) O F bis(trifluor0methy1)phenyl)-1H—l ,2,4- cu triazol— 1 —y1)(3 ,3 -difluoroazetidin CB y1)pr0p-2—en-1—one F30 [7/5/ny— (Z)-1—(3—(aminomethyl)—3-flu0roazetidin— 1 — N H2“ 60 y1)-3—(3-(3,5-bis(trifluoromethyl)pheny1)— 01:3 1H—1,2,4—triazoly1)prop-2—enone — F N’N (Z)-3 -(3 —(3 ,5 rifluoromethy1)pheny1)- N 0 ’ [qr—0} (>801 \ F30 1H—1,2,4—triazolyl)(3-flu0ro(2- 61 methoxyacetyl)azetidin-1—y1)prop-2—en — F N’N (Z)—3-(3-(3 ,5—bis(trifluoromethy1)phenyl)- N OH ’ N9} 0801 F30 1H—1,2,4-triazol—1-y1)(3—flu0ro-3 -(2- 62 hydroxyacetyl)azetidin—1—y1)prop-2—en , My (Z)-3 —(3 —(3 , 5 -bis(trifluoromethy1)pheny1)~ 0 1H-1,2,4-triazoly1)(3— F c by”; 63 3 N thylamino)methy1)-3 —fluoroazetidin- 1-yl)prop—2-enone N N:><F FSC 00 F (Z)(3 ,5~bis(trifluoromethyl)pheny1)— 1 - 64 (3 —(3,3—difluoroazetidin-1—y1)-3—oxoprop—1— en— 1 -y1)pyrrolidin-2~0ne F30 (Z)-3 —(2-(2,4-bis(trifluoromethy1)pheny1)— / N/-_O>—N:>(FF lH—pyrrol-l-y1)(3,3-diflu0roazetidin CFs / yl)prop—2—en— 1 -one PCT/U52012/048368 Compound Structure Name N’NWNO' (Z)(3-(3,5-bis(trifluoromethyl)phenyl)- IN/>o 66 1H—l ,2,4~triazol-1—yl)-l—(4- hydroxypiperidin— 1 -yl)propen— 1 —one / (3 —(3 ~(3,5-bis(trifluoromethyl)phenyl)-1H-l,2,4- FC / o triazol- l —yl)0xiran—2-y1)(3 ,3 —difluoroazetidin- l - yl)methanone F30 N o (Z)-3 -(5 -(3 ,5 -bis(trifluoromethyl)phenyl)- 68 H 1H—l,2,4-triazol-3 -yl)(3 ,3 - oazetidin—1-yl)prop—2—en-l-one D D N/N>:$/~N:><F D3—(Z)—3—(3-(3,5- F30 O F bis(triflu0romethyl)phenyl)-lH—l,2,4- 69 N D triazol-l-yl)-l-(3,3—difluoroazetidin—1— yl)pr0p-2—en-l -one Another embodiment of the invention is a compound represented by structural formula (VI): _ R1 /’N\ R|\7 / / o R2 CF3 (V1), or a pharmaceutically able salt thereof, wherein: Z is selected from N, CH and C(Cl); R1 is hydrogen; and -80— R2 is selected from —CH2—oxazol-5—y1, —CH2-pyrimidin—5—yl, —CH2—(l—-methylpyrrolidin—3—yl), or NH; or: R1 and R2 are taken together with the nitrogen atom to which they are bound to KN KN form do An, ”(DOW , 4-hydroxypiperidin—1—yl, pyrrolidiny—l —yl, or azetidin— 1 ~yl, wherein the pyrrolidiny—1—yl and azetidin— l —yl are each optionally and independently substituted at the 3—position with up to two substituents independently ed from fluoro, -CF3, —CH3, —OH, pyridin—Z-yl, —CH2-N(CH3)2, -CH2—NH—CH3, —CH2—NH2, -CN, —C(O)—O-CH3; and R7 is ed from fluoro, -OH and —CF3.
Representative compounds of structural formula VI include: Structure Name (2)43 4(3-(3 ,5 -bis(trifluoromethyl)phenyl)— 1H— 1 ,2,4—triazol- 1 —yl)— 1 —(3 ,3 — difluoroazetidin— l —yl)prop—2—enone (Z)—1-(3 ,3-difluoroazetidin—1-y1)—3—(3 —(3 — fluoro—S—(trifluoromethyl)pheny1)— 1H— l riazol—l uyl)prop—2-enone (Z)—1—(3 ,3 roazetidin— 1 —yl)—3 —(3 -(3 - hydroxy—5—(trifluoromethyl)phenyl)- l H- 1 ,2,4—triazol—1—yl)prop—2—en—l—one Compound Structure Name N’N N F / N)? :>‘ F30 (Z)—3 ~(3 -(3 ,5 —bis(triflu0romethy1)pheny1)- 7 1H—1,2,4-triazol—1—y1)(3—fluoroazetidin- 1—y1)prop-2—en-1—one —« OH Fae 1’$?N9< (Z)-3~(3-(3,5—bis(trifluoromethyl)pheny1)- 8 1H—1,2,4—triazoly1)(3-hydroxy ca methylazetidin—1—y1)pr0p—2—en-1—0ne N’NF>'NO<F/ F30 / o F Z -3 - 3 — 2,6-bis trifluoromethyl pyridin—4— 9 \ N N! y1)—1H—1,2,4-triazol—1-y1)—1-(3,3- oazetidin-l —y1)prop—2-en— 1 -0ne "”; N” O (3—(3,5-bis(trifluoromethy1)pheny1)- 1 1 o \ 1H—1,2,4-triaz01—1—y1)-N—(oxazol \QN y1methy1)acry1amide N/N NH F3C / o (Z)(3 -(3 ,5 —bis(trifluoromethyl)pheny1)- lH—l ,2,4-triazoly1)-N—(pyrimidin—5- 14 / N ylmethyl)acry1am1de \\/ [(1 ' 9/N FC O ”0% (Z)-3~(3—(3,5—bis(triflu0r0methyl)pheny1)- 3 N 1H—1,2,4-triazol-1—y1)(3,3- difluoropyrrolidin— 1 op—2—en- 1 —0ne (3F3 N’N/VNO/ F30 / 0 (Z)- 1 —(azetidin— 1 -y1)-3 —(3 -(3,5- 23 bis(trifluoromethyl)phenyl)-1H—1,2,4- triazol— 1 -y1)prop-2—en- 1 —one -82— nd Structure Name (Z)—3 —(3 -(3 , 5 -bis(triflu0romethyl)pheny1)- 24' 1H—1,2,4-triazoly1)-1—(3 -(pyridin y1)azetidiny1)propen—1-one (Z)~3 —(3 —(3 ,5 -bis(trifluoromethy1)phenyl)— lH-l ,2,4-tria201y1)—1 -(3 - ((dimethylamino)methy1)azetidin— 1 - 0F3 y1)propenone (Z)-3 —(3 —(3 ,5-bis(trifluoromethy1)pheny1)- 1H—1,2,4-triaz01y1)—N—((1- methylpyrrolidin-3—y1)methy1)acry1amide (Z)—3 ~(3-(4-chloro-3 ,5— F30 bis(trifluoromethy1)pheny1)—1H—1,2,4- 32 triazol— 1 -y1)(3 ,3 -diflu0roazetidin y1)pr0p-2—en-1—one F30 (Z)—3 -(3 -(3 ,5 -bis(triflu0r0methyl)phenyl)— 38 ,4—triazoly1)(pyrrolidin—1- y1)propenone (Z)—3 -(3 —(3 ,5 -bis(trifluoromethyl)pheny1)— 1H— 1 ,2,4-triazoly1)— 1 -(3 - 39 ((methylamino)methy1)azetidin— 1 -y1)prop- 2-en— 1 -one Compound Structure Name N,NF§/‘N:><F D2~(Z)(3-(3,5- 40 / F30 / O bis(trifluoromethyl)pheny1)-1H-1,2,4- N D l-l-yl)—1-(3,3-difluor0azetidin-1— y1)propen-1—one N/NWNOJ— D3— Z 3— 3,5-( ) ( ( F30 o F bis(triflu0romethyl)pheny1)-1H- 1 ,2,4- 4 1 N/ D triazol-l -y1)— 1 —(3 ,3 -difluoroazetidin—1 - CF3 y1)pr0p—2-en-1—one W’NWN- OH (Z)(3-(3,5 -b1s(tr1flu0romethy1)pheny1)—. .
F30 N/ 0 3 lH—l,2,4-triazoly1)-1—(3-hydroxy-3— 51 (trifluoromethy1)azetidiny1)pr0p—2-en CF3 one ”90‘“ F30 W; O (Z)(3—(3,5—bis(trifluoromethy1)pheny1)- 52 1H-1,2,4-triaz01-1—y1)(2,6— diazaspiro [3 .3]heptan—2-y1)pr0pen— 1 -0ne N’NWNyOH (Z)(3—(3 —(3 ,5- Fac IN) bis(trifluoromethyl)pheny1)-1H—1,2,4— 53 l—l-y1)acryloyl)azetidine CFS carbonitrile N CN N, C?, (Z)-1—(3-(3—(3,5- 54 bis(trifluoromethy1)pheny1)-1H-1,2,4- CF3 l- 1 —y1)acry10y1)azetidine carbonitrile —84- Compound Structure Name N’N/:>"‘NH F30 // 0 (Z)-N—(3-azabicyclo [3 . 1 .0]hexany1)-3 — 56 5NH HCI (3 -(3 ,5-bis(trifluoromethy1)pheny1)- 1 H- CF3 1 ,2 ,4-triazol-1 —y1)acrylamide _ ~37 . 1 .0]hexan—6—yl)- ’ (Z)-N-(3—aminobicyclo [3 x) o 57 FaC\©/kN 3-(3-(3,5—bis(trifluoromethy1)pheny1)-1H- CFa 1 riazoly1)acry1amide N’NWN (Z)-N—(2,6-diazaspiro [3 .4] octan F30 / 0 N y1)-3 -(3 —(3 ,5 - 58 bis(trifluoromethyl)pheny1)- 1 H— 1 ,2,4- CF3 triazoly1)acry1amide (Z)—3 -(3 -(4-chloro—3 ,5 - F30 bis(trifluoromethy1)phenyl)-1H-1 ,2,4— 59 triazol- 1 —y1)- 1 —(3 ,3 —difluoroazetidin— 1 - y1)prop-2—en0ne (Z)-1 —(3 -(aminomethyl)—3 -fluoroazetidin 60 y1)-3 —(3 -(3 ,5—bis(trifluoromethy1)pheny1)- 1H—1,2,4-triaz01-1—y1)pr0p—2—en-1 -one fl NWO (Z)-3 —(3 -(3 ,5 -bis(triflu0romethy1)pheny1)- ’ N) \ F30 o 1H—1,2,4-triazoly1)(3 -flu0r0-3 -(2- 61 methoxyacety1)azetidin-1 -y1)prop—2-en (Z)-3 -(3 —(3 ,5 rifluoromethy1)pheny1)- //>° 1H—1,2,4—triazol-1—y1)(3 — 63 F3C ((dimethylamino)methy1)flu0roazetidin- 1-y1)pr0p-2—en— 1 —one Compound Structure Name ac skiffNQOH (Z)—3-(3-(3,5-bis(trifluoromethyl)phenyl)- 66 EDA“ lH-l,2,4-triazol-l-yl)—1-(4— F3C hydroxypiperidin—l -yl)prop-2—en—1 -one D D N,N N:><F D3-(Z)(3—(3,5- / NAB F3C o F bis(trifluorornethyl)phenyl)-lH—l ,2,4- 69 lyl)— 1 —(3 ,3 roazetidin- 1 — yl)prop—2-enone Another embodiment of the invention is a nd represented by any of the following structural formulas, or a pharmaceutically acceptable salt thereof: Name Compound Structure F C 5‘": —O \\ (Z)—3-(3~(3,5—bis(trifluoromethyl)phenyl)— 3 N / 23 lH-l,2,4-triazolyl)-N-(6,7-dihydro-5H— CF3 cyclopenta[b]pyridin—5-y1)acrylamide I‘ll/N>‘>/"N:><F— F (E)—3 -(3 -(3 ,5 -bis(trifluoromethyl)phenyl)- F30 O lH-l ,2,4—triazolyl)—3-bromo-l-(3,3- 42 N/ difluoroazetidin— 1 -yl)prop-2—enone ’_ F N N F30 #0» :><F 3-(3-(3,5- 43 bis(trifluoromethyl)phenyl)pyrrolidinyl)— 1—(3 ,3 —difluoroazetidinyl)propan—l -one CF3 .
Compound Structure Name (E)-4—(3 ,5 -bis(trifluoromethyl)phenyl)-1 - 44 (3 ~(3 ,3 -difluoroazetidin— 1 —yl)—3 —oxoprop- 1 — en-l —yl)pyrrolidin—2-one NVNyF— "l F30 00 F (Z)—4-(3 ,5—bis(trifluoromethyl)phenyl)- 1 — 64 (3 —(3 ,3 -difluoroazetidiny1)—3 -oxoprop~ 1 - en— 1 -yl)pyrrolidin—2-one NW7 F ",1 N§< (3 —(3 —(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4- F30 / o F 67 N triazol-l-y1)oxiran—2-yl)(3,3 -difluoroazetidin—l- yl)methanone Formulation and stration Another embodiment of the invention is a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in a composition of the invention is an amount that is effective to measurably t CRM] in a biological sample or in a patient.
In certain embodiments, a composition of the invention is formulated for administration to a t in need of the composition. In some ments, a composition of the ion is ated for oral, intravenous, subcutaneous, intraperitoneal or dermatological administration to a patient in need thereof.
The term “patient,” as used herein, means an animal. In some embodiments, the animal is a mammal. In certain embodiments, the patient is a veterinary patient (i.e., a non— human mammal patient). In some embodiments, the patient is a dog. In other embodiments, the patient is a human. —87— “Pharmaceutically or cologically acceptable” includes molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards, as required by FDA Office of Biologics standards.
The phrase “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non- toxic earrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is ated and is nontoxic when stered in doses sufficient to deliver a therapeutic amount of the compound. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, a, aluminum stearate, lecithin, serum ns, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine e, um hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, Zinc salts, colloidal silica, ium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium ymethylcellulose, polyacrylates, waxes, polyethylene—polyoxypropylene-block rs, polyethylene glycol and wool fat.
Compositions of the present invention may be administered orally, parenterally ding subcutaneous, intramuscular, intravenous and intradermal), by inhalation spray, topically, rectally, nasally, buccally, vaginally or Via an implanted reservoir. In some embodiments, provided compounds or compositions are administrable intravenously and/or intraperitoneally.
The term “parenteral,” as used herein, includes subcutaneous, intracutaneous, intravenous, intramuscular, intraocular, intravitreal, articular, intra-arterial, intra- synovial, intrasternal, intrathecal, intralesional, intrahepatic, intraperitoneal intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally or enously. ceutically acceptable compositions of this invention can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, dispersions and ons. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, —88— useful diluents include lactose and dried cornstarch. When aqueous suspensions and/or emulsions are required for oral use, the active ingredient can be ded or dissolved in an oily phase and combined with emulsifying and/or suspending agents. If desired, n ning, flavoring or ng agents may also be added.
In some embodiments, an oral formulation is formulated for immediate release or sustained/delayed e.
. Solid dosage forms for oral stration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active nd is mixed with at least one inert, ceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar—-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium ate, e) solution retarding agents such as paraffin, f) absorption rators such as quaternary ammonium salts, g) wetting agents, such as acetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Compositions suitable for buccal or gual stration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
Solid compositions of a r type may also be employed as fillers in soft and hard- filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain ying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of ing compositions that can be used include polymeric substances and waxes.
A compound of the invention can also be in micro—encapsulated form with one or more excipients, as noted above. In such solid dosage forms, the compound of the invention can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also comprise, as is normal practice, additional nces other than inert diluents, e. g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
Compositions for oral administration may be designed to protect the active ingredient against degradation as it passes h the alimentary tract, for example, by an outer coating of the formulation on a tablet or capsule.
In r embodiment, a compound of the invention can be provided in an extended (or ed” or “sustained”) release composition. This delayed-release composition comprises a compound of the invention in combination with a delayed—release component.
Such a composition allows targeted release of a provided compound into the lower gastrointestinal tract, for example, into the small intestine, the large intestine, the colon and/or the . In certain embodiments, the delayed-release composition comprising a compound of the invention further comprises an enteric or pH-dependent coating, such as cellulose acetate phthalates and other phthalates (e. g., polyvinyl acetate phthalate, methacrylates (Eudragits)). Alternatively, the delayed-release composition provides controlled release to the small intestine and/0r colon by the provision ofpH ive methacrylate coatings, pH sensitive ric pheres, or polymers which undergo degradation by hydrolysis. The delayed-release composition can be ated with hobic or gelling excipients or coatings. Colonic delivery can further be provided by coatings which are digested by bacterial s such as amylose or pectin, by pH dependent polymers, by hydrogel plugs swelling with time (Pulsincap), by time-dependent hydrogel coatings and/or by acrylic acid linked to azoaromatic bonds coatings.
In n embodiments, the delayed—release composition of the present invention comprises ellose, rystalline ose, and a lubricant. The mixture of a compound of the invention, hypromellose and microcrystalline ose can be formulated into a tablet or capsule for oral administration. In certain embodiments, the mixture is granulated and pressed into tablets.
Alternatively, pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the compound of the invention with a suitable non—irritating excipient that is solid at room temperature but liquid at rectal temperature and, therefore, will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
Pharmaceutically acceptable compositions of this invention can also be administered topically, especially when the target of ent includes areas or organs y accessible by topical application, including diseases of the eye, the skin, or the lower inal tract.
Suitable topical formulations are readily prepared for each of these areas or organs.
Topical ation for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema ation. Topically-transdermal patches can also be used.
. For other topical applications, the pharmaceutically acceptable compositions of the invention can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, ypropylene compound, emulsifying wax and water and penetration enhancers. Alternatively, pharmaceutically acceptable compositions of the invention can be formulated in a le lotion or cream containing the active component suspended or ved in one or more ceutically acceptable carriers. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. In some embodiments, le carriers include, but are not d to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2—octyldodecanol, benzyl alcohol and water. In other embodiments, suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, rbate 60, cetyl esters ers. wax, cetearyl alcohol, 2-octyldodecanol, benzyl l and water and penetration For ophthalmic use, pharmaceutically acceptable compositions of the invention can be formulated as micronized suspensions in isotonic, pH adjusted e saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.
Pharrnaceutically acCeptable compositions of this invention can also be administered by nasal l or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
W0 2013/019561 PCT/U82012/048368 In some embodiments, pharmaceutically acceptable compositions of this invention are formulated for oral administration.
In some embodiments, pharmaceutically acceptable itions of this invention are formulated for intra—peritoneal stration.
In some‘embodiments, pharmaceutically acceptable itions of this invention are formulated for topical administration.
The amount of compounds of the present invention that can be combined with the carrier als to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration and the activity of the compound employed. Preferably, compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a t receiving the composition.
It should also be understood that a specific dosage and treatment regimen for any particular t will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician and the severity the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular nd in the composition.
Other ceutically acceptable carriers, nts and vehicles that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, a, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-oc-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen ate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl idone, cellulose-based nces, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as or-, [3-, and y-cyclodextrin, 2- and 3- or chemically modified derivatives such as hydroxyalkylcyclodextrins, ing ypropyl— B-cyclodextrins, or other solubilized tives can also be advantageously used to enhance delivery of compounds described herein.
The pharmaceutical compositions of this invention are ably administered by oral administration or by injection. The pharmaceutical compositions of this invention can contain any conventional non-toxic pharmaceutically-acceptable carriers, nts or vehicles. In some cases, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulath compound or its delivery form.
The pharmaceutical compositions can be in the form of a sterile able preparation, for example, as a sterile inj ectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using suitable sing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile inj ectable preparation can also be a sterile inj ectable solution or suspension in a non- toxic erally acceptable diluent or solvent, for example, as a on in 1,3-butanediol.
Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer’s on and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono— or diglycerides. Fatty acids, such as oleic acid and its glyceride tives are useful in the preparation of inj es, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or sant, or ymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or ilability ers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.
When the compositions of this invention se a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agent(s) can be administered separately, as part of a multiple dose regimen, from the compounds of this invention. atively, the additional agent(s) can be part of a single dosage form, mixed together with the compound of this ion in a single composition.
WO 19561 The compounds described herein can, for example, be stered by injection, intravenously, intraarterially, intraocularly, intravitreally, subderrnallym, orally, buccally, nasally, transmucosally, topically, in an lmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of body weight or, alternatively, in a dosage ranging from about 1 mg to about 1000 e, every 4 to 120 hours, or according to the requirements of the ular drug. The methods herein contemplate administration of an effective amount of a compound of the invention, or a composition thereof, to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or, atively, as a continuous infusion.
Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of stration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, a preparation can contain from about 20% to about 80% active compound.
Doses lower or higher than those recited above may be required. Specific dosage and treatment ns for any particular patient will depend upon a variety of factors, including the activity of the specific compound ed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the ty and course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the ng physician.
Upon improvement of a patient’s condition, a maintenance dose of a compound, composition or combination of this invention can be administered, if necessary.
Subsequently, the dosage or frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long—term basis upon recurrence of disease symptoms.
Uses ofCompounds and Pharmaceutically able Compositions Compounds and compositions bed herein are lly usefiil for the inhibition of CRMl and are, therefore, useful for treating one or more disorders associated with activity of CRMI. Thus, in certain embodiments, the present invention provides a method for treating a ediated disorder comprising the step of stering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable salt or composition thereof. The compounds and compositions described herein can also be administered to cells in culture, e. g., in vitro or ex vivo, or to a subject, e. g., in vivo, to treat, prevent, and/or se a variety of disorders, ing those described herein below.
The activity of a compound ed in this invention as an inhibitor of CRMl may be assayed in vitro, in vivo or in a cell line. Detailed ions for ng a compound utilized in this invention as an inhibitor of CRMl are set forth in the Exemplification.
As used , the term “trea ” or “treatment” is defined as the application or administration of a compound, alone or in combination with a second compound, to a subject, e. g, a patient, or application or stration of the nd to an isolated tissue or cell, e. g., cell line, from a subject, e. g, a patient, who has a disorder (e.g., a disorder as described herein), a symptom of a disorder, or a predisposition toward a disorder, in order to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder, one or more symptoms of the disorder or the predisposition toward the disorder (e. g., to prevent at least one symptom of the er or to delay onset of at least one symptom of the disorder).
As used herein, an amount of a compound effective to treat a er, or a “therapeutically effective amount” refers to an amount of the compound which is effective, upon single or multiple dose administration to a subject or a cell, in curing, alleviating, relieving or improving one or more symptoms of a er.
As used herein, an amount of a compound effective to prevent a disorder, or a 2O “prophylactically effective amount” of the compound refers to an amount effective, upon single— or multiple—dose administration to the subject, in preventing or delaying the onset or recurrence of a er or one or more symptoms of the disorder.
As used herein, the term “subject” is intended to include human and non-human animals. Exemplary human subjects e a human patient having a disorder, 6. g., a disorder described herein or a normal subject. The term “non-human animals” of the ion includes all vertebrates, e. g, mmals (such as chickens, amphibians, reptiles) and mammals, such as man primates, domesticated and/or agriculturally useful animals, e. g, sheep, cow, pig, etc., and companion animals (dog, cat, horse, etc).
As used herein, the term “CRMl—mediated disorder or condition” or “disorder or condition associated with CRMl activity” means any disease or other deleterious condition in which CRMl plays a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which CRMl plays a role.
Specifically, the present invention relates to a method of treating or lessening the severity of a WO 19561 proliferative disorder, the method comprising administering to a patient in need thereof a compound of the invention, or a pharmaceutically acceptable salt or composition thereof.
Other disorders are set forth in detail below.
In some embodiments, the present invention provides methods of treating a e associated with expression or activity of p53, p73, p21, pRB, p27, IKB, NFKB, c—Abl, FOXO proteins, COX-2 in a patient, comprising stering to the patient a therapeutically ive amount of a compound described herein, or a pharmaceutically acceptable salt or composition thereof. For example, provided herein are methods of treating various cancers in mammals (including humans and non-humans), comprising administering to a patient in need thereof a compound of the invention, or a pharmaceutically acceptable salt thereof. Such cancers include hematologic malignancies (leukemias, lymphomas, myelomas, myelodysplastic and myeloproliferative mes) and solid tumors (carcinomas such as prostate, breast, lung, colon, pancreatic, renal, ovarian as well as soft tissue and osteo- sarcomas, and stromal ). Breast cancer (BC) can include basal-like breast cancer (BLBC), triple negative breast cancer (TNBC) and breast cancer that is both BLBC and TNBC. In addition, breast cancer can include invasive or vasive ductal or lobular carcinoma, tubular, medullary, mucinous, papillary, cribriform carcinoma of the breast, male breast cancer, recurrent or metastatic breast cancer, phyllodes tumor of the breast and Paget’s disease of the nipple.
In some embodiments, the present invention provides a method of treating inflammatory ers in a patient, comprising stering to the patient a compound of the invention, or a pharmaceutically acceptable salt thereof. Such inflammatory disorders include toid arthritis, systemic lupus, systemic sclerosis, vasculitis syndromes , medium and large vessel), atherosclerosis, sis and other dermatological inflammatory disorders (such as pemphigous, pemphigoid, allergic dermatitis), and urticarial syndromes.
In some embodiments, the er or ion associated with CRMl activity is muscular dystrophy, arthritis, for example, osteoarthritis and rheumatoid arthritis, ankylosing spondilitis, traumatic brain injury, spinal cord injury, sepsis, rheumatic disease, cancer atherosclerosis, type 1 diabetes, type 2 diabetes, leptospiriosis renal disease, glaucoma, l disease, ageing, headache, pain, complex regional pain syndrome, cardiac rophy, musclewasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, ischemia/reperfusion, stroke, cerebral aneurysm, angina pectoris, pulmonary disease, cystic s, acid-induced lung injury, pulmonary —96- ension, asthma, chronic obstructive pulmonary disease, Sjogren’s syndrome, e membrane disease, kidney e, glomerular disease, alcoholic liver disease, gut es, peritoneal triosis, skin diseases, nasal sinusitis, mesothelioma, anhidrotic ecodermal dysplasia—ID, behcet’s e, incontinentia pigmenti, tuberculosis, asthma, crohn’s disease, colitis, ocular allergy, appendicitis, paget’s disease, pancreatitis, periodonitis, endometriosis, inflammatory bowel disease, inflammatory lung disease, silica—induced es, sleep apnea, AIDS, HIV—l, autoimmune diseases, antiphospholipid syndrome, lupus, lupus nephritis, familial mediterranean fever, hereditary periodic fever syndrome, psychosocial stress diseases, neuropathological diseases, familial amyloidotic polyneuropathy, inflammatory neuropathy, parkinson’s disease, multiple sclerosis, alzheimer’s disease, amyotropic lateral sclerosis, huntington’s disease, cataracts, or hearing loss.
In other embodiments, the disorder or condition associated with CRMl activity is head injury, uveitis, inflammatory pain, allergen induced asthma, lergen induced asthma, glomerular nephritis, tive colitis, necrotizing enteroColitis, hyperimmunoglobulinemia D with recurrent fever (HIDS), TNF receptor associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndromes, Muckle-Wells syndrome (urticaria deafness amyloidosis),familial cold urticaria, neonatal onset multisystem inflammatory disease (NOMID), periodic fever, aphthous itis, pharyngitis and is (PFAPA syndrome), Blau syndrome, pyogenic sterile arthritis, pyoderma gangrenosum,acne (PAPA), deficiency of the interleukin-l—receptor antagonist (DIRA), subarachnoid hemorrhage, polycystic kidney disease, transplant, organ transplant, tissue transplant, myelodysplastic syndrome, irritant-induced inflammation, plant irritant-induced inflammation, poison ivy/ urushiol oil-induced inflammation, chemical nt—induced inflammation, bee sting—induced inflammation, insect bite-induced ation, sunburn, burns, dermatitis, endotoxemia, lung injury, acute respiratory distress syndrome, lic hepatitis, or kidney injury caused by parasitic infections.
In further aspects, the present invention provides a use of a compound of of the ion, of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease associated with expression or activity of p53, p73, p21, pRB, p27, IKB, NFKB, c—Abl, FOXO ns or COX-2. In some ments, the present invention provides a use of a nd of of the invention in the manufacture of a medicament for the treatment of any of cancer and/or neoplastic ers, angiogenesis, autoimmune ers, inflammatory disorders and/or es, epigenetics, hormonal 2012/048368 disorders and/or diseases, viral diseases, neurodegenerative disorders and/or diseases or malogic disorders.
In some embodiments, the present invention provides a method for inhibiting CRMl in a biological. sample or in a patient, comprising contacting the biological sample with, or administering to the patient, a pharmaceutically acceptable salt of a compound of the invention, or a pharmaceutically acceptable salt or composition thereof.
Neoplastic ers A compound or composition described herein can be used to treat a neoplastic disorder. A “neoplastic disorder” is a disease or disorder characterized by cells that have the ty for autonomous growth or replication, e.g., an abnormal state or condition characterized by proliferative cell growth. Exemplary neoplastic disorders include: carcinoma, sarcoma, metastatic disorders, e.g., tumors arising from prostate, brain, bone, colon, lung, breast, ovarian, and liver origin, poietic neoplastic disorders, e.g., leukemias, mas, myeloma and other malignant plasma cell disorders, and metastatic tumors. Prevalent s include: breast, prostate, colon, lung, liver, and pancreatic cancers.
Treatment with the compound can be in an amount effective to ameliorate at least one etc. symptom of the stic disorder, e.g., reduced cell proliferation, reduced tumor mass, The disclosed methods are useful in the prevention and treatment of cancer, including for example, solid tumors, soft tissue tumors, and metastases thereof, as well as in familial Cancer (BRCAl cancer syndromes such as Li Fraumeni Syndrome, Familial Breast-Ovarian s are also useful in or BRAC2 mutations) mes, and others. The disclosed treating non-solid s. Exemplary solid tumors include malignancies (e.g., sarcomas, adenocarcinomas, and omas) of the s organ systems, such as those of lung, breast, lymphoid, gastrointestinal (e. g., , and genitourinary (e.g., renal, urothelial, or testicular tumors) tracts, pharynx, prostate, and ovary. ary adenocarcinomas include colorectal cancers, renal-cell carcinoma, liver cancer, non—small cell carcinoma of the lung, and cancer of the small intestine.
Exemplary cancers described by the al Cancer Institute include: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS—Related Lymphoma; AIDS-Related ancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, —98- Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteos’arcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stern Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, al Astrocytoma/Malignant , Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, entorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male; Bronchial Adenomas/Carcinoids, Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; oma, Islet Cell; oma of Unknown Primary; l s System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative ers; Clear Cell Sarcoma of Tendon s; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-CeIl Lymphoma; Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; epatic Bile Duct Cancer; Eye Cancer, cular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric ch) Cancer; c (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult ry); Hepatocellular (Liver) Cancer, Childhood ry); Hodgkin's ma, Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma; Islet Cell Carcinoma rine Pancreas); Kaposi's Sarcoma; Kidney ; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood; Leukemia, Chronic cytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; Lung , Small Cell; Lymphoblastic Leukemia, Adult Acute; Lymphoblastic Leukemia, Childhood Acute; Lymphocytic Leukemia, c; Lymphoma, AIDS- Related; ma, Central Nervous System (Primary);Lymphoma, Cutaneous T-CeIl; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's, Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's, Adult; Lymphoma, Non— Hodgkin's, Childhood; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom’s; Male Breast Cancer; ant Mesothelioma, Adult; Malignant elioma, Childhood; ant Thymoma; Medulloblastoma, Childhood; Melanoma; ma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; atic us Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, ood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; d Leukemia, Childhood Acute; a, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma; Non—Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood; Non- Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous cytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic ; Pancreatic Cancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile ; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; y Liver Cancer, Adult; y Liver Cancer, Childhood; Prostate Cancer; Rectal ; Renal Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter, tional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; ry Gland Cancer, Childhood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma (Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, Soft Tissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Childhood; us Neck Cancer with Occult Primary, Metastatic; -100— Stomach (Gastric) Cancer; h (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T— Cell Lymphoma, Cutaneous; Testicular ; Thymoma, Childhood; Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; n Primary Site, Cancer of, Childhood; Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma, ood; Vulvar Cancer; Waldenstrom's Macro globulinemia; and Wilms’ Tumor. Metastases of the aforementioned cancers can also be treated or prevented in accordance with the methods described herein.
Cancer Combination Therapies In some embodiments, a compound described herein is administered together with an additional cancer ent. Exemplary cancer treatments e, for example, chemotherapy, targeted therapies such as antibody therapies, kinase inhibitors, immunotherapy, and hormonal therapy, and anti-angiogenic therapies. Examples of each of these treatments are ed below.
As used , the term “combination,9) (4combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention can be administered With r therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the invention, an additional eutic agent, and a ceutically acceptable carrier, adjuvant, or vehicle.
The amount of both a compound of the invention and onal therapeutic agent (in those itions which comprise an additional therapeutic agent as described above) that can be combined with the carrier materials to produce a single dosage form will vary ing upon the host treated and the partiCular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a compound of the invention can be stered.
Chemotherapy In some embodiments, a compound described herein is administered with a chemotherapy. Chemotherapy is the treatment of cancer with drugs that can destroy cancer -l 0 l - cells. “Chemotherapy” usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy. Chemotherapy drugs interfere with cell division in various possible ways, e.g., with the duplication ofDNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not ic for cancer cells, gh some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can.
Examples of chemotherapeutic agents used in cancer therapy include, for example, antimetabolites (e. g., folic acid, purine, and dine tives) and alkylating agents (e.g., nitrogen ds, nitrosoureas, platinum, alkyl sulfonates, ines, triazenes, aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitors and others). Exemplary agents include Aclarubicin, Actinomycin, Alitretinon, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin, ine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan, Belotecan, Bexarotene, Bendamustine, cin, Bortezomib, Busulfan, Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur, Carmustine, Celecoxib, Chlorambucil, ethine, tin, Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine, Docetaxel, Doxorubicin, xiral, Elesclomol, Elsamitrucin, Enocitabine, Epirubicin, Estramustine, Etoglucid, Etoposide, Floxuridine, Fludarabine, Fluorouracil (SFU), Fotemustine, Gemcitabine, Gliadel implants, Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomal bicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone, Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate, Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, cin, Mitoxantrone, Nedaplatin, Nimustine, Oblimersen, Omacetaxine, xel, Oxaliplatin, Paclitaxel, argase, Pemetrexed, Pentostatin, Pirarubicin, Pixantrone, Plicamycin, P-orfimer sodium, Prednimustine, Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitabine, Semustine, Sitimagene novec, Strataplatin, Streptozocin, Talaporfin, Tegafur-uracil, Temoporfin, lomide, Teniposide, Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurine, Tioguanine, Tipifarnib, Topotecan, Trabectedin, Triaziquone, Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, famide,’Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vorinostat, Zorubicin,’ and other cytostatic or cytotoxic agents described herein. - l 02- Because some drugs work better together than alone, two or more drugs are often given at the same time. Often, two or more chemotherapy agents are used as ation chemotherapy. In some embodiments, the chemotherapy agents (including ation chemotherapy) can be used in ation with a compound described herein.
Targeted therapy ed therapy constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule targeted y drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within a cancer cell.
Prominent examples are the tyrosine kinase inhibitors such as axitinib, bosutinib, cediranib, desatinib, erolotinib, imatinib, gefitinib, lapatinib, lestaurtinib, nib, semaxanib, sorafenib, sunitinib, and anib, and also cyclin-dependent kinase tors such as alvocidib and seliciclib. Monoclonal dy therapy is another strategy in which the therapeutic agent is an dy which specifically binds to a protein on the surface of the cancer cells. es e the anti—HERZ/neu antibody trastuzumab (Herceptin®) typically used in breast cancer, and the anti-CD20 antibody rituximab and tositumomab typically used in a variety of B-cell malignancies. Other exemplary antibodies include cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, edrecolomab, and umab. Exemplary fusion proteins include aflibercept and denileukin diftitox. In some embodiments, targeted therapy can be used in combination with a compound bed herein, e.g., Gleevec (Vignari and Wang 2001).
Targeted therapy can also involve small peptides as “homing devices” which can bind to cell surface receptors or affected extracellular matrix surrounding a tumor. Radionuclides which are attached to these peptides (e.g, RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. An example of such therapy includes BEXXAR®.
Angiogenesis Compounds and methods described herein may be used to treat or prevent a disease or disorder associated with angiogenesis. Diseases associated with angiogenesis e cancer, cardiovascular disease and macular degeneration.
Angiogenesis is the physiological process involving the growth of new blood s from pre—existing vessels. Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in granulation tissue. However, it is also a - l 03 — fundamental step in the transition of tumors from a dormant state to a malignant one.
Angiogenesis may be a target for combating diseases characterized by either poor vascularisation or al lature.
Application of specific compounds that may inhibit or induce the on of new blood vessels in the body may help combat such diseases. The presence of blood vessels where there should be none may affect the ical properties of a tissue, increasing the likelihood of failure. The absence of blood vessels in a repairingor otherwise metabolically active tissue may inhibit repair or other essential ons. Several diseases, such as ischemic chronic wounds, are the result of failure or insufficient blood vessel formation and may be treated by a local expansion of blood vessels, thus bringing new nutrients to the site, facilitating repair. Other diseases, such as age-related macular degeneration, may be created by a local expansion of blood vessels, interfering with normal physiological processes.
Vascular endothelial growth factor (VEGF) has been demonstrated to be a major contributor to angiogenesis, increasing the number of capillaries in a given network.
Upregulation of VEGF is a major ent of the physiological response to exercise and its role in angiogenesis is suspected to be a possible ent in vascular injuries. In vitro studies clearly demonstrate that VEGF is a potent stimulator of angiogenesis because, in the presence of this growth factor, plated endothelial cells will proliferate and migrate, eventually forming tube structures resembling capillaries.
Tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (e.g., VEGF). Growth factors such as bFGF and VEGF can induce capillary growth into the tumor, which some researchers suspect supply required nutrients, allowing for tumor expansion.
Angiogenesis represents an excellent therapeutic target for the treatment of cardiovascular e. It is a potent, physiological process that underlies the l manner in which our bodies respond to a diminution of blood supply to vital organs, namely the production of new collateral vessels to overcome the ischemic insult.
Overexpression of VEGF causes increased permeability in blood vessels in addition to stimulating angiogenesis. ln wet macular degeneration, VEGF causes proliferation of capillaries into the retina. Since the increase in enesis also causes edema, blood and other retinal fluids leak into the retina, causing loss of .
Anti-angiogenic therapy can include kinase tors ing vascular elial growth factor (VEGF) such as sunitinib, sorafenib, or monoclonal antibodies or receptor “decoys” to VEGF or VEGF receptor including bevacizumab or VEGF-Trap, or thalidomide or its analogs (lenalidomide, pomalidomide), or agents targeting non-VEGF enic targets such as fibroblast growth factor (FGF), angiopoietins, or angiostatin or endostatin.
Epigenetics Compounds and methods described herein may be used to treat or t a disease or disorder associated with epigenetics. Epigenetics is the study of heritable changes in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA sequence. One example of epigenetic changes in eukaryotic biology is the process of cellular differentiation. During morphogenesis, stem cells become the various cell lines of the embryo which in turn become fully differentiated cells. In other words, a single fertilized egg cell changes into the many cell types including neurons, muscle cells, epithelium, blood vessels etc. as it continues to divide. It does so by activating some genes while inhibiting others.
Epigenetic changes are preserved when cells divide. Most epigenetic s only occur within the course of one individual organism's lifetime, but, if a mutation in the DNA has been caused in sperm or egg cell that results in fertilization, then some epigenetic s are inherited from one generation to the next. Specific epigenetic processes include paramutation, bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, ramming, ection, maternal effects, the progress of ogenesis, many effects of gens, regulation of histone modifications and heterochromatin, and technical limitations ing parthenogenesis and cloning.
Exemplary diseases associated with epigenetics e ndrome, fragile X— . syndrome, ICF syndrome, Angelman’s syndrome, Prader—Wills syndrome, BWS, Rett syndrome, oc-thalassaemia, cancer, leukemia, Rubinstein-Taybi syndrome and -Lowry syndrome.
The first human disease to be linked to epigenetics was cancer. Researchers found that ed tissue from patients with colorectal cancer had less DNA methylation than normal tissue from the same ts. Because methylated genes are typically turned off, loss of DNA methylation can cause abnormally high gene activation by altering the arrangement of chromatin. On the other hand, too much methylation can undo the work of protective tumor suppressor genes. -1 05 - DNA methylation occurs at CpG sites, and a majority of CpG cytosines are methylated in mammals. However, there are stretches ofDNA near promoter regions that have higher concentrations of CpG sites (known as CpG islands) that are free of ation in normal cells. These CpG islands become excessively methylated in cancer cells, thereby causing genes that should not be silenced to turn off. ‘This abnormality is the trademark epigenetic change that occurs in tumors and happens early in the pment of cancer.
Hypermethylation of CpG islands can cause tumors by shutting off tumor—suppressor genes.
In fact, these types of changes may be more common in human cancer than DNA sequence mutations.
Furthermore, although epigenetic changes do not alter the sequence of DNA, they can cause mutations. About half of the genes that cause familial or inherited forms of cancer are turned off by ation. Most of these genes normally suppress tumor formation and help repair DNA, including O6—methylguanine—DNA methyltransferase (MGMT), MLHl cyclin- dependent kinase inhibitor 2B (CDKNZB), and RASSF1A. For example, hypermethylation of the promoter ofMGMT causes the number of G-to-A mutations to increase.
Hypermethylation can also lead to instability of microsatellites, which are repeated sequences of DNA. Microsatellites are common in normal individuals, and they usually consist of repeats of the dinucleotide CA. Too much methylation of the er of the DNA repair gene MLH] can make a microsatellite le and en or shorten it.
Microsatellite instability has been linked to many cancers, including colorectal, endometrial, ovarian, and gastric cancers.
Fragile X syndrome is the most ntly inherited mental disability, particularly in males. Both sexes can be ed by this condition, but because males only have one X some, one fragile X will impact them more severely. Indeed, fragile X syndrome occurs in approximately 1 in 4,000 malesand l in 8,000 females. People with this syndrome have severe intellectual disabilities, delayed verbal development, and “antistic-like” behavior.
Fragile X syndrome gets its name from the way the part of the X chromOsome that contains the gene abnormality looks under a cope; it usually appears as if it is hanging by a thread and easily breakable. The syndrome is caused by an abnormality in the FMRI (fragile X mental retardation 1) gene. People who do not have fragile X syndrome have 6 to 50 repeats of the trinucleotide CGG in their FMR] gene. r, duals with over 200 repeats have a full mutation, and they usually show symptoms of the syndrome. Too many CGGs cause the CpG islands at the promoter region of the FMR] gene to become — 1 06- methylated; normally, they are not. This methylatiOn turns the gene off, stopping the FMRZ gene from producing an important protein called fragile X mental retardation protein. Loss of this specific protein causes fragile X syndrome. gh a lot of attention has been given to the CGG expansion mutation as the cause of fragile X, the epigenetic change associated with FMR] methylation is the real me culprit.
Fragile X syndrome is not the only disorder associated with mental retardation that involves epigenetic changes. Other such conditions include Rubenstein-Taybi-, Coffin-Lowry, Prader—Willi, Angelman, Beckwith—Wiedemann, ATR-X, and Rett syndromes.
Epigenetic therapies include inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases and e deacetylases, which have shown promising anti—tumorigenic effects for some malignancies, as well as nse oligonucloetides and siRNA.
Immunoz‘herapy In some embodiments, a compound described herein is administered with an immunotherapy. Cancer immunotherapy refers to a e set of therapeutic strategies designed to induce the t’s own immune system to fight the tumor. Contemporary methods for generating an immune response against tumors include esicular BCG immunotherapy for superficial bladder cancer, prostate cancer vaccine ge, and use of erons and other cytokines to induce an immune se in renal cell carcinoma and ma patients.
Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, since the donor’s immune cells will often attack the tumor in a graft-versus- tumor effect. In some embodiments, the immunotherapy agents can be used in ation with a compound described herein.
Hormonal therapy In some embodiments, a compound described herein is administered with a al therapy. The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone—sensitive tumors include certain types of breast and prostate cancers, as well as certain types of leukemia which respond to certain retinoids/retinoic acids. Removing or ng estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as -107— progestogens may be therapeutically beneficial. In some embodiments, the hormonal therapy agents can be used in combination with a nd bed herein.
Inflammation andAutoimmune Disease The compounds and methods described herein may be used to treat or prevent a disease or disorder associated with inflammation, particularly in humans and other mammals.
A compound described herein may be administered prior to the onset of, at, or after the initiation of inflammation. When used prophylactically, the compounds are preferably provided in advance of any atory response or symptom. Administration of the compounds can prevent or attenuate inflammatory ses or symptoms. Exemplary inflammatory conditions include, for example, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, degenerative joint disease, spondouloarthropathies, other seronegative inflammatory arthridities, polymyalgia rheumatica, s vasculidities (e.g., giant cell arteritis, ANCA+ vasculitis), gouty arthritis, systemic lupus erythematosus, juvenile arthritis, le rheumatoid arthritis, osteoarthritis, osteoporosis, diabetes (e.g., insulin dependent diabetes mellitus or juvenile onset diabetes), ual cramps, cystic fibrosis, inflammatory bowel e, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis, gastritis, esophagitis, pancreatitis, peritonitis, mer's disease, shock, ankylosing spondylitis, gastritis, conjunctivitis, pancreatis (acute or chronic), multiple organ injury syndrome (e. g., secondary to septicemia or trauma), myocardial infarction, atherosclerosis, , reperfusion injury (e. g., due to cardiopulmonary bypass or kidney dialysis), acute glomerulonephritis, thermal injury (i.e., n), necrotizing enterocolitis, granulocyte usion associated syndrome, and/or Sjogren's me. Exemplary inflammatory conditions of the skin include, for example, eczema, atopic dermatitis, contact itis, urticaria, schleroderma, psoriasis, and dermatosis with acute inflammatory ents.
In another embodiment, a compound or method described herein may be used to treat or t allergies and respiratory conditions, including asthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome, and any chronic obstructive pulmonary disease . The compounds C. may be used to treat chronic hepatitis infection, including hepatitis B and hepatitis Additionally, a compound or method described herein may be used to treat autoimmune diseases and/or inflammation associated with autoimmune diseases, such as organ-tissue autoimmune diseases (6. g., Raynaud's syndrome), derma, myasthenia WO 19561 - l 0 8— graVis, transplant rejection, endotoxin shock, , psoriasis, eczema, dermatitis, multiple sclerosis,- autoimmune thyroiditis, uveitis, systemic lupus matosis, Addison's disease, autoimmune polyglandular disease (also known as mune polyglandular syndrome), and Grave’s disease.
In a particular embodiment, the compounds described herein can be used to treat multiple sclerosis. In a specific aspect, the compound used to treat multiple sclerosis is nd 1 : (Z)—3 —(3-(3 ,5—bis(trifluoromethyl)phenyl)— l H— 1 ,2,4-triazol— l -yl)— l -(3 ,3- difluoroazetidin- l open—l -one).
Combination therapy In certain embodiments, a compound described herein may be administered alone or in combination with other compounds useful for treating or preventing inflammation.
Exemplary anti-inflammatory agents include, for example, steroids (e. g., Cortisol, cortisone, fludrocortisone, sone, a]—methylprednisone, triamcinolone, betamethasone or dexamethasone), nonsteroidal antiinflammatory drugs (NSAIDS (e. g., aspirin, acetaminophen, tolmetin, ibuprofen, mefenamic acid, piroxicam, nabumetone, rofecoxib, celecoxib, etodolac or nimesulide). In r embodiment, the other therapeutic agent is an antibiotic (e. g., vancomycin, penicillin, amoxicillin, ampicillin, cefotaxime, ceftriaxone, cefixime, rifampinmetronidazole, doxycycline or streptomycin). In another embodiment, the other therapeutic agent is a PDE4 inhibitor (e. g., last or rolipram). In another embodiment, the other therapeutic agent is an antihistamine (e. g. , cyclizine, hydroxyzine, promethazine or diphenhydramine). In another embodiment, the other therapeutic agent is an anti—malarial (e. g., artemisinin, artemether, artsunate, chloroquine phosphate, mefloquine hydrochloride, doxycycline hyclate, nil hydrochloride, atovaquone or halofantrine). In one embodiment, the other compound is drotrecogin alfa.
Further examples of anti-inflammatory agents e, for example, aceclofenac, acemetacin, e-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid, S-adenosylmethionine, alclofenac, alclometasone, alfentanil, algestone, allylprodine, alminoprofen, aloxiprin, alphaprodine, aluminum bis(acetylsalicylate), amcinonide, c, aminochlorthenoxazin, 3-amino hydroxybutyric acid, 2-amino—4— ne, ropylon, yrine, rine, ammonium salicylate, ampiroxicam, amtolmetin guacil, idine, antipyrine, antrafenine, apazone, beclomethasone, bendazac, benorylate, benoxaprofen, benzpiperylon, benzydamine, benzylmorphine, bermoprofen, -1 O9- betamethasone, betamethasone- 17-Valerate, bezitramide, [alpha] —bisabolol, bromfenac, p— bromoacetanilide, 5-bromosa1icylic acid e, bromosaligenin, bucetin, bucloxic acid, bucolome, nide, bufexamac, bumadizon, buprenorphine, butacetin, butibufen, butorphanol, carbamazepine, carbiphene, caiprofen, carsalam, chlorobutanol, chloroprednisone, chlorthenoxazin, e salicylate, cinchophen, cinmetacin, ciramadol, clidanac, clobetasol, clocortolone, clometacin, clonitazene, clonixin, clopirac, cloprednol, clove, codeine, codeine methyl bromide, codeine phosphate, codeine sulfate, cortisone, cortivazol, cropropamide, crotethamide, cyclazocine, deflazacort, dehydrotestosterone, desomorphine, desonide, metasone, dexamethasone, dexamethasone isonicotinate, ‘ dexoxadrol, moramide, dextropropoxyphene, deoxycorticosterone, dezocine, diampromide, diamorphone, diclofenac, difenamizole, difenpiramide, diflorasone, diflucortolone, diflunisal, difluprednate, dihydrocodeine, dihydrocodeinone enol e, dihydromorphine, dihydroxyaluminum acetylsalicylate, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, diprocetyl, dipyrone, l, droxicam, emorfazone, enfenamic acid, enoxolone, epirizole, eptazocine, etersalate, ethenzamide, ethoheptazine, ethoxazene, ethylmethylthiambutene, ethylmorphine, etodolac, etofenamate, etonitazene, eugenol, felbinac, fenbufen, fenclozic acid, fendosal, fenoprofen, fentanyl, fentiazac, fepradinol, one, enine, fluazacort, flucloronide, flufenamic acid, flumethasone, flunisolide, flunixin, flunoxaprofen, fluocinolone acetonide, fluocinonide, fluocinolone acetonide, fluocortin butyl, fluocoitolone, fluoresone, fluorometholone, fluperolone, flupirtine, fluprednidene, fluprednisolone, fluproquazone, flurandrenolide, flurbiprofen, fluticasone, formocortal, al, gentisic acid, glafenine, glucametacin, glycol salicylate, guaiazulene, halcinonide, halobetasol, tasone, haloprednone, heroin, hydrocodone, hydro cortamate, ortisone, hydrocortisone acetate, hydrocortisone succinate, hydrocortisone hemisuccinate, ortisone 21—1ysinate, hydrocortisone cypionate, hydromorphone, hydroxypethidine, ibufenac, ibuprofen, ibuproxam, imidazole salicylate, thacin, indoprofen, isofezolac, isoflupredone, redone acetate, ol, isomethadone, isonixin, isoxepac, isoxicam, ketobemidone, ketoprofen, ketorolac, p- lactophenetide, lefetamine, levallorphan, levorphanol, levophenacyl-morphan, lofentanil, lonazolac, lornoxicam, loxoprofen, lysine acetylsalicylate, mazipredone, meclofenamic acid, one, mefenamic acid, meloxicam, meperidine, meprednisone, meptazinol, mine, metazocine, methadone, methotrimeprazine, prednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, methylprednisolone -1 10- suleptnate, metiazinic acid, metofoline, metopon, mofebutazone, mofezolac, mometasone, ne, ne, ne hydrochloride, morphine sulfate, morpholine salicylate, myrophine, nabumetone, nalbuphine, nalorphine, l-naphthyl salicylate, naproxen, narceine, nefopam, nicomorphine, nifenazone, niflumic acid, nimesulide, 5'-nitro-2'- propoxyacetanilide,norlevorphanol, normethadone, normorphine, norpipanone, olsalazine, opium, oxaceprol, oxametacine, zin, one, oxymorphone, oxyphenbutazone, papaveretum, paramethasone, paranyline, parsalmide, pentazocine, perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridine hydrochloride, phenocoll, phenoperidine, phenopyrazone, phenomorphan, phenyl acetylsalicylate, phenylbutazone, phenyl salicylate, phenyramidol, piketoprofen, piminodine, pipebuzone, piperylone, pirazolac, piritramide, piroxicam, pirprofen, pranoprofen, prednicarbate, prednisolone, prednisone, prednival, prednylidene, proglumetacin, proheptazine, promedol, propacetamol, properidine, propiram, propoxyphene, propyphenazone, proquazone, protizinic acid, proxazole, ramifenazone, remifentanil, rimazolium ulfate, salacetamide, salicin, lamide, salicylamide o— acetic acid, salicylic acid, salicylsulfuric acid, salsalate, salverine, simetride, sufentanil, alazine, sulindac, xide dismutase, suprofen, suxibuzone, talniflumate, tenidap, tenoxicam, terofenamate, tetrandrine, linobutazone, tiaprofenic acid, tiaramide, tilidine, tinoridine, tixocortol, tolfenamic acid, tolmetin, tramadol, triamcinolone, triamcinolone acetonide, tropesin, Viminol, xenbucin, Ximoprofen, zaltoprofen and zomepirac.
In one embodiment, a compound described herein may be administered with a selective COX—2 inhibitor for treating or preventing inflammation. Exemplary selective COX—2 inhibitors include, for example, deracoxib, parecoxib, celecoxib, valdecoxib, rofecoxib, etoricoxib, and lumiracoxib.
In some embodiments, a provided nd is administered in combination with an anthracycline or a Topo II tor. In certain embodiments, a ed compound is administered in combination with Doxorubicin (Dox). In certain embodiments, a provided nd is administered in combination with bortezomib (and more broadly including omib). It was surprisingly found that a provided compound in combination with Dox or bortezomib resulted in a ystic effect (216., more than ve).
Viral infections Compounds and methods described herein may be used to treat or prevent a e or disorder associated with a viral infection, particularly in humans and other mammals. A -1 1 1- compound'described herein may be administered prior to the onset of, at, or after-the initiation of Viral infeCtion. When used prophylactically, the compounds are ably provided in advance of any viral infection or symptom thereof.
Exemplary viral diseases e acute febrile pharyngitis, pharyngoconjunctival fever, ic keratoconjunctivitis, infantile gastroenteritis, Coxsackie infections, infectious mononucleosis, Burkitt lymphoma, acute hepatitis, c hepatitis, hepatic cirrhosis, hepatocellular carcinoma, primary HSV—l infection (e. g., ostomatitis in children,‘ tonsillitis and pharyngitis in adults, keratoconjunctivitis), latent HSV—l infection (6. g., herpes labialis and cold sores), primary HSV—2 infection, latent HSV-2 infection, aseptic meningitis, infectious mononucleosis, Cytomegalic inclusion disease, Kaposi’s a, entric Castleman disease, primary effusion lymphoma, AIDS, influenza, Reye syndrome, measles, postinfectious alomyelitis, Mumps, hyperplastic epithelial lesions (6. g., common, flat, plantar and anogenital warts, laryngeal papillomas, epidermodysplasia verruciformis), cervical carcinoma, squamous cell carcinomas, croup, pneumonia, bronchiolitis, common cold, Poliomyelitis, Rabies, influenza-like syndrome, severe bronchiolitis with pneumonia, German measles, ital rubella, Varicella, and herpes zoster.
Exemplary viral pathogens include Adenovirus, Coxsackievirus, Dengue virus, Encephalitis Virus, n—Barr virus, Hepatitis A virus, Hepatitis B Virus, Hepatitis C virus, Herpes simplex virus type 1, Herpes simplex Virus type 2, galovirus, Human 2O herpesvirus type 8, Human deficiency virus, Influenza virus, measles Virus, Mumps virus, Human papillomavirus, Parainfluenza virus, Poliovirus, Rabies virus, atory syncytial virus, Rubella virus, Varicella-zoster Virus, West Nile virus, Dungee, and Yellow virus. Viral pathogens may also include s that cause resistant Viral infections.
Antiviral drugs are a class of medicatiOns used specifically for treating viral infections. Antiviral action generally falls into one of three mechanisms: interference with the ability of a Virus to infiltrate a target cell (e. g., amantadine,‘rimantadine and pleconaril), inhibition of the synthesis of Virus (e.g., nucleoside ues, e.g., acyclovir and zidovudine (AZT), and inhibition of the release of virus (e.g., zanamivir and oseltamivir).
- Ophthamology Compounds and methods described herein may be used to treat or prevent an ophthamology disorder. Exemplary ophthamology disorders include macular edema (diabetic and nondiabetic macular edema), age related macular degeneration wet and dry -1 12- forrns, aged orm macular degeneration, d macular edema, palpebral edema, retina edema, diabetic retinopathy, retinopathy, neovaScular maculopathy, neovascular glaucoma, uveitis, iritis, retinal vasculitis, endophthalmitis, panophthalmitis, atic ophthalmia, ditis, retinal pigment epithelitis, conjunctivitis, cyclitis, scleritis, episcleritis, optic neuritis, retrobulbar optic neuritis, keratitis, blepharitis, exudative retinal detachment, l ulcer, conjunctival ulcer, chronic nummular keratitis, ophthalmic disease associated with hypoxia or ischemia, retinopathy of prematurity, proliferative diabetic retinopathy, polypoidal choroidal vasculopathy, retinal angiomatous proliferation, retinal artery occlusion, retinal vein occlusion, Coats' disease, familial exudative retinopathy, pulseless disease (Takayasu's disease), Eales disease, antiphospholipid antibody syndrome, leukemic retinopathy, blood hyperviscosity syndrome, macroglobulinemia, interferon- associated retinopathy, ensive retinopathy, radiation retinopathy, corneal epithelial stem cell deficiency and ct.
Neurodegenerative disease Neurodegeneration is the umbrella term for the progressive loss of ure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes.
As research progresses, many similarities appear which relate these es to one another on a sub—cellular level. Discovering these similarities offers hope for therapeutic advances that could ameliorate many diseases simultaneously. There are many parallels between ent neurodegenerative disorders including al protein assemblies as well as d cell death.
Alzheimer's disease is characterized by loss of neurons and synapses in the cerebral cortex and n subcortical regions.» This loss results in gross atrophy of the affected regions, including ration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.
Huntington’s disease causes astrogliosis and loss of medium spiny neurons. Areas of the brain are affected according to their structure and the types of neurons they n, reducing in size as they cumulatively lose cells. The areas affected are mainly in the striatum, but also the frontal and temporal es. The striatum's subthalamic nuclei send control signals to the globus pallidus, which initiates and modulates motion. The weaker signals from subthalamic nuclei thus cause reduced initiation and modulation of movement, resulting in —1 13 — the characteristic movements of the disorder. Exemplary treatments for Huntington’s disease include tetrabenazine, neuroleptics, benzodiazepines, amantadine, remacemide, valproic acid, selective serotonin reuptake tors (S SRIs), mirtazapine and antipsychotics.
The mechanism by which the brain cells in Parkinson's are lost may consist of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. The alpha-synuclein-ubiquitin complex cannot be directed to the proteosome. This protein accumulation forms proteinaceous cytoplasmic inclusions called Lewy . The latest ch on pathogenesis of disease has shown that the death of dopaminergic s by alpha-synuclein is due to a defect in the machinery that transports ns between two major cellular organelles — the endoplasmic lum (ER) and the Golgi apparatus. Certain ns like Rabl may reverse this defect caused by alpha-synuclein in animal models.
Exemplary Parkinson’s e therapies include levodopa, dopamine agonists such as include bromocriptine, pergolide, pramipexole, role, piribedil, cabergoline, apomorphine and lisuride, dopa decarboxylate inhibitors, MAO-B inhibitors such as selegilene and rasagilene, anticholinergics and dine.
Amyotrophic lateral sclerosis (ALS/Lou Gehrig’s Disease) is a disease in which motor neurons are selectively targeted for degeneration. Exemplary ALS therapies include riluzole, baclofen, diazepam, trihexyphenidyl and amitriptyline.
Other exemplary neurodegenerative therapeutics include antisense oligonucleotides and stem cells.
Other disorders Compounds and compositions described herein may also be used to treat ers of abnormal tissue growth and fibrosis including dilative cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, pulmonary fibrosis, hepatic fibrosis, glomerulonephritis, and other renal disorders; The above disclosure generally describes the present invention. A more complete understanding can be obtained by reference to the following specific es. These Examples are bed solely for purposes of illustration and are not intended to limit the scope of the invention. Changes in form and substitution of equivalents are contemplated as circumstances may suggest or render expedient. Although c terms have been employed herein, such terms are intended in a descriptive sense and not for purposes of limitation. —ll4- EXEMPLIFICATION Abbreviations atm Atmosphere aq. s BINAP 2,2'—bis(diphenylphosphino)- 1 ,1 '-binaphthyl Boc tert-butoxycarbonyl CDI N,N’-Carbonyldiimidazole DCC N,N—Dicyclohexylcarbodiimide DCM Dichloromethane DBU Diaza(l ,3)bicyclo[5 .4.0]undecane DEA N,N—Diisopropyl ethylamine DIBAL-H Diisobutylaluminium hydride DIC N,N’-Diisopropylcarbodiimide DMAP N,N—Dimethylaminopyridine DMF Dimethylformamide DMSO Dimethylsulfoxide DPPF Diphenylphosphinoferrocene EA Ethyl acetate EDCI N—[3 thylamino)propyl]~N'—ethylcarbodiimide hydrochloride EDC l -Ethy1-3 -(3 ~dimethylaminopropyl)carbodiimide EtZO lether EtOAc Ethyl acetate EtOH Ethanol Etl Iodoethane Et Ethyl Fmoc 9—fluorenylmethyloxycarbonyl h hour(s) HetAr Heteroaryl HOBt N—Hydroxybenzotriazole HBTU O-(Benzotriazol-l -yl)-N,N,N’,N'—tetramethyluronium hexafluorophosphate HPLC High performance liquid tography LAH Lithium aluminium hydride LCMS HPLC mass spec -llS- MCPBA m—Chlorbenzoic acid MeCN Acetonitrile MeOH Methanol min Minutes Mel Iodomethane MeMgCl Methyl magnesium de Methyl n-BuLi 1 lithium NaOAc Sodium acetate NMR Nuclear magnetic resonance NMP N—Methyl pyrrolidinone nBuLi l-Butyl lithium 0.1’1. Over night Round-bottomed flask RT, rt, r.t. Room temperature T3P Propylphosphonic anhydride (available from Archimica) TEA Triethylamine THF Tetrahydrofurane nBu normal Butyl OMS Mesylate or methane sulfonate ester OTs Tosylate, toluene sulfonate or 4-methylbenzene ate ester PCC Pyridinium chlorochromate PPTS Pyridinium p—toluenesulfonate TBAF Tetrabutylammonium fluoride stOH p-Toluenesulfonic acid SPE Solid phase extraction (usually containing silica gel for mini-chromatography) sat. Saturated GP Protecting group mins minutes Throughout the ing description of such ses it is to be understood that, where appropriate, suitable protecting groups will be added to, and uently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting —l 1 6— groups as well as examples of le protecting groups are described, for example, in “Protective Groups in Organic Synthesis”, T.W. Green, P.G.M. Wuts, Wiley-Interscience, New York, (1999). It is also to be tood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such nt incompatibilities, and ways to circumvent them by carrying Out appropriate transformations and tic steps in a le order, will be readily understood to the one skilled in the art of organic synthesis. Examples of ormations are given below, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and ptions on other suitable transformations are given in “Comprehensive Organic Transformations — A Guide to Functional Group ations” R.
C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry”, March, 4th ed. McGraw Hill (1992) or, “Organic Synthesis”, Smith, McGraw Hill, (1994). Techniques for purification of intermediates and final products include for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid—liquid extraction, which will be readily understood by the one skilled in the art. The definitions of tuents and groups are as in a 1 except where defined differently. The term “room temperature” and “ambient temperature” shall mean, unless otherwise ed, a temperature between 16 and 25 °C.
The term “reflux” shall mean, unless otherwise stated, in reference to an employed t a temperature at or above the boiling point-of named solvent.
Synthesis on intermediate 4 Synthesis of 3,5-bis(trifluor0methyl)benzothioamide (1): F30 CN \ NaSH/MgCl2 F30 1 2 Step1 ‘ CFs CF3 A 3-neck round—bottom flask was charged with a solution 3,5- -1 17- bis(trifluoromethyl)benzonitrile (200 g, 1.0 eq) in DMF (1 L), to which was added NaSH (123.7 g, 2.0 eq.) and MgClz (186.7 g, 1 eq.). The reaction mixture was stirred at ambien ature for 2-3 h before being poured in to ice water slurry (10 L) and extracted with EtOAc (3 X l L). The combined organic layers were washed with brine (3 X 100 mL), dried over anhydrous Na2804, filtered, and concentrated under reduced pressure to afford 205 g (90% yield) of crude desired thioamide (1), used as such in the subsequent step. sis of 3-(3,5-bis(trifluoromethyl)phenyl)—1H-1,2,4-triazole (2): F3C F C “Vi; NH2 HCOOH 3 Step 2 CF3 CF3 (1) (2) A solution of 3,5—bis(trifluoromethyl)benzothioamide (1) (205.65 g) in DMF (1.03 L) was treated with hydrazine hydrate (73.16 mL, 2.0 eq). The reaction e was stirred at ambient temperature for 1 h. before being treated with formic acid (1.03 L). The on mixture was refluxed at 90 °C for 2-3 h then allowed to cool down to ambient temperature, poured into saturated aqueous sodium bicarbonate (7 L) and extracted with EtOAc (3 X IL), The ed organic layers were washed with brine (3 X 500 mL), dried over anhydrous Na2804, filtered, and concentrated under reduced pressure to afford 180 g of crude compound. This crude material was washed with petroleum ether (3 x 500 mL) , filtered and dried well to afford 160 grams (75% yield) of triazole (2) obtained as a pale yellow solid.
Synthesis of (Z)-is0propyl 3-(3-(3,5-bis(triflu0r0methyl)phenyl)-1H-1,2,4-triazol- 1-yl)acrylate (3): i5; mom WSW}N (2) (3) A 3—neck round-bottom flask was d with a solution of 3-(3,5- bis(trifluoromethyl)phenyl)—lH—l,2,4-triazole (2) (160 g, 1.0 eq.) in DMF (960 mL). The solution was treated DABCO (127.74 g, 2 eq.) and stirred for 30 min before being treated -118— with (Z)~isopropyl 3-iodoacry1ate (150.32g, 1.1 eq.). After 1 hm the reaction mixture was poured into ice water slurry (5 L) and extracted with EtOAc (3 X 1 L) . The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous NaZSO4, filtered, and concentrated under reduced pressure to afford 250 g of crude compound.
Purification by column chromatography (silica gel, eluting with EtOAc/hexane) afforded 138 g (61% yield) of pure isopropyl ester (3).
Synthesis of (Z)(3-(3,5-bis(trifluoro'methyl)phenyl)-1H-1,2,4-triazol—1- yl)acrylic acid (4): N’NW , ” " o N’NWOH » /> o , /> o F3C >’ .
N LIOH F3C N ———————-———> 01:3 CF3 (3) A 3-neck round—botom flask was charged with a on of (Z)—isopropyl 3—(3-(3,5- bis(trifluoromethyl)phenyl)-1H—l,2,4-triazolyl)acrylate (3) (130 g, 1.0 eq.) in THF (1.3 L) and treated with a solution of LiOH (69.3 g, 5 eq) in water (1.3 L). The reaction mixture was stirred at t temperature for 3-4 h before being diluted with 400 mL water, acidified (pH= 2-3) with dilute aqueous HCl and extracted with EtOAc (3 x 1 L). The combined c layers were washed with brine, dried over anhydrous NaZSO4 and concentrated under reduced pressure to afford 110 g (94% yield) of desired compound (4); Z/E ratio= 90.0/8.2 by LCMS.
Synthesis of (Z)iod0acrylic acid (1a): \fOH\ Nal ——-——> WOH/ 0 Step 13 I 0 (1a) A solution of propiolic acid (50.0 g, 1.0 eq) in acetic acid (500 mL,), was treated with sodium iodide (213.97 g, 2.0 eq). The reaction e was refluxed at 100 ° C for 2-3 h then cooled down to ambient temperature, poured into ice water (5.0 L), neutralized with saturated aqueous sodium bicarbonate and ted with EtOAc (3 x 1 L). The combined organic layers were washed with brine (3 x l L), dried over MgSO4, filtered, and trated under reduced pressure to afford 90.0 g of crude compound which was -1 19— purified by column chromatography a gel, elution with MeOH1CH2C12) affording 56.0 g (39.7% yield) of pure carboxylic acid (la).
Example 1 . Synthesis of (Z)—1-(3,3-diflu0r0azetidinyl)iod0propen0ne (2a): A solution of (Z)iodoacrylic acid (la) (2.75 g, 1.0 eq.) in CHZClz (25.0 mL) was cooled to 0 °C and sequentially treated with DIPEA (1.96 g 1.1 eq), HATU (5.78 g, 1.1 eq) and 3,3-difluoroazetidine hydrochloride (1.98 g, 1.1 eq). The on mixture was stirred at 0 0C for 2—3 hr before being filtered, and concentrated under reduced pressire affording 3 .5 elution with g of crude compound. Purification by column chromatography (silica gel, EtOAc/hexane) afforded 1.89 g of pure desired compound. Yield (49.87 %). Mass: (ES+) 273.8 (M+1).
Synthesis of (Z)(3-(3,5—bis(trifluoromethyl)phenyl)—1H-1,2,4-triazol—1-yl) (3,3-«difiu0r0azetidin-l—yl)pr0penone: NzNH / Fgc\ /> W F30 CF3 CFs A solution of 3—(3-(difluoromethyl)—5-(trifluoromethyl)phenyl)-1H—1,2,4-triazole (2) (1.5 g, 1.0 eq.) in DMF (9.0 mL) was d with DABCO (1.19 g, 2.0 eq) and stirred for 30 mins before being d (Z)—1—(3,3-difluoroazetidin—1—yl)iodopropen-l-one (2a) (1.60 in g, 1.1 eq). The reaction mixture was stirred at ambient temperature for 2-3 hr then poured to ice water (90 mL) and ted with EtOAc (3x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford 2.0 g of crude amide. (cis : 71.1%, trans isomer: .87%). Purification by column chromatography (silica gel, eluting with EtOAC/hexane) afforded 500 mg of pure desired amide (22.0% yield): 1H NMR (CDC13): 5 9.63 (s, 1H), 7.95-7.65 (m, 3H), .27 (d, J=10.8Hz, 1H), .66-5.69 (d, J=10.8 Hz, 1H), 4.46-4.59 (m, 4H). LCMS for C16H10F3N4O: [M+H]Jr = 427.27; found , RT: 3.03 min (98.17%).
(E)(3-(3,5—bis(trifluoromethyl)phenyl)-1H-1,2,4-triazolyl)-1—(3,3- difluoroazetidinyl)propen0ne: 1H NMR (CDC13): 8 9.18 (s, 1H), 8.59 (s, 2H), 8.32 (s, 1H), 8.24—8.27 (d, J=13.6 Hz, 1H), 6.80-6.84 (d, J=13.6 Hz, 1H), 4.83-4.88 (m, 2H), 4.40—4.46 (m, 2H). LCMS for C16H10F3N4O: [M+H]+ = 427.27; found 42734, RT: 3.13 min (100%).
Alternative synthesis of (Z)-3—(3-(3,5-bis(trifluoromethyl)phenyl)—1H-1,2,4- triazolyl)—1-(3,3-diflu0r0azetidinyl)pr0penone: OH WNOQF NI’N/ o :><:NH N"N/> o .HCl F3C N F3C N EDC, HOBt, DIPEA CF3 A solution of (Z)—3-(3-(3,5~bis(trifluoromethyl)phenyl)—1H—1,2,4-triazolyl)acrylic acid (33.0 g, 1.0 eq.) in CH2C12 (660 mL) was cooled to 0 OC and then treated tially with HOBT (17.27 g, 1.2 eq), EDCHCI (27.029 g, 1.5 eq.),3,3—difluoroazetidine hydrOchloride (14.61 mixture was g, 1.2 eq.) and DIPEA (24.31 mL, 1.5 eq). The on stirred at 0 0C for 1.15 hr before being quenched with 1 L water and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO4 and concentrated under reduced pressure to afford 35 g of crude compound. Purification by column chromatography (silica gel, eluting with MeOHzCHzClg) ed pure desired amide (15 g, 37% yield): (Z)—3-(3-(3,5-(trifluoromethyl)-1H-1,2,4-triazol—1-yl)(3,3-difluoroazetidin yl)propenone: 1H NMR(CDC13):6 9.63 (s, 1H), 7.95-7.65 (m, 3H), 7.24-7.27 (d, J=10.8 Hz, 1H), 5.66-5.69 (d, J=10.8 Hz, 1H), 4.46-4.59 (m, 4H). LCMS for C16H10F3N4O: [M+H]+ 427.27; found , RT: 3.027 %).
Example 2 , E>CNH ”Mfg/’0 ' I 7 .
F3C N) >’ N’Ngfg/(OH HOBt/ EDé-IHICI LIOH FaC N/ DIPEA Step 1 Step 2 F F (1) -l 21 - sis of (Z)(3-(3-fluoro(trifluoromethyl)phenyl)-1H-l,2,4-triazol yl)acrylic acid (1): N’NW {WNW’4 i o OH O ’ F3C ’N/> O f LiOH F30 /> —-———--—> Step1 F F (1) A on of opropyl 3—(3-(3-fluoro(trifluoromethyl)phenyl)-1H—1,2,4- triazol—l-yl)acrylate (0.400 g, 1.0 eq.) in THF (5 mL) and water (5 mL,) was treated with LiOH (0.097 g, 2.0 eq.). The reaction mixture was stirred at RT for 2-3 hrs, quenched with ice cold water (10 mL), acidified to pH 1-2 with diute aqueous HCl and extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over anhydrous NaZSO4 and concentrated under reduced pressure to afford 150 mg (42% yield) desired carboxylic acid, used in the subsequent step. Mass: (ES+) 302.19 (M+1).
Synthesis of (Z)(3,3—difluoroazetidin-1—yl)-3—(3-(3-flu0ro (trifluor0methyl)phenyl)—1H-1,2,F4-triazolyl)propen0ne: N’NWOH F N.HC| HOBt/ EDC. HCI F3C / DIPEA —-——————-————-—> \ Step 2 A 25-mL flask was charged with (Z)(3—(3—fluoro—5-(trifluoromethyl)phenyl)-1H- 1,2,4-triazol—1-yl)acry1ic acid (1) (0.150 g, 1.0 eq) followed by dichloromethane (3 mL) before being treated sequentially with DIPEA (0.102mL, 1.2 eq) EDC.HCl (0.143 g, 1.5 eq), 3,3-difluoroazetidine hydrochloride (0.077 g, 1.2 eq) and HOBT (0.091 g, 1.2eq) at 0 °C.
The reaction mixture was stirred at 0 ° C for 1 hr., diluted with.water (5mL) and extracted with dichloromethane (3 x 5 mL). Drying over NaiSO4 and tration under reduced 49 %: Trans 42 %). cation by pressure aforded 0.150 g of crude compound. (Cis column chromatography (silica gel, eluting with MeOH/CH2C12) afforded pure desired amide (0.025 g; 13% yield): (Z)(3,3-diflu0roazetidinyl)(3-(3-fluor0(triflu0romethyl)phenyl)—1H- triazol—1-yl)pr0penone: 1H NMR (400MHz, CDCl3) 5 9.6 (s, 1H), 7.40-8.37 (m, 3H), 7.22-7.25 (d, J=10.8 Hz, 1H), 5.64—5.67 (d, J=10.8 Hz, 1H), 4.46-4.59 (m, 4H). LCMS for C15H10F6N4O [l\/1'+H]+ 377.26 found 377.24 at RT 2.79 min purity (92.79%). Mass: (ES+) 377.2 (M+1).
Example 3 F><>NH N’NWO/ .HCI , /> o HOBt/EDCHCI F3C >2 LIOH_ F c N’N//>/OHF 3 DIPEA Step 1 . Step 2 OH OH (1) Synthesis of (Z)(3-(3-hydroxy(trifluoromethyl)phenyl)—1H-1,2,4-triazol ylic acid (1): “fir/v0Of_~_>Step--1 N I N l 0 F30 N/> , Fac LiOH Molecular : 341-29 Molecular Weight: 299.21 V-211 A solution of (Z)-isopropyl 3—(3—(3-hydroxy(trifluoromethyl)phenyl)—1H-1,2,4— triazol-l-yl)acrylate (4 g, 1.0 eq.) in THF (40 mL) and water (40 mL) was d with LiOH (1.92 g, 4 eq.). The reaction mixture was stirred at RT for 2—3 hrs then quenched with acidic ice-water slurry (300 mL) and extracted with EtOAc (3 X 250 mL). The combined c layers were washed with dil HCl solution (50 mL), dried over anhydrous NaZSO4 and concentrated under reduced pressure to afford 3 g of crude compound. The resulting crude off-white compound was used as such in the following step. Yield: 85.5%. Mass: (ES+) 299.92 (M+1).
Synthesis of (Z)—1-(3,3-difluor0azetidin-1—yl)(3-(3-hydr0xy—5- (trifluoromethyl)phenyl)-1H-1,2,4-triazol—1-yl)propen0ne (2): NNQ/OH F N.HCI HOBt/ EDC HCI FsC DIPEA ——————————> Step? A cold (0 °C) solution of (Z)(3-(3-hydroxy(trifluoromethyl)phenyl)—lH—l,2,4- l-l-yl)acry1ic acid (1) (1.5 g, 1.0 eq) in 30 ml of CH2C12 was treated sequentially with DIPEA (0.78 g, 1.2 eq), EDC.HC1 (01.15 g, 1.2 eq), 3,3-difluoroazetidine hydrochloride (0.78 g, 1.2 eq) and HOBt (0.92 g, 1.2 eq). The reaction mixture was stirred at 0 ° C for 3-4 hrs before being concentrated under d pressure to afford 0.5 g of crude compound. (trans isomer was not observed during reaction). The crude reaction mixture was purified by column chromatography affording pure desired amide (0.5 g). Yield: 26.7%: (Z)(3,3—difluoroazetidinyl)(3-(3—hydr0xy(trifluoromethyl)phenyl)-1H- 1,2,4-triazolyl)pr0pen-1—one: 1H NMR (400MHz, CDClg) 5 10.53 (1H, D20 ' exchangeable), 9.17 (s, 1H), 7.14—7.71 (m, 3H), 7.41—7.43 (d, J=10.4 Hz, 1H), .95 (d, J=10.4 Hz, 1H), 4.41-4.49 (m, 4H). LCMS for C15H11F5N402 [M+H]+ 375.27; found 375.24 at RT 2.44 min, purity (97.03%). Mass: (ES+) 375.2 (M+l).
Example 5 Synthesis of '(Z)(3-(3,5-bis(trifluoromethyl)phenyl)—1H-1,2,4-triazolyl)—1- (3,3-diflu0ropiperidin-1—yl)propenone: , ”No ,N/—>—N— OH hi (73>— F HC' [i 0 §F /) F30 N/ _>- F3C N EDCI/HOBT CFs CF3 A cold (0 °C) solution of (Z)-3—(3—(3,5-bis(trifluoromethyl)phenyl)-lH-l ,2,4-triazol- 1-yl)acrylic acid (4) (1.0 g, 1.0 eq.) in CH2C12 (20 mL) was treated sequentially with EDC HCl (0.656 g, 1.2 eq.), 3,3-difluoropiperidine hydrochloride (0.540 , DIPEA (435 mg, 1.2 eq) and HOBT (25.92 g, 1.2 eq.). The clear reaction mixture was d at 0 0C for 1.5 -2 h then quenched with 50 mL ice—water slurry and extracted with CH2C12 (2 x 25 mL). The combined organic layers were washed with brine, dried overanhydrous NazSO4 and concentrated under d pressure to afford 0.70 g of crude compound. No trans compound was formed as confirmed by LCMS and 1H NMR. Purification by column chromatography afforded 0.20 g of material that was further recrystallized/triturated using ether: petroleum ether to remove tic impurity affording 0.180 g (14.1% yield) of desired pure compound.
(Z)(3-(3,5-bis(trifluor0methyl)phenyl)-1H-1,2,4-triazol-1—yl)(3,3- -l24- difluoropiperidin-1—yl)pr0penone: 1H NMR (400 MHZ, CDCl3) 5 8.739 (s, 1H), 7.94- 8.59 (m,3H), 7.13-7.15 (d, J=10.4 Hz, 1H), 5.99—6.016(d, J= 10.4 Hz, 1H), 3.95-4.01 (t, 1H), .77 (m, 2H), 3.56—3.53 (t, 1H), 2.11-2.05 (m, 2H), 1.77-1.89 (m, 2H). LCMS for C18H14F8N4O [M+H]+ 455.33; found 455.07 at RT 3.82 min, purity (98.64%).
Example6 N/NWOH .
’ N) O N’NWNOfl: T3P,D|PEA F30 o ————-————> /N/ H~C><E ‘ CF3 F3C Synthesis of (Z)—3-(3-(3,5-bis(triflu0r0methyl)phenyl)—1H-l,2,4-triazol—1-yl)—1- (4,4-diflu0r0piperidin-l-yl)propen0ne: A cold (0 0C) solution of (Z)—3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H—1,2,4-triazol- l-y1)acrylic acid (4) (0.500 g, 1.0 eq.) in CH2C12 (20 mL).was treated sequentially with EDC HCl (0.409 g, 1.5 eq), 4,4-difluoropiperidine hydrochloride (0.269 g,1.2), DIPEA (0.220 g, 1.2 eq) and HOBT (0.261 g, 1.2 eq.). The clear reaction mixture was stirred at 0 0C for 1.5-2 h then quenched with 50 mL ice-water slurry. The aqueous layer was extracted with CH2C12 (2 X 25 mL) and the combined organic layers were washed With brine, dried over anhydrous Na2804 and concentrated under d pressure to afford 0.60 g of crude compound. Purification by ative TLC (eluting with HzClz) afforded 0.090 g compound which was r triturated using ether; petroleum ether to remove aliphatic impurity ing 0.06 g pure compound. Yield: 9.28%.
(Z)(3-(3,5-bis(triflu0romethyl)phenyl)-1H-1,2,4-triazol—1-yl)(4,4- difluoropiperidin-l-yl)pr0p—2-en0ne: 1H NMR (400 MHZ, CDCl3) 8 8.705 (s, 1H), 8.557 (s, 2H), 7.950 (s, 1H), 7.111-7.l36 (d, J=10.0 Hz, 1H), 024 ((1, J=10.8 Hz; 1H), 3886—3916 (t, 2H), 3.654-3683 (t, 2H), 2055-2152 (m, 2H), 1940-2035 (m, 2H). LCMS for C18H15F3N4O [M+H]+ 455.33; found 455.38 at RT 3.057 min purity (99.77%).
Example 7 —125- — ’HN:>'F ~ OH N’N N:>‘F I O ’ / O F C N’N>/ _-—’ F C / 3 N 3 HOBT, EDC HCI N DIPEA, 0°C CF3 CF3 Synthesis of (Z)—3-(3-(3,5-bis(triflu0r0methyl)phenyl)-1H-1,2,4-triazol-1—yl)(3- zetidin—l-yl)pr0pen0ne: To a stirred solution of (Z)—3-(3 —(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol—l- ylic acid (4) (0.500 g, 1 eq.) dichloromethane (10 mL, 20 V) in 3 necked 100 mL round-bottomed flask ed with nitrogen bubbler HOBT (0.19 g, 1.2 eq.), EDC.HC1 (0.41 g, 1.5 eq.) and DIPEA (0.27 g, 1.5 eq.) were added at 0 °C. After 1 hr, the reaction mixture was quenched with water (50 m1) and ted with dichloromethane (3 x 30 mL).
The combined organic layers were washed with brine (50 mL), dried over anhydrous NazSO4 and concentrated under reduced pressure affording 0.25 g crude titled compound.
Purification by flash chromatography (eluting with EtOAc/hexane) afforded 0.03 g of pure titled compound.
(Z)(3—(3,5-bis(triflu0r0methyl)phenyl)-1H-1,2,4-triaz01—1—yl)(3- fluoroazetidin-l-yl)pr0p-2—en0ne: 1H NMR (400 MHZ, CDCl3) 5 9.76 (s, 1H), 8.62 (s, 2H), 7.94 (s, 1H), 7.21—7.24 (d, J=10.8 Hz, 1H), 5.65-5.68 (d, J=10.8 Hz, 1H), 5.45-5.48 (m, 1H), 5.31-5.34 (m, 1H), 4.44-4.56 (m, 4H), 4.23—4.43 (m, 2H). LCMS for C16H11F7N4O [M+H]+ 409.28; found 409.38 at RT 2.963 min purity (96.03%).
Example8 HCI ‘ m— HN:><OH More— OH F30 IN) 0 ———> F3C ’N/> O CF3 CF3 (4) Synthesis of (Z)—3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazolyl)(3- hydroxymethylazetidinyl)pr0pen0ne: In a 25 mL 3N round-bottomed flask ed with nitrogen inlet, (Z)(3-(3,5- bis(trifluoromethyl)phenyl)-lH—l,2,4-triazol—1-yl)acrylic acid (4) (0.250 g, 1.0 eq.) was charged along with dichloromethane (5.0 mL, 20 V). The on mixture was cooled to 0°C and then added HOBT (0.119 g, 1.1 eq.) followed by EDC HCl (0.149 g, 1.1 eq.) and 3- methyl azetidin-3—ol HCl (0.096 g g,1.1 eq.). DIPEA (0.101 g, 1.1 eq) was added to this reaction mixture dropwise at the same temperature. The clear reaction e was stirred at 0 0C for 1.5 h. The progress of the reaction was followed by TLC analysis on silica gel with 10% methanol in romethane as mobile phase and Visualization with UV.
Reaction mixture was quenched in 20 mL ter slurry. Organic layer was separated and aqueous layer was extracted with dichloromethane (2X10 mL) to ensure complete extraction. The c layer was washed with brine solution and dried over anhydrous NagsO4 and concentrated by rotary evaporation under reduced pressure (35 °C, 20 mm Hg) to afford 0.280 g of crude compound. (cis: 61.9%, trans: 16.46%) The crude reaction mixture was purified by column chromatography using 60/120 mesh silica and ol: dichloromethane as mobile phase. The column was packed in dichloromethane and d eluting in MeOH in gradient manner starting with fraction collection (500 mL fractions). The compound started eluting from 0.2 — 2.0 % methanol in dichloromethane. Fractions containing such TLC profile were collected together to obtain pure compound 90 mg. Yield: 30.1%.
(Z)(3-(3,5-bis(trifluoromethyl)phenyl)-1H-l,2,4-triazol—1-yl)(3-hydroxy methylazetidin-l-yl)propen-one: 1H NMR (400 MHZ, DMSO) 5 9.39 (s, 1H), 8.55 (s, 2H), 8.301 (s, 1H), 7.37-7.40 (d, J=10.4 Hz, 1H), 5.95-5.98 (d, J=10.0 Hz, 1H), 5.69 (s, 1H), 3.90 (s, 2H), 3.78-3.85 (m, 2H), 1.32 (s, 3H). LCMS for C17H14F6N402 [M+H]+: 420.31; found 421.4 at RT 2.665 min purity (99.54%).
Example9 ,N—SEM Bis pinacolatodiborane i/> §EM ['r(OMd‘::)(COD)]2 N ' F3C N\ CF3 F30 N\ CF3 Br I py "fl; , ‘ F30 \ N/ / / Step1 3)4,K2C03 NI / ,B\ Step2 O O CF3 Dioxane HCI Step 3 o F F C3 O N I /> <——-——— I F C3 \ N N / | DMF, DABCO Step4 CF3 CF3 (3) Synthesis of 4-(4,4,5,5-tetramethyl—1,3,2-di0xab0rolanyl)-2,6- bis(trifluoromethyl)pyridine (1): Bis pinacolatodiborane [|r(OMe)(COD)]2 F3C N CF3 F30 N CF3 \ dtbpy \ ‘ i / / Step 1 / B\ O O In a 10 mL seal tube, bispinacolatodiborane (0.146 g, 0.5eq), DTBPY (0.0015 g, 0.005eq) and [Ir(OMe)(COD)]2 (0.0019 g, 0.0025eq) was ved in 5 mL dry hexane under N2 here. This reaction mixture was stirred for 10 min at RT to give dark red solution. 3,5—bis(trifluoromethyl)pyridine (0.250 g, 1 eq.) was charged in seal tube. Seal tube was closed and heated at 50 °C for 6 h. on completion was monitored on TLC using ethyl acetate:hexane(l :9) as mobile phase. The reaction mixture was quenched into the ice— water slurry (50 mL) and was extracted with ethyl acetate (3x50 mL). Organic layer was washed with brine solution (3x50 mL). The organic layer was dried using anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the 0.40 g crude titled compound. This crude material was directly used for next step without purification.
Synthesis of s(triflu0romethyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- 1,2,4-triazol—3-yl)pyridine (2): 2012/048368 N,N—SEM 1 / ,SE'V' F3C N CF3 Br N’N \ / /> I F3C \ N / n Pd(PPh3)4, K2003 N / ,B\ Step2 0 0 CF3 In a 10 mL seal tube, 4—(4,4,5,5-tetramethyl—1,3,2-dioxaborolanyl)—2,6- bis(trifluoromethyl)pyridine(1) (0.395 g, 1 eq.) was dissolved in DME (5 mL), then ol —((2—(trimethy1silyl)ethoxy)methyl)—1H-1,2,4—triazole (0.323 g, 1 eq.) and K2CO3 (0.480 g, 3 eq.) in water (1 mL) was added. Mixture was degassed by purging nitrogen for 1h. Tetrakis (0.067 g, 0.05 eq.) was added in the reaction mixture and seal tube was heated at 90 °C for 18 h. Reaction completion was monitored on TLC using ethyl acetatezhexane (2:8) as mobile phase The on mixture was quenched into the ice—water solution (50 mL) and was extracted with ethyl e (3x50 mL). Organic layer was washed with brine solution (3X50 mL). The organic layer was dried using anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to e the 0.30 g crude compound. The compound was purified by column chromatography using ethyl acetate/n-hexane as mobile phase. Compound was eluted out at 8% ethylaetate in hexane to afford (intermediate-2) 0.150 g. Yield: 31.0%.
Synthesis of 4-(1H-1,2,4-triazolyl)-2,6-bis(trifluoromethyl)pyridine (3): N’N NrNH , FC 9 I 3 F30 /> \ N Dioxane HCl \ N I . I N / ”—4 N / Step3 CF3 CF3 In a 10 mL seal tube, 2,6-bis(trifluoromethyl)—4-(l—((2-(trimethylsilyl)ethoxy)methyl)- 1H-1,2,4-triazol—3—yl)pyridine (2) (0.15 g, 1 eq.) was dissolved in dioxane HCl (5 mL) and seal tube was heated to 60 0C for 6 h. Reaction tion was monitored on TLC using ethyl acetate2hexane (5:5) as mobile phase. The reaction mixture was quenched into the ice— water NaHC03 solution (50 mL) and was extracted with ethyl acetate (3x50 mL). Organic layer was washed with brine solution (3x50 mL). The organic layer was dried using anhydrous sodium sulfate, filtered, and concentrated under reduced re to provide the 0.3 g of crude compound. The compound was purified by column chromatography using ethyl acetate/hexane as mobile phase. Compound was eluted out at 30% ethyl acetate in hexane to afford 4-(1H-1,2,4-triazol—3-yl)—2,6-bis(trifluoromethyl)pyridine (3) 0.060g. Yield: 58.4%.
Synthesis of (Z)—3-(3-(2,6-bis(triflu0r0methyl)pyridinyl)-1H-1,2,4-triazol—1-yl)- -difluor0azetidinyl)propen0ne: — F “i , ’NWNyF N; ,0 F30 N)“ '/—>/‘N9<F F C /> O 3 \ N \ N l l N / N / DMF,DABCO CF3 Step4 CF3 In a 3—neck 50 mL round-bottomed flask, 4-(1H—1,2,4-triazol—3—yl)-2,6- bis(trifluoromethyl)pyridine (3) (0.060 g, 1 eq.) and (Z)—1-(3,3-difluoroazetidin-1—y1) iodoprop-2—enone (0.064 g, 1.1eq) was dissolved in DMF (2 mL). DABCO (0.047 g, 2eq.) was added at RT. Reaction mixture was stirred for 1 h at RT. Reaction completion was monitored on TLC using chloromethane (0.25:9.75) as mobile phase. The reaction mixture was quenched into the ice-water slurry (50 mL) and was extracted with ethyl acetate (3x25 mL). Organic layer was washed with brine solution (3x25 mL). The organic layer was dried using anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the 0.70 g crude nd which was d by preparative TLC using 2.5% methanol in dichloromethane as mobile phase to afford 0.011g (12%) title compound.
(Z)(3—(2,6-bis(trifluoromethyl)pyrid.inyl)-1H—1,2,4-triazolyl)—1-(3,3- difluoroazetidin-l-yl)pr0pen0ne: 1H NMR (400 MHZ, DMSO) 8 9.768 , 8.590 (s,2H), 7268-7295 (d, J=10.8, 1H), 5732-5759 (d, J =10.8 Hz, 1H), 4.56-4.62 (t, 2H), 4.46- 4.52 (t, 2H). LCMS for C15H9F3N5O [M+H]-+ 427.25 found 428.5 at 2.901 min purity ( 95.46%).
Example 10 Synthesis of (Z)(3-(3,5-bis(trifluoromethyl)phenyl)—1H-1,2,4-triazolyl)—N- ethyl-N-(l-(pyridinyl)ethyl)acrylamide: WNW N’NfgfM" ,N HOBt/EDC.HCI \ ’ F c )0 /> - F c 3 3 DIPEA \'N N / Step 1 CF3 ' CF3 ' In a 3—neck 50 mL round—bottomed flask, (Z)—3—(3—(3,5—bis(trifluoromethyl)phenyl)- 1H—1,2,4-triazol-1—yl)acrylic acid (0.2 g, 1.0 eq..) was dissolved in dichloromethane(15 mL) at 0°C under NZ atmosphere. To this reaction DIPEAC (0.088 g, 1.2 eq.), EDCHCl (0.131 g, 1.2 eq.) and N;ethyl—1-(pyridinyl)ethanarnine (0.102g, 1.2 eq.) was added followed by HOBt (0.104 g, 1.2 eq.). Reaction mixture was d at 20 0C for 1 h. The progress of the reaction was followed by TLC is on silica gel with 10% methanol: dichloromethane as mobile phase and visualization with UV, SM Rf: 0.15 and Product Rf: 0.40. Reaction was stirred for 3-4 h and yellow reaction mixture was evaporated on rotary evaporator under reduced pressure to afford 0.4 g of crude compound.
The crude reaction mixture was purified by column chromatography using silica 60/120 using methanol: dichloromethane as mobile phase. The column (2 x 10 cm) was packed in dichloromethane and started eluting in ol in gradient manner starting with on tion (25 mL fractions) from 1.5 % to 2.5 % methanol in dichloromethane. nd d eluting with 1.5 % methanol in dichloromethane. Fraction ning such TLC profile was collected together to obtain pure compound (0.006 g). Yield: 3%.
(Z)-3—(3-(3,5-bis(trifluor0methyl)phenyl)-1H-1,2,4-triazolyl)-N—ethyl-N-(1- (pyridin-S-yl)ethyl)acrylamide: 1H NMR (400 MHz, DMSO) 8 9.04 (s, 1H), 7.3 8-8.73 (m, 7H), 8.19-8.22 (d, J=12.4, 1H), 6.01-6.04 (d, J =12.8 Hz, 1H), 4.77-4.79 (d, 1H), 3.29—3.46 (m, 2H), 1.79—1.81 (d, 3H),1.24-1.27(t, 3H). LCMS for C22H19F6N50 [M+H]+ 483.4 found 484.55 at 3.283 min purity (91.38%).
ExampleII HNJ>. a) —~ ’ /> O ’ F3C ————* /> O F30 J N N O EDC/HOBT CF3 CF3 Synthesis of (Z)(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazolyl)-N- (oxazolylmethyl)acrylamide: In a 25 rnL 3N round-bottomed flask equipped with nitrogen inlet, (Z)-3—(3-(3,5ebis(trifluoromethyl)phenyl)-1H-1,2,4—triazoly1)acrylic acid (4) (0.250 g, 1.0 eq.) was dissolved in dichloromethane (5.0 mL, 20 V).The reaction mixture was cooled to 0 CC and then added HOBT (0.119 g, 1.1 eq.) followed by EDC HCl (0.150 g, 1.1 eq.) and oxazol—S-ylmethanamine HCl (0.143 g,1.1 eq.). DIPEA (0.101 g, 1.1 eq) was 2012/048368 — l 3 1— added to this reaction mixture dropwise at the same temperature. The clear reaction mixture was stirred at 0 0C for 1.5 h. The progress of the on was followed by TLC analysis on silica gel with 5 % methanol in dichloromethane as mobile phase and Visualization with Reaction mixture was quenched in ice-water slurry (20 mL). Organic layer was separated and aqueous layer was extracted with dichloromethane (2x1 OmL) to ensure complete extraction. The c layer was washed with brine solution and dried over anhydrous NaZSO4 and concentrated by rotary evaporation under reduced pressure (35 0C, mm Hg) to afford 0.280 g of crude compound (cis: 30.71 %; trans: 28.02 %).
The crude on mixture was purified by column tography using 60/120 mesh silica and Methanol: dichloromethane as mobile phase. The column was packed in dichloromethane and started eluting in MeOH in nt manner starting with fraction collection (500 mL fractions). The nd started eluting from 0.2 -2.0 % Methanol in dichloromethane. Fractions containing such TLC profile were collected together to obtain 90 mg of compound cis and trans mixture. (cis: 57.86 %; trans: 52.49 %).
The mixture was purified by Prep TLC using 5% methanol: dichloromethane as mobile phase. Fractions containing such TLC profile were ted together to obtain 15 mg of compOund pure compound. (4.88% Yield).
(Z)—3-(3(3,5-bis(trifluoromethyl)phenyl)—1H-1,2,4-triazol—1-yl)-N-(oxazol ylmethyl) acrylamide: 1H NMR (400 MHZ, DMSO) 8 9.62(s, 1H), 9.05 (s, 1H), 8.53 (s, 2H), 8.30 (s,2H), 7.41-7.44 (d, J=10.4Hz, 1H), 7.07 (s,lH), 5.95-5.98 (d, J=10.8 Hz, 1H), 4.47—4.48 (d, 2H). LCMS for C17H11F6N502 [M+H] +2 431.28 found 432.39 at RT 2.822 min purity (95.52%). -l32- e 12 HNflfl FSCOCN \\N NaSH Hydrazine Step 1 Step 2 EDC/|F~|OBT HN/QNyFI F3C \N« Synthesis of (Z)(5-(3,5-bis(triflu0romethyl)phenyl)-4H-1,2,4-triazol yl)acrylic acid (2): FacgiwzoHydrazmeOFngNNOOStep 2 HNflI In a 3—neck 100 mL round—bottomed flask, s(trifluoromethyl)benzothioamide (0.564 g, 1 eq.) was dissolved in DMF (5 mL, 10 Vol), then hydrazine hydrate (0.123 g, 1.2 eq.) was added at 0 °C. The reaction mixture was stirred at RT till all SM consumed and converted in to polar hydrazine adduct. Preserve sample from this reaction mass for TLC. At last Maleic anhydride (0.242 g mL, 1.2 eq.) was added at 0 °C. Then reaction mixture was stirred at RT till all hydrazine adduct ed and converted in to ised intermediate.
Again preserve this uncyclised intermediate sample for TLC. Reaction mixture was heated at 80 °C for 6 h. Reaction completion was monitored on TLC using MeOH: dichloromethane (2:8) as mobile phase and uncyclised intermediate as a SM. The reaction mixture was quenched into the ice—water solution (100 mL) and was extracted with ethyl acetate (3x5OmL). Organic layer was washed with brine solution (3x5OmL). The organic layer was dried using anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the 0.51 g crude compound. This crude nd was dissolved in minimum -133— amount of diethyl ether. This solution was stirred at -5 °C and precipitated compound filtered and washed with chilled diethylether to give 0.150 g (20%) pure (Z)-3—(5 -(3,5- bis(trifluoromethy1)phenyl)-4H— 1 riaZol-3 -yl)acrylic acid.
Synthesis of (Z)(5-(3,5-bis(triflu0r0methyl)phenyl)-4H—1,2,4-triazoIyl) (3,3-difluoroazetidinyl)pr0penone: OH HN fly F3C \N, F F30 \N/N EDC/HOBT CF3 Step3 CF3 In a 3—neck 50 mL round-bottomed flask, (Z)(5-(3,5—bis(trifluoromethyl)phenyl)— 4H—1,2,4—triazol-3—yl)acrylic acid (2) (0.065 g, 1 eq.), fluoroazetidine HCl (0.028 g, 1.2 eq.) and EDC. HCl (0.042 g, 1.2 eq.) was dissolved in dichloromethane (5 mL). DIPEA ' (0.028 g, 1.2 eq.) was added at -5 °C followed by HOBt (0.033 g, 1.2 eq.) added at same temperature. Reaction was maintained at this temp for 1h. Reaction completion was monitored on TLC using MeOH: dichloromethane (0.5295) as mobile phase. The reaction mixture was ed into the ice-water slurry (50 mL) and was extracted with ethyl acetate (3x20 mL). Organic layer was washed with brine on (3x25 mL). The organic layer was dried using ous sodium e, filtered, and concentrated under reduced pressure to provide the 0.80 g crude compound which was purified by column chromatography using ethylacetate and hexane as mobile phase. Product was eluted in 35 % ethylacetate in hexane to afford 0.055 g (78%) title compound.
(Z)—3-(5-(3,S-bis(trifluoromethyl)phenyl)-4H-1,2,4-triazolyl)—1-(3,3- difluoroazetidin-l-yl)pr0pen-1—one: 1H NMR (400 MHz, DMSO) 6 14.826 (s, 1H, D20 exchangeable), 8.557 (s,2H), 8.259 (s,1H), 6847—6877 ((1, J=12, 1H), 6445-6476 (d, J =12.4 Hz, 1H), 4.611 (m, 2H), 4.480 (m, 2H). LCMS for C16H10F8N4O [M+H]+ 426.26 found 427.3 at 3.303 min purity (99.83%). -134— Example 13 N/:>/—OH H2N/—<\:l\l>_ I /> O O F30 ———~——> F30 N NN/>F>VN\H_C/>__ T3P/DIPEA CF3 CF3 Synthesis of (Z)(3-(3,5-bis(trifluoromethyl)phenyl)—1H—1,2,4-triazolyl)-N— ((2-methylpyrimidinyl)methyl)acrylamide: In a 25 mL 3N round-bottomed flask equipped with nitrogen inlet, (Z)-3—(3-(3,5-bis(trifluoromethyl)phenyl)—1H—1,2,4—triazol-l- y1ic acid (4) (0.1 g, 1.0 eq.) was charged along with dichloromethane (5.0 mL, 50 V) and ethyl acetate (5.0 mL, 50 V). The reaction mixture was cooled to 0 0C and then added T3P (50% in ethyl acetate) (0.214 g, 1.2 eq.) followed by DIPEA (0.073 g, 2.0 eq.) and (2- methylpyrimidin—S—yl) anmine (0.038 g, 1.1eq.). The clear reaction mixture was stirred at 0°C for 30 min. The ss of the reaction was followed by TLC analysis on silica gel with 10 % Methanol in dichloromethane as mobile phase and Visualization with UV. Reaction mixture was quenched in 30 mL ice—water slurry. Organic layer was separated and s layer was extracted with dichloromethane (2X20 mL) to ensure complete extraction. The organic layer was washed with brine solution and dried over anhydrous NaZSO4 and concentrated by rotary ation under reduced pressure (35 °C, mm Hg) to afford 0.129 g of crude compound. ‘(cis: 81.98 %; trans: not detected; unreacted SM: 13.95 %).
The crude reaction e was purified by column tography using 60/120 mesh silica and methanol: dichloromethane as mobile phase. The column was packed in dichloromethane and started eluting in MeOH in gradient manner starting with fraction collection (500 mL fractions). The compound started eluting from 0.2 % to 4.0 % methanol in romethane. Fractions ning such TLC profile were collected together to obtain 65 mg of pure compound. Yield: 50.38%.
(Z)(3—(3,5-bis(trifluor0methyl)-1H—l,2,4-triazolyl)—N-(2-methylpyrimidin-S- yl)acrylamide: 1H NMR (400 MHz, DMSO) 5 9.57 (s, 1H), 9.12 (s, 1H), 8.62 (s, 2H), 8.55 (s, 2H), 7.41—7.43 (d, J=10.4Hz, 1H), 5.98-6.01 (d, J=10.4 Hz, 1H), 4.38-4.39 (d, 2H). LCMS for C19H14F6N6O [M+H] +1 456.34 found 457.39 at RT 2.725 min purity (99.81%). -13 5- Example 14 ‘ Synthesis of (Z)(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazolyl)-N— (pyrimidin-S-ylmethyl)acrylamide: ‘ N’N’ / ' W014 NHZ F c NQ,CN> ’ o /> O \ F3C '14:) 3 N + I W, NVN DCM In a 50 mL, 3N round-bottomed flask equipped with nitrogen inlet, (Z)—3—(3—(3,5- bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-l-yl)acrylic acid (0.2 g, 1.0 eq.) was charged along with dichloromethane (5 mL, 10V). The on mixture was cooled to -20 °C and then added pyrimidiney1methanamine (0.075 g,l .2 eq), TSP (50% in EtOAc) (0.4 mL, 1.2 eq) ed by DIPEA (0.2 ml, 2 eq) dropwise into the reaction mixture. The reaction mixture was stirred at —20 °C for another 30 min. The progress of the reaction was followed by TLC analysis on silica gel with 5% Methanol in dichloromethane as mobile phase and ization with UV. Reaction mixture was concentrated by rotary evaporation (25 °C, 20 mm Hg) to afford crude compound. The crude reaction mixture was purified by column chromatography using 60/120 mesh silica and methanol: dichloromethane as mobile phase.
The column was packed in dichloromethane and started g in MeOH in gradient manner starting with fraction collections (500 mL fractions). The nd started eluting from 4 % methanol in dichloromethane. Fractions containing such TLC profile were collected together to obtain pure nd 0.2 g. Yield: 80%.
(Z)(3-(3,S-bis(trifluoromethyl)phenyl)-1H-1,2,4—triazole—1—yl)-N-(pyrimidine- 5-yl)methyl)acrylamide: 1H NMR (400 MHZ, DMSO) 8 = 9.58 (s, 1H), 9.07 (s, 2H), 8.76 (s, 2H), 8.50 (s, 2H), 8.28 (s, 1H), 7.44—7.41 (d, J = 10.4 Hz, 1H), 6.02-5.99 (d, J = 10.4 Hz, 1H), 4.45— 4.43 (d, J: 5.6 Hz, 2H). LCMS (%):100 %.
Example 15 F30 B\ Pd(()dppfCi2 DCM F30 _0 DOH HUG12——dimethoxyethane N‘ \ / Step1 ‘ (1a) (1) HO OH piperidine O NyF Dyridine 0 F3C fl F :><F EDCi/HOBT \ / ‘——“ Step 3 i_____ntemediate J_assynthesis BrUBr Br N Step 13 \ \O n—BuLi DMF (18) Synthesis of 6-br0mopicolinaldehyde (1a): Br N\ Br St69 13 , Br N\ I \O n-BuLI DMF | / / A three necked 100 mL round—bottomed flask with magnetic ng, an immersion thermometer, and an addition funnel was charged with THF (30 mL) and cooled to -78 °C. n— butyllithium (1.35 g, 21.10 mmol) was carefully added to the reaction maintaining an internal temperature of -70 0C. After the on of 2,6—dibromopyridine (5.0 g, 21.10 mmol),the resulting dark green on was stirred for 15 min, then neat DMF (2.31 g, 31.66 mmol) was added over a period of 30 seconds. The reaction mass was stirred for 15 min at -70°C.
The progress of the reaction was monitored by TLC analysis on silica gel with ethyl acetatezhexane (3 :7) as mobile phase. Reaction mixture was poured into saturated NH4Cl (50 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine solution (3x50 mL), dried over MgSO4, filtered, and concentrated by rotary ation to afford 5.0 g of crude compound which was d by chromatography.
Product elute at 3% ethyl acetate in hexane to give 1.5 g of pure product (Yield 38.4 %).
Synthesis of 6—(3,5-bis(triflu0r0methyl)phenyl)picolinaldehyde: -l 3 7- 3C Pd(()dppf 012. DCM F30 —0 \Q/B\OH BrU/%O 1 ,2-d—imethoxyethane N“ \ / Step 1 CF3 F30 In a 35 mL, microwave vial, 3,5-bis(trifluoromethyl)phenylboronic acid (2.0 g, 7.7 mmol) and opicolinaldehyde (1a) (1.44 g, 7.7 mmol) dissolved in 1,2- oxyethane (20 mL) was d with a solution of K2C03 (3.22 g, 23.3mrnol) in water at room temperature. Pd(dppf)Clz.dichloromethane was added to reaction mass and charged in microwave for 30 min at 90°C. The ss of the reaction was monitored by TLC analysis on silica gel with ethyl e:hexane (3:7) as mobile phase. Reaction mixture was poured into water (50 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine solution (3x50 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation to afford 2.5 g of Crude compound which was purified by chromatography. Product elute at 4% ethyl acetate in hexane to give 1.2 g of pure product. (Yield 48.38 %).
Synthesis of (E)—3-(6-(3,5-bis(trifluoromethyl)phenyl)pyridin-2~yl)acrylic acid: HOWOH F3C _ O Q N._ —-————————> \ / Step 2 In a 35 mL, microwave vial, 6-(3,5—bis(trifluoromethyl)phenyl)picolinaldehyde (l) (0.3 g, 0.93 mmol) and malonic acid (0.097 g, 0.93 mmol) was dissolved in ethanol.
Piperidine (2-3 drops) was added in on in microwave for 20 min at 90 °C. The progress of the reaction was ed by TLC analysis on silica gel with 10% MeOH- dichloromethane as mobile phase. Reaction mixture was poured into water (15 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine solution (3x50 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation to afford 0.4 g of crude compound which was used for next step without further purification.
Synthesis of (E)(6-(3,5-bis(trifluoromethyl)phenyl)pyridinyl)(3,3- difluoroazetidinyl)pr0penone: - l 3 8— EDCl/HOBT F30 F Step 3 DR / , F30 .
In a 50—mL round—bottomed flask Intermediate 2 (0.4 g, 1.1 mmol) and 3,3- difluoroazetidine hydrochloride (0.17 g, 1.3 mmol ) was dissolved in dichloromethane (20 mL). Propylphosphonic anhydride (0.42g, 1.3 mmol), DIPEA (0.28 g, 2.2 mmol) was added at room temperature and stirred reaction mixture for 30 min. The ss of the reaction was ed by TLC analysis on silica gel with 0.5 % Methanolzdichloromethane as mobile phase and Visualization with U. V light, reaction mixture was quenched into ice water , filter it, compound was extracted in dichloromethane, dried over Na2SO4, filtered, and concentrated by rotary evaporation (28 0C, 20 mmHg) to afford 0.5 g of a solid crude, The purification done by Flash chromatography and t elute at neat dichloromethane to afford pure compound 0.030 g yield (6.2 %).
(E)(6-(3,5-bis(trifluoromethyl)phenyl)pyridinyl)(3,3-diflu0r0azetidin yl)prop—2-en0ne: 1H NMR (400 MHZ, CDC13) 8 8.55(S, 2H), 7.97(s, 1H), 7.89-7.93(t, 1H), .83(d, 2H), 7.75-7.79 (d, J=15.2,lH), 7.45-7.47(d, 1H), 7.18-7.22(d, J=15.2, 1H), 4.68-4.70 (t, 2H), 4.50-4.53(t,2H) LCMS for C19H12F8N20 [M+H]+ 436.3 found 437.39 at RT 3.34 min purity (93.47%). —139— Example 16 F30 EH 1 F30 /> f» \ OH N | C Pd(dppf)C|2DCM Step 2 1 ,4-Dioxane CF3 Step 1 C(F13) (2) IN) 0 EDC,HOBt,D1PEA 0 F3C F30 IN) Step4 CF3 CF3 Synthesis of 4-(3,5-bis(triflu0r0methyl)phenyl)—lH-imidazole (1): F30 B\OH £9 I“; I N Pd(dppf)C|2.DCM CF3 1,4-Dioxane 01:3 Step 1 In a 35 mL, microwave vial, 3,5-bis(trifluoromethyl)phenylboronic acid (2.5 g, 9.69 mmol) and 4—Iodo-1H-imidazole (2.068 g, 10.66 mmol) was dissolved in 1,4-dioxane (18 mL). To this reaction mixture aq. solution 03 (1.628 g, 19.38 mmol) was added at room temperature. The reaction mixture was degassed for 30 min and Pd(dppt)C12.dichloromethane (0.791 g 0.1 eq.) was charged in microwave for 16 h at 90°C.
The progress of the reaction was monitored by TLC using methanol: dichloromethane (05:95) as mobile phase. Reaction mixture was poured into water (50 mL) and filtered through celite bed. The filtrate was extracted with EtOAc (3x20 mL). The combined organic layers was washed with brine solution (3X50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure using rotary evaporator to afford 2.5 g of crude compound which was d by column chromatography. Compound was eluted at 40% ethylacetate in hexane to give 0.640 g of pure product (Yield 23.61 %). The same batch was ed with same quantities of chemicals to give 0.781 g of pure product (Yield 28.78 %).
Synthesis of (Z)-isopr0pyl 3-(4-(3,5-bis(trifluoromethyl)phenyl)—1H-imidazol—1- yl)acrylate (2): TEA,MDC Step 2 In a 100 mL, 3N round-bottomed flask equipped with nitrogen inlet, thermometer pocket and stopper, 4—(3,5-bis(trifluoromethyl)phenyl)—lH—imidazole (1) (1.1 g, 1.0 eq.) was dissolved in dichloromethane (20 mL, 19V) the reaction mixture was cooled to 0 0C. To this reaction mixture TEA (0.709 mL, 1.3 eq.) followed by ‘lsopropyl acrylate (0.571 g, 1.3 eq.) was added at 0 °C and reaction mixture was stirred for 30 min. The progress of the reaction was followed by TLC analysis on silica gel with 20% Ethyl acetate-n-Hexane as mobile phase. Reaction mixture was poured into water (50 mL). The filtrate was extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine solution (3x50 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation to afford 1.2 g of Crude compound which was d by column chromatography. Product elute at 4% ethyl e in hexane to give 1.0 g of crude product (Cis 39 %+Trans 56 %) (Yield 65.35 %).
Synthesis of (Z)(4-(3,5-bis(trifluoromethyl)phenyl)-1H-imidazol-l-yl)acrylic acid (3): NW0 NWOH /> O 0 FSC IN) I LiOH F3C Step3 CFs CF3 In a 50 mL, 3N round—bottomed flask equipped with nitrogen inlet, thermometer pocket and stopper, (Z)-isopropyl 3-(4-(3,5-bis(trifluoromethyl)phenyl)-lH—imidazol—l- ylate (2) (1.0 g, 1.0 eq.) was dissolved in THF: H20 (20 mL, 1:1, 20V) . To this reaction e LiOH.H2O (0.535 g, 5.0 eq.) was added at 0 °C. This reaction mixture was stirred for 3-4 h and progress of the reaction was ed by TLC using 20% ethyl acetate/n-hexane as mobile phase. Reaction mixture was acidified using dilute HCl. The reaction mixture was ted with EtOAc (3x20 mL). The combined organic layers was washed with brine solution (3x50 mL), dried over MgSO4, filtered, and concentrated ~141— under reduced re by rotary evaporation to afford 0.4 g of crude compound which was used for next step without purification.
Synthesis of (Z)(4-(3,5-bis(trifluoromethyl)phenyl)-1H—imidazolyl)(3,3- oazetidinyl)propen0ne: NW0”” HCI HN:><F Nfl/Nyl: I N) O I F3C /> F3C N EDC, HOBt, DIPEA Step 4 or:3 CF3 In a 50 mL, 3N round-bottomed flask equipped with nitrogen inlet, thermometer pocket, stopper, (Z)(4-(3,5-bis(trifluoromethyl)phenyl)-lH-imidazol-l—yl)acrylic acid (3) (0.4 g, 1.0 eq.) was dissolved in dichloromethane (8 mL, 20V) and reaction mixture was cooled to 0 °C. To this reaction mixture HOBT (0.209 g, 1.2 eq.), azitidine HCl (0.177 g, 1.2 eq.) and l (0.328 g, 1.5 eq.) was added at 0°C. To this reaction mixture DIPEA (0.177 g, 1.2 eq.) was added dropwise at 0°C. The progress of the reaction was followed by TLC using 5% Methanol—dichloromethane as mobile phase. Reaction mixture was poured into water (50 mL) and compound was extracted with EtOAc (3x20 mL). The combined organic layer was washed with brine solution (3x50 mL), dried over MgSO4, filtered, and concentrated by rotary ation to afford 0.420 g of Crude compound was purified by column chromatography. Compound was eluted at 05-06% methanol in romethane to give 0.05 g of pure product (Yield 10.41 %).
(Z)(4-(3,5-bis(trifluor0methyl)phenyl)-1H-imidazolyl)(3,3- difluoroazetidinyl)prop-2—enone: 1H NMR (400 MHZ, CDC13) 8 8.57 (s, 1H), 8.27 (s, 2H), 8.06 (s, 1H), 7.78 (s, 1H), 6.94-6.91 (d, J=12,1H), 5.47—5.45 (d, J=8,1H), 4.58—4.45(m, 4H). LCMS for C17H11F8N30 [M+H]+ found 281.34 at RT 2.54 min purity (99.13%).
Example I 7 Synthesis of (Z)(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazolyl)-N- methyl-N-(pyrimidin-S-ylmethyl)acrylamide: -142— NW >0 / _,. / . /N ,N NH N F30 //>0 \N 4» F30 lN/>O \N O)NaH,THF m)CH§ CF3 CF3 In a 50 mL, 3N round-bottomed flask equipped with nitrogen inlet, (Z)(3-(3,5- bis(trifluoromethyl)phenyl)- l H— 1 ,2,4—triazol(pyrimidinylmethy1)acrylamide (0.05 g, 1.0 eq.) was charged along with THF (5 mL, 5V).The reaction mixture was cooled to ~20 °C and sodium hydride (60% in mineral oil) was added (0.051 g, 1.1 eq.), . Reaction mixture was allowed to stir for l h. Methyl Iodide (0.018g, 1.1) was added into the reaction mixture and stirred at -20 °C for l h. The progress of the reaction was ed by TLC analysis on silica gel with 5% Methanol in dichloromethane as mobile phase and Visualization with UV. on mixture was quenched in water (50 mL) and extracted with EtOAc (50X2). The c layer was washed with brine solution, dried over Na2SO4 and concentrated by rotary evaporation (25 0C, 20 mm Hg) to afford 0.060 g of Crude compound. The crude reaction mixture was purified by column chromatography using 60/120 mesh silica and Methanol: dichloromethane as mobile phase. The column was packed in dichloromethane and started eluting in MeOH in gradient manner ng with fraction collection (500 mL fractions). The compound started eluting from 4 % Methanol in dichloromethane. Fractions containing such TLC profile were collected together to obtain pure compound 0.015 g Yield (30%).
(Z)—3-(3-(3,5-bis(trifluoromethyl)phenyl)—1H-1,2,4-triazoleyl)-N-methyl-N- (pyrimidine—S-ylmethyl)acrylamide: 1H NMR (400 MHZ, DMSO) 5 = 9.04-8.99 (d, J: 21.6 Hz, 2H), .71 (d, J= 24 Hz, 2H), 8.46 (s, 1H), 8.39 (s, 1H), 8.29 (s, 1H), 7.42-7.38 (m, 1H), .35, 6.31-6.28 (d, J: 10 Hz, J: 10.4 Hz, 1H), 4.68- 4.61 (d, J= 28 Hz, 2H), 2.99- 2.96 (d, J: 14 Hz, 3H). LCMS for C19H14F6N6O [M+H]+ 456.3 found 457.44 at RT 2.59 min purity (94.12%). Compound was observed as rotamers as confirmed by NMR. -l43- Examplelé’ . *fi H O N . H2N\ /.
\ Na(BH3)CN / NI *W" N N IN T Step1 T — rd—/N \ NN/>+ONNWOH I N\ 0 F30 \N/>—_M__32P______>CFaC N) Step2 CF3 CF3 . (1) Synthesis of yl(2-methylpyrimidin-S-yl)methanamine (1): H o N H2N\ \ Na(BH3)CN / | ————> | Step 1 NT” In a three necked 100 mL round-bottomed flask equipped with magnetic stirring, an immersion thermometer, and nitrogen bubbler was charged 5—pyrimidine carboxaldehyd methyl (1 g, 0.0082 mol.) in methanol (10 mL) and cooled to 0 °C. Methyl amine (20.5 mL, 0.0409 mol.) and acetic acid (2.4 mL, 0.0409 mol.) was added to the reaction maintaining an 0 °C. The ing dark yellow solution was stirred for 2 h. Sodium cyanoborohydride (2.05 g, 0.0328 mol.) was added over a period of 10 min. The reaction mass was stirred for 2—3 h at RT. The progress of the reaction was monitored by TLC analysis on silica gel with ol: dichloromethane (05:95) with TEA (1%) as mobile phase. Which shows that starting material was consumed after 3 hr. ng at RT. Solvent was remove under reduce pressure, e quenched by water and extracted with EtOAc (3X50 mL). The combined organic layers were washed with brine solution (3X15 mL), dried over Sodium sulfate, filtered, and concentrated by rotary evaporation to afford 0.5 g of crude compound.The crude material was subjected to column purification using Silica 60/120 as a stationary phase and dichloromethane: methanol as mobile phase. The column was packed in -144— dichloromethane and started eluting in methanol in gradient manner starting with fraction collection from 0.5.0 % to 3.0 % methanol in romethane with 1% TBA. Compound started eluting with 2.5 % methanol in romethane with 1% TBA. Fraction containing such TLC profile was collected together to obtain compound 200 mg of pure product. (Yield 17.78 %). sis of (Z)(3-(3,5-bis(trifluor0methyl)phenyl)-1H-l,2,4-triazolyl)-N- methyl-N-((Z—methylpyrimidin—S-yl)methyl)acrylamide: N’ N’N O ’ 0 FC /> T3P F30 /> N /—</>——N 3 N + w" H—N N \ Step2 CF3 CFa In a 25 mL, 3N round-bottomed flask equipped with nitrogen inlet, N—methyl-l—(2— methylpyrimidin—5-yl)methanamine (l) (0.1 g, 1.0 eq.) and (Z)—3—(3—(3,5- bis(trifluoromethyl)phenyl)-1H—1,2,4—triazol-l—y1)acrylic acid (0.178 g, 0.7 eq.) was charged along with dichloromethane (2 mL, 10 V).The reaction e was cooled to -20 °C and then added T3P (50% in EtOAc) (0.550 mL, 1.2 eq.) ed by DIPEA (0.250 mL, 2 eq.) was added to reaction mixture. The clear reaction mixture was stirred at -20 °C for 30 min.
The progress of the reaction was followed by TLC analysis on silica gel with 5% Methanol in dichloromethane as mobile phase and Visualization with UV, which shows that starting material was consumed after 30 min stirring at —30 °C. Reaction mixture was diluted by dichloromethane wash with water (2x10 mL), organic layer dried over sodium sulfate and concentrated by rotary evaporation (25 °C, 20 mm Hg) to afford crude compound (0.2 g). The crude reaction mixture was purified by column chromatography using 60/120 mesh silica and methanol: dichloromethane as mobile phase. The column was packed in dichloromethane and d eluting in MeOH in gradient manner starting with fraction collection (500 mL fractions). The compound started eluting from 2 % ol in romethane. Fractions containing such TLC profile were collected together to obtain pure compound 0.01 g Yield (4.19%).
(Z)(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1~yl)—N-methyl-N-((2- methylpyrimidin-S-yl)methyl)acrylamide: 1H NMR (400 MHz, CDCl3) 5 9.02 (s, 1H), 8.65 (s, 2H), 8.52-8.59 (m, 3H), 7.15-7.17 (d, J=10.8 Hz, 1H), 6.02-6.04 (d, J=10.4 Hz, —145- 1H), 4.69 (s, 2H), 3.07(s, 3H), 2.75 (s, 3H). LCMS for C20H16F6N6O [M+H]+ 470.4 found 471.20 at RT 4.215 min purity (91.16 %).
Example 19 hi, WOH H2N N o N/N F3C /> T3P,DIPEA, H N F3C / / O MDC N N + Boc BOG/N Step 1 (1) CF3 F3C ' MDC Step2 N/N N F3C / / o H/Tj N N Synthesis of (Z)-tert-butyl (3-(3,5-bis(triflu0r0methyl)phenyl)-1H-1,2,4- triazol-l~yl)acrylamido)methyl)piperidine-l-carboxylate (1): N’NWOH H2N / /> O N/N/:>'N F3C\ T3P,D|PEA, F30 / H / o MDC N ’ N + BOG Boc Step1 (1) CF3 F30 In a 50 mL, 3N round-bottomed flask (Z)—3 ,5—bis(trifluoromethyl)phenyl)-1H- 1,2,4~triazol-l—y1)acrylic acid (0.2 g, 1.0 eq.) and tert-butyl—3-(aminomethyl)piperidine-l- ylate (0.134 g) was dissolved in dichloromethane (5.0 mL) and T3P (50%)(0.453 g) was added. DIPEA (0.147g) was added under nitrogen atmosphere. The progress of the reaction was followed by TLC analysis on TLC with 5% methanol: dichloromethane as mobile phase and Visualization with U.V light. Reaction mixture was concentrated by rotary evaporation (40 °C, 20 mmHg) to afford 0.35 g of a white solid. The resulting crude nd Was purified by column chromatography using silica 60/120 and methanol: dichloromethane as mobile phase. The column was packed in dichloromethane and started eluting in methanol in gradient manner starting with fraction collection from 2-4 % methanol in dichloromethane. Compound started eluting with 3 % ol in dichloromethane.
Fraction containing such TLC profile was collected together to obtain compound (230 mg) yield 80%.
(Z)-tert-butyl((3-(3-(3,S-bis(trifluoromethyl)phenyl)—1H—1,2,4-triazol ylamid0)methyl)piperidinecarboxylate: 1H NMR (400MHz, DMSO) 5: 9.61 (s, 1H), 8.52—8.57 (q, 3H), 8.28(s, 1H), 7.37-7.39 (d, J=10.4Hz, 1H), 5.95-5.97 (d, J=10.4Hz, 1H), 3.74—3.87 (br. s, 2H), 3.06 (s, 2H), 2.67-2.77 (m, 1H), 1.46 (brs, 2H), 1.31 (s, 9H).
LCMS for F6N503 [M+H]Jr 547.49 found 548.6 at RT 3.51 min purity (96.47%).
Synthesis of (Z)(3-(3,5-bis(trifluoromethyl)phenyl)—1H-1,2,4-triazolyl)-N- idin-3—ylmethyl)acrylamide: F30 / F30 / 0 / O Boc TFA MDC N) Step 2 HN F3C F30 In a 25 mL single neck round—bottomed flask (Z)—tert-butyl 3-((3-(3-(3,5- bis(trifluoromethyl)phenyl)— l H-1 ,2,4-triazolyl)acrylamido)methyl)piperidine carboxylate (l) (0.1 g) was dissolved in dichloromethane (5 mL) and TFA (1.0 mL) dissolved in dichloromethane added dropwise. The progress of the reaction was followed by TLC on silica gel in 10 % methanol in dichloromethane as a mobile phase in UV visualization.
Reaction mixture was concentrated by rotary ation (40 °C, 20 mmHg) to afford 0.12 g of compound. The resulting crude compound was purified by ‘SAEX’ column chromatography. Fraction collected together to obtain nd (40 mg) yield 49%.
(Z)(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol—1-yl)—N-(piperidin ylmethyl)acrylamide 1H NMR (400 MHz, DMSO) 5: 9.69 (s, 1H), 8.61 (s, 2H), 7.94 (s, 1H), 7.13-7.16 (d, J =10.8Hz, 1H), 6.55 (s 1H), 5.66-5.68 (d, J =10.8Hz, 1H), 3.23—3.37 (m, 2H), 2.98-3.10 (m, 2H), 2.58-2.65 (t, 1H), 2.40—2.45 (t, 1H), 1.68-1.80 (m, 2H), 1.43— 1.54 (m, 1H), 1.15—1.29 (m, 1H). LCMS for C19H19F6N50 [M+H]+ 447.38 found 448.44 at RT 3.13 min purity (99.12%). -147— Example 20 F . m “”8 N’N/W'OH HC' N'NWNQLF.— ‘ / N/> o ————> / > o F3C F30 N/ EDCI, HOBT DIPEA CFs CF3 Synthesis of (Z)(3—(3,5-bis(trifluor0methyl)phenyl)—1H-l,2,4-triazolyl) (3,3-diflu0ropyrrolidinyl)propen0ne: In a 100 mL, 3N round-bottomed flask equipped with nitrogen inlet, (Z)(3-(3,5—bis(trifluoromethyl)phenyl)-lH—l,2,4—triazol- 1-y1)acrylic acid (4) (1g, 1.0 eq.) was charged in dichloromethane (20 mL, 20 V). The reaction mixture was cooled to 0 0C. HOBT (0.461 g, 1.2 eq.), EDC.HC1 (0.819 g, 1.5 eq.), 3,3—Difluoropyrrolidine hydrochloride (0.490 g, 1.2) and DIPEA (0.731 mL, 1.5 eq.) was added to the reaction mixture. The clear reaction mixture was stirred at 0°C for 1.5 h. The progress of the on was followed by TLC using 5% methanol in romethane as mobile phase and ization with UV. Reaction mixture was ed in water(50 mL).
Organic layer was separated and aqueous layer was extracted with dichloromethane (20 X 2). The combined organic layer was washed with brine solution, dried over NaZSO4 and concentrated by rotary evaporation (25 °C, 20 mm Hg) to afford 0.67 g of crude compound.
The crude compound was d by column chromatography using 60/120 mesh silica and methanol: dichloromethane as mobile phase. The column was packed in dichloromethane and started eluting in MeOH in gradient manner ng with fraction collection (25 mL ons). The compound started eluting from 0.9 % to 1.0% methanol in dichloromethane.
Fractions containing such TLC profile were collected together to obtain pure compound 0.115 g Yield (9.2%).
(Z)(3-(3,5-bis(trifluoromethyl)phenyl)—1H-1,2,4-triazol—1-yl)(3,3- difluoropyrrolidinyl)pr0pen0ne: 1H NMR (400 MHZ, CDC13) 5 9.25—9.30 (d, 1H), 8.59 (s, 2H), 7.94 (s, 1H), 7.17-7.28 (m, J=10.8 Hz, 1H), 5.82-5.91 (m, J=10.8 Hz, 1H), 3.78- 4.00 (m, 4H), 2.41-2.54 (m, 2H); LCMS for C17H12F8N4O [M+H]+ 440.29 found 441.39 at RT 2.982 min purity (99.75 %). —l48- Example 21.
O H ,HO . . 0 Step-1 \ \+/ St -2 - Bryr ~\ —» ~\ _ep_, / _Step3 | . / OH PoCI3 I \N ZBF4' N\ N MeMgBr N\ N DMF / \ H N NH HCI T T Diphenyl phosphoric azide' Step-4 HZN N3 HdeK: N smps N\ N\ N (6) T (5) T N/,N> H2N NH / ____f__>Ste -6 F3C NfN) 0 N Fgc // h{ g, + | T3P N / N\ N DiPEA fN CF3 ‘d/' DCM Synthesis of Intermediate-2 Br\/fi\ Step-1 \TYN\\+/ OH PoCI3 \N ZBF4‘ DMF /\ NaBF4 In a , 3N round-bottomed flask equipped with thermometer pocket fitted with nitrogen inlet and a rubber septum, DMF (40 mL, 14.67 eq.) was cool to -lO°C and POC13 (10.58 mL, 3.21 eq.) was added. The reaction mixture was stirred at 0°C for 3 h. To this reaction mixture bromo acetic acid (5 g, 1 eq.) was added at 0°C. Resulting reaction mixture was stirred for 6 h at 85-90°C. After tion of 6 h stirring, DMF was removed by high vacuum distillation. Dark red residue was observed, residue was cool down to room temperature and sodium tetrafluoro borate was added in to the residue and exotherm was observed. on mass was cooled using ice bath. The solid residue (6.5 g) was observed which was filtered and used for next step directly. 2012/048368 —149— Synthesis of Intermediate-3 O H \N \ \fi< Step-2 / \fi N TN ZBF4‘ / k \ H2N NH HCl (3) (2) Molecular Weight: 122.12 Molecular Weight: 183.3 In a 100-mL, 3N round-bottomed flask equipped with thermometer pocket fitted with water condenser, nitrogen inlet and a rubber septum, Vinamidium salt (5.65 g, 0.5 eq.) and acetamidine HCl (3 g, 1 eq) was dissolved in ethanol (30 mL) and sodium ethoxide was added, ing reaction mixture was stirred at reflux for 2-3 h, The progress of the reaction was followed by TLC is on silica gel with 70% ethyl acetate-Hexane as mobile phase which shows that starting material was consumed after 3 h. Solvent was removed under reduce pressure to give crude mass which was dissolved in water, and compound was extracted by ethyl acetate. Combined organic layer were dried over sodium sulfate and distilled under reduce pressure to obtain crude material. The crude material was subjected to column purification using Silica 60/120 as a stationary phase and hexane: ethyl e as mobile phase. The column was packed in hexane and started eluting in Ethylacetate in gradient manner starting with fraction collection from 20-24 % ethyl e in hexane. nd started eluting with 22 % ethyl acetate in hexane. Fraction containing such TLC profile was collected er to obtain compound 700 mg.
Synthesis of Intermediate-4 o H HO % Step-3 % NYN MeMgBr NTN (3) (4) Molecular Weight: 122.1 Molecular Weight: 138-2 In a 50 mL, 3N round—bottomed flask equipped with thermometer pocket fitted with nitrogen inlet and a rubber septum, Intermediate—3 (1.0 g, 1.0 eq.) was added methyl magnesium e (2.47 mL, 1.0 eq.) at -3 0°C. Resulting reaction mixture was d at - °C. The progress of the reaction was followed by TLC analysis on silica gel with 70% EtOAc-hexane as mobile phase which shows that little starting material was observed after min stirring, reaction was stirred again for l h at 0°C temperature. Reaction was — 1 50- quenched by cold water, ted by ethyl acetate, dried over sodium sulfate and led under reduce pressure to obtain crude material. The crude material was subjected to column purification by using silica (60-120 mesh size) as stationary phase and Ethyl acetate: Hexane as mobile phase. Required compound eluted at 25% ethyl acetatezhexane.
Fraction containing such TLC profile was collected together to obtain compound 1.5 g yield (82.41%); LCMS (%): Retention Time: 4.532 min. (84.82 %) (M+H)+ 139.
Synthesis of Intermediate-5 HO HN\N,Nx , / Step-4 / | ———> | N\ N DCU N\ N Diphenyl phosphoric azide T5) Molecular Weight: 138.17 Molecular Weight: 164.19 In a 25 mL, 3N round-bottomed flask equipped with meter pocket fitted with nitrogen inlet and a rubber septum, Intermediate—4 (0.25 g, 1.0 eq.) was dissolved in toluene (5 mL). To this reaction e diphenyl phosphoryl azide (0.87 mL, 2.4 eq.) and DBU (0.65 mL, 2.4 eq.) was added at 0°C temperature. Resulting reaction e was stirred at 0°C for 30 min at RT for 3-4 h. The progress of the reaction was followed by TLC analysis on silica gel with 70% EtOAc— hexane as mobile phase which shows that ng al was consumed after 4 h. Reaction was quenched into ice cold water, extracted by ethyl acetate (50 x 3 mL). Combined organic layer was dried over sodium sulfate and trated under reduce pressure to give crude compound. Crude compound was subjected to column chromatography using ethyl acetate: hexane as mobile phase.
Compound was eluted in 30% ethyl acetate in hexane. Fractions containing such TLC profile was collected together to obtain compound 0.14 g yield (29.7%); LCMS (%): + 164. ion Time: 2454 min (14.35 %), (M+H) Synthesis of Intermediate-6 HN¢ ,,N HZN N (:g ~ Step-5 / ‘———--—-——-—-————-—-—> | “TN H2,Pd/C (5) ‘ “TN('6) Molecular Weight: 164.19 Molecular Weight: 137.18 In a 25 mL, single neck round-bottomed flask equipped with rubber septum, Intermediate-5 (0140 g), palladium carbon(0.07 g) was suspended in methanol (2 mL) and H2 WO 19561 -15 1- was purged into it. Resulting reaction mixture was stirred at RT. The progress of the reaction was followed by TLC analysis on silica gel with 5% Methanol- dichloromethane and ammonia atmosphere as mobile phase which shows that starting material was consumed after 15 h. Reaction was Filter through Celite Bed, e was concentrated under reduce pressure to give crude (0.19 g). The crude material was subjected to column ation using silica as stationary phase and MeOH: dichloromethane with 1% of TEA as mobile phase. Required nd eluted in 2% MeOH: dichloromethane with 1% TBA as mobile phase. Fraction containing such TLC profile was collected together to obtain compound 0.09 g yield (76.9%). 1H NMR (400 MHz, DMSO): 6:8.73 (s, 2H), 5.72 (Broad singlet, 2H D20 exchangeable), 423 (quartet, 2H), 2.6 (s, 3H), .4 (d, 3H); LCMS (%): LC-MS Retention time: 5.457 min (1.2 %) (M+H) + N’ NH2 N;Nff>zNHHM} / 0 F3C F c /> 3 N I T3P,D|PEA + N/ N \ DCM In a 250 mL, 3N round-bottomed flask equipped with nitrogen inlet, ediate 1 (0.19 g, 1.0 eq.) was charged along with dichloromethane (5 mL, 10 V).The reaction mixture was cooled to -20 °C and then added 1~(5-methylpyrimidiney1)ethanamine (0.09 g,l.2 eq.), T3P(50% in. EtOAc) (0.2 mL, 1.2 eq.) followed by DIPEA (0.18 mL, 2 eq.) was added into the reaction mixture. The clear reaction mixture was stirred at -20 °C for 30 min. The ss ofthe reaction was followed by TLC analysis on silica gel with 5% Methanol in dichloromethane as mobile phase and Visualization with UV. Reaction mixture was concentrated by rotary evaporation (25 °C, 20 mm Hg) to afford Crude compound. The crude reaction mixture was purified by column chromatography using 60/120 mesh silica and methanol: dichloromethane as mobile phase. The column was packed in dichloromethane and d eluting in MeOH in gradient manner starting with fraction collection (500 mL fractions). The compound started eluting from 5 % Methanol in dichloromethane. Fractions ' containing such TLC profile were collected together to obtain pure nd 0.5 gm Yield (20%).
(Z)-‘3-(3-(3,5-bis(trifluoromethyl)phenyl)—1H—1,2,4—triazole—1-yl)-N-(1-(5- methylpyrimidine-Z-yl)ethyl)acrylamide; 1H NMR (400 MHZ, DMSO) 6 = 9.48 (s, 1H), 9.01-8.99 (d, J = 8 Hz, 1H), 8.64 (s, 2H), 8.47 (s, 2H), 8.28 (s, 1H), 7.42—7.39 (d, J = 10.4 Hz, -1 52— 1H), 6.01-5.99 (d, J = 10.4 Hz, 1H), 5.058 (m, 1H), 2.53 (s, 3H), 1.44-1.42 (d, J = 7.2 Hz, 3H) LCMS for C20H16N6F60 [M+H]+ 470.35 found 471.49 at RT 2.775 min purity .
Example 22 Synthesis of (Z)(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazolyl)-N— methyl-N-(oxazol—S-ylmethyl)acrylamide: '74:) 0 NM” NaH F3C NNWNV'QJ N _+> F30 Mel, THF CF3 CF3 (Z)-3 -(3 -(3 ,5 -Bis(trifluoromethyl)phenyl)-1H—1,2,4—triazolyl)-N~methyl-N-(oxazol- —yl )acry1amide (0.15 g, 0.34 mmol) was dissolved in THF (30 mL). The reaction mixture was cooled to 0 OC; NaH (0.012 g, 0.52 mmol) was added and the reaction mixture was stirred for 0.5 h. Methyl iodide (1.5 mL) was added dropwise at the same temperature.
The clear reaction mixture was further stirred at 0 °C for 1.5 h. Reaction mixture was partitioned in 20 mL ice-water and ted with DCM (3 X 50 mL). The combined organic layers were washed with saturated brine and dried over‘anhydrous NaZSO4 and concentrated under reduced re to afford 0.180 g of crude t, which was purified by column chromatography (0-2% methanolzDCM) to give 15 mg of (Z)—3-(3-(3,5- bis(trifluoromethyl)phenyl)- 1H-l ,2,4—triazol— l —yl)—N—methyl—N—(oxazol-5 —ylmethyl) acrylamide (Yield : 9.6%). 1H NMR (400 MHZ, DMSO-d6) 8: 9.01 (s, 1H); 8.61 (s, 1H); 8.48 (s, 1H); 8.39 (s, 1H); 8.30 (s,1H); 8.07 (s,1H);7.38—7.41 (d, J=10 Hz, 1H); 6.99 (s,1H); 6.23—6.26 (d, J=lO Hz, 1H); 4.72 (s,1H); 4.62(s,1H);3.02(s,3H) LCMS for C18H14F6N502 [M+H] +z 446.32 found 446.03 (retention time: 3.432 min).
Example 23 —— WNW ON OH , F3C F30 N —> N HOBt EDC.HC| DIPEA CF3 CF3 HNU In a 100 mL, 3N round-bottomed flask equipped with nitrogen inlet, Intermediate- 4 (lg, 1.0 eq.) was dissolved in dichloromethane (20 mL, 20 V). The reaction mixture was cooled to 0°C. HOBT (0.461 g, 1.2 eq.), EDC.HC1 (0.819 g, 1.5 eq.), azetidine (0.195 g, 1.2 eq.) and DIPEA (0.731 mL, 1.5 eq.) was added to the reaction mixture, and the clear on mixture was stirred at 0°C for 1.5 h. The progress of reaction was monitored by TLC using % ol in dichloromethane as mobile phase and Visualization with UV. The reaction e was quenched in 50 mL water, the dichloromethane layer separated, and aqueous layer extracted with dichloromethane (20 X 2). The combined organic layer was washed with brine solution, dried over Nast4 and concentrated under reduced pressure by rotary evaporation (25 °C, 20 mmHg) to afford 0.980 g of crude nd. The crude compound was purified by column chromatography using 60/120 mesh silica and ol: dichloromethane as the mobile phase. The column was packed in dichloromethane and elutied with MeOH in a gradient manner. The compound started eluting from 09-10% methanol in dichloromethane. Fractions containing the requiredTLC profile were collected together to obtain pure compound 0.225 gm Yield (20.25%).
(Z)—1-(azetidin-1—yl)(3-(3, 5-bis (trifluoromethyl) phenyl)—1H-1, 2, zol yl) prop-Z-en-l-one‘ 1H NMR (400 MHz, CDC13) 5 9.87 (s, 1H), 8.62 (s, 2H), 7.93 (s, 1H), 7.18—7.20 (d, J=10.8 Hz, 1H), 5.65-5.68 (d, J=10.8 Hz, 1H), 4.26—4.30(t, 2H), 4.16-4.20 (t, 2H), 2.34-2.42(m, 2H); LCMS for C16H12F6N4O [M+H]+ 390.28 found 391.39 at RT 2.935 min purity (100%).
Example 24' NvNF:>/OH ‘ ”TN/v.”__ N I O / \ F c /> 3 F c N 3 l N) Step-5 0 “ ’ —-——-—-—-> CFa (4) V-324 —~N (5A) 2HCL F3C Molecular Weight: 351 -2 T3P,D|PEA Molecular : 467.4 In a 50-mL, 3N bottomed flask equipped with a nitrogen inlet and a rubber septum, Intermediate—4 (acid) was suspended in dichloromethane (5 mL). Intermediate-5a & DIPEA and T31) (50% in ethyl acetate) was added at -20°C, and the on stirred at the same temperature for 50-60 min. Progress of the reaction was followed by TLC using 30% acetone- hexane as mobile phase. The on mixture was then concentrated under vacuum at 30°C at 20mbar, and the resulting crude compound d by flash chromatography using hexane & Acetone as mobile phase. The crude compound mixture was eluted out at 15—20% acetone-hexane to afford a semi—pure compound with purity 55.91% (Yield: 200 mg); LCMS: m/z 468.03 (M+l). This semi-pure nd was further purified by flash chromatography using same solvent ratio to afford 100 mg, which was further purified by preparative TLC using 30% Acetone- hexane as mobile phase affording 14mg of product (Yield 15%). 1H NMR (400' MHZ, DMSO—d6, ppm) 8‘: 9.63 (s, 1H); 8.63-8.60 (t, 1H); 8.53 (s, 2H); 8.29 (s, 1H); 7.39-7.37 (d, J=10.4 Hz, 1H); 6.01—5.99 (d, J=10.4 Hz, 1H); 5.46-5.44 (d, J=5.5 Hz, 1H); 3.82 — 3.77 (m, 2H) 3.63- 3.59 (m, 2H): LCMS calcd for C21H16F6N50 [M+H]Jr 468.13, found: 468.3 (retention time 3.719 min).
Example 25 __ OH F3C N/ o HCI (N I / o N— H T3P N / CF3 DMF DIPEA In a 50-mL 3—neck round-bottomed flask under nitrogen atmosphere (Z)(3-(3,5— bis(trifluoromethyl) phenyl)-1H—l,2,4—triazol—1-yl)acrylic acid (0.529 g, 0.91 eq.) & 1- (azetidinyl)-N,N— dimethyl methanamine hydrochloride (0.250 g, 1.0eq) were dissolved in DMF(lO mL, 15 Vol). Then T3P (1.055 g, 1.0 eq.) followed by DIPEA (0.748g, 3.5 eq.) were added slowly and the reaction mixture stirred at 0°C for 30-45 min. The Completion of the reaction was confirmed by TLC using 5% ol in dichloromethane with a atmosphere as mobile phase. The on mixture was quenched into ice water slurry extracted with ethylacetate and the aqueous layer washed with cetate (100 mLX2). The combined organic extracts were dried over NaZSO4, filtered and concentrated by rotary evaporation (40 °C, 20 mmHg) to afford an off-white semisolid (0.490 g). The product was purified by Prep.TLC using 4% methanol and dichloromethane with ammonia atmosphere to afford 30 mg compound (4.0%).
(Z)—3-(3—(3,5—bis(triflu0romethyl)phenyl)-1H-1,2,4-triazolyl)—1-(3- ((dimethylamino)methyl) azetidin-l-yl)prop-2~en-1—0ne: 1H NMR (400 MHz DMSO) 6 9.80-9.84(d, J=17.6Hz, 1H),8.62(s, 2H), , 1H), 7.19—7.22 (d, J=10.4, 1H), 5.63-5.67 WO 19561 —155- (d, , 1H), 4.30-4.35 (t, 1H), 4.21-4.26 (t,1H), 3.89-3.93 (q, 1H), 3.76—3.80 (q, 1H), 2.84-2.87 (q, lH),2.50-2.61 (m, 2H),2.24 (s, 6H); LCMS for C19H19F6N50 [M-l—H] + 447.38 found 448.05 at RT 3.77 min purity (84.74%).
Example 26 N’NW" OH ‘F3C I /> 0 N N/N/—>*NH , F3C // O -—-—-—-—-———-————-—> N T3p,D|PEA,MDC CF3 T In a 50 mL, 3N round—bottomed flask under a nitrogen atmosphere, (Z)(3—(3,5- ifluoromethyl)phenyl)—1H-1,2,4—triazolyl)acrylic acid (Intermediate-4) (0.200 g, 1.0 eq.) and (1-methylpiperidin—4-y1)methanamine (0.073 g, 1 eq.) were suspended in dichloromethane (10.0 mL) and T3P(50%)(0.432 g, 1.2 eq.) added maintaining the temp at - 40°C, followed by DIPEA (0.147g, 2.0eq.) . The progress of the reaction was followed by TLC analysis on TLC with 5% Methanol: dichloromethane with ammonia atmosphere as mobile phase and Visualization with UV light. The reaction mixture was concentrated by rotary evaporation (35 °C, 20 mmHg) to afford 0.250 g of an oil. The resulting crude nd was purified by Preparative TLC using Methanol: dichloromethane (5:5) as mobile phase with ammonia atmosphere, affording 40 mg (yield—15%) pure compound; (Z)- 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazolyl)-N-((1-methylpiperidin yl)methyl)acrylamide: 1H NMR (400 MHZ, DMSO) 6 ,9.59 (s, 1H), 8.52(s, 2H), 8.46-8.49 (t, 1H), 8.29(s, 1H), 7.35—7.37 (d, J=lO.4Hz,lH), 5.95-5.98(d, J=10.4Hz,lH),3.03—3.06 (m, 2H), 2.67—2.70(m, 2H), 2.09 (s, 3H), 1.69-1.74(m, 2H), 1.56-1.59(m, 2H), 1.07—1.17(m, 2H); LCMS for F6N50 [M+H]Jr 461.4 found 462.5 at RT 3.69 min purity (94.31%).
Example27 N’NW" 0H I /> .0 F3c / \ N F36 / o -—-———-——-> T3P, DIPEA I s In a 50 mL, 3N round—bottomed flask under nitrogen atmosphere, intermediate 4 (acid) (0.100 g, 1.0 eq.) and (l—methylpiperidin —3-yl)methanamine (0.036 g, 1.0 eq.) were suspended in dichloromethane (10.0 mL) then T3P(50%)(0.216 g, 1.2 eq.) and DIPEA (0.073 g, 2.0 eq.) were added at -40°C . The progress of the reaction was ed by TLC analysis on TLC with 5% Methanol: dichloromethane with ammonia atmosphere as mobile phase and Visualization with UV light. The reaction mixture was concentrated by rotary evaporation (35 0C, 20 mmHg) to afford 0.120 g of an oil. The resulting crude compound was d by Preparative TLC using Methanol: dichloromethane (5:5) as mobile phase with ammonia atmosphere, ing 11 mg (yield-15%) pure compound; (Z)- 3-(3-(3,5—bis(triflu0romethyl)phenyl)-1H~1,2,4-triazolyl)-N-((1~methylpiperidin hyl)acrylamide: 1H NMR (400 MHz, DMSO) 5 ,9.72 (s, 1H), 8.61(s, 2H), 7.94(s, 1H), 7.14-7.16 (d, J=10.8 Hz,1H), 5.66—5.68(d, J=10.8 Hz,1H),3.71-3.76 (m, 2H), , 2H), 2.73-2.79 (m, 2H), 2.26(s, 3H) 2.02(m, 1H), 1.87(m, 2H), , 2H) LCMS for C20H21F6N50 [M+H]+ 461.4 found 462.5 at RT 3.81 min purity (88.64%).
Example 28 Synthesis of (Z)-6,7-dihydro-5H-cyclopenta[b]pyridin-S-one oxime o HQN \ NHZOH.HCI / | \ / i N N/ In a 100—mL, 3N round-bottomed flask 6,7—dihydro-5H-cyclopenta[b]pyridin—5-one (2.0 g, 1.0 eq.) was dissolved in EtOH (24.0 mL) and H20 (6.0 mL) at RT. ThenSodium acetate trihydrate (8.175 g, 4.0 eq.) and Hydroxyl amine hydrochloride (4.174 g, 4.0 eq.) were added at the same temperature. The progress of the reaction was followed by TLC analysis on TLC with 5% Methanol: dichloromethane with ammonia atmosphere as mobile phase and visualization with UV light. The reaction mixture was quenched in 50 mL water and extracted by dichloromethane. Organic layer was concentrated by rotary evaporation (35 0C, 20 mmHg) to afford 2.10 g of crude nd which was used in the next step without purification.
Synthesis of 6,7—dihydro-5H-cyclopenta[blpyridin-S-amine HO\ ' /N ””2 \ NaBH4 \ l —> I / / N N In a 50 mL, 3N round-bottomed flask Intermediate Step (1) (1.0 g, 1.0 eq.) was dissolved in MeOH (15.0 mL, 15 V) at RT. Nickel Chloride Hexahydrate (0.010 g) was added at same temperature to this reaction mixture. The reaction mixture was cooled to — 400C and NaBH4 (2.5 g, 10.0 eq.) was added at the same temperature in portions over 30 min. The progress of the reaction was followed by TLC analysis on TLC with 5% Methanol: romethane with ammonia atmosphere as mobile phase and visualization with UV light. The reaction mixture was quenched in 50 mL water and extracted by Ethyl acetate. The c phase was concentrated by rotary evaporation (35 °C, 20 mmHg) to afford 0.64g of crude compound which was used in the next step without ation.
”NF/274)” N/ TN) 0 / \\'/ F33 N/> W...____> F3C N/ N T3P ,DIPEA >CF3 CF3 In a 100 mL, 3N round-bottomed flask equipped with nitrogen inlet, the acid (0.327 g, 1.0 eq.) was dissolved in dichloromethane (20 mL). To this reaction mixture (1 a) (0.150 g, 1.2 eq.) was added and the reaction mixture cooled to —700C. T3P (Propyl phosponic anhydride) mL, 1.2 eq.) was added dropwise followed by DIPEA (0.318 mL, 2.0). The progress of the reaction was followed by TLC analysis on silica gel with 5% Methanol: dichloromethane with ammonia atmosphere as mobile phase and visualization with UV light. The reaction mixture was quenched in 50 mL water and extracted by dichloromethane. The organic layer was concentrated by rotary evaporation (35 °C, 20 mmHg) to afford 0.369 g of crude compound which was purified by column chromatography. The t eluted at 0.6% Methanol in dichloromethane to give 0.017 g of pure t. (Yield 3.90 %); (Z)(3-(3,5-bis(triflu0r0methyl)phenyl)—1H-1,2,4-triazol—1- yl)-N-(6,7-dihydro-SH-cyclopenta[b]pyridin-S-yl)acrylamide: 1H NMR (400 MHz, DMSO) 5 9.6l(s, 1H), 9.03-9.01(d, 1H), 8.54 (s, 2H), 8.49-8.47 (d, 1H), 8.307 (s, 1H), 8.02-8.00 (d, 1H), 8.19—8.18(m,1H), 7.45-7.42 (d, J=10.4Hz,1H),5.97-5.45 (d, J=10.4 Hz,lH), 5.53-5.47 (m, 1H), 3.12—3.03 (m, 1H), 2.50-2.28 (m, 2H), 2.03-2.02 (m, 1H).
LCMS for C21H15F6N50 [M+H]+ found 480.44 at RT 3.21 min. purity (95.48%).
Example 29 Synthesis of azin—2-yl)ethanamine OW__N . 3 H2N)—(::N\ J/ CH3COONH4’ N NaBH3CN To a 3—necked 100 mL round-bottomed flask equipped with a magnetic stirrer, and immersion thermometer, 1-(pyrazin—2-y1)ethanone (1.0g, 1.0 eq.), and MeOH (30 mL), was added ammonium acetate (6.31 g, 10 eq.) at room temperature. To this reaction mixture sodium cyanoborohydride (0.360 g, 0.7 eq.) was added, and the reaction mass stirred overnight at room temperature. The progress of the on was monitored by TLC analysis on silica gel with MeOszichloromethane (2.5%) as mobile phase and visualization with UV, SM Rf=0.70 and product 0. The reaction mixture was trated and poured into water(100 mL) and basifed (PH=13) using aqueous NaOH solution. The ing mixture was extracted with romethane (2x100 mL) and the combined organic layers were washed with brine solution (2x50 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation to afford 0.3 g of desired amine Yield: 30%.
WNW/>10 ~— /> H0 H N2%N N NH N / ‘ F C3 F C3 [7/ N / 0 H: . \NJ \j \ N/ \N—/) T3P, DIPEA / CF3 F3C In a 100 mL 3-neck round bottom flask ed with , nitrogen bubbler and thermometer pocket, intermediate-1A (0.300 g, 1.0 eq.) was dissolved in dichloromethane (20 mL). A second portion of Intermediate-1A (0.126 g, 1.2 eq.) was added and the reaction mixture cooled to -60°C. To this reaction mixture T3P (Propyl Phosphonic anhydride) (0.60 mL, 1.2 eq.) and DIPEA (0.29mL, 2.0 eq.) were added at the same temperature, and the -1 5 9- mixture stirred for 30 min. The progress of the reaction was ed by TLC analysis on silica gel with 5% MeOH: dichloromethane as mobile phase and Visualization with UV, SM 0 and product Rf=0.50.The reaction mixture was then poured into water (100 mL) and extracted with dichloromethane (2X100 mL). The combined organic layers were washed with brine solution (2X50mL), dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation (25°C, 20mmHg) to afford the crude compound which was purified by column chromatography (diameter: 2.5 cm) using silica 60/120 and MeOH: dichloromethane as mobile phase. Column purification was d with 0.5 % MeOH in dichloromethane upto 2.0% MeOH in dichloromethane. The desired product started eluting in 1.5 % methanol.
Fractions containing the compound were distilled using rotary evaporation at 40 °C / 250 mm Hg to obtain 0.2 g of pure compound.Yield:51.4%; (Z)—3-(3-(3,5— bis(trifluoromethyl)phenyl)—1H—1,2,4-triazolyl)-N—(1—(pyrazinyl)ethyl)acrylamide: 1H NMR (400 MHZ, DMSO) 6 ,9.52 (s, 1H), 8.28-9.13 (m, 6H), 7.40—7.42 (d, J=10.4HZ,1H), 6.04—6.07(d, Hz,1H),5.12—5.19 (m, 1H), 1.46-1.47 (d, 3H); LCMS for C19H14F6N50 [M+H]+ 456.3 found 457.44 at RT 2.894 min purity (99.91%).
Example 30 F3C "T xN‘N \ ”’N I /> 0 ”Cir J N“ F30 \ N O OH N +H2N —'_____._> F3C PYBROP ,DMF Synthesis of (Z)—3-(3-(3,5-bis(trifluoromethyl)phenyl)—1H-1,2,4-triazolyl)—N -((1-methylpyrrolidinyl)methyl)acrylamidez p In a 50 mL 3N round-bottomed flask, (Z)-3 —(3—(3,5-bis(trifluoromethyl)phenyl)-1H- 1,2,4—triazol-1—y1)acrylic acid (0.100 g, 1.0 eq) and (1—methylpyrolidin—3-yl)rnethanamine (0.035g, 1.1eq ) was dissolved in DMF (10 mL) and PYBROP(0.140 g, 1.1 eq.) with DIPEA (0.073mg, 2.0 eq.) was added under nitrogen atmosphere. The progress of the reaction was followed by TLC analysis on silica gel with 0.5% Methanol:dichloromethane with ammonia here as mobile phase and ization with UV light. The reaction mixture was quenched into ice water and compound was extracted by Ethylacetate (25x3 mL), dried over anhydrous NaZSO4, d, and concentrated by rotary evaporation (25 ' CC, 20 mmHg) to afford 0.232 g of solid crude. Purification was achieved via column chromatography in dichloromethane and ol. Compound started eluting at 10% —160- methanol in dichloromethane with ammonia. Fractions containing compound was distilled out using rotary evaporation at 25 0C, 20 mmHg to afford 98.0 mg of pure compound. Yield 77%; (3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol—1-yl)-N-((1- methylpyrrolidin—3-yl)methyl)acrylamide:1H NMR (400 MHz, DMSO) 8 9.83 (s,' 1H), 8.61-8.65 (d, J=12.4Hz,v2H), 7.93 (s, 1H), '.15(d, J=10.8Hz, 1H), 5.69—5.71 (d, J=10.8Hz, 1H), 3.34-3.43 (m, 2H), 2.87-2.91 (m, 1H), 2.63-2.65 (d, J=9.2Hz, 1H), 2.41- 2.154 (m, 2H),2.73(s, 3H), 2.05-2.11(m, 2H),1.71(s, 1H), LCMS for C19H19F6N50 [M+H] + 447.24 found 448.26 at RT 6.50 min purity (89.08%).
Example 31 LN) O T3P DIPEA / NO) I if g” In a 50 ‘mL, 3N round-bottomed flask, Intermediate 4 (0.2 g, 1.0 eq.) was added to dichloromethane:ethylacetate (25.0 mL, 1:1). (2,4-dimethylpyrimidinyl)methanamine (0.078 g, 1 eq.) was then added at -40°C. T3P (50% ethyl acetate) (0.432 g, 1.2 eq.) and DIPEA (0.147 g, 2.0 eq.) were added simultaneously at the same temperature, and the reaction mixture stirred for 30 min at -40°C. The progress of the reaction was monitored by TLC using 5% methanol: dichloromethane with ammonia here as mobile phase and ization with UV light. The reaction mixture was concentrated by rotary evaporation (35 0C, 20 mmHg) to afford 0.270 g of an oil. The resulting crude mixture was purified by column chromatography using dichloromethanezmethanol as a mobile phase, the compound eluted at 4% methanol in dichloromethane. The compound containing fractions were concentrated under reduced pressure to obtain 80 mg -29.85%) of pure compound.
(Z)-3—(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazolyl)-N-((2,4- dimethylpyrimidinyl)methyl)acrylamide:1H NMR (400 MHZ, DMSO) 5 ,9.57 (s, 1H), 8.91~8.94 (t, 1H), 8.51 (s, 2H), 8.43 (s, 1H), 8.29 (s, 1H), 7.40-7.42 (d, Hz, 1H), .98-6.01 (d, J=10.4, 1H), 4.37-4.38 (d, J=5.6 Hz, 2H), 3.35 (s, 3H), 2.50 (s, 3H); LCMS for C20H16F6N6O [M+H]+ 470.37 found 471.25 at RT 2.69 min purity (99.89%). -l 61- e 32 Synthesis of (Z)(3-(4—chloro-3,5-bis(trifluoromethyl)phenyl)—1H-1,2,4-triazol- 1-(3,3-diflu0roazetidinyl)propen0ne N’NH N’NW ©<F’ N l ————————-——-> F30 N) / F30 /> O DABCO N «WN:><—— F CI CI CF3 o F CF3 In a 50 mL, 3N round—bottomed flask equipped with nitrogen inlet, Intermediate-3 (0.1 g, 1.0 eq.) was dissolved in DMF (5 mL). To this reaction mixture DABCO (0.071g, 2 eq.) was added and stirred for 30 min. Then (Z)-1—(3,3-difluoroazetidinyl)iodoprop-2— en-l—one (0.095 g, 1.1eq.) was added, and the reaction mixture stirred at room temperature for 5 h. The progress of the on was followed by TLC using dichloromethane: methanol (95:05) mobile phase and ization with UV. The reaction mixture was poured into ice water (50 mL), then extracted with EtOAc (3X15 mL). The combined organic layers were washed with brine solution, (20 mL), dried over , filtered, and concentrated by rotary evaporation (25 °C, 20 mmHg) to afford 0.150 g of crude compound which was purified by preparative TLC obtain pure compound 0.004g yield (3%).
(Z)(3-(4-chloro-3,5-bis(triflu0romethyl)phenyl)-1H-1,2,4-triazol—1-yl)(3,3- difluoroazetidinyl)propenone: 1H NMR (400 MHZ, DMSO) 6 = 9.32 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 7.47-7.49 (d, J= 10.4 Hz, 1H), 6.00-5.04 (d, J= 10.4 Hz, 1H), 4.55- 4.58 (m, 2H), 4.33—4.36 (m, 2H) LCMS for C16H9C1F8N4O [M+H]+: 460.7, Found: 461.14, Purity 98.77 % at 2.99 min retention time Example 35 F " _ F FaC F / / . F3C ———————-———>- ' THF,NAH CF3 CF3 In a 25 ml sealed tube NaH (0.064 g, 1.5 eq.) was suspended in THF (10 mL) and then cooled to 0°C. To this mixture, a solution of intermediate 3 (0.3 g, 1.0 eq.) in THF was added se at 0°C and then the mixture was heated under reflux at 807°C for 2 h. The -l62- progress of the reaction was followed by TLC analysis using 10% ethyl acetate in hexane as mobile phase. The reaction mixture was then concentrated and resulted mass extracted with ethyl acetate (2X150mL). The combined c layers were washed with brine solution (2X100 mL), dried over anhydrous NazSO4, filtered, and concentrated by rotary evaporation (40°C, 20 mmHg) to afford 0.43 g of crude mixture. The mixture was purified by column chromatography using ethyl e in . The nd eluted in 25%ethyl acetate , and the cis product was isolated Via ative TLC using a mobile phase consisting of 10%‘acetone in . The pure product obtained was 0.016 g; (Z)(3-(3,5- lbis(triflu0romethyl)phenyl)-1H-pyrazolyl)(3,3-difluor0azetidinyl)pr0pen one: 1H NMR (400 MHz, CDClg) 5 ,8.78-8.79 (d, J=2.4,1H), 8.28 (s, 2H), 7.19-7.22 (d, J=lO.8Hz, 1H), 6.81-6.82 (d, J=2.4, 1H), 5.44-5.47 (d, J=10.8Hz, 1H), 4.44-4.51 (m, 4H); LCMS for C17H11F8N3O [M—I—l]+ 425.28 found 426.09 at RT 3.202 min. purity (22.42%).
Example40 HO D 0% F%N D N/N g ______> I o FC />\D T3P,DCM >718 3 N HN:><F / N’N>\/ D F F3C ' HCI CF3 In a 25 mL 3-neck round bottom flask equipped with septum, Nitrogen bubbler and thermometer , intermediate-1 (acid) (0.080 g, 1.0 eq.) and dichloromethane (6.0 mL) were added. Then 3,3-difluoroazetidineHCl (0.0.035 g, 1.2 eq.) was added and the reaction mixture cooled to —60°C. To this mixture, T3P (Propyl Phosphonic anhydride) (0.161 ml, 1.2 eq.), and DIPEA (0.077 ml, 2.0 eq.) were added at the same temperature, and the resulting mixture stirred for 1h. The progress of the reaction was followed by TLC analysis using 5% MeOH: dichloromethane as mobile phase and Visualization with UV SM Rf: 0.20 and product Rf: 0.70.The reaction mixture was then poured into D20 (10 mL) and extracted with dichloromethane (2X20 ml). The combined organic layers were dried over anhydrous MgSO4, d and concentrated by rotary evaporation (25°C, 20 mmHg) to afford a crude compound which was purified by column chromatography using silica 60/120 and MeOH: -163— dichloromethane as mobile phase. Column purification was d with 1.5 % MeOH in dichloromethane upto 2.0% MeOH in dichloromethane. The desired t d eluting in 1.5 % methanol and the fractions containing compound Were distilled using a rotary evaporation at 40 °C / 250 mm Hg to obtain 0.020 g of pure nd.Yield:20%’. 1H NMR (400MHz, CDCl3) 6 9.63-9.66(d, J=10.8Hz; 1H), 8.61(s, 2H), 7.95(s,1H), 7.24-7.27(t, J=4.4Hz,1H),5.67-5.69(d, J=1018Hz, 1H ), 4.46—4.60(m, 4H); LCMS for ChemiCal Formula: C16H8D2F8N4O [M+H]+ 428.28 found 42914 at RT 2.992 min purity (98.62%).
Example 43 ON CN 0 F C3 FBC Step—1 O/\ + Br/\[(O\/ ——> o NaHMDS/THF CFS CF3 (1) COC|2.6H20 Step-2 NaBH4 MeOH NH NH N?I NO< F 0 F30 F 3 Step—3 Step-4 <— F C3 DABCO, ' LAH, THF DMF Ca ca CF3 (3) (2) IQ‘NyF Synthesis of Intermediate (1) CN 0 FC3 ‘ Step-1 3 o“ . erov —> 0 NaHMDS/THF In a , 3N RBF equipped with nitrogen inlet, a Thermometer pocket and stopper, 3,5-bis(trifluoromethy1)-phenylacetonitril.e (1.4 mL, 1.0 eq.) was dissolved in THF (20 mL, 10V). The reaction mixture was cooled to -78°C. NaHMDS (35% in THF) (4.34 mL, 1.05 eq.) was added dropwise in this reaction mixture. After completion of addition reaction WO 19561 mixture was brought to 10°C and stirred for 15 min. Again this reaction mixture was cooled to —78°C and ethyl bromoacetate (0.87 mL, 1.0eq.) was added. Reaction mixture was brought to room temperature. This reaction mixture was stirred at room temperature for 16 hrs. The progress of the reaction was monitored by TLC is using 20% Ethyl e-Hexane as mobile phase. on mixture was poured into water (50 mL) and extracted with EtOAc (3x20 mL). The combined organic layer was washed with brine solution (50 mL), dried over Na2804,ifiltered, and concentrated by rotary evaporation to afford 3.5 g of Crude compound. The crude compound was purified by column tography using 60/120 mesh silica and ethyl acetate: hexane as mobile phase. The column was packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection (25-mL fractions). The compound started eluting from 4% to 6% ethyl acetate in hexane. Fractions containing such TLC profile were collected together to obtain pure compound 1.2 gm Yield (44.94%). sis of Intermediate (2) CN’ 0 F3C 0 1 F30 o/\ Step-2 ———> COCI2.6HZO - CF22) (1) In a 100-mL, 3N RBF equipped with nitrogen inlet, a Thermometer pocket and stopper, ediate-1(l .2 g, 1.0 eq.) was dissolved in MeOH (48 mL, 40V).
Dichlorocobalt hexahydrate (1.68 g,2.0 eq.) was added portion Wise. The reaction mixture was cooled to 20°C. NaBH4 (1.98 g, 15 eq.) was added portion wise slowly by maintaining ature below 25°C in this reaction mixture. Then the reaction mixture was stirred for 18 hrs at 25°C. The progress of the reaction was ed by TLC analysis using 50% Ethyl acetate-hexane as mobile phase. The reaction mixture was concentrated under reduce pressure and residue was partitioned between ethyl acetate (25 mL) and water (25 mL).
Reaction mixture was d through celite and organic layer separated, dried over NaZSO4, filtered, and concentrated by rotary evaporation. This crude compound was triturated with pet ether to afford 0.5 g of pure compound.(Yield 47.61 %).
Synthesis of Intermediate (3) -l65- ‘ NH -. F30 o Step~3 . FsC LAH, THF CF3 (2) . CF3 In a 100-mL, 3N RBF equipped with nitrogen inlet, a Thermometer pocket and r, Intermediate-2 (1.0 g, 1.0 eq.) was dissolved in THF (20mL, 20V). The reaction mixture was cooled to 0°C. To this reaction mixture LAH (6.7mL, 2.0eq.) was added dropwise by maintaining temperature 0°C. After completion of addition, temperature of reaction mixture was brought to room temperature and then refluxed to 70°C for 1h. The progress of the reaction was ed by TLC analysis using 5% MeOHzDCM as mobile phase. The reaction mixture was cooled to 0°C. Reaction mixture was quenched by on of 1.5 mL of 5 % KOH on. Then reaction mass was filtered through celite and washed with EtOAc (20mL). Filtrate was concentrated by rotary evaporation to afford 1.0 g of crude compound. The crude compound was purified by column chromatography using 60/120 mesh silica and MeOH : DCM as mobile phase. The column was packed in DCM and started eluting in MeOH in gradient manner starting with fraction collection (25- mL fractions). The compound started eluting from 4% to 6% MeOH in DCM. Fractions containing such TLC profile were collected together to obtain pure compound 0.18 gm Yield (19%).
Synthesis of (Z)(3-(3,5-bis(trifluoromethyl)phenyl)pyrrolidin-l-yl)-1—(3,3- oazetidinyl)propenone . F NH ‘ . NEE/’Nyp F3C Step—4 F3C DABCO, DMF CF — F CF ' 3 (3) Ir—O>7N:><F 3 (1A) In a 50 mL 3—neck round bottom flask equipped with septum, Nitrogen bubbler and thermometer , Intermediate -3 (0.050g, 1.0 eq.) in DMF ) were added. Then DABCO (0.039 g, 2.0 eq.) was added at room ature. on mixture was stirred at room temperature for 30 min. Intermediate-1A (0.053 g, 1.1 eq.) was added at room temperature drop wise. Reaction mixture was stirred for 30 min. The progress of the reaction —166- was followed by TLC analysis using 5% MeOH: DCM as mobile phase and Visualization with UV, SM Rf=0.20 and product Rf=0.70. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (2X50mL). The combined organic layer was washed with brine on (5OmL), dried over anhydrous Na2804, filtered, and concentrated by rotary evaporation (25°C, 20mmHg) to afford crude compound 50 mg. The crude material was purified by Prep.TLC using 2% MeOH: DCM as mobile phase. It was again purified by Prep.TLC using 50% EtOAc: Hexane as mobile phase to obtained 0.018g of pure compound --24%)(Z)(3-(3,5-bis(trifluoromethyl)phenyl)pyrrolidinyl)(3,3-diflu0roazetidin- 1-yl)prop-2—en-1—0ne: 1H NMR (400 MHZ, CDC13) 8, 7.82 (s, 1H), 7.73 (s, 1H), 7.69 (s, 2H), 4.43-4.46 (d, J=12.4Hz, 1H), 4.32-4.38 (t, J=12Hz, 4H), 3.61 (s, 2H), 2.47 (5,1H), 2.18 (s, 1H), 2.16 (s, 1H), 1.27 (s, 1H); LCMS for C18H16F8N20 [M+1]+ 428.3 found 429.09 at RT 3.047 min. purity (95.45%).
Example 44 CN 0 Step-1 3 F3C o/\ + Br/\n/o\/ ___> 0 NaHMDS/THF COC|2.6H20 NaBH4 Step-2 O F MeOH " ' ,~ NH N ' 0 o . F3C ‘ Step_3_- KELNSVF + CF3 (2) Synthesis of ethyl 3-(3,5-bis(triflu0r0methyl)phenyl)cyan0pr0pan0ate (1) -‘167- CN 0 F3C Br/\H/O\/ Step-1 O -———> - 0 NaHMDS/THF 3,5-Bis(trifluoromethyl)-phenylacetonitrile (1.4 mL, 1.0 eq.) was dissolved in THF (20 mL). The reaction mixture was cooled to —78 °C where a solution ofNaHMDS (35% in THF) (4.34 mL, 1.05 eq.) was added dropwise. The reaction mixture was allowed to warm to °C and stirred for 15 min. Then it‘was cooled to -78 °C where ethyl bromoacetate (0.87 mL, 1.0 eq.) was added. The on mixture was then allowed to warm to room temperature where it was stirred for 16 h. Reaction mixture was poured into water (50 mL) and was extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine solution (3x50 mL), dried over Na2804, filtered, and concentrated under reduced pressure to afford 3 .5 g of crude product, which was purified by chromatography (4% ethyl acetate in hexane) to give 1.2 g of ethyl 3-(3,5-bis(trifluoromethyl)phenyl)—3— cyanopropanoate (Yield 44.94%). sis of 4—(3,5-bis(trifluoromethyl)phenyl)pyrrolidin0ne (2) CN 0 F3C o F3C 0/\ Step-2 __._._—> COC12.6H20 CF3 NaBH4 MeOH (1) (2) Ethyl 3-(3,5-bis(trifluoromethyl)phenyl)—3-cyanopropanoate (1.2 g, 1.0 eq.) was dissolved in MeOH (48 mL). Dichlorocobalt hexahydrate (1.68 g, 2.0 eq.) was added and the reaction mixture was cooled to 20 CC. NaBH4 (1.98 g, 15 eq.) was added portion wise by maintaining temperature below 30 °C. After completion of on, this reaction mixture was stirred for 18 h at 25 OC. The on mixture was trated under d pressure and the residue was partitioned between ethyl acetate (25 mL) and water (25 mL).
The reaction mixture was filtered through CeliteTM and the c layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 0.65 g of crude product, which after trituration with petroleum ether gave 0.5 g of 4-(3,5- bis(trifluoromethyl)phenyl)pyrrolidin—2-one (Yield 47.61 %).
WO 19561 2012/048368 sis of (E)(3,5-bis(trifluor0methyl)phenyl)—1-(3—(3,3-diflu0roazetidin yl)-3—oxopr0penyl)pyrr01idin—2-one NH o . F C F3C O 3 O F N/VLN F I\fN:>< Step-3 — F NaH,DMF F CF3 F3C 4—(3,5-bis(trifluoromethyl)phenyl)pyrrolidinone (0.5 g, 1.0 eq.) was dissolved in DMF (5 mL) and cooled to 0 0C. A solution ofNaH in DMF (0.133 g, 2.0 eq.) was added at 0 °C. (Z)(3,3-difluoroazetidin—l-yl)iodopropen-l—one (0.689 g, 1.5 eq.) was then introduced. The reaction mixture was d for 30 min at room temp. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3x20 mL). ,The combined organic layers were washed with brine (3x50 mL), dried over Na2804, filtered, and concentrated under reduced pressure to afford 0.502 g of crude product, which was purified by chromatography (1% Methanol in DCM) to give 0.030 g of (3,5- bis(trifluoromethyl)phenyl)—1 -(3 —(3 ,3 —difluoroazetidinyl)-3 -oxopropenyl)pyrrolidin one (Yield 4.03%). 1H NMR (400 MHZ, CDC13) 8 8.15-8.19 (d, J=14Hz, 1H),7.69-7.87 (m, 3H), 5.27-5.31 (d, J=14Hz, 1H), 4.05-4.47 (m,4H), 3.89-3.93 (s,lH), 3.73-3.77(s,lH), 3.60- 3.62 (s,1H),‘3.08-3.l3 (s,lH), 2.78-2.90 (s,lH); LCMS calcd. for C18H14F8N202 [M+H]+ found 443.44 at retention time 2.97 min.
Example 51 Synthesis of (7)-(3-(3,5-bis(trifluoromethyl)phenyl)-1H—1,2,4-triazol-—1-yl)--(3- y-3—(trifluor0111ethyl)azetidin-1——-yl)pr0p2-enone «WW/(0H “I’M/”>7“ OH N/> O ‘ / . / O F3C CF3 F3C ) “0' T3PID|PEA CFs CF3 (Z)(3—(3,5—bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol—l-yl)acrylic acid (0.10 g, 1.0 eq.) and 3—(trifluoromethyl)azetidin-3—ol hydrochloride (0.055 g, 1.1 eq.) were dissolved . 469- in DCM (3.0 mL). The reaction mixture was cooled to -30 °C where T3P (0.3 mL, 1.5 eq.) and DIPEA (0.12 mL, 2.5 eq.) were added. The reaction e was stirred at -30 °C for 30 min. and diluted by DCM, washed with water. The combined organic layers were dried over sodium sulfate and distilled under reduce pressure (250 °C, 20 mmHg) to obtain crude product. The crude product was purified by peparative TLC (70% ethyl acetate- Hexane) to yield to 0.020 g of (Z)(3—(3,5—bis(trifluoromethyl)phenyl)—lH—l,2,4-triazol yl)(3 —hydroxy—3-(trifluoromethyl)azetidin-l—yl)propenone .(Yield:l4.8%). 1H NMR (400 MHZ, MeOD) 8 9.20 (s, 1H), 8.65 (s, 2H), 8.09 (s, 1H), 7.40—7.43 (d, J=10 Hz, 1H), .95—5.93 (d, J=10.6 Hz, 1H), 4.42-4.43 (m, 2H), 4.33—4.05 (m, 2H); LCMS calcd for C17H11F9N402 [M+H]+ 474.3 Found: 475.14 Retention time: 2.872 min, Synthesis of 1-benzhydryl-3—(triflu0romethyl)azetidinol (1A) 0 N/jo TFTS O TBAF N/jfgb __—___> O THF l«Benzhydrylazetidinone (5.0 g, 1.0 eq.) was dissolved in THF (50 mL).
Trifluoromethyl hylsilane was added at 5-10 °C. The on mixture was stirred at 10 0C for 10 min. Tetrabutyl ammonium fluoride was then added. The reaction mixture was d to warm to room ature and stirred for l h. The reaction mixture was diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced re to give the crude product, which was purified by chromatography (6% ethyl acetate—hexane) to give 3 g of l-benzhydry1—3- (trifluoromethyl)azetidin—3-ol (Yield:46.32%).
Synthesis of 3—(triflu0r0methyl)azetidinol hydrochloride (2a) 1~Benzhydryl(trifluoromethyl)azetidin-3—ol (0.25 g) was dissolved in ethanol (3 mL). Palladium hydroxide on carbon (0.25 g) was added and en gas was purged in to the reaction mixture. The reaction mixture was maintained at 25-30 °C for 2h. The solid ~170- formed was removed by filtration and ethanolic HCl was added to the filtrate at 0 OC and further stirred for 30 min. The reaction mixture was concentrated under reduced pressure to give an oily residue, which was ated with ether to give 3— (trifluoromethyl)azetidinol hydrochloride as solid product, which was used in the next step without further purification. 1H—NMR (400 MHZ, MeOD) 5: 4.39-4.43 (d, 2H), 4.13— 4.16 (d, 2H).
Example 52 sis of (Z)—tert-buty1 6—(3 -(3 -(3,5—bis(trifluoromethyl)phenyl)-lH—1,2,4-triazol- l-yl)acryloyl)-2,6—diazaspiro [3 .3 ne—2-carboxylate WNWT OH ” N O N, r5499 / F3C /> T3P o N , DIPEA / N) —-——)> htN DCM . cs:3 HCI GUN cr=3 (Z)(3-(3,5—bis(trifluoromethyl)phenyl)—lH-l,2,4-triazol-l-yl)acrylic acid (0.50 g, .1 .0 eq.) was dissolved in DCM (5 mL). tert—Butyl 2,6-diazaspiro[3.3]heptanecarboxylate hydrochloride (0.40 g, 1.2 eq.) was added and the reaction mixture was cooled to -70 OC.
T3P (1.02 mL, 1.2 eq.) was added dropwise followed by DIPEA (0.73 mL, 3.0 eq.). The reaction mixture was quenched with 50 mL of water and extracted by DCM. The organic layer was concentrated under reduced pressure (35 0C, 20 mmHg) to afford 0.603 g of crude product which was purified by chromatography (1% Methanol in DCM) to give 0.350 g of rt-butyl 6—(3 -(3 -(3 ,5-bis(trifluoromethyl)phenyl)- lH— 1 ,2,4-triazolyl)acryloyl)- 2,6-diazaspiro[3.3]heptanecarboxylate. (Yield 46.29 %). sis of (Z)(3—(3,5-bis(triflu0r0methyl)phenyl)-lH-l,2,4-triazol—1-yl)-l- (2,6-diazaspir0[3.3]heptanyl)pr0pen0ne 2,2,2-triflu0roacetate: -l 71 — I. X0 N’NWNOCNH,_ , o N NWNXN’ FC /> H . 3 l /> O TFA, DCM CFs Chemical Formula: C18H15F6N5O lar Weight: 431.34 (Z)—tert-butyl 6-(3-(3~(3,5-bis(trifluoromethyl)phenyl)~1H-1,2,4-triazolyl)acryloyl)— 2,6—diazaspiro[3.3]heptane—2-carboxylate (0.13 g) was dissolved'in DCM (1.5 mL). The reaction mixture was cooled to 0 °C and CF3COOH (1.5 mL) was added. The reaction mixture was allowed to warm to room temp. where it was stirred for 4 h. The reaction mixture was concentrated under reduced pressure (35 0C, 20 mmHg) to afford 0.100 g of (Z)—3 —(3-(3,5-bis(trifluoromethyl)phenyl)- 1 H- 1 ,2,4-triazol-1 -yl)— 1 -(2,6- diazaspiro[3.3]heptanyl)prop—2-enone 2,2,2-trifluoroacetate (Yield 95.23 %). 1H NMR (400 MHz, DMSO) 8 9.49 (s, 1H), 852-8.5 (m, 3H) 8.32 (s, 1H), 7.44-742 (d 1H, J=10.4 Hz), 5.97—5.94 (d, J:104Hz,1H,,) 437—393 (m, 8H); LCMS calcd for C13H16F6N50 [M+H]+ 43234; found 432.29 at retention time 2.256 min Example 53 Synthesis of (Z)—3-(3-(3,5-bis(trifluor0methyl)phenyl)-1H-1,2,4-triazolyl)(3- hydroxyazetidin-l-yl)prop-2—en0ne WNWOH N’NWNO/”’ OH / /> O F3C INC) T3P DIPEA FBC + H_‘“—‘” .HCI c1=3 CF3 (Z)(3—(3,5—bis(trifluoromethyl)phenyl)-1H—1,2,4—triazol-l-yl)acrylic acid (0.2 g, 1.0 eq.) was ved in DCM (20 mL). The reaction e was cooled to —60 0C where azetidinol hydrochloride (0.075 g, 1.2 eq), T3P (50% in EtOAc) (0.4 mL, 1.2 eq) followed by DIPEAT (0.2 mL, 2 eq) were added dropwise. The clear reaction mixture was stirred at —60 °C for 45 min. The reaction mixture was concentrated under reduced pressure (25 0C, 20 mm Hg) to afford the crude product, which was ed by chromatography (5% Methanol in DCM with ammonia) to obtain 30 mg of (Z)—3-(3-(3,5-bis(trifluoromethyl)phenyl)—1H— triazolyl)—1-(3-hydroxyazetidin-1~yl)prop—2—en—1-one Yield (13 %). 1H NMR (400MHz, DMSO) 6 = 9.4 (s, 1H), 8.56 (s, 2H), 8.29 (s, 1H), 7.48-7.40 (d, J: 10.4 Hz, 1H), .95-5.97 (d, J= 10 Hz, 1H), 5.77-5.79 (d, J: 5.6, 1H, D20 exchangeable), 4.47-4.48 (d, J: 5.6, 1H),14.25-4.29 (t, 1H), 4.15—4.19(m, 1H), 38-384 (m, 1H), .73 (m, 1H); LCMS calcd. for C16H13F6N402 [M+H]+ 407.28 found: 407.14, at 2.462 min retention time.
Example 54 Synthesis of (Z)(3-(3-(3,5-bis(triflu0r0methyl)phenyl)-1H-1,2,4-triazol-l- yl)acryloyl)azetidine—3-carbonitrile ,NWOH N’NWNyCN I) ,/> o / /> O F30 F30 + HN CN —-—> HCI T3P, DIPEA CF3 CF3 (Z)-3—(3—(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol—1—yl)acrylic acid (0.2 g, 1.0 eq.) was dissolved in DCM (20 mL). The reaction mixture was cooled to -60 °C where azetidine-3—carbonitrile hydrochloride (0.08 g, 1.2 eq), T3P (50% in EtOAc) (0.4 mL, 1.2 eq) followed by DIPEA (0.2 mL, 2 eq) were added se. The clear reaction mixture stirred at -60 °C for 45 min. The reaction mixture was concentrated under reduced pressure (25 0C, 20 mm Hg) to afford the crude t, which was purified by chromatography (3 - % Methanol in DCM). to obtain (Z)-1—(3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4— triazol-l-yl)acryloyl)azetidine—3—carbonitrile (0.14 g, 60% yield). 1H NMR (400MHz, DMSO) 6 = 9.36 (s, 1H), 8.54 (s, 2H), 8.30 (s, 1H), 7.45—7.43 (d, J: 10 Hz, 1H), .92 (d, J: 10 Hz, 1H), 4.39-4.37 (t, 1H), 4.29—4.11 (m, 3H), 3.84-3.82 (m, 1H); LCMS calcd. for C17leF6N50 [M-I—H]+ ; found 416.14, at 2.64 min retention time Example 55 Synthesis of methyl azetidine—3-carb0xylate hydrochloride 2012/048368 OH o—~ HN:>_\< SOCIz CIHHN:>—\< 0 O CH3OH A suspension of azetidine-3—carboxylic acid (1 g, 9.8 mmol) in MeOH (10 mL) was cooled to 5 °C. Thionyl chloride (5.83 g, 49.45 mmol) was added dropwise maintaining the reaction temperature below 30 CC. The mixture was then heated to 65 °C for 10-12 h. The reaction mixture was concentrated under reduced pressure to yield methyl azetidine carboxylate hydrochloride as viscous brown oil (1.3 g, 90%), which was used without further purification.
Synthesis of (Z)-methyl 1-(3-(3-(3,5~bis(trifluoromethyl)phenyl)—1H-1,2,4-triazol- 1-yl)acryloyl)azetidine—3-carb0xylate f/OHm [VIN/t» %oN / /> o F3C N/> F30 T3P DlPEA N + HN::>_<— CFs (Z)(3—(3,5-bis(trifluoromethyl)phenyl)—1H-l,2,4—triazolyl)acrylic acid (0.5 g, 1.0 eq.) was ved in DCM (20 mL). The reaction mixture was cooled to -60 °C Where methylazetidinecarboxylate hydrochloride (0.25 g, 1.2 eq.), T3P (50% in EtOAc) (1.0 mL, 1.2 eq.) followed by DlPEA (0.48 mL, 2 eq.) were added. The clear reaction mixture was stirred at ~60 °C for 45 min. The reaction e was concentrated under reduced pressure (25 °C, 20 mm Hg) to afford the crude product, which was purified by chromatography (2 - 3% Methanol in DCM) to give (Z)—methy1 1-(3-(3—(3,5-bis(trifluoromethyl)phenyl)-lH-l ,2,4- triazol-l—yl)acryloyl)azetidine—3-carboxylate (0.15 g, 24% .
Synthesis of (Z)(3-(3-(3,5-bis(triflu0r0methyl)phenyl)—lH-l,2,4-triazol yl)acryloyl)azetidinecarb0xylic acid ”NW"A N::>*‘*$ N’h(—’W>r’,, ex0 0 / O / F3C /> 4} O F3C IJOH N N ._..__..—___> ol/Water (Z)-methyl 1-(3 -(3 -(3 ,5 —bis(trifluoromethyl)phenyl)—lH—l ,2,4-triazol yl)acryloyl)azetidinecarboxylate (0.1 g, 1.0 eq.) was dissolved in methanolzwater (10 mL, —l 74- 1:1). LiOH (0.010 g, 1.0 eq.) was added. The on mixture was stirred at room temperature for 1-2 h. The reaction mixture was quenched with 10 mL water and acidified with dilute HCl until pH=2—3. The aqueous layer was extracted with ethyl acetate (10 mL X 3). The organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford 0.060 g of (Z)-l-(3 ~(3-(3,5— bis(trifluoromethyl)phenyl)- 1H- 1 ,2,4—triazol— l —yl)acryloyl)azetidine—3 -carboxylic acid (62.5% yield); 1H NMR (400MHz, DMSO) 5 = 9.38 (s, 1H), 8.54 (s, 2H), 8.29 (s, 1H), 7.40- 7.42 (d, J: 10.4 Hz, 1H), 5.93—5.96 (d, J: 10.4 Hz, 1H), 4.23—4.27 (m, 2H), 4.12-4.16 (m, 3H). LCMS calcd. for C17H13F6N4O3 [M+H]+: 435.29, Found: 435.14, at 2.55 min retention time.
Example 56 Synthesis of (Z)—tert-butyl6-(3-(3-(3,5-bis(triflu0r0methyl)phenyl)—1H-l,2,4- triazol-l-yl)acrylamido)—3-azabicyclo[3.1.0]hexanecarb0xylate H N’N_ NH N ’ .
FC /) O 3 BPMWA HZN—<<[::N—Boc F3C C><O (3-(3,5-bis(trifluoromethyl)phenyl)—1H—1,2,4—triazol-l-y1)acrylic acid (0.250 g, 1.0 eq.) was dissolved in DCM(12 mL). tert-butyl 6-amino-3—azabicyclo[3. l .0]hexane carboxylate (0.17 g, 1.2 eq.) was added and the reaction mixture was cooled to - 60°C. T3P (0.51 mL, 1.2 eq.), followed by DIPEA (0.24 mL, 2.0 eq.) was then added at the same temperature. The reaction mixture was stirred for 30 min. and erred into water (50 mL) and extracted with DCM (2X50 mL). The combined organic layer was washed with brine (50 mL), dried over ous MgSO4, filtered, and concentrated under reduced pressure (25°C, 20 mmHg) to afford crude product, which was purified by chromatography (0-5% MeOH in DCM) to give rt—butyl 6-(3—(3-(3,5-bis(trifluoromethy1)phenyl)-lH—l,2,4- triazol-l-yl)acrylamido)-3—azabicyclo[3.‘l.0]hexane§3-carboxylate (0.28 g; 66.1% yield).
Synthesis of (Z)-N-(3-azabicyclo[3.1.0]hexanyl)(3-(3,5- ifluoromethyl)phenyl)-1H—1,2,4-triazolyl)acrylamide hydrochloride —175- IN>O NH Dioxane: HCI [NM \E}NH (Z)-tert-butyl 6—(3 -(3 -(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol yl)acrylamido)azabicyclo[3.1.0]hexanecarboxylate (0.05 g, 1.0 eq.) was dissolved in DCM (3 mL) and cooled to 0 °C where dioxanezHCl (0.2 mL) was added dropwise and stirred for 30 min. The reaction was allowed to warm to room temperature and stirred for 30 min, concentrated under reduced pressure. The crude t was ated with ether to afford (Z)-N-(3 -azabicyclo[3.1.0]hexanyl)—3 -(3 -(3,5—bis(trifluoromethyl)phenyl)-1H-l,2,4- triazol-l-yl)acrylamide hydrochloride (0.015 g, 37.5% yield). 1H NMR (400 MHZ, DMSO) 8 ,9.61 (s, 1H), 8.75 (s, 2H), 8.60 (s, 2H), 8.30 (s, 1H), .40 (d, J=10.4Hz, 1H), 5.87- 5.89 (d, J=10.4Hz, 1H), 2.91 (s, 1H), 2.14 (s, 2H), 1.23 (s, 3H) ;LCMS for Chemical Formula: C18H16F6N50 [M+H]+ 432.34 found 432.19 at retention time 2.302 min.
Example 57 Synthesis of tert—butyl 6--((((9H-fluoren-yl)meth0xy)carbonyl)amino)- yclo[3.1.0]hexane—3--carboxylate > 0 $0 >FN<E FMOC-Cl lNaHCO3 0 O O 0%NCE\ 2L0 . dioxane:H20 fl 0 tert—Butyl 6-aminoazabicyclo[3.1.0]hexane-3—carboxylate (1 g, 1.0 eq.) was added to a solution of sodium bicarbonate (0.84 g, 2.0 eq.) in water (5 m1) at 5 0C. FMOC-Cl (1.56 g, 1.2 eq.) in oxane (10 ml) was added dropwise. The reaction mixture was stirred at room temperature for 3 h, erred into iced water (50 mL), and extracted with EtOAc (2 X 100 mL). The combined organic layers was washed with brine (2X50 mL) dried over NaQSO4, filtered, and concentrated under reduced pressure (25°C, 20 mmHg) to afford WO 19561 1.9 g of tert—butyl 6-((((9H—fluoren—9-yl)methoxy)carbonyl)amino) azabicyclo[3. 1 .0]hexanecarboxylate (yield 90%).
Synthesis of (9H-flu0renyl)methyl 3-azabicyclo[3.1.0]hexanylcarbamate tert-Butyl 6-((((9H—fluorenyl)methoxy)carbonyl)amino) yclo[3.1.0]hexane—3—carboxylate (1.9 g, 1.0 eq.) was dissolved in DCM (20 mL). TFA (1.38 ML, 4 eq) was added dropwise at 0 °C and the reaction mixture was d at room ature for 4 h. The reaction mixture was cooled to 0 °C and neutralized by saturated NaHCO3. The solid precipitated out was collected by filtration to afford 1.0 g of (9H- fluorenyl)methyl 3-azabicyclo[3.1.0]hexanylcarbamate (69% yield).
Synthesis of (Z)—(9H—fluorenyl)methyl (3-(3-(3-(3,5- bis(triflu0r0methyl)phenyl)-1Iii-J,2,4-triazol~1-yl)acryloyl)azabicyclo[3.1.0]hexan yl)carbamate ch 0 O 0 F30 Va. 04A T3P, DIPEA, DCM N F3C (Z)—3—(3-(3,5-Bis(trifluoromethyl)phenyl)-lH—1,2,4-triazolyl)acrylic acid (1.0 g, 1.0 eq.) was dissolved in DCM (50 mL) and cooled to -60 °C where (9H-fluorenyl)methyl 3—azabicyclo[3.1.0]hexan—6—ylcarbamate (1.09 g, 1.2 eq.), T3P (50% in EtOAc) (2.02 mL, 1.2 eq.) and DIPEA (0.95 mL, 2 eq.) was added. The clear reaction mixture was stirred at -60 °C for 1 h, quenched with water, and extracted with DCM.
The organic layer was dried over -177, sodium sulphate, concentrated under reduced pressure (25 0C, 20 mm Hg) to afford the crude product, which was purified by chromatography ( 2% Methanol in DCM) to yield (Z)— oren—9-yl)methyl (3~(3,5~bis(trifluOromethyl)phenyl)-1H—1,2,4-triazol yl)acryloyl)—3-azabicyclo[3.1.0]hexanyl)‘carbamate (1.26 g, 69% yield).
Synthesis of (6-aminoazabicyclo[3.1.0]hexanyl)(3-(3,5- bis(trifluoromethyl)phenyl)—1H-l,2,4-triaz01—1-yl)pr0p-2—en0ne 9 A m Eth IN) 0 N\ 1,1 (Z)—(9H—Fluoren—9—yl)methyl (3 —(3 -(3 -(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4— triazol—1—yl)acryloyl)—3-azabicyclo[3.1.0]hexanyl)carbamate (0.3 g, 1.0 eq.) in was dissolved in DMF (0.75 ml). TEA (0.75 ml) was added dropwise and the reaction mixture was stirred at room temperature for 4 h, quenched with water (10 mL) and extracted with ethyl acetate (3X50 mL). The combined organic layers was washed with brine (50 mL), dried over NaZSO4, filtered, and concentrated under reduced pressure (25°C, 20 mmHg) to afford 0.2 g of the crude product, which was purified by chromatography (10% Methanol in DCM) to obtain (6—amino-3—azabicyclo[3.1.0]hexan—3-yl)-3—(3-(3,5- bis(trifluoromethyl)phenyl)—lH-1,2,4-triazol-1—yl)prop—2-en—1-one (0.1 g; 50% yield). 1H NMR (400 MHZ, DMSO) 6 = 9.10 (s, 1H), 8.49 (s, 2H), 8.30(s,1H), 7.30—7.32 (d, J= 10 Hz, 1H), 6.07-6.09 (d,J=10Hz,1H), .68 (d,1H), 3.48 (s,1H), 3.35-3.45 (m,1H), 3.29-3.30 (d,1H), 2.28 (3,1H), .49 (m,2H),1.22(s,1H); LCMS calcd. for C13H16F6N50 [M+H]+ 432.34, found 432.19 at 2.1 min retention time. -178— Example 58 Synthesis of (Z)-tert-butyl 6-(3-(3-(3,5-bis(triflu0r0methyl)phenyl)-1H-1,2,4- triazol-l-yl)acryloyl)-2,6-diazaspiro[3.4]octane-Z-carboxylate N70 N/Nf—>*N N T3P DIPEA N N\Iéo EtOAc XO F3C :0 (Z)(3—(3,5-Bis(trifluoromethyl)phenyl)-1H—1,2,4—triazolyl)acrylic acid (0.3 g, 1 eq.) dissolved in ethylacetate (20 mL) and cooled to —70 0C where tert—butyl-2,6- diazaspiro[3.4]octanecarboxylate (0.22 g, 1.2 eq.), T3P (50% in EtOAc) (0.61 mL, 1.2 eq.), followed by DIPEA (0.6 mL, 4 eq) were added. The clear reaction mixture was stirred at -60 °C for 1h, concentrated under reduced pressure (25°C, 20 mm Hg) to afford the crude product, which was d by tography (3-4% Methanol in DCM) to yield (Z)-tert- butyl 6-(3 ~(3 -(3 ,5 —bis(trifluoromethyl)phenyl)— 1 H— 1 ,2,4-triazol— l —y1)acryloyl)-2,6- diazaspiro[3.4]octane—2-carboxylate (0.2 g; 43% yield).
Synthesis of (Z)(3-(3,5-bis(trifluoromethyl)phenyl)—lH-l,2,4-triazol—1-yl)—1- (2,6-diazaspir0[3.4]0ctanyl)pr0pen—1-0ne 2,2,2-triflu0r0acetate CI ,NWNUC 0 F3C N/> NYC [i NH O F3C /> TFA, DCM N ———-——-—> CFs CF3 (Z)—tert-Butyl 6—(3—(3—(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol y1)acryloyl)—2,6-diazaspiro[3.4]octanecarboxy1ate (0.05 g) was dissolved in DCM (20 mL), cooled to 0 °C and CF3COOH (0.5 mL) was added. The reaction mixture was stirred at room ature for 4 hi, concentrated under reduced pressure (35°C, 20 mmHg) to give (Z)(3~(3,5—bis(trifluoromethy1)pheny1)—lH-l,2,4—triazol—1-yl)-1—(2,6—diazaspiro[3.4]octan- 6-yl)prop-2—en—1—one 2,2,2-trifluoroacetate (0.03 g, 95 % yield). 1H NMR (400 MHZ, DMSO) 5: 9.25 (s, 1H), 8.77 (brs, 1H), 8.59 (s, 2H), 8.30 (s, 1H), .37(d, 1H, J: 10.4 Hz), 6.15—6.12(d, J= 10.4Hz, 1H), 3.86—3.65 (brs, 4H), 2.14 (s, 2H), 1.49 (s, 2H), 0.85- ~179— 1.23 (m, 2H); LCMS calcd. for C19H13F6N5O [M+H]+ 446.36; found 446.12 at retention time 2.161 min.
Example 59 O S F3C CN F C Lawesson's F30 H202 NH2 NH2 reagent ___, CI 0| CI K2003 CFs CF3 CF3 NH2NH2H20 HCOOH ,, ~o< N’N>Hw F30 N’ If? F DABCO N F3C /> * N Cl _ F Cl | N:>< O F CF3 sis of r0-3,5-bis(trifluor0methyl)benzamide F3C CN F c3 H202 NH2 -—-——-—> 0‘ K2C03 CI CF3 CF3 4—Chloro-3,5-bis(trifluoromethyl) benzonitrile (1 g, 1.0 eq.) was dissolved in DMSO (10 mL). K2C03 (0.55 g, 1.1 eq.) and H202 (1 mL) were added to the reaction mixture and stirred at room temperature for 2-3 h, then poured into ice water (20 mL). The precipitate formed was collected by filtration and washed with petroleum ether to afford 1.0 g of crude product (90% yield), which was used without further purification in the next step.
Synthesis of 4-chlor0—3,5-bis(triflu0romethyl)benzothioamide o S F C Lawesson‘s F3C 3 NH2 NH2 reagent CI CI CF3 CF3 4-Chloro-3,5-bis(trifluoromethyl)benzamide (1.2 g, 1.0 eq.) was dissolved in toluene (20 mL) and Lawesson’s reagent (3.32 g, 2.0 eq.) was added. The reaction e was stirred at 90 0C for 8 h then d. The filtrate was poured into water. The compound was extracted with EtOAc (3X100 mL). The combined organic layers was washed with —180— brine (3x50 mL), dried over NaZSO4, filtered, and concentrated under reduced re (25°C, 20 mmHg) to afford 2 g of 4-chloro-3,5-bis(trifluoromethyl)benzothioamide (95% yield), which was used in the next step with no further purification.
Synthesis of 3-(4-chloro-3,5-bis(triflu0romethyl)phenyl)—1H—1,2,4—triazole s N’NH F3C F c /> NH2 N IHZO —~—————> C' 9' HCOOH CF3 CF3 4-Chloro-3,5—bis(trifluoromethy1)benzothioamide (lg, 1.0 eq.) was dissolved in DMF (10 mL). Hydrazine e (0.32 g, 2.0 eq.) was added and the reaction mixture was stirred at room temperature for 1 h. Formic acid (3 mL) was then added and the reaction mixture was heated to 90 °C for 2-3 h. The reaction mixture was poured into saturated sodium bicarbonate solution slowly maintaining the temperature at 25 -3 0°C. The desired t was extracted with EtOAc (3X50 mL). The combined organic layers was washed with brine (50 mL), dried over Na2804, filtered, and concentrated under reduced pressure (25°C, 20 mmHg) to afford 1.5 g of crude product, which was purified by chromatography (40% ethyl acetate in Hexane) to afford 0.150 g of 3-(4-chloro—3,5- ifluoromethyl)phenyl)-lH—l ,2,4-triazole (15% yield) Synthesis of (Z)—3-(3-(4-chlor0-3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol- 1-yl)(3,3-difluoroazetidinyl)propenone I /> N’N F F3C DABCO N I /> O F30 N '/—>/*N:><— F CF3 O F 3-(4—Chloro-3,5-bis(trifluoromethyl)phenyl)-lH—l,2,4-triazole (0.1 g, 1.0 eq.) was dissolved in DMF (5 mL). DABCO (0.07lg, 2 eq.) was added and stirred for 30 min. (Z)-l- (3,3-difluoroazetidinyl)—3-iodoprop-2—en—l—one (0.095 g, 1.1eq.) was then added. The reaction mixture was d at room temperature for 5 h and then poured into iced water (50 mL). Product was extracted with EtOAc (3X15 mL). The combined organic layers was washed with brine, (20 mL), dried over , filtered, and concentrated by rotary evaporation (25 °C, 20 mmHg) to afford 0.150 g of crude product, which was purified by chroamotgraphy to obtain (Z)-3—(3—(4-chloro-3,5-bis(trifluoromethy1)phenyl)—1H-l,2,4- -181— triazol-l-yl)—1-(3,3—difluoroazetidin—l-yl)prop—2-en—l-one (0.004g, 3% yield). 1H NMR (400 MHz, DMSO) 8 = 9.32 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 7.47-7.49 (d, J= 10.4 Hz, 1H), 6.00—5.04 (d, J: 10.4 Hz, 1H), 4.55—4.58 (m, 2H), 4.33-4.36 (m, 2H) LCMS calcd for C16H10C1F8N4O [M+H]+: 461.7, Found: 461.14, at 2.99 min retention time. e 60 Synthesis of (Z)(3-(aminomethyl)—3-flu0r0azetidinyl)(3-(3,5- bis(triflu0romethyl) phenyl)-1H-1,2,4~triazolyl)propen-l-one NN/> WNWa g ,2 F N’N7» O / N) O ’ N> O F30 F30 / T3P, DIPEA TFA HN:>(\NHBoc CFa CF3 Synthesis of tert—butyl ((3 -fluoroazetidin-3 -yl)methyl)carbamate O O MO We ——~ MEN ~5< NaHSOs DAST CN NaBH4Ow o O o Q Boc ide N’BOC HNOCHF N:><:\NHBoc Pd(OH)2 Ethanol O Synthesis of 1-benzhydryl—3 -hydroxyazetidinecarbonitrile N o __. My KCN CN O 0 1-Benzhydrylazetidin—3~one (50 g, 210 mmol) was dissolved in methanol (250 mL).
KCN (15 g, 316 mmol) and NaHSO3 (32.86 g, 316 mmol) was added at 25 °C and the reaction mixture was stirred at rt for 16 h. The reaction mixture was acidified with dilute HCl and the t was extracted with ethyl acetate (200 mL x 3). Organic layers were -182— washed with brine, dried over anhydrous NaZSO4 and concentrated under reduced pressure to obtain 45.0 g crude product, which was purified by chromatography to give 10.5 g of 1- benzhydrylhydroxyazetidinecarbonitrile (18% . 1H NMR (400 MHz, CDC13, ppm) 6 = 7.5-7.2 (m, 10 H); 4.43 (s, 1H); 3.73—3.71 (d, 2H); 3.27-3.24 (t, 2H). sis of 1-benzhydryl—3-flu0r0azetidinecarbonitrile O O (>32: N©<.C” O O 1—Benzhydryl—3~hydroxyazetidine—3~carbonitrile (10.5 g, 39.7 mmol) was dissolved in DCM and cooled to -78 °C. DAST (12.80 g, 79.45 mmol) was slowly added and the reaction mixture was allowed to warm to rt where it was further stirred for 5 h. Reaction e was cooled to 0 °C and transferred into 500 mL NaHC03 solution and extracted with (100 mL x 3) DCM. Combined organic layers were washed with brine, dried over Na2804, and concentrated under reduced pressure to obtain 15.0 g of crude product, which was purified by chromatography to obtain 6.0 g of 1—benzhydryl-3 -fluoroazetidine-3—carbonitrile. (57.14% yield). 1H NMR (400 MHz, CDC13, ppm) 5 = 7.6-7.1 (m, 10 H); 4.46 (s, 1H); 3.9-3.6 (m, 2H); 3.5-3.2 (m, 2H).
Synthesis of (1-benzhydry1—3—flu0r0azetidinyl)methanamine F NaBH4O My CN NiCI2 1-Benzhydrylfluoroazetidine—3-carbonitrile (0.5 g, 1.88 mmol) was dissolved in ol (25 mL). NaBH4 (0.49 g, 13.14 mmol) and NiClz (0.044 g, 0.34 mmol) were added at 0 °C and the reaction mixture was stirred at rt for 14 h. The solids formed were removed by filtration and and the e was concentrated under reduced pressure. The crude product was purified by chromatography (0-5% methanol—DCM) to give 0.15 g of (1- benzhydryl-3 -fluoroazetidinyl)methanamine (3 0% yield). 1H NMR (400 MHz, CDC13, ppm) 5 = 7.46-7.19 (m, 10H); 4.48 (s, 1H); 3.38—3.34 (t, 2H); 3.26—3.09 (m, 4H). sis of tert-butyl (1-benzhydrylflu0r0azetidinyl)methylcarbamate: ‘ 800 ide NOQNH (1—Benzhydryl—3—fluoroazetidin-3—y1)methanamine (0.5 g, 1.85 mmol) was dissolved in DCM (20 mL) and Boo anhydride (0.20 g, 0.924 mmol) was added at 0 °C. The reaction mixture was allowed to warm to rt, at which temperature it was stirred for 4 h. The reaction mixture was concentrated under reduced pressure to afford 0.5 g of tert-butyl (1— benzhydrylfluoroazetidin—3-yl)methylcarbamate (100% yield). 1H NMR (400 MHz, CDC13, ppm) 5 = 7.44-7.19 (m, 10H); 5.32 (s, 1H); 4.84 (s,1H); 3.69-3.61 (m, 2H); 3.38— 3.033 (m, 2H); 3.18-3.10 (m, 2H).
Synthesis of tert-butyl (3-flu0roazetidin-3—yl)methylcarbamate NXNH Pd(OH)2 HN NH F B00 0 tert—Butyl (1—benzhydrylfluoroazetidin—3-yl)methylcarbamate (0.6 g, 1.35 mmol) was dissolved in ethanol and Pd(OH)2 (0.38 gm, 2.7 mmol) was added. The reaction mixture was d at It for 14 h under H2 atmosphere. The solids were removed by ion and the filtrate was concentrated under reduced re to afford 0.2 g of tert—butyl (3— zetidin-3—yl)methylcarbamate (66% yield).
Synthesis of (Z)-tert-butyl (1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4- triazol—l-yl)acryloyl)flu0roazetidin-S-yl)methylcarbamate .~ Boc N’NWOHI N’NWN/ %F / N) 0 T3PDIPEA / /> O F30 F30 HNTVHBoo N CFS CFS (Z)(3-(3,5—Bis(trifluoromethyl)phenyl)—1H-1,2,4-triazol—1-yl)acrylic acid (0.20 g, 0.56 mmol) was dissolved in DCM (10 mL). The reaction mixture was cooled to -60 °C, at which temperature tert—butyl(3—fluoroazetidinyl)methylcarbamate (0.127 g, 0.62 mmol), was added, followed by T3P (50% in EtOAc) (0.434 g, 0.67 mmol). DIPEA (0.144 g, 1.11 mrnol ) was then introduced slowly. The clear reaction mixture was stirred at -60 °C for a further 45 min. The reaction e was concentrated under d pressure to obtain crude t, which was purified by column chromatography (0-15% ethyl actetate- hexane) to afford 150 mg of (Z)-tert-butyl(l-(3-(3—(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4- triazol-l-y1)acryloyl)—3-fluoroazetidin—3-yl)methylcarbamate (Yield 50%). 1H NMR (400 MHZ, CDClg, ppm) 8 = 9.7 (s, 1H); 8.63 (s, 2H); 7.94 (s,1H); 7.24—7.21 (d, J=10.8 Hz, 1H); 5.67—5.64 (d, J: 10.8, 1H); 4.41-4.16 (m, 4H); 3.76 - 3.54 (m,3H).
Synthesis of (Z)(3-(aminomethyl)—3-flu0roazetidinyl)(3—(3,5- bis(trifluoromethyl) phenyl)-1H-1,2,4-triazol—1-yl)pr0pen-1—0ne ”Mfg/N, yF N’NWNWNH,, 2 F3C N/ / o F3C /> CF3 (Z)-tert—Butyl(l-(3-(3-(3,5~bis(trifluoromethyl)phenyl)-1H—l,2,4-triazol—1— yl)acryloyl)-3 -fluoroazetidinyl)methylcarbamate (0.15 g, 0.279 mmol) was dissolved in DCM (10 mL) and TFA (0.1 mL) was added at 0 °C. The reaction e was stirred at rt for 4 h and trated under reduced re to afford 0.5 g of crude product, which was purified by chromatography (0-5% methanol in DCM) to afford 15 mg of (Z)—l-(3— (aminomethyl)—3-fluoroazetidin— 1 -yl)-3 -(3 -(3 ,5 —bis(trifluorornethyl)phenyl)- 1 H—l ,2,4—triazol- 1-yl)prop—2-en-l-one (Yield 15%). 1H NMR (400 MHZ, CDC13, ppm) 5 = 9.4 (s,1H); 8.54 (s, 2H); 8.32 (3,1H); 8.13 (s, 3H); 7.49-7.46 (d, J=10 Hz,1H);6.0-5.97(d, J=10 Hz, 1H); 4.41-4.06 (m, 4H); 3.49 - 3.36 (m, 3H). LCMS calcd for C17H15F7N5O [M+H]+ 438.3, found: 438.19 (retention time 2.298 min).
Example 61 Synthetic scheme for methyl 3-fluoroazetidine-3—carb’oxylate hydrochloride Synthesis of 1-benzhydrylfluoroazetidinecarboxylic acid —l85- 0 A3N O 1—Benzhydry1fluoroazetidine-3—carbonitrile (3.5 g, 1.0 eq.) was dissolved in ethanol, and aq. NaOH solution (1N) was added. The reaction mixture was refluxed for 5 h, then was allowed to cool to room temperature, at which temperature, it was acidified with dilute HCl (pH~3) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced re to obtain 0.5 g of hydrylfluoroazetidinecarboxylic acid (13% yield).
The product was used in the next step without further purification.
Synthesis of 3-flu0r0azetidinecarboxylic acid hydrochloride 0 HCI H2 HN OH —. 0 “SA O“ Pd<OH)2 F O l F 1-Benzhydrylfluoroazetidine—3-carboxylic acid (0.5 g, 1.0 eq.) was dissolved in ethanol. Pd(OH)2 (0.5 g) was added and the reaction mixture was stirred for 14 h at room temperature under H2 atmosphere. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford 150 mg of 3-fluoroazetidinecarboxylic acid hydrochloride (30% . The product was used in the next step without further purification.
Synthesis of methyl 3-flu0r0azetidinecarb0xylate hydrochloride o HCI HNM 30012 —_—> OH HNSKZE / F Methanol roazetidinecarboxy1ic acid hydrochloride (0.10 g, 8.4 mmol) was dissolved in methanol (2 mL) and cooled to 5 OC. Thionyl chloride (0.05 g, 4.2 mmol) was added dropwise. The reaction e was heated at 65 °C ght and concentrated under reduced pressure to afford methyl 3-fluoroazetidinecarboxylate hydrochloride. The product was used in the next step without further purification.
Synthesis of (Z)—methyl 1-(3-(3—(3,5-bis(trifluoromethyl)phenyl)—lH-l,2,4-triazol- 1-yl)acryloyl)—3-flu0r0azetidine-S-carboxylate —186- HCI O / 0 o ’ /> O F30 F N N . N’N7;» Of F ’ O FC /> T3P,D|PEA 3 N (Z)(3—(3,5—Bis(trifluoromethyl) )-1H-1,2,4-triazol-1—yl)acrylic acid (0.20 g, 1.0 eq.) was dissolved in DCM (4 mL). The reaction mixture was cooled to -60 °C, at which temperature methyl 3-fluoroazetidine—3-carboxylate hydrochloride (0.09 g, 1.2 eq.) and T3P (50% in EtOAc) (0.427g, 1.2 eq.) were added, followed by DIPEA (0.146g, 2 eq.). The clear reaction mixture was stirred at -60 °C for 45 min and concentrated under reduced pressure (25 0C, 20 mm Hg) to afford the crude product, which was purified by chromatography (20- % ethyl acetate in hexane) to give (Z)-methyl(3 -(3 -(3,5-bis(trifluoromethyl)phenyl)~ 1H—1,2,4-triazol—1-yl)acryloyl)fluoroazetidine—3-carboxylate. (40 mg; 24% yield). 1H NMR (400 MHZ, CDCL3) 5 9.51 (S, 1H), 8.62 (s, 2H), 7.96 (s, 1H), 7.20—7.18 0.8, 1H), 5.70-5.68 (d, J=10.8Hz, 1H), 4.15-3.82 (m, 4H), 3.82 (s, 3H).
Example 62 Synthesis of (Z)-1—(3—(3-(3,5-bis(trifluor0methyl)phenyl)—1H-l,2,4-triazol—l- yl)acryloyl)—3-flu0roazetidine-3—carb0xylic acid 0 (I) N’NWN, of r 53““ F N’NWN F / /> O O F3C ’N/> FSC N LiOH CF3 CFs (Z)—Methyl 1-(3-(3-(3,5—bis(trifluoromethyl)phenyl)—1H-1,2,4—triazol-1—yl)acryloyl)—3- fluoroazetidine-3—carboxylate (0.01 g, 1.0 eq.) was dissolved in olzwater (0.2 mL, 1:1), and LiOH (1.0 mg, 1.0 eq) was added. The reaction e was stirred at room temperature for 2 h. The reaction mixture was quenched with 10 mL of water and acidified with dilute HCl to pH 2-3. The aqueous layer was extracted with ethyl acetate (10 mL x —1 87- 3). The ed organic layers were then washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 0.002 g of (Z)—l—(3-(3-(3,5- bis(trifluoromethyl)phenyl)~ 1 H— l ,2,4—triazol- l -yl)acryloyl)—3 —fluoroazetidine-3 -carboxylic acid. Yield (20.83%). 1H NMR (400 MHZ, CDCL3) 5 8.92 (S, 1H), 8.54 (s, 2H), 8.29 (s, ‘ 1H), 7.45-7.42(d, J=10.4, 1H), 6.00-5.98 (d, J=10.4Hz, 1H), 3.73 (m, 4H).
Example 63 4 t N’N/IQWOH N/ \ I N) HN . \ N F3C HCI F N’ r? F ’ N) T3P,D|PEA Synthesis of 1-(1-benzhydrylfluoroazetidin-3—yl)-N,N—dimethylmethanamine NH2 CHZO NaCNBH3 ONSFKW/ (l-Benzhydryl—3—fluoroazetidinyl)methanamine (0.5 g, 1.0 eq.) was dissolved in methanol and HCHO (0.138 g, 2.5 eq.) and 3 (0.47g, 4.0 eq.) were added at 0 °C.
The reaction e was stirred for 14 h at room temperature, then quenched with aqueous ammonium chloride solution and extracted with DCM. The organic layer was washed with brine, dried over sodium e, and concentrated under reduced pressure to afford 150 mg of 1-(1-benzhydrylfluoroazetidin—3-yl)-N,N—dimethylmethanamine , which was used in the next step Without further purification.
Synthesis of 1-(3-flu0roazetidinyl)-N,N-dimethylmethanamine I H2 0 NSH Pd(OH)2 HNS:\P/ Ethanol 1-(1-Benzhydryl—3—fluoroazetidin—3—y1)-N,N—dimethylmethanamine (0.6 g, 1.0 eq.) was ved in ethanol. Pd(OH)2 (0.6g) was added. The reaction mixture was stirred for 14 h at room temperature under H2 atmosphere. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford 300 mg of l—(3 -fluoroazetidin y1)-N,N—dimethylmethanamine (68% , which was used in the next step without further purification.
Synthesis of (Z)(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazolyl)-l-(3- ((dimethylamino)methyl)fluor0azetidin—1-yl)pr0penone NINV/OH \ /> HNQ(\ , X F30 N/ F N WNW/N F \ / > O —> FSC N/ CF3 T3P,D|PEA (Z)(3-(3,5—Bis(trifluoromethy1) phenyl)-1H-1,2,4-triazolyl)acry1ic acid (0.50 g, 1.0 eq.) was dissolved in DCM (10 mL). The on mixture was cooled to —60 °C, at which temperature 1-(3 -fluoroazetidin—3-yl)—N,N—dimethylmethanarnine (0.22 g, 1.2 eq) and T3P (50% in EtOAc) (1.08 g, 1.2 eq.) were added, followed by DIPEA (0.36 g, 2 eq.). The clear reaction mixture was stirred at -60 °C for 45 min. The reaction mixture was concentrated under reduced pressure (25 °C, 20 mm Hg) to afford the crude product, which was d by chromatography to give 12 mg of (Z)-3—(3—(3,5-bis(trifluoromethyl)phenyl)- 1H- 1 ,2,4-triazoly1)— 1 -(3 -((dimethylamino)methyl)—3 -fluoroazetidinyl)propenone (3 % yield). 1H NMR (400 MHz, CDClg) 8 = 9.75 (s, 1H), 8.62 (s, 2H), 7.94 (s, 1H), 7.24- 7.21 (d, J= 10.8Hz, 1H), 5.69-5.66 (d, J: 10.8 Hz, 1H), 4.37—4.25 (m, 2H), .15 (m, 2H), 2.82-2.76 (d,2H), 2.35 (5,2,35,1H); LCMS for C19H19F7N50 [M+H]+ 466.4 found 466.3 at retention time 2.263 min Example 64 F30 0 0m ———-——-——-——-—> F — F3C 0 CF3 F>CN{\I NaH,DMF THF (5 mL) and sodium hydride (0.08 g, 2.02 mmol) were added under nitrogen here to a 25-mL sealed tube equipped with septum. The reaction mixture was cooled to 0 °C and 4—(3, 5—bis(trifluoromethyl)pheny1)pyrrolidinone (0.3 g, 1.01 mmol) was added portionwise, maintaining a temperature below 0 °C. The on mixture was refluxed for 3.5 h and later cooled to -10 ° C. To this reaction e, (Z)—isopropyl 3-iodoacrylate (0.33 ° C for g, 1.21 mmol) was added dropwise. Reaction e was further d at —10 another 30 min. The reaction mixture was transferred into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with saturated brine solution (50 mL), dried over anhydrous NaZSO4, filtered, and concentrated under d pressure to obtain crude compound. The crude material was purified by column chromatography (silica 60/ 120, EtOAc-hexane gradient) and again purified by preparative TLC using 60% EtOAc- hexane as mobile phase to afford 0.015 g (Z)-4—(3,5—bis(trifluoromethyl)phenyl)(3-(3,3- ‘ oazetidin—l—yl)-3—oxoprop-1—enyl)pyrrolidin—2-one (Yield 3.3%). 1H NMR (400 MHZ, CDC13) 5 ,7.83(s, 1H); 7.73(s, 2H); 7.16-7.19 (d, J=10.4Hz, 1H); 5.08-5.11 (d, J=10.4Hz, 1H); 4.43-4.51 (m, 3H); 4.30—4.36 (t, J=12Hz, 2H); 3.96—4.01 (m, 1H); 3.75-3.79 (m, 1H); 2.95—3.02 (m, 1H); 2.68—2.75 (m, 1H); LCMS for C13H15F8N202 [M+1]+ 442.3 found 443.14 at RT 2.932 min.
Example 65 Synthesis of (Z)(2-(3,5—bis(trifluor0methyl)phenyl)—1H-pyrr01—1-yl)—1-(3,3- difluoroazetidinyl)propen—1-0ne: —190- F30 Br f N H/THFa FsC /\ \ MDC,FTEA 0% E ZnCI2/ Pd(OAc)/ CF3 2, 2— (dicyclohexyl phosphino)biphenyl FsCm 20LiOH QDQLNkFTPDIPEAlngOH HN:><F CF3 Synthesis of 2-(3,5-bis(triflu0romethyl)phenyl)-lH-pyrrole: 3 QC Br U NaH/THF F30 /N\ fl H ZnCI2/Pd(OAc)/ CF3 . 22-(d Icyclohexyi phosphino)biphenyl F3C(1) A 500 mL 3—neck round-bottomed flask was d with a solution of pyrrole (5.15 g, 76.79 mmol) in THF (120 mL) at rt and cooled to 0 °C. NaH( 2.21 g, 92.12 mmol) was added portionwise and the reaction mixture was stirred at 0 °C for 1 h. To this reaction mixture, ZnClz (10.4 g, 77 mmol) was added and stirred at 0 °C for l h. 1—Bromo-3,5— bis(trifluoromethyl)benzene (5.0 g, 17.0 mmol) was added and reaction was properly degassed for 10 min and palladium diacetate (0.172 g, 0.76 mmol) and 2-(dicyclohexy1 phosphino)biphenyl (0.269 g, 0.76 mmol) were added and reaction was d for 48 h.
Reaction mixture was transferred into water (100 mL) and extracted with EtOAc (3 x 300 mL) and the combined organic layers were washed with saturated brine solution (3 X 150 mL), dried over MgSO4, filtered, and trated under reduced pressure to afford 7 g of crude 2-(3,5-bis(trifluoromethyl)phenyl)-1H—pyrrole which was d by chromatography to afford 0.8 g of pure product. LCMS calcd for: C12H6F6N [M-H]' 278.18 found 278.19 (retention time 3.383 min) Synthesis of (Z)-is0propyl 3-(2-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrrol yl)acrylate: I \ /N\ FC3 O k F30 MDCTEA N \ o F30(1) o (2) A 100 mL 3-neck round-bottomed flask was charged with a solution of 2-(3,5- bis(trifluoromethyl)pheny1)-lH—pyrrole (1) (0.7 g, 2.50 mmol)) in DCM (14 mL) and reaction mixture was cooled to 0 °C. TEA (0.379 g, 3.76 mmol) and isopropyl acrylate (0.421 g, 3.76 mmol) were added simultaneously at 0 °C and stirred for 1.5 h. Reaction mixture was transferred into water (50 mL), extracted with EtOAc (3 x 20 mL) and ed organic layers were washed with saturated brine solution (3 x 50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford 1.5 g of crude compound which was purified by column chromatography to obtain 0.150 g of (Z)—isopropyl 3—(2-(3,5—bis(trifluoromethyl)phenyl)-lH—pyrrol—l—yl)acrylate (Yield 15 %). 1H NMR (400 MHz, CDCl3, ppm) 5 =1.279—1.318 (m, 6H); 5.106 (m, 1H); 5.521—545 (d, J=9.6 Hz, 1H); 6.377 (s, 1H); 6.494 (s,1H); 6.643-6.763 (d, J=10 Hz, 1H); 7800—7831 (m,3H): LCMS calcd for: F6N02 [M+H]+ 392.31 found 392.4 (retention time 3.820 min).
Synthesis of (Z)—3-(2-(3,5-bis(trifluoromethyl)phenyl)—1H-pyrrol—1-yl)acrylic acid (3): F3C N\@Ok0 LiOH THF/HZO CFs (2) (:QLOH A 100 mL 3-neck round-bottomed flask was charged with a solution of (Z)- isopropyl 3—(2-(3,5-bis(trifluoromethyl)phenyl)—lH-pyrrol—1-yl)acrylate (0.15 g, 0.383 mmol) in THF (10 mL) and water (10 mL) and stirred at rt. To this reaction mixture, LiOH.H20 (0.027 g, 1.15 mmol) was added and reaction was further stirred for 16 h. Reaction mixture was acidified by dilute HCl and ted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine solution (3 x 50 mL), dried over MgSO4, filtered, and concentrated under reduced re to afford 0.15 g of (Z)-3—(2-(3,5- bis(trifluoromethyl)phenyl)-lH—pyrrol—l—yl)acrylic acid (3) (Yield: 88%) which was used for next step without ation. LCMS calcd for: C15H10F6N02 [M+H]+ 350.23 found 350.39 ( retention time 3.129 min). -192— sis of (2-(3,S-bis(trifluoromethyl)phenyl)—1H-pyrrolyl)(3,3- difluoroazetidin-l-yl)pr0penone: I \ l \ @OH T3P,D|PEA \ NQ<F (3) .HCI F ( ) A 100 mL 3-neck round-bottomed flask was charged with a solution of (Z)(2— (3,5-bis(trifluoromethyl)phenyl)-lH—pyrrol—l—y1)acrylic acid (0.15 g, 0.429 mmol) in DCM (10 mL) and cooled to 0 °C and 3,3-difluoroazetidine hydrochloride (0.052 g, 0.558 mmol) was added dropwise. T3P (50% in EtOAc) (0.163 g, 0.514 mmol) was added dropwise followed by DIPEA (0.11 g, 0.858 mmol) and the reaction e was stirred for 1 h at 0 °C. The reaction mixture was concentrated under reduced pressure to afford 0.2 g of crude product which was purified by column chromatography (60/120 silica gel, 0—3% ethylacetate : n-hexane gradient) to afford 0.01 g of (Z)(2—(3,5— bis(trifluoromethyl)phenyl)- 1 H-pyrroly1)(3 ,3 roazetidin- 1 —yl)propenone (Yield 6.6%). 1H NMR (400 MHz, CDC13, ppm) 8: 4307—4425 (m, 4H); 5523—5443 ((1, J=10 Hz, 1H); 6387-6404 (t, 1H); 6500—6509 (t, 1H); 6.765-6.79O (d, J=10 Hz, 1H); 7.715 (t, 1H); 7.811-7.845 (m, 3H). LCMS calcd for: C18H13F8N20 [M+H]+ 435.29 found 425.49 (retention time 3.292 min).
Example 66 Synthesis of (Z)(3-(3,5-bis(trifluoromethyl)phenyl)—1H-l,2,4-triazolyl)—1-(4- hydroxypiperidin-l—yl)pr0penone N’NW/OH N/N/—>—NC>~OH I 0 F30 /> F30 0 N HNC>—OH /N/) T3P, DIPEA (Z)-3—(3—(3,5—Bis(trifluoromethy1)phenyl)—1H—1,2,4—triazol-1—y1)acrylic acid (0.20 g, 1.0 eq.) was dissolved in DCM (10 mL). Piperidin—4—ol (0.07 g, 1.2 eq.) was added and the reaction mixture was cooled to -60°C. T3P (propyl phosphonic anhydride) (0.40 mL, 1.2 eq.) and DIPEA (0.19 mL, 2.0 eq.) were added. Reaction mixture was stirred for 30 min. The on mixture was then transferred into water (50 mL) and extracted with DCM (2X50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced re (25°C, 20mmHg) to afford crude product, which was purified by chromatography (0-3% MeOH in DCM) to obtain 0.025 g of (Z)-3 ~(3 —(3 ,5 —bis(trifluoromethyl)phenyl)- 1 H- 1 ,2,4-triazol-1 -yl)- l droxypiperidin yl)propen-l-one (Yield:10%). 1H NMR (400 MHZ, CDC13) 8 ,8.75 (s,lH), 8.58 (s, 2H), 7.93 (s, 1H), 7.08—7.11 (d, J=10.4 Hz,lH) ,6.01~6.04 (d, J=10.4Hz, 1H), 4.02-4.14 (m, 1H), 3.98-4.01 (m, 1H), 3.78-3.85 (m, 1H), 3.47-3.52 (s, 1H), 3.32—3.38 (s, 1H), 1.96 (s, 1H), 1.83 (s, 1H), 1.27 (s, 1H), 0.90 (s, 1H); LCMS for Chemical Formula: C13H17F6N402 [M+H]+ 435.34 found 435.24 at RT 2.408 min.
Inhibition ofNuclear Export The y of exemplary compounds of the invention to inhibit CRMl-mediated nuclear export was assessed in a ReVGFP assay. Rev is a protein from human immunodeficiency virus type 1 (HIV-1) and contains a nuclear export signal (NES) in its C— terminal domain and a nuclear localization signal (NLS) in its N-terminal domain. Nuclear export of Rev protein is dependent on the classical NES/CRMl pathway le et a1. 1997).
Nuclear accumulation of Rev can be observed in cells treated with specific inhibitors of CRMl, such as LMB (Kau et a1. 2003).
In this assay, evGFP cells were seeded onto clear-bottomed, black, 384-well plates the day before the experiment. Compounds were serially diluted 1:2 in DMEM, starting from 40 uM in a separate, 384-well plate, and then transferred onto the cells. The cells were incubated with compound for about 1 hr before fixation with 3.7% formaldehyde and nuclei ng with Hoechst 33258. The amount of GFP in cell nuclei was measured and the IC5o of each compound was determined (Kau et al. 2003). nds of the invention are considered active in the Rev-GFP assay outlined above if they haVe an IC50 of less than about 10 uM, with the most preferred compounds having an IC5o of less than about 1 uM.
The results of the RevGFP assay appear in Table 3.
Cell Proliferation Assay The ter 96® AQueous One Solution cell proliferation assay (Promega) was used on MM. 1 S multiple myeloma cell line to study the cytotoxic and cytostatic properties of the compounds. The assay is based on the cleavage of the tetrazolium salt, MTS, in the ce of an electron—coupling reagent PES (phenazine ethosulfate). The MTS tetrazolium nd is bioreduced by cells into a colored formazan product that is soluble in tissue -1 94- culture medium. This conversion is presumably accomplished by NADPH or NADH produced by dehydrogenase enzymes in metabolically active cells. Assays are performed by adding a small amount of the CellTiter 96® AQueous One solution reagent ly to culture wells, incubating for 1—4 hours and then recording the ance at 490nm with a 96-well plate . The absorbance revealed directly correlates to the cell number and their metabolic activity.
The cells were seeded at 5x103 to 1.5x104 cells (depending on cell type) in each well of a 96-well plate in 100 uL of fresh culture medium and adherent cells were allowed to attach overnight. The stock solutions of the nds were diluted in cell culture medium to obtain eight concentrations of each drug, ranging from 1 nM to 30 MM and DMSO at less than 1% v/v was used as a negative control. The resulting drug solutions were transferred onto the cells. After 72 h of treatment, 20 ul of CellTiter 96® AQueous reagent was added into each well of the 96-well assay plates and the plate was incubated at 37°C for 1—4 hours in a humidified, 5% C02 atmosphere. Then the absorbance of each well was recorded at 490 nm using a 96-well plate reader. In most cases, the assay was performed in triplicate and the results were presented as half l inhibitory concentration (IC50). Optical density versus compound concentration was plotted and ed using non-linear regression equations (IDBS XLfit) and the IC50 for each compound was calculated. cokineiic (PK) Assay and BrainxPlasma Ratio Determination Pharmacokinetics (PK) play an increasing role in drug discovery and development.
Pharmacokinetics is the quantitative study of the time course of drug absorption, distribution, metabolism and/or excretion. When a drug is administered, it distributes y from its administration site into the ic blood circulation. One measure of the extent of a therapeutic agent’s distribution is the area under the plasma concentration-time curve (AUC), calculated to the last measured concentration (AUCt) and extrapolated to infinity (AUCInf).
AUC is thus a useful metric to quantitate drug re.
Generally, the higher the exposure of a therapeutic agent, the r the effects of the agent. However, high exposure of a therapeutic agent may have deleterious effects on n tissues such as the brain. While the blood-brain r (BBB), a protective network consisting of tight junctions between endothelial cells, restricts the diffusion of hydrophilic and/or large molecules, drugs with high AUC are still capable of ating the BBB and/or cerebrospinal fluid. Such penetration can lead to unwanted side effects. Current drug -1 95— discovery efforts are aimed, in part, at striking a balance between maximizing drug exposure (e.g., AUC), while zing brain penetration.
The brain to plasma (B:P) ratio is one method of quantifying the relative distribution of a therapeutic agent in brain tissue to that in ation and, as such, provides one indication of the brain penetration of a given therapeutic agent. A high brain to plasma ratio is preferred when targeting diseases zed in the central nervous system (CNS), including the brain and the ospinal fluid. However, a lower brain to plasma ratio is generally preferable for non-CNS eutic agents to minimize brain penetration and avoid potential side s caused by unwanted accumulation of the therapeutic agents in the brain and CNS tissue.
AUC. Blood was collected from mice (N = 3) to contribute to the total of 10 time points (pre-dose, 5 min, 15 min, 30 min, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours post dose). Mice were bled on a rotating basis, each mouse contributing 3 time points to the blood collection. At the designated time points, animals were anaesthetized under isoflurane, and approximately 110 uL of blood per time point was collected via retro—orbital puncture into pre-cooled KzEDTA (anti-coagulant) tubes. Blood samples were put on wet ice and centrifuged (2000g, 5 min at 4 °C) to obtain plasma within 30 minutes of sample collection. All samples were stored frozen at approximately -80 °C until analysis. Prior to analysis, samples were mixed with internal rd (dexamethasone) in itrile, vortexed, centrifuged, and supernatant was injected for analysis. Concentration of compounds in plasma was determined using LC—MS—MS instrumentation (API 4000, Triple Quadruple with electrospray ionization; Acuity Ultra Performance Liquid Chromatography column C18, with MeOH and formic acid as organic solvents). AUC values were calculated using WinNonlin Professional 6.2 re package, non-compartmental pharmacokinetic model NCA200.
Brain t0 Plasma (B:P) Ratio. A separate group of mice (N = 3) were dosed (PO at 10 mg/kg) and then sacrificed at the time of maximal plasma concentration ated Tmx at 2 hours post-dose), at which time al plasma and brain tissue were collected. Following collection, brain tissue was rinsed with cold saline, dried on filter paper, weighed and snap- frozen by placing on dry ice. All samples were stored frozen at approximately -80 °C until is. At the time of analysis, brain tissue was homogenized (homogenizing solution PBS, pH 7.4), mixed with internal standard (dexamethasone) in acetonitrile, vortexed, centrifuged, and supernatant was injected for analysis of compound concentration using LC-MS-MS -l96- methodology (API 4000, Triple Quadruple with electrospray ionization; Acuity Ultra Performance Liquid Chromatography column C18, with MeOH and formic acid as organic solvents). Plasma samples were treated with the cal method (except homogenization step) and the concentration of compound in each matrix was calculated based on ted standard curves. The results of the PK assay and the B:P ratio determination are presented in Table 3.
Table 3. Assay Results for Exemplary Compounds of the Invention (A = <l uM; B = 1—10 uM; C = >10 uM; NT = not tested).
AUCInf hr : Rev Cmpd.
Structure (“101186, PO, B/P Export Cytotoxicity NO- 10mpk) [IC50] [EC50] N’NWNyF/ I O F30 /> 1 N 12300 5 A A N’NWNyF, ’ O FC /> 2 N 396 NT NT A N, 72/498 F3C /> 3 N NT NT NT A AUCInf hr ng/mL7% Rev Cmpd.
Structure 18891’0, B/P Export Cytotoxicity 10mm [ICsol [ECSO] JNQVF // F 4 F30 N) NT NT A A N/NF>VN F30 ’N/ o F F NT NT NT B _ F F30 ’N) 0 F 6 NT NT NT B N/N N F m ,Nflor y_ 7 2510 NT NT A ~—' OH DIN)IN Na F30 0 8 9050/\ 3.16 NT A N’N/_>7N9<— F FC / o F 9 3 \ N N' / NT NT NT A -198— AUCInf hr*ng/mL Rev Cmpd.
Structure (mouse, P0, B/P Export xicity lOmpk) [IC50] [EC50] N/N/:>vN/// F3C N/ o / NT NT NT B \ K: N’N NH F30 N/ o 11 O \ 3080/\ NT NT A HNQNyF F c ' 3 UL“, 12 NT NT NT B cr=3 N’N NH F30 ’N) o 13 / NT NT NT B N / CF3 7/” MN NH F30 ’N) o 14 / NT NT NT A N / NT NT NT C WO 19561 ~199- AUCInf hr*ng/mL Rev Cmpd Structure (mouse, P0, B/P Export Cytotoxicity 10m“) [K1501 [ECSO] NT NT NT A NT NT NT B NT NT NT B NT NT NT B NT ‘ NT NT A N’N NH F30 ’N/ o 21 N/ NT NT NT B CF3 7/N 2012/048368 AUCInf hr*ng/mL Rev Cmpd.
Structure (mouse, P0, B/P Export Cytotoxicity N0. ”mp” [10501 [ECSO] — / N/N N ’ N) F30 0 22 o \ NT NT NT B N’NWNO/ F30 N/ O 23 521 NT NT A N’N N F30 ’N/ o 24 N’/ NT NT NT A CI:3 N’N N F30 ’N/ 0 SN /N\ 2640 NT NT A (3F3 N’N NH ’ N) F30 o 26 NT NT NT A CF3 T N/N/an F30 ’N) 0 27 NT NT NT A _.____J __l______ WO 19561 AUCInf hr ng/mL9: Rev Cmpd.
Structure (“101156, PO, B/P Export Cytotoxicity NO' lOmpk) [IC50] [EC50] 28 VN)?NK/>N NT NT NT B “I‘M/QWNHN/W/N _._ 29 NT NT NT B N’N NH F30 N/ o NT NT NT A F30 51;?) o 31 NHL<\;N/N NT NT NT A _ F N/NW} %FN 32 NT NT NT A (3F3 — F N’N N F30 ,NQr % 33 NT NT NT NT wo 2013/019561 PCT/U82012/048368 hr ng/mL9: Rev Cmpd.
Structure (11101156, P0, B/P Export xicity NO- 10mpk) [ICso] [EC50] ///—o>r 9%— F N N 34 NT NT NT NT N’N N F30 Uro} 9% NT NT NT A —— F / N\ F30 o yF 36 H NT NT NT N/T —— F N N 37 H NT NT NT NT N’N N ’ N) 38 NT NT NT NT N/NF} IN) 0 39 NT NT NT NT W0 19561 PCT/U82012/048368 AUCInf hr*ng/mL Rev Cmpd Structure (mouse, P0, B/P Export Cytotoxicity ”mp” [10501 [E0501 NT NT NT A N/ N / NA F 0 9%F 41 NT NT NT NT NW F F30 le o “0% 42 NT NT NT NT — F N N F30 #0} 9% 43 NT NT NT C WO 19561 —204- AUCInf hr ng/mLv': Cmpd.
Structure (11101186, P09 Cytotoxicity 10mpk) [EC50] gym/>2:N F .
.F (“N 44 Fri”; 22‘C3 1 Kirk/k F 9" h ___...
N/N N F30 ’N/ o 45 NT NT NT NT ~ OH N’N N F30 ’N/ o 46 / N NT NT NT NT L_.___—_________ —- F N’N N F30 N/ o 47 / NT NT NT NT N / \\/N — F N’N N F30 N/ o 48 / NT NT NT NT N\ / -205— AUCM hr ng/mL7': Rev Cmpd. ure (mouse, P0, B/P Export Cytotoxicity 10mpk) [IC50] [ECSO] ‘ F ’ xro>rN 49 / N NT NT NT NT N/N N ’ N) F30 0 x05 50 NT NT NT NT —- OH N’N NO< F30 ’N/ o CFa 51 NT NT NT A N’N N NH F30 Rig—o)? QC 52 NT NT NT A N'NWNO/OH F3C ’N) 53 NT NT NT A N; 70W“! F3C N/ 54 NT NT A V NT 2012/048368 —206- AUCInf hr*ng/mL Rev Cmpd Structure (mouse, P0, B/P Export Cytotoxicity N0. 10mpk) [ICsol [EC50] F3C DI’TWNO—COZHO 55 NT ”19—0 5 ¥ 56 NT NT A A NH HCI _ NH2 F3C 51/5/—O>_N9/ 57 NT NT NT A F30 SIN) O NQCNH 58 NT NT NT A A; / :1) o N<><FF 59 NT NT A 0| NT [NZ—2T :3?— F N’N N 60 2 1240/\ 13.3 NT A —207— AUCM hr*ng/mL Rev Cmpd.
Structure 186, P0, B/P Export Cytotoxicity 10mpk) [ICSO] [EC50] 61 NT A 62 NT B 63 NT A 64 NT C N F 65 N NT NT NT C / To} 9? F30 V;$?NC}°H 66 Q} NT NT NT A 2012/048368 Structure Cytotoxicity [ECSO] A tested at 5 mpk. -209— Inhibition 0fHCT-116Xen0grafis In Vivo Mice were inoculated on the hind flank with HCT-l 16 cell line and the HCT-116 xenografts were grown to approximately 150mm3, at which time treatment was initiated.
Treatment groups were as follows: Vehicle SC; 50 mg/kg 5—FU IP, days 1-3; 25mg/kg Compound 1 compound QDXS SC (low dose); 75mg/kg Compound 1 compound QDx5 SC (high dose). is a graph of tumor volume as a percentage of the initial tumor volume versus time and shows that treatment with Compound 1 ted tumor growth, and showed superior anti-tumor effects compared to 5-FU. Compound 1 compound was well-tolerated at both the low and high doses.
Induction 0fp21, p53 and apoptosis in HCT—I 16 Cells HCT-116 cells were incubated with 10 uM Compound 1 for 24 hours, at which time the cells were fixed and stained with antibodies to p21 or p53, or the DNA stain, DAPI.
Subsequent analysis by immunofluorescence showed that both p21 and p53 were trated in the s in cells treated with Compound 1, while cells treated with e only (DMSO) contained only low levels of p53 and p21 in cytoplasm and nucleus.
This experiment showed that Compound 1 inhibited the nuclear export function of CRMl the subcellular zation of the tumor suppressor gene protein p53 and the , altering cyclin dependent kinase inhibitor, p21.
HCT-116 cells were incubated with 10 uM Compound 1 for 2, 4, 6, 16, or 24 hours (indicated in FIGS. 2A and 2B as “2+,” 4+,” etc), or with 10 uM Compound 1 for 22 hours and an additional 1 uM Compound 1 for another 2 hours (indicated in FIGS. 2A and 2B as “22+ 2+”). At the end of the incubation period, total protein ts were prepared. In on, protein cell extracts were made from cells incubated with vehicle (DMSO) for 2 and 24 hours (indicated in FIGS. 2A and 2B as “-”). Cytoplasmic and nuclear proteins were separated, blotted and reacted with antibodies to p53, p21, full-length (FL) PARP, cleaved PARP and lamin B.
FIGS. 2A and 2B are images of Western blots obtained from the experiment and show that Compound 1 induces p21 and p53 in both cytoplasmic and nuclear ons.
Particularly strong induction of p53 was observed in the nuclear fraction of cells treated with -210— Compound 1. In addition, FIGS. 2A and 2B show that Compound 1 induces sis in HCT-l 16 cells after 24 hours, as indicated by the decrease in PARP, an apoptosis marker, and the increase in cleaved PARP. d PARP marks the initiation of cell death ing 16 hrs of tion, lamin is a marker for nuclear proteins and actin is a loading control.
Induction oprb Nuclear Localization and Phosphorylation in HCT-l l 6 Cells HCT-l 16 cells were incubated with 10 uM Compound 1 for 24 hours, at which time the cells were fixed and stained with antibodies to pr or DAPI. Subsequent analysis by immunofluorescence showed that treatment with Compound 1 induced nuclear localization of the tumor suppressor gene protein, pr.
HGT—116 cells were incubated with 10 uM Compound 1 for 2, 4, 6, 16, or 24 hours (indicated in FIGS. 3A and 3B as “2+,” 4+,” etc), or with 10 uM Compound 1 for 22 hours and an additional 1 uM Compound 1 for another 2 hours (indicated in FIGS. 3A and 3B as “22+ 2+”). At the end of the incubation period, total n extracts were prepared. In addition, n cell extracts were made from cells incubated with vehicle (DMSO) for 2 and 24 hours (indicated in FIGS. 3A and 3B as “-”). Cytoplasmic and r proteins were separated, immunoblotted and reacted with antibodies to phosphorylated pr (prphOS), pr, actin and lamin B.
FIGS. 3A and 3B are images of Western blots obtained from the experiment and show higher levels ofpr in the nuclear fraction and a loss of the upper band ofpr protein in samples treated with Compound 1 for more than 6 hours. The upper pr bands correspond to the inactive, phosphorylated protein and the lower bands correspond to the unphosphorylated, active form of the protein that induces cell cycle arrest. FIGS. 3A and 3B Show that Compound 1 induces phorylation ofpr in both cytoplasmic and nuclear fractions.
Induction ofAPC and [KB Nuclear Localization in HCT-II 6 Cells HCT-116 cells were incubated with 10 uM nd 1 for 24 hours, at which time the cells were fixed and stained with antibodies to APC or IKB, or DAPI. Subsequent analysis by fluorescence shows that ent with Compound 1 induced the nuclear localization of the tumor suppressor proteins, APC and IKB, respectively, in HCT—l 16 cells. —21 l - Cells treated with vehicle only showed clear cytoplasmic (ring-like staining) of both APC and IKB.
Experimental Autoimmune Encephalomyelitis (EAE) Model The EAE Model is an ed model for the study of human CNS demyelinating diseases such as le sis. The model described herein used 5—8-week—old female C57BL/6 or CD40'/' mice (13—16-week—old BM chimeric mice). The mice were immunized subcutaneously with 200 ug ofMOG3 5—55 peptide (peptide 35-55 of myelin oligodendrocyte ' glycoprotein) fied in CFA ete Freund’s Adjuvant) supplemented with 500 ug of Mycobacterium tuberculosis (DIFCO). The mice received intraperitoneal ions with 250 ng of pertussis toxin (Sigma-Aldrich) at the time of immunization and 48 h later to increase the permeability of the blood brain barrier. After 7 days, the mice received an identical boost immunization with MOG/CFA without pertussis toxin. Clinical disease commenced between days 13 and 18 after immunization. The administration of Compound I started when all mice displayed flaccid tail and weakness of hind limbs. The study design was as described below and all dosing was med in a blinded fashion.
The study consisted of 3 groups: (i) e—treated; (ii) 25 mg/kg of Compound 1; and (iii) 75 mg/kg Compound 1 (oral gavage, 3 days per week — Monday, Wednesday, Friday). Each group had 16-18 animals and was color coded. Body weight and condition and clinical score were recorded daily by two independent investigators. The clinical g of the mice was conducted four times per week as follows: 0, no detectable signs of EAE; 0.5, distal limp tail; 1, complete limp tail; 1.5, limp tail and hind limb weakness; 2, unilateral partial hind limb paralysis; 2.5, bilateral partial hind limb paralysis; 3, complete bilateral hind limb paralysis; 3.5, complete hind limb paralysis and unilateral forelimb paralysis; 4, total sis of fore and hind limbs (score > 4 to be sacrificed); 5, death. During the course of the experiment, supplementation of soft and palatable food such as gelatin and Nutrical was is a graph of EAE score as a function of time and shows that administration of Compound 1 in the above-described regimen reduced the clinical score in a tically significant manner for both the 25 mg/kg (low dose) and 75 mg/kg (high dose) groups. is a graph of body weight as a function of time and shows that administration of Compound 1 in the above-described regimen did not dramataically affect body weight. -2 12- On day 26, a subset of mice was ced and immunce cells were subjected to fluorescence—activated cell sorting (FACS) using rd methods. shows the results of the FACS experiment, which indicated a modest decrease in the number of cytes and circulating CD8 cells associated with the high dose of Compound 1.
Compound 1 and Example 1 are used hangeably herein and refer to Compound 1 of Table 2 having the chemical name (Z)—3-(3-(3,5—bis(trifluoromethyl)pheny1)—lH-l,2,4- triazoly1)— l -(3 ,3 -difluoroazetidiny1)prop-2—en-l-one.
Bibliography 1. aw JM and Matunis MJ. 2004. The nuclear pore x: disease associations and functional ations TRENDS Endocrin Metab. 15:34-39 2. Falini B et a1. 2006. Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML Blood. 107:4514-4523 3. Cai X and Liu X. 2008. Inhibition of Thr-55 phosphorylation restores p53 nuclear zation and sensitizes cancer cells to DNA damage.PNAS. 105: 1695 8-16963. 4. Daelemans D, Afonina E, Nilsson J 2002 A synthetic HIV-1 Rev inhibitor interfering with the CRMl-mediated nuclear export. Proc Natl Acad Sci U S A 99(22): 14440- 598052-2517 5. Davis JR et a1. 2007. Controlling protein compartmentalization to overcome disease Pharmaceut Res. 24: 17-27 6. t B, Yu L, Park E, et a1 2009 Molecular determinants for subcellular localization of the severe acute respiratory syndrome coronavirus open reading frame 3b protein. J Virol 83(13):6631-40 7. Ghildyal R, Ho A, Dias M, et a1 2009 The atory syncytial virus matrix protein possesses a Crml -mediated nuclear export mechanism. J Virol 83(11):5353-62 8. Ghosh CC et a1 2008 Analysis of nucleocytoplasmic shuttling ofNF kappa B proteins in human 1eukocytes.Methods Mol Biol. 457:279-92. 9. Gupta N et a1 2008 Retinal tau pathology in human glaucomasCan J lmol. 2008 Feb;43(1):53-60 . HoshinoL et a1. 2008. Combined effects of p53 gene therapy and leptomycin B in human esophageal squamous cell carcinoma. Oncology. 75:1 13-1 19. —213- ll. Lain S et al. 1999a An inhibitor of nuclear export activates the p53 response and induces the localization of HDM2 and p53 to UlA—positive r bodies associated with the PODs Exp Cell Res. 248:457-472. 12. Lain S et al. 1999b. Accumulating active p53 in the nucleus by inhibition of nuclear export: a novel strategy to promote the p53 tumor suppressor on Exp Cell Res. 253 :3 15. 13. Muller PA et al. 2009 Nuclear—cytosolic transport of COMMDl regulates NF-kappaB and HIE-1 activity. Traffic on-line publication 14. Mutka S 2007 Nuclear Export tors (NEIs) as novel cancer therapies AACR Annual g. Poster 5609.
. Mutka S, Yang W, Dong S, et al. 2009. Identification of nuclear export inhibitors with potent anticancer activity in vivo. Cancer Res. 69: 510-7. 16. Nakahara J et al. 2009. Abnormal expression of TIP30 and arrested cytoplasmic transport within oligodendrocyte precursor cells in multiple sclerosis J Clin Invest. 1 1 9: 1 69-1 8 1 l7. Noske A et al. 2008. Expression of the nuclear export protein chromosomal region maintenance/exportin l/Xpol is a prognostic factor in human ovarian cancer 18. Cancer. 112:1733—1743 19. Pollard V & Malim M. 1998 The HIV-1 Rev protein 52:491—532. 20. Rawlinson S, Pryor M, Wright P, Jans D 2009 CRMl-mediated nuclear export of dengue virus RNA polymerase NS5 modulates interleukin-8 induction and Virus production J Biol Chem 284(23):15589-97 21. Sanchez V, Mahr J et al 2007 Nuclear export of the human cytomegalovirus , Orazio N, tegument protein pp65 requires cyclin-dependent kinase ty and the Crml exporter J 1(21):11730—6. 22. Sorokin AV et al. 2007. Nucleocytoplasmic transport of proteins Biochemistry. 72:1439— 1457. 23. Terry LJ et al. 2007. Crossing the nuclear envelope: chical regulation of nucleocytoplasmic transport Science. 318:1412-1416 24. Van der Watt PJ et al. 2008. The Karyopherin ns, Crml and Karyopherin betal, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation Int J Canc. 124: 1 829-1 840 —214- . Walsh MD et al. 2008 Exportin 1 inhibition attenuates nuclear factor-kappaB-dependent gene expression. Shock 29: 1 60-166 26. Williams P, Verhagen J, Elliott G 2008 Characterization of a CRMl-dependent nuclear export signal in the C us of herpes simplex virus type 1 tegument protein UL47 J Virol 82(21): 10946-52. 27. Yang W 2007 Anti-tumor activity of novel nuclear export tors (NEIs) in multiple murine ia models AACR Annual Meeting. Poster 5597. 28. Yao Y et al. 2009. The expression of CRMl is associated with prognosis in human osteosarcoma Oncol Rep. 21 :229-35. 29. Zimmerman TL et a1 2006 Nuclear export of retinoid X receptor alpha in response to interleukin-lbeta-mediated cell signaling: roles for JNK and SER260 J Biol Chem281215434-15440 The relevant teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.
While this invention has been particularly shown and described with references to example embodiments thereof, it will be tood by those skilled in the art that various changes in form and details may be made therein Without departing from the scope of the invention encompassed by the appended claims.
WE

Claims (8)

CLAIM :
1. A compound of formula I: (I), or a pharmaceutically acceptable salt thereof, n: Ring A is a triazolyl ring; Ring B is represented by the following structural formula: X is O; Y is a covalent bond; R1 and R2 are taken together with their intervening atoms to form a ted heterocyclic ring represented by the following structural formula: each of m, and p is independently an integer selected from 0, 1, 2, 3 and 4; q is 0; each of R4, and R5 is independently n, –NO2, –CN, –N3, or -L-R6, or: two R4 groups on Ring A are taken together with their intervening atoms to form a fused 4-8 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and ; or: two R5 groups on the ring formed by R1 and R2 are taken together with their intervening atoms to form a fused 4-8 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent C1-6 hydrocarbon group, wherein one or two methylene units of L is ally and independently replaced by 11269563 –Cy–, –O–, –S–, –, –C(O)–, –C(S)–, (R6)–, –N(R6)C(O)N(R6)–, –N(R6)C(O)–, –N(R6)C(O)O–, -OC(O)N(R6)–, –S(O)–, –S(O)2–, N(R6)–, –N(R6)S(O)2–, –OC(O)– or –C(O)O–; –Cy– is a bivalent ring selected from a 3-7 membered ted or partially unsaturated cycloalkylenylene ring, a 4membered ted or partially unsaturated heterocycloalkylene ring having 1–4 atoms independently selected from nitrogen, oxygen, and sulfur, phenylene, a 5-6 membered monocyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and , an 8-10 membered bicyclic arylene, and an 8-10 ed bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R6 is independently hydrogen or a group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, a 4membered saturated or partially unsaturated heterocyclic ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 atoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: two R6 on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or aromatic heterocyclic ring having 1- 2 heteroatoms ndently selected from nitrogen, oxygen, and sulfur.
2. The compound according to claim 1, wherein Ring A is
3. The compound according to any one of claim 1 or claim 2, wherein the saturated heterocyclic ring formed by R1, R2 and their intervening atoms is ented by the following ural formula: 11269563
4. The nd according to any one of claims 1 to 3, wherein the nd is represented by the following structural formula: (I-b), or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1, wherein the compound is represented by any one of the following structural formulas, or a pharmaceutically acceptable salt thereof: Compound Structure 11269563 Compound ure 11269563 Compound Structure
6. The compound of Claim 1, wherein the compound is represented by the ing structural formula: 11269563 or a pharmaceutically acceptable salt thereof.
7. A composition comprising the compound of any one of claims 1 to 5, or a ceutically acceptable salt thereof, and a pharmaceutically acceptable r, nt, or vehicle.
8. Use of the compound of any one of claims 1 to 5, or the composition of claim 7 in the manufacture of a medicament for the treatment, prevention and/or modulation of a disorder associated with CRM1, wherein the disorder is selected from cancer, neoplastic disorders, inflammatory diseases, disorders of abnormal tissue growth, fibrosis, renal ers, and viral infections. Karyopharm Therapeutics, Inc. By the Attorneys for the Applicant SPRUSON & FERGUSON Per: 11269563
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US201261653588P 2012-05-31 2012-05-31
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