WO2014152725A1 - S1p and/or atx modulating agents - Google Patents

S1p and/or atx modulating agents Download PDF

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Publication number
WO2014152725A1
WO2014152725A1 PCT/US2014/027664 US2014027664W WO2014152725A1 WO 2014152725 A1 WO2014152725 A1 WO 2014152725A1 US 2014027664 W US2014027664 W US 2014027664W WO 2014152725 A1 WO2014152725 A1 WO 2014152725A1
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Prior art keywords
galkyl
alkyl
pyrazolo
amino
diazepine
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PCT/US2014/027664
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French (fr)
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Hairuo Peng
Zhili Xin
Lei Zhang
Lihong Sun
Gnanasambandam Kumaravel
Art Taveras
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Biogen Idec Ma Inc.
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Priority to EP14721638.6A priority Critical patent/EP2970302A1/en
Priority to US14/772,481 priority patent/US20160039825A1/en
Publication of WO2014152725A1 publication Critical patent/WO2014152725A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9068—Zingiber, e.g. garden ginger
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • agents that modulate SIP and/or ATX are provided.
  • Sphingosine 1-phosphate is a lysophospholipid mediator that evokes a variety of cellular responses by stimulation of five members of the endothelial cell differentiation gene (EDG) receptor family.
  • EDG receptors are G-protein coupled receptors (GPCRs) and on stimulation propagate second messenger signals via activation of heterotrimeric G-protein alpha (G a ) subunits and beta-gamma (Gp 7 ) dimers.
  • GPCRs G-protein coupled receptors
  • GPCRs G-protein coupled receptors
  • GPCRs G-protein coupled receptors
  • Gp 7 beta-gamma
  • FTY720 (2-amino-2-[2-(4-octylphenyl) ethyl] propane 1,3-diol), that following phosphorylation, is an agonist at 4 of 5 SIP receptors, revealed that affecting SIP receptor activity influences lymphocyte trafficking.
  • SIP type 1 receptor S1P antagonists cause leakage of the lung capillary endothelium, which suggests that SIP may be involved in maintaining the integrity of the endothelial barrier in some tissue beds.
  • SIP type 4 receptors are expressed mainly in leukocytes, and specifically S1P 4 mediates immunosuppressive effects of SIP by inhibiting proliferation and secretion of effector cytokines, while enhancing secretion of the suppressive cytokine IL-10. See, for example, Wang, W. et. al., (2005) FASEB J. 19(12): 1731-3, which is incorporated by reference in its entirety.
  • SIP type 5 receptors S1P 5
  • SIP type 5 are exclusively expressed in oligodendrocytes and oligodendrocyte precursor cells (OPCs) and are vital for cell migration. Stimulation of SIP 5 inhibits OPC migration, which normally migrate considerable distances during brain development. See, for example, Novgorodov, A. et al., (2007) FASEB J, 21: 1503-1514, which is incorporated by reference in its entirety.
  • SIP has been demonstrated to induce many cellular processes, including those that result in platelet aggregation, cell proliferation, cell morphology, tumor-cell invasion, endothelial cell chemotaxis and angiogenesis. For these reasons, SIP receptors are good targets for therapeutic applications such as wound healing, tumor growth inhibition, and autoimmune diseases.
  • Sphingosine-1 -phosphate signals cells in part via a set of G protein-coupled receptors named SIPi, S1P 2 , S1P 3 , S1P 4 , and S1P 5 (formerly EDG1, EDG5, EDG3, EDG6 and EDG8).
  • the EDG receptors are G-protein coupled receptors (GPCRs) and on stimulation propagate second messenger signals via activation of heterotrimeric G-protein alpha (G a ) subunits and beta-gamma (Gp 7 ) dimers. These receptors share 50-55% amino acid sequence identity and cluster with three other receptors (LPA 1; LPA 2 , and LPA (formerly EDG2, EDG4 and EDG7) for the structurally related lysophosphatidic acid (LPA).
  • LPA 1 LPA 2
  • LPA previously EDG2, EDG4 and EDG7
  • a conformational shift is induced in the G-Protein Coupled Receptor (GPCR) when the ligand binds to that receptor, causing GDP to be replaced by GTP on the a-subunit of the associated G-proteins and subsequent release of the G-proteins into the cytoplasm.
  • the a-subunit then dissociates from the ⁇ -subunit and each subunit can then associate with effector proteins, which activate second messengers leading to a cellular response.
  • the GTP on the G-proteins is hydrolyzed to GDP and the subunits of the G-proteins reassociate with each other and then with the receptor.
  • Amplification plays a major role in the general GPCR pathway.
  • the binding of one ligand to one receptor leads to the activation of many G-proteins, each capable of associating with many effector proteins leading to an amplified cellular response.
  • SIP receptors make good drug targets because individual receptors are both tissue and response specific. Tissue specificity of the SIP receptors is desirable because development of an agonist or antagonist selective for one receptor localizes the cellular response to tissues containing that receptor, limiting unwanted side effects. Response specificity of the SIP receptors is also of importance because it allows for the development of agonists or antagonists that initiate or suppress certain cellular responses without affecting other responses. For example, the response specificity of the SIP receptors could allow for an SIP mimetic that initiates platelet aggregation without affecting cell morphology.
  • Sphingosine-1 -phosphate is formed as a metabolite of sphingosine in its reaction with sphingosine kinase and is stored in abundance in the aggregates of platelets where high levels of sphingosine kinase exist and sphingosine lyase is lacking. SIP is released during platelet aggregation, accumulates in serum, and is also found in malignant ascites. Reversible biodegradation of SIP most likely proceeds via hydrolysis by
  • ectophosphohydrolases specifically the sphingosine-1 -phosphate phosphohydrolases. Irreversible degradation of SIP is catalyzed by SIP lyase yielding ethanolamine phosphate and hexadecenal.
  • Autotaxin (ATX, ENPP2) is a secreted glycoprotein widely present in biological fluids, including blood, cancer ascites, synovial, pleural and cerebrospinal fluids, originally isolated from the supernatant of melanoma cells as an autocrine motility stimulation factor (Stracke, M.L., et al. Identification, purification, and partial sequence analysis of autotaxin, a novel motility- stimulating protein. J Biol Chem 267, 2524-2529 (1992), which is incorporated by reference in its entirety).
  • ATX is encoded by a single gene on human chromosome 8 (mouse chromosome 15) whose transcription, regulated by diverse transcription factors (HoxaB, NFAT-1 and v-jun), results in four alternatively spliced isoforms ( ⁇ , ⁇ , ⁇ , and ⁇ ).
  • human chromosome 8 mouse chromosome 15
  • HoxaB diverse transcription factors
  • NFAT-1 and v-jun four alternatively spliced isoforms
  • ATX is synthesized as a prepro-enzyme, secreted into the extracellular space after the proteolytic removal of its N-terminal signal peptide (Jansen, S., el al Proteolytic maturation and activatio of autotaxin (NPP2), a secreted metastasis-enhancing lysophospho lipase D. J Cell Sci 118, 3081-3089 (2005), which is incorporated by reference in its entirety).
  • ATX is a member of the ectonucleotide pyrophosphatase/phosphodiesterase family of ectoenzymes (E-NPP) that hydrolyze phosphodiesterase (PDE) bonds of various nucleotides and derivatives (Stefan, C, Jansen, S. & Bollen, M. NPP-type
  • ectophosphodiesterases unity in diversity. Trends Biochem Sci 30, 542-550 (2005), which is incorporated by reference in its entirety).
  • the enzymatic activity of ATX was enigmatic, until it was shown to be identical to lysophospholipase D (lysoPLD) (Umezu-Goto, M., et al. Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J Cell Biol 158, 227-233 (2002), which is incorporated by reference in its entirety), which is widely present in biological fluids.
  • ATX is a constitutively active enzyme
  • the major lysophospholipid substrate for ATX is secreted by the liver and is abundantly present in plasma (at about 100 ⁇ ) as a predominantly albumin bound form (Croset, M., Brossard, N., Polette, A. & Lagarde, M. Characterization of plasma unsaturated lysophosphatidylcholines in human and rat Biochem J 345 Pt 1, 61-67 (2000), which is incorporated by reference in its entirety).
  • LPC is also detected in tumor-cell conditioned media (Umezu-Goto, M., et al.), presumably as a constituent of shed micro vesicles.
  • ATX through its lysoPLD activity converts LPC to lysophosphatidic acid (LPA).
  • LPC is an important inflammatory mediator with recognized effects in multiple cell types and pathophysiological processes. It is a major component of oxidized low density lipoprotein (oxLDL) and it can exist in several other forms including free, micellar, bound to hydrophobic proteins such as albumin and incorporated in plasma membranes. It is produced by the hydrolysis of phosphatidylcholine (PC) by PLA2 with concurrent release of arachidonic acid and in turn of other pro-inflammatory mediators (prostaglandins and leukotrienes). Moreover, LPC externalization constitutes a chemo tactic signal to phagocytic cells, while interaction with its receptors can also stimulate lymphocytic responses. LPC has been shown to have therapeutic effects in experimental sepsis, possibly by suppressing endo toxin-induced HMGB1 release from macrophages/monocytes.
  • oxLDL oxidized low density lipoprotein
  • LPA is a bioactive phospholipid with diverse functions in almost every mammalian cell line (Moolenaar, W.H., van Meeteren, L.A. & Giepmans, B.N. The ins and outs of lysophosphatidic acid signaling. Bioessays 28, 870-881 (2004), which is incorporated by reference in its entirety).
  • LPA is a major constituent of serum bound tightly to albumin, gelsolin and possibly other as yet unidentified proteins. See, e.g., Goetzl, E.J., et al Gelsolin binding and. cellular presentation of lysophosphatidic acid. J Biol Chem 275, 14573-14578 (2000); and Tigyi, G.
  • LPA is also found in other biofluids, such as saliva and follicular fluid, and has been implicated in a wide array of functions, such as wound healing, tumor invasion and metastasis, neurogenesis, myelination, astrocytes outgrowth and neurite retraction.
  • GPCRs G-protein coupled receptors
  • LPA receptors can couple to at least three distinct G proteins (G q , Gj and G 12 / 13 ), which, in turn, feed into multiple effector systems. LPA activates G q and thereby stimulates
  • PLC phospholipase C
  • Gj Gj
  • PI3K phosphatidylinositol 3-kinase
  • LPA activates G 12/ i 3 , leading to activation of the small GTPase RhoA, which drives cytoskeletal contraction and cell rounding. So, LPA not only signals via classic second messengers such as calcium, diacylglycerol and cAMP, but it also activates RAS- and RHO- family GTPases, the master switches that control cell proliferation, migration and
  • LPA signaling through the RhoA-Rho kinase pathway mediates neurite retraction and inhibition of axon growth. Interfering with LPA signaling has been shown to promote axonal regeneration and functional recovery after CNS injury or cerebral ischemia. (See Broggini, et al., Molecular Biology of the Cell (2010), 27:521-537.) It has been reported that addition of LPA to dorsal root fibers in ex vivo culture causes demyelination, whereas LPC fails to cause significant demyelination of nerve fibers in ex vivo cultures without further addition of recombinant ATX to the culture which when added caused significant
  • a number of diseases or disorders involve demyelination of the central or peripheral nervous system which can occur for a number of reasons such as immune dysfunction as in multiple sclerosis, encephalomyelitis, Guillain-Barre Syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis, and optic neuritis; demyelination due to injury such as spinal cord injury, traumatic brain injury, stroke, acute ischemic optic neuropathy, or other ischemia, cerebral palsy, neuropathy (e.g. neuropathy due to diabetes, chronic renal failure, hypothyroidism, liver failure, or compression of the nerve (e.g.
  • CMT Charcot-Marie-Tooth disease
  • Sjogren- Lars son syndrome Refsum disease
  • Krabbe disease Canavan disease
  • Alexander disease Friedreich's ataxia
  • Pelizaeus- Merzbacher disease Bassen-Kornzweig syndrome
  • MLD metachromatic leukodystrophy
  • adrenoleukodystrophy nerve damage due to pernicious anemia
  • viral infection such as progressive multifocal leukoencephalopathy (PML), Lyme disease, or tabes dorsalis due to untreated syphilis
  • toxic exposure due to chronic alcoholism which is a possible cause of Marchiafava-Bignami disease
  • chemotherapy or exposure to chemicals
  • demyelination disorders may have unknown causes or multiple causes such as trigeminal neuralgia, Marchiafava-Bignami disease and Bell's palsy.
  • One practically successful approach to treating demyelination disorders which are caused by autoimmune dysfunction has been to attempt to limit the extent of demyelination by treating the patient with immunoregulatory drugs.
  • This approach has merely postponed but not avoided the onset of disability in these patients.
  • Patients with demyelination due to other causes have even fewer treatment options. Therefore, the need exists to develop new treatments for patients with demyelination diseases or disorders.
  • agents that can modulate SIP and/or ATX e.g., an S1P4 antagonist and/or ATX inhibitor.
  • SIP Session Initiation Protocol
  • ATX anti-viral X
  • LPA inhibits remyelination of neurons that have suffered demyelination due to injury or disease and that inhibition of ATX will prevent the conversion of LPC to LPA and thus allow remyelination to occur.
  • activation of PLC, ERK and Rho via LPA receptors results in cell proliferation, cell survival and changes in cell morphology. Therefore, inhibition of ATX is expected to be useful for treating demyelination due to injury or disease, as well as for treating proliferative disorders such as cancer.
  • L is -C(O)-, -O-C(O)-, -NR 6 -C(0)-, or -S(0) 2 -;
  • L 2 is a bond, -0-, or -NR-; provided that L 2 is not -O- when R 2 is structure (iv);
  • R for each occurrence, is independently hydrogen or a Ci ⁇ alkyl;
  • R 1 is a Ci-galkylene;
  • R is selected form the group consisting of:
  • R 3 is hydrogen, -CN, C 1-8 alkyl, Ci-ghaloalkyl, -(CR 10 R n ) m -N(R 16 ) 2 , -(CR 10 R n ) m - OR 15 , -(CR 10 R n ) m -C(O)OR 15 , -(CR 10 R n ) m -C(O)N(R 16 ) 2 , -(CR 10 R n ) m -S(O) 2 N(R 16 ) 2 , - (CR 10 R u ) m -S(O) 2 NHS(O) 2 R 15 , -C(0)N(R 15 )-S(0) 2 R 15 , -S(0) 2 OR 15 , -C(0)NHC(0)R 15 , - Si(0)OH, -B(OH) 2 , -N(R 15 )S(0) 2 R 15 , -0-P(0)(OR 15 ) 2 , -
  • R 4 is Ci-galkyl, C 3 _gcycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R 4 may be optionally substituted with from one to four R 5 ;
  • R 5 is halo, cyano, Ci-galkyl, Ci-ghaloalkyl, C 3 - 8 cycloalkyl, -(CR 10 R u ) m -N(R 16 ) 2 , -(CR 10 R n ) m -OR 15 , -(CR 10 R n ) m -C(O)OR 15 , -C(0)N(R 16 ) 2 , -C(0)N(R 15 )-S(0) 2 R 15 , - S(0) 2 OR 15 , -C(0)NHC(0)R 15 , -Si(0)OH, -B(OH) 2 , -N(R 15 )S(0) 2 R 15 , -S(0) 2 N(R 15 ) 2 , O P(0)(OR 15 ) 2 , -P(0)(OR 15 ) 2 , -S(0) 2 NHC(0)R 15 , -C(0)NHS(0) 2 R 15 , C(0)NHOH,
  • C(0)NHCN, -C(0)R 15 , a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, 0, Ci_ 4 alkyl, Ci_ 4 haloalkyl, Ci_ 4 alkoxy, cyano, nitro, hydroxyl, amino, N-(C M alkyl)amino, N,N-di-(C M alkyl)amino, carbamoyl, N-(Ci- 4 alkyl)carbamoyl, N,N-di-(C M alkyl)carbamoyl, Ci_ 4 alkylamido, Ci_ 4 alkylsulfonyl, Ci_ 4 alkylsulfonamido, sulfamoyl, N-Ci_ 4 alkylsulfamoyl
  • R 6 is hydrogen or a Ci-galkyl
  • R for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, Ci-galkyl, Ci_ghaloalkyl, C 3 _gcycloalkyl,
  • C 3 _ghalocycloalkyl Ci-galkoxy, Ci_ghaloalkoxy, C 3 _gcycloalkoxy, C 3 _ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci_galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl,
  • R for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C 3 _gcycloalkyl, C 3 _ghalocycloalkyl, Ci_galkoxy, Ci_ghaloalkoxy, C 3 _gcycloalkoxy, C 3 _ghalocycloalkoxy, Q-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci_galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , s
  • R 9 for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci-galkyl, Ci-galkoxy, Ci-ghaloalkyl, Ci-ghaloalkoxy,
  • R 9a is hydrogen or R 9 ; or R 9a and R 6 , together with the intervening atoms, form a 3- to 8-membered heterocyclyl which is optionally substituted with from one to three R 9 ;
  • R 10 and R 11 are independently hydrogen, halo, hydroxyl, carboxy, C 1 _ 4 alkyl, or a C ⁇ haloalkyl;
  • R 15 for each occurrence is independently selected from the group consisting of hydrogen, Ci-galkyl, C 2 -galkenyl, C 2 _galkynyl, C 3 -gcycloalkyl, C 3 -gcycloalkenyl, C6-ioaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R 15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1-4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N,N-di-(C M alkyl)amino, carboxyl, carbamoyl,
  • R 16 is Ci-galkoxy, or R 15 ; or two R 16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci ⁇ alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N-(C M alkyl)amino,
  • h 0, 1, or 2;
  • n for each occurrence, is independently 0, 1, 2, 3, or 4;
  • n for each occurrence, is independently 0 or an integer from 1 to 6;
  • p 0, 1, 2, or 3;
  • q 1, 2, 3, or 4;
  • r is 1, 2, or 3;
  • t is 0 or 1, provided that the compound is not: 3-(5-(2-(4-isopropylphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
  • composition comprising at least one compound represented by structural formula (I), or a pharmaceutically acceptable salt thereof:
  • L is -C(O)-, -O-C(O)-, -NR 6 -C(0)-, or -S(0) 2 -;
  • L 2 is a bond, -0-, or -NR-;
  • R for each occurrence, is independently hydrogen or a Ci ⁇ alkyl;
  • R 1 is a Ci ⁇ alkylene;
  • R is selected form the group consisting of:
  • R 3 is hydrogen, -CN, Ci_ 8 alkyl, Ci_ 8 haloalkyl, -(CR 10 R n ) m -N(R 16 ) 2 , -(CR 10 R n ) m - OR 15 , -(CR 10 R n ) m -C(O)OR 15 , -(CR 10 R n ) m -C(O)N(R 16 ) 2 , -(CR 10 R n ) m -S(O) 2 N(R 16 ) 2 , - (CR 10 R u ) m -S(O) 2 NHS(O) 2 R 15 , -C(0)N(R 15 )-S(0) 2 R 15 , -S(0) 2 OR 15 , -C(0)NHC(0)R 15 , - Si(0)OH, -B(OH) 2 , -N(R 15 )S(0) 2 R 15 , -0-P(0)(OR 15 ) 2 ,
  • L 1 is Ci-galkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0) 2 NR-, or -C(0)NR-S(0) 2 -;
  • R 4 is Ci-galkyl, C 3 _gcycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R 4 may be optionally substituted with from one to four R 5 ;
  • R 5 is halo, cyano, Ci-galkyl, Ci-ghaloalkyl, C 3 - 8 cycloalkyl, -(CR 10 R u ) m -N(R 16 ) 2 , -(CR 10 R n ) m -OR 15 , -(CR 10 R n ) m -C(O)OR 15 , -C(0)N(R 16 ) 2 , -C(0)N(R 15 )-S(0) 2 R 15 , - S(0) 2 OR 15 , -C(0)NHC(0)R 15 , -Si(0)OH, -B(OH) 2 , -N(R 15 )S(0) 2 R 15 , -S(0) 2 N(R 15 ) 2 , O P(0)(OR 15 ) 2 , -P(0)(OR 15 ) 2 , -S(0) 2 NHC(0)R 15 , -C(0)NHS(0) 2 R 15 , C(0)NHOH, C(0)NHCN,
  • R 6 is hydrogen or a Ci-galkyl
  • R for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C 3 _gcycloalkyl,
  • R for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C 3 _gcycloalkyl, C 3 _ghalocycloalkyl, Ci-galkoxy, Ci-ghaloalkoxy, C 3 _gcycloalkoxy, C 3 _ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci_galkoxycarbonyl, Ci_galkanoyloxy, carbamoyl, Ci_galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl, N-( ⁇ galkyl)sulfamoyl,
  • R 9 for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci_galkyl, Ci_galkoxy, Ci_ghaloalkyl, Ci_ghaloalkoxy,
  • R 9a is hydrogen or R 9 ; or R 9a and R 6 , together with the intervening atoms, form a 3- to 8-membered heterocyclyl which is optionally substituted with from one to three R 9 ;
  • R 10 and R 11 are independently hydrogen, halo, hydroxyl, carboxy, C 1-4 alkyl, or a Ci ⁇ haloalkyl;
  • R 15 for each occurrence is independently selected from the group consisting of hydrogen, Ci-galkyl, C 2 -galkenyl, C 2 _galkynyl, C 3 _gcycloalkyl, C 3 _gcycloalkenyl, C 6-1 oaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R 15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci_ 4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N-(Ci_ 4 alkyl)amino, N,N-di-(Ci_ 4 alkyl)amino, carboxyl, carbamoyl,
  • R 16 is Ci-galkoxy, or R 15 ; or two R 16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci_ 4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N-(Ci_ 4 alkyl)amino,
  • n for each occurrence, is independently 0, 1, 2, 3, or 4;
  • n for each occurrence, is independently 0 or an integer from 1 to 6;
  • p 0, 1, 2, or 3;
  • q 1, 2, 3, or 4;
  • r is 1, 2, or 3; and t is 0 or 1, provided that the compound is not 2-(4-fluorophenyl)-l-(3-(quinolin-2-yl)- 5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone; and at least one pharmaceutically acceptable carrier or excipient.
  • Also provided is a method of preventing, treating, or reducing symptoms of a condition mediated by SIP activity and/or ATX activity in a mammal comprising delivering (e.g., administering) to said mammal an effective amount of a compound represented by structural formula (I):
  • L is -C(O)-, -O-C(O)-, -NR 6 -C(0)-, or -S(0) 2 -;
  • L 2 is a bond, -0-, or -NR-;
  • R for each occurrence, is independently hydrogen or a C 1 _ 4 alkyl;
  • R 1 is a Ci-galkylene;
  • R is selected form the group consisting of:
  • R 3 is hydrogen, -CN, C 1-8 alkyl, Ci-ghaloalkyl, -(CR 10 R n ) m -N(R 16 ) 2 , -(CR 10 R n ) m - OR 15 , -(CR 10 R n ) m -C(O)OR 15 , -(CR 10 R n ) m -C(O)N(R 16 ) 2 , -(CR 10 R n ) m -S(O) 2 N(R 16 ) 2 , - (CR 10 R u ) m -S(O) 2 NHS(O) 2 R 15 , -C(0)N(R 15 )-S(0) 2 R 15 , -S(0) 2 OR 15 , -C(0)NHC(0)R 15 , - Si(0)OH, -B(OH) 2 , -N(R 15 )S(0) 2 R 15 , -0-P(0)(OR 15 ) 2 , -
  • L 1 is Ci_ 8 alkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0) 2 NR-, or -C(0)NR-S(0) 2 -;
  • R 4 is Ci- 8 alkyl, C3_ 8 cycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R 4 may be optionally substituted with from one to four R 5 ;
  • R 5 is halo, cyano, Ci.galkyl, Ci.ghaloalkyl, C 3 - 8 cycloalkyl, -(CR 10 R u ) m -N(R 16 ) 2 , -(CR 10 R n ) m -OR 15 , -(CR 10 R n ) m -C(O)OR 15 , -C(0)N(R 16 ) 2 , -C(0)N(R 15 )-S(0) 2 R 15 , - S(0) 2 OR 15 , -C(0)NHC(0)R 15 , -Si(0)OH, -B(OH) 2 , -N(R 15 )S(0) 2 R 15 , -S(0) 2 N(R 15 ) 2 , O P(0)(OR 15 ) 2 , -P(0)(OR 15 ) 2 , -S(0) 2 NHC(0)R 15 , -C(0)NHS(0) 2 R 15 , C(0)NHOH, C(0)NHCN,
  • R 6 is hydrogen or a Ci_galkyl
  • R for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C 3 _ 8 cycloalkyl,
  • R for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C 3 _gcycloalkyl, C 3 _ghalocycloalkyl, Ci-galkoxy, Ci-ghaloalkoxy, C 3 _gcycloalkoxy, C 3 _ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci_galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , s
  • R 9 for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci_galkyl, Ci-ghaloalkyl, Ci_ghaloalkoxy,
  • R 9a is hydrogen or R 9 ; or R 9a and R 6 , together with the intervening atoms, form a 3- to 8-membered heterocyclyl which is optionally substituted with from one to three R 9 ;
  • R 10 and R 11 are independently hydrogen, halo, hydroxyl, carboxy, Ci_ 4 alkyl, or a Ci_ 4 haloalkyl;
  • R for each occurrence is independently selected from the group consisting of hydrogen, Ci-galkyl, C 2 _galkenyl, C 2 _galkynyl, C 3 _gcycloalkyl, C 3 _gcycloalkenyl, C 6 -ioaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R 15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1 _ 4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N,N-di-(C M alkyl)amino, carboxy
  • R 16 is Ci-galkoxy, or R 15 ; or two R 16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci ⁇ alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N-(C M alkyl)amino,
  • h 0, 1, or 2;
  • n for each occurrence, is independently 0, 1, 2, 3, or 4;
  • n for each occurrence, is independently 0 or an integer from 1 to 6;
  • p 0, 1, 2, or 3;
  • q 1, 2, 3, or 4;
  • r is 1, 2, or 3;
  • t 0 or 1.
  • the condition can be selected from the group consisting of an inflammatory disorder, an autoimmune disorder, a fibrosis of the lung, or a malignancy of the lung.
  • the inflammatory disorder can be rheumatoid arthritis.
  • the autoimmune disorder can be multiple sclerosis.
  • the method can further include administering to said mammal an effective amount of one or more drugs selected from the group consisting of: a corticosteroid, a bronchodilator, an antiasthmatic, an antiinflammatory, an antirheumatic, an immunosuppressant, an antimetabolite, an immunomodulator, an antipsoriatic, and an antidiabetic.
  • Also provided is a method of preventing, treating, or reducing chronic pain in a mammal comprising delivering (e.g., administering) to said mammal an effective amount of at least one compound, or a pharmaceutically acceptable salt thereof, represented by formula
  • L is -C(O)-, -O-C(O)-, -NR-C(O)-, or -S(0) 2 -;
  • R for each occurrence, is independently hydrogen or a C 1 _ 4 alkyl
  • R 1 is a Ci ⁇ alkylene
  • R is selected form the group consisting of:
  • R 3 is hydrogen, -CN, C 1-8 alkyl, Ci-ghaloalkyl, -(CR 10 R n ) m -N(R 16 ) 2 , -(CR 10 R n ) m - OR 15 , -(CR 10 R n ) m -C(O)OR 15 , -(CR 10 R n ) m -C(O)N(R 16 ) 2 , -(CR 10 R n ) m -S(O) 2 N(R 16 ) 2 , - (CR 10 R u ) m -S(O) 2 NHS(O) 2 R 15 , -C(0)N(R 15 )-S(0) 2 R 15 , -S(0) 2 OR 15 , -C(0)NHC(0)R 15 , - Si(0)OH, -B(OH) 2 , -N(R 15 )S(0) 2 R 15 , -0-P(0)(OR 15 ) 2 , -
  • L 1 is Ci-galkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0) 2 NR-, or -C(0)NR-S(0) 2 -;
  • R 4 is Ci-galkyl, C3_ 8 cycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R 4 may be optionally substituted with from one to four R 5 ;
  • R 5 is halo, cyano, Ci_galkyl, Ci_ghaloalkyl, C 3 - 8 cycloalkyl, -(CR 10 R u ) m -N(R 16 ) 2 , -(CR 10 R n ) m -OR 15 , -(CR 10 R n ) m -C(O)OR 15 , -C(0)N(R 16 ) 2 , -C(0)N(R 15 )-S(0) 2 R 15 , - S(0) 2 OR 15 , -C(0)NHC(0)R 15 , -Si(0)OH, -B(OH) 2 , -N(R 15 )S(0) 2 R 15 , -S(0) 2 N(R 15 ) 2 , O P(0)(OR 15 ) 2 , -P(0)(OR 15 ) 2 , -S(0) 2 NHC(0)R 15 , -C(0)NHS(0) 2 R 15 , C(0)NHOH,
  • C(0)NHCN, -C(0)R 15 , a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, 0, Ci_ 4 alkyl, Ci_ 4 haloalkyl, Ci_ 4 alkoxy, cyano, nitro, hydroxyl, amino, N-(CMalkyl)amino, N,N-di-(Ci_ 4 alkyl)amino, carbamoyl, N,N-di-(Ci_ 4 alkyl)carbamoyl, Ci_ 4 alkylamido, Ci_ 4 alkylsulfonyl, Ci_ 4 alkylsulfonamido, sulfamoyl, N-Ci_ 4 alkylsulfamoyl, and N,N ⁇ CMdialkyl)-sulf
  • R for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C 3 _gcycloalkyl,
  • C 3 _ghalocycloalkyl Ci-galkoxy, Ci_ghaloalkoxy, C 3 _gcycloalkoxy, C 3 _ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl,
  • R for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, Ci_galkyl, Ci_ghaloalkyl, C 3 _gcycloalkyl, C 3 _ghalocycloalkyl, Ci-galkoxy, Ci-ghaloalkoxy, C 3 _gcycloalkoxy, C 3 _ghalocycloalkoxy, Ci-galkanoyl, amino, N,N-di-( ⁇ galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci_galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
  • R 9 for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci_galkyl, Ci_galkoxy, Ci_ghaloalkyl, Ci-ghaloalkoxy,
  • R 10 and R 11 are independently hydrogen, halo, hydroxyl, carboxy, C 1-4 alkyl, or a C ⁇ haloalkyl;
  • R 15 for each occurrence is independently selected from the group consisting of hydrogen, Ci_galkyl, C 2 -galkenyl, C 2 _galkynyl, C 3 -gcycloalkyl, C 3 -gcycloalkenyl, C 6-1 oaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R 15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C ⁇ alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N-(Ci_ 4 alkyl)amino, N,N-di-(Ci_ 4 alkyl)amino, carboxyl, carbamoyl,
  • R 16 is Ci-galkoxy, or R 15 ; or two R 16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1 _ 4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N-(C 1-4 alkyl)amino,
  • h 0, 1, or 2;
  • n for each occurrence, is independently 0, 1, 2, 3, or 4;
  • n for each occurrence, is independently 0 or an integer from 1 to 6;
  • p 0, 1, 2, or 3;
  • q 1, 2, 3, or 4;
  • r is 1, 2, or 3;
  • t is 0 or 1, provided that the compound is not 2-(4-fluorophenyl)-l-(3-(quinolin-2-yl)- 5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone.
  • the chronic pain can be inflammatory pain or neuropathic pain.
  • alkyl refers to a fully saturated branched or unbranched hydrocarbon moiety.
  • the alkyl comprises 1 to 20 carbon atoms, such as 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec -butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, or n-decyl.
  • alkylene refers to a divalent alkyl group.
  • alkylene groups include methylene, ethylene, propylene, n-butylene, and the like.
  • the alkylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the carbon chain.
  • haloalkyl refers to an alkyl, as defined herein, that is substituted by one or more halo groups as defined herein.
  • the haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl.
  • a monohaloalkyl can have one iodo, bromo, chloro or fluoro substituent.
  • Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halo atoms or a combination of different halo groups.
  • Non-limiting examples of haloalkyl include
  • a perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halo atoms.
  • a haloalkyl group is trifluoromethyl or difluoromethyl.
  • halogen or halo may be fluoro, chloro, bromo or iodo.
  • Alkenyl refers to an unsaturated hydrocarbon group which may be linear or branched and has at least one carbon-carbon double bond. Alkenyl groups with 2-8 carbon atoms can be preferred. The alkenyl group may contain 1, 2 or 3 carbon-carbon double bonds, or more. Examples of alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl and the like.
  • Alkynyl refers to an unsaturated hydrocarbon group which may be linear or branched and has at least one carbon-carbon triple bond. Alkynyl groups with 2-8 carbon atoms can be preferred. The alkynyl group may contain 1, 2 or 3 carbon-carbon triple bonds, or more. Examples of alkynyl groups include ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and the like.
  • alkoxy refers to alkyl-O-, wherein alkyl is defined herein above.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like.
  • representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy, and the like.
  • alkoxy groups have about 1-6 carbon atoms, such as about 1-4 carbon atoms.
  • haloalkoxy refers to haloalkyl-O-, wherein haloalkyl is defined herein above.
  • Representative example of haloalkoxy groups are trifluoromethoxy, difluoromethoxy, and 1,2-dichloroethoxy.
  • haloalkoxy groups have about 1-6 carbon atoms, such as about 1-4 carbon atoms.
  • alkylthio refers to alkyl-S-, wherein alkyl is defined herein above.
  • Carbocyclyl refers to saturated or partially unsaturated (but not aromatic) monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-14 carbon atoms, such as 3-9, for example, 3-8 carbon atoms. Carbocyclyls include fused or bridged ring systems. The term “carbocyclyl” encompasses cycloalkyl groups. The term “cycloalkyl” refers to completely saturated monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, such as 3-9, for example, 3-8 carbon atoms.
  • Exemplary monocyclic carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl.
  • Exemplary bicyclic carbocyclyl groups include bornyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6- trimethylbicyclo[3.1.1]heptyl, or bicyclo[2.2.2]octyl.
  • Exemplary tricyclic carbocyclyl groups include adamantyl.
  • halocycloalkyl refers to a cycloalkyl, as defined herein, that is substituted by one or more halo groups as defined herein.
  • halocycloalkyl can be monohalocycloalkyl, dihalocycloalkyl or
  • polyhalocycloalkyl including perhalocyclo alkyl.
  • a monohalocycloalkyl can have one iodo, bromo, chloro or fluoro substituent.
  • Dihalocycloalkyl and polyhalocycloalkyl groups can be substituted with two or more of the same halo atoms or a combination of different halo groups.
  • cycloalkoxy refers to cyclo alkyl- 0-, wherein cycloalkyl is defined herein above.
  • halocycloalkoxy refers to halocycloalkyl-O-, wherein halocycloalkyl is defined herein above.
  • aryl refers to monocyclic, bicyclic or tricyclic aromatic hydrocarbon groups having from 6 to 14 carbon atoms in the ring portion. In some embodiments, the term aryl refers to monocyclic and bicyclic aromatic hydrocarbon groups having from 6 to 10 carbon atoms. Representative examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracenyl.
  • aryl also refers to a bicyclic or tricyclic group in which at least one ring is aromatic and is fused to one or two non-aromatic hydrocarbon ring(s).
  • Nonlimiting examples include tetrahydronaphthalene, dihydronaphthalenyl and indanyl.
  • heterocyclyl refers to a saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic ring system which has from 3- to 15-ring members at least one of which is a heteroatom, and up to 10 of which may be heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and wherein N and S can be optionally oxidized to various oxidation states.
  • a heterocyclyl is a 3-8-membered monocyclic.
  • a heterocyclyl is a 6-12-membered bicyclic.
  • a heterocyclycyl is a 10-15-membered tricyclic ring system.
  • the heterocyclyl group can be attached at a heteroatom or a carbon atom.
  • Heterocyclyls include fused or bridged or spiro ring systems.
  • the term “heterocyclyl” encompasses heterocycloalkyl groups.
  • the term “heterocycloalkyl” refers to completely saturated monocyclic, bicyclic or tricyclic heterocyclyl comprising 3-15 ring members, at least one of which is a heteroatom, and up to 10 of which may be heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and wherein N and S can be optionally oxidized to various oxidation states.
  • Examples of heterocyclyls include dihydrofuranyl,
  • thiomorpholinyl oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, azepinyl, oxapinyl, oxazepinyl and diazepinyl.
  • heterocyclyls include azepanyl, azetidinyl, 1,4-diazepanyl, 4,5-dihydrothiazolyl, morpholinyl, oxetanyl, piperidinyl, piperidin-2-one, piperazinyl, piperazin-2-one, pyrrolidinyl, tetrahydro-2H-pyranyl, 1,2,3,6-tetrahydropyridinyl, 3- azabicyclo [3.1.0]hexanyl, hexahydro- 1 H-pyrrolo [2, 1 -c] [ 1 ,4] oxazinyl, octahydropyrido [2,1- c] [ 1 ,4]oxazinyl, octahydropyrrolo[ 1 ,2-a]pyrazinyl, octahydropyrrolo[2,3-b]pyrrolyl, octahydropyr
  • heteroaryl refers to a 5-14 membered monocyclic-, bicyclic-, or tricyclic-ring system, having 1 to 10 heteroatoms independently selected from N, O or S, wherein N and S can be optionally oxidized to various oxidation states, and wherein at least one ring in the ring system is aromatic.
  • the heteroaryl is monocyclic and has 5 or 6 ring members.
  • Examples of monocyclic heteroaryl groups include pyridyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl.
  • Examples of monocyclic heteroaryl groups further include imidazolyl, oxadiazolyl, pyridinyl (or pyridyl), pyrazolyl, thiazolyl, and tetrazolyl.
  • the heteroaryl is bicyclic and has from 8 to 10 ring members.
  • bicyclic heteroaryl groups include indolyl, benzofuranyl, quinolyl, isoquinolyl indazolyl, indolinyl, isoindolyl, indolizinyl, benzamidazolyl, quinolinyl, 5,6,7, 8-tetrahydroquinoline and 6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine.
  • amino refers to a group having the formula NH 2 .
  • N-(alkyl) amino is an amino group in which one of the hydrogen atoms is replaced with an alkyl group.
  • N,N-(dialkyl)amino is an amino group in which each hydrogen atoms is replaced with an alkyl group which may be the same or different.
  • N- alkylcarbamoyl refers to a carbamoyl group in which one of the hydrogen atoms is replaced with an alkyl group.
  • ⁇ , ⁇ -dialkylcarbamoyl refers to a carbamoyl group in which each hydrogen atoms is replaced with an alkyl group which may be the same or different.
  • bridged ring system is a ring system that has a carbocyclyl or heterocyclyl ring wherein two non-adjacent atoms of the ring are connected (bridged) by one or more (such as from one to three) atoms.
  • a bridged ring system can have more than one bridge within the ring system (e.g. , adamantyl).
  • a bridged ring system may have from 6-10 ring members, such as from 7-10 ring members.
  • bridged ring systems include adamantly, 9-azabicyclo[3.3.1]nonan-9-yl, 8-azabicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, 3-azabicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, (1R,5S)- bicyclo[3.2.1]octanyl, 3-azabicyclo[3.3.1]nonanyl, and bicyclo[2.2.1]heptanyl.
  • the bridged ring system is selected from 9-azabicyclo[3.3.1]nonan-9-yl, 8- azabicyclo[3.2.1]octanyl, and bicyclo[2.2.2]octanyl.
  • the bridged ring system is selected from 9-azabicyclo[3.3.1]nonanyl, 8-azabicyclo[3.2.1]octanyl, 8- azabicyclo[3.2.1]oct-2-enyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.2]octanyl, 3,6-diazabicyclo[3.2.1]octanyl, and 3,9- diazabicyclo[3.3. l]nonanyl.
  • spiro ring system is a ring system that has a carbocyclyl or heterocyclyl with rings connected through just one atom.
  • the rings can be different in nature or identical.
  • a spiro ring system may have from 6-12 ring members, such as from 8- 10 ring members. Examples of spiro ring systems include 2,8- diazaspiro[4.5]decane, 5,8-diazaspiro[3.5]nonane, 4,7-diazaspiro[2.5]octane, and 6, 9- diazaspiro [4.5 ] decane .
  • C x _ xx The number of carbon atoms in a group is specified herein by the prefix "C x _ xx", wherein x and xx are integers.
  • Ci ⁇ alkyl is an alkyl group which has from 1 to 4 carbon atoms
  • C ⁇ alkoxy is an alkoxy group having from 1 to 6 carbon atoms
  • C 6 - 10 aryl is an aryl group which has from 6 to 10 carbon atoms
  • C 1 _ 4 haloalkyl is a haloalkyl group which has from 1 to 4 carbon atoms
  • N ⁇ -di-Ci-ealkylamino is a N,N-dialkylamino group in which the nitrogen is substituted with two alkyl groups each of which is
  • the disclosed compounds, or pharmaceutically acceptable salts thereof can contain one or more asymmetric centers in the molecule.
  • any structure that does not designate the stereochemistry is to be understood as embracing all the various optical isomers (e.g. , diastereomers and enantiomers) in pure or substantially pure form, as well as mixtures thereof (such as a racemic mixture, or an enantiomerically enriched mixture).
  • optically active forms for example, resolution of the racemic form by recrystallization techniques, synthesis from optically- active starting materials, by chiral synthesis, or chromatographic separation using a chiral stationary phase.
  • the disclosed compounds may exist in tautomeric forms and mixtures and separate individual tautomers are contemplated. In addition, some compounds may exhibit polymorphism.
  • H represents any isotopic form of hydrogen including H, H (D), and
  • compounds represented by formula (I) comprises isotopes of the atoms therein in their naturally occurring abundance.
  • a compound of the invention when, for example, hydrogen is enriched in the deuterium isotope, the symbol "D" may be used to represent the enrichment in deuterium.
  • a compound of the invention when enriched in a radioactive isotope, for example 3 H and 14 C, they may be useful in drug and/or substrate tissue distribution assays. It is to be understood that the invention encompasses all such isotopic forms which modulate ATX or SIP receptor activity.
  • L is -C(O)-, -O-C(O)-, -NR 6 -C(0)-, or -S(0) 2 -;
  • L 2 is a bond, -0-, or -NR-; provided that L 2 is not -O- when R 2 is structure (iv); R, for each occurrence, is independently hydrogen or a Ci ⁇ alkyl; R 1 is a Ci-galkylene;
  • R is selected form the group consisting of:
  • R 3 is hydrogen, -CN, C 1-8 alkyl, Ci-ghaloalkyl, -(CR 10 R n ) m -N(R 16 ) 2 , -(CR 10 R n ) m - OR 15 , -(CR 10 R n ) m -C(O)OR 15 , -(CR 10 R n ) m -C(O)N(R 16 ) 2 , -(CR 10 R n ) m -S(O) 2 N(R 16 ) 2 , - (CR 10 R u ) m -S(O) 2 NHS(O) 2 R 15 , -C(0)N(R 15 )-S(0) 2 R 15 , -S(0) 2 OR 15 , -C(0)NHC(0)R 15 , - Si(0)OH, -B(OH) 2 , -N(R 15 )S(0) 2 R 15 , -0-P(0)(OR 15 ) 2 , -
  • L 1 is Ci_ 8 alkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0) 2 NR-, or -C(0)NR-S(0) 2 -;
  • R 4 is Ci-galkyl, C 3 _gcycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R 4 may be optionally substituted with from one to four R 5 ;
  • R 5 is halo, cyano, Ci-galkyl, Ci-ghaloalkyl, C 3 - 8 cycloalkyl, -(CR 10 R u ) m -N(R 16 ) 2 , -(CR 10 R n ) m -OR 15 , -(CR 10 R n ) m -C(O)OR 15 , -C(0)N(R 16 ) 2 , -C(0)N(R 15 )-S(0) 2 R 15 , - S(0) 2 OR 15 , -C(0)NHC(0)R 15 , -Si(0)OH, -B(OH) 2 , -N(R 15 )S(0) 2 R 15 , -S(0) 2 N(R 15 ) 2 , O P(0)(OR 13 ) 2 , -P(0)(OR 13 ) 2 , -S(0) 2 NHC(0)R , -C(0)NHS(0) 2 R , C(0)NHOH,
  • C(0)NHCN, -C(0)R 15 , a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, 0, Ci_ 4 alkyl, Ci_ 4 haloalkyl, Ci_ 4 alkoxy, cyano, nitro, hydroxyl, amino, N-(Ci_ 4 alkyl)amino, N,N-di-(Ci_ 4 alkyl)amino, carbamoyl, N-iC ⁇ alky ⁇ carbamoyl, N,N-di-(Ci_ 4 alkyl)carbamoyl, C 1-4 alkylamido, Ci_ 4 alkylsulfonyl, Ci ⁇ alkylsulfonamido, sulfamoyl, N-Ci- 4 alkylsulfamo
  • R 6 is hydrogen or a Ci_galkyl
  • R for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C 3 _ 8 cycloalkyl,
  • R for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, Ci_galkyl, Ci-ghaloalkyl, C 3 _gcycloalkyl, C 3 _ghalocycloalkyl, Ci-galkoxy, Ci-ghaloalkoxy, C 3 _gcycloalkoxy, C 3 _ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N,N-di-(Ci_galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci_galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)
  • R 9 for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci_galkyl, Ci_galkoxy, Ci_ghaloalkyl, Ci-ghaloalkoxy,
  • R 9a is hydrogen or R 9 ; or R 9a and R 6 , together with the intervening atoms, form a 3- to 8-membered heterocyclyl which is optionally substituted with from one to three R 9 ; R and R , for each occurrence, are independently hydrogen, halo, hydroxyl, carboxy, C 1 _ 4 alkyl, or a C ⁇ haloalkyl;
  • R 15 for each occurrence is independently selected from the group consisting of hydrogen, Ci-galkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 cycloalkyl, C 3 - 8 cycloalkenyl, C6-ioaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R 15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C ⁇ alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N-iC ⁇ alky ⁇ amino, N ⁇ -di-iC ⁇ alky ⁇ amino, carboxyl, carbamoyl,
  • R 16 is Ci-salkoxy, or R 15 ; or two R 16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C ⁇ alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N-iC ⁇ alky ⁇ amino,
  • h 0, 1, or 2;
  • n for each occurrence, is independently 0, 1, 2, 3, or 4;
  • n for each occurrence, is independently 0 or an integer from 1 to 6;
  • p 0, 1, 2, or 3;
  • q 1, 2, 3, or 4;
  • r is 1, 2, or 3;
  • t is 0 or 1, provided that the compound is not:
  • R 2 is selected form the group consisting of:
  • p is 0, 1, or 2.
  • p is 1, and r is 1 or 2. In some embodiments, p is 2, and r is 1.
  • n is 1, and R 7 is Ci-salkyl. In some embodiments, n is 0.
  • t is 1 and R 8 is halo. In some embodiments, t is 0.
  • L 2 is a bond
  • R 1 is C 2 -8alkylene.
  • R 6 is hydrogen
  • R 9a is hydrogen
  • the compound of formula (I) is represented by formula (II):
  • L is -C(O)-, -O-C(O)-, or -NR-C(O)-.
  • L is -O-C(O)-.
  • R 1 is a Ci-galkylene
  • R 3 is hydrogen, -CN, Ci_ 8 alkyl, Ci_ 8 haloalkyl, -(CR 10 R n ) m -N(R 16 ) 2 , -(CR 10 R n ) m - OR 15 , -(CR 10 R n ) m -C(O)OR 15 , -(CR 10 R n ) m -C(O)N(R 16 ) 2 , -(CR 10 R n ) m -S(O) 2 N(R 16 ) 2 , - (CR 10 R u ) m -S(O) 2 NHS(O) 2 R 15 , -C(0)N(R 15 )-S(0) 2 R 15 , -S(0) 2 OR 15 , -C(0)NHC(0)R 15 , - Si(0)OH, -B(OH) 2 , -N(R 15 )S(0) 2 R 15 , -0-P(0)(OR 15 ) 2 ,
  • L 1 is Ci-galkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0) 2 NR-, or -C(0)NR-S(0) 2 -;
  • R for each occurrence, is independently hydrogen or C 1 _ 4 alkyl
  • R 4 is Ci-galkyl, C 3 _gcycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R 4 may be optionally substituted with from one to four R 5 ;
  • R 5 is halo, cyano, Ci-galkyl, Ci-ghaloalkyl, C 3 - 8 cycloalkyl, -(CR 10 R u ) m -N(R 16 ) 2 , -(CR 10 R n ) m -OR 15 , -(CR 10 R n ) m -C(O)OR 15 , -C(0)N(R 16 ) 2 , -C(0)N(R 15 )-S(0) 2 R 15 , - S(0) 2 OR 15 , -C(0)NHC(0)R 15 , -Si(0)OH, -B(OH) 2 , -N(R 15 )S(0) 2 R 15 , -S(0) 2 N(R 15 ) 2 , O P(0)(OR 15 ) 2 , -P(0)(OR 15 ) 2 , -S(0) 2 NHC(0)R 15 , -C(0)NHS(0) 2 R 15 , C(0)NHOH,
  • C(0)NHCN, -C(0)R 15 , a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, 0, Ci_ 4 alkyl, Ci_ 4 haloalkyl, Ci_ 4 alkoxy, cyano, nitro, hydroxyl, amino, N-(CMalkyl)amino, N,N-di-(CMalkyl)amino, carbamoyl, N-(Ci- 4 alkyl)carbamoyl, N,N-di-(CMalkyl)carbamoyl, Ci_ 4 alkylamido, Ci_ 4 alkylsulfonyl, Ci_ 4 alkylsulfonamido, sulfamoyl, N-Ci_ 4 alkylsulfamoyl, and N
  • R 9 for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci-galkyl, Ci_galkoxy, Ci-ghaloalkyl, Ci-ghaloalkoxy, C3_gcycloalkyl, C 3 _ghalocycloalkyl, C 3 _gcycloalkoxy, C 3 _ghalocycloalkoxy, Ci-galkanoyl, amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl, N-( ⁇ galkyl)sulfamoyl,
  • Ci-galkylsulfonamido C 6-1 oaryl, Ci-galkoxy-Ci-ealkyl, and tri-(Ci- 8 alk l)silyl;
  • R 10 and R 11 are independently hydrogen, halo, hydroxyl, carboxy, C 1-4 alkyl, Ci ⁇ haloalkyl;
  • R 15 for each occurrence is independently selected from the group consisting of hydrogen, Ci-galkyl, C 2 -galkenyl, C 2 _galkynyl, C 3 _gcycloalkyl, C 3 _gcycloalkenyl, C6-ioaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R 15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1 _ 4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N,N-di-(C M alkyl)amino, carboxyl, carbamoyl,
  • R 16 is Ci-galkoxy, or R 15 ; or two R 16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci ⁇ alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N-(C M alkyl)amino,
  • n for each occurrence, is independently 0 or an integer from 1 to 6;
  • q 1, 2, 3, or 4.
  • R 3 is hydrogen, -CN, Ci-galkyl, Ci-ghaloalkyl, -
  • R 16 for each occurrence, is independently selected from the group consisting of hydrogen, Ci-galkyl, C 3 _gcycloalkyl, or two R 16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1 _ 4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N-iC ⁇ alky ⁇ amino, N ⁇ -di-iC ⁇ alky ⁇ amino, carboxyl, carbamoyl,
  • R is H or Ci-galkyl.
  • m is 0.
  • R 3 is -C(0)OH.
  • q is 1 or 2.
  • R 9 for each occurrence, is independently selected from the group consisting of halo, Ci-galkyl, Ci-ghaloalkyl, and C6-ioaryl.
  • R 9 for each occurrence, is independently selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, and phenyl.
  • R 1 is methylene or ethylene.
  • R 1 is methylene
  • L is -O-C(O)-, -NR 6 -C(0)-, or -C(O)-; L 2 is a bond,
  • R 1 is C ⁇ alkylene
  • R 2 is selected form the group consisting of:
  • R 7 for each occurrence, is independently selected from the group consisting of halo, hydroxyl, cyano, carboxy, Ci_galkyl, Ci-ghaloalkyl, Ci_galkoxy, Ci-ghaloalkoxy, Ci_galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino,
  • Ci-galkoxycarbonyl Ci_galkanoyloxy, carbamoyl,
  • R for each occurrence, is independently selected from the group consisting of halo, hydroxyl, cyano, carboxy, Ci-galkyl,
  • Ci-ghaloalkyl Ci_galkoxy, Ci_ghaloalkoxy, Ci_galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci_galkoxycarbonyl, Ci_galkanoyloxy, carbamoyl,
  • R 7 for each occurrence, is independently selected from the group consisting of halo, hydroxyl, carboxy, C 1-4 alkyl, Ci_ 4 haloalkyl, Ci_ 4 alkoxy, C 1 _ 4 haloalkoxy, Ci-galkoxycarbonyl, and Ci-galkanoyloxy;
  • R for each occurrence, is independently selected from the group consisting of halo, cyano, C 1 _ 4 alkyl, C ⁇ haloalkyl, amino, N,N-di-( ⁇ galkyl)amino, and Ci-galkylamido; h is 0 or 1 ; n is 0 or 1 ; and t is 0 or 1.
  • R 7 for each occurrence, is independently selected from the group consisting of hydroxyl, carboxy, C 1-4 alkyl, and Ci-galkoxycarbonyl; R , for each occurrence, is independently selected from the group consisting of halo, cyano, C 1-4 alkyl, Ci ⁇ haloalkyl, and Ci ⁇ alkylamido; h is 0 or 1 ; n is 0 or 1 ; and t is 0 or 1.
  • R 7 is methyl, -OH, -COOH, -COOCH 3 or -
  • R 8 is chloro, bromo, CN, methyl, CF 3 , or NHC(0)CH 3 ; h is 0 or 1 ; n is 0 or 1 ; and t is 0 or 1.
  • R 9 for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci-galkyl, Ci-galkoxy, Ci-ghaloalkyl, Ci-ghaloalkoxy, Ci-galkanoyl, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl,
  • Ci-galkylthio Ci-galkylsulfonyl , sulfamoyl, N-( ⁇ galkyl)sulfamoyl,
  • R 9 for each occurrence, is independently selected from the group consisting of halo, cyano, carboxy, Ci-galkyl, Ci-galkoxy, Ci-ghaloalkyl, Ci- ghaloalkoxy, C 6-1 oaryl, and C 1-8 alkoxy-C 1-6 aLkyl; and q is 1, 2, or 3.
  • R 9 for each occurrence, is independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 haloalkyl, and phenyl; and q is 1, 2, or 3.
  • each R 9 is independently selected from methyl, fluoro, chloro, bromo, trifluoro methyl, and phenyl; q is 1, 2, or 3.
  • each R 9 is independently selected from methyl, fluoro, chloro, bromo, and trifluoromethyl; and q is 1, 2, or 3.
  • R is hydrogen or C 1-4 alkyl
  • R 6 is hydrogen or a Q-
  • R 9a is hydrogen or R 9 ; or R 9a and R 6 , together with the intervening atoms, form a 3- to 8-membered heterocyclyl which is optionally substituted with from one to three R 9 .
  • R is hydrogen or methyl;
  • R 9a is -hydrogen and R 6 is hydrogen; or
  • R 9a and R 6 together with the intervening atoms, form a tetrahydroisoquinolinyl ring.
  • R 9a is -hydrogen
  • t is 0.
  • t is l .
  • n is
  • n is 1.
  • h is 0.
  • h is 1.
  • R 3 is hydrogen, -CN, C 1-8 alkyl, Ci-ghaloalkyl, -(CR 10 R n ) m -N(R 16 ) 2 , -(CR 10 R n ) m - OR 15 , -(CR 10 R n ) m -C(O)OR 15 , -(CR 10 R n ) m -C(O)N(R 16 ) 2 , -(CR 10 R n ) m -S(O) 2 N(R 16 ) 2 , - C(0)NHS(0) 2 R 15 , a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -L 1 - R 4 ; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R 5 groups selected from Ci_ 4 alkyl, -OH, Ci_ 4 alkoxy, hydroxy(Ci_ 4 alkyl), -COOH, -COO
  • L 1 is Ci_ 8 alkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0) 2 NR-, or -C(0)NR-S(0) 2 -;
  • R for each occurrence, is independently hydrogen or a C 1-4 alkyl
  • R 4 is Ci ⁇ alkyl, C 3 _ 8 cycloalkyl, a 5 to 14 membered heteroaryl, or a 3 to 15 membered heterocyclyl, wherein R 4 may be optionally substituted with from one to four R 5 groups selected from halo, cyano, Ci-galkyl, Ci-ghaloalkyl, -COOH, -C(0)0-(Ci_ 4 alkyl), C 1-4 alkoxy, -OH, hydroxyCi_ 4 alkyl, -NH 2 , (Ci_ 4 alkyl)amino, C 3 _ 8 cycloalkyl, and a 3 to 15 membered heterocyclyl selected from 3-azabicyclo[3.1.0]hexanyl, azetidinyl, morpholinyl, piperidinyl, or pyrrolidinyl, wherein the heterocyclyl may be optionally substituted with one or two substituents independently selected from the group consisting of optionally substituted with C
  • R 10 and R 11 are independently hydrogen, carboxy, Ci_ 4 alkyl, or Ci_ 4 haloalkyl;
  • R 15 for each occurrence is independently selected from the group consisting of hydrogen, Ci_ 8 alkyl, C 2 _ 8 alkenyl, C 2 _ 8 alkynyl, C 3 _ 8 cycloalkyl, wherein R 15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci_ 4 alkoxy, Ci_ 4 alkyl, hydroxyl, amino, N-(Ci_ 4 alkyl)amino, N,N-di-(Ci_ 4 alkyl)amino, and carboxyl;
  • Each R is independently selected from hydrogen, Ci-galkoxy, Ci-galkyl, C 2 _galkenyl, C 2 _galkynyl, C 3 _gcycloalkyl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S;
  • Ci ⁇ alkylamidol or two R 16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1-4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, carboxyl, carbamoyl, and m, for each occurrence, is independently 0 or 1.
  • R 3 is hydrogen, -CN, C M alk l, Ci_ 4 haloalkyl, -N(R 16 ) 2, -CR 10 R U -N(R 16 ) 2 , -OR 15 , -CR 10 R U -OR 15 , -C(0)OR 15 , -CR 10 R n -C(O)OR 15 , -C(0)N(R 16 ) 2 , -CR 10 R n -C(O)N(R 16 ) 2 , - S(0) 2 N(R 16 ) 2 , C(0)NHS(0) 2 R 15 , a 5 to 14 membered heteroaryl selected from 1,2,4- oxadiazolyl, pyridinyl, pyrazolyl, and tetrazolyl; a 3 to 15 membered heterocyclyl selected from 8-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]oct-2-enyl, 3,8- di
  • L 1 is -CH 2 -, -CH(CH 3 )-, -C(O)-, -C(0)0-, -C(0)NR-, -S(0) 2 NR-, or -C(0)NR-
  • R for each occurrence, is independently hydrogen or a C 1-4 alkyl;
  • R 4 is C 1-4 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a 3 to 15 membered heterocyclyl selected from 3-azabicyclo[3.1.0]hexanyl,
  • R 4 may be optionally substituted with from one to four groups selected from halo, -CN, Ci- 4 alkyl, -CF 3 ,-COOH, -COOCH 3 , -COO-t-butyl, -OH, -CH 2 CH 2 OH, -OCH 3 , -NH 2 ,
  • heterocyclyl selected from 3- azabicyclo[3.1.0]hexanyl, azetidinyl, morpholinyl, piperidinyl, or pyrrolidinyl, wherein the heterocyclyl may be optionally substituted with one or two substituents independently selected from the group consisting of optionally substituted with C ⁇ alkyl, -OH, and COOH;
  • R 10 and R 11 are independently hydrogen, carboxy, methyl, or
  • R 15 for each occurrence is independently selected from the group consisting of hydrogen, C 1-4 alkyl
  • Each R 16 is independently selected from hydrogen, C ⁇ alkoxy, C 1-4 alkyl, C 2 _galkenyl, C 2 _galkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 3 to 15 membered heterocyclyl selected from 8-azabicyclo[3.2.1]octanyl, 9-azabicyclo[3.3.1]nonanyl, azepanyl, 4,5-dihydroimidazolyl, 4,5-dihydrothiazolyl, oxetanyl, piperidinyl,
  • R 16 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1-4 alkoxy, C 1-4 alkyl, hydroxyl, amino, N,N-di-(C ⁇ alkyl)amino, and carboxyl; or two R 16 together with the nitrogen atom to which they are attached a 3 to 15 membered heterocyclyl selected from 9-azabicyclo[3.3.1]nonanyl,
  • octahydropyrrolo[2,3-b]pyrrolyl piperazin-2-onyl, piperidinyl, piperizinyl, and pyrrolidinyl and wherein the heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1 _ 4 alkoxy, C 1-4 alkyl, cyano, hydroxyl, amino, N,N-di-(C ⁇ alkyl)amino, and carboxyl.
  • R 3 is hydrogen; -CN; -CH 3 ; -CF 3 ; CH 2 Br; -NH 2 ; -NH-
  • -NH-piperidinyl optionally substituted with 1 or 2 groups selected from methyl, ethyl, isopropyl or t-butyl; -CH 2 NH 2 ; -CH(COOH)NH 2 ; -CH 2 NHCH 3 ; -CH 2 N(CH 3 ) 2 ;
  • -CH(CH 3 )NH 2 ; -CH 2 NH-cyclopropyl; -CH 2 NH-cyclobutyl optionally substituted with 1, 2 or 3 groups selected from methyl or carboxyl; -CH 2 NH-cyclohexyl optionally substituted with carboxyl; -CH(CH 3 )NH-cyclopropyl; -CH 2 -8-azabicyclo[3.2.1]octanyl optionally substituted with carboxy; -CH 2 -9-azabicyclo[3.3.1]nonane optionally substituted with carboxy;
  • -C(0)CH 2 -morpholino optionally substituted with 1 or 2 methyl groups; -C(0)CH 2 - piperidinyl; -C(0)CH 2 -pyrrolidinyl optionally substituted with methyl orhydroxyl; 1,2,4- oxadiazolyl optionally substituted with methyl; pyridinyl optionally substituted with methyl; pyrazolyl optionally substituted with CH 2 COOH; tetrazolyl; 8-azabicyclo[3.2.1]octanyl optionally substituted with methyl; 8-azabicyclo[3.2.1]oct-2-enyl optionally substituted with methyl; 3,8-diazabicyclo[3.2.1]octanyl; 1,4-diazepanyl optionally substituted with methyl; 4,7-diazaspiro[2.5]octanyl optionally substituted with methyl; hexahydro-lH-pyrrolo[2,l- c] [ 1 ,4
  • L is a bond
  • R is C ⁇ alkylene
  • R 3 is -(CR 10 R n ) m -C(O)OR 15 , a 3 to 15 membered heterocyclyl selected from 8- azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]oct-2-enyl, 3,8-diazabicyclo[3.2.1]octanyl, 1,4-diazepanyl, 4,7-diazaspiro[2.5]octanyl, hexahydro-lH-pyrrolo[2,l-c][l,4]oxazinyl, octahydropyrido[2, 1 -c] [ 1 ,4] oxazinyl, octahydropyrrolo[ 1 ,2-a]pyrazinyl,
  • octahydropyrrolo[3,2-b]pyrrole octahydropyrrolo[3,4-c] piperidin-2-only, piperidinyl, piperizinyl, pyrrolidinyl, 1,2,3,6-tetrahydropyridinyl, wherein heterocyclyl is optionally substituted with one to four groups selected from C 1 _ 4 alkyl, hydroxyC ⁇ alkyl, -COOH, - COO-Ci_ 4 alkyl, -CH 2 COOH, and -CH 2 COO-C alk l; or -L x -R 4 ;
  • L 1 is -C(O)-
  • R 4 is 3 to 15 membered heterocyclyl selected from 9-azabicyclo[3.3.1]nonanyl, 8-azabicyclo[3.2. l]octanyl, azetidinyl, 2,5-diazabicyclo[2.2. l]heptanyl,
  • R 9a is -hydrogen
  • R 10 and R 11 are independently hydrogen or C 1-4 alkyl;
  • R 15 is hydrogen or C 1-4 alkyl;
  • m is 0 or 1 ;
  • n is 0 or 1 ;
  • q is 1, 2, or 3;
  • p is 1 or 2;
  • r is 1 or 2; and
  • t is 0 or 1.
  • L is -O-C(O)-
  • R 3 is -C(0)OR 15 ; -CR 10 R n -C(O)OR 15 a 3 to 15 membered heterocyclyl selected from azetidinyl, morpholinyl, piperazin-2-onyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl, hexahydro- 1 H-pyrrolo [2, 1 -c] [ 1 ,4] oxazinyl, octahydropyrido [2, 1 -c] [ 1 ,4] oxazinyl,
  • heterocyclyl is optionally substituted with one to four groups selected from C ⁇ alkyl, hydroxyCwalkyl, -COOH, -COO-C ⁇ alkyl, -CH 2 COOH, and -CHaCOO-Ci ⁇ alkyl; or -I ⁇ -R 4 ;
  • L 1 is -C(O)-
  • R 4 is 3 to 15 membered heterocyclyl selected azetidinyl, morpholinyl, piperazin-2- onyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl, tetrahydro-2H-pyranyl, the
  • heterocyclyl may be optionally substituted with from one to four groups selected from halo, Ci_ 4 alkyl, -CF 3 ,-COOH, -COOCH 3 , -COO-t-butyl; each R 9 is independently selected from halo and Ci ⁇ haloalkyl;
  • R 9a is -hydrogen
  • R 10 and R 11 are independently hydrogen or C 1-4 alkyl; R is hydrogen or C 1 _ 4 alkyl; and q is 1, 2, or 3.
  • R 3 is -C(0)OH; -CH 2 C(0)OH, hexahydro- 1H- pyrrolo[2,l-c][l,4]oxazinyl, piperizinyl; -C(0)-piperizinyl, wherein the piperizinyl is optionally substituted with 1, 2 or 3 C ⁇ alkyl groups.
  • the invention is any one the compounds disclosed in the Exemplification section as a neutral compound or a pharmaceutically acceptable salt thereof.
  • a compound provided herein is sufficiently basic or acidic to form stable nontoxic acid or base salts
  • preparation and administration of the compounds as pharmaceutically acceptable salts may be appropriate.
  • pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a-ketoglutarate, or a-glycerophosphate.
  • Inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • Salts from inorganic bases can include but are not limited to, sodium, potassium, lithium, ammonium, calcium or magnesium salts.
  • Salts derived from organic bases can include, but are not limited to, salts of primary, secondary or tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cyclo
  • amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.
  • Non-limiting examples of amines can include, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N- alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, or N- ethylpiperidine, and the like.
  • Other carboxylic acid derivatives can be useful, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, or dialkyl carboxamides, and the like.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof can modulate the activity of SIP receptors.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof can have SIP receptor agonist or antagonist activity.
  • the compound, or a pharmaceutically acceptable salt thereof can be selective for the S1P4 receptor.
  • the compound, or a pharmaceutically acceptable salt thereof can be a selective S1P4 antagonist. Being selective can mean that the compound, or a pharmaceutically acceptable salt thereof, binds to the receptor (or relatively small group of related molecules or proteins) in a complex mixture, or in other words, when exposed to a variety of closely related receptor types, the compound, or a pharmaceutically acceptable salt thereof, can bind preferentially to just one of the receptor types.
  • the compound, or a pharmaceutically acceptable salt thereof can have a greater affinity for the S1P4 receptor, by at by at least 100-fold, by at least 50-fold, by at least 10-fold, by at least 5-fold or by at least 2-fold, than for S1P1 receptor, S1P2 receptor, S1P3 receptor, or S1P5 receptor.
  • An inhibitor of S1P4 mediated activity can block SIP interaction with an S1P4 receptor.
  • the inhibitor can be an antagonist of an S1P4 receptor.
  • An antagonist can be a molecule that has affinity for the receptor but does not induce activity or a specific activity from the receptor.
  • the antagonist can bind with an S1P4 receptor with an IC 50 value of less than 1 ⁇ , less than 750 nM, less than 500 nM, less than 250 nM or less than 100 nM.
  • the antagonist can bind with an S1P4 receptor with an IC 50 value in a range between 1 nM and 1 ⁇ , between 1 nM and 500 nM, between 10 nM and 250 nM, between 25 nm and 100 nM, or between 50 nM and 100 nM.
  • the compound, or a pharmaceutically acceptable salt thereof can also promote oligodendrocyte progenitor cell differentiation.
  • the compound, or a pharmaceutically acceptable salt thereof can also promote oligodendrocyte progenitor cell differentiation.
  • pharmaceutically acceptable salt thereof can promote myelination or remyelination.
  • SIP modulating agent refers a compound, or a pharmaceutically acceptable salt thereof, or composition that is capable of inducing a detectable change in SIP receptor activity in vivo or in vitro (e.g., at least 10% increase or decrease in SIP activity as measured by a given assay such as the assays described in the examples and known in the art.
  • SIP receptor refers to all of the SIP receptor subtypes (for example, the SIP receptors S1P1, S1P2, S1P3, S1P4, or S1P5), unless the specific subtype is indicated. It is well known in the art how to determine SIP agonist or antagonist activity using the standard tests described herein, or using other similar tests which are well known in the art. In some cases, depending on the cell type and conditions used, an SIP modulating agent can have agonist or antagonist activity, even at the same receptor subtype.
  • an SIP modulating agent vary depending on whether the compound, or a pharmaceutically acceptable salt thereof, has SIP receptor agonist or antagonist activity.
  • Potential uses of an SIP modulating agent include, but are not limited to, prevention or treatment of a pathological condition or symptom in a mammal.
  • the condition can include asthma, an inflammatory neuropathies, arthritis, lupus
  • the condition can alter lymphocyte trafficking as a method of treatment for neuropathic pain, inflammation- induced pain (e.g., where prostaglandins are involved) or treatment of autoimmune pathologies such as uveitis, type I diabetes, rheumatoid arthritis, chronic inflammatory disorders, inflammatory bowel diseases (e.g., Crohn's disease and ulcerative colitis), multiple sclerosis, and in drug-eluting stents. Additional uses can include treatment of brain degenerative diseases, heart diseases, cancers, or hepatitis C. See, for example, WO
  • PCT/US2008/073378 filed August 15, 2008, each of which is incorporated by reference in its entirety. See also provisional U.S. Application no. 61/231,539, filed August 5, 2009, and PCT/US2010/44607, filed August 5, 2010, each of which is incorporated by reference in its entirety. See also provisional U.S. Application no. 61/440,254, filed February 7, 2011, and PCT/US2012/23799 filed February 6, 2012, each of which is incorporated by reference in its entirety.
  • SIP modulating agent include, but are not limited to, prevention or treatement of a pathological condition or symptom in a mammal.
  • the condition can include inhibited cell migration of oligodendrocyte precursor cells (OPCs).
  • OPCs oligodendrocyte precursor cells
  • SIP receptor antagonist and S1P4 receptor type selective antagonists particularly, include, but are not limited to, prevention or treatment of a pathological condition or symptom in a mammal.
  • LPA has been shown to be involved in lymphocyte trafficking and helps promote entry of lymphocytes into secondary lymphoid organs (see Kanda, et al., Nat.
  • the disclosed compounds and salts thereof are expected to be useful for altering lymphocyte trafficking as a method for prolonging allograft survival, for example transplantation including solid organ transplants, treatment of graft vs. host disease, bone marrow transplantation, and the like.
  • an "ATX modulating agent” refers a compound, or a pharmaceutically acceptable salt thereof, or composition that is capable of inducing a detectable change in ATX activity in vivo or in vitro (e.g., at least 10% increase or decrease in ATX activity as measured by a given assay such as the assays described in the examples and known in the art.
  • the compound, or a pharmaceutically acceptable salt thereof be an ATX modulating agent, i.e., it can modulate the activity of ATX.
  • the compound, or a pharmaceutically acceptable salt thereof can be an ATX inhibitor.
  • the compound, or a pharmaceutically acceptable salt thereof can be a selective ATX modulating agent. Being selective can mean that the compound, or a pharmaceutically acceptable salt thereof, binds to ATX preferentially when exposed to a variety of potential binding partners.
  • compositions can have a greater affinity for the ATX, by at by at least 100-fold, by at least 50-fold, by at least 10-fold, by at least 5-fold or by at least 2-fold, than for other binding partners.
  • Affinity can be measured, for example, as a dissociation constant (K ⁇ , as an inhibition constant (such as IC 50 ), or another measure; provided that affinity is measured in a consistent fashion between ATX and the other binding partners it is compared to.
  • K ⁇ dissociation constant
  • An inhibitor of ATX mediated activity can block interaction of ATX with its native substrate(s), such as LPC.
  • the inhibitor can show an IC 50 value of less than 1 ⁇ , less than 750 nM, less than 500 nM, less than 250 nM, less than 100 nM, less than 50 nM, less than 25 nM, or less than 10 nM, when measured in a FRET-based assay using FS-3 substrate (see, e.g., Ferguson, C.G., et al., Org Lett. 2006 May 11; 8(10): 2023-2026, which is incorporated by reference in its entirety).
  • an ATX modulating agent includes, but are not limited to, prevention or treatment of a pathological condition or symptom in a mammal.
  • the pathological disorder can be an inflammatory disorder, an autoimmune disorder, a fibrosis of the lung, or a malignancy of the lung.
  • the pathological disorder can also be an inflammatory disorder, an autoimmune disorder, a fibrosis of the lung, a malignancy of the lung, liver fibrosis, or renal fibrosis.
  • the pathological disorder is a fibrotic disease, including, for example, a fibrosis of the lung, liver fibrosis, kidney fibrosis, and scleroderma.
  • Prevention or treatment of the pathological condition or symptom can include administering to the mammal an effective amount of an ATX modulating agent, e.g., an ATX inhibitor, to prevent, treat or reduce symptoms of the inflammatory disorder, autoimmune disorder, the fibrosis of the lung, or the malignancy of the lung.
  • Prevention or treatment of the pathological condition or symptom can also include administering to the mammal an effective amount of an ATX modulating agent, e.g., an ATX inhibitor, to prevent, treat or reduce symptoms of the inflammatory disorder, autoimmune disorder, the fibrosis of the lung, the malignancy of the lung, liver fibrosis, or renal fibrosis.
  • Prevention or treatment of the pathological condition or symptom can also include administering to the mammal an effective amount of an ATX modulating agent, e.g., an ATX inhibitor, to prevent, treat or reduce symptoms of the fibrotic disease, including, for example, a fibrosis of the lung, liver fibrosis, kidney fibrosis, and scleroderma.
  • an ATX modulating agent e.g., an ATX inhibitor
  • the inflammatory disorder is rheumatoid arthritis (RA).
  • the inflammatory disorder is asthma.
  • the inflammatory disorder is periodontal disease.
  • the autoimmune disorder is multiple sclerosis (MS).
  • the autoimmune disorder is scleroderma.
  • lung fibrosis is an interstitial lung disease, for instance, pulmonary fibrosis. See, for example, WO 2011/151461, which is incorporated by reference in its entirety.
  • an ATX inhibitor of the present invention can be used to treat or prevent a demyelinating disease or disorder.
  • Demyelinating diseases or disorders include multiple sclerosis, Guillain-Barre Syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis, and optic neuritis, spinal cord injury, stroke or other ischemia, cerebral palsy, Charcot-Marie-Tooth disease (CMT), Sjogren-Larsson syndrome, Refsum disease, Krabbe disease, Canavan disease, Alexander disease, nerve damage due to pernicious anemia, progressive multifocal leukoencephalopathy (PML), Lyme disease, tabes dorsalis due to untreated syphilis, demyelination due to exposure to an organophosphates, demyelination due to vitamin B12 deficiency or copper deficiency.
  • CBi antagonism is associated with a decrease in body weight and an improvement in blood lipid profiles.
  • the CBi antagonism could be in concert with SIP receptor activity, or be independent of activity at any SIP receptor.
  • disclosed compounds and salts can be useful for inhibition of group IVA cytosolic PLA 2 (cPLA 2 ).
  • cPLA 2 catalyzes the release of eicosanoic acids (e.g., arachidonic acid).
  • the eicosanoic acids are transformed to pro-inflammatory eicosanoids such as prostaglandins and leukotrienes.
  • disclosed compounds and salts may be useful as anti-inflammatory agents. This inhibition could be in concert with SIP receptor activity, or be independent of activity at any SIP receptor.
  • lipid kinase MuLK
  • MuLK multiple substrate lipid kinase
  • MS can begin with a relapsing-remitting pattern of neurologic involvement, which then can progress to a chronic phase with increasing neurological damage.
  • MS can be associated with the destruction of myelin, oligodendrocytes or axons localized to chronic lesions.
  • the demyelination observed in MS may not always permanent and remyelination has been documented in early stages of the disease. Remyelination of neurons can require oligodendrocytes.
  • Axons and dendrites can extend from neurons.
  • the distal tip of an extending axon or neurite can include a specialized region, known as the growth cone.
  • Growth cones can sense the local environment and can guide axonal growth toward a neuron's target cell. Growth cones can respond to environmental cues, for example, surface adhesiveness, growth factors, neurotransmitters and electric fields.
  • the growth cones can advance at a rate of one to two millimeters per day.
  • the growth cone can explore the area ahead of it and on either side, by means of elongations classified as lamellipodia and filopodia. When an elongation contacts an unfavorable surface, it can withdraw. When an elongation contacts a favorable growth surface, it can continue to extend and guides the growth cone in that direction. When the growth cone reaches an appropriate target cell a synaptic connection can be created.
  • Nerve cell function can be influenced by contact between neurons and other cells in their immediate environment (Rutishauser, et al., 1988, Physiol. Rev. 68:819, which is incorporated by reference in its entirety). These cells can include specialized glial cells, oligodendrocytes in the central nervous system (CNS), and Schwann cells in the peripheral nervous system (PNS), which can sheathe the neuronal axon with myelin (Lemke, 1992, in An Introduction to Molecular Neurobiology, Z. Hall, Ed., p. 281, Sinauer, each of which is incorporated by reference in its entirety).
  • CNS central nervous system
  • PNS peripheral nervous system
  • LPA causes the collapse of the neuron growth cone and tends to inhibit or reverse the morphological differentiation of many neuronal cell lines (see Gendaszewska-Darmach, Acta Biochimica Polonica (2008), 55(2):227-240). Since ATX activity is involved in the generation of LPA, inhibitors of ATX should increase the ability of the nervous system to make synaptic connections. Thus, ATX inhibitors may be useful in treating neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, Parkinson's disease (including Parkinson's dementia), Lewy Body Dementia, amylotrophic lateral sclerosis (ALS), Friedreich's ataxia, spinal muscular atrophy.
  • neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, Parkinson's disease (including Parkinson's dementia), Lewy Body Dementia, amylotrophic lateral sclerosis (ALS), Friedreich's ataxia, spinal muscular atrophy.
  • CNS neurons can have the inherent potential to regenerate after injury, but they can be inhibited from doing so by inhibitory proteins present in myelin (Brittis et al., 2001, Neuron 30: 11-14; Jones et al., 2002, /. Neurosci. 22:2792-2803; Grimpe et al., 2002, /. Neurosci. :22:3144-3160, each of which is incorporated by reference in its entirety).
  • myelin inhibitory proteins found on oligodendrocytes have been characterized.
  • myelin inhibitory proteins can include NogoA (Chen et al., Nature, 2000, 403, 434-439; Grandpre et al., Nature 2000, 403, 439-444, each of which is incorporated by reference in its entirety), myelin associated glycoprotein (MAG)
  • OM-gp neuronal Nogo receptor- 1
  • NgRl Neuronal Nogo receptor- 1
  • Nogo receptor- 1 is a GPI- anchored membrane protein that contains 8 leucine rich repeats (Fournier et al., 2001, Nature 409:341-346, which is incorporated by reference in its entirety).
  • inhibitory proteins e.g., NogoA, MAG and OM-gp
  • the NgRl complex can transduce signals that lead to growth cone collapse and inhibition of neurite outgrowth.
  • Such diseases, disorders or injuries can include, but are not limited to, multiple sclerosis (MS), progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelolysis (CPM), adrenoleukodystrophy, Alexander's disease, Pelizaeus Merzbacher disease (PMZ), Globoid cell Leucodystrophy (Krabbe's disease) and Wallerian Degeneration, optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, AR, Bassen-Kornzweig syndrome, Marchiafava-Bignami syndrome,
  • MS multiple sclerosis
  • PML progressive multifocal leukoencephalopathy
  • EPL
  • MS metachromatic leukodystrophy, trigeminal neuralgia, or Bell's palsy.
  • MS may the most widespread, affecting approximately 2.5 million people worldwide.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof can promote myelination or remyelination.
  • a method can include administering a compound provided herein, or a pharmaceutically acceptable salt thereof, to cells.
  • a method of promoting oligodendrocyte progenitor cell differentiation can include administering a compound provided herein, or a pharmaceutically acceptable salt thereof, to cells.
  • a method of treating multiple sclerosis can include administering a compound provided herein, or a pharmaceutically acceptable salt thereof, to a subject.
  • ATX is expressed in non-pathological conditions, throughout development, with high expression levels in the CNS among other tissues.
  • ATX mRNA was identified as highly upregulated during oligodendrocyte
  • ATX protein expression is also apparent in maturing ODCs, temporally correlated with the process of myelination.
  • ATX is expressed in secretory epithelial cells, such as the choroid plexus, ciliary, iris pigment, and retinal pigment epithelial cells, whereas there is evidence for ATX expression in leptomenigneal cells and cells of the CNS vasculature.
  • ATX is highly upregulated in astrocytes following brain lesion.
  • LPA reactive astrogliosis
  • astrocytes upregulate the LPA- generating enzyme ATX and become activated by its metabolite LPA, while increased amounts of the metabolite inhibit the catalytic activity of ATX.
  • ATX expression levels were shown to be elevated in glioblastoma multiform samples, and ATX was shown to augment invasiveness of cells transformed with ras, a key signaling molecule that promotes gliomagenesis. ATX expression was also detected in primary tumor tissues from neuroblastoma patients and retinoic acid induced expression of ATX in N-myc-amplified neuroblastoma cells.
  • EAE autoimmune encephalitis
  • Hoelzinger D.B., et al. Neoplasia 7, 7-16 (2005); Nam, S.W., et al., Oncogene 19, 241-247 (2000); Kawagoe, H., et al., Cancer Res 57, 2516-2521 (1997); Dufner-Beattie, J., et al., Mol Carcinog 30, 181- 189 (2001); Umemura, K., et al., Neuroscience Letters 400, 97-100 (2006); and Fuss, B., et al., J Neurosci 17, 9095-9103 (1997); each of which is incorporated by reference in its entirety.
  • ATX mRNA expression was found to be elevated in the frontal cortex of Alzheimer-type dementia patients indicating a potential involvement for ATX signaling in neurodegenerative diseases.
  • LPA receptors are enriched in the CNS and their expression patterns suggest their potential involvement in developmental process including neurogenesis, neuronal migration, axon extension and myelination.
  • only two receptors have the same spatiotemporal expression as ATX in the CNS (Contos, J.J., et al., Mol Cell Biol 22, 6921-6929 (2002); Jaillard, C, ei al, Edg8/Sl P5: an oligodendroglial receptor with dual function on process retraction and cell survival.
  • LPAi and SIP5 are specific for ODCs, and their expression highly correlates with the process of myelination.
  • LPA1 is expressed in restricted fashion within the neuroblasts of the neuroproliferatve Ventricular Zone (VZ) of the developing cortex, in the dorsal olfactory bulb, along the pial cells of neural crest origin, and in developing facial bone tissue. Expression is observed during E11-E18, corresponding to a time period during which neurogenesis occurs.
  • VZ Neuroproliferatve Ventricular Zone
  • LPA1 expression is undetectable in the VZ after this point, to reappear during the first postnatal week within ODCs.
  • Schwann cells the myelinating cells of the Peripheral Nervous System; PNS express high levels of LPA1 early in development and persistently throughout life, suggesting an influence of LPA on myelinating processes (Weiner. J. A. & Chun, J., Proc Natl Acad Sci U S A 96, 5233-5238 (1999), which is incorporated by reference in its entirety).
  • SIP modulating agents and/or ATX modulating agents of formula (I) can be used to various forms of MS including relapsing-remitting, secondary-progressive, primary-progressive, and progressive-relapsing forms.
  • SIP modulating agents and/or ATX modulating agents of formula (I) can be used alone or in conjunction with other agents to treat or prevent MS.
  • the compounds and salts described herein can be used to treat or prevent MS in combination with an immunomodulating therapy such as corticosteroids, beta interferon- la (such as Avonex® or Rebif®), beta interferon- lb (Betaseron®), natalizumab (Tysabri®), glatiramer,and mitoxantrone.
  • an immunomodulating therapy such as corticosteroids, beta interferon- la (such as Avonex® or Rebif®), beta interferon- lb (Betaseron®), natalizumab (Tysabri®), glatiramer,and mitoxantrone.
  • Promoting myelination, remyelination or oligodendrocyte progenitor cell differentiation can prevent or can treat a pathological condition or symptom in a mammal.
  • a number of diseases or disorders involve demyelination of the central or peripheral nervous system which can occur for a number of reasons such as immune dysfunction as in multiple sclerosis, encephalomyelitis, Guillain-Barre Syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis, and optic neuritis; demyelination due to injury such as spinal cord injury, traumatic brain injury, stroke, acute ischemic optic neuropathy, or other ischemia, cerebral palsy, neuropathy (e.g.
  • CMT Charcot-Marie-Tooth disease
  • Sjogren-Larsson syndrome Refsum disease
  • Krabbe disease Canavan disease
  • Alexander disease Friedreich's ataxia
  • Pelizaeus-Merzbacher disease Bassen-Kornzweig syndrome
  • MLD metachromatic leukodystrophy
  • adrenoleukodystrophy nerve damage due to pernicious anemia
  • viral infection such as progressive multifocal leukoencephalopathy (PML), Lyme disease, or tabes dorsalis due to untreated syphilis
  • toxic exposure due to chronic alcoholism (which is a possible cause of Marchiafava-Bignami disease)
  • demyelination disorders can have unknown or multiple causes such as trigeminal neuralgia, Marchiafava-Bignami disease and Bell's palsy.
  • demyelination can contribute to neuropathic pain.
  • Compounds and salts described herein are expected to be useful in treating demyelination disorders.
  • LPA is a proinflammatory factor reducing the amount of LPA producted by inhibiting ATX is useful for treating inflammatory disorders such as asthma, allergies, arthritis, inflammatory neuropathies, transplantation rejection, Crohn's disease, ulcerative colitis, lupus erythematosis, psoriasis, an inflammatory bowel condition, and diabetes.
  • Pain experienced by mammals can be divided into two main categories: acute pain (or nociceptive) and chronic pain which can be subdivided into chronic inflammatory pain and chronic neuropathic pain.
  • Acute pain is a response to stimulus that causes tissue injury and is a signal to move away from the stimulus to minimize tissue damage.
  • Chronic pain serves no biological function and develops as a result of
  • Chronic pain is generally characterized by stimulus-independent, persistent pain or by abnormal pain perception triggered by innocuous stimuli.
  • LPA has been found to be a mediator of both inflammatory pain and neuropathic pain.
  • the transient receptor potential channel TRPV1 is known to be the originator of inflammatory pain.
  • LPA has been shown to directly activate TRPV1 thereby creating pain stimulus by binding to its intracellular C-terminus (Tigyi, Nature Chemical Biology (January 2012), 8:22-23).
  • compounds and salts which inhibit the formation of LPA by inhibiting the action of ATX would be useful in treating inflammatory pain.
  • LPA has also been shown to play a role in neuropathic pain.
  • the pathological disorder can be selected from pain, acute pain, chronic pain, neuropathic pain, visceral pain, nociceptive pain including post-surgical pain, and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back and orofacial pain; and pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia, causalgia, and conditions of lower urinary tract dysfunction.
  • WO2013061297 which is incorporated by reference in its entirety
  • the compounds and salts described herein are useful in treating or preventing chronic pain such as inflammatory pain and neuropathic pain in mammals.
  • ATX plays a role in the development and progress of the disease.
  • increased ATX mRNA expression was detected in synovial fibroblasts (SFs) from animal models of RA during differential expression profiling, and human RA SFs were shown to express mRNA for both ATX and LPARs (Aidinis, V., et al., PLoS genetics 1, e48 (2005); Zhao, C, et al., Molecular pharmacology 73, 587-600 (2008); each of which is incorporated by reference in its entirety).
  • ATX is overexpressed from activated SFs in arthritic joints, both in animal models and human patients (see WO 2011/151461).
  • ATX expression was shown to be induced from TNF, the major pro-inflammatory factor driving RA.
  • ATX expression was conditionally ablated specifically in SFs, the lack of ATX expression in the joints resulted in marked decreased inflammation and synovial hyperplasia. This suggested an active involvement of the ATX-LPA axis in the pathogenesis of the disease. Similar results were also obtained with pharmacologic inhibition of ATX enzymatic activity and LPA signaling.
  • ECM extracellular matrix
  • MMPs matrix metalloproteinases
  • LPA effect was shown to be synergistic with TNF and dependent on the activation of MAPK cellular signaling pathways. See, e.g., Armaka, M., et al., The Journal of experimental medicine 205, 331-337 (2008); which is incorporated by reference in its entirety.
  • a method for treating an individual with RA or the individual at risk of suffering thereof comprises administering to said individual an SIP modulating agent and/or ATX modulating agent of formula (I) in conjunction with an anti- TNF antibody for use in the treatment of RA.
  • suitable anti-TNF antibodies are adalimumab, etanercept, golimumab, and infliximab (Taylor PC, Feldmann M. Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol. 2009 Oct;5(10):578-82).
  • the ATX-LPA pathway appears to have role in the pathogenesis of asthma, for example, see Park, et al, Am J Respir Crit Care Med Vol 188, Iss. 8, pp 928-940, 2013, the entire teachings of which are incorporated herein by reference.
  • the compounds and salts described herein are useful in preventing, treating, or reducing symptoms of asthma in a mammal in need thereof.
  • Elevated levels of LPA may contribute to the pathogenesis and progression of periodontal diseases, see Bathena, et al, Journal of Pharmaceutical and Biomedical Analysis 56 (2011) 402- 407, the entire teachings of which are incorporated herein by reference.
  • the compounds and salts described herein are useful in preventing, treating, or reducing symptoms of periodontal disease in a mammal in need thereof.
  • the compounds and salts described herein are useful in preventing, treating, or reducing symptoms of pulmonary fibrosis in a mammal in need thereof.
  • liver fibrosis may exhibit increased ATX and LPA levels in the blood, see, for example, Ikeda, et al., Clinica Chimica Acta 413 (2012) 1817-1821; and Budd, et al., Future Med. Chem. (2013) 5(16), 1935-1952, the entire teachings of both are incorporated herein by reference.
  • the compounds and salts described herein are useful in preventing, treating, or reducing symptoms of liver fibrosis in a mammal in need thereof. Renal Fibrosis
  • LPA has been shown to be involved in wound healing and stimulates the proliferation and migration of endothelial cells promoting processes such as angiogenesis.
  • processes when deregulated can promote tumor growth and metastasis, and LPA is thought to contribute to the development, progression, and metastasis of several types of cancer including ovarian, prostate, melanoma, breast, head and neck cancers (see Gendaszewska-Darmach, Acta Biochimica Polonica (2008), 55(2):227-240).
  • ATX inhibitors are expected to be of most benefit outside the cell. Therefore, ATX inhibitors are expected to be useful in treating cancer, particularly multidrug resistant (MDR) cancers where drug efflux mechanisms are the largest contributor to the drug resistance.
  • MDR multidrug resistant
  • the pathological disorder can be selected from renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, angiogenesis, and tumor metastasis and progression, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.
  • inflammatory conditions conditions of the nervous system
  • conditions of the respiratory system vascular and cardiovascular conditions
  • fibrotic diseases cancer
  • angiogenesis angiogenesis
  • tumor metastasis and progression ocular conditions
  • metabolic conditions cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.
  • Renal conditions include, but are not limited to, acute kidney injury and chronic renal disease with and without proteinuria including end-stage renal disease (ESRD).
  • ESRD end-stage renal disease
  • this includes decreased creatinine clearance and decreased glomerular filtration rate, microalbuminuria, albuminuria and proteinuria, glomerulosclerosis with expansion of reticulated mesangial matrix with or without significant hypercellularity (particularly diabetic nephropathy and amyloidosis), focal thrombosis of glomerular capillaries (particularly thrombotic microangiopathies), global fibrinoid necrosis, ischemic lesions, malignant nephrosclerosis (such as ischemic retraction, reduced renal blood flow and renal arteriopathy), swelling and proliferation of intracapillary (endothelial and mesangial) and/or extracapillary cells (crescents) like in glomerular nephritis entities, focal segmental glomerular sclerosis, IgA n
  • Liver conditions include, but are not limited to, liver cirrhosis, hepatic congestion, cholestatic liver disease including pruritus, nonalcoholic steatohepatitis and acute and chronic liver transplant rejection.
  • Inflammatory conditions include, but are not limited to, arthritis, osteoarthritis, systemic lupus erythematodes, psoriasis, chronic inflammation, inflammatory bowel disease, irritable bowel syndrome, functional bowel disorders, abnormal evacuation disorder and the like as well as inflammatory airways diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or chronic asthma bronchiale.
  • IPF idiopathic pulmonary fibrosis
  • COPD chronic obstructive pulmonary disease
  • Conditions of the respiratory system include, but are not limited to, other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, systemic diseases and vasculitides, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis,
  • lymphangioleiomyomatosis inherited diseases (Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease), radiation induced fibrosis, silicosis, asbestos induced pulmonary fibrosis or acute respiratory distress syndrome (ARDS).
  • ARDS acute respiratory distress syndrome
  • Conditions of the nervous system include, but are not limited to,
  • neuro-inflammation e.g. astrogliosis
  • peripheral and/or autonomic (diabetic) neuropathies e.g. astrogliosis
  • neuropathies e.g. astrogliosis
  • autonomic neuropathies e.g. abetic neuropathies
  • neuropathies e.g. astrogliosis
  • peripheral and/or autonomic neuropathies e.g. abetic neuropathies
  • Vascular conditions include, but are not limited to, atherosclerosis, thrombotic vascular disease as well as thrombotic micro angiopathies, proliferative arteriopathy (such as swollen myointimal cells surrounded by mucinous extracellular matrix and nodular thickening), decreased vascular compliance (such as stiffness, reduced ventricular
  • Cardiovascular conditions include, but are not limited to, acute coronary syndrome, coronary heart disease, myocardial infarction, arterial and pulmonary
  • Fibrotic diseases include, but are not limited to myocardial and vascular fibrosis, organ fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma and encapsulating peritonitis.
  • the fibrotic disease is renal tubulo-interstitial fibrosis or glomerulosclerosis.
  • the fibrotic disease is idiopathic pulmonary fibrosis.
  • the fibrotic disease is non-alcoholic liver steatosis, liver fibrosis or liver cirrhosis.
  • fibrotic diseases include endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, nephrogenic systemic fibrosis, Keloid, atherofibrosis and adhesive capsulitis.
  • Cancer and cancer metastasis include, but are not limited to, lung cancer, mesothelioma, glioma, hepatic carcinoma, gastrointestinal cancers and progression and metastatic aggressiveness thereof.
  • Ocular conditions include, but are not limited to, proliferative and nonproliferative (diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central arterial/venous occlusion, traumatic injury, glaucoma and the like.
  • proliferative and nonproliferative (diabetic) retinopathy dry and wet age-related macular degeneration (AMD), macular edema, central arterial/venous occlusion, traumatic injury, glaucoma and the like.
  • AMD age-related macular degeneration
  • Metabolic conditions include, but are not limited to, obesity and diabetes.
  • compositions can include a compound of formula (I), or a pharmaceutically acceptable salt thereof. More particularly, such compounds and salts can be formulated as pharmaceutical compositions using standard pharmaceutically acceptable carriers, fillers, solubilizing agents and stabilizers known to those skilled in the art. For example, a pharmaceutical composition including a compound of formula (I), or a pharmaceutically acceptable salt thereof, as described herein, is used to administer the appropriate compound, or a pharmaceutically acceptable salt thereof, to a subject.
  • the compounds of formula (I), or a pharmaceutically acceptable salt thereof are useful for treating a disease or disorder associated with SIP receptor activity, and/or ATX activity.
  • a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof is delivered (e.g. administered) to a subject in need thereof.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically- acceptable carrier is administered to a subject in need thereof.
  • the compounds and salts described herein can be used in combination with at least one further active ingredient, such as a medicament used in the treatment of multiple sclerosis such as Tysabri®, dimethyl fumarate, an interferon (such as pegylated or non- pegylated interferons, such as interferon ⁇ -la or pegylated interferon ⁇ -la), glatiramer acetate, a compound improving vascular function, an immunomodulating agent (such as Fingolimod, cyclosporins, rapamycins or ascomycins, or their immunosuppressive analogs, e.g.
  • a medicament used in the treatment of multiple sclerosis such as Tysabri®, dimethyl fumarate
  • an interferon such as pegylated or non- pegylated interferons, such as interferon ⁇ -la or pegylated interferon ⁇ -la
  • glatiramer acetate such as a compound improving vascular function
  • cyclosporin A cyclosporine G
  • corticosteroids cyclophosphamide
  • azathioprine azathioprine
  • daclizumab dactinomycine; desonide; desoximetasone; dexamethasone; dexamethasone acetate; dexamethasone isonicotinate; dexamethasone metasulfobenzoate sodique;
  • dexamethasonephosphate dexamethasone tebutate; dichlorisone acetate; doxorubicinee chlorhydrate; epirubicine chlorhydrate; fluclorolone acetonide; fludrocortisone acetate;
  • fludroxycortide flumetasone pivalate; flunisolide; fluocinolone acetonide; fluocinonide; fluocortolone; fluocortolone hexanoate; fluocortolone pivalate; fluorometholone;
  • fluprednidene acetate fluticasone propionate
  • gemcitabine chlorhydrate halcinonide
  • hydrocortisone hydrocortisone acetate; hydrocortisone butyrate; hydrocortisone
  • methylprednisolone acetate methylprednisolone hemisuccinate; misoprostol; muromonab- cd3; mycophenolate mofetil; paramethansone acetate; prednazoline, prednisolone;
  • prednisolone acetate prednisolone caproate; prednisolone metasulfobenzoate sodique;
  • prednisolone phosphate sodique prednisone; prednylidene; rifampicine; rifampicine sodique; tacrolimus; teriflunomide; thalidomide; thiotepa; tixocortol pivalate; triamcinolone;
  • immunosuppressive monoclonal antibodies e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4,CD7, CD20 (e.g., rituximab and ocrelizumab), CD25, CD28, B7, CD40, CD45, CD56 (e.g., daclizumab), or CD58 or their ligands; or other immunomodulating agenty compounds, e.g. CTLA41g, or other adhesion molecule inhibitors, e.g.
  • mAbs or low molecular weight inhibitors including Selectin antagonists and VLA-4 antagonists (such as Tysabri®); remyelinating agents such as BIIB033.
  • VLA-4 antagonists such as Tysabri®
  • remyelinating agents such as BIIB033.
  • Compounds and salts described herein can also be used in combination with agents which treat the symptoms of multiple sclerosis such as fampridine.
  • the dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, administered to a subject can be less than 10 ⁇ g, less than 25 ⁇ g, less than 50 ⁇ g, less than 75 ⁇ g, less than 0.10 mg, less than 0.25 mg, less than 0.5 mg, less than 1 mg, less than 2.5 mg, less than 5 mg, less than 10 mg, less than 15 mg, less than 20 mg, less than 50 mg, less than 75 mg, less than 100 mg, or less than 500 mg.
  • Delivering a compound of formula (I) to a mammal comprises any delivery method whereby the compound comes in contact with any part of the mammal's body.
  • Delivering a compound of formula (I) to a mammal includes administering a compound of formula (I) topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally or intravitreally to the mammal.
  • Delivering a compound of formula (I) to a mammal also includes administering topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally or intravitreally to a mammal a compound that metabolizes within or on a surface of the body of the mammal to a compound of formula (I).
  • the duration of administering can be less than 30 seconds, less than 1 minute, about 1 minute, between 1 minute and 5 minutes, between 5 minutes and 10 minutes, between 10 minutes and 20 minutes, between 20 minutes and 30 minutes, between 30 minutes and 1 hour, between 1 hour and 3 hours, between 3 hours and 6 hours, between 6 hours and 12 hours, between 12 hours and 24 hours or for more than 24 hours.
  • Administering the compound, or a pharmaceutically acceptable salt thereof can include multiple administrations.
  • the duration between administrations can be less than 30 seconds, less than 1 minute, about 1 minute, between 1 minute and 5 minutes, between 5 minutes and 10 minutes, between 10 minutes and 20 minutes, between 20 minutes and 30 minutes, between 30 minutes and 1 hour, between 1 hour and 3 hours, between 3 hours and 6 hours, between 6 hours and 12 hours, between 12 hours and 24 hours or for more than 24 hours.
  • the duration between successive administrations can be less than 30 seconds, less than 1 minute, about 1 minute, between 1 minute and 5 minutes, between 5 minutes and 10 minutes, between 10 minutes and 20 minutes, between 20 minutes and 30 minutes, between 30 minutes and 1 hour, between 1 hour and 3 hours, between 3 hours and 6 hours, between 6 hours and 12 hours, between 12 hours and 24 hours, between 24 hours and 48 hours, between 48 hours and 72 hours, between 72 hours and 1 week or between 1 week and 2 weeks.
  • Administering the compound, or a pharmaceutically acceptable salt thereof, to cells can include cells of an in vitro or in vivo system or model.
  • the cells can be part of a cell line.
  • the cell line can be a primary or secondary cell line.
  • the cell line can be an immortal cell line.
  • the cells can be ruptured and be in the form of a cell lysate.
  • the cells can be part of a living organism, i.e., a subject, for example, a mammal.
  • a mammal can include a rat, a mouse, a gerbil, a hamster, a rabbit or a human.
  • the human can be a subject or a patient.
  • a method can further include monitoring a property of a sample or a subject.
  • a sample can be removed from a subject.
  • a sample can include a sample of cells or a tissue from a subject.
  • a sample can include blood, plasma, or neuronal tissue including neurons or glial cells.
  • a sample can also remain in the subject.
  • a sample can be a tissue or cells that are observed within the patient.
  • a method can further include providing untreated control cells, sample or subject and measuring a property of a sample of the untreated control cells, sample or subject.
  • a property can include the presence or absence of a molecule
  • concentration of a molecule for example myelin basic protein, myelin associated
  • determining the presence of a molecule can include determining the concentration of the molecule, determining the purity of the molecule or determining the quantity of the molecule.
  • a property can be the conductivity of a tissue or cell.
  • a property can be an emission, for example, electromagnetic radiation.
  • Monitoring a property can include observing the property of the sample or subject alone. Monitoring a property can include monitoring the property before the sample or subject has been administered a compound provided herein, or a pharmaceutically acceptable salt thereof. Monitoring a property can include monitoring the property after the sample or subject has been administered a compound, or a pharmaceutically acceptable salt thereof. Monitoring a property can include monitoring a property after the sample or subject has been administered a known concentration of a compound, or a pharmaceutically acceptable salt thereof.
  • Monitoring a property of a sample or subject can include observing the property through a microscope. Monitoring a property of the composition can include measuring the property using a microscope. Monitoring a property of the composition can include monitoring the property using still photography or movies. The photography or movies can be on film media or digital form. Monitoring a property can include taking a scan, for example, an MRI or CT scan.
  • compound provided herein, or a pharmaceutically acceptable salt thereof may be systemically administered, e.g., orally, in combination with a
  • compositions and preparations should contain at least about 0.1% of active compound, or a pharmaceutically acceptable salt thereof,.
  • compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • amount of active compound, or a pharmaceutically acceptable salt thereof, in such therapeutically useful compositions can be such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like can include the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; or a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound, or a pharmaceutically acceptable salt thereof may be incorporated into sustained-release preparations and devices.
  • the active compound, or a pharmaceutically acceptable salt thereof may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms.
  • Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium
  • glycerol for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like
  • vegetable oils or nontoxic glyceryl esters, and mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, or thimerosal, and the like. In many cases, isotonic agents, for example, sugars, buffers or sodium chloride, will be included.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate or gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound, or a pharmaceutically acceptable salt thereof, in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the methods of preparation can be vacuum drying and the freeze drying techniques, which can yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof may be applied in pure form, e.g., when they are liquids. However, it can be generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • Exemplary solid carriers can include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds and salts can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts or esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deliver the compounds provided herein, or a pharmaceutically acceptable salt thereof, to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No.
  • Useful dosages of the compounds provided herein, or a pharmaceutically acceptable salt thereof can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949, which is incorporated by reference in its entirety.
  • the concentration of the compound(s) provided herein, or a pharmaceutically acceptable salt thereof, in a liquid composition, such as a lotion can be from about 0.1 to about 25 weight percent, such as from about 0.5-10 weight percent.
  • concentration in a semi-solid or solid composition such as a gel or a powder can be about 0.1- 5 wt-%, such as about 0.5-2.5 weight percent based on the total weight of the composition.
  • the amount of the compound, or a pharmaceutically acceptable salt thereof, required for use in treatment can vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and can be ultimately at the discretion of the attendant physician or clinician. In general, however, a dose can be in the range of from about 0.1 to about 10 mg/kg of body weight per day.
  • the compound, or a pharmaceutically acceptable salt thereof can be conveniently administered in unit dosage form; for example, containing 0.01 to 10 mg, or 0.05 to 1 mg, of active ingredient per unit dosage form. In some embodiments, a dose of 5 mg/kg or less can be suitable.
  • the active ingredient can be administered so as to achieve a desired peak plasma concentration of the active compound, or a pharmaceutically acceptable salt thereof.
  • the desired peak plasma concentration can be from about 0.5 ⁇ to about 75 ⁇ , such as, about 1 ⁇ to 50 ⁇ , or about 2 ⁇ to about 30 ⁇ . This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing between about 1 mg to about 100 mg of the active ingredient.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four, or more sub- doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • the disclosed method can include a kit comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and instructional material which can describe administering the compound, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound, or a pharmaceutically acceptable salt thereof, to a cell or a subject.
  • instructional material which can describe administering the compound, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound, or a pharmaceutically acceptable salt thereof, to a cell or a subject.
  • a kit comprising a (such as sterile) solvent for dissolving or suspending the compound, or a pharmaceutically acceptable salt thereof, or composition prior to administering the compound or composition to a cell or a subject.
  • the subject can be a human.
  • the compounds provided herein, or a pharmaceutically acceptable salt thereof can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mol ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [0207] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • the compounds provided herein may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art.
  • racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • Compound 1-1 is reacted with at least a stoichiometric amount and in some embodiments an excess of H-R .
  • the reaction is typically conducted under conventional coupling conditions well known in the art.
  • the reaction is conducted with the use of a coupling agent such as carbonyldiimidazole (for compounds whereing L is - OC(O)-) and HATU (for compounds wherein L is -C(O)-) in the presence of triethylamine in a suitable solvent, such as DMF.
  • a coupling agent such as carbonyldiimidazole (for compounds whereing L is - OC(O)-) and HATU (for compounds wherein L is -C(O)-) in the presence of triethylamine in a suitable solvent, such as DMF.
  • a coupling agent such as carbonyldiimidazole (for compounds whereing L is - OC(O)-) and HATU (for compounds wherein L is
  • the coupling reaction of Scheme 1 can be performed either before or after the installation of such groups.
  • the reaction is typically conducted under conventional coupling conditions well known in the art.
  • the reaction is conducted with the use of a coupling agent such as DIAD in the presence of PPh 3 in a suitable solvent, such as toluene.
  • the reaction is continued until substantially complete which typically occurs within about 1 to 12 hours.
  • the final compound can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like.
  • Example 1 (1.49 g, yield 78%).
  • Example 1 (159 mg, yield 67%).
  • Example 1 (116 mg, yield 58%).
  • Example 7 (17 mg, yield 14%).
  • the mixture was purified by pre-HPLC (MeCN/H 2 0 with 10 mM NH 4 HCO 3 as mobile phase; from 5% to 95%).
  • Example 7 (30 mg, yield 26%).
  • the mixture was purified by pre-HPLC (MeCN/H 2 0 with 10 mM NH 4 HC0 3 as mobile phase; from 5% to 95%).
  • 1H NMR 400 MHz, METHANOL-d 4 ) ⁇ 8.03 (s, 2H), 7.95 (s, 1H), 7.46 (s, 1H), 5.34 (s, 2H), 4.88-4.84 (m, 2H), 3.85-3.73 (m, 4H), 3.15-3.14 (m, 2H); LCMS m/z 452.1 [M+H] + .
  • Example 7 (10 mg, yield 10%). The mixture was purified by pre-HPLC (MeCN/H 2 0 with 10 mM NH 4 HC0 3 as mobile phase; from 5% to 95%).
  • 1H NMR 400 MHz, METHANOL-d ) ⁇ 7.95-7.83 (m, 3H), 5.24 (s, 2H), 5.17-5.11 (m, 2H), 4.72-4.67 (m, 2H), 3.90-3.79 (m, 2H), 2.02-1.98 (m, 2H); LCMS m/z 453.1 [M+H] + .
  • Example 12
  • Example 12 (65 mg, yield 65%). The mixture was purified by pre-HPLC (MeCN/H 2 0 with 10 mM NH 4 HC0 3 as mobile phase; from 5% to 95%).
  • Example 12 (74 mg, yield 72%).
  • the mixture was purified by pre-HPLC (MeCN/H 2 0 with 10 mM NH 4 HC0 3 as mobile phase; from 5% to 95%).
  • Example 12 (77 mg, yield 84%). The mixture was purified by pre-HPLC (MeCN/H 2 0 with 10 mM NH 4 HCO 3 as mobile phase; from 5% to 95%).
  • 1H NMR 400 MHz, METHANOL- d 4 ) ⁇ 7.37-7.16 (m, 3H), 6.65-6.62 (m, IH), 5.09-5.06 (m, 2H), 4.64-4.59 (m, 2H), 4.51-4.45 (m, 3H), 3.86-3.81 (m, 2H), 2.33-2.31 (m, 2H), 2.12-2.07 (m, 2H), 1.91 (bs, 2H), 1.78-1.74 (m, 2H); LCMS m/z 437.1 [M+H] + .
  • Example 12 (78 mg, yield 83%). The mixture was purified by pre-HPLC (MeCN/H 2 0 with 10 mM NH 4 HC0 3 as mobile phase; from 5% to 95%).
  • 1H NMR 400 MHz, METHANOL- d 4 ) ⁇ 7.37-7.16 (m, 3H), 6.66-6.64 (m, IH), 5.10-5.06 (m, 2H), 4.65-4.60 (m, 2H), 4.52-4.49 (m, 2H), 4.30-4.26 (m, IH), 3.86-3.81 (m, 2H), 2.04-1.91 (m, 4H), 1.77-1.54 (m, 6H); LCMS m/z 451.1 [M+H] + .
  • Example 12 (76 mg, yield 69%).
  • the mixture was purified by pre-HPLC (MeCN/H 2 0 with 10 mM NH 4 HC0 3 as mobile phase; from 5% to 95%).
  • 1H NMR 400 MHz, METHANOL- d 4 ) ⁇ 7.37-7.16 (m, 3H), 6.66-6.64 (m, IH), 5.10-5.06 (m, 2H), 4.65-4.60 (m, 2H), 4.52-4.49 (m, 2H), 3.86-3.81 (m, 3H), 1.93-1.91 (m, 4H), 1.81-1.78 (m, 2H), 1.69-1.65 (m, IH), 1.43- 1.25 (m, 5H); LCMS m/z 465.1 [M+H] + .
  • Example 18 Example 18
  • Example 12 (71 mg, yield 65%). The mixture was purified by pre-HPLC (MeCN/H 2 0 with 10 mM NH 4 HCO 3 as mobile phase; from 5% to 95%).

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Abstract

Compounds of formula (I), and pharmaceutically acceptable salts thereof, can modulate the activity of one or more SIP receptors and/or the activity of autotaxin (ATX). Formula (1)

Description

SIP AND/OR ATX MODULATING AGENTS
[0001] This application claims the benefit of U.S. Provisional Patent Application No.
61/790281, filed March 15, 2013, the entire contents of which are hereby incorporated by reference.
[0002] Provided are agents that modulate SIP and/or ATX, and methods of making and using such agents.
[0003] Sphingosine 1-phosphate (SIP) is a lysophospholipid mediator that evokes a variety of cellular responses by stimulation of five members of the endothelial cell differentiation gene (EDG) receptor family. The EDG receptors are G-protein coupled receptors (GPCRs) and on stimulation propagate second messenger signals via activation of heterotrimeric G-protein alpha (Ga) subunits and beta-gamma (Gp7) dimers. Ultimately, this SlP-driven signaling results in cell survival, increased cell migration and, often, mitogenesis. The recent development of agonists targeting SIP receptors has provided insight regarding the role of this signaling system in physiologic homeostasis. For example, the
immunomodulating agent, FTY720 (2-amino-2-[2-(4-octylphenyl) ethyl] propane 1,3-diol), that following phosphorylation, is an agonist at 4 of 5 SIP receptors, revealed that affecting SIP receptor activity influences lymphocyte trafficking. Further, SIP type 1 receptor (S1P antagonists cause leakage of the lung capillary endothelium, which suggests that SIP may be involved in maintaining the integrity of the endothelial barrier in some tissue beds. SIP type 4 receptors (S1P4) are expressed mainly in leukocytes, and specifically S1P4 mediates immunosuppressive effects of SIP by inhibiting proliferation and secretion of effector cytokines, while enhancing secretion of the suppressive cytokine IL-10. See, for example, Wang, W. et. al., (2005) FASEB J. 19(12): 1731-3, which is incorporated by reference in its entirety. SIP type 5 receptors (S1P5) are exclusively expressed in oligodendrocytes and oligodendrocyte precursor cells (OPCs) and are vital for cell migration. Stimulation of SIP5 inhibits OPC migration, which normally migrate considerable distances during brain development. See, for example, Novgorodov, A. et al., (2007) FASEB J, 21: 1503-1514, which is incorporated by reference in its entirety.
[0004] SIP has been demonstrated to induce many cellular processes, including those that result in platelet aggregation, cell proliferation, cell morphology, tumor-cell invasion, endothelial cell chemotaxis and angiogenesis. For these reasons, SIP receptors are good targets for therapeutic applications such as wound healing, tumor growth inhibition, and autoimmune diseases.
[0005] Sphingosine-1 -phosphate signals cells in part via a set of G protein-coupled receptors named SIPi, S1P2, S1P3, S1P4, and S1P5 (formerly EDG1, EDG5, EDG3, EDG6 and EDG8). The EDG receptors are G-protein coupled receptors (GPCRs) and on stimulation propagate second messenger signals via activation of heterotrimeric G-protein alpha (Ga) subunits and beta-gamma (Gp7) dimers. These receptors share 50-55% amino acid sequence identity and cluster with three other receptors (LPA1; LPA2, and LPA (formerly EDG2, EDG4 and EDG7) for the structurally related lysophosphatidic acid (LPA).
[0006] A conformational shift is induced in the G-Protein Coupled Receptor (GPCR) when the ligand binds to that receptor, causing GDP to be replaced by GTP on the a-subunit of the associated G-proteins and subsequent release of the G-proteins into the cytoplasm. The a-subunit then dissociates from the βγ-subunit and each subunit can then associate with effector proteins, which activate second messengers leading to a cellular response. Eventually the GTP on the G-proteins is hydrolyzed to GDP and the subunits of the G-proteins reassociate with each other and then with the receptor. Amplification plays a major role in the general GPCR pathway. The binding of one ligand to one receptor leads to the activation of many G-proteins, each capable of associating with many effector proteins leading to an amplified cellular response.
[0007] SIP receptors make good drug targets because individual receptors are both tissue and response specific. Tissue specificity of the SIP receptors is desirable because development of an agonist or antagonist selective for one receptor localizes the cellular response to tissues containing that receptor, limiting unwanted side effects. Response specificity of the SIP receptors is also of importance because it allows for the development of agonists or antagonists that initiate or suppress certain cellular responses without affecting other responses. For example, the response specificity of the SIP receptors could allow for an SIP mimetic that initiates platelet aggregation without affecting cell morphology.
[0008] Sphingosine-1 -phosphate is formed as a metabolite of sphingosine in its reaction with sphingosine kinase and is stored in abundance in the aggregates of platelets where high levels of sphingosine kinase exist and sphingosine lyase is lacking. SIP is released during platelet aggregation, accumulates in serum, and is also found in malignant ascites. Reversible biodegradation of SIP most likely proceeds via hydrolysis by
ectophosphohydrolases, specifically the sphingosine-1 -phosphate phosphohydrolases. Irreversible degradation of SIP is catalyzed by SIP lyase yielding ethanolamine phosphate and hexadecenal.
[0009] Autotaxin (ATX, ENPP2) is a secreted glycoprotein widely present in biological fluids, including blood, cancer ascites, synovial, pleural and cerebrospinal fluids, originally isolated from the supernatant of melanoma cells as an autocrine motility stimulation factor (Stracke, M.L., et al. Identification, purification, and partial sequence analysis of autotaxin, a novel motility- stimulating protein. J Biol Chem 267, 2524-2529 (1992), which is incorporated by reference in its entirety). ATX is encoded by a single gene on human chromosome 8 (mouse chromosome 15) whose transcription, regulated by diverse transcription factors (HoxaB, NFAT-1 and v-jun), results in four alternatively spliced isoforms (α, β, γ, and δ). See, for example, Giganti, A., et al Murine and Human Autotaxin alpha, beta, and gamma Isoforms: Gene organization, tissue distribution and biochemical characterization. J Biol Chem 283, 7776-7789 (2008); and van Meeteren, L.A. & Moolenaar, W.H. Regulation and biological activities of the autotaxin-LPA axis. Prog Lipid Res 46, 145- 160 (2007); Hashimoto, et al, "Identification and Biochemical Charaterization of a Novel Autotaxin Isoform, ΑΤΧδ," J. of Biochemistry Advance Access (October 11, 2011); each of which is incorporated by reference in its entirety.
[0010] ATX is synthesized as a prepro-enzyme, secreted into the extracellular space after the proteolytic removal of its N-terminal signal peptide (Jansen, S., el al Proteolytic maturation and activatio of autotaxin (NPP2), a secreted metastasis-enhancing lysophospho lipase D. J Cell Sci 118, 3081-3089 (2005), which is incorporated by reference in its entirety). ATX is a member of the ectonucleotide pyrophosphatase/phosphodiesterase family of ectoenzymes (E-NPP) that hydrolyze phosphodiesterase (PDE) bonds of various nucleotides and derivatives (Stefan, C, Jansen, S. & Bollen, M. NPP-type
ectophosphodiesterases: unity in diversity. Trends Biochem Sci 30, 542-550 (2005), which is incorporated by reference in its entirety). The enzymatic activity of ATX was enigmatic, until it was shown to be identical to lysophospholipase D (lysoPLD) (Umezu-Goto, M., et al. Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J Cell Biol 158, 227-233 (2002), which is incorporated by reference in its entirety), which is widely present in biological fluids. Since ATX is a constitutively active enzyme, the biological outcome of ATX action will largely depend on its expression levels and the local availability of its substrates. The major lysophospholipid substrate for ATX, lysophosphatidylcholine (LPC), is secreted by the liver and is abundantly present in plasma (at about 100 μΜ) as a predominantly albumin bound form (Croset, M., Brossard, N., Polette, A. & Lagarde, M. Characterization of plasma unsaturated lysophosphatidylcholines in human and rat Biochem J 345 Pt 1, 61-67 (2000), which is incorporated by reference in its entirety). LPC is also detected in tumor-cell conditioned media (Umezu-Goto, M., et al.), presumably as a constituent of shed micro vesicles. ATX, through its lysoPLD activity converts LPC to lysophosphatidic acid (LPA).
[0011] LPC is an important inflammatory mediator with recognized effects in multiple cell types and pathophysiological processes. It is a major component of oxidized low density lipoprotein (oxLDL) and it can exist in several other forms including free, micellar, bound to hydrophobic proteins such as albumin and incorporated in plasma membranes. It is produced by the hydrolysis of phosphatidylcholine (PC) by PLA2 with concurrent release of arachidonic acid and in turn of other pro-inflammatory mediators (prostaglandins and leukotrienes). Moreover, LPC externalization constitutes a chemo tactic signal to phagocytic cells, while interaction with its receptors can also stimulate lymphocytic responses. LPC has been shown to have therapeutic effects in experimental sepsis, possibly by suppressing endo toxin-induced HMGB1 release from macrophages/monocytes.
[0012] LPA is a bioactive phospholipid with diverse functions in almost every mammalian cell line (Moolenaar, W.H., van Meeteren, L.A. & Giepmans, B.N. The ins and outs of lysophosphatidic acid signaling. Bioessays 28, 870-881 (2004), which is incorporated by reference in its entirety). LPA is a major constituent of serum bound tightly to albumin, gelsolin and possibly other as yet unidentified proteins. See, e.g., Goetzl, E.J., et al Gelsolin binding and. cellular presentation of lysophosphatidic acid. J Biol Chem 275, 14573-14578 (2000); and Tigyi, G. & Miledi, R, Lysophosphatidates bound to serum albumin activate membrane currents in Xenopus oocytes and neurite retraction in PC 12 pheochromocytoma cells. J Biol Chem 267, 21360-21367 (1992); each of which is incorporated by reference in its entirety.
[0013] LPA is also found in other biofluids, such as saliva and follicular fluid, and has been implicated in a wide array of functions, such as wound healing, tumor invasion and metastasis, neurogenesis, myelination, astrocytes outgrowth and neurite retraction. The long list of LPA functions was also explained with the discovery that it signals through G-protein coupled receptors (GPCRs), via classical second messenger pathways. Five mammalian cell- surface LPA receptors have been identified so far. The best known are LPA 1-3 (namely Edg- 2, Edg-4 and Edg7) which are all members of the so-called 'endothelial differentiation gene' (EDG) family of GPCRs (Contos, J.J., Ishii, I. & Chun, J. Lysophosphatidic acid receptors. Mol Pharmacol 58, 1188-1196 (2000), which is incorporated by reference in its entirety). LPA receptors can couple to at least three distinct G proteins (Gq, Gj and G12/13), which, in turn, feed into multiple effector systems. LPA activates Gq and thereby stimulates
phospholipase C (PLC), with subsequent phosphatidylinositol - bisphosphate hydrolysis and generation of multiple second messengers leading to protein kinase C activation and changes in cytosolic calcium. LPA also activates Gj, which leads to at least three distinct signaling routes: inhibition of adenylyl cyclase with inhibition of cyclic AMP accumulation;
stimulation of the mitogenic RAS-MAPK (mitogen-activated protein kinase) cascade; and activation of phosphatidylinositol 3-kinase (PI3K), leading to activation of the guanosine diphosphate/guanosine triphosphate (GDP/GTP) exchange factor TIAM1 and the
downstream RAC GTPase, as well as to activation of the AKT/PKB antiapoptotic pathway. Finally, LPA activates G12/i3, leading to activation of the small GTPase RhoA, which drives cytoskeletal contraction and cell rounding. So, LPA not only signals via classic second messengers such as calcium, diacylglycerol and cAMP, but it also activates RAS- and RHO- family GTPases, the master switches that control cell proliferation, migration and
morphogenesis.
[0014] LPA signaling through the RhoA-Rho kinase pathway mediates neurite retraction and inhibition of axon growth. Interfering with LPA signaling has been shown to promote axonal regeneration and functional recovery after CNS injury or cerebral ischemia. (See Broggini, et al., Molecular Biology of the Cell (2010), 27:521-537.) It has been reported that addition of LPA to dorsal root fibers in ex vivo culture causes demyelination, whereas LPC fails to cause significant demyelination of nerve fibers in ex vivo cultures without further addition of recombinant ATX to the culture which when added caused significant
demyelination at equivalent levels to LPA presumable due to conversion of LPC to LPA through the enzymatic activity of ATX. Moreover, injury induced demyelination was attenuated by about 50% in atx+/" mice (Nagai, et al., Molecular Pain (2010), (5:78).
[0015] A number of diseases or disorders involve demyelination of the central or peripheral nervous system which can occur for a number of reasons such as immune dysfunction as in multiple sclerosis, encephalomyelitis, Guillain-Barre Syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis, and optic neuritis; demyelination due to injury such as spinal cord injury, traumatic brain injury, stroke, acute ischemic optic neuropathy, or other ischemia, cerebral palsy, neuropathy (e.g. neuropathy due to diabetes, chronic renal failure, hypothyroidism, liver failure, or compression of the nerve (e.g. in Bell's palsy)), post radiation injury, and central pontine myelolysis (CPM); inherited conditions such as Charcot-Marie-Tooth disease (CMT), Sjogren- Lars son syndrome, Refsum disease, Krabbe disease, Canavan disease, Alexander disease, Friedreich's ataxia, Pelizaeus- Merzbacher disease, Bassen-Kornzweig syndrome, metachromatic leukodystrophy (MLD), adrenoleukodystrophy, and nerve damage due to pernicious anemia; viral infection such as progressive multifocal leukoencephalopathy (PML), Lyme disease, or tabes dorsalis due to untreated syphilis; toxic exposure due to chronic alcoholism (which is a possible cause of Marchiafava-Bignami disease), chemotherapy, or exposure to chemicals such as
organophosphates; or dietary deficiencies such as vitamin B12 deficiency, vitamin E deficiency and copper deficiency. Other demyelination disorders may have unknown causes or multiple causes such as trigeminal neuralgia, Marchiafava-Bignami disease and Bell's palsy. One practically successful approach to treating demyelination disorders which are caused by autoimmune dysfunction has been to attempt to limit the extent of demyelination by treating the patient with immunoregulatory drugs. However, typically this approach has merely postponed but not avoided the onset of disability in these patients. Patients with demyelination due to other causes have even fewer treatment options. Therefore, the need exists to develop new treatments for patients with demyelination diseases or disorders.
SUMMARY
[0016] Provided are agents that can modulate SIP and/or ATX, e.g., an S1P4 antagonist and/or ATX inhibitor. Without wishing to be bound by any theory, it is believed that LPA inhibits remyelination of neurons that have suffered demyelination due to injury or disease and that inhibition of ATX will prevent the conversion of LPC to LPA and thus allow remyelination to occur. In addition, activation of PLC, ERK and Rho via LPA receptors results in cell proliferation, cell survival and changes in cell morphology. Therefore, inhibition of ATX is expected to be useful for treating demyelination due to injury or disease, as well as for treating proliferative disorders such as cancer.
[0017] Provided is a compound represented by formula (I), or a pharmaceutically acceptable salt thereof:
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof, wherein: L is -C(O)-, -O-C(O)-, -NR6-C(0)-, or -S(0)2-;
L 2 is a bond, -0-, or -NR-; provided that L 2 is not -O- when R 2 is structure (iv);
R, for each occurrence, is independently hydrogen or a Ci^alkyl; R1 is a Ci-galkylene;
R is selected form the group consisting of:
Figure imgf000008_0001
R3 is hydrogen, -CN, C1-8alkyl, Ci-ghaloalkyl, -(CR10Rn)m-N(R16)2, -(CR10Rn)m- OR15, -(CR10Rn)m-C(O)OR15, -(CR10Rn)m-C(O)N(R16)2, -(CR10Rn)m-S(O)2N(R16)2, - (CR10Ru)m-S(O)2NHS(O)2R15, -C(0)N(R15)-S(0)2R15, -S(0)2OR15, -C(0)NHC(0)R15, - Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -0-P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, - C(0)NHS(0)2R15, -C(0)NHOH, -C(0)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -Lx-R4; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R 5 ; provided that when R 2 is structure (ii), (iii), (iv), or (xi), R 3 is not hydrogen; and provided that when R 2 is structure (iv), R 3 is not pyrrolidinyl, piperidinyl , an N-methylpyrrolidinyl, an N-acetyl-pyrrolidinyl, an N-methylpiperidinyl, or an N-acetyl- piperidinyl; L1 is Ci_8alkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0)2NR-, or -C(0)NR-S(0)2-;
R4 is Ci-galkyl, C3_gcycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R4 may be optionally substituted with from one to four R5;
R5 is halo, cyano, Ci-galkyl, Ci-ghaloalkyl, C3-8cycloalkyl, -(CR10Ru)m-N(R16)2, -(CR10Rn)m-OR15, -(CR10Rn)m-C(O)OR15, -C(0)N(R16)2, -C(0)N(R15)-S(0)2R15, - S(0)2OR15, -C(0)NHC(0)R15, -Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -S(0)2N(R15)2, O P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, -C(0)NHS(0)2R15, C(0)NHOH,
C(0)NHCN, -C(0)R15, a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, =0, Ci_ 4alkyl, Ci_4haloalkyl, Ci_4alkoxy, cyano, nitro, hydroxyl, amino, N-(CMalkyl)amino, N,N-di-(CMalkyl)amino, carbamoyl, N-(Ci-4alkyl)carbamoyl, N,N-di-(CMalkyl)carbamoyl, Ci_4alkylamido, Ci_4alkylsulfonyl, Ci_4alkylsulfonamido, sulfamoyl, N-Ci_4alkylsulfamoyl, and N,N^Ci_4dialkyl)-sulfamoyl;
R6 is hydrogen or a Ci-galkyl;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, Ci-galkyl, Ci_ghaloalkyl, C3_gcycloalkyl,
C3_ghalocycloalkyl, Ci-galkoxy, Ci_ghaloalkoxy, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci_galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl,
Ci-galkylamido, mercapto, Ci_galkylthio, Ci_galkylsulfonyl , sulfamoyl,
N-(Ci_galkyl)sulfamoyl, N,N-di-(Ci_galkyl)sulfamoyl, and Ci_galkylsulfonamido;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C3_gcycloalkyl, C3_ghalocycloalkyl, Ci_galkoxy, Ci_ghaloalkoxy, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Q-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci_galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(Ci_galkyl)sulfamoyl, and Ci_galkylsulfonamido;
R9, for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci-galkyl, Ci-galkoxy, Ci-ghaloalkyl, Ci-ghaloalkoxy,
C3_gcycloalkyl, C3_ghalocycloalkyl, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino,
Figure imgf000010_0001
Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl,
Figure imgf000010_0002
Ci-galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl, N-(^galkyl)sulfamoyl,
N,N-di-(^galkyl)sulfamoyl, Ci-galkylsulfonamido, C6-1oaryl,
Figure imgf000010_0003
and tri-(Ci-8alk l)silyl;
R9a is hydrogen or R9; or R9a and R6, together with the intervening atoms, form a 3- to 8-membered heterocyclyl which is optionally substituted with from one to three R9;
R10 and R11, for each occurrence, are independently hydrogen, halo, hydroxyl, carboxy, C1_4alkyl, or a C^haloalkyl;
R15 for each occurrence is independently selected from the group consisting of hydrogen, Ci-galkyl, C2-galkenyl, C2_galkynyl, C3-gcycloalkyl, C3-gcycloalkenyl, C6-ioaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1-4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino,
Figure imgf000010_0004
N,N-di-(CMalkyl)amino, carboxyl, carbamoyl,
Figure imgf000010_0005
C^alkylsulfonamido, sulfamoyl, N-iC^alky^sulfamoyl, and N^-iC^dialky^-sulfamoyl;
R16 is Ci-galkoxy, or R15; or two R16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci^alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-(CMalkyl)amino,
Figure imgf000010_0006
carboxyl, carbamoyl,
Figure imgf000010_0007
sulfamoyl, N-Ci^alkylsulfamoyl, and N,N-(CMdialkyl)-sulfamoyl;
h is 0, 1, or 2;
n, for each occurrence, is independently 0, 1, 2, 3, or 4;
m, for each occurrence, is independently 0 or an integer from 1 to 6;
p is 0, 1, 2, or 3;
q is 1, 2, 3, or 4;
r is 1, 2, or 3; and
t is 0 or 1, provided that the compound is not: 3-(5-(2-(4-isopropylphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
2- (2,3-difluorophenyl)-l-(2-((dimethylamino)methyl)-6,7-dihydropyrazolo[l,5- a]pyrazin-5(4H)-yl)ethanone;
3- (5-((2-fluorophenethyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
3-(5-((4-methylbenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
3-(5-(2-(2-chloro-4-fluorophenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
N-(3-fluorobenzyl)-2-(pyrrolidine-l-carbonyl)-6,7-dihydropyrazolo[l,5-a]pyrazine- 5(4H)-carboxamide;
l-(2-(4-methylpiperazine-l-carbonyl)-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)- 3-(p-tolyl)propan-l-one;
methyl 5-((3-fluorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carboxylate;
methyl 5-((4-fluorophenethyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[ 1 ,5-a]pyrazine- 2-carboxylate;
3-(5-(2-(3-(methylthio)phenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid;
3-(5-(2-(4-chlorophenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepin- 2-yl)propanoic acid;
3-(5-(2-(2,3-difluorophenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid;
l-(2-(pyridin-4-yl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepin-5(6H)-yl)-2-(3- (trifluoromethyl)phenyl)ethanone;
l-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepin-5(6H)-yl)-2-(3- (trifluoromethyl)phenyl)ethanone;
l-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepin-5(6H)-yl)-2-(2- fluorophenyl)ethanone ;
N-(3-fluorobenzyl)-2-(pyrrolidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxamide;
5-(2-(3,4-difluorophenyl)acetyl)-N-(2-hydroxyethyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxamide; 3-(5-(2-(2-methoxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid;
3-(5-(2-(4-ethoxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepin- 2-yl)propanoic acid;
1- (2-((l,4-oxazepan-4-yl)methyl)-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-2-(4- methoxyphenyl)ethanone ;
3-(5-(2-(2-methoxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
3- (2-methoxyphenyl)-l-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4] diazepin- 5 (6H) -yl)propan- 1 - one ;
2- (2-methoxyphenyl)-l-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4] diazepin- 5 (6H) -yl)ethanone ;
2-(4-ethoxyphenyl)-l-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4] diazepin- 5 (6H) -yl)ethanone ;
methyl 5-(3-(3-methoxyphenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carboxylate;
N2-cyclopropyl-N5-(3-methoxybenzyl)-6,7-dihydropyrazolo[l,5-a]pyrazine-2,5(4H)- dicarboxamide;
5-((l-(3-methoxyphenyl)ethyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
4- (4-chlorophenyl)- 1 -(6,7-dihydro-5H-imidazo[ 1 ,5-a] [ 1 ,4]diazepin-8(9H)-yl)butan- 1 - one;
N-(2-fluorophenethyl)-6,7-dihydro-5H-imidazo[l,5-a][l,4]diazepine-8(9H)- carboxamide;
1 -(6,7-dihydro-5H-imidazo[ 1 ,5-a] [ 1 ,4]diazepin-8(9H)-yl)-2-(4- ethoxyphenyl)ethanone;
l-(6,7-dihydro-5H-imidazo[l,5-a][l,4]diazepin-8(9H)-yl)-2-(o-tolyl)ethanone;
N-(4-chlorobenzyl)-6,7-dihydro-5H-imidazo[l,5-a][l,4]diazepine-8(9H)- carboxamide;
l-ethyl-6-methyl-N-(4-methylbenzyl)-3,4-dihydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide;
N-(4-fluorobenzyl)-6-methyl- l-propyl-3,4-dihydropyrrolo[ 1 ,2-a]pyrazine-2( 1H)- carboxamide; l-ethyl-N-(4-fluorobenzyl)-6-methyl-3,4-dihydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide;
1- ethyl-N-(3-methoxybenzyl)-6-methyl-3,4-dihydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide;
2- (2-aminophenyl)-l-(l,6-dimethyl-3,4-dihydropyrrolo[l,2-a]pyrazin-2(lH)- yl)ethanone;
2-(4-aminophenyl)-l-(l,6-dimethyl-3,4-dihydropyrrolo[l,2-a]pyrazin-2(lH)- yl)ethanone;
N-(3-methoxybenzyl)-6-methyl-l-propyl-3,4-dihydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide;
l-isopropyl-6-methyl-N-(4-methylbenzyl)-3,4-dihydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide;
1- isopropyl-N-(3-methoxybenzyl)-6-methyl-3,4-dihydropyrrolo[l,2-a]pyrazine- 2(lH)-carboxamide;
6-methyl-N-(4-methylbenzyl)-l-propyl-3,4-dihydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide;
5-(((4-methoxybenzyl)oxy)carbonyl)-2-methyl-l,4,5,6-tetrahydropyrrolo[3,4- b]pyrrole-4-carboxylic acid;
2- (3-bromophenyl)-2-methyl- l-(2-methyl-5,6-dihydro-[ 1 ,2,4]triazolo[ 1 ,5-a]pyrazin- 7(8H)-yl)propan- 1 -one;
1- (5,6-dihydro-[l,2,4]triazolo[l,5-a]pyrazin-7(8H)-yl)-2-(3-methoxyphenyl)ethanone;
2- (4-fluorophenyl)-l-(3-(quinolin-2-yl)-5,6-di ydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
2- (p-tolyl)-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)ethanone;
3- (m-tolyl) -(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
3- (p-tolyl)-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
2-(2-chloro-6-fluorophenyl)-l-(3-isopropyl-5,6-di ydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
4- (3-oxo-3-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propyl)benzonitrile; 2- (2-fluorophenyl)-l-(3-isopropyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)-2-methylpropan- 1 -one;
3- (2-methoxyphenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
2-(3,4-dimethoxyphenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
2-(3-chloro-4-methoxyphenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
2- (2-chloro-4-methoxyphenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
3- (4-methoxyphenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
3-(3-methoxyphenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
2-(2-fluorophenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)ethanone;
2- (2-chloro-6-fluorophenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
l-(3-ethyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-2-(2-fluorophenyl)-2- methylpropan- 1 -one;
3- (3-chloro-4-methylphenyl)-l-(3-isopropyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)propan-l-one;
3-(2,5-dimethoxyphenyl)-l-(3-ethyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
3-(3-chloro-4-methylphenyl)-l-(3-ethyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)propan- 1 -one;
1- (3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-5-(p-tolyl)pentan-l- one;
2- (2-chloro-6-fluorophenyl)-l-(3-ethyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
3- (2-ethoxyphenyl)-l-(3-ethyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
3-(2-methoxyphenyl)-l-(3-(tetrahydrofuran-2-yl)-8,9-dihydro-5H-[l,2,4]triazolo[4,3- d][l,4]diazepin-7(6H)-yl)propan-l-one; 2-(3,4-dichlorophenyl)-l-(3-(tetrahydrofuran-2-yl)-8,9-dihydro-5H- [ 1 ,2,4]triazolo[4,3-d] [ 1 ,4]diazepin-7(6H)-yl)ethanone;
2-([l,l'-biphenyl]-4-yl)-l-(3-isopropyl-8,9-dihydro-5H-[l,2,4]triazolo[4,3- d][l,4]diazepin-7(6H)-yl)ethanone;
2-(2-chloro-6-fluorophenyl)-l-(3-methyl-8,9-dihydro-5H-[l,2,4]triazolo[4,3- d][l,4]diazepin-7(6H)-yl)ethanone;
2-(3-fluorophenyl)-l-(3-methyl-8,9-dihydro-5H-[l,2,4]triazolo[4,3-d][l,4]diazepin- 7(6H)-yl)ethanone;
1- (3-isopropyl-8,9-dihydro-5H-[l,2,4]triazolo[4,3-d][l,4]diazepin-7(6H)-yl)-2-(4- (methylthio)phenyl)ethanone;
2- (2-chloro-6-fluorophenyl)-l-(3-(hydroxymethyl)-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)ethanone;
2-(2-chlorophenyl)-l-(3-(hydroxymethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
5-(4-bromophenyl)-l-(l-methyl-6,7-dihydro-lH-[l,2,3]triazolo[4,5-c]pyridin-5(4H)- yl)pentan-l-one;
3 4-ethoxyphenyl)-l-(l-methyl-6,7-dihydro-lH-[l,2,3]triazolo[4,5-c]pyridin-5(4H)- yl)propan-l-one;
2- (2-ethoxyphenoxy)-l-(l-methyl-6,7-dihydro-lH-[l,2,3]triazolo[4,5-c]pyridin- 5(4H)-yl)ethanone;
1- (5,6-dihydro-[l,2,4]triazolo[l,5-a]pyrazin-7(8H)-yl)-2-(3-fluorophenoxy)ethanone;
3- (5-(2-(3,4-dimethylphenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid;
3-(5-(2-(2,3-dimethylphenoxy)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
3-(5-(2-(2,3-dimethylphenoxy)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
2- (4-ethylphenoxy)-l-(2-(pyrrolidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4] diazepin- 5 (6H) -yl)ethanone ;
l-(2-(4-methylpiperazine-l-carbonyl)-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)- 2- (m-tolyloxy)ethanone ;
methyl 5-(2-(3,4-dimethylphenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylate; 5-(2-((3-methoxyphenyl)amino)butanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carbonitrile;
5-(2-(2-(sec-butyl)phenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carbonitrile;
1- (2,3-dimethyl-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-yl)-2-(4- fluorophenyl)ethanone ;
2- (2-chloro-6-fluorophenyl)-l-(2,3-dimethyl-6,7-dihydro-3H-imidazo[4,5-c]pyridin- 5(4H)-yl)ethanone;
methyl 3-ethyl-5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5- c] pyridine-6 -carboxylate ;
methyl 3-ethyl-5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5- c] pyridine-6 -carboxylate ;
3- (5-(2-(3-hydroxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid;
3-(5-(3-(4-hydroxyphenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
3-(5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin- 2-yl)propanoic acid;
3-(5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid;
methyl 5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[ 1 ,5- a]pyrazine-2-carboxylate;
5-(2-(2-hydroxyphenyl)acetyl)-N-phenyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine- 2-carboxamide;
2-(2-hydroxyphenyl)-l-(2-(pyrrolidine-l-carbonyl)-6,7-dihydropyrazolo[l,5- a]pyrazin-5(4H)-yl)ethanone;
7-(3-(2-hydroxyphenyl)propanoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-2- carboxamide;
2-(3-chloro-4-hydroxyphenyl)- 1 -(6,7-dihydro-5H-imidazo[ 1 ,5-a] [ 1 ,4]diazepin-8(9H)- yl)ethanone;
l-(5,6-dihydroimidazo[l,5-a]pyrazin-7(8H)-yl)-2-(2-hydroxyphenoxy)ethanone; or l-(5,6-dihydroimidazo[l,5-a]pyrazin-7(8H)-yl)-3-(2-hydroxyphenyl)propan-l-one. [0018] Also provided is a pharmaceutical composition comprising at least one compound represented by structural formula (I), or a pharmaceutically acceptable salt thereof:
Figure imgf000017_0001
or a pharmaceutically acceptable salt thereof, wherein: L is -C(O)-, -O-C(O)-, -NR6-C(0)-, or -S(0)2-; L2 is a bond, -0-, or -NR-;
R, for each occurrence, is independently hydrogen or a Ci^alkyl; R1 is a Ci^alkylene;
R is selected form the group consisting of:
Figure imgf000017_0002
R3 is hydrogen, -CN, Ci_8alkyl, Ci_8haloalkyl, -(CR10Rn)m-N(R16)2, -(CR10Rn)m- OR15, -(CR10Rn)m-C(O)OR15, -(CR10Rn)m-C(O)N(R16)2, -(CR10Rn)m-S(O)2N(R16)2, - (CR10Ru)m-S(O)2NHS(O)2R15, -C(0)N(R15)-S(0)2R15, -S(0)2OR15, -C(0)NHC(0)R15, - Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -0-P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, - C(0)NHS(0)2R15, -C(0)NHOH, -C(0)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -Lx-R4; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R5;
L1 is Ci-galkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0)2NR-, or -C(0)NR-S(0)2-;
R4 is Ci-galkyl, C3_gcycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R4 may be optionally substituted with from one to four R5;
R5 is halo, cyano, Ci-galkyl, Ci-ghaloalkyl, C3-8cycloalkyl, -(CR10Ru)m-N(R16)2, -(CR10Rn)m-OR15, -(CR10Rn)m-C(O)OR15, -C(0)N(R16)2, -C(0)N(R15)-S(0)2R15, - S(0)2OR15, -C(0)NHC(0)R15, -Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -S(0)2N(R15)2, O P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, -C(0)NHS(0)2R15, C(0)NHOH, C(0)NHCN, -C(0)R15, a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, =0, Ci_ 4alkyl, Ci_4haloalkyl, Ci_4alkoxy, cyano, nitro, hydroxyl, amino, N-(Ci_4alkyl)amino, N,N-di-(CMalkyl)amino, carbamoyl, N-(Ci-4alkyl)carbamoyl, N,N-di-(CMalkyl)carbamoyl, Ci_4alkylamido, Ci_4alkylsulfonyl, Ci-4alkylsulfonamido, sulfamoyl, N-Ci^alkylsulfamoyl, and N,N^Ci_4dialkyl)-sulfamoyl;
R6 is hydrogen or a Ci-galkyl;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C3_gcycloalkyl,
C3_ghalocycloalkyl, Ci_galkoxy, Ci_ghaloalkoxy, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci_galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci_galkylsulfonyl , sulfamoyl,
N-(Ci_galkyl)sulfamoyl, N,N-di-(Ci_galkyl)sulfamoyl, and Ci_galkylsulfonamido;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C3_gcycloalkyl, C3_ghalocycloalkyl, Ci-galkoxy, Ci-ghaloalkoxy, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci_galkoxycarbonyl, Ci_galkanoyloxy, carbamoyl,
Figure imgf000019_0001
Ci_galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl, N-(^galkyl)sulfamoyl,
N,N-di-(^galkyl)sulfamoyl, and Ci-galkylsulfonamido;
R9, for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci_galkyl, Ci_galkoxy, Ci_ghaloalkyl, Ci_ghaloalkoxy,
C3_gcycloalkyl, C3_ghalocycloalkyl, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci-galkyl)amino, N,N-di-(^galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl,
Figure imgf000019_0002
N,N-di-(Ci_galkyl)carbamoyl, Ci_galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(Ci_galkyl)sulfamoyl, Ci-galkylsulfonamido, C6-1oaryl, Ci-galkoxy-Ci_6alkyl, and tri-(Ci-galkyl)silyl;
R9a is hydrogen or R9; or R9a and R6, together with the intervening atoms, form a 3- to 8-membered heterocyclyl which is optionally substituted with from one to three R9;
R10 and R11, for each occurrence, are independently hydrogen, halo, hydroxyl, carboxy, C1-4alkyl, or a Ci^haloalkyl;
R15 for each occurrence is independently selected from the group consisting of hydrogen, Ci-galkyl, C2-galkenyl, C2_galkynyl, C3_gcycloalkyl, C3_gcycloalkenyl, C6-1oaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci_4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-(Ci_4alkyl)amino, N,N-di-(Ci_4alkyl)amino, carboxyl, carbamoyl,
N-(Ci_4alkyl)carbamoyl, N,N-di-(Ci_4alkyl)carbamoyl, Ci^alkylamido, Ci^alkylsulfonyl, Ci_4alkylsulfonamido, sulfamoyl, N-(Ci_4alkyl)sulfamoyl, and N,N-(Ci_4dialkyl)-sulfamoyl;
R16 is Ci-galkoxy, or R15; or two R16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci_4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-(Ci_4alkyl)amino,
N,N-di-(Ci_4alkyl)amino, carboxyl, carbamoyl, N-(C1-4alkyl)carbamoyl,
N,N-di-(C1-4alkyl)carbamoyl, C1-4alkylamido, C1-4alkylsulfonyl, C1-4alkylsulfonamido, sulfamoyl, N-C1-4alkylsulfamoyl, and N,N-(C1-4dialkyl)-sulfamoyl; h is 0, 1, or 2;
n, for each occurrence, is independently 0, 1, 2, 3, or 4;
m, for each occurrence, is independently 0 or an integer from 1 to 6;
p is 0, 1, 2, or 3;
q is 1, 2, 3, or 4;
r is 1, 2, or 3; and t is 0 or 1, provided that the compound is not 2-(4-fluorophenyl)-l-(3-(quinolin-2-yl)- 5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone; and at least one pharmaceutically acceptable carrier or excipient.
[0019] Also provided is a method of preventing, treating, or reducing symptoms of a condition mediated by SIP activity and/or ATX activity in a mammal comprising delivering (e.g., administering) to said mammal an effective amount of a compound represented by structural formula (I):
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof, wherein: L is -C(O)-, -O-C(O)-, -NR6-C(0)-, or -S(0)2-; L2 is a bond, -0-, or -NR-;
R, for each occurrence, is independently hydrogen or a C1_4alkyl; R1 is a Ci-galkylene;
R is selected form the group consisting of:
Figure imgf000021_0001
R3 is hydrogen, -CN, C1-8alkyl, Ci-ghaloalkyl, -(CR10Rn)m-N(R16)2, -(CR10Rn)m- OR15, -(CR10Rn)m-C(O)OR15, -(CR10Rn)m-C(O)N(R16)2, -(CR10Rn)m-S(O)2N(R16)2, - (CR10Ru)m-S(O)2NHS(O)2R15, -C(0)N(R15)-S(0)2R15, -S(0)2OR15, -C(0)NHC(0)R15, - Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -0-P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, - C(0)NHS(0)2R15, -C(0)NHOH, -C(0)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -Lx-R4; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R5;
L1 is Ci_8alkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0)2NR-, or -C(0)NR-S(0)2-;
R4 is Ci-8alkyl, C3_8cycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R4 may be optionally substituted with from one to four R5;
R5 is halo, cyano, Ci.galkyl, Ci.ghaloalkyl, C3-8cycloalkyl, -(CR10Ru)m-N(R16)2, -(CR10Rn)m-OR15, -(CR10Rn)m-C(O)OR15, -C(0)N(R16)2, -C(0)N(R15)-S(0)2R15, - S(0)2OR15, -C(0)NHC(0)R15, -Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -S(0)2N(R15)2, O P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, -C(0)NHS(0)2R15, C(0)NHOH, C(0)NHCN, -C(0)R15, a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, =0, Ci_ 4alkyl, Ci_4haloalkyl, Ci_4alkoxy, cyano, nitro, hydroxyl, amino, N-(Ci_4alkyl)amino, N,N-di-(CMalkyl)amino, carbamoyl, N-(Ci-4alkyl)carbamoyl, N,N-di-(CMalkyl)carbamoyl, C1-4alkylamido, Ci_4alkylsulfonyl, Ci^alkylsulfonamido, sulfamoyl, N-Ci-4alkylsulfamoyl, and N,N-(C1-4dialkyl)-sulfamoyl;
R6 is hydrogen or a Ci_galkyl;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C3_8cycloalkyl,
C3_ghalocycloalkyl, Ci_galkoxy, Ci_ghaloalkoxy, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci_galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci-galkyl)carbamoyl, N,N-di-(^galkyl)carbamoyl,
Ci-galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl,
N-(Ci_galkyl)sulfamoyl, N,N-di-(Ci_galkyl)sulfamoyl, and Ci-galkylsulfonamido;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C3_gcycloalkyl, C3_ghalocycloalkyl, Ci-galkoxy, Ci-ghaloalkoxy, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci_galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(Ci_galkyl)sulfamoyl, and Ci-galkylsulfonamido;
R9, for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci_galkyl,
Figure imgf000022_0001
Ci-ghaloalkyl, Ci_ghaloalkoxy,
C3_gcycloalkyl, C3_ghalocycloalkyl, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Q-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci_galkylthio, Ci_galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(Ci-galkyl)sulfamoyl, Ci-galkylsulfonamido, C6-1oaryl, Ci-galkoxy-Ci_6alkyl, and tri-(Ci-galkyl)silyl;
R9a is hydrogen or R9; or R9a and R6, together with the intervening atoms, form a 3- to 8-membered heterocyclyl which is optionally substituted with from one to three R9;
R10 and R11, for each occurrence, are independently hydrogen, halo, hydroxyl, carboxy, Ci_4alkyl, or a Ci_4haloalkyl; R for each occurrence is independently selected from the group consisting of hydrogen, Ci-galkyl, C2_galkenyl, C2_galkynyl, C3_gcycloalkyl, C3_gcycloalkenyl, C6-ioaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1_4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino,
Figure imgf000023_0001
N,N-di-(CMalkyl)amino, carboxyl, carbamoyl,
Figure imgf000023_0002
C^alkylsulfonamido, sulfamoyl, N-iC^alky^sulfamoyl, and N^-iC^dialky^-sulfamoyl;
R16 is Ci-galkoxy, or R15; or two R16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci^alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-(CMalkyl)amino,
N,N-di-(CMalkyl)amino, carboxyl, carbamoyl,
Figure imgf000023_0003
Figure imgf000023_0004
h is 0, 1, or 2;
n, for each occurrence, is independently 0, 1, 2, 3, or 4;
m, for each occurrence, is independently 0 or an integer from 1 to 6;
p is 0, 1, 2, or 3;
q is 1, 2, 3, or 4;
r is 1, 2, or 3; and
t is 0 or 1.
[0020] The condition can be selected from the group consisting of an inflammatory disorder, an autoimmune disorder, a fibrosis of the lung, or a malignancy of the lung. The inflammatory disorder can be rheumatoid arthritis. The autoimmune disorder can be multiple sclerosis. The method can further include administering to said mammal an effective amount of one or more drugs selected from the group consisting of: a corticosteroid, a bronchodilator, an antiasthmatic, an antiinflammatory, an antirheumatic, an immunosuppressant, an antimetabolite, an immunomodulator, an antipsoriatic, and an antidiabetic. [0021] Also provided is a method of promoting myelination or remyelination in a mammal in need thereof, comprising administering to cells an effective amount of at least one compound, or a pharmaceutically acceptable salt thereof, described herein.
[0022] Also provided is a method of preventing, treating, or reducing chronic pain in a mammal comprising delivering (e.g., administering) to said mammal an effective amount of at least one compound, or a pharmaceutically acceptable salt thereof, represented by formula
(I):
Figure imgf000024_0001
or a pharmaceutically acceptable salt thereof, wherein:
L is -C(O)-, -O-C(O)-, -NR-C(O)-, or -S(0)2-;
R, for each occurrence, is independently hydrogen or a C1_4alkyl;
R1 is a Ci^alkylene;
R is selected form the group consisting of:
Figure imgf000024_0002
Figure imgf000025_0001
R3 is hydrogen, -CN, C1-8alkyl, Ci-ghaloalkyl, -(CR10Rn)m-N(R16)2, -(CR10Rn)m- OR15, -(CR10Rn)m-C(O)OR15, -(CR10Rn)m-C(O)N(R16)2, -(CR10Rn)m-S(O)2N(R16)2, - (CR10Ru)m-S(O)2NHS(O)2R15, -C(0)N(R15)-S(0)2R15, -S(0)2OR15, -C(0)NHC(0)R15, - Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -0-P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, - C(0)NHS(0)2R15, -C(0)NHOH, -C(0)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -Lx-R4; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R5;
L1 is Ci-galkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0)2NR-, or -C(0)NR-S(0)2-;
R4 is Ci-galkyl, C3_8cycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R4 may be optionally substituted with from one to four R5;
R5 is halo, cyano, Ci_galkyl, Ci_ghaloalkyl, C3-8cycloalkyl, -(CR10Ru)m-N(R16)2, -(CR10Rn)m-OR15, -(CR10Rn)m-C(O)OR15, -C(0)N(R16)2, -C(0)N(R15)-S(0)2R15, - S(0)2OR15, -C(0)NHC(0)R15, -Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -S(0)2N(R15)2, O P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, -C(0)NHS(0)2R15, C(0)NHOH,
C(0)NHCN, -C(0)R15, a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, =0, Ci_ 4alkyl, Ci_4haloalkyl, Ci_4alkoxy, cyano, nitro, hydroxyl, amino, N-(CMalkyl)amino, N,N-di-(Ci_4alkyl)amino, carbamoyl,
Figure imgf000025_0002
N,N-di-(Ci_4alkyl)carbamoyl, Ci_4alkylamido, Ci_4alkylsulfonyl, Ci_4alkylsulfonamido, sulfamoyl, N-Ci_4alkylsulfamoyl, and N,N^CMdialkyl)-sulfamoyl;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C3_gcycloalkyl,
C3_ghalocycloalkyl, Ci-galkoxy, Ci_ghaloalkoxy, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl,
Ci-galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl,
N-(Ci_galkyl)sulfamoyl, N,N-di-(Ci_galkyl)sulfamoyl, and Ci-galkylsulfonamido;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, Ci_galkyl, Ci_ghaloalkyl, C3_gcycloalkyl, C3_ghalocycloalkyl, Ci-galkoxy, Ci-ghaloalkoxy, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino,
Figure imgf000026_0001
N,N-di-(^galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl,
Figure imgf000026_0002
Ci-galkylamido, mercapto, Ci-galkylthio, Ci_galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(Ci_galkyl)sulfamoyl, and Ci-galkylsulfonamido;
R9, for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci_galkyl, Ci_galkoxy, Ci_ghaloalkyl, Ci-ghaloalkoxy,
C3_gcycloalkyl, C3_ghalocycloalkyl, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci_galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci_galkylthio, Ci_galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(Ci_galkyl)sulfamoyl, Ci_galkylsulfonamido, C6-1oaryl, Ci-galkoxy-Ci-ealkyl, and tri-(Ci-galkyl)silyl;
R10 and R11, for each occurrence, are independently hydrogen, halo, hydroxyl, carboxy, C1-4alkyl, or a C^haloalkyl;
R15 for each occurrence is independently selected from the group consisting of hydrogen, Ci_galkyl, C2-galkenyl, C2_galkynyl, C3-gcycloalkyl, C3-gcycloalkenyl, C6-1oaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C^alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-(Ci_4alkyl)amino, N,N-di-(Ci_4alkyl)amino, carboxyl, carbamoyl,
N-(C1_4alkyl)carbamoyl, N,N-di-(Ci_4alkyl)carbamoyl, C^alkylamido, Ci_4alkylsulfonyl, Ci_4alkylsulfonamido, sulfamoyl, N-(Ci_4alkyl)sulfamoyl, and N,N-(Ci_4dialkyl)-sulfamoyl;
R16 is Ci-galkoxy, or R15; or two R16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1_4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-(C1-4alkyl)amino,
N,N-di-(CMalkyl)amino, carboxyl, carbamoyl,
Figure imgf000027_0001
Figure imgf000027_0002
h is 0, 1, or 2;
n, for each occurrence, is independently 0, 1, 2, 3, or 4;
m, for each occurrence, is independently 0 or an integer from 1 to 6;
p is 0, 1, 2, or 3;
q is 1, 2, 3, or 4;
r is 1, 2, or 3; and
t is 0 or 1, provided that the compound is not 2-(4-fluorophenyl)-l-(3-(quinolin-2-yl)- 5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone.
[0023] In some embodiments, the chronic pain can be inflammatory pain or neuropathic pain.
[0024] Other features or advantages will be apparent from the following detailed description of several embodiments, and also from the appended claims.
[0025] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
[0026] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. In some embodiments, the alkyl comprises 1 to 20 carbon atoms, such as 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec -butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, or n-decyl.
[0027] As used herein, the term "alkylene" refers to a divalent alkyl group. Examples of alkylene groups include methylene, ethylene, propylene, n-butylene, and the like. The alkylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the carbon chain. [0028] As used herein, the term "haloalkyl" refers to an alkyl, as defined herein, that is substituted by one or more halo groups as defined herein. In some embodiments, the haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodo, bromo, chloro or fluoro substituent. Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halo atoms or a combination of different halo groups. Non-limiting examples of haloalkyl include
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halo atoms. In some embodiments, a haloalkyl group is trifluoromethyl or difluoromethyl.
[0029] As used herein, the term "halogen" or "halo" may be fluoro, chloro, bromo or iodo.
[0030] "Alkenyl" refers to an unsaturated hydrocarbon group which may be linear or branched and has at least one carbon-carbon double bond. Alkenyl groups with 2-8 carbon atoms can be preferred. The alkenyl group may contain 1, 2 or 3 carbon-carbon double bonds, or more. Examples of alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl and the like.
[0031] "Alkynyl" refers to an unsaturated hydrocarbon group which may be linear or branched and has at least one carbon-carbon triple bond. Alkynyl groups with 2-8 carbon atoms can be preferred. The alkynyl group may contain 1, 2 or 3 carbon-carbon triple bonds, or more. Examples of alkynyl groups include ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and the like.
[0032] As used herein, the term "alkoxy" refers to alkyl-O-, wherein alkyl is defined herein above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like. Alternatively, representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy, and the like. In some embodiments, alkoxy groups have about 1-6 carbon atoms, such as about 1-4 carbon atoms.
[0033] As used herein, the term "haloalkoxy" refers to haloalkyl-O-, wherein haloalkyl is defined herein above. Representative example of haloalkoxy groups are trifluoromethoxy, difluoromethoxy, and 1,2-dichloroethoxy. In some embodiments, haloalkoxy groups have about 1-6 carbon atoms, such as about 1-4 carbon atoms. [0034] As used herein, the term "alkylthio" refers to alkyl-S-, wherein alkyl is defined herein above.
[0035] As used herein, the term "carbocyclyl" refers to saturated or partially unsaturated (but not aromatic) monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-14 carbon atoms, such as 3-9, for example, 3-8 carbon atoms. Carbocyclyls include fused or bridged ring systems. The term "carbocyclyl" encompasses cycloalkyl groups. The term "cycloalkyl" refers to completely saturated monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, such as 3-9, for example, 3-8 carbon atoms. Exemplary monocyclic carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl. Exemplary bicyclic carbocyclyl groups include bornyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6- trimethylbicyclo[3.1.1]heptyl, or bicyclo[2.2.2]octyl. Exemplary tricyclic carbocyclyl groups include adamantyl.
[0036] As used herein, the term "halocycloalkyl" refers to a cycloalkyl, as defined herein, that is substituted by one or more halo groups as defined herein. In some
embodiments the halocycloalkyl can be monohalocycloalkyl, dihalocycloalkyl or
polyhalocycloalkyl including perhalocyclo alkyl. A monohalocycloalkyl can have one iodo, bromo, chloro or fluoro substituent. Dihalocycloalkyl and polyhalocycloalkyl groups can be substituted with two or more of the same halo atoms or a combination of different halo groups.
[0037] As used herein, the term "cycloalkoxy" refers to cyclo alkyl- 0-, wherein cycloalkyl is defined herein above.
[0038] As used herein, the term "halocycloalkoxy" refers to halocycloalkyl-O-, wherein halocycloalkyl is defined herein above.
[0039] As used herein, the term "the term "aryl" refers to monocyclic, bicyclic or tricyclic aromatic hydrocarbon groups having from 6 to 14 carbon atoms in the ring portion. In some embodiments, the term aryl refers to monocyclic and bicyclic aromatic hydrocarbon groups having from 6 to 10 carbon atoms. Representative examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracenyl.
[0040] The term "aryl" also refers to a bicyclic or tricyclic group in which at least one ring is aromatic and is fused to one or two non-aromatic hydrocarbon ring(s). Nonlimiting examples include tetrahydronaphthalene, dihydronaphthalenyl and indanyl. [0041] As used herein, the term "heterocyclyl" refers to a saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic ring system which has from 3- to 15-ring members at least one of which is a heteroatom, and up to 10 of which may be heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and wherein N and S can be optionally oxidized to various oxidation states. In some embodiments, a heterocyclyl is a 3-8-membered monocyclic. In some embodiments, a heterocyclyl is a 6-12-membered bicyclic. In some embodiments, a heterocyclycyl is a 10-15-membered tricyclic ring system. The heterocyclyl group can be attached at a heteroatom or a carbon atom. Heterocyclyls include fused or bridged or spiro ring systems. The term "heterocyclyl" encompasses heterocycloalkyl groups. The term "heterocycloalkyl" refers to completely saturated monocyclic, bicyclic or tricyclic heterocyclyl comprising 3-15 ring members, at least one of which is a heteroatom, and up to 10 of which may be heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and wherein N and S can be optionally oxidized to various oxidation states. Examples of heterocyclyls include dihydrofuranyl,
[l,3]dioxolane, 1,4-dioxane, 1,4-dithiane, 1,3-dioxolane, imidazolidinyl, imidazolinyl, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithianyl, oxathianyl,
thiomorpholinyl, oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, azepinyl, oxapinyl, oxazepinyl and diazepinyl. Further examples of heterocyclyls include azepanyl, azetidinyl, 1,4-diazepanyl, 4,5-dihydrothiazolyl, morpholinyl, oxetanyl, piperidinyl, piperidin-2-one, piperazinyl, piperazin-2-one, pyrrolidinyl, tetrahydro-2H-pyranyl, 1,2,3,6-tetrahydropyridinyl, 3- azabicyclo [3.1.0]hexanyl, hexahydro- 1 H-pyrrolo [2, 1 -c] [ 1 ,4] oxazinyl, octahydropyrido [2,1- c] [ 1 ,4]oxazinyl, octahydropyrrolo[ 1 ,2-a]pyrazinyl, octahydropyrrolo[2,3-b]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl, octahydropyrrolo[3,4- c]pyrrolyl, 9-azabicyclo[3.3.1]nonanyl, 8-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]oct- 2-enyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5- diazabicyclo[2.2.2]octanyl, 3,6-diazabicyclo[3.2. l]octanyl, 3,9-diazabicyclo[3.3. l]nonanyl, 2,8-diazaspiro[4.5]decane, 5,8-diazaspiro[3.5]nonane, 4,7-diazaspiro[2.5]octane, and 6, 9- diazaspiro [4.5 ] decane .
[0042] As used herein, the term "heteroaryl" refers to a 5-14 membered monocyclic-, bicyclic-, or tricyclic-ring system, having 1 to 10 heteroatoms independently selected from N, O or S, wherein N and S can be optionally oxidized to various oxidation states, and wherein at least one ring in the ring system is aromatic. In one embodiment, the heteroaryl is monocyclic and has 5 or 6 ring members. Examples of monocyclic heteroaryl groups include pyridyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl. Examples of monocyclic heteroaryl groups further include imidazolyl, oxadiazolyl, pyridinyl (or pyridyl), pyrazolyl, thiazolyl, and tetrazolyl. In another embodiment, the heteroaryl is bicyclic and has from 8 to 10 ring members. Examples of bicyclic heteroaryl groups include indolyl, benzofuranyl, quinolyl, isoquinolyl indazolyl, indolinyl, isoindolyl, indolizinyl, benzamidazolyl, quinolinyl, 5,6,7, 8-tetrahydroquinoline and 6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine.
[0043] As used herein, the term "amino" refers to a group having the formula NH2.
The term N-(alkyl) amino is an amino group in which one of the hydrogen atoms is replaced with an alkyl group. The term N,N-(dialkyl)amino is an amino group in which each hydrogen atoms is replaced with an alkyl group which may be the same or different.
[0044] As used herein, the term "alkanoyl" refers to alkyl-C(=0)-, where alkyl is defined herein above.
[0045] As used herein, the term "alkoxycarbonyl" refers to alkyl-0-C(=0)-, where alkyl is defined herein above.
[0046] As used herein, the term "alkanoyloxy" refers to alkyl-C(=0)-0-, where alkyl is defined herein above.
[0047] As used herein, the term "alkylamido" refers to alkyl-C(=0)-NH-, where alkyl is defined herein above.
[0048] As used herein, the term "carbamoyl" refers to -C(=0)-NH2. The term N- alkylcarbamoyl refers to a carbamoyl group in which one of the hydrogen atoms is replaced with an alkyl group. The term Ν,Ν-dialkylcarbamoyl refers to a carbamoyl group in which each hydrogen atoms is replaced with an alkyl group which may be the same or different.
[0049] As used herein, the term "carboxy" or "carboxyl" refers to -C(=0)-OH.
[0050] As used herein, the term "bridged ring system," is a ring system that has a carbocyclyl or heterocyclyl ring wherein two non-adjacent atoms of the ring are connected (bridged) by one or more (such as from one to three) atoms. A bridged ring system can have more than one bridge within the ring system (e.g. , adamantyl). A bridged ring system may have from 6-10 ring members, such as from 7-10 ring members. Examples of bridged ring systems include adamantly, 9-azabicyclo[3.3.1]nonan-9-yl, 8-azabicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, 3-azabicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, (1R,5S)- bicyclo[3.2.1]octanyl, 3-azabicyclo[3.3.1]nonanyl, and bicyclo[2.2.1]heptanyl. In some embodiments, the bridged ring system is selected from 9-azabicyclo[3.3.1]nonan-9-yl, 8- azabicyclo[3.2.1]octanyl, and bicyclo[2.2.2]octanyl.In some embodiments, the bridged ring system is selected from 9-azabicyclo[3.3.1]nonanyl, 8-azabicyclo[3.2.1]octanyl, 8- azabicyclo[3.2.1]oct-2-enyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.2]octanyl, 3,6-diazabicyclo[3.2.1]octanyl, and 3,9- diazabicyclo[3.3. l]nonanyl.
[0051] As used herein, the term "spiro ring system," is a ring system that has a carbocyclyl or heterocyclyl with rings connected through just one atom. The rings can be different in nature or identical. A spiro ring system may have from 6-12 ring members, such as from 8- 10 ring members. Examples of spiro ring systems include 2,8- diazaspiro[4.5]decane, 5,8-diazaspiro[3.5]nonane, 4,7-diazaspiro[2.5]octane, and 6, 9- diazaspiro [4.5 ] decane .
[0052] The number of carbon atoms in a group is specified herein by the prefix "Cx_ xx", wherein x and xx are integers. For example, "Ci^alkyl" is an alkyl group which has from 1 to 4 carbon atoms; C^alkoxy is an alkoxy group having from 1 to 6 carbon atoms; C6- 10aryl is an aryl group which has from 6 to 10 carbon atoms; C1_4haloalkyl is a haloalkyl group which has from 1 to 4 carbon atoms; and N^-di-Ci-ealkylamino is a N,N-dialkylamino group in which the nitrogen is substituted with two alkyl groups each of which is
independently from 1 to 6 carbon atoms.
[0053] The disclosed compounds, or pharmaceutically acceptable salts thereof, can contain one or more asymmetric centers in the molecule. In accordance with the present disclosure any structure that does not designate the stereochemistry is to be understood as embracing all the various optical isomers (e.g. , diastereomers and enantiomers) in pure or substantially pure form, as well as mixtures thereof (such as a racemic mixture, or an enantiomerically enriched mixture). It is well known in the art how to prepare such optically active forms (for example, resolution of the racemic form by recrystallization techniques, synthesis from optically- active starting materials, by chiral synthesis, or chromatographic separation using a chiral stationary phase). The disclosed compounds may exist in tautomeric forms and mixtures and separate individual tautomers are contemplated. In addition, some compounds may exhibit polymorphism.
[0054] By way of clarity, compounds of the invention included all isotopes of the atoms present in formula (I) and any of the examples or embodiments disclosed herein. For
1 2 example, H (or hydrogen) represents any isotopic form of hydrogen including H, H (D), and
3 12 13 14
H (T); C represents any isotopic form of carbon including C, C, and C; O represents any isotopic form of oxygen including 160, 170 and 180; N represents any isotopic form of nitrogen including 13N, 14N and 15N; P represents any isotopic form of phosphorous including 31 P and 32 P; S represents any isotopic form of sulfur including 32 S and 35 S; F represents any isotopic form of fluorine including 19F and 18F; CI represents any isotopic form of chlorine including 35 CI, 3 V CI and 36 CI; and the like. In a preferred embodiment, compounds represented by formula (I) comprises isotopes of the atoms therein in their naturally occurring abundance. However, in certain instances, it is desirable to enrich one or more atom in a particular isotope which would normally be present in less abundance. For example, 1H would normally be present in greater than 99.98% abundance; however, a compound of the invention can be enriched in 2 H or 3 H at one or more positions where H is present. In particular embodiments of the compounds of formula (I), when, for example, hydrogen is enriched in the deuterium isotope, the symbol "D" may be used to represent the enrichment in deuterium. In one embodiment, when a compound of the invention is enriched in a radioactive isotope, for example 3H and 14C, they may be useful in drug and/or substrate tissue distribution assays. It is to be understood that the invention encompasses all such isotopic forms which modulate ATX or SIP receptor activity.
[0055] Provided is a compound represented by formula (I), or a pharmaceutically acceptable salt thereof:
Figure imgf000033_0001
or a pharmaceutically acceptable salt thereof, wherein: L is -C(O)-, -O-C(O)-, -NR6-C(0)-, or -S(0)2-;
L 2 is a bond, -0-, or -NR-; provided that L 2 is not -O- when R 2 is structure (iv); R, for each occurrence, is independently hydrogen or a Ci^alkyl; R1 is a Ci-galkylene;
R is selected form the group consisting of:
Figure imgf000034_0001
R3 is hydrogen, -CN, C1-8alkyl, Ci-ghaloalkyl, -(CR10Rn)m-N(R16)2, -(CR10Rn)m- OR15, -(CR10Rn)m-C(O)OR15, -(CR10Rn)m-C(O)N(R16)2, -(CR10Rn)m-S(O)2N(R16)2, - (CR10Ru)m-S(O)2NHS(O)2R15, -C(0)N(R15)-S(0)2R15, -S(0)2OR15, -C(0)NHC(0)R15, - Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -0-P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, - C(0)NHS(0)2R15, -C(0)NHOH, -C(0)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -Lx-R4; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R 5 ; provided that when R 2 is structure (ii), (iii), (iv), or (xi), R 3 is not hydrogen; and provided that when R 2 is structure (iv), R 3 is not pyrrolidinyl, piperidinyl , an N-methylpyrrolidinyl, an N-acetyl-pyrrolidinyl, an N-methylpiperidinyl, or an N-acetyl- piperidinyl;
L1 is Ci_8alkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0)2NR-, or -C(0)NR-S(0)2-;
R4 is Ci-galkyl, C3_gcycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R4 may be optionally substituted with from one to four R5;
R5 is halo, cyano, Ci-galkyl, Ci-ghaloalkyl, C3-8cycloalkyl, -(CR10Ru)m-N(R16)2, -(CR10Rn)m-OR15, -(CR10Rn)m-C(O)OR15, -C(0)N(R16)2, -C(0)N(R15)-S(0)2R15, - S(0)2OR15, -C(0)NHC(0)R15, -Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -S(0)2N(R15)2, O P(0)(OR13)2, -P(0)(OR13)2, -S(0)2NHC(0)R , -C(0)NHS(0)2R , C(0)NHOH,
C(0)NHCN, -C(0)R15, a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, =0, Ci_ 4alkyl, Ci_4haloalkyl, Ci_4alkoxy, cyano, nitro, hydroxyl, amino, N-(Ci_4alkyl)amino, N,N-di-(Ci_4alkyl)amino, carbamoyl, N-iC^alky^carbamoyl, N,N-di-(Ci_4alkyl)carbamoyl, C1-4alkylamido, Ci_4alkylsulfonyl, Ci^alkylsulfonamido, sulfamoyl, N-Ci-4alkylsulfamoyl, and N,N-(C1-4dialkyl)-sulfamoyl;
R6 is hydrogen or a Ci_galkyl;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C3_8cycloalkyl,
C3_8halocycloalkyl, C^alkoxy, Ci-ghaloalkoxy, C3_8cycloalkoxy, C3_8halocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl,
Ci-galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl,
N-(^galkyl)sulfamoyl, N,N-di-(^galkyl)sulfamoyl, and Ci-galkylsulfonamido;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, Ci_galkyl, Ci-ghaloalkyl, C3_gcycloalkyl, C3_ghalocycloalkyl, Ci-galkoxy, Ci-ghaloalkoxy, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl,
Figure imgf000035_0001
N,N-di-(Ci_galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci_galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(Ci_galkyl)sulfamoyl, and Ci-galkylsulfonamido;
R9, for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci_galkyl, Ci_galkoxy, Ci_ghaloalkyl, Ci-ghaloalkoxy,
C3_gcycloalkyl, C3_ghalocycloalkyl, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci_galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci_galkylthio, Ci_galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(Ci_galkyl)sulfamoyl, Ci_galkylsulfonamido, C6-1oaryl, Ci-galkoxy-Ci-ealkyl, and tri-(Ci-galkyl)silyl;
R9a is hydrogen or R9; or R9a and R6, together with the intervening atoms, form a 3- to 8-membered heterocyclyl which is optionally substituted with from one to three R9; R and R , for each occurrence, are independently hydrogen, halo, hydroxyl, carboxy, C1_4alkyl, or a C^haloalkyl;
R15 for each occurrence is independently selected from the group consisting of hydrogen, Ci-galkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C3-8cycloalkenyl, C6-ioaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C^alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-iC^alky^amino, N^-di-iC^alky^amino, carboxyl, carbamoyl,
Figure imgf000036_0001
R16 is Ci-salkoxy, or R15; or two R16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C^alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-iC^alky^amino,
Figure imgf000036_0002
sulfamoyl, N-Ci^alkylsulfamoyl, and N,N-(CMdialkyl)-sulfamoyl;
h is 0, 1, or 2;
n, for each occurrence, is independently 0, 1, 2, 3, or 4;
m, for each occurrence, is independently 0 or an integer from 1 to 6;
p is 0, 1, 2, or 3;
q is 1, 2, 3, or 4;
r is 1, 2, or 3; and
t is 0 or 1, provided that the compound is not:
3-(5-(2-(4-isopropylphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
2- (2,3-difluorophenyl)-l-(2-((dimethylamino)methyl)-6,7-dihydropyrazolo[l,5- a]pyrazin-5(4H)-yl)ethanone;
3- (5-((2-fluorophenethyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid; 3-(5-((4-methylbenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
3-(5-(2-(2-chloro-4-fluorophenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
N-(3-fluorobenzyl)-2-(pyrrolidine-l-carbonyl)-6,7-dihydropyrazolo[l,5-a]pyrazine- 5(4H)-carboxamide;
l-(2-(4-methylpiperazine-l-carbonyl)-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)- 3-(p-tolyl)propan-l-one;
methyl 5-((3-fluorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carboxylate;
methyl 5-((4-fluorophenethyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[ 1 ,5-a]pyrazine- 2-carboxylate;
3-(5-(2-(3-(methylthio)phenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid;
3-(5-(2-(4-chlorophenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepin- 2-yl)propanoic acid;
3-(5-(2-(2,3-difluorophenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid;
l-(2-(pyridin-4-yl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepin-5(6H)-yl)-2-(3- (trifluoromethyl)phenyl)ethanone;
l-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepin-5(6H)-yl)-2-(3- (trifluoromethyl)phenyl)ethanone;
l-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepin-5(6H)-yl)-2-(2- fluorophenyl)ethanone ;
N-(3-fluorobenzyl)-2-(pyrrolidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxamide;
5-(2-(3,4-difluorophenyl)acetyl)-N-(2-hydroxyethyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxamide;
3-(5-(2-(2-methoxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid;
3-(5-(2-(4-ethoxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepin- 2-yl)propanoic acid;
l-(2-((l,4-oxazepan-4-yl)methyl)-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-2-(4- methoxyphenyl)ethanone; 3-(5-(2-(2-methoxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
3- (2-methoxyphenyl)-l-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4] diazepin- 5 (6H) -yl)propan- 1 - one ;
2-(2-methoxyphenyl)-l-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4] diazepin- 5 (6H) -yl)ethanone ;
2-(4-ethoxyphenyl)-l-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4] diazepin- 5 (6H) -yl)ethanone ;
methyl 5-(3-(3-methoxyphenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carboxylate;
N2-cyclopropyl-N5-(3-methoxybenzyl)-6,7-dihydropyrazolo[l,5-a]pyrazine-2,5(4H)- dicarboxamide;
5-((l-(3-methoxyphenyl)ethyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
4- (4-chlorophenyl)- 1 -(6,7-dihydro-5H-imidazo[ 1 ,5-a] [ 1 ,4]diazepin-8(9H)-yl)butan- 1 - one;
N-(2-fluorophenethyl)-6,7-dihydro-5H-imidazo[l,5-a][l,4]diazepine-8(9H)- carboxamide;
1 -(6,7-dihydro-5H-imidazo[ 1 ,5-a] [ 1 ,4]diazepin-8(9H)-yl)-2-(4- ethoxyphenyl)ethanone;
l-(6,7-dihydro-5H-imidazo[l,5-a][l,4]diazepin-8(9H)-yl)-2-(o-tolyl)ethanone;
N-(4-chlorobenzyl)-6,7-dihydro-5H-imidazo[l,5-a][l,4]diazepine-8(9H)- carboxamide;
l-ethyl-6-methyl-N-(4-methylbenzyl)-3,4-dihydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide;
N-(4-fluorobenzyl)-6-methyl- l-propyl-3,4-dihydropyrrolo[ 1 ,2-a]pyrazine-2( 1H)- carboxamide;
l-ethyl-N-(4-fluorobenzyl)-6-methyl-3,4-dihydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide;
1- ethyl-N-(3-methoxybenzyl)-6-methyl-3,4-dihydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide;
2- (2-aminophenyl)-l-(l,6-dimethyl-3,4-dihydropyrrolo[l,2-a]pyrazin-2(lH)- yl)ethanone; 2-(4-aminophenyl)-l-(l,6-dimethyl-3,4-dihydropyrrolo[l,2-a]pyrazin-2(lH)- yl)ethanone;
N-(3-methoxybenzyl)-6-methyl-l-propyl-3,4-dihydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide;
l-isopropyl-6-methyl-N-(4-methylbenzyl)-3,4-dihydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide;
1- isopropyl-N-(3-methoxybenzyl)-6-methyl-3,4-dihydropyrrolo[l,2-a]pyrazine- 2(lH)-carboxamide;
6-methyl-N-(4-methylbenzyl)-l-propyl-3,4-dihydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide;
5-(((4-methoxybenzyl)oxy)carbonyl)-2-methyl-l,4,5,6-tetrahydropyrrolo[3,4- b]pyrrole-4-carboxylic acid;
2- (3-bromophenyl)-2-methyl- l-(2-methyl-5,6-dihydro-[ 1 ,2,4]triazolo[ 1 ,5-a]pyrazin- 7(8H)-yl)propan- 1 -one;
1- (5,6-dihydro-[l,2,4]triazolo[l,5-a]pyrazin-7(8H)-yl)-2-(3-methoxyphenyl)ethanone;
2- (4-fluorophenyl)-l-(3-(quinolin-2-yl)-5,6-di ydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
2- (p-tolyl)-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)ethanone;
3- (m-tolyl) -(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
3- (p-tolyl)-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
2-(2-chloro-6-fluorophenyl)-l-(3-isopropyl-5,6-di ydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
4- (3-oxo-3-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propyl)benzonitrile;
2- (2-fluorophenyl)-l-(3-isopropyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)-2-methylpropan- 1 -one;
3- (2-methoxyphenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
2-(3,4-dimethoxyphenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone; 2-(3-chloro-4-methoxyphenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
2- (2-chloro-4-methoxyphenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
3- (4-methoxyphenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
3-(3-methoxyphenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
2-(2-fluorophenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)ethanone;
2- (2-chloro-6-fluorophenyl)-l-(3-methyl-5,6-di ydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
l-(3-ethyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-2-(2-fluorophenyl)-2- methylpropan- 1 -one;
3- (3-chloro-4-methylphenyl)-l-(3-isopropyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)propan-l-one;
3-(2,5-dimethoxyphenyl)-l-(3-ethyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
3-(3-chloro-4-methylphenyl)-l-(3-ethyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)propan- 1 -one;
1- (3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-5-(p-tolyl)pentan-l- one;
2- (2-chloro-6-fluorophenyl)-l-(3-ethyl-5,6-di ydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
3- (2-ethoxyphenyl)-l-(3-ethyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
3-(2-methoxyphenyl)-l-(3-(tetrahydrofuran-2-yl)-8,9-dihydro-5H-[l,2,4]triazolo[4,3- d][l,4]diazepin-7(6H)-yl)propan-l-one;
2-(3,4-dichlorophenyl)-l-(3-(tetrahydrofuran-2-yl)-8,9-dihydro-5H- [ 1 ,2,4]triazolo[4,3-d] [ 1 ,4]diazepin-7(6H)-yl)ethanone;
2-([l,l'-biphenyl]-4-yl)-l-(3-isopropyl-8,9-dihydro-5H-[l,2,4]triazolo[4,3- d][l,4]diazepin-7(6H)-yl)ethanone;
2-(2-chloro-6-fluorophenyl)-l-(3-methyl-8,9-dihydro-5H-[l,2,4]triazolo[4,3- d][l,4]diazepin-7(6H)-yl)ethanone; 2-(3-fluorophenyl)-l-(3-methyl-8,9-dihydro-5H-[l,2,4]triazolo[4,3-d][l,4]diazepin- 7(6H)-yl)ethanone;
1- (3-isopropyl-8,9-dihydro-5H-[l,2,4]triazolo[4,3-d][l,4]diazepin-7(6H)-yl)-2-(4- (methylthio)phenyl)ethanone;
2- (2-chloro-6-fluorophenyl)-l-(3-(hydroxymethyl)-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)ethanone;
2-(2-chlorophenyl)-l-(3-(hydroxymethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
5-(4-bromophenyl)-l-(l-methyl-6,7-dihydro-lH-[l,2,3]triazolo[4,5-c]pyridin-5(4H)- yl)pentan-l-one;
3 4-ethoxyphenyl)-l-(l-methyl-6,7-dihydro-lH-[l,2,3]triazolo[4,5-c]pyridin-5(4H)- yl)propan-l-one;
2- (2-ethoxyphenoxy)-l-(l-methyl-6,7-dihydro-lH-[l,2,3]triazolo[4,5-c]pyridin- 5(4H)-yl)ethanone;
1- (5,6-dihydro-[l,2,4]triazolo[l,5-a]pyrazin-7(8H)-yl)-2-(3-fluorophenoxy)ethanone;
3- (5-(2-(3,4-dimethylphenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid;
3-(5-(2-(2,3-dimethylphenoxy)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
3-(5-(2-(2,3-dimethylphenoxy)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
2- (4-ethylphenoxy)-l-(2-(pyrrolidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4] diazepin- 5 (6H) -yl)ethanone ;
l-(2-(4-methylpiperazine-l-carbonyl)-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)- 2- (m-tolyloxy)ethanone ;
methyl 5-(2-(3,4-dimethylphenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylate;
5-(2-((3-methoxyphenyl)amino)butanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carbonitrile;
5-(2-(2-(sec-butyl)phenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carbonitrile;
l-(2,3-dimethyl-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-yl)-2-(4- fluorophenyl)ethanone ; 2- (2-chloro-6-fluorophenyl)-l-(2,3-dimethyl-6,7-dihydro-3H-imidazo[4,5-c]pyridin- 5(4H)-yl)ethanone;
methyl 3-ethyl-5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5- c] pyridine-6 -carboxylate ;
methyl 3-ethyl-5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5- c] pyridine-6 -carboxylate ;
3- (5-(2-(3-hydroxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid;
3-(5-(3-(4-hydroxyphenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
3-(5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin- 2-yl)propanoic acid;
3-(5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid;
methyl 5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[ 1 ,5- a]pyrazine-2-carboxylate;
5-(2-(2-hydroxyphenyl)acetyl)-N-phenyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine- 2-carboxamide;
2-(2-hydroxyphenyl)-l-(2-(pyrrolidine-l-carbonyl)-6,7-dihydropyrazolo[l,5- a]pyrazin-5(4H)-yl)ethanone;
7-(3-(2-hydroxyphenyl)propanoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-2- carboxamide;
2-(3-chloro-4-hydroxyphenyl)- 1 -(6,7-dihydro-5H-imidazo[ 1 ,5-a] [ 1 ,4]diazepin-8(9H)- yl)ethanone;
l-(5,6-dihydroimidazo[l,5-a]pyrazin-7(8H)-yl)-2-(2-hydroxyphenoxy)ethanone; or l-(5,6-dihydroimidazo[l,5-a]pyrazin-7(8H)-yl)-3-(2-hydroxyphenyl)propan-l-one.
[0056] In some embodiments, R2 is selected form the group consisting of:
Figure imgf000043_0001
[0057] In some embodiments, p is 0, 1, or 2.
[0058] In some embodiments, p is 1, and r is 1 or 2. In some embodiments, p is 2, and r is 1.
[0059] In some embodiments, n is 1, and R7 is Ci-salkyl. In some embodiments, n is 0.
[0060] In some embodiments, t is 1 and R8 is halo. In some embodiments, t is 0.
[0061] In some embodiments, L2 is a bond.
[0062] In some embodiments, when L ' is O or NR, R1 is C2-8alkylene.
[0063] In some embodiments, R6 is hydrogen.
[0064] In some embodiments, R9a is hydrogen.
[0065] In some embodiments, the compound of formula (I) is represented by formula (II):
Figure imgf000043_0002
(II).
[0066] In some embodiments, L is -C(O)-, -O-C(O)-, or -NR-C(O)-.
[0067] In some embodiments, L is -O-C(O)-.
[0068] Provided is a compound represented by formula (III), or a pharmaceutically acceptable salt thereof:
Figure imgf000044_0001
(III) or a pharmaceutically acceptable salt thereof, wherein: R1 is a Ci-galkylene;
R3 is hydrogen, -CN, Ci_8alkyl, Ci_8haloalkyl, -(CR10Rn)m-N(R16)2, -(CR10Rn)m- OR15, -(CR10Rn)m-C(O)OR15, -(CR10Rn)m-C(O)N(R16)2, -(CR10Rn)m-S(O)2N(R16)2, - (CR10Ru)m-S(O)2NHS(O)2R15, -C(0)N(R15)-S(0)2R15, -S(0)2OR15, -C(0)NHC(0)R15, - Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -0-P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, - C(0)NHS(0)2R15, -C(0)NHOH, -C(0)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -Lx-R4; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R5;
L1 is Ci-galkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0)2NR-, or -C(0)NR-S(0)2-;
R, for each occurrence, is independently hydrogen or C1_4alkyl;
R4 is Ci-galkyl, C3_gcycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R4 may be optionally substituted with from one to four R5;
R5 is halo, cyano, Ci-galkyl, Ci-ghaloalkyl, C3-8cycloalkyl, -(CR10Ru)m-N(R16)2, -(CR10Rn)m-OR15, -(CR10Rn)m-C(O)OR15, -C(0)N(R16)2, -C(0)N(R15)-S(0)2R15, - S(0)2OR15, -C(0)NHC(0)R15, -Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -S(0)2N(R15)2, O P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, -C(0)NHS(0)2R15, C(0)NHOH,
C(0)NHCN, -C(0)R15, a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, =0, Ci_ 4alkyl, Ci_4haloalkyl, Ci_4alkoxy, cyano, nitro, hydroxyl, amino, N-(CMalkyl)amino, N,N-di-(CMalkyl)amino, carbamoyl, N-(Ci-4alkyl)carbamoyl, N,N-di-(CMalkyl)carbamoyl, Ci_4alkylamido, Ci_4alkylsulfonyl, Ci_4alkylsulfonamido, sulfamoyl, N-Ci_4alkylsulfamoyl, and N,N^Ci_4dialkyl)-sulfamoyl;
R9, for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci-galkyl, Ci_galkoxy, Ci-ghaloalkyl, Ci-ghaloalkoxy, C3_gcycloalkyl, C3_ghalocycloalkyl, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino,
Figure imgf000045_0001
Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl,
Figure imgf000045_0002
Ci-galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl, N-(^galkyl)sulfamoyl,
Figure imgf000045_0003
Ci-galkylsulfonamido, C6-1oaryl, Ci-galkoxy-Ci-ealkyl, and tri-(Ci-8alk l)silyl;
R10 and R11, for each occurrence, are independently hydrogen, halo, hydroxyl, carboxy, C1-4alkyl, Ci^haloalkyl;
R15 for each occurrence is independently selected from the group consisting of hydrogen, Ci-galkyl, C2-galkenyl, C2_galkynyl, C3_gcycloalkyl, C3_gcycloalkenyl, C6-ioaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1_4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino,
Figure imgf000045_0004
N,N-di-(CMalkyl)amino, carboxyl, carbamoyl,
Figure imgf000045_0005
C^alkylsulfonamido, sulfamoyl, N-iC^alky^sulfamoyl, and N^-iC^dialky^-sulfamoyl;
R16 is Ci-galkoxy, or R15; or two R16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci^alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-(CMalkyl)amino,
N,N-di-(CMalkyl)amino, carboxyl, carbamoyl,
Figure imgf000045_0006
Figure imgf000045_0007
m, for each occurrence, is independently 0 or an integer from 1 to 6; and
q is 1, 2, 3, or 4.
[0069] In some embodiments, R3 is hydrogen, -CN, Ci-galkyl, Ci-ghaloalkyl, -
(CR10Ru)m-N(R16)2, -(CR10Ru)m-OR15, -(CR10Rn)m-C(O)OR15, -(CR10Rn)m-C(O)N(R16)2, a 5 to 14 membered heteroaryl, or -Lx-R4; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R5.
[0070] In some embodiments, R16, for each occurrence, is independently selected from the group consisting of hydrogen, Ci-galkyl, C3_gcycloalkyl, or two R16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1_4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-iC^alky^amino, N^-di-iC^alky^amino, carboxyl, carbamoyl,
Figure imgf000046_0001
[0071] In some embodiments, R is H or Ci-galkyl.
[0072] In some embodiments, m is 0.
[0073] In some embodiments, R3 is -C(0)OH.
[0074] In some embodiments, q is 1 or 2.
[0075] In some embodiments, R9, for each occurrence, is independently selected from the group consisting of halo, Ci-galkyl, Ci-ghaloalkyl, and C6-ioaryl.
[0076] In some embodiments, R9, for each occurrence, is independently selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, and phenyl.
[0077] In some embodiments, R1 is methylene or ethylene.
[0078] In some embodiments, R1 is methylene.
[0079] In some embodiments, provided is a compound selected from the group consisting of:
5-(3,5-Dichlorobenzyl) 2-ethyl 7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine- 2,5(6H)-dicarboxylate;
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2,5(6H)-dicarboxylate;
7-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 5,6-dihydroimidazo[ 1 ,2-a]pyrazine- 2,7(8H)-dicarboxylate;
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 6,7-dihydropyrazolo[l,5-a]pyrazine- 2,5(4H)-dicarboxylate;
7-(3,5-Bis(trifluoromethyl)benzyl) 3-methyl 8,9-dihydro-5H-imidazo[l,2- d][l,4]diazepine-3,7(6H)-dicarboxylate;
5-(3,5-Bis(trifluoromethyl)benzyl) 3-ethyl 7,8-dihydro-4H-[l,2,3]triazolo[l,5- a][l,4]diazepine-3,5(6H)-dicarboxylate; 5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
7-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydroimidazo[l,2- a]pyrazine-2-carboxylic acid;
7-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-6,7,8,9-tetrahydro-5H- imidazo[ 1 ,2-d] [ 1 ,4]diazepine-3-carboxylic acid;
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- [ 1 ,2,3]triazolo[ 1 ,5-a] [ 1 ,4]diazepine-3-carboxylic acid;
3,5-Dichlorobenzyl 2-(9-azabicyclo[3.3.1]nonane-9-carbonyl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(isopropylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(tert-butylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(cyclobutylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(cyclopentylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(cyclohexylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(pyrrolidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(piperidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(4-fluoropiperidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate; 3,5-Dichlorobenzyl 2-(4-methylpiperidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(4-(trifluoromethyl)piperidine-l-carbonyl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(morpholine-4-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(piperazine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(4-methylpiperazine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(4-aminopiperidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(methylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(dimethylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(ethylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(morpholine-4-carbonyl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(4-hydroxypiperidine-l-carbonyl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(4-fluoropiperidine-l-carbonyl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(piperazine-l-carbonyl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
9-(5-((3,5-Dichlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid; 9-(5-((3-chlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3-(trifluoromethyl)benzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((4-Chlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((4-(Trifluoromethyl)benzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3-Chloro-5-fluorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3,5-Difluorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine- 2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(((3-chlorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(((3-(Trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(((4-chlorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(((4-(Trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(((3-Chloro-5-fluorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(((3,5-Difluorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine- 2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid; 9-(5-((3,5-Dichlorobenzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(3-Chlorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(3-(Trifluoromethyl)benzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(4-Chlorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(4-(Trifluoromethyl)benzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(3-Chloro-5-fluorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(3,5-Difluorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3,5-Dichlorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3-Chlorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3-(Trifluoromethyl)benzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((4-Chlorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((4-(Trifluoromethyl)benzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3-Chloro-5-fluorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3,5-Trifluorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3,5-Bis(trifluoromethyl)benzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
5-(((3-Fluoro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3-Chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((4-Fluoro-3-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3-(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3-Chloro-5-fluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3,5-Difluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3,4,5-Trifluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3-Fluoro-4-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((2-Fluoro-4-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((4-(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
5-((3,5-Dichlorophenethoxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3-Bromo-5-fluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3-Fluoro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-((3,5-Dichlorobenzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid; 5-(7-Chloro-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(7-(Trifluoromethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8-tetrahydro- 4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(5-(Trifluoromethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8-tetrahydro- 4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(5-Chloro-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(3-(3,5-bis(Trifluoromethyl)phenyl)propanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(3-(3,5-Dichlorophenyl)propanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
3-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxamido)propanoic acid;
(ci5,)-4-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxamido)cyclohexanecarboxylic acid;
(iraw5,)-4-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxamido)cyclohexanecarboxylic acid; l-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carbonyl)piperidine-4-carboxylic acid; l-(5-(((3,5-dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carbonyl)piperidine-3-carboxylic acid;
9-(5-(3-(3,5-Dichlorophenyl)propanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
5-(3-(3,5-Dichlorophenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carboxylic acid;
9-(5-(3-(3,5-Dichlorophenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid; 8-(5-(3-(3,5-Dichlorophenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
1- (2-(9-Azabicyclo[3.3.1]nonane-9-carbonyl)-6,7-dihydropyrazolo[l,5-a]pyrazin- 5(4H)-yl)-3-(3,5-dichlorophenyl)propan-l-one;
3,5-Dichlorobenzyl 2-(3-(methoxycarbonyl)-9-azabicyclo[3.3.1]nonane-9-carbonyl)- 7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate;
3-(3,5-Dichlorophenyl)-l-(2-(morpholine-4-carbonyl)-6,7-dihydropyrazolo[l,5- a] pyrazin- 5 (4H)- yl)propan- 1 - one ;
8- (5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
2- (3,5-Dichlorobenzyl) 7-ethyl 3,4-dihydropyrrolo[l,2-a]pyrazine-2,7(lH)- dicarboxylate;
2-(3,5-Dichlorobenzyl) 8-ethyl 4,5-dihydro-lH-pyrrolo[l,2-a][l,4]diazepine-2,8(3H)- dicarboxylate;
2-(((3,5-Dichlorobenzyl)oxy)carbonyl)-2,3,4,5-tetrahydro-lH-pyrrolo[l,2- a] [ 1 ,4]diazepine-8-carboxylic acid;
3,5-Dichlorobenzyl 2-(4-hydroxypiperidine-l-carbonyl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-carbamoyl-7,8-dihydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine- 5(6H)-carboxylate;
9- (2-(((3,5-dichlorobenzyl)oxy)carbonyl)-2,3,4,5-tetrahydro-lH-pyrrolo[l,2- a][l,4]diazepine-8-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
3,5-Bis(trifluoromethyl)benzyl 2-carbamoyl-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
2-Ethyl 5-(3-methyl-5-(trifluoromethyl)benzyl) 7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2,5(6H)-dicarboxylate;
2-(3,5-Bis(trifluoromethyl)benzyl) 8-ethyl 4,5-dihydro-lH-pyrrolo[l,2- a][l,4]diazepine-2,8(3H)-dicarboxylate; 5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 7-methyl-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2,5(6H)-dicarboxylate;
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 3-chloro-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2,5(6H)-dicarboxylate;
5-(((3-Methyl-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-3-chloro-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-7-methyl-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 3-chloro-6,7-dihydropyrazolo[l,5- a]pyrazine-2,5(4H)-dicarboxylate;
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-3-chloro-4,5,6,7- tetrahydropyrazolo[ 1 ,5-a]pyrazine-2-carboxylic acid;
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 3-bromo-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2,5(6H)-dicarboxylate;
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-3-bromo-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(2-((3,5-Bis(trifluoromethyl)phenyl)amino)acetyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(2-(3,5-Bis(trifluoromethyl)phenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
3,5-Bis(trifluoromethyl)benzyl 2-(3-methyl-l,2,4-oxadiazol-5-yl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(5-methyl-l,3,4-oxadiazol-2-yl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
5-(((5-Fluoro-[l,l'-biphenyl]-3-yl)methoxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
3,5-Dichlorobenzyl 7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate; 3 , 5-Dichlorobenzyl 2-cyano-7 , 8-dihydro-4H-pyrazolo [ 1 ,5-a] [ 1 ,4] diazepine-5 (6H)- carboxylate;
3,5-Dichlorobenzyl 2-(lH-tetrazol-5-yl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-methyl-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-cyano-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3-Fluoro-5-(trifluoromethyl)benzyl 2-(trifluoromethyl)-5,6-dihydroimidazo[ 1 ,2- a]pyrazine-7(8H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(trifluoromethyl)-5,6-dihydroimidazo[l,2- a]pyrazine-7(8H)-carboxylate;
3-Fluoro-5-(trifluoromethyl)benzyl 2-methyl-7,8-dihydro-4H-pyrazolo[ 1 ,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3-Fluoro-5-(trifluoromethyl)benzyl 2-methyl-7,8-dihydro-4H-pyrazolo[ 1 ,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-methyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)- carboxylate;
3,5-Dichlorobenzyl 2-(trifluoromethyl)-5,6-dihydroimidazo[l,2-a]pyrazine-7(8H)- carboxylate;
3,5-Bis(trifluoromethyl)benzyl 6,7-dihydro-5H-imidazo[l,5-a][l,4]diazepine-8(9H)- carboxylate;
3,5-Dichlorobenzyl 6,7-dihydro-5H-imidazo[l,5-a][l,4]diazepine-8(9H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazine-7(8H)-carboxylate;
3-Chloro-5-(trifluoromethyl)benzyl 3-(trifluoromethyl)-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(lH-tetrazol-5-yl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate; 3-Chloro-5-(trifluoromethyl)benzyl 7,8-dihydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine- 5(6H)-carboxylate;
3-(3,5-Bis(trifluoromethyl)phenyl)-l-(7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepin- 5(6H)-yl)propan- 1 -one;
5-(l-(3,5-Bis(trifluoromethyl)phenyl)ethyl) 2-ethyl 7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2,5(6H)-dicarboxylate;
5-((l-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(3,5-Bis(trifluoromethyl)phenethyl) 2-ethyl 7,8-dihydro-4H-pyrazolo[ 1,5- a] [ 1 ,4]diazepine-2,5(6H)-dicarboxylate;
5-((3,5-Bis(trifluoromethyl)phenethoxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-((3,5-Dichlorophenethoxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
3,5-Bis(trifluoromethyl)benzyl 2-(methoxy(methyl)carbamoyl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-acetyl-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(l-hydroxyethyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(l-aminoethyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(l-(piperidin-l-yl)ethyl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate; and l-(l-(5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepin-2-yl)ethyl)piperidine-4-carboxylic acid; or a pharmaceutically acceptable salt thereof.
[0080] In some embodiments, L is -O-C(O)-, -NR6-C(0)-, or -C(O)-; L2 is a bond,
-0-, or -NR-; R 1 is C^alkylene; R 2 is selected form the group consisting of:
Figure imgf000057_0001

Figure imgf000058_0001
[0082] In some embodiments,!, is -O-C(O)-; L 2 is a bond; R 1 is methylene; and
Figure imgf000058_0002
[0083] In some embodiments, R7, for each occurrence, is independently selected from the group consisting of halo, hydroxyl, cyano, carboxy, Ci_galkyl, Ci-ghaloalkyl, Ci_galkoxy, Ci-ghaloalkoxy, Ci_galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino,
Ci-galkoxycarbonyl, Ci_galkanoyloxy, carbamoyl,
Figure imgf000058_0003
N,N-di-(Ci-gaIkyl)carbamoyl, and Ci-galkylamido; R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, cyano, carboxy, Ci-galkyl,
Ci-ghaloalkyl, Ci_galkoxy, Ci_ghaloalkoxy, Ci_galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci_galkoxycarbonyl, Ci_galkanoyloxy, carbamoyl,
N-(Ci-gaIkyl)carbamoyl, N,N-di-(Ci-gaIkyl)carbamoyl, and Ci-galkylamido; h is 0 or 1; n is 0 or 1 ; and t is 0 or 1.
[0084] In some embodiments, R7, for each occurrence, is independently selected from the group consisting of halo, hydroxyl, carboxy, C1-4alkyl, Ci_4haloalkyl, Ci_4alkoxy, C1_4haloalkoxy, Ci-galkoxycarbonyl, and Ci-galkanoyloxy; R , for each occurrence, is independently selected from the group consisting of halo, cyano, C1_4alkyl, C^haloalkyl, amino,
Figure imgf000059_0001
N,N-di-(^galkyl)amino, and Ci-galkylamido; h is 0 or 1 ; n is 0 or 1 ; and t is 0 or 1.
[0085] In some embodiments, R7, for each occurrence, is independently selected from the group consisting of hydroxyl, carboxy, C1-4alkyl, and Ci-galkoxycarbonyl; R , for each occurrence, is independently selected from the group consisting of halo, cyano, C1-4alkyl, Ci^haloalkyl, and Ci^alkylamido; h is 0 or 1 ; n is 0 or 1 ; and t is 0 or 1.
[0086] In some embodiments, R7 is methyl, -OH, -COOH, -COOCH3 or -
COOCH2CH3; R8 is chloro, bromo, CN, methyl, CF3, or NHC(0)CH3; h is 0 or 1 ; n is 0 or 1 ; and t is 0 or 1.
[0087] In some embodiments, R9, for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci-galkyl, Ci-galkoxy, Ci-ghaloalkyl, Ci-ghaloalkoxy, Ci-galkanoyl, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl,
Figure imgf000059_0002
Ci-galkylamido, mercapto,
Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl, N-(^galkyl)sulfamoyl,
Figure imgf000059_0003
Ci-galkylsulfonamido, C6-1oaryl, and Ci-galkoxy-Ci-ealkyl; and q is 1, 2, or 3.
[0088] In some embodiments, R9, for each occurrence, is independently selected from the group consisting of halo, cyano, carboxy, Ci-galkyl, Ci-galkoxy, Ci-ghaloalkyl, Ci- ghaloalkoxy, C6-1oaryl, and C1-8alkoxy-C1-6aLkyl; and q is 1, 2, or 3.
[0089] In some embodiments,R9, for each occurrence, is independently selected from the group consisting of halo, C1-4alkyl, C1-4haloalkyl, and phenyl; and q is 1, 2, or 3.
[0090] In some embodiments, each R9 is independently selected from methyl, fluoro, chloro, bromo, trifluoro methyl, and phenyl; q is 1, 2, or 3.
[0091] In some embodiments, each R9 is independently selected from methyl, fluoro, chloro, bromo, and trifluoromethyl; and q is 1, 2, or 3.
[0092] In some embodiments, R is hydrogen or C1-4alkyl; R6 is hydrogen or a Q-
4alkyl; R9a is hydrogen or R9; or R9a and R6, together with the intervening atoms, form a 3- to 8-membered heterocyclyl which is optionally substituted with from one to three R9. [0093] In some embodiments, R is hydrogen or methyl; R9a is -hydrogen and R6 is hydrogen; or R9a and R6, together with the intervening atoms, form a tetrahydroisoquinolinyl ring.
[0094] In some embodiments,R9a is -hydrogen.
[0095] In some embodiments, t is 0. Alternatively, t is l .In some embodiments, n is
0. Alternatively, n is 1. In some embodiments, h is 0. Alternatively, h is 1.
[0096] In some embodiments,
R3 is hydrogen, -CN, C1-8alkyl, Ci-ghaloalkyl, -(CR10Rn)m-N(R16)2, -(CR10Rn)m- OR15, -(CR10Rn)m-C(O)OR15, -(CR10Rn)m-C(O)N(R16)2, -(CR10Rn)m-S(O)2N(R16)2, - C(0)NHS(0)2R15, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -L1- R4; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R5 groups selected from Ci_4alkyl, -OH, Ci_4alkoxy, hydroxy(Ci_4alkyl), -COOH, -COO-Ci_ 4alkyl, -CH2COOH, and -CH2COO-Ci_4alkyl;
L1 is Ci_8alkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0)2NR-, or -C(0)NR-S(0)2-;
R, for each occurrence, is independently hydrogen or a C1-4alkyl;
R4 is Ci^alkyl, C3_8cycloalkyl, a 5 to 14 membered heteroaryl, or a 3 to 15 membered heterocyclyl, wherein R4 may be optionally substituted with from one to four R5 groups selected from halo, cyano, Ci-galkyl, Ci-ghaloalkyl, -COOH, -C(0)0-(Ci_4alkyl), C1-4alkoxy, -OH, hydroxyCi_4alkyl, -NH2, (Ci_4alkyl)amino, C3_8cycloalkyl, and a 3 to 15 membered heterocyclyl selected from 3-azabicyclo[3.1.0]hexanyl, azetidinyl, morpholinyl, piperidinyl, or pyrrolidinyl, wherein the heterocyclyl may be optionally substituted with one or two substituents independently selected from the group consisting of optionally substituted with C1-4alkyl, -OH, and COOH;
R10 and R11, for each occurrence, are independently hydrogen, carboxy, Ci_4alkyl, or Ci_4haloalkyl;
R15 for each occurrence is independently selected from the group consisting of hydrogen, Ci_8alkyl, C2_8alkenyl, C2_8alkynyl, C3_8cycloalkyl, wherein R15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci_4alkoxy, Ci_4alkyl, hydroxyl, amino, N-(Ci_4alkyl)amino, N,N-di-(Ci_4alkyl)amino, and carboxyl; Each R is independently selected from hydrogen, Ci-galkoxy, Ci-galkyl, C2_galkenyl, C2_galkynyl, C3_gcycloalkyl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R16 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1_4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino,
Figure imgf000061_0001
carboxyl carbamoyl,
Figure imgf000061_0002
and
Ci^alkylamidol; or two R16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1-4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino,
Figure imgf000061_0003
carboxyl, carbamoyl,
Figure imgf000061_0004
and m, for each occurrence, is independently 0 or 1.
[0097] In some embodiments,
R3 is hydrogen, -CN, CMalk l, Ci_4haloalkyl, -N(R16)2, -CR10RU-N(R16)2, -OR15, -CR10RU-OR15, -C(0)OR15, -CR10Rn-C(O)OR15, -C(0)N(R16)2, -CR10Rn-C(O)N(R16)2, - S(0)2N(R16)2, C(0)NHS(0)2R15, a 5 to 14 membered heteroaryl selected from 1,2,4- oxadiazolyl, pyridinyl, pyrazolyl, and tetrazolyl; a 3 to 15 membered heterocyclyl selected from 8-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]oct-2-enyl, 3,8- diazabicyclo[3.2.1]octanyl, 1,4-diazepanyl, 4,7-diazaspiro[2.5]octanyl, hexahydro- lH- pyrrolo [2, 1 -c] [ 1 ,4] oxazinyl, octahydropyrido [2, 1 -c] [ 1 ,4] oxazinyl, octahydropyrrolo [ 1 ,2- a]pyrazinyl, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-c], piperidin-2-only, piperidinyl, piperizinyl, pyrrolidinyl, 1,2,3,6-tetrahydropyridinyl, wherein the heteroaryl and heterocyclyl are optionally substituted with one to four groups selected from C1-4alkyl, -OH, C1-4alkoxy, hydroxyC^alkyl, -COOH, -COO-C1-4alkyl, -CH2COOH, and -CH2COO-Ci- 4alkyl; or -Ll-R4;
L1 is -CH2-, -CH(CH3)-, -C(O)-, -C(0)0-, -C(0)NR-, -S(0)2NR-, or -C(0)NR-
S(0)2-;
R, for each occurrence, is independently hydrogen or a C1-4alkyl; R4 is C1-4alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a 3 to 15 membered heterocyclyl selected from 3-azabicyclo[3.1.0]hexanyl,
9-azabicyclo[3.3. l]nonanyl, 8-azabicyclo[3.2. l]octanyl, azetidinyl,
2,5-diazabicyclo[2.2.1]heptanyl, 3,9-diazabicyclo[3.3.1]nonanyl, 3,8- diazabicyclo[3.2. l]octanyl, 2,5-diazabicyclo[2.2.2]octanyl, 3,6-diazabicyclo[3.2. l]octanyl, 6,9— diazaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, 5,8-diazaspiro[3.5]nonanyl, 4,7-diazaspiro[2.5]octanyl, 1,4-diazepanyl, 4,5-dihydrothiazolyl, morpholinyl,
octahydropyrrolo[ 1 ,2-a]pyrazinyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,2- b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[2,3-b]pyrrolyl, piperazin-2- onyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl, tetrahydro-2H-pyranyl, wherein the R4 may be optionally substituted with from one to four groups selected from halo, -CN, Ci- 4alkyl, -CF3,-COOH, -COOCH3, -COO-t-butyl, -OH, -CH2CH2OH, -OCH3, -NH2,
-NHCH , cyclopropyl, and 3 to 15 membered heterocyclyl selected from 3- azabicyclo[3.1.0]hexanyl, azetidinyl, morpholinyl, piperidinyl, or pyrrolidinyl, wherein the heterocyclyl may be optionally substituted with one or two substituents independently selected from the group consisting of optionally substituted with C^alkyl, -OH, and COOH;
R10 and R11, for each occurrence, are independently hydrogen, carboxy, methyl, or
CF3;
R15 for each occurrence is independently selected from the group consisting of hydrogen, C1-4alkyl;
Each R16 is independently selected from hydrogen, C^alkoxy, C1-4alkyl, C2_galkenyl, C2_galkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 3 to 15 membered heterocyclyl selected from 8-azabicyclo[3.2.1]octanyl, 9-azabicyclo[3.3.1]nonanyl, azepanyl, 4,5-dihydroimidazolyl, 4,5-dihydrothiazolyl, oxetanyl, piperidinyl,
tetrahydro-2H-pyranyl; and wherein R16 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1-4alkoxy, C1-4alkyl, hydroxyl, amino,
Figure imgf000062_0001
N,N-di-(C^alkyl)amino, and carboxyl; or two R16 together with the nitrogen atom to which they are attached a 3 to 15 membered heterocyclyl selected from 9-azabicyclo[3.3.1]nonanyl,
8-azabicyclo[3.2. l]octanyl, azetidinyl, 2,5-diazabicyclo[2.2. l]heptanyl,
3,9-diazabicyclo[3.3.1]nonanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5- diazabicyclo[2.2.2]octanyl, 3,6-diazabicyclo[3.2.1]octanyl, 2,8-diazaspiro[4.5]decanyl 6,9— diazaspiro[4.5]decanyl, 4,7-diazaspiro[2.5]octanyl, 5,8-diazaspiro[3.5]nonanyl, 1,4-diazepanyl, morpholinyl, octahydropyrrolo[l,2-a]pyrazinyl, octahydropyrrolo[3,4- b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl,
octahydropyrrolo[2,3-b]pyrrolyl, piperazin-2-onyl, piperidinyl, piperizinyl, and pyrrolidinyl and wherein the heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1_4alkoxy, C1-4alkyl, cyano, hydroxyl, amino,
Figure imgf000063_0001
N,N-di-(C^alkyl)amino, and carboxyl.
[0098] In some embodiments, R3 is hydrogen; -CN; -CH3; -CF3; CH2Br; -NH2; -NH-
CH(CH3)COOH;-NHCH(CH2CH3)COOH; -NHCH(CH(CH3)2)COOH;
-NH-8-azabicyclo[3.2.1]octanyl; -NH-9-azabicyclo[3.3.1]nonanyl; -NH-azepanyl;
-NH-piperidinyl optionally substituted with 1 or 2 groups selected from methyl, ethyl, isopropyl or t-butyl; -CH2NH2; -CH(COOH)NH2; -CH2NHCH3; -CH2N(CH3)2;
-CH(CH3)NH2; -CH2NH-cyclopropyl; -CH2NH-cyclobutyl optionally substituted with 1, 2 or 3 groups selected from methyl or carboxyl; -CH2NH-cyclohexyl optionally substituted with carboxyl; -CH(CH3)NH-cyclopropyl; -CH2-8-azabicyclo[3.2.1]octanyl optionally substituted with carboxy; -CH2-9-azabicyclo[3.3.1]nonane optionally substituted with carboxy;
-CH2NH-4,5-dihydroimidazolyl; -CH2NH-4,5-dihydrothiazolyl; -CH2NH-oxetanyl; -CH2- piperidinyl optionally substituted with halo; -CH2-piperizinyl optionally substituted with methyl; -CH(CH3)-3,8-diazabicyclo[3.2.1]octanyl optionally substituted with methyl or -COO-t-butyl; - CH(CH3)-9-azabicyclo[3.3.1]nonane optionally substituted with COOH; -CH(CH3)NH-4,5-dihydroimidazolyl; -CH(CH3)NH-4,5-dihydrothiazolyl; - CH(CH3)NH-oxetanyl; -CH(CH3)-piperdinyl optionally substituted with COOH, hydroxyl, or halo; -CH(CH3)- piperizinyl optionally substituted with methyl or -COO-t-butyl; -CH(CH3)- pyrrolidinyl; -COOH; -COOCH3; -COOCH2CH3; -CH2COOH; -CH2COOCH2CH3;
-CH(CH3)COOH; -CH(CH3)COOCH2CH3; -C(CH3)2COOH; -C(CH3)2COOCH2CH3;
-CH2OH; -CH2OCH3; -CH(CH3)OH; -CH(CF3)OH; -CONH2; -C(0)NHCH3;
-C(0)NHCH2CH3; -CO-NHCH2CH2CH3; -C(0)NHCH(CH3)CH3; -C(0)NHCH(CH3)2;
-C(0)NHC(CH3)3; -CON(CH3)2; -C(0)NHCH2CH2CH2CH2CCH; C(0)NHCH2CH2NH2; -C(0)NHCH2CH2CH2CH2NH2; -C(0)NHCH2CH2COOH; -CONHCH2CH2OH;
-CONHCH(CH3)CH2OH; -C(0)N(CH3)OCH3; -C(0)NH-cyclopropyl; -C(0)NH-cyclobutyl optionally substituted with hydroxyl; -C(0)NH-cyclopentyl; -C(0)NH-cyclohexyl optionally substituted with COOH; -C(0)NH-4,5-dihydrothiazolyl; -C(0)NH-oxetanyl;
-C(0)NH-tetrahydro-2H-pyran; -C(0)NHCH2-cyclopropyl; -C(0)-8-azabicyclo[3.2. l]octanyl optionally substituted with -COOH; -C(0)-9-azabicyclo[3.3.1]nonanyl optionally substituted with -COOH; -C(0)-azetidinyl optionally substituted with NH2, NHCH3, or OH;
-C(0)-2,5-diazabicyclo[2.2.1]heptanyl; -C(0)-3,9-diazabicyclo[3.3.1]nonanyl optionally substituted with methyl; -C(0)-2,5-diazabicyclo[2.2.2]octanyl optionally substituted with methyl; -C(0)-3,8-diazabicyclo[3.2.1]octanyl optionally substituted with methyl or -COO-t- butyl; -C(0)-3,6-diazabicyclo[3.2.1]octanyl; -C(0)-6,9— diazaspiro[4.5]decanyl optionally substituted with methyl; -C(0)-4,7-diazaspiro[2.5]octanyl optionally substituted with methyl or ethyl; -C(0)-2,8-diazaspiro[4.5]decanyl; -C(0)-5,8-diazaspiro[3.5]nonanyl octane optionally substituted with methyl; -CO-l,4-diazepanyl; -C(O)- morpholinyl,
-C(0)-octahydropyrrolo[l,2-a]pyrazinyl; -C(0)-octahydropyrrolo[3,4-b]pyrrolyl; -C(O)- octahydropyrrolo[3,2-b]pyrrolyl; -C(0)-octahydropyrrolo[3,4-c]pyrrolyl;
-C(0)-octahydropyrrolo[2,3-b]pyrrolyl; -C(0)-piperazin-2-one; -C(O)- pyrrolidinyl optionally substituted with NHCH ; -C(O)- piperidinyl optionally substituted with methyl, halo, CF , hydroxyl, COOH, COOCH , or amino; -C(0)-piperazinyl optionally substituted with 1, 2 or 3 groups selected from methyl, ethyl, carboxyl, cyano, hydroxyl, hydroxyethyl, CF3, or -COO-t-butyl; -CONHS02CH3; -S02NH2; -S02N(CH3)2; -S02-8- azabicyclo[3.2.1]octanyl; -S02-9-azabicyclo[3.3.1]nonanyl; -S02-piperidinyl; -S02- piperizinyl optionally substituted with methyl; -C(0)CH ; -C(0)CH2-3- azabicyclo[3.1.0]hexanyl; -C(0)CH2-azetidinyl optionally substituted with -COOH;
-C(0)CH2-morpholino optionally substituted with 1 or 2 methyl groups; -C(0)CH2- piperidinyl; -C(0)CH2-pyrrolidinyl optionally substituted with methyl orhydroxyl; 1,2,4- oxadiazolyl optionally substituted with methyl; pyridinyl optionally substituted with methyl; pyrazolyl optionally substituted with CH2COOH; tetrazolyl; 8-azabicyclo[3.2.1]octanyl optionally substituted with methyl; 8-azabicyclo[3.2.1]oct-2-enyl optionally substituted with methyl; 3,8-diazabicyclo[3.2.1]octanyl; 1,4-diazepanyl optionally substituted with methyl; 4,7-diazaspiro[2.5]octanyl optionally substituted with methyl; hexahydro-lH-pyrrolo[2,l- c] [ 1 ,4] oxazinyl; octahydropyrido[2, 1 -c] [ 1 ,4] oxazinyl; octahydropyrrolo[ 1 ,2-a]pyrazinyl; octahydropyrrolo[3,2-b]pyrrole optionally substituted methyl; octahydropyrrolo[3,4- c]pyrrolyl optionally substituted with methyl or ethyl; piperizinyl optionally substituted with 1 or 2 groups independently selected from methyl, ethyl, propyl, isopropyl or hydroxyethyl; piperidinyl optionally substituted with 1 or 2 groups independently selected from methyl or - COO-t-butyl; piperidin-2-one; pyrrolidinyl optionally substituted with methyl or -COO-t- butyl; 1,2,3,6-tetrahydropyridinyl optionally substituted with 1 or 2 groups independently selected from methyl or -COO-C1_4alkyl. [0099] some embodiments, L is -O-C(O)-, -NR6-C(0)-, or -C(O)
L is a bond;
R is C^alkylene;
Figure imgf000065_0001
R3 is -(CR10Rn)m-C(O)OR15, a 3 to 15 membered heterocyclyl selected from 8- azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]oct-2-enyl, 3,8-diazabicyclo[3.2.1]octanyl, 1,4-diazepanyl, 4,7-diazaspiro[2.5]octanyl, hexahydro-lH-pyrrolo[2,l-c][l,4]oxazinyl, octahydropyrido[2, 1 -c] [ 1 ,4] oxazinyl, octahydropyrrolo[ 1 ,2-a]pyrazinyl,
octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-c], piperidin-2-only, piperidinyl, piperizinyl, pyrrolidinyl, 1,2,3,6-tetrahydropyridinyl, wherein heterocyclyl is optionally substituted with one to four groups selected from C1_4alkyl, hydroxyC^alkyl, -COOH, - COO-Ci_4alkyl, -CH2COOH, and -CH2COO-C alk l; or -Lx-R4;
L1 is -C(O)-,
R4 is 3 to 15 membered heterocyclyl selected from 9-azabicyclo[3.3.1]nonanyl, 8-azabicyclo[3.2. l]octanyl, azetidinyl, 2,5-diazabicyclo[2.2. l]heptanyl,
3,9-diazabicyclo[3.3.1]nonanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5- diazabicyclo[2.2.2]octanyl, 3,6-diazabicyclo[3.2.1]octanyl, 6,9— diazaspiro[4.5]decanyl, 2,8- diazaspiro[4.5]decanyl, 5,8-diazaspiro[3.5]nonanyl, 4,7-diazaspiro[2.5]octanyl,
1,4-diazepanyl, 4,5-dihydrothiazolyl, morpholinyl, octahydropyrrolo[l,2-a]pyrazinyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl, octahydropyrrolo[3,4- c]pyrrolyl, octahydropyrrolo[2,3-b]pyrrolyl, piperazin-2-onyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl, tetrahydro-2H-pyranyl, wherein the heterocyclyl may be optionally substituted with from one to four groups selected from halo, -CN, C1-4alkyl, -CF3,-COOH, -COOCH3, -COO-t-butyl, -OH, -CH2CH2OH, -OCH3, -NH2, and -NHCH3; each R9 is independently selected from halo and Ci-ghaloalkyl;
R9a is -hydrogen;
R10 and R11, for each occurrence, are independently hydrogen or C1-4alkyl; R15 is hydrogen or C1-4alkyl; m is 0 or 1 ; n is 0 or 1 ; q is 1, 2, or 3; p is 1 or 2; r is 1 or 2; and t is 0 or 1.
[0100] In some embodiments, L is -O-C(O)-;
L is a bond; R1 is methylene;
Figure imgf000066_0001
R3 is -C(0)OR15; -CR10Rn-C(O)OR15 a 3 to 15 membered heterocyclyl selected from azetidinyl, morpholinyl, piperazin-2-onyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl, hexahydro- 1 H-pyrrolo [2, 1 -c] [ 1 ,4] oxazinyl, octahydropyrido [2, 1 -c] [ 1 ,4] oxazinyl,
octahydropyrrolo[l,2-a]pyrazinyl, and octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4- c], wherein the heterocyclyl is optionally substituted with one to four groups selected from C^alkyl, hydroxyCwalkyl, -COOH, -COO-C^alkyl, -CH2COOH, and -CHaCOO-Ci^alkyl; or -I^-R4;
L1 is -C(O)-,
R4 is 3 to 15 membered heterocyclyl selected azetidinyl, morpholinyl, piperazin-2- onyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl, tetrahydro-2H-pyranyl, the
heterocyclyl may be optionally substituted with from one to four groups selected from halo, Ci_4alkyl, -CF3,-COOH, -COOCH3, -COO-t-butyl; each R9 is independently selected from halo and Ci^haloalkyl;
R9a is -hydrogen;
R10 and R11, for each occurrence, are independently hydrogen or C1-4alkyl; R is hydrogen or C1_4alkyl; and q is 1, 2, or 3.
[0101] In some embodiments,n R3 is -C(0)OH; -CH2C(0)OH, hexahydro- 1H- pyrrolo[2,l-c][l,4]oxazinyl, piperizinyl; -C(0)-piperizinyl, wherein the piperizinyl is optionally substituted with 1, 2 or 3 C^alkyl groups.
[0102] In another embodiment, the invention is any one the compounds disclosed in the Exemplification section as a neutral compound or a pharmaceutically acceptable salt thereof.
[0103] In cases where a compound provided herein is sufficiently basic or acidic to form stable nontoxic acid or base salts, preparation and administration of the compounds as pharmaceutically acceptable salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a-ketoglutarate, or a-glycerophosphate. Inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
[0104] Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
[0105] Pharmaceutically-acceptable base addition salts can be prepared from inorganic and organic bases. Salts from inorganic bases, can include but are not limited to, sodium, potassium, lithium, ammonium, calcium or magnesium salts. Salts derived from organic bases can include, but are not limited to, salts of primary, secondary or tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, or mixed di- and tri-amines where at least two of the substituents on the amine can be different and can be alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocyclic and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group. Non-limiting examples of amines can include, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N- alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, or N- ethylpiperidine, and the like. Other carboxylic acid derivatives can be useful, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, or dialkyl carboxamides, and the like.
[0106] A compound of formula (I), or a pharmaceutically acceptable salt thereof, can modulate the activity of SIP receptors. A compound provided herein, or a pharmaceutically acceptable salt thereof, can have SIP receptor agonist or antagonist activity. The compound, or a pharmaceutically acceptable salt thereof, can be selective for the S1P4 receptor. The compound, or a pharmaceutically acceptable salt thereof, can be a selective S1P4 antagonist. Being selective can mean that the compound, or a pharmaceutically acceptable salt thereof, binds to the receptor (or relatively small group of related molecules or proteins) in a complex mixture, or in other words, when exposed to a variety of closely related receptor types, the compound, or a pharmaceutically acceptable salt thereof, can bind preferentially to just one of the receptor types.
[0107] The compound, or a pharmaceutically acceptable salt thereof, can have a greater affinity for the S1P4 receptor, by at by at least 100-fold, by at least 50-fold, by at least 10-fold, by at least 5-fold or by at least 2-fold, than for S1P1 receptor, S1P2 receptor, S1P3 receptor, or S1P5 receptor.
[0108] An inhibitor of S1P4 mediated activity can block SIP interaction with an S1P4 receptor. For example, the inhibitor can be an antagonist of an S1P4 receptor. An antagonist can be a molecule that has affinity for the receptor but does not induce activity or a specific activity from the receptor. The antagonist can bind with an S1P4 receptor with an IC50 value of less than 1 μΜ, less than 750 nM, less than 500 nM, less than 250 nM or less than 100 nM. The antagonist can bind with an S1P4 receptor with an IC50 value in a range between 1 nM and 1 μΜ, between 1 nM and 500 nM, between 10 nM and 250 nM, between 25 nm and 100 nM, or between 50 nM and 100 nM.
[0109] The compound, or a pharmaceutically acceptable salt thereof, can also promote oligodendrocyte progenitor cell differentiation. The compound, or a
pharmaceutically acceptable salt thereof, can promote myelination or remyelination.
[0110] An "SIP modulating agent" refers a compound, or a pharmaceutically acceptable salt thereof, or composition that is capable of inducing a detectable change in SIP receptor activity in vivo or in vitro (e.g., at least 10% increase or decrease in SIP activity as measured by a given assay such as the assays described in the examples and known in the art. "SIP receptor," refers to all of the SIP receptor subtypes (for example, the SIP receptors S1P1, S1P2, S1P3, S1P4, or S1P5), unless the specific subtype is indicated. It is well known in the art how to determine SIP agonist or antagonist activity using the standard tests described herein, or using other similar tests which are well known in the art. In some cases, depending on the cell type and conditions used, an SIP modulating agent can have agonist or antagonist activity, even at the same receptor subtype.
[0111] The biological effects of an SIP modulating agent vary depending on whether the compound, or a pharmaceutically acceptable salt thereof, has SIP receptor agonist or antagonist activity. Potential uses of an SIP modulating agent include, but are not limited to, prevention or treatment of a pathological condition or symptom in a mammal. For example, the condition can include asthma, an inflammatory neuropathies, arthritis, lupus
erythematosis, psoriasis, an ischemia reperfusion injury, a solid tumor, a tumor metastasis, a disease associated with angiogenesis, a vascular disease, a pain condition, an acute viral disease, or insulin-dependent diabetes, and non-insulin dependent diabetes. The condition can alter lymphocyte trafficking as a method of treatment for neuropathic pain, inflammation- induced pain (e.g., where prostaglandins are involved) or treatment of autoimmune pathologies such as uveitis, type I diabetes, rheumatoid arthritis, chronic inflammatory disorders, inflammatory bowel diseases (e.g., Crohn's disease and ulcerative colitis), multiple sclerosis, and in drug-eluting stents. Additional uses can include treatment of brain degenerative diseases, heart diseases, cancers, or hepatitis C. See, for example, WO
2005/085295, WO 2004/010987, WO 03/097028, and WO 2006/072562, each of which is incorporated by reference in its entirety. A class of SIP receptor agonists are described in provisional U.S. Application no. 60/956,111, filed August 15, 2007, and
PCT/US2008/073378, filed August 15, 2008, each of which is incorporated by reference in its entirety. See also provisional U.S. Application no. 61/231,539, filed August 5, 2009, and PCT/US2010/44607, filed August 5, 2010, each of which is incorporated by reference in its entirety. See also provisional U.S. Application no. 61/440,254, filed February 7, 2011, and PCT/US2012/23799 filed February 6, 2012, each of which is incorporated by reference in its entirety.
[0112] Additional potential uses of an SIP modulating agent include, but are not limited to, prevention or treatement of a pathological condition or symptom in a mammal. For example, the condition can include inhibited cell migration of oligodendrocyte precursor cells (OPCs).
[0113] Potential uses of an SIP receptor antagonist, and S1P4 receptor type selective antagonists particularly, include, but are not limited to, prevention or treatment of a pathological condition or symptom in a mammal.
[0114] LPA has been shown to be involved in lymphocyte trafficking and helps promote entry of lymphocytes into secondary lymphoid organs (see Kanda, et al., Nat.
Immunology (2008), 9:415-423). Therefore, the disclosed compounds and salts thereof are expected to be useful for altering lymphocyte trafficking as a method for prolonging allograft survival, for example transplantation including solid organ transplants, treatment of graft vs. host disease, bone marrow transplantation, and the like.
[0115] An "ATX modulating agent" refers a compound, or a pharmaceutically acceptable salt thereof, or composition that is capable of inducing a detectable change in ATX activity in vivo or in vitro (e.g., at least 10% increase or decrease in ATX activity as measured by a given assay such as the assays described in the examples and known in the art. The compound, or a pharmaceutically acceptable salt thereof, be an ATX modulating agent, i.e., it can modulate the activity of ATX. For example, the compound, or a pharmaceutically acceptable salt thereof, can be an ATX inhibitor. The compound, or a pharmaceutically acceptable salt thereof, can be a selective ATX modulating agent. Being selective can mean that the compound, or a pharmaceutically acceptable salt thereof, binds to ATX preferentially when exposed to a variety of potential binding partners. The compound, or a
pharmaceutically acceptable salt thereof, can have a greater affinity for the ATX, by at by at least 100-fold, by at least 50-fold, by at least 10-fold, by at least 5-fold or by at least 2-fold, than for other binding partners. Affinity can be measured, for example, as a dissociation constant (K< , as an inhibition constant (such as IC50), or another measure; provided that affinity is measured in a consistent fashion between ATX and the other binding partners it is compared to. [0116] An inhibitor of ATX mediated activity can block interaction of ATX with its native substrate(s), such as LPC. For example, the inhibitor can show an IC50 value of less than 1 μΜ, less than 750 nM, less than 500 nM, less than 250 nM, less than 100 nM, less than 50 nM, less than 25 nM, or less than 10 nM, when measured in a FRET-based assay using FS-3 substrate (see, e.g., Ferguson, C.G., et al., Org Lett. 2006 May 11; 8(10): 2023-2026, which is incorporated by reference in its entirety).
[0117] Some substrates and inhibititors of ATX are described in WO 2011/151461, which is incorporated by reference in its entirety.
[0118] Potential uses of an ATX modulating agent include, but are not limited to, prevention or treatment of a pathological condition or symptom in a mammal. The pathological disorder can be an inflammatory disorder, an autoimmune disorder, a fibrosis of the lung, or a malignancy of the lung. The pathological disorder can also be an inflammatory disorder, an autoimmune disorder, a fibrosis of the lung, a malignancy of the lung, liver fibrosis, or renal fibrosis. In one embodiment, the pathological disorder is a fibrotic disease, including, for example, a fibrosis of the lung, liver fibrosis, kidney fibrosis, and scleroderma. Prevention or treatment of the pathological condition or symptom can include administering to the mammal an effective amount of an ATX modulating agent, e.g., an ATX inhibitor, to prevent, treat or reduce symptoms of the inflammatory disorder, autoimmune disorder, the fibrosis of the lung, or the malignancy of the lung. Prevention or treatment of the pathological condition or symptom can also include administering to the mammal an effective amount of an ATX modulating agent, e.g., an ATX inhibitor, to prevent, treat or reduce symptoms of the inflammatory disorder, autoimmune disorder, the fibrosis of the lung, the malignancy of the lung, liver fibrosis, or renal fibrosis. Prevention or treatment of the pathological condition or symptom can also include administering to the mammal an effective amount of an ATX modulating agent, e.g., an ATX inhibitor, to prevent, treat or reduce symptoms of the fibrotic disease, including, for example, a fibrosis of the lung, liver fibrosis, kidney fibrosis, and scleroderma. In one embodiment, the inflammatory disorder is rheumatoid arthritis (RA). In another embodiment, the inflammatory disorder is asthma. In another embodiment, the inflammatory disorder is periodontal disease. In another embodiment, the autoimmune disorder is multiple sclerosis (MS). In another embodiment, the autoimmune disorder is scleroderma. A particular example of lung fibrosis is an interstitial lung disease, for instance, pulmonary fibrosis. See, for example, WO 2011/151461, which is incorporated by reference in its entirety. [0119] In some embodiments, an ATX inhibitor of the present invention can be used to treat or prevent a demyelinating disease or disorder. Demyelinating diseases or disorders include multiple sclerosis, Guillain-Barre Syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis, and optic neuritis, spinal cord injury, stroke or other ischemia, cerebral palsy, Charcot-Marie-Tooth disease (CMT), Sjogren-Larsson syndrome, Refsum disease, Krabbe disease, Canavan disease, Alexander disease, nerve damage due to pernicious anemia, progressive multifocal leukoencephalopathy (PML), Lyme disease, tabes dorsalis due to untreated syphilis, demyelination due to exposure to an organophosphates, demyelination due to vitamin B12 deficiency or copper deficiency.
[0120] In addition, disclosed compounds and salts can be useful as antagonists of the cannabinoid CBi receptor. CBi antagonism is associated with a decrease in body weight and an improvement in blood lipid profiles. The CBi antagonism could be in concert with SIP receptor activity, or be independent of activity at any SIP receptor.
[0121] In addition, disclosed compounds and salts can be useful for inhibition of group IVA cytosolic PLA2 (cPLA2). cPLA2 catalyzes the release of eicosanoic acids (e.g., arachidonic acid). The eicosanoic acids are transformed to pro-inflammatory eicosanoids such as prostaglandins and leukotrienes. Thus, disclosed compounds and salts may be useful as anti-inflammatory agents. This inhibition could be in concert with SIP receptor activity, or be independent of activity at any SIP receptor.
[0122] In addition, disclosed compounds and salts may be useful for inhibition of the multiple substrate lipid kinase (MuLK). MuLK is highly expressed in many human tumor cells and thus its inhibition might slow the growth or spread of tumors.
Neurological Disorders
[0123] MS can begin with a relapsing-remitting pattern of neurologic involvement, which then can progress to a chronic phase with increasing neurological damage. MS can be associated with the destruction of myelin, oligodendrocytes or axons localized to chronic lesions. The demyelination observed in MS may not always permanent and remyelination has been documented in early stages of the disease. Remyelination of neurons can require oligodendrocytes.
[0124] Axons and dendrites can extend from neurons. The distal tip of an extending axon or neurite can include a specialized region, known as the growth cone. Growth cones can sense the local environment and can guide axonal growth toward a neuron's target cell. Growth cones can respond to environmental cues, for example, surface adhesiveness, growth factors, neurotransmitters and electric fields. The growth cones can advance at a rate of one to two millimeters per day. The growth cone can explore the area ahead of it and on either side, by means of elongations classified as lamellipodia and filopodia. When an elongation contacts an unfavorable surface, it can withdraw. When an elongation contacts a favorable growth surface, it can continue to extend and guides the growth cone in that direction. When the growth cone reaches an appropriate target cell a synaptic connection can be created.
[0125] Nerve cell function can be influenced by contact between neurons and other cells in their immediate environment (Rutishauser, et al., 1988, Physiol. Rev. 68:819, which is incorporated by reference in its entirety). These cells can include specialized glial cells, oligodendrocytes in the central nervous system (CNS), and Schwann cells in the peripheral nervous system (PNS), which can sheathe the neuronal axon with myelin (Lemke, 1992, in An Introduction to Molecular Neurobiology, Z. Hall, Ed., p. 281, Sinauer, each of which is incorporated by reference in its entirety). LPA causes the collapse of the neuron growth cone and tends to inhibit or reverse the morphological differentiation of many neuronal cell lines (see Gendaszewska-Darmach, Acta Biochimica Polonica (2008), 55(2):227-240). Since ATX activity is involved in the generation of LPA, inhibitors of ATX should increase the ability of the nervous system to make synaptic connections. Thus, ATX inhibitors may be useful in treating neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, Parkinson's disease (including Parkinson's dementia), Lewy Body Dementia, amylotrophic lateral sclerosis (ALS), Friedreich's ataxia, spinal muscular atrophy.
[0126] CNS neurons can have the inherent potential to regenerate after injury, but they can be inhibited from doing so by inhibitory proteins present in myelin (Brittis et al., 2001, Neuron 30: 11-14; Jones et al., 2002, /. Neurosci. 22:2792-2803; Grimpe et al., 2002, /. Neurosci. :22:3144-3160, each of which is incorporated by reference in its entirety).
[0127] Several myelin inhibitory proteins found on oligodendrocytes have been characterized. Known examples of myelin inhibitory proteins can include NogoA (Chen et al., Nature, 2000, 403, 434-439; Grandpre et al., Nature 2000, 403, 439-444, each of which is incorporated by reference in its entirety), myelin associated glycoprotein (MAG)
(McKerracher et al., 1994, Neuron 13:805-811; Mukhopadhyay et al., 1994, Neuron 13:757- 767, each of which is incorporated by reference in its entirety) or oligodendrocyte
glycoprotein (OM-gp), Mikol et al., 1988, /. Cell. Biol.106: 1273- 1279, each of which is incorporated by reference in its entirety). Each of these proteins can be a ligand for the neuronal Nogo receptor- 1 (NgRl (Wang et al., Nature 2002, 417, 941-944; Grandpre et al., Nature 2000, 403, 439-444; Chen et al., Nature, 2000, 403, 434-439; Domeniconi et al., Neuron 2002, published online June 28, 2002, each of which is incorporated by reference in its entirety).
[0128] Nogo receptor- 1 (NgRl) is a GPI- anchored membrane protein that contains 8 leucine rich repeats (Fournier et al., 2001, Nature 409:341-346, which is incorporated by reference in its entirety). Upon interaction with inhibitory proteins (e.g., NogoA, MAG and OM-gp), the NgRl complex can transduce signals that lead to growth cone collapse and inhibition of neurite outgrowth.
[0129] There is a need for molecules and methods for inhibiting NgRl -mediated growth cone collapse and the resulting inhibition of neurite outgrowth. Additionally, there is a need for molecules which increase neuronal survival and axon regeneration, particularly for the treatment of disease, disorders or injuries that involve axonal injury, neuronal or oligodendrocyte cell death, demyelination or dymyelination or generally relate to the nervous system.
[0130] Such diseases, disorders or injuries can include, but are not limited to, multiple sclerosis (MS), progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelolysis (CPM), adrenoleukodystrophy, Alexander's disease, Pelizaeus Merzbacher disease (PMZ), Globoid cell Leucodystrophy (Krabbe's disease) and Wallerian Degeneration, optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, AR, Bassen-Kornzweig syndrome, Marchiafava-Bignami syndrome,
metachromatic leukodystrophy, trigeminal neuralgia, or Bell's palsy. Among these diseases, MS may the most widespread, affecting approximately 2.5 million people worldwide.
[0131] Various disease-modifying treatments may be available for MS, including the use of corticosteroids and immunomodulating agents such as interferon beta or Tysabri®. In addition, because of the central role of oligodendrocytes and myelination in MS, there have been efforts to develop therapies to increase oligodendrocyte numbers or enhance
myelination. See, e.g., Cohen et al., U.S. Pat. No. 5,574,009; Chang et al., N. Engl. J. Med. 346: 165-73 (2002), each of which is incorporated by reference in its entirety. However, there remains an urgent need to devise additional therapies for MS and other demyelination and dismyelination disorders.
[0132] A compound provided herein, or a pharmaceutically acceptable salt thereof, can promote myelination or remyelination. A method can include administering a compound provided herein, or a pharmaceutically acceptable salt thereof, to cells. A method of promoting oligodendrocyte progenitor cell differentiation can include administering a compound provided herein, or a pharmaceutically acceptable salt thereof, to cells. A method of treating multiple sclerosis can include administering a compound provided herein, or a pharmaceutically acceptable salt thereof, to a subject.
[0133] A number of studies have shown that ATX is expressed in non-pathological conditions, throughout development, with high expression levels in the CNS among other tissues. ATX mRNA was identified as highly upregulated during oligodendrocyte
differentiation and ATX protein expression is also apparent in maturing ODCs, temporally correlated with the process of myelination. Finally, in the adult brain ATX is expressed in secretory epithelial cells, such as the choroid plexus, ciliary, iris pigment, and retinal pigment epithelial cells, whereas there is evidence for ATX expression in leptomenigneal cells and cells of the CNS vasculature. See, for example, Fuss, B., et al., J Neurosci 17, 9095-9103 (1997); Kawagoe, H., et al. Genomics 30, 380-384 (1995); Lee, H.Y., et al. J Biol Chem 271, 24408- 24412 (1996); Narita, M., et al., J Biol Chem 269, 28235-28242 (1994); Bachner, D., et al., Mechanisms of Development 84, 121- 125 (1999); Awatramani, R., et al., Nat Genet 35, 70-75 (2003); Li, Y., et al., J Neurol Sci 193, 137-146 (2002); Dugas, J.C., et al., J Neurosci 26, 10967-10983 (2006); Fox, M.A., et al., Molecular and Cellular Neuroscience 27, 140- 150 (2004); Hoelzinger, D.B., et al., Neoplasia 7, 7-16 (2005); and Sato, K., et al., J Neurochem 92, 904-914 (2005); each of which is incorporated by reference in its entirety.
[0134] Although neurons and astrocytes do not seem to express ATX under physiological conditions, ATX is highly upregulated in astrocytes following brain lesion. Two hallmarks of reactive astrogliosis can be induced by LPA itself: hypertrophy of astrocytes and stress fiber formation. This may indicate an autoregulation loop of astrocytic activation, in which astrocytes upregulate the LPA- generating enzyme ATX and become activated by its metabolite LPA, while increased amounts of the metabolite inhibit the catalytic activity of ATX. See, e.g., Savaskan, N.E., et al., Cell Mol Life Sci 64, 230-243 (2007); Ramakers, G.J, & Moolenaar, W.H., Exp Cell Res 245, 252-262 (1998); and van Meeteren, L.A., et al., J Biol Chem 280, 21155-21161 (2005); each of which is incorporated by reference in its entirety.
[0135] ATX expression levels were shown to be elevated in glioblastoma multiform samples, and ATX was shown to augment invasiveness of cells transformed with ras, a key signaling molecule that promotes gliomagenesis. ATX expression was also detected in primary tumor tissues from neuroblastoma patients and retinoic acid induced expression of ATX in N-myc-amplified neuroblastoma cells.
[0136] There is significant evidence for ATX signaling in demyelination processes and in other neurodegenerative conditions. As noted above, it has been reported that addition of LPA to dorsal root fibers in ex vivo culture causes demyelination, whereas LPC fails to cause significant demyelination of nerve fibers in ex vivo cultures without further addition of recombinant ATX to the culture. Addition of recombinant ATX caused significant demyelination at equivalent levels to LPA presumable due to conversion of LPC to LPA through the enzymatic activity of ATX. In addition, injury induced demyelination was attenuated by about 50% in atx+/" mice over their wild type counterparts (Nagai, et al., Molecular Pain (2010), 6:78).
[0137] ATX protein levels were found deregulated in an animal model of MS
(experimental autoimmune encephalitis; EAE) at the onset of clinical symptoms. See, e.g., Hoelzinger, D.B., et al. Neoplasia 7, 7-16 (2005); Nam, S.W., et al., Oncogene 19, 241-247 (2000); Kawagoe, H., et al., Cancer Res 57, 2516-2521 (1997); Dufner-Beattie, J., et al., Mol Carcinog 30, 181- 189 (2001); Umemura, K., et al., Neuroscience Letters 400, 97-100 (2006); and Fuss, B., et al., J Neurosci 17, 9095-9103 (1997); each of which is incorporated by reference in its entirety. Moreover, significant ATX expression was been detected in the cerebrospinal fluid of patients suffering with multiple sclerosis (MS), while completely lacking from the control samples, suggesting a role for ATX in maintenance of cerebrospinal fluid homeostasis during pathological/ demyelinating conditions. Hammack, B.N., et al. Proteomic analysis of multiple sclerosis cerebrospinal fluid. Mult Scler 10, 245-260 (2004); and Dennis, J., et al., J Neurosci Res 82, 737-742 (2005); each of which is incorporated by reference in its entirety.
[0138] Interestingly, ATX mRNA expression was found to be elevated in the frontal cortex of Alzheimer-type dementia patients indicating a potential involvement for ATX signaling in neurodegenerative diseases. LPA receptors are enriched in the CNS and their expression patterns suggest their potential involvement in developmental process including neurogenesis, neuronal migration, axon extension and myelination. Noteworthy, only two receptors have the same spatiotemporal expression as ATX in the CNS (Contos, J.J., et al., Mol Cell Biol 22, 6921-6929 (2002); Jaillard, C, ei al, Edg8/Sl P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J Neurosci 25, 1459-1469 (2005); and Saba, J.D. Journal of cellular biochemistry 92, 967-992 (2004); each of which is incorporated by reference in its entirety). LPAi and SIP5 are specific for ODCs, and their expression highly correlates with the process of myelination. LPA1 is expressed in restricted fashion within the neuroblasts of the neuroproliferatve Ventricular Zone (VZ) of the developing cortex, in the dorsal olfactory bulb, along the pial cells of neural crest origin, and in developing facial bone tissue. Expression is observed during E11-E18, corresponding to a time period during which neurogenesis occurs. LPA1 expression is undetectable in the VZ after this point, to reappear during the first postnatal week within ODCs. Notably, Schwann cells (the myelinating cells of the Peripheral Nervous System; PNS) express high levels of LPA1 early in development and persistently throughout life, suggesting an influence of LPA on myelinating processes (Weiner. J. A. & Chun, J., Proc Natl Acad Sci U S A 96, 5233-5238 (1999), which is incorporated by reference in its entirety).
[0139] The above data strongly support a critical role for ATX and LPA signaling in neuronal development, oligodendrocyte differentiation and myelination, as well as possibly in the autoregulation of astrocyte activation. Moreover, the regulation of ATX and thus LPA production at local sites of CNS injury, inflammatory or autoimmune, could contribute to tissue homeostasis through the numerous effects of LPA. As demyelination and deregulated cerebrospinal fluid homeostasis are the hallmarks of multiple sclerosis, a role of ATX and LPA signaling in the pathophysiology of multiple sclerosis seems very likely.
[0140] The SIP modulating agents and/or ATX modulating agents of formula (I) can be used to various forms of MS including relapsing-remitting, secondary-progressive, primary-progressive, and progressive-relapsing forms. In addition, SIP modulating agents and/or ATX modulating agents of formula (I) can be used alone or in conjunction with other agents to treat or prevent MS. In some embodiments, the compounds and salts described herein can be used to treat or prevent MS in combination with an immunomodulating therapy such as corticosteroids, beta interferon- la (such as Avonex® or Rebif®), beta interferon- lb (Betaseron®), natalizumab (Tysabri®), glatiramer,and mitoxantrone.
[0141] Promoting myelination, remyelination or oligodendrocyte progenitor cell differentiation can prevent or can treat a pathological condition or symptom in a mammal. A number of diseases or disorders involve demyelination of the central or peripheral nervous system which can occur for a number of reasons such as immune dysfunction as in multiple sclerosis, encephalomyelitis, Guillain-Barre Syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis, and optic neuritis; demyelination due to injury such as spinal cord injury, traumatic brain injury, stroke, acute ischemic optic neuropathy, or other ischemia, cerebral palsy, neuropathy (e.g. neuropathy due to diabetes, chronic renal failure, hypothyroidism, liver failure, or compression of the nerve), post radiation injury, and central pontine myelolysis (CPM); inherited conditions such as Charcot-Marie-Tooth disease (CMT), Sjogren-Larsson syndrome, Refsum disease, Krabbe disease, Canavan disease, Alexander disease, Friedreich's ataxia, Pelizaeus-Merzbacher disease, Bassen-Kornzweig syndrome, metachromatic leukodystrophy(MLD), adrenoleukodystrophy, and nerve damage due to pernicious anemia; viral infection such as progressive multifocal leukoencephalopathy (PML), Lyme disease, or tabes dorsalis due to untreated syphilis; toxic exposure due to chronic alcoholism (which is a possible cause of Marchiafava-Bignami disease),
chemotherapy, or exposure to chemicals such as organophosphates; or dietary deficiencies such as vitamin B12 deficiency, vitamin E deficiency, and copper deficiency. Some demyelination disorders can have unknown or multiple causes such as trigeminal neuralgia, Marchiafava-Bignami disease and Bell's palsy. In addition, demyelination can contribute to neuropathic pain. Compounds and salts described herein are expected to be useful in treating demyelination disorders.
Inflammatory Disorders
[0142] Since LPA is a proinflammatory factor reducing the amount of LPA producted by inhibiting ATX is useful for treating inflammatory disorders such as asthma, allergies, arthritis, inflammatory neuropathies, transplantation rejection, Crohn's disease, ulcerative colitis, lupus erythematosis, psoriasis, an inflammatory bowel condition, and diabetes.
Pain Mediation
[0143] Pain experienced by mammals can be divided into two main categories: acute pain (or nociceptive) and chronic pain which can be subdivided into chronic inflammatory pain and chronic neuropathic pain. Acute pain is a response to stimulus that causes tissue injury and is a signal to move away from the stimulus to minimize tissue damage. Chronic pain, on the other hand, serves no biological function and develops as a result of
inflammation caused by tissue damage (inflammatory pain) or by damage to the nervous system such as demyelination (neuropathic pain). Chronic pain is generally characterized by stimulus-independent, persistent pain or by abnormal pain perception triggered by innocuous stimuli.
[0144] LPA has been found to be a mediator of both inflammatory pain and neuropathic pain. The transient receptor potential channel TRPV1 is known to be the originator of inflammatory pain. LPA has been shown to directly activate TRPV1 thereby creating pain stimulus by binding to its intracellular C-terminus (Tigyi, Nature Chemical Biology (January 2012), 8:22-23). Thus, compounds and salts which inhibit the formation of LPA by inhibiting the action of ATX would be useful in treating inflammatory pain. [0145] LPA has also been shown to play a role in neuropathic pain. For example, sciatic nerve injury has been shown to induce demyelination, down-regulation of myelin- associated glycoprotein (MAG) and damage to Schwann cell partitioning of C-fiber- containing Remak bundles in the sciatic nerve and dorsal root. However, demyelination, MAG down-regulation and Remak bundle damage in the dorsal root were abolished in LPAi receptor-deficient (Lparl_/~) mice (Nagai, et al., Molecular Pain (2010), (5:78). These results indicate that compounds and salts that inhibit the formation of LPA by inhibiting the action of ATX would decrease dorsal root demyelination following nerve injury and decrease or eliminate neuropathic pain.
[0146] Additionally, the pathological disorder can be selected from pain, acute pain, chronic pain, neuropathic pain, visceral pain, nociceptive pain including post-surgical pain, and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back and orofacial pain; and pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia, causalgia, and conditions of lower urinary tract dysfunction. (See, for example, WO2013061297, which is incorporated by reference in its entirety)
[0147] Thus the compounds and salts described herein are useful in treating or preventing chronic pain such as inflammatory pain and neuropathic pain in mammals.
Rheumatoid Arthritis (RA)
[0148] Studies in human and animal models of RA suggest that ATX plays a role in the development and progress of the disease. For example, increased ATX mRNA expression was detected in synovial fibroblasts (SFs) from animal models of RA during differential expression profiling, and human RA SFs were shown to express mRNA for both ATX and LPARs (Aidinis, V., et al., PLoS genetics 1, e48 (2005); Zhao, C, et al., Molecular pharmacology 73, 587-600 (2008); each of which is incorporated by reference in its entirety). ATX is overexpressed from activated SFs in arthritic joints, both in animal models and human patients (see WO 2011/151461). ATX expression was shown to be induced from TNF, the major pro-inflammatory factor driving RA.
[0149] Disease development was assessed in well-established animal models of RA.
When ATX expression was conditionally ablated specifically in SFs, the lack of ATX expression in the joints resulted in marked decreased inflammation and synovial hyperplasia. This suggested an active involvement of the ATX-LPA axis in the pathogenesis of the disease. Similar results were also obtained with pharmacologic inhibition of ATX enzymatic activity and LPA signaling. A series of ex vivo experiments on primary SFs revealed that ATX, through LPA production, stimulates rearrangements of the actin cyto skeleton, proliferation and migration to the extracellular matrix (ECM), as well as the secretion of proinflammatory cytokines and matrix metalloproteinases (MMPs). Moreover, the LPA effect was shown to be synergistic with TNF and dependent on the activation of MAPK cellular signaling pathways. See, e.g., Armaka, M., et al., The Journal of experimental medicine 205, 331-337 (2008); which is incorporated by reference in its entirety.
[0150] In one embodiment a method for treating an individual with RA or the individual at risk of suffering thereof comprises administering to said individual an SIP modulating agent and/or ATX modulating agent of formula (I) in conjunction with an anti- TNF antibody for use in the treatment of RA. Examples of suitable anti-TNF antibodies are adalimumab, etanercept, golimumab, and infliximab (Taylor PC, Feldmann M. Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol. 2009 Oct;5(10):578-82).
Asthma
[0151] The ATX-LPA pathway appears to have role in the pathogenesis of asthma, for example, see Park, et al, Am J Respir Crit Care Med Vol 188, Iss. 8, pp 928-940, 2013, the entire teachings of which are incorporated herein by reference. Thus the compounds and salts described herein are useful in preventing, treating, or reducing symptoms of asthma in a mammal in need thereof.
Periodontal Disease
[0152] Elevated levels of LPA may contribute to the pathogenesis and progression of periodontal diseases, see Bathena, et al, Journal of Pharmaceutical and Biomedical Analysis 56 (2011) 402- 407, the entire teachings of which are incorporated herein by reference. Thus the compounds and salts described herein are useful in preventing, treating, or reducing symptoms of periodontal disease in a mammal in need thereof.
Pulmonary Fibrosis
[0153] Evidence also suggests a role for ATX in pulmonary fibrosis. Mice lacking lysophosphatidic acid (LPA) receptor l(LPARl) were protected from Bleomycin (BLM)- induced pulmonary fibrosis and mortality, suggesting a major role for LPA in disease pathophysiology. The majority of circulating LPA is produced by the phospholipase D activity of Autotaxin (ATX) and the hydrolysis of lysophosphatidylcholine (LPC). Increased ATX expression has been previously reported in the hyperplastic epithelium of fibrotic lungs of human patients and animal models. See, for example, Sakai, et al., Inflammation and Regeneration Vol 33, No. 2 (2013), 78-89; and Budd, et al, Future Med. Chem. (2013) 5(16), 1935-1952,the entire teachings of both are incorporated herein by reference.
[0154] Therefore, we hypothesized that genetic or pharmacologic inhibition of ATX activity would reduce local or circulating LPA levels and hence attenuate disease
pathogenesis. Thus the compounds and salts described herein are useful in preventing, treating, or reducing symptoms of pulmonary fibrosis in a mammal in need thereof.
Liver Fibrosis
[0155] Subjects with liver fibrosis may exhibit increased ATX and LPA levels in the blood, see, for example, Ikeda, et al., Clinica Chimica Acta 413 (2012) 1817-1821; and Budd, et al., Future Med. Chem. (2013) 5(16), 1935-1952, the entire teachings of both are incorporated herein by reference. Thus the compounds and salts described herein are useful in preventing, treating, or reducing symptoms of liver fibrosis in a mammal in need thereof. Renal Fibrosis
[0156] Evidence also suggests a role for ATX in renal fibrosis, see for example,
Sakai, et al., Inflammation and Regeneration Vol 33, No. 2 (2013), 78-89, and Budd, et al., Future Med. Chem. (2013) 5(16), 1935-1952, the entire teachings of both are incorporated herein by reference. Thus the compounds and salts described herein are useful in preventing, treating, or reducing symptoms of renal fibrosis in a mammal in need thereof.
Scleroderma
[0157] Evidence also suggests a role for ATX in scleroderma/systemic sclerosis , see, for example, Sakai, et al., Inflammation and Regeneration Vol 33, No. 2 (2013), 78-89, the entire teachings of which are incorporated herein by reference. Thus the compounds and salts described herein are useful in preventing, treating, or reducing symptoms of scleroderma in a mammal in need thereof.
Cancer
[0158] Increased ATX expression has been detected in a large number of
malignancies, including mammary, thyroid, hepatocellular and renal cell carcinomas, glioblastoma and neuroblastoma, as well as NSCLC. Strikingly, transgenic overexpression of ATX was shown to induce spontaneous mammary carcinogenesis. In accordance, in vitro ATX overexpression in various cell types promotes proliferation and metastasis while inhibiting apoptosis. LPA's actions are concordant with many of the "hallmarks of cancer", indicating a role for LPA in the initiation or progression of malignant disease. Indeed LPA levels are significantly increased in malignant effusions, and its receptors are aberrantly expressed in several human cancers.
[0159] LPA has been shown to be involved in wound healing and stimulates the proliferation and migration of endothelial cells promoting processes such as angiogenesis. However, these same processes when deregulated can promote tumor growth and metastasis, and LPA is thought to contribute to the development, progression, and metastasis of several types of cancer including ovarian, prostate, melanoma, breast, head and neck cancers (see Gendaszewska-Darmach, Acta Biochimica Polonica (2008), 55(2):227-240). In addition, since ATX is located outside the cell in circulation, ATX inhibitors are expected to be of most benefit outside the cell. Therefore, ATX inhibitors are expected to be useful in treating cancer, particularly multidrug resistant (MDR) cancers where drug efflux mechanisms are the largest contributor to the drug resistance.
[0160] See, for example: Euer, N., et al., Anticancer Res 22, 733-740 (2002); Liu, S., et al., Cancer Cell 15, 539-550 (2009); Zhang, G., et al., Chin Med J (Engl) 112, 330- 332 (1999); Stassar, M.J., et al., Br J Cancer 85. 1372- 1382 (2001); Kishi, Y., et al., J Biol Chem 281, 17492- 17500 (2006); Kawagoe, H., et al., Cancer Res 57, 2516-2521 (1997); Yang, Y., et al., Am J Respir Cell Mol Biol 21, 216-222 (1999); and Toews, M.L., et al. Biochim Biophys Acta 1582, 240-250 (2002); each of which is incorporated by reference in its entirety.
Additional Diseases
[0161] Additionally, the pathological disorder can be selected from renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, angiogenesis, and tumor metastasis and progression, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection. (See, for example, WO2013186159 and WO2013061297, both of which are incorporated by reference in its entirety).
[0162] Renal conditions include, but are not limited to, acute kidney injury and chronic renal disease with and without proteinuria including end-stage renal disease (ESRD). In more detail, this includes decreased creatinine clearance and decreased glomerular filtration rate, microalbuminuria, albuminuria and proteinuria, glomerulosclerosis with expansion of reticulated mesangial matrix with or without significant hypercellularity (particularly diabetic nephropathy and amyloidosis), focal thrombosis of glomerular capillaries (particularly thrombotic microangiopathies), global fibrinoid necrosis, ischemic lesions, malignant nephrosclerosis (such as ischemic retraction, reduced renal blood flow and renal arteriopathy), swelling and proliferation of intracapillary (endothelial and mesangial) and/or extracapillary cells (crescents) like in glomerular nephritis entities, focal segmental glomerular sclerosis, IgA nephropathy, vasculitides/systemic diseases as well as acute and chronic kidney transplant rejection and chronic allograft nephropathy.
[0163] Liver conditions include, but are not limited to, liver cirrhosis, hepatic congestion, cholestatic liver disease including pruritus, nonalcoholic steatohepatitis and acute and chronic liver transplant rejection.
[0164] Inflammatory conditions include, but are not limited to, arthritis, osteoarthritis, systemic lupus erythematodes, psoriasis, chronic inflammation, inflammatory bowel disease, irritable bowel syndrome, functional bowel disorders, abnormal evacuation disorder and the like as well as inflammatory airways diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or chronic asthma bronchiale.
[0165] Conditions of the respiratory system include, but are not limited to, other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, systemic diseases and vasculitides, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis,
lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease), radiation induced fibrosis, silicosis, asbestos induced pulmonary fibrosis or acute respiratory distress syndrome (ARDS).
[0166] Conditions of the nervous system include, but are not limited to,
schizophrenia, neuro-inflammation (e.g. astrogliosis), peripheral and/or autonomic (diabetic) neuropathies, neuropathies and the like.
[0167] Vascular conditions include, but are not limited to, atherosclerosis, thrombotic vascular disease as well as thrombotic micro angiopathies, proliferative arteriopathy (such as swollen myointimal cells surrounded by mucinous extracellular matrix and nodular thickening), decreased vascular compliance (such as stiffness, reduced ventricular
compliance and reduced vascular compliance), endothelial dysfunction and the like.
[0168] Cardiovascular conditions include, but are not limited to, acute coronary syndrome, coronary heart disease, myocardial infarction, arterial and pulmonary
hypertension, thrombosis, stroke and other vascular damage.
[0169] Fibrotic diseases include, but are not limited to myocardial and vascular fibrosis, organ fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma and encapsulating peritonitis. In some embodiments, the fibrotic disease is renal tubulo-interstitial fibrosis or glomerulosclerosis. In another embodiment, the fibrotic disease is idiopathic pulmonary fibrosis. In another embodiment, the fibrotic disease is non-alcoholic liver steatosis, liver fibrosis or liver cirrhosis. Additionally, fibrotic diseases include endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, nephrogenic systemic fibrosis, Keloid, atherofibrosis and adhesive capsulitis.
[0170] Cancer and cancer metastasis include, but are not limited to, lung cancer, mesothelioma, glioma, hepatic carcinoma, gastrointestinal cancers and progression and metastatic aggressiveness thereof.
[0171] Ocular conditions include, but are not limited to, proliferative and nonproliferative (diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central arterial/venous occlusion, traumatic injury, glaucoma and the like.
[0172] Metabolic conditions include, but are not limited to, obesity and diabetes.
[0173] Pharmaceutical compositions can include a compound of formula (I), or a pharmaceutically acceptable salt thereof. More particularly, such compounds and salts can be formulated as pharmaceutical compositions using standard pharmaceutically acceptable carriers, fillers, solubilizing agents and stabilizers known to those skilled in the art. For example, a pharmaceutical composition including a compound of formula (I), or a pharmaceutically acceptable salt thereof, as described herein, is used to administer the appropriate compound, or a pharmaceutically acceptable salt thereof, to a subject.
[0174] The compounds of formula (I), or a pharmaceutically acceptable salt thereof, are useful for treating a disease or disorder associated with SIP receptor activity, and/or ATX activity. In one embodiment, a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is delivered (e.g. administered) to a subject in need thereof. In another embodiment, a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically- acceptable carrier is administered to a subject in need thereof.
[0175] The compounds and salts described herein can be used in combination with at least one further active ingredient, such as a medicament used in the treatment of multiple sclerosis such as Tysabri®, dimethyl fumarate, an interferon (such as pegylated or non- pegylated interferons, such as interferon β-la or pegylated interferon β -la), glatiramer acetate, a compound improving vascular function, an immunomodulating agent (such as Fingolimod, cyclosporins, rapamycins or ascomycins, or their immunosuppressive analogs, e.g. cyclosporin A, cyclosporine G, FK-506, ABT-281, ASM981, rapamycin, 40-O-(2- hydroxy)ethyl-rapamycin etc.); corticosteroids; cyclophosphamide; azathioprine;
mitoxanthrone, methotrexate; lefhinomide; mizoribine; mycophenolic add; mycophenolate mofetil; 15-deoxyspergualine; diflucortolone valerate; difluprednate; Alclometasone dipropionate; amcinonide; amsacrine; asparaginase; azathioprine; basiliximab; beclometasone dipropionate; betamethasone; betamethasone dipropionate; betamethasone phosphate sodique; betamethasone valerate; budesonide; captopril; chlormethine chlorhydrate;
clobetasol propionate; cortisone acetate; cortivazol; cyclophosphamide; cytarabine;
daclizumab; dactinomycine; desonide; desoximetasone; dexamethasone; dexamethasone acetate; dexamethasone isonicotinate; dexamethasone metasulfobenzoate sodique;
dexamethasonephosphate; dexamethasone tebutate; dichlorisone acetate; doxorubicinee chlorhydrate; epirubicine chlorhydrate; fluclorolone acetonide; fludrocortisone acetate;
fludroxycortide; flumetasone pivalate; flunisolide; fluocinolone acetonide; fluocinonide; fluocortolone; fluocortolone hexanoate; fluocortolone pivalate; fluorometholone;
fluprednidene acetate; fluticasone propionate; gemcitabine chlorhydrate; halcinonide;
hydrocortisone; hydrocortisone acetate; hydrocortisone butyrate; hydrocortisone
hemisuccinate; melphalan; meprednisone; mercaptopurine; methylprednisolone;
methylprednisolone acetate; methylprednisolone hemisuccinate; misoprostol; muromonab- cd3; mycophenolate mofetil; paramethansone acetate; prednazoline, prednisolone;
prednisolone acetate; prednisolone caproate; prednisolone metasulfobenzoate sodique;
prednisolone phosphate sodique; prednisone; prednylidene; rifampicine; rifampicine sodique; tacrolimus; teriflunomide; thalidomide; thiotepa; tixocortol pivalate; triamcinolone;
triamcinolone acetonide hemisuccinate; triamcinolone benetonide; triamcinolone diacetate; triamcinolone hexacetonide; immunosuppressive monoclonal antibodies, e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4,CD7, CD20 (e.g., rituximab and ocrelizumab), CD25, CD28, B7, CD40, CD45, CD56 (e.g., daclizumab), or CD58 or their ligands; or other immunomodulating agenty compounds, e.g. CTLA41g, or other adhesion molecule inhibitors, e.g. mAbs or low molecular weight inhibitors including Selectin antagonists and VLA-4 antagonists (such as Tysabri®); remyelinating agents such as BIIB033. Compounds and salts described herein can also be used in combination with agents which treat the symptoms of multiple sclerosis such as fampridine.
[0176] The dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, administered to a subject can be less than 10 μg, less than 25 μg, less than 50 μg, less than 75 μg, less than 0.10 mg, less than 0.25 mg, less than 0.5 mg, less than 1 mg, less than 2.5 mg, less than 5 mg, less than 10 mg, less than 15 mg, less than 20 mg, less than 50 mg, less than 75 mg, less than 100 mg, or less than 500 mg.
[0177] Delivering a compound of formula (I) to a mammal comprises any delivery method whereby the compound comes in contact with any part of the mammal's body.
Delivering a compound of formula (I) to a mammal includes administering a compound of formula (I) topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally or intravitreally to the mammal. Delivering a compound of formula (I) to a mammal also includes administering topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally or intravitreally to a mammal a compound that metabolizes within or on a surface of the body of the mammal to a compound of formula (I). [0178] The duration of administering can be less than 30 seconds, less than 1 minute, about 1 minute, between 1 minute and 5 minutes, between 5 minutes and 10 minutes, between 10 minutes and 20 minutes, between 20 minutes and 30 minutes, between 30 minutes and 1 hour, between 1 hour and 3 hours, between 3 hours and 6 hours, between 6 hours and 12 hours, between 12 hours and 24 hours or for more than 24 hours.
[0179] Administering the compound, or a pharmaceutically acceptable salt thereof, can include multiple administrations. The duration between administrations can be less than 30 seconds, less than 1 minute, about 1 minute, between 1 minute and 5 minutes, between 5 minutes and 10 minutes, between 10 minutes and 20 minutes, between 20 minutes and 30 minutes, between 30 minutes and 1 hour, between 1 hour and 3 hours, between 3 hours and 6 hours, between 6 hours and 12 hours, between 12 hours and 24 hours or for more than 24 hours.
[0180] The duration between successive administrations can be less than 30 seconds, less than 1 minute, about 1 minute, between 1 minute and 5 minutes, between 5 minutes and 10 minutes, between 10 minutes and 20 minutes, between 20 minutes and 30 minutes, between 30 minutes and 1 hour, between 1 hour and 3 hours, between 3 hours and 6 hours, between 6 hours and 12 hours, between 12 hours and 24 hours, between 24 hours and 48 hours, between 48 hours and 72 hours, between 72 hours and 1 week or between 1 week and 2 weeks.
[0181] Administering the compound, or a pharmaceutically acceptable salt thereof, to cells can include cells of an in vitro or in vivo system or model. The cells can be part of a cell line. The cell line can be a primary or secondary cell line. The cell line can be an immortal cell line. The cells can be ruptured and be in the form of a cell lysate. The cells can be part of a living organism, i.e., a subject, for example, a mammal. A mammal can include a rat, a mouse, a gerbil, a hamster, a rabbit or a human. The human can be a subject or a patient.
[0182] A method can further include monitoring a property of a sample or a subject.
A sample can be removed from a subject. For instance, a sample can include a sample of cells or a tissue from a subject. A sample can include blood, plasma, or neuronal tissue including neurons or glial cells. A sample can also remain in the subject. For example, a sample can be a tissue or cells that are observed within the patient.
[0183] A method can further include providing untreated control cells, sample or subject and measuring a property of a sample of the untreated control cells, sample or subject.
[0184] A property can include the presence or absence of a molecule, the
concentration of a molecule, for example myelin basic protein, myelin associated
glycoprotein or myelin oligodendrocyte glycoprotein. In some embodiments, determining the presence of a molecule can include determining the concentration of the molecule, determining the purity of the molecule or determining the quantity of the molecule.
[0185] A property can be the conductivity of a tissue or cell. A property can be an emission, for example, electromagnetic radiation.
[0186] Monitoring a property can include observing the property of the sample or subject alone. Monitoring a property can include monitoring the property before the sample or subject has been administered a compound provided herein, or a pharmaceutically acceptable salt thereof. Monitoring a property can include monitoring the property after the sample or subject has been administered a compound, or a pharmaceutically acceptable salt thereof. Monitoring a property can include monitoring a property after the sample or subject has been administered a known concentration of a compound, or a pharmaceutically acceptable salt thereof.
[0187] Monitoring a property of a sample or subject can include observing the property through a microscope. Monitoring a property of the composition can include measuring the property using a microscope. Monitoring a property of the composition can include monitoring the property using still photography or movies. The photography or movies can be on film media or digital form. Monitoring a property can include taking a scan, for example, an MRI or CT scan.
[0188] A compound of formula (I), or a pharmaceutically acceptable salt thereof, formulated as a pharmaceutical composition and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally, as eyedrops, by intravenous, intramuscular, topical or subcutaneous routes.
[0189] Thus, compound provided herein, or a pharmaceutically acceptable salt thereof, may be systemically administered, e.g., orally, in combination with a
pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound, or a pharmaceutically acceptable salt thereof, may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, or wafers, and the like. Such compositions and preparations should contain at least about 0.1% of active compound, or a pharmaceutically acceptable salt thereof,. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound, or a pharmaceutically acceptable salt thereof, in such therapeutically useful compositions can be such that an effective dosage level will be obtained.
[0190] The tablets, troches, pills, capsules, and the like can include the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; or a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, or a pharmaceutically acceptable salt thereof, sucrose or fructose as a sweetening agent, methyl or propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound, or a pharmaceutically acceptable salt thereof, may be incorporated into sustained-release preparations and devices.
[0191] The active compound, or a pharmaceutically acceptable salt thereof, may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms.
[0192] Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium
comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, or nontoxic glyceryl esters, and mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, or thimerosal, and the like. In many cases, isotonic agents, for example, sugars, buffers or sodium chloride, will be included. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate or gelatin.
[0193] Sterile injectable solutions can be prepared by incorporating the active compound, or a pharmaceutically acceptable salt thereof, in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation can be vacuum drying and the freeze drying techniques, which can yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
[0194] For topical administration, a compound provided herein, or a pharmaceutically acceptable salt thereof, may be applied in pure form, e.g., when they are liquids. However, it can be generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
[0195] Exemplary solid carriers can include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds and salts can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
[0196] Thickeners such as synthetic polymers, fatty acids, fatty acid salts or esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
[0197] Examples of useful dermatological compositions which can be used to deliver the compounds provided herein, or a pharmaceutically acceptable salt thereof, to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No.
4,820,508), each of which is incorporated by reference in its entirety.
[0198] Useful dosages of the compounds provided herein, or a pharmaceutically acceptable salt thereof, can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949, which is incorporated by reference in its entirety.
[0199] Generally, the concentration of the compound(s) provided herein, or a pharmaceutically acceptable salt thereof, in a liquid composition, such as a lotion, can be from about 0.1 to about 25 weight percent, such as from about 0.5-10 weight percent. The concentration in a semi-solid or solid composition such as a gel or a powder can be about 0.1- 5 wt-%, such as about 0.5-2.5 weight percent based on the total weight of the composition.
[0200] The amount of the compound, or a pharmaceutically acceptable salt thereof, required for use in treatment can vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and can be ultimately at the discretion of the attendant physician or clinician. In general, however, a dose can be in the range of from about 0.1 to about 10 mg/kg of body weight per day.
[0201] The compound, or a pharmaceutically acceptable salt thereof, can be conveniently administered in unit dosage form; for example, containing 0.01 to 10 mg, or 0.05 to 1 mg, of active ingredient per unit dosage form. In some embodiments, a dose of 5 mg/kg or less can be suitable. [0202] The active ingredient can be administered so as to achieve a desired peak plasma concentration of the active compound, or a pharmaceutically acceptable salt thereof. The desired peak plasma concentration can be from about 0.5 μΜ to about 75 μΜ, such as, about 1 μΜ to 50 μΜ, or about 2 μΜ to about 30 μΜ. This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing between about 1 mg to about 100 mg of the active ingredient.
[0203] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four, or more sub- doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
[0204] The disclosed method can include a kit comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and instructional material which can describe administering the compound, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound, or a pharmaceutically acceptable salt thereof, to a cell or a subject. This should be construed to include other embodiments of kits that are known to those skilled in the art, such as a kit comprising a (such as sterile) solvent for dissolving or suspending the compound, or a pharmaceutically acceptable salt thereof, or composition prior to administering the compound or composition to a cell or a subject. In some embodiments, the subject can be a human.
[0205] In accordance with the disclosed methods, as described above or as discussed in the Examples below, there can be employed conventional chemical, cellular,
histochemical, biochemical, molecular biology, microbiology, and in vivo techniques which are known to those of skill in the art. Such techniques are explained fully in the literature.
EXAMPLES
[0206] The compounds provided herein, or a pharmaceutically acceptable salt thereof, can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mol ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [0207] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
[0208] Furthermore, the compounds provided herein may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art.
Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
[0209] The compounds of formula (I) can be prepared by the synthetic protocols illustrated in Scheme 1, where L, L2, R1, R2, R9, R9a and q are as defined herein.
Scheme 1
Figure imgf000092_0001
1-1 (I)
[0210] Compound 1-1 is reacted with at least a stoichiometric amount and in some embodiments an excess of H-R . The reaction is typically conducted under conventional coupling conditions well known in the art. In one embodiment, the reaction is conducted with the use of a coupling agent such as carbonyldiimidazole (for compounds whereing L is - OC(O)-) and HATU (for compounds wherein L is -C(O)-) in the presence of triethylamine in a suitable solvent, such as DMF. The reaction is continued until substantially complete which typically occurs within about 1 to 12 hours. Upon reaction completion, compound (I) can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like.
[0211] For compounds wherein one of R3, R6 and/or R8 comprise an amide or a carboxyl group (either a carboxilic acid or ester functionality), the coupling reaction of Scheme 1 can be performed either before or after the installation of such groups. For the amide, the reaction is typically conducted under conventional coupling conditions well known in the art. In one embodiment, the reaction is conducted with the use of a coupling agent such as DIAD in the presence of PPh3 in a suitable solvent, such as toluene. The reaction is continued until substantially complete which typically occurs within about 1 to 12 hours. Upon reaction completion, the final compound can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like.
List of Abbreviations and Acronyms
Figure imgf000093_0001
HPCD Hydroxypropyl-P-cyclodextrin
HPLC High-performance liquid chromatography
Hz Hertz
ICso The half maximal inhibitory concentration
J Coupling constant
Kg Kilogram
LCMS Liquid chromatography-mass spectrometry
LPC Lysolecithin
M Molar
m multiplet
m/z mass-to-charge ratio
M+H Mass peak plus hydrogen
Me Methyl
mg Milligram
MHz Megahertz
min Minute
mL Milliliter
mM Millimolar
mmol Millimole
MS Mass spectrometry
MW Microwave
N Normal
nL Nanoliter
nm Nanometer
NMR Nuclear magnetic resonance
PBS Phosphate buffered saline
Ph Phenyl
prep Preparative
q Quartet
rt Room temperature
s Singlet
sec Second t Triplet
TFA Trifluoroacetic acid
THF Tetrahydrofuran
δ Chemical shift
μ Microgram
Microliter
μΜ Micromolar
Example 1
5-(3,5-Dichlorobenzyl) 2-ethyl 7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-2,5(6H)-
Figure imgf000095_0001
[0212] To a mixture of (3,5-dichloro-phenyl)-methanol (97 mg, 0.55 mmol) and N,N- carbonyldiimidazole (89 mg, 0.55 mmol) in DMF (2 mL) was added triethylamine (139 μί, 1.00 mmol). The reaction mixture was stirred at rt for lh. It was then added a solution of ethyl 5,6,7, 8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2-carboxylate (105 mg, 0.50 mmol) in DMF ( 1 mL). The reaction mixture was stirred at rt over weekend. It was purified by prep-HPLC (MeCN/H20 with 0.1% TFA) to get the desired ester as a white powder after lyophilization (68 mg, yield 33%). 1H NMR (400 MHz, METHANOL-d4) δ 7.11 - 7.42 (m, 3H), 6.72, 6.66 (s, s, 1H), 5.10, 5.06 (s, s, 2H), 4.65, 4.53 (s, s, 2H), 4.46 - 4.54 (m, 2H), 4.32 (q, J = 7.03 Hz, 2H), 3.69 - 3.94 (m, 2H), 1.85- 1.95 (m, 2H), 1.35 (t, J = 7.03 Hz, 3H); LCMS m/z 411.9 [M+H]+.
Example 2
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-
Figure imgf000095_0002
[0213] The titled compound was synthesized according to the procedure described in
Example 1 (1.49 g, yield 78%). 1H NMR (400 MHz, METHANOL-d4) δ 7.78 - 8.16 (m, 3H), 6.65, 6.59 (s, s, 1H), 5.25, 5.22 (s, s, 2H), 4.66, 4.57 (s, s, 2H), 4.43 - 4.54 (m, 2H), 4.14 - 4.31 (m, 2H), 3.64 - 3.86 (m, 2H), 1.72- 1.86 (m, 2H), 1.25 (t, J = 6.90 Hz, 3H); LCMS m/z 480.2 [M+H]+. Example 3
7-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 5,6-dihydroimidazo[l,2-a]pyrazine-2,7(8H)- dicarboxylate
Figure imgf000096_0001
[0214] The titled compound was synthesized according to the procedure described in
Example 1 (159 mg, yield 67%). 1H NMR (400 MHz, METHANOL-d4) δ 8.05 (s, 2H), 7.96 (s, 1H), 7.76 (s, 1H), 5.36 (s, 2H), 4.79-4.74 (m, 2H), 4.31 (q, J = 12 Hz, 2H), 4.15 (t, J = 4.8 Hz, 2H), 3.97 (bs, 2H), 1.35 (t, J = 1.2 Hz, 3H); LCMS m/z 466.1 [M+H]+.
Example 4
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 6,7-dihydropyrazolo[l,5-a]pyrazine-2,5(4H)- dicarboxylate
Figure imgf000096_0002
[0215] The titled compound was synthesized according to the procedure described in
Example 1 (116 mg, yield 58%). 1H NMR (400 MHz, METHANOL-d4) δ 8.03 (s, 2H), 7.94 (s, 1H), 6.63 (s, 1H), 5.34 (s, 2H), 4.82-4.76 (m, 2H), 4.33 (q, J = 1.2 Hz, 2H), 4.26-3.21 (m, 2H), 4.02 (bs, 2H), 1.35 (t, J = 1.2 Hz, 3H); LCMS m/z 466.1 [M+H]+.
Example 5
7-(3,5-Bis(trifluoromethyl)benzyl) 3-methyl 8,9-dihydro-5H-imidazo[l,2- d][l,4]diazepine-3,7(6H)-dicarboxylate
Figure imgf000096_0003
[0216] The titled compound was synthesized according to the procedure described in
Example 1 (121 mg, yield 61%). LCMS m/z 466.1 [M+H]+.
Example 6
5-(3,5-Bis(trifluoromethyl)benzyl) 3-ethyl 7,8-dihydro-4H-[l,2,3]triazolo[l,5- a][l,4]diazepine-3,5(6H)-dicarboxylate
Figure imgf000096_0004
[0217] The titled compound was synthesized according to the procedure described in
Example 1 (115 mg, yield 59%). LCMS m/z 481.1 [M+H]+.
Example 7
5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-
Figure imgf000097_0001
[0218] To the above ethyl ester (65 mg, 0.16 mmol) in MeOH (0.8 mL) and THF (0.8 mL) was added 3 N NaOH (0.2 mL, 0.6 mmol). The reaction mixture was stirred at rt for 2h. It was acidified by adding 2N HCl (pH~3-4), and purified by prep-HPLC (MeCN/H20 with 0.1% TFA) to get the desired acid as a white solid (55 mg, yield 91%). 1H NMR (400 MHz, METHANOL-d4) δ 7.13 - 7.42 (m, 3H), 6.71, 6.66 (s, s, 1H), 5.10, 5.07 (s, s, 2H), 4.66, 4.53 (s, s, 2H), 4.46 - 4.54 (m, 2H), 3.74 - 3.96 (m, 2H), 1.85- 1.96 (m, 2H); LCMS m/z 383.9 [M+H]+.
Example 8
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-
Figure imgf000097_0002
[0219] To 5-(3,5-bis(trifluoromethyl)benzyl) 2-ethyl 7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-2,5(6H)-dicarboxylate (2.98 g, 6.22 mmol) in THF (20 mL) was added 3 N NaOH (8 mL, 20 mmol), followed by MeOH (4 mL). The reaction mixture was stirred at rt for 1.5 h. It was acidified by adding 2N HCl (pH~3-4), diluted with brine, and extracted with EtOAc. The organic phase was dried over MgS04, filtered and concentrated to get 5-(((3,5- bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carboxylic acid as a white solid (2.79 g, yield 99%). 1H NMR (400 MHz, METHANOL-d ) δ 7.75 - 8.01 (m, 3H), 6.71, 6.62 (s, s, 1H), 5.27, 5.25 (s, s, 2H), 4.67, 4.61 (s, s, 2H), 4.41 - 4.55 (m, 2H), 3.71 - 3.97 (m, 2H), 1.78- 1.99 (m, 2H); LCMS m/z 452.1 [M+H]+. Example 9
7-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydroimidazo[l,2- a]pyrazine-2-carboxylic acid
Figure imgf000098_0001
[0220] The titled compound was synthesized according to the procedure described in
Example 7 (17 mg, yield 14%). The mixture was purified by pre-HPLC (MeCN/H20 with 10 mM NH4HCO3 as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL-d4) δ 8.04 (s, 2H), 7.96 (s, 1H), 7.68 (s, 1H), 5.35 (s, 2H), 4.80-4.73 (m, 2H), 4.14 (t, J = 5.6 Hz, 2H), 3.96 (bs, 2H); LCMS m/z 438.1 [M+H]+.
Example 10
7-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-6,7,8,9-tetrahydro-5H-imidazo[l,2-
Figure imgf000098_0002
[0221] The titled compound was synthesized according to the procedure described in
Example 7 (30 mg, yield 26%). The mixture was purified by pre-HPLC (MeCN/H20 with 10 mM NH4HC03 as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL-d4) δ 8.03 (s, 2H), 7.95 (s, 1H), 7.46 (s, 1H), 5.34 (s, 2H), 4.88-4.84 (m, 2H), 3.85-3.73 (m, 4H), 3.15-3.14 (m, 2H); LCMS m/z 452.1 [M+H]+.
Example 11
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- [l,2,3]triazolo[l,5-a][l,4]diazepine-3-carboxylic acid
Figure imgf000098_0003
[0222] The titled compound was synthesized according to the procedure described in
Example 7 (10 mg, yield 10%). The mixture was purified by pre-HPLC (MeCN/H20 with 10 mM NH4HC03 as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL-d ) δ 7.95-7.83 (m, 3H), 5.24 (s, 2H), 5.17-5.11 (m, 2H), 4.72-4.67 (m, 2H), 3.90-3.79 (m, 2H), 2.02-1.98 (m, 2H); LCMS m/z 453.1 [M+H]+. Example 12
3,5-Dichlorobenzyl 2-(9-azabicyclo[3.3.1]nonane-9-carbonyl)-7,8-dihydro-4H-
Figure imgf000099_0001
[0223] To a mixture of 5-(((3,5-dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a][l,4]diazepine-2-carboxylic acid (12 mg, 0.031 mmol) and 9- azabicyclo[3.3.1]nonane hydrochloride (6.0 mg, 0.037 mmol) in DMF (0.5 mL) was added HATU (14 mg, 0.037 mmol), followed by N,N-diisopropylethylamine (22 μΐ,, 0.12 mmol). The mixture was stirred at room temperature for lh, and purified by prep HPLC (TFA method) to provide the desired product as a white solid (11 mg, yield 72%). 1H NMR (400 MHz, METHANOL-d4) δ 7.21 - 7.40 (m, 3H), 6.50, 6.47 (s, s, IH), 5.08, 5.07 (s, s, 2H), 4.55 - 4.79 (m, 4H), 4.39 - 4.52 (m, 2H), 3.76 - 3.96 (m, 2H), 2.10 - 2.30 (m, 2H), 1.57 - 2.00 (m, 12H); LCMS m/z 491.0 [M+H]+.
Example 13
3,5-Dichlorobenzyl 2-(isopropylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l, ylate
Figure imgf000099_0002
[0224] The titled compound was synthesized according to the procedure described in
Example 12 (65 mg, yield 65%). The mixture was purified by pre-HPLC (MeCN/H20 with 10 mM NH4HC03 as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL- d4) δ 7.37-7.28 (m, 2H), 7.16 (s, IH), 6.66-6.63 (m, IH), 5.10-5.06 (m, 2H), 4.65-4.59 (m, 2H), 4.52-4.49 (m, 2H), 4.19-4.12 (m, IH), 3.86-3.81 (m, 2H), 1.91 (bs, 2H), 1.23 (d, J = 6.8 Hz, 6H); LCMS m/z 425.1 [M+H]+.
Example 14
3,5-Dichlorobenzyl 2-(tert-butylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l, ylate
Figure imgf000099_0003
[0225] The titled compound was synthesized according to the procedure described in
Example 12 (74 mg, yield 72%). The mixture was purified by pre-HPLC (MeCN/H20 with 10 mM NH4HC03 as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL- d4) δ 7.37-7.32 (m, IH), 7.27 (s, IH), 7.15 (s, IH), 6.62-6.60 (m, IH), 5.09-5.06 (m, 2H), 4.65-4.59 (m, 2H), 4.49 (t, J = 5.2 Hz, 2H), 3.85-3.80 (m, 2H), 1.90 (bs, 2H), 1.43 (s, 9H); LCMS m/z 439.1 [M+H]+.
Example 15
3,5-Dichlorobenzyl 2-(cyclobutylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l te
Figure imgf000100_0001
[0226] The titled compound was synthesized according to the procedure described in
Example 12 (77 mg, yield 84%). The mixture was purified by pre-HPLC (MeCN/H20 with 10 mM NH4HCO3 as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL- d4) δ 7.37-7.16 (m, 3H), 6.65-6.62 (m, IH), 5.09-5.06 (m, 2H), 4.64-4.59 (m, 2H), 4.51-4.45 (m, 3H), 3.86-3.81 (m, 2H), 2.33-2.31 (m, 2H), 2.12-2.07 (m, 2H), 1.91 (bs, 2H), 1.78-1.74 (m, 2H); LCMS m/z 437.1 [M+H]+.
Example 16
3,5-Dichlorobenzyl 2-(cyclopentylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l te
Figure imgf000100_0002
[0227] The titled compound was synthesized according to the procedure described in
Example 12 (78 mg, yield 83%). The mixture was purified by pre-HPLC (MeCN/H20 with 10 mM NH4HC03 as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL- d4) δ 7.37-7.16 (m, 3H), 6.66-6.64 (m, IH), 5.10-5.06 (m, 2H), 4.65-4.60 (m, 2H), 4.52-4.49 (m, 2H), 4.30-4.26 (m, IH), 3.86-3.81 (m, 2H), 2.04-1.91 (m, 4H), 1.77-1.54 (m, 6H); LCMS m/z 451.1 [M+H]+.
Example 17
3,5-Dichlorobenzyl 2-(cyclohexylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l, ylate
Figure imgf000100_0003
[0228] The titled compound was synthesized according to the procedure described in
Example 12 (76 mg, yield 69%). The mixture was purified by pre-HPLC (MeCN/H20 with 10 mM NH4HC03 as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL- d4) δ 7.37-7.16 (m, 3H), 6.66-6.64 (m, IH), 5.10-5.06 (m, 2H), 4.65-4.60 (m, 2H), 4.52-4.49 (m, 2H), 3.86-3.81 (m, 3H), 1.93-1.91 (m, 4H), 1.81-1.78 (m, 2H), 1.69-1.65 (m, IH), 1.43- 1.25 (m, 5H); LCMS m/z 465.1 [M+H]+. Example 18
3,5-Dichlorobenzyl 2-(pyrrolidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5-
Figure imgf000101_0001
[0229] The titled compound was synthesized according to the procedure described in
Example 12 (71 mg, yield 65%). The mixture was purified by pre-HPLC (MeCN/H20 with 10 mM NH4HCO3 as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL- d4) δ 7.39-7.21 (m, 3H), 6.67-6.63 (m, IH), 5.10-5.07 (m, 2H), 4.66-4.62 (m, 2H), 4.53-4.51 (m, 2H), 3.91-4.82 (m, 4H), 3.59 (t, J = 6.8 Hz, 2H), 1.99-1.92 (m, 6H); LCMS m/z 437.1 [M+H]+.
Example 19
3,5-Dichlorobenzyl 2-(piperidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
[0230] The titled compound was synthesized according to the procedure described in
Example 12 (66 mg, yield 62%). The mixture was purified by pre-HPLC (MeCN/H20 with 10 mM NH4HC03 as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL- d4) δ 7.37-7.27 (m, 3H), 6.51-6.49 (m, IH), 5.09-5.08 (m, 2H), 4.66-4.62 (m, 2H), 4.51-4.48 (m, 2H), 3.88-3.82 (m, 4H), 3.68 (t, J = 4.2 Hz, 2H), 1.93-1.92 (m, 2H), 1.74-1.70 (m, 2H), 1.64-1.59 (m, 4H); LCMS m/z 451.1 [M+H]+.
Example 20
3,5-Dichlorobenzyl 2-(4-fluoropiperidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l, ylate
Figure imgf000101_0002
[0231] The titled compound was synthesized according to the procedure described in
Example 12 (48 mg, yield 43%). The mixture was purified by pre-HPLC (MeCN/H20 with 10 mM NH4HC03 as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL- d4) δ 7.39-7.26 (m, 3H), 6.56-6.54 (m, IH), 5.09-5.07 (m, 2H), 4.96-4.83 (m, IH), 4.67-4.62 (m, 2H), 4.50 (t, J = 5.6 Hz, 2H), 4.03-3.71 (m, 6H), 1.99-1.86 (m, 6H); LCMS m/z 469.1 [M+H]+. Example 21
3,5-Dichlorobenzyl 2-(4-methylpiperidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l, late
Figure imgf000102_0001
[0232] The titled compound was synthesized according to the procedure described in
Example 12 (60 mg, yield 55%). The mixture was purified by pre-HPLC (MeCN/H20 with 10 mM NH4HCO3 as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL- d4) δ 7.37 (s, 1H), 7.30-7.26 (m, 2H), 6.50-6.48 (m, 1H), 5.09-5.07 (m, 2H), 4.66 (s, 1H), 4.61-4.56 (m, 3H), 4.49 (t, J= 5.2 Hz, 2H), 3.88-3.82 (m, 2H), 3.11-3.09 (m, 1H), 2.81-2.79 (m, 1H), 1.93-1.92 (m, 2H), 1.78-1.66 (m, 3H), 1.18-1.15 (m, 2H), 0.98 (d, J= 4.2 Hz, 3H); LCMS m/z 465.1 [M+H]+.
Example 22
3,5-Dichlorobenzyl 2-(4-(trifluoromethyl)piperidine-l-carbonyl)-7,8-dihydro-4H- pyrazolo[l, arboxylate
Figure imgf000102_0002
[0233] The titled compound was synthesized according to the procedure described in
Example 12 (80 mg, yield 65%). The mixture was purified by pre-HPLC (MeCN/H20 with 0.05 TFA as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL-d ) δ 7.39- 7.36 (m, 1H), 7.31-7.25 (m, 2H), 6.57-6.55 (m, 1H), 5.10-5.08 (m, 2H), 4.88-4.79 (m, 1H), 4.74-4.62 (m, 3H), 4.52-4.50 (m, 2H), 3.88-3.82 (m, 2H), 3.18-3.12 (m, 1H), 2.85-2.79 (m, 1H), 2.59-2.50 (m, 1H), 2.01-1.93 (m, 4H), 1.61-1.48 (m, 2H); LCMS m/z 519.1 [M+H]+.
Example 23
3,5-Dichlorobenzyl 2-(morpholine-4-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4 ylate
Figure imgf000102_0003
[0234] The titled compound was synthesized according to the procedure described in
Example 12 (59 mg, yield 56%). The mixture was purified by pre-HPLC (MeCN/H20 with 10 mM NH4HC03 as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL- d4) δ 7.39-7.37 (m, 1H), 7.30 (s, 1H), 7.25 (s, 1H), 6.59-6.57 (m, 1H), 5.10-5.07 (m, 2H), 4.67-4.62 (m, 2H), 4.51-4.49 (m, 2H), 4.06-4.01 (m, 2H), 3.88-3.81 (m, 2H), 3.73-3.69 (m, 6H), 1.93-1.92 (m, 2H); LCMS m/z 453.0 [M+H]+. Example 24
3,5-Dichlorobenzyl 2-(piperazine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l, ylate
Figure imgf000103_0001
[0235] The titled compound was synthesized according to the procedure described in
Example 12 (80 mg, yield 75%). The mixture was purified by pre-HPLC (MeCN/H20 with 10 mM NH4HCO3 as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL- d4) δ 7.38-7.37 (m, 1H), 7.30-7.25 (m, 2H), 6.56-6.54 (m, 1H), 5.10-5.07 (m, 2H), 4.67-4.62 (m, 2H), 4.51-4.49 (m, 2H), 3.97-3.83 (m, 4H), 3.70 (bs, 2H), 2.87-2.84 (m, 4H), 1.93-1.92 (m, 2H); LCMS m/z 452.1 [M+H]+.
Example 25
3,5-Dichlorobenzyl 2-(4-methylpiperazine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l, ylate
Figure imgf000103_0002
[0236] The titled compound was synthesized according to the procedure described in
Example 12 (72 mg, yield 66%). The mixture was purified by pre-HPLC (MeCN/H20 with 10 mM NH4HC03 as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL- d4) δ 7.38-7.37 (m, 1H), 7.30-7.25 (m, 2H), 6.56-6.65 (m, 1H), 5.09-5.07 (m, 2H), 4.66-4.61 (m, 2H), 4.50 (t, J= 5.0 Hz, 2H), 4.04 (bs, 2H), 3.88-3.82 (m, 2H), 3.75 (bs, 2H), 2.50-2.47 (m, 4H), 2.33 (s, 3H), 1.93-1.92 (m, 2H); LCMS m/z 466.1 [M+H]+.
Example 26
3,5-Dichlorobenzyl 2-(4-aminopiperidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000103_0003
Step 1
3,5-Dichlorobenzyl 2-(4-((tert-butoxycarbonyl)amino)piperidine-l-carbonyl)-7,8- dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
[0237] The titled compound was synthesized according to the procedure described in
Example 12 (121 mg, yield 82%); LCMS m/z 566.1 [M+H]+. Step 2
3,5-Dichlorobenzyl 2-(4-aminopiperidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000104_0001
[0238] A mixture of 3,5-dichlorobenzyl 2-(4-((tert- butoxycarbonyl)amino)piperidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate (120 mg, 0.21 mmol), TFA (2 mL) in dichloromethane (4 mL) was stirred at rt for 3 h. The mixture was evaporated in vacuo, the residue was dissolved in dichloromethane (50 mL), washed with saturated aqueous NaHC03 solution, dried over anhydrous Na2S04 and concentrated in vacuo to give the crude product, which was purified by prep-HPLC (MeCN/H20 with 10 mM NH4HC03 as mobile phase; from 5% to 95%) to afford 3,5-dichlorobenzyl 2-(4-aminopiperidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate as a brown solid (36 mg, yield 36%). 1H NMR (400 MHz, METHANOL-d4) δ 7.38-6.37 (m, 1H), 7.31-7.26 (m, 2H), 6.53-6.51 (m, 1H), 5.10- 5.07 (m, 2H), 4.68-4.53 (m, 4H), 4.50 (t, J= 5.6 Hz, 2H), 3.88-3.82 (m, 2H), 3.21-3.15 (m, 1H), 2.95-2.85 (m, 2H), 1.94-1.83 (m, 4H), 1.38-1.32 (m, 2H); LCMS m/z 466.1 [M+H]+.
Example 27
3,5-Dichlorobenzyl 2-(methylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-
5(6H)-carboxylate
Figure imgf000104_0002
[0239] The titled compound was synthesized according to the procedure described in
Example 12 (70 mg, yield 75%). The mixture was purified by pre-HPLC (MeCN/H20 with 10 mM NH4HC03 as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL- d4) δ 7.38-7.18 (m, 3H), 6.64-6.61 (m, 1H), 5.09-5.06 (m, 2H), 4.65-4.60 (m, 2H), 4.52-4.49 (m, 2H), 3.86-3.81 (m, 2H), 2.88 (s, 3H), 1.92-1.91 (m, 2H); LCMS m/z 397.1 [M+H]+.
Example 28
3,5-Dichlorobenzyl 2-(dimethylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000104_0003
[0240] The titled compound was synthesized according to the procedure described in
Example 12 (68 mg, yield 70%). The mixture was purified by pre-HPLC (MeCN/H20 with 10 mM NH4HCO3 as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL- d4) δ 7.29-7.17 (m, 3H), 6.59-6.54 (m, IH), 5.03 (s, 2H), 4.55-4.54 (m, 2H), 4.45-4.43 (m, 2H), 3.78 (t, J = 4.8 Hz, 2H), 3.31 (bs, 3H), 3.07 (s, 3H), 1.98-1.97 (m, 2H); LCMS m/z 411.1 [M+H]+.
Example 29
3,5-Dichlorobenzyl 2-(ethylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine- -carboxylate
Figure imgf000105_0001
[0241] The titled compound was synthesized according to the procedure described in
Example 12 (68 mg, yield 70%). The mixture was purified by pre-HPLC (MeCN/H20 with 10 mM NH4HC03 as mobile phase; from 5% to 95%). 1H NMR (400 MHz, METHANOL- d4) δ 7.38-7.18 (m, 3H), 6.65-6.62 (m, IH), 5.10-5.06 (m, 2H), 4.66-4.60 (m, 2H), 4.52-4.49 (m, 2H), 3.87-3.81 (m, 2H), 3.37 (q, J = 7.2 Hz, 2H), 1.92-1.91 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H); LCMS m/z 411.1 [M+H]+.
Example 30
3,5-Bis(trifluoromethyl)benzyl 2-(morpholine-4-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l, ylate
Figure imgf000105_0002
[0242] The titled compound was synthesized according to the procedure described in
Example 12 (63 mg, yield 55%). 1H NMR (400 MHz, METHANOL-d ) δ 7.94-7.89 (m, 3H), 6.58-6.55 (m, IH), 5.27-5.26 (m, 2H), 4.68-4.62 (m, 2H), 4.51-4.49 (m, 2H), 4.05-4.01 (m, 2H), 3.90-3.83 (m, 2H), 3.73-3.68 (m, 6H), 1.93-1.92 (m, 2H); LCMS m/z 521.1
[M+H]+.
Example 31
3,5-Bis(trifluoromethyl)benzyl 2-(4-hydroxypiperidine-l-carbonyl)-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000105_0003
[0243] The titled compound was synthesized according to the procedure described in
Example 12 (71 mg, yield 60%). 1H NMR (400 MHz, METHANOL-d ) δ 7.95-7.91 (m, 3H), 6.54-6.50 (m, IH), 5.27-5.26 (m, 2H), 4.68-4.62 (m, 2H), 4.51-4.49 (m, 2H), 4.33-4.29 (m, IH), 4.20-4.16 (m, IH), 3.90-3.84 (m, 3H), 3.52-3.50 (m, IH), 3.22-3.21 (m IH), 1.93 (bs, 4H), 1.52-1.51 (m, 2H); LCMS m/z 535.1 [M+H]+.
Example 32
3,5-Bis(trifluoromethyl)benzyl 2-(4-fluoropiperidine-l-carbonyl)-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000106_0001
[0244] The titled compound was synthesized according to the procedure described in
Example 12 (67 mg, yield 57%). 1H NMR (400 MHz, METHANOL-d4) δ 7.95-7.91 (m, 3H), 6.57-6.52 (m, IH), 5.28-5.27 (m, 2H), 4.98-4.77 (m, IH), 4.69-4.63 (m, 2H), 4.52-4.50 (m, 2H), 4.04-3.96 (m, 2H), 3.90-3.84 (m, 3H), 3.72 (bs, IH), 1.94-1.93 (m, 6H); LCMS m/z 535.1 [M+H]+.
Example 33
3,5-Bis(trifluoromethyl)benzyl 2-(piperazine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l, late
Figure imgf000106_0002
[0245] The titled compound was synthesized according to the procedure described in
Example 12 (64 mg, yield 56%). 1H NMR (400 MHz, METHANOL-d4) δ 8.04 (bs, 2H), 7.97 (s, IH), 6.45, 6.40 (s, s, IH), 5.25, 5.23 (s, s, 2H), 4.65, 4.57 (s, s, 2H), 4.45-4.44 (m, 2H), 3.78-3.74 (m, 4H), 3.49 (bs, 2H), 2.67-2.65 (m, 4H), 1.84-1.80 (m, 2H); LCMS m/z 520.2 [M+H]+.
Example 34
9-(5-((3,5-Dichlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-a rboxylic acid
Figure imgf000106_0003
Step 1
tert-Butyl 2-(3-(ethoxycarbonyl)-9-azabicyclo[3.3.1]nonane-9-carbonyl)-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate
Figure imgf000106_0004
[0246] To a solution of 5-(iert-butoxycarbonyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carboxylic acid (2.3 g, 8.6 mmol) in DMF (8 mL) was added HATU (4.9 g, 12.9 mmol) and Et3N (2.6 g, 25.8 mmol). After stirring at rt for 2 h, ethyl 9- azabicyclo[3.3.1]nonane-3-carboxylate hydrochloride (2.2 g, 9.5 mmol) was added to the reaction solution. The mixture was stirred at rt for 16 h, and was purified with prep-HPLC (MeOH/H20 with 0.05% TFA as mobile phase; from 20% to 95%) to furnish the compound ie/t-butyl 2-(3-(ethoxycarbonyl)-9-azabicyclo[3.3.1]nonane-9-carbonyl)-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate as a yellow solid (1.9 g, yield 51%). LCMS m/z 447.2 [M+H]+.
Step 2
Ethyl 9-(4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2-carbonyl)-9- azabicyclo[3.3.1]nonane-3-carboxylate
Figure imgf000107_0001
[0247] To a solution of iert-butyl 2-(3-(ethoxycarbonyl)-9-azabicyclo[3.3.1]nonane-
9-carbonyl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (1.9 g, 4.26 mmol) in EtOH (20 mL) was added SOCl2 (2.0 g, 17.04 mmol) dropwise. The mixture was stirred at reflux for 4 h. The mixture was evaporated and saturated aqueous NaHC03 (10 mL) was added. The aqueous layer was extracted with CH2C12 (2 x 25 mL), and the organic layer washed with brine and dried over anhydrous Na2S04. The solvent was removered in vacuo to afford ethyl 9-(4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2-carbonyl)-9- azabicyclo[3.3.1]nonane-3-carboxylate (1.3 g, yield 92%) which was used without further purification. LCMS m/z 347.2 [M+H]+.
Step 3
Ethyl 9-(5-((3,5-dichlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-
Figure imgf000107_0002
[0248] To a solution of triphosgene (35 mg, 0.12 mmol) in dichloromethane (3 mL) was added a solution of ethyl 9-(4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2-carbonyl)-9- azabicyclo[3.3.1]nonane-3-carboxylate (100 mg, 0.29 mmol) in dichloromethane (3 mL) and Et3N (58 mg, 0.58 mmol). The mixture was stirred at rt for 2.5 h, followed by (3,5- dichlorophenyl)methanamine (56 mg, 0.32 mmol) and Et3N (58 mg, 0.58 mmol). The mixture was stirred at rt for 16 h. To the reaction mixture was added methanol (10 mL) and the solvent was evaporated. The residue was purified with prep-HPLC (MeOH/H20 with 0.05% TFA as mobile phase; from 20% to 95%) to furnish ethyl 9-(5-((3,5- dichlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2-carbonyl)-9- azabicyclo[3.3.1]nonane-3-carboxylate as a yellow oil (89 mg, yield 56%). LCMS m/z 548.2 [M+H]+.
Step 4
9-(5-((3,5-Dichlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2-
Figure imgf000108_0001
[0249] To a solution of ethyl 9-(5-((3,5-dichlorobenzyl)carbamoyl)-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate (89 mg, 0.16 mmol) in THF (2 mL) and H20 (0.5 mL) was added lithium hydroxide monohydrate (27 mg, 0.64 mmol). The reaction mixture was stirred at rt for 16 h. Then it was adjusted to pH = 6 with aq. HC1 (IN). The mixture was concentrated in vacuo. The redidue was purified by prep-HPLC (MeCN/H20 with 10 mM NH4HCO3 as mobile phase; from 20% to 95%) to furnish 9-(5-((3,5-Dichlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid as a yellow solid (55 mg, yield 65%). 1H NMR (400 MHz, METHANOL-d4) δ 7.31 (s, 1H), 7.28-7.27 (m, 2H), 6.44 (s, 1H), 4.85 (bs, 2H), 4.74 (s, 2H), 4.36 (s, 2H), 4.22 (t, J = 5.2 Hz, 2H), 3.97 (t, J = 5.2 Hz, 2H), 3.35- 3.31 (m, 1H), 2.17-1.63 (m, 10H); LCMS m/z 520.1 [M+H]+.
Example 35
9-(5-((3-chlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-az arboxylic acid
Figure imgf000108_0002
[0250] The titled compound was synthesized according to the procedure described in
Example 34 (46 mg, yield 53%). The mixture was purified by prep-HPLC (MeCN/H20 with 0.05% TFA as mobile phase; from 20% to 95%). 1H NMR (400 MHz, METHANOL-d ) δ 7.32-7.23 (m, 4H), 6.44 (s, 1H), 4.86-4.84 (m, 2H), 4.74 (s, 2H), 4.38 (s, 2H), 4.22 (t, J = 5.6 Hz, 2H), 3.97 (t, J = 5.6 Hz, 2H), 3.23-3.21 (m, 1H), 2.12-1.81 (m, 10H); LCMS m/z 486.2 [M+H]+.
Example 36
9-(5-((3-(trifluoromethyl)benzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine- 2-carbonyl)-9-a -carboxylic acid
Figure imgf000109_0001
[0251] The titled compound was synthesized according to the procedure described in
Example 34 (46 mg, yield 51 ). The mixture was purified by prep-HPLC (MeOH/H20 with 0.05% TFA as mobile phase; from 20% to 95%). 1H NMR (400 MHz, METHANOL-d4) δ 7.62-7.51 (m, 4H), 6.44 (s, 1H), 4.86-4.84 (m, 2H), 4.74 (s, 2H), 4.46 (s, 2H), 4.22 (t, J = 5.6 Hz, 2H), 3.98 (t, J = 5.6 Hz, 2H), 3.23-3.21 (m, 1H), 2.08-1.81 (m, 10H); LCMS m/z 520.2 [M+H]+.
Example 37
9-(5-((4-Chlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000109_0002
[0252] The titled compound was synthesized according to the procedure described in
Example 34 (40 mg, yield 58%). The mixture was purified by prep-HPLC (CH3CN/H20 with 0.05% TFA as mobile phase; from 20% to 95%). 1H NMR (400 MHz, METHANOL- d4) δ 7.32-7.30 (m, 4H), 6.44 (s, 1H), 4.86-4.84 (m, 2H), 4.73 (s, 2H), 4.37 (s, 2H), 4.21 (t, J = 5.6 Hz, 2H), 3.96 (t, J = 5.6 Hz, 2H), 3.23-3.21 (m, 1H), 2.11-1.79 (m, 10H); LCMS m/z 486.2 [M+H]+.
Example 38
9-(5-((4-(Trifluoromethyl)benzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine- 2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000109_0003
[0253] The titled compound was synthesized according to the procedure described in
Example 34 (47 mg, yield 88%). The mixture was purified by prep-HPLC (MeCN/H20 with 0.05% TFA as mobile phase; from 20% to 95%). 1H NMR (400 MHz, METHANOL-d4) δ 7.60 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 6.43 (s, 1H), 4.86 (bs, 2H), 4.74 (s, 2H), 4.46 (s, 2H), 4.22 (t, J = 5.2 Hz, 2H), 3.97 (t, J = 5.2 Hz, 2H), 3.37-3.35 (m, 1H), 2.09-1.66 (m, 10H); LCMS m/z 520.2 [M+H]+.
Example 39
9-(5-((3-Chloro-5-fluorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9- rboxylic acid
Figure imgf000110_0001
[0254] The titled compound was synthesized according to the procedure described in
Example 34 (64 mg, yield 58%). The mixture was purified by prep-HPLC (MeCN/H20 with 0.05% TFA as mobile phase; from 20% to 95%). 1H NMR (400 MHz, METHANOL-d ) δ 7.17 (s, 1H), 7.08-7.01 (m, 2H), 6.45 (s, 1H), 4.86-4.84 (m, 2H), 4.74 (s, 2H), 4.38 (s, 2H), 4.22 (t, J = 5.6 Hz, 2H), 3.97 (t, J = 5.6 Hz, 2H), 3.23-3.21 (m, 1H), 2.10-1.79 (m, 10H); LCMS m/z 504.1 [M+H]+.
Example 40
9-(5-((3,5-Difluorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9- rboxylic acid
Figure imgf000110_0002
[0255] The titled compound was synthesized according to the procedure described in
Example 34 (33 mg, yield 46%). The mixture was purified by prep-HPLC (MeCN/H20 with 0.05% TFA as mobile phase; from 20% to 95%). 1H NMR (400 MHz, METHANOL-d ) δ 6.92-6.91 (m, 2H), 6.81-6.80 (m, 1H), 6.45 (s, 1H), 4.86-4.84 (m, 2H), 4.74 (s, 2H), 4.39 (s, 2H), 4.23 (t, J = 5.6 Hz, 2H), 3.97 (t, J = 5.6 Hz, 2H), 3.35-3.32 (m, 1H), 2.12-1.79 (m, 10H); LCMS m/z 488.1 [M+H]+.
Example 41
9-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000110_0003
0 Step 1
3,5-Dichlorobenzyl 2-(3-(ethoxycarbonyl)-9-azabicyclo[3.3.1]nonane-9-carbonyl)-6,7-
Figure imgf000111_0001
[0256] To a solution of (3,5-dichlorophenyl)methanol (153 mg, 0.87 mmol) in DMF
(3 mL) was added CDI (141 mg, 0.87 mmol). After stirring at rt for 2 h, ethyl 9-(4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate (100 mg, 0.29 mmol) was added to the reaction mixture. The mixture was stirred at rt for 16 h, quenched with brine (5 mL), and extracted with ethyl acetate (3 x 5 mL). The combined organic phase was washed with brine (5 mL), dried over sodium sulfate and evaporated in vacuo. The crude product was purified by prep-HPLC (MeOH/H20 with 0.05% TFA as mobile phase; from 20% to 95%) to furnish 3,5-dichlorobenzyl 2-(3-(ethoxycarbonyl)-9- azabicyclo[3.3.1]nonane-9-carbonyl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate as a yellow oil (111 mg, yield 70%). LCMS m/z 549.2 [M+H]+.
Step 2
9-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2-
Figure imgf000111_0002
[0257] To a solution of 3,5-dichlorobenzyl 2-(3-(ethoxycarbonyl)-9- azabicyclo[3.3.1]nonane-9-carbonyl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (111 mg, 0.21 mmol) in THF (2 mL) and H20 (0.5 mL) was added lithium hydroxide monohydrate (35 mg, 0.84 mmol). The reaction mixture was stirred at rt for 5 min, then the reaction was stored in refrigerator (0-5 °C) overnight. After that the mixture was adjusted to pH = 6 with aq. HC1 (IN) under ice bath. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (MeOH/H20 with 10 mM NH4HCO3 as mobile phase; from 20% to 95%) to furnish the target compound 9-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3- carboxylic acid as a white solid (45 mg, yield 43%). 1H NMR (400 MHz, METHANOL-d4) δ 7.41-7.40 (m, 3H), 6.44 (s, 1H), 4.85 (s, 2H), 4.84-4.77 (m, 4H), 4.22 (t, J = 5.2 Hz, 2H), 4.02 (bs, 2H), 3.30-3.28 (m, 1H), 2.09-1.67 (m, 10H). LCMS m/z 521.2 [M+H]+. Example 42
9-(5-(((3-chlorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000112_0001
[0258] The titled compound was synthesized according to the procedure described in
Example 41 (41 mg, yield 71%). The mixture was purified by pre-HPLC (MeOH/H20 with 10 mM NH4HCO3 as mobile phase; from 20% to 95%). 1H NMR (400 MHz, METHANOL- d4) δ 7.42 (s, 1H), 7.35-7.33 (m, 3H), 6.43 (s, 1H), 5.17 (bs, 2H), 4.91-4.81 (m, 4H), 4.20 (t, J = 5.2 Hz, 2H), 3.99 (bs, 2H), 3.36-3.32 (m, 1H), 2.11-1.77 (m, 10H); LCMS m/z 487.2
[M+H]+.
Example 43
9-(5-(((3-(Trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000112_0002
[0259] The titled compound was synthesized according to the procedure described in
Example 41 (32 mg, yield 43%). The mixture was purified by pre-HPLC (MeOH/H20 with 0.05% TFA as mobile phase; from 20% to 95%). 1H NMR (400 MHz, CDC13) δ 7.61-7.48 (m, 4H), 6.41 (s, 1H), 5.22 (s, 2H), 4.93-4.74 (m, 4H), 4.21 (bs, 2H), 3.96 (bs, 2H), 3.34 (bs, 1H), 2.05-1.68 (m, 10H); LCMS m/z 521.2 [M+H]+.
Example 44
9-(5-(((4-chlorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000112_0003
[0260] The titled compound was synthesized according to the procedure described in
Example 41 (38 mg, yield 64%). The mixture was purified by pre-HPLC (MeOH/H20 with 10 mM NH4HC03 as mobile phase; from 20% to 95%). 1H NMR (400 MHz, METHANOL- d4) δ 7.41-7.36 (m, 4H), 6.43 (s, 1H), 5.18 (s, 2H), 4.81-4.78 (m, 4H), 4.21 (t, J= 4.8 Hz, 2H), 4.00 (bs, 2H), 3.35-3.33 (m, 1H), 2.09-1.68 (m, 10H); LCMS m/z 487.2 [M+H]+.
Example 45
9-(5-(((4-(Trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000113_0001
[0261] The titled compound was synthesized according to the procedure described in
Example 41 (75 mg, yield 49%). The mixture was purified by pre-HPLC (MeOH/H20 with 0.05% TFA as mobile phase; from 20% to 95%). 1H NMR (400 MHz, CDC13) δ 7.57 (d, J = 8.0 Hz, 2H), 7.42 (d, J= 8.0 Hz, 2H), 6.39 (s, 1H), 5.17 (s, 2H), 4.89-4.69 (m, 4H), 4.17 (bs, 2H), 3.92 (bs, 2H), 3.28 (bs, 1H), 2.03-1.64 (m, 10H); LCMS m/z 521.2 [M+H]+.
Example 46
9-(5-(((3-Chloro-5-fluorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000113_0002
[0262] The titled compound was synthesized according to the procedure described in
Example 41 (20 mg, yield 31%). The mixture was purified by pre-HPLC (MeOH/H20 with 0.05% TFA as mobile phase; from 20% to 95%). 1H NMR (400 MHz, CDC13) δ 7.15 (s, 1H), 7.07-7.05 (m, 1H), 6.99 (d, J= 8.8 Hz, 1H), 6.43 (s, 1H), 5.30 (s, 2H), 4.94-4.76 (m, 4H), 4.23 (t, J= 5.2 Hz, 2H), 3.99 (bs, 2H), 3.41-3.22 (m, 1H), 2.08-1.69 (m, 10H); LCMS m/z 505.2 [M+H]+.
Example 47
9-(5-(((3,5-Difluorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000113_0003
[0263] The titled compound was synthesized according to the procedure described in
Example 41 (46 mg, yield 43%). The mixture was purified by pre-HPLC (MeOH/H20 with 0.05% TFA as mobile phase; from 20% to 95%). 1H NMR (400 MHz, CDC13) δ 6.88-6.87 (m, 2H), 6.79-6.74 (m, 1H), 6.43 (s, 1H), 5.14 (s, 2H), 4.94-4.74 (m, 4H), 4.22 (t, J= 5.2 Hz, 2H), 3.98-3.96 (m, 2H), 3.24-3.21 (m, 1H), 2.07-1.68 (m, 10H); LCMS m/z 489.2 [M+H]+.
Example 48
9-(5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carbon ne-3-carboxylic acid
Figure imgf000114_0001
[0264] The titled compound was synthesized according to the procedure described in
Example 41 (12 mg, yield 19%). The mixture was purified by pre-HPLC (MeOH/H20 with 0.05% TFA as mobile phase; from 20% to 95%). 1H NMR (400 MHz, METHANOL-d4) δ 8.04 (s, 2H), 7.96 (s, 1H), 6.45 (s, 1H), 5.36 (s, 2H), 4.78-4.75 (m, 4H), 4.23 (t, J= 5.2 Hz, 2H), 4.03 (bs, 2H), 3.41-3.32 (m, 1H), 2.11-1.67 (m, 10H); LCMS m/z 589.2 [M+H]+.
Example 49
9-(5-((3,5-Dichlorobenzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-c ne-3-carboxylic acid
Figure imgf000114_0002
Step 1
9-(5-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000114_0003
[0265] To a solution of 5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4] diazepine-2-carboxylic acid (500 mg, 1.78 mmol) in DMF (8 mL) were added ethyl 9-azabicyclo[3.3.1]nonane-3-carboxylate hydrochloride (414 mg, 1.78 mmol), HATU (676 mg, 1.78 mmol) and DIPEA (918 mg, 7.12 mmol). The mixture was stirred at room temperature for 12 h. The mixture was purified by prep-HPLC (MeCN in water from 5% to 95%) to give 9-(5-(ieri-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid as a white solid (450 mg, yield 58%). 1H NMR (400 MHz, CDC13) δ 6.49 (s, 1H), 4.95-4.80 (m, 4H), 4.49-
4.40 (m, 2H), 3.77-3.63 (m, 2H), 3.41-3.28 (m, 1H), 1.98-1.94 (m, 9H), 1.79-1.69 (m, 3H),
1.41 (s, 9H); LCMS m/z 433.2 [M+H]+. Step 2
Ethyl 9-(5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2-carbonyl)-9-
Figure imgf000115_0001
[0266] To a solution of 9-(5-(iert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a][l,4]diazepine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid (210 mg, 0.49 mmol) in EtOH (5 mL) was added SOCl2 (230 mg, 1.90 mmol) dropwise at 0 °C. The reaction mixture was stirred at 80 °C for 2 h. After cooling down to rt, the mixture was basified to pH = 7 with NaHC03 (sat.), and was extracted with Ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give ethyl 9- (5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2-carbonyl)-9- azabicyclo[3.3.1]nonane-3-carboxylate as a yellow oil (138 mg, yield 79%). 1H NMR (400 MHz, CDC13) δ 6.42 (s, 1H), 4.96-4.88 (m, 2H), 4.40-4.37 (m, 2H), 3.92 (s, 2H), 3.31-3.22 (m, 1H), 3.22 (t, J = 5.2 Hz, 2H), 2.09-2.05 (m, 4H), 2.02-1.92 (m, 4H), 1.89-1.85 (m, 2H), 1.77-1.68 (m, 3H), 1.27-1.23 (m, 5H); LCMS m/z 361.7 [M+H]+.
Step 3
9-(5-((3,5-Dichlorobenzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000115_0002
[0267] To a solution of ethyl 9-(5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-
2-carbonyl) -9-azabicyclo[3.3.1]nonane-3-carboxylate (138 mg, 0.38 mmol) in
dichlormethane (3 mL) was added triphosgene (45 mg, 0.15 mmol) and Et3N (46 mg, 0.46 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 30 min. Then (3,5-dichlorophenyl)methanamine (80 mg, 0.46 mmol) and Et N (76 mg, 0.76 mmol) were added, and the mixture was stirred at room temperature for 12 h. The reaction mixture was purified by prep-TLC (DCM / MeOH = 10 / 1) to give ethyl 9-(5-((3,5- dichlorobenzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carbonyl)- 9-azabicyclo[3.3.1]nonane-3-carboxylate. To a mixture of above ester (100 mg, 0.18 mmol, 1.0 eq) in MeOH (5 mL) and H20 (5 mL) was added NaOH (29 mg, 0.72 mmol). The mixture was stirred at 60 °C for 2 h. The organic solvent was removed under reduced pressure. The resulting mixture was acidified to pH = 5 with HC1 (1 N). The precipitate was filtered, washed with water (5 mL) and dried to give the target compound 9-(5-((3,5- dichlorobenzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carbonyl)- 9-azabicyclo[3.3.1]nonane-3-carboxylic acid as a white solid (62 mg, yield 30%). 1H NMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 7.40 (s, 1H), 7.23 (t, J = 8 Hz, 1H), 7.17 (d, J = 1.6 Hz, 2H), 6.53 (s, 1H), 4.964-4.963 (m, 1H), 4.69-4.68 (m, 1H), 4.569 (s, 2H), 4.19 (d, J = 5.6 Hz, 2H), 4.42-4.44 (m, 2H), 3.73-3.65 (m, 2H), 3.25-3.18 (m, 1H), 1.96-1.75 (m, 11H), 1.57- 1.53 (m, 1H); LCMS m/z 533.1 [M+H]+.
Example 50
9-(5-(3-Chlorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2- carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000116_0001
[0268] The titled compound was synthesized according to the procedure described in
Example 49 (61 mg, yield 44%). 1H NMR (400 MHz, METHANOL-d4) δ 7.27-7.09 (m, 3H), 7.11 (d, J = 8 Hz, 1H), 6.58 (s, 1H), 4.83 (s, 2H), 4.63 (ABq, 2H), 4.49 (t, J = 4.8 Hz, 2H), 4.30 (s, 2H), 3.88-3.75 (m, 2H), 3.30-3.23 (m, 1H), 2.18-1.61 (m, 12H); LCMS m/z 500.2 [M+H]+.
Example 51
9-(5-(3-(Trifluoromethyl)benzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000116_0002
[0269] The titled compound was synthesized according to the procedure described in
Example 49 (48 mg, yield 32%). 1H NMR (400 MHz, METHANOL-d ) δ 7.53-7.43 (m, 4H), 6.58 (s, 1H), 4.82 (s, 2H), 4.63 (ABq, 2H), 4.49 (t, J = 4.8 Hz, 2H), 4.38 (s, 2H), 3.87-3.75 (m, 2H), 3.28-3.20 (m, 1H), 2.17-1.64 (m, 12H); LCMS m/z 534.2 [M+H]+.
Example 52
9-(5-(4-Chlorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2- carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000116_0003
[0270] The titled compound was synthesized according to the procedure described in
Example 49 (55 mg, yield 39%). 1H NMR (400 MHz, METHANOL-d ) δ 7.26 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 6.57 (s, 1H), 4.84-4.79 (m, 2H), 4.63 (Abq, 2H), 4.49 (t, J = 4.8 Hz, 2H), 4.34 (s, 2H), 3.87-3.74 (m, 2H), 3.29-3.22 (m, 1H), 2.18-1.67 (m, 12H); LCMS m/z 500.2 [M+H]+.
Example 53
9-(5-(4-(Trifluoromethyl)benzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-ca ne-3-carboxylic acid
Figure imgf000117_0001
[0271] The titled compound was synthesized according to the procedure described in
Example 49 (50 mg, yield 34%). 1H NMR (400 MHz, METHANOL-d4) δ 7.56 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 6.59 (s, 1H), 4.85 (s, 2H), 4.63 (ABq, 2H), 4.50 (t, J = 4.8 Hz, 2H), 4.40 (s, 2H), 3.88-3.76 (m, 2H), 3.36-3.27 (m, 1H), 2.16-1.65 (m, 12H); LCMS m/z 534.2 [M+H]+.
Example 54
9-(5-(3-Chloro-5-fluorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000117_0002
[0272] The titled compound was synthesized according to the procedure described in
Example 49 (26 mg, yield 18%). 1H NMR (400 MHz, DMSO-d6) δ 12.1 (s, 1H), 7.22 (d, J = 6 Hz, 2H), 7.05 (s, 1H), 7.36 (d, J = 9.6 Hz, 1H), 6.53 (s, 1H), 4.94 (s, 1H), 4.74 (s, 1H), 4.69 (s, 2H), 4.42 (t, J = 4 Hz, 2H), 4.20 (s, J = 5.6 Hz, 2H), 3.70 (s, 2H), 3.18-3.26 (m, 1H), 1.99- 1.54 (m, 12H); LCMS m/z 518.2 [M+H]+.
Example 55
9-(5-(3,5-Difluorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000117_0003
[0273] The titled compound was synthesized according to the procedure described in
Example 49 (42 mg, yield 30%). 1H NMR (400 MHz, METHANOL-d4) δ 6.80-6.72 (m, 3H), 6.59 (s, 1H), 4.84 (br. s, 2H), 4.68 (s, 2H), 4.50 (t, J = 5.2 Hz, 2H), 4.31 (s, 2H), 3.87-3.78 (m, 2H), 3.40-3.34 (m, 1H), 2.17-1.66 (m, 12H); LCMS m/z 502.2 [M+H]+. Example 56
9-(5-((3,5-Dichlorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4 c acid
Figure imgf000118_0001
[0274] To a solution of (3,5-dichlorophenyl)methanol (138 mg, 0.76 mmol) in DMF
(2 mL) was added CDI (124 mg, 0.76 mmol). The reaction mixture was stirred at room temperature for 2 h. Ethyl 9-(5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate (138 mg, 0.38 mmol) was added, and the mixture was stirred at room temperature for 12 h. The reaction mixture was purified by prep- HPLC (MeCN in water from 5% to 95%) to give 3,5-dichlorobenzyl 2-(3-(ethoxycarbonyl)- 9-azabicyclo[3.3.1]nonane-9-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)- carboxylate. To a mixture of above ester in THF (5 mL) and H20 (5 mL) was added LiOH (36mg, 1.52 mmol). The mixture was stirred at room temperature for 12 h. The organic solvent was removed under reduced pressure. The resulting mixture was acidified to pH = 5 with HC1 (I N). The mixture was extracted with EA (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo to give 9-(5-((3,5-dichlorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid as a yellow oil (50 mg, yield 24%). 1H NMR (400 MHz, METHANOL-d4) δ 7.37 (s, 1H), 7.30-7.27 (m, 2H), 6.53-6.52 (m, 1H), 5.09-5.07 (m, 2H), 4.83-4.78 (m, 2H), 4.67-4.62 (m, 2H), 4.50-4.48 (m, 2H), 3.91-3.78 (m, 2H), 3.29-3.25 (m, 1H), 2.15-1.65 (m, 12H); LCMS m/z 535.1
[M+H]+.
Example 57
9-(5-((3-Chlorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine acid
Figure imgf000118_0002
[0275] The titled compound was synthesized according to the procedure described in
Example 56 (73 mg, yield 38%). 1H NMR (400 MHz, METHANOL-d ) δ 7.35-7.29 (m, 3H), 7.25 (t, J = 5.6 Hz, 1H), 6.53 (s, 0.44H), 6.47 (s, 0.56H), 5.08 (s, 2H), 4.82-4.81 (m, 2H), 4.64-4.61 (m, 2H), 4.49 (t, J = 4.8 Hz, 2H), 3.85-3.81 (m, 2H), 3.28-3.22 (m, 1H), 2.17-2.09 (m, 1H), 2.04-1.90 (m, 8H), 1.86-1.64 (m, 3H); LCMS m/z 501.2 [M+H]+. Example 58
9-(5-((3-(Trifluoromethyl)benzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carb nane-3-carboxylic acid
Figure imgf000119_0001
[0276] The titled compound was synthesized according to the procedure described in
Example 56 (47 mg, yield 23%). 1H NMR (400 MHz, METHANOL-d4) δ 7.63-7.53 (m, 4H), 6.54 (s, 0.45H), 6.47 (s, 0.55H), 5.18 (s, 2H), 4.83-4.78 (m, 2H), 4.65-4.62 (m, 2H), 4.50 (t, J = 4.8 Hz, 2H), 3.87-3.83 (m, 2H), 3.35-3.26 (m, IH), 2.16-1.65 (m, 12H); LCMS m/z 535.2 [M+H]+.
Example 59
9-(5-((4-Chlorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine acid
Figure imgf000119_0002
[0277] The titled compound was synthesized according to the procedure described in
Example 56 (42 mg, yield 22%). 1H NMR (400 MHz, METHANOL-d ) δ 7.36-7.28 (m, 4H), 6.54 (s, 0.44H), 6.45 (s, 0.56H), 5.07 (s, 2H), 4.86-4.85 (m, 2H), 4.62-4.61 (m, 2H), 4.49 (t, J = 4.8 Hz, 2H), 3.83-3.82 (m, 2H), 3.40-3.34 (m, IH), 2.14-1.67 (m, 12H); LCMS m/z 501.1 [M+H]+.
Example 60
9-(5-((4-(Trifluoromethyl)benzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carb nane-3-carboxylic acid
Figure imgf000119_0003
[0278] The titled compound was synthesized according to the procedure described in
Example 56 (98 mg, yield 48%). 1H NMR (400 MHz, METHANOL-d ) δ 7.54 (d, J = 8 Hz, 2H), 7.39 (t, J = 9.6 Hz, 2H), 6.43-6.40 (m, IH), 5.07 (s, 2H), 4.80-4.79 (m, 2H), 4.56-4.51 (m, 2H), 4.39 (t, J = 4.8 Hz, 2H), 3.77-3.71 (m, 2H), 3.31-3.23 (m, IH), 2.01-1.67 (m, 12H); LCMS m/z 535.2 [M+H]+. Example 61
9-(5-((3-Chloro-5-fluorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000120_0001
[0279] The titled compound was synthesized according to the procedure described in
Example 56 (101 mg, yield 51%). 1H NMR (400 MHz, METHANOL-d4) δ 7.09-7.12 (m, 2H), 6.96-6.89 (m, IH), 6.44-6.41 (m, IH), 5.00 (s, 2H), 4.84 (s, 2H), 4.57-4.50 (m, 2H), 4.40-4.38 (m, 2H), 3.78-3.72 (m, 2H), 3.32-3.24 (m, IH), 2.00-1.59 (m, 12H); LCMS m/z 519.2 [M+H]+.
Example 62
9-(5-((3,5-Trifluorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000120_0002
[0280] The titled compound was synthesized according to the procedure described in
Example 56 (96 mg, yield 50%). 1H NMR (400 MHz, METHANOL-d4) δ 6.83-6.71 (m, 3H), 6.45-6.41 (m, IH), 4.99 (s, 2H), 4.82 (s, 2H), 4.56 (s, IH), 4.51(s, IH), 4.38 (t, J = 4.8 Hz, 2H), 3.77-3.71 (m, 2H), 3.31-3.23 (m, IH), 2.00-1.55 (m, 12H); LCMS m/z 502.2, 503.2 [M+H]+.
Example 63
9-(5-((3,5-Bis(trifluoromethyl)benzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000120_0003
[0281] The titled compound was synthesized according to the procedure described in
Example 56 (118 mg, yield 51%). 1H NMR (400 MHz, METHANOL-d ) δ 7.84-7.81 (m, 3H), 6.44-6.40 (m, IH), 5.16-5.15 (m, 2H), 4.84 (s, 2H), 4.57-4.51 (m, 2H), 4.40-4.38 (m, 2H), 3.79-3.72 (m, 2H), 3.31-3.23 (m, IH), 2.01-1.76 (m, 9H), 1.72-1.55 (m, 3H); LCMS m/z 603.2 [M+H]+. Example 64
5-(((3-Fluoro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a] [l,4]diazepine-2-carboxylic acid
Figure imgf000121_0001
[0282] To a solution of (3-fluoro-5-(trifluoromethyl)phenyl)methanol (178 mg, 0.92 mmol) in DMF (2 mL), CDI (198 mg, 0.92 mmol) was added. The mixture was stirred at room temperature for 2 h. Ethyl 5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2- carboxylate hydrochloride (150 mg, 0.61 mmol) was added, and the resulted mixture was stirred at room temperature for 12 h. The resulting solution was diluted with ethyl acetate (30 ml) and washed with H20 (20 ml x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by pre-TLC (MeOH / DCM = 1 / 20) to give 2-ethyl 5-(3-fluoro-5-(trifluoromethyl)benzyl) 7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-2,5(6H)-dicarboxylate. To a solution of above ester in THF (10 mL) and H20 (5 mL) was added NaOH (50 mg, 1.2 mmol). The reaction mixture was stirred at room temperature for 12 h. After removed THF under reduced pressure, the resulting solution was adjusted to pH = 4-5 with aqueous HCI (I N) solution and extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacyi to give 5-(((3-fluoro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8- tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2-carboxylic acid as a white solid (74 mg, yield
30%). 1H NMR (400 MHz, CDC13) δ 7.37-7.35 (m, 1H), 7.29-7.24 (m, 1H), 7.21-7.17 (m, 1H), 6.86-6.72 (m, 1H), 5.15 (s, 2H), 4.59-4.56 (m, 4H), 3.90-3.79 (m, 2H), 2.06-1.94 (m, 2H); LCMS m/z 402.0 [M+H]+.
Example 65
5-(((3-Chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5- rboxylic acid
Figure imgf000121_0002
[0283] Using ethyl 5,6,7, 8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2- carboxylate and (3-chloro-5-(trifluoromethyl)phenyl)methanol as starting material, following the procedure described in Example 64 (81 mg, yield 31%). 1H NMR (400 MHz, CDC13) δ 7.83-7.58 (m, 3H), 6.58 (s, 1H), 5.15 (s, 2H), 4.65-4.49 (m, 4H), 3.78-3.72 (m, 2H), 1.80- 1.78 (m, 2H); LCMS m/z 418.0 [M+H]+. Example 66
5-(((4-Fluoro-3-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a] [l,4]diazepine-2-carboxylic acid
F3C
N-N
o o
[0284] The titled compound was synthesized according to the procedure described in
Example 64 (69 mg, yield 23%). 1H NMR (400 MHz, CDC13) δ 7.57-7.48 (m, 2H), 7.22-7.17 (m, IH), 6.85-6.68 (m, IH), 5.10 (s, 2H), 4.58-4.54 (m, 4H), 3.87-3.77 (m, 2H), 2.05-1.93 (m, 2H); LCMS m/z 402.0 [M+H]+.
Example 67
5-(((3-(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4] diazepine-2-carboxylic acid
[0285] The titled compound was synthesized according to the procedure described in
Example 64 (58 mg, yield 24%). 1H NMR (400 MHz, DMSO-d6) δ 7.69-7.60 (m, 4H), 6.36 (s, IH), 5.14 (s, 2H), 4.58-4.51 (m, 2H), 4.42-4.41 (m, 2H), 3.75-3.71 (m, 2H), 1.85-1.72 (m, 2H); LCMS m/z 384.1 [M+H]+.
Example 68
5-(((3-Chloro-5-fluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4] diazepine-2-carboxylic acid
Figure imgf000122_0001
[0286] The titled compound was synthesized according to the procedure described in
Example 64 (124 mg, yield 55%). 1H NMR (400 MHz, CDC13) δ 7.09-7.03 (m, 2H), 6.93- 6.87 (m, IH), 6.85-6.73 (m, IH), 5.06 (s, 2H), 4.58-4.54 (m, 4H), 3.84-3.82 (m, 2H), 2.00 (m, 2H); LCMS m/z 368.0 [M+H]+.
Example 69
5-(((3,5-Difluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4] c acid
Figure imgf000122_0002
[0287] The titled compound was synthesized according to the procedure described in
Example 64 (93 mg, yield 44%). 1H NMR (400 MHz, DMSO-d6) δ 7.19-7.00 (m, 3H), 6.42 (s, IH), 5.06-5.05 (m, 2H), 4.61-4.43 (m, 4H), 3.77-3.71 (m, 2H), 1.79 (m, 2H); LCMS m/z 352.1 [M+H]+. Example 70
5-(((3,4,5-Trifluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-
Figure imgf000123_0001
[0288] The titled compound was synthesized according to the procedure described in
Example 64 (103 mg, yield 45%). 1H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1 H), 7.34- 7.20 (m, 2H), 6.60-6.56 (m, IH), 5.03-5.00 (m, 2H), 4.63-4.47 (m, 4H), 3.77-3.71 (m, 2H), 1.84-1.79 (m, 2H); LCMS m/z 370.1 [M+H]+.
Example 71
5-(((3-Fluoro-4-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- acid
Figure imgf000123_0002
[0289] The titled compound was synthesized according to the procedure described in
Example 64 (130 mg, yield 53%). 1H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1 H), 7.79- 7.72 (m, IH), 7.48-7.31 (m, 2H), 6.62-6.61 (m, IH), 5.16-5.14 (m, 2H), 4.66-4.48 (m, 4H), 3.80-3.73 (m, 2H), 1.87-1.81 (m, 2H); LCMS m/z 402.1 [M+H]+.
Example 72
5-(((2-Fluoro-4-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a] [l,4]diazepine-2-carboxylic acid
[0290] The titled compound was synthesized according to the procedure described in
Example 64 (78 mg, yield 31%). 1H NMR (400 MHz, DMSO-d6) δ 7.72-7.56 (m, 3H), 6.57- 6.51 (m, IH), 5.17 (s, 2H), 4.60-4.46 (m, 4H), 3.75-3.72 (m, 2H), 1.81 (m, 2H); LCMS m/z 402.1 [M+H]+.
Example 73
5-(((4-(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4] diazepine-2-carboxylic acid
[0291] The titled compound was synthesized according to the procedure described in
Example 64 (78 mg, yield 33%). 1H NMR (400 MHz, CDC13) δ 7.63-7.61 (m, 2H), 7.44-7.40 (m, 2H), 6.85-6.70 (m, IH), 5.16 (s, 2H), 4.59-4.55 (m, 4H), 3.84-3.82 (m, 2H), 2.05-1.93 (m, 2H); LCMS m/z 384.1 [M+H]+. Example 74
5-((3,5-Dichlorophenethoxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4] diazepine-2-carboxylic acid
Figure imgf000124_0001
[0292] The titled compound was synthesized according to the procedure described in
Example 64 (56 mg, yield 28%). 1H NMR (400 MHz, DMSO-d6) δ 7.28 (s, IH), 7.19 (s, 2H), 6.61-6.48 (m, IH), 4.53-4.45 (m, 4H), 4.28-4.22 (m, 2H), 3.74 (bs, 2H), 2.95-2.90 (m, 2H), 1.87-1.89 (m, 2H); LCMS m/z 398.1 [M+H]+.
Example 75
5-(((3-Bromo-5-fluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4 acid
Figure imgf000124_0002
[0293] The titled compound was synthesized according to the procedure described in
Example 64 (30 mg, yield 53%). 1H NMR (400 MHz, CDC13) δ 7.25-7.19 (m, 2H), 6.98-6.92 (m, IH), 6.85-6.74 (m, IH), 5.25 (s, 2H), 4.57 (bs, 4H), 3.83 (s, 2H), 2.02 (bs, 2H); LCMS m/z 412.0, 414.0 [M+H]+.
Example 76
5-(((3-Fluoro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- -a] [l,4]diazepine-2-carboxylic acid
Figure imgf000124_0003
[0294] To a solution of ethyl 5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2- carboxylate hydrochloride (150 mg, 0.61 mmol) in dichloromethane (5 mL) was added triphosgene (71 mg, 0.24 mmol) and Et3N (74 mg, 0.73 mmol). After stirred at room temperature for 30 min, (3,5-bis(trifluoromethyl)phenyl)methanamine (224 mg, 0.92 mmol) and Et N (123 mg, 1.22 mmol, 2.0 eq) were added. The reaction mixture was stirred at room temperature for 12 h. After removed solvents under reduced pressure, the residue was purified by pre-TLC (MeOH / DCM = 1 / 20) to ethyl 5-((3,5- bis(trifluoromethyl)benzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine- 2-carboxylate. To a solution of above ester in THF (10 mL) and H20 (5 mL) was added NaOH (50 mg, 1.2 mmol). The mixture was stirred at room temperature for 12 h. After removed THF under reduced pressure, the resulting solution was adjusted to pH = 4-5 with aqueous HC1 (I N) solution and extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give 5- (((3-fluoro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carboxylic acid as a white solid (109 mg, yield 39%). 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, IH), 7.91 (s, IH), 7.78 (s, IH), 7.37-7.34 (m, IH), 6.65 (s, IH), 4.58 (s, 2H), 4.48-4.46 (m, 2H), 4.37-4.35 (m, 2H), 3.70 (m, 2H), 1.76 (m, 2H); LCMS m/z 451.1 [M+H]+.
Example 77
5-((3,5-Dichlorobenzyl)carbamoy H-pyrazolo[l,5-a][l,4]diazepine-
2-carboxylic acid
Figure imgf000125_0001
[0295] The titled compound was synthesized according to the procedure described in
Example 76 (84 mg, yield 36%). 1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, IH), 7.43-7.41 (m, IH), 7.31-7.24 (m, 2H), 6.98 (s, IH), 6.68 (s, IH), 4.61 (s, 2H), 4.50-4.47 (m, 2H), 4.25- 4.23 (m, 2H), 3.77 (m, 2H), 1.78 (m, 2H); LCMS m/z 383.0 [M+H]+.
Example 78
5-(7-Chloro-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5 oxylic acid
Figure imgf000125_0002
[0296] The titled compound was synthesized according to the procedure described in
Example 76 (50 mg, yield 32%). 1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, IH), 7.28-7.17 (m, 3H), 6.61 (s, IH), 4.44 (s, 4H), 4.32 (s, 2H), 3.58-3.55 (m, 2H), 3.36 (t, J = 5.6 Hz, 2H), 2.83 (t, J = 5.6 Hz, 2H), 1.95 (bs, 2H); LCMS m/z 376.1 [M+H]+.
Example 79
5-(7-(Trifluoromethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8-tetrahydro- 4H-pyrazolo[l rboxylic acid
Figure imgf000125_0003
[0297] The titled compound was synthesized according to the procedure described in
Example 76 (50 mg, yield 32%). 1H NMR (400 MHz, DMSO-d6) δ 7.46-7.43 (m, 2H), 7.35 (d, J = 7.8 Hz, IH), 6.67 (s, IH), 4.51-4.49 (m, 6H), 3.68 (bs, 2H), 3.52 (t, J = 6.0 Hz, 2H), 2.99 (bs, 2H), 2.04 (bs, 2H); LCMS m/z 409.1 [M+H]+. Example 80
5-(5-(Trifluoromethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8-tetrahydro- 4H-pyrazolo[l,5-a][l,4]diazepine-2-carboxylic acid
0
[0298] The titled compound was synthesized according to the procedure described in
Example 76 (40 mg, yield 23%). 1H NMR (400 MHz, DMSO-d6) δ 7.53 (d, J = 7.2 Hz, 1H), 7.30-7.22 (m, 2H), 6.77 (s, 1H), 4.53-4.50 (m, 2H), 4.46 (s, 4H), 3.70-3.65 (m, 2H), 3.51 (t, J = 6.0 Hz, 2H), 3.08 (t, J = 6.0 Hz, 2H), 2.11 (bs, 2H); LCMS m/z 409.1 [M+H]+.
Example 81
5-(5-Chloro-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5- rboxylic acid
Figure imgf000126_0001
[0299] The titled compound was synthesized according to the procedure described in
Example 76 (8 mg, yield 5%). 1H NMR (400 MHz, DMSO-d6) δ 7.24 (d, J = 7.6 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.48 (s, 4H), 4.41 (s, 2H), 3.69 (t, J = 5.2 Hz, 2H), 3.53 (t, J = 6.0 Hz, 2H), 2.93 (t, J = 6.0 Hz, 2H), 2.08 (bs, 2H); LCMS m/z 75.1 [M+H]+.
Example 82
5-(3-(3,5-bis(Trifluoromethyl)phenyl)propanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- -2-carboxylic acid
Figure imgf000126_0002
[0300] To a mixture of ethyl 5,6,7, 8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2- carboxylate hydrochloride (150 mg, 0.61 mmol) and 3-(3,5- bis(trifluoromethyl)phenyl)propanoic acid (263 mg, 0.92 mmol) in dichloromethane (10 mL), DIPEA(197 mg, 1.53 mmol) and HATU (350 mg, 0.92 mmol) were added. The mixture was stirred at room temperature for 12 h. After removed solvents under reduced pressure, the residue was purified by pre-TLC (MeOH / DCM = 1 / 20) to give ethyl 5-(3-(3,5- bis(trifluoromethyl)phenyl) propanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine- 2-carboxylate. To a solution of above ester in THF (10 mL) and H20 (5 mL) was added NaOH (50 mg, 1.2 mmol). The mixture was stirred at room temperature for 12 h. After removed THF under reduced pressure, the resulting solution was adjusted to pH = 4-5 with aqueous HC1 (I N) solution and extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give 5- (3-(3,5-bis(trifluoromethyl)phenyl)propanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carboxylic acid as a white solid (111 mg, yield 40%). 1H NMR (400 MHz, CDC13) δ 7.74-7.64 (m, 3H), 6.80-6.71 (m, 1H), 4.66-4.54 (m, 4H), 3.91-3.78 (m, 2H), 3.12-3.07 (m, 2H), 2.79-2.67 (m, 2H), 2.00 (m, 2H); LCMS m/z 450.1 [M+H]+.
Example 83
5-(3-(3,5-Dichlorophenyl)propanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4] c acid
Figure imgf000127_0001
[0301] The titled compound was synthesized according to the procedure described in
Example 82 (68 mg, yield 29%). 1H NMR (400 MHz, DMSO-d6) δ 7.38-7.30 (m, 3H), 6.49- 6.36 (m, 1H), 4.66-4.56 (m, 2H), 4.43-4.35 (m, 2H), 3.80-3.71 (m, 2H), 2.79-2.64 (m, 4H), 1.84-1.73 (m, 2H); LCMS m/z 382.0 [M+H]+.
Example 84
3-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [l,4]diazepine-2-carboxamido)propanoic acid
Figure imgf000127_0002
Step 1
3,5-Dichlorobenzyl 2-((3-ethoxy-3-oxopropyl)carbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000127_0003
[0302] The titled compound was synthesized according to the procedure described in
Example 12 (70 mg, yield 62%). LCMS m/z 483.1 [M+H]+.
Step 2
3-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [l,4]diazepine-2-carboxamido)propanoic acid
Figure imgf000127_0004
[0303] To a solution of above ester (70 mg, 0.14 mmol) in THF (2 mL) was added sodium hydroxide (12 mg, 0.29 mmol) and H20 (0.5 mL). The reaction mixture was stirred at rt for 15 h, and was adjusted to pH = 5 with HC1 (I N). The resulted solution was purified by prep-HPLC (MeCN/H20 with 10 mM NH4HCO3 as mobile phase; from 5% to 95%) to afford 3-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carboxamido)propanoic acid as a white solid (35 mg, yield 53%) as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.39-7.17 (m, 3H), 6.66-6.63 (m, IH), 5.10- 5.07 (m, 2H), 4.66-4.60 (m, 2H), 4.52-4.50 (m, 2H), 3.87-3.81 (m, 2H), 3.60 (t, J= 6.8 Hz, 2H), 2.60 (t, J= 6.8 Hz, 2H), 1.92-1.91 (m, 2H); LCMS m/z 455.1 [M+H]+.
Example 85
(ds)-4-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [l,4]diazepine-2-carboxamido)cyclohexanecarboxylic acid
CI o
[0304] The titled compound was synthesized according to the procedure described in
Example 84 (73 mg, yield 62% over two steps). 1H NMR (400 MHz, DMSO-d6) δ 7.38-7.16 (m, 3H), 6.67-6.65 (m, IH), 5.11-5.07 (m, 2H), 4.66-4.60 (m, 2H), 4.53-4.50 (m, 2H), 3.98 (bs, IH), 3.87-3.82 (m, 2H), 2.52 (m, IH), 2.06-1.97 (m, 2H), 1.92 (bs, 2H), 1.78-1.64 (m, 6H); LCMS m/z 509.1 [M+H]+.
Example 86
(trans)-4-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [l,4]diazepine-2-carboxamido)cyclohexanecarboxylic acid
Figure imgf000128_0001
[0305] The titled compound was synthesized according to the procedure described in
Example 84 (44 mg, yield 37% over two steps). 1H NMR (400 MHz, DMSO-d6) δ 7.39-7.34 (m, IH), 7.29 (s, IH), 7.17 (s, IH), 6.67-6.65 (m, IH), 5.11-5.08 (m, 2H), 4.67-4.61 (m, 2H), 4.52 (t, J = 5.2 Hz, 2H), 3.87-3.81 (m, 3H), 2.27-2.23 (m, IH), 2.07-2.01 (m, 4H), 1.92 (bs, 2H), 1.58-1.55 (m, 2H), 1.42-1.40 (m, 2H); LCMS m/z 509.1 [M+H]+.
Example 87
l-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [l,4]diazepine-2-carbonyl)piperidine-4-carboxylic acid
Figure imgf000128_0002
[0306] The titled compound was synthesized according to the procedure described in
Example 84 (40 mg, yield 34% over two steps). 1H NMR (400 MHz, DMSO-d6) δ 7.39-7.37 (m, IH), 7.31-7.26 (m, 2H), 6.64-6.52 (m, IH), 5.10-5.08 (m, 2H), 4.67-4.44 (m, 6H), 3.88- 3.83 (m, 2H), 3.32-3.31 (m, IH), 3.06-3.00 (m, IH), 2.68-1.60 (m, IH), 2.03-1.93 (m, 4H), 1.73-1.64 (m, 2H); LCMS m/z 495.1 [M+H]+.
Example 88
l-(5-(((3,5-dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-
Figure imgf000129_0001
[0307] The titled compound was synthesized according to the procedure described in
Example 84 (55 mg, yield 42% over two steps). 1H NMR (400 MHz, DMSO-d6) δ 7.37-7.26 (m, 3H), 6.54-6.53 (m, IH), 5.09-5.07 (m, 2H), 4.67-4.62 (m, 3H), 4.52-4.49 (m, 3H), 3.88- 3.82 (m, 2H), 3.29-3.28 (m, IH), 3.15-3.13 (m, IH), 2.55-2.53 (m, IH), 2.15-2.12 (m, IH), 1.80-1.74 (m, 4H), 1.58-1.55 (m, IH); LCMS m/z 495.1 [M+H]+.
Example 89
9-(5,6,7,8-Tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2-carbonyl)-9-
Figure imgf000129_0002
[0308] To 9-(5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid (11 mg, 0.025 mmol) was added a solution of TFA (0.1 mL) in dichloromethane (1 mL). The reaction mixture was stirred at rt for lh. It was concentrated to get 9-(5,6,7,8-Tetrahydro-4H- pyrazolo[l,5-a][l,4]diazepine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
TFA salt as a white solid. (14 mg, yield 100%). 1H NMR (300 MHz, METHANOL-d4) δ 6.77 (s, IH), 4.86 - 4.94 (m, 2H), 4.56 - 4.64 (m, 2H), 4.54 (s, 2H), 3.53 - 3.64 (m, 2H), 3.36 - 3.47 (m, IH), 1.24 - 2.26 (m, 12H); LCMS m/z 333.1 [M+H]+.
Example 90
9-(5-(3-(3,5-Dichlorophenyl)propanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000129_0003
[0309] The titled compound was synthesized according to the procedure described in
Example 82 (26 mg, yield 70% over two steps). 1H NMR (400 MHz, METHANOL-d ) δ 7.01 - 7.16 (m, 3H), 6.42 - 6.51 (m, IH), 4.86 -4.92 (m, 2H), 4.63, 4.59 (s, s, 2H), 4.31 - 4.41 (m, 2H), 3.70 - 3.82 (m, 2H), 3.24 - 3.33 (m, 1H), 2.73 - 2.82 (m, 2H), 2.58 - 2.71 (m, 2H), 1.50 - 2.13 (m, 12H); LCMS m/z 532.9.2 [M+H]+.
Example 91
5-(3-(3,5-Dichlorophenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carboxylic acid
Figure imgf000130_0001
[0310] The titled compound was synthesized according to the procedure described in
Example 82 (98 mg, yield 89% over two steps). 1H NMR (300 MHz, METHANOL-d4) δ 7.08 - 7.35 (m, 3H), 6.52 - 6.71 (m, 1H), 4.83, 4.79 (s, s, 2H), 3.94 - 4.29 (m, 4H), 2.73 - 3.04 (m, 4H); LCMS m/z 368.0 [M+H]+.
Example 92
9-(5-(3-(3,5-Dichlorophenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000130_0002
[0311] The titled compound was synthesized according to the procedure described in
Example 84 (33 mg, yield 79%, two steps). 1H NMR (400 MHz, METHANOL-d4) δ 6.99 - 7.22 (m, 3H), 6.21 - 6.38 (m, 1H), 4.78 - 4.87 (m, 2H), 4.72, 4.66 (s, s, 2H), 3.83 - 4.14 (m, 4H), 3.26 - 3.34 (m, 1H), 2.59 - 2.92 (m, 4H), 1.49 - 2.10 (m, 10H); LCMS m/z 519.2
[M+H]+.
Example 93
8-(5-(3-(3,5-Dichlorophenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid
Figure imgf000130_0003
[0312] The titled compound was synthesized according to the procedure described in
Example 84 (20 mg, yield 79% over two steps). 1H NMR (400 MHz, METHANOL-d ) δ 7.05 - 7.31 (m, 3H), 6.44 - 6.61 (m, 1H), 5.14 - 5.43 (m, 1H), 4.81, 4.76 (s, s, 2H), 4.41 - 4.67 (m, 1H), 3.91 - 4.26 (m, 4H), 3.26 - 3.36 (m, 1H), 2.75 - 2.99 (m, 4H), 1.62 - 2.18 (m, 8H); LCMS m/z 504.9 [M+H]+. Example 94
l-(2-(9-Azabicyclo[3.3.1]nonane-9-carbonyl)-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)- yl) -3- (3,5-dichlorophenyl)propan- 1 -one
Figure imgf000131_0001
[0313] The titled compound was synthesized according to the procedure described in
Example 12 (18 mg, yield 77%). 1H NMR (400 MHz, METHANOL-d4) δ 7.05 - 7.36 (m, 3H), 6.27 - 6.44 (m, 1H), 4.53 - 4.82 (m, 4H), 3.89 - 4.24 (m, 4H), 2.69 - 3.06 (m, 4H), 1.53 - 2.29 (m, 12H); LCMS m/z 475.0 [M+H]+.
Example 95
3,5-Dichlorobenzyl 2-(3-(methoxycarbonyl)-9-azabicyclo[3.3.1]nonane-9-carbonyl)-7,8- dihydro-4H-py H)-carboxylate
Figure imgf000131_0002
[0314] The titled compound was synthesized according to the procedure described in
Example 1 (14 mg, yield 17%). 1H NMR (400 MHz, METHANOL-d ) δ 7.19 - 7.47 (m, 3H), 6.45 - 6.58 (m, 1H), 5.03 - 5.13 (m, 2H), 4.75 - 4.95 (m, 2H), 4.55 - 4.71 (m, 2H), 4.42 - 4.52 (m, 2H), 3.76 - 3.93 (m, 2H), 3.67 (s, 3H), 3.35 - 3.49 (m, 1H), 1.59 - 2.21 (m, 12H); LCMS m/z 549.0 [M+H]+.
Example 96
3-(3,5-Dichlorophenyl)-l-(2-(morpholine-4-carbonyl)-6,7-dihydropyrazolo[l,5- a]pyrazin-5(4H)-yl)propan-l-one
Figure imgf000131_0003
[0315] The titled compound was synthesized according to the procedure described in
Example 12 (12 mg, yield 92%). 1H NMR (400 MHz, METHANOL-d4) δ 7.09 - 7.33 (m, 3H), 6.38 - 6.52 (m, 1H), 4.81, 4.76 (s, s, 2H), 3.91 - 4.22 (m, 6H), 3.57 - 3.81 (m, 6H), 2.73 - 3.00 (m, 4H); LCMS m/z 436.9 [M+H]+.
Example 97
8-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid
Figure imgf000131_0004
[0316] The titled compound was synthesized according to the procedure described in
Example 84 (22 mg, yield 57%). 1H NMR (400 MHz, METHANOL-d4) δ 7.14 - 7.44 (m, 3H), 6.56 - 6.69 (m, 1H), 5.22 - 5.41 (m, 1H), 5.02 - 5.13 (m, 2H), 4.79 - 4.82 (m, 1H), 4.58 - 4.72 (m, 2H), 4.40 - 4.54 (m, 2H), 3.73 - 3.97 (m, 2H), 2.88 - 3.06 (m, 1H), 1.74 - 2.09 (m, 10H); LCMS m/z 520.9 [M+H]+.
Example 98
2-(3,5-Dichlorobenzyl) 7-ethyl 3,4-dihydropyrrolo[l,2-a]pyrazine-2,7(lH)-dicarboxylate
Figure imgf000132_0001
[0317] The titled compound was synthesized according to the procedure described in
Example 1 (195 mg, yield 49%). 1H NMR (400 MHz, METHANOL-d ) δ 7.24 - 7.45 (m, 3H), 6.32 (s, 1H), 5.15 (s, 2H), 4.51 - 4.74 (m, 2H), 4.22 (q, J = 7.03 Hz, 2H), 3.98 - 4.10 (m, 2H), 3.86 (br. s., 2H), 1.30 (t, J = 7.03 Hz, 3H); LCMS m/z 396.9 [M+H]+.
Example 99
2-(3,5-Dichlorobenzyl) 8-ethyl 4,5-dihydro-lH-pyrrolo[l,2-a][l,4]diazepine-2,8(3H)-
Figure imgf000132_0002
[0318] The titled compound was synthesized according to the procedure described in
Example 1 (315 mg, yield 77%). 1H NMR (400 MHz, METHANOL-d ) δ 7.09 - 7.43 (m, 3H), 6.32 - 6.49 (m, 1H), 4.99 - 5.15 (m, 2H), 4.39 - 4.57 (m, 2H), 4.10 - 4.27 (m, 4H), 3.68 - 3.72 (m, 2H), 1.78 - 1.90 (m, 2H), 1.30 (t, J = 7.15 Hz, 3H); LCMS m/z 410.9 [M+H]+.
Example 100
2-(((3,5-Dichlorobenzyl)oxy)carbonyl)-2,3,4,5-tetrahydro-lH-pyrrolo[l,2- a] [ 1 ,4 c acid
Figure imgf000132_0003
[0319] The titled compound was synthesized according to the procedure described in
Example 7 (28 mg, yield 34%). 1H NMR (400 MHz, DMSO-d6) δ 7.23 - 7.60 (m, 4H), 6.21 - 6.32 (m, 1H), 4.96 - 5.13 (m, 2H), 4.33 - 4.55 (m, 2H), 4.15 - 4.21 (m, 2H), 3.57 - 3.76 (m, 2H), 1.66 - 1.79 (m, 2H); LCMS m/z 382.9 [M+H]+. Example 101
3,5-Dichlorobenzyl 2-(4-hydroxypiperidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000133_0001
[0320] The titled compound was synthesized according to the procedure described in
Example 12 (46 mg, yield 100%). 1H NMR (400 MHz, METHANOL-d4) δ 7.18 - 7.43 (m, 3H), 6.44 - 6.58 (m, 1H), 5.02 - 5.14 (m, 2H), 4.57 - 4.70 (m, 2H), 4.43 - 4.53 (m, 2H), 4.04 - 4.41 (m, 4H), 3.74 - 3.95 (m, 3H), 3.43 - 3.63 (m, 1H), 1.77 - 2.00 (m, 4H), 1.45 - 1.58 (m, 2H); LCMS m/z 466.9 [M+H]+.
Example 102
3,5-Dichlorobenzyl 2-carbamoyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)- carboxylate
Figure imgf000133_0002
[0321] The titled compound was synthesized according to the procedure described in
Example 12 (41 mg, yield 100%). 1H NMR (400 MHz, METHANOL-d4) δ 7.10 - 7.45 (m, 3H), 6.53 - 6.72 (m, 1H), 5.00 - 5.14 (m, 2H), 4.57 - 4.73 (m, 2H), 4.41 - 4.54 (m, 2H), 3.62 - 3.93 (m, 2H), 1.78 - 2.01 (m, 2H); LCMS m/z 382.9 [M+H]+.
Example 103
9-(2-(((3,5-dichlorobenzyl)oxy)carbonyl)-2,3,4,5-tetrahydro-lH-pyrrolo[l,2- a][l,4]diazepine-8-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid
Figure imgf000133_0003
[0322] The titled compound was synthesized according to the procedure described in
Example 84 (17 mg, yield 72%). 1H NMR (400 MHz, METHANOL-d ) δ 7.21 - 7.47 (m, 3H), 7.08 (s, 1H), 6.18 - 6.31 (m, 2H), 5.07 - 5.09 (m, 2H), 4.38 - 4.79 (m, 4H), 4.09 - 4.29 (m, 2H), 3.65 - 3.88 (m, 2H), 3.28 - 3.40 (m, 1H), 1.57 - 2.18 (m, 12H); LCMS m/z 533.9 [M+H]+.
Example 104
3,5-Bis(trifluoromethyl)benzyl 2-carbamoyl-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000133_0004
[0323] The titled compound was synthesized according to the procedure described in
Example 12 (63 mg, yield 93%). 1H NMR (400 MHz, METHANOL-d4) δ 7.76 - 7.98 (m, 3H), 6.50 - 6.74 (m, 1H), 5.17 - 5.34 (m, 2H), 4.58 - 4.73 (m, 2H), 4.40 - 4.55 (m, 2H), 3.70 - 3.96 (m, 2H), 1.81 - 2.00 (m, 2H); LCMS m/z 450.9 [M+H]+.
Example 105
2-Ethyl 5-(3-methyl-5-(trifluoromethyl)benzyl) 7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-2,5(6H)-dicarboxylate
Figure imgf000134_0001
[0324] The titled compound was synthesized according to the procedure described in
Example 1 (43 mg, yield 20%). 1H NMR (400 MHz, METHANOL-d4) δ 7.20 - 7.48 (m, 3H), 6.57 - 6.78 (m, 1H), 5.06 - 5.18 (m, 2H), 4.57 - 4.70 (m, 2H), 4.46 - 4.55 (m, 2H), 4.32 (q, J = 7.11 Hz, 2H), 3.75 - 3.91 (m, 2H), 2.38 (s, 3H), 1.91 (br. s., 2H), 1.35 (t, J = 7.15 Hz, 3H); LCMS m/z 426.0 [M+H]+.
Example 106
2-(3,5-Bis(trifluoromethyl)benzyl) 8-ethyl 4,5-dihydro-lH-pyrrolo[l,2-a][l,4]diazepine-
2,8(3H)-dicarboxylate
Figure imgf000134_0002
[0325] The titled compound was synthesized according to the procedure described
Example 1 (141 mg, yield 59%). 1H NMR (400 MHz, METHANOL-d4) δ 7.76 - 7.95 (m, 3H), 7.32 (br. s., 1H), 6.30 - 6.50 (m, 1H), 5.16 - 5.40 (m, 2H), 4.40 - 4.62 (m, 2H), 4.12 - 4.29 (m, 4H), 3.63 - 3.93 (m, 2H), 1.84 (br. s., 2H), 1.29 (t, J = 7.15 Hz, 6H); LCMS m/z 496.0 [M+H]+.
Example 107
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 7-methyl-7,8-dihydro-4H-pyrazolo[l,5- a][
Figure imgf000134_0003
[0326] The titled compound was synthesized according to the procedure described in
Example 1 (54 mg, yield 55%). 1H NMR (400 MHz, METHANOL-d4) δ 7.76 - 8.01 (m, 3H), 6.55 - 6.79 (m, 1H), 5.34 (s, 2H), 4.78 - 4.94 (m, 2H), 4.50 (s, 2H), 4.34 (q, J = 7.11 Hz, 2H), 3.85 - 3.94 (m, 2H), 1.68 (s, 3H), 1.36 (t, J = 7.03 Hz, 3H); LCMS m/z 493.9 [M+H]+. Example 108
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 3-chloro-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-2,5(6H)-dicarboxylate
Figure imgf000135_0001
[0327] The titled compound was synthesized according to the procedure described in
Example 1 (77 mg, yield 75%). 1H NMR (400 MHz, METHANOL-d4) δ 7.76 - 8.02 (m, 3H), 5.24 -5.29 (m, 2H), 4.64 - 4.71 (m, 2H), 4.49 - 4.56 (m, 2H), 4.34 (q, J = 7.19 Hz, 2H), 3.77 - 3.94 (m, 2H), 1.88 - 1.97 (m, 2H), 1.36 (t, J = 7.15 Hz, 3H); LCMS m/z 513.9
[M+H]+.
Example 109
5-(((3-Methyl-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a] [l,4]diazepine-2-carboxylic acid
[0328] The titled compound was synthesized according to the procedure described in
Example 8 (32 mg, yield 80%). 1H NMR (400 MHz, METHANOL-d4) δ 7.20 - 7.51 (m, 3H), 6.57 - 6.75 (m, 1H), 5.03 - 5.22 (m, 2H), 4.57 - 4.69 (m, 2H), 4.45 - 4.56 (m, 2H), 3.74 - 3.93 (m, 2H), 2.38 (s, 3H), 1.81 - 1.96 (m, 2H); LCMS m/z 398.0 [M+H]+.
Example 110
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-3-chloro-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a] [l,4]diazepine-2-carboxylic acid
Figure imgf000135_0002
[0329] The titled compound was synthesized according to the procedure described in
Example 8 (69 mg, yield 99%). 1H NMR (400 MHz, METHANOL-d ) δ 7.74 - 8.14 (m, 3H), 5.22 - 5.31 (m, 2H), 4.62 - 4.73 (m, 2H), 4.45 - 4.58 (m, 2H), 3.74 - 3.93 (m, 2H), 1.86 - 1.99 (m, 2H); LCMS m/z 486.1 [M+H]+.
Example 111
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-7-methyl-5,6,7,8-tetrahydro-4H-
Figure imgf000135_0003
[0330] The titled compound was synthesized according to the procedure described in
Example 7 (18 mg, yield 40%). 1H NMR (400 MHz, METHANOL-d4) δ 7.78 - 8.04 (m, 3H), 6.52 - 6.77 (m, 1H), 5.34 (br. s., 2H), 4.90 (br. s., 2H), 4.50 (s, 2H), 3.89 - 3.96 (m, 2H), 1.68 (br. s., 3H); LCMS m/z 466.2 [M+H]+.
Example 112
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 3-chloro-6,7-dihydropyrazolo[l,5-a]pyrazine-
Figure imgf000136_0001
[0331] The titled compound was synthesized according to the procedure described in
Example 1 (68 mg, yield 68%). 1H NMR (400 MHz, METHANOL-d4) δ 8.04 (s, 2H), 7.95 (s, 1H), 5.36 (s, 2H), 4.68 - 4.75 (m, 2H), 4.36 (q, J = 7.03 Hz, 2H), 4.16 - 4.27 (m, 2H), 4.02 (br. s., 2H), 1.37 (t, J = 7.15 Hz, 3H); LCMS m/z 500.1 [M+H]+.
Example 113
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-3-chloro-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazine-2-carboxylic acid
Figure imgf000136_0002
[0332] The titled compound was synthesized according to the procedure described in
Example 7 (36 mg, yield 60%). 1H NMR (400 MHz, METHANOL-d ) δ 8.04 (s, 2H), 7.95 (s, 1H), 5.36 (s, 2H), 4.65 - 4.77 (m, 2H), 4.17 - 4.28 (m, 2H), 4.02 (br. s., 2H); LCMS m/z 472.0 [M+H]+.
Example 114
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 3-bromo-7,8-dihydro-4H-pyrazolo[l,5-
Figure imgf000136_0003
[0333] The titled compound was synthesized according to the procedure described in
Example 1 (77 mg, yield 69%). 1H NMR (400 MHz, METHANOL-d4) δ 7.74 - 8.01 (m, 3H), 5.21 - 5.34 (m, 2H), 4.70 (s, 2H), 4.49 - 4.62 (m, 2H), 4.34 (q, J = 7.03 Hz, 2H), 3.71 - 3.97 (m, 2H), 1.81 - 2.07 (m, 2H), 1.37 (t, J= 7.15 Hz, 3H); LCMS m/z 558, 560.0 [M+H]+.
Example 115
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-3-bromo-5,6,7,8-tetrahydro-4H- pyrazolo[l, oxylic acid
Figure imgf000136_0004
[0334] The titled compound was synthesized according to the procedure described in
Example 8 (66 mg, yield 96%). 1H NMR (400 MHz, METHANOL-d4) δ 7.74 - 8.01 (m, 3H), 5.22 - 5.32 (m, 2H), 4.70 (s, 2H), 4.47 - 4.60 (m, 2H), 3.76 - 3.95 (m, 2H), 1.83 - 2.03 (m, 2H); LCMS m/z 530.0, 532.0 [M+H]+.
Example 116
5-(2-((3,5-Bis(trifluoromethyl)phenyl)amino)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5 a] [ 1 acid
Figure imgf000137_0001
Step 1
Ethyl 5-(2-bromoacetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2-
Figure imgf000137_0002
[0335] 2-Bromoacetyl chloride (70 mg, 0.45 mmol) was added dropwise to a stirred solution of ethyl 5,6,7, 8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2-carboxylate hydrochloride (100 mg, 0.41 mmol) in dichloromethane (5 mL) at 0°C. The reaction mixture was stirred for 15 min, diluted with dichloromethane (10 mL), washed with water (3 mL), brine (3 mL), dried over sodium sulfate and evaporated in vacuo to give the crude product ethyl 5-(2-bromoacetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2-carboxylate (130 mg) as a black oil, which was used in the next step without further purification. LCMS m/z 330.0, 332.0 [M+H]+.
Step 2
Ethyl 5-(2-((3,5-bis(trifluoromethyl)phenyl)amino)acetyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a][l,4]diazepine-2-carboxylate
Figure imgf000137_0003
[0336] A mixture of ethyl 5-(2-bromoacetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carboxylate (160 mg, 0.49 mmol), 3,5-bis(trifluoromethyl)aniline (224 mg, 0.98 mmol), K2C03 (203 mg, 1.47 mmol) and KI (81 mg, 0.49 mmol) in DMF (2 mL) was stirred at 100 °C for 16 h in a sealed tube. The mixture was diluted with EtOAc (10 mL), washed with water (3 mL x 2) and brine (3 mL). The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was purified by prep-HPLC (CH CN/H20 with 0.05% TFA as mobile phase; from 20% to 95%) to furnish the target compound ethyl 5-(2- ((3,5-bis(trifluoromethyl)phenyl)amino)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carboxylate as a colorless oil (56 mg, putity 65%-70%) as a colorless oil. LCMS m/z 479.1 [M+H]+.
Step 3
5-(2-((3,5-Bis(trifluoromethyl)phenyl)amino)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-
Figure imgf000138_0001
[0337] To a solution of ethyl 5-(2-((3,5-bis(trifluoromethyl)phenyl)amino)acetyl)-
5,6,7, 8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2-carboxylate (56 mg, 0.12 mmol) in THF (2.0 mL) and H20 (0.5 mL) was added NaOH (19 mg, 0.48 mmol). The reaction mixture was stirred at rt for 16 h, and was adjusted to pH = 6 with HC1 (I N). The reaction mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (CH3CN/H20 with 0.05% TFA as mobile phase; from 20% to 95%) to give 5-(2-((3,5- bis(trifluoromethyl)phenyl)amino)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carboxylic acid as a white solid (21 mg, yield 39%). 1H NMR (400 MHz, CDCI3) δ 7.19-7.17 (m, 1H), 6.91-6.88 (m, 3H), 4.76-4.58 (m, 4H), 4.00-3.84 (m, 4H), 2.13- 2.12 (m, 2H).LCMS m/z 451.1 [M+H]+.
Example 117
5-(2-(3,5-Bis(trifluoromethyl)phenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4 acid
Figure imgf000138_0002
Step 1
Ethyl 5-(2-(3,5-bis(trifluoromethyl)phenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- -2-carboxylate
Figure imgf000138_0003
[0338] The titled compound was synthesized according to the procedure described in
Example 116, step 2 (103 mg, yield 54%). LCMS m/z 480.1 [M+H]+. Step 2
5-(3-(3,5-Bis(trifluoromethyl)phenyl)propyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-
Figure imgf000139_0001
[0339] The titled compound was synthesized according to the procedure described in
Example 7 (10 mg, yield 10%). 1H NMR (400 MHz, CDC13) δ 7.49-7.32 (m, 3H), 6.80 (bs, 1H), 4.85-4.80 (m, 2H), 4.68-4.57 (m, 4H), 3.93-3.87 (m, 2H), 2.09-2.02 (m, 2H); LCMS m/z 452.0 [M+H]+.
Example 118
3,5-Bis(trifluoromethyl)benzyl 2-(3-methyl-l,2,4-oxadiazol-5-yl)-7,8-dihydro-4H- pyrazolo[l,5 carboxylate
Figure imgf000139_0002
Step 1
3,5-Bis(trifluoromethyl)benzyl 2-(chlorocarbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000139_0003
[0340] To 5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a][l,4]diazepine-2-carboxylic acid (200 mg, 0.44 mmol) in dichloromethane (6 mL) was added SOCl2 (208 mg, 1.76 mmol) and DMF (0.1 mL). The mixture was refluxed for 16 h. The solvent was removed under reduced pressure to provide 3,5- bis(trifluoromethyl)benzyl 2-(chlorocarbonyl)-7,8-dihydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine- 5(6H)-carboxylate as a yellow solid, which was used in next step without further purification.
Step 2
3,5-Dichlorobenzyl 2-(4-aminopiperidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000139_0004
[0341] 3,5-bis(trifluoromethyl)benzyl 2-(chlorocarbonyl)-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate from previous step was mixed with N'- hydroxyacetimidamide (33 mg, 0.44 mmol) and diisoproylethylamine (68 mg, 0.53 mmol) in CH3CN (3 mL) in a microwave vial. The mixture was heated with microwave irritation at 150 °C for 25 min. The solvent was removed under reduced pressure, the residue was purified by prep-HPLC (CH3CN/H20 with 0.05% TFA as mobile phase; from 20% to 95%) to furnish the target compound 3,5-dichlorobenzyl 2-(4-aminopiperidine-l-carbonyl)-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate as a white solid (71 mg, yield 30%). 1H NMR (400 MHz, METHANOL-d4) δ 7.93-7.84 (m, 3H), 6.90-6.79 (m, 1H), 5.30-5.26 (m, 2H), 4.73-4.68 (m, 2H), 4.62-4.59 (m, 2H), 3.92-3.86 (m, 2H), 2.42 (s, 3H), 1.95 (bs, 2H); LCMS m/z 490.1 [M+H]+.
Example 119
3,5-Bis(trifluoromethyl)benzyl 2-(5-methyl-l,3,4-oxadiazol-2-yl)-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000140_0001
Step 1
3,5-Bis(trifluoromethyl)benzyl 2-(2-acetylhydrazinecarbonyl)-7,8-dihydro-4H-
Figure imgf000140_0002
[0342] To a solution of 5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8- tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2-carboxylic acid (300 mg, 0.67 mmol) in DMF (4 mL) was added HATU (304 mg, 0.80 mmol) and Et3N (203 mg, 2.01 mmol). After stirring at rt for 1 h, acetohydrazide (59 mg, 0.80 mmol) was added to the reaction solution. The mixture was stirred at rt for 16 h, and was purified by prep-HPLC (CH3CN/H20 with 0.05% TFA as mobile phase; from 20% to 95%) to furnish 3,5-bis(trifluoromethyl)benzyl 2-(2- acetylhydrazinecarbonyl)-7,8-dihydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate as a white solid (194 mg, yield 57%). 1H NMR (400 MHz, CDC13) δ 9.12 (bs, 1H), 8.68-8.65 (m, 1H), 7.83 (s, 1H), 7.77-7.73 (m, 2H), 6.78-6.66 (m, 1H), 5.20 (s, 2H), 4.56 (s, 2H), 4.46 (bs, 2H), 3.82 (s, 2H), 2.10 (s, 3H), 1.99 (s, 2H); LCMS m/z 508.1 [M+H]+.
Step 2
3,5-Bis(trifluoromethyl)benzyl 2-(5-methyl-l,3,4-oxadiazol-2-yl)-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000140_0003
[0343] A mixture of 3,5-bis(trifluoromethyl)benzyl 2-(2-acetylhydrazinecarbonyl)-
7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (140 mg, 0.28 mmol) in POCl3 (2 mL) was heated at 100 °C for 6 h. After POCl3 was removed under reduced pressure, EtOAc (10 mL) was added. The mixture was washed with 1 N NaOH (3 mL) and brine (3 mL), and the organic layer was then dried over Na2S04 and concentrated in vaccuo. The residue was purified by prep-HPLC (CH3CN/H2O with 0.05% TFA as mobile phase; from 20% to 95%) to furnish 3,5-bis(trifluoromethyl)benzyl 2- (5 -methyl- 1,3,4- oxadiazol-2- yl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate as a white solid (111 mg, yield 79%). 1H NMR (400 MHz, CD3OD) δ 7.93-7.84 (m, 3H), 6.82-6.74 (m, 1H), 5.26-5.26 (m, 2H), 4.72-4.66 (m, 2H), 4.59-4.56 (m, 2H), 3.91-3.85 (m, 2H), 2.60 (s, 3H), 1.95-1.93 (m, 2H); LCMS m/z 490.1 [M+H]+.
Example 120
5-(((5-Fluoro-[l,l'-biphenyl]-3-yl)methoxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l, oxylic acid
Figure imgf000141_0001
Step 1
2-Ethyl 5-((5-fluoro-[l,l'-biphenyl]-3-yl)methyl) 7,8-dihydro-4H-pyrazolo[l,5- -2,5(6H)-dicarboxylate
Figure imgf000141_0002
[0344] Under an argon atmosphere, 5-(3-bromo-5-fluorobenzyl) 2-ethyl 7,8-dihydro-
4H-pyrazolo[l,5-a][l,4]diazepine-2,5(6H)-dicarboxylate (120 mg, 0.27 mmol),
phenylboronic acid (40 mg, 0.32 mmol), K2C03 (112 mg, 0.81 mmol) and Pd(PPh3)4 (31 mg, 0.027 mmol) were dissolved in dioxane (3 mL) and H20 (1 mL). After stirring at 110 °C for 4 h, the reaction mixture was diluted with EtOAc (10 mL). The mixture was washed with water (3 mL), brine (5 mL), dried over sodium sulfate and evaporated in vacuo. The residue was purified by prep-HPLC (CH3CN/H20 with 0.05% TFA as mobile phase; from 20% to 95%) to get 2-ethyl 5-((5-fluoro-[l,l'-biphenyl]-3-yl)methyl) 7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-2,5(6H)-dicarboxylate as a white solid (102 mg, yield 56%). LCMS m/z 438.2 [M+H]+. Step 2
5-(((5-Fluoro-[l,l'-biphenyl]-3-yl)methoxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a] [l,4]diazepine-2-carboxylic acid
Figure imgf000142_0001
[0345] The titled compound was synthesized according to the procedure described in
Example 7 (48 mg, yield 50%). 1H NMR (400 MHz, CDC13) δ 8.76 (bs, 1H), 7.54-7.53 (m, 2H), 7.46-7.43 (m, 2H), 7.38-7.22 (m, 3H), 7.01-6.97 (m, 1H), 6.85-6.72 (m, 1H), 5.15 (s, 2H), 4.59-4.57 (m, 4H), 3.83 (s, 2H), 2.00 (bs, 2H); LCMS m/z 410.2 [M+H]+.
Example 121
3,5-Dichlorobenzyl 7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000142_0002
[0346] To a mixture of (3, 5-bis-trifluoromethyl-phenyl)-methanol (87 mg, 0.36 mmol) and /V, /V-carbonyldiimidazole (58 mg, 0.36 mmol) in THF (4.0 mL) was added 1.0 M of chlorotrimethylsilane in tetrahydrofuran (0.02 mL, 0.02 mmol). The mixture was stirred at RT for lh. The above mixture was added to a stirring mixture of 5,6,7, 8-tetrahydro-4H- pyrazolo[l,5-a][l,4]diazepine (50 mg, 0.24 mmol) and N,N-diisopropylethylamine (0.08 mL, 0.48 mmol). The reaction mixture was stirred at rt for 3 days. The reaction was diluted with EtOAc, washed with brine. The organic phase was dried and concentrated. The crude was purified by prep-HPLC (MeCN/H20 with 0.1% TFA) to give the desired product as a white powder (22 mg, TFA salt). 1H NMR (400 MHz, METHANOL-d4) δ 7.81 - 7.98 (m, 3H), 7.23 - 7.37 (m, 1H), 6.13 - 6.31 (m, 1H), 5.19 - 5.31 (m, 2H), 4.57 - 4.72 (m, 2H), 4.38 - 4.51 (m, 2H), 3.74 - 3.94 (m, 2H), 1.89 (d, J = 4.52 Hz, 2H); LCMS m/z 408.1 [M+H]+.
Example 122
3, 5-Dichlorobenzyl 2-cyano-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-
Figure imgf000142_0003
[0347] The titled compound was synthesized according to the procedure described in
Example 1 as a white powder (57 mg, yield 62%). 1H NMR (400 MHz, METHANOL-d ) δ 7.34 - 7.44 (m, 1H), 7.16 - 7.32 (m, 2H), 6.64 - 6.76 (m, 1H), 5.03 - 5.15 (m, 2H), 4.59 - 4.71 (m, 2H), 4.49 - 4.57 (m, 2H), 3.77 - 3.92 (m, 2H), 1.84 - 1.98 (m, 2H); LCMS m/z 365.1 [M+H]+. Example 123
3,5-Dichlorobenzyl 2-(lH-tetrazol-5-yl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-
Figure imgf000143_0001
[0348] To a solution of 2-cyano-7,8-dihydro-4H,6H-l,5,8a-triaza-azulene-5- carboxylic acid 3,5-dichloro-benzyl ester (15 mg, 0.04 mmol) in N,N-dimethylformamide (0.5 mL) was added zinc dibromide (20 mg, 0.09 mmol), followed by sodium azide (11.7 mg, 0.18 mmol). The mixture was heated in microwave vial at 175 °C for 20 min. The reaction was then diluted with ethyl acetate, washed with water, the organiic phase was then dried and purified by HPLC (acetonitrile/water with 0.1% TFA) to give desired product as a white powder (6 mg). 1H NMR (400 MHz, METHANOL-d4) δ 7.22 - 7.42 (m, 2H), 7.15(s, 1H), 6.77 - 6.89 (m, 1H), 5.04 - 5.17 (m, 2H), 4.65 - 4.76 (m, 2H), 4.54 - 4.63 (m, 2H), 3.79 - 3.96 (m, 2H), 1.88 - 2.01 (m, 2H); LCMS m/z 408.1 [M+H]+.
Example 124
3,5-Bis(trifluoromethyl)benzyl 2-methyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-
Figure imgf000143_0002
[0349] The titled compound was synthesized according to the procedure described in
Example 1 as a white powder (67 mg, yield 30%). 1H NMR (400 MHz, METHANOL-d4) δ 7.79 - 8.00 (m, 3H), 5.91 - 6.12 (m, 1H), 5.19 - 5.32 (m, 2H), 4.48 - 4.65 (m, 2H), 4.29 - 4.43 (m, 2H), 3.71 - 3.91 (m, 2H), 2.08 - 2.23 (m, 3H), 1.88 (d, J = 4.52 Hz, 2H); LCMS m/z 422.1 [M+H]+.
Example 125
3,5-Bis(trifluoromethyl)benzyl 2-cyano-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-
5(6H)-carboxylate
Figure imgf000143_0003
[0350] The titled compound was synthesized according to the procedure described in
Example 1 as a white powder (97 mg, yield 90%). 1H NMR (400 MHz, METHANOL-d4) δ 7.79 - 7.99 (m, 3H), 6.57 - 6.79 (m, 1H), 5.19 - 5.34 (m, 2H), 4.59 - 4.72 (m, 2H), 4.49 - 4.57 (m, 2H), 3.76 - 3.94 (m, 2H), 1.91 (d, J = 4.52 Hz, 2H); LCMS m/z 433.1 [M+H]+. Example 126
3-Fluoro-5-(trifluoromethyl)benzyl 2-(trifluoromethyl)-5,6-dihydroimidazo[l,2- a]pyrazine-7(8H)-carboxylate
Figure imgf000144_0001
[0351] The titled compound was synthesized according to the procedure described in
Example 1 as a white powder (83 mg, yield 77%). 1H NMR (400 MHz, METHANOL-d4) δ 7.53 - 7.63 (m, 2H), 7.39 - 7.51 (m, 2H), 5.28 (s, 2H), 4.68 - 4.81 (m, 2H), 4.10 - 4.19 (m, 2H), 3.97 (br. s., 2H); LCMS m/z 412.1 [M+H]+.
Example 127
3,5-Bis(trifluoromethyl)benzyl 2-(trifluoromethyl)-5,6-dihydroimidazo[l,2-a]pyrazine-
7(8H)-carboxylate
Figure imgf000144_0002
[0352] The titled compound was synthesized according to the procedure described in
Example 1 as a white powder (86 mg, yield 71%). 1H NMR (400 MHz, METHANOL-d4) δ 8.04 (br. s., 2H), 7.95 (br. s., 1H), 7.58 (s, 1H), 5.35 (s, 2H), 4.79 (d, J = 7.53 Hz, 2H), 4.13 (d, J = 5.02 Hz, 2H), 3.97 (br. s., 2H); LCMS m/z 462.1 [M+H]+.
Example 128
3-Fluoro-5-(trifluoromethyl)benzyl 2-methyl-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000144_0003
[0353] The titled compound was synthesized according to the procedure described in
Example 1 as a white powder (67 mg, yield 81%). 1H NMR (400 MHz, METHANOL-d ) δ 7.18 - 7.53 (m, 3H), 5.94 - 6.13 (m, 1H), 5.12 - 5.25 (m, 2H), 4.51 - 4.64 (m, 2H), 4.28 - 4.42 (m, 2H), 3.71 - 3.92 (m, 2H), 2.17 (s, 3H), 1.88 (d, J = 4.02 Hz, 2H); LCMS m/z 372.1 [M+H]+.
Example 129
3-Fluoro-5-(trifluoromethyl)benzyl 2-methyl-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000144_0004
[0354] The titled compound was synthesized according to the procedure described in
Example 1 as a white powder (82 mg, yield 85%). 1H NMR (400 MHz, DMSO-d6) δ 7.35 - 7.76 (m, 3H), 6.77 - 6.98 (m, 1H), 5.15 (d, J = 10.79 Hz, 2H), 4.48 - 4.73 (m, 4H), 3.64 - 3.86 (m, 2H), 1.72 - 1.93 (m, 2H); LCMS m/z 383.1 [M+H]+.
Example 130
3,5-Dichlorobenzyl 2-methyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-
Figure imgf000145_0001
[0355] The titled compound was synthesized according to the procedure described in
Example 1 as a white powder (53 mg, yield 67%). 1H NMR (400 MHz, METHANOL-d4) δ 7.37 (br. s., 1H), 7.17 - 7.32 (m, 2H), 5.99 - 6.12 (m, 1H), 5.02 - 5.13 (m, 2H), 4.49 - 4.63 (m, 2H), 4.30 - 4.41 (m, 2H), 3.72 - 3.90 (m, 2H), 2.20 (s, 3H), 1.88 (d, J = 4.77 Hz, 2H); LCMS m/z 354.1 [M+H]+.
Example 131
3,5-Dichlorobenzyl 2-(trifluoromethyl)-5,6-dihydroimidazo[l,2-a]pyrazine-7(8H)-
Figure imgf000145_0002
[0356] The titled compound was synthesized according to the procedure described in
Example 1 as a white powder (77 mg, yield 80%). 1H NMR (400 MHz, METHANOL-d4) δ 7.60 (d, J = 1.00 Hz, 1H), 7.33 - 7.44 (m, 3H), 5.17 (s, 2H), 4.77 (br. s., 2H), 4.10 - 4.19 (m, 2H), 3.96 (br. s., 2H); LCMS m/z 394.0 [M+H]+.
Example 132
3,5-Bis(trifluoromethyl)benzyl 6,7-dihydro-5H-imidazo[l,5-a][l,4]diazepine-8(9H)- carboxylate o
[0357] The titled compound was synthesized according to the procedure described in
Example 1 as a white powder (23 mg, yield 24%). 1H NMR (400 MHz, METHANOL-d ) δ 8.88 (d, / = 9.04 Hz, 1H), 7.85 - 8.00 (m, 3H), 7.50 (d, / = 10.04 Hz, 1H), 5.28 (d, / = 11.80 Hz, 2H), 4.62 - 4.79 (m, 2H), 4.48 - 4.61 (m, 2H), 3.73 - 3.98 (m, 2H), 2.00 (d, / = 3.26 Hz, 2H); LCMS m/z 408.1 [M+H]+. Example 133
3,5-Dichlorobenzyl 6,7-dihydro-5H-imidazo[l,5-a][l,4]diazepine-8(9H)-carboxylate
Figure imgf000146_0001
[0358] The titled compound was synthesized according to the procedure described in
Example 1 as a white powder (15 mg, yield 18%). 1H NMR (400 MHz, METHANOL-d4) δ 8.87 (d, J= 8.53 Hz, 1H), 7.50 (d, J= 10.79 Hz, 1H), 7.40 (t, J= 1.63 Hz, 1H), 7.28 (d, J = 17.82 Hz, 2H), 5.10 (d, J= 14.05 Hz, 2H), 4.61 - 4.78 (m, 2H), 4.47 - 4.59 (m, 2H), 3.87 (d, J = 16.31 Hz, 2H), 2.00 (br. s., 2H); LCMS m/z 340.0 [M+H]+.
Example 134
3,5-Bis(trifluoromethyl)benzyl 3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazine-7(8H)-carboxylate
Figure imgf000146_0002
[0359] The titled compound was synthesized according to the procedure described in
Example 1 as a white powder (17 mg, TFA salt, yield 17%). 1H NMR (400 MHz,
METHANOL-d ) δ 7.87 - 8.14 (m, 3H), 5.36 (s, 2H), 4.96 (d, J = 3.51 Hz, 2H), 4.26 (t, J = 5.40 Hz, 2H), 4.01 (br. s., 2H); 19F NMR (376 MHz, METHANOL-d4) δ ppm 77.72 (br. s., 3F, TFA), 64.67 (s, 3F), 64.40 (s, 6F); LCMS m/z 463.1 [M+H]+.
Example 135
3-Chloro-5-(trifluoromethyl)benzyl 3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazine-7(8H)-carboxylate
Figure imgf000146_0003
[0360] The titled compound was synthesized according to the procedure described in
Example 1 as a white powder (25 mg, TFA salt, yield 27%). 1H NMR (400 MHz, METHANOL-d ) δ 7.75 (s, 1H), 7.68 (s, 2H), 5.27 (s, 2H), 4.96 (br. s., 2H), 4.26 (t, J = 5.40 Hz, 2H), 4.01 (br. s., 2H); 19F NMR (376 MHz, METHANOL-d ) δ ppm 77.75 (br. s., 3F, TFA), 64.66 (s, 3F), 64.36 (s, 3F); LCMS m/z 429.0 [M+H]+.
Example 136
3,5-Bis(trifluoromethyl)benzyl 2-(lH-tetrazol-5-yl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000146_0004
[0361] The titled compound was synthesized according to the procedure described in
Example 123 as a white powder (25 mg, yield 32%). 1H NMR (400 MHz, METHANOL-d4) δ 7.86 - 7.96 (m, 1H), 7.80 (br. s., 2H), 6.74 - 6.90 (m, 1H), 5.21 - 5.34 (m, 2H), 4.64 - 4.78 (m, 2H), 4.54 - 4.63 (m, 2H), 3.79 - 3.98 (m, 2H), 1.94 (d, J = 5.27 Hz, 2H); LCMS m/z 476.1 [M+H]+.
Example 137
3-Chloro-5-(trifluoromethyl)benzyl 7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-
5(6H)-carboxylate
[0362] The titled compound was synthesized according to the procedure described in
Example 1 as a white powder (21 mg). 1H NMR (400 MHz, METHANOL-d4) δ 7.46 - 7.71 (m, 3H), 7.29 (d, J = 1.76 Hz, 1H), 6.12 - 6.29 (m, 1H), 5.11- 5.23 (m, 2H), 4.55 - 4.70 (m, 2H), 4.38 - 4.51 (m, 2H), 3.73 - 3.94 (m, 2H), 1.89 (d, J = 4.77 Hz, 2H); LCMS m/z 374.1 [M+H]+.
Example 138
3-(3,5-Bis(trifluoromethyl)phenyl)-l-(7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepin-
Figure imgf000147_0002
[0363] To a mixture of 3-(3,5-bis-trifluoromethyl-phenyl)-propionic acid (133 mg,
0.46 mmol) in DMF (4 mL) was added HATU (194 mg, 0.51 mmol) and N,N- diisopropylethylamine (0.16 mL, 0.93 mmol). The mixture was stirred at rt for 10 min.
5,6,7, 8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine (65 mg, 0.31 mmol) was then added. The reaction mixture was stirred at rt overnight. The reaction was diluted with ethyl acetate, washed with brine. The organic phase was dried and concentrated. The crude product was purified by HPLC (MeCN/H20 with 0.1% TFA) to give 3-(3,5-bis(trifluoromethyl)phenyl)-l- (7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepin-5(6H)-yl)propan-l-one as a white powder (108 mg, TFA salt). 1H NMR (400 MHz, METHANOL-d ) δ 7.83 (s, 1H), 7.68 - 7.79 (m, 2H), 7.28 (dd, J = 1.88, 14.43 Hz, 1H), 6.19- 6.29 (m, 1H), 4.69 (d, J = 11.04 Hz, 2H), 4.35 - 4.49 (m, 2H), 3.79 - 3.94 (m, 2H), 3.06 (t, J = 7.03 Hz, 2H), 2.72 - 2.92 (m, 2H), 1.78 -1.97 (m, 2H); LCMS m/z 406.1 [M+H]+. Example 139
5-(l-(3,5-Bis(trifluoromethyl)phenyl)ethyl) 2-ethyl 7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-2,5(6H)-dicarboxylate
Figure imgf000148_0001
[0364] The titled compound was synthesized according to the procedure described in
Example 1 as a white solid (100 mg, yield 50%). 1H NMR (400 MHz, METHANOL-d4) δ 7.89-7.80 (m, 3H), 6.75, 6.67 (s, s, IH), 5.85-5.80 (m, IH), 4.61-4.47 (m, 4H), 4.37-4.31 (m, 2H), 4.00-3.55 (m, 2H), 2.01-1.73 (m, 2H), 1.60-1.56 (m, 3H), 1.38-1.24 (m, 3H); LCMS m/z 494.1 [M+H]+.
Example 140
5-((l-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a] [l,4]diazepine-2-carboxylic acid
Figure imgf000148_0002
[0365] The titled compound was synthesized according to the procedure described in
Example 8 as a white solid (50 mg, yield 53%). 1H NMR (400 MHz, METHANOL-d4) δ 7.92-7.84 (m, 3H), 6.71,6.63 (s,s, IH), 5.87-5.79 (m, IH), 4.79-4.50 (m, 4H), 3.99-3.68 (m, 2H), 1.95-1.82 (m, 2H), 1.61-1.56 (m, 3H); LCMS m/z 466.1 [M+H]+.
Example 141
5-(3,5-Bis(trifluoromethyl)phenethyl) 2-ethyl 7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-2,5(6H)-dicarboxylate
CF3
[0366] The titled compound was synthesized according to the procedure described in
Example 1 as a white solid (43 mg, yield 12%). 1H NMR (400 MHz, CDC13) δ 7.80-7.77 (m, IH), 7.67-7.66 (m, 2H), 6.77, 6.49 (s, s, IH), 4.53-4.50 (m, 3H), 4.42-4.30 (m, 5H), 3.78-3.70 (m, 2H), 3.09 (q, J = 6.4 Hz, 2H), 2.01-1.85 (m, 2H), 1.41-1.35 (m, 3H); LCMS m/z 494.1 [M+H]+.
Example 142
5-((3,5-Bis(trifluoromethy 8-tetrahydro-4H-pyrazolo[l,5- acid
Figure imgf000148_0003
[0367] The titled compound was synthesized according to the procedure described in
Example 8 as a white solid (35 mg, yield 85%). 1H NMR (400 MHz, METHANOL-d4) δ 7.87-7.84 (m, 3H), 6.68, 6.30 (s, s, 1H), 4.55-4.49 (m, 4H), 4.40-4.33 (m, 2H), 3.75-3.73 (m, 2H), 3.18-3.13 (m, 2H), 1.88-1.78 (m, 2H); LCMS m/z 466.2 [M+H]+.
5-((3,5-Dichlorophe -4H-pyrazolo[l,5-
Figure imgf000149_0001
[0368] The titled compound was synthesized according to the procedure described in
Example 64 as a white solid (56 mg, yield 28% over two steps). 1H NMR (400 MHz, METHANOL-d ) δ 7.28 (s, 1H), 7.19 (s, 2H), 6.61-6.48 (m, 1H), 4.53-4.45 (m, 4H), 4.28- 4.22 (m, 2H), 3.74 (bs, 2H), 2.95-2.90 (m, 2H), 1.87-1.89 (m, 2H); LCMS m/z 398.0 [M+H]+.
Example 144
3,5-Bis(trifluoromethyl)benzyl 2-(methoxy(methyl)carbamoyl)-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000149_0002
[0369] A mixture of 5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5, 6,7,8- tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2-carboxylic acid (1.0 g, 2.2 mmol), DIPEA (567 mg, 4.4 mmol), HATU (1.25 g, 3.3 mmol) and Ν,Ο-dimethylhydroxylamine
hydrochloride (256 mg, 2.64 mmol) in DMF (10 mL) was stirred at rt for 3 h, the reaction mixture was diluted with EtOAc (80 mL) and washed with brine (50 mL x 2). The organic layer was dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc) to give 3,5-bis(trifluoromethyl)benzyl 2- (methoxy(methyl)carbamoyl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)- carboxylate as a yellow solid (1.1 g, yield 100%) as a yellow solid. 1H NMR (400 MHz, CDC13) δ 7.83 (s, 1H), 7.77-7.76 (m, 2H), 6.74, 6.62 (s, s, 1H), 5.19 (s, 2H), 4.56-4.52 (m, 4H), 3.82-3.81 (m, 2H), 3.70, 3.66 (s, s, 3H), 3.41, 4.40 (s, s, 3H), 1.99-1.98 (m, 2H); LCMS m/z 494.8 [M+H]+. Example 145
3,5-Bis(trifluoromethyl)benzyl 2-acetyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine- -carboxylate
Figure imgf000150_0001
[0370] To a solution of 3,5-bis(trifluoromethyl)benzyl 2-
(methoxy(methyl)carbamoyl)-7,8-dihydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)- carboxylate (1.0 g, 2.0 mmol) in THF (15 mL) was added CH3MgBr (3 mL, 6.0 mol) at 0 °C. The reaction mixture was stirred at 0 °C for 2.5 h, quenched with water and concentrated in vacuo. The residue was diluted with EtOAc (50 mL), washed with H20 (50 mL) and brine (50 mL), dried over sodium sulfate, and concentrated to give 3,5-bis(trifluoromethyl)benzyl 2-acetyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate as a yellow solid (700 mg, yield 77%). 1H NMR (400 MHz, CDC13) δ 7.82 (s, 1H), 7.75 (s, 1H), 7.69 (s, 1H), 6.75, 6.63 (s, s, 1H), 5.20 (s, 2H), 4.56-4.55 (m, 2H), 4.51 (d, J = 4.8 Hz, 2H), 3.84 (d, J = 4.8 Hz, 2H), 2.53 (s, 3H), 2.00-1.99 (m, 2H); LCMS m/z 450.1 [M+H]+.
Example 146
3,5-Bis(trifluoromethyl)benzyl 2-(l-hydroxyethyl)-7,8-dihydro-4H-pyrazolo[l,5-
Figure imgf000150_0002
[0371] To a solution of 3,5-bis(trifluoromethyl)benzyl 2-acetyl-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (100 mg, 0.22 mmol) in methanol (10 mL) was added NaBH4 (25 mg, 0.66 mol, 3.0 eq). The reaction mixture was stirred at rt for 4 h. It was quenched with water and adjusted to pH = 7. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (CH3CN/H20 with 0.05% TFA as mobile phase; from 5% to 95%) to furnish the target compound as a yellow oil (86 mg, yield 86%). 1H NMR (400 MHz, METHANOL-d ) δ 7.94 (s, 3H), 6.25, 6.17 (s, s, 1H), 5.25 (s, 2H), 4.79- 4.76 (m, 1H), 4.64-4.58 (m, 2H), 4.41-4.40 (m, 2H), 3.87-3.78 (m, 2H), 1.91-1.90 (m, 2H), 1.43-1.41 (m, 3H);LCMS m/z 451.8 [M+H]+.
Example 147
3,5-Bis(trifluoromethyl)benzyl 2-(l-aminoethyl)-7,8-dihydro-4H-pyrazolo[l,5-
Figure imgf000150_0003
[0372] To a solution of 3,5-bis(trifluoromethyl)benzyl 2-acetyl-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (180 mg, 0.40 mmol) in methanol (3 mL) was added ammonium acetate (308 mg, 4.00 mmol). The mixture was heated at 65°C for 2 h, followed by adding NaBH3CN (76 mg, 1.20 mmol) and heated at 65°C for 4 h. The reaction mixture was concentrated and purified by prep-HPLC (MeOH/H20 with 0.05% TFA as mobile phase; from 20% to 95%) to furnish the target compound as a pale yellow oil (36 mg, yield 24%) as a pale yellow oil. 1H NMR (400 MHz, CDC13) δ 7.95 (bs, 3H), 6.31, 6.23 (s, s, 1H), 5.25 (s, 2H), 4.68-4.65 (m, 2H), 4.48-4.39 (m, 3H), 3.90-3.84 (m, 2H), 1.91 (s, 2H), 1.58 (t, J = 6.0 Hz, 3H); LCMS m/z 451.2 [M+H]+.
Example 148
3,5-Bis(trifluoromethyl)benzyl 2-(l-(piperidin-l-yl)ethyl)-7,8-dihydro-4H-pyrazolo[l,5- -5(6H)-carboxylate
Figure imgf000151_0001
[0373] To a mixture of 3,5-bis(trifluoromethyl)benzyl 2-acetyl-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (110 mg, 0.24 mmol) in THF (2 mL) were added piperidine (41 mg, 0.48 mmol) and Ti(j-OPr)4 (136 mg, 0.48 mmol). The mixture was stirred under reflux for 16 h, followed by adding NaBH4 (102 mg, 0.48 mmol). The reaction mixture was stirred under reflux for additional 5 h, diluted with water (3 mL) and methanol (3 mL), filtered and concentrated, the residue was purified by prep-HPLC (MeOH/H20 with 10 mM NH4HC03 as mobile phase; from 5% to 95%) to furnish the target compound as a yellow oil (33 mg, yield 26%). 1H NMR (400 MHz, METHANOL-d4) δ 7.93 (s, 3H), 6.40, 6.34 (s, s, 1H), 5.27 (s, 2H), 4.69-4.61 (m, 2H), 4.50-4.42 (m, 3H), 3.90-3.79 (m, 2H), 3.52- 3.40 (m, 2H), 2.96-2.70 (m, 2H), 1.93-1.72 (m, 8H), 1.67 (t, J = 6.8 Hz, 3H); LCMS m/z 519.2 [M+H]+.
Example 149
l-(l-(5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyra acid
Figure imgf000151_0002
[0374] To a mixture of 3,5-bis(trifluoromethyl)benzyl 2-acetyl-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (300 mg, 0.67 mmol) in THF (2 mL) were added Ti (j-OPr)4 (951 mg, 3.35 mmol) and ethyl piperidine-4-carboxylate (210 mg, 1.34 mmol). The mixture was stirred under reflux for 4 h, followed by adding NaBH4 (284 mg, 1.34 mmol). The reaction mixture was stirred under reflux for additional 16 h, diluted with water (3 mL) and methanol (3 mL), filtered and concentrated. The residue was purified by prep-HPLC (MeOH/H20 with 0.05% TFA as mobile phase; from 5% to 95%) to provide a mixture of ethyl ester and isopropyl ester as an oil (110 mg).
[0375] To a solution of above ester (100 mg, 0.16 mmol) in methanol (10 mL) was added LiOH monohydrate (20 mg, 0.48 mmol). The reaction mixture was stirred at 40 °C for 4 h. It was adjusted to pH = 6 with IN HC1, concentrated in vacuo. The residue was purified by prep-HPLC (CH3CN/H20 with 0.05% NH4HC03 as mobile phase; from 5% to 95%) to get l-(l-(5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a][l,4]diazepin-2-yl)ethyl)piperidine-4-carboxylic acid as a yellow oil (44 mg, yield 47%). 1H NMR (400 MHz, METHANOL-d ) δ 7.82 (s, 3H), 6.26, 6.18 (s, s, 1H), 5.16 (s, 2H), 4.62-4.45 (m, 2H), 4.37-4.36 (m, 2H), 4.21-4.15 (m, 1H), 3.78-3.70 (m, 2H), 3.27- 3.24 (m, 1H), 3.20-3.11 (m, 1H), 2.72-2.59 (m, 2H), 2.12-2.06 (m, 1H), 1.92-1.81 (m, 6H), 1.52-1.47 (m, 3H); LCMS m/z 563.3 [M+H]+.
Example 150
5-(3-chloro-5-(trifluoromethyl)benzyl) 2-ethyl 7,8-dihydro-4H-pyrazolo[l,5- a][l,4] xylate
Figure imgf000152_0001
[0376] A mixture of (3-chloro-5-(trifluoromethyl)phenyl)methanol (15.1 g, 72.0 mmol) and CDI (11.7 g, 72.0 mmol) in DMF (100 mL) was stirred at rt for 3 h. Then ethyl 5,6,7, 8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2-carboxylate (14.7 g, 60.0 mmol) and TEA (7.9 g, 78.0 mmol) were added. The mixture was stirred at rt for 16 h. After the reaction completed, the mixture was diluted with water (300 mL) and extracted with EtOAc (200 mLX 2). The combined organic layers were washed with water (300 mL), dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc = 4: 1) to give the title compound as a white solid (22.2 g, 83% yield); ESI-MS m/z 446.1 [M+H]+. Example 151
3-chloro-5-(trifluoromethyl)benzyl 2-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4] diazepine-5(6H) -carboxylate
Figure imgf000153_0001
[0377] To a solution of 5-(3-chloro-5-(trifluoromethyl)benzyl) 2-ethyl 7,8-dihydro-
4H-pyrazolo[l,5-a][l,4]diazepine-2,5(6H)-dicarboxylate (20 g, 44.8 mmol) in THF (200 mL) was added 2N lithium borohydride in THF (45 mL, 89.6 mmol) at 0 °C. The reaction was stirred for 6h at rt and quenched with sat. aq. NH4C1 (200 mL). The mixture was extracted with ethyl acetate (200 mLX 2). The combined organic phase was washed with brine (200 mL X 2), dried over sodium sulfate and evaporated in vacuum to give the title compound as white solid (17.1 g, 95% yield), which was used for the next step without further purification; ESI-MS m/z 404.1 [M+H]+.
Example 152
3-chloro-5-(trifluoromethyl)benzyl 2-formyl-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4] diazepine-5(6H) -carboxylate
Figure imgf000153_0002
[0378] A mixture of 3-chloro-5-(trifluoromethyl)benzyl 2-(hydroxymethyl)-7,8- dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (16 g, 40 mmol) and IBX (33 g, 120 mmol) in EtOAc (200 mL) was stirred at reflux for 3 h. After cooled to rt, the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc = 4: 1) to give the title compound as a white solid (13.6 g, 85% yield). 1H NMR (400 MHz, CDC13) δ: 9.89 (s, 1H), 7.55 (s, 1H), 7.49-7.39 (m, 2H), 6.77-6.65 (m, 1H), 5.13 (s, 2H), 4.59-4.53 (m, 4H), 3.84 (t, J = 5.2 Hz, 2H), 2.04-2.02 (m, 2H); ESI-MS m/z 402.0 [M+H]+.
Example 153
3-chloro-5-(trifluoromethyl)benzyl 2-(((4,5-dihydrothiazol-2-yl)amino)methyl)-7,8- dihydro-4H-py (6H)-carboxylate
Figure imgf000153_0003
[0379] To a mixture of 3-chloro-5-(trifluoromethyl)benzyl 2-formyl-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (150 mg, 0.36 mmol) and 4,5- dihydrothiazol-2-amine (51 mg, 0.48 mmol) in THF (4 mL) was added Ti(OiPr)4 (213 mg, 0.72 mmol). The mixture was stirred at 100 °C for 2 h under microwave, then NaBH3CN (48 mg, 0.75 mmol) was added. The mixture was stirred at 100 °C for 16 h. After cooling to rt, the mixture was filtered and the filtrate was purified by reversed phase HPLC (CH3CN/H20 with 0.05% TFA as mobile phase; from 5% to 95%) to give the title compound as a white solid. (50 mg, 20% yield) 1H NMR (400 MHz, CD3OD) δ: 7.65-7.63 (m, IH), 7.59-7.57 (m, 2H), 6.21-6.17 (m, IH), 5.17-5.16 (m, 2H), 4.62-4.56 (m, 2H), 4.40-4.39 (m, 2H), 4.33 (s, 2H), 3.93-3.79 (m, 4H), 3.33-3.28 (m, 2H), 1.90-1.87 (m, 2H), ESI-MS m/z 488.1 [M+H]+
Example 154
3-chloro-5-(trifluoromethyl)benzyl 2-(((4,5-dihydro-lH-imidazol-2-yl)amino)methyl)- 7,8-dihydro-4H-py (6H)-carboxylate
Figure imgf000154_0001
[0380] Following the same condition as in Example 153, the title compound is obtained as a white solid (21 mg, 9% yield). 1H NMR (400 MHz, DMSO-J6) δ: 8.60 (br s, IH), 7.82 (s, IH), 7.74-7.65 (m, 2H), 6.16- 6.12 (m, IH), 5.14-5.12 (m, 2H), 4.62-4.53 (m, 2H), 4.39-4.35 (m, 2H), 4.24 (d, J = 5.6 Hz, 2H), 3.77-3.72 (m, 2H), 3.60-3.58 (m, 4H), 1.80- 1.75 (m, 2H); ESI-MS m/z 471.1 [M+H]+
Example 155
3-chloro-5-(trifluoromethyl)benzyl 2-(l-hydroxyethyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4] late
Figure imgf000154_0002
[0381] To a solution of 3-chloro-5-(trifluoromethyl)benzyl 2-formyl-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (481 mg, 1.2 mmol) in THF (15 mL) was added CH3MgBr (3 M, 0.8 mL, 2.4 mmol) at 0 °C. The mixture was stirred at rt for 4 h and quenched with sat. aq. NH4C1 (20 mL). The mixture was extracted with EtOAc (3 X 40 mL). The organic phase was dried over sodium sulfate and evaporated in vacuum, the residue was purified by prep-TLC on silica gel (petroleum ether/EtOAc = 2/1) to afford the title compound as a white solid (350 mg, 70% yield). ESI-MS m/z 418.1 [M+H]+. Example 156
3-chloro-5-(trifluoromethyl)benzyl 2-(l-((4,5-dihydrothiazol-2-yl)amino)ethyl)-7,8- dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000155_0001
[0382] To a solution of 3-chloro-5-(trifluoromethyl)benzyl 2-(l-hydroxyethyl)-7,8- dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (136 mg, 0.33 mmol) in DCM (5 mL) was added SOCl2 (196 mg, 1.65 mmol) at 0°C. After stirring at rt for 6 h, the reaction mixture was evaporated in vacuum. The residue was mixed with 4,5- dihydrothiazol-2-amine (44 mg, 0.43 mmol), Cs2C03 (645 mg, 1.98 mmol) and KI (84 mg, 0.5 mmol) in acetonitrile (5 mL). The mixture was stirred at 85 °C for 16 h. After cooled to rt, the reaction mixture was filtered, the filtrate was purified by reversed phase HPLC
(CH3CN/H20 with 0.05% TFA as mobile phase; from 5% to 95%) to give the title
compound as a brown solid (46 mg, 19% yield): 1H NMR (400 MHz, CD3OD) δ: 7.70-7.66 (m, 1H), 7.65-7.57 (m, 2H), 6.31-6.26 (m, 1H), 5.25 (q, J = 6.8 Hz, 1H), 5.18-5.17 (m, 2H), 4.69-4.57 (m, 2H), 4.46 (t, J = 4.8 Hz, 2H), 4.12-3.99 (m, 1H), 3.92-3.70 (m, 3H), 3.52- 3.37 (m, 2H), 1.95-1.91 (m, 2H), 1.67-1.64 (m, 3H). ESI-MS m/z 502.1 [M+H]+.
Example 157
3-chloro-5-(trifluoromethyl)benzyl 2-(l-((4,5-dihydro-lH-imidazol-2-yl)amino)ethyl)- 7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000155_0002
[0383] Following the same condition as Example 156 the title compound was obtained as a white solid (8 mg, 4% yield): 1H NMR (400 MHz, CD3OD) δ: 7.67 (s, 1H), 7.65-7.57 (m, 2H), 6.22-6.17 (m, 1H), 5.22-5.13 (m, 2H), 4.70-4.55 (m, 3H), 4.47-4.40 (m, 2H), 3.92-3.75 (m, 2H), 3.71-3.68 (m, 1H), 3.70 (s, 3H), 1.94-1.86 (m, 2H), 1.53 (d, J = 6.8 Hz, 3H). ESI-MS m/z 485.1 [M+H]+. Example 158
3-chloro-5-(trifluoromethyl)benzyl 2-(piperazine-l-carbonyl)-7,8-dihydi
pyrazolo[ -a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000156_0001
[0384] A mixture of 5-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5, 6,7,8- tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2-carboxylic acid (150 mg, 0.36 mmol), DIEPA (93 mg, 0.72 mmol), HATU (138 mg, 0.36 mmol) and tert-butyl piperazine-l-carboxylate (67 mg, 0.36 mmol) in DMF (2 mL) was stirred at rt for 2 h, the reaction mixture was diluted with EtOAc (30 mL) and washed with brine (2 x 5 mL). The organic layer was dried over anhydrous Na2S04 and concentrated in vacuum. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 1/2) to give the Boc-protected intermediate as a yellow solid (160 mg, 76% yield): ESI-MS m/z 586.2 [M+H]+.
[0385] To a solution of the above intermediate (160 mg, 0.27 mmol) in dioxane (4 mL) was added hydrochloric acid (12 M, 1 mL). The reaction mixture was stirred at rt for 4 h and was evaporated in vacuum, the residue was dissolved in methanol (4 mL) and was adjusted pH = 8-9 with NaOH (4 N). The resulted solution was purified by prep-HPLC (CH3CN/H20 with 10 mM NH4HC03 as mobile phase; from 10% to 95%) to give the title compound as a white solid (100 mg, 76% yield): 1H NMR (400 MHz, DMSO-J6) & 7.82- 7.80 (m, 1H), 7.74-7.68 (m, 1H), 7.66-7.62 (m, 1H), 6.45, 6.43 (s, s, 1H), 5.16, 5.13 (s, s, 2H), 4.64, 4.56 (s, s, 2H), 4.45-4.44 (m, 2H), 3.79-3.72 (m, 4H), 3.50 (bs, 2H), 3.39-3.36 (m, 1H), 2.73-2.59 (m, 4H), 1.88-1.74 (m, 2H); ESI-MS m/z 486.2 [M+H]+.
Example 159
3-chloro-5-(trifluoromethyl)benzyl 2-(5-methyl-2,5-diazabicyclo[2.2.2]octane-2- carboxylate
Figure imgf000156_0002
[0386] To a mixture of 3-chloro-5-(trifluoromethyl)benzyl 2-(2,5- diazabicyclo[2.2.2]octane-2-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine- 5(6H)-carboxylate (130 mg, 0.247 mmol) in CH3OH (5 mL) were added aqueous formalin solution (12 M, 0.103 mL, 1.235 mmol) and NaBH3CN (78 mg, 1.235 mmol). The mixture was stirred at rt for 3 h, diluted with EtOAc (20 mL), washed with saturated aqueous NaHC03 (2 x 5 mL), dried over sodium sulfate anhydrate and concentrated in vacuum. The residue was purified by prep-HPLC (CH3CN/H20 with 10 mM NH4HC03 as mobile phase; from 5% to 95%) to give the title compound as a white solid (70 mg, 52% yield): 1H NMR (400 MHz, DMSO- ) δ: 7.81 (d, J = 9.6 Hz, IH), 7.73-7.56 (m, 2H), 6.54, 6.46 (s, s, IH), 5.16, 5.13 (s, s, 2H), 4.74-4.33 (m, 5H), 3.82-3.63 (m, 3H), 3.41-3.28 (m, IH), 2.90-2.65 (m, 3H), 2.29, 2.28 (s, s, 3H), 2.04-1.89 (m, IH), 1.89-1.63 (m, 4H), 1.60-1.47 (m, IH); ESI-MS m/z 526.0 [M+H]+.
Example 162
3-chloro-5-(trifluoromethyl)benzyl 2-(2,6-dimethylpiperazine-l-carbonyl)-6,7- dihydrop -carboxylate
Figure imgf000157_0001
Stepl
5-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5-
Figure imgf000157_0002
[0387] A mixture of (3-chloro-5-(trifluoromethyl)phenyl)methanol (484 mg, 2.30 mmol, 1.5 eq) and CDI (376 mg, 2.30 mmol, 1.5 eq) in DMF (2 mL) was stirred at rt for 3 h, then ethyl 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2-carboxylate (300 mg, 1.54 mmol) and Et N (155 mg, 1.54 mmol) were added. The mixture was stirred at rt for 16 h, quenched with brine (50 mL), and extracted with ethyl acetate (3 X 50 mL). The combined organic phase was washed with brine (2 X 50 mL), dried over sodium sulfate and evaporated in vacuum to give the crude product which was purified by column chromatography on silica gel (petroleum ether/EtOAc = 5: 1) to give the ester intermediate (400 mg, 60% yield) as a white solid. ESI-MS (M+H)+: 432.1.
[0388] To a solution of above intermediate (400 mg, 0.93 mmol) in THF (6 mL) and H20 (1 mL) was added NaOH (74 mg, 1.86 mmol). The reaction mixture was stirred at rt for 16 h and acidified pH = 6 with IN HC1. The mixture was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (50 mL X 2). The combined organics were dried and concentrated to give the title intermediate as yellow solid (300 mg, 80% yield). ESI-MS (M+H)+: 404.1.
Step2
3-chloro-5-(trifluoromethyl)benzyl 2-(2,6-dimethylpiperazine-l-carbonyl)-6,7- dihydropyrazolo[ 1 ,5-a]pyrazine-5(4H)-carboxylate
Figure imgf000158_0001
[0389] To a mixture of 5-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazine-2-carboxylic acid (140 mg, 0.35 mmol), tert-butyl 3,5- dimethylpiperazine-l-carboxylate (97 mg, 0.45 mmol) and HATU (198 mg, 0.52 mmol) in DMF (3 mL) was added DIPEA (90 mg, 0.69 mmol). The mixture was stirred at rt for 2 h and then concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc = 1:2) to give the Boc-protected intermediate as yellow oil (120 mg, 57% yield). ESI-MS (M+H)+: 600.2.
[0390] To a solution of the above Boc-protected intermediate (120 mg, 0.2 mmol) in dioxane (2 mL) was added cone. HC1 (1 mL). The reaction mixture was stirred at rt for 2 h and concentrated. The residue was purified by reversed phase HPLC (0.05%TFA/H2O: CH3CN = 65%: 35%) to give the title compound as a white solid (87 mg, 87% yield): 1H NMR (400 MHz, CD3OD) ά 7.74 (s, 1H), 7.69 (s, 2H), 6.54 (s, 1H), 5.27 (s, 2H), 5.26-5.15 (m, 2H), 4.84-4.78 (m, 2H), 4.25-4.22 (m, 2H), 4.05-4.01 (m, 2H), 3.40-3.30 (m, 4H), 1.48 (d, J = 7.2 Hz, 6H); ESI-MS (M+H)+: 500.2.
Example 176
3-chloro-5-(trifluoromethyl)benzyl 2-(2,2,4-trimethylpiperazine-l-carbonyl)-7,8- dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000159_0001
[0391] Using 5-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a][l,4]diazepine-2-carboxylic acid and 1,3,3-trimethylpiperazine as starting materials, and following the same condition as described in example 158, the title compound was obtained as a white solid: 1H NMR (400 MHz, CD3OD) ά 7.67-7.51 (m, 3H), 6.58, 6.56 (s, s, IH), 5.19, 5.16 (s s, 2H), 4.72-4.59 (m, 2H), 4.50 (t, J = 4.8 Hz, 2H), 3.99-3.34 (m, 6H), 3.30-3.09 (m, 2H), 2.97 (s, 3H), 1.98-1.87 (m, 2H), 1.63 (s, 6H); ESI-MS m/z 528.2 [M+H]+.
Example 207
3-chloro-5-(trifluoromethyl)benzyl 2-(2,2-dimethylpiperazine-l-carbonyl)-7,8-dihydro- 4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000159_0002
[0392] Using 5-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a][l,4]diazepine-2-carboxylic acid and tert-butyl 3,3-dimethylpiperazine-l- carboxylate as starting materials, and following the same condition as described in example 158, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-Je) S: 7.82-7.79 (m, IH), 7.74-7.62 (m, 2H), 6.46-6.38 (m, IH), 5.15, 5.13 (s, s, 2H), 4.65, 4.56 (s, s, 2H), 4.44-4.43 (m, 2H), 3.80-3.73 (m, 3H), 3.55-3.44 (m, 2H), 3.30-3.29 (m, IH), 2.71 (s, 2H), 1.96-1.94 (m, IH), 1.86-1.74 (m, 2H), 1.00-0.86 (m, 6H); MS m/z 514.0 [M+H]+.
[0393] The following compounds were synthesized using the same conditions as in Examples 158 or 159
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Example 250
3-Chloro-5-(trifluoromethyl)benzyl 2-(2-chloroacetyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000177_0002
[0394] 5-(((3-Chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a][l,4]diazepine-2-carboxylic acid (10 g, 23.4 mmol) was added to thionyl chloride (60 mL) at rt under N2 atmosphere and was heated to reflux for 4 h. Excess thionyl chloride was removed under vacuum and traces were removed by co-evaporation of the residue with toluene under vacuum. The crude acid chloride was then dissolved in anhydrous acetonitrile and cooled to 0 °C under N2 atmosphere. TMSCHN2 (2 M, 24 mL, 48 mmol) was added slowly. The reaction mixture was allowed to warm to rt and stirred for 18 h. The reaction mixture was then cooled again to 0 °C and HCl (6 M, 25 mL) was added and stirring was continued for additional 3h. The reaction mixture was then neutralized with 1.0 M NaOH solution and extracted with ethyl acetate (3 x 150 mL). The combined organic phase was washed with brine (2 xlOO mL), dried over sodium sulfate and evaporated under vacuum to give the crude product which was purified by silica gel column chromatography
(Petroleum ether/EtOAc = 2/1) to yield the titled compound (7 g) which was further purified by crystallization from EtOAc (20 mL) to give the title compound as a white solid (5 g, 48% yield). 1H NMR (400 MHz, DMSO) ά 7.80-7.54 (m, 3H), 6.73, 6.70 (s, s, 1H), 5.14, 5.11 (s, s, 2H), 4.92 (s, 2H), 4.68, 4.60 (s, s, 2H), 4.55-4.52 (m, 2H), 3.80-3.73 (m, 2H), 1.83-1.80 (m, 2H). ESI-MS m/z 450 [M+H]+.
Example 251
3-Chloro-5-(trifluoromethyl)benzyl 2-((8aS)-hexahydro-lH-pyrrolo[2,l-c][l,4]oxazin-3- yl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000178_0001
[0395] To a mixture of 3-chloro-5-(trifluoromethyl)benzyl 2-(2-chloroacetyl)-7,8- dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (100 mg, 0.2 mmol) and (S)- pyrrolidin-2-ylmethanol (20 mg, 0.2 mmol) in DCM (5 mL) was added DIPEA (52 mg, 0.4 mmol). The reaction was stirred at rt for 16 h, then triethylsilane (70 mg, 0.6 mmol) and TFA (680 mg, 6.0 mmol, 30.0 eq) were added. The mixture was stirred at 40 °C for 16 h. After cooling to rt, the mixture was concentrated and the residue was purified by reversed phase HPLC (0.05% ammonia/H20: CH3CN = 40%: 60%) to give the title compound (53 mg, 40% yield) as a yellow solid as a mixture of diastereomers. 1H NMR (400 MHz, CD3OD) δ: 7.67- 7.58 (m, 3H), 6.30-6.18 (m, IH), 5.16 (s, 2H), 4.67-4.53 (m, 3H), 4.43-4.41 (m, 2H), 4.08- 3.95 (m, IH), 3.87-3.77 (m, 3H), 3.47-3.08 (m, IH), 2.98-2.89 (m, IH), 2.69-2.62 (m, 2H), 2.40-2.19 (m, IH), 1.98-1.73 (m, 6H); ESI-MS m/z 499.1; [M+H]+.
Example 252A and 252B
3-Chloro-5-(trifluoromethyl)benzyl 2-((8aR)-hexahydro-lH-pyrrolo[2,l-c][l,4]oxazin-3- yl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000178_0002
[0396] Using (R)-pyrrolidin-2-ylmethanol and following the same condition as in
Example 251, the title compound was obtain and purified by reversed phase HPLC (0.05% ammonia/H20: CH CN = 40%: 60%) to give the title compound as two diastereomers as yellow solids. A (22 mg, 33% yield) 1H NMR (400 MHz, CD3OD) δ: 7.67-7.59 (m, 3H), 6.26-6.18 (m, IH), 5.17 (s, 2H), 4.62-4.52 (m, 3H), 4.43-4.41 (m, 2H), 4.09-4.06 (m, IH), 3.87-3.81 (m, 2H), 3.47-2.32 (m, IH), 3.20-3.10 (m, 2H), 2.43-2.35 (m, IH), 2.28-2.17 (m, 2H), 1.91-1.81 (m, 5H), 1.41-1.34 (m, IH); ESI-MS m/z 499.2[M+H]+. B (60 mg, 72% yield) 1H NMR (400 MHz, CD3OD) δ: 7 '.66-7 '.59 (m, 3H), 6.30-6.21 (m, IH), 5.16 (s, 2H), 4.63-4.57 (m, 3H), 4.43-4.41 (m, 2H), 3.97-3.93 (m, IH), 3.87-3.80 (m, 3H), 2.95-2.88 (m, 2H), 2.68-2.60 (m, 3H), 1.95-1.89 (m, 3H), 1.78-1.74 (m, 3H); ESI-MS m/z 499.2 [M+H]+. Example 253
3-chloro-5-(trifluoromethyl)benzyl 2-((9aS)-octahydropyrido[2,l-c][l,4]oxazin-3-yl)-7,8- dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000179_0001
[0397] Using (S)-piperidin-2-ylmethanol and following the same condition as in
Example 251, the title compound was obtain as a white solid (55 mg, 48% yield) as a mixture of diastereomers. 1H NMR (400 MHz, CD3OD) δ: 7 '.66- '.51 (m, 3H), 6.86-6.81 (m, IH), 5.18-5.16 (m, 2H), 5.04-4.99 (m, IH), 4.85-4.72 (m, 2H), 4.65-4.60 (m, 3H), 4.10-3.60 (m, 6H), 3.40-3.35 (m, IH), 3.30-3.25 (m, IH), 1.96-1.91 (m, 2H), 1.38-1.18 (m, 6H); ESI-MS m/z 513.2 [M+H]+.
Example 254
3-chloro-5-(trifluoromethyl)benzyl 2-((9aR)-octahydropyrido[2,l-c][l,4]oxazin-3-yl)- 7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000179_0002
[0398] Using (R)-piperidin-2-ylmethanol and following the same condition as in
Example 251, the title compound was obtained as a white solid (20 mg, 40% yield) as a mixture of diastereomers. 1H NMR (400 MHz, CD3OD) δ: 7.67-7.56 (m, 3H), 6.39-6.26 (m, IH), 5.37-4.99 (m, 3H), 4.86-4.43 (m, 4H), 4.11-3.36 (m, 8H), 3.30-3.05 (m, IH), 2.36-1.39 (m, 8H); ESI-MS m/z 513.2 [M+H]+.
Example 255
3,5-bis(trifluoromethyl)benzyl 2-((8aS)-hexahydro-lH-pyrrolo[2,l-c][l,4]oxazin-3-yl)- 6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate
Figure imgf000180_0001
Step 1
3,5-bis(trifluoromethyl)benzyl 2-(2-chloroacetyl)-6,7-dihydropyrazolo[ 1 ,5-a]pyrazine- carboxylate
Figure imgf000180_0002
[0399] A solution of 5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazine-2-carboxylic acid (400 mg, 0.91 mmol) in thionyl chloride (8 mL) was heated at reflux for 4 h. Excess thionyl chloride was removed under reduced pressure. The crude acid chloride was then dissolved in anhydrous acetonitrile (10 mL) and cooled to 0 °C under N2 atmosphere. TMSCHN2 (2 M, 0.91 mL, 1.83 mmol) was added slowly. The reaction mixture was allowed to warm to rt and stirred for 18 h. The reaction mixture was then cooled again to 0 °C and HC1 (6 M, 2 mL) was added and stirring was continued for additional 3 h. The reaction mixture was then neutralized with 1.0 M NaOH solution and extracted with ethyl acetate (3 X 15 mL). The combined organic phase was washed with brine (2 X 20 mL), dried over sodium sulfate and evaporated in vacuum to give the crude product which was purified by column chromatography on silica gel (petroleum ether/EtOAc = 2/1) to give the title compound as yellow solid (300 mg, 69% yield). ESI-MS m/z 470.1 [M+H]+.
Step 2
(S)-3,5-bis(trifluoromethyl)benzyl 2-(2-(2-(hydroxymethyl)pyrrolidin-l-yl)acetyl)-6,7- dihydropyrazolo[ 1 ,5-a]pyrazine-5(4H)-carboxylate
Figure imgf000180_0003
[0400] To a mixture of 3,5-bis(trifluoromethyl)benzyl 2-(2-chloroacetyl)-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (100 mg, 0.21 mmol) and (S)-pyrrolidin- 2-ylmethanol (24 mg, 0.23 mmol) in DCM (3 mL) was added DIPEA (55 mg, 0.42 mmol, 2.0 eq). The reaction mixture was stirred at rt for 16 h. Then the mixture was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether/EtOAc = 1 :2) to give the title compound as a yellow solid (70 mg, 60% yield). ESI-MS 535.2 [M+H]+
Step 3
3,5-bis(trifluoromethyl)benzyl 2-((8aS)-hexahydro-lH-pyrrolo[2,l-c] [l,4]oxazin-3-yl)-6,7- dihydropyrazolo[ 1 ,5-a]pyrazine-5(4H)-carboxylate
Figure imgf000181_0001
[0401] To a solution of (S)-3,5-bis(trifluoromethyl)benzyl 2-(2-(2-
(hydroxymethyl)pyrrolidin-l-yl)acetyl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carboxylate
(70 mg, 0.13 mmol, 1.0 eq) in DCM (2 mL) was added triethylsilane (46 mg, 0.39 mmol, 3.0 eq) and TFA (445 mg, 3.90 mmol, 30.0 eq). The reaction mixture was stirred at 40 °C for 16 h. After cooling to rt, the mixture was concentrated and the residue was purified by reversed phase HPLC (0.05%TFA/H2O: CH3CN = 65%: 35%) to give the title compound (50 mg, 74% yield) as a yellow solid: 1H NMR (400 MHz, CD3OD) δ: 8.03 (s, 2H), 7.96 (s, 1H), 6.27-6.25 (m, 1H), 5.35 (s, 2H), 4.80-4.73 (m, 3H), 4.18-4.12 (m, 3H), 4.14-4.08 (m, 2H), 3.90-3.48 (m, 5H), 3.28-3.25 (m, 1H), 2.38-2.25 (m, 4H); ESI-MS m/z 519.2 [M+H]+.
Example 256
3,5-bis(trifluoromethyl)benzyl 2-((8aR)-hexahydro-lH-pyrrolo[2,l-c][l,4]oxazin-3-yl)- 6,7-dihydro carboxylate
Figure imgf000181_0002
[0402] Using (R)-pyrrolidin-2-ylmethanol and 3,5-bis(trifluoromethyl)benzyl 2-(2- chloroacetyl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate as starting material and following the same condition as in Example 255, the title compound was obtained as a yellow solid (16 mg, 23% yield). 1H NMR (400 MHz, CD3OD) δ: 8.02 (s, 2H), 7.95 (s, 1H), 6.26-6.24 (m, 1H), 5.34 (s, 2H), 4.89-4.73 (m, 3H), 4.18-4.15 (m, 3H), 4.05-3.95 (m, 2H), 3.75-3.36 (m, 5H), 3.27-3.24 (m, 1H), 2.32-2.23 (m, 4H); ESI-MS m/z 519.1 [M+H]+. Example 257
3-chloro-5-(trifluoromethyl)benzyl 2-(2-(3-methylmorpholino)acetyl)-7,8-dihydro-4H-
Figure imgf000182_0001
[0403] To a solution of 5-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-
5,6,7, 8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2-carboxylic acid (50 mg, 0.1 mmol) in acetonitrile (3 mL) were added 3-methylmorpholine (20 mg, 0.2 mmol) and TEA (23 mg, 0.22 mmol). The mixture was stirred at 50 °C for 3 h. After cooling to rt, the mixture was purified by reversed phase HPLC (MeCN and H20 with 0.05% TFA as mobile phase) to give the title compound as a white solid (33 mg, 55% yield). 1H NMR (400 MHz, CD3OD) δ: 7.66-7.64 (m, IH), 7.55-7.51 (m, 2H), 6.84-6.80 (m, IH), 5.18-5.15 (m, 2H), 4.82-4.59 (m, 5H), 4.03-4.00 (m, 2H), 3.91-3.88 (m, 2H), 3.68-3.59 (m, 2H), 3.35 (s, 4H), 1.96-1.90 (m, 2H), 1.34 (br, 3H); ESI-MS m/z 515.1 [M+H]+.
[0404] The following compounds were synthesized using the same conditions as in
Example 257
Figure imgf000182_0002
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Example 274
3-chloro-5-(trifluoromethyl)benzyl 2-(piperidin-4-ylamino)-6,7-dihydropyrazolo[l,5-
Figure imgf000185_0002
[0405] A mixture of 3-chloro-5-(trifluoromethyl)benzyl 2-amino-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (190 mg, 0.5 mmol), tert-butyl 4- oxopiperidine-1 -carboxylate (150 mg, 0.75 mmol) and Ti(OEt)4 (290 mg, 1.0 mmol) in THF (3 mL) was heated at 100 °C for 2 h under microwave condition. The mixture was cooled down and NaBH3CN (67 mg, 1.0 mmol) was added. The reaction was heated at 100 °C for 1 h and diluted with water (50 mL). The mixture was extracted with EtOAc (50 mLX 2). The combined organic layer was concentrated and the residue was purified by prep. TLC on silica gel (petroleum ether/EtOAc = 1 : 1) to give the Boc-protected intermediate as a yellow solid (120 mg, 40% yield): 1H NMR (400 MHz, CDC13) δ: 7.59 (s, IH), 7.55 (s, IH), 7.50 (s, IH), 5.40 (s, IH), 5.19 (s, 2H), 4.68-4.64 (m, 2H), 4.01-3.94 (m, 5H), 3.51-3.39 (m, 4H), 2.93-2.88 (m, 2H), 2.04-2.00 (m, 2H), 1.46 (s, 9H); ESI-MS m/z 558.2 [M+H] . [0406] To a solution of the above intermediate (120 mg, 0.2 mmol) in dioxane (2 mL) was added cone. HC1 (1 mL). The reaction mixture was stirred at rt for 3 h and concentrated. [0407] The residue was purified by reversed phase HPLC (MeCN and H20 with 0.05% TFA as mobile phase) to give the title compound as a yellow solid (62 mg, 50% yield). 1H NMR (400 MHz, CD3OD) δ: 7.73 (s, 1H), 7.71-7.69 (m, 2H), 5.25 (s, 2H), 4.91 (s, 1H), 4.74-4.69 (m, 2H), 4.04-4.00 (m, 4H), 3.60-3.55 (m, 1H), 3.47-3.43 (m, 2H), 3.15-3.08 (m, 2H), 2.25-2.21 (m, 2H), 1.78-1.68 (m, 2H);
ESI-MS m/z 458.2 [M+H].
Example 275
2-(3-chloro-5-(trifluoromethyl)benzyl) 8-ethyl 4,5-dihydro-lH-pyrrolo[l,2- a] [ 1 ,4] diazepine-2,8(3H)-dicarboxylate
Figure imgf000186_0001
[0408] A mixture of (3-chloro-5-(trifluoromethyl)phenyl)methanol (305 mg, 1.5 mmol), CDI (243 mg, 1.5 mmol) in DMF (5 mL) was stirred at rt for 2 h, followed by adding DMAP (122 mg, 1.0 mmol), TEA (202 mg, 2.0 mmol) and ethyl 2,3,4,5-tetrahydro-lH- pyrrolo[l,2-a][l,4]diazepine-8-carboxylate (305 mg, 1.0 mmol). The mixture was stirred at rt for 16 h, quenched with brine (10 mL), and extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with brine (2 x 15 mL), dried over sodium sulfate and evaporated in vacuum to give a crude product which was purified by prep-TLC (petroleum ether/ethyl acetate = 3/1) to give the title compound as a white solid. (354 mg, 66% yield); ESI-MS m/z 445.1 [M+H].
Example 276
2-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-2,3,4,5-tetrahydro-lH- pyrrolo[l ,2 ylic acid
Figure imgf000186_0002
[0409] To a mixture of 2-(3-chloro-5-(trifluoromethyl)benzyl) 8-ethyl 4,5-dihydro- lH-pyrrolo[l,2-a][l,4]diazepine-2,8(3H)-dicarboxylate (222 mg, 0.5 mmol) in EtOH (10 mL) and water (2 mL) was added NaOH (160 mg, 4.0 mmol). Then the mixture was stirred at 80°C for 8 h and was adjusted to pH = 4 with HC1 (1 N). The solid was collected and was washed with water (5 mL), dried in vacuum to give the title compound as white solid (150 mg, 72% yield).
Example 277
3-chloro-5-(trifluoromethyl)benzyl 8-(4-methylpiperazine-l-carbonyl)-4,5-dihydro-lH- pyrrolo[l , rboxylate
Figure imgf000187_0001
[0410] To a solution of 2-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-
2,3,4,5-tetrahydro-lH-pyrrolo[l,2-a][l,4]diazepine-8-carboxylic acid (100 mg, 0.24 mmol) in DMF (3 mL) were added 1-methylpiperazine (48 mg, 0.48 mmol), HATU (91 mg, 0.24 mmol) and DIPEA (62 mg, 0.48 mmol). The mixture was stirred at rt for 3 h, quenched with brine (15 mL), and extracted with ethyl acetate (3 x 30 mL). The combined organic phase was washed with brine (2 x 10 mL), dried over sodium sulfate and evaporated in vacuum to give the crude product which was purified by prep-HPLC (ACN/H20 with 0.05% TFA as mobile phase; from 5% to 95%) to yield the title compound as white solid (41 mg, 34% yield). 1H NMR (400 MHz, CD3OD) ά 7.65-7.58 (m, 3H), 7.11-7.09 (m, 1H), 6.26, 6.21 (s, s, 1H), 5.18, 5.13 (s, s, 2H), 4.55-4.48 (m, 2H), 4.23-4.21 (m, 2H), 3.75-3.73 (m, 6H), 2.47-2.43 (m, 4H), 2.33, 2.32 (s, s, 3H), 1.87 (bs, 2H); ESI-MS m/z 499.0 [M+H].
Example 278
3-chloro-5-(trifluoromethyl)benzyl 8-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3- carbonyl)-4,5-dihydro-l ine-2(3H)-carboxylate
Figure imgf000187_0002
[0411] Following the same condition as in Example 277, the titled compound was obtained as a white solid (36 mg, 29% yield). 1H NMR (400 MHz, CD3OD) ά 7.65-7.59 (m, 3H), 7.11-7.09 (m, 1H), 6.27, 6.21 (s, s, 1H), 5.18, 5.13 (s, s, 2H), 4.54-4.48 (m, 2H), 4.35-4.21 (m, 4H), 3.81-3.67 (m, 2H), 3.49-3.37 (m, 1H), 3.20-2.96 (m, 3H), 2.32, 2.31 (s, s, 3H), 2.05-1.97 (m, 2H), 1.94-1.82 (m, 2H), 1.74-1.44 (m, 2H); ESI-MS m/z 525.1
[M+H]. Example 279
3,5-Bis(trifluoromethyl)benzyl 2-amino-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-
5(6H)-carboxylate
Stepl
3,5-Bis(trifluoromethyl)benzyl 2-((tert-butoxycarbonyl)amino)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate
Figure imgf000188_0001
[0412] To a solution of 5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5, 6,7,8- tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2-carboxylic acid (15.0 g, 33 mmol) in t-BuOH (60 mL)/dry toluene (60 mL) were added triethylamine (6.6 g, 66 mmol) and DPPA (11 g, 39.6 mmol). The reaction mixture was stirred at RT for 16 h and then heated at refluxed for 8 h. The mixture was cooled down, concentrated, diluted with water (80 mL) and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated. The crude was purified by column chromatography on silica gel (PE/EA 2: 1-1/1) to give the title compound as a yellow solid (7.75 g, 45% yield); ESI-MS m/z 523.1 [M+H]+.
Step2
3,5-Bis(trifluoromethyl)benzyl 2-amino-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-
5(6H)-carboxylate
Figure imgf000188_0002
[0413] To a solution of 3,5-bis(trifluoromethyl)benzyl 2-((tert- butoxycarbonyl)amino)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (5.9 g, 11.3 mmol) in dioxane (20 mL) were added cone. HC1 (6 mL). The mixture was stirred at RT for 8 h. The reaction mixture was then diluted with water (30 mL). The mixture was extracted with ethyl acetate/petroleum ether (50 mLx2, 20: 1). The aqueous phase was adjusted to pH = 8 and extracted with ethyl acetate (100 mL x 2). The combined organics was dried and concentrated to give the title compound as a white solid (4.54 g, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ: 8.06-2.03 (m, 3H), 5.35-5.31 (m, 1H), 5.23 (s, 2H), 4.45-4.37 (m, 4H), 4.09-4.08 (m, 2H), 3.70-3.65 (m, 2H), 1.73-1.72 (m, 2H); ESI-MS m/z 423.0
[M+H]+. Example 280
3,5-bis(trifluoromethyl)benzyl 2-amino-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-
5(6H)-carboxylate
Figure imgf000189_0001
[0414] To a solution of 3,5-bis(trifluoromethyl)benzyl 2-amino-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (5.0 g, 11.8 mmol, 1.0 eq) in CH3CN (25 mL) was added TsOH (2.45 g, 14.2 mmol) and CuBr2 (26 mg, 0.12 mmol). The reaction mixture was cooled to 0 °C, tert-Butyl nitrite (1.82 g, 17.7 mmol) and TBAB (7.6 g, 23.6 mmol) were then added. The reaction mixture was stirred at RT for 1 h. After concentrated, the residue was purified by silica gel column (PE/EA = 2/1) to give the title compound as a white solid (3.21 g, 59% yield). 1H NMR (400 MHz, DMSO-d6) δ: 8.05 (s, 2H), 7.97 (s, 1H), 6.32-6.20 (m, 1H), 5.25 (s, 2H), 4.60-4.53 (m, 2H), 4.40-4.37 (m, 2H), 3.75-3.70 (m, 2H), 1.82-1.77 (m, 2H); ESI-MS m/z 485.9 [M+H]+.
Example 282
3,5-bis(trifluoromethyl)benzyl 2-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000189_0002
[0415] Methanol (76 uL, 1.87 mmol) was added to a mixture of 2.0 M of lithium tetrahydroborate in tetrahydrofuran(l mL) in tetrahydrofuran (4.8 mL, 59 mmol) at RT. 5- (3,5-bis(trifluoromethyl)benzyl) 2-ethyl 7,8-dihydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine- 2,5(6H)-dicarboxylate (0.6 g, 1.2 mmol) was then added. The mixture was then stirred at RT for 4h. The reaction was queched with IN HC1 to pH = 1, stirred at RT for lh. Solid K2C03 was then added to adjust the pH to 8. The mixture was extracted with ethyl acetate. The organic layer was then separated, dried and concentrated. The crude was purified by HPLC to give the the title compound as a light yellow oil (536 mg) which was used in the next step without further purifications. ESI-MS m/z 438.1 [M+H]+.
Example 283
3,5-bis(trifluoromethyl)benzyl 2-(bromomethyl)-7,8-dihydro-4H-pyrazolo[l,5-
Figure imgf000189_0003
[0416] To a solution of 3,5-bis(trifluoromethyl)benzyl 2-(hydroxymethyl)-7,8- dihydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate, 3,5-bis-trifluoromethyl-benzyl ester (0.53 g, 1.2 mmol) in tetrahydrofuran (10 mL) under nitrogen was dropwise added 1 M of phosphorus tribromide in methylene chloride (2.4 mL, 2.42 mmol) at 0 °C. The reaction mixture was stirred at RT for 30min. The reaction mixture was quenched with water, washed with water. The organic phase was separated, dried, filtered and concentrated to give the title compound as a light yellow oil (0.66g) which was immediately in next step without further purifications.
Example 284
3,5-bis(trifluoromethyl)benzyl 2-(aminomethyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000190_0001
[0417] To a stirred solution of 2,4,6-Trimethoxybenzylamine hydrochloride (117 mg,
0.50 mmol) in N,N-dimethylformamide (2.0 mL) was added N,N-diisopropylethylamine (87 uL, 0.50 mmol). The mixture was stirred at RT for 10 min. Potassium carbonate (28 mg, 0.20 mmol) was then added. The mixture was stirred at RT for 20min. A solution of 3,5- bis(trifluoromethyl)benzyl 2-(bromomethyl)-7,8-dihydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine- 5(6H)-carboxylate (50 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL) was then added. The reaction mixture was then stirred at RT overnight. Diluted with ethyl acetate, washed with water (3x). The organic phase was dried, and concentrated. The crude was stirred in a solution of methylene chloride (5 mL) and trifluoroacetic acid (0.1 mL, 1 mmol) at RT overnight. The reaction was then neutralized with 3N NaOH, the organic phase was dried and concentrated. The crude was then purified by HPLC to give the title compound as a white powder (15 mg): 1H NMR (400 MHz, METHANOL-d4) δ 7.85 - 8.01 (m, 3H), 6.19 - 6.38 (m, 1H), 5.25 (d, J = 2.76 Hz, 2H), 4.56 - 4.70 (m, 2H), 4.39 - 4.52 (m, 2H), 4.02 (s, 2H), 3.74 - 3.95 (m, 2H), 1.81 - 1.96 (m, 2H); ESI-MS m/z 437.1 [M+H]+.
Example 285
3,5-bis(trifluoromethyl)benzyl 2-(methoxymethyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000190_0002
[0418] To a solution of 3,5-bis(trifluoromethyl)benzyl 2-(hydroxymethyl)-7,8- dihydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate 3,5-bis-trifluoromethyl-benzyl ester (90 mg, 0.21 mmol) and methyl iodide (64 uL, 1.03 mmol) in N,N-dimethylformamide (2.0 mL) was added sodium hydride (10 mg, 0.25 mmol). The mixture was then stirred at RT for 2h. The mixture was extracted with ethyl acetate. The organic layer was then separated, dried and concentrated. The crude was purified by HPLC to give the title compound as a light yellow oil (38 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.85 (s, 1H), 7.77 (d, J = 5.77 Hz, 2H), 6.14 - 6.39 (m, 1H), 5.21 (s, 2H), 4.39 - 4.63 (m, 6H), 3.78 - 3.88 (m, 2H), 3.41 (s, 3H), 2.02 (br. s., 2H); ESI-MS m/z 452.1 [M+H]+.
Example 286
3-chloro-5-(trifluoromethyl)benzyl 2-(2,2,2-trifluoro-l-hydroxyethyl)-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000191_0001
[0419] To a solution of 3-chloro-5-(trifluoromethyl)benzyl 2-formyl-7,8-dihydro-4H- pyrazolo-[l,5-a][l,4]diazepine-5(6H)-carboxylate (175 mg, 0.44 mmol) in THF (5 mL) were added (trifluoromethyl)trimethylsilane (125 mg, 0.88 mmol) and tetrabutylamonium fluoride (44 uL, 1 N in THF, 0.044 mmol) at RT under nitrogen atmosphere and the resulting mixture was stirred for 16 h. A solution of HC1 (6N, 1 mL) was added and the reaction mixture was stirred for another hour, diluted with water (10 mL), extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with brine (10 mL), dried over sodium sulfate and concentrated. The crude product was purified by HPLC (ACN/H20 with 0.05% NH3 H20 as mobile phase) to give the title compound as a white solid (70 mg, 34% yield): 1H NMR (400 MHz, CD3OD) ά 7.64-7.58 (m, 3H), 6.37, 6.30 (s, s, 1H), 5.16-5.15 (m, 2H), 4.50-4.93 (m, 1H), 4.64-4.57 (m, 2H), 4.45 (t, / = 5.2 Hz, 2H), 3.90-3.81 (m, 2H), 1.91 (s, 2H); ESI-MS m/z 472.0 [M+H]+. Example 287
3-(((5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetra-hydro-4H- pyrazolo[l,5-a][l,4]diazepin-2-yl)methyl)amino)-2,2-dimethylcyclo-butanecarboxylic acid
Figure imgf000192_0001
[0420] To a mixture of 3,5-bis(trifluoromethyl)benzyl 2-formyl-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (160 mg, 0.37 mmol) and 3-Amino-2,2- dimethyl-cyclobutanecarboxylic acid (105 mg, 0.74 mmol) in methanol (2 mL) was heated in microwave at 100 °C for lOmin, 1.0 M of sodium cyanoborohydride in tetrahydrofuran(0.74 mL, 0.74 mmol) was then added. The reaction was stirred ar RT for 16h. The reaction was quenched with water, worked up with ethyl acetate and brine. Dried over MgS04 and concentrated. The crude was purified by HPLC to give the title compound as a white powder (161 mg, TFA salt): 1H NMR (400 MHz, METHANOL-d4) δ 7.93 (br. s., 3H), 6.26 - 6.42 (m, 1H), 5.25 (d, J = 6.27 Hz, 2H), 4.56 - 4.72 (m, 2H), 4.43 - 4.53 (m, 2H), 4.07 (t, J = 6.27 Hz, 2H), 3.77 - 3.95 (m, 2H), 3.44 - 3.57 (m, 1H), 2.73 (t, J = 9.04 Hz, 1H), 2.25 (t, J = 8.91 Hz, 2H), 1.90 (br. s., 2H), 1.31 (s, 3H), 1.17 (s, 3H); ESI-MS m/z 563.2 [M+H]+.
[0421] The following compounds were synthesized using the same conditions as in
Example 287
Figure imgf000192_0002
1H NMR (400 MHz,
METHANOL-d4) δ
7.83 - 8.00 (m, 3H),
6.26 - 6.42 (m, 1H),
5.25 (d, J = 3.01 Hz, 2H), 4.57 - 4.73 (m,
289
563.2 2H), 4.41 - 4.54 (m,
2H), 4.14 (d, J = 3.26
Hz, 2H), 3.76 - 3.95 (m,
2H), 3.13 (d, J = 3.76 Hz, 1H), 2.05 - 2.41 (m,
5H), 1.82 - 1.98 (m, 2H), 1.35 - 1.60 (m, 4H)
Example 290
3,5-bis(trifluoromethyl)benzyl 2-((4-methylpiperazin-l-yl)methyl)-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000193_0001
[0422] To a stirred solution of piperazine, 1-methyl- (50 mg, 0.50 mmol) in N,N- dimethylformamide (2.0 mL) was added potassium carbonate (28mg, 0.20 mmol). The mixture was stirred at rt for lOmin. A solution of 3,5-bis(trifluoromethyl)benzyl 2- (bromomethyl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (50 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL) was then added. The reaction mixture was then stirred at RT for 16h. Diluted with ethyl acetate, washed with water (3x). The organic phase was dried, and concentrated. The crude was purified by HPLC to give the title compound (7 mg). 1H NMR (400 MHz, METHANOL-d4) δ 7.85 - 8.00 (m, 3H), 6.14 - 6.32 (m, 1H), 5.26 (s, 2H), 4.54 - 4.68 (m, 2H), 4.37 - 4.48 (m, 2H), 3.77 - 3.96 (m, 2H), 3.63 - 3.75 (m, 2H), 3.26 (td, J = 1.63, 3.26 Hz, 4H), 2.67 - 3.04 (m, 7H), 1.83 - 1.96 (m, 2H); ESI- MS m/z 520.2 [M+H]+. [0423] The following compounds were synthesized using the same conditions as in Examples 290
Figure imgf000194_0001
Figure imgf000195_0001
1H NMR (400 MHz,
CDC13) δ: 7.94-7.90 (m,
3H), 6.42, 6.37 (s, s, 1H),
5.27 (s, 2H), 4.69-4.62 (m,
2H), 4.52-4.50 (m, 2H),
510
523.2 4.26-4.25 (m, 2H), 3.91- 3.84 (m, 2H), 3.61-3.46
(m, 2H), 3.35-3.32 (m,
1H), 3.30-3.09 (m, 2H),
2.33-2.22 (m, 2H), 2.10- 1.92 (m, 4H)
Example 298
3,5-bis(trifluoromethyl)benzyl 2-(4-(2-hydroxyethyl)piperazine-l-carbonyl)-7,8-
Figure imgf000196_0001
[0424] To a solution of 5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5, 6,7,8- tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2-carboxylic acid (110 mg, 0.24 mmol) in N,N- dimethylformamide (3.3 mL, 43 mmol) was added N,N,N',N'-tetramethyl-0-(7- azabenzotriazol-l-yl)uronium hexafluorophosphate (158 mg, 0.41 mmol) and N,N- diisopropylethylamine (0.13 mL, 0.73 mmol). Stirred at RT for 10 min, 1-piperazineethanol (63 mg, 0.49 mmol) was then added. The reaction was stirred at RT for 2h. Diluted with ethyl acetate, washed with water (3x). The organic phase was then dried and concentrated. The crude was purified by HPLC to give the title compound as a white powder (114 mg). 1H NMR (400 MHz, DMSO-d6) δ 7.92 - 7.92 (m, OH), 7.91 - 8.10 (m, 3H), 6.55 (d, J = 17.57 Hz, 1H), 5.23 (br. s., 2H), 4.37 - 4.77 (m, 6H), 3.65 - 3.88 (m, 4H), 3.55 (br. s., 3H), 2.96 - 3.29 (m, 5H), 1.72 - 1.93 (m, 2H); ESI-MS m/z 564.2 [M+H]+.
Example 299
3,5-bis(trifluoromethyl)benzyl 2-((methylsulfonyl)carbamoyl)-7,8-dihydro-4H-
Figure imgf000196_0002
[0425] To a solution of 3,5-bis(trifluoromethyl)benzyl 2-(chlorocarbonyl)-7,8- dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (151 mg, 0.32 mmol) in dichloromethane (5 mL) was added methanesulfonamide (61 mg, 0.64 mmol),
diisopropylethylamine (83 mg, 0.64 mmol) and DMAP (10 mg). The mixture was stirred at RT for 5 h, and then diluted with dichloromethane (60 mL), washed with aqueous NH4C1 (30 mL x 2) and brine (15 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by HPLC (CH3CN/H2O with lOmM NH4HCC"3 as mobile phase) to give the title compound as a white solid (62 mg, 37% yield). 1H NMR (400 MHz, DMSO-J6) & 11.61 (s, 1H), 8.07-8.04 (m, 2H), 7.94 (s, 1H), 6.82, 6.74 (s, s, 1H), 5.25, 5.22 (s, s, 2H), 4.69, 4.59 (s, s, 2H), 4.54-4.53 (m, 2H), 3.80-3.74 (m, 2H), 3.28 (s, 3H), 1.86-1.81 (m, 2H); ESI-MS m/z 529.1 [M+H]+.
Example 300
3,5-bis(trifluoromethyl)benzyl 2-(chlorosulfonyl)-7,8-dihydro-4H-pyrazolo[l,5-
Figure imgf000197_0001
[0426] A solution of sodium nitrite (258 mg, 3.73 mmol) in water (3 mL) was added to a stirred solution of 3,5-bis(trifluoromethyl)benzyl 2-amino-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]-diazepine-5(6H)-carboxylate (1.5 g, 3.55 mmol) in acetic acid/concentrated hydrochloric acid/water (2: 1: 1, 20 mL) at -10°C and stirred for 30 minutes. The solution was added to a stirred suspension of copper sulfate (97 mg, 0.60 mmol) in acetic acid saturated with sulphur dioxide (16 mL) at -10°C for 1 h. The mixture was allowed to warm to RT for another hour and adjusted to PH = 7 with LiOH, diluted with ethyl acetate (60 mL), washed with water (10 mL x 2) and brine (15 mL). The organic phase was dried over sodium sulfate and concentrated. The crude was purified by column chromatography (PE/EA = 1/2) to give the title compound as a yellow solid (900 mg, 50% yield); ESI-MS m/z 506.0 [M+H]+.
Example 301
3,5-bis(trifluoromethyl)benzyl 2-sulfamoyl-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000197_0002
[0427] A mixture of 3,5-bis(trifluoromethyl)benzyl 2-(chlorosulfonyl)-7,8-dihydro-
4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (80 mg, 0.16 mmol), ammonia (1 mL, 37% in water) in THF (4 mL) was stirred at RT for 16 h. The mixture was concentrated, the residue was purified by HPLC (CH3CN/H20 with lOmM NH4HC03 as mobile phase) to give the title compound as a yellow solid (26 mg, 34% yield). 1H NMR (400 MHz, DMSO-J6) & 8.08 (s, 3H), 7.39-7.36 (m, 2H), 6.53, 6.46 (s, s, 1H), 5.24, 5.22 (s, s, 2H), 4.69, 4.59 (s, s, 2H), 4.49-4.48 (m, 2H), 3.79-3.74 (m, 2H), 1.86 (bs, 2H); ESI-MS m/z 487.1 [M+H]+.
Example 302
3,5-bis(trifluoromethyl)benzyl 2-(N,N-dimethylsulfamoyl)-7,8-dihydro-4H-pyrazolo[l,5-
Figure imgf000198_0001
[0428] To a mixture of 3,5-bis(trifluoromethyl)benzyl 2-(chlorosulfonyl)-7,8-dihydro-
4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (80 mg, 0.16 mmol) in THF (4 mL) were added triethylamine (32 mg, 0.32 mmol) and dimethylamine hydrochloride (26 mg, 0.32 mmol). The reaction was stirred at RT for 16h. The reaction mixture was then concentrated under reduced pressure. The crude was purified by HPLC (CH3CN/H2O with lOmM
NH4HCO3 as mobile phase) to give the title compound as a yellow solid (40 mg, 49% yield): 1H NMR (400 MHz, CDC13) & 7.85 (s, 1H), 7.78 (s, 2H), 6.63, 6.51 (s, s, 1H), 5.22, 5.20 (s, s, 2H), 4.58, 4.54 (s, s, 2H), 4.53-4.52 (m, 2H), 3.86-3.83 (m, 2H), 2.80 (s, 6H), 2.03-2.01 (m, 2H); ESI-MS m/z 515.1 [M+H]+.
[0429] The following compounds were synthesized using the same conditions as in Example 302
Figure imgf000198_0002
Figure imgf000199_0001
Example 313
3,5-bis(trifluoromethyl)benzyl 2-(piperidin-4-ylamino)-7,8-dihydro-4H-pyrazolo[l,5- a] te
Figure imgf000199_0002
[0430] To a mixture of 3,5-bis(trifluoromethyl)benzyl 2-amino-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (500 mg, 1.18 mmol) in THF (10 mL) were added tert-butyl 4-oxopiperidine-l-carboxylate (235 mg, 1.18 mmol) and Ti (OiPr)4 (1.67 g, 5.90 mmol). The mixture was stirred at 30 °C for 16 h, followed by the addition of
NaB¾CN (148 mg, 2.36 mmol), and the reaction mixture was stirred at 70 °C for 5 h. The mixture was diluted with ethyl acetate, washed with water, and the organic layer was dried and concentrated. The crude was purified by column chromatography on silica gel (PE/EA = 1/1) to give the Boc-protected intermediate as a yellow oil (390 mg, 54% yield): ESTMS m/z 606.1 [M+H]+.
To a solution of 3,5-bis(trifluoromethyl)benzyl 2-((l-(tert-butoxycarbonyl)piperidin-4- yl)amino)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (90 mg, 0.15 mmol) in dichloromethane (4 mL) was added TFA (0.5 mL). The mixture was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure. The crude was purified by HPLC (CH3CN/H20 with 0.05% TFA as mobile phase) to give the title compound as a yellow solid (60 mg, 71% yield): 1H NMR (400 MHz, DMSO-J6) δ: 8.56-8.55 (m, IH), 8.39-8.38 (m, IH), 8.05-8.00 (m, 3H), 5.49, 5.39 (s, s, IH), 5.22 (s, 2H), 4.49-4.40 (m, 2H), 4.13-4.07 (m, 2H), 3.71-3.65 (m, 2H), 3.40-3.37 (m, IH), 3.25-3.22 (m, 2H), 2.93-2.92 (m, 2H), 1.99-1.97 (m, 2H), 1.74- 1.73 (m, 2H), 1.56- 1.49 (m, 2H); ESI-MS m/z 506.0 [M+H]+.
Example 352
3,5-bis(trifluoromethyl)benzyl 2-((l-methylpiperidin-4-yl)amino)-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000200_0001
[0431] Using 3,5-bis(trifluoromethyl)benzyl 2-(piperidin-4-ylamino)-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate as starting material and following the same condition as in example 159, the title compound was obtained as a white powder: 1H NMR (400 MHz, METHANOL-d4) δ 7.84-7.78 (m, 3H), 5.17 (s, 2H), 4.49-4.43 (m, 2H), 4.17-4.16 (m, 2H), 3.74-3.66 (m, 2H), 3.48-3.38 (m, 2.5H), 3.28-3.13 (m, IH), 3.02-2.96 (m, 1.5H), 2.77 (s, 3H), 2.18-2.15 (m, 1.5H), 2.02-1.91 (m, IH), 1.83- 1.82 (m, 2H), 1.66-1.55 (m, 1.5H); ESI-MS m/z 520.1 [M+H]+.
[0432] The following compounds were synthesized using the same conditions as in Example 313:
Figure imgf000200_0002
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Example 328
3,5-bis(trifluoromethyl)benzyl 2-(2-oxopiperidin-l-yl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Stepl
3,5-bis(trifluoromethyl)benzyl 2-(5-bromopentanamido)-7,8-dihydro-4H-pyrazolo[l,5-
Figure imgf000203_0002
[0433] A mixture of 3,5-bis(trifluoromethyl)benzyl 2-amino-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (200 mg, 0.47 mmol), 5-bromopentanoyl chloride (279 mg, 1.41 mmol) and DIEA (182 mg, 1.41 mmol) in THF (3 mL) was stirred at RT for 16 h. Then the mixture was diluted with ethyl acetate (15 mL), washed with water (2x) and brine. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was concentrated to give the title compound as a brown oil (220 mg, Y: 79%) which was used in next step without further purification. ESI-MS m/z 585.1 [M+H]+.
Step2
3,5-bis(trifluoromethyl)benzyl 2-(2-oxopiperidin-l-yl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000204_0001
3,5-bis(trifluoromethyl)benzyl 2-(2- oxopiperidin-1-yl)-7,8-dihydro-4 - - pyrazolo[1 ,5-a][1 ,4]diazepine-5(6H)- carboxylate
[0434] To a solution of 3,5-bis(trifluoromethyl)benzyl 2-(5-bromopentanamido)-7,8- dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (220 mg, 0.38 mmol) in dry THF (5 mL) was added sodium hydride (46 mg, 60%, 1.14 mmol) at 0° C. The mixture was stirred at RT for 4 h. Cooled to 0° C, the reaction was quenched with methanol (5 mL). The reaction mixture was then concentrated under reduced pressure. The crude was purified by HPLC (CH3CN/H20 with 0.05% TFA as mobile phase) to give the title compound as a white solid (68 mg, 35% yield): 1H NMR (400 MHz, CD3OD) δ: 7.95-7.85 (m, 3H), 6.57-6.50 (m, 1H), 5.28, 5.26 (s, s, 2H), 4.62, 4.57 (s, s, 2H), 4.39 (t, J = 5.2 Hz, 2H), 3.93-3.74 (m, 4H), 2.51 (t, J = 6.4 Hz, 2H), 1.99-1.82 (m, 6H); ESI-MS m/z 505.0 [M+H]+.
Example 337
3,5-bis(trifluoromethyl)benzyl 2-acetamido-7,8-dihydro-4H-pyrazolo[l,5- a][l, ylate
Figure imgf000204_0002
[0435] Using 3,5-bis(trifluoromethyl)benzyl 2-amino-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate and acetyl chloride as stating material and following the same condition as in example 328, step 1, the title compound was prepared as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ 7.95-7.84 (m, 3H), 6.48, 6.45 (s, s, 1H), 5.28, 5.26
(s, s, 2H), 4.60, 4.55 (s, s, 2H), 4.36-4.30 (m, 2H), 3.88-3.76 (m, 2H), 2.08 (s, 3H), 1.88- 1.85 (m, 2H).; ESI-MS m/z 465.1 [M+H]+. Example 338
Synthesis of 3,5-bis(trifluoromethyl)benzyl 2-(4-methylpiperazin-l-yl)-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000205_0001
[0436] To a mixture of 3,5-bis(trifluoromethyl)benzyl 2-bromo-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (280 mg, 0.78 mmol), 1-methylpiperazine (312 mg, 3.12 mmol) and t-BuONa (83 mg, 0.86 mmol) in THF (4 mL) were added Pd2(dba)3 (71 mg, 0.078 mmol) and 2-(di-tert-butyl-phosphino)biphenyl (93 mg, 0.3 mmol) under nitrogen atmosphere. The reaction mixture was heated in microwave at 80 °C for 3 h. After cooled to RT, the reaction mixture was filtered, concentrated and purified by HPLC
(CH3CN/H20 with 0.05% TFA as mobile phase) to give the title compound as a white solid (50 mg, 16% yield): 1H NMR (400 MHz, CD3OD) δ: 7 '.95-7.92 (m, 3H), 5.75, 5.64 (s, s, 1H), 5.26 (s, 2H), 4.55, 4.50 (s, s, 2H), 4.25 (t, J = 5.2 Hz, 2H), 3.82-3.75 (m, 2H), 3.14-3.11 (m, 4H), 2.54 (bs, 4H), 2.32 (s, 3H), 1.89-1.85 (m, 2H); ESI-MS m/z 506.0 [M+H]+.
[0437] The following compounds were synthesized using the same conditions as in Example 338
Figure imgf000205_0002
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Example 361
2-((5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetra-hydro-4H- pyrazolo[l,5-a][l,4]diazepin-2-yl)amino)propanoic acid
Figure imgf000210_0002
[0438] To a solution of 2 3,5-bis(trifluoromethyl)benzyl 2-amino-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate 3,5-bis-trifluoromethyl-benzyl ester (110 mg, 0.26 mmol) in acetone (2 mL) was added sodium carbonate (138 mg, 1.3 mmol) and 3.0 M of aqueous sodium hydroxide solution (1 mL, 3 mmol). Water (0.5 mL) was also added. 2- Bromopropionic acid (0.3 mL, 3 mmol) was then added. When gas formation stopped, the mixture was heated in microwave at 100 °C for lOmin. Another portion of 2-bromopropionic acid (0.3 mL, 3 mmol) was added. The mixture was then heated in microwave at 100 °C for another lOmin. The mixture was then diluted with ethyl acetate, neutralized with 2N HC1. The organic layer was separated, dried and concentrated. The crude was purified by HPLC to give the title compound as a white powder (51 mg). 1H NMR (400 MHz, METHANOL-d4) δ 7.86 - 8.04 (m, 3H), 5.62 - 5.81 (m, 1H), 5.29 (s, 2H), 4.58 (d, J = 19.07 Hz, 2H), 4.28 (d, J = 4.77 Hz, 2H), 4.09 (dd, J = 7.15, 17.69 Hz, 1H), 3.72 - 3.91 (m, 2H), 1.96 (br. s. 2H), 1.41 - 1.51 (m, 3H); ESI-MS m/z 495.1 [M+H]+.
[0439] The following compounds were synthesized using the same conditions as in
Example 361
Figure imgf000211_0002
Example 369
3-chloro-5-(trifluoromethyl)benzyl 2-(pyridin-4-yl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000211_0001
[0440] To a mixture of 3-chloro-5-(trifluoromethyl)benzyl 2-bromo-7,8-dihydro pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (100 mg, 0.22 mmol), pyridin-4-ylboronic acid (30 mg, 0.24 mmol) and K2C03 (60 mg, 0.44 mmol) in dioxane (5 mL) and H20 (1 mL) was added Pd(PPh3)4 (25 mg, 0.022 mmol). The mixture was stirred at 90 °C for 16 h under N2. After cooling to rt, the mixture was filtered and the filtrate was purified by reversed phase HPLC (0.05% TFA/H20: CH3CN = 65%: 35%) to give the title compound (60 mg, 50% yield) as a white solid: 1H NMR (400 MHz, CD3OD) δ: 8.76-8.73 (m, 2H), 8.38-8.33 (m, 2H), 7.63-7.49 (m, 3H), 7.07-7.01 (m, 1H), 5.21-5.17 (m, 2H), 4.74-4.69 (m, 2H), 4.64-4.62 (m, 2H), 3.92-3.87 (m, 2H), 1.99-1.95 (m, 2H); ESI-MS m/z 451.1 [M+H]+.
[0441] The following compounds were synthesized using the same conditions as in Example 369
Figure imgf000212_0001
Example 371
3,5-bis(trifluoromethyl)benzyl 2-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-7,8-dihydro- 4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000213_0001
[0442] A solution of l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-
1,2,3,6-tetrahydro-pyridine hydrochloride (96 mg, 0.37 mmol) and 3,5- bis(trifluoromethyl)benzyl 2-bromo-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)- carboxylate (120 mg, 0.25 mmol) in 1,4-dioxane (2.4 mL, 31 mmol) and dimethyl sulfoxide (0.6 mL) was degassed for 10 min. Bis(tricyclohexylphosphine)palladium (0) (16 mg, 0.024 mmol) and 1.2 M of saturated aqueous NaHC03 solution (0.6 mL, 0.74 mmol) were then added. The reaction was heated in microwave at 120 °C for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water. The organic layer was then dried, concentrated. The crude was then purified by HPLC to give the title compound as a white powder (86 mg): 1H NMR (400 MHz, DMSO-d6) δ 7.90 - 8.13 (m, 3H), 6.25 - 6.48 (m, 1H), 5.94 - 6.18 (m, 1H), 5.23 (d, J = 7.28 Hz, 2H), 4.48 - 4.70 (m, 2H), 4.38 (d, J = 4.52 Hz, 2H), 3.93 (d, J = 17.07 Hz, 1H), 3.63 - 3.83 (m, 3H), 3.54 (br. s., 1H), 3.19 (br. s., 1H), 2.87 (d, J = 4.02 Hz, 3H), 2.55 - 2.80 (m, 2H), 1.78 (br. s., 2H); ESI-MS m/z 503.2 [M+H]+.
Example 372
3,5-bis(trifluoromethyl)benzyl 2-(l-methylpiperidin-4-yl)-7,8-dihydro-4H-pyrazolo[l,5-
Figure imgf000213_0002
[0443] To a dry, nitrogen filled flask was added 10% palladium on carbon (16 mg,
0.015 mmol). A mixture of 3,5-bis(trifluoromethyl)benzyl 2-(l-methyl-l,2,3,6- tetrahydropyridin-4-yl)-7,8-dihydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate (60 mg, 0.1 mmol) in ethanol (4.0 mL) was then added to the flask under nitrogen. The flask was then applied vacuum, followed by flashing with hydrogen. The degas process repeated for three times. The reaction mixture was then stirred under hydrogen bolloon overnight. Filter off the catalyst, the solution was concentrated. The crude was then purified by HPLC to give the title compound as a white powder (18 mg): 1H NMR (300 MHz, DMSO-d6) d 7.92 - 8.13 (m, 3H), 5.88 - 6.10 (m, 1H), 5.23 (br. s., 2H), 4.46 - 4.64 (m, 2H), 4.34 (br. s., 2H), 3.71 (br. s., 2H), 3.46 (d, J = 11.33 Hz, 2H), 2.89 - 3.14 (m, 2H), 2.60 - 2.86 (m, 4H), 1.92 - 2.16 (m, 2H), 1.57 - 1.88 (m, 4H). ESI-MS m/z 505.3 [M+H]+.
Example 373
3,5-bis(trifluoromethyl)benzyl 2-(l,2,3,6-tetrahydropyridin-4-yl)-7,8-dihydro-4H- pyrazolo boxylate
Figure imgf000214_0001
[0444] A solution of tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-l(2H)-carboxylate (134 mg, 0.43 mmol) and 3,5-bis(trifluoromethyl)benzyl 2-bromo-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (140 mg, 0.29 mmol) in 1,4-dioxane (2.8 mL, 36 mmol) was degassed with nitrogen for 10 min.
Bis(tricyclohexylphosphine)palladium (0) (19 mg, 0.03 mmol) and 1.2 M of saturated aqueous NaHC03 solution (0.5 mL, 0.6 mmol) were then added. The reaction was heated in microwave at 120 °C for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water. The organic layer was then dried, concentrated. The crude was then purified by ISCO (EtOAc/hexanes gradient 5% to 100%, silica gel 12g column) to give the Boc-protected intermediate as a white powder (120 mg). ESI-MS m/z 589.2 [M+H]+.
[0445] 3,5-bis(trifluoromethyl)benzyl 2-( l-(tert-butoxycarbonyl)- 1,2,3,6- tetrahydropyridin-4-yl)-7,8-dihydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate (50mg) was dissolved in methylene chloride (2.0 mL), and trifluoroacetic acid (0.2 mL) was then added. The mixture was stirred at RT for 2h. Remove the solvent. The crude was purified by HPLC to give the title compound as a white powder (35mg): 1H NMR (400 MHz, DMSO-d6) d 8.75 (br. s., 1H), 7.93 - 8.13 (m, 3H), 6.23 - 6.49 (m, 1H), 5.95 - 6.20 (m, 1H), 5.23 (d, J = 8.53 Hz, 2H), 4.49 - 4.66 (m, 2H), 4.39 (br. s., 2H), 3.64 - 3.84 (m, 4H), 3.26 (br. s., 2H), 2.59 (br. s., 2H), 1.78 (br. s., 2H); ESI-MS m/z 489.3 [M+H]+.
Example 374
3,5-bis(trifluoromethyl)benzyl 2-(l-(tert-butoxycarbonyl)piperidin-4-yl)-7,8-dihydro-
Figure imgf000214_0002
[0446] To a dry, nitrogen filled flask was added 10% palladium on carbon(13 mg,
0.012 mmol). A mixture of 3,5-bis(trifluoromethyl)benzyl 2-(l-(tert-butoxycarbonyl)-l,2,3,6- tetrahydropyridin-4-yl)-7,8-dihydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate (70.0 mg, 0.119 mmol) in ethanol (5.0 mL) was then added to the flask under nitrogen. The flask was then applied vacuum, followed by flashing with hydrogen (3x). The reaction mixture was then striied under hydrogen bolloon overnight. Filter off the catalyst, the solution was concentrated. The crude was then purified by HPLC to give the title compound as a white powder (46 mg): ESI-MS m/z 591.3 [M+H]+.
Example 375
3,5-bis(trifluoromethyl)benzyl 2-(piperidin-4-yl)-7,8-dihydro-4H-pyrazolo[l,5-
Figure imgf000215_0001
[0447] A solution of 3,5-bis(trifluoromethyl)benzyl 2-(l-(tert- butoxycarbonyl)piperidin-4-yl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)- carboxylate (36mg) in methylene chloride (2.0 mL) and trifluoroacetic acid (0.2 mL) was stirred at RT for 2h. Remove the solvent. The crude was purified by HPLC to give the title compound as a white powder (16 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.20 - 8.64 (m, 1H), 7.91 - 8.12 (m, 3H), 5.89 - 6.10 (m, 1H), 5.23 (d, J = 4.02 Hz, 2H), 4.45 - 4.64 (m, 2H), 4.33 (br. s., 2H), 3.73 (d, J = 19.07 Hz, 2H), 3.29 (d, J = 11.80 Hz, 2H), 2.90 - 3.07 (m, 2H), 2.78 (d, J = 10.79 Hz, 1H), 1.97 (d, J = 11.80 Hz, 2H), 1.57 - 1.88 (m, 4H); ESI-MS m/z 491.3 [M+H]+.
[0448] The following compounds were synthesized using the same conditions as in Examples 371-375
Figure imgf000215_0002
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Example 386
2-(5-(((3,5-bis(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahyd]
pyrazolo[ -a][l,4]diazepin-2-yl)acetic acid
Figure imgf000218_0002
Step 1
3,5-bis(Trifluoromethyl)benzyl 2-(2-diazoacetyl)-7,8-dihydro-4H-pyrazolo[l,5- -5(6H)-carboxylate
Figure imgf000218_0003
[0449] To a solution of 5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5, 6,7,8- tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine-2-carboxylic acid (1.0 g, 2.2 mmol, 1.0 eq) in DCM (5 mL) were added SOCl2 (2.64 g, 22 mg, 10.0 eq). The reaction mixture was stirred at rt for 3 h, concentrated in vacuum. DCM (5 mL) was added to the residue, followed by adding 2 M of Trimethylsilyldiazomethane in THF (5.5 mL, 11 mmol, 5 eq) at 0 °C. The mixture was stirred at rt for 16 h, quenched with brine (5 mL), and extracted with DCM (3 x 10 mL). The combined organic phase was washed with brine (2 x 5 mL), dried over sodium sulfate and evaporated in vacuum to give the crude product which was purified by column chromatography on silica gel (PE/EA = 10/1) to yield 3,5-bis(trifluoromethyl) benzyl 2-(2- diazoacetyl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (0.6 g, 57% yield) as a white solid; ESI-MS m/z 476.1 [M+H]+.
Step 2
3,5-bis(Trifluoromethyl)benzyl 2-(2-ethoxy-2-oxoethyl)-7,8-dihydro-4H-pyrazolo[l,5- -5(6H)-carboxylate
Figure imgf000219_0001
[0450] To a solution of 3,5-bis(trifluoromethyl) benzyl 2-(2-diazoacetyl)-7,8-dihydro-
4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (600 mg, 1.26 mmol, 1.0 eq) in EtOH (2 mL) were added pyridine (1 mL). The reaction mixture was heated in a microwave reactor at 170 °C for 20 mins. The resulted solution was purified by column chromatography on silica gel (PE/EA = 5/1) to afford 3,5-bis(trifluoromethyl)benzyl 2-(2-ethoxy-2-oxoethyl)-7,8- dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (350 mg, 56% yield) as white solid: ESI-MS m/z 494.1 [M+H]+.
Step 3
2-(5-(((3,5-bis(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepin-2-yl)acetic acid
Figure imgf000219_0002
[0451] A mixture of 3,5-bis(trifluoromethyl)benzyl 2-(2-ethoxy-2-oxoethyl)-7,8- dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (100 mg, 0.2 mmol, 1.0 eq), lithium hydroxide monohydrate (17 mg, 0.4 mmol, 2.0 eq) in THF (4 mL) and water (1 ml) was stirred at rt for 16 h, adjusted to pH 3-4 with 1 N HCl, concentrated and the residue was purified by prep-HPLC (ACN/H20 with 0.05% TFA as mobile phase; from 5% to 95%) to give the title compound as a white solid (30 mg, 28% yield). 1H NMR (400 MHz, CD3OD) δ: 7.94-7.89 (m, 3H), 6.20, 6.14 (s, s, 1H), 5.26 (s, 2H), 4.61, 4.56 (s, s, 2H), 4.39 (t, J= 4.4 Hz, 2H), 3.87-3.79 (m, 2H), 3.53 (s, 2H), 1.90-1.87 (m, 2H); ESI-MS m/z 466.2 [M+H]+. Example 387
2-(5-(((3,5-bis(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahyd]
pyrazolo[l,5-a][l,4]diazepin-2-yl)propanoic acid
Figure imgf000220_0001
Step 1
3,5-bis(Trifluoromethyl)benzyl 2-(l-ethoxy-l-oxopropan-2-yl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate
Figure imgf000220_0002
[0452] To a solution of 3,5-bis(trifluoromethyl)benzyl 2-(2-ethoxy-2-oxoethyl)-7,8- dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (150 mg, 0.30 mmol, 1.0 eq) in dry THF (5 mL) was added Lithium diisopropylamide (0.18 mL, 2M in THF, 0.36 mmol, 1.2 eq) at -70°C under a nitrogen atmosphere, the reaction mixture was stirred at -70°C for 15 min, followed by adding CH3I (37 uL, 0.6 mmol, 2.0 eq).The reaction mixture was slowly warmed to rt and stirred for 16 h, quenched with saturated ammonium chloride aqueous solution (10 mL), extracted with ethyl acetate (3x15 mL). The combined organic phase was washed with water (5 mL), dried over MgS04 and concentrated, the residue was purified by prep-HPLC (ACN/H20 with 0.05% TFA as mobile phase; from 5% to 95%) to give the product as a white solid (100 mg, 65% yield). ESI-MS m/z 508.1 [M+H]+.
Step 2
2-(5-(((3,5-bis(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid
Figure imgf000220_0003
[0453] The title compound was synthesized according to the procedure described in
Example 7 (26 mg, yield 28%). 1H NMR (400 MHz, CD3OD) δ: 7.95-7.93 (m, 3H), 6.20, 6.13 (s, s, 1H), 5.26 (s, 2H), 4.63-4.57 (m, 2H), 4.42-4.39 (m, 2H), 3.87-3.80 (m, 2H), 3.72- 3.69 (m, 1H), 1.91 (bs, 2H), 1.44 (m, 3H); ESI-MS m/z 480.1 [M+H]+. Example 388
2-(5-(((3,5-bis(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a][l,4]diazepin-2-yl)propanoic acid
Figure imgf000221_0001
Step 1
3,5-bis(Trifluoromethyl)benzyl 2-(l-ethoxy-l-oxopropan-2-yl)-7,8-dihydro-4H-pyrazolo[l,5- -5(6H)-carboxylate
Figure imgf000221_0002
[0454] To a solution of T15-63-E (150 mg, 0.30 mmol, 1.0 eq) in dry DMF (5 mL) was added NaH (48 mg, 60%, 1.2 mmol, 4.0 eq) at 0°C under a nitrogen atmosphere, the reaction mixture was stirred at 0°C for 15 min, followed by adding CH3I (75 uL, 1.2 mmol, 4.0 eq). The mixture was stirred at rt 16 h, quenched with water (15 mL), extracted with ethyl acetate (3x20 mL). The combined organic phase was washed with water (10 mL), dried over MgS04 and concentrated, the residue was purified by prep-HPLC (ACN/H20 with 0.05% TFA as mobile phase; from 5% to 95%) to give the product as a white solid (105 mg, 66% yield). ESI-MS m/z 522.1 [M+H]+.
Step 2
2-(5-(((3,5-bis(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid
Figure imgf000221_0003
[0455] The titled compound was synthesized according to the procedure described in
Example 7 (19 mg, 19% yield). 1H NMR (400 MHz, CD3OD) δ: 7.96-7.95 (m, 3H), 6.20, 6.12 (s, s, 1H), 5.25 (s, 2H), 4.61, 4.56 (s, s, 2H), 4.40 (t, J = 4.8 Hz, 2H), 3.86-3.80 (m, 2H), 1.91 (bs, 2H), 1.50, 1.48 (s, s, 6H); ESI-MS m/z 494.1 [M+H]+.
Example 389
3,5-bis(Trifluoromethyl)benzyl 2-(l,2-diamino-2-oxoethyl)-7,8-dihydro-4H-pyrazolo[l,5- a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000221_0004
Step 1
3,5-bis(Trifluoromethyl)benzyl 2-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[ 1 ,5- -5(6H)-carboxylate
Figure imgf000222_0001
[0456] To a mixture of 5-(3,5-bis(trifluoromethyl)benzyl) 2-ethyl 7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-2,5(6H)-dicarboxylate (479 mg, 1 mmol, 1.0 eq) in anhydrous THF (10 mL) was added LiBH4 (109 mg, 5 mmol, 5.0 eq). The mixture was stirred at rt for 16 h, quenched with saturated aqueous NH4C1 solution (20 mL), extracted with ethyl acetate (3 x 40 mL). The combined organic phase was washed with brine (2 x 10 mL), dried over sodium sulfate and evaporated in vacuum to give the crude product 3,5- bis(trifluoromethyl)benzyl 2-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[ 1 ,5- a][l,4]diazepine-5(6H)-carboxylate (328 mg, Y: 75%), which was used in the next step reaction without purification. ESI-MS m/z 438.1 [M+H]+.
Step 2
3,5-bis(Trifluoromethyl)benzyl 2-formyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine- -carboxylate
Figure imgf000222_0002
[0457] To a solution of 3,5-bis(trifluoromethyl)benzyl 2-(hydroxymethyl)-7,8- dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (800 mg, 1.83 mmol, 1.0 eq) in EA (30 mL) was added IBX (1.54 g, 5.49 mmol, 3.0 eq). The reaction mixture was stirred under reflux for 3 h. The mixture was washed with saturated aqueous sodium bicarbonate (2 x 20 mL) and H20 (20 mL). The organic layer was dried and concentrated off to give 3,5- bis(trifluoromethyl)benzyl 2-formyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)- carboxylate (716 mg, 90% yield) as a yellow oil. ESI-MS m/z 436.1 [M+H]+.
Step 3
3,5-bis(Trifluoromethyl)benzyl 2-(amino(cyano)methyl)-7,8-dihydro-4H-pyrazolo[l,5- -5(6H)-carboxylate
Figure imgf000222_0003
[0458] To a solution of 3,5-bis(trifluoromethyl)benzyl 2-formyl-7,8-dihydro-4H- pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (660 mg, 1.52 mmol, 1.0 eq) in CH3OH (2 mL) were added TMSCN (165 mg, 1.67 mmol, 1.1 eq), Znl2 (48 mg, 0.152 mmol, 0.1 eq) and NH3 (7 M CH3OH, 2.2 mL, 15.4 mmol, 10 eq). The reaction mixture was stirred at rt for 16 h, concentrated and the residue was purified by prep-HPLC (ACN/H20 with 0.05% TFA as mobile phase; from 5% to 95%) to give 3,5-bis(trifluoromethyl)benzyl 2- (amino(cyano)methyl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (300 mg, 42% yield) as a yellow oil. ESI-MS m/z 462.1 [M+H]+.
Step 4
3,5-bis(Trifluoromethyl)benzyl 2-(l,2-diamino-2-oxoethyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate
Figure imgf000223_0001
[0459] To a solution of 3,5-bis(trifluoromethyl)benzyl 2-(amino(cyano)methyl)-7,8- dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (150 mg, 0.325 mmol, 1.0 eq) in CH3OH (8 mL) and DMSO (4 mL) were added NaOH (26 mg, 0.65 mmol, 2.0 eq) and H202 ( 35% in water, 159 mg, 1.625 mmol, 5.0 eq). The mixture was stirred at rt for 30 min, concentrated and the residue was purified by prep-HPLC (ACN/H20 with 0.05% TFA as mobile phase, from 5% to 95%) to give 3,5-bis(trifluoromethyl)benzyl 2-(l,2-diamino-2- oxoethyl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (100 mg, 64% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ: 8.47 (s, 2H), 8.09-8.07 (m, 3H), 7.86-7.82 (m, 1H), Ί .62-1.59 (m, 1H), 6.32, 6.25 (s, s, 1H), 5.21 (s, 2H), 4.79-4.78 (m, 1H), 4.72-4.56 (m, 2H), 4.43-4.42 (m, 2H), 3.79-3.78 (m, 2H), 1.83-1.82 (m, 2H); ESI-MS m/z 480.1 [M+H]+.
Example 390
2-Amino-2-(5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- -a][l,4]diazepin- -yl)acetic acid
Figure imgf000223_0002
[0460] To a solution of 3,5-bis(trifluoromethyl)benzyl 2-(l,2-diamino-2-oxoethyl)-
7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate (70 mg, 0.146 mmol, 1.0 eq) in CH3OH (1 mL) were added H20 (1 mL) and TFA (1 mL). The reaction mixture was stirred at 100 °C for 16 h. The mixture was concentrated off and the residue was purified by prep-HPLC (ACN/H20 with lOmM NH4HC03 as mobile phase; from 5% to 95%) to give 2- amino-2-(5-(((3,5-bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a][l,4]diazepin-2-yl)acetic acid (10.5 mg, 15% yield) as a white solid. 1H NMR (400 MHz, DMSO- ) S: 8.07 (s, 3H), 6.08, 6.03 (s, s, 1H), 5.26-5.18 (m, 2H), 4.65-4.46 (m, 2H), 4.33-4.32 (m, 2H), 4.05-4.04 (m, 1H), 3.75-3.61 (m, 2H), 1.79-1.78 (m, 2H); ESI-MS m/z 481.1 [M+H]+.
Example 391
3,5-bis(Trifluoromethyl)benzyl 2-(N'-hydroxycarbamimidoyl)-7,8-dihydro-4H- -a][l,4]diazepine-5(6H)-carboxylate
Figure imgf000224_0001
[0461] To a mixture of compound 3,5-bis(trifluoromethyl)benzyl 2-cyano-7,8- dihydro-4H-pyrazolo[l,5-a] [l,4]diazepine-5(6H)-carboxylate (100 mg, 0.23 mmol, 1.0 eq) in ethanol (3 mL) and CH2C12 (0.3 mL) were added hydroxylamine hydrochloride (24 mg, 0.35 mmol, 1.5 eq) and triethylamine (40 mg, 0.39 mmol, 1.7 eq). The mixture was stirred at rt for 16 h, diluted with EtOAc (10 mL), washed with brine (10 mL), filtered and concentrated to give the crude product which was purified by prep-HPLC (CH3CN/H20 with 10 mM
NH4HC03 as mobile phase; from 20% to 95%) to furnish compound 3,5- bis(trifluoromethyl)benzyl 2-(N'-hydroxycarbamimidoyl)-7,8-dihydro-4H-pyrazolo[ 1 ,5- a] [l,4]diazepine-5(6H)-carboxylate (93 mg, Y: 87%) as a white solid. 1H NMR (400 MHz, CD3OD) δ: 7.95-7.88 (m, 3H), 6.49, 6.43 (s, s, 1H), 5.27, 5.25 (s, s, 2H), 4.65, 4.59 (s, s, 2H), 4.49-4.47 (m, 2H), 3.88-3.82 (m, 2H), 1.91 (s, 2H). ESI-MS m/z 466.1 [M+H]+.
Example 392
3,5-bis(Trifluoromethyl)benzyl 2-(5-methyl-l,2,4-oxadiazol-3-yl)-7,8-dihydro-4H- -a][l,4]diazepine-5(6H)-carboxylate
[0462] To a mixture of 3,5-bis(trifluoromethyl)benzyl 2-(N'-hydroxycarbamimidoyl)-
7,8-dihydro-4H-pyrazolo[l,5-a] [l,4]diazepine-5(6H)-carboxylate (73 mg, 0.16 mmol, 1.0 eq) with CH CN (1.5 mL) in a microwave vial were added acetyl chloride (25 mg, 0.31 mmol, 2.0 eq) and N,N-diisopropylethylamine (59 mg, 0.46 mmol, 2.9 eq). The mixture was heated with microwave irritation at 150 °C for 45 min and then diluted with EtOAc (10 mL), washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated in vacuum to give the crude product which was purified by prep-HPLC (CH3CN/H20 with 10 mM NH4HC03 as mobile phase; from 20% to 95%) to furnish the compound 3,5-bis(trifluoromethyl)benzyl 2- (5-methyl- 1 ,2,4-oxadiazol-3-yl)-7,8-dihydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)- carboxylate (55 mg, 72% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ: 7 '.94-7.91 (m, 1H), 7.86 (s, 2H), 6.77, 6.67 (s, s, 1H), 5.29, 5.26 (s, s, 2H), 4.71, 4.66 (s, s, 2H), 4.57- 4.55 (m, 2H), 3.91-3.85 (m, 2H), 2.64 (s, 3H), 1.94-1.93 (m, 2H). ESI-MS m/z 490.1
[M+H]+.
Example 393
3,5-bis(Trifluoromethyl)benzyl 2-(4-methylpiperazin-l-yl)-6,7-dihydropyrazolo[l,5-a] pyrazine-5(4H)-carboxylate
Figure imgf000225_0001
[0463] Using 3,5-bis(trifluoromethyl)benzyl 2-bromo-6,7-dihydropyrazolo[l,5- a]pyrazine-5(4H)-carboxylate and 1-methylpiperazine as starting materials, the title compound was synthesized according to the coupling conditions described in Example 338. 1H NMR (400 MHz, CD3CN) δ: 8.01 (br, 3H), 5.60 (s, 1H), 5.28 (s, 2H), 4.66-4.61 (m, 2H), 3.96-3.92 (m, 4H), 3.55-3.47 (m, 4H), 3.25-3.18 (m, 4H), 2.74 (s, 3H). ESI-MS m/z 492.2 [M+H]+.
Example 394
3,5-bis(trifluoromethyl)benzyl 2-(piperazin-l-yl)-6,7-dihydropyrazolo[l,5-a]pyrazine- -carboxylate
Figure imgf000225_0002
[0464] Using 3,5-bis(trifluoromethyl)benzyl 2-bromo-6,7-dihydropyrazolo[l,5- a]pyrazine-5(4H)-carboxylate and tert-butyl piperazine-l-carboxylate as starting materials, the title compound was synthesized according to the coupling conditions described in Example 338 followed by standard Boc-deprotection step as in example 158. 1H NMR (400 MHz, Methanol-d4) δ 7.89 - 8.05 (m, 3H), 5.70 (s, IH), 5.33 (s, 2H), 4.62 - 4.74 (m, 2H), 3.90 - 4.05 (m, 4H), 3.35 - 3.45 (m, 4H), 3.25 - 3.33 (m, 4H); ESI-MS m/z 478.2 [M+H]+.
Example 395
3,5-bis(Trifluoromethyl)benzyl 2-(l-aminoethyl)-6,7-dihydropyrazolo[l,5-a]pyrazine- -carboxylate
Figure imgf000226_0001
[0465] The titled compound was synthesized according to the procedure described in
Example 147. 1H NMR (400 MHz, Methanol-d4) δ: 8.04 (s, 2H), 7.97 (s, IH), 6.23 (s, IH), 5.36 (s, 2H), 4.88-4.76 (m, 2H), 4.46 (q, J = 6.8 Hz, IH), 4.19 (t, J = 5.6 Hz, 2H), 4.02 (brs, 2H), 1.62 (d, J = 6.8 Hz, 3H). ESI-MS m/z 437.1 [M+H]+.
Example 396
3,5-bis(Trifluoromethyl)benzyl 2-(l-hydroxyethyl)-6,7-dihydropyrazolo[l,5-a]pyrazine- -carboxylate
Figure imgf000226_0002
[0466] The titled compound was synthesized according to the procedure described in
Example 146. 1H NMR (400 MHz, Methanol-d4) δ: 8.05 (s, 2H), 7.97 (s, IH), 6.38 (s, IH), 5.37 (s, 2H), 4.97-4.84 (m, 3H), 4.28 (t, J = 5.2 Hz, 2H), 4.06 (brs, 2H), 1.51 (t, J = 6.8 Hz, 3H). LCMS m/z 438.1 [M+H]+
Example 398
3,5-bis(trifluoromethyl)benzyl 2-(l-(tert-butoxycarbonyl)piperidin-4-yl)-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate
Figure imgf000226_0003
[0467] The titled compound was synthesized according to the procedure described in
Example 371. 1H NMR (400 MHz, Methanol--^) d 7.88 - 8.07 (m, 3H), 6.03 (s, 1H), 5.33 (s, 2H), 4.53 - 4.81 (m, 2H), 4.06 - 4.20 (m, 4H), 3.98 (br. s., 2H), 2.71 - 2.95 (m, 3H), 1.78 - 1.96 (m, 2H), 1.55 (dd, J = 3.89, 12.67 Hz, 2H), 1.46 (s, 9H); LCMS m/z 577.2 [M+H]+.
Example 399
5-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-3-fluoro-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a] [l,4]diazepine-2-carboxylic acid
Figure imgf000227_0001
[0468] To a mixture of 5-(3-chloro-5-(trifluoromethyl)benzyl) 2-ethyl 7,8-dihydro-
4H-pyrazolo[l,5-a][l,4]diazepine-2,5(6H)-dicarboxylate (250 mg, 0.56 mmol) in acetonitrile (6 mL) was added Selectfluor (994 mg, 2.8 mmol). The reaction mixture was heated in a microwave reactor at 100 °C for 3 h. After cooled to rt, the mixture was filtered and concentrated, the residue was purified by prep-TLC (PE/EA = 1/1) to afford the ester intermediate (30 mg, 11% yield) as a colourless oil. LCMS m/z 464.1 [M+H]+.
[0469] To a solution of the ester intermediate (120 mg, 0.26 mmol) in THF (4 mL) were added LiOH.H20 (22 mg, 0.52 mmol) and H20 (1 mL). The reaction mixture was stirred at rt for 16 h and was adjusted to pH = 4-5 with HC1 (1 N). The precipitate was collected and dissolved in EtOAc (100 mL), washed with water (10 mL x 2), dried over sodium sulfate and evaporated in vacuum to give the crude product which was purified by prep-HPLC (CH3CN/H20 with 0.05% TFA as mobile phase; from 5% to 95%) to give the title compound as a white solid (80 mg, 71% yield). 1H NMR (400 MHz, CD3OD) & 7.66- 7.60 (m, 2H), 7.54 (d, J = 6.4 Hz, 1H), 5.20, 5.18 (s, s, 2H), 4.66, 4.62 (s, s, 2H), 4.49 (t, J = 4.8 Hz, 2H), 3.90-3.80 (m, 2H), 1.96-1.87 (m, 2H); LCMS m/z 436.0 [M+H]+.
Example 507
5-(((3,5-bis(Trifluoromethyl)benzyl)oxy)carbonyl)-3-fluoro-5,6,7,8-tetrahydro-4H- pyrazolo[l -a] [l,4]diazepine-2-carboxylic acid
Figure imgf000227_0002
[0470] The titled compound was synthesized according to the procedure described in Example 399. 1H NMR (400 MHz, Methanol-d4) δ 7.75 - 8.04 (m, 3H), 5.13 - 5.36 (m, 2H), 4.56 - 4.73 (m, 2H), 4.34 - 4.55 (m, 2H), 3.67 - 3.97 (m, 2H), 1.86 - 1.95 (m, 2H); LCMS m/z 470.0 [M+H]+.
Example 400
3,5-bis(trifluoromethyl)benzyl 2-(methoxy(methyl)carbamoyl)-6,7-dihydropyrazolo[l,5- a]pyrazine-5(4H)-carboxylate
Figure imgf000228_0001
[0471] The titled compound was synthesized according to the procedure described in
Example 144. 1H NMR (400 MHz, Methanol-d4) δ: 8.05 (s, 2H), 7.96 (s, IH), 6.64 (s, IH), 5.37 (s, 2H), 4.85-4.79 (m, 2H), 4.27 (t, J = 5.2 Hz, 2H), 4.05 (brs, 2H), 3.78 (s, 3H), 3.44 (s, 3H). LCMS m/z 481.0 [M+H]+.
Example 401
3,5-bis(trifluoromethyl)benzyl 2-acetyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carboxylate
Figure imgf000228_0002
[0472] The titled compound was synthesized according to the procedure described in
Example 145. 1H NMR (400 MHz, Methanol-d4) δ: 8.05 (s, 2H), 7.97 (s, IH), 6.64 (s, IH), 5.37 (s, 2H), 4.85-4.62 (m, 2H), 4.29 (t, J = 5.2 Hz, 2H), 4.05 (brs, 2H), 2.53 (s, 3H). LCMS m/z 436.0 [M+H]+
Example 402
5-(3-chloro-5-(trifluoromethyl)benzyl) 2-ethyl 6,7-dihydropyrazolo[l,5-a]pyrazine-
2,5(4H)-dicarboxylate
Figure imgf000228_0003
[0473] The title compound was synthesized according to the procedure described in
Example 1. 1HNMR (400 MHz, CDC13) δ: 7.59 (s, IH), 7.55 (s, IH), 7.51 (s, IH), 6.64 (s, IH), 5.20 (s, 2H), 4.77 (s, 2H), 4.40 (q, J = 12 Hz, 2H), 4.31-4.29 (m, 2H), 4.01-3.98 (m, 2H), 1.39 (t, J= 7.2 Hz, 3H). LCMS m/z 453.9 [M+Na]+
[0474] The procedure for Example 402 was used for all of the compounds shown in the table below:
Figure imgf000229_0001
Example 410
5-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carboxylic acid
Figure imgf000230_0001
[0475] The title compound was synthesized according to the procedure described in
Example 7. 1H NMR (400 MHz, Methanol-d4) δ: 7.74 (s, 1H), 7.69 (s, 2H), 6.66 (s, 1H), 5.27 (s, 2H), 4.77-4.75 (m, 2H), 4.28-4.26 (m, 2H), 4.05-4.03 (m, 2H). LCMS m/z 403.8 [M+H]+
The procedure for Example 410 was used for all of the compounds shown in the table below:
Figure imgf000230_0002
Figure imgf000231_0001
Example 422
3,5-bis(trifluoromethyl)benzyl 2-(4-aminopiperidine-l-carbonyl)-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate hydrochloride
Figure imgf000231_0002
[0476] A mixture of compound 3,5-bis(trifluoromethyl)benzyl 2-(4-((tert- butoxycarbonyl)amino)piperidine-l-carbonyl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carboxylate (100 mg, 0.20 mmol, 1.0 eq.) in HCl/EA (2 mL) was stirred at room temperature for 1 h. TLC (PE/EA = 1/1) showed the starting material was consumed completely. The solvent was removed in vacuum and the crude was purified by prep-HPLC to give 3,5- bis(trifluoromethyl)benzyl 2-(4-aminopiperidine-l-carbonyl)-6,7-dihydropyrazolo[l,5- a]pyrazine-5(4H)-carboxylate hydrochloride (75 mg, 90% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ: 8.05 (s, 2H), 7.97 (s, IH), 6.50 (s, IH), 5.37 (s, 2H), 4.89-4.71 (m, 4H), 4.25 (t, J = 5.2 Hz, 2H), 4.05 (brs, 2H), 3.48-3.44 (m, IH), 3.33-3.26 (m, IH), 2.97-2.94 (m, IH), 2.17-2.06(m, 2H), 1.62-1.60 (m, 2H). LCMS m/z 520.1 [M+H]+ [0477] The procedure for Example 422 was used for all of the compounds shown in the table below:
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
1H NMR (400 MHz, Methanol-d4) δ
7.82 - 8.09 (m, 3H), 6.45 (br. s.,
444 IH), 6.36 (s, IH), 5.34 (s, 2H), 4.73
475.1
- 4.81 (m, 2H), 4.09 - 4.20 (m, 2H), 3.89 - 4.04 (m, 4H), 3.36 (t, J = 6.15 Hz, 2H), 2.48 - 2.64 (m, 2H)
1H NMR (400 MHz, Methanol-d4) δ 7.87 - 8.13 (m, 3H), 6.03 - 6.41 (m, 2H), 5.34 (s, 2H), 4.76 (d, J = 17.32
516 475.2 Hz, 2H), 4.11 - 4.23 (m, 2H), 4.00
(br. s., 2H), 3.82 (d, J = 2.76 Hz,
F 0 2H), 3.42 (t, J = 6.27 Hz, 2H), 2.71 - 2.90 (m, IH)
Example 445
8-(l-(5-(((3,5-dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepin-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid
Figure imgf000235_0001
[0478] The titled compound was synthesized according to the procedure described in
Example 149. 1H NMR (400 MHz, CD3OD) δ: 7.40 (s, IH), 7.30-7.27 (m, 2H), 6.38, 6.31 (s, s, IH), 5.14-5.03 (m, 2H), 4.74-4.70 (m, IH), 4.61-4.54 (m, IH), 4.45 (t, J = 5.2 Hz, 2H), 4.13-4.11 (m, IH), 3.93-3.69 (m, 3H), 3.58-3.52 (m, IH), 2.62-2.57 (m, IH), 2.16-2.09 (m, 3H), 1.80-1.55 (m, 7H), 1.56 (t, J = 9.6 Hz, 3H); LCMS m/z 521.1 [M+H]+
[0479] The procedure described in Example 445 was used for all of the compounds shown in the table below:
Figure imgf000235_0002
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Example 460
3,5-bis(trifluoromethyl)benzyl 2-((2-hydroxyethyl)carbamoyl)-6,7-dihydropyrazolo[l,5- a]pyrazine-5(4H)-carboxylate
Figure imgf000239_0001
[0480] The titled compound was synthesized according to the procedure described in
Example 12. 1H NMR (400 MHz, Methanol-d4) δ: 8.05 (s, 2H), 7.97 (s, 1H), 6.59 (s, 1H), 5.36 (s, 2H), 4.85-4.83 (m, 2H), 4.25 (t, J = 5.6 Hz, 2H), 4.03 (brs, 2H), 3.69 (t, J = 6.0 Hz, 2H), 3.49 (t, J = 6.0 Hz, 2H). LCMS m/z 481.1.1 [M+H]+
[0481] The procedure for Example 460 was used for all of the compounds shown in the table below:
Figure imgf000239_0002
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
1H NMR (400 MHz, Methanol-d4) δ: 8.05 (s, 2H), 7.96 (s, 1H), 6.45
F
F-SLF (s, 1H), 5.37 (s, 2H), 4.78-4.48 (m,
2H), 4.55-4.45 (m, 2H), 4.24 (t, J =
494
585(+Na) 5.2 Hz, 2H), 4.04 (brs, 2H), 3.70 (s,
3H), 3.34-3.32 (m, 1H), 3.05-
C02Me 3.01(m, 1H), 2.75-2.69 (m, 1H),
2.03-1.92 (m, 2H), 1.71-1.66 (m,
2H)
1H NMR (400 MHz, Methanol-d4) δ 7.56 - 7.83 (m, 3H), 6.47 (s, 1H),
495 5.25 (s, 2H), 4.71 - 4.87 (m, 2H),
514.2
4.14 - 4.27 (m, 2H), 4.02 (br. s.,
F
\ 2H), 3.20 - 3.35 (m, 6H), 2.96 (s,
3H), 1.62 (br. s., 6H)
Example 496
3,5-bis(trifluoromethyl)benzyl 2-(pyridin-3-yl)-6,7-dihydropyrazolo[l,5-a]pyrazine-
5(4H)-carboxylate
Figure imgf000243_0001
[0482] The titled compound was synthesized according to the procedure described in
Example X (7-member analog, suzuki coupling). 1H NMR (400 MHz, Methanol-d4) δ 9.12 (s, 1H), 8.56 - 8.76 (m, 2H), 7.80 - 8.10 (m, 4H), 6.75 (s, 1H), 5.36 (s, 2H), 4.78 - 4.88 (m, 2H), 4.22 - 4.38 (m, 2H), 4.06 (br. s., 2H); LCMS m/z 471.1 [M+H]+
[0483] The above general procedure was used for all of the compounds shown in the table below:
Figure imgf000243_0002
1H NMR (400 MHz, Methanol-d4) L δ 8.73 (d, J = 6.78 Hz, 2H), 8.32 (d,
499 J = 6.78 Hz, 2H), 7.97 - 8.08 (m,
471.1
2H), 7.95 (s, 1H), 6.95 (s, 1H), 5.36
(s, 2H), 4.90 (br. s., 2H), 4.33 (t, J
= 5.52 Hz, 2H), 4.07 (br. s., 2H)
1H NMR (400 MHz, Methanol-d4)
500 δ 7.77 - 8.09 (m, 5H), 6.32 (s, 1H),
460.1
5.35 (s, 2H), 4.76 (br. s., 2H), 4.14
F1 ° - 4.23 (m, 2H), 4.03 (br. s., 2H)
[0484] The following compounds were synthesized by the methods described above, and have an IC50 value of greater than 10 μΜ for the Autotaxin (ATX) assay described in Example 514:
Figure imgf000244_0001
Example 517
Activity Measurements
SIP Receptor Activity Assays
[0485] Agonist percentage activation determinations were obtained by assaying sample compounds and referencing the Emax control for each receptor profiled. Antagonist percentage inhibition determinations were obtained by assaying sample compounds and referencing the control EC80 wells for each receptor profiled. The samples were run using a "Single Addition" assay protocol for the agonist and antagonist assay run. The protocol design was as follows: Compound Preparation
[0486] Master stock solution: Unless specified otherwise, all sample compounds were diluted in 100% anhydrous DMSO including all serial dilutions. All control wells contained identical solvent final concentrations as did the sample compound wells.
[0487] Compound plate for assay: The sample compounds were transferred from a master stock solution into a daughter plate that was used in the assay. Each sample compound was diluted into assay buffer (lx HBSS with 20 mM HEPES and 2.5 mM Probenecid) at an appropriate concentration to obtain final concentrations.
Calcium Flux Assay: Agonist Assay Format
[0488] Sample compounds were plated in an eight-point, four-fold dilution series in duplicate with a top concentration of 10 μΜ. The concentrations described here reflect the final concentration of the compounds during the antagonist assay. During the agonist assay the compound concentrations were 1.25 fold higher to allow for the final desired
concentration to be achieved with further dilution by ECgo of reference agonists during the antagonist assay.
[0489] Reference agonists were handled as mentioned above serving as assay control.
The reference agonists were handled as described above for Emax.
[0490] Assay was read for 180 seconds using the FLIPRTETRA (This assay run added sample compounds and reference agonist to respective wells). At the completion of the first "Single Addition" assay run, assay plate was removed from the FLIPRTETRA and placed at 25 °C for seven (7) minutes.
Calcium Flux Assay: Antagonist Assay Format
[0491] Using the ECso values determined during the agonist assay, stimulated all pre- incubated sample compound and reference antagonist (if applicable) wells with ECso of reference agonist. Read for 180 seconds using the FLIPRTETRA (This assay added reference agonist to respective wells— then fluorescence measurements were collected to calculate percentage inhibition values).
Data processing
[0492] All plates were subjected to appropriate baseline corrections. Once baseline corrections were processed, maximum fluorescence values were exported and data manipulated to calculate percentage activation, percentage inhibition and Z' .
Autotaxin (ATX) Assay
[0493] ATX (Autotaxin) is a 125 KDa glycoprotein with lysophospholipase D
(LPLD) activity that generates the bioactive lipid lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). The ATX biochemical assay utilizes a FRET (fluorescence resonance energy transfer) technology platform. The fluorescence signal of FRET substrate FS-3 is quenched due to intra-molecular FRET of a fluorophore to a non-fluorescing quencher (Ferguson, C.G., et al., Org Lett. 2006 May 11 ; 8(10): 2023-2026, which is incorporated by reference in its entirety). ATX catalyzes the hydrolysis of the substrate which separates the dabsyl quencher from the fluorescein reporter, which becomes fluorescent. The reaction is monitored by a SpectraMax M5 (Molecular Devices, Sunnyvale, CA) with at excitation wavelength 485 nm and emission wavelength 535 nm.
Reagents
[0494] Fatty acid free-BSA (Sigma A8806): 10 mg/mL in H20, stored at 4 °C.
[0495] 2X ATX assay buffer: 100 mM Tris, 280 mM NaCl, 10 mM KC1, 2 mM
CaCl2, 2 mM MgCl2, pH 7.4.
[0496] Human ATX protein: expressed and purified in house. Stored at - 80 °C.
[0497] Substrate FS-3 (Echelon, L-2000): 100 μg in 77.74 H20 (1 mM stock), stored at -20 °C.
[0498] 384-well flat bottom plates- Corning # 3575.
Assay
[0499] Compound dilution - All compounds were provided at 10 mM in 100%
DMSO. In the first well, 2 of 10 mM compound was added to 78 μΐ, of DMSO (1 :40 dilution). In subsequent wells 3-fold dilution (total 10 dilutions) were performed.
[0500] IX ATX assay buffer was made up with a final concentration of 1 mg/mL fatty acid free-BSA using 2X ATX assay buffer, 10 mg/ml fatty acid free-BSA and ddH20.
[0501] ATX protein was diluted with lx ATX assay buffer to a concentration of 1.32 μg/mL (1.32X). 38 μΐ^ was added per well to the assay plate. The final concentration of ATX in the reaction as 1.0 μg/mL.
[0502] 2 μϊ^ per well of compounds was transferred to provide the desired
concentration. The plate was centrifuged, then incubated at room temperature for 30 minutes on the shaker.
[0503] FS-3 was diluted with lx ATX assay buffer to a concentration of FS-3 of 10 μΜ (5X). Then, 10 μΐ^ was added per well to the assay plate. The final concentration of FS-3 in the reaction was 2 μΜ. The plate was centrifuged. The plate was kept shaking at room temperature for 2 hours. Because FS-3 substrate is light sensitive, plates were kept covered and protected from light. [0504] Fluorescence was measured using SpectraMax M5 (excitation at 485 nm/ emission at 538 nm, top read).
[0505] The compounds of examples 2-4, 7-8, 12, 15-32, 41, 43, 46, 48-49, 58-65, 82-
83, 85, 87, 90, 92, 94-95, 97, 100-103, 105-106, 108-111, 114-115, 118-119, 124-125, 127, 132-133, 136, 144-146, 148, 153, 156, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174,175, 176, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190,191, 192, 193, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252A, 252B, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 277, 278, 280, 285, 286, 293, 298, 299, 302, 304, 305, 306, 308, 314, 315, 316, 318, 319, 320, 322, 323, 326, 328, 337, 338, 340, 341, 342, 343, 345, 346, 347, 348, 349, 350, 351, 353, 354, 355,356, 357, 358, 359,
360, 362, 363, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 386, 387, 388, 390, 392, 393, 394, 395, 396, 398, 399, 400, 402, 403, 404, 409, 412, 418, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 448, 449, 450, 458, 460, 462, 464, 466,467, 469, 470, 471, 472, 474, 475, 476, 478, 479, 481, 482, 483, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 502, 503, 504, 505, 506, 507, 508, 510, 512, 514, 515, and 516 had an IC50 of no greater than 100 nM. The compounds of examples 14, 45, 57, 86, 88, 112, 113, 122, 123, 128, 154, 157, 289, 291, 292, 296, 297, 301, 313, 317, 339, 344, 352,
361, 384, 385, 410, 415, 419, 446, 453, 456, 457, 480, 509, 511, and 513 had an IC50 of no greater than 250 nM. The compounds of examples 1, 10, 42, 67, 68, 75, 93, 99, 116, 117, 126, 129-131, 134, 135, 141, 147, 149, 287, 288, 290, 294, 401, 420, 421, and 454 had an IC50 of no greater than 500 nM. The compounds of examples 9, 11, 34, 36, 38, 39, 40, 44, 47, 50-55, 66, 69-74, 76, 78-81, 84, 91, 96, 98, 140, 141, 284, 295, 408, 413, 417, 445, 447, 451, 452, 455, and 459 had an IC50 between 500 nM and 10 μΜ. The compounds of examples 405 and 406 had an IC50 greater than 10 μΜ. The compound of example 407 had 50% inhibition at 10 uM. The compounds of examples 279 and 282 had 60% inhibition at 10 uM.
OPC Differentiation Assay
[0506] Enriched populations of oligodendrocytes were grown from post-natal day 2
(P2) female Sprague Dawley rats. The forebrain was dissected out and placed in Hank's buffered saline solution (HBSS; Invitrogen, Grand Island, NY). The tissue was cut into 1 mm fragments and incubated at 37 °C for 15 minutes in 0.01% trypsin and 10 μg/mL DNase. Dissociated cells were plated on poly-L-lysine-coated T75 tissue culture flasks and grown at 37 °C for 10 days in Dulbecco's modified Eagle's medium (DMEM) with 20% fetal calf serum (Invitrogen). A2B5+ OPCs were collected by shaking the flask overnight at 200 rpm and 37 °C, resulting in a 95% pure population.
[0507] For the differentiation assay, 2 μΜ and 20 μΜ antagonist or the same concentrations of vehicle (DMSO) were applied to OPCs cultured in CNTF/T3 containing media. After a 3-day incubation, after a 3-day incubation, cell were lysed and then subjected to MSD (Meso Scale Discovery- R) analysis. EC50 was calculated by Prism using a nonlinear sigmoidal dose-response curvecells. Alternatively, cells were lysed in 80 μΐ^ lysis buffer (50 mM HEPES [4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid], pH 7.5, 150 mM NaCl, 1.5 mM MgCl2, 1 mM ethylene glycol tetraacetic acid (EGTA), 1% Triton X-100 and 10% glycerol) for 30 minutes at 4 °C. After centrifugation at 14,000 g for 15 minutes, the supernatants were boiled in Laemmli sample buffer, subjected to 4-20% SDS-PAGE, and analyzed by Western blotting with anti-MBP, anti-myelin-associated glycoprotein (MAG), or anti-beta actin antibodies. The secondary antibodies used were anti-mouse IgG-HRP
(horseradish peroxidase) and anti-rabbit IgG-HRP respectively.
LPA Plasma assay and IC50 assay by LC-MS/MS
[0508] 20:4 LPA (Lysophosphatidic acid) and 18: 1 LPA were purchased from Avanti
Polar Lipids, INC at a concentration of 10 mg/mL in chloroform, respectively. Stock solutions for 20:4 LPA and 18: 1 LPA were separately prepared at 1.00 mg/mL in Methanol and were stored in a -20°C freezer. 18:3 LPA, the internal standard, was purchased from Eschelon Bioscience, Inc. as 1 mg in powder form. A stock solution was prepared at 1 mg/mL in chloroform and then diluted to 100 μg/mL in Methanol and was stored in a -20°C freezer. The internal standard solution of 125 ng/mL in acetonitrile was prepared and stored in a 4°C refrigerator.
Plasma LPA assays
[0509] 2% BSA (Bovine serum albumin) was used as a surrogate matrix for preparation of standards and QC samples due to the presence of endogenous LPAs in rat plasma samples. 20:4 LPA and 18: 1 LPA calibration standards were prepared fresh with each batch at concentrations ranging from 0.5 ng/mL to 1000 ng/mL in 2% BSA. 20:4 LPA and 18: 1 LPA QC samples were prepared fresh with each batch at concentrations of 1, 5, 20, 50, 250, and 1000 ng/mL in 2% BSA. Study samples were thawed on ice and processed within 2 hours on ice. The protein precipitation method was applied for sample preparation. The injection plate was loaded onto a CTC PAL autosampler for injection to determine the concentration of 20:4 LP A and 18: 1 LP A by LC/MS/MS. Reverse phase HPLC using a C8 column was used for the separation.
IC50 assay
[0510] The stock solution (10 mM) for each compound was made in DMSO. For each compound, the stock solution (lOmM in DMSO) was diluted in 60% DMSO to make ten intermediate stock solutions. The ten intermediate stocks were then diluted in rat K2 EDTA plasma to make ten samples at concentrations ranging from 30 μΜ to 0.00152 μΜ. One control sample was made by spiking DMSO into rat K2 EDTA plasma. All eleven samples were placed in 37°C incubator for 18 hours, extracted right after 18hr incubation and transferred to an autosampler tray for injection onto the LC-MS/MS system. The quantitation of IC50 assay was performed by determining the peak area ratio of 20:4 LPA (or 18: 1 LPA) over internal standard (18:3 LPA). The IC50 value for each compound was calculated by using GraphPad Prism software.
[0511] The compounds of examples 7, 8, 12, 18, 20, 25, 49, 60, 65, 82, 90, 101, 158,
159, 168, 169, 170, ,173, 176, 181, 189, 195, 196, 197, 198, 199, 200, 201, 203, 204, 205, 206, 207, 208, 209, 210, 212, 213, 214, 215, 216, 222, 223, 224, 225, 227, 271, 272, 277, 298, 299, 302, 304, 305, 306, 308, 319, 338, 346, 347, 349, 367, 368, 376, 386, 387, 388, 429, 432, 436, 437, 442, 503, 504, 506, 507, 514 and 515 had an IC50 of no greater than 500 nM. The compounds of examples 41, 100, 270, 280, 390, 392, 394, 421, 424, 430, 434, 440, 441, 444, 479, 488, 490, 500, 502, 505, 508 and 516 had an IC50 between 500 nM and 10 μΜ. The compounds of examples 472 and 499 had an IC50 greater than 10 μΜ.
OPC Oligodendrocyte Myelination Assay
[0512] Embryonic neocortical neurons are dissected from embryonic day 18 (El 8)
Sprague Dawley rats, and then plated on poly-D-lysine (100 μg/mL)-coated cover slips and grown in neurobasal medium supplemented with B27 (Invitrogen) for one week. A2B5+ OPCs are prepared as described above and then added into the cultured neocortical neurons. One day later, different concentrations of a compound or salt as described herein and control reagents are applied into the co-cultures. Fresh media containing the different concentrations of a compound or salt as described herein or control compounds are supplied every three days. After ten days, co-cultures are subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE)/Western blot analyses to quantify MAG, MBP, and MOG. Remyelination Assay in Brain Slice Culture
[0513] Approximately three to four consecutive 300 μιη slices are taken from the junction of the corpus callosum to the hippocampus in post-natal, day 17 Sprague Dawley rats (Charles River, Willmington, MA). Slices are cultured in basal DMEM supplemented with 25% horse serum for three days, before being treated with 6 mg/mL LPC (Sigma L- 4129) for a further three days. The medium is then changed, and slices incubated with medium containing a compound or salt as described herein or vehicle control for a final period of three days, after which myelination is visualized by black gold staining (Millipore, Bedford, MA) following the manufacture's protocol. Images are acquired using a Leica M420 microscope (Bannockburn, IL) and the staining intensity of corpus callosum is analyzed using Metamorph software (Molecular Devices, Downingtown, PA). Three or four brain slices are used for each treatment group.
Lysolecithin Demyelination Model
[0514] Adult Sprague Dawley rats (220-260 g) are anesthetized by intraperitoneal injection of a cocktail, consisting of Ketamine (35 mg/kg), Xylazine (6 mg/kg) and
Acepromazine (1 mg/kg). The back of the animal is shaved from the lower thoracic to the lumbar region, subsequently sanitized with 70% isopropanol, Betadine Scrub solution, and 70% isopropanol again. The animal is then placed onto stereotaxic frame.
[0515] After ensuring an adequate anesthetic level, the skin is incised along the midline over the thoracic region. The dorsal fascia is incised and the paraspinal muscles separated from the spinous processes of the thoracic vertebrae T-9 through T-l 1. The T-10 vertebra is demolished, and the lamina removed with micro-rongeurs. Once the dorsal spinal cord region is exposed, a microcapillary glass needle is inserted into the dorsal column to a depth of 0.6 mm. The demyelinating reagent, 1.5 μΐ^ of 1% Lysolecithin (LPC, Sigma# L1381) in saline is injected with the infusion rate of 2 nL/sec controlled by a micro-pump (World Precision Instrument #micro4). Once the injection is completed, the needle is placed for additional 1 min before removal. The paraspinal muscles and the lumbar fascia are closed with suture (#5, silk). The skin incision is closed with wound clips. Animals are allowed to recover from the anesthesia and are observed in the humidified incubator.
[0516] Buprenorphine (0.05 mg/kg) is administrated subcutaneously (s.c.) twice a day for additional two days following operation.
[0517] Three days following the primary surgery, treatments with a compound or salt as described herein (30 pmol), LPA (30 pmol) or control (0.1% DMSO in saline) are injected at the primary injection region in a volume of 1.5 μΐ^ with the same infusion speed as indicated above. Nine days following the primary surgery, the animals are anesthetized and perfused trans-cardially with heparin (10 iu/mL) in saline followed by 4% PFA in PBS. The spinal cords are removed and post fixed in PFA overnight. Then the cords are cut into 100 μΜ thickness longitudinally and then 1% loxuol fast blue is stained and histological evaluation for remyelination and repair is assessed under microscope.
[0518] For systemic treatment, the animals are administered once daily
intraperitoneally with either a compound or salt as described herein (10 mg/kg) or control (15% HPCD (hydroxypropyl-P-cyclodextrin)) 2 days following the primary surgery. Nine days after the primary surgery, animals are sacrificed and the spinal cords were processed as indicated above.
CFA Inflammatory Pain Model
[0519] In the CFA (complete Freund' s adjuvant) model, adult male SD (250-300 g) rats are anesthetized with isoflurane inhalation (4.5% induction/ 2.0% maintenance). Heat- killed M. Tuberculosis H37 RA (non- viable) suspended at a concentration of 1.0 mg/ml in incomplete Freund's adjuvant is used (Chondrex Inc., catalog#7008). At day 0, intradermal injection (i.d.) of 100 μΐ of CFA (1: 1 oil/saline) is slowly perfused into the right footpad of the rats. At day 1, baseline tactile allodynia test are conducted: rats that develop sensitive painful response are enrolled to the study. At day 2, rats are orally dosed once with either vehicle or ATX inhibitor, then at 2 hrs, 4 hrs, 6 hrs and 24 hrs after dosage, all rats are tested for mechanical allodynia response.
[0520] Tactile allodynia is tested as follows. A rat is placed in an elevated Plexiglas observation chamber (approximately 4"x6"xl0") having a wire grid (1 cm spacing) mesh floor under polycarbonate cages. The rat is left to acclimate to the experimental conditions for 20 minutes before testing begins. After the rat is calm, tactile allodynia is assessed using a series of von Frey filaments ranging from 2.04 - 28.84 g (Stoelting, Wood Dale, IL). Graded pressure is presented to a localized area on the plantar surface of the paw via the use of Von Frey hairs (monofilaments which are calibrated to bend at a known pressure). A response to the VonFrey hair is recorded as the rat withdrawing the tested paw and is usually followed by lifting and licking. A series of filaments are used to determine the threshold response using the established "Up-Down" method. Each paw is tested 4-6 times repeatedly with 1-2 seconds (modified from Seltzer et ah, 1991) in between each probe to accurately assess the behavior. A sharp lifting of the paw is scored as a positive response. Rat Model of Neuropathic Pain
[0521] Chronic Constriction Injury (CCI) Surgery: In the CCI model (Bennett and
Xie, Pain, 1989, which is incorporated by reference in its entirety), adult male SD (250-275 g) rats are anesthetized with isoflurane inhalation (4.5% induction/ 2.0% maintenance). The surgery is performed under aseptic conditions and involves exposing the sciatic nerve at the mid-thigh level. Ocular lubricant is used as needed to prevent corneal drying. After shaving and disinfecting the skin (betadine followed by 70% ethanol), a small incision is made just caudal to the biceps femoris. Care is taken to not disturb the sciatic nerve. The nerve is slightly elevated, and 4 loose ligatures of 4-0 chromic gut suture are inserted under the nerve, and then are loosely tied around it. The sutures constrict the nerve but do not strangle it. Prior to inserting the chromic gut, it is rinsed twice in sterile saline. The incision is closed with wound clips, and rats are allowed to recover from anesthesia on a circulating water heating pad before being returned to their home cages. In the sham controls the skin is opened, and the sciatic nerve is identified and elevated, but no sutures are tied around the nerve. All rats are screened for pain response around post-surgery day 7 and only rats with sensitive pain response are enrolled to the study.
[0522] Animals are orally dosed twice/day for 3 times/week with either vehicle or
ATX inhibitor post-surgery at days 10, 12, 14, 17, 19 and 21, and animals are also tested at the same schedule for three types of neuropathic pain: thermal hyperalgesia, tactile allodynia and incapacitance.
[0523] (1) Plantar thermal hyperalgesia: Rats are tested for hyperalgesia using a plantar device (Ugo Basile Inc., Cat.#37370). After acclimation to the testing room, rats are placed on an elevated glass floor beneath inverted clear plastic cages, and a radiant heat source beneath the glass is aimed at the mid-plantar surface of the hindpaw after they have ceased all exploratory behavior. The onset of light activates a timer, which is terminated by a hindpaw withdrawal response. A cutoff time of 30 seconds is used to avoid tissue damage in the absence of a response. The average withdrawal latency value of three trials from the ipsilateral hindpaw is measured with at least 5-10 minutes between each trial to avoid any tissue damage.
[0524] (2) Tactile allodynia is tested as described above.
[0525] (3) Incapacitance: The incapacitance test measures the weight the rat places on each of its hindpaws. The rat is placed in a small, clear Plexiglas box (6" long x 3" wide x 4" tall). The box is tilted up and opens in the front. The rat is placed in the box so that its hindpaws are at the back (lower) portion of the box, and the forepaws are at the front (raised) part of the box. The rat's head is at the opening in the front of the box. The box is placed on a divided scale such that each of the rat's hindpaws is on one of the two weighing pans of the scale. The weight that the rat placed on each hindpaw is then measured. The procedure is rapid (about 10 sec) and does not cause the animal any pain.
Calcium Mobilization
[0526] Compounds that are not specific for a particular SIP receptor can cause undesirable side effects. Accordingly, compounds are tested to identify those that are specific. Accordingly, the test compounds are tested in a calcium mobilization assay. The procedure is essentially as described in Davis et al. (2005) Journal of Biological Chemistry, vol. 280, pp. 9833-9841, which is incorporated by reference in its entirety with the following modifications. Calcium mobilization assays are performed in recombinant CHEM cells expressing human SlPi, S1P2, S1P3, S1P4, or SIP5 purchased from Millipore (Billerica, MA). To detect free intracellular calcium, SIP^ S1P2, SIP3, S1P4, or SIP5 cells are loaded with FLIPR Calcium 4 dye from Molecular Devices (Sunnyvale, CA). Cells are imaged for calcium mobilization using a FLIPRTETRA equipped with a 96-well dispense head.
In vivo Screening Assays
[0527] Measurement of circulating lymphocytes: Compounds are dissolved in 30%
HPCD. Mice (C57bl/6 male, 6-10 week-old) are administered 0.5 and 5 mg/kg of a compound via oral gavage 30% HPCD is included as a negative control.
[0528] Blood is collected from the retro-orbital sinus 5 and 24 hours after drug administration under short isoflurane anesthesia. Whole blood samples are subjected to hematology analysis. Peripheral lymphocyte counts are determined using an automated analyzer (HEMAVET™ 3700). Subpopulations of peripheral blood lymphocytes are stained by fluorochrome-conjugated specific antibodies and analyzed using a fluorescent activating cell sorter (FACSCALIBUR™). Three mice are used to assess the lymphocyte depletion activity of each compound screened.
[0529] Compounds of formula (I), or pharmaceutically acceptable salts thereof, can induce full lymphopenia at times as short as 4 hours or less to as long as 48 hours or more; for example, 4 to 36 hours, or 5 to 24 hours. In some cases, a compound of formula can induce full lymphopenia at 5 hours and partial lymphopenia at 24 hours. The dosage required to induce lymphopenia can be in the range of, e.g., 0.001 mg/kg to 100 mg/kg; or 0.01 mg/kg to 10 mg/kg. The dosage can be 10 mg/kg or less, such as 5 mg/kg or less, 1 mg/kg or less, or 0.1 mg/kg or less.
[0530] Other embodiments are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:
1. A compound represented by formula (I):
Figure imgf000254_0001
or a pharmaceutically acceptable salt thereof, wherein:
L is -C(O)-, -O-C(O)-, -NR6-C(0)-, or -S(0)2-;
L 2 is a bond, -0-, or -NR-; provided that L 2 is not -O- when R 2 is structure (iv); R, for each occurrence, is independently hydrogen or a Ci^alkyl;
R1 is a Ci^alkylene;
R is selected form the group consisting of:
Figure imgf000254_0002
R3 is hydrogen, -CN, Ci_8alkyl, Ci_8haloalkyl, -(CR10Rn)m-N(R16)2, -(CR10Rn)m- OR15, -(CR10Rn)m-C(O)OR15, -(CR10Rn)m-C(O)N(R16)2, -(CR10Rn)m-S(O)2N(R16)2, - (CR10Ru)m-S(O)2NHS(O)2R15, -C(0)N(R15)-S(0)2R15, -S(0)2OR15, -C(0)NHC(0)R15, - Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -0-P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, - C(0)NHS(0)2R15, -C(0)NHOH, -C(0)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -Lx-R4; where in the heteroaryl and heterocyclyl are optionally
5 2 3 substituted with one to four R ; provided that when R is structure (ii), (iii), (iv), or (xi), R is
2 3
not hydrogen; and provided that when R is structure (iv), R is not pyrrolidinyl, piperidinyl , an N-methylpyrrolidinyl, an N-acetyl-pyrrolidinyl, an N-methylpiperidinyl, or an N-acetyl- piperidinyl;
L1 is Ci-galkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0)2NR-, or -C(0)NR-S(0)2-;
R4 is Ci-galkyl, C3_8cycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R4 may be optionally substituted with from one to four R5;
R5 is halo, cyano, Ci.galkyl, Ci.ghaloalkyl, C3-8cycloalkyl, -(CR10Ru)m-N(R16)2, -(CR10Rn)m-OR15, -(CR10Rn)m-C(O)OR15, -C(0)N(R16)2, -C(0)N(R15)-S(0)2R15, - S(0)2OR15, -C(0)NHC(0)R15, -Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -S(0)2N(R15)2, O P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, -C(0)NHS(0)2R15, C(0)NHOH,
C(0)NHCN, -C(0)R15, a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, =0, Ci_
Figure imgf000255_0001
Ci^alkylamido, Ci^alkylsulfonyl, Ci^alkylsulfonamido, sulfamoyl, N-Ci^alkylsulfamoyl, and N,N-(CMdialkyl)-sulfamoyl;
R6 is hydrogen or a Ci-galkyl;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C3_8cycloalkyl,
C3_8halocycloalkyl, Ci-galkoxy, Ci-ghaloalkoxy, C3_8cycloalkoxy, C3_8halocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino,
Figure imgf000255_0002
Ci_galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl,
Ci-galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl,
N-(^galkyl)sulfamoyl, N,N-di-(^galkyl)sulfamoyl, and Ci-galkylsulfonamido; R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, Ci_galkyl, Ci_ghaloalkyl, C3_gcycloalkyl, C3_ghalocycloalkyl, Ci-galkoxy, Ci-ghaloalkoxy, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl,
Figure imgf000256_0001
Ci_galkylamido, mercapto, Ci-galkylthio, Ci_galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(^galkyl)sulfamoyl, and Ci-galkylsulfonamido;
R9, for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci_galkyl, Ci-galkoxy, Ci_ghaloalkyl, Ci-ghaloalkoxy,
C3_gcycloalkyl, C3_ghalocycloalkyl, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci_galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(Ci_galkyl)sulfamoyl, Ci-galkylsulfonamido, C6-1oaryl, Ci_galkoxy-Ci_6alkyl, and tri-(Ci-galkyl)silyl;
R9a is hydrogen or R9; or R9a and R6, together with the intervening atoms, form a 3- to 8-membered heterocyclyl which is optionally substituted with from one to three R9;
R10 and R11, for each occurrence, are independently hydrogen, halo, hydroxyl, carboxy, C1-4alkyl, or Ci^haloalkyl;
R15 for each occurrence is independently selected from the group consisting of hydrogen, Ci-galkyl, C2-galkenyl, C2_galkynyl, C3_gcycloalkyl, C3_gcycloalkenyl, C6-1oaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci_4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-(C1_4alkyl)amino, N,N-di-(Ci_4alkyl)amino, carboxyl, carbamoyl,
N-(Ci_4alkyl)carbamoyl, N,N-di-(Ci_4alkyl)carbamoyl, Ci^alkylamido, Ci^alkylsulfonyl, Ci^alkylsulfonamido, sulfamoyl, N-(Ci_4alkyl)sulfamoyl, and N,N-(Ci_4dialkyl)-sulfamoyl;
R16 is Ci-galkoxy, or R15; or two R16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci_4alkoxy, Ci_4alkyl, cyano, nitro, hydroxyl, amino, N-(Ci_4alkyl)amino, N,N-di-(C1_4alkyl)amino, carboxyl, carbamoyl, N-(C1_4alkyl)carbamoyl,
Figure imgf000257_0001
sulfamoyl, N-Ci^alkylsulfamoyl, and N,N-(CMdialkyl)-sulfamoyl;
h is 0, 1, or 2;
n, for each occurrence, is independently 0, 1, 2, 3, or 4;
m, for each occurrence, is independently 0 or an integer from 1 to 6;
p is 0, 1, 2, or 3;
q is 1, 2, 3, or 4;
r is 1, 2, or 3; and
t is 0 or 1, provided that the compound is not:
3-(5-(2-(4-isopropylphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
2- (2,3-difluorophenyl)-l-(2-((dimethylamino)methyl)-6,7-dihydropyrazolo[l,5- a]pyrazin-5(4H)-yl)ethanone;
3- (5-((2-fluorophenethyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
3-(5-((4-methylbenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
3-(5-(2-(2-chloro-4-fluorophenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
N-(3-fluorobenzyl)-2-(pyrrolidine-l-carbonyl)-6,7-dihydropyrazolo[l,5-a]pyrazine- 5(4H)-carboxamide;
l-(2-(4-methylpiperazine-l-carbonyl)-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)- 3-(p-tolyl)propan-l-one;
methyl 5-((3-fluorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carboxylate;
methyl 5-((4-fluorophenethyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[ 1 ,5-a]pyrazine- 2-carboxylate;
3-(5-(2-(3-(methylthio)phenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid;
3-(5-(2-(4-chlorophenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepin- 2-yl)propanoic acid;
3-(5-(2-(2,3-difluorophenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid; l-(2-(pyridin-4-yl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepin-5(6H)-yl)-2-(3- (trifluoromethyl)phenyl)ethanone;
l-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepin-5(6H)-yl)-2-(3- (trifluoromethyl)phenyl)ethanone;
l-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepin-5(6H)-yl)-2-(2- fluorophenyl)ethanone ;
N-(3-fluorobenzyl)-2-(pyrrolidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxamide;
5-(2-(3,4-difluorophenyl)acetyl)-N-(2-hydroxyethyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxamide;
3-(5-(2-(2-methoxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid;
3-(5-(2-(4-ethoxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepin- 2-yl)propanoic acid;
1- (2-((l,4-oxazepan-4-yl)methyl)-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-2-(4- methoxyphenyl)ethanone ;
3-(5-(2-(2-methoxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
3- (2-methoxyphenyl)-l-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4] diazepin- 5 (6H) -yl)propan- 1 - one ;
2- (2-methoxyphenyl)-l-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4] diazepin- 5 (6H) -yl)ethanone ;
2-(4-ethoxyphenyl)-l-(2-(thiophen-2-yl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4] diazepin- 5 (6H) -yl)ethanone ;
methyl 5-(3-(3-methoxyphenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carboxylate;
N2-cyclopropyl-N5-(3-methoxybenzyl)-6,7-dihydropyrazolo[l,5-a]pyrazine-2,5(4H)- dicarboxamide;
5-((l-(3-methoxyphenyl)ethyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
4- (4-chlorophenyl)- 1 -(6,7-dihydro-5H-imidazo[ 1 ,5-a] [ 1 ,4]diazepin-8(9H)-yl)butan- 1 - one;
N-(2-fluorophenethyl)-6,7-dihydro-5H-imidazo[l,5-a][l,4]diazepine-8(9H)- carboxamide; 1 -(6,7-dihydro-5H-imidazo[ 1 ,5-a] [ 1 ,4]diazepin-8(9H)-yl)-2-(4- ethoxyphenyl)ethanone;
l-(6,7-dihydro-5H-imidazo[l,5-a][l,4]diazepin-8(9H)-yl)-2-(o-tolyl)ethanone;
N-(4-chlorobenzyl)-6,7-dihydro-5H-imidazo[l,5-a][l,4]diazepine-8(9H)- carboxamide;
l-ethyl-6-methyl-N-(4-methylbenzyl)-3,4-dihydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide;
N-(4-fluorobenzyl)-6-methyl- l-propyl-3,4-dihydropyrrolo[ 1 ,2-a]pyrazine-2( 1H)- carboxamide;
l-ethyl-N-(4-fluorobenzyl)-6-methyl-3,4-dihydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide;
1- ethyl-N-(3-methoxybenzyl)-6-methyl-3,4-dihydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide;
2- (2-aminophenyl)-l-(l,6-dimethyl-3,4-dihydropyrrolo[l,2-a]pyrazin-2(lH)- yl)ethanone;
2-(4-aminophenyl)-l-(l,6-dimethyl-3,4-dihydropyrrolo[l,2-a]pyrazin-2(lH)- yl)ethanone;
N-(3-methoxybenzyl)-6-methyl-l-propyl-3,4-dihydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide;
l-isopropyl-6-methyl-N-(4-methylbenzyl)-3,4-dihydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide;
1- isopropyl-N-(3-methoxybenzyl)-6-methyl-3,4-dihydropyrrolo[l,2-a]pyrazine- 2(lH)-carboxamide;
6-methyl-N-(4-methylbenzyl)-l-propyl-3,4-dihydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide;
5-(((4-methoxybenzyl)oxy)carbonyl)-2-methyl-l,4,5,6-tetrahydropyrrolo[3,4- b]pyrrole-4-carboxylic acid;
2- (3-bromophenyl)-2-methyl- l-(2-methyl-5,6-dihydro-[ 1 ,2,4]triazolo[ 1 ,5-a]pyrazin- 7(8H)-yl)propan- 1 -one;
1- (5,6-dihydro-[l,2,4]triazolo[l,5-a]pyrazin-7(8H)-yl)-2-(3-methoxyphenyl)ethanone;
2- (4-fluorophenyl)-l-(3-(quinolin-2-yl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
2-(p-tolyl)-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)ethanone; 3 m-tolyl) -(3 trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
3- (p-tolyl)-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
2-(2-chloro-6-fluorophenyl)-l-(3-isopropyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
4- (3-oxo-3-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propyl)benzonitrile;
2- (2-fluorophenyl)-l-(3-isopropyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)-2-methylpropan- 1 -one;
3- (2-methoxyphenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
2-(3,4-dimethoxyphenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
2-(3-chloro-4-methoxyphenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
2- (2-chloro-4-methoxyphenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
3- (4-methoxyphenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
3-(3-methoxyphenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
2-(2-fluorophenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)ethanone;
2- (2-chloro-6-fluorophenyl)-l-(3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
l-(3-ethyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-2-(2-fluorophenyl)-2- methylpropan- 1 -one;
3- (3-chloro-4-methylphenyl)-l-(3-isopropyl-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)propan-l-one;
3-(2,5-dimethoxyphenyl)-l-(3-ethyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
3-(3-chloro-4-methylphenyl)-l-(3-ethyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)propan- 1 -one; 1- (3-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-5-(p-tolyl)pentan-l- one;
2- (2-chloro-6-fluorophenyl)-l-(3-ethyl-5,6-di ydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
3- (2-ethoxyphenyl)-l-(3-ethyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)propan-l-one;
3-(2-methoxyphenyl)-l-(3-(tetrahydrofuran-2-yl)-8,9-dihydro-5H-[l,2,4]triazolo[4,3- d][l,4]diazepin-7(6H)-yl)propan-l-one;
2-(3,4-dichlorophenyl)-l-(3-(tetrahydrofuran-2-yl)-8,9-dihydro-5H- [ 1 ,2,4]triazolo[4,3-d] [ 1 ,4]diazepin-7(6H)-yl)ethanone;
2-([l,l'-biphenyl]-4-yl)-l-(3-isopropyl-8,9-dihydro-5H-[l,2,4]triazolo[4,3- d][l,4]diazepin-7(6H)-yl)ethanone;
2-(2-chloro-6-fluorophenyl)-l-(3-methyl-8,9-dihydro-5H-[l,2,4]triazolo[4,3- d][l,4]diazepin-7(6H)-yl)ethanone;
2-(3-fluorophenyl)-l-(3-methyl-8,9-dihydro-5H-[l,2,4]triazolo[4,3-d][l,4]diazepin- 7(6H)-yl)ethanone;
1- (3-isopropyl-8,9-dihydro-5H-[l,2,4]triazolo[4,3-d][l,4]diazepin-7(6H)-yl)-2-(4- (methylthio)phenyl)ethanone;
2- (2-chloro-6-fluorophenyl)-l-(3-(hydroxymethyl)-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)ethanone;
2-(2-chlorophenyl)-l-(3-(hydroxymethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)ethanone;
5-(4-bromophenyl)-l-(l-methyl-6,7-dihydro-lH-[l,2,3]triazolo[4,5-c]pyridin-5(4H)- yl)pentan-l-one;
3 4-ethoxyphenyl)-l-(l-methyl-6,7-dihydro-lH-[l,2,3]triazolo[4,5-c]pyridin-5(4H)- yl)propan-l-one;
2- (2-ethoxyphenoxy)-l-(l-methyl-6,7-dihydro-lH-[l,2,3]triazolo[4,5-c]pyridin- 5(4H)-yl)ethanone;
l-(5,6-dihydro-[l,2,4]triazolo[l,5-a]pyrazin-7(8H)-yl)-2-(3-fluorophenoxy)ethanone;
3- (5-(2-(3,4-dimethylphenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid;
3-(5-(2-(2,3-dimethylphenoxy)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid; 3-(5-(2-(2,3-dimethylphenoxy)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
2-(4-ethylphenoxy)-l-(2-(pyrrolidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4] diazepin- 5 (6H) -yl)ethanone ;
l-(2-(4-methylpiperazine-l-carbonyl)-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)- 2- (m-tolyloxy)ethanone ;
methyl 5-(2-(3,4-dimethylphenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylate;
5-(2-((3-methoxyphenyl)amino)butanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carbonitrile;
5-(2-(2-(sec-butyl)phenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carbonitrile;
1- (2,3-dimethyl-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-yl)-2-(4- fluorophenyl)ethanone ;
2- (2-chloro-6-fluorophenyl)-l-(2,3-dimethyl-6,7-dihydro-3H-imidazo[4,5-c]pyridin- 5(4H)-yl)ethanone;
methyl 3-ethyl-5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5- c] pyridine-6 -carboxylate ;
methyl 3-ethyl-5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5- c] pyridine-6 -carboxylate ;
3- (5-(2-(3-hydroxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid;
3-(5-(3-(4-hydroxyphenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)propanoic acid;
3-(5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin- 2-yl)propanoic acid;
3-(5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepin-2-yl)propanoic acid;
methyl 5-(2-(3-chloro-4-hydroxyphenyl)acetyl)-4,5,6,7-tetrahydropyrazolo[ 1 ,5- a]pyrazine-2-carboxylate;
5-(2-(2-hydroxyphenyl)acetyl)-N-phenyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine- 2-carboxamide;
2-(2-hydroxyphenyl)-l-(2-(pyrrolidine-l-carbonyl)-6,7-dihydropyrazolo[l,5- a]pyrazin-5(4H)-yl)ethanone; 7-(3-(2-hydroxyphenyl)propanoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-2- carboxamide;
2-(3-chloro-4-hydroxyphenyl)- 1 -(6,7-dihydro-5H-imidazo[ 1 ,5-a] [ 1 ,4]diazepin-8(9H)- yl)ethanone;
l-(5,6-dihydroimidazo[l,5-a]pyrazin-7(8H)-yl)-2-(2-hydroxyphenoxy)ethanone; or l-(5,6-dihydroimidazo[l,5-a]pyrazin-7(8H)-yl)-3-(2-hydroxyphenyl)propan-l-one.
2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R is selected form the group consisting of:
Figure imgf000263_0001
3. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.
4. The compound of any one of Claims 1-3, or a pharmaceutically acceptable salt thereof, wherein p is 1, and r is 1 or 2.
5. The compound of any one of Claims 1-3, or a pharmaceutically acceptable salt thereof, wherein p is 2, and r is 1.
6. The compound of any one of Claims 1-5, or a pharmaceutically acceptable salt thereof, wherein n is 1, and R is C^aUcyl.
7. The compound of any one of Claims 1-5, or a pharmaceutically acceptable salt thereof, wherein n is 0.
8. The compound of any one of Claims 1-7, or a pharmaceutically acceptable salt thereof, wherein t is 1 and R is halo.
9. The compound of any one of Claims 1-7, or a pharmaceutically acceptable salt thereof, wherein t is 0.
10. The compound of any one of Claims 1-9, or a pharmaceutically acceptable salt thereof, wherein L is a bond.
11. The compound of any one of Claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R6 is hydrogen.
12. The compound of any one of Claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R9a is hydrogen.
13. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (II):
Figure imgf000264_0001
14. The compound of any one of Claims 1-13, or a pharmaceutically acceptable salt thereof, wherein L is -C(O)-, -O-C(O)-, or -NR-C(O)-.
15. The compound of any one of Claims 1-14, or a pharmaceutically acceptable salt thereof, wherein L is -O-C(O)-.
16. A compound represented by structural formula (III):
Figure imgf000264_0002
(III) or a pharmaceutically acceptable salt thereof, wherein: R1 is a Ci^alkylene;
R3 is hydrogen, -CN, C1-8alkyl, Ci-ghaloalkyl, -(CR10Rn)m-N(R16)2, -(CR10Rn)m- OR15, -(CR10Rn)m-C(O)OR15, -(CR10Rn)m-C(O)N(R16)2, -(CR10Rn)m-S(O)2N(R16)2, - (CR10Ru)m-S(O)2NHS(O)2R15, -C(0)N(R15)-S(0)2R15, -S(0)2OR15, -C(0)NHC(0)R15, - Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -0-P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, - C(0)NHS(0)2R15, -C(0)NHOH, -C(0)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -Lx-R4; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R5; L1 is Ci_8alkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0)2NR-, or -C(0)NR-S(0)2-;
R, for each occurrence, is independently hydrogen or C1_4alkyl;
R4 is Ci-galkyl, C3_8cycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R4 may be optionally substituted with from one to four R5;
R5 is halo, cyano, Ci.galkyl, Ci.ghaloalkyl, C3-8cycloalkyl, -(CR10Ru)m-N(R16)2, -(CR10Rn)m-OR15, -(CR10Rn)m-C(O)OR15, -C(0)N(R16)2, -C(0)N(R15)-S(0)2R15, - S(0)2OR15, -C(0)NHC(0)R15, -Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -S(0)2N(R15)2, O P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, -C(0)NHS(0)2R15, C(0)NHOH,
C(0)NHCN, -C(0)R15, a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, =0, Ci_ 4alkyl, Ci^haloalkyl, C^alkoxy, cyano, nitro, hydroxyl, amino, N-(CMalkyl)amino,
Figure imgf000265_0001
C^alkylamido, C^alkylsulfonyl, C^alkylsulfonamido, sulfamoyl, N-C^alkylsulfamoyl, and N,N^CMdialkyl)-sulfamoyl;
R9, for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci-galkyl, Ci_galkoxy, Ci_ghaloalkyl, Ci_ghaloalkoxy,
C3_gcycloalkyl, C3_ghalocycloalkyl, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci_galkanoyl, amino, N-(Ci-galkyl)amino, N,N-di-(^galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci-galkyl)carbamoyl, N,N-di-(^galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci_galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(Ci_galkyl)sulfamoyl, Ci_galkylsulfonamido, C6-ioaryl, Ci-galkoxy-Ci-ealkyl, and tri-(Ci-galkyl)silyl;
R10 and R11, for each occurrence, are independently hydrogen, halo, hydroxyl, carboxy, C1-4alkyl, or Cl-4haloalkyl;
R15 for each occurrence is independently selected from the group consisting of hydrogen, Ci-galkyl, C2_galkenyl, C2_galkynyl, C3_gcycloalkyl, C3_gcycloalkenyl, C6-ioaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1-4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-(CMalkyl)amino, N,N-di-(Ci-4alkyl)amino, carboxyl, carbamoyl, N-(C1_4alkyl)carbamoyl,
Figure imgf000266_0001
C^alkylsulfonamido, sulfamoyl, N-iC^alky^sulfamoyl, and N^-iC^dialky^-sulfamoyl;
R16 is Ci-8alkoxy, or R15; or two R16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1-4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-(CMalkyl)amino,
Figure imgf000266_0002
sulfamoyl, N-Ci^alkylsulfamoyl, and N,N-(CMdialkyl)-sulfamoyl;
m, for each occurrence, is independently 0 or an integer from 1 to 6; and
q is 1, 2, 3, or 4.
17. The compound of any one of Claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, -CN, Ci-8alkyl, Ci-8haloalkyl, -(CR10Rn)m-N(R16)2, - (CR10Ru)m-OR15, -(CR10Rn)m-C(O)OR15, -(CR10Rn)m-C(O)N(R16)2, a 5 to 14 membered heteroaryl, or -Lx-R4; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R5.
18. The compound of any one of Claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R16, for each occurrence, is independently selected from the group consisting of hydrogen, Ci-galkyl, C3_gcycloalkyl, or two R16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C^alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-iC^alky^amino, N,N-di-(CMalkyl)amino, carboxyl, carbamoyl,
Figure imgf000266_0003
Figure imgf000266_0004
19. The compound of any one of Claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R15 is H or Ci-salkyl.
20. The compound of any one of Claims 1-19, or a pharmaceutically acceptable salt thereof, wherein m is 0.
21. The compound of any one of Claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R3 is -C(0)OH.
22. The compound of any one of Claims 1-21, or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2.
23. The compound of any one of Claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R9, for each occurrence, is independently selected from the group consisting of halo, C^aUcyl, Ci-shaloalkyl, and C6-ioaryl.
24. The compound of Claim 23, or a pharmaceutically acceptable salt thereof, wherein R9, for each occurrence, is independently selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, and phenyl.
25. The compound of any one of Claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R1 is methylene or ethylene.
26. The compound of Claim 25, or a pharmaceutically acceptable salt thereof, wherein R1 is methylene.
27. The compound of Claim 1, wherein the compound is selected from the group consisting of:
5-(3,5-Dichlorobenzyl) 2-ethyl 7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine- 2,5(6H)-dicarboxylate;
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2,5(6H)-dicarboxylate;
7-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 5,6-dihydroimidazo[ 1 ,2-a]pyrazine- 2,7(8H)-dicarboxylate;
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 6,7-dihydropyrazolo[l,5-a]pyrazine- 2,5(4H)-dicarboxylate;
7-(3,5-Bis(trifluoromethyl)benzyl) 3-methyl 8,9-dihydro-5H-imidazo[l,2- d][l,4]diazepine-3,7(6H)-dicarboxylate;
5-(3,5-Bis(trifluoromethyl)benzyl) 3-ethyl 7,8-dihydro-4H-[l,2,3]triazolo[l,5- a][l,4]diazepine-3,5(6H)-dicarboxylate;
5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid; 5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
7-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydroimidazo[l,2- a]pyrazine-2-carboxylic acid;
7-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-6,7,8,9-tetrahydro-5H- imidazo[ 1 ,2-d] [ 1 ,4]diazepine-3-carboxylic acid;
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- [ 1 ,2,3]triazolo[ 1 ,5-a] [ 1 ,4]diazepine-3-carboxylic acid;
3,5-Dichlorobenzyl 2-(9-azabicyclo[3.3.1]nonane-9-carbonyl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(isopropylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(tert-butylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(cyclobutylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(cyclopentylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(cyclohexylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(pyrrolidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(piperidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(4-fluoropiperidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(4-methylpiperidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate; 3,5-Dichlorobenzyl 2-(4-(trifluoromethyl)piperidine-l-carbonyl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(morpholine-4-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(piperazine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(4-methylpiperazine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(4-aminopiperidine-l-carbonyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(methylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(dimethylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-(ethylcarbamoyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(morpholine-4-carbonyl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(4-hydroxypiperidine-l-carbonyl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(4-fluoropiperidine-l-carbonyl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(piperazine-l-carbonyl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
9-(5-((3,5-Dichlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3-chlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid; 9-(5-((3-(trifluoromethyl)benzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((4-Chlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((4-(Trifluoromethyl)benzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3-Chloro-5-fluorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3,5-Difluorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine- 2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(((3-chlorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(((3-(Trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(((4-chlorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(((4-(Trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(((3-Chloro-5-fluorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(((3,5-Difluorobenzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine- 2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3,5-Dichlorobenzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(3-Chlorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(3-(Trifluoromethyl)benzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(4-Chlorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(4-(Trifluoromethyl)benzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(3-Chloro-5-fluorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-(3,5-Difluorobenzylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3,5-Dichlorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3-Chlorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3-(Trifluoromethyl)benzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((4-Chlorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((4-(Trifluoromethyl)benzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3-Chloro-5-fluorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3,5-Trifluorobenzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-((3,5-Bis(trifluoromethyl)benzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a][l,4]diazepine-2-carbonyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
5-(((3-Fluoro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid; 5-(((3-Chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((4-Fluoro-3-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3-(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3-Chloro-5-fluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3,5-Difluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3,4,5-Trifluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3-Fluoro-4-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((2-Fluoro-4-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((4-(Trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
5-((3,5-Dichlorophenethoxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3-Bromo-5-fluorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3-Fluoro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-((3,5-Dichlorobenzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(7-Chloro-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid; 5-(7-(Trifluoromethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8-tetrahydro- 4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(5-(Trifluoromethyl)-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8-tetrahydro- 4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(5-Chloro-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(3-(3,5-bis(Trifluoromethyl)phenyl)propanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(3-(3,5-Dichlorophenyl)propanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
3-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxamido)propanoic acid;
(ci5,)-4-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxamido)cyclohexanecarboxylic acid;
(iraw5,)-4-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxamido)cyclohexanecarboxylic acid; l-(5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carbonyl)piperidine-4-carboxylic acid; l-(5-(((3,5-dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carbonyl)piperidine-3-carboxylic acid;
9-(5-(3-(3,5-Dichlorophenyl)propanoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
5-(3-(3,5-Dichlorophenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carboxylic acid;
9-(5-(3-(3,5-Dichlorophenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-(5-(3-(3,5-Dichlorophenyl)propanoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2- carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid; 1- (2-(9-Azabicyclo[3.3.1]nonane-9-carbonyl)-6,7-dihydropyrazolo[l,5-a]pyrazin- 5(4H)-yl)-3-(3,5-dichlorophenyl)propan-l-one;
3,5-Dichlorobenzyl 2-(3-(methoxycarbonyl)-9-azabicyclo[3.3.1]nonane-9-carbonyl)- 7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate;
3-(3,5-Dichlorophenyl)-l-(2-(morpholine-4-carbonyl)-6,7-dihydropyrazolo[l,5- a] pyrazin- 5 (4H)- yl)propan- 1 - one ;
8- (5-(((3,5-Dichlorobenzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
2- (3,5-Dichlorobenzyl) 7-ethyl 3,4-dihydropyrrolo[l,2-a]pyrazine-2,7(lH)- dicarboxylate;
2-(3,5-Dichlorobenzyl) 8-ethyl 4,5-dihydro-lH-pyrrolo[l,2-a][l,4]diazepine-2,8(3H)- dicarboxylate;
2-(((3,5-Dichlorobenzyl)oxy)carbonyl)-2,3,4,5-tetrahydro-lH-pyrrolo[l,2- a] [ 1 ,4]diazepine-8-carboxylic acid;
3,5-Dichlorobenzyl 2-(4-hydroxypiperidine-l-carbonyl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-carbamoyl-7,8-dihydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine- 5(6H)-carboxylate;
9- (2-(((3,5-dichlorobenzyl)oxy)carbonyl)-2,3,4,5-tetrahydro-lH-pyrrolo[l,2- a][l,4]diazepine-8-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
3,5-Bis(trifluoromethyl)benzyl 2-carbamoyl-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
2-Ethyl 5-(3-methyl-5-(trifluoromethyl)benzyl) 7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2,5(6H)-dicarboxylate;
2-(3,5-Bis(trifluoromethyl)benzyl) 8-ethyl 4,5-dihydro-lH-pyrrolo[l,2- a][l,4]diazepine-2,8(3H)-dicarboxylate;
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 7-methyl-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2,5(6H)-dicarboxylate; 5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 3-chloro-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2,5(6H)-dicarboxylate;
5-(((3-Methyl-5-(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-3-chloro-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-7-methyl-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 3-chloro-6,7-dihydropyrazolo[l,5- a]pyrazine-2,5(4H)-dicarboxylate;
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-3-chloro-4,5,6,7- tetrahydropyrazolo[ 1 ,5-a]pyrazine-2-carboxylic acid;
5-(3,5-Bis(trifluoromethyl)benzyl) 2-ethyl 3-bromo-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2,5(6H)-dicarboxylate;
5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-3-bromo-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(2-((3,5-Bis(trifluoromethyl)phenyl)amino)acetyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(2-(3,5-Bis(trifluoromethyl)phenoxy)acetyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
3,5-Bis(trifluoromethyl)benzyl 2-(3-methyl-l,2,4-oxadiazol-5-yl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(5-methyl-l,3,4-oxadiazol-2-yl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
5-(((5-Fluoro-[l,l'-biphenyl]-3-yl)methoxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
3,5-Dichlorobenzyl 7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)-carboxylate;
3 , 5-Dichlorobenzyl 2-cyano-7 , 8-dihydro-4H-pyrazolo [ 1 ,5-a] [ 1 ,4] diazepine-5 (6H)- carboxylate; 3,5-Dichlorobenzyl 2-(lH-tetrazol-5-yl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-methyl-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-cyano-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3-Fluoro-5-(trifluoromethyl)benzyl 2-(trifluoromethyl)-5,6-dihydroimidazo[ 1 ,2- a]pyrazine-7(8H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(trifluoromethyl)-5,6-dihydroimidazo[l,2- a]pyrazine-7(8H)-carboxylate;
3-Fluoro-5-(trifluoromethyl)benzyl 2-methyl-7,8-dihydro-4H-pyrazolo[ 1 ,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3-Fluoro-5-(trifluoromethyl)benzyl 2-methyl-7,8-dihydro-4H-pyrazolo[ 1 ,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Dichlorobenzyl 2-methyl-7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepine-5(6H)- carboxylate;
3,5-Dichlorobenzyl 2-(trifluoromethyl)-5,6-dihydroimidazo[l,2-a]pyrazine-7(8H)- carboxylate;
3,5-Bis(trifluoromethyl)benzyl 6,7-dihydro-5H-imidazo[l,5-a][l,4]diazepine-8(9H)- carboxylate;
3,5-Dichlorobenzyl 6,7-dihydro-5H-imidazo[l,5-a][l,4]diazepine-8(9H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazine-7(8H)-carboxylate;
3-Chloro-5-(trifluoromethyl)benzyl 3-(trifluoromethyl)-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(lH-tetrazol-5-yl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3-Chloro-5-(trifluoromethyl)benzyl 7,8-dihydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine- 5(6H)-carboxylate; 3-(3,5-Bis(trifluoromethyl)phenyl)-l-(7,8-dihydro-4H-pyrazolo[l,5-a][l,4]diazepin- 5(6H)-yl)propan- 1 -one;
5-(l-(3,5-Bis(trifluoromethyl)phenyl)ethyl) 2-ethyl 7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2,5(6H)-dicarboxylate;
5-((l-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-(3,5-Bis(trifluoromethyl)phenethyl) 2-ethyl 7,8-dihydro-4H-pyrazolo[ 1,5- a] [ 1 ,4]diazepine-2,5(6H)-dicarboxylate;
5-((3,5-Bis(trifluoromethyl)phenethoxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carboxylic acid;
5-((3,5-Dichlorophenethoxy)carbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-2-carboxylic acid;
3,5-Bis(trifluoromethyl)benzyl 2-(methoxy(methyl)carbamoyl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-acetyl-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(l-hydroxyethyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(l-aminoethyl)-7,8-dihydro-4H-pyrazolo[l,5- a] [ 1 ,4]diazepine-5(6H)-carboxylate;
3,5-Bis(trifluoromethyl)benzyl 2-(l-(piperidin-l-yl)ethyl)-7,8-dihydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-5(6H)-carboxylate; and l-(l-(5-(((3,5-Bis(trifluoromethyl)benzyl)oxy)carbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[ 1 ,5-a] [ 1 ,4]diazepin-2-yl)ethyl)piperidine-4-carboxylic acid; or a pharmaceutically acceptable salt thereof.
28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound represented by formula (I):
Figure imgf000278_0001
(I)
or a pharmaceutically acceptable salt thereof, wherein: L is -C(O)-, -O-C(O)-, -NR6-C(0)-, or -S(0)2-; L2 is a bond, -0-, or -NR-;
R, for each occurrence, is independently hydrogen or a Ci^alkyl; R1 is a Ci-galkylene;
R2 is selected form the group consisting of:
Figure imgf000278_0002
i) (ii) (iii)
Figure imgf000278_0003
R3 is hydrogen, -CN, d-8alkyl, Ci_8haloalkyl, -(CR10Rn)m-N(R16)2, -(CR10Rn) -(CR10Rn)m-C(O)OR15, -(CR10Rn)m-C(O)N(R16)2, -(CR10Rn)m-S(O)2N(R16)2, -
, 15 15 , 15
(CR10Ru)m-S(O)2NHS(O)2R , 1153, -C(0)N(R°)-S(0)2R°, -S(0)2OR , 11J, -C(0)NHC(0)R", Si(0)OH, -B(OH)2, -N(R13)S(0)2R , -0-P(0)(OR13)2, -P(0)(OR13)2, -S(0)2NHC(0)R , - C(0)NHS(0)2R15, -C(0)NHOH, -C(0)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -Lx-R4; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R5;
L1 is Ci_8alkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0)2NR-, or -C(0)NR-S(0)2-;
R4 is Ci-galkyl, C3_gcycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R4 may be optionally substituted with from one to four R5;
R5 is halo, cyano, Ci-galkyl, Ci-ghaloalkyl, C3-8cycloalkyl, -(CR10Ru)m-N(R16)2, -(CR10Rn)m-OR15, -(CR10Rn)m-C(O)OR15, -C(0)N(R16)2, -C(0)N(R15)-S(0)2R15, - S(0)2OR15, -C(0)NHC(0)R15, -Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -S(0)2N(R15)2, O P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, -C(0)NHS(0)2R15, C(0)NHOH,
C(0)NHCN, -C(0)R15, a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, =0, Ci_ 4alkyl, Ci_4haloalkyl, C1-4alkoxy, cyano, nitro, hydroxyl, amino, N-(CMalkyl)amino, N,N-di-(CMalkyl)amino, carbamoyl, N-(Ci-4alkyl)carbamoyl, N,N-di-(CMalkyl)carbamoyl, Ci_4alkylamido, Ci_4alkylsulfonyl, Ci_4alkylsulfonamido, sulfamoyl, N-Ci_4alkylsulfamoyl, and N,N^Ci_4dialkyl)-sulfamoyl;
R6 is hydrogen or a Ci-galkyl;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, Ci-galkyl, Ci_ghaloalkyl, C3_gcycloalkyl,
C3_ghalocycloalkyl, Ci-galkoxy, Ci_ghaloalkoxy, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Q-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl,
Ci-galkylamido, mercapto, Ci_galkylthio, Ci-galkylsulfonyl , sulfamoyl,
N-(Ci_galkyl)sulfamoyl, N,N-di-(Ci_galkyl)sulfamoyl, and Ci_galkylsulfonamido;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C3_gcycloalkyl, C3_ghalocycloalkyl, Ci_galkoxy, Ci_ghaloalkoxy, C3_gcycloalkoxy, C3_ghalocycloalkoxy,
Figure imgf000279_0001
amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci_galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci_galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(Ci_galkyl)sulfamoyl, and Ci_galkylsulfonamido;
R9, for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci-galkyl, Ci-galkoxy, Ci-ghaloalkyl, Ci-ghaloalkoxy,
C3_gcycloalkyl, C3_ghalocycloalkyl, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci_galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci_galkoxycarbonyl, Ci_galkanoyloxy, carbamoyl, N-(Ci-galkyl)carbamoyl, N,N-di-(Ci-galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl, N-(^galkyl)sulfamoyl,
N,N-di-(Ci_galkyl)sulfamoyl, Ci_galkylsulfonamido, C6-1oaryl, Ci-galkoxy-Ci-ealkyl, and tri-(Ci-8alk l)silyl;
R9a is hydrogen or R9; or R9a and R6, together with the intervening atoms, form a 3- to 8-membered heterocyclyl which is optionally substituted with from one to three R9;
R10 and R11, for each occurrence, are independently hydrogen, halo, hydroxyl, carboxy, C1_4alkyl, or a Ci_4haloalkyl;
R15 for each occurrence is independently selected from the group consisting of hydrogen, Ci-galkyl, C2-galkenyl, C2_galkynyl, C3-gcycloalkyl, C3-gcycloalkenyl, C6-ioaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci_4alkoxy, Ci_4alkyl, cyano, nitro, hydroxyl, amino, N-(Ci_4alkyl)amino, N,N-di-(Ci_4alkyl)amino, carboxyl, carbamoyl,
N-(Ci_4alkyl)carbamoyl, N,N-di-(Ci_4alkyl)carbamoyl, Ci_4alkylamido, Ci_4alkylsulfonyl, Ci_4alkylsulfonamido, sulfamoyl, N-(Ci_4alkyl)sulfamoyl, and N,N-(Ci_4dialkyl)-sulfamoyl;
R16 is Ci-galkoxy, or R15; or two R16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci_4alkoxy, Ci_4alkyl, cyano, nitro, hydroxyl, amino, N-(Ci_4alkyl)amino,
N,N-di-(Ci_4alkyl)amino, carboxyl, carbamoyl, N-(Ci_4alkyl)carbamoyl,
N,N-di-(Ci_4alkyl)carbamoyl, Ci_4alkylamido, Ci_4alkylsulfonyl, Ci_4alkylsulfonamido, sulfamoyl, N-Ci_4alkylsulfamoyl, and N,N-(Ci_4dialkyl)-sulfamoyl;
h is 0, 1, or 2;
n, for each occurrence, is independently 0, 1, 2, 3, or 4; m, for each occurrence, is independently 0 or an integer from 1 to 6; p is 0, 1, 2, or 3;
q is 1, 2, 3, or 4;
r is 1, 2, or 3; and t is 0 or 1, provided that the compound is not 2-(4-fluorophenyl)-l-(3-(quinolin-2-yl)-,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone.
The compound of Claim 1, wherein L is -O-C(O)-, -NR6-C(0)-, or -C(O)- L2 is a bond, -0-, or -NR-; R1 is Ci^alkylene;
R is selected form the group consisting
Figure imgf000281_0001
p is 1 or 2; and r is 1 or 2.
The compound of Claim 29, wherein R1 is methylene or ethylene; and R is selected from
Figure imgf000282_0001
31. The compound of Claim 1, 29 or 30 wherein L is -O-C(O)-;
L is a bond;
R1 is methylene; and
Figure imgf000283_0001
32. The compound of Claim 1 or 29-31, wherein
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, Ci_galkoxy, Ci-ghaloalkoxy, Ci_galkanoyl, amino,
Figure imgf000283_0002
N,N-di-(Ci_galkyl)amino, Ci-galkoxycarbonyl, Ci_galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl,
Figure imgf000283_0003
and Ci_galkylamido;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, Q-galkoxy, Ci-ghaloalkoxy, Ci-galkanoyl, amino, N-(Ci-galkyl)amino, N,N-di-(^galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl,
Figure imgf000283_0004
N,N-di-(Ci_galkyl)carbamoyl, and Ci_galkylamido; h is 0 or 1 ; n is 0 or 1 ; and t is 0 or 1.
33. The compound of Claim 1 or 29-32, wherein
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, carboxy, C1-4alkyl, Ci^haloalkyl, Ci^alkoxy, Ci^haloalkoxy, Ci-galkoxycarbonyl, and Ci-galkanoyloxy;
R , for each occurrence, is independently selected from the group consisting of halo, cyano, Ci_4alkyl, C^haloalkyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, and Ci-galkylamido;
h is 0 or 1 ; n is 0 or 1 ; and t is 0 or 1.
34. The compound of Claim 1 or 29-33, wherein
R , for each occurrence, is independently selected from the group consisting of hydroxyl, carboxy, C1-4alkyl, and Ci-galkoxycarbonyl;
R , for each occurrence, is independently selected from the group consisting of halo, cyano, C1_4alkyl, C^haloalkyl, and Ci-galkylamido;
h is 0 or 1 ; n is 0 or 1 ; and t is 0 or 1.
35. The compound of Claim 1 or 29-34, wherein
R7 is methyl, -OH, -COOH, -COOCH3 or -COOCH2CH3;
R8 is chloro, bromo, CN, methyl, CF3, or NHC(0)CH3; h is 0 or 1 ; n is 0 or 1 ; and t is 0 or 1.
36. The compound of Claim 1, 16 or 29-35, wherein R9, for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy,
Ci-galkyl, Ci-galkoxy, Ci-ghaloalkyl, Ci-ghaloalkoxy, Ci-galkanoyl, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci-galkyl)carbamoyl, N,N-di-(^galkyl)carbamoyl,
Ci-galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl,
N-(Ci_galkyl)sulfamoyl, N,N-di-(Ci_galkyl)sulfamoyl, Ci_galkylsulfonamido, C6-1oaryl, and Ci-galkoxy-Ci-ealkyl; and q is 1, 2, or 3.
37. The compound of Claim 1, 16 or 29-36, wherein R9, for each occurrence, is independently selected from the group consisting of halo, cyano, carboxy, Ci-galkyl,
Ci-galkoxy, Ci_ghaloalkyl, Ci_ghaloalkoxy, C6-ioaryl, and Ci-galkoxy-Ci-ealkyl; and q is 1, 2, or 3.
38. The compound of Claim 1, 16 or 29-37 wherein R9, for each occurrence, is independently selected from the group consisting of halo, C1-4alkyl, Ci_4haloalkyl, and phenyl; and q is 1, 2, or 3.
39. The compound of Claim 1, 16 or 29-38, wherein each R9 is independently selected from methyl, fluoro, chloro, bromo, trifluoromethyl, and phenyl; and q is 1, 2, or 3.
40. The compound of Claim 1, 16 or 29-39, wherein each R9 is independently selected from methyl, fluoro, chloro, bromo, and trifluoromethyl; and q is 1, 2, or 3.
41. The compound of Claim 1 or 29-40, wherein R is hydrogen or C1-4alkyl; R6 is hydrogen or a C1-4alkyl; R9a is hydrogen or R9; or R9a and R6, together with the intervening atoms, form a 3- to 8-membered heterocyclyl which is optionally substituted with from one to three R9.
42. The compound of Claim 1, or 29-41, wherein R is hydrogen or methyl; R9a is - hydrogen and R6 is hydrogen; or R9a and R6, together with the intervening atoms, form a tetrahydroisoquinolinyl ring.
43. The compound of Claim 1, 16 or 29-42, wherein R9a is -hydrogen.
44. The compound of any one of Claims 1, 16, and 29-43,
R3 is hydrogen, -CN, C1-8alkyl, Ci-ghaloalkyl, -(CR10Rn)m-N(R16)2, -(CR10Rn)m- OR15, -(CR10Rn)m-C(O)OR15, -(CR10Rn)m-C(O)N(R16)2, -(CR10Rn)m-S(O)2N(R16)2, - C(0)NHS(0)2R15, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -L1- R4; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R5 groups selected from C1-4alkyl, -OH, Ci_4alkoxy, hydroxy(Ci_4alkyl), -COOH, -COO-Ci_ 4alkyl, -CH2COOH, and -CH2COO-Ci_4alkyl;
L1 is Ci_8alkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0)2NR-, or -C(0)NR-S(0)2-;
R, for each occurrence, is independently hydrogen or a C1-4alkyl;
R4 is Ci^alkyl, C3_8cycloalkyl, a 5 to 14 membered heteroaryl, or a 3 to 15 membered heterocyclyl, wherein R4 may be optionally substituted with from one to four R5 groups selected from halo, cyano, Ci-galkyl, Ci-ghaloalkyl, -COOH, -C(0)0-(Ci_4alkyl), C1-4alkoxy, -OH, hydroxyCi_4alkyl, -NH2, (Ci_4alkyl)amino, C3_8cycloalkyl, and a 3 to 15 membered heterocyclyl selected from 3-azabicyclo[3.1.0]hexanyl, azetidinyl, morpholinyl, piperidinyl, or pyrrolidinyl, wherein the heterocyclyl may be optionally substituted with one or two substituents independently selected from the group consisting of optionally substituted with C1-4alkyl, -OH, and COOH;
R10 and R11, for each occurrence, are independently hydrogen, carboxy, Ci_4alkyl, or Ci_4haloalkyl;
R15 for each occurrence is independently selected from the group consisting of hydrogen, Ci_8alkyl, C2_8alkenyl, C2_8alkynyl, C3_8cycloalkyl, wherein R15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1_4alkoxy, C1-4alkyl, hydroxyl, amino, N-iC^alky^amino, N^-di-iC^alky^amino, and carboxyl;
Each R16 is independently selected from hydrogen, Ci^alkoxy, C1-8alkyl, C2_8alkenyl, C2_8alkynyl, C3_8cycloalkyl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R16 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1-4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-(CMalkyl)amino, N,N-di-(CMalkyl)amino, carboxyl carbamoyl, N-iC^alky^carbamoyl, N^-di-iC^alky^carbamoyl, and
C^alkylamidol; or two R16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1-4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino,
Figure imgf000286_0001
N,N-di-(CMalkyl)amino, carboxyl, carbamoyl,
Figure imgf000286_0002
and m, for each occurrence, is independently 0 or 1.
45. The compound of any one of Claims 1, 16, and 29-44, wherein
R3 is hydrogen, -CN, C1-4alkyl, C1-4haloalkyl, -N(R16)2, -CR10RU-N(R16)2, -OR15, -CR10RU-OR15, -C(0)OR15, -CR10Rn-C(O)OR15, -C(0)N(R16)2, -CR10Rn- C(0)N(R16)2, -S(0)2N(R16)2, C(0)NHS(0)2R15, a 5 to 14 membered heteroaryl selected from 1,2,4-oxadiazolyl, pyridinyl, pyrazolyl, and tetrazolyl; a 3 to 15 membered heterocyclyl selected from 8-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]oct-2-enyl, 3,8- diazabicyclo[3.2.1]octanyl, 1,4-diazepanyl, 4,7-diazaspiro[2.5]octanyl, hexahydro-lH- pyrrolo [2, 1 -c] [ 1 ,4] oxazinyl, octahydropyrido [2, 1 -c] [ 1 ,4] oxazinyl, octahydropyrrolo [ 1 ,2- a]pyrazinyl, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-c], piperidin-2-only, piperidinyl, piperizinyl, pyrrolidinyl, 1,2,3,6-tetrahydropyridinyl, wherein the heteroaryl and heterocyclyl are optionally substituted with one to four groups selected from C1-4alkyl, -OH, Ci_4alkoxy, hydroxyCi^alkyl, -COOH, -COO-C^alkyl, -CH2COOH, and -CH2COO-Ci_ 4alkyl; or -Ll-R4; L1 is -CH2-, -CH(CH3)-, -C(O)-, -C(0)0-, -C(0)NR-, -S(0)2NR-, or -C(0)NR-
S(0)2-;
R, for each occurrence, is independently hydrogen or a C^alkyl;
R4 is Ci^alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a 3 to 15 membered heterocyclyl selected from 3-azabicyclo[3.1.0]hexanyl,
9-azabicyclo[3.3. l]nonanyl, 8-azabicyclo[3.2. l]octanyl, azetidinyl,
2,5-diazabicyclo[2.2.1]heptanyl, 3,9-diazabicyclo[3.3.1]nonanyl, 3,8- diazabicyclo[3.2. l]octanyl, 2,5-diazabicyclo[2.2.2]octanyl, 3,6-diazabicyclo[3.2. l]octanyl, 6,9— diazaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, 5,8-diazaspiro[3.5]nonanyl, 4,7-diazaspiro[2.5]octanyl, 1,4-diazepanyl, 4,5-dihydrothiazolyl, morpholinyl,
octahydropyrrolo[ 1 ,2-a]pyrazinyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,2- b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[2,3-b]pyrrolyl, piperazin-2- onyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl, tetrahydro-2H-pyranyl, wherein the R4 may be optionally substituted with from one to four groups selected from halo, -CN, C . 4alkyl, -CF3,-COOH, -COOCH3, -COO-t-butyl, -OH, -CH2CH2OH, -OCH3, -NH2,
-NHCH3, cyclopropyl, and 3 to 15 membered heterocyclyl selected from 3- azabicyclo[3.1.0]hexanyl, azetidinyl, morpholinyl, piperidinyl, or pyrrolidinyl, wherein the heterocyclyl may be optionally substituted with one or two substituents independently selected from the group consisting of optionally substituted with C^alkyl, -OH, and COOH;
R10 and R11, for each occurrence, are independently hydrogen, carboxy, methyl, or
CF3;
R15 for each occurrence is independently selected from the group consisting of hydrogen, C1-4alkyl;
Each R16 is independently selected from hydrogen, C^alkoxy, C1-4alkyl, C2_8alkenyl, C2_galkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 3 to 15 membered heterocyclyl selected from 8-azabicyclo[3.2.1]octanyl, 9-azabicyclo[3.3.1]nonanyl, azepanyl, 4,5-dihydroimidazolyl, 4,5-dihydrothiazolyl, oxetanyl, piperidinyl,
tetrahydro-2H-pyranyl; and wherein R16 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1-4alkoxy, C1-4alkyl, hydroxyl, amino, N-iC^alkyl) amino, N^-di-iC^alky^amino, and carboxyl; or two R16 together with the nitrogen atom to which they are attached a 3 to 15 membered heterocyclyl selected from 9-azabicyclo[3.3.1]nonanyl, 8-azabicyclo[3.2. l]octanyl, azetidinyl, 2,5-diazabicyclo[2.2. l]heptanyl,
3,9-diazabicyclo[3.3.1]nonanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5- diazabicyclo[2.2.2]octanyl, 3,6-diazabicyclo[3.2.1]octanyl, 2,8-diazaspiro[4.5]decanyl 6,9— diazaspiro[4.5]decanyl, 4,7-diazaspiro[2.5]octanyl, 5,8-diazaspiro[3.5]nonanyl,
1,4-diazepanyl, morpholinyl, octahydropyrrolo[l,2-a]pyrazinyl, octahydropyrrolo[3,4- b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl,
octahydropyrrolo[2,3-b]pyrrolyl, piperazin-2-onyl, pipendinyl, piperizinyl, and pyrrolidinyl and wherein the heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1_4alkoxy, C1-4alkyl, cyano, hydroxyl, amino, N-(C1-4alkyl) amino, N^-di-iC^alky^amino, and carboxyl.
46. The compound of any one of Claims 1, 16, and 29-45, wherein R is hydrogen; -CN; -CH3; -CF3; CH2Br; -NH2; -NH-CH(CH3)COOH;-NHCH(CH2CH3)COOH;
-NHCH(CH(CH3)2)COOH; -NH-8-azabicyclo[3.2.1]octanyl;
-NH-9-azabicyclo[3.3.1]nonanyl; -NH-azepanyl; -NH-piperidinyl optionally substituted with 1 or 2 groups selected from methyl, ethyl, isopropyl or t-butyl; ~CH2NH2;
-CH(COOH)NH2; -CH2NHCH3; -CH2N(CH3)2; -CH(CH3)NH2; -CH2NH-cyclopropyl; -CH2NH-cyclobutyl optionally substituted with 1, 2 or 3 groups selected from methyl or carboxyl; -CH2NH-cyclohexyl optionally substituted with carboxyl;
-CH(CH )NH-cyclopropyl; -CH2-8-azabicyclo[3.2.1]octanyl optionally substituted with carboxy; -CH2-9-azabicyclo[3.3.1]nonane optionally substituted with carboxy;
-CH2NH-4,5-dihydroimidazolyl; -CH2NH-4,5-dihydrothiazolyl; -CH2NH-oxetanyl; -CH2- piperidinyl optionally substituted with halo; -CH2-piperizinyl optionally substituted with methyl; -CH(CH3)-3,8-diazabicyclo[3.2.1]octanyl optionally substituted with methyl or -COO-t-butyl; - CH(CH3)-9-azabicyclo[3.3.1]nonane optionally substituted with COOH; -CH(CH3)NH-4,5-dihydroimidazolyl; -CH(CH3)NH-4,5-dihydrothiazolyl; - CH(CH3)NH-oxetanyl; -CH(CH3)-piperdinyl optionally substituted with COOH, hydroxyl, or halo; ~CH(CH )- piperizinyl optionally substituted with methyl or -COO-t-butyl;
-CH(CH3)- pyrrolidinyl; -COOH; -COOCH3; -COOCH2CH3; -CH2COOH;
-CH2COOCH2CH3; -CH(CH3)COOH; -CH(CH3)COOCH2CH3; -C(CH3)2COOH;
-C(CH3)2COOCH2CH3; -CH2OH; -CH2OCH3; -CH(CH3)OH; -CH(CF3)OH; -CONH2; -C(0)NHCH3; -C(0)NHCH2CH3; -CO-NHCH2CH2CH3; -C(0)NHCH(CH3)CH3; -C(0)NHCH(CH3)2; -C(0)NHC(CH3)3; -CON(CH3)2; -C(0)NHCH2CH2CH2CH2CCH;
C(0)NHCH2CH2NH2; -C(0)NHCH2CH2CH2CH2NH2; -C(0)NHCH2CH2COOH;
-CONHCH2CH2OH; -CONHCH(CH3)CH2OH; -C(0)N(CH3)OCH3; -C(0)NH-cyclopropyl; -C(0)NH-cyclobutyl optionally substituted with hydroxyl; -C(0)NH-cyclopentyl;
-C(0)NH-cyclohexyl optionally substituted with COOH; -C(0)NH-4,5-dihydrothiazolyl; -C(0)NH-oxetanyl; -C(0)NH-tetrahydro-2H-pyran; -C(0)NHCH2-cyclopropyl; -C(0)-8- azabicyclo[3.2.1]octanyl optionally substituted with -COOH; -C(0)-9- azabicyclo[3.3.1]nonanyl optionally substituted with -COOH; -C(0)-azetidinyl optionally substituted with NH2, NHCH3, or OH; -C(0)-2,5-diazabicyclo[2.2.1]heptanyl;
-C(0)-3,9-diazabicyclo[3.3.1]nonanyl optionally substituted with methyl; -C(0)-2,5- diazabicyclo[2.2.2]octanyl optionally substituted with methyl;
-C(0)-3,8-diazabicyclo[3.2.1]octanyl optionally substituted with methyl or -COO-t-butyl; -C(0)-3,6-diazabicyclo[3.2.1]octanyl; -C(0)-6,9— diazaspiro[4.5]decanyl optionally substituted with methyl; -C(0)-4,7-diazaspiro[2.5]octanyl optionally substituted with methyl or ethyl; -C(0)-2,8-diazaspiro[4.5]decanyl; -C(0)-5,8-diazaspiro[3.5]nonanyl octane optionally substituted with methyl; -CO-l,4-diazepanyl; -C(O)- morpholinyl,
-C(0)-octahydropyrrolo[l,2-a]pyrazinyl; -C(0)-octahydropyrrolo[3,4-b]pyrrolyl; ~C(0)- octahydropyrrolo[3,2-b]pyrrolyl; -C(0)-octahydropyrrolo[3,4-c]pyrrolyl;
-C(0)-octahydropyrrolo[2,3-b]pyrrolyl; -C(0)-piperazin-2-one; -C(O)- pyrrolidinyl optionally substituted with NHCH ; -C(O)- piperidinyl optionally substituted with methyl, halo, CF , hydroxyl, COOH, COOCH , or amino; -C(0)-piperazinyl optionally substituted with 1, 2 or 3 groups selected from methyl, ethyl, carboxyl, cyano, hydroxyl, hydroxyethyl, CF3, or -COO-t-butyl; -CONHS02CH3; -S02NH2; -S02N(CH3)2; -S02-8- azabicyclo[3.2.1]octanyl; -S02-9-azabicyclo[3.3.1]nonanyl; -S02-piperidinyl; ~S02- piperizinyl optionally substituted with methyl; -C(0)CH ; -C(0)CH2-3- azabicyclo[3.1.0]hexanyl; -C(0)CH2-azetidinyl optionally substituted with -COOH;
-C(0)CH2-morpholino optionally substituted with 1 or 2 methyl groups; -C(0)CH2- piperidinyl; -C(0)CH2-pyrrolidinyl optionally substituted with methyl orhydroxyl; 1,2,4- oxadiazolyl optionally substituted with methyl; pyridinyl optionally substituted with methyl; pyrazolyl optionally substituted with CH2COOH; tetrazolyl; 8-azabicyclo[3.2.1]octanyl optionally substituted with methyl; 8-azabicyclo[3.2.1]oct-2-enyl optionally substituted with methyl; 3,8-diazabicyclo[3.2.1]octanyl; 1,4-diazepanyl optionally substituted with methyl; 4,7-diazaspiro[2.5]octanyl optionally substituted with methyl; hexahydro-lH-pyrrolo[2,l- c] [ 1 ,4] oxazinyl; octahydropyrido[2, 1 -c] [ 1 ,4] oxazinyl; octahydropyrrolo[ 1 ,2-a]pyrazinyl; octahydropyrrolo[3,2-b]pyrrole optionally substituted methyl; octahydropyrrolo[3,4- c]pyrrolyl optionally substituted with methyl or ethyl; piperizinyl optionally substituted with 1 or 2 groups independently selected from methyl, ethyl, propyl, isopropyl or hydroxyethyl; piperidinyl optionally substituted with 1 or 2 groups independently selected from methyl or - COO-t-butyl; piperidin-2-one; pyrrolidinyl optionally substituted with methyl or -COO-t- butyl; 1,2,3,6-tetrahydropyridinyl optionally substituted with 1 or 2 groups independently selected from methyl or -COO-C1_4alkyl.
47. The compound of Claim 1, wherein
L is -O-C(O)-, -NR6-C(0)-, or -C(O)-;
L is a bond;
R1 is C^alkylene;
Figure imgf000290_0001
R3 is -(CR10Rn)m-C(O)OR15, a 3 to 15 membered heterocyclyl selected from 8- azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]oct-2-enyl, 3,8-diazabicyclo[3.2.1]octanyl, 1,4-diazepanyl, 4,7-diazaspiro[2.5]octanyl, hexahydro- lH-pyrrolo [2, l-c][ 1,4] oxazinyl, octahydropyrido[2, 1 -c] [ 1 ,4] oxazinyl, octahydropyrrolo[ 1 ,2-a]pyrazinyl,
octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-c], piperidin-2-only, piperidinyl, piperizinyl, pyrrolidinyl, 1,2,3,6-tetrahydropyridinyl, wherein heterocyclyl is optionally substituted with one to four groups selected from C1-4alkyl, hydroxyCi^alkyl, -COOH, - COO-C1-4alkyl, -CH2COOH, and -CH2COO-C1-4alkyl; or -Lx-R4;
L1 is -C(O)-,
R4 is 3 to 15 membered heterocyclyl selected from 9-azabicyclo[3.3.1]nonanyl, 8-azabicyclo[3.2. l]octanyl, azetidinyl, 2,5-diazabicyclo[2.2. l]heptanyl,
3,9-diazabicyclo[3.3.1]nonanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5- diazabicyclo[2.2.2]octanyl, 3,6-diazabicyclo[3.2.1]octanyl, 6,9— diazaspiro[4.5]decanyl, 2,8- diazaspiro[4.5]decanyl, 5,8-diazaspiro[3.5]nonanyl, 4,7-diazaspiro[2.5]octanyl, 1,4-diazepanyl, 4,5-dihydrothiazolyl, morpholinyl, octahydropyrrolo[l,2-a]pyrazinyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl, octahydropyrrolo[3,4- c]pyrrolyl, octahydropyrrolo[2,3-b]pyrrolyl, piperazin-2-onyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl, tetrahydro-2H-pyranyl, wherein the heterocyclyl may be optionally substituted with from one to four groups selected from halo, -CN, C1_4alkyl, -CF3,-COOH, -COOCH3, -COO-t-butyl, -OH, -CH2CH2OH, -OCH3, -NH2, and -NHCH3; each R9 is independently selected from halo and Ci-shaloalkyl;
R9a is -hydrogen;
R10 and R11, for each occurrence, are independently hydrogen or C1-4alkyl;
R15 is hydrogen or C1-4alkyl; m is 0 or 1 ; n is 0 or 1 ; q is 1, 2, or 3; p is 1 or 2; r is 1 or 2; and t is 0 or 1.
48. The compound of any one of Claim 1, wherein L is -O-C(O)-; L is a bond; R1 is methylene;
Figure imgf000291_0001
R3 is -C(0)OR15; -CR10Rn-C(O)OR15 a 3 to 15 membered heterocyclyl selected from azetidinyl, morpholinyl, piperazin-2-onyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl, hexahydro- 1 H-pyrrolo [2, 1 -c] [ 1 ,4] oxazinyl, octahydropyrido [2, 1 -c] [ 1 ,4] oxazinyl, octahydropyrrolo[l,2-a]pyrazinyl, and octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4- c], wherein the heterocyclyl is optionally substituted with one to four groups selected from C^alkyl, hydroxyCwalkyl, -COOH, -COO-C^alkyl, -CH2COOH, and -CHaCOO-Ci^alkyl; or -I^-R4;
L1 is -C(O)-,
R4 is 3 to 15 membered heterocyclyl selected azetidinyl, morpholinyl, piperazin-2- onyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl, tetrahydro-2H-pyranyl, the
heterocyclyl may be optionally substituted with from one to four groups selected from halo, Ci_4alkyl, -CF3,-COOH, -COOCH3, -COO-t-butyl; each R9 is independently selected from halo and C^haloalkyl;
R9a is -hydrogen;
R10 and R11, for each occurrence, are independently hydrogen or C1-4alkyl; R15 is hydrogen or C^alkyl; and q is 1, 2, or 3.
49. The compound of Claim 48, wherein R3 is -C(0)OH; -CH2C(0)OH, hexahydro-lH- pyrrolo[2,l-c][l,4]oxazinyl, piperizinyl; -C(0)-piperizinyl, wherein the piperizinyl is optionally substituted with 1, 2 or 3 C^alkyl groups.
50. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of any one of Claims 1-49.
51. A method of preventing, treating, or reducing symptoms of a condition mediated by
ATX activity in a mammal comprising administering to said mammal an effective amount of a compound represented by formula (I):
Figure imgf000292_0001
(I)
or a pharmaceutically acceptable salt thereof, wherein:
L is -C(O)-, -O-C(O)-, -NR6-C(0)-, or -S(0)2-; L2 is a bond, -0-, or -NR-;
R, for each occurrence, is independently hydrogen or a C1_4alkyl; R1 is a Ci^alkylene;
R is selected form the group consisting of:
Figure imgf000293_0001
R3 is hydrogen, -CN, C1-8alkyl, Ci-ghaloalkyl, -(CR10Rn)m-N(R16)2, -(CR10Rn)m- OR15, -(CR10Rn)m-C(O)OR15, -(CR10Rn)m-C(O)N(R16)2, -(CR10Rn)m-S(O)2N(R16)2, - (CR10Ru)m-S(O)2NHS(O)2R15, -C(0)N(R15)-S(0)2R15, -S(0)2OR15, -C(0)NHC(0)R15, - Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -0-P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, - C(0)NHS(0)2R15, -C(0)NHOH, -C(0)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -Lx-R4; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R5;
L1 is Ci_8alkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0)2NR-, or -C(0)NR-S(0)2-;
R4 is Ci-8alkyl, C3_8cycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R4 may be optionally substituted with from one to four R5;
R5 is halo, cyano, Ci.galkyl, Ci.ghaloalkyl, C3-8cycloalkyl, -(CR10Ru)m-N(R16)2, -(CR10Rn)m-OR15, -(CR10Rn)m-C(O)OR15, -C(0)N(R16)2, -C(0)N(R15)-S(0)2R15, - S(0)2OR15, -C(0)NHC(0)R15, -Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -S(0)2N(R15)2, O P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, -C(0)NHS(0)2R15, C(0)NHOH,
C(0)NHCN, -C(0)R15, a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, =0, Ci_ 4alkyl, Ci_4haloalkyl, Ci_4alkoxy, cyano, nitro, hydroxyl, amino, N-(CMalkyl)amino, N,N-di-(CMalkyl)amino, carbamoyl, N-(Ci-4alkyl)carbamoyl, N,N-di-(CMalkyl)carbamoyl, C1-4alkylamido, Ci_4alkylsulfonyl, Ci_4alkylsulfonamido, sulfamoyl, N-Ci^alkylsulfamoyl, and N,N-(C1-4dialkyl)-sulfamoyl;
R6 is hydrogen or a Ci-galkyl;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, Ci_galkyl, Ci_ghaloalkyl, C3_gcycloalkyl,
C3_ghalocycloalkyl, Ci_galkoxy, Ci_ghaloalkoxy, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci-galkyl)amino, N,N-di-(Ci-galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci-galkyl)carbamoyl, N,N-di-(^galkyl)carbamoyl,
Ci-galkylamido, mercapto, Ci_galkylthio, Ci_galkylsulfonyl , sulfamoyl,
N-(Ci_galkyl)sulfamoyl, N,N-di-(Ci_galkyl)sulfamoyl, and Ci_galkylsulfonamido;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C3_gcycloalkyl, C3_ghalocycloalkyl, Ci-galkoxy, Ci_ghaloalkoxy, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci-galkoxycarbonyl, Ci_galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci_galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(Ci_galkyl)sulfamoyl, and Ci_galkylsulfonamido;
R9, for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci-galkyl, Ci-galkoxy, Ci-ghaloalkyl, Ci-ghaloalkoxy,
C3_gcycloalkyl, C3_ghalocycloalkyl, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci-galkoxycarbonyl, Ci_galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(Ci-galkyl)sulfamoyl, Ci-galkylsulfonamido, C6-1oaryl, Ci-galkoxy-Ci^alkyl, and tri-(Ci_galkyl)silyl; R9a is hydrogen or R9; or R9a and R6, together with the intervening atoms, form a 3- to 8-membered heterocyclyl which is optionally substituted with from one to three R9;
R10 and R11, for each occurrence, are independently hydrogen, halo, hydroxyl, carboxy, C1-4alkyl, or a Ci^haloalkyl;
R15 for each occurrence is independently selected from the group consisting of hydrogen, Ci-galkyl, C2_galkenyl, C2_galkynyl, C3_gcycloalkyl, C3_gcycloalkenyl, C6-ioaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1_4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino,
Figure imgf000295_0001
N,N-di-(CMalkyl)amino, carboxyl, carbamoyl,
Figure imgf000295_0002
C^alkylsulfonamido, sulfamoyl, N-iC^alky^sulfamoyl, and N^-iC^dialky^-sulfamoyl;
R16 is Ci-galkoxy, or R15; or two R16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci^alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-(CMalkyl)amino,
N,N-di-(CMalkyl)amino, carboxyl, carbamoyl,
Figure imgf000295_0003
Figure imgf000295_0004
h is 0, 1, or 2;
n, for each occurrence, is independently 0, 1, 2, 3, or 4;
m, for each occurrence, is independently 0 or an integer from 1 to 6;
p is 0, 1, 2, or 3;
q is 1, 2, 3, or 4;
r is 1, 2, or 3; and t is 0 or 1.
52. A method of preventing, treating, or reducing symptoms of a condition mediated by ATX activity in a mammal comprising administering to said mammal an effective amount of a compound of any one of Claims 1-49.
53. The method of Claim 51 or 52, wherein the condition is an inflammatory disorder, an autoimmune disorder, a fibrosis of the lung, or a malignancy of the lung.
54. The method of Claim 51 or 52, wherein the condition is an inflammatory disorder, an autoimmune disorder, a fibrosis of the lung, a malignancy of the lung, liver fibrosis, or renal fibrosis.
55. The method of Claim 51 or 52, wherein the condition is a fibrotic disease.
56. The method of Claim 55, wherein the fibrotic disease is selected from a fibrosis of the lung, liver fibrosis, kidney fibrosis, and scleroderma.
57. The method of Claim 53, wherein the inflammatory disorder is rheumatoid arthritis.
58. The method of Claim 53, wherein the inflammatory disorder is asthma.
59. The method of Claim 53, wherein the inflammatory disorder is periodontal disease.
60. The method of Claim 53, wherein the autoimmune disorder is multiple sclerosis.
61. The method of Claim 53, wherein the autoimmune disorder is scleroderma.
62. The method of anyone of Claims 51-61, further comprising administering to said mammal an effective amount of one or more drugs selected from the group consisting of: a corticosteroid, a bronchodilator, an antiasthmatic, an antiinflammatory, an antirheumatic, an immunosuppressant, an antimetabolite, an immunomodulator, an antipsoriatic, and an antidiabetic.
63. A method of preventing, treating, or reducing chronic pain in a mammal comprising administering to said mammal an effective amount of a compound represented by formula
(I):
Figure imgf000296_0001
(I)
or a pharmaceutically acceptable salt thereof, wherein:
L is -C(O)-, -O-C(O)-, -NR-C(O)-, or -S(0)2-;
R, for each occurrence, is independently hydrogen or a Ci^alkyl; R1 is a Ci-galkylene;
R is selected form the group consisting of:
Figure imgf000297_0001
R3 is hydrogen, -CN, Ci_8alkyl, Ci_8haloalkyl, -(CR10Rn)m-N(R16)2, -(CR10Rn)m- OR15, -(CR10Rn)m-C(O)OR15, -(CR10Rn)m-C(O)N(R16)2, -(CR10Rn)m-S(O)2N(R16)2, - (CR10Ru)m-S(O)2NHS(O)2R15, -C(0)N(R15)-S(0)2R15, -S(0)2OR15, -C(0)NHC(0)R15, - Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -0-P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, - C(0)NHS(0)2R15, -C(0)NHOH, -C(0)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -Lx-R4; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R5;
L1 is Ci-galkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0)2NR-, or -C(0)NR-S(0)2-;
R4 is Ci-galkyl, C3_gcycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R4 may be optionally substituted with from one to four R5;
R5 is halo, cyano, Ci-galkyl, Ci-ghaloalkyl, C3-8cycloalkyl, -(CR10Ru)m-N(R16)2, -(CR10Rn)m-OR15, -(CR10Rn)m-C(O)OR15, -C(0)N(R16)2, -C(0)N(R15)-S(0)2R15, - S(0)2OR15, -C(0)NHC(0)R15, -Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -S(0)2N(R15)2, O P(0)(OR13)2, -P(0)(OR13)2, -S(0)2NHC(0)R , -C(0)NHS(0)2R , C(0)NHOH,
C(0)NHCN, -C(0)R15, a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, =0, Ci_ 4alkyl, Ci_4haloalkyl, Ci_4alkoxy, cyano, nitro, hydroxyl, amino, N-(Ci_4alkyl)amino, N,N-di-(Ci_4alkyl)amino, carbamoyl, N-iC^alky^carbamoyl, N,N-di-(Ci_4alkyl)carbamoyl, C1-4alkylamido, Ci_4alkylsulfonyl, Ci^alkylsulfonamido, sulfamoyl, N-Ci-4alkylsulfamoyl, and N,N-(C1-4dialkyl)-sulfamoyl;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, Ci_galkyl, Ci_ghaloalkyl, C3_gcycloalkyl,
C3_8halocycloalkyl, Ci_galkoxy, Ci-ghaloalkoxy, C3_8cycloalkoxy, C3_8halocycloalkoxy, Ci-galkanoyl, amino, N-(Ci-galkyl)amino, N,N-di-(Ci-galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl,
Ci-galkylamido, mercapto, Ci_galkylthio, Ci_galkylsulfonyl , sulfamoyl,
N-(^galkyl)sulfamoyl, N,N-di-(^galkyl)sulfamoyl, and Ci-galkylsulfonamido;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, Ci_galkyl, Ci_ghaloalkyl, C3_gcycloalkyl, C3_ghalocycloalkyl, Ci-galkoxy, Ci-ghaloalkoxy, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci_galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(^galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci-galkyl)carbamoyl, N,N-di-(^galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci_galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(Ci_galkyl)sulfamoyl, and Ci-galkylsulfonamido;
R9, for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci_galkyl, Ci_galkoxy, Ci-ghaloalkyl, Q-ghaloalkoxy,
C3_gcycloalkyl, C3_ghalocycloalkyl, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci-galkoxycarbonyl, Ci_galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(Ci_galkyl)sulfamoyl, Ci-galkylsulfonamido, C6-1oaryl, Ci_galkoxy-Ci_6alkyl, and tri-(Ci_galkyl)silyl;
R10 and R11, for each occurrence, are independently hydrogen, halo, hydroxyl, carboxy, Ci_4alkyl, or a Ci_4haloalkyl; R for each occurrence is independently selected from the group consisting of hydrogen, Ci-galkyl, C2_galkenyl, C2_galkynyl, C3_gcycloalkyl, C3_gcycloalkenyl, C6-ioaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1_4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino,
Figure imgf000299_0001
N,N-di-(CMalkyl)amino, carboxyl, carbamoyl,
Figure imgf000299_0002
C^alkylsulfonamido, sulfamoyl, N-iC^alky^sulfamoyl, and N^-iC^dialky^-sulfamoyl;
R16 is Ci-galkoxy, or R15; or two R16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci^alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-(CMalkyl)amino,
N,N-di-(CMalkyl)amino, carboxyl, carbamoyl,
Figure imgf000299_0003
Figure imgf000299_0004
h is 0, 1, or 2;
n, for each occurrence, is independently 0, 1, 2, 3, or 4;
m, for each occurrence, is independently 0 or an integer from 1 to 6;
p is 0, 1, 2, or 3;
q is 1, 2, 3, or 4;
r is 1, 2, or 3; and t is 0 or 1, provided that the compound is not 2-(4-fluorophenyl)-l-(3-(quinolin-2-yl)-5,6- dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone.
64. A method of preventing, treating, or reducing chronic pain in a mammal comprising administering to said mammal an effective amount of a compound of any one of Claims 1-49.
65. The method of Claim 63 or 64, wherein the chronic pain is inflammatory pain.
66. The method of Claim 63 or 64, wherein the chronic pain is neuropathic pain.
67. A method of preventing, treating, or reducing symptoms of a condition mediated by ATX activity in a mammal comprising delivering to said mammal an effective amount of a compound represented by formula (I):
Figure imgf000300_0001
or a pharmaceutically acceptable salt thereof, wherein: L is -C(O)-, -O-C(O)-, -NR6-C(0)-, or -S(0)2-; L2 is a bond, -0-, or -NR-;
R, for each occurrence, is independently hydrogen or a Ci^alkyl; R1 is a Ci^alkylene;
R is selected form the group consisting of:
Figure imgf000300_0002
R3 is hydrogen, -CN, Ci_8alkyl, Ci_8haloalkyl, -(CR10Rn)m-N(R16)2, -(CR10Rn)m- OR15, -(CR10Rn)m-C(O)OR15, -(CR10Rn)m-C(O)N(R16)2, -(CR10Rn)m-S(O)2N(R16)2, - (CR10Ru)m-S(O)2NHS(O)2R15, -C(0)N(R15)-S(0)2R15, -S(0)2OR15, -C(0)NHC(0)R15, - Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -0-P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, - C(0)NHS(0)2R15, -C(0)NHOH, -C(0)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -Lx-R4; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R5;
L1 is Ci-galkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0)2NR-, or -C(0)NR-S(0)2-;
R4 is Ci-galkyl, C3_gcycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R4 may be optionally substituted with from one to four R5;
R5 is halo, cyano, Ci-galkyl, Ci-ghaloalkyl, C3-8cycloalkyl, -(CR10Ru)m-N(R16)2, -(CR10Rn)m-OR15, -(CR10Rn)m-C(O)OR15, -C(0)N(R16)2, -C(0)N(R15)-S(0)2R15, - S(0)2OR15, -C(0)NHC(0)R15, -Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -S(0)2N(R15)2, O P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, -C(0)NHS(0)2R15, C(0)NHOH, C(0)NHCN, -C(0)R15, a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, =0, Ci_ 4alkyl, Ci_4haloalkyl, Ci_4alkoxy, cyano, nitro, hydroxyl, amino, N-(Ci_4alkyl)amino, N,N-di-(CMalkyl)amino, carbamoyl, N-(Ci-4alkyl)carbamoyl, N,N-di-(CMalkyl)carbamoyl, Ci_4alkylamido, Ci_4alkylsulfonyl, Ci-4alkylsulfonamido, sulfamoyl, N-Ci^alkylsulfamoyl, and N,N^Ci_4dialkyl)-sulfamoyl;
R6 is hydrogen or a Ci-galkyl;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C3_gcycloalkyl,
C3_ghalocycloalkyl, Ci_galkoxy, Ci_ghaloalkoxy, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci_galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci_galkylsulfonyl , sulfamoyl,
N-(Ci_galkyl)sulfamoyl, N,N-di-(Ci_galkyl)sulfamoyl, and Ci_galkylsulfonamido;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, Ci-galkyl, Ci-ghaloalkyl, C3_gcycloalkyl, C3_ghalocycloalkyl, Ci-galkoxy, Ci-ghaloalkoxy, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci_galkoxycarbonyl, Ci_galkanoyloxy, carbamoyl,
Figure imgf000302_0001
Ci_galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl, N-(^galkyl)sulfamoyl,
N,N-di-(^galkyl)sulfamoyl, and Ci-galkylsulfonamido;
R9, for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci_galkyl, Ci_galkoxy, Ci_ghaloalkyl, Ci_ghaloalkoxy,
C3_gcycloalkyl, C3_ghalocycloalkyl, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci-galkyl)amino, N,N-di-(^galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl,
Figure imgf000302_0002
N,N-di-(Ci_galkyl)carbamoyl, Ci_galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(Ci_galkyl)sulfamoyl, Ci-galkylsulfonamido, C6-1oaryl, Ci-galkoxy-Ci_6alkyl, and tri-(Ci-galkyl)silyl;
R9a is hydrogen or R9; or R9a and R6, together with the intervening atoms, form a 3- to 8-membered heterocyclyl which is optionally substituted with from one to three R9;
R10 and R11, for each occurrence, are independently hydrogen, halo, hydroxyl, carboxy, C1-4alkyl, or a Ci^haloalkyl;
R15 for each occurrence is independently selected from the group consisting of hydrogen, Ci-galkyl, C2-galkenyl, C2_galkynyl, C3_gcycloalkyl, C3_gcycloalkenyl, C6-1oaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci_4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-(Ci_4alkyl)amino, N,N-di-(Ci_4alkyl)amino, carboxyl, carbamoyl,
N-(Ci_4alkyl)carbamoyl, N,N-di-(Ci_4alkyl)carbamoyl, Ci^alkylamido, Ci^alkylsulfonyl, Ci_4alkylsulfonamido, sulfamoyl, N-(Ci_4alkyl)sulfamoyl, and N,N-(Ci_4dialkyl)-sulfamoyl;
R16 is Ci-galkoxy, or R15; or two R16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci_4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-(Ci_4alkyl)amino,
N,N-di-(Ci_4alkyl)amino, carboxyl, carbamoyl, N-(C1-4alkyl)carbamoyl,
N,N-di-(C1-4alkyl)carbamoyl, C1-4alkylamido, C1-4alkylsulfonyl, C1-4alkylsulfonamido, sulfamoyl, N-C1-4alkylsulfamoyl, and N,N-(C1-4dialkyl)-sulfamoyl; h is 0, 1, or 2;
n, for each occurrence, is independently 0, 1, 2, 3, or 4;
m, for each occurrence, is independently 0 or an integer from 1 to 6;
p is 0, 1, 2, or 3;
q is 1, 2, 3, or 4;
r is 1, 2, or 3; and t is 0 or 1.
68. A method of preventing, treating, or reducing symptoms of a condition mediated by ATX activity in a mammal comprising delivering to said mammal an effective amount of a compound of any one of Claims 1-49.
69. The method of Claim 67 or 68, wherein the condition is an inflammatory disorder, an autoimmune disorder, a fibrosis of the lung, or a malignancy of the lung.
70. The method of Claim 69, wherein the inflammatory disorder is rheumatoid arthritis.
71. The method of Claim 69, wherein the autoimmune disorder is multiple sclerosis.
72. The method of anyone of Claims 67-71, further comprising administering to said mammal an effective amount of one or more drugs selected from the group consisting of: a corticosteroid, a bronchodilator, an antiasthmatic, an antiinflammatory, an antirheumatic, an immunosuppressant, an antimetabolite, an immunomodulator, an antipsoriatic, and an antidiabetic.
73. A method of preventing, treating, or reducing chronic pain in a mammal comprising delivering to said mammal an effective amount of a compound represented by formula (I):
Figure imgf000303_0001
or a pharmaceutically acceptable salt thereof, wherein:
L is -C(O)-, -O-C(O)-, -NR-C(O)-, or -S(0)2-;
R, for each occurrence, is independently hydrogen or a Ci^alkyl; R1 is a Ci-galkylene;
R is selected form the group consisting of:
Figure imgf000304_0001
R3 is hydrogen, -CN, Ci_8alkyl, Ci_8haloalkyl, -(CR10Rn)m-N(R16)2, -(CR10Rn)m- OR15, -(CR10Rn)m-C(O)OR15, -(CR10Rn)m-C(O)N(R16)2, -(CR10Rn)m-S(O)2N(R16)2, - (CR10Ru)m-S(O)2NHS(O)2R15, -C(0)N(R15)-S(0)2R15, -S(0)2OR15, -C(0)NHC(0)R15, - Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -0-P(0)(OR15)2, -P(0)(OR15)2, -S(0)2NHC(0)R15, - C(0)NHS(0)2R15, -C(0)NHOH, -C(0)NHCN, a 5 to 14 membered heteroaryl, a 3 to 15 membered heterocyclyl, or -Lx-R4; where in the heteroaryl and heterocyclyl are optionally substituted with one to four R5;
L1 is Ci-galkylene, -C(O)-, -C(0)0-, -C(0)NR-, -S(0)2NR-, or -C(0)NR-S(0)2-;
R4 is Ci-galkyl, C3_gcycloalkyl, or a 3 to 15 membered heterocyclyl, wherein R4 may be optionally substituted with from one to four R5;
R5 is halo, cyano, Ci-galkyl, Ci-ghaloalkyl, C3-8cycloalkyl, -(CR10Ru)m-N(R16)2, -(CR10Rn)m-OR15, -(CR10Rn)m-C(O)OR15, -C(0)N(R16)2, -C(0)N(R15)-S(0)2R15, - S(0)2OR15, -C(0)NHC(0)R15, -Si(0)OH, -B(OH)2, -N(R15)S(0)2R15, -S(0)2N(R15)2, O P(0)(OR13)2, -P(0)(OR13)2, -S(0)2NHC(0)R , -C(0)NHS(0)2R , C(0)NHOH,
C(0)NHCN, -C(0)R15, a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, =0, Ci_ 4alkyl, Ci_4haloalkyl, Ci_4alkoxy, cyano, nitro, hydroxyl, amino, N-(Ci_4alkyl)amino, N,N-di-(Ci_4alkyl)amino, carbamoyl, N-iC^alky^carbamoyl, N,N-di-(Ci_4alkyl)carbamoyl, C1-4alkylamido, Ci_4alkylsulfonyl, Ci^alkylsulfonamido, sulfamoyl, N-Ci-4alkylsulfamoyl, and N,N-(C1-4dialkyl)-sulfamoyl;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, carboxy, Ci_galkyl, Ci_ghaloalkyl, C3_gcycloalkyl,
C3_8halocycloalkyl, Ci_galkoxy, Ci-ghaloalkoxy, C3_8cycloalkoxy, C3_8halocycloalkoxy, Ci-galkanoyl, amino, N-(Ci-galkyl)amino, N,N-di-(Ci-galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl,
Ci-galkylamido, mercapto, Ci_galkylthio, Ci_galkylsulfonyl , sulfamoyl,
N-(^galkyl)sulfamoyl, N,N-di-(^galkyl)sulfamoyl, and Ci-galkylsulfonamido;
R , for each occurrence, is independently selected from the group consisting of halo, hydroxyl, nitro, cyano, carboxy, Ci_galkyl, Ci_ghaloalkyl, C3_gcycloalkyl, C3_ghalocycloalkyl, Ci-galkoxy, Ci-ghaloalkoxy, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci_galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(^galkyl)amino, Ci-galkoxycarbonyl, Ci-galkanoyloxy, carbamoyl, N-(Ci-galkyl)carbamoyl, N,N-di-(^galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci_galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(Ci_galkyl)sulfamoyl, and Ci-galkylsulfonamido;
R9, for each occurrence, is independently selected from the group consisting of halo, cyano, hydroxyl, carboxy, Ci_galkyl, Ci_galkoxy, Ci-ghaloalkyl, Q-ghaloalkoxy,
C3_gcycloalkyl, C3_ghalocycloalkyl, C3_gcycloalkoxy, C3_ghalocycloalkoxy, Ci-galkanoyl, amino, N-(Ci_galkyl)amino, N,N-di-(Ci_galkyl)amino, Ci-galkoxycarbonyl, Ci_galkanoyloxy, carbamoyl, N-(Ci_galkyl)carbamoyl, N,N-di-(Ci_galkyl)carbamoyl, Ci-galkylamido, mercapto, Ci-galkylthio, Ci-galkylsulfonyl , sulfamoyl, N-(Ci_galkyl)sulfamoyl,
N,N-di-(Ci_galkyl)sulfamoyl, Ci-galkylsulfonamido, C6-1oaryl, Ci_galkoxy-Ci_6alkyl, and tri-(Ci_galkyl)silyl;
R10 and R11, for each occurrence, are independently hydrogen, halo, hydroxyl, carboxy, Ci_4alkyl, or a Ci_4haloalkyl; R for each occurrence is independently selected from the group consisting of hydrogen, Ci-galkyl, C2_galkenyl, C2_galkynyl, C3_gcycloalkyl, C3_gcycloalkenyl, C6-ioaryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein R15 may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C1_4alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino,
Figure imgf000306_0001
N,N-di-(CMalkyl)amino, carboxyl, carbamoyl,
Figure imgf000306_0002
C^alkylsulfonamido, sulfamoyl, N-iC^alky^sulfamoyl, and N^-iC^dialky^-sulfamoyl;
R16 is Ci-galkoxy, or R15; or two R16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, or S; and wherein the heteroaryl or heterocyclyl may be optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, Ci^alkoxy, C1-4alkyl, cyano, nitro, hydroxyl, amino, N-(CMalkyl)amino,
N,N-di-(CMalkyl)amino, carboxyl, carbamoyl,
Figure imgf000306_0003
Figure imgf000306_0004
h is 0, 1, or 2;
n, for each occurrence, is independently 0, 1, 2, 3, or 4;
m, for each occurrence, is independently 0 or an integer from 1 to 6;
p is 0, 1, 2, or 3;
q is 1, 2, 3, or 4;
r is 1, 2, or 3; and t is 0 or 1, provided that the compound is not 2-(4-fluorophenyl)-l-(3-(quinolin-2-yl)-5,6- dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone.
74. A method of preventing, treating, or reducing chronic pain in a mammal comprising delivering to said mammal an effective amount of a compound of any one of Claims 1-49.
75. The method of Claim 73 or 74, wherein the chronic pain is inflammatory pain.
76. The method of Claim 73 or 74, wherein the chronic pain is neuropathic pain.
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