Tricyclic GPR65 Modulators

Abstract

One aspect of the invention is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein Ring B is a monocyclic aromatic group, or a monocyclic or bicyclic heteroaromatic group, each of which is selected from the group consisting of halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, NHCO-aryl, -(CH 2 ) q -O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl and CO 2 -alkyl, and the aryl group, heteroaryl group, heterocycloalkyl group, O-cycloalkyl group, NHCO-aryl group, -(CH 2 ) q -O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl and O-aryl are halo, alkyl, haloalkyl, alkoxy, NHCO-alkyl, NR 13 R 13’ , S.O. 2 -Alkyl, CN, Hydroxyalkyl, CONR 14 R 14’ , alkyl-NR 15 R 15’ , heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH 2 ) m -NHSO 2 -Alkyl, CO 2 R 16 , alkoxy-alkyl, haloalkoxy, O-heterocycloalkyl, heteroaryl, alkoxy-alkoxy and O-(CH 2 ) p-cycloalkyl, wherein the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups, or alkoxy groups; m is an integer of 0 to 3; p and q are each independently 0 to 3; Z is CR 12 and Y is CR 10 R 10’ and R 10 and R 10’ are each independently selected from H, F, alkyl, and haloalkyl; R a and R b are each independently selected from H and alkyl; R 6 is selected from H, alkyl, cycloalkyl, and hydroxyalkyl; R 12 is selected from H, alkyl, haloalkyl, halo, OH and O-alkyl; R 13 , R 13’ , R 14 , R 14’ , R 15 , R 15’ and R 16 are each independently selected from H, alkyl and alkoxyalkyl. A further aspect of the present invention relates to compounds of formula (I) for use as a medicament, especially in the fields of immuno-oncology, immunology and related applications. [Formula 1] TIFF2024538178000464.tif47170

Description

[Technical Field]

[0001] The present invention relates to compounds capable of modulating GPR65, which have potential therapeutic applications in the treatment of a variety of disorders, including proliferative and immune disorders. [Background technology]

[0002] GPR65 is a G-protein-coupled receptor (GPCR) that is primarily expressed in immune cells and is activated by an acidic extracellular pH, leading to an increase in cytoplasmic cyclic adenosine monophosphate (cAMP) (Wang, J. et al. (2004). TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor. Journal of Biological Chemistry, 45626-45633). It has long been known that tumors typically undergo a shift in cellular metabolism from oxidative phosphorylation to aerobic glycolysis, which then leads to an acidic extracellular microenvironment (Damaghi, M. et al. (2013). pH Sensing and Regulation in Cancer. Frontiers in Physiology). Recently, it has been shown that this acidic microenvironment triggers GPR65 activation in tumor-associated macrophages, leading to elevated cytosolic cAMP and transcription of inducible cAMP early repressor (ICER). This, in turn, suppresses tumor necrosis factor alpha (TNFα) secretion and biases macrophages toward an anti-inflammatory, tumor-permissive phenotype (Bohn, T. et al. (2018). Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nature Immunology, 1319-1326). Therefore, this GPR65-dependent pathway appears to represent a mechanism by which tumors exploit their acidic microenvironment to evade immune system detection.

[0003] Autoimmune diseases are also often associated with an acidic local microenvironment (e.g., inflamed joints). Recent studies also suggest that GPR65 acts via ICER in CD4+ T cells to suppress IL-2, thereby biasing the cells toward a pro-inflammatory Th17 phenotype that is associated with increased pathogenicity in the context of autoimmune diseases (Korn, T. et al. (2009). IL-17 and Th17 Cells. Annual Reviews in Immunology, 485-517). This is supported by recent findings that ICER is required for Th17 differentiation (Yoshida, N. et al. (2016). ICER is requisite for Th17 differentiation. Nature Communications, 12993) and that agonism of GPR65 leads to increased Th17 differentiation (Hernandez, J. (2018). GPR65, a critical regulator of Th17 cell pathogenesis, is regulated by the CRTC2 / CREB pathway. The Journal of Immunology, 200 (Supplement)). Indeed, mutations in the GPR65 locus are associated with several autoimmune diseases, such as multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, and Crohn's disease (Gaublomme, J. et al. (2015). Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell, 1400-1412). A recent study found that mice with CD4+ T cells lacking GPR65 were protected from the progression of autoimmune encephalomyelitis (EAE) disease (Gaublomme, J. et al. (2015). Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell, 1400-1412).

[0004] Thus, GPR65 appears to act through ICER to promote an anti-inflammatory, tumor-tolerant phenotype in tumor-associated macrophages and a pro-inflammatory Th17 phenotype in CD4+ T cells associated with autoimmune disease. GPR65 signaling therefore represents an interesting pathway for therapeutic intervention in the treatment of both cancer and autoimmune disease. Therefore, there is currently a need to develop new small molecule GPR65 modulators.

[0005] WO 2021 / 245427 (Pathios Therapeutics Limited) discloses a series of small molecule GPR65 modulators. The present invention seeks to provide further compounds capable of modulating GPR65. As is apparent from the above discussion, such compounds have potential therapeutic applications in the treatment of various disorders, including proliferative and immune disorders, as well as asthma and chronic obstructive pulmonary disease. Advantageously, the compounds claimed herein may also exhibit one or more of the following properties: improved activity against GPR65 (even in wild-type cells), better in vitro selectivity and toxicity profiles, and / or improved oral pharmacokinetic profiles suitable for chronic, once-daily oral administration. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2021 / 245427 Brochure [Non-patent literature]

[0007] [Non-Patent Document 1] Wang, J. et al. (2004). TDAG8 is aproton-sensing and psychosine-sensitive G-protein-coupled receptor. Journal of Biological Chemistry, 45626-45633 [Non-patent document 2] Damaghi, M. et al. (2013). pH Sensing andRegulation in Cancer. Frontiers in Physiology [Non-patent document 3] Bohn, T. et al. (2018). Tumor immunoevasionvia acidosis-dependent induction of regulatory tumor-associated macrophages.Nature Immunology, 1319-1326 [Non-patent document 4] Korn, T. et al. (2009). IL-17 and Th17 Cells. Annual Reviews in Immunology, 485-517 [Non-Patent Document 5] Yoshida, N. et al. (2016). ICER is requisite for Th17 differentiation. Nature Communications, 12993 [Non-patent document 6] Hernandez, J. (2018). GPR65, a critical regulator of Th17 cell pathogenicity, is regulated by the CRTC2 / CREB pathway.The Journal of Immunology, 200 (Supplement) [Non-Patent Document 7] Gaublomme, J. et al. (2015). Single-CellGenomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell,1400-1412 Summary of the Invention [Means for solving the problem]

[0008] A first aspect of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, Ring B is a monocyclic aromatic group, or Monocyclic or bicyclic heteroaromatic groups and Each of which is halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, NHCO-aryl, -(CH2) q -O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and CO2-alkyl, and the aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, NHCO-aryl, -(CH2) q -O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl and O-aryl are halo, alkyl, haloalkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2) m -NHSO2-alkyl, CO2R 16 , alkoxy-alkyl, haloalkoxy, O-heterocycloalkyl, heteroaryl, alkoxy-alkoxy and O-(CH2) p-cycloalkyl, wherein said cycloalkyl is optionally further substituted with one or more halo, haloalkyl, alkyl, or alkoxy groups; m is an integer from 0 to 3; p and q each independently represent 0 to 3; Z is CR 12 and Y is CR 10 R 10 ' and R 10 and R 10 each ' is independently selected from H, F, alkyl and haloalkyl; R a and R b are each independently selected from H and alkyl; R6 is selected from H, alkyl, cycloalkyl and hydroxyalkyl; R 12 is selected from H, alkyl, haloalkyl, halo, OH and O-alkyl; R 13 , R 13 ', R 14 , R 14 ', R 15 , R 15 ' and R 16 are each independently selected from H, alkyl and alkoxyalkyl.

[0009] Another aspect of the present invention is a compound of formula (If), or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, R 11 is selected from H, alkyl, haloalkyl, halo, OH and O-alkyl; B, Y, Z, R a and R b is as defined hereinabove).

[0010] Another aspect of the present invention is a compound of formula (Ij) or a pharmaceutically acceptable salt or solvate thereof: [ka] (Ij) (Wherein, ring A is [ka] is selected from Y is CR 10 R 10 ' and R 10 and R 10 each ' is independently selected from H, F, alkyl and haloalkyl; R a and R b are each independently selected from H and alkyl; R1', R2', R4', and R5' are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, and halo; R3' is CN, haloalkyl, haloalkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, O-(CH2) q -heterocycloalkyl, alkoxy-alkoxy, alkylamino-alkoxy, dialkylamino-alkoxy, alkoxy-alkyl and O-(CH2) p -a pyridinyl group substituted by one or more substituents selected from cycloalkyl, wherein the cycloalkyl group is optionally substituted by one or more halo, alkyl or alkoxy groups, and the pyridinyl is optionally further substituted by one or more substituents selected from halo, alkyl and alkoxy; R6' is H or alkyl, more preferably H; R7, R8, and R9 are each independently selected from H, halo, and alkyl; R 13 and R 13 each ' is independently selected from H, alkyl, and alkoxy-alkyl; p and q each independently represent 0 to 3).

[0011] Advantageously, the presently claimed compounds are capable of modulating GPR65 and are therefore of therapeutic interest in the treatment of a variety of disorders, for example in the fields of oncology, immuno-oncology and immunology.

[0012] Another aspect of the present invention pertains to a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, for use as a pharmaceutical.

[0013] Another aspect of the present invention relates to a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prophylaxis of a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).

[0014] Another aspect of the present invention pertains to pharmaceutical compositions comprising a compound as described herein and a pharmaceutically acceptable diluent, excipient, or carrier.

[0015] Another aspect of the present invention relates to a pharmaceutical composition as described herein for use as a medicament.

[0016] Another aspect of the present invention relates to a pharmaceutical composition as described herein for use in the treatment or prevention of a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).

[0017] Another aspect of the invention relates to a method of treating a disorder, comprising administering to a subject a compound or pharmaceutical composition as described herein. DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention relates to compounds capable of modulating GPR65.

[0019] "Alkyl" refers to a linear or branched alkyl radical, preferably C 1-20 Alkyl, more preferably C 1-12 Alkyl, even more preferably C 1-10 Alkyl or C 1-6 Alkyl is defined herein as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl. More preferably, said alkyl is C 1-3 It is alkyl.

[0020] "Cycloalkyl" refers to a monocyclic alkyl ring, preferably C 3-7 Cycloalkyl, more preferably C 3-6 As cycloalkyl is defined herein, preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or fused bicyclic ring systems such as norbornane.

[0021] As used herein, the term "aryl" refers to a C cyclic group which may be a monocyclic group or a fused bicyclic group, including a benzofused group. 6-12 Refers to an aromatic group. Examples include phenyl and naphthyl.

[0022] "Haloalkyl" is defined herein as a straight or branched alkyl radical as defined above, substituted with one or more halogen atoms (which may be the same or different), such as fluorine, chlorine, bromine, and iodine, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl. Preferably, haloalkyl is C 1-20 haloalkyl, more preferably C 1-12 haloalkyl, and even more preferably C 1-10 Haloalkyl or C 1-6 Haloalkyl or C 1-3haloalkyl. Preferred examples are CF3 and CHF2, with CF3 being especially preferred.

[0023] "Alkoxy" is defined herein as an oxygen atom attached to an alkyl group as defined above, e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, and hexoxy. Preferably, alkoxy is C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, even more preferably C 1-10 Alkoxy or C 1-6 Alkoxy or C 1-3 Alkoxy is a particularly preferred example. A particularly preferred example is methoxy (-OCH). "Alkoxy-alkyl" is defined as an alkyl group substituted with one or more alkoxy groups, e.g., MeOCHCH-. "Alkoxy-alkoxy" is defined as an alkoxy group substituted with one or more further alkoxy groups, e.g., MeOCHCHO- (also called an ether group).

[0024] "Haloalkoxy" is defined herein as an alkoxy group, as described above, substituted with one or more halogen atoms (which may be the same or different), such as fluorine, chlorine, bromine, and iodine.

[0025] "Heteroaryl" or "heteroaromatic" refers to a monocyclic or bicyclic C ring containing one or more heteroatoms (which may be the same or different), such as oxygen, nitrogen, or sulfur. 2-12Examples of suitable heteroaryl groups include thienyl, furanyl, pyrrolyl, pyridinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, and the like, or pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and the like.

[0026] "Heterocycloalkyl" refers to a cyclic aliphatic group containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, which may be interrupted by one or more -(CO)- groups in the ring and / or may contain one or more double bonds in the ring. Preferably, the heterocycloalkyl group is monocyclic or bicyclic. Preferably, the heterocycloalkyl group is C 3-7 Heterocycloalkyl, more preferably C 3-6 or the heterocycloalkyl group is C 4-7 Heterocycloalkyl, more preferably C 4-6 Heterocycloalkyl. Preferred heterocycloalkyl groups include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl, and tetrahydropyranyl. Examples of heterocycloalkyl groups containing a CO group and one or more double bonds include 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, oxoisoindolinyl, oxoindolinyl, 1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl, 1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl, and the like.

[0027] "Aralkyl" is defined herein as an alkyl group, as defined above, substituted with one or more aryl groups, as defined above.

[0028] Preferably, alkyl is C1-C6 alkyl, haloalkyl is C1-C6 haloalkyl, alkoxy is C1-C6 alkoxy, and haloalkoxy is C1-C6 haloalkoxy.

[0029] Compound structure representation The compounds of the present invention comprise a structure in which an optionally substituted six-membered nitrogen-containing ring is fused to a bicyclic nitrogen-containing moiety to form a tricyclic structure, which can exist in two different configurations as shown below. [ka] (I.1) (I.2)

[0030] For the avoidance of doubt, the present invention covers compounds of any of the above configurations as well as mixtures thereof, including racemic mixtures.

[0031] Alternatively, the structure can be shown, for example, as follows (R a Groups and R b groups omitted for clarity). [ka]

[0032] For the avoidance of doubt, the present invention encompasses compounds of the above configurations as well as the corresponding enantiomers and mixtures thereof, including racemic mixtures. As used throughout, and for ease of presentation, specific examples of compounds according to the invention shown in the above configuration (I.3) refer to mixtures of both enantiomers (particularly racemates), while each enantiomer, as synthesized or isolated, is shown as either the wedge bond or dashed bond configuration (I.1) or configuration (I.2), respectively.

[0033] The compounds described herein contain an optionally substituted six-membered ring fused to a bicyclic nitrogen-containing moiety to form a tricyclic structure. The six-membered ring contains a C=O group and can exist in two or more tautomeric forms. For example, a compound of formula (I) in which R6 is H can exist in the following tautomeric forms: [ka]

[0034] The pyradazin-3(2H)-one tautomer is believed to be the predominant solid-state form. In solution, the energy difference between the two tautomeric forms is believed to be very small and depends on the polarity of the solvent. The present invention encompasses all tautomeric forms of the compounds described herein.

[0035] Compounds of formula (I) The present invention relates to compounds of formula (I) as defined above.

[0036] For the embodiments described throughout, preferably, p and q are each independently 0 or 1. In one preferred embodiment, p and q are both 0.

[0037] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: Ring B a monocyclic aromatic group, or Monocyclic or bicyclic heteroaromatic groups and each of which is optionally substituted by one or more substituents selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, NHCO-aryl, O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl and CO2-alkyl, wherein the aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, NHCO-aryl, O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl and O-aryl groups are each optionally substituted by one or more substituents selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2) m -NHSO2-alkyl, CO2R 16 , alkoxy-alkyl, O-cycloalkyl, haloalkoxy, O-heterocycloalkyl, and heteroaryl; m is an integer from 1 to 3; Z is CR 12 and Y is CR 10 R 10 ' and R 10 and R 10 each ' is independently selected from H, F, alkyl and haloalkyl; R a and R b are each independently selected from H and alkyl; R6 is selected from H, alkyl, cycloalkyl, and hydroxyalkyl; R 12is selected from H, alkyl, haloalkyl, halo, OH, and O-alkyl; R 13 , R 13 ', R 14 , R 14 ', R 15 , R 15 ' and R 16 are each independently selected from H, alkyl, and alkoxyalkyl.

[0038] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: Ring B a monocyclic aromatic group, or Monocyclic or bicyclic heteroaromatic groups and each of which is optionally substituted with one or more substituents selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, and CO2-alkyl, wherein the aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, and O-aryl groups are each optionally substituted with one or more substituents selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2) m -NHSO2-alkyl, CO2R 16 , alkoxy-alkyl, O-cycloalkyl, haloalkoxy, and heteroaryl; m is an integer from 1 to 3; Z is CR 12 and Y is CR 10 R 10 ' and R 10 and R 10 each ' is independently selected from H, F, alkyl and haloalkyl; R a and R b are each independently selected from H and alkyl; R6 is selected from H, alkyl, cycloalkyl, and hydroxyalkyl; R 12 is selected from H, alkyl, haloalkyl, halo, OH, and O-alkyl; R 13 , R 13 ', R 14 , R 14 ', R 15 , R 15 ' and R 16 are each independently selected from H, alkyl, and alkoxyalkyl.

[0039] In one preferred embodiment, m is an integer of 1 to 3, more preferably 1 or 2, and more preferably 1.

[0040] Throughout each of the embodiments described herein, preferably, R 13 , R 13 ', R 14 , R 14 ', R 15 , R 15 ' and R 16 are each independently selected from H and alkyl. More preferably, R 13 , R 13 ', R 14 , R 14 ', R 15 , R 15 In one preferred embodiment, R 16 is alkyl, more preferably Me.

[0041] In one preferred embodiment, Ring B a monocyclic aromatic group, or Monocyclic or bicyclic heteroaromatic groups and each of which is optionally substituted with one or more substituents selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, and CO2-alkyl, wherein the aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, and O-aryl groups are each optionally substituted with one or more substituents selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, and heteroaryl; Z is CR 12 and Y is CR 10 R 10 ' and R 10 and R 10 each ' is independently selected from H, F, alkyl and haloalkyl; R a and R b are each independently selected from H and alkyl; R6 is selected from H, alkyl, cycloalkyl, and hydroxyalkyl; R 12 is selected from H, alkyl, haloalkyl, halo, OH, and O-alkyl; R 13 , R 13 ', R 14 , R 14 ', R 15 and R 15 each ' is independently selected from H, alkyl and alkoxyalkyl;

[0042] In one preferred embodiment, Ring B a monocyclic aromatic group, or Monocyclic or bicyclic heteroaromatic groups and each of which is optionally substituted with one or more substituents selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, and CO2-alkyl, and each of said aryl, heteroaryl, O-cycloalkyl, and O-aryl groups is optionally further substituted with one or more groups independently selected from halo, alkyl, and alkoxy; Z is CR 12 and Y is CR 10 R 10’ and R 10 and R 10’ are each independently selected from H, F, alkyl, and haloalkyl; R a and R b are each independently selected from H and alkyl; R6 is selected from H, alkyl, cycloalkyl, and hydroxyalkyl; R 12 is selected from H, alkyl, haloalkyl, halo, OH and O-alkyl.

[0043] In one preferred embodiment, R a and R b are each independently selected from H and methyl. In one preferred embodiment, R a and R b One of R is alkyl (more preferably methyl) and the other is H. In one particularly preferred embodiment, R a and R b are both H.

[0044] In one preferred embodiment, Y is CR 10 R 10 ' and R 10 and R 10 are each independently selected from H, F, Me and CF, more preferably selected from H, F and Me. In one preferred embodiment, Y is selected from CH, CHF and CHMe. More preferably, Y is CH.

[0045] In one preferred embodiment, R6 is selected from H, methyl and hydroxymethyl, more preferably H.

[0046] In one preferred embodiment, R 12 is H or alkyl.

[0047] In one particularly preferred embodiment, Z is CH (i.e., R 12 is H) and the compound is of formula (Ie), or a pharmaceutically acceptable salt or solvate thereof [ka] (In the formula, R6, R a , R b , Y and B are as described above).

[0048] In one preferred embodiment, Ring B is a phenyl group optionally substituted with one or more substituents each independently selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, and CO2-alkyl, and the aryl group, heteroaryl group, O-cycloalkyl group, and O-aryl group are each optionally further substituted with one or more groups independently selected from halo, alkyl, and alkoxy.

[0049] In one preferred embodiment, the compound is of formula (Ia): [ka] (In the formula, R1, R4, and R5 are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, and halo; R2 and R3 are each independently H, OH, halo, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, NHCO-alkenyl, NHCO-aryl, -(CH2) q -O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl and CO2-alkyl, wherein the aryl group, heteroaryl group, heterocycloalkyl group, O-cycloalkyl group, NHCO-aryl group, -(CH2) q -O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl and O-aryl groups are halo, haloalkyl, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2) m -NHSO2-alkyl, CO2R 16 , alkoxy-alkyl, O-cycloalkyl, haloalkoxy, O-heterocycloalkyl, heteroaryl, alkoxy-alkoxy and O-(CH2) p-cycloalkyl, wherein the cycloalkyl group is optionally further substituted with one or more halo groups, haloalkyl groups, alkyl groups, or alkoxy groups.

[0050] Preferably, for compounds of formula (Ia), R1, R4, and R5 are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, and halo; R2 and R3 are each independently selected from H, halo, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, NHCO-alkenyl, NHCO-aryl, O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and CO2-alkyl, and the aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, NHCO-aryl, O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and O-aryl groups are each independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2) m -NHSO2-alkyl, CO2R 16 , alkoxy-alkyl, O-cycloalkyl, haloalkoxy, O-heterocycloalkyl, and heteroaryl; Z, Y, R a , R b , m and R6 are as described above; R 13 , R13 ', R 14 , R 14 ', R 15 , R 15 ' and R 16 are each independently selected from H, alkyl, and alkoxyalkyl.

[0051] R6, R as described above a , R b The preferred definitions of Y and Z apply analogously to compounds of formula (Ia).

[0052] In one preferred embodiment, R3 is an aryl or heteroaryl group, each of which is selected from the group consisting of halo, haloalkyl, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2) m -NHSO2-alkyl, CO2R 16 , alkoxy-alkyl, O-cycloalkyl, haloalkoxy, O-heterocycloalkyl, heteroaryl, alkoxy-alkoxy, O-(CH2) p -cycloalkyl, wherein the cycloalkyl group is optionally further substituted with one or more halo groups, haloalkyl groups, alkyl groups, or alkoxy groups.

[0053] In one preferred embodiment, R3 is phenyl, pyridyl, pyrimidinyl, pyrazolyl, pyrazinyl, [1,2,5]thiadiazolo[3,4-b]pyridinyl, indazolyl, triazolyl, benzotriazolyl, oxoisoindolinyl, oxoindolinyl, imidazolyl, benzoxazinyl, pyrrolopyridinyl, oxotetrohydroisoquinolinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazolyl, pyridazinyl, oxazolyl, isothiazolyl, benzo[d]isoxazolyl, benzo[c]isothiazolyl, imidazo[1,5-a]pyridinyl, O-pyridinyl, CONHPh, NHCOPh, OCHPh, CHOPh, [1,2,5]oxadiazolo[3,4-b]pyridinyl, benzo[c]isoxazolyl or 2H-benzo[b][1,4]oxazin-3(4H)-onyl, each of which is selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2) m -NHSO2-alkyl, CO2R 16 , alkoxy-alkyl, O-cycloalkyl, haloalkoxy, and heteroaryl.

[0054] In one preferred embodiment, R3 is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, indazolyl, triazolyl, benzotriazolyl, oxoisoindolinyl, oxoindolinyl, imidazolyl, benzoxazinyl, pyrrolopyridinyl, oxotetrohydroisoquinolinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazolyl, pyridazinyl, oxazolyl, isothiazolyl, benzo[d]isoxazolyl, imidazo[1,5-a]pyridinyl, [1,2,5]oxadiazolo[3,4-b]pyridinyl, benzo[c]isoxazolyl, or 2H-benzo[b][1,4]oxazin-3(4H)-onyl, each of which is selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, alkyl-NHSO2-alkyl, CO2R 16 , alkyl-alkoxy, O-cycloalkyl, haloalkoxy, and heteroaryl.

[0055] In one preferred embodiment, R3 is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, indazolyl, triazolyl, benzotriazolyl, oxoisoindolinyl, oxoindolinyl, imidazolyl, benzoxazinyl, pyrrolopyridinyl, oxotetrohydroisoquinolinyl, benzo[c][1,2,5]oxadiazolyl, or 2H-benzo[b][1,4]oxazin-3(4H)-onyl, each of which is selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, and heteroaryl.

[0056] In the compounds of formula (Ia), preferably, R2 and R3 are each independently selected from H, halo, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, NHCO-alkenyl and CO2-alkyl, wherein said aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl and O-aryl groups are each halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 Each of the aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, and O-aryl groups may be further substituted with one or more groups independently selected from halo, alkyl, and alkoxy.

[0057] In one preferred embodiment, R1 and R4 are both H.

[0058] In one preferred embodiment, R5 is selected from H, F, Me, MeO, Cl, OH and CN, preferably H or F, more preferably F.

[0059] In one preferred embodiment, R2 is selected from Cl, Br and CF3, more preferably Cl.

[0060] In another preferred embodiment, R1 and R4 are selected from halo and haloalkyl (more preferably halo), and R2 and R5 are both H.

[0061] In one preferred embodiment, R1 is F, R2 is H, R4 is Cl, and R5 is H, i.e., ring B is [ka] is.

[0062] Preferably, R3 is defined as follows:

[0063] In one preferred embodiment of formula (Ia), R3 is [ka] TIFF2024538178000013.tif188170 each of which is selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2) m -NHSO2-alkyl, CO2R 16 , alkoxy-alkyl, haloalkoxy, O-heterocycloalkyl, heteroaryl, alkoxy-alkoxy, O-(CH2) p-cycloalkyl, wherein the cycloalkyl group is optionally further substituted with one or more halo groups, haloalkyl groups, alkyl groups, or alkoxy groups. Preferably, R1 and R4 are selected from halo and haloalkyl (more preferably halo), and R2 and R5 are both H. More preferably, R1 is F, R2 is H, R4 is Cl, and R5 is H.

[0064] In one preferred embodiment, R3 is selected from the above groups (a-1) to (a-38), each of which is halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2) m -NHSO2-alkyl, CO2R 16 , alkoxy-alkyl, O-cycloalkyl, haloalkoxy, heterocycloalkyl, and heteroaryl; R 13 , R 13 ', R 14 , R 14 ', R 15 , R 15 ' and R 16 are each independently selected from H, alkyl, and alkoxyalkyl. Preferably, R1 and R4 are selected from halo and haloalkyl (more preferably halo), and R2 and R5 are both H. More preferably, R1 is F, R2 is H, R4 is Cl, and R5 is H.

[0065] In one preferred embodiment, R3 is selected from the above groups (a-1) to (a-28), each of which is halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2) m -NHSO2-alkyl, CO2R 16 , alkoxy-alkyl, O-cycloalkyl, haloalkoxy, and heteroaryl; R 13 , R 13 ', R 14 , R 14 ', R 15 , R 15 ' and R 16 are each independently selected from H, alkyl, and alkoxyalkyl. Preferably, R1 and R4 are selected from halo and haloalkyl (more preferably halo), and R2 and R5 are both H. More preferably, R1 is F, R2 is H, R4 is Cl, and R5 is H.

[0066] In one preferred embodiment, R3 is selected from the groups listed above, each of which is halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 In one preferred embodiment, R3 is selected from the above groups (a-1) to (a-16), each of which is selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, and heteroaryl. In one preferred embodiment, R3 is a pyridinyl group optionally substituted as described above for definitions (a-1) to (a-39). More preferably, R3 is a 3-pyridinyl group optionally substituted as described above for definitions (a-1) to (a-39). Preferably, R1 and R4 are selected from halo and haloalkyl (more preferably halo), and R2 and R5 are both H. More preferably, R1 is F, R2 is H, R4 is Cl, and R5 is H.

[0067] In one preferred embodiment, in formula (Ia), R1 is F, R2 is H, R3 is an optionally substituted pyridinyl group, R4 is Cl or CF3, and R5 is H. More preferably, R1 is F, R2 is H, R3 is an optionally substituted pyridinyl group, R4 is Cl, and R5 is H.

[0068] In one preferred embodiment, in formula (Ia), R3 is [ka] (In the formula, R 17 H, alkyl, CN, haloalkyl, NHCO-alkyl, NR 13 R 13’ , alkoxy, SO2-alkyl, halo, O-(CH2) q -heterocycloalkyl, alkoxy-alkoxy, alkylamino-alkoxy, dialkylamino-alkoxy, alkoxy-alkyl, haloalkoxy and O-(CH2) p -cycloalkyl, which cycloalkyl groups are optionally substituted with one or more halo, alkyl, or alkoxy groups; R 18 is selected from H and halo; R 19is selected from H, alkoxy and alkoxy-alkyl; R 20 H, halo and CO2R 16 Preferably, R1 and R4 are selected from halo and haloalkyl (more preferably halo), and R2 and R5 are both H. More preferably, R1 is F, R2 is H, R4 is Cl, and R5 is H.

[0069] In one preferred embodiment, R 17 H, alkyl, CN, haloalkyl, NHCO-alkyl, NR 13 R 13’ , alkoxy, SO2-alkyl, halo, O-(CH2) q -heterocycloalkyl, alkoxy-alkoxy, alkoxy-alkyl, haloalkoxy and O-(CH2) p -cycloalkyl, which cycloalkyl groups may be optionally substituted with one or more halo, alkyl or alkoxy groups.

[0070] In one preferred embodiment, R 17 H, alkyl, CN, haloalkyl, NHCO-alkyl, NR 13 R 13 ', alkoxy, SO2-alkyl, halo, O-heterocycloalkyl, alkoxy-alkoxy, alkoxy-alkyl, haloalkoxy and O-cycloalkyl, wherein the cycloalkyl group is optionally substituted with one or more halo, alkyl or alkoxy groups.

[0071] In one preferred embodiment, R 17 is selected from haloalkyl and haloalkoxy, more preferably fluoroalkyl and fluoroalkoxy.

[0072] In one preferred embodiment, R 17 is selected from —O—CH2CF3, —O—CH2CH2CF3 and —OCHF2, —OCH2CHF2.

[0073] In one preferred embodiment, R 17 is fluoroalkyl, fluoroalkoxy, methylamino-alkoxy, dimethylamino-alkoxy, (piperidin-1-yl)-alkoxy, O—(CH2) p -cyclopropyl, O-(CH2) p -cyclobutyl, wherein the cyclopropyl and cyclobutyl groups are optionally substituted with alkoxy groups; R 18 , R 19 and R 20 are all H.

[0074] In one preferred embodiment, R 17 is selected from CF3, -O-CH2CF3, -O-CH2CH2CF3, -OCHF2, -OCH2CHF2, -OCH2CH2NHMe, -OCH2CH2NHMe, (piperidin-1-yl)-CH2CH2-O-, -O-cyclopropyl, -O-CH2-cyclopropyl, methoxycyclobutyl-O-; R 18 , R 19 and R 20 are all H.

[0075] In one preferred embodiment, R 17 is selected from H, alkoxy, SO2-alkyl, halo, O-cycloalkyl, O-heterocycloalkyl and haloalkoxy; R 18 is selected from H and halo; R 19 is selected from H, alkoxy and alkoxy-alkyl; R 20 H, halo and CO2R 16 is selected from.

[0076] In one preferred embodiment, R 17 H, OMe, OEt, O i selected from Pr, F, SO2Me, halo, O-cyclobutyl, O-oxetanyl and O-CH2CF3; R 18 is selected from H and F; R19 is selected from H and MeOCH2-; R 20 is selected from H, F and CO2Me; R1 is F, R2 is H, R4 is Cl or CF3; R5 is H.

[0077] In one preferred embodiment, R 17 H, OMe, OEt, O i selected from Pr, F, SO2Me, halo, O-cyclobutyl, O-oxetanyl and O-CH2CF3; R 18 is selected from H and F; R 19 is selected from H and MeOCH2-; R 20 is selected from H, F and CO2Me; R1 is F, R2 is H, R4 is Cl or CF3; R5 is H.

[0078] In one preferred embodiment, the compound is of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: R1, R4, and R5 are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, and halo; R2 and R3 are each independently selected from H, halo, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, NHCO-alkenyl, and CO2-alkyl, wherein the aryl, heteroaryl, and O-aryl groups are each optionally further substituted with one or more groups independently selected from halo, alkyl, and alkoxy; Z, Y, R a , R b and R6 is as described above.

[0079] Preferably, for compounds of formula (Ia), Z is CH.

[0080] In one preferred embodiment, at least one of R1, R2, R3, R4 and R5 is other than H.

[0081] In one preferred embodiment, one of R1, R2, R3, R4 and R5 is other than H.

[0082] In one preferred embodiment, two of R1, R2, R3, R4 and R5 are other than H.

[0083] In one preferred embodiment, three of R1, R2, R3, R4 and R5 are other than H.

[0084] In one preferred embodiment, R2 and R3 are each independently selected from H, F, Cl, Br, CN, methoxy, OCF3, CF3, OCHF2, Me, Ph, pyrazolyl, oxazolyl, thiazolyl, OPh, NHCO-CH=CH2, and CO2Me, and the Ph group, OPh group, pyrazolyl group, oxazolyl group, and thiazolyl group may each be further substituted with one or more alkyl groups.

[0085] In one preferred embodiment, R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, methoxy, haloalkyl, haloalkoxy, and CO2 alkyl.

[0086] In one preferred embodiment, R3 is selected from H, F, Cl, Br, CN, methoxy, OCF3, CF3, OCHF2, Me, Ph, pyrazolyl, oxazolyl, thiazolyl, OPh, NHCO-CH=CH2, and CO2Me, and the Ph group, OPh group, pyrazolyl group, oxazolyl group, and thiazolyl group may each be further substituted with one or more alkyl groups. Preferably, the pyrazolyl group is a 1H-pyrazol-1-yl group. Preferably, the oxazolyl group is an oxazol-5-yl group. Preferably, the thiazolyl group is a thiazol-4-yl group.

[0087] In one preferred embodiment, R2 is selected from H, F, Cl, Br, CN, Me, methoxy, OCF3, CF3, OCHF2, Ph, pyrazolyl, and CO2Me, wherein the Ph and pyrazolyl groups are each optionally further substituted with one or more alkyl groups. Preferably, the pyrazolyl is a 1H-pyrazol-1-yl group.

[0088] In one preferred embodiment, R2 and R3 are each independently selected from F, Cl, Br, I, CN, CO2-alkyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0089] In one preferred embodiment, R2 and R3 are each independently selected from F, Cl, Br, I, CN, C1-C6 haloalkyl, C1-C6 haloalkoxy and CO2-alkyl, more preferably Cl, Br and CF3, even more preferably Cl and CF3.

[0090] In one preferred embodiment, R2 and R3 are each independently selected from F, Cl, Br, I, CN, and C1-C6 haloalkyl.

[0091] In one preferred embodiment, R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl.

[0092] In one preferred embodiment, R2 and R3 are each independently selected from CN, Cl, Br, OCF3 and CF3, more preferably each independently selected from Cl and CF3.

[0093] In one preferred embodiment, R2 and R3 are each independently selected from Cl, Br and CF3, more preferably independently selected from Cl and CF3.

[0094] In one preferred embodiment, one of R2 and R3 is Cl and the other is OCF3 or OCHF2.

[0095] In one preferred embodiment, one of R2 and R3 is Cl and the other is CO2Me.

[0096] In one preferred embodiment, R2 and R3 are both Cl, or one of R2 and R3 is Cl and the other is CF3.

[0097] In one preferred embodiment, R2 and R3 are both Cl.

[0098] In one preferred embodiment, one of R2 and R3 is Cl and the other is CF3.

[0099] In one preferred embodiment, one of R2 and R3 is CN and the other is CF3.

[0100] In one preferred embodiment, one of R2 and R3 is Br and the other is CF3.

[0101] In one preferred embodiment, one of R2 and R3 is Cl and the other is OCF3.

[0102] In one preferred embodiment, one of R2 and R3 is Cl and the other is Br.

[0103] In one preferred embodiment, one of R2 and R3 is Cl and the other is selected from OCF3, CO2Me, OCHF2 and CF3.

[0104] In one preferred embodiment, R1, R4, and R5 are each independently selected from H, alkyl, alkoxy, OH, F, Cl, Br, and I.

[0105] In one preferred embodiment, R1, R4, and R5 are each independently selected from H, Me, OMe, OH, F, Cl, Br, and I.

[0106] In one preferred embodiment, R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I.

[0107] In one preferred embodiment, R5 is selected from H, F, Me, MeO and Cl, preferably H or F, more preferably H.

[0108] In one preferred embodiment, R5 is selected from H, F and Cl, preferably H or F, more preferably H.

[0109] In one preferred embodiment, R5 is selected from H, F and CN, preferably H.

[0110] In one preferred embodiment, R1 and R4 are both H.

[0111] In one preferred embodiment, R1 is H, R2 is selected from H, F, Cl, Br, CN, Me, methoxy, OCF3, CF3, OCHF2, Ph, pyrazolyl, and CO2Me, R3 is selected from H, F, Cl, Br, CN, methoxy, OCF3, CF3, OCHF2, Me, Ph, pyrazolyl, oxazolyl, thiazolyl, OPh, NHCO-CH=CH2, and CO2Me, wherein the Ph, OPh, pyrazolyl, oxazolyl, and thiazolyl groups are each optionally further substituted with one or more alkyl groups, R4 is H or CF3, more preferably H, and R5 is selected from H, F, Me, MeO, Cl, OH, and CN, preferably H or F, more preferably H. Preferably, for this embodiment, at least one of R2 and R3 is other than H. Even more preferably, both R2 and R3 are other than H.

[0112] In another preferred embodiment, one of R2 and R3 is selected from aryl, O-aryl, and heteroaryl, each of which is optionally substituted; the other of R2 and R3 is H; and R1, R4, and R5 are all H.

[0113] In one preferred embodiment, the compound is of formula (Ib): [ka] wherein n is 0 or 1, X1 to X5 form a 5- or 6-membered heteroaromatic group containing at least one nitrogen atom, and the heteroaromatic group is selected from the group consisting of halo, CN, OH, alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, NHCO-alkenyl, NHCO-aryl, -(CH2) q-O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and O-aryl, and the aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, NHCO-aryl, -(CH2) q -O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, CO2-alkyl and O-aryl groups are halo, haloalkyl, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2) m -NHSO2-alkyl, CO2R 16 , alkoxy-alkyl, O-cycloalkyl, haloalkoxy, O-heterocycloalkyl, heteroaryl, alkoxy-alkoxy and O-(CH2) p -cycloalkyl, wherein the cycloalkyl group is optionally further substituted with one or more halo groups, haloalkyl groups, alkyl groups, or alkoxy groups.

[0114] In one preferred embodiment, the compound is of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0 or 1, and X1 to X5 form a 5- or 6-membered heteroaromatic group containing at least one nitrogen atom, the heteroaromatic group being optionally substituted with one or more substituents selected from halo, CN, alkyl, alkoxy, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, NHCO-aryl, O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and O-aryl, wherein the aryl group, heteroaryl group, heterocycloalkyl group, O-cycloalkyl group, NHCO-aryl group, O-heteroaryl group, CONH-aryl group, aryloxy-alkyl group, O-aralkyl group, and O-aryl group are each selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2) m -NHSO2-alkyl, CO2R 16 , alkoxy-alkyl, O-cycloalkyl, haloalkoxy, O-heterocycloalkyl, and heteroaryl; Z, Y, R a , R b and R6 is as described above, R 13 , R 13 ', R 14 , R 14 ', R 15 and R 15 each ' is independently selected from H, alkyl and alkoxyalkyl.

[0115] R6, R as described above a , R bThe preferred definitions of Y and Z apply analogously to compounds of formula (Ib).

[0116] In one preferred embodiment, n is 0 or 1, and X1 to X5 form a 5- or 6-membered heteroaromatic group containing at least one nitrogen atom, which is optionally substituted with one or more substituents selected from halo, CN, alkyl, alkoxy, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, and O-aryl, and the aryl group, heteroaryl group, heterocycloalkyl group, O-cycloalkyl group, and O-aryl group are each selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2) m -NHSO2-alkyl, CO2R 16 , alkoxy-alkyl, O-cycloalkyl, haloalkoxy, and heteroaryl.

[0117] In one preferred embodiment, n is 0 or 1, and X1 to X5 form a 5- or 6-membered heteroaromatic group containing at least one nitrogen atom, which is optionally substituted with one or more substituents selected from halo, CN, alkyl, alkoxy, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, and O-aryl, and the aryl group, heteroaryl group, heterocycloalkyl group, O-cycloalkyl group, and O-aryl group are each selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, and heteroaryl.

[0118] In one preferred embodiment of Formula (Ib), X3 is CR3 and R3 is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, indazolyl, triazolyl, benzotriazolyl, oxoisoindolinyl, oxoindolinyl, imidazolyl, benzoxazinyl, pyrrolopyridinyl, oxotetrohydroisoquinolinyl, benzo[c][1,2,5]oxadiazolyl, or 2H-benzo[b][1,4]oxazin-3(4H)-onyl, each of which is halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, and heteroaryl.

[0119] In one preferred embodiment of formula (Ib), X1 is CR1, X4 is CR4, and R1 and R4 are both H.

[0120] In one preferred embodiment of formula (Ib), X5 is CR5, and R5 is selected from H, F, Me, MeO, Cl, OH and CN, preferably H or F, more preferably F.

[0121] In one preferred embodiment of formula (Ib), X2 is CR2, and R2 is selected from Cl, Br and CF3, more preferably Cl.

[0122] In one preferred embodiment of Formula (Ib), X3 is CR3, and R3 is as described above for Formula (Ia).

[0123] In one preferred embodiment of formula (Ib), X3 is CR3 and R3 is selected from (a-1) to (a-38), more preferably (a-1) to (a-28), and even more preferably (a-1) to (a-16), as described above. Preferably, R3 is selected from (a-1) to (a-16), each of which is halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 , heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, and heteroaryl; R 13 , R 13 ', R 14 , R 14 ', R 15 and R 15 each ' is independently selected from H, alkyl and alkoxyalkyl;

[0124] In another particularly preferred embodiment, the compound is of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0 or 1, and X1 to X5 form a 5- or 6-membered heteroaromatic group containing at least one nitrogen atom, said heteroaromatic group being optionally substituted with one or more substituents selected from halo, CN, alkyl, alkoxy, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, and O-aryl; and Z, Y, R a , R b and R6 are as described above).

[0125] Preferably, for compounds of formula (Ib), Z is CH.

[0126] Preferably, for compounds of formula (Ib), R1 and R4 are H.

[0127] In one preferred embodiment, n is 1 and X1 to X5 form a 6-membered heteroaromatic group selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl and 1,2,3,4-tetrazinyl, each of which is selected from halo, CN, alkoxy, alkyl, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloaromatic. and each of the aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, NHCO-aryl, O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and O-aryl groups is optionally substituted with one or more substituents selected from halo, alkyl, alkoxy, NHCO-alkyl, NHCO-alkyl, NHCO-aryl, O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and O-aryl, more preferably H, halo, CN, alkoxy, alkyl, and haloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, NHCO-aryl, O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and O-aryl groups are each optionally substituted with one or more substituents selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2) m -NHSO2-alkyl, CO2R 16, alkoxy-alkyl, O-cycloalkyl, haloalkoxy, O-heterocycloalkyl, and heteroaryl.

[0128] In one preferred embodiment, n is 1 and X1 to X5 form a 6-membered heteroaromatic group selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl and 1,2,3,4-tetrazinyl, each of which is optionally substituted with one or more substituents selected from halo, CN, alkoxy, alkyl, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl and O-aryl, more preferably H, halo, CN, alkoxy, alkyl and haloalkyl.

[0129] In one preferred embodiment, the compound is of formula (Ic): [ka] (In the formula, X1 is N or CR1; X2 is N or CR2; X4 is N or CR4; R1, R2, R3 and R4 are each independently selected from H, halo, haloalkyl, alkyl, alkoxy, CN, aryl, heterocycloalkyl, heteroaryl and O-aryl, more preferably H, halo, CN, alkoxy, alkyl and haloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl and O-aryl groups are each independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2) m -NHSO2-alkyl, CO2R 16 , alkoxy-alkyl, O-cycloalkyl, haloalkoxy, and heteroaryl; Z, Y, R a , R b and R6 is as defined above, R 13 , R 13 ', R 14 , R 14 ', R 15 and R 15 each ' is independently selected from H, alkyl and alkoxyalkyl.

[0130] R6, R as described above a , R b The preferred definitions of Y and Z apply analogously to compounds of formula (Ic).

[0131] In one preferred embodiment of formula (Ic), R1, R2, R3 and R4 are each independently selected from H, halo, haloalkyl, alkyl, alkoxy, CN, aryl, heterocycloalkyl, heteroaryl and O-aryl, more preferably H, halo, CN, alkoxy, alkyl and haloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl and O-aryl groups are each independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, and heteroaryl.

[0132] In one preferred embodiment of Formula (Ic), R3 is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, indazolyl, triazolyl, benzotriazolyl, oxoisoindolinyl, oxoindolinyl, imidazolyl, benzoxazinyl, pyrrolopyridinyl, oxotetrohydroisoquinolinyl, benzo[c][1,2,5]oxadiazolyl, or 2H-benzo[b][1,4]oxazin-3(4H)-onyl, each of which is halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, and heteroaryl.

[0133] In one preferred embodiment of formula (Ic), X1 is CR1, X4 is CR4, and R1 and R4 are both H.

[0134] In one preferred embodiment of formula (Ic), X2 is CR2, and R2 is selected from Cl, Br and CF3, more preferably Cl.

[0135] In one preferred embodiment of formula (Ic), R3 is as described above for formula (Ia).

[0136] In one preferred embodiment of Formula (Ic), X3 is CR3 and R3 is selected from (a-1) to (a-38), more preferably (a-1) to (a-28), more preferably (a-1) to (a-16), as described above. In one preferred embodiment of Formula (Ic), R3 is selected from (a-1) to (a-28), each of which is halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 , heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, and heteroaryl; R 13 , R 13 ', R 14 , R 14 ', R 15 and R 15 each ' is independently selected from H, alkyl and alkoxyalkyl;

[0137] In one particularly preferred embodiment, the compound is of formula (Ic): (In the formula, X1 is N or CR1; X2 is N or CR2; X4 is N or CR4; R1, R2, R3 and R4 are each independently selected from H, halo, haloalkyl, alkyl, alkoxy, CN, aryl, heteroaryl and O-aryl, more preferably H, halo, CN, alkoxy, alkyl and haloalkyl; Z, Y, R a , R b and R6 are as described above).

[0138] Preferably, for compounds of formula (Ic), Z is CH.

[0139] Preferably, for compounds of formula (Ic), R1 and R4 are H.

[0140] In one preferred embodiment, for compounds of formula (Ic), R3 is selected from halo and haloalkyl, more preferably selected from Cl, F and CF3.

[0141] In one preferred embodiment, the compound is of formula (Ic), X1 is N or CR1, X2 is N or CR2, and X4 is CR4.

[0142] In one preferred embodiment, the compound is of formula (Ic), X1 is CR1, X2 is CR2, and X4 is CR4. Preferably, for this embodiment, R3 is selected from halo, haloalkyl, alkyl, alkoxy, and CN. Even more preferably, R3 is selected from halo and haloalkyl. More preferably still, R3 is selected from Cl, F, and CF3, even more preferably from Cl and CF3. Preferably, for this embodiment, R1, R2, and R4 are each independently selected from H and halo, more preferably from H and Cl. More preferably, at least one of R2 and R4 is halo.

[0143] In one particularly preferred embodiment, X3 is CR3, where R3 is selected from halo, haloalkyl, alkyl, alkoxy, and CN; X1 is CR1 and R1 is H; X2 is CR2, where R2 is selected from H, halo, haloalkyl, alkyl, alkoxy, and CN; X4 is CR4, where R4 is selected from H, halo, haloalkyl, alkyl, alkoxy, and CN; At least one of R2 and R4 is other than H.

[0144] In one particularly preferred embodiment, X3 is CR3, and R3 is selected from halo and haloalkyl; X1 is CR1 and R1 is H; X2 is CR2, and R2 is selected from H, halo, and haloalkyl; X4 is CR4, and R4 is selected from H, halo, and haloalkyl; At least one of R2 and R4 is other than H.

[0145] In one particularly preferred embodiment, X3 is CR3, and R3 is selected from halo and haloalkyl; X1 is CR1 and R1 is H; X2 is CR2, and R2 is selected from halo and haloalkyl; X4 is CR4 and R4 is H.

[0146] In one particularly preferred embodiment, X3 is CR3, and R3 is selected from halo and haloalkyl; X1 is CR1 and R1 is H; X2 is CR2 and R2 is H; X4 is CR4, where R4 is selected from halo and haloalkyl.

[0147] In one particularly preferred embodiment, X3 is CR3, R3 being selected from Cl, F and CF3, even more preferably Cl and CF3; X1 is CR1 and R1 is H; X2 is CR2, where R2 is selected from H and Cl; X4 is CR4, R4 is selected from H and Cl; At least one of R2 and R4 is other than H.

[0148] In one particularly preferred embodiment, X3 is CR3, R3 being selected from Cl, F and CF3, even more preferably Cl and CF3; X1 is CR1 and R1 is H; X2 is CR2 and R2 is Cl; X4 is CR4 and R4 is H.

[0149] In one particularly preferred embodiment, X3 is CR3, R3 being selected from Cl, F and CF3, even more preferably Cl and CF3; X1 is CR1 and R1 is H; X2 is CR2 and R2 is H; X4 is CR4 and R4 is Cl.

[0150] In one preferred embodiment of the invention, for compounds of formula (Ic), X4 is N, X1 is CR1, and X2 is CR2. Preferably, for this embodiment, R1 and R2 are each independently selected from H and halo, more preferably H and Cl.

[0151] In one preferred embodiment of the present invention, for compounds of formula (Ic), X1 is N, X2 is CR2, and X4 is CR4. Preferably, for this embodiment, R2 and R4 are both H.

[0152] In one preferred embodiment of the invention, for compounds of formula (Ic), X2 is N, X1 is CR1, and X4 is CR4. Preferably, for this embodiment, R1 and R4 are each independently selected from H and halo, more preferably H and Cl.

[0153] In one preferred embodiment, the compound is of formula (Ib), wherein n is 0 and X1-X4 form a 5-membered heteroaromatic group containing at least one nitrogen atom, said heteroaromatic group being optionally substituted with one or more substituents selected from halo, CN, alkyl, alkoxy, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, and O-aryl.

[0154] In one preferred embodiment, the compound is of formula (Ib), wherein n is 0 and X1-X4 form a 5-membered heteroaromatic group selected from oxadiazolyl, thiadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, diazolyl, triazolyl, isoxazolyl, isothiazolyl, tetrazolyl, oxazolyl, and thiazolyl, wherein the heteroaromatic group is optionally substituted with one or more substituents selected from halo, CN, alkyl, alkoxy, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, and O-aryl.

[0155] In one preferred embodiment, the compound is of formula (Ib) (wherein n is 0 and X1 to X4 are selected from the group consisting of 1H-imidazol-5-yl, 1H-imidazol-4-yl, 1H-imidazol-2-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1H-pyrrol-4-yl, 1H-pyrazol-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, oxaz ...4-yl, oxazol-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, oxazol-5-yl, 1H-pyrazol-4-yl, oxazol-5-yl, 1H-pyrazol-4-yl, oxazol-5-yl, 1H-pyrazol 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, thiazol-5-yl, thiazol-4-yl, thiazol-2-yl, 1H-tetrazolyl, 2H-tetrazolyl, oxazol- and forming a 5-membered heteroaromatic group selected from 1,3,4-oxadiazole-2-yl, 1,3,4-oxadiazole-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, and 1,2,4-oxadiazol-5-yl, each of which is optionally substituted with one or more substituents selected from alkyl, halo, CN, alkoxy, and haloalkyl.

[0156] In one highly preferred embodiment, the 5-membered heteroaromatic group is selected from 1,2,4-oxadiazol-3-yl, 1,2,5-oxadiazol-3-yl, and 1,3,4-thiadiazol-2-yl, each of which is optionally substituted with one or more substituents selected from alkyl, halo, CN, alkoxy, and haloalkyl.

[0157] In one preferred embodiment, the compound is of formula (Id), or a pharmaceutically acceptable salt or solvate thereof: [ka] X1 to X4 form a heterocyclic aromatic group containing at least one nitrogen atom; X1 is N or CR1; X2 is N or CR2; X3 is N, O or CR3; X4 is NR 15 ", O and S; R 15 " is H, alkyl or haloalkyl, R1-R3 are each independently selected from H, halo, CN, alkoxy, alkyl, haloalkyl, aryl, heteroaryl, and O-aryl, more preferably H, halo, CN, alkoxy, alkyl, and haloalkyl; Z, Y, R a , R b and R6 is as described above.

[0158] R6, R as described above a , R b The preferred definitions of Y and Z apply analogously to compounds of formula (Id).

[0159] In one preferred embodiment, the compound is of formula (Id) wherein X1 is N, X2 is N, and X3 is CR 3 and X 4 is S).

[0160] Preferably, for compounds of formula (Id), Z is CH.

[0161] In one preferred embodiment, the compound is of formula (Ih): [ka] (Ih) (In the formula, X1 to X4 form a heterocyclic aromatic group containing at least one nitrogen atom; X1 is N or CR1; X2 is N or CR2; X3 is NR 15 ", O and S; R 15 " is H, alkyl or haloalkyl, X4 is N or CR4; R1, R2 and R4 are each independently selected from H, halo, CN, alkoxy, alkyl, haloalkyl, aryl, heteroaryl and O-aryl, more preferably H, halo, CN, alkoxy, alkyl and haloalkyl).

[0162] R6, R as described above a , R b The preferred definitions of Y and Z apply analogously to compounds of formula (Ih).

[0163] In one preferred embodiment, the compound has formula (Ih) (wherein X1 is CR1, X2 is N, X3 is O, and X4 is N, or X1 is N, X2 is CR2, X3 is O, and X4 is N).

[0164] In one preferred embodiment, ring B is an optionally substituted bicyclic heteroaromatic group containing at least one nitrogen atom, preferably an optionally substituted 9- or 10-membered bicyclic heteroaromatic group containing at least one nitrogen atom.

[0165] In one preferred embodiment, Ring B is a bicyclic heteroaromatic group selected from benzimidazolyl, pyrazolopyridinyl, indolyl, indolizinyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, and naphthyridinyl, wherein the bicyclic heteroaromatic group is optionally substituted with one or more substituents selected from halo, CN, alkyl, alkoxy, haloalkyl, aryl, heteroaryl, and O-aryl.

[0166] In one highly preferred embodiment, B is a quinolin-6-yl group or a 2H-pyrazolo[3,4-c]pyridin-5-yl group, each of which is optionally substituted with one or more substituents selected from halo, CN, alkyl, alkoxy, and haloalkyl.

[0167] In one preferred embodiment, the compound is of formula (Ii): [ka] wherein X2 and X3 are both C, one, two or three of X1, X4, and X5 to X9 are N, and the remainder are selected from CH, C-alkyl and C-haloalkyl, and Y, Z, R6, R a , R b as described above).

[0168] R6, R as described above a , R b The preferred definitions of Y and Z apply analogously to compounds of formula (Ii).

[0169] In one preferred embodiment, the compound is of formula (Ii) wherein X9 is N, X2 and X3 are both C, X1, X4, X5, X6 and X7 are CH, and X8 is C-haloalkyl, more preferably CF3.

[0170] In one preferred embodiment, B is a bicyclic heteroaromatic group containing at least one nitrogen atom selected from [ka] (In the formula, X2 and X3 are both C; X7 is O, S and NR 15 " is selected from R 15 " is H, alkyl or haloalkyl, one, two or three of X1, X4, X5, X6 and X8 are N, and the remainder are selected from CH, C-alkyl and C-haloalkyl).

[0171] In one preferred embodiment, B is of the formula [ka] (wherein X5 and X8 are N, X2 and X3 are both C, X1, X4, X5 and X6 are CH, and X7 is N-haloalkyl, more preferably N-CHF2).

[0172] In one preferred embodiment of the compounds described herein, Ring B is preferably selected from the following groups: [ka] (i) (ii) (iii) (iv) (v) TIFF2024538178000023.tif23170 (vi) (vii) (viii) (ix) (x) TIFF2024538178000024.tif25170 (xi) (xii) (xiii) (xiv) (xv) TIFF2024538178000025.tif21170 (xvi) (xvii) (xviii) (xix) (xx) TIFF2024538178000026.tif25170 (xxi) (xxii) (xxiii) (xxiv) (xxv) TIFF2024538178000027.tif13170 (xxvi) TIFF2024538178000028.tif30170 (xxvii) (xxviii) (ixxx) (xxx) (xxxi) TIFF2024538178000029.tif41170 (xxxii) (xxxiii) (xxxiv) (xxxv) TIFF2024538178000030.tif38170 (xxxvi) (xxxvii) (xxxviii) (xxxix) TIFF2024538178000031.tif31170 (xl) (xli) (xlii)

[0173] In one preferred embodiment, ring B is selected from groups (i) to (xxviii) above.

[0174] In one preferred embodiment, ring B is selected from groups (i) to (xxviii) above, Z is CH, and R a , R b and R6 is H and Y is CH2.

[0175] In another preferred embodiment, ring B is [ka] (Where R3 is [ka] TIFF2024538178000034.tif201170 TIFF2024538178000035.tif238170 TIFF2024538178000036.tif160170 (selected from:

[0176] In one preferred embodiment, ring B is selected from the groups listed above, Z is CH, and R a , R b and R6 is H and Y is CH2.

[0177] In one particularly preferred embodiment, the compound has formula (I.1) [ka] (I.1) (In the formula, B, Y, R a , R b , Z and R6 are as described above).

[0178] In one preferred embodiment, the compound is in enantiomerically pure form. In one preferred embodiment, the compound is in the form of an enantiomerically enriched mixture of the compound of formula (I.1).

[0179] In another embodiment, the compound has formula (I.2) [ka] (I.2) (In the formula, B, Y, R a , R b , Z and R6 are as described above).

[0180] The enantiomeric forms (I.1) and (I.2) apply equally to all of the various subformulas described herein.

[0181] In one preferred embodiment, the compound is in enantiomerically pure form. In one preferred embodiment, the compound is in the form of an enantiomerically enriched mixture of the compound of formula (I.2).

[0182] In one preferred embodiment, the compound is in the form of a mixture comprising a compound of formula (I.1) and its corresponding enantiomer of formula (I.2). In one preferred embodiment, the mixture is a racemic mixture, i.e., a 50:50 mixture of a compound of formula (I.1) and its corresponding enantiomer of formula (I.2).

[0183] The racemic mixture can be used to prepare enantiomerically pure compounds of Formula (I.1) or Formula (I.2) by separating the compound of Formula (I.1) or the compound of Formula (I.2) by standard methods, such as chemical resolution with an optically active acid, or by column chromatography using a substantially optically active (or "chiral") stationary phase or reverse-phase column chromatography as known to those skilled in the art. The racemic mixture can also be used to prepare mixtures that are enantiomerically enriched in the compound of Formula (I.1) or the compound of Formula (I.2). Mixtures enriched in either the compound of Formula (I.1) or the compound of Formula (I.2) can also be obtained from appropriate enantiomerically enriched precursors.

[0184] In one preferred embodiment of the invention, the compound is in the form of a mixture containing enantiomers in a weight:weight ratio of at least about 2:1 or greater, preferably at least about 5:1 or greater, and most preferably at least about 10:1 or greater in favor of the enantiomer (eutomer) that exhibits significant in vitro and / or in vivo activity.

[0185] In one particularly preferred embodiment, the compound is in the form of a mixture comprising a compound of formula (I.1) and its corresponding enantiomer of formula (I.2), wherein the weight:weight ratio of said compound of formula (I.1) to said compound of formula (I.2) is greater than 1.05:1, more preferably greater than 2:1, even more preferably greater than 5:1, and even more preferably greater than 10:1.

[0186] In one particularly preferred embodiment, the compound is in the form of a mixture comprising the compound of formula (I.1) and its corresponding enantiomer of formula (I.2), which mixture is substantially enriched in the compound of formula (I.1).

[0187] In one embodiment, the compound is in the form of a mixture comprising a compound of formula (I.1) and its corresponding enantiomer of formula (I.2), wherein the weight:weight ratio of said compound of formula (I.2) to said compound of formula (I.1) is greater than 1.05:1, more preferably greater than 2:1, even more preferably greater than 5:1, and even more preferably greater than 10:1.

[0188] In one embodiment, the compound is in the form of a mixture comprising a compound of formula (I.1) and its corresponding enantiomer of formula (I.2), which is substantially enriched in the compound of formula (I.2).

[0189] In one preferred embodiment, the compound is [Table 1] TIFF2024538178000040.tif237170 TIFF2024538178000041.tif227170 TIFF2024538178000042.tif234170 TIFF2024538178000043.tif241170 TIFF2024538178000044.tif244170 TIFF2024538178000045.tif222170 TIFF2024538178000046.tif214170 TIFF2024538178000047.tif244170 TIFF2024538178000048.tif251170 TIFF2024538178000049.tif228170 TIFF2024538178000050.tif250170 TIFF2024538178000051.tif252170 TIFF2024538178000052.tif214170 TIFF2024538178000053.tif232170 TIFF2024538178000054.tif235170 TIFF2024538178000055.tif224170 TIFF2024538178000056.tif229170 TIFF2024538178000057.tif224170 and its enantiomers, and mixtures of its enantiomers, including racemic mixtures, and pharmaceutically acceptable salts and solvates thereof.

[0190] Another aspect of the present invention is a compound of formula (If), or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, R 11 is selected from H, alkyl, haloalkyl, halo, OH and O-alkyl; B, Y, Z, R a and R b is as described herein above).

[0191] In one preferred embodiment, for compounds of formula (If), ring B is a monocyclic aromatic group, or Monocyclic or bicyclic heteroaromatic groups and each of which is optionally substituted with one or more substituents selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, and CO2-alkyl, and each of said aryl, heteroaryl, and O-aryl groups is optionally further substituted with one or more groups independently selected from halo, alkyl, and alkoxy; Z is CR 12 and Y is CR 10 R 10 ' and R 10 and R 10 each ' is independently selected from H, F, alkyl and haloalkyl; R a and R b are each independently selected from H and alkyl; R 11 and R 12 are each independently selected from H, alkyl, haloalkyl, halo, OH, and O-alkyl.

[0192] In one preferred embodiment, R 11 is selected from H, alkyl, haloalkyl, halo, and O-alkyl.

[0193] In one preferred embodiment, R 11 is OH.

[0194] In one preferred embodiment, R 12 is selected from H, CF3, Me, Cl, F, Br, OH and OMe. Even more preferably, R 12 is H, that is, Z is CH.

[0195] B, R as described above a、 R b The preferred definitions of Y and Z apply analogously to compounds of formula (If).

[0196] Another aspect of the present invention is a compound of formula (Ij) or a pharmaceutically acceptable salt or solvate thereof: [ka] (Ij) (Wherein, ring A is [ka] is selected from Y is CR 10 R 10 ' and R 10 and R 10 each ' is independently selected from H, F, alkyl and haloalkyl, preferably Y is CH; R a and R b are each independently selected from H and alkyl, preferably R a and R b are both H, R1', R2', R4', and R5' are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, and halo; R3' is CN, haloalkyl, haloalkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, O-(CH2) q -heterocycloalkyl, alkoxy-alkoxy, alkylamino-alkoxy, dialkylamino-alkoxy, alkoxy-alkyl and O-(CH2) p -a pyridinyl group substituted by one or more substituents selected from cycloalkyl, wherein the cycloalkyl group is optionally substituted by one or more halo, alkyl or alkoxy groups, and the pyridinyl is optionally further substituted by one or more substituents selected from halo, alkyl and alkoxy; R6' is H or alkyl, more preferably H; R7, R8, and R9 are each independently selected from H, halo, and alkyl; R 13 and R 13’ are each independently selected from H, alkyl, and alkoxy-alkyl; p and q each independently represent 0 to 3).

[0197] In one preferred embodiment, R1' and R4' are selected from halo and haloalkyl; R2' and R5' are H; R3' is [ka] (In the formula, R 17 ', CN, haloalkyl, haloalkoxy, NHCO-alkyl, NR 13 R 13 ', SO2-alkyl, O-(CH2) q -heterocycloalkyl, alkoxy-alkoxy, alkylamino-alkoxy, dialkylamino-alkoxy, alkoxy-alkyl and O-(CH2) p -cycloalkyl, said cycloalkyl groups being optionally substituted with one or more halo, alkyl or alkoxy groups; R 18 ' is selected from H and halo; R 19 ' is selected from H, alkoxy and alkoxy-alkyl; R 20 ' is selected from H and halo.

[0198] More preferably, p and q are each independently 0 or 1.

[0199] In one preferred embodiment, R1' and R4' are both halo.

[0200] In one preferred embodiment, R1' and R4' are selected from Cl and F.

[0201] In one preferred embodiment, R1' is F and R4' is Cl.

[0202] In one preferred embodiment, Ring A [ka] is selected from Y is CH2; R a and R b are both H, R1' is F and R4' is Cl; R 17 ' is haloalkyl, haloalkoxy, alkylamino-alkoxy, dialkylamino-alkoxy, O-(CH2) q -heterocycloalkyl, O-(CH2) p -cycloalkyl, said cycloalkyl being optionally substituted with one or more alkoxy groups; p is 0 or 1, q is 0 or 1, R 18 ', R 19 ' and R 20 ' are all H.

[0203] In one preferred embodiment, ring A is [ka] is.

[0204] In one preferred embodiment, ring A is [ka] is.

[0205] In one preferred embodiment, R 17 ' is selected from haloalkyl and haloalkoxy, more preferably fluoroalkyl and fluoroalkoxy.

[0206] In one preferred embodiment, R 17 ' is selected from -O-CH2CF3, -O-CH2CH2CF3 and -OCHF2, -OCH2CHF2.

[0207] In one preferred embodiment, R 17 ' is fluoroalkyl, fluoroalkoxy, methylamino-alkoxy, dimethylamino-alkoxy, (piperidin-1-yl)-alkoxy, O—(CH2) p -cyclopropyl, O-(CH2) p -cyclobutyl, wherein the cyclopropyl and cyclobutyl groups are optionally substituted with alkoxy groups; R 18 ', R 19 ' and R 20 ' are all H.

[0208] In one preferred embodiment, R 17 ' is selected from CF3, -O-CH2CF3, -O-CH2CH2CF3, -OCHF2, -OCH2CHF2, -OCH2CH2NHMe, -OCH2CH2NHMe, (piperidin-1-yl)-CH2CH2-O-, -O-cyclopropyl, -O-CH2-cyclopropyl, methoxycyclobutyl-O-; R 18 ', R 19 ' and R 20 ' are all H.

[0209] In one preferred embodiment, the compound of formula (Ij) is selected from compounds 220, 222, 223, 239, 240, 241, 300, 301, 309, 312, 317, 321, 322, 324, 325, 332 and 334 described herein.

[0210] Further aspects of the present invention include: [Table 2] TIFF2024538178000066.tif232170 TIFF2024538178000067.tif217170 TIFF2024538178000068.tif224170 TIFF2024538178000069.tif225170 TIFF2024538178000070.tif222170 TIFF2024538178000071.tif241170 TIFF2024538178000072.tif206170 TIFF2024538178000073.tif235170 TIFF2024538178000074.tif247170 TIFF2024538178000075.tif248170 TIFF2024538178000076.tif235170 TIFF2024538178000077.tif246170 TIFF2024538178000078.tif127170 and its enantiomers, and mixtures of its enantiomers, including racemic mixtures, and pharmaceutically acceptable salts and solvates thereof.

[0211] In one preferred embodiment, the compound of the present invention is [Table 3] TIFF2024538178000080.tif236170 TIFF2024538178000081.tif242170 TIFF2024538178000082.tif236170 TIFF2024538178000083.tif242170 TIFF2024538178000084.tif236170 TIFF2024538178000085.tif236170 TIFF2024538178000086.tif247170 TIFF2024538178000087.tif247170 TIFF2024538178000088.tif242170 TIFF2024538178000089.tif242170 TIFF2024538178000090.tif236170 TIFF2024538178000091.tif247170 TIFF2024538178000092.tif247170 TIFF2024538178000093.tif247170 TIFF2024538178000094.tif247170 TIFF2024538178000095.tif247170 TIFF2024538178000096.tif247170 TIFF2024538178000097.tif242170 TIFF2024538178000098.tif247170 TIFF2024538178000099.tif242170 TIFF2024538178000100.tif247170 TIFF2024538178000101.tif247170 TIFF2024538178000102.tif19170 and its enantiomers, and mixtures of its enantiomers, including racemic mixtures, and pharmaceutically acceptable salts and solvates thereof.

[0212] In one preferred embodiment, the compound is selected from the following: 1-28, 31, 32, 35, 37-39, 41-44, 46-49, 51-53, 55-60, 63-89, 91-93, 96-118, 120-141, 143-150, 152-157, 159-173, 175-286 and 289-343.

[0213] In a further preferred embodiment, the compound is one of the following: 1 to 11, 15 to 20, 20, 22 to 24, 26, 28, 31, 32, 35, 37, 39, 41, 42, 44, 46, 47, 49, 51, 52, 55, 59, 60, 63 to 67, 69, 70, 74 to 77, 79, 81, 82, 84 to 87, 92, 96 to 98, 100 to 105, 108 to 115, 120, 121, 123 to 127, 131, 132, 134, 136 , 138, 139, 141, 144, 145, 147, 152-155, 157, 159, 162-173, 175-178, 182-185, 188-191, 193-195, 197-202, 205-223, 225-227, 229, 230, 232-235, 237-270, 272-279, 281, 282, 285, 286, 289-297, 301-307 and 309-343.

[0214] method A further aspect of the present invention is a compound of formula (Ie) as described above, wherein Y is CH and R a , R b and R6 is H, (i) treating a compound of formula I-1a with glyoxylic acid monohydrate to obtain a compound of formula I-1b; (ii) treating said compound of formula I-1b with N2H4.H2O to form a compound of formula I-1c; (ii) removing the Boc protecting group from the compound of formula I-1c and reacting the compound thereby formed with triphosgene and a compound of formula I-1g in NEt3 / DCM to form a compound of formula (Ie); The present invention relates to a method comprising: [ka]

[0215] Other suitable protecting groups may also be used in place of the Boc group and are well known to those skilled in the art.

[0216] Alternatively, the compound of formula I-1c (i) treating a compound of formula I-1b with morpholine to form a compound of formula I-1d; (ii) treating the compound of formula I-1d with N2H4.H2O to form a mixture comprising a compound of formula I-1c and a compound of formula I-1f; and (iii) treating the mixture of compounds I-1c and I-1f with NaOH in ethanol to obtain compound I-1c. It is prepared by a method comprising: [ka]

[0217] A further aspect of the present invention relates to a method for preparing a compound of formula (Ia) as described above, wherein R3 is an optionally substituted heteroaryl ("Het"), comprising coupling a heteroaryl boronic acid with a bromophenyl intermediate as shown below. [ka]

[0218] Preferably, the coupling reaction is carried out in the presence of a palladium complex, such as Pd-170 / XPhos (XPhos = dicyclohexyl[2',4',6'-tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane). Those skilled in the art will recognize that other suitable catalysts are also available.

[0219] Compounds with a pyrimidin-2(1H)-one group fused to a bicyclic nitrogen-containing core (e.g., 15-17 and 22-29) (i) reacting a compound of formula I-3a with 1,1-dimethoxy-N,N-dimethylmethanamine to form a compound of formula I-3b; (ii) treating said compound of formula I-3b with sodium ethoxide / urea to form a compound of formula I-3c; (iii) removing the Boc protecting group from the compound of formula I-3c and reacting the compound thereby formed with triphosgene and a compound of formula I-3d in NEt3 / DCM; It can be prepared by a method comprising: [ka]

[0220] Further details of the above syntheses are provided in the accompanying examples.

[0221] Therapeutic applications A further aspect of the present invention relates to a compound as described herein for use in medicine. The compound is particularly used in the fields of oncology, immuno-oncology and immunology, as described in more detail below. In a preferred embodiment, the compound of the present invention modulates GPR65, more preferably inhibits GPR65 signaling.

[0222] Yet another aspect of the present invention relates to a compound as described herein for use as a pharmaceutical, preferably for use in the treatment or prevention of a disorder selected from a proliferative disorder and an immune disorder.

[0223] Another aspect of the present invention relates to a compound as described herein for use in the treatment or prevention of asthma and / or chronic obstructive pulmonary disease (COPD). A GPR65 variant / SNP (rs6574978) has been shown to be associated with asthma / COPD syndrome with a significant p-value (1.18×10e-7) in most GWAS studies (Hardin, M. et al. (2014). The clinical and genetic features of COPD-asthma overlap syndrome. Eur Respir J. 2014Aug;44(2):341-50). Furthermore, pH-induced GPR65 activation (low / acidic pH in asthmatic lungs) increases eosinophil survival in a cAMP-dependent manner, contributing to disease progression / exacerbation. Furthermore, it is known that GPR65 knockout mice have attenuated asthma symptoms (Kottyan, L. et al. (2009). Eosinophil viability is increased byacidic pH in a cAMP- and GPR65-dependent manner. Blood. 2009 Sep24;114(13):2774-82).

[0224] Another aspect of the present invention relates to a compound as described herein for use in the treatment or prevention of acute respiratory distress syndrome (ARDS). GPR65 has been shown to be protective in a model of LPS-induced acute lung injury (Tsurumaki, H. et al. (2015). Int J Mol Sci. Protective Role of Proton-Sensing TDAG8 in Lipopolysaccharide-Induced Acute Lung Injury. Dec 4;16(12):28931-42).

[0225] One aspect of the present invention relates to a compound as described herein for use in the treatment of a proliferative disorder. Preferably, the proliferative disorder is cancer or leukemia.

[0226] In one preferred embodiment, the cancer is a solid tumor and / or its metastases.

[0227] In another preferred embodiment, the cancer is selected from melanoma, renal cell carcinoma (RCC), gastric cancer, acute myeloid leukemia (AML), triple-negative breast cancer (TNBC), colon cancer, head and neck cancer, colorectal adenocarcinoma, pancreatic adenocarcinoma, lung cancer, sarcoma, ovarian cancer and glioma, preferably glioblastoma (GBM).

[0228] Without wishing to be bound by theory, it is believed that GPR65 modulators can prevent the increase in cytosolic cAMP in a subset of tumor-associated macrophages (TAMs), natural killer (NK) cells, and T cells, which typically results from their exposure to the acidic tumor microenvironment and the resulting activation of GPR65. This reduction in cytosolic cAMP levels, in turn, reduces the levels of ICER and inflammatory mediators, such as CXCL10 and TNFα, preventing the polarization of TAMs and other immune cell changes associated with a non-inflammatory, tumor-permissive environment. Therefore, GPR65 modulators are predicted to increase tumor recognition by the immune system and lead to improved immune-mediated tumor clearance. This suggests that modulation of GPR65 activity could be an effective treatment for cancer, either as a standalone therapy or in combination with cancer immunotherapy (vaccines, substances that promote T cell-mediated immune responses), or in patients who do not respond to immunomodulatory approaches, such as PD1 / PDL-1 blockade.

[0229] Another aspect of the present invention relates to a compound as described herein for use in the treatment or prevention of an immune disorder, preferably an autoimmune disease.

[0230] In one embodiment, the autoimmune disease is selected from psoriasis, psoriatic arthritis, rheumatoid arthritis (RA, rheumatoid arthritis), multiple sclerosis (MS, multiple sclerosis), systemic lupus erythematosus (SLE, systemic lupus erythematosus), autoimmune thyroiditis (Hashimoto's thyroiditis), Graves' disease, uveitis (including intermediate uveitis), ulcerative colitis, Crohn's disease, autoimmune uveoretinitis, systemic vasculitis, polymyositis-dermatomyositis, systemic sclerosis (scleroderma), Sjogren's syndrome, ankylosing spondylitis and related spondyloarthropathy, sarcoidosis, autoimmune hemolytic anemia, immunological platelet disorders, autoimmune polyendocrinopathy, autoimmune myocarditis, type 1 diabetes, and atopic dermatitis.

[0231] In particularly preferred embodiments, the autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease and multiple sclerosis (MS).

[0232] Without wishing to be bound by theory, GPR65 modulators are thought to prevent the upregulation of ICER in CD4+ T cells. This, in turn, is predicted to prevent ICER-associated IL-2 suppression, which biases CD4+ T cells toward the pro-inflammatory Th17 phenotype associated with increased pathogenicity in the context of autoimmune diseases. This is supported by the fact that mutations in the GPR65 locus are associated with several autoimmune diseases, such as multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, and Crohn's disease (Gaublomme, J. et al. (2015). Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell, 1400-1412). This suggests that modulation of GPR65 activity could be an effective treatment for autoimmune diseases.

[0233] Another aspect relates to a compound as described herein for use in the treatment or prevention of a disorder caused by, related to, or associated with abnormal activity towards GPR65.

[0234] Another aspect relates to a compound as described herein for use in the treatment or prevention of a disease or disorder associated with GPR65.

[0235] Another aspect of the present invention relates to a method of treating a disorder as described above, comprising administering to a subject a compound as described herein.

[0236] Another aspect of the present invention relates to a method of treating a disease or disorder associated with GPR65 in a subject. The method according to this aspect of the present invention is achieved by administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention as described herein above, either by itself or, more preferably, as part of a pharmaceutical composition, e.g., mixed with a pharmaceutically acceptable carrier, as detailed herein below.

[0237] Yet another aspect of the present invention relates to a method of treating a subject having a condition alleviated by modulation of GPR65, comprising administering to the subject a therapeutically effective amount of a compound according to the present invention.

[0238] Another aspect relates to a method of treating a condition alleviated by modulation of GPR65, comprising administering to a subject a therapeutically effective amount of a compound according to the invention.

[0239] Preferably, the subject is a mammal, more preferably a human.

[0240] The term "method" refers to ways, means, techniques, and procedures for accomplishing a given task, and includes, but is not limited to, ways, means, techniques, and procedures that are either known to those skilled in the arts of chemistry, pharmacology, biology, biochemistry, and medicine or that can be readily developed by them from known ways, means, techniques, and procedures.

[0241] As used herein, the term "treatment" includes abolishing, substantially inhibiting, slowing, or reversing the progression of a disease or disorder, substantially ameliorating the clinical symptoms of a disease or disorder, or substantially preventing the appearance of clinical symptoms of a disease or disorder.

[0242] As used herein, the term "prevention" refers to a method of preventing an organism from acquiring a disorder or disease in the first place.

[0243] The term "therapeutically effective amount" refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disease or disorder being treated.

[0244] For any compound used in the invention, the therapeutically effective amount, also referred to herein as the therapeutically effective dose, can be initially estimated from cell culture assays, e.g., the IC 50 or IC 100 Doses can be formulated in animal models to achieve a blood concentration range that includes the range of doses that are most effective in humans. Such information can be used to more accurately determine useful doses in humans. Initial doses can also be estimated from in vivo data. Using these initial guidelines, one skilled in the art can determine effective doses in humans.

[0245] Furthermore, the toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., LD 50 and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 Therapeutic indices can be expressed as a ratio between ED and ED. Compounds that exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used to formulate a non-toxic dosage range for use in humans. The dosage of such compounds preferably achieves the ED with little or no toxicity. 50 The blood concentration range includes: 0.05 to 0.05 mg / kg body weight; ...

[0246] Dosage and administration intervals can be individually adjusted to provide plasma concentrations of the active compound sufficient to maintain therapeutic efficacy. Typical patient dosages for oral administration range from about 50 to 2000 mg / day, generally about 100 to 1000 mg / day, preferably about 150 to 700 mg / day, and most preferably about 250 to 500 mg / day or 50 to 100 mg / day. Preferably, therapeutically effective serum concentrations are achieved by administering multiple doses daily. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration. One of ordinary skill in the art can optimize a therapeutically effective local dosage without undue experimentation.

[0247] As used herein, "GPR65-related disease or disorder" refers to a disease or disorder characterized by inappropriate GPR65 activity. Inappropriate GPR65 activity refers to either increased or decreased GPR65 activity, for example, as measured by an enzyme assay or a cellular assay, compared to the activity in a healthy subject. Inappropriate activity may also be due to overexpression of GPR65 in diseased tissue compared to healthy adjacent tissue.

[0248] Preferred diseases or disorders that the compounds described herein may be useful in preventing include proliferative disorders and immune disorders as described herein above, as well as asthma and chronic obstructive pulmonary disease.

[0249] Thus, the present invention further provides the use of a compound as defined herein in the preparation of a medicament for the treatment of a disease in which it is desirable to modulate GPR65, including proliferative and immune disorders as described herein above, as well as asthma and chronic obstructive pulmonary disease.

[0250] As used herein, the phrase "medicament preparation" includes the use of the components of the present invention directly as a medicament, as well as their use in any stage of the preparation of such a medicament.

[0251] In one preferred embodiment, the compound prevents the expected rise in cytoplasmic cAMP levels following GPR65 activation at acidic pH. This prevention of cAMP accumulation in turn prevents downstream signaling by ICER as described above. The "Human GPR65 Cyclic Adenosine Monophosphate (cAMP) Homogeneous Time Resolved Fluorescence (HTRF) Antagonist Assay," or simply "cAMP Assay," as described in the accompanying Examples, measures the concentration of compound required to reduce by 50% the rise in cAMP levels upon GPR65 activation (i.e., IC 50 ) can be used to measure the efficacy of GPR65 modulators.

[0252] In one preferred embodiment, the compound has an IC in the cAMP assay of less than about 25 μM. 50 More preferably, the compounds have an IC in the cAMP assay of less than about 10 μM, more preferably less than about 5 μM, even more preferably less than about 1 μM, and even more preferably less than about 0.1 μM. 50 Indicates the value.

[0253] In another preferred embodiment, the compounds exhibit hGPR65 IC50 values ​​of less than 5 μM, more preferably less than 500 nM in the above-described assay.

[0254] In one preferred embodiment, a compound or compound for use according to the invention exhibits an IC50 of greater than 500 nM and less than 5 μM in a human GPR65 cyclic adenosine monophosphate (cAMP) homogeneous time-resolved fluorescence (HTRF) antagonist assay such as that described in the accompanying Examples. In one preferred embodiment, the compound is selected from those designated as "high" or "moderate" in Table 1.

[0255] In a more preferred embodiment, a compound or compound for use according to the invention exhibits an IC50 of less than 500 nM in the human GPR65 cAMP HTRF antagonist assay as described in the Examples. In one preferred embodiment, the compound is selected from those designated "High" in Table 1.

[0256] Pharmaceutical Composition For use in accordance with the present invention, the compounds described herein, or physiologically acceptable salts, esters, or other physiologically functional derivatives thereof, can be provided as pharmaceutical formulations comprising the compounds, or physiologically acceptable salts, esters, or other physiologically functional derivatives thereof, together with one or more pharmaceutically acceptable carriers, excipients, or diluents thereof, and optionally other therapeutic and / or prophylactic ingredients. The carrier must be acceptable, in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. The pharmaceutical compositions can be for human or animal use in human and veterinary medicine.

[0257] Examples of such suitable excipients for the various different forms of pharmaceutical compositions described herein can be found in "Handbook of Pharmaceutical Excipients, 2000." nd Edition, (1994), Edited by A. Wade and P. J. Weller." The carrier, or each of the carriers, if more than one is present, must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0258] Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985).

[0259] Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, etc. Examples of suitable diluents include ethanol, glycerol and water.

[0260] The choice of pharmaceutical carrier, excipient, or diluent can be selected according to the intended route of administration and standard pharmaceutical practice. The pharmaceutical composition can include as, or in addition to, the carrier, excipient, or diluent any suitable binders, lubricants, suspending agents, coating agents, solubilizers, buffers, flavoring agents, surfactants, thickeners, preservatives (including antioxidants), and the like, as well as substances included to render the formulation isotonic with the blood of the intended recipient.

[0261] Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, and polyethylene glycol.

[0262] Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.

[0263] Preservatives, stabilizers, dyes, and even flavoring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0264] Pharmaceutical formulations include those suitable for oral administration, topical administration (including transdermal, buccal and sublingual), rectal administration or parenteral administration (including subcutaneous, intradermal, intramuscular and intravenous), intranasal administration and pulmonary administration, e.g., inhalation. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0265] Pharmaceutical formulations suitable for oral administration in which the carrier is solid are most preferably provided as unit-dose formulations, such as boluses, capsules, or tablets each containing a predetermined amount of the active compound. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active compound in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, glidant, surfactant, or dispersing agent. Molded tablets can be made by molding the active compound with an inert liquid diluent. Tablets can be coated or, if uncoated, can be scored. Capsules can be prepared by filling capsule shells with the active compound, either alone or in admixture with one or more accessory ingredients, and then sealing them in the usual manner. Cachets are similar to capsules, in that the active compound, along with any accessory ingredients, is sealed in a rice paper membrane. The active compound can also be formulated as dispersible granules, which can be suspended in water or sprinkled on food before administration, for example. The granules may be packaged, for example, in a sachet.Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion.

[0266] Formulations for oral administration include controlled-release formulations, such as tablets in which the active compound is formulated in a suitable release-controlling matrix or coated with a suitable release-controlling film. Such formulations may be particularly advantageous for prophylactic use.

[0267] Pharmaceutical preparations suitable for rectal administration, in which the carrier is solid, are most preferably provided as unit-dose suppositories.Suitable carriers include cocoa butter and other materials commonly used in the art.Suppositories can be conveniently formed by mixing the active compound with a softened or melted carrier, followed by cooling and shaping in molds.Pharmaceutical preparations suitable for parenteral administration include sterile solutions or suspensions of the active compound in aqueous or oily media.

[0268] Injectable formulations can be adapted for bolus injection or continuous infusion. Such formulations are conveniently provided in unit-dose or multi-dose containers that are sealed after introduction of the formulation until needed for use. Alternatively, the active compound can be in powder form, which is reconstituted with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0269] The active compound can also be formulated as a long-acting depot preparation, which can be administered by intramuscular injection or by implantation, for example, subcutaneously or intramuscularly. Depot preparations can include, for example, suitable polymeric or hydrophobic materials, or ion exchange resins. Such long-acting preparations are particularly advantageous for prophylactic use.

[0270] Formulations suitable for pulmonary administration via the buccal cavity provide particles comprising the active compound, desirably having a diameter in the range of 0.5 to 7 microns, for delivery to the recipient's bronchial tree.

[0271] One possibility is that such formulations are in the form of a finely divided powder, conveniently presented either in a suitable pierceable capsule, e.g., gelatin, for use in an inhalation device, or alternatively, as a self-propelling formulation containing the active compound, a suitable liquid or gaseous propellant, and optionally other ingredients, such as surfactants and / or solid diluents. Suitable liquid propellants include propane and chlorofluorocarbons, and suitable gaseous propellants include carbon dioxide. Self-propelling formulations in which the active compound is dispensed in the form of droplets of a solution or suspension can also be employed.

[0272] Such self-propelling formulations are similar to those known in the art and can be prepared by established procedures. Suitably, they are provided in a container equipped with either a manually operable or automatically functioning valve having the desired spray characteristics, advantageously the valve being of the metered type that delivers a fixed volume, e.g., 25-100 microliters, upon each actuation thereof.

[0273] As a further possibility, the active compound can be in the form of a solution or suspension for use in an atomizer or nebulizer, whereby an accelerated air stream or ultrasonic agitation is used to produce a mist of fine droplets for inhalation.

[0274] Formulations suitable for intranasal administration include formulations generally similar to those described above for pulmonary administration. When dispensed, such formulations should desirably have a particle size in the range of 10-200 microns to enable retention in the nasal cavity; this can be achieved, if necessary, by the use of powders of an appropriate particle size or by the selection of an appropriate valve. Other suitable formulations include coarse powders having a particle size in the range of 20-500 microns, for administration by rapid inhalation through the nostrils from a container held close to the nose, and nasal sprays containing 0.2-5% w / v of the active compound in an aqueous or oily solution or suspension.

[0275] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.1 M, preferably 0.05 M, phosphate buffer or 0.8% saline. Furthermore, such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions, or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's solution, or fixed oils. Preservatives and other additives, such as antibacterial agents, antioxidants, chelating agents, inert gases, and the like, may also be present.

[0276] Formulations suitable for topical use may be provided, for example, as gels, creams, or ointments. Such preparations may be applied, for example, to a wound or ulcer, either by spreading it directly on the surface of the wound or ulcer, or by being held on a suitable support, such as a bandage, gauze, mesh, etc., which may be applied to and cover the area to be treated.

[0277] Liquid or powder formulations may also be provided that can be sprayed or sprinkled directly onto the area to be treated, such as a wound or ulcer. Alternatively, a carrier, such as a bandage, gauze, mesh, etc., may be sprayed or sprinkled with the formulation and then applied to the area to be treated.

[0278] According to a further aspect of the present invention there is provided a process for the preparation of a pharmaceutical or veterinary composition as described above which comprises the step of bringing into association, for example by mixing, an active compound with the carrier.

[0279] In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. The present invention extends to a method of preparing a pharmaceutical composition, which includes the step of combining or bringing into association a compound as described herein with a pharmaceutically or veterinarily acceptable carrier or vehicle.

[0280] Salts / Esters The compounds of the present invention may exist as salts or esters, particularly pharmaceutically and veterinarily acceptable salts or esters.

[0281] Pharmaceutically acceptable salts of the compounds of the present invention include, where appropriate, acid addition or base salts thereof. A review of suitable pharmaceutical salts can be found in Berge et al., J Pharm Sci, 66, 1-19 (1977). Salts are formed, for example, with strong inorganic acids, such as mineral acids, for example hydrohalic acids such as hydrochlorides, hydrobromides and hydroiodides, sulfuric acid, phosphates, sulfates, bisulfates, hemisulfates, thiocyanates, persulfates and sulfonic acids; strong organic carboxylic acids, for example unsubstituted or substituted (e.g. by halogens) alkanecarboxylic acids of 1 to 4 carbon atoms, such as acetic acid; saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or tetraphthalic acid; hydroxycarboxylic acids, such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; amino acids, such as aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acids, for example unsubstituted or substituted (e.g. by halogens) (C1-C4)-alkyl- or aryl-sulfonic acids, such as methane-sulfonic acid or p-toluenesulfonic acid. Salts that are not pharmaceutically or veterinarily acceptable may still be of value as intermediates.

[0282] Preferred salts are, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanoate, glucoheptanoate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate, These include tartrates, lactobionates, pivolates, camphorates, undecanoates, and succinates, organic sulfonates such as methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, camphorsulfonates, 2-naphthalenesulfonates, benzenesulfonates, p-chlorobenzenesulfonates, and p-toluenesulfonates, and inorganic acids such as hydrochlorides, hydrobromides, hydroiodides, sulfates, bisulfates, hemisulfates, thiocyanates, persulfates, phosphoric acids, and sulfonic acids.

[0283] Esters are formed using either organic acids or alcohol / hydroxides, depending on the functional group to be esterified. Organic acids include carboxylic acids, such as unsubstituted or substituted (e.g., by halogen) alkanecarboxylic acids of 1 to 12 carbon atoms, such as acetic acid; saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or terephthalic acid; hydroxycarboxylic acids, such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid; amino acids, such as aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acids, such as unsubstituted or substituted (e.g., by halogen) (C1-C4)-alkyl- or aryl-sulfonic acids, such as methanesulfonic acid or p-toluenesulfonic acid. Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and aluminum hydroxide. Alcohols include alkanealcohols of 1 to 12 carbon atoms, which may be unsubstituted or substituted, e.g., by halogen.

[0284] Enantiomers / Tautomers In all aspects of the invention discussed above, the invention includes, where appropriate, all enantiomers, diastereoisomers, and tautomers of the compounds of the invention. Those skilled in the art will recognize compounds that have optical properties (one or more chiral carbon atoms) or tautomeric characteristics. The corresponding enantiomers and / or tautomers can be isolated / prepared by methods known in the art.

[0285] Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold, and Prelog, conventions well known in the art (see, e.g., 'Advanced Organic Chemistry', 3rd edition, ed. March, J., John Wiley and Sons, New York, 1985).

[0286] Compounds of the invention that contain chiral centers can be used as racemic mixtures, enantiomerically enriched mixtures, or racemic mixtures can be separated using well-known techniques and the individual enantiomers used singly.

[0287] Stereoisomers and geometric isomers Some of the compounds of the present invention may exist as stereoisomers and / or geometric isomers; for example, they may possess one or more asymmetric and / or geometric centers and, therefore, may exist in two or more stereoisomeric and / or geometric isomeric forms. The present invention contemplates the use of all individual stereoisomers and geometric isomers of these compounds, as well as mixtures thereof. The terms used in the claims encompass such forms, provided that they retain the appropriate functional activity (though not necessarily to the same degree).

[0288] The present invention also includes all suitable isotopic variations of the compound or its pharmaceutically acceptable salt. An isotopic variation of the compound of the present invention or its pharmaceutically acceptable salt is defined as one in which at least one atom is replaced with an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into the drug and its pharmaceutically acceptable salt include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 31 P, 32 P, 35 S, 18 F and 36 Certain isotopic variations of the Agents and pharmaceutically acceptable salts thereof, such as radioactive isotopes, e.g. 3 H or 14 Those incorporating C are useful in drug and / or substrate tissue distribution studies. Tritiated, i.e. 3Isotopes of H and carbon-14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, isotopes such as deuterium, i.e. 2 Substitution with H can provide certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced required dosage, and therefore may be preferable in some circumstances. For example, the present invention includes compounds of general formula (I) in which any hydrogen atom is replaced with a deuterium atom. Isotopic variations of the agents of the present invention and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.

[0289] Atropisomers Some of the compounds of the present invention may exist as atropisomers. Atropisomers are stereoisomers that arise due to restricted rotation about a single bond, where the energy difference due to steric strain or other factors creates a barrier to rotation high enough to allow isolation of individual conformers. The present invention encompasses all such atropisomers. The present invention also extends to rotational isomers of the compounds.

[0290] Prodrug The present invention further includes prodrug forms of the compounds of the invention, i.e., covalently bonded compounds that release the active parent drug in vivo. Such prodrugs are generally compounds of the invention in which one or more suitable groups have been modified such that the modification can be reversed after administration to a human or mammalian subject. While a second agent can be administered with such a prodrug to effect in vivo reversal, reversal is usually effected by enzymes naturally occurring in such subjects. Examples of such modifications include esters (e.g., any of those described above), which can be effected by esterases, etc. Other such systems are well known to those skilled in the art.

[0291] solvate The present invention also includes solvated forms of the compounds of the present invention. The terms used in the claims encompass these forms. Preferably, the solvates are hydrates.

[0292] combination Another aspect of the present invention relates to a combination comprising the compound as described herein and one or more additional active agents.In a particularly preferred embodiment, one or more compounds of the present invention are administered in combination with one or more additional active agents, such as existing drugs available on the market.In such cases, the compound of the present invention can be administered sequentially, simultaneously or sequentially with one or more other active agents.

[0293] Drugs are generally more effective when used in combination. In particular, combination therapy is desirable to avoid overlapping of primary toxicities, mechanisms of action, and resistance mechanisms. Furthermore, it is also desirable to administer most drugs at their maximum tolerated doses and within the minimum time interval between such doses. The main advantage of combining chemotherapy drugs is that it can promote additive or possible synergistic effects due to biochemical interactions, and can also reduce the development of resistance.

[0294] Beneficial combinations may be suggested by studying the activity of a test compound with agents known or suspected to be of value in the treatment of a particular disorder. This procedure may also be used to determine the order of administration of the agents, i.e., before, simultaneously with, or after delivery. Such scheduling may be characteristic of all active agents identified herein.

[0295] In the context of cancer, the compounds of the present invention can be used in combination with immunotherapy, e.g., cancer vaccines, and / or other immune modulators, such as agents that block the PD1 / PDL-1 interaction. Other examples of agents that can be used in combination with the presently claimed compounds include immune modulators that block CTLA-4 or LAG-3. Thus, in one preferred embodiment, the additional active agent is an immunotherapeutic agent, more preferably a cancer immunotherapeutic agent. "Immunotherapeutic agent" refers to a treatment that uses the subject's own immune system to fight disease, e.g., cancer. For other disorders, the compounds of the present invention can be used in combination with agents that block or reduce inflammation, e.g., antibodies that target inflammatory cytokines. The compounds of the present invention can also be used in combination with other chemotherapeutic agents and / or with radiation therapy.

[0296] polymorph The present invention further relates to the compounds of the present invention in their various crystalline, polymorphic and (an)hydrate forms. It is well established in the pharmaceutical industry that chemical compounds can be isolated in any of such forms by slightly varying the methods of purification and / or isolation form, solvents used in the synthetic preparation of such compounds.

[0297] Administration The pharmaceutical compositions of the present invention may be adapted for rectal, intranasal, intrabronchial, topical (including buccal and sublingual), intravaginal, or parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, and intradermal), intraperitoneal, or intrathecal administration. Preferably, the formulation is an oral formulation. The formulations may conveniently be presented in unit dosage form, i.e., in the form of discrete portions containing a unit dose, or as multiples or subunits of a unit dose. For example, the formulations may be in the form of tablets and sustained-release capsules, and may be prepared by any method well known in the art of pharmacy.

[0298] Formulations for oral administration in the present invention can be provided as discrete units such as capsules, gels, drops, cachets, pills, or tablets, each containing a predetermined amount of active agent; powders or granules; a solution, emulsion, or suspension of the active agent in an aqueous or non-aqueous liquid; or an oil-in-water or water-in-oil liquid emulsion; or a bolus. Preferably, these compositions contain 1 to 250 mg, more preferably 10 to 100 mg, of active ingredient per dose.

[0299] For compositions for oral administration (e.g., tablets and capsules), the term "acceptable carrier" includes vehicles, such as common excipients, including binders such as syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl-methylcellulose, sucrose, and starch; fillers and carriers such as corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid; and lubricants such as magnesium stearate, sodium stearate, and other metallic stearates, glycerol stearate, silicone fluid, talc wax, oils, and colloidal silica. Flavoring agents, such as peppermint, oil of wintergreen, cherry flavoring, and the like, can also be used. It may be desirable to add a coloring agent to facilitate easy identification of the dosage form. Tablets can also be coated by methods well known in the art.

[0300] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active agent in a free-flowing form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets can be coated or scored and can be formulated to provide sustained or controlled release of the active agent.

[0301] Other formulations suitable for oral administration include lozenges containing the active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles containing the active agent in an inert base, such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active agent in a suitable liquid carrier.

[0302] Other administration forms include solutions or emulsions prepared from sterile or sterilizable solutions that can be injected intravenously, intraarterially, intrathecally, subcutaneously, intradermally, intraperitoneally, or intramuscularly. Injectable forms typically contain 10 to 1000 mg, preferably 10 to 250 mg, of active ingredient per dose.

[0303] Pharmaceutical compositions of the present invention can also be in the form of a suppository, pessary, suspension, emulsion, lotion, ointment, cream, gel, spray, solution or dusting powder.

[0304] Another means of transdermal administration is by use of a skin patch. For example, the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycol or liquid paraffin. The active ingredient can also be incorporated into an ointment consisting of a white wax or white soft paraffin base at a concentration of 1 to 10% by weight, together with such stabilizers and preservatives as may be required.

[0305] Dosage Those skilled in the art can easily determine the appropriate dosage of one of the compositions to be administered to a subject without undue experimentation.Typically, a doctor will determine the actual dosage that is most suitable for each individual patient, and it will depend on various factors, including the activity of the specific compound employed, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, administration method and time, excretion rate, drug combination, the severity of the specific condition, and the individual's current therapy.The dosages disclosed herein are examples of average cases.Of course, there may be individual cases where higher or lower dosage ranges are merited, and these are within the scope of the present invention.

[0306] Dosages are further modified according to the mode of administration of the compound. For example, parenteral administration of the compound is typically preferred to achieve an "effective dose" in emergency care. Intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation using appropriate excipients, is most effective, although intramuscular bolus injections are also useful. Typically, parenteral doses range from about 0.01 to about 100 mg, preferably 0.1 to 20 mg, in a manner that maintains plasma drug concentrations effective to modulate GPR65. The compound can be administered one to four times per day at a level that achieves a total daily dose of about 0.4 to about 400 mg. The precise amount of a compound of the present invention that is therapeutically effective, and the route by which such a compound is best administered, can be readily determined by one of skill in the art by comparing the blood concentration of the drug with the concentration required to have a therapeutic effect.

[0307] The compounds of the present invention can also be administered orally to a patient in a manner that provides a drug concentration sufficient to achieve one or more of the therapeutic indices disclosed herein. Typically, pharmaceutical compositions containing the compounds are administered at oral doses of about 0.1 to about 500 mg, or about 0.1 to about 50 mg, in a manner consistent with the patient's condition. Preferably, the oral dose is about 0.5 to about 50 mg, or about 0.5 to about 20 mg.

[0308] When the compounds of the present invention are administered in accordance with the present invention, no unacceptable toxic effects are expected. The compounds of the present invention can have good bioavailability and can be tested in one of several biological assays to determine the concentration of the compound required to have a given pharmacological effect.

[0309] The invention will now be further described with reference to the following non-limiting examples. [Example]

[0310] Where the preparation of starting materials is not described, they are either commercially available, known in the literature, or readily obtainable by those skilled in the art using standard procedures. Where compounds are shown to have been prepared analogously to preceding examples or intermediates, it will be understood by those skilled in the art that reaction times, number of equivalents of reagents, solvents, concentrations, and temperatures may vary depending on each specific reaction, and that it may be necessary or desirable to employ different work-up or purification techniques.

[0311] General Scheme Abbreviation A list of some common abbreviations is provided below, however, other abbreviations not listed will be understood by those skilled in the art if used.

[0312] AIBN: azobisisobutyronitrile; AcOH: acetic acid; BINAP: (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); Boc: tert-butyloxycarbonyl; br.: broad; CAN: ceric ammonium nitrate; CBS: Corey-Bakshi-Shibata catalyst; CCl4: tetrachloromethane; CMBP: (tributylphosphoranylidene)acetonitrile; d: doublet; DAST: diethylaminosulfur trifluoride; DCM: dichloromethane; DIAD: diisopropyl azodicarboxylate; DIBAL: diisobutylalanide aluminum; DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; dppf: 1,1'-bis(diphenylphosphino)ferrocene; (ES+): electrospray ionization positive mode; Et3N: triethylamine; EtOAc: ethyl acetate; EtOH: ethanol; h: hour; hept: septuplet; HPLC: high-performance liquid chromatography; HCl: hydrochloric acid; Hz: hertz; J: coupling constant; l: liter; LDA: lithium diisopropylamide; M: molar concentration; m: multiplet [M+H]+: protonated molecular ion; MeCN: acetonitrile; MeOH: methanol; MHz: megahertz; min: minute; ml: milliliter; MS: mass spectrometry; MTBE: methyl tert-butyl ether; m / z: mass-to-charge ratio; NBS: N-bromosuccinimide; NMO: N-methylmorpholine N-oxide; NMP: N-methyl-2-pyrrolidone; NMR: nuclear magnetic resonance; p: quintet; PDA: photodiode array; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd-161: AmPhos Pd(crotyl)Cl; Pd-172: SPhos Pd(crotyl)Cl; Pd-178: P(Cy3) Pd(crotyl)Cl; PIDA: (diacetoxyiodo)benzene; Prep TLC: preparative thin layer chromatography; q: quintuplet; RT: room temperature; Rt: retention time; s: singlet; SFC: supercritical fluid chromatography; t: triplet; TBAF: tetra-n-butylammonium fluoride; THF: tetrahydrofuran;TLC: Thin-layer chromatography; UPLC: Ultra-performance liquid chromatography; UV: Ultraviolet; Xantphos: (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane); XPhos: Dicyclohexyl[2',4',6'-tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane;

[0313] Other abbreviations are intended to convey their generally accepted meaning.

[0314] General experimental conditions All starting materials and solvents were obtained from commercial sources or prepared according to literature methods. Appropriate isocyanate and aniline starting materials were commercially available, e.g., from Sigma-Aldrich, Fluorochem, or Enamine stores, or synthesized as described herein. Appropriate tricyclic amine starting materials were synthesized as described herein. Unless otherwise indicated, reaction mixtures were magnetically stirred and reactions were carried out at room temperature (approximately 20°C).

[0315] Silica gel chromatography was performed on an automated flash chromatography system such as a CombiFlash Companion, CombiFlash Rf system, or Revelis X2 flash system using RediSep® Rf or Revelis® or GraceResolv™ prepacked silica (230-400 mesh, 40-63 μm) cartridges.

[0316] Analytical UPLC-MS experiments to determine retention times and associated mass ions were performed using a Waters ACQUITY UPLC® H-Class system equipped with an ACQUITY PDA detector and an ACQUITY QDa mass spectrometer or a Waters SQD mass spectrometer, running the analytical method described below.

[0317] Analytical LC-MS experiments to determine retention times and associated mass ions were performed using an Agilent 1200 series HPLC system coupled to an Agilent 1956, 6100, or 6120 series single quadrupole mass spectrometer running one of the analytical methods described below, or a Shimadzu-2020-P2 system consisting of a Shimadzu LC-20AD series LC system and a Shimadzu-2020 single quadrupole mass spectrometer running one of the analytical methods described below.

[0318] Analytical SFC experiments to determine retention times were performed using one of the analytical methods described, using a Waters SFC system UPC2 system at a column temperature of 40°C and a back pressure of 1750 psi (ABPR).

[0319] Preparative HPLC purification was performed using either a Waters Xbridge Prep OBD C18, 10 μm, 40×150 mm column using a gradient of MeCN and 0.1% ammonia in water or a gradient of MeCN and 0.1% formic acid in water. Fractions were collected using a PDA, and in some cases an SQD2 or ACQUITY QDa mass spectrometer with UV detection across all wavelengths.

[0320] Preparative SFC purification was performed using a mixture of CO2 and a co-solvent (MeOH, EtOH, or IPA) at a flow rate of 15-65 ml / min. The column was a Phenomenex Lux® Cellulose-4 column (1 x 25 cm, 5 μm particle size) or a Chiralpak® IG (Daicel) column (1 x 25 cm, 5 μm particle size) or a Chiralpak IC 10 x 250 mm, 5 μm particle size column or a Chiralpak IA 10 x 250 mm, 5 μm particle size column or a Phenomenex Lux® 5 μm i-Cellulose-5 LC column (250 x 21 mm) or a Phenomenex Lux® A1 5 μm LC column (250 x 10 mm) or a Chiralpak IH 10 x 250 mm, 5 μm particle size column or a Chiralpak AY-H. Analysis was performed using either a Waters SFC prep 15 system, a Waters SFC prep 100 system, or a Sepiatec Prep SFC 50 using either a 10 x 250 mm, 5 μm particle size column. Fractions were collected using a PDA with UV detection from 210 to 400 nm.

[0321] NMR spectra were recorded using either a Bruker Avance III HD 500 MHz instrument, a Bruker Avance Neo 400 MHz, a Bruker Avance III 400 MHz instrument or a QOne AS400 400 MHz spectrometer using either residual non-deuterated solvent or tetra-methylsilane as a reference.

[0322] In the absence of absolute stereochemistry explicitly indicated by wedges and dashed bonds, chemical structures disclosed throughout the examples (e.g., in the configuration (I.3) above) should be interpreted as representing a racemate. For the avoidance of doubt, the present invention encompasses compounds of either configuration, as well as mixtures thereof.

[0323] Separation of enantiomers by chiral chromatography It will be appreciated that enantiomers of the above compounds can be isolated using techniques well known in the art, including, but not limited to, chiral chromatography. For example, the racemic mixture can be dissolved in a solvent such as methanol and subsequently separated by chiral SFC on a Waters Prep 15 with UV detection by DAD at 210-400 nm, 40°C, 120 bar. The column was a Chiralpak IG 10 x 250 mm, 5 μm, 45% MeOH (0.1% DEA), 55% CO2 at a flow rate of 15 ml / min, and both enantiomers were obtained as separated pure compounds.

[0324] Analysis method Method 1 - Basic Trichotomy Column: Waters ACQUITY UPLC® BEH C18, 1.7 μm, 2.1 × 30 mm at 40°C Detection: UV at 210-400 nm, MS with electrospray ionization unless otherwise indicated Solvents: A: 0.1% ammonia in water, B: MeCN gradient: [Table 4]

[0325] Method 2 - Acidic trisection method 1 Column: Waters CSH C18, 1.7 μm, 2.1 × 30 mm, at 40 °C Detection: UV at 210-400 nm, MS with electrospray ionization unless otherwise indicated Solvents: A: 0.1% formic acid in water, B: MeCN gradient: [Table 5]

[0326] Method 3 - Acidic quintuple method 1 Column: Agilent EclipsePlus RRHD C18, 1.8 μm, 3.0 × 50 mm at 25 °C Detection: UV at 214 and 254 nm, MS with electrospray ionization unless otherwise indicated Solvents: A: 0.05% formic acid in water, B: 0.05% formic acid in MeCN gradient: [Table 6]

[0327] Method 4 - Acidic quintuple method 2 Column: Waters Sunfire, 3.5 μm, 4.6 × 50 mm column at 25°C Detection: UV at 214 and 254 nm, MS with electrospray ionization unless otherwise indicated Solvents: A: 0.05% formic acid in water, B: 0.05% formic acid in MeCN gradient: [Table 7]

[0328] Method 5 - Acidic trisection method 2 Column: Waters CORTECS UPLC, C18, 1.6 μm, 2.1 × 50 mm column at 25°C Detection: UV at 210-400 nm, MS with electrospray ionization unless otherwise indicated Solvents: A: 0.1% formic acid in water, B: MeCN gradient: [Table 8]

[0329] Experimental Scheme 1 Compound 1 (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10-carboxamide [ka] A solution of triphosgene (113 mg, 381 μmol) in DCM (5 mL) was prepared and cooled to 0° C. A separate solution of 5-chloro-2-fluoro-4-(trifluoromethyl)aniline (199 mg, 931 μmol) and EtN (708 μL, 5.08 mmol) in DCM (2 mL) was prepared and added dropwise to the stirred triphosgene solution. The reaction was stirred at 0° C. for 1 hour. (±)-2,5,6,7,8,9-Hexahydro-3H-6,9-epiminocyclohepta[c]pyridazin-3-one (150 mg, 846 μmol) in DMF (6 mL) was added slowly, and the reaction was stirred at room temperature for 3 hours. The solvent was removed in vacuo. The product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10-carboxamide as a white powder. LCMS (Method 1) m / z 415.1, 417.1 (M+H) at 1.14 min. + (ES + ); 1 H NMR(400MHz,DMSO-d6)δ12.73(s,1H), 9.13(s,1H), 8.03(d,J=6.8Hz,1H), 7.79(d,J=11.0Hz,1H), 6.68(s,1H), 5.10(d,J=5.7Hz,1H), 4 .67(d,J=6.1Hz,1H), 3.18(dd,J=18.5,5.3Hz,1H), 2.67(s,1H), 2.18(dd,J=11.4,6.3Hz,2H), 1.80(t,J=9.4Hz,1H), 1.72~1.63(m,1H).

[0330] The following compounds were prepared using the appropriate starting materials in a similar manner to that described in Experimental Scheme 1. In cases where the starting materials are not described in the literature, their synthesis is described below. [Table 9] TIFF2024538178000114.tif245170 TIFF2024538178000115.tif245170 TIFF2024538178000116.tif252170 TIFF2024538178000117.tif239170 TIFF2024538178000118.tif235170 TIFF2024538178000119.tif242170 TIFF2024538178000120.tif238170 TIFF2024538178000121.tif242170 TIFF2024538178000122.tif206170 TIFF2024538178000123.tif235170 TIFF2024538178000124.tif218170 TIFF2024538178000125.tif222170 TIFF2024538178000126.tif240170 TIFF2024538178000127.tif172170 TIFF2024538178000128.tif241170 TIFF2024538178000129.tif236170 TIFF2024538178000130.tif237170 TIFF2024538178000131.tif244170 TIFF2024538178000132.tif238170 TIFF2024538178000133.tif165170 TIFF2024538178000134.tif178170 TIFF2024538178000135.tif244170 TIFF2024538178000136.tif250170 TIFF2024538178000137.tif178170 TIFF2024538178000138.tif238170 TIFF2024538178000139.tif220170 TIFF2024538178000140.tif236170 TIFF2024538178000141.tif181170 TIFF2024538178000142.tif252170 TIFF2024538178000143.tif161170 TIFF2024538178000144.tif252170 TIFF2024538178000145.tif241170 TIFF2024538178000146.tif160170 TIFF2024538178000147.tif184170 TIFF2024538178000148.tif246170 TIFF2024538178000149.tif181170 TIFF2024538178000150.tif178170 TIFF2024538178000151.tif247170 TIFF2024538178000152.tif242170 TIFF2024538178000153.tif188170 TIFF2024538178000154.tif195170 TIFF2024538178000155.tif245170 TIFF2024538178000156.tif239170 TIFF2024538178000157.tif167170 TIFF2024538178000158.tif184170 TIFF2024538178000159.tif167170 TIFF2024538178000160.tif161170 TIFF2024538178000161.tif150170

[0331] Intermediate 1 (I-1) Route 1 [ka]

[0332] Step 1: tert-Butyl (±)-2-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-1a (2.00 g, 8.88 mmol) and glyoxylic acid monohydrate (1.14 g, 12.4 mmol) were added to a round-bottom flask, followed by EtOH (20 ml). Once all solids had dissolved, 2 M aqueous sodium hydroxide (7.10 ml, 14.2 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The aqueous solution was washed once with DCM (5 ml). 1 M HCl was carefully added to the remaining aqueous solution until a pH of approximately 6 was reached. The product was extracted with DCM (100 ml). The aqueous layer was further extracted with 10% MeOH / DCM (3 × 50 ml) and the combined organic layers were dried over MgSO, filtered and concentrated to give 2-((±)-8-(tert-butoxycarbonyl)-2-oxo-8-azabicyclo[3.2.1]octan-3-ylidene)acetic acid I-1b as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 6.64–6.54 (m, 1H), 5.75 (s, 1H), 4.35 (d, J = 8.1 Hz, 1H), 3.32 (s, 1H), 3.06 (t, J = 2.6 Hz, 1H), 2.32–2.16 (m, 1H), 2.16–1.96 (m, 1H), 1.79–1.51 (m, 2H), 1.37 (s, 9H). (No exchangeable –OH groups observed.)

[0333] Step 2: 2-((±)-8-(tert-butoxycarbonyl)-2-oxo-8-azabicyclo[3.2.1]octan-3-ylidene)acetic acid I-1b (1.6 g, 5.7 mmol) in EtOH (10 ml) was added hydrazine in THF (23 ml, 1 molar, 23 mmol). The resulting mixture was heated to 78° C. for 16 h. The reaction was cooled to room temperature and concentrated in vacuo. The resulting solid was dissolved in DCM and passed through a hydrophobic frit to remove residual water. Concentration in vacuo gave a sticky orange solid. The product was purified by chromatography on silica gel (0-10% MeOH / DCM) to give tert-butyl (±)-3-hydroxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridazine-10-carboxylate I-1c as a colorless solid. 1 H NMR (400 MHz, DMSO-d6) δ 6.67 (s, 1H), 4.71 (d, J = 6.2 Hz, 1H), 4.31 (br s, 1H), 3.03 (d, J = 17.9 Hz, 1H), 2.61 (d, J = 18.1 Hz, 1H), 2.22–2.07 (m, 2H), 1.73 (t, J = 9.6 Hz, 1H), 1.60 (t, J = 8.1 Hz, 1H), 1.35 (s, 9H). (No exchangeable protons are visible in the spectrum.)

[0334] Step 3: tert-Butyl (±)-3-hydroxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridazine-10-carboxylate. 1c (471 mg, 1.70 mmol) was dissolved in DCM (4 mL) and a solution of HCl in 1,4-dioxane (4.25 mL, 4 molar, 17.0 mmol) was added. The reaction was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo. The resulting brown solid was dissolved in MeOH and stirred over MP-carbonate resin (2.2 g, 6.84 mmol) for 1 h. The mixture was filtered, and the resin was washed with MeOH (2 × 10 mL). The filtrate was concentrated in vacuo to give (±)-2,5,6,7,8,9-hexahydro-3H-6,9-epiminocyclohepta[c]pyridazin-3-one I-1 as a brown solid.

[0335] Intermediate 1 (I-1) Pathway 2 [ka]

[0336] Step 1: To a solution of 2-((±)-8-(tert-butoxycarbonyl)-2-oxo-8-azabicyclo[3.2.1]octan-3-ylidene)acetic acid (4.1 g, 13 mmol) in EtOH (30 mL) at 0 °C was added morpholine (2.3 mL, 27 mmol) dropwise. The reaction was stirred at this temperature for 1 h and then allowed to warm to room temperature and stir for 72 h. The mixture was concentrated in vacuo to afford 2-((±)-8-(tert-butoxycarbonyl)-2-oxo-8-azabicyclo[3.2.1]octan-3-yl)-2-morpholinoacetic acid, morpholine salt I-1d as a sticky yellow oil, which was used in the next step without further purification or analysis.

[0337] Step 2: To a solution of 2-((±)-8-(tert-butoxycarbonyl)-2-oxo-8-azabicyclo[3.2.1]octan-3-yl)-2-morpholinoacetic acid, morpholine salt I-1d (17.02 g, 37.37 mmol) in EtOH (120 mL) was added hydrazine monohydrate in water (11.3 mL, 149.5 mmol). The resulting mixture was heated to 78 °C for 2.5 h. The reaction was cooled to room temperature, and the mixture was concentrated in vacuo. The resulting yellow residue was dissolved in DCM (500 mL) and water (150 mL). The layers were separated, and the aqueous layer was extracted with 10% MeOH in DCM (3 × 200 mL). The combined organic layers were dried over MgSO and concentrated in vacuo to give a pale yellow solid. The solid was dissolved in a minimum amount of EtOH and allowed to stand at room temperature for 16 h. A precipitate formed which was filtered to give tert-butyl (±)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10-carboxylate I-1e as a white powder. The filtrate was concentrated to give a 50:50 mixture of tert-butyl (±)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10-carboxylate I-1e and tert-butyl (±)-4-morpholino-3-oxo-3,4,4a,5,6,7,8,9-octahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10-carboxylate I-1f as a sticky brown oil. I-1e: 1 H NMR (400 MHz, DMSO-d6) δ 6.67 (s, 1H), 4.71 (d, J = 6.2 Hz, 1H), 4.31 (br s, 1H), 3.03 (d, J = 17.9 Hz, 1H), 2.61 (d, J = 18.1 Hz, 1H), 2.22–2.07 (m, 2H), 1.73 (t, J = 9.6 Hz, 1H), 1.60 (t, J = 8.1 Hz, 1H), 1.35 (s, 9H). (No exchangeable protons are visible in the spectrum.) I-1f: 1H NMR(400MHz,DMSO-d6)δ10.48(s,1H), 4.42(d,J=6.9Hz,1H), 4.22(d,J=6.7Hz,1H), 3.55~3.48(m,4H), 3.09~2.92(m,4H), 2.6 9(dd,J=12.1,6.0Hz,2H), 2.06~2.00(m,2H), 1.92(d,J=10.1Hz,1H), 1.69~1.65(m,2H), 1.56(d,J=12.7Hz,1H), 1.38(s,9H).

[0338] Step 3: To a solution of tert-butyl (±)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10-carboxylate I-1e and tert-butyl (±)-4-morpholino-3-oxo-3,4,4a,5,6,7,8,9-octahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10-carboxylate I-1f (3.2 g, 66% mol.wt I-1f) in EtOH (40 ml), 2 M NaOH solution (10 ml, 20 mmol) was added, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The aqueous solution was neutralized to pH 7 using 1 M HCl. The product was extracted with 10% MeOH in DCM (3 × 150 ml). The combined organics were dried over MgSO. The solvent was removed in vacuo to give tert-butyl (±)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10-carboxylate I-1e as a white solid.

[0339] Step 4: To a solution of tert-butyl (±)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10-carboxylate (2.6 g, 9.4 mmol) in DCM (20 ml) was added a solution of HCl in 1,4-dioxane (23 ml, 4 M, 94 mmol). The reaction was stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo to give the HCl salt of I-1. The HCl salt was dissolved in MeOH (150 ml), AcOH was added, and the solution was loaded onto SCX resin (50 g). The cartridge was washed with MeOH and the product was eluted with 0.7 M NH3 in MeOH to give (±)-2,5,6,7,8,9-hexahydro-3H-6,9-epiminocyclohepta[c]pyridazin-3-one I-1 as an off-white solid.

[0340] Alternatively, HCl was dissolved in MeOH, MP-carbonate (3 equiv.) was added, and the mixture was allowed to stand for 1 h. The mixture was filtered. The resin was washed with MeOH. The filtrate was concentrated in vacuo to give (±)-2,5,6,7,8,9-hexahydro-3H-6,9-epiminocyclohepta[c]pyridazin-3-one I-1 as an off-white solid.

[0341] Intermediate 2 (I-2) [ka] To a solution of (±)-2,5,6,7,8,9-hexahydro-3H-6,9-epiminocyclohepta[c]pyridazin-3-one (200 mg, 1.13 mmol) in MeOH (10 ml) was added a solution of dibenzoyl-L-tartaric acid in MeOH (5 ml). The solvent was removed in vacuo, and the residue was redissolved in EtOH (40 ml), heated to 60°C for 1 hour, allowed to cool, and allowed to stand for 2 hours. The solid was filtered off and dried in vacuo. The solid was dissolved in MeOH (10 ml), MP-carbonate (600 mg, 1.8 mmol) was added, and the mixture was allowed to stand for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give (5R,8S)-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidin-2-one as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 6.56 (s, 1H), 4.05–3.99 (m, 1H), 3.63 (t, J = 5.9 Hz, 1H), 2.90–2.78 (m, 1H), 2.45 (t, J = 1.4 Hz, 1H), 1.98–1.81 (m, 2H), 1.65 (t, J = 9.3 Hz, 1H), 1.53–1.39 (m, 1H). (NH not observed.)

[0342] Intermediate 4 (I-4) [ka]

[0343] Step 1: To a mixture of 2-chloro-1-fluoro-4-nitrobenzene I-4a (1 g, 5.70 mmol) and cyclobutanol (1.2 g, 17.09 mmol) in DMF (30 mL) was added CsCO (6.5 g, 19.94 mmol). The reaction was heated at 80 °C for 16 h and then concentrated in vacuo. The product was purified by silica gel chromatography (5% EtOAc / petroleum ether) to give 2-chloro-1-cyclobutoxy-4-nitrobenzene I-4b as a yellow oil. 1HNMR: (400MHz,DMSO-d6)δ8.30~8.29(m,1H), 8.19~8.16(m,1H), 7.19(d,J=9.2Hz,1H), 4.9 7~4.90(m,1H), 2.49~2.50(m,2H), 2.16~2.06(m,2H), 1.87~1.79(m,1H), 1.73~1.62(m,1H).

[0344] Step 2: To a solution of 2-chloro-1-cyclobutoxy-4-nitrobenzene I-4b (500 mg, 2.20 mmol) in a mixture of EtOH and saturated aqueous NH4Cl (12 mL, 1:1) was added iron powder (614 mg, 10.98 mmol). The reaction was heated at 80 °C for 2 h, cooled, and then concentrated in vacuo. The product was purified by silica gel chromatography (5% EtOAc / petroleum ether) to give 3-chloro-4-cyclobutoxyaniline I-4 as a yellow oil. 1 HNMR (400MHz, DMSO-d6) δ6.70~6.68(m,1H), 6.62(d,J=2.8Hz,1H), 6.45~6.42(m,1H), 4.87(s,2H), 4.53~4.46(m,1H), 2.35~2.27(m,2H). 2.05~1.95(m,2H),1.76~1.51(m,2H).

[0345] Intermediate 16 (I-16) [ka]

[0346] Step 1: To a suspension of 2-((±)-8-(tert-butoxycarbonyl)-2-oxo-8-azabicyclo[3.2.1]octan-3-yl)-2-morpholinoacetic acid, morpholine salt I-1d (490 mg, 1.08 mmol) in EtOH (5.0 ml), methylhydrazine (229 μl, 4.30 mmol) was added, and the resulting solution was stirred at 80° C. for 2 h and then at room temperature for 16 h. The solvent was removed in vacuo. The residue was dissolved in DCM (20 ml) and washed with 1 M HCl (20 ml). The aqueous layer was extracted with 10% MeOH in DCM (2 × 15 mL), and the combined organics were dried over MgSO and concentrated in vacuo to give a mixture of tert-butyl (±)-2-methyl-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10-carboxylate I-16b and tert-butyl (±)-2-methyl-4-morpholino-3-oxo-3,4,4a,5,6,7,8,9-octahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10-carboxylate I-16a as a viscous yellow oil, which was used in the next step without further purification.

[0347] Step 2: A mixture of tert-butyl (±)-2-methyl-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10-carboxylate I-16b and tert-butyl (±)-2-methyl-4-morpholino-3-oxo-3,4,4a,5,6,7,8,9-octahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10-carboxylate I-16a (315 mg, 1.08 mmol) in EtOH (10.0 mL) was added to a vial containing sodium hydroxide (300 mg, 7.5 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. The residue was dissolved in water and acidified to pH 2 by careful addition of 1 M HCl. DCM (20 ml) was added and the layers were separated. The aqueous layer was further extracted with DCM (2 × 15 ml) and the combined organics were washed with water (20 ml), dried over MgSO and concentrated in vacuo to give tert-butyl (±)-2-methyl-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10-carboxylate I-16b as an orange oil. 1 H NMR(400MHz,DMSO-d6)δ6.74(s,1H), 4.79~4.70(m,1H), 4.43~4.25(m,1H), 3.58(s,3H), 3.03(dd,J=18.1, 5.4Hz,1H), 2.63(d,J=18.1Hz,1H), 2.22~2.06(m,2H), 1.79~1.71(m,1H), 1.65~1.55(m,1H), 1.36(s,9H).

[0348] Step 3: tert-Butyl (±)-2-methyl-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10-carboxylate I-16b (280 mg, 702 μmol) in DCM (7 mL) was added HCl in dioxane (3.0 mL, 4.0 molar, 12 mmol), and the resulting mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo, and the residue was dissolved in MeOH and loaded onto an SCX (approximately 3 g). The SCX was washed with MeOH, and the product was eluted with 0.7 M NH in MeOH to give (±)-2-methyl-2,5,6,7,8,9-hexahydro-3H-6,9-epiminocyclohepta[c]pyridazin-3-one as a yellow oil, which solidified upon standing to give a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 6.63 (t, J = 1.7 Hz, 1H), 4.07-4.01 (m, 1H), 3.67-3.60 (m, 1H), 3.56 (s, 3H), 2.90-2.81 (m, 1H), 2.52-2.43 (m, 1H), 1.99-1.83 (m, 2H), 1.73-1.64 (m, 1H), 1.49-1.40 (m, 1H). No exchangeable protons observed.

[0349] Intermediate 32 (I-32) [ka] To a vial was added 4-bromo-5-chloro-2-fluoroaniline I-8a (316 mg, 1.41 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole (346 mg, 1.41 mmol), and Pd-118 (22.9 mg, 35.2 μmol). The vial was evacuated under vacuum and refilled with N. This was repeated three times. 1,4-Dioxane (4.00 mL) was added, followed by an aqueous solution of potassium phosphate tribasic (2.11 mL, 2.00 M, 4.22 mmol) sparged with N. After the addition, the vial was once again evacuated and refilled with N. The reaction was heated to 95 °C for 2 h. The reaction was cooled to room temperature, filtered through a pad of Celite, and washed with DCM (20 mL). The filtrate was diluted with water (4 mL) and the layers were separated. The aqueous phase was extracted with DCM (3 × 10 mL). The combined organics were dried over MgSO, filtered, and concentrated in vacuo. The product was purified by chromatography on silica gel (0–30% EtOAc / isohexane) to give 4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-2-fluoroaniline I-32 as a light yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.06(dd,J=9.3,1.0Hz,1H), 8.00(t,J=1.3Hz,1H), 7.68( dd,J=9.3,1.4Hz,1H), 7.31(d,J=11.9Hz,1H), 6.95(d,J=8.2Hz,1H), 5.81(s,2H).

[0350] Intermediate 33 (I-33) [ka] 5-Chloro-2-fluoro-4-(5-fluoropyridin-3-yl)aniline I-33 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and (6-fluoropyridin-3-yl)boronic acid using essentially the same procedure as for I-32. 1H NMR(400MHz,DMSO-d6)δ8.23(d,J=2.6Hz,1H), 8.02(td,J=8.2,2.6Hz,1H), 7.23( dd,J=8.5,2.9Hz,1H), 7.20(d,J=11.9Hz,1H), 6.93(d,J=8.3Hz,1H), 5.68(s,2H).

[0351] Intermediate 34 (I-34) [ka] To a solution of 4-bromo-5-chloro-2-fluoroaniline (100 mg, 446 μmol) and 4-bromo-5-chloro-2-fluoroaniline I-8a (100 mg, 446 μmol) in 1,4-dioxane (5 mL) was added K2CO3 (185 mg, 1.34 mmol) in water (1 mL). The mixture was purged with N2 for 10 minutes, and Pd(dppf)Cl2 (16.3 mg, 22.3 μmol) was added. The reaction mixture was heated to 80 °C for 2 hours. The reaction mixture was concentrated in vacuo. The product was purified by chromatography on silica gel (0–2% 0.7 M NH3 / MeOH in DCM) to give 2-chloro-5-fluoro-[1,1'-biphenyl]-4-amine I-34 as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ7.45~7.30(m,5H), 7.06(d,J=12.0Hz,1H), 6.90(d,J=8.4Hz,1H), 5.55(s,2H).

[0352] Intermediate 35 (I-35) [ka] To a vial containing cataCXium® A Pd G3 (3.2 mg, 4.5 μmol) was added (1H-pyrazol-4-yl)boronic acid (29.9 mg, 267 μmol) and 4-bromo-5-chloro-2-fluoroaniline I-8a (20.0 mg, 89.1 μmol) in 1,4-dioxane (1.00 ml), along with a solution of KCO in water (208 μl, 1.5 M, 312 μmol). The mixture was stirred at 95° C. for 2 hours. The reaction mixture was loaded onto SCX (1 g), washed with MeOH, and the product was eluted with 0.7 M ammonia in MeOH to give 5-chloro-2-fluoro-4-(1H-pyrazol-4-yl)aniline I-35. LCMS (Method 1) m / z 212.2, 214.2 (M+H) at 0.85 min. + (ES + ).

[0353] Intermediate 36 (I-36) [ka] 5-Chloro-2-fluoro-4-(1-methyl-1H-indazol-4-yl)aniline I-34 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a using essentially the same procedure as for I-35. LCMS (Method 1) m / z 275.8 (M+H) at 1.40 min + (ES + )

[0354] Intermediate 37 (I-37) [ka] A vial containing (1-methyl-1H-indazol-6-yl)boronic acid (31 mg, 178 μmol) was purged with N. A solution of 4-bromo-5-chloro-2-fluoroaniline I-8a (20.0 mg, 89.1 μmol) and cataCXium A Pd G3 (3.2 mg, 4.45 μmol) in 1,4-dioxane (1.00 ml) and a solution of 1.5 M potassium phosphate tribasic in water (119 μl, 1.5 M, 178 μmol) were added. The mixture was stirred at 95° C. for 2 hours. The reaction mixture was loaded onto SCX (1 g), washed with MeOH, and the product was eluted with 0.7 M ammonia in MeOH to give 5-chloro-2-fluoro-4-(1-methyl-1H-indazol-6-yl)aniline. LCMS (Method 1) at 1.37 min, m / z 275.7, 278.4 (M+H) + (ES + )

[0355] Intermediate 38 (I-38) [ka] 6-(4-amino-2-chloro-5-fluorophenyl)indolin-2-one I-38 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and (2-oxoindolin-6-yl)boronic acid using essentially the same procedure as for I-37. LCMS (Method 1) m / z 276.2, 278.4 (M+H) at 1.37 min + (ES + )

[0356] Intermediate 39 (I-39) [ka] 6-(4-Amino-2-chloro-5-fluorophenyl)-1-methylindolin-2-one I-39 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ7.27(d,J=7.6Hz,1H), 7.09(d,J=11.9Hz,1H), 7.01(dd,J=7.6,1.6Hz,1H ), 6.95(d,J=1.5Hz,1H), 6.90(d,J=8.4Hz,1H), 5.56(s,2H), 3.56(d,J=1.1Hz,2H), 3.13(s,3H).

[0357] Intermediate 40 (I-40) [ka] 5-Chloro-2-fluoro-4-(1-methyl-1H-indazol-5-yl)aniline I-40 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and (1-methyl-1H-indazol-5-yl)boronic acid using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ8.05(d,J=0.9Hz,1H), 7.73~7.68(m,1H), 7.67~7.62(m,1H), 7.40(dd ,J=8.7,1.6Hz,1H), 7.10(d,J=11.9Hz,1H), 6.91(d,J=8.4Hz,1H), 5.52(s,2H), 4.06(s,3H).

[0358] Intermediate 41 (I-41) [ka] 4-([1,2,5]oxadiazolo[3,4-b]pyridin-6-yl)-5-chloro-2-fluoroaniline I-41 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,5]oxadiazolo[3,4-b]pyridine using essentially the same procedure as for I-32. 1 H NMR (400MHz, DMSO-d6) δ9.15(d,J=2.1Hz,1H), 8.55(d,J=2.1Hz,1H), 7.42(d,J=11.9Hz,1H), 6.98(d,J=8.2Hz,1H), 5.95(s,2H).

[0359] Intermediate 42 (I-42) [ka] 4-(Benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-2-fluoroaniline I-42 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]thiadiazole using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ8.10(dd,J=9.1,0.8Hz,1H), 8.05(dd,J=1.8,0.8Hz,1H), 7. 78(dd,J=9.0,1.8Hz,1H), 7.29(d,J=11.9Hz,1H), 6.96(d,J=8.3Hz,1H), 5.73(s,2H)

[0360] Intermediate 43 (I-43) [ka] 5-Chloro-2-fluoro-4-(2-methyl-3a,7a-dihydrobenzo[d]oxazol-6-yl)aniline I-43 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and (2-methylbenzo[d]oxazol-6-yl)boronic acid using essentially the same procedure as for I-32. 1 H NMR (400MHz, DMSO-d6) δ7.69~7.62(m,2H), 7.32(dd,J=8.3,1.6Hz,1H), 7.13(d,J=12.0Hz,1H), 6.92(d,J=8.4Hz,1H), 5.59(s,2H), 2.62(s,3H).

[0361] Intermediate 44 (I-44) [ka] 5-Chloro-2-fluoro-4-(6-methoxypyridin-3-yl)aniline I-44 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and (6-methoxypyridin-3-yl)boronic acid using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ8.15(dd,J=2.6,0.7Hz,1H), 7.73(dd,J=8.6,2.5Hz,1H), 7.12(d,J =11.9Hz,1H), 6.91(d,J=8.3Hz,1H), 6.85(dd,J=8.6,0.8Hz,1H), 5.58(s,2H), 3.88(s,3H).

[0362] Intermediate 45 (I-45) [ka] 5-Chloro-2-fluoro-4-(pyridin-4-yl)aniline I-45 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and pyridin-4-ylboronic acid using essentially the same procedure as for I-32. 1H NMR (400MHz, DMSO-d6) δ8.62~8.56(m,2H), 7.46~7.40(m,2H), 7.19(d,J=12.0Hz,1H), 6.92(d,J=8.3Hz,1H), 5.76(s,2H).

[0363] Intermediate 46 (I-46) [ka] 5-Chloro-2-fluoro-4-(pyridazin-4-yl)aniline I-46 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ9.31(dd,J=2.5,1.2Hz,1H), 9.24(dd,J=5.4,1.2Hz,1H), 7.7 6(dd,J=5.4,2.4Hz,1H), 7.36(d,J=12.0Hz,1H), 6.95(d,J=8.2Hz,1H), 5.92(s,2H).

[0364] Intermediate 47 (I-47) [ka] 6-Bromo-2-methyl-3,4-dihydroisoquinolin-1-one (141 mg, 589 μmol), 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b (160 mg, 589 μmol), and Pd-118 (10.0 mg, 15.3 μmol) were added to a scintillation vial. The vial was flushed with N2. 1,4-Dioxane (3.00 mL) was added, followed by degassed aqueous potassium phosphate (884 μL, 2 M, 1.77 mmol). The reaction was heated to 95 °C for 2 h. The reaction was cooled to room temperature, and water (15 mL) was added, followed by extraction with DCM (3 × 10 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo. The product was purified by chromatography on silica gel (10-30% EtOAc / DCM) to give 6-(4-amino-2-chloro-5-fluorophenyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one 1-47 as a light grey solid. 1 H NMR(400MHz,DMSO-d6)δ7.87(d,J=8.0Hz,1H), 7.35(dd,J=8.0,1.8Hz,1H), 7.30(d,J=1.7Hz,1H), 7.11(d,J =11.9Hz,1H), 6.91(d,J=8.3Hz,1H), 5.63(s,2H), 3.56(t,J=6.7Hz,2H), 3.03(s,3H), 3.00(t,J=6.7Hz,2H).

[0365] Intermediate 49 (I-49) [ka] 5-Chloro-2-fluoro-4-(2-fluoropyrimidin-5-yl)aniline I-49 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 5-bromo-2-fluoropyrimidine using essentially the same procedure as for I-47. 1H NMR (400MHz, DMSO-d6) δ8.85(d,J=1.6Hz,2H), 7.32(d,J=11.9Hz,1H), 6.95(d,J=8.2Hz,1H), 5.80(s,2H).

[0366] Intermediate 50 (I-50) [ka] 4-(4-Amino-2-chloro-5-fluorophenyl)nicotinonitrile I-50 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ9.08(d,J=0.7Hz,1H), 8.87(d,J=5.2Hz,1H), 7.59(dd, J=5.2,0.8Hz,1H), 7.28(d,J=11.6Hz,1H), 6.96(d,J=8.1Hz,1H), 5.93(s,2H).

[0367] Intermediate 51 (I-51) [ka] 5-Chloro-2-fluoro-4-(6-(methylsulfonyl)pyridin-3-yl)aniline I-50 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and (6-(methylsulfonyl)pyridin-3-yl)boronic acid using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ8.81(dt,J=2.7,1.3Hz,1H), 8.19(dd,J=8.1,2.2Hz,1H), 8.0 8(dd,J=8.2,0.8Hz,1H), 7.31(d,J=11.9Hz,1H), 6.96(d,J=8.2Hz,1H), 5.84(s,2H).

[0368] Intermediate 52 (I-52) [ka] 5-Chloro-2-fluoro-4-(oxazol-2-yl)aniline I-52 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 2-bromooxazole using essentially the same procedure as for I-47. 1 H NMR (400MHz, DMSO-d6) δ8.17(d,J=0.9Hz,1H), 7.56(d,J=12.1Hz,1H), 7.33(d,J=0.8Hz,1H), 6.89(d,J=8.1Hz,1H), 6.06(s,2H).

[0369] Intermediate 53 (I-53) [ka] 5-Chloro-4-(2,5-difluoropyridin-3-yl)-2-fluoroaniline I-53 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and (2,5-difluoropyridin-3-yl)boronic acid using essentially the same procedure as for I-32. 1 H NMR (400MHz, DMSO-d6) δ8.27(dd,J=3.1,1.8Hz,1H), 7.98(td,J=7.8,3.0Hz,1H), 7.23(d,J=11.7Hz,1H), 6.92(d,J=8.2Hz,1H), 5.79(s,2H).

[0370] Intermediate 54 (I-54) [ka] Methyl 5-(4-amino-2-chloro-5-fluorophenyl)nicotinate I-54 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and methyl 5-bromonicotinate using essentially the same procedure as for I-47.1 H NMR(400MHz,DMSO-d6)δ9.04(d,J=2.0Hz,1H), 8.83(d,J=2.3Hz,1H), 8.27(t,J=2 .1Hz,1H), 7.28(d,J=11.9Hz,1H), 6.95(d,J=8.3Hz,1H), 5.75(s,2H), 3.91(s,3H)

[0371] Intermediate 55 (I-55) [ka] 5-Chloro-2-fluoro-4-(isothiazol-3-yl)aniline I-55 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 3-bromoisothiazole using essentially the same procedure as for I-47. 1 H NMR (400MHz, DMSO-d6) δ9.11(d,J=4.7Hz,1H), 7.70(d,J=4.7Hz,1H), 7.41(d,J=12.2Hz,1H), 6.89(d,J=8.2Hz,1H), 5.81(s,2H).

[0372] Intermediate 56 (I-56) [ka] 5-Chloro-2-fluoro-4-(2-(methoxymethyl)pyridin-4-yl)aniline I-56 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 3-bromo-4-(methoxymethyl)pyridine using essentially the same procedure as for I-47. 1H NMR(400MHz,DMSO-d6)δ8.55(d,J=5.1Hz,1H), 8.30(d,J=0.8Hz,1H), 7.46(dd,J=5.1,0.9Hz,1H) , 7.06(d,J=11.6Hz,1H), 6.92(d,J=8.3Hz,1H), 5.65(s,2H), 4.23(d,J=3.1Hz,2H), 3.25(s,3H).

[0373] Intermediate 57 (I-57) [ka] 5-Chloro-2-fluoro-4-(pyridin-2-yl)aniline I-57 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 2-bromopyridine using essentially the same procedure as for I-47. 1 H NMR(400MHz,DMSO-d6)δ8.62(ddd,J=4.8,1.8,1.0Hz,1H), 7.83(td,J=7.7,1.9Hz,1H), 7.65(dt,J=7.9,1 .1Hz,1H), 7.32(ddd,J=7.5,4.9,1.1Hz,1H), 7.28(d,J=12.2Hz,1H), 6.89(d,J=8.3Hz,1H), 5.70(s,2H).

[0374] Intermediate 58 (I-58) [ka] 4-(Benzo[d]isoxazol-6-yl)-5-chloro-2-fluoroaniline I-58 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 6-bromobenzo[d]isoxazole using essentially the same procedure as for I-47. 1H NMR (400MHz, DMSO-d6) δ11.06(s,1H), 7.61(d,J=8.1Hz,1H), 7.09(d,J=11.9Hz,1H), 7.01(t,J=2.2Hz,1H), 6.95~6.87(m,2H), 5.69(s,2H).

[0375] Intermediate 59 (I-59) [ka] 5-Chloro-2-fluoro-4-(imidazo[1,5-a]pyridin-6-yl)aniline I-59 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 6-bromoimidazo[1,5-a]pyridine using essentially the same procedure as for I-47. 1 H NMR (400MHz, DMSO-d6) δ8.41~8.32 (m, 2H), 7.55 (dt, J=9.4, 1.0Hz, 1H), 7.37 (s, 1H), 7 .19(d,J=11.9Hz,1H), 6.92(d,J=8.3Hz,1H), 6.81(dd,J=9.4,1.5Hz,1H), 5.63(s,2H).

[0376] Intermediate 60 (I-60) [ka] 4-(Benzo[c]isoxazol-6-yl)-5-chloro-2-fluoroaniline I-60 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 6-bromobenzo[c]isoxazole using essentially the same procedure as for I-47. 1 H NMR (400MHz, CDCl3) δ9.14(s,1H), 7.62~7.52(m,2H), 7.11(dd,J=8.9,1.4Hz,1H), 7.06(d,J=11.2Hz,1H), 6.90(d,J=8.2Hz,1H).

[0377] Intermediate 61 (I-61) [ka] 5-Chloro-2-fluoro-4-(2-methoxypyridin-4-yl)aniline I-61 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and (2-methoxypyridin-4-yl)boronic acid using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ8.17(dd,J=5.3,0.7Hz,1H), 7.16(d,J=12.0Hz,1H), 7.02(dd,J=5. 3,1.5Hz,1H), 6.90(d,J=8.3Hz,1H), 6.81(dd,J=1.5,0.7Hz,1H), 5.74(s,2H), 3.87(s,3H).

[0378] Intermediate 63 (I-63) [ka] 5-Chloro-2-fluoro-4-(2-fluoro-6-methoxypyridin-3-yl)aniline I-63 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and (2-fluoro-6-methoxypyridin-3-yl)boronic acid using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ7.79(dd,J=10.0,8.2Hz,1H), 7.10(d,J=11.8Hz,1H), 6.91(d,J=8.3Hz,1H), 6.82(dd,J=8.2,1.2Hz,1H), 5.64(s,2H), 3.87(s,3H).

[0379] Intermediate 64 (I-64) [ka] N-((4'-amino-2'-chloro-5'-fluoro-[1,1'-biphenyl]-3-yl)methyl)methanesulfonamide I-63 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methanesulfonamide using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ7.57(t,J=6.4Hz,1H), 7.38(d,J=7.5Hz,1H), 7.35(t,J=1.7Hz,1H), 7.30(ddt,J=7.2 ,3.3,1.7Hz,2H), 7.11~7.00(m,1H), 6.90(d,J=8.4Hz,1H), 5.57(s,2H), 4.19(d,J=6.3Hz,2H), 2.86(s,3H).

[0380] Intermediate 66 (I-66) [ka] 5-Chloro-2-fluoro-4-(5-fluoro-6-methoxypyridin-3-yl)aniline I-66 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and (5-fluoro-6-methoxypyridin-3-yl)boronic acid using essentially the same procedure as for I-32. 1 H NMR (400MHz, DMSO-d6) δ8.17(d,J=3.0Hz,1H), 7.62(dd,J=8.5,3.0Hz,1H), 7.08(d,J=11.8Hz,1H), 6.97~6.81(m,1H), 5.62(s,2H), 3.82(s,3H).

[0381] Intermediate 67 (I-67) [ka] 5-Chloro-4-(6-ethoxypyridin-3-yl)-2-fluoroaniline I-67 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and (6-ethoxypyridin-3-yl)boronic acid using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ8.14(dd,J=2.5,0.7Hz,1H), 7.72(dd,J=8.6,2.6Hz,1H), 7.12(d,J=11.9Hz,1H),6. 91(d,J=8.4Hz,1H), 6.83(dd,J=8.5,0.7Hz,1H), 5.58(s,2H), 4.33(q,J=7.0Hz,2H), 1.34(t,J=7.0Hz,3H).

[0382] Intermediate 68 (I-68) [ka] 5-Chloro-2-fluoro-4-(6-isopropoxypyridin-3-yl)aniline I-68 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and (6-isopropoxypyridin-3-yl)boronic acid using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ8.13(dd,J=2.6,0.8Hz,1H), 7.70(dd,J=8.6,2.6Hz,1H), 7.12(d,J=11.9Hz,1H), 6.9 1(d,J=8.4Hz,1H), 6.77(dd,J=8.6,0.7Hz,1H), 5.58(s,2H), 5.27(septet, J=6.2Hz,1H), 1.31(d,J=6.2Hz,6H).

[0383] Intermediate 69 (I-69) [ka] 4-(Benzo[c][1,2,5]oxadiazol-4-yl)-5-chloro-2-fluoroaniline I-69 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 4-bromobenzo[c][1,2,5]oxadiazole using essentially the same procedure as for I-47. 1 H NMR(400MHz,DMSO-d6)δ8.03(dd,J=9.1,0.8Hz,1H), 7.68(dd,J=9.0,6.7Hz,1H),7.5 4(dd,J=6.7,0.8Hz,1H), 7.33(d,J=11.9Hz,1H), 6.97(d,J=8.3Hz,1H), 5.82(s,2H).

[0384] Intermediate 70 (I-70) [ka] 5-Chloro-2-fluoro-4-(5-methoxypyridin-2-yl)aniline I-70 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 2-bromo-5-methoxypyridine using essentially the same procedure as for I-47. 1 H NMR(400MHz,DMSO-d6)δ8.34(dd,J=4.3,2.8Hz,1H), 7.66~7.55(m,1H), 7.44(dd,J=8. 7,3.0Hz,1H), 7.23(d,J=12.2Hz,1H), 6.88(d,J=8.3Hz,1H), 5.63(s,2H), 3.87(s,3H).

[0385] Intermediate 71 (I-71) [ka] 2-Fluoro-4-(6-fluoropyridin-3-yl)-5-(trifluoromethyl)aniline I-71 was synthesized from 4-bromo-2-fluoro-5-(trifluoromethyl)aniline I-71a and (6-fluoropyridin-3-yl)boronic acid using essentially the same procedure as for I-32. 1 H NMR (400MHz, DMSO-d6) δ8.13(d,J=2.5Hz,1H), 7.90(td,J=8.3,2.6Hz,1H), 7.23(dd,J=8.5,2.8Hz,2H), 7.16(d,J=11.6Hz,1H), 5.82(s,2H).

[0386] Intermediate 74 (I-74) [ka] 2-Fluoro-4-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)aniline I-74 was synthesized from 4-bromo-2-fluoro-5-(trifluoromethyl)aniline I-71a and (6-methoxypyridin-3-yl)boronic acid using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ8.04(d,J=2.5Hz,1H), 7.60(dd,J=8.4,2.5Hz,1H), 7.22(d,J=8. 7Hz,1H), 7.08(d,J=11.8Hz,1H), 6.84(dd,J=8.4,0.8Hz,1H), 5.74(s,2H), 3.88(s,3H).

[0387] Intermediate 75 (I-75) [ka]

[0388] Step 1: A solution of 5-bromo-2-fluoropyridine (117 μl, 1.14 mmol) and trifluoroethanol (330 μl, 4.55 mmol) in THF (2.5 ml) was treated with KO in THF. tA solution of Bu (2.75 ml, 20% w / w, 4.55 mmol) was added. The reaction was stirred at room temperature for 24 h and then partitioned between DCM (25 ml) and water (25 ml). The aqueous phase was extracted with additional DCM (25 ml). The organics were combined, washed with water (2 x 50 ml) and brine (50 ml), and dried over magnesium sulfate. The filtrate was concentrated in vacuo to give 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine I-75a as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ8.35(dd,J=2.5,0.7Hz,1H), 8.02(dd,J=8.8,2.6Hz,1H), 7.01(dd,J=8.8,0.7Hz,1H), 4.98(q,J=9.0Hz,2H).

[0389] Step 2: 5-Chloro-2-fluoro-4-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)aniline I-75 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine I-75a using essentially the same procedure as for I-47. LCMS (Method 2) m / z 321.3, 323.3 (M+H) at 2.15 min + (ES + )

[0390] Alternative Synthesis of Intermediate 75 (I-75) [ka] To a solution of 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 (15.0 g, 59.2 mmol) and trifluoroethanol (17.2 ml, 237 mmol) in THF (100 ml) at 0 °C was added KO tA solution of Bu (143 ml, 20% w / w, 237 mmol) was added. The reaction was allowed to warm to room temperature for 24 h. Water (200 ml) was added and the layers were separated. The organics were washed with more water (200 ml) and separated. The aqueous phase was extracted with more DCM (3 x 200 ml). The combined organics were dried over Na2SO4 and concentrated in vacuo. The product was purified by chromatography on silica gel (0-30% EtOAc / isohexane) to give 5-chloro-2-fluoro-4-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)aniline I-75 as an orange oil. 1 H NMR(400MHz,DMSO-d6)δ8.19(dd,J=2.5,0.8Hz,1H), 7.83(dd,J=8.6,2.5Hz,1H), 7.15(d,J=11. 9Hz,1H), 7.03(dd,J=8.5,0.8Hz,1H), 6.92(d,J=8.3Hz,1H), 5.63(s,2H), 5.02(q,J=9.1Hz,2H),

[0391] Intermediate 76 (I-76) [ka]

[0392] Step 1: 5-Bromo-2-cyclobutoxypyridine I-76a was synthesized from 5-bromo-2-fluoropyridine and cyclobutanol using essentially the same procedure as for I-75a. LCMS (Method 2) m / z 228.2, 230.3 (M+H) at 2.14 min + (ES + )

[0393] Step 2: 5-Chloro-4-(6-cyclobutoxypyridin-3-yl)-2-fluoroaniline I-76 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 5-bromo-2-cyclobutoxypyridine I-76a using essentially the same procedure as for I-47. LCMS (Method 2) m / z 293.3, 295.3 (M+H) at 2.16 min + (ES + )

[0394] Intermediate 77 (I-77) [ka] 5-Chloro-2-fluoro-4-(2-isopropoxypyridin-4-yl)aniline I-77 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and 2-(isopropoxy)pyridine-4-boronic acid I-77a using essentially the same procedure as for I-32. LCMS (Method 2) m / z 281.7, 283.7 (M+H) at 1.95 min + (ES + )

[0395] Intermediate 79 (I-79) [ka]

[0396] Step 1: To a mixture of sodium hydride (145 mg, 60% w / w, 3.64 mmol) in THF (10 ml) was added a suspension cooled to 0 °C. To this was added cyclopropanol (0.216 ml, 3.41 mmol), and the resulting suspension was stirred at 0 °C for 30 min, followed by the addition of 5-bromo-2-fluoropyridine (234 μl, 2.27 mmol). The resulting mixture was allowed to warm to room temperature for 6 h. Water (10 ml) was added. The reaction mixture was diluted with a 1:1 mixture of NaCl:aqueous NaHCO3 (25 ml). The product was extracted with DCM (2 × 25 ml), and the combined organics were concentrated in vacuo. The product was purified by chromatography on silica gel (0–50% EtOAc / isohexane) to afford 5-bromo-2-cyclopropoxypyridine I-79a as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ8.32(dd,J=2.6,0.7Hz,1H), 7.92(dd,J=8.8,2.6Hz,1H), 6.87(dd,J=8.8,0 .7Hz,1H), 4.16(tt,J=6.3,3.1Hz,1H), 0.80~0.73(m,2H), 0.66(dddd,J=6.2,4.6,3.1,0.8Hz,2H).

[0397] Step 2: 5-Bromo-2-cyclopropoxypyridine I-79a (186 mg, 869 μmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (287 mg, 1.13 mmol) were dissolved in a solution of potassium 2-ethylhexanoate in iPrOAc (2.00 mL, 0.5 M, 1.0 mmol). The resulting solution was sparged with N, and then Pd-170 (29.3 mg, 43.4 μmol) was added. The reaction mixture was heated to 50 °C for 50 min. After allowing the reaction mixture to cool to room temperature for 30 min, 4-bromo-5-chloro-2-fluoroaniline (195 mg, 869 μmol) and a degassed solution of KCO in water (1.16 mL, 1.5 M, 1.74 mmol) were added. The reaction mixture was heated to 50° C. for 3.5 hours. The reaction mixture was partitioned between brine (25 ml) and DCM (25 ml). The aqueous was extracted with DCM (25 ml) and the combined organics were concentrated in vacuo. The product was purified by chromatography on silica gel (0-15% (0.7 M ammonia / MeOH) / DCM) to give 5-chloro-4-(6-cyclopropoxypyridin-3-yl)-2-fluoroaniline I-79 as a pale yellow oil. 1 H NMR(400MHz,DMSO-d6)δ8.18(dd,J=2.5,0.7Hz,1H), 7.75(dd,J=8.5,2.5Hz,1H), 7.13(d,J=11.9Hz,1 H), 6.96~6.85(m,2H), 5.60(s,2H), 4.22(tt,J=6.3,3.1Hz,1H), 0.81~0.71(m,2H), 0.74~0.63(m,2H).

[0398] Intermediate 80 (I-80) [ka] To a solution of (5-fluoropyridin-3-yl)boronic acid (170 mg, 1.21 mmol), 5-bromo-4-chloropyridin-2-amine I-80a (250 mg, 1.21 mmol), and Pd-118 (23.6 mg, 36.2 μmol) in pre-degassed 1,4-dioxane (8.00 mL) was added a pre-degassed aqueous solution of potassium phosphate tribasic (1.81 mL, 2.0 M, 3.62 mmol). The resulting mixture was heated to 95 °C for 8 h. The reaction was cooled to room temperature, saturated aqueous NaHCO (20 mL) was added, and the product was extracted with DCM (3 × 10 mL). The combined organics were passed through a hydrophobic frit, and the filtrate was concentrated in vacuo. The product was purified by chromatography on silica gel (0-80% EtOAc / DCM) to give 4-chloro-5'-fluoro-[3,3'-bipyridine]-6-amine as a light brown solid. LCMS (Method 2) m / z 224.2, 226.2 (M+H) at 0.91 min. + (ES + ).

[0399] Intermediate 81 (I-81) [ka] 4-Chloro-6'-fluoro-[3,3'-bipyridine]-6-amine I-81 was synthesized from 5-bromo-4-chloropyridin-2-amine I-80a and (6-fluoropyridin-3-yl)boronic acid using essentially the same procedure as for I-80. LCMS (Method 2) m / z 224.2, 226.2 (M+H) at 0.90 min + (ES + )

[0400] Intermediate 82 (I-82) [ka] 5-Chloro-2-fluoro-4-(2-methylbenzo[d]oxazol-5-yl)aniline I-82 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ7.72~7.58(m,2H), 7.32(dd,J=8.4,1.8Hz,1H), 7.11(d,J=11.9Hz,1H), 6.91(d,J=8.4Hz,1H), 5.55(s,2H), 2.62(s,3H)

[0401] Intermediate 83 (I-83) [ka] 5-(Benzo[c][1,2,5]oxadiazol-5-yl)-4-chloropyridin-2-amine I-83 was synthesized from 5-bromo-4-chloropyridin-2-amine I-80a and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole using essentially the same procedure as for I-80. 1 H NMR (400MHz, DMSO-d6) δ8.11~8.06(m,2H), 8.04(t,J=1.2Hz,1H), 7.68(dd,J=9.3,1.4Hz,1H), 6.65(s,1H), 6.60(s,2H).

[0402] Intermediate 84 (I-84) [ka] 2,5-Difluoro-4-(6-fluoropyridin-3-yl)aniline I-84 was synthesized from 4-bromo-2,5-difluoro-phenylamine I-84a and (6-fluoropyridin-3-yl)boronic acid using essentially the same procedure as for I-32. 1H NMR (400MHz, DMSO-d6) δ8.35~8.30(m,1H), 8.12~8.03(m,1H), 7.36~7.20(m,2H), 6.65(dd,J=12.6,7.6Hz,1H), 5.73(s,2H).

[0403] Intermediate 85 (I-85) [ka] 2,5-Difluoro-4-(6-methoxypyridin-3-yl)aniline I-85 was synthesized from 4-bromo-2,5-difluoro-phenylamine I-84a and (6-methoxypyridin-3-yl)boronic acid using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ8.28~8.23(m,1H), 7.80(ddd,J=8.6,2.6,1.5Hz,1H), 7.22(dd,J=12.0, 7.3Hz,1H), 6.86(dd,J=8.6,0.8Hz,1H), 6.62(dd,J=12.6,7.7Hz,1H), 5.60(s,2H), 3.87(s,3H)

[0404] Intermediate 87 (I-87) [ka] 5-(Benzo[c][1,2,5]oxadiazol-5-yl)-2-fluoro-4-(trifluoromethyl)aniline I-87 was synthesized from 5-bromo-2-fluoro-4-(trifluoromethyl)aniline I-87a and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole using essentially the same procedure as for I-32. 1 H NMR (400MHz, DMSO-d6) δ8.10(dd,J=9.3,1.1Hz,1H), 7.99(d,J=1.3Hz,1H), 7.57~7.45(m,2H), 6.77(d,J=8.6Hz,1H), 6.16(s,2H).

[0405] Intermediate 88 (I-88) [ka] 2-Fluoro-5-(5-fluoropyridin-3-yl)-4-(trifluoromethyl)aniline I-88 was synthesized from 5-bromo-2-fluoro-4-(trifluoromethyl)aniline I-87a and (5-fluoropyridin-3-yl)boronic acid using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ8.64(d,J=2.7Hz,1H), 8.37(d,J=1.9Hz,1H), 7.75(dt, J=9.6,2.3Hz,1H), 7.49(d,J=12.0Hz,1H), 6.71(d,J=8.6Hz,1H), 6.13(s,2H).

[0406] Intermediate 89 (I-89) [ka] 4-Fluoro-6-(trifluoromethyl)-[1,1′-biphenyl]-3-amine I-89 was synthesized from 5-bromo-2-fluoro-4-(trifluoromethyl)aniline I-87a and 4,4,5-trimethyl-2-phenyl-1,3,2-dioxaborolane using essentially the same procedure as for I-32. 1 H NMR (400MHz, DMSO-d6) δ7.46~7.33(m,4H), 7.31~7.19(m,2H), 6.65(d,J=8.8Hz,1H), 5.99(s,2H).

[0407] Intermediate 90 (I-90) [ka] 5-Chloro-4-(5,6-difluoropyridin-3-yl)-2-fluoroaniline I-90 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and (5,6-difluoropyridin-3-yl)boronic acid using essentially the same procedure as for I-32. 1 H NMR (400MHz, DMSO-d6) δ8.14(ddd,J=10.8,9.3,2.1Hz,1H), 8.08(t,J=1.9Hz,1H), 7.24(d,J=11.9Hz,1H), 6.93(d,J=8.3Hz,1H), 5.76(s,2H).

[0408] Intermediate 91 (I-91) [ka] 5-Chloro-2-fluoro-4-(2-fluoropyridin-4-yl)aniline I-91 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and 5-chloro-2-fluoro-4-(2-fluoropyridin-4-yl)aniline using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ8.25(d,J=5.2Hz,1H), 7.42(ddd,J=5.3,2.1,1.4Hz,1H), 7.27(d,J=12.0Hz,1H), 7.23(q,J=1.2Hz,1H), 6.92(d,J=8.2Hz,1H), 5.87(s,2H)

[0409] Intermediate 92 (I-92) [ka]

[0410] Step 1: 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline I-92b was synthesized from 4-bromo-2-fluoro-5-(trifluoromethyl)aniline I-92a using essentially the same procedure as for I-8b. 1H NMR (400MHz, DMSO-d6) δ7.28(d,J=11.8Hz,1H), 7.14(dd,J=8.4,6.5Hz,1H), 5.97(s,2H), 1.25(s,12H).

[0411] Step 2: 4-([1,2,5]oxadiazolo[3,4-b]pyridin-6-yl)-2-fluoro-5-(trifluoromethyl)aniline I-92 was synthesized from 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline I-92b and 6-bromo-[1,2,5]oxadiazolo[3,4-b]pyridine using essentially the same procedure as for I-47. 1 H NMR(400MHz,DMSO-d6)δ9.01(dd,J=2.1,0.9Hz,1H), 8.54(d,J=2.1Hz,1H), 7.38(d,J=11.8Hz,1H), 7.29(d,J=8.5Hz,1H), 6.05(s,2H)

[0412] Intermediate 93 (I-93) [ka] 4-(Benzo[c]isothiazol-6-yl)-5-chloro-2-fluoroaniline I-93 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c]isothiazole using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ9.78(d,J=1.1Hz,1H), 7.95~7.86(m,1H), 7.73(d,J=1.8Hz,1H), 7.32(dd,J=8.9,1.5Hz,1H), 7.22(d,J=11.9Hz,1H), 6.93(d,J=8.3Hz,1H), 5.67(s,2H).

[0413] Intermediate 94 (I-94) [ka] To a stirred solution of 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b (250 mg, 921 μmol) in 1,4-dioxane (4.00 mL) and water (1.00 mL) was added potassium carbonate (191 mg, 1.38 mmol) and 2-bromopyrazine (100 μL, 1.10 mmol). The reaction mixture was sparged with N for 5 minutes, after which Pd(dppf) (75.2 mg, 92.1 μmol) was added. The reaction mixture was heated at 90° C. for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was diluted with EtOAc. The reaction mixture was diluted with water (25 mL), and the layers were separated. The organics were washed with brine (25 mL), dried over MgSO, and concentrated in vacuo. The product was purified by chromatography on silica gel (10-100% EtOAc / DCM) to afford 5-chloro-2-fluoro-4-(pyrazin-2-yl)aniline I-94 as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.90(d,J=1.6Hz,1H), 8.70(dd,J=2.6,1.6Hz,1H), 8.5 7(d,J=2.5Hz,1H), 7.36(d,J=12.0Hz,1H), 6.92(d,J=8.1Hz,1H), 5.87(s,2H).

[0414] Intermediate 95 (I-95) [ka]

[0415] Step 1: To a solution of 5-bromo-2-fluoropyridine (200 mg, 1.14 mmol) and oxetan-3-ol (299 μl, 4.55 mmol) in THF (2.50 ml) was added KO in THF. tA solution of Bu (2.75 mL, 20% w / w, 4.55 mmol) was added. The reaction was stirred at room temperature for 24 h. The reaction mixture was diluted with DCM (25 ml) and water (25 ml) and the layers were separated. The aqueous phase was extracted with DCM (25 ml). The combined organics were washed with water (2 x 50 ml) and brine (50 ml) and dried over MgSO4. The organics were concentrated in vacuo to give 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine I-94a as a colorless oil. LCMS (Method 2) at 1.56 min: m / z 229.7, 231.7 (M+H) + (ES + ).

[0416] Step 2: 5-Chloro-2-fluoro-4-(6-(oxetan-3-yloxy)pyridin-3-yl)aniline I-94 was synthesized from 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine I-94a and 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b using essentially the same procedure as for I-47. LCMS (Method 2) m / z 295.3, 297.3 (M+H) at 1.73 min + (ES + ).

[0417] Intermediate 96 (I-96) [ka] 4-([1,2,5]thiadiazolo[3,4-b]pyridin-6-yl)-5-chloro-2-fluoroaniline I-95 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 6-bromo-[1,2,5]thiadiazolo[3,4-b]pyridine using essentially the same procedure as for I-47. 1H NMR(400MHz,DMSO-d6)δ9.18(d,J=2.3Hz,1H), 8.54(d,J=2.3Hz,1H), 7.41(d,J=11.9Hz,1H), 6.99(d,J=8.2Hz,1H), 5.84(s,2H)

[0418] Intermediate 97 (I-97) [ka] 5-Chloro-2-fluoro-4-(6-(methoxymethyl)pyridin-3-yl)aniline I-97 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 5-bromo-2-(methoxymethyl)pyridine using essentially the same procedure as for I-47. 1 H NMR(400MHz,DMSO-d6)δ8.52(d,J=2.2Hz,1H), 7.83(dd,J=8.1,2.3Hz,1H), 7.44(d,J=8.0Hz ,1H), 7.17(d,J=11.9Hz,1H), 6.93(d,J=8.3Hz,1H), 5.66(s,2H), 4.52(s,2H), 3.39(s,3H).

[0419] Intermediate 98 (I-98) [ka] 5-Chloro-2-fluoro-4-(5-(methoxymethyl)pyridin-3-yl)aniline I-98 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and (5-(methoxymethyl)pyridin-3-yl)boronic acid using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ8.51(d,J=2.2Hz,1H), 8.48(d,J=2.0Hz,1H), 7.74(t,J=2.2Hz,1 H), 7.18(d,J=11.9Hz,1H), 6.93(d,J=8.3Hz,1H), 5.67(s,2H), 4.49(s,2H), 3.33(s,3H).

[0420] Intermediate 99 (I-99) [ka] 5-Chloro-2-fluoro-4-(2-methoxypyrimidin-5-yl)aniline I-99 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 5-bromo-2-methoxypyrimidine using essentially the same procedure as for I-47. 1 H NMR(400MHz,DMSO-d6)δ8.63(s,2H), 7.23(d,J=12.0Hz,1H), 6.93(d,J=8.3Hz,1H), 5.69(s,2H), 3.95(s,3H)

[0421] Intermediate 100 (I-100) [ka] 5-Chloro-2-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline I-100 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ8.28(d,J=4.9Hz,1H), 7.53(d,J=3.5Hz,1H), 7.13(d,J=11.8Hz,1H), 7.03(d,J=4.9Hz,1H), 6.96(d,J=8.3Hz,1H), 6.26(d,J=3.5Hz,1H), 5.69(s,2H), 3.84(s,3H).

[0422] Intermediate 101 (I-101) [ka]

[0423] Step 1: To a solution of 1-chloro-2,4-difluoro-5-nitrobenzene I-101a (580 mg, 3.00 mmol) and benzo[c][1,2,5]oxadiazol-5-ol I-101b (410 mg, 3.02 mmol) in MeCN (20 mL) was added KCO (1.24 g, 8.98 mmol). The reaction was stirred at room temperature for 3 h. After diluting the reaction mixture with water (5 mL), the product was extracted with DCM (3 × 10 mL). The combined organics were concentrated in vacuo. The product was purified by chromatography on silica gel (3% EtOAc / petroleum ether) to give 5-(4-chloro-5-fluoro-2-nitrophenoxy)benzo[c][1,2,5]oxadiazole I-101c as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.60(d,J=7.6Hz,1H), 8.19(d,J=9.6Hz,1H), 7.88(d,J=10.4Hz,1H), 7.59(dd,J=2.0,9.6Hz,1H), 7.53~7.50(m,1H)

[0424] Step 2: To a solution of 5-(4-chloro-5-fluoro-2-nitrophenoxy)benzo[c][1,2,5]oxadiazole I-101c (70 mg, 0.23 mmol) in EtOH (2 mL) was added saturated aqueous NH4Cl (1 mL) and Fe (50 mg, 0.90 mmol). The reaction was stirred at 80 °C for 30 min. The reaction mixture was cooled, filtered, and diluted with water (5 mL). The product was extracted with DCM (3 × 10 mL). The combined organics were concentrated in vacuo. The product was purified by preparative TLC (25% EtOAc / petroleum ether) to give 2-(benzo[c][1,2,5]oxadiazol-5-yloxy)-5-chloro-4-fluoroaniline I-101 as a yellow solid. LCMS (Method 5) m / z 279.9, 281.9 (M+H) at 1.78 min. + (ES + )

[0425] Intermediate 102 (I-102) [ka]

[0426] Step 1: To a solution of 1-chloro-4-fluoro-2-methyl-5-nitrobenzene I-102a (3 g, 15.8 mmol) in CCl4 (60 mL) was added AIBN (260 mg, 1.58 mmol) and NBS (3.1 g, 17.38 mmol) at room temperature. The mixture was heated at 80 °C for 16 h. The reaction mixture was concentrated in vacuo. The product was purified by chromatography on silica gel (1% EtOAc / petroleum ether) to give 1-(bromomethyl)-2-chloro-5-fluoro-4-nitrobenzene I-102b as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ8.32 (d, J = 6.8 Hz, 1H), 7.95 (d, J = 11.6 Hz, 1H), 4.75 (s, 2H).

[0427] Step 2: To a solution of 1-(bromomethyl)-2-chloro-5-fluoro-4-nitrobenzene I-102b (2 g, 5.61 mmol) in MeCN (45 ml) was added KCO (2.33 g, 16.83 mmol) and phenol (528 mg, 5.61 mmol). After stirring at room temperature for 2 h, the mixture was diluted with water (10 ml). The product was extracted with DCM (3 × 30 ml). The combined organics were dried over NaSO and concentrated in vacuo. The product was purified by chromatography on silica gel (2% EtOAc / petroleum ether) to give 1-chloro-4-fluoro-5-nitro-2-(phenoxymethyl)benzene I-102c as a pale yellow solid. LCMS (Method 1) m / z 282 (M+H) at 1.76 min + (ES + ).

[0428] Step 3: To a solution of 1-chloro-4-fluoro-5-nitro-2-(phenoxymethyl)benzene I-102c (200 mg, 0.71 mmol) in EtOH (4 mL) was added a solution of NH4Cl (305 mg, 5.68 mmol) in water (2 mL) and Fe (200 mg, 3.55 mmol) at room temperature. After stirring at 70 °C for 2 h, the reaction mixture was quenched with water (10 mL) and the product was extracted with DCM (3 × 30 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo. The product was purified by chromatography on silica gel (2.5% EtOAc / petroleum ether) to give 5-chloro-2-fluoro-4-(phenoxymethyl)aniline as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.29~7.27(m,3H), 6.99~6.83(m,4H), 5.54(s,2H), 4.93(s,2H).

[0429] Intermediate 103 (I-103) [ka]

[0430] Step 1: To a solution of 2-chloro-5-fluorophenol I-103a (200 mg, 1.37 mmol) in EtOH (5 mL) was added Fe(NO3)3·9H2O (553 mg, 1.37 mmol). The solution was stirred at 85 °C for 4 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The product was purified by preparative TLC (50% EtOAc / petroleum ether) to give 2-chloro-5-fluoro-4-nitrophenol I-103b as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.20 (d, J = 8.0Hz, 1H), 7.63~7.60 (m, 1H), 6.94~6.90 (m, 1H).

[0431] Step 2: To a solution of 2-chloro-5-fluoro-4-nitrophenol I-103b (163 mg, 0.85 mmol) in MeCN (4 ml) was added benzyl bromide (145 mg, 0.85 mmol) and K2CO3 (352 mg, 2.55 mmol). The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was cooled, diluted with water (20 ml), and the product was extracted with DCM (3 × 20 ml). The combined organics were dried over Na2SO4 and concentrated in vacuo. The product was purified by preparative TLC (10% EtOAc / petroleum ether) to give 1-(benzyloxy)-2-chloro-5-fluoro-4-nitrobenzene I-103c as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ8.32(d,J=8.0Hz,1H), 7.58(d,J=13.2Hz,1H), 7.50~7.36(m,5H), 5.37(s,2H).

[0432] Step 3: 4-(Benzyloxy)-5-chloro-2-fluoroaniline I-103 was synthesized from 1-(benzyloxy)-2-chloro-5-fluoro-4-nitrobenzene I-103c using essentially the same procedure as for I-101. LCMS (Method 5) m / z 252.1 (M+H) at 1.68 min + (ES + )

[0433] Intermediate 105 (I-105) [ka] 2,5-Difluoro-4-(6-(trifluoromethyl)pyridin-3-yl)aniline I-105 was synthesized from 4-bromo-2,5-difluoroaniline and (6-(trifluoromethyl)pyridin-3-yl)boronic acid using essentially the same procedure as for I-32. 1H NMR (400 MHz, CDCl) δ 8.83 (s, 1H), 8.01–7.94 (m, 1H), 7.72 (dd, J = 8.2, 0.9 Hz, 1H), 7.11 (dd, J = 11.1, 6.8 Hz, 1H), 6.61 (dd, J = 11.5, 7.4 Hz, 1H), no two exchangeable protons observed.

[0434] Intermediate 106 (I-106) [ka] To a suspension of sodium hydride (80 mg, 60% w / w, 1.99 mmol) in THF (8 ml) at 0 °C, 2-fluoroethan-1-ol (110 μl, 1.87 mmol) was added, and the resulting mixture was stirred at 0 °C for 45 min before the addition of 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 (300 mg, 1.25 mmol). The reaction mixture was allowed to warm to room temperature for 20 h. The reaction mixture was partitioned between brine (25 ml) and DCM (25 ml), and the layers were separated. The aqueous was extracted with DCM (25 ml). The combined organics were concentrated in vacuo. The product was purified by chromatography on silica gel (0–35% EtOAc / isohexane) to give 5-chloro-2-fluoro-4-(6-(2-fluoroethoxy)pyridin-3-yl)aniline I-106 as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ8.14(dd,J=2.5,0.7Hz,1H), 7.76(dd,J=8.6,2.5Hz,1H), 7.13(d,J=11.9Hz,1H), 6.92~6.92 (m,1H), 6.91~6.89(m,1H), 5.61(s,2H), 4.85~4.79(m,1H), 4.72~4.68(m,1H), 4.59~4.54(m,1H), 4.52~4.46(m,1H).

[0435] Intermediate 107 (I-107) [ka] 5-Chloro-4-(6-(3,3-difluorocyclobutoxy)pyridin-3-yl)-2-fluoroaniline I-107 was synthesized from 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 and 3,3-difluorocyclobutan-1-ol using essentially the same procedure as for I-106. 1 H NMR(400MHz,DMSO-d6)δ8.15(dd,J=2.5,0.7Hz,1H), 7.77(dd,J=8.6,2.5Hz,1H), 7.12(d,J=11.9Hz) ,1H), 6.94~6.86(m,2H), 5.61(s,2H), 5.14(t,J=6.4Hz,1H), 3.26~3.08(m,2H), 2.83~2.64(m,2H).

[0436] Intermediate 108 (I-108) [ka] 5-Chloro-2-fluoro-4-(3-methoxypyridin-4-yl)aniline I-108 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and (3-methoxypyridin-4-yl)boronic acid using essentially the same procedure as for I-32. 1 H NMR (400 MHz, CDCl) δ 8.36 (s, 1H), 8.30 (d, J = 4.9 Hz, 1H), 7.20 (d, J = 4.8 Hz, 1H), 6.94 (d, J = 11.1 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 3.90 (s, 3H). Two exchangeable protons were not observed.

[0437] Intermediate 110 (I-110) [ka]

[0438] Step 1: To a solution of 1-(bromomethyl)-2-chloro-5-fluoro-4-nitrobenzene I-102b (236 mg, 0.88 mmol) in MeCN (3 ml) was added KCO (367 mg, 2.65 mmol) and 6-fluoropyridin-3-ol (100 mg, 0.88 mmol). After stirring at room temperature for 2 h, the reaction was diluted with water (10 ml). The product was extracted with DCM (3 × 30 ml), and the combined organics were dried over NaSO and concentrated in vacuo. The product was purified by preparative TLC (20% EtOAc / petroleum ether) to give 5-((2-chloro-5-fluoro-4-nitrobenzyl)oxy)-2-fluoropyridine I-110-a as a pale yellow solid. LCMS (Method 5) m / z 301.0 (M+H) at 1.52 min + (ES + ).

[0439] Step 2: To a solution of 5-((2-chloro-5-fluoro-4-nitrobenzyl)oxy)-2-fluoropyridine I-110-a (100 mg, 0.33 mmol) in EtOH (4 ml) was added Fe (94 mg, 1.66 mmol) and a solution of NH4Cl (144 mg, 2.66 mmol) in water (2 ml) at room temperature. After stirring at 70 °C for 2 h, the reaction was diluted with water (10 ml). The product was extracted with DCM (3 × 30 ml). The combined organics were dried over Na2SO4 and concentrated in vacuo. The product was purified by chromatography on silica gel (20% EtOAc / petroleum ether) to give 5-chloro-2-fluoro-4-(((6-fluoropyridin-3-yl)oxy)methyl)aniline I-110 as a white solid. 1 H NMR(400MHz,DMSO-d6)δ7.95(s,1H), 7.68~7.64(m,1H), 7.26(d,J=7.6Hz,1H) , 7.12(dd,J=9.2,3.6Hz,1H), 6.84(d,J=8.0Hz,1H), 5.60(s,2H), 5.00(s,2H).

[0440] Intermediate 111 (I-111) [ka]

[0441] Step 1: To a solution of 1-chloro-2,4-difluoro-5-nitrobenzene I-101b (159 mg, 0.82 mmol) and benzo[c][1,2,5]oxadiazol-5-ol I-101a (112 mg, 0.82 mmol) in MeCN (10 mL) was added KCO (341 mg, 2.47 mmol). The reaction was stirred at room temperature for 3 h. The reaction mixture was diluted with water (5 mL), and the product was extracted with DCM (3 × 10 mL). The combined organics were concentrated in vacuo, and the product was purified by chromatography on silica gel (3% EtOAc / petroleum ether) to give 5-(2-chloro-5-fluoro-4-nitrophenoxy)benzo[c][1,2,5]oxadiazole I-111a as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.56(d,J=7.6Hz,1H), 8.24~8.21(m,1H), 7.76(dd,J=9.6,2.0Hz,1H), 7.63~7.59(m,2H).

[0442] Step 2: To a solution of 5-(2-chloro-5-fluoro-4-nitrophenoxy)benzo[c][1,2,5]oxadiazole I-111a (130 mg 0.42 mmol) in EtOH (4 mL) was added a saturated aqueous solution of NH4Cl (2 mL) and Fe (94 mg, 1.68 mmol). The reaction was stirred at 80 °C for 30 min. After the reaction mixture was filtered and diluted with water (5 mL), the product was extracted with DCM (3 × 10 mL). The combined organics were concentrated in vacuo, and the product was purified by preparative TLC (25% EtOAc / petroleum ether) to give 4-(benzo[c][1,2,5]oxadiazol-5-yloxy)-5-chloro-2-fluoroaniline I-111 as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.12(d,J=9.6Hz,1H), 7.53(dd,J=9.6,2.0Hz,1H), 7.2 8(d,J=11.6Hz,1H), 6.97(d,J=8.8Hz,1H), 6.84(t,J=0.8Hz,1H), 5.54(s,2H).

[0443] Intermediate 113 (I-113) [ka]

[0444] Step 1: To a solution of methyl 4-bromo-2-chloro-5-fluorobenzoate I-113a (400 mg, 1.49 mmol) in THF (3 ml) was added a solution of DIBAL in hexane (3.8 ml, 1 M, 3.80 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. Water (15 ml) was added, and the product was extracted with EtOAc (3 × 15 ml). The combined organics were washed with brine (15 ml), dried over NaSO, and concentrated in vacuo to give (4-bromo-2-chloro-5-fluorophenyl)methanol I-113b as a white solid. 1 H NMR (400MHz, DMSO-d6): δppm: 7.84 (d, J = 6.0 Hz, 1H), 7.44 (d, J = 9.6 Hz, 1H), 5.63 (t, J = 5.2 Hz, 1H), 4.50 (d, J = 4.8 Hz, 2H).

[0445] Step 2: To a solution of benzo[c][1,2,5]oxadiazol-5-ol (227 mg, 1.67 mmol), (4-bromo-2-chloro-5-fluorophenyl)methanol I-113b (400 mg, 1.67 mmol), and triphenylphosphine (879 mg, 3.34 mmol) in THF (20 mL) at 0 °C, DIAD (674 mg, 3.34 mmol) was added. The reaction was stirred at room temperature for 16 h. Water (40 mL) was added, and the product was extracted with EtOAc (3 × 40 mL). The combined organics were washed with brine (40 mL), dried over NaSO, and concentrated in vacuo. The product was purified by chromatography on silica gel (20% EtOAc / petroleum ether) to give 5-((4-bromo-2-chloro-5-fluorobenzyl)oxy)benzo[c][1,2,5]oxadiazole 113-c as a white solid. 1H NMR (400MHz, DMSO-d6) δ8.00~7.97(m,2H), 7.75(d,J=9.2Hz,1H), 7.41~7.38(m,2H), 5.29(s,2H).

[0446] Step 3: To a solution of 5-((4-bromo-2-chloro-5-fluorobenzyl)oxy)benzo[c][1,2,5]oxadiazole 113c (300 mg, 0.84 mmol), diphenylmethanimine (152 mg, 0.84 mmol), Pd(OAc) (19 mg, 0.084 mmol), and BINAP (53 mg, 0.084 mmol) in 1,4-dioxane (10 ml), CsCO (819 mg, 2.52 mmol) was added. The reaction was stirred at 100 °C for 16 h. The reaction was cooled to room temperature. Water (20 ml) was added, and the product was extracted with EtOAc (3 × 20 ml). The combined organics were washed with brine (20 ml), dried over NaSO, and concentrated in vacuo. The product was purified by chromatography on silica gel (20% EtOAc / petroleum ether) to give N-(4-((benzo[c][1,2,5]oxadiazol-5-yloxy)methyl)-5-chloro-2-fluorophenyl)-1,1-diphenylmethanimine 113-d as a white solid. 1 H NMR(400MHz,DMSO-d6)δ7.98(d,J=9.6Hz,1H), 7.70~7.67(m,2H), 7.61~7.57(m,1H), 7.5 2~7.46(m,3H), 7.41~7.34(m,5H), 7.23~7.20(m,2H), 7.10(d,J=7.2Hz,1H), 5.14(s,2H).

[0447] Step 4: To a solution of N-(4-((benzo[c][1,2,5]oxadiazol-5-yloxy)methyl)-5-chloro-2-fluorophenyl)-1,1-diphenylmethanimine 113-d (150 mg, 0.33 mmol) in 1,4-dioxane (2 ml), 4 M HCl in 1,4-dioxane (2 ml, 8 mmol) was added. The reaction was stirred at room temperature for 2 h. The reaction mixture was basified to pH = 8 by addition of saturated aqueous NaHCO3, and the product was extracted with EtOAc (3 x 10 ml). The combined organics were washed with brine (20 ml), dried over Na2SO4, and concentrated in vacuo to give 4-((benzo[c][1,2,5]oxadiazol-5-yloxy)methyl)-5-chloro-2-fluoroaniline I-113 as a yellow solid. LCMS (Method 5) at 1.45 min, m / z 294.0 (M+H) + (ES + ).

[0448] Intermediate 114 (I-114) [ka] 5-Chloro-2-fluoro-4-(6-(2-methoxyethoxy)pyridin-3-yl)aniline I-114 was synthesized from 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 and 2-methoxyethan-1-ol using essentially the same procedure as for I-106. 1 H NMR(400MHz,DMSO-d6)δ8.13(dd,J=2.6,0.9Hz,1H), 7.73(dd,J=8.6,2.5Hz,1H), 7.12(d,J=12.0Hz,1H), 6.90 (d,J=8.4Hz,1H), 6.86(dd,J=8.6,0.8Hz,1H), 5.60(s,2H), 4.49~4.30(m,2H), 3.73~3.59(m,2H), 3.30(s,3H).

[0449] Intermediate 115 (I-115) [ka] 5-Chloro-2-fluoro-4-(6-((1s,3s)-3-methoxycyclobutoxy)pyridin-3-yl)aniline I-115 was synthesized from 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 and (1s,3s)-3-methoxycyclobutan-1-ol using essentially the same procedure as for I-106. 1 H NMR(400MHz,DMSO-d6)δ8.11(dd,J=2.6,0.9Hz,1H), 7.72(dd,J=8.6,2.6Hz,1H), 7.12(d,J=11.9Hz,1H), 6.90(d,J=8.3Hz,1H), 6.83(dd,J=8.6,0.9 Hz,1H), 5.59(s,2H), 4.83(p,J=7.3Hz,1H), 3.64(p,J=6.9Hz,1H), 3.16(s ,3H), 2.82(dtt,J=8.6,6.6,2.4Hz,2H), 1.91(dtt,J=9.2,7.3,2.4Hz,2H).

[0450] Intermediate 116 (I-116) [ka] 5-Chloro-4-(6-(2,2-difluoroethoxy)pyridin-3-yl)-2-fluoroaniline I-116 was synthesized from 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 and 2,2-difluoroethan-1-ol using essentially the same procedure as for I-106. 1 H NMR(400MHz,DMSO-d6)δ8.17(dd,J=2.6,0.9Hz,1H), 7.80(dd,J=8.6,2.4Hz,1H), 7.13(d,J=11.9Hz,1H), 6.97(dd, J=8.6,0.9Hz,1H), 6.91(d,J=8.4Hz,1H), 6.41(tt,J=54.7,3.6Hz,1H), 5.62(s,2H), 4.59(td,J=15.1,3.6Hz,2H).

[0451] Intermediate 117 (I-117) [ka] 5-Chloro-2-fluoro-4-(6-((1r,3r)-3-methoxycyclobutoxy)pyridin-3-yl)aniline I-117 was synthesized from 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 and (1r,3r)-3-methoxycyclobutan-1-ol using essentially the same procedure as for I-106. 1 H NMR(400MHz,DMSO-d6)δ8.17~8.07(m,1H), 7.77~7.67(m,1H), 7.11(d,J=11.9Hz,1H), 6.90(d,J=8.3Hz,1H), 6.83(dd,J=8.5,0.7Hz,1H), 5.60(s,2H), 5.26(tt,J=7.1,4.8Hz,1H), 4.07(tt,J=6.9,4.1Hz,1H), 3.17(s,3H), 2.40(ddd,J=13.5,7.1,3.9Hz,2H), 2.36~2.24(m,2H).

[0452] Intermediate 118 (I-118) [ka] 5-Chloro-4-(6-((1,3-difluoropropan-2-yl)oxy)pyridin-3-yl)-2-fluoroaniline I-118 was synthesized from 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 and 1,3-difluoropropan-2-ol using essentially the same procedure as for I-106. 1 H NMR(400MHz,DMSO-d6)δ8.15(dd,J=2.5,0.8Hz,1H), 7.79(dd,J=8.6,2.6Hz,1H), 7.14(d,J= 11.9Hz,1H), 6.97~6.93(m,1H), 6.91(d,J=8.4Hz,1H), 5.69~5.55(m,3H), 4.89~4.62(m,4H).

[0453] Intermediate 119 (I-119) [ka] 5-Chloro-2-fluoro-4-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)aniline I-119 was synthesized from 5-chloro-2-fluoro-4-(2-fluoropyridin-4-yl)aniline I-91 and trifluoroethanol using essentially the same procedure as for I-106. 1 H NMR(400MHz,DMSO-d6)δ8.21(dd,J=5.4,0.7Hz,1H), 7.21(d,J=12.0Hz,1H), 7.17(dd,J=5.4,1. 5Hz,1H), 6.99(dd,J=1.6,0.7Hz,1H), 6.91(d,J=8.3Hz,1H), 5.79(s,2H), 5.02(q,J=9.2Hz,2H).

[0454] Intermediate 120 (I-120) [ka] 5-Chloro-2-fluoro-4-(6-(trifluoromethyl)pyridin-3-yl)aniline I-120 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-8a and (6-(trifluoromethyl)pyridin-3-yl)boronic acid using essentially the same procedure as for I-32. 1 H NMR(400MHz,DMSO-d6)δ8.79(d,J=2.2Hz,1H), 8.12(dd,J=8.1,2.2Hz,1H), 7.95( dd,J=8.2,0.9Hz,1H), 7.30(d,J=11.9Hz,1H), 6.95(d,J=8.2Hz,1H), 5.81(s,2H).

[0455] Intermediate 121 (I-121) [ka]

[0456] Step 1: To a solution of 6-chloro-3-nitropyridin-2-ylamine I-121a (1.00 g, 5.76 mmol) in acetone (60 ml) was added PIDA (4.64 g, 14.4 mmol). The reaction mixture was heated to 80 °C for 6 h. The reaction was concentrated in vacuo. The product was purified by chromatography on silica gel (0-100% EtOAc / DCM) to give 5-chloro-[1,2,5]oxadiazolo[3,4-b]pyridine 1-oxide I-121b as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.77(d,J=9.1Hz,1H), 7.16(d,J=9.2Hz,1H).

[0457] Step 2: A solution of 5-chloro-[1,2,5]oxadiazolo[3,4-b]pyridine 1-oxide I-121b (403 mg, 2.35 mmol) in DCM (60 ml) was cooled to 0 °C, and triphenylphosphine (924 mg, 3.52 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 16 h. 1 M aqueous NaOH (30 ml) was added, and the mixture was stirred vigorously for 15 min. The product was extracted with DCM (3 × 50 ml). The combined organics were dried over sodium sulfate and concentrated in vacuo. The product was purified by chromatography on silica gel (0–50% EtOAc / isohexane). The product was further purified by chromatography on silica gel (0–30% EtOAc / isohexane) to give 5-chloro-[1,2,5]oxadiazolo[3,4-b]pyridine I-121c as a yellow oil that solidified upon standing. 1 H NMR(400MHz,CDCl3)δ8.22(d,J=9.2Hz,1H), 7.40(d,J=9.2Hz,1H)

[0458] Step 3: 4-([1,2,5]oxadiazolo[3,4-b]pyridin-5-yl)-5-chloro-2-fluoroaniline I-121 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 5-chloro-[1,2,5]oxadiazolo[3,4-b]pyridine I-121c using essentially the same procedure as for I-47. 1 H NMR (400MHz, DMSO-d6) δ8.57(d,J=9.4Hz,1H), 7.99(d,J=9.4Hz,1H), 7.53(d,J=12.1Hz,1H), 6.95(d,J=8.0Hz,1H), 6.21(s,2H).

[0459] Intermediate 122 (I-122) [ka] 5-Chloro-4-(6-(difluoromethoxy)pyridin-3-yl)-2-fluoroaniline I-122 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 5-bromo-2-(difluoromethoxy)pyridine I-122a using essentially the same procedure as for I-47. 1 H NMR(400MHz,DMSO-d6)δ8.26(dd,J=2.5,0.7Hz,1H), 7.95(dd,J=8.5,2.5Hz,1H), 7.74(t,J=72.9 Hz,1H), 7.18(d,J=11.9Hz,1H), 7.13(dd,J=8.5,0.7Hz,1H), 6.92(d,J=8.3Hz,1H), 5.67(s,2H).

[0460] Intermediate 123 (I-123) [ka]

[0461] Step 1: To a solution of 1-bromo-5-chloro-2-fluoro-4-methylbenzene I-123a (3.7 g, 16.55 mmol) in CCl (30 ml) was added NBS (3.2 g, 18.21 mmol) and AIBN (272 mg, 0.27 mmol) at room temperature. The reaction was then stirred at 80 °C for 16 h. Water (15 ml) was added, and the mixture was extracted with EtOAc (3 × 15 ml). The combined organics were washed with brine (15 ml), dried over NaSO, and concentrated in vacuo to give 1-bromo-4-(bromomethyl)-5-chloro-2-fluorobenzene I-123b as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.95 (d, J = 6.4 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 4.68 (s, 2H).

[0462] Step 2: To a solution of 1-bromo-4-(bromomethyl)-5-chloro-2-fluorobenzene I-123b (1.0 g, 3.30 mmol) in MeCN (10 ml) was added 5-fluoropyridin-3-ol (374 mg, 3.30 mmol) and K2CO3 (1.3 g, 9.92 mmol). The reaction was stirred at room temperature for 1 h. Water (10 ml) was added, and the mixture was extracted with EtOAc (3 × 20 ml). The combined organics were washed with brine (15 ml), dried over Na2SO4, and concentrated in vacuo. The product was purified by chromatography on silica gel (10% EtOAc / petroleum ether) to give 3-((4-bromo-2-chloro-5-fluorobenzyl)oxy)-5-fluoropyridine I-123c as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.31(s,1H), 9.24(d,J=2.0Hz,1H), 7.99(d,J=6.0Hz,1H), 7.70(d,J=9.2Hz,1H), 7.61(dt,J=10.8,2.4Hz,1H), 5.22(s,2H).

[0463] Step 3: To a solution of 3-((4-bromo-2-chloro-5-fluorobenzyl)oxy)-5-fluoropyridine I-123c (377 mg, 1.12 mmol) in 1,4-dioxane (3 ml), diphenylmethanimine (204 mg, 1.12 mmol), Pd(dba) (116 mg, 0.11 mmol), CsCO (917 mg, 2.81 mmol), and Xantphos (130 mg, 0.22 mmol) were added. The reaction was stirred at 110 °C for 3 h. Water (20 ml) was added, and the mixture was extracted with EtOAc (3 × 20 ml). The combined organics were washed with brine (20 ml), dried over NaSO, and concentrated in vacuo. The product was purified by chromatography on silica gel (20% EtOAc / petroleum ether) to give N-(5-chloro-2-fluoro-4-(((5-fluoropyridin-3-yl)oxy)methyl)phenyl)-1,1-diphenylmethanimine I-123d as a white solid. LCMS (Method 3) m / z 434.9 (M+H) at 2.44 min + (ES + ).

[0464] Step 4: To a solution of N-(5-chloro-2-fluoro-4-(((5-fluoropyridin-3-yl)oxy)methyl)phenyl)-1,1-diphenylmethanimine I-123d (72 mg, 0.16 mmol) in 1,4-dioxane (6 ml) and water (1.4 ml) was added TFA (14 drops). The reaction was stirred at room temperature for 10 minutes. The pH of the reaction mixture was adjusted to 8 by the addition of saturated aqueous NaHCO3, and the product was extracted with EtOAc (3 x 5 ml). The combined organics were washed with brine (5 ml), dried over Na2SO4, and concentrated in vacuo to give 5-chloro-2-fluoro-4-(((5-fluoropyridin-3-yl)oxy)methyl)aniline) I-123 as a yellow solid. LCMS (Method 3) at 1.89 min, m / z 271 (M+H) + (ES + ).

[0465] Intermediate 124 (I-124) [ka] 5-Chloro-4-(6-(cyclopropylmethoxy)pyridin-3-yl)-2-fluoroaniline I-124 was synthesized from 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 and cyclopropylmethanol using essentially the same procedure as for I-106. 1 H NMR(400MHz,DMSO-d6)δ8.11(dd,J=2.6,0.8Hz,1H), 7.71(dd,J=8.6,2.5Hz,1H), 7.11(d,J=11.9Hz,1H), 6.90(d,J=8.4Hz,1 H), 6.85(dd,J=8.6,0.7Hz,1H), 5.59(s,2H), 4.10(d,J=7.1Hz,2H), 1.33~1.18(m,1H), 0.60~0.49(m,2H), 0.37~0.28(m,2H).

[0466] Intermediate 125 (I-125) [ka] 5-Chloro-2-fluoro-4-(6-isobutoxypyridin-3-yl)aniline I-125 was synthesized from 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 and 2-methylpropan-1-ol using essentially the same procedure as for I-106. 1H NMR(400MHz,DMSO-d6)δ8.12(dd,J=2.5,0.7Hz,1H), 7.72(dd,J=8.6,2.6Hz,1H), 7.11(d,J=11.9Hz,1H), 6.90(d,J=8.4Hz) ,1H), 6.84(dd,J=8.6,0.8Hz,1H), 5.59(s,2H), 4.05(d,J=6.6Hz,2H), 2.03(dq,J=13.4,6.7Hz,1H), 0.97(d,J=6.7Hz,6H).

[0467] Intermediate 126 (I-126) [ka] 5-Chloro-2-fluoro-4-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)aniline I-126 was synthesized from 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 and 3,3,3-trifluoropropan-1-ol using essentially the same procedure as for I-106. 1 H NMR(400MHz,DMSO-d6)δ8.16(dd,J=2.5,0.8Hz,1H), 7.76(dd,J=8.6,2.5Hz,1H), 7.13(d,J=11.9Hz,1H), 6.91( d,J=8.3Hz,1H), 6.87(dd,J=8.5,0.8Hz,1H), 5.61(s,2H), 4.51(t,J=6.0Hz,2H), 2.81(qt,J=11.6,6.0Hz,2H).

[0468] Intermediate 127 (I-127) [ka]

[0469] Step 1: 6-Bromo-4-fluorobenzo[c][1,2,5]oxadiazole 1-oxide I-127b was synthesized from 4-bromo-2-fluoro-6-nitroaniline I-127a and PIDA using essentially the same procedure as for I-121b. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.83–7.57 (m, 1H).

[0470] Step 2: To a solution of 5-bromo-7-fluorobenzo[c][1,2,5]oxadiazole 1-oxide I-127b (499 mg, 2.08 mmol) in EtOH (1.50 mL) was added triethyl phosphite (535 μL, 3.12 mmol), and the reaction mixture was heated to 70 °C for 2 h. The reaction was cooled to room temperature, diluted with DCM (15 mL) and 10% v / v aqueous sodium hypochlorite, and then stirred vigorously for 20 min. After which, the dark brown solution was passed through a phase separator, and the filtrate was concentrated in vacuo. The product was purified by chromatography on silica gel (0–40% EtOAc / isohexane) to afford 6-bromo-4-fluorobenzo[c][1,2,5]oxadiazole I-127c as an orange oil, which solidified over time to give a colorless oil.

[0471] Step 3: 6-Bromo-4-fluorobenzo[c][1,2,5]oxadiazole I-127 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 6-bromo-4-fluorobenzo[c][1,2,5]oxadiazole I-127c using essentially the same procedure as for I-47. 1 H NMR (400MHz, DMSO-d6) δ7.92(d,J=1.0Hz,1H), 7.63(dd,J=11.5,1.1Hz,1H), 7.33(d,J=12.0Hz,1H), 6.94(d,J=8.3Hz,1H), 5.87(s,2H).

[0472] Intermediate 128 (I-128) [ka]

[0473] Step 1: 5-Bromo-2-fluoro-4-(6-fluorobenzo[c][1,2,5]oxadiazol-5-yl)aniline I-128b was synthesized from 4-bromo-2-fluoro-6-nitroaniline I-128a and PIDA using essentially the same procedure as for I-121b. 1H NMR (400MHz, DMSO-d6) δ8.39(s,1H), 7.93(s,1H).

[0474] Step 2: 5-Bromo-2-fluoro-4-(6-fluorobenzo[c][1,2,5]oxadiazol-5-yl)aniline I-128c was synthesized from triethyl phosphite and 5-bromo-2-fluoro-4-(6-fluorobenzo[c][1,2,5]oxadiazol-5-yl)aniline I-128b using essentially the same procedure as for I-121b. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (dd, J = 6.4, 0.6 Hz, 1H), 8.19 (dd, J = 8.1, 0.6 Hz, 1H).

[0475] Step 3: 5-Chloro-2-fluoro-4-(6-fluorobenzo[c][1,2,5]oxadiazol-5-yl)aniline I-28 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 6-bromo-4-fluorobenzo[c][1,2,5]oxadiazole I-128b using essentially the same procedure as for I-47. 1 H NMR (400MHz, DMSO-d6) δ8.17(dd,J=6.7,0.7Hz,1H), 8.05(dd,J=9.2,0.7Hz,1H), 7.27(d,J=11.6Hz,1H), 6.95(d,J=8.2Hz,1H), 5.83(s,2H).

[0476] Intermediate 129 (I-129) [ka]

[0477] Step 1: 5-Bromo-4-fluorobenzo[c][1,2,5]oxadiazole 1-oxide I-129b was synthesized from 4-bromo-3-fluoro-2-nitroaniline I-129a and PIDA using essentially the same procedure as for I-121b. 1H NMR (400MHz, CDCl3) δ7.28~7.22 (m, 1H), 7.14 (d, J = 9.5Hz, 1H).

[0478] Step 2: 5-Bromo-4-fluorobenzo[c][1,2,5]oxadiazole I-129c was synthesized from 5-bromo-4-fluorobenzo[c][1,2,5]oxadiazole 1-oxide I-129b and triethyl phosphite using essentially the same procedure as for I-121b. 1 H NMR (400MHz, DMSO-d6) δ7.95 (d,J=9.5Hz,1H), 7.82 (dd,J=9.4,6.0Hz,1H).

[0479] Step 3: 5-Chloro-2-fluoro-4-(4-fluorobenzo[c][1,2,5]oxadiazol-5-yl)aniline I-129 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 5-bromo-4-fluorobenzo[c][1,2,5]oxadiazole I-129c using essentially the same procedure as for I-47. 1 H NMR (400MHz, DMSO-d6) δ7.97(d,J=9.2Hz,1H), 7.59(dd,J=9.2,6.3Hz,1H), 7.30(d,J=11.7Hz,1H), 6.98(d,J=8.2Hz,1H), 5.88(s,2H).

[0480] Intermediate 130 (I-130) [ka] 5-Chloro-2-fluoro-4-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)aniline I-130 was synthesized from 5-chloro-4-(5,6-difluoropyridin-3-yl)-2-fluoroaniline I-90 and trifluoroethanol using essentially the same procedure as for I-106. 1H NMR(400MHz,DMSO-d6)δ8.04(d,J=2.0Hz,1H), 7.90(dd,J=11.4,2.0Hz,1H), 7. 20(d,J=11.9Hz,1H), 6.92(d,J=8.3Hz,1H), 5.69(s,2H), 5.12(q,J=9.0Hz,2H).

[0481] Intermediate 131 (I-131) [ka] 5-Chloro-2-fluoro-4-(6-((1,1,3,3-tetrafluoropropan-2-yl)oxy)pyridin-3-yl)aniline I-131 was synthesized from 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 and 1,1,3,3-tetrafluoropropan-2-ol using essentially the same procedure as for I-106. 1H NMR(400MHz,DMSO-d6)δ8.19(dd,J=2.5,0.8Hz,1H), 7.86(dd,J=8.5,2.5Hz,1H), 7.17(d,J=11.9Hz,1H), 7.0 6(dd,J=8.6,0.7Hz,1H), 6.91(d,J=8.4Hz,1H), 6.70~6.33(m,2H), 6.07(pt,J=12.6,3.2Hz,1H), 5.65(s,2H).

[0482] Intermediate 132 (I-132) [ka]

[0483] Step 1: 4-(5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)-5-chloro-2-fluoroaniline. To a solution of 128-3 (300 mg, 818 μmol) in DCM (4 ml) was added EtN (251 μl, 1.80 mmol), followed by di-tert-butyl dicarbonate (282 μl, 1.23 mmol). The reaction mixture was stirred at room temperature for 16 h. Further portions of EtN (114 μl, 818 μmol) and di-tert-butyl dicarbonate (94 μl, 409 μmol) were added and the reaction was further stirred at room temperature for 24 h. The reaction was diluted with DCM (15 ml) and washed with a saturated aqueous solution of NaHCO (20 ml). The organics were passed through a hydrophobic frit and the filtrate concentrated in vacuo. The product was purified by chromatography on silica gel (0 to 10% EtOAc / isohexane) to afford tert-butyl (4-(5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)-5-chloro-2-fluorophenyl)carbamate I-132a as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ9.40(s,1H), 8.54(dd,J=11.3,2.2Hz,2H), 7.95(d,J=7.3Hz,1H), 7.8 0(t,J=2.2Hz,1H), 7.43(d,J=11.2Hz,1H), 4.83(s,2H), 1.49(s,9H), 0.90(s,9H), 0.10(s,6H)

[0484] Step 2: A solution of tert-butyl (4-(5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)-5-chloro-2-fluorophenyl)carbamate I-132a (201 mg, 430 μmol) in THF (5 ml) was cooled to 0 °C, a solution of TBAF in THF (646 μl, 1 M, 646 μmol) was added, and the reaction mixture was allowed to warm slowly to room temperature and stirred for 18 h. The reaction mixture was diluted with a saturated aqueous solution of NaHCO (25 ml), and the product was extracted with DCM (3 × 10 ml). The combined organics were dried over MgSO and concentrated in vacuo. The product was purified by chromatography on silica gel (0–50% EtOAc / isohexane) to give tert-butyl (5-chloro-2-fluoro-4-(5-(hydroxymethyl)pyridin-3-yl)phenyl)carbamate I-132b as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.40(s,1H), 8.53(dd,J=15.5,2.1Hz,2H), 7.95(d,J=7.3Hz,1H), 7.80(t ,J=2.2Hz,1H), 7.42(d,J=11.1Hz,1H), 5.40(t,J=5.7Hz,1H), 4.60(d,J=5.8Hz,2H), 1.49(s,9H).

[0485] Step 3: To a solution of tert-butyl (5-chloro-2-fluoro-4-(5-(hydroxymethyl)pyridin-3-yl)phenyl)carbamate I-132b (141 mg, 332 μmol) in DCM (5 ml) and THF (2 ml) was added manganese dioxide (173 mg 1.99 mmol). The reaction mixture was stirred at room temperature for 24 hours. The reaction was filtered over Celite, and the Celite pad was rinsed with DCM and THF (50 ml). The filtrate was concentrated in vacuo to give tert-butyl (5-chloro-2-fluoro-4-(5-formylpyridin-3-yl)phenyl)carbamate I-132c as a white solid. 1H NMR(400MHz,DMSO-d6)δ10.18(s,1H), 9.46(s,1H), 9.11(d,J=2.0Hz,1H), 8.94(d,J=2.3H) z,1H), 8.34(t,J=2.1Hz,1H), 8.00(d,J=7.2Hz,1H), 7.55(d,J=11.2Hz,1H), 1.49(s,9H).

[0486] Step 4: To a suspension of tert-butyl (5-chloro-2-fluoro-4-(5-formylpyridin-3-yl)phenyl)carbamate I-132c (114 mg, 325 μmol) in DCM (10.0 ml) at −20 °C, DAST (172 μl, 1.30 mmol) was slowly added. The reaction was slowly warmed to room temperature and stirred at room temperature for 4 h. A saturated aqueous solution of NaHCO3 (20 ml) was added, and the product was extracted with DCM (3 × 15 ml). The combined organics were washed with brine (20 ml), dried over MgSO4, and concentrated in vacuo. The product was purified by chromatography on silica gel (0–30% EtOAc / isohexane) to afford tert-butyl (5-chloro-4-(5-(difluoromethyl)pyridin-3-yl)-2-fluorophenyl)carbamate I-32d as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.44(s,1H), 8.86~8.77(m,2H), 8.13~8.08(m,1H), 7.9 9(d,J=7.3Hz,1H), 7.52(d,J=11.2Hz,1H), 7.22(t,J=55.2Hz,1H), 1.49(s,9H).

[0487] Step 5: To a solution of tert-butyl (5-chloro-4-(5-(difluoromethyl)pyridin-3-yl)-2-fluorophenyl)carbamate (88.0 mg, 236 μmol) in DCM (3 ml) at 0° C. was added HCl in 1,4-dioxane (590 μl, 4 M, 2.36 mmol) and the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour. A further portion of HCl in 1,4-dioxane (3 mL, 4 M 12.0 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give a white solid. The material was dissolved in 1,4-dioxane (1 ml) and HCl in 1,4-dioxane (3 ml, 4 M, 12.0 mmol) was added. The reaction was stirred at room temperature for 2 hours. The reaction was warmed to 30° C. for 16 hours. The reaction mixture was heated to 77° C. for 3 hours. The reaction was cooled to room temperature and concentrated in vacuo to afford 5-chloro-4-(5-(difluoromethyl)pyridin-3-yl)-2-fluoroaniline I-132 as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 3.3 Hz, 2H), 8.03 (s, 1H), 7.26 (d, J = 11.9 Hz, 1H), 7.19 (t, J = 55.2 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H). Two exchangeable protons were not observed.

[0488] Intermediate 133 (I-133) [ka] To a solution of cyclopentanol (107 mg, 1.25 mmol) in THF (3.0 ml) at 0 °C was added sodium hydride (53 mg, 60% w / w, 1.33 mmol), and the resulting suspension was stirred at room temperature for 30 min, followed by the addition of 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 (200 mg, 831 μmol) in THF (3 ml). The resulting suspension was heated to 60 °C for 2.5 h. The reaction mixture was cooled to room temperature, and water (0.1 ml) was added. Brine (25 ml) and DCM (25 ml) were added, and the layers were separated. The aqueous phase was extracted with DCM (25 ml). The combined organics were dried over MgSO and concentrated in vacuo. The product was purified by chromatography on silica gel (0-20% EtOAc / isohexane) to afford 5-chloro-4-(6-(cyclopentyloxy)pyridin-3-yl)-2-fluoroaniline I-133 as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ8.13(dd,J=2.6,0.7Hz,1H), 7.69(dd,J=8.6,2.5Hz,1H), 7.11(d,J=11.9Hz,1H), 6.90(d,J=8.3Hz, 1H), 6.77(dd,J=8.5,0.7Hz,1H), 5.58(s,2H), 5.48~5.31(m,1H), 1.99~1.86(m,2H), 1.82~1.66(m,4H), 1.66~1.45(m,2H).

[0489] Intermediate 134 (I-134) [ka] 5-Chloro-2-fluoro-4-(6-(((1r,4r)-4-methoxycyclohexyl)oxy)pyridin-3-yl)aniline I-134 was synthesized from 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 and (1r,4r)-4-methoxycyclohexan-1-ol using essentially the same procedure as for I-133. 1H NMR(400MHz,DMSO-d6)δ8.12(dd,J=2.5,0.7Hz,1H), 7.70(dd,J=8.6,2.6Hz,1H), 7.10(d,J=11.9Hz,1H), 6.90(d,J=8.3Hz,1H), 6 .78(dd,J=8.5,0.7Hz,1H), 5.58(s,2H), 5.10~4.94(m,1H), 3.25(s,4H), 2.14~1.89(m,4H), 1.62~1.40(m,2H), 1.42~1.26(m,2H).

[0490] Intermediate 135 (I-135) [ka] 5-Chloro-4-(6-((2,2-difluorocyclopropyl)methoxy)pyridin-3-yl)-2-fluoroaniline I-135 was synthesized from 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 and (2,2-difluorocyclopropyl)methanol using essentially the same procedure as for I-133. 1 H NMR(400MHz,DMSO-d6)δ8.14(dd,J=2.6,0.8Hz,1H), 7.75(dd,J=8.6,2.5Hz,1H), 7.12(d,J=11.9Hz,1H), 6.99~6.78(m,2H), 5.59(s,2H), 4.61~4.39(m,1H), 4.22(ddd,J=11.7,8.6,1.8Hz,1H), 2.36~2.14(m,1H), 1.79~1.71(m,1H), 1.53~1.46(m,1H).

[0491] Intermediate 136 (I-136) [ka] To a solution of 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 (200 mg, 831 μmol) in NMP (5 mL) was added DIPEA (316 μL, 1.83 mmol), followed by morpholine (109 μL, 1.25 mmol). The reaction mixture was heated to 56°C for 1 h. The reaction was heated to 88°C for 1 h. The reaction was heated to 111°C for 16 h. The reaction mixture was diluted with water (25 mL) and the product was extracted with DCM (3 × 25 mL). The combined organics were dried over MgSO4 and concentrated in vacuo. The product was purified by chromatography on silica gel (0–30% EtOAc / isohexane) to give a product containing approximately 20% NMP. The material was dissolved in EtOAc (25 mL) and washed with water (4 × 25 mL), 1 M aqueous LiCl (20 mL), and brine (20 mL). The organics were dried over MgSO4 and concentrated in vacuo to afford 5-chloro-2-fluoro-4-(6-morpholinopyridin-3-yl)aniline I-136 as a yellow oil which solidified upon standing to form a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.15~8.10(m,1H), 7.59(dd,J=8.8,2.5Hz,1H),7.07(d,J=12.0Hz,1 H), 6.92~6.82(m,2H), 5.52(s,2H), 3.70(dd,J=5.7,4.0Hz,4H), 3.47(dd,J=5.7,4.1Hz,4H).

[0492] Intermediate 137 (I-137) [ka] To a solution of 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 (200 mg, 831 μmol) in NMP (5 ml) was added DIPEA (316 μl, 1.83 mmol), followed by azetidine (84 μl, 1.25 mmol). The reaction was heated to 55° C. for 2 hours and then to 86° C. for 1 hour. The reaction mixture was cooled to room temperature. Water (30 ml) was added, the precipitate was isolated by filtration, and the solid was dried in vacuo to give 4-(6-(azetidin-1-yl)pyridin-3-yl)-5-chloro-2-fluoroaniline as a colorless solid. 1 H NMR(400MHz,DMSO-d6)δ8.04(dd,J=2.5,0.8Hz,1H), 7.53(dd,J=8.6,2.4Hz,1H), 7.04(d,J=12.0Hz,1H), 6. 88(d,J=8.5Hz,1H), 6.37(dd,J=8.5,0.8Hz,1H), 5.50(s,2H), 3.95(t,J=7.4Hz,4H), 2.33(p,J=7.4Hz,2H).

[0493] Intermediate 138 (I-138) [ka] 5-Chloro-2-fluoro-4-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)aniline I-138 was synthesized from 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 and tetrahydrofuran-3-ol using essentially the same procedure as for I-133. 1H NMR(400MHz,DMSO-d6)δ8.14(dd,J=2.6,0.7Hz,1H), 7.74(dd,J=8.5,2.5Hz,1H) , 7.12(d,J=11.9Hz,1H), 6.91(d,J=8.4Hz,1H), 6.85(dd,J=8.6,0.8Hz,1H), 5.5 9(s,2H), 5.52(ddt,J=6.6,4.3,2.0Hz,1H), 3.93(dd,J=10.2,4.7Hz,1H), 3.86( td,J=8.2,6.9Hz,1H), 3.80~3.71(m,2H), 2.30~2.16(m,1H), 2.08~2.00(m,1H).

[0494] Intermediate 139 (I-139) [ka] 5-Chloro-2-fluoro-4-(6-(((1s,4s)-4-methoxycyclohexyl)oxy)pyridin-3-yl)aniline I-139 was synthesized from 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 and (1s,4s)-4-methoxycyclohexan-1-ol using essentially the same procedure as for I-133. 1 H NMR(400MHz,DMSO-d6)δ8.11(dd,J=2.6,0.7Hz,1H), 7.70(dd,J=8.6,2.6Hz,1H), 7.11(d,J=11.9Hz,1H), 6.90(d,J=8 .4Hz,1H), 6.79(dd,J=8.5,0.7Hz,1H), 5.58(s,2H), 5.07(dt,J=7.8,4.1Hz,1H), 3.34~3.28(m,4H), 1.85~1.54(m,8H)

[0495] Experimental Scheme 2 Compound 15: (±)-N-(5-bromo-4-chloro-2-fluorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide [ka] A solution of triphosgene (53 mg, 0.18 mmol) and 5-bromo-4-chloro-2-fluoroaniline (89 mg, 0.39 mmol) in DCM (4 mL) at room temperature was treated with EtN (0.16 mL, 1.2 mmol). The mixture was stirred at room temperature for 10 minutes. The resulting solution was added to a pre-sonicated suspension of (±)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidin-2-ol, HCl I-3 (86 mg, 0.39 mmol), and DIPEA (0.21 mL, 1.2 mmol) in DCM (4 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was treated with MTBE (20 mL) and allowed to settle for 72 hours. The resulting suspension was filtered, and the solid was washed with MTBE. The solid was dissolved in MeOH (100 ml) and treated with MP-carbonate resin (1 g, 3 mmol), and the suspension was stirred at room temperature for 18 hours. The suspension was filtered, and the filtrate was concentrated in vacuo to give (±)-N-(5-bromo-4-chloro-2-fluorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide 15 as an off-white solid. LCMS (Method 1) m / z 427.0, 429.0 (M+H) at 0.84 min. + (ES + ), 1 H NMR (400 MHz, DMSO-d6) δ 11.63 (br s, 1H), 8.74 (s, 1H), 7.99-7.61 (m, 3H), 5.05 (d, J = 5.8 Hz, 1H), 4.72-4.57 (m, 1H), 3.12 (dd, J = 18.7, 5.1 Hz, 1H), 2.26-2.16 (m, 1H), 2.12-2.02 (m, 1H), 1.84-1.67 (m, 2H), one CH is hidden by the DMSO-d6 peak.

[0496] The following compounds were prepared using procedures similar to those described in Experimental Scheme 2 using the appropriate starting materials. [Table 10] TIFF2024538178000268.tif155170 TIFF2024538178000269.tif195170 TIFF2024538178000270.tif178170 TIFF2024538178000271.tif243170 TIFF2024538178000272.tif216170 TIFF2024538178000273.tif178170 TIFF2024538178000274.tif166170 TIFF2024538178000275.tif189170 TIFF2024538178000276.tif239170 TIFF2024538178000277.tif232170 TIFF2024538178000278.tif221170 TIFF2024538178000279.tif232170 TIFF2024538178000280.tif231170 TIFF2024538178000281.tif231170 TIFF2024538178000282.tif241170 TIFF2024538178000283.tif177170 TIFF2024538178000284.tif189170 TIFF2024538178000285.tif243170 TIFF2024538178000286.tif249170 TIFF2024538178000287.tif240170 TIFF2024538178000288.tif237170 TIFF2024538178000289.tif156170 TIFF2024538178000290.tif213170 TIFF2024538178000291.tif209170 TIFF2024538178000292.tif202170 TIFF2024538178000293.tif249170 TIFF2024538178000294.tif195170 TIFF2024538178000295.tif249170 TIFF2024538178000296.tif244170 TIFF2024538178000297.tif170170 TIFF2024538178000298.tif180170 TIFF2024538178000299.tif161170 TIFF2024538178000300.tif189170 TIFF2024538178000301.tif167170 TIFF2024538178000302.tif178170 TIFF2024538178000303.tif171170 TIFF2024538178000304.tif240170 TIFF2024538178000305.tif184170 TIFF2024538178000306.tif184170 TIFF2024538178000307.tif178170 TIFF2024538178000308.tif218170 TIFF2024538178000309.tif178170 TIFF2024538178000310.tif200170 TIFF2024538178000311.tif195170 TIFF2024538178000312.tif117170

[0497] Intermediate 3 (I-3) [ka]

[0498] Step 1: tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-3a (10 g, 44 mmol) was dissolved in 1,1-dimethoxy-N,N-dimethylmethanamine (24 mL, 0.18 mol), and the reaction mixture was heated to reflux for 16 h. The solvent was removed in vacuo. The product was purified by silica gel chromatography (0-5% (0.7 M ammonia / MeOH) in DCM) to give tert-butyl (E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-3b as a yellow solid. LCMS (Method 2) m / z 281.2 [M+H] at 1.60 min.+ (ES + ). 1 H NMR(500MHz,DMSO-d6)δ7.25~7.14(m,1H), 5.20(d,J=5.7Hz,1H), 4.21(t,J=6.3Hz,1H), 3. 07(s,6H), 2.54(s,1H), 2.09(s,3H), 1.77(t,J=9.0Hz,1H), 1.68~1.56(m,1H), 1.38(s,9H).

[0499] Step 2: To a solution of urea (0.2 g, 4 mmol) in EtOH (10 mL) was added a solution of sodium ethoxide (2 mL, 21% w / w in EtOH, 4 mmol). tert-Butyl (E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-3b (1 g, 4 mmol) in EtOH (10 mL) was added, and the reaction mixture was heated to 90 °C for 16 h. Saturated NH4Cl solution (5 mL) was added, and the product was extracted with 10% (0.7 M ammonia / MeOH) solution in DCM (2 × 35 mL). The product was purified by silica gel chromatography (0-10% (0.7 M ammonia / MeOH) in DCM) to give tert-butyl 2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-3c as a white solid. LCMS (Method 2) m / z 278.1 (M+H) at 1.3 min. + (ES + ). 1 H NMR (500 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.96 (s, 1H), 4.79 (d, J = 6.0 Hz, 1H), 4.35 (s, 1H), 2.97 (d, J = 17.7 Hz, 1H), 2.16 (s, 1H), 2.02 (dt, J = 11.9, 5.6 Hz, 1H), 1.78–1.69 (m, 1H), 1.67 (d, J = 17.0 Hz, 1H), 1.36 (s, 9H). One proton is hidden by the DMSO-d6 peak.

[0500] Step 3: To a solution of tert-butyl (±)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-3c (600 mg, 1.73 mmol) in DCM (17 ml) was added HCl in 1,4-dioxane (4.33 ml, 4.0 molar, 17.3 mmol), and the mixture was stirred at room temperature for 16 hours. The precipitate was filtered and washed with DCM (2 × 10 ml). The collected solid was dried in vacuo for 2 hours to give (±)-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-2-one hydrochloride I-3d as a brown solid. The material was used without further purification.

[0501] Intermediate 5 (I-5) [ka] The following scheme utilizes the synthetic methodology described in (Schultz and Wolfe (2011), Organic Letters, Intramolecular Alkene Carboamination Reactions for the Synthesis of Enantiomerically Enriched Tropane Derivatives, 13 (11), 2962-2965).

[0502] Step 1: To a solution of 2-chloro-6-fluoronicotinaldehyde (I-5a) (9.50 g, 59.6 mmol) in THF (57 ml) was added Ti(OEt) (24.7 ml, 119 mmol) in one portion at room temperature under N. The reaction mixture was stirred at room temperature for 5 minutes, and then tert-butanesulfinamide (7.94 g, 65.5 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured onto water (50 ml) at 0 °C. The reaction mixture was filtered. The filter cakes were combined and washed with EtOAc (3 × 10 ml), and the filtrate was then extracted with EtOAc (3 × 30 ml). The combined organics were concentrated in vacuo. The product was purified by silica gel chromatography (1% to 100% EtOAc / petroleum ether) to afford (E)-N-((2-chloro-6-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (I5b) as a white solid. 1 H NMR (400MHz, CDCl3) δ8.93(s,1H), 8.48(t,J=8.4Hz,1H), 7.02~6.99(m,1H), 1.28(m,9H).

[0503] Step 2: To a solution of (E)-N-((2-chloro-6-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (I5b) (13.6 g, 51.8 mmol) in THF (79 ml) was added a solution of 3-butenylmagnesium bromide (0.5 M, 11.4 ml) at 0 °C. The mixture was warmed to room temperature for 1 h. Water (50 ml) was added at 0 °C, and the product was extracted with EtOAc (3 × 30 ml). The combined organics were washed with brine, dried over NaSO, and concentrated in vacuo. The product was purified by silica gel chromatography (1% to 100% EtOAc / petroleum ether) to give N-(1-(2-chloro-6-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I5c) as a yellow oil. 1H NMR: (400MHz, CDCl3) δ7.82~7.87(m,1H), 6.87~6.90(m,1H), 5.76(t,J=10.4Hz,1H), 5.01~5.05(m ,2H), 4.98~4.84(m,1H), 5.82~3.79(m,1H), 2.20~2.05(m,2H), 1.94~1.88(m,2H)1.16~1.22(m,9H)

[0504] Step 3: To a solution of N-(1-(2-chloro-6-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I5c) (15.0 g, 47.1 mmol) in MeOH (104 ml) was added a solution of HCl in EtOAc (4 M, 33.0 ml) at 0° C. The mixture was allowed to warm to room temperature for 1 h. The mixture was concentrated in vacuo and the residue was triturated with MTBE (20 ml) at room temperature for 30 min. The mixture was filtered. The combined filter cakes were washed with MTBE (2×10 ml) and concentrated in vacuo to give a yellow solid. The yellow solid was dissolved in water (15 ml). The mixture was basified with NaOH solution to a pH greater than 11 at 0° C. and the product was extracted with DCM (6×15 ml). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (1% to 100% EtOAc / petroleum ether) to afford 1-(2-chloro-6-fluoropyridin-3-yl)pent-4-en-1-amine (I5d) as a yellow liquid. 1 H NMR(400MHz,CDCl3)δ8.00(t,J=8.4Hz,1H), 6.87~6.90(m,1H), 5.72~5.83(m 1H), 5.96~5.05(m,2H), 4.36(t,J=5.6Hz,1H)2.09~2.15(m,2H), 1.65~1.69(m,2H), 1.48(s,2H).

[0505] Step 4: To a solution of 1-(2-chloro-6-fluoropyridin-3-yl)pent-4-en-1-amine (I5d) (5.52 g, 23.4 mmol) and 4-methoxyphenylboronic acid (7.11 g, 46.8 mmol) in 1,4-dioxane (300 mL), Cu(OAc) (10.6 g, 58.5 mmol), 4 Å molecular sieves (10.0 g), and EtN (4.23 mL, 30.4 mmol) were added at room temperature. The mixture was warmed to 35 °C for 16 h. The reaction mixture was filtered. The filter cake was washed with EtOAc (3 × 10 mL), and the filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (1-100% EtOAc / petroleum ether) to afford N-(1-(2-chloro-6-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline (I-5e) as a yellow oil. 1 H NMR (400 MHz, CDCl) δ 7.88 (t, J = 8.0 Hz, 1H), 6.78–6.83 (m, 1H), 6.70 (t, J = 4.4 Hz, 2H), 6.40 (d, J = 4.4 Hz, 2H), 5.80–5.87 (m, 1H), 5.01–5.05 (m, 2H), 3.70 (s, 3H), 2.19–2.31 (m, 2H), 1.77–1.92 (m, 2H), 1.43 (s, 1H) (one exchangeable NH not observed).

[0506] Step 5: To a solution of N-(1-(2-chloro-6-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline (I-5e) (3.00 g, 9.35 mmol) in toluene (60 ml), NaO t Bu (1.35 g, 14.0 mmol) and Pd-172 (567 mg, 935 μmol) were added at 20 °C. The mixture was stirred at 110 °C for 16 h. The reaction mixture was concentrated in vacuo. The product was purified by silica gel chromatography (EtOAc / petroleum ether 1% to 100%) to give (±)-2-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (I-5f) as a yellow solid. 1H NMR (400MHz, CDCl3) δ7.55(t,J=8.0Hz,1H), 6.68~6.77(m,5H), 4.72(d,J=2.4Hz,1H), 4.52(d,J=5.6Hz,1 H), 3.71(s,3H), 3.28(dd,J=8.8,4.4Hz,1H), 2.53(d,J=8.8Hz,1H), 2.42~2.56(m,3H), 1.82~1.96(m,2H).

[0507] Step 6: To a solution of (±)-2-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (I-5f) (113 mg, 397 μmol) in MeOH (4 ml) was added a solution of sodium methoxide in methanol (110 μl, 5.4 molar, 596 μmol). The resulting mixture was heated at 65° C. for 20 hours. THF (1 ml) was added, followed by an additional portion of sodium methoxide (110 μl, 5.4 molar, 596 μmol). The reaction was stirred at 65° C. for an additional 24 hours. The reaction was cooled. The solid was filtered off, washed with MeOH (2 x 5 ml), and the solid was dried in vacuo to give (±)-2-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (I-5g) as a white solid. LC-MS (Method 1) m / z 297.1 (M+H) at 1.68 min. + (ES + )

[0508] Step 7: To a solution of (±)-2-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (I-5g) (424 mg, 1.43 mmol) in MeCN (21 ml) at 0 °C was added dropwise a solution of CAN (2.51 g, 4.58 mmol) in water (21 ml). After the addition, the reaction was stirred at 0 °C for 1 h. 2 M NaOH (25 ml) was added, and the mixture was filtered. DCM was added, and the precipitate was washed with DCM and water. The layers were separated, and the aqueous was extracted with DCM (3 × 30 ml). The combined organics were dried over MgSO to give (±)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine I-5 as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.32 (d, J = 8.2 Hz, 1H), 6.53–6.44 (m, 1H), 4.08 (d, J = 5.3 Hz, 1H), 3.76 (s, 4H), 3.01 (dd, J = 17.4, 5.1 Hz, 1H), 2.44 (d, J = 17.3 Hz, 1H), 1.97–1.78 (m, 2H), 1.73–1.63 (m, 1H), 1.53–1.42 (m, 1H). (NH protons not observed.)

[0509] Intermediate 6 (I-6) [ka]

[0510] Step 1: To a solution of 3-chloro-2-fluoroisonicotinaldehyde I-6a (1.00 g, 6.27 mmol) in THF (17 ml) was added titanium(IV) ethoxide (2.63 ml, 12.5 mmol) in one portion at room temperature. The mixture was stirred at room temperature for 5 minutes, and then (S)-tert-butylsulfinamide (760 mg, 6.27 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 16 hours. Brine (30 ml) was added, and the mixture was stirred for 10 minutes and then filtered through Celite. The filtrate was extracted with EtOAc (2 × 20 ml). The combined organics were dried over MgSO and concentrated in vacuo to give (S)—N-((3-chloro-2-fluoropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (I-6b) as a pale yellow solid. LCMS (Method 1) m / z 227.5 (M-Cl) at 1.36 min + (ES + ). 1 H NMR (500MHz, DMSO-d6) δ8.81(s,1H), 8.33(dt,J=5.1,0.8Hz,1H), 7.90(d,J=5.1Hz,1H), 1.22(s,9H).

[0511] Step 2: To a solution of (S)—N-((3-chloro-2-fluoropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.38 g, 5.26 mmol) (I-6b) in THF (22 ml) was added but-3-en-1-ylmagnesium bromide (31.6 ml, 0.5 M, 15.8 mmol) dropwise at −78° C. The mixture was slowly warmed to room temperature and stirred for 72 h. Saturated NH4Cl solution (10 ml) was added and the product was extracted with EtOAc (3×10 ml). The combined organics were dried over MgSO4 and concentrated in vacuo. The product was purified by silica gel chromatography (0-100% EtOAc / isohexane) to give (S)-N-(I-1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-6c-1) as a pale yellow solid. LCMS (Method 1) m / z 316.7, 319.1 (M−H) at 1.39 min. -(ES - ). 1 H NMR(500MHz,DMSO-d6)δ8.21(dd,J=5.2,0.8Hz,1H), 7.53(d,J=5.2Hz,1H),5. 90(d,J=7.3Hz,1H), 5.81(dddd,J=17.3,10.2,7.1,6.1Hz,1H), 5.10(dq,J=17 .2,1.7Hz,1H), 5.02(ddt,J=10.2,2.3,1.2Hz,1H), 4.66(ddd,J=8.6,7.3,5.3 Hz,1H), 2.27~2.08(m,2H), 1.-7~1.87(m,1H), 1.-0~1.70(m,1H), 1.07(s,9H). (S)-N-((S)-1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-6c-2) was also obtained from the purification.

[0512] Step 3: t To a solution of (S)-I(R)-1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-6c) (714 mg, 2.015 mmol) in BuOH (7.2 ml) was added a solution of HCl in 1,4-dioxane (3.0 ml, 4 M, 12.09 mmol) at room temperature and stirred for 2.5 hours. The reaction mixture was quenched with saturated aqueous NaHCO (100 ml) and extracted with DCM (3 × 30 ml). The combined organics were dried over MgSO and concentrated in vacuo to give (R)-1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-amine (I-6d) as a pale yellow liquid. LCMS (Method 1): at 1.17 min, m / z 215.4, 217.3 (M+H) + (ES + ), 1H NMR (500 MHz, DMSO-d) δ 8.16 (dd, J = 5.1, 0.9 Hz, 1H), 7.62 (d, J = 5.1 Hz, 1H), 5.80 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.02 (dq, J = 17.4, 1.8 Hz, 1H), 4.96 (ddt, J = 10.2, 2.3, 1.3 Hz, 1H), 4.22 (dd, J = 8.1, 5.1 Hz, 1H), 2.23–2.01 (m, 2H), 1.76–1.50 (m, 2H), two NH protons not observed.

[0513] Step 4: To a solution of (R)-1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-amine (I-6d) (644.3 mg, 3.001 mmol), (4-methoxyphenyl)boronic acid (1.37 g, 9.0 mmol), and Cu(OAc) (820 mg, 4.50 mmol) in DCM (100 mL), pyridine (1.2 mL, 15.0 mmol) was added dropwise. The mixture was stirred at room temperature and open to the atmosphere for 16 hours. 2M aqueous NaOH (20 mL) was added, followed by water (20 mL), and the mixture was extracted with DCM (3 × 20 mL). The combined organics were dried over MgSO and concentrated in vacuo. The product was purified by silica gel chromatography (0% to 100% DCM / isohexane) to give (R)-N-(1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-6e) as a yellow oil. LCMS (Method 1): m / z 321.1, 323.4 (M+H) at 1.73 min. + (ES + ), 1 H NMR(500MHz,DMSO-d6)δ8.10(d,J=5.1Hz,1H), 7.41(d,J=5.1Hz,1H), 6.65(d,J=8.9Hz,2H), 6.38(d,J=8.9Hz,2H), 6.09(d,J=8.3Hz,1H), 5.84(dd t,J=17.0,10.2,6.6Hz,1H), 5.10~4.88(m,2H), 4.68(td,J=8.5,4.7Hz,1 H), 3.57(s,3H), 2.34~2.24(m,1H), 2.23~2.12(m,1H), 1.87~1.69(m,2H).

[0514] Step 5: A three-neck flask was charged with Pd-178 (7.4 mg, 15.6 μmol) and sodium tert-butoxide (22.5 mg, 234 μmol) and purged with N. A solution of (R)-N-(1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-6e) (50.0 mg, 156 μmol) in toluene (1 ml) was added dropwise. The resulting mixture was heated to 95° C. for 1.5 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with EtOAc (3×20 ml). The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (0% to 50% EtOAc / heptane) to give (5R,8S)-1-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-6f) as a white solid. LCMS (Method 1) m / z 285.3 (M+H) at 1.35 min. + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ7.95(d,J=4.9Hz,1H), 7.29(dd,J=5.0,1.7Hz,1H), 6.80(d,J=9.1Hz,2H), 6.71(d,J=9.1Hz,2H), 4.92(d,J=5.6Hz,1H), 4 .56(t,J=5.9Hz,1H), 3.61(s,3H), 2.92(dd,J=17.6,4.9Hz,1H), 2.35(d, J=17.5Hz,1H), 2.32~2.19(m,2H), 1.91~1.82(m,1H), 1.81~1.74(m,1H).

[0515] Step 6: A solution of (5R,8S)-1-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-6f) (69 mg, 232 μmol) in MeCN (3.2 mL) was cooled to 0 °C, followed by the dropwise addition of a solution of CAN (381 mg, 696 μmol) in water (3.2 mL). After the addition was complete, the reaction was stirred at 0 °C for 1 h. 2 M aqueous NaOH (5 mL) and water (5 mL) were added, and the mixture was extracted with DCM (3 × 10 mL). The combined organics were dried over MgSO and concentrated in vacuo to give (5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-6) as a pale pink solid. LCMS (Method 1): at 0.69 min, m / z 179.2 (M+H) + (ES + ), 1 H NMR(500MHz,DMSO-d6)δ7.91(dd,J=5.0,0.9Hz,1H), 7.04(dd,J=5.0,1.9Hz,1H), 4.17(d,J=5.3Hz,1H), 3.78(t,J=6.0Hz,1H), 2.85 (dd,J=17.1,5.2Hz,1H), 2.74(s,1H), 2.38(d,J=17.0Hz,1H), 2.01~1.85(m,2H), 1.73(t,J=9.1Hz,1H), 1.51(dt,J=9.4,5.4Hz,1H).

[0516] Intermediate 7 (I-7) - Route 1 [ka]

[0517] Step 1: (S)—N-((4-bromo-6-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-7b was synthesized from 4-bromo-6-fluoronicotinaldehyde I-7a using essentially the same procedure as for I-6b. LCMS (Method 2): m / z 307.0, 308.9 (M+H) at 2.05 min + (ES + ), 1H NMR (500MHz, DMSO-d6) δ8.81(s,1H), 8.73(s,1H), 7.88(d,J=2.4Hz,1H), 1.21(s,9H).

[0518] Step 2: To a solution of ((S)—N-((4-bromo-6-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-7b (7.00 g, 22.8 mmol) in THF (114 ml) was added but-3-en-1-ylmagnesium bromide (2.54 M, 17.9 ml, 45.6 mmol) dropwise at −78 °C. The mixture was slowly warmed to room temperature and stirred for 16 h. Saturated NH4Cl solution (10 ml) was added and the product extracted with EtOAc (2 × 10 ml). The combined organics were dried over MgSO4 and concentrated in vacuo. The product was purified by silica gel chromatography (0–10% IPA / isohexane) to give (±)-N-(1-(4-bromo-6-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide A 2:1 mixture of diastereomers of I-7c was obtained as a pale yellow oil. LCMS (Method 1) m / z 363.3, 365.4 (M+H) at 1.39 and 1.42 min. + (ES + ). Major diastereomer: 1H NMR(500MHz,DMSO-d6)δ8.43(s,1H), 7.60(d,J=2.6Hz,1H), 6.00(d,J=9.5Hz,1H), 5.82(ddt,J=16.7,10.3,6.6Hz,1H), 5.1 2~4.97(m,2H), 4.64~4.50(m,1H), 2.26~2.14(m,1H), 2.16~2.05(m,1H), 1.94~1.78(m,1H), 1.78~1.66(m,1H), 1.13(s,9H). Minor diastereomer: 1H NMR(500MHz,DMSO-d6)δ8.33(s,1H), 7.61(d,J=2.5Hz,1H), 5.82(ddt,J=16.7,10.3,6.6Hz,1H), 5.76(d,J=7.0Hz,1H), 5.1 2~4.97(m,2H), 4.64~4.50(m,1H), 2.26~2.14(m,1H), 2.16~2.05(m,1H), 2.03~1.92(m,1H), 1.94~1.78(m,1H), 1.07(s,9H).

[0519] Step 3: (±)-1-(4-Bromo-6-fluoropyridin-3-yl)pent-4-en-1-amine I-7d was synthesized from (±)-N-(1-(4-bromo-6-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-7c using essentially the same procedure as for I-6d. LCMS (Method 1) m / z 259.2, 261.2 (M+H) at 1.21 min + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ8.41(s,1H), 7.55(d,J=2.7Hz,1H), 5.82(ddt,J=16.9,10.2,6.6Hz,1H), 5.03(dq,J=17.2,1.8Hz,1H ), 4.95(ddt,J=10.2,2.3,1.3Hz,1H), 4.12(dd,J=8.2,4.9Hz,1H), 2.25~1.98(m,4H), 1.75~1.64(m,1H), 1.64~1.54(m,1H).

[0520] Step 4: (±)-N-(1-(4-Bromo-6-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-7e was synthesized from (±)-1-(4-bromo-6-fluoropyridin-3-yl)pent-4-en-1-amine I-7d using essentially the same procedure as for I-6e. LCMS (Method 1) m / z 365.0, 367.1 (M+H) at 1.76 min + (ES + ). 1H NMR(500MHz,DMSO-d6)δ8.21(s,1H), 7.61(d,J=2.5Hz,1H), 6.66(d,J=8.9Hz,2H), 6.40(d,J=9.0Hz,2H), 6.04(d,J=8.3Hz,1H), 5.86(ddt,J= 17.0,10.2,6.6Hz,1H), 5.08~4.90(m,2H), 4.59(td,J=8.5,4.8Hz,1H) , 3.58(s,3H), 2.35~2.26(m,1H), 2.23~2.13(m,1H), 1.92~1.71(m,2H).

[0521] Step 5: In a three-neck flask, add Pd-178 (0.29 g, 0.61 mmol) and NaO t Bu (0.88 g, 9.2 mmol) was charged and purged with N. A solution of N-(1-(4-bromo-6-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-7e (2.3 g, 6.1 mmol) in toluene (66 ml) was added dropwise. The resulting mixture was heated to 95 °C for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the solid was washed with EtOAc (150 ml). The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (0% to 50% EtOAc / isohexane) to give a mixture of enantiomers, which was dissolved in DCM:methanol (1:4) to 30 mg / ml and then separated by chiral SFC on a Waters prep 15 with UV detection at 210 nm, 40 °C, 100 bar on a Lux C3 column (21.2 mm × 250 mm, 5 μm particle size) using 40% methanol at a flow rate of 50 ml / min to give (6S,9R)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-7f) as a pale yellow solid. LCMS (Method 1) m / z 285.3 (M+H) at 1.35 min. + (ES + ). 1H NMR (500 MHz, DMSO-d6) δ 8.10 (s, 1H), 6.79 (t, J = 9.7 Hz, 3H), 6.70 (d, J = 9.1 Hz, 2H), 4.95 (d, J = 5.5 Hz, 1H), 4.47 (t, J = 6.0 Hz, 1H), 3.61 (s, 3H), 3.11 (dd, J = 18.2, 4.9 Hz, 1H), 2.31–2.19 (m, 2H), 1.88–1.55 (m, 2H), one proton obscured by residual DMSO peak. Also obtained was (6R,9S)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-7g) as a pale yellow solid. LCMS (Method 1) m / z 285.3 (M+H) at 1.35 min. + (ES + ). 1 H NMR (500 MHz, DMSO-d6) δ 8.10 (s, 1H), 6.79 (t, J = 9.7 Hz, 3H), 6.70 (d, J = 9.1 Hz, 2H), 4.95 (d, J = 5.5 Hz, 1H), 4.47 (t, J = 6.0 Hz, 1H), 3.61 (s, 3H), 3.11 (dd, J = 18.2, 4.9 Hz, 1H), 2.31–2.19 (m, 2H), 1.88–1.55 (m, 2H), one proton obscured by residual DMSO peak.

[0522] Step 6: (6S,9R)-3-Fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-7h) was synthesized from (6S,9R)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-17f) using essentially the same procedure as for I-6. LCMS (Method 1) m / z 179.2 (M+H) at 0.71 min + (ES + ).

[0523] Step 7: (6S,9R)-3-Fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-6 (300 mg, 1.68 mmol) was dissolved in HBr (1.90 ml, 48% w / w in water, 16.8 mmol) and heated at 100 °C for 18 h. The reaction mixture was cooled to room temperature, diluted with MeOH, loaded onto an SCX cartridge (20 g), and the product was eluted with ammonia solution in MeOH (0.7 M) to give (6S,9R)-2,5,6,7,8,9-hexahydro-3H-6,9-epiminocyclohepta[c]pyridin-3-one (I-7) as an off-white solid. LCMS (Method 1) m / z 176.9 (M+H) at 0.41 min. + (ES + ),

[0524] Intermediate 7 (I-7) - Route 2 [ka]

[0525] Step 1: To a solution of 4,6-dichloronicotinaldehyde I-7i (17.3 g, 88.5 mmol) and (S)-2-methylpropane-2-sulfinamide (10.7 g, 88.5 mmol) in DCM (150 ml) was added cesium carbonate (28.8 g, 88.5 mmol). The resulting mixture was stirred at room temperature for 16 hours. The material was filtered, and the solid residue was washed with DCM (150 ml). The solvent was evaporated to give (S)-N-((4,6-dichloropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-7j as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ8.97(s,1H), 8.76(s,1H), 8.04(s,1H), 1.21(s,9H).

[0526] Step 2: A solution of but-3-en-1-ylmagnesium bromide (0.5 M in THF) (60.9 ml, 30.4 mmol) was slowly added to a solution of (S)—N-((4,6-dichloropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-7j (5.00 g, 1 equiv., 17.9 mmol) in THF (100 mL) at −78° C. The reaction mixture was allowed to warm slowly to room temperature over 16 h. The reaction was cooled to 0–10° C., saturated aqueous NH4Cl (100 ml) was added, and stirred for 5 min. The layers were separated, and the aqueous phase was extracted with EtOAc (2×250 ml). The combined organics were washed with brine (50 ml), dried over Na2SO4, and concentrated in vacuo. The product was purified by chromatography on silica gel (0 to 30% MTBE in DCM) to afford (S)—N-((R)-1-(4,6-dichloropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-7k as a clear yellow oil. 1 H NMR(400MHz,DMSO-d6)δ8.53(s,1H), 7.77(s,1H), 5.85~5.75(m,2H), 5.07(dq,J=17.2,1.6Hz,1H), 5.00(ddt,J=10.3,2.3,1.3Hz ,1H), 4.66~4.56(m,1H), 2.20~2.05(m,2H), 1.98(dtd,J=13.9,8.0,5.7Hz,1H), 1.83(ddt,J=13.3,8.7,6.5Hz,1H), 1.07(s,9H).

[0527] Step 3: A solution of HCl (4M in dioxane) (41 ml, 0.16 mol) tTo a solution of (S)—N—((R)-1-(4,6-dichloropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-7k (11 g, 33 mmol) in BuOH (50 ml) was added, and the reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was cooled in an ice bath, and water (220 ml) was added and stirred for 10 minutes. The aqueous was extracted with MTBE (3×30 ml). The organic layer was extracted with water (2×30 ml). The aqueous was basified using saturated aqueous NaHCO3 and additional solid NaHCO3, and the mixture was stirred for 15 minutes. The product was extracted with MTBE (3×100 ml). The combined organics were washed with water (500 ml), dried over Na2SO4 and concentrated in vacuo to give (R)-1-(4,6-dichloropyridin-3-yl)pent-4-en-1-amine I-7l as an orange oil. 1 H NMR(400MHz,DMSO-d6)δ8.60(s,1H), 7.69(s,1H), 5.80(ddt,J=16.9,10.1,6.6Hz,1H), 5.01(dq,J=17.2,1.7H z,1H), 4.94(ddt,J=10.2,2.3,1.3Hz,1H), 4.15(dd,J=8.0,5.2Hz,1H), 2.17~2.01(m,4H), 1.74~1.54(m,2H).

[0528] Step 4: To a solution of (R)-1-(4,6-dichloropyridin-3-yl)pent-4-en-1-amine I-7l (7.04 g, 30.5 mmol) in DCM (70 mL) was added (4-methoxyphenyl)boronic acid (13.9 g, 91.4 mmol), copper(II) acetate (6.09 g, 33.5 mmol), and EtN (21.2 mL, 152 mmol). The resulting mixture was stirred at room temperature for 20 hours. An additional portion of copper(II) acetate (2.21 g, 12.2 mmol), (4-methoxyphenyl)boronic acid (5.55 g, 36.6 mmol), and EtN (5.09 mL, 36.6 mmol) was added, and the mixture was stirred for an additional 20 hours. 1 M HCl (200 mL) was added, and the layers were separated. Ammonium hydroxide solution (28% w / v, 100 and 200 ml) was added to the organic and aqueous layers, respectively. The layers were separated, and the aqueous was extracted with DCM (100 ml). The combined organics were washed with water (100 ml) and dried over MgSO. The product was purified by chromatography on silica gel (0–50% EtOAc / isohexane) to give (R)-N-(1-(4,6-dichloropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-7m as a thick, colorless oil. 1 H NMR(400MHz,DMSO-d6)δ8.42(s,1H), 7.75(s,1H), 6.70~6.59(m,2H), 6.46~6.34(m,2H), 6.01(d,J=8.5Hz,1H), 5.90~5.77(m,1H), 5. 08~4.94(m,2H), 4.64(td,J=8.6,4.9Hz,1H), 3.58(s,3H), 2.27(ddd,J=12.7,9.3,6.1Hz,1H), 2.22~2.08(m,1H), 1.92~1.72(m,2H).

[0529] Step 5: To a solution of (R)-N-(1-(4,6-dichloropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-7m (2.73 g, 8.10 mmol) in toluene (20 ml), N,N-dimethylethane-1,2-diamine (86.8 μl, 810 μmol), copper(I) iodide (30.8 mg, 162 μmol), and sodium methoxide (656 mg, 243 μmol) were added. The resulting mixture was heated at 100° C. for 96 hours. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The product was purified by chromatography on silica gel (0 to 30% MTBE in isohexane) to give (R)-N-(1-(4-chloro-6-methoxypyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-7n as a thick yellow oil. 1 H NMR(400MHz,DMSO-d6)δ8.17(s,1H), 6.94(s,1H), 6.66~6.62(m,2H), 6.43 ~6.37(m,2H), 5.91(d,J=8.5Hz,1H), 5.89~5.78(m,1H), 5.07~4.93(m,2H) , 4.57(td,J=8.5,5.1Hz,1H), 3.79(s,3H), 3.58(s,3H), 2.27(dt,J=14.3, 7.3Hz,1H), 2.22~2.07(m,1H), 1.80(dddd,J=20.8,13.8,10.1,5.1Hz,2H).

[0530] Step 6: Pd-161 (763.6 mg, 1.65 mmol) and NaO tBu (2.38 g, 24.8 mmol) was placed in a three-neck round-bottom flask, which was purged under vacuum and refilled with N (three times). (R)-N-(1-(4-chloro-6-methoxypyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-7n (5.79 g, 16.52 mmol) was purged under vacuum and refilled with N (three times). Toluene (180 ml) was added to the amine, and the resulting solution was transferred to a three-neck round-bottom flask. The round-bottom flask was purged under vacuum and refilled with N (three times). The resulting mixture was heated at 95 °C for 2 h. The reaction was cooled and filtered through a pad of Celite. The filter cake was washed with EtOAc. The filtrate was concentrated in vacuo. The product was purified by chromatography on silica gel (0–50% EtOAc / isohexane) to afford (6S,9R)-3-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-7o as a pale orange solid. 1 H NMR(500MHz,DMSO-d6)δ8.01(s,1H), 6.82~6.73(m,2H), 6.73~6.64(m,2H), 6.39(s,1H), 4.83(d,J=5.5Hz,1H), 4.43(m,1 H), 3.74(s,3H), 3.61(s,3H), 3.04(dd,J=18.0,4.9Hz,1H), 2.41(d,J=17.9Hz,1H), 2.32~2.14(m,2H), 1.84~1.63(m,2H).

[0531] Step 7: To a solution of (6S,9R)-3-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-7o (2.00 g, 6.61 mmol) in MeCN (75 mL) and water (75 mL), sulfuric acid (6.6 mL, 1 M, 6.61 mmol) was added, followed by trichloroisocyanuric acid (769 mg, 3.31 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was extracted with DCM (3 × 200 mL). The combined organics were extracted with water (50 mL). The aqueous layer was basified with KOH (3.6 mL, 5 M) and extracted with 10% MeOH in DCM (300 mL). Additional KOH (1.8 ml, 5 M) was added and the aqueous layer was extracted with 10% MeOH in DCM (100 ml). Another portion of KOH (1.8 ml, 5 M) was added and the aqueous layer was extracted with 10% MeOH in DCM (150 ml). The combined organics were dried over Na2SO4 and concentrated in vacuo to give (6S,9R)-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-7p as a brown oil. 1 H NMR(400MHz,DMSO-d6)δ7.78(s,1H), 6.47(s,1H), 4.17~4.11(m,1H), 3.76(s,3H), 3.66(td,J=5.2,2.7Hz,1H), 2.95(ddd,J =17.4,3.9,2.4Hz,1H), 2.57(s,1H), 2.46(dt,J=17.3,1.2Hz,1H), 1.96~1.81(m,2H), 1.72~1.60(m,1H), 1.50~1.36(m,1H).

[0532] Step 8: A solution of (6S,9R)-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-7p (0.99 g, 5.2 mmol) in HBr (48% in water) (8.8 mL, 78 mmol) was heated to reflux for 16 h. The mixture was concentrated in vacuo, the concentrate was diluted with MeOH, loaded onto an SCX cartridge (80 g), the cartridge was washed with MeOH, and the product was eluted with a solution of NH in MeOH (0.7 M) to give (6S,9R)-2,5,6,7,8,9-hexahydro-3H-6,9-epiminocyclohepta[c]pyridin-3-one I-7 as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 7.03 (s, 1H), 6.01 (s, 1H), 4.04 (d, J = 5.4 Hz, 1H), 3.62 (t, J = 5.9 Hz, 1H), 2.83 (dd, J = 17.7, 5.1 Hz, 1H), 2.40 (dt, J = 17.7, 1.3 Hz, 1H), 1.92-1.78 (m, 2H), 1.68-1.56 (m, 1H), 1.45 (dt, J = 9.3, 4.8 Hz, 1H). No exchangeable NH groups observed.

[0533] Intermediate 8 (I-8) [ka]

[0534] Step 1: To a mixture of 4-bromo-5-chloro-2-fluoroaniline I-8a (300 mg, 1.34 mmol) in 1,4-dioxane (5 mL), bis(pinacolato)diboron (509 mg, 2.00 mmol), KOAc (394 mg, 4.00 mmol), and Pd(dppf)Cl (98 mg, 0.13 mmol) were added under N. The reaction mixture was heated to reflux for 1 h and then poured into water, and the product was extracted with DCM (2 × 20 mL). The combined organics were washed with brine, dried over NaSO, and concentrated in vacuo. The product was purified by silica gel chromatography (10% EtOAc / petroleum ether) to give 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b as a white solid. 1 H NMR:(400MHz,DMSO-d6)δ7.14(d,J=12Hz,1H), 6.73(d,J=7.6Hz,1H), 5.86(s,2H), 1.25(s,12H)

[0535] Step 2: To a mixture of 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b (314 mg, 1.16 mmol) in a mixture of 1,4-dioxane (5 mL) and water (1 mL) was added 2-bromo-5-methyl-1,3,4-thiadiazole (138 mg, 0.77 mmol), NaCO (245 mg, 2.31 mmol), and Pd(PPh) (89 mg, 0.08 mmol) under N. The reaction was heated at 100 °C for 16 h, then poured into water and extracted with DCM (2 × 20 mL). The combined organics were washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel chromatography (20% EtOAc / petroleum ether) to give 5-chloro-2-fluoro-4-(5-methyl-1,3,4-thiadiazol-2-yl)aniline I-8 as a white solid. LCMS (Method 3): m / z 244 (M+H) at 1.06 min. + (ES + )

[0536] Intermediate 9 (I-9) [ka] 5-Chloro-2-fluoro-4-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)aniline I-9 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-8b and 2-bromo-5-(trifluoromethyl)-1,3,4-thiadiazole using essentially the same procedure as I-8. 1 H NMR (400MHz, DMSO-d6) δ8.02(d,J=12Hz,1H), 7.00(d,J=8Hz,1H), 6.51(s,2H).

[0537] Intermediate 10 (I-10) [ka]

[0538] Step 1: tert-Butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate I-10a (413.0 mg, 1.29 mmol), 2-bromo-5-(trifluoromethyl)-1,3,4-thiadiazole (200.0 mg, 0.86 mmol), K2CO3 (357.0 mg, 2.58 mmol), and Pd(PPh3)4 (100.0 mg, 0.08 mmol) in a mixture of 1,4-dioxane (5 mL) and water (1 mL) was heated at 100 °C for 5 h under N2. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 × 10 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (33% EtOAc / petroleum ether) to give tert-butyl (4-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)phenyl)carbamate I-10b as a yellow solid. LCMS (Method 5) m / z 345.9 (M+H) at 1.82 min. + (ES + ).

[0539] Step 2: To a solution of tert-butyl (4-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)phenyl)carbamate I-10b (200.0 mg, 0.58 mmol) in MeOH (3 ml) was added a solution of HCl in 1,4-dioxane (725 ul, 4 M). The reaction was stirred at room temperature for 1 h. The pH was adjusted to 7-8 by addition of 2 M NaHCO3. The mixture was diluted with water (5 ml) and extracted with DCM (2 x 10 ml). The combined organics were dried over Na2SO4 and concentrated in vacuo. The product was purified by preparative TLC (33% EtOAc / petroleum ether) to give 4-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)aniline I-10 as a yellow solid. LCMS (Method 5) at 1.17 min, m / z 245.9 (M+H) + (ES + ). 1 H NMR (400MHz, DMSO-d6) δ7.75~7.73(m,2H), 6.68~6.66(m,2H), 6.13(s,2H).

[0540] Intermediate 11 (I-11) [ka]

[0541] Step 1: To a solution of 2-chloro-1-fluoro-4-nitrobenzene I-4a (1.0 g, 5.7 mmol) and oxetan-3-ol (845 mg, 11.4 mmol) in DMF (20 mL) was added CsCO (5.6 g, 17.1 mol). The mixture was heated at 80 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3 × 10 mL). The combined organics were washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography (10% EtOAc / petroleum ether) to afford 3-(2-chloro-4-nitrophenoxy)oxetane I-11a as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ8.36(t,J=2.2Hz,1H), 8.17(ddd,J=9.1,2.8,1.2Hz,1H) , 7.01(d,J=9.1Hz,1H), 5.60~5.48(m,1H), 5.03~4.95(m,2H), 4.67~4.54(m,2H).

[0542] Step 2: To a solution of 3-(2-chloro-4-nitrophenoxy)oxetane I-11a (900 mg, 3.9 mmol) in a mixture of EtOH (10 mL) and saturated aqueous NH4Cl (10 mL) was added iron powder (1.7 g, 31.4 mmol). The reaction was heated at 80 °C for 16 h, cooled, and filtered. The product was extracted from the filtrate with EtOAc (2 × 20 mL). The combined organics were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 3-chloro-4-(oxetan-3-yloxy)aniline 1-11 as a gray solid. The product was used directly in the next step without further purification. LCMS (Method 3) m / z 200.1 (M+H)+ (ES+) at 1.66 min. 1 H NMR(400MHz,DMSO-d6)δ6.65(d,J=2.6Hz,1H), 6.54(d,J=8.7Hz,1H), 6.43(dd,J=8.7,2.6Hz ,1H), 5.10(p,J=5.6Hz,1H), 4.95(s,2H), 4.84(t,J=6.6Hz,2H), 4.54(dd,J=7.2,5.2Hz,2H).

[0543] Intermediate 12 (I-12) [ka]

[0544] Step 1: 2-Chloro-1-((1s,3s)-3-methoxycyclobutoxy)-4-nitrobenzene I-12a was synthesized from 2-chloro-1-fluoro-4-nitrobenzene I-4a and (1s,3s)-3-methoxycyclobutan-1-ol using essentially the same procedure as I-11a. 1H NMR(400MHz,DMSO-d6)δ8.30(d,J=2.8Hz,1H), 8.18(dd,J=9.2,2.8Hz,1H), 7.20(d,J=9.2Hz,1H), 4.65(p ,J=6.9Hz,1H), 3.67(p,J=6.8Hz,1H), 3.17(s,3H), 2.95(ddp,J=9.8,6.8,3.8Hz,2H), 1.98~1.93(m,2H).

[0545] Step 2: 3-Chloro-4-((1s,3s)-3-methoxycyclobutoxy)aniline I-12 was synthesized from 2-chloro-1-((1s,3s)-3-methoxycyclobutoxy)-4-nitrobenzene I-12a using essentially the same procedure as I-11. 1 H NMR(400MHz,DMSO-d6)δ6.71(d,J=8.8Hz,1H), 6.62(d,J=2.8Hz,1H), 6.45(dd,J=8.8,2.8Hz,1H), 4.90( s,2H), 4.20(p,J=7.0Hz,1H), 3.55(p,J=6.8Hz,1H), 3.14(s,3H), 2.77~2.70(m,2H), 1.86~1.83(m,2H).

[0546] Intermediate 13 (I-13) [ka]

[0547] Step 1: To a solution of 4-amino-2-chloro-5-fluorophenol I-13a (0.250 g, 1.55 mmol) in DCM (5 mL) was added di-tert-butyl dicarbonate (371 mg, 1.70 mmol). The resulting mixture was stirred at room temperature for 48 h. THF (5 mL), an additional portion of di-tert-butyl dicarbonate (169 mg, 774 μmol), followed by EtN (216 μL, 1.55 mmol) were added. The mixture was stirred at room temperature for 2 days. The mixture was concentrated in vacuo. The product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl (4-((tert-butoxycarbonyl)oxy)-5-chloro-2-fluorophenyl)carbamate I-13b. 1 H NMR (400MHz, CDCl3) δ8.28(d,J=8.1Hz,1H), 7.00(d,J=10.9Hz,1H), 6.65(s,1H), 1.55(s,9H), 1.53(s,9H).

[0548] Step 2: To a solution of tert-butyl (4-((tert-butoxycarbonyl)oxy)-5-chloro-2-fluorophenyl)carbamate I-13b (200 mg, 547 μmol) in DCM (4 ml) was added morpholine (1.50 ml, 17.4 mmol), and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The product was purified by chromatography on silica gel (0–100% EtOAc / isohexane) to give the product as a mixture containing morpholine. The material was dissolved in DCM (15 ml) and washed with 1 M aqueous HCl (2 × 15 ml). The organics were dried over MgSO and concentrated in vacuo to give tert-butyl (5-chloro-2-fluoro-4-hydroxyphenyl)carbamate I-13c as an orange oil. 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H), 8.76(s,1H), 7.43(d,J=8.2Hz,1H), 6.78(d,J=11.7Hz,1H), 1.43(s,9H).

[0549] Step 3: To a solution of tert-butyl (5-chloro-2-fluoro-4-hydroxyphenyl)carbamate I-13c (144 mg, 479 μmol) in DMF (1.0 mL) was added potassium carbonate (165 mg, 1.20 mmol) and bromocyclobutane (55.6 μl, 575 μmol), and the resulting mixture was stirred at 100 °C for 4 h. After cooling, the mixture was diluted with EtOAc (20 mL) and brine (20 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (20 mL). The combined organics were washed with brine (2 × 20 mL), dried over MgSO4, and concentrated in vacuo. The product was purified by chromatography on silica gel (0–30% EtOAc / isohexane) to afford tert-butyl (5-chloro-4-cyclobutoxy-2-fluorophenyl)carbamate I-13d as a colorless solid. 1 H NMR(400MHz,DMSO-d6)δ8.89(s,1H), 7.56(d,J=8.1Hz,1H), 6.92(d,J=12.1Hz,1H), 4.74(p,J=7.1 Hz,1H), 2.48~2.40(m,2H), 2.11~1.97(m,2H), 1.85~1.72(m,1H), 1.69~1.56(m,1H), 1.44(s,9H).

[0550] Step 4: To a solution of tert-butyl (5-chloro-4-cyclobutoxy-2-fluorophenyl)carbamate I-13d (50 mg, 0.16 mmol) in DCM (1.0 mL) was added HCl in dioxane (1.00 mL, 4.0 molar, 4.00 mmol), and the resulting mixture was stirred at room temperature for 16 h. The mixture was loaded onto an SCX (approximately 10 g), the SCX was washed with MeOH (50 mL), and the product was then eluted with 0.7 M NH in MeOH (50 mL) to give 5-chloro-4-cyclobutoxy-2-fluoroaniline I-13 as a colorless oil. 1H NMR(400MHz,DMSO-d6)δ6.82(d,J=9.3Hz,1H), 6.77(d,J=12.6Hz,1H), 4.89(s,2H), 4.62 ~4.52(m,1H), 2.42~2.29(m,2H), 2.08~1.92(m,2H), 1.82~1.69(m,1H), 1.64~1.50(m,1H)

[0551] Intermediate 14 (I-14) [ka] To a vial containing 4-bromo-5-chloro-2-fluoroaniline I-14a (200 mg, 891 μmol), CsCO (871 mg, 2.67 mmol), cyclopropylboronic acid (76.5 mg, 891 μmol), and Pd(dppf)Cl (65.2 mg, 89.1 μmol) was added 1,4-dioxane (5.0 mL) and water (0.5 mL). The vial was degassed with N for 5 minutes. The mixture was heated at 90 °C for 16 hours. The mixture was cooled and diluted with EtOAc (30 mL), water (30 mL), and brine (10 mL). The layers were separated, and the aqueous was extracted with EtOAc (2 × 20 mL). The combined organics were dried over MgSO and concentrated in vacuo. The product was purified by chromatography on silica gel (0-100% DCM / isohexane) to give 5-chloro-4-cyclopropyl-2-fluoroaniline I-14 as a clear yellow oil. 1 H NMR (400MHz, DMSO-d6) δ6.79(d,J=8.5Hz,1H), 6.67(d,J=12.6Hz,1H), 5.21(s,2H), 1.98~1.86(m,1H), 0.92~0.79(m,2H), 0.60~0.51(m,2H).

[0552] Intermediate 15 (I-15) [ka]

[0553] Step 1: To a solution of methyl 2-chloro-4,5-difluorobenzoate I-15a (377 mg, 1.83 mmol) in DMSO-d6 (3 mL) was added (2,4-dimethoxyphenyl)methanamine (333 μL, 2.19 mmol) and potassium dihydrogen phosphate (373 mg, 2.74 mmol). The reaction mixture was heated at 80 °C for 18 h. The mixture was cooled and diluted with a solution of 10% MeOH in DCM (30 mL) and water. The organics were washed with saturated NH4Cl solution (3 × 50 mL). The solvent was concentrated in vacuo. The product was purified by chromatography on silica gel (0–10% MeOH / DCM) to give methyl 2-chloro-4-((2,4-dimethoxybenzyl)amino)-5-fluorobenzoate I-15b as a colorless solid. 1 H NMR(400MHz,DMSO-d6)δ7.54(d,J=12.6Hz,1H), 7.08(t,J=7.0Hz,2H), 6.62(d,J=7.8Hz,1H), 6.58(d,J =2.4Hz,1H), 6.48(dd,J=8.4,2.4Hz,1H), 4.27(d,J=6.1Hz,2H), 3.84(s,3H), 3.74(s,3H), 3.73(s,3H).

[0554] Step 2: To a solution of methyl 2-chloro-4-((2,4-dimethoxybenzyl)amino)-5-fluorobenzoate I-15b (350 mg, 989 μmol) in THF (15 ml) was added titanium(IV) isopropoxide (420 μl, 1.39 mmol), followed by the dropwise addition of a solution of ethylmagnesium bromide in diethyl ether (923 μl, 3 M, 2.77 mmol). The reaction mixture was stirred for 2 h. Further portions of titanium(IV) isopropoxide (420 μl, 1.39 mmol) and ethylmagnesium bromide in diethyl ether (923 μl, 3 molar, 2.77 mmol) were added at room temperature, and the reaction mixture was stirred for 16 h. The mixture was diluted with water (25 ml) and saturated NH4Cl solution (20 ml). The product was extracted with EtOAc (3 × 100 ml). The combined organics were dried over NaSO and concentrated in vacuo. The product was purified by sequential chromatography on silica gel (0–10% (0.7 M ammonia / MeOH) / DCM) followed by (0–40% EtOAc / isohexane) to afford 1-(2-chloro-4-((2,4-dimethoxybenzyl)amino)-5-fluorophenyl)cyclopropan-1-ol I-15c as a colorless oil. 1 H NMR(500MHz,DMSO-d6)δ7.11~7.02(m,2H), 6.57(d,J=2.4Hz,1H), 6.52~6.44(m,2H), 6.18(dt,J=6.6,3.4H z,1H), 5.47(s,1H), 4.19(d,J=6.2Hz,2H), 3.84(s,3H), 3.73(s,3H), 0.92~0.87(m,2H), 0.75~0.70(m,2H).

[0555] Step 3: To a solution of 1-(2-chloro-4-((2,4-dimethoxybenzyl)amino)-5-fluorophenyl)cyclopropan-1-ol I-15c (17 mg, 48 μmol) in DCM (3 ml) was added TFA (0.37 ml, 4.8 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was dissolved in MeCN and the material was loaded onto an SCX cartridge. The cartridge was washed with MeOH and the product was eluted with 0.7 M NH3 in MeOH to give 1-(4-amino-2-chloro-5-fluorophenyl)cyclopropan-1-ol I-5 as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.02 (d, J = 11.9 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 3.74 (s, 2H), 0.94–0.87 (m, 2H), 0.77–0.70 (m, 2H). One exchangeable proton was not observed.

[0556] Intermediate 17 (I-17) [ka]

[0557] Step 1: To a solution of LDA (2.0 M in THF / heptane / ethylbenzene) (2.90 ml, 5.77 mmol) in THF (18 ml) at −78°C, a solution of tert-butyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-3a (1.00 g, 4.44 mmol) in THF (2 ml) was added, and the resulting mixture was allowed to stir at −78°C for 30 min. A pre-cooled (−78°C) solution of cinnamaldehyde (726 μL, 5.77 mmol) in THF (2 ml) was slowly added to the reaction mixture, and stirring was continued for 5 h while maintaining the temperature below −70°C. Saturated aqueous NaHCO3 (50 ml) was added at −78°C, followed by MTBE (100 ml). The layers were warmed to above 0°C and separated. The aqueous layer was extracted with MTBE (2 x 100 ml). The combined organics were dried over MgSO4 and concentrated in vacuo to give a yellow oil. The product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl (±)-2-((E)-1-hydroxy-3-phenylallyl)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-17a as a thick yellow oil. 1H NMR (400MHz, DMSO-d6) δ7.45~7.38(m,2H), 7.37~7.29(m,2H), 7.29~7.20(m,1H), 6.5 7(d,J=15.9Hz,1H), 6.38(dd,J=15.9,6.4Hz,1H), 5.19(d,J=5.1Hz,1H), 4.50(br.S, 1H), 4.45(d,J=6.5Hz,1H), 4.40~4.30(m,1H), 2.68~2.59(m,1H), 2.34(d,J=8.6Hz,1 H), 2.20(dt,J=14.9,1.8Hz,1H), 1.96~1.80(m,2H), 1.58~1.42(m,2H), 1.41(s,9H).

[0558] Step 2: A solution of tert-butyl (±)-2-((E)-1-hydroxy-3-phenylallyl)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-17a (630 mg, 1.50 mmol) in DCM (25 ml) and MeOH (25 ml) was stirred under N and cooled to −78 °C. Oxygen was then bubbled through the solution for 5 minutes, followed by ozone until the solution turned deep blue, and then oxygen until the solution became colorless. The reaction was then stirred under nitrogen, and dimethyl sulfide (2.22 ml, 30.0 mmol) was added. The resulting mixture was stirred overnight while slowly warming to room temperature. Nitrogen was bubbled through the solution for 20 minutes, and then the mixture was concentrated in vacuo. The product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl (±)-2-(1-hydroxy-2-oxoethyl)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-17b as a pale yellow oil.

[0559] Step 3: To a solution of tert-butyl (±)-2-(1-hydroxy-2-oxoethyl)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-17b (289 mg, 918 μmol) in toluene (10 ml), hydrazine hydrate (90.6 μl, 1.01 mmol) was added, and the resulting mixture was stirred at 120 °C for 1 h. The solvent was removed in vacuo, and the residue was dissolved in MeOH (10 ml), and the solvent was removed. This was repeated three times. The residue was dissolved in DCM (10 ml), TFA (10 ml) was added, and the resulting mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo. The resulting residue was azeotroped with MeOH (3 x 10 ml) to give (±)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridazine 2,2,2-trifluoroacetate as a brown oil. 1H NMR(400MHz,DMSO-d6)δ9.62(s,1H), 9.46(s,1H), 9.14(d,J=5.1Hz,1H), 7.61(d,J=5.1Hz,1H), 5.01(d,J=5.3Hz,1H), 4.52~ 4.47(m,1H), 3.58(dd,J=18.2,5.1Hz,1H), 3.24(d,J=17.5Hz,1H), 2.32~2.19(m,2H), 2.11~1.97(m,1H), 1.96~1.84(m,1H).

[0560] Intermediate 18 (I-18) [ka]

[0561] Step 1: To a solution of (5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-6 (500 mg, 2.81 mmol) in DCM (5 mL) was added EtN (781 μL, 4.22 mmol) and di-tert-butyl dicarbonate (919 mg, 5.62 mol). The reaction was stirred at room temperature for 16 h, then poured into water (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organics were washed with brine, dried over NaSO, and concentrated in vacuo. The product was purified by chromatography on silica gel (10% EtOAc / petroleum ether) to afford tert-butyl (5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxylate I-18a as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ7.99(d,J=4.4Hz,1H), 7.20(d,J=4.8Hz,1H), 4.92(d,J=6.0Hz,1H), 4.45(s,1H) , 3.07~3.02(m,1H), 2.56(s,1H), 2.17~2.09(m,2H), 1.81~1.76(m,1H), 1.70~1.65(m,1H), 1.32(s,9H).

[0562] Step 2: To a solution of tert-butyl (5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxylate (200 mg, 0.72 mol) in MeOH (2 ml) was added NaOMe (117 mg, 2.16 mmol). The reaction was heated at 80 °C for 16 h, cooled, and concentrated in vacuo. The product was purified by preparative TLC (20% EtOAc / petroleum ether) to give tert-butyl (5R,8S)-1-methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxylate I-18b as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ7.93(d,J=5.2Hz,1H), 6.81(d,J=5.2Hz,1H), 4.78(d,J=5.6Hz,1H), 4.41(s,1H), 3.83( s,3H), 2.93(d,J=16.4Hz,1H), 2.37(d,J=17.4Hz,1H), 2.13~2.07(m,2H), 1.77~1.73(m,1H), 1.63~1.57(m,1H).

[0563] Step 3: tert-Butyl (5R,8S)-1-methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxylate I-18b (140 mg, 0.48 mmol) in 1,4-dioxane (1 ml) was added a solution of 4 M HCl in 1,4-dioxane (1 ml). The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give (5R,8S)-1-methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine HCl salt as a red solid. 1 H NMR(400MHz,DMSO-d6)δ7.85(d,J=5.2Hz,1H), 6.68(d,J=5.2Hz,1H), 4.04(d,J=5.2Hz,1H), 3.83~3.81(m,3H), 3 .75(t,J=6Hz,1H), 2.77~2.71(m,1H), 2.27~2.22(m,1H), 1.92~1.88(m,2H), 1.77~1.68(1H), 1.48~1.41(m,1H). 1.32(s,1H).

[0564] Intermediate 19 (I-19) [ka]

[0565] Step 1: To a mixture of 2,3-dichloro-4-methylpyridine I-19a (15.0 g, 92.59 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (14.3 g, 92.59 mmol) in a mixture of 1,4-dioxane (200 mL) and water (40 mL), Pd(dppf)Cl (3.4 g, 6.43 mmol) and NaCO (29.4 g, 280 mmol) were added. The mixture was heated at 110 °C under a N atmosphere for 16 h. The mixture was cooled and diluted with water (100 mL). The product was extracted with EtOAc (3 × 50 mL). The combined organics were washed with brine, dried over NaSO, and concentrated in vacuo. The product was purified by chromatography on silica gel (10% EtOAc / petroleum ether) to afford 3-chloro-4-methyl-2-vinylpyridine I-19b as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ8.38(d,J=4.8Hz,1H), 7.32(d,J=4.8Hz,1H), 7.24(dd,J=18.8, 25.2Hz,1H), 6.40(dd,J=3.2,25.6Hz,1H), 5.60(dd,J=2.4Hz,10.8Hz,1H), 2.37(s,3H).

[0566] Step 2: To a solution of 3-chloro-4-methyl-2-vinylpyridine I-19b (11 g, 71.61 mol) in a mixture of DCM (1 mL) and MeOH (25 mL) at −78 °C, O was bubbled through for 30 min. The reaction was quenched with dimethyl sulfide, and the mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (10% EtOAc / petroleum ether) to give 3-chloro-4-methylpicolinaldehyde I-19c as a colorless oil. 1H NMR (400MHz, DMSO-d6) δ10.15(s,1H), 8.62(d,J=4.8Hz,1H), 7.69(d,J=5.2Hz,1H), 2.45(s,3H).

[0567] Step 3: To a solution of 3-chloro-4-methylpicolinaldehyde I-19c (5 g, 32.14 mmol) in DCM (30 ml) at 0 °C was added DAST (15.5 g, 96.41 mmol). The mixture was stirred at 0 °C for 2 h, and then the reaction mixture was poured onto saturated aqueous NaHCO (30 ml). The aqueous was extracted with DCM (3 × 30 ml), and the combined organics were dried over NaSO and concentrated in vacuo. The product was purified by chromatography on silica gel (10% EtOAc / petroleum ether) to give 3-chloro-2-(difluoromethyl)-4-methylpyridine I-19d as a pale yellow oil. 1 H NMR (400MHz, DMSO-d6) δ8.50 (d, J = 4.8 Hz, 1H), 7.62 (d, J = 4.4 Hz, 1H), 7.18 (t, J = 61.2 Hz, 1H), 2.43 (s, 3H).

[0568] Step 4: To a mixture of 3-chloro-2-(difluoromethyl)-4-methylpyridine I-19d (1.9 g, 10.70 mmol) and AIBN (265 mg, 1.07 mmol) in CCl4 (20 mL) was added NBS (2.3 g, 12.84 mmol). The reaction was heated at 80 °C for 16 h. The reaction mixture was concentrated in vacuo. The product was purified by chromatography on silica gel (5% EtOAc / petroleum ether) to give 4-(bromomethyl)-3-chloro-2-(difluoromethyl)pyridine I-19e as a colorless oil. 1 H NMR: (400MHz, DMSO-d6) δ8.65 (d, J = 4.8 Hz, 1H), 7.85 (d, J = 4.4 Hz, 1H), 7.24 (t, J = 53.2 Hz, 1H), 4.78 (s, 2H).

[0569] Step 5: To a solution of 4-(bromomethyl)-3-chloro-2-(difluoromethyl)pyridine I-19e (1 g, 3.90 mmol) in MeCN (10 ml) was added NMO (913 mg, 7.80 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column (10% EtOAc / petroleum ether) to give 3-chloro-2-(difluoromethyl)isonicotinaldehyde I-19f as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H), 8.85(d,J=4.8Hz,1H), 7.93(d,J=4.8Hz,1H), 7.34(t,J=61.2Hz,1H).

[0570] Step 6: (S)—N-((3-chloro-2-(difluoromethyl)pyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide I-19g was synthesized from 3-chloro-2-(difluoromethyl)isonicotinaldehyde I-19f using essentially the same procedure as for I-7j. 1 H NMR(400MHz,DMSO-d6)δ8.87(s,1H), 8.79(d,J=5.2Hz,1H), 8.11(d,J=4.8Hz,1H), 7.31(t,J=53.2Hz,1H), 1.22(s,9H)

[0571] Step 7: To a solution of (S)—N-((3-chloro-2-(difluoromethyl)pyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide I-19g (600 mg, 2.04 mmol) in THF (8 ml) at −78° C. was added a solution of but-3-en-1-ylmagnesium bromide (8.1 ml, 0.5 M, 4.07 mmol) in THF (8 ml) dropwise. The mixture was stirred at −78° C. for 2 h, then the reaction was quenched with saturated aqueous NH4Cl (10 ml). The product was extracted with EtOAc (3×10 ml). The combined organics were washed with brine, dried over Na2SO4, and concentrated in vacuo. The product was purified by chromatography on silica gel (2% MeOH / DCM) to give (S)—N-((R)-1-(3-chloro-2-(difluoromethyl)pyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-19h as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.65(d,J=4.8Hz,1H), 7.75(d,J=5.2Hz,1H), 7.21(t,J=53.2Hz,1H), 5.89(d,J=7.2Hz,1H), 5.85~5.77(m,1 H), 5.12~5.08(m,1H), 5.03~4.99(m,1H), 4.74~4.68(m,1H), 2.27~2.09(m,2H), 1.95~1.86(m,1H), 1.80~1.71(m,1H), 1.07(s,9H).

[0572] Step 8: (R)-1-(3-chloro-2-(difluoromethyl)pyridin-4-yl)pent-4-en-1-amine I-19i was synthesized from (S)—N-((R)-1-(3-chloro-2-(difluoromethyl)pyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-19h using essentially the same procedure as for I-7m. 1H NMR(400MHz,DMSO-d6)δ8.60(d,J=4.8Hz,1H), 7.85(d,J=5.2Hz,1H), 7.20(t,J=53.2Hz,1H), 5.86~5.76 (m,1H), 5.05~4.94(m,2H), 4.26~4.22(m,1H), 2.20~2.04(m,4H), 1.69~1.60(m,1H), 1.58~1.51(m,1H).

[0573] Step 9: (R)—N-(1-(3-chloro-2-(difluoromethyl)pyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline I-19j was synthesized from I-1-(3-chloro-2-(difluoromethyl)pyridin-4-yl)pent-4-en-1-amine I-19i using essentially the same procedure as for I-7m. 1 H NMR(400MHz,DMSO-d6)δ8.54(d,J=5.2Hz,1H), 7.63(d,J=4.8Hz,1H), 7.22(t,J=53.6Hz,1H), 6.64(d,J=8.8Hz,2H), 6.38(d,J=9.2Hz, 2H), 6.10(d,J=8.4Hz,1H), 5.90~5.80(m,1H), 5.05~4.98(m,2H), 4.75~4.70(m,1H), 3.57(s,3H), 2.35~2.15(m,2H), 1.83~1.70(m,2H)

[0574] Step 10: (R)—N-(1-(3-chloro-2-(difluoromethyl)pyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline I-19j (150 mg, 0.43 mmol) in toluene (5 ml), NaO t A mixture of Bu (61 mg, 0.64 mmol) and Pd-178 (10 mg, 0.02 mmol) was heated at 95 °C for 3 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by preparative TLC (50% EtOAc / petroleum ether) to give (5R,8S)-1-(difluoromethyl)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-19k as an orange solid. 1H NMR(400MHz,DMSO-d6)δ8.37(d,J=4.8Hz,1H), 7.47(d,J = 4.8Hz,1H), 6.98~6.80(m,3H), 6.72~6.70(m,2H), 4.94(d,J=5.6Hz,1H), 4.56(t,J=5.2Hz,1H), 3.61(s,3H), 3.20(dd,J = 4.0,18.0Hz,1H), 2.62(d,J=17.6Hz,1H), 2.33~2.24(m,2H), 1.88~1.83(m,1H), 1.81~1.72(m,1H).

[0575] Step 11: (5R,8S)-1-(Difluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-19 was synthesized from (5R,8S)-1-(difluoromethyl)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-19k using essentially the same procedure as I-6. 1 H NMR(400MHz,DMSO-d6)δ8.33(d,J=4.8Hz,1H), 7.22(d,J = 4.8Hz,1H), 6.89(t,J = 54.0Hz,1H), 4.18(d,J=5.6Hz,1H), 3.79(t,J=5.2Hz,1H), 3.11(dd,J = 4.4Hz,17.6Hz,1H), 2.74(s,1H), 2.67(d,J=17.2Hz,1H), 1.99~1.89(m,2H), 1.75~1.70(m,1H), 1.51~1.45(m,1H).

[0576] Intermediate 20 (I-20) [ka]

[0577] Step 1: To a solution of 3-bromopicolinic acid I-20a (5.0 g, 24.8 mmol) in DMF (60 mL) was added N,O-dimethylhydroxylamine hydrochloride (3.6 g, 37.2 mmol), DIPEA (21.6 mL, 124 mmol), and HATU (14.1 g, 37.2 mmol). The reaction was stirred at room temperature for 16 h, then poured into water, and the product was extracted with EtOAc (2 × 100 mL). The combined organics were washed with brine, dried over NaSO, and concentrated in vacuo. The product was purified by chromatography on silica gel (25–50% EtOAc / petroleum ether) to afford 3-bromo-N-methoxy-N-methylpicolinamide I-20b as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ8.59~8.57(m,1H), 8.18~8.15(m,1H), 7.45~7.42(m,1H), 3.49(s,3H), 3.30(s,3H).

[0578] Step 2: To a solution of 3-bromo-N-methoxy-N-methylpicolinamide I-20b (5.8 g, 23.8 mmol) in THF (50 ml) at −78 °C, a solution of but-3-en-1-ylmagnesium bromide (0.5 M in 52 ml THF, 26.1 mmol) in THF (52 ml) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was poured into saturated aqueous NH₄Cl (100 ml) and extracted with EtOAc (2 × 200 ml). The combined organics were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The product was purified by chromatography on silica gel (5% EtOAc / petroleum ether) to give 1-(3-bromopyridin-2-yl)pent-4-en-1-one I-20c as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ8.66~8.64(m,1H), 8.24~8.21(m,1H), 7.54~7.50(m,1H) , 5.91~5.81(m,1H), 5.09~4.96(m,2H), 3.14(t,J=7.2Hz,2H), 2.39~2.33(m,2H).

[0579] Step 3: To a solution of 1-(3-bromopyridin-2-yl)pent-4-en-1-one I-20c (3.4 g, 14.1 mmol) in THF (50 mL) was added (S)-2-methylpropane-2-sulfinamide (5.1 g, 42.4 mmol) and titanium tetraisopropoxide (20.1 g, 70.8 mmol). The reaction mixture was heated at 80 °C for 16 h, then poured into water and extracted with EtOAc (2 × 100 mL). The combined organics were washed with brine, dried over NaSO, and concentrated in vacuo. The product was purified by chromatography on silica gel (10–20% EtOAc / petroleum ether) to afford (S)-N-(1-(3-bromopyridin-2-yl)pent-4-en-1-ylidene)-2-methylpropane-2-sulfinamide I-20d as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ8.53(d,J=4.8Hz,1H), 8.06(d,J=8.4Hz,1H), 7.36~7.33(m,1H), 5.93~5.84(m,1H), 5.13~4.98(m,2H), 2.89~2.67(m,2H), 2.43~2.38(m,2H), 1.16(s,9H).

[0580] Step 4: To a solution of (S)—N-(1-(3-bromopyridin-2-yl)pent-4-en-1-ylidene)-2-methylpropane-2-sulfinamide I-20d (2 g, 5.9 mmol) in THF (20 ml) at 0 °C was added LiAlH (333 mg, 8.8 mmol). The reaction was slowly warmed to room temperature and stirred for 2 h. Upon completion, the reaction was quenched by careful addition of water (20 ml) and the product was extracted with EtOAc (2 × 30 ml). The combined organics were washed with brine, dried over NaSO, and concentrated in vacuo. The product was purified by chromatography on silica gel (20-33% EtOAc / petroleum ether) to afford (S)—N-((R)-1-(3-bromopyridin-2-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-20e as a yellow oil. 1HNMR(400MHz,DMSO-d6)δ8.59~8.57(m,1H), 8.05~8.03(m,1H), 7.25(dd,J=8.0,4.4Hz,1H), 5.84~5.74(m,1H), 5.48(d,J=8.4Hz,1H), 5.04~4.95(m,2H), 4.82~4.77(m,1H), 2.10~2.00(m,2H), 1.99~1.94(m,2H), 1.01(s,9H).

[0581] Step 5: (R)-1-(3-Bromopyridin-2-yl)pent-4-en-1-amine I-20f was synthesized from (S)—N-((R)-1-(3-bromopyridin-2-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-20e using essentially the same procedure as I-7l. LCMS (Method 5) m / z 241.1 (M+H) at 0.64 min + (ES + ).

[0582] Step 6: To a solution of (R)-1-(3-bromopyridin-2-yl)pent-4-en-1-amine I-20f (430 mg, 1.7 mmol) in DCM (15 mL) was added (4-methoxyphenyl)boronic acid (1.1 g, 7.5 mmol), EtN (1.51 mL, 11.04 mmol), and Cu(OAc) (648 mg, 3.56 mmol). The reaction was stirred at room temperature under an O atmosphere for 2 days. The reaction solution was poured into aqueous NaOH (10 mL, 2 M) and filtered through Celite. The aqueous layer was extracted with DCM (2 × 30 mL), and the combined organics were washed with brine, dried over NaSO, and concentrated in vacuo. The product was purified by preparative TLC (33% EtOAc / petroleum ether) to afford (R)-N-(1-(3-bromopyridin-2-yl)pent-4-en-1-yl)-4-methoxyaniline I-20g as a yellow oil. 1H NMR(400MHz,DMSO-d6)δ8.52~8.50(m,1H), 8.01~7.99(m,1H), 7.19(dd,J=7.2,4.8Hz,1H), 6.64~6.61(m,2H), 6.54~6.50(m,2H), 5.88~5.78 (m,1H), 5.56(d,J=10.0Hz,1H), 5.03~4.95(m,2H), 4.88~4.82(m,1H), 3.58(s,3H), 2.26~2.18(m,1H), 2.10~2.03(m,1H), 1.85~1.78(m,2H).

[0583] Step 7: To a solution of (R)-N-(1-(3-bromopyridin-2-yl)pent-4-en-1-yl)-4-methoxyaniline I-20g (180 mg, 0.52 mmol) in toluene (4 ml), NaO t Bu (75 mg, 0.78 mmol) and Pd-178 (12.3 mg, 0.03 mmol) were added. The reaction solution was heated at 95 °C under a N atmosphere for 2 h. Upon completion, the reaction mixture was poured into water and extracted with EtOAc (2 × 20 ml). The combined organics were washed with brine, dried over NaSO, and concentrated in vacuo. The product was purified by preparative TLC (50% EtOAc / petroleum ether) to afford (6S,9R)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[b]pyridine I20h as a pink solid. 1 H NMR(400MHz,DMSO-d6)δ8.26~8.24(m,1H), 7.34~7.32(m,1H), 7.10~7.06(m,1H), 6.75~6.68(m,4H), 4.68(d,J=5.6Hz,1H), 4.49(t, J=5.6Hz,1H), 3.60(s,3H), 3.18~3.10(m,1H), 2.43(d,J=17.2Hz,1H), 2.30~2.26(m,2H), 1.84(t,J=9.2Hz,1H), 1.73~1.66(m,1H).

[0584] Step 8: (6S,9R)-6,7,8,9-Tetrahydro-5H-6,9-epiminocyclohepta[b]pyridine I-20 was synthesized from (6S,9R)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[b]pyridine I20h using essentially the same procedure as I-6. 1 H NMR(400MHz,DMSO-d6)δ8.19(d,J=4.8Hz,1H), 7.41(d,J=7.6Hz,1H), 7.11~7.08(m,1H), 4.09(br.s, 1H), 3.72(br.s,1H), 3.05~3.00(m,2H), 1.96~1.91(m,2H), 1.73(t,J=9.6Hz,1H), 1.46~1.41(m,1H)

[0585] Intermediate 21 (I-21) [ka]

[0586] Step 1: To a solution of diisopropylamine (317 mg, 3.14 mmol) in THF (8 ml) at -78 °C under N2 atmosphere, n A solution of BuLi (1.26 mL, 2.5 M in hexanes, 3.14 mmol) was added. The mixture was stirred at −78° C. for 30 minutes, then a solution of 3-bromo-4-fluoropyridine I-21a (500 mg, 2.86 mmol) in THF (8 mL) was added. The reaction was stirred at −78° C. for 30 minutes, then TMS-Cl (376 mg, 3.43 mmol) was added, and the reaction was stirred at −78° C. for an additional 30 minutes. Upon completion, the reaction was poured into a cooled solution of 1 M HCl (20 mL) at 0° C. The product was extracted with EtOAc (2×20 mL). The combined organics were concentrated in vacuo, and the residue was purified by preparative TLC (20% EtOAc / petroleum ether) to afford 3-bromo-4-fluoro-5-(trimethylsilyl)pyridine I-21b as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.82(d,J=10.0Hz,1H), 8.50(d,J=8.0Hz,1H), 0.35(s,9H).

[0587] Step 2: To a solution of diisopropylamine (3.12 ml, 22.2 mmol) in THF (10 ml) at -78 °C under N2 atmosphere, n BuLi (8.9 mL, 2.5 M in hexane, 22.2 mmol) was added. The mixture was stirred at -78 °C for 30 minutes, then a solution of 3-bromo-4-fluoro-5-(trimethylsilyl)pyridine I-21b (3.65 g, 14.8 mmol) in THF (40 ml) was added. The reaction was stirred at -78 °C for 2 hours, then a solution of (S)-2-methyl-N-(pent-4-en-1-ylidene)propane-2-sulfinamide (3.6 g, 17.7 mmol) in THF (20 ml) was added. The synthesis of (S)-2-methyl-N-(pent-4-en-1-ylidene)propane-2-sulfinamide is described in J. Am. Chem. Soc. 2020, 142, 21, 9850-9857. The reaction was stirred at −78° C. for 2 hours and then poured into a cooled solution of 1 M HCl (50 ml) at 0° C. The product was extracted with EtOAc (2×50 ml) and the combined organics were concentrated in vacuo. The product was purified by chromatography on silica gel (20% EtOAc / petroleum ether) to afford (S)—N-((R)-1-(3-bromo-4-fluoro-5-(trimethylsilyl)pyridin-2-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-21c as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.24(d,J=8.0Hz,1H), 5.84~5.74(m,1H), 5.06~4.96(m,2H), 4.80~4.76(br.s,1H), 2.20~2.09(m,2H), 2.05~1.86(m,2H), 1.00(s,9H), 0.31(s,9H)

[0588] Step 3: (R)-1-(3-Bromo-4-fluoro-5-(trimethylsilyl)pyridin-2-yl)pent-4-en-1-amine I-21d was synthesized from (S)—N-((R)-1-(3-bromo-4-fluoro-5-(trimethylsilyl)pyridin-2-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-21c using essentially the same procedure as I-7l. LCMS (Method 5) m / z 331.1 (M+H) at 2.89 min + (ES + )

[0589] Step 4: (R)-N-(1-(3-bromo-4-fluoro-5-(trimethylsilyl)pyridin-2-yl)pent-4-en-1-yl)-4-methoxyaniline I-21e was synthesized from (R)-1-(3-bromo-4-fluoro-5-(trimethylsilyl)pyridin-2-yl)pent-4-en-1-amine I-21d using essentially the same procedure as I-7m. LCMS (Method 5) m / z 437.2 (M+H) at 3.26 min + (ES + )

[0590] Step 5: To a solution of (R)—N-(1-(3-bromo-4-fluoro-5-(trimethylsilyl)pyridin-2-yl)pent-4-en-1-yl)-4-methoxyaniline I-21e (340 mg, 0.78 mmol, 1 equiv) in THF (2 ml) and water (2 ml) at 0° C. was added a solution of TBAF (850 μl, 1 M in THF, 0.85 mmol). The reaction was heated at 60° C. for 2 hours. The reaction was cooled and concentrated in vacuo. The residue was partitioned between EtOAc and water and the product was extracted with EtOAc (2×20 ml). The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The product was purified by chromatography on silica gel (10% EtOAc / petroleum ether) to give (R)-N-(1-(3-bromo-4-fluoropyridin-2-yl)pent-4-en-1-yl)-4-methoxyaniline I-21f as a yellow oil. LCMS (Method 5) m / z 365.0 (M+H) at 3.75 min.+ (ES + )

[0591] Step 6: (6S,9R)-4-Fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[b]pyridine I-21g was synthesized from (R)—N-(1-(3-bromo-4-fluoropyridin-2-yl)pent-4-en-1-yl)-4-methoxyaniline I-21f using essentially the same procedure as for I-20h. LCMS (Method 5) m / z 285.2 (M+H) at 2.43 min + (ES + )

[0592] Step 7: (6S,9R)-4-Fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[b]pyridine I-21 was synthesized from (6S,9R)-4-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[b]pyridine I-21g using essentially the same procedure as I-6. LCMS (Method 5) m / z 179.1 (M+H) at 2.23 min + (ES + )

[0593] Intermediate 22 (I-22) [ka]

[0594] Step 1: To a solution of diisopropylamine (30.7 g, 304 mmol) in dry THF (300 ml) at -70°C, nBuLi (121 ml, 2.5 M in hexanes, 303 mmol) was added. After stirring at −70° C. for 30 min, a solution of 2,3-dichloropyridine I-22a (30 g, 203 mmol) in dry THF (100 ml) was added. The reaction was stirred at −70° C. for an additional 1 h, then dry DMF (39.2 ml, 304 mmol) was added, and the mixture was stirred for an additional 1 h. The reaction was warmed to room temperature and poured into saturated aqueous NH4Cl (200 ml). The product was extracted with EtOAc (3 × 200 ml), and the combined organics were washed with water and brine (200 ml), dried over Na2SO4, and concentrated in vacuo. The product was purified by chromatography on silica gel (20% EtOAc / petroleum ether) to give 2,3-dichloroisonicotinaldehyde I-22b as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.28 (s, 1H), 8.58 (d, J = 4.8Hz, 1H), 7.75 (d, J = 4.8Hz, 1H).

[0595] Step 2: (S)—N-((2,3-Dichloropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide I-22c was synthesized from 2,3-dichloroisonicotinaldehyde I-22b using essentially the same procedure as for I-7j. 1 H NMR(400MHz,DMSO-d6)δ8.80(s,1H), 8.52(d,J=4.8Hz,1H), 7.93(d,J=4.8Hz,1H), 1.21(s,9H)

[0596] Step 3: To a solution of (S)—N-((2,3-dichloropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide I-22c (34.2 g, 123 mmol) in THF (400 ml) at −70° C. was added a solution of but-3-en-1-ylmagnesium bromide (68 ml, 2.0 M in THF, 136 mmol). The reaction was stirred at −70° C. for 4 h and then quenched by the addition of saturated aqueous NH4Cl (200 ml). The product was extracted with EtOAc (3×200 ml), and the combined organics were washed with water and brine (200 ml), dried over Na2SO4, and concentrated in vacuo. The product was purified by chromatography on silica gel (20% EtOAc / petroleum ether) to give (S)—N-((R)-1-(2,3-dichloropyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-22d as a white solid and (S)—N-((S)-1-(2,3-dichloropyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide P2 as a white solid. I-22d: 1 H NMR(400MHz,DMSO-d6)δ8.40(d,J=5.0Hz,1H), 7.59(d,J=5.0Hz,1H), 5.90~5.74(m,2H), 5. 17~4.96(m,2H), 4.65(q,J=3.0Hz,1H), 2.23~2.11(m,2H), 1.95~1.67(m,2H), 1.07(s,9H). P2: 1 H NMR(400MHz,DMSO-d6)δ8.39(d,J=5.2Hz,1H), 7.68(d,J=5.2Hz,1H), 6.08(d,J=9.8Hz,1H), 5.85~5. 74(m,1H), 5.11~4.93(m,2H), 4.64~4.58(m,1H), 2.24~2.02(m,2H), 1.90~1.60(m,2H), 1.12(s,9H).

[0597] Step 4: A mixture of (S)—N—((R)-1-(2,3-dichloropyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-22d (500 mg, 1.49 mmol), Zn(CN) (105 mg, 0.89 mmol), Zn (9.8 mg, 0.15 mmol), and Pd(dppf)Cl (105 mg, 0.15 mmol) was heated in a microwave at 160° C. for 1 hour. After completion of the reaction, the mixture was concentrated in vacuo, and the residue was purified by silica gel column (50% EtOAc / petroleum ether) to give (S)—N—((R)-1-(3-chloro-2-cyanopyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-22e as a yellow oil. LCMS (Method 5) at 2.67 min, m / z 326.1, 328.1 (M+H) + (ES + )

[0598] Step 5: (R)-4-(1-aminopent-4-en-1-yl)-3-chloropicolinonitrile I-22f was synthesized from (S)—N-((R)-1-(3-chloro-2-cyanopyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-22e using essentially the same procedure as for I-7l. LCMS (Method 5) m / z 222.0, 224.0 (M+H) at 0.55 min + (ES + )

[0599] Step 6: (R)-3-chloro-4-(1-((4-methoxyphenyl)amino)pent-4-en-1-yl)picolinonitrile I-22g was synthesized from (R)-4-(1-aminopent-4-en-1-yl)-3-chloropicolinonitrile I-22f using essentially the same procedure as I-7m. LCMS (Method 5) m / z 328.0, 330.0 (M+H) at 1.69 min + (ES + )

[0600] Step 7: (R)-3-chloro-4-(1-((4-methoxyphenyl)amino)pent-4-en-1-yl)picolinonitrile I-22g (100 mg, 0.31 mmol) in toluene (1.5 ml), NaO t A mixture of Bu (45 mg, 0.47 mmol) and Pd-172 (9.2 mg, 0.015 mmol) was heated at 95 °C under a N atmosphere for 2 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The product was purified by preparative TLC (33% EtOAc / petroleum ether) to give (5R,8S)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-1-carbonitrile I-22h as a yellow solid. LCMS (Method 5) m / z 292.1 (M+H) at 1.44 min + (ES + )

[0601] Step 8: (5R,8S)-6,7,8,9-Tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-1-carbonitrile I-22 was synthesized from (5R,8S)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-1-carbonitrile I-22h using essentially the same procedure as I-6. LCMS (Method 5) m / z 186.1 (M+H) at 0.45 min + (ES + )

[0602] Intermediate 23 (I-23) [ka]

[0603] Step 1: To a solution of 3-bromo-4-methylpyridin-2-ol I-23a (4 g, 21.39 mmol) in MeCN (40 ml) was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (4.57 g, 25.67 mmol) and NaSO (3.51 g, 24.72 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was then diluted with water (40 ml), and the product was extracted with DCM (2 × 40 ml). The combined organics were washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by chromatography on silica gel (5% EtOAc / petroleum ether) to give 3-bromo-2-(difluoromethoxy)-4-methylpyridine 1-23b as a colorless oil. LCMS (Method 5) m / z 238 (M+H) at 0.45 min + (ES + ). 1 H NMR (400MHz, CDCl3) δ7.96(d,J=5.2Hz,1H), 7.44(t,J=72.4Hz,1H), 6.98(d,J=5.2Hz,1H), 2.45(s,3H).

[0604] Step 2: To a solution of 3-bromo-2-(difluoromethoxy)-4-methylpyridine 1-23b (4 g, 16.88 mmol) in CCl4 (40 mL) was added AIBN (284 mg, 1.68 mmol) and NBS (9.24 g, 50.63 mmol). The reaction was heated at 90 °C for 16 h. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (5-10% EtOAc / petroleum ether) to give 3-bromo-4-(dibromomethyl)-2-(difluoromethoxy)pyridine I-23c as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.35 (d, J = 5.6 Hz, 1H), 7.72 (t, J = 72.0 Hz, 1H), 7.77 (d, J = 5.2 Hz, 1H), 7.34 (s, 1H).

[0605] Step 3: To a solution of 3-bromo-4-(dibromomethyl)-2-(difluoromethoxy)pyridine I-23c (5 g, 12.72 mmol) in a mixture of THF (50 mL) and water (10 mL) was added AgNO (7.57 g, 44.53 mmol). The resulting mixture was heated to reflux for 16 h and then diluted with water (70 mL). The product was extracted with DCM (2 × 100 mL), and the combined organics were washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel column (2% EtOAc / petroleum ether) to afford 3-bromo-2-difluoromethoxy)isonicotinaldehyde I-23d as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H), 8.41(d,J=4.8Hz,1H), 7.77(t,J=72.0Hz,1H), 7.55(d,J=5.2Hz,1H).

[0606] Step 4: (S)—N-((3-Bromo-2-(difluoromethoxy)pyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide I-23e was synthesized from 3-bromo-2-difluoromethoxy)isonicotinaldehyde I-23d using essentially the same procedure as for I-7j. 1 H NMR (400MHz, DMSO-d6) δ8.79(s,1H), 8.35(d,J=12.0Hz,1H), 7.76(t,J=71.6Hz,1H), 7.74(d,J=4.8Hz,1H), 1.22(s,9H).

[0607] Step 5: To a solution of (S)—N-((3-bromo-2-(difluoromethoxy)pyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide I-23e (2 g, 5.65 mmol) in THF (20 ml) at −70° C. was added a solution of but-3-en-1-ylmagnesium bromide (17 ml, 0.5 M in THF, 8.47 mmol) dropwise. The resulting solution was stirred at −70° C. for 1 h. Aqueous NH4Cl solution was added to the reaction mixture. The mixture was diluted with water (20 ml) and the aqueous layer was extracted with DCM (2×20 ml). The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The product was purified by chromatography on a silica gel column (10% MeOH / DCM) to give (S)—N-((R)-1-(3-bromo-2-(difluoromethoxy)pyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-23f as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ8.23(d,J=5.2Hz,1H), 7.71(t,J=72.4Hz,1H), 7.40(d,J=5.2Hz,1H), 5.89~5 .78(m,2H), 5.13~5.00(m,2H), 4.68~4.63(m,1H), 2.27~2.08(m,2H), 1.92~1.69(m,2H), 1.01(s,9H).

[0608] Step 6: 0°C tTo a solution of (S)—N—((R)-1-(3-bromo-2-(difluoromethoxy)pyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-23f (1.5 g, 3.66 mmol) in BuOH (15 ml) was added a solution of HCl in dioxane (4.57 ml, 4 M, 18.29 mmol). The reaction was stirred at room temperature for 2.5 h, and then water was added. The pH of the aqueous layer was adjusted to 7–8 by the addition of saturated aqueous NaHCO3. The aqueous layer was extracted with DCM (2 × 30 ml), and the combined organics were washed with brine, dried over Na2SO4, and concentrated in vacuo to give (R)-1-(3-bromo-2-(difluoromethoxy)pyridin-4-yl)pent-4-en-1-amine I-23f as a yellow oil. LCMS (Method 5) m / z 306.9, 308.9 (M+H) at 1.06 min + (ES + )

[0609] Step 7: (R)—N-(1-(3-bromo-2-(difluoromethoxy)pyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline I-23g was synthesized from (R)-1-(3-bromo-2-(difluoromethoxy)pyridin-4-yl)pent-4-en-1-amine I-23f using essentially the same procedure as for I-7m. 1 H NMR(400MHz,DMSO-d6)δ8.11(d,J=5.2Hz,1H), 7.71(t,J=72.0Hz,1H), 7.28(d,J=5.2Hz,1H), 6.64(d,J=8.8Hz,2H), 6.36(d,J=9.2Hz,2 H), 6.11(d,J=8.0Hz,1H), 5.91~5.81(m,1H), 5.06~4.98(m,2H), 4.66~4.60(m,1H), 3.57(s,3H), 2.34~2.15(m,2H), 1.78~1.72(m,2H).

[0610] Step 8: (5R,8S)-1-(Difluoromethoxy)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-23h was synthesized from (R)—N-(1-(3-bromo-2-(difluoromethoxy)pyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline I-23g using essentially the same procedure as for I-20h. LCMS (Method 5) m / z 333.0 (M+H) at 1.61 min + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ7.97(d,J=5.2Hz,1H), 7.59(t,J=73.2Hz,1H), 7.20(d,J=4.8Hz,1H), 6.80(d,J=9.2Hz,2H), 6.70(d,J=9.2Hz, 2H), 4.89(d,J=5.2Hz,1H), 4.54(t,J=5.2Hz,1H), 3.61(s,3H), 2.88(dd,J=4.8Hz,18.0Hz,1H), 2.30~2.26(m,3H), 1.86~1.74(m,2H).

[0611] Step 9: (5R,8S)-1-(Difluoromethoxy)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-23 was synthesized from (5R,8S)-1-(difluoromethoxy)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-23h using essentially the same procedure as I-6. LCMS (Method 5) m / z 227.0 (M+H) at 0.24 min + (ES + )

[0612] Intermediate 25 (I-25) [ka]

[0613] Step 1: To a solution of 3-bromo-5-fluoropicolinic acid I-25a (5 g, 22.72 mmol) in DCM (100 mL) at 0 °C, N,O-dimethylhydroxylamine hydrochloride (2.43 g, 25 mmol), DIPEA (15.86 mL, 90.88 mmol), and HATU (12.95 g, 34.08 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (50 mL) and washed with water (2 × 100 mL). The combined organics were dried over NaSO and concentrated in vacuo. The product was purified by chromatography on silica gel (20% EtOAc / petroleum ether) to give 3-bromo-5-fluoro-N-methoxy-N-methylpicolinamide as an oil. 1 H NMR(400MHz,DMSO-d6)δ8.66(d,J=2.4Hz,1H), 8.33(dd,J = 2.4,8.8Hz,1H), 3.48(s,3H), 3.30(s,3H).

[0614] Step 2: To a solution of 3-bromo-5-fluoro-N-methoxy-N-methylpicolinamide (4.2 g, 16.03 mmol) in THF (80 mL) at 0 °C, a solution of but-3-en-1-ylmagnesium bromide (48 mL, 0.5 M in THF, 24 mmol) was added dropwise. The reaction was stirred for 30 minutes and then poured into saturated aqueous NH4Cl (50 mL), and the product was extracted with EtOAc (4 x 50 mL). The combined organics were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The product was purified by chromatography on silica gel (5% EtOAc / petroleum ether) to give 1-(3-bromo-5-fluoropyridin-2-yl)pent-4-en-1-one I-25c as a yellow oil. 1 H NMR(400MHz, CDCl3) δ8.44(d,J=2Hz,1H), 7.75(dd,J = 2.4Hz,7.6Hz,1H), 5.93~5.83(m,1H), 5.10~4.99(m,2H), 3.19(t,J=7.2Hz,2H), 2.49~2.44(m,2H).

[0615] Step 3: (S)—N-(1-(3-bromo-5-fluoropyridin-2-yl)pent-4-en-1-ylidene)-2-methylpropane-2-sulfinamide I-25d was synthesized from 1-(3-bromo-5-fluoropyridin-2-yl)pent-4-en-1-one I-25c using essentially the same procedure as for I-20d. 1 H NMR(400MHz, CDCl3) 8.40(s,1H), 7.61(d,J=6.6Hz,1H), 5.96~5.83(m,1H), 5.06(dd,J=31.8,13.8 Hz,2H), 2.97~2.89(m,1H), 2.76~2.68(m,1H), 2.51~2.46(m,2H), 1.26(s,9H).

[0616] Step 4: To a solution of (S)—N-(1-(3-bromo-5-fl...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof 【Chemical 1】 (In the formula, Ring B is a monocyclic aromatic group, or is a monocyclic or bicyclic heteroaromatic group, Each of which is halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, NHCO-aryl, -(CH ２ ) ｑ -O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl and CO ２ -alkyl, and the aryl group, heteroaryl group, heterocycloalkyl group, O-cycloalkyl group, NHCO-aryl group, -(CH ２ ) ｑ -O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl and O-aryl are each halo, alkyl, haloalkyl, alkoxy, NHCO-alkyl, NR １３ R １３ ', SO ２ -Alkyl, CN, hydroxyalkyl, CONR １４ R １４ ', alkyl-NR １５ R １５ ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH ２ ) ｍ -NHSO ２ -Alkyl, CO ２ R １６ , alkoxy-alkyl, haloalkoxy, O-heterocycloalkyl, heteroaryl, alkoxy-alkoxy and O—(CH ２ ) ｐ -cycloalkyl, wherein said cycloalkyl is optionally further substituted with one or more halo, haloalkyl, alkyl, or alkoxy groups; m is an integer from 0 to 3; p and q each independently represent 0 to 3; Z is CR １２ and Y is CR １０ R １０ ' and R １０ and R １０ each ' is independently selected from H, F, alkyl, and haloalkyl; R ａ and R ｂ are each independently selected from H and alkyl; R ６ is selected from H, alkyl, cycloalkyl, and hydroxyalkyl; R １２ is selected from H, alkyl, haloalkyl, halo, OH, and O-alkyl; R １３ , R １３ ', R １４ , R １４ ', R １５ , R １５ ' and R １６ are each independently selected from H, alkyl, and alkoxyalkyl.

2. 2. The compound of claim 1, wherein Z is CH.

3. R ａ and R ｂ The compound of claim 1 , wherein both are H.

4. Y is CH ２ 2. The compound of claim 1, wherein:

5. R ６ 2. The compound of claim 1, wherein is selected from H, methyl and hydroxymethyl, more preferably H.

6. 2. The compound of claim 1, which is of formula (Ia): 【Chemistry 2】 (In the formula, R １ , R ４ and R ５ are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, and halo; R ２ and R ３ are each independently H, OH, halo, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, NHCO-alkenyl, NHCO-aryl, -(CH ２ ) ｑ -O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl and CO ２ -alkyl, and the aryl group, heteroaryl group, heterocycloalkyl group, O-cycloalkyl group, NHCO-aryl group, -(CH ２ ) ｑ -O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl and O-aryl groups are each selected from halo, haloalkyl, alkyl, alkoxy, NHCO-alkyl, NR １３ R １３ ', SO ２ -Alkyl, CN, hydroxyalkyl, CONR １４ R １４ ', alkyl-NR １５ R １５ ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH ２ ) ｍ -NHSO ２ -Alkyl, CO ２ R １６ , alkoxy-alkyl, haloalkoxy, O-heterocycloalkyl, heteroaryl, alkoxy-alkoxy and O—(CH ２ ) ｐ -cycloalkyl, wherein in the latter group, the cycloalkyl may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups, or alkoxy groups.

7. R ２ and R ３ are each independently H, halo, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, NHCO-alkenyl, and CO ２ -alkyl, wherein the aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl and O-aryl groups are each optionally further substituted with one or more groups independently selected from halo, alkyl and alkoxy.

8. R ２ and R ３ are each independently F, Cl, Br, I, CN, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy and CO ２ - alkyl, more preferably Cl, Br and CF ３ , and even more preferably Cl and CF ３ 7. The compound of claim 6, selected from:

9. R ３ is an aryl or heteroaryl group, preferably a pyridinyl group, each of which is selected from halo, haloalkyl, alkyl, alkoxy, NHCO-alkyl, NR １３ R １３ ', SO ２ -Alkyl, CN, hydroxyalkyl, CONR １４ R １４ ', alkyl-NR １５ R １５ ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH ２ ) ｍ -NHSO ２ -Alkyl, CO ２ R １６ , alkoxy-alkyl, O-cycloalkyl, haloalkoxy, O-heterocycloalkyl, heteroaryl, alkoxy-alkoxy, O—(CH ２ ) ｐ -cycloalkyl, wherein the cycloalkyl group is optionally further substituted with one or more halo groups, haloalkyl groups, alkyl groups, or alkoxy groups.

10. R ３ are phenyl, pyridyl, pyrimidinyl, pyrazolyl, pyrazinyl, [1,2,5]thiadiazolo[3,4-b]pyridinyl, indazolyl, triazolyl, benzotriazolyl, oxoisoindolinyl, oxoindolinyl, imidazolyl, benzoxazinyl, pyrrolopyridinyl, oxotetrohydroisoquinolinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazolyl, pyridazinyl, oxazolyl, isothiazolyl, benzo[d]isoxazolyl, benzo[c]isothiazolyl, imidazo[1,5-a]pyridinyl, O-pyridinyl, CONHPh, NHCOPh, OCH ２ Ph, CH ２ OPh, [1,2,5]oxadiazolo[3,4-b]pyridinyl, benzo[c]isoxazolyl or 2H-benzo[b][1,4]oxazin-3(4H)-onyl, more preferably a pyridinyl group, each of which may be selected from halo, alkyl, alkoxy, NHCO-alkyl, NR １３ R １３ ', SO ２ -Alkyl, CN, hydroxyalkyl, CONR １４ R １４ ', alkyl-NR １５ R １５ ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH ２ ) ｍ -NHSO ２ -Alkyl, CO ２ R １６ 7. The compound of claim 6, which is optionally further substituted with one or more groups independently selected from alkoxy-alkyl, O-cycloalkyl, haloalkoxy, and heteroaryl.

11. R ３ but 【Chemistry 3】 【change】 each of which is selected from halo, alkyl, alkoxy, NHCO-alkyl, NR １３ R １３ ', SO ２ -Alkyl, CN, hydroxyalkyl, CONR １４ R １４ ', alkyl-NR １５ R １５ ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH ２ ) ｍ -NHSO ２ -Alkyl, CO ２ R １６ , alkoxy-alkyl, haloalkoxy, O-heterocycloalkyl, heteroaryl, alkoxy-alkoxy, O—(CH ２ ) ｐ -cycloalkyl and -(CH ２ ) ｑ The compound according to claim 6, wherein the cycloalkyl group is optionally further substituted with one or more groups independently selected from -O-heteroaryl, and wherein in the latter group, the cycloalkyl group is optionally further substituted with one or more halo groups, haloalkyl groups, alkyl groups, or alkoxy groups.

12. R ３ but 【Chemistry 4】 (In the formula, R １７ is H, alkyl, CN, haloalkyl, NHCO-alkyl, NR １３ R １３’ , alkoxy, SO ２ -Alkyl, halo, O-(CH ２ ) ｑ -heterocycloalkyl, alkoxy-alkoxy, alkoxy-alkyl, haloalkoxy, alkylamino-alkoxy, dialkylamino-alkoxy and O—(CH ２ ) ｐ -cycloalkyl, said cycloalkyl groups being optionally substituted with one or more halo, alkyl or alkoxy groups; R １８ is selected from H and halo; R １９ is selected from H, alkoxy and alkoxy-alkyl; R ２０ is H, halo and CO ２ R １６ 7. The compound of claim 6, wherein

13. R １７ is H, OMe, OEt, O ｉ Pr, F, SO ２ Me, halo, O-cyclobutyl, O-oxetanyl and O—CH ２ CF ３ is selected from R １８ is selected from H and F; R １９ is H and MeOCH ２ - is selected from, R ２０ is H, F and CO ２ Me, R １ is F, R ２ is H, R ４ is Cl or CF ３ and R ５ The compound of claim 12, wherein is H.

14. R ２ and R ５ The compound of any one of claims 6 to 13, wherein both are H.

15. R １ A compound according to any one of claims 6 to 13, wherein is selected from H, F, Me, MeO, Cl, OH and CN, preferably H or F.

16. R ４ is Cl, Br and CF ３ The compound according to any one of claims 6 to 13, wherein the compound is selected from the group consisting of , more preferably Cl.

17. R １ is F and R ２ is H and R ４ is Cl, and R ５ The compound according to any one of claims 6 to 13, wherein is H.

18. 2. The compound of claim 1, which is of formula (Ib): 【Chemistry 5】 (wherein n is 0 or 1, and X １ ~X ５ form a 5- or 6-membered heteroaromatic group containing at least one nitrogen atom, said heteroaromatic group being selected from the group consisting of halo, CN, OH, alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, NHCO-alkenyl, NHCO-aryl, -(CH ２ ) ｑ -O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and O-aryl, and the aryl group, heteroaryl group, heterocycloalkyl group, O-cycloalkyl group, NHCO-aryl group, -(CH ２ ) ｑ -O-heteroaryl group, CONH-aryl group, aryloxy-alkyl group, O-aralkyl group, CO ２ -alkyl group and O-aryl group are halo, haloalkyl, alkyl, alkoxy, NHCO-alkyl, NR １３ R １３ ', SO ２ -Alkyl, CN, hydroxyalkyl, CONR １４ R １４ ', alkyl-NR １５ R １５ ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH ２ ) ｍ -NHSO ２ -Alkyl, CO ２ R １６ , alkoxy-alkyl, O-cycloalkyl, haloalkoxy, O-heterocycloalkyl, heteroaryl, alkoxy-alkoxy and O—(CH ２ ) ｐ -cycloalkyl, wherein the cycloalkyl group is optionally further substituted with one or more halo groups, haloalkyl groups, alkyl groups, or alkoxy groups.

19. n is 1 and X １ ~X ５ form a 6-membered heteroaromatic group selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl and 1,2,3,4-tetrazinyl, each of which is selected from halo, CN, alkoxy, alkyl, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, and the aryl group, heteroaryl group, heterocycloalkyl group, O-cycloalkyl group, NHCO-aryl group, O-heteroaryl group, CONH-aryl group, aryloxy-alkyl group, O-aralkyl group and O-aryl group are each optionally substituted with one or more substituents selected from halo, alkyl, alkoxy, NHCO-alkyl, NR １３ R １３ ', SO ２ -Alkyl, CN, hydroxyalkyl, CONR １４ R １４ ', alkyl-NR １５ R １５ ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH ２ ) ｍ -NHSO ２ -Alkyl, CO ２ R １６ 19. The compound of claim 18, optionally further substituted with one or more groups independently selected from alkoxy-alkyl, O-cycloalkyl, haloalkoxy, O-heterocycloalkyl, and heteroaryl.

20. 19. The compound of claim 18, which is of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 6】 (In the formula, X １ is N or CR １ and X ２ is N or CR ２ and X ４ is N or CR ４ and R １ , R ２ , R ３ and R ４ are each independently selected from H, halo, haloalkyl, alkyl, alkoxy, CN, aryl, heterocycloalkyl, heteroaryl and O-aryl, more preferably H, halo, CN, alkoxy, alkyl and haloalkyl, and the aryl, heteroaryl, heterocycloalkyl and O-aryl groups are each independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR １３ R １３ ', SO ２ -Alkyl, CN, hydroxyalkyl, CONR １４ R １４ ', alkyl-NR １５ R １５ ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH ２ ) ｍ -NHSO ２ -Alkyl, CO ２ R １６ , alkoxy-alkyl, O-cycloalkyl, haloalkoxy, and heteroaryl).

21. X ３ is CR ３ or a compound of formula (Ib) according to claim 18, wherein R ３ 21. A compound of formula (Ic) according to claim 20, wherein:

22. X １ is R １ and X ４ is R ４ and R １ and R ４ and R are both H.

23. X ２ is R ２ and R ２ is Cl, Br and CF ３ 22. The compound of claim 21, wherein the compound is selected from the group consisting of:

24. Formula (I.1) 【Chemistry 7】 (I.1) (In the formula, B, Y, R ａ , R ｂ , Z and R ６ as defined in claim 1) or in the form of an enantiomerically enriched mixture of compounds of formula (I.1).

25. Formula (I.2) 【Chemistry 8】 (I.2) (In the formula, B, Y, R ａ , R ｂ , Z and R ６ as defined in claim 1) or in the form of an enantiomerically enriched mixture of compounds of formula (I.2).

26. 2. The compound of claim 1 selected from the following: and its enantiomers and mixtures of enantiomers, including racemic mixtures, and pharmaceutically acceptable salts and solvates thereof: 【Table 1】

27. A compound of formula (If) or a pharmaceutically acceptable salt or solvate thereof 【Chemistry 9】 (In the formula, R １１ is selected from H, alkyl, haloalkyl, halo, OH, and O-alkyl; B, Y, Z, R ａ and R ｂ is as defined in claim 1).

28. A compound of formula (Ij) or a pharmaceutically acceptable salt or solvate thereof 【Chemistry 10】 (Ij) (Wherein, ring A is 【Chemistry 11】 is selected from Y is CR １０ R １０ ' and R １０ and R １０ each ' is independently selected from H, F, alkyl, and haloalkyl; R ａ and R ｂ are each independently selected from H and alkyl; R １ ', R ２ ', R ４ ' and R ５ each ' is independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, and halo; R ３ ' is CN, haloalkyl, haloalkoxy, NHCO-alkyl, NR １３ R １３ ', SO ２ -alkyl, O—(CH ２ ) ｑ -heterocycloalkyl, alkoxy-alkoxy, alkylamino-alkoxy, dialkylamino-alkoxy, alkoxy-alkyl and O—(CH ２ ) ｐ - a pyridinyl group substituted by one or more substituents selected from cycloalkyl, wherein the cycloalkyl group is optionally substituted by one or more halo, alkyl or alkoxy groups, and the pyridinyl is optionally further substituted by one or more substituents selected from halo, alkyl and alkoxy; R ６ ' is H or alkyl, more preferably H; R ７ , R ８ and R ９ are each independently selected from H, halo, and alkyl; R １３ and R １３ each ' is independently selected from H, alkyl and alkoxy-alkyl; p and q each independently represent 0 to 3.

29. R １ ' and R ４ ' is selected from halo and haloalkyl; R ２ ' and R ５ ' is H, R ３ 'but 【Chemistry 12】 (In the formula, R １７ ' is CN, haloalkyl, haloalkoxy, NHCO-alkyl, NR １３ R １３’ , S.O. ２ -alkyl, O—(CH ２ ) ｑ -heterocycloalkyl, alkoxy-alkoxy, alkylamino-alkoxy, dialkylamino-alkoxy, alkoxy-alkyl and O—(CH ２ ) ｐ -cycloalkyl, said cycloalkyl groups being optionally substituted with one or more halo, alkyl or alkoxy groups; R １８ ' is selected from H and halo; R １９ ' is selected from H, alkoxy and alkoxy-alkyl; R ２０ 29. The compound of claim 28, wherein ' is selected from H and halo.

30. Ring A is 【Chemistry 13】 is selected from Y is CH ２ and R ａ and R ｂ are both H, R １ ' is F and R ４ ' is Cl, R １７ ' is haloalkyl, haloalkoxy, alkylamino-alkoxy, dialkylamino-alkoxy, O—(CH ２ ) ｑ -heterocycloalkyl, O—(CH ２ ) ｐ -cycloalkyl, said cycloalkyl being optionally substituted with one or more alkoxy groups; p is 0 or 1; q is 0 or 1, and R １８ ', R １９ ' and R ２０ 30. The compound of claim 29, wherein all of ' are H.

31. A compound selected from the following: and its enantiomers and mixtures of enantiomers, including racemic mixtures, and pharmaceutically acceptable salts and solvates thereof: 【Table 2】 32. A pharmaceutical composition comprising a compound according to claim 1, or claim 27, or claim 28, or claim 31, and a pharmaceutically acceptable diluent, excipient or carrier.

33. 32. A compound according to claim 1, or claim 27, or claim 28, or claim 31 for use as a pharmaceutical.

34. A compound according to claim 1, or claim 27, or claim 28, or claim 31 for use in the treatment or prevention of a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).

35. 35. The compound for use according to claim 34, wherein the use comprises modulation of GPR65, preferably the use comprises inhibition of GPR65 signalling.

36. 35. The compound for use according to claim 34, wherein the disorder is a proliferative disorder.

37. 37. The compound for use according to claim 36, wherein the proliferative disorder is cancer, preferably a solid tumor and / or its metastases.

38. 38. The compound for use according to claim 37, wherein the proliferative disorder is a cancer selected from melanoma, renal cell carcinoma (RCC), gastric cancer, acute myeloid leukemia (AML), triple-negative breast cancer (TNBC), colon cancer, head and neck cancer, colorectal adenocarcinoma, pancreatic adenocarcinoma, sarcoma, lung cancer, ovarian cancer and glioma, preferably glioblastoma (GBM).

39. 35. The compound for use according to claim 34, wherein the disorder is an immune disorder.

40. 40. The compound for use according to claim 39, wherein the immune disorder is an autoimmune disease.

41. 41. The compound for use according to claim 40, wherein the autoimmune disease is selected from psoriasis, psoriatic arthritis, rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), autoimmune thyroiditis (Hashimoto's thyroiditis), Graves' disease, uveitis (including intermediate uveitis), ulcerative colitis, Crohn's disease, autoimmune uveoretinitis, systemic vasculitis, polymyositis-dermatomyositis, systemic sclerosis (scleroderma), Sjogren's syndrome, ankylosing spondylitis and related spondyloarthropathy, sarcoidosis, autoimmune hemolytic anemia, immunological platelet disorders, and autoimmune polyendocrinopathy.

42. 42. The compound for use according to claim 41, wherein the autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease and multiple sclerosis (MS).

43. 35. The compound for use according to claim 34, wherein the use comprises the treatment or prevention of a disorder selected from asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).

44. A method for treating a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS), said method comprising the step of administering to a subject a compound described in claim 1, or claim 27, or claim 28, or claim 31.

45. 32. A compound according to claim 1, or claim 27, or claim 28, or claim 31, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a disease or disorder associated with GPR65.

46. Use of a compound described in claim 1, or claim 27, or claim 28, or claim 31, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for treating or preventing a disease or disorder associated with GPR65 in a subject.

47. Use of a compound of claim 1, or claim 27, or claim 28, or claim 31, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for treating or preventing a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).

48. A pharmaceutical composition comprising a compound of claim 1, or claim 27, or claim 28, or claim 31, and a pharmaceutically acceptable diluent, excipient, or carrier, wherein the composition is for the treatment of a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS).

49. A pharmaceutical composition comprising a compound according to claim 1, or claim 27, or claim 28, or claim 31, and a pharmaceutically acceptable diluent, excipient or carrier, said composition being for use in the treatment or prevention of a disease or disorder associated with GPR65.

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