Method for preparing (6S,9R)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[C]pyridazine-10-carboxamide derivatives

Abstract

The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof 【Chemical 1】 TIFF2026516783000088.tif45170(wherein ring B is a monocyclic aromatic group which may be 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, NHCO-aryl, -(CH2) q -O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl and CO2-alkyl, and the aryl group, heteroaryl group, heterocycloalkyl group, O-cycloalkyl group, NHCO-aryl group, -(CH2) q -O-heteroaryl group, CONH-aryl group, aryloxy-alkyl group, O-aralkyl group and O-aryl group are each independently selected from 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, and may be further substituted with one or more groups independently selected therefrom, and in the latter groups, the cycloalkyl may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups, m is an integer from 0 to 3, p and q are each independently from 0 to 3, Y is CR 10 R 10 ’ and R 10 and R10 ' is independently selected from H, F, alkyl and haloalkyl, and R a and R b Each is independently selected from H and alkyl, and R6 is selected from H, alkyl, cycloalkyl and hydroxyalkyl, R 13 , R 13 ', R 14 , R 14 ', R 15 , R 15 'and R 16 A method for preparing a compound of formula (IV) (wherein B is as defined above) and a compound of formula (V) (wherein R is independently selected from H, alkyl, haloalkyl and alkoxyalkyl), wherein (i) a compound of formula (IV) (wherein B is as defined above) is used to prepare a compound of formula (V) (wherein R is independently selected from H, alkyl, haloalkyl and alkoxyalkyl), the method comprising: (i) a compound of formula (IV) (wherein B is as defined above) 21 (ii) Treating the compound of formula (III) with a phenyl which may be substituted with 1 to 5 fluorine atoms to form a compound of formula (III), and (ii) treating the compound of formula (III) with a compound of formula (II) or a pharmaceutically acceptable salt thereof (wherein Y, R a , R b The present invention relates to a method comprising the steps of treating (and R6 as described above) to form a compound of formula (I). Further embodiments relate to intermediates useful in the claimed method.

Description

[Technical Field]

[0001] The present invention relates to a method for preparing compounds that can modulate GPR65. These compounds have potential therapeutic applications in the treatment of various disorders, including proliferative disorders and immunological disorders. [Background technology]

[0002] GPR65 is a Gs-coupled G protein-coupled receptor (GPCR) primarily expressed in immune cells, activated by an acidic extracellular pH, and triggering an increase in cytoplasmic cyclic adenosine monophosphate (cAMP) (Non-Patent Literature 1). It has long been known that tumors typically undergo a transition in cellular metabolism from oxidative phosphorylation to aerobic glycolysis, subsequently leading to an acidic extracellular microenvironment (Non-Patent Literature 2). Recently, it has been shown that this acidic microenvironment triggers GPR65 activation in tumor-associated macrophages, leading to an increase in cytoplasmic cAMP and the transcription of inducible cAMP early suppressor (ICER). This then suppresses the secretion of tumor necrosis factor alpha (TNFα), shifting macrophages towards an anti-inflammatory and tumor-tolerant phenotype (Non-Patent Literature 3). Therefore, this GPR65-dependent pathway appears to represent a mechanism by which tumors utilize these acidic microenvironments to evade detection by the immune system.

[0003] Autoimmune diseases are also often associated with acidic local microenvironments (e.g., inflamed joints). Recent studies have also suggested that GPR65 acts on CD4+ T cells via ICER, suppressing IL-2 and thereby shifting cells towards an inflammatory Th17 phenotype associated with increased pathogenicity from an autoimmune disease perspective (Non-Patent Literature 4). This is supported by recent discoveries that ICER is required for Th17 differentiation (Non-Patent Literature 5) and that GPR65 agonism leads to increased Th17 differentiation (Non-Patent Literature 6). 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 (Non-Patent Literature 7). One recent study found that mice with CD4+ T cells lacking GPR65 were protected from the progression of autoimmune encephalomyelitis (EAE) disease (Non-Patent Literature 7).

[0004] Therefore, GPR65 appears to act via ICER, promoting an anti-inflammatory and tumor-permissive phenotype in tumor-associated macrophages and an inflammatory Th17 phenotype in CD4+ T cells associated with autoimmune diseases. Thus, GPR65 signaling presents an interesting pathway for therapeutic inclusion in the treatment of both cancer and autoimmune diseases. Therefore, the development of novel small molecule GPR65 modulators and methods for their preparation is continuously needed.

[0005] International Publication No. 2021245427 (Pathios Therapeutics Limited) discloses a series of small molecule GPR65 modulators and methods for preparing them. The synthetic preparations described therein involve coupling a secondary amine with a primary amine in the presence of triphosgene (bis(trichloromethyl) carbonate) to form a substituted urea derivative. An alternative route involves coupling a secondary amine with an isocyanate intermediate to form a substituted urea derivative. The isocyanate intermediate itself can be produced in situ from the corresponding amine by reacting it with triphosgene in the presence of a suitable base. Triphosgene is a toxic solid that may decompose during the reaction to form phosgene.

[0006] This invention attempts to provide further synthetic methods for preparing small molecule substituted urea derivatives that can regulate GPR65. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International Publication No. 2021245427 [Non-patent literature]

[0008] [Non-Patent Document 1] Wang, J. et al. (2004). TDAG8 is a proton-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 and Regulation in Cancer. Frontiers in Physiology [Non-Patent Document 3] Bohn, T. et al. (2018). Tumor immunoevasion via 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-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell, 1400-1412 [Overview of the Initiative] [Means for solving the problem]

[0009] The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. [ka] (In the formula, Ring B is a monocyclic aromatic group 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, NHCO-aryl, -(CH2) q -O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl and CO2-alkyl, and the aryl group, heteroaryl group, heterocycloalkyl group, O-cycloalkyl group, NHCO-aryl group, -(CH2) q -O-heteroaryl group, CONH-aryl group, aryloxy-alkyl group, O-aralkyl group and O-aryl group are each independently 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 and may be further substituted with one or more groups independently selected therefrom, and in the latter groups, the cycloalkyl may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups, m is an integer from 0 to 3, p and q are each independently from 0 to 3, Y is CR 10 R 10 ’, and R 10 and R 10 ’ are each independently selected from H, F, alkyl and haloalkyl, Ra and R b Each is independently selected from H and alkyl, R6 is selected from H, alkyl, cycloalkyl, and hydroxyalkyl. R 13 , R 13 ', R 14 , R 14 ', R 15 , R 15 'and R 16 A method for preparing (each independently selected from H, alkyl, haloalkyl and alkoxyalkyl), (i) Compound of formula (IV) (wherein B is as defined above) to compound of formula (V) (wherein R 21 The steps include treating with a phenyl compound (which may be substituted with 1 to 5 fluorine atoms) to form the compound of formula (III), (ii) The compound of formula (III) above, the compound of formula (II) or a pharmaceutically acceptable salt thereof (wherein Y, R a , R b The steps include treating R6 (as described above) to form a compound of formula (I), and Regarding methods including [ka]

[0010] Advantageously, the method claimed herein avoids the use of triphosgene as a reagent. Triphosgene is extremely dangerous, causing severe skin burns, eye damage, and can be fatal if inhaled. Therefore, an alternative synthesis method that avoids the use of triphosgene is particularly attractive in drug development and the potential scaling up of work processes.

[0011] Another aspect relates to carbamates, which are useful intermediates in the methods according to the present invention. Thus, one aspect of the present invention relates to the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof. [ka] (In the formula, Ring B 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 A monocyclic aromatic group which may be substituted with one or more substituents selected from -O-heteroaryl, CONH-aryl, aryloxyalkyl, O-aralkyl and CO2-alkyl, wherein the aryl group, heteroaryl group, heterocycloalkyl, O-cycloalkyl, NHCO-aryl group, -(CH2) q -O-heteroaryl group, CONH-aryl group, aryloxy-alkyl group, O-aralkyl group, and O-aryl group are respectively halo, alkyl, haloalkyl, alkoxy, NHCO-alkyl, and 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 -The cycloalkyl group may be further substituted with one or more groups independently selected from the cycloalkyl group, and in the latter group, the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups. m is an integer between 0 and 3. p and q are independently between 0 and 3. R 13 , R 13 ', R 14 , R 14 ', R 15, R 15 'and R 16 Each of these is independently selected from H, alkyl, haloalkyl, and alkoxyalkyl. R 21 This is a phenyl compound that may be substituted with 1 to 5 fluorine atoms.

[0012] Another aspect relates to an aniline intermediate useful in the method according to the present invention. Therefore, further aspects of the present invention are as follows: [Table 1] The present invention relates to compounds selected from pharmaceutically acceptable salts and solvates thereof.

[0013] definition "Alkyl" refers to a linear or branched alkyl radical, preferably C 1-20 Alkyl, more preferably C 1-12 Alkyl, and 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, and hexyl. More preferably, the alkyl is C 1-3 It is alkyl.

[0014] As used herein, the term “alkenyl” refers to both linear and branched carbon chains having at least one carbon-carbon double bond. In some embodiments, the alkenyl group is C2-C 12 An alkenyl group may be present. In other embodiments, the alkenyl group may be C2-C 10 The alkenyl group may be C2-C8, C2-C6, or C2-C4. In one embodiment of the alkenyl, the number of double bonds is 1 to 3, and in another embodiment of the alkenyl, the number of double bonds is 1. Depending on the position of the alkenyl moiety on the molecule, other ranges of carbon-carbon double bonds and carbon numbers are also considered. 10 The "-alkenyl" group may contain more than one double bond in its chain.

[0015] "Cycloalkyl" refers to a monocyclic alkyl ring, preferably C 3-7 Cycloalkyl, more preferably C 3-6 As defined herein, cycloalkyl. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or condensed bicyclic ring systems, such as norbornane.

[0016] As used herein, the term "aryl" may refer to a monocyclic group or a fused bicyclic group containing a benzo-condensed group. 6-12 This refers to aromatic groups. Examples include phenyl and naphthyl.

[0017] "Haloalkyl" is defined herein as a linear 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, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. Preferably, the haloalkyl is C 1-20 It is a haloalkyl, more C 1-12 It is a haloalkyl, and more preferably C 1-10 Haloalkyl or C 1-6 Haloalkyl or C 1-3 It is a haloalkyl group. Preferred examples are CF3 and CHF2, with CF3 being particularly preferred.

[0018] "Alkoxy" is defined herein as an oxygen atom bonded to an alkyl group as defined above, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, and hexoxy. Preferably, the alkoxy is C 1-20 It is an alkoxy, and more preferably C 1-12 It is an alkoxy, and more preferably C 1-10 Alkoxy or C 1-6 Alkoxy or C 1-3It is an alkoxy. A particularly preferred example is methoxy(-OCH3).

[0019] "Alkoxy-alkyl" is defined as an alkyl group substituted with one or more alkoxy groups, for example, MeOCH2CH2-. "Alkoxy-alkoxy" is defined as an alkoxy group substituted with one or more further alkoxy groups, for example, MeOCH2CH2O- (also called an ether group).

[0020] "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.

[0021] A "heteroaryl" or "heterocyclic aromatic" is a monocyclic or bicyclic carbon atom containing one or more heteroatoms (which may be the same or different), such as oxygen, nitrogen, or sulfur. 2-12 As defined herein, an aromatic ring. Suitable examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, pyridinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and their benzo derivatives, such as benzofuranyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, etc., or pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, isoquinolinyl, sinnolinyl, phthalazinyl, quinazolyl, quinoxalinyl, naphthilidinyl, etc.

[0022] "Hypercycloalkyl" refers to a cyclic aliphatic group containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, which may have one or more -(CO)- groups interposed 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 3-7It is heterocycloalkyl, and more preferably C 3-6 It is a heterocycloalkyl group. Alternatively, the heterocycloalkyl group is C 4-7 It is heterocycloalkyl, and more preferably C 4-6 These are heterocycloalkyl groups. Preferred heterocycloalkyl groups include, but are not limited to, piperadinyl, piperidinyl, morphonyl, thiomorphonyl, 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]oxazine-6-yl, oxoisoindlinyl, oxoindlinyl, 1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl, and 1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl.

[0023] "Aralkyl" is defined herein as an alkyl group as defined above, which is substituted with one or more aryl groups as defined above.

[0024] Preferably, the alkyl is a C1-C6 alkyl, the haloalkyl is a C1-C6 haloalkyl, the alkoxy is a C1-C6 alkoxy, and the haloalkoxy is a C1-C6 haloalkoxy.

[0025] Compound structure notation The compounds described herein include structures in which an optional six-membered nitrogen-containing ring is condensed with a bicyclic nitrogen-containing moiety to form a tricyclic structure. The resulting tricyclic structure can exist in two different stereoconfigurations as shown below. [ka] (I.1) (I.2)

[0026] To avoid misunderstanding, the present invention encompasses compounds with any of the above stereoconfigurations, as well as mixtures thereof, including racemic mixtures.

[0027] Alternatively, the structure can be shown as follows (R a Base and R b (The base is omitted for clarity.) [ka]

[0028] To avoid misunderstanding, the present invention encompasses compounds of the above configurations, their corresponding enantiomers, and mixtures thereof, including racemic mixtures. For use throughout and for ease of illustration, specific examples of compounds according to the present invention shown in configuration (I.3) refer to mixtures of both enantiomers (in particular, racemic compounds), but each synthesized or isolated enantiomer is shown as either configuration (I.1) or configuration (I.2) with a wedge-shaped or dashed bond, respectively.

[0029] The compounds described herein include a substituted or otherwise substituted six-membered ring that condenses with 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 tautomers. For example, a compound of formula (I) where R6 is H can exist in the following tautomers. [ka]

[0030] The pyridazine-3(2H)-one tautomer is considered to be the primary solid-state form. In solution, the energy difference between the two tautomer forms is considered to be very small and depends on the polarity of the solvent. This invention encompasses all tautomer forms of the compounds described herein. [Modes for carrying out the invention]

[0031] Preferred embodiments of the present invention are described below.

[0032] In one particularly preferred embodiment, the compound prepared by the method of the present invention is of formula (I.1). [ka] (In the formula, B, Y, R a , R b (and R6 is as defined above).

[0033] In one preferred embodiment, the compound is in an enantiomerically pure form. In one preferred embodiment, the compound is in the form of a mixture in which the compound of formula (I.1) is enantiomerically enriched.

[0034] In another embodiment, the compound is of formula (I.2) [ka] (In the formula, B, Y, R a , R b (and R6 is as specified above).

[0035] Enantiomers (I.1) and (I.2) apply similarly to all of the various sub-formulas described herein.

[0036] In one preferred embodiment, the compound is in an enantiomerically pure form. In one preferred embodiment, the compound is in the form of a mixture in which the compound of formula (I.2) is enantiomerically enriched.

[0037] In one 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). In one preferred embodiment, the mixture is a racemic mixture, i.e., a 50:50 mixture of the compound of formula (I.1) and its corresponding enantiomer of formula (I.2).

[0038] A 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 decomposition using an optically active acid, or by column chromatography or reversed-phase column chromatography using a substantially optically active (or "chiral") stationary phase as known to those skilled in the art. The racemic mixture can also be used to prepare mixtures enriched with either the compound of formula (I.1) or the compound of formula (I.2) enantiomerically. A mixture enriched with either the compound of formula (I.1) or the compound of formula (I.2) can also be obtained from a suitable enantiomerically enriched precursor.

[0039] In one preferred embodiment of the present invention, the compound is in the form of a mixture containing enantiomers, where the weight:weight ratio is at least about 2:1, preferably at least about 5:1, and most preferably at least about 10:1, with a preference for the enantiomer (utemer) exhibiting important in vitro and / or in vivo activity.

[0040] 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 the compound of formula (I.1) to the 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.

[0041] 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), wherein the compound of formula (I.1) is substantially enriched.

[0042] In one 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), wherein the weight:weight ratio of the compound of formula (I.2) to the 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.

[0043] In one 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), wherein the compound of formula (I.2) is substantially enriched.

[0044] In one preferred embodiment, R a and R b Both are H.

[0045] In one preferred embodiment, Y is CH2.

[0046] In one preferred embodiment, R6 is selected from H, methyl, and hydroxymethyl, and more preferably H.

[0047] In one preferred embodiment, B 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 A phenyl group which may be substituted with one or more substituents selected from -O-heteroaryl, CONH-aryl, aryloxyalkyl, O-aralkyl and CO2-alkyl, and the aryl group, heteroaryl group, heterocycloalkyl, O-cycloalkyl, NHCO-aryl group, -(CH2) q -O-heteroaryl group, CONH-aryl group, aryloxy-alkyl group, O-aralkyl group, and O-aryl group are respectively halo, alkyl, haloalkyl, alkoxy, NHCO-alkyl, and 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 may be further substituted with one or more groups independently selected from, and in the latter groups, said cycloalkyl may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups.

[0048] In one preferred embodiment, ring B is

Chemical formula

[0049] In one preferred embodiment, R2 and R3 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 CO2-alkyl, and said aryl group, heteroaryl group, heterocycloalkyl group, O-cycloalkyl group and O-aryl group may each be further substituted with one or more groups independently selected from halo, alkyl and alkoxy.

[0050] In one preferred embodiment, R2 and R3 are each independently F, Cl, Br, I, CN, C1-C6 haloalkyl, optionally substituted heteroaryl, C1-C6 haloalkoxy and CO2-alkyl, more preferably Cl, Br and CF3, even more preferably optionally substituted heteroaryl, Cl and CF3.

[0051] In one preferred embodiment, R3 is an aryl or heteroaryl group, preferably a pyridinyl group, each of which may be halo, haloalkyl, alkyl, alkoxy, NHCO-alkyl, or 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 -The cycloalkyl group may be further substituted with one or more groups independently selected from the cycloalkyl group, and in the latter group, the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups.

[0052] In one preferred embodiment, R3 is phenyl, pyridyl, pyrimidinyl, pyrazolyl, pyrazinyl, [1,2,5]thiadiazolo[3,4-b]pyridinyl, indazolyl, triazolyl, benzotriazolyl, oxoisoindlinyl, oxoindlinyl, imidazolyl, benzooxazinyl, pyrrolopyridinyl, oxotetrohydroisoquinolinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazolyl, pyridadinyl, Oxazolyl, isothiazolyl, benzo[d]isoxazolyl, benzo[c]isothiazolyl, imidazo[1,5-a]pyridinyl, O-pyridinyl, CONHPh, NHCOPh, OCH2Ph, CH2OPh, [1,2,5]oxadiazolo[3,4-b]pyridinyl, benzo[c]isoxazolyl, or 2H-benzo[b][1,4]oxazine-3(4H)-onyl, more preferably selected from a pyridinyl group, each of which may be halo, alkyl, alkoxy, NHCO-alkyl, or NR. 13 R13 ', 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 and heteroaryl and O-(CH2) p -The cycloalkyl group may be further substituted with one or more groups independently selected from the cycloalkyl group, and in the latter group, the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups.

[0053] In one preferred embodiment, R3 is [ka] Selected from TIFF2026516783000013.tif222170, each of which is a halo, alkyl, haloalkyl, alkoxy, NHCO-alkyl, or 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, -(CH2) q -O-heteroaryl and O-(CH2) p-The cycloalkyl group may be further substituted with one or more groups independently selected from the cycloalkyl group, in which case the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups. Preferably, R3 is selected from the groups (a-1), (a-3), (a-5), (a-6), (a-10), (a-14), (a-17), (a-20), (a-25), (a-26), (a-27), (a-39) and (a-40), each of which may be substituted.

[0054] In one preferred embodiment, 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, alkoxy-alkyl, haloalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy and O-(CH2) p - Selected from cycloalkyl groups, the cycloalkyl group may be substituted with one or more halo groups, alkyl groups, or alkoxy groups. R 18 It is selected from H and Halo, R 19 is selected from H, alkoxy, and alkoxy-alkyl, R 20 H, halo and CO2R 16 (Selected from) That is the case.

[0055] In one preferred embodiment, R 13 , R 13 ', R 14 , R 14 ', R 15 , R 15 'and R 16Each of these is independently selected from H, alkyl, and alkoxyalkyl.

[0056] In one preferred embodiment, R 13 , R 13 ', R 14 , R 14 ', R 15 , R 15 'and R 16 Each of these is independently selected from H, alkyl, and haloalkyl.

[0057] In one preferred embodiment, R 13 and R 13 Each of the elements is independently selected from H, alkyl, and haloalkyl.

[0058] In one preferred embodiment, p is 0 or 1.

[0059] In one preferred embodiment, q is 0 or 1.

[0060] In one preferred embodiment, m is 0 or 1.

[0061] In one preferred embodiment, R 17 H, OMe, OEt, O i Selected from Pr, F, SO2Me, halo, O-cyclobutyl, O-oxetanyl, O-CH2CF3, CH2CF3, O-CH2-cyclobutyl, O-cyclopentyl, NHCH2CF3-, N(Me)CH2CF3 and O-CH2-(difluorocyclopropyl) and O-CH2-cyclopropyl, R 18 The following is selected from H and F: R 19 The selected element is from H and MeOCH2-. R 20 The is selected from H, F, and CO2Me. R1 is F, R2 is H, R4 is Cl or CF3, R5 is H

[0062] 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 The following is selected from H and F: R 19 The selected element is from H and MeOCH2-. R 20 The element is selected from H, F, and CO2Me. R1 is F, R2 is H, R4 is Cl or CF3, R5 is H

[0063] In one preferred embodiment, both R2 and R5 are H.

[0064] In one preferred embodiment, R1 is selected from H, F, Me, MeO, Cl, OH, and CN, and is preferably H or F.

[0065] In one preferred embodiment, R4 is selected from Cl, Br, and CF3, and more preferably Cl.

[0066] In one preferred embodiment, R1 is F, R2 is H, R4 is Cl, and R5 is H.

[0067] In one preferred embodiment, the compound of formula (V) is selected from phenyl chloroformate and pentafluorophenyl chloroformate.

[0068] In one very preferred embodiment, the compound of formula (V) is phenylchloroformate. [ka]

[0069] In one preferred embodiment, step (i) is carried out in the absence of a base.

[0070] In one preferred embodiment, step (i) is carried out in a solvent. Preferred solvents include organic solvents such as tetrahydrofuran, dichloromethane, DMSO, and 2-methyltetrahydrofuran, as well as mixtures thereof. Those skilled in the art will understand that other suitable solvents and solvent mixtures may also be used.

[0071] In one preferred embodiment, the ratio of compound (V) to compound (IV) in step (i) is about 3:1 to about 1:1. More preferably, it is about 2:1 to about 1:1, more preferably about 1.5:1 to about 1:1, and even more preferably about 1.2:1 to about 1:1. In one particularly preferred embodiment, the ratio of compound (V) to compound (IV) in step (i) is about 1.2:1 to about 1:1, and more preferably about 1.1:1 to about 1:1.

[0072] In one preferred embodiment, step (i) is carried out at a temperature of about 0°C to about 45°C, preferably about 10°C to about 40°C, more preferably about 20°C to about 40°C, more preferably about 30°C to about 40°C, and more preferably about 25°C to about 35°C.

[0073] In one preferred embodiment, step (ii) is carried out in the presence of a base. Preferably, the base is an amine base. More preferably, the base is N,N-diisopropylethylamine (DIEA), triethylamine, tri- n Propylamine, triisopropylamine, N-methylmorpholine, N-methylpiperidine and tri- n The base is selected from butylamines. In one particularly preferred embodiment, the base is triethylamine.

[0074] In one preferred embodiment, step (ii) is carried out in the absence of a base.

[0075] In one preferred embodiment, step (ii) is carried out in a solvent. Preferred solvents include organic solvents such as tetrahydrofuran, dichloromethane, dimethyl sulfoxide (DMSO), and 2-methyltetrahydrofuran, as well as mixtures thereof. Those skilled in the art will understand that other suitable solvents may also be used. In one preferred embodiment, the solvent is 2-methyltetrahydrofuran.

[0076] In one preferred embodiment, step (ii) is carried out at a temperature of about 35°C to about 65°C, more preferably about 40°C to about 60°C, and more preferably about 40°C to about 50°C.

[0077] In one preferred embodiment, steps (i) and (ii) are carried out sequentially without isolating the compound of formula (III) from the reaction mixture obtained in step (i). Preferably, step (ii) is carried out on the crude reaction mixture obtained from step (i).

[0078] In one preferred embodiment, steps (i) and (ii) are carried out sequentially without isolating the compound of formula (III) from the reaction mixture obtained in step (i) and without purifying the compound of formula (III). Preferably, step (ii) is carried out on the crude reaction mixture obtained from step (i) without further isolating or purifying the compound of formula (III).

[0079] In an alternative preferred embodiment, the compound of formula (III) is isolated from the reaction mixture obtained in step (i) before proceeding with step (ii). Preferably, the compound of formula (III) is isolated and purified from the reaction mixture obtained in step (i) before proceeding with step (ii).

[0080] In one preferred embodiment, the compound of formula (II) is in the form of a pharmaceutically acceptable salt, and more preferably in the form of a hydrochloride salt.

[0081] In one preferred embodiment, the ratio of compound (II) or a pharmaceutically acceptable salt thereof to compound (III) in step (ii) is approximately 1:1.

[0082] In one preferred embodiment, the compound of formula (I) is as follows: [Table 2] TIFF2026516783000017.tif228170 Selected from TIFF2026516783000018.tif46170 and its enantiomers, as well as mixtures of its enantiomers including racemic mixtures, and pharmaceutically acceptable salts and solvates thereof.

[0083] Further aspects of the present invention relate to intermediates useful in the methods described herein.

[0084] Therefore, one aspect of the present invention relates to a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof. [ka] (In the formula, Ring B 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 A monocyclic aromatic group which may be substituted with one or more substituents selected from -O-heteroaryl, CONH-aryl, aryloxyalkyl, O-aralkyl and CO2-alkyl, wherein the aryl group, heteroaryl group, heterocycloalkyl, O-cycloalkyl, NHCO-aryl group, -(CH2) q-O-heteroaryl group, CONH-aryl group, aryloxy-alkyl group, O-aralkyl group, and O-aryl group are respectively halo, alkyl, haloalkyl, alkoxy, NHCO-alkyl, and 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 -The cycloalkyl group may be further substituted with one or more groups independently selected from the cycloalkyl group, and in the latter group, the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups. m is an integer between 0 and 3. p and q are independently between 0 and 3. R 13 , R 13 ', R 14 , R 14 ', R 15 , R 15 'and R 16 Each of these is independently selected from H, alkyl, haloalkyl, and alkoxyalkyl. R 21 (This is a phenyl compound that may be substituted with 1 to 5 fluorine atoms.)

[0085] In one preferred embodiment, ring B is [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 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, aryloxyalkyl, O-aralkyl and CO2-alkyl are selected, and the aryl group, heteroaryl group, heterocycloalkyl, O-cycloalkyl, NHCO-aryl group, -(CH2) q -O-heteroaryl group, CONH-aryl group, aryloxy-alkyl group, O-aralkyl group, and O-aryl group are respectively halo, haloalkyl, alkyl, alkoxy, NHCO-alkyl, and 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 -The cycloalkyl group may be further substituted with one or more groups independently selected from the cycloalkyl group, and in the latter group, the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups, or alkoxy groups. That is the case.

[0086] In one preferred embodiment, 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, and the aryl group, heteroaryl group, heterocycloalkyl, O-cycloalkyl, and O-aryl group may each be further substituted with one or more groups independently selected from halo, alkyl, alkoxy, and haloalkoxyl.

[0087] In one preferred embodiment, R3 is an aryl or heteroaryl group, each of which may be halo, haloalkyl, alkyl, alkoxy, NHCO-alkyl, or 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 -The cycloalkyl group may be further substituted with one or more groups independently selected from the cycloalkyl group, and in the latter group, the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups.

[0088] In one preferred embodiment, R3 is phenyl, pyridyl, pyrimidinyl, pyrazolyl, pyrazinyl, [1,2,5]thiadiazolo[3,4-b]pyridinyl, indazolyl, triazolyl, benzotriazolyl, oxoisoindlinyl, oxoindlinyl, imidazolyl, benzooxazinyl, pyrrolopyridinyl, oxotetrohydroisoquinolinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazolyl, pyridadinyl, Oxazolyl, isothiazolyl, benzo[d]isoxazolyl, benzo[c]isothiazolyl, imidazo[1,5-a]pyridinyl, O-pyridinyl, CONHPh, NHCOPh, OCH2Ph, CH2OPh, [1,2,5]oxadiazolo[3,4-b]pyridinyl, benzo[c]isoxazolyl, or 2H-benzo[b][1,4]oxazine-3(4H)-onyl, more preferably selected from a pyridinyl group, each of which may be halo, alkyl, alkoxy, NHCO-alkyl, or 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, heteroaryl and O-(CH2) p -The cycloalkyl group may be further substituted with one or more groups independently selected from the cycloalkyl group, and in the latter group, the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups.

[0089] In one preferred embodiment, R3 is [ka] Selected from TIFF2026516783000022.tif222170, each of which is a halo, alkyl, haloalkyl, alkoxy, NHCO-alkyl, or 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, -(CH2) q -O-heteroaryl and O-(CH2) p -The cycloalkyl group may be further substituted with one or more groups independently selected from the cycloalkyl group, in which case the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups. Preferably, R3 is selected from the groups (a-1), (a-3), (a-5), (a-6), (a-10), (a-14), (a-17), (a-20), (a-25), (a-26), (a-27), (a-39) and (a-40), each of which may be substituted.

[0090] In one preferred embodiment, 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, alkoxy-alkyl, haloalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy and O-(CH2) p-Selected from cycloalkyl groups, the cycloalkyl group may be substituted with one or more halo groups, alkyl groups, or alkoxy groups. R 18 H and Halo are selected, R 19 is selected from H, alkoxy, and alkoxy-alkyl, R 20 H, halo and CO2R 16 (Selected from) That is the case.

[0091] In one preferred embodiment, R 17 H, OMe, OEt, O i Selected from Pr, F, SO2Me, halo, O-cyclobutyl, O-oxetanyl, O-CH2CF3, CH2CF3, O-CH2-cyclobutyl, O-cyclopentyl, NHCH2CF3-, N(Me)CH2CF3, O-CH2-(difluorocyclopropyl) and O-CH2-cyclopropyl, R 18 The following is selected from H and F: R 19 The selected element is from H and MeOCH2-. R 20 The element is selected from H, F, and CO2Me. R1 is F, R2 is H, R4 is Cl or CF3, R5 is H

[0092] In one preferred embodiment, both R2 and R5 are H.

[0093] In one preferred embodiment, R1 is selected from H, F, Me, MeO, Cl, OH, and CN, and is preferably H or F.

[0094] In one preferred embodiment, R4 is selected from Cl, Br, and CF3, and more preferably Cl.

[0095] In one preferred embodiment, R1 is F, R2 is H, R4 is Cl, and R5 is H.

[0096] In one preferred embodiment, R 21 is phenyl or pentafluorophenyl, and more preferably phenyl.

[0097] In one preferred embodiment, the compound is as follows: [Table 3] Selected from TIFF2026516783000025.tif144170 and its enantiomers, as well as mixtures of its enantiomers including racemic mixtures, and pharmaceutically acceptable salts and solvates thereof.

[0098] Another aspect of the present invention relates to the use of the compound of formula (III) as defined above in the preparation of the compound of formula (I) as defined above.

[0099] Another aspect relates to aniline intermediates useful in the method according to the present invention. Therefore, further aspects of the present invention relate to compounds selected from the following. [Table 4]

[0100] salt In all aspects of the present invention discussed herein, the present invention includes, where appropriate, all enantiomers, diastereoisomers, and tautomers of the compounds described herein.

[0101] As used herein, pharmaceutically acceptable salts include appropriate acid addition salts or base salts. A comprehensive list of appropriate pharmaceutically acceptable salts can be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are formed from, for example, strong inorganic acids, such as mineral acids, hydrohalic acids such as hydrochlorides, hydrobroms and hydroiodides, sulfuric acid, sulfate phosphates, bisulfates, hemisulfates, thiocyansates, persulfates and sulfonic acids; strong organic carboxylic acids, such as unsubstituted or (e.g., halogen-substituted) 1-4 carbon atom alkanecarboxylic acids, 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, such as unsubstituted or (e.g., halogen-substituted) (C1-C4)-alkyl-sulfonic acids or aryl-sulfonic acids, such as methane-sulfonic acid or p-toluenesulfonic acid. Salts that are not pharmaceutically or veterinarily acceptable may still have value as intermediates.

[0102] Preferred salts include, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipine, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentane, glucoheptane, glycerophosphate, oxalate, heptane, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate, This includes tartrates, lactobionates, pivoates, 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, hydrobroms, hydroiodides, sulfates, bisulfates, hemisulfates, thiocyanates, persulfates, phosphoric acids, and sulfonic acids.

[0103] enantiomers / tautomers In all aspects of the present invention discussed herein, the invention includes, as necessary, all enantiomers, diastereoisomers, and tautomers of the compounds described herein. Those skilled in the art will identify compounds having optical properties (one or more chiral carbide atoms) or tautomerism. The corresponding enantiomers and / or tautomers can be isolated / prepared by methods known in the art.

[0104] Enantiomers are characterized by the absolute configuration of their chiral centers and described according to the R- and S-ranking rules of Cahn, Ingold, and Prelog. Such conventions are well known in the field (see, for example, 'Advanced Organic Chemistry', 3rd edition, ed. March, J., John Wiley and Sons, New York, 1985).

[0105] The compounds of the present invention containing a chiral center can be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture can be separated using well-known methods, and the individual enantiomers can be used individually.

[0106] Stereoisomers and geometric isomers Some of the compounds of the present invention may exist as stereoisomers and / or geometric isomers, for example, they may have one or more chiral centers and / or geometric centers, and therefore may exist in two or more stereoisomeric and / or geometric isomeric forms. The present invention considers all of the individual stereoisomers and geometric isomers of these compounds, as well as the use of mixtures thereof. The terms used in the claims encompass these forms, provided that they retain appropriate functional activity (though not necessarily to the same degree).

[0107] The present invention also includes all suitable isotopic variations of compounds or their pharmaceutically acceptable salts. An isotopic variation of a compound or its pharmaceutically acceptable salt is defined as one in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass than that normally found in nature. Examples of isotopes that can be incorporated into drugs and their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, respectively. 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 Contains Cl. Certain isotopic variations of drugs and their pharmaceutically acceptable salts, e.g., radioactive isotopes, e.g. 3 H or 14 Those incorporating C are useful in studies of the tissue distribution of drugs and / or substrates. Tritiated, i.e. 3H isotopes, and carbon-14, that is 14 Isotopes of 1C are particularly preferred due to their ease of preparation and detectability. Furthermore, isotopes, such as deuterium, i.e. 2 Substitution with hydrogen (H) can offer certain therapeutic advantages, such as greater metabolic stability, an increased in vivo half-life, or a reduced required dose, which may be preferable in some environments. For example, the present invention includes compounds of general formulas (I) and (II) in which either hydrogen atom is substituted with a deuterium atom. Isotope variations of the agents of the present invention and its pharmaceutically acceptable salts can generally be prepared by conventional procedures using appropriate isotope variations of appropriate reagents.

[0108] Atropisomer Some of the compounds described herein may exist as atropisomers. Atropisomers are stereoisomers arising from bound rotation of a single bond, where an energy difference due to steric strain or other contributing factors creates a sufficiently high barrier to rotation to allow for the isolation of individual conformational isomers. The present invention encompasses all such atropisomers. The present invention also extends to rotational isomers of compounds.

[0109] solvate The present invention also includes solvate forms of the compounds described herein. The terms used in the claims encompass these forms. Preferably, the solvate is a hydrate.

[0110] polymorph The present invention further relates to the various crystalline, polymorphic, and (un)hydrated forms of the compounds described herein. It is well established in the pharmaceutical industry that chemical compounds can be isolated in any of these forms by slightly altering the purification method and / or the isolated form, and the solvent used in the synthetic preparation of such compounds.

[0111] The present invention will be further described with reference to the following non-limiting embodiments.

[0112] General scheme Abbreviation A list of some common abbreviations is provided below; if other abbreviations not listed are used, they will be understood by those skilled in the art.

[0113] br.: broad; d: doublet; DCM: dichloromethane; DMSO: dimethyl sulfoxide; (ES+): electrospray ionization positive mode; Et3N: triethylamine; Depositphotos: ethyl acetate; EtOH: ethanol; h: time; hept: heptet; HPLC: high-performance liquid chromatography; HCl: hydrochloric acid; Hz: Hertz; J: coupling constant; l: liter; M: molar concentration; m: multiplet; [M+H]+: protonated molecular ion; MeCN: acetonitrile; MeOH: methanol; MHz: megahertz; 2-MeTHF: 2-methyltetrahydrofuran; min: minute; m L: milliliter; MS: mass spectrometry; MTBE: methyl tert-butyl ether; m / z: mass-to-charge ratio; NMR: nuclear magnetic resonance; p: pentet; PDA: photodiode array; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II), PIDA: (diacetoxyiodo)benzene; preparative TLC: preparative thin-layer chromatography; q: quintet; RT: room temperature; Rt: retention time; s: singlet; t: triplet; THF: tetrahydrofuran; TLC: thin-layer chromatography; ULC: ultrahigh-performance liquid chromatography; UV: ultraviolet light;

[0114] Other abbreviations are intended to convey their generally accepted meanings.

[0115] General experimental conditions All starting materials and solvents were obtained from commercial sources or prepared according to literature methods. Suitable isocyanate and aniline starting materials are commercially available, for example, from the stores of Sigma Aldrich, Fluorochem, or Enamine, or synthesized as described herein. Suitable tricyclic amine starting materials were synthesized as described herein. Unless otherwise indicated, the reaction mixtures were magnetically stirred, and the reactions were carried out at room temperature (approximately 20°C).

[0116] Silica gel chromatography was performed on automated flash chromatography systems such as the CombiFlash Companion, CombiFlash Rf system, or Reveleris X2 flash system, using RediSep® Rf, Reveleris®, or GraceResolv® pre-packed silica (230-400 mesh, 40-63 μm) cartridges.

[0117] Analytical UPLC-MS experiments to determine retention time and associated mass ions were performed using a Waters ACQUITY UPLC® H-Class system equipped with an ACQUITY PDA detector and either an ACQUITY QDa mass spectrometer or a Waters SQD mass spectrometer, performing the analytical methods described below.

[0118] Analytical LC-MS experiments to determine retention time 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 performing one of the analytical methods described below. NMR spectra were recorded using either a residual non-deuterated solvent or tetramethylsilane as reference, with either a Bruker Avance III HD 500 MHz instrument, a Bruker Avance Neo 400 MHz instrument, a Bruker Avance III 400 MHz instrument, or a QOne AS400 400 MHz spectrometer.

[0119] Where there is no absolute stereochemistry explicitly indicated by the combination of wedges and dashed lines, the chemical structures disclosed throughout the examples (e.g., in the above configuration (I.3)) should be interpreted as representing racemates. To avoid doubt, the present invention encompasses compounds of any configuration, as well as mixtures thereof.

[0120] Analytical methods Method 1 - Basic ternary method Column: ACQUITY UPLC® BEH C18, 1.7 μm, 2.1×30 mm from Waters at 40 °C Detection: UV at 210 - 400 nm and MS by electrospray ionization, unless otherwise indicated. Solvent: A: 0.1% ammonia in water, B: MeCN Gradient: [Table 5]

[0121] Method 2 - Acidic ternary method 1 Column: CSH C18, 1.7 μm, 2.1×30 mm from Waters at 40 °C Detection: UV at 210 - 400 nm and MS by electrospray ionization, unless otherwise indicated. Solvent: A: 0.1% formic acid in water, B: MeCN Gradient: [Table 6]

[0122] Method 3 - Acidic ternary method 2 Column: CORTECS UPLC, C18, 1.6 μm, 2.1×50 mm column from Waters at 25 °C Detection: UV at 210 - 400 nm and MS by electrospray ionization, unless otherwise indicated. Solvent: A: 0.1% formic acid in water, B: MeCN Gradient: [Table 7]

[0123] Method 4 - Acidic quintuple method 2 Column: Waters Sunfire, 3.5 μm, 4.6 × 50 mm column at 25°C Detection: Unless otherwise specified, MS is performed using UV at 214 and 254 nm and electrospray ionization. Solvents: A: 0.05% formic acid in water, B: 0.05% formic acid in MeCN gradient: [Table 8]

[0124] Experimental Scheme 1 Compound 1: (6S,9R)-N-(4-(benzo[c][1,2,5]oxadiazole-5-yl)-5-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10-carboxamide [ka] Step 1: A solution of phenylchloroformate (428 μL, 3.41 mmol) in 2-MeTHF (1 mL) was gradually added at 0°C to a solution of 4-(benzo[c][1,2,5]oxadiazole-5-yl)-5-chloro-2-fluoroaniline I-2 (1.00 g, 3.79 mmol) in 2-MeTHF (7 mL). The reaction mixture was heated to 40°C for 3 hours, after which an additional phenylchloroformate (80 μL, 379 μmol) in 2-MeTHF (0.1 mL) was added, and the mixture was stirred at 40°C for a further 20 hours. The resulting mixture was used as is in the next step. A small amount of the reaction mixture was concentrated under vacuum and triturated with n-pentane and MTBE (1:1) to obtain phenyl(4-(benzo[c][1,2,5]oxadiazole-5-yl)-5-chloro-2-fluorophenyl)carbamate as a brown solid. LCMS (Method 2) at 2.27 min showed m / z 290.6 (M-OPh). - (ES - ), 1 H NMR(400MHz,DMSO-d6)δ10.42(bs,1H), 8.18(s,1H), 8.14(d,J=9.3Hz,1H), 8.05(d,J=7.0H) z,1H), 7.72(d,J=9.2Hz,1H), 7.64(d,J=11.0Hz,1H), 7.50~7.41(m,2H), 7.34~7.23(m,3H).

[0125] Step 2: To a suspension of (6S,9R)-2,5,6,7,8,9-hexahydro-3H-6,9-epiminocyclohepta[c]pyridazine-3-one I-1 (810 mg, 3.79 mmol) and Et3N (2.11 mL, 15.2 mmol) hydrochloride in 2-MeTHF (5 mL), a solution of phenyl(4-(benzo[c][1,2,5]oxadiazole-5-yl)-5-chloro-2-fluorophenyl)carbamate (1.45 g, 3.79 mmol) in 2-MeTHF (8 mL) was added, and the reaction mixture was heated at 40°C for 3 hours. The resulting mixture was cooled to room temperature, diluted with 2-MeTHF (10 mL), water (50 mL) was added, and the layers were separated. The organic matter was washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The product was purified by silica gel chromatography (0-100% ELISA:EtOH (3:1) / isohexane) to obtain (6S,9R)-N-(4-(benzo[c][1,2,5]oxadiazole-5-yl)-5-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10-carboxamide (1.56 g, 80%) as a yellowish-brown solid. LC-MS (Method 2) m / z 467.2,469.2 (M+H) + (ES + ), at 1.70 minutes. 1 H NMR(400MHz,DMSO-d6)δ12.73(bs,1H), 8.97(s,1H), 8.16~8.09(m,2H), 7.86 (d,J=7.2Hz,1H), 7.73~7.66(m,1H), 7.54(d,J=11.0Hz,1H), 6.69(bs,1H), 5. 10(d,J=5.6Hz,1H), 4.66(t,J=6.2Hz,1H), 3.21(dd,J=18.3,5.3Hz,1H), 2.6 6(d,J=18.2Hz,1H), 2.29~2.14(m,2H), 1.88~1.76(m,1H), 1.73~1.61(m,1H).

[0126] The following compounds can be prepared using appropriate starting materials and following a procedure similar to that described in Experimental Scheme 1. If the starting materials are not described in the literature, their synthesis is described below. [Table 9] TIFF2026516783000033.tif250170 TIFF2026516783000034.tif220170 TIFF2026516783000035.tif247170 TIFF2026516783000036.tif221170 TIFF2026516783000037.tif253170 TIFF2026516783000038.tif237170 TIFF2026516783000039.tif247170 TIFF2026516783000040.tif132170

[0127] Intermediate 1 (I-1) Pathway 1 [ka] Step 1: To a solution of 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) in EtOH (20 ml), 2 M sodium hydroxide aqueous solution (7.10 ml, 14.2 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour, and the reaction mixture was concentrated under vacuum. The aqueous solution was washed once with DCM (5 ml), and then 1 M HCl aqueous solution was carefully added to the remaining aqueous mixture until the pH reached approximately 6. The product was extracted with DCM (100 ml), the aqueous layer was further extracted with 10% MeOH / DCM (3 × 50 ml), the combined organic layer was dried over MgSO4, filtered, and concentrated to obtain 2-((±)-8-(tert-butoxycarbonyl)-2-oxo-8-azabicyclo[3.2.1]octane-3-ylidene)acetic acid I-1b as an off-white solid. 1 ¹H NMR (400MHz, DMSO-d6): δ 6.64~6.54 (m, 1H), 5.75 (s, 1H), 4.35 (d, J=8.1Hz, 1H), 3.32 (s, 1H), 3.06 (t, J=2.6Hz, 1H), 2.32~2.16 (m, 1H), 2.16~1.96 (m, 1H), 1.79~1.51 (m, 2H), 1.37 (s, 9H). (No replaceable -OH groups were observed.)

[0128] Step 2: To a solution of 2-((±)-8-(tert-butoxycarbonyl)-2-oxo-8-azabicyclo[3.2.1]octan-3-ylidene)acetic acid I-1b (4.1 g, 13 mmol) in EtOH (30 ml), morpholine (2.3 ml, 27 mmol) was added dropwise at 0°C. The reaction mixture was stirred at this temperature for 1 hour, then warmed to room temperature and stirred for 72 hours. The mixture was concentrated under vacuum to obtain 2-((±)-8-(tert-butoxycarbonyl)-2-oxo-8-azabicyclo[3.2.1]octan-3-yl)-2-morpholinoacetic acid, morpholine salt I-1c as a viscous yellow oil, which was used in the next step without further purification or analysis.

[0129] Step 3: To a solution of 2-((±)-8-(tert-butoxycarbonyl)-2-oxo-8-azabicyclo[3.2.1]octan-3-yl)-2-morpholinoacetic acid, morpholine salt I-1c (17.02 g, 37.37 mmol) in EtOH (120 ml), hydrazine monohydrate in water (11.3 ml, 149.5 mmol) was added. The resulting mixture was heated at 78 °C for 2.5 hours, cooled to room temperature, and then concentrated under vacuum. 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 (3 × 200 ml) in DCM. The combined organic layers were dried over MgSO4 and concentrated under vacuum to obtain a pale yellow solid. The solid was dissolved in a minimum amount of EtOH, left at room temperature for 16 hours, and the resulting precipitate was isolated by filtration to obtain 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 obtain a 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-1d as a sticky brown oily substance. I-1e: 1 ¹H NMR (400MHz, DMSO-d6): δ 6.67 (s, 1H), 4.71 (d, J=6.2Hz, 1H), 4.31 (br s, 1H), 3.03 (d, J=17.9Hz, 1H), 2.61 (d, J=18.1Hz, 1H), 2.22~2.07 (m, 2H), 1.73 (t, J=9.6Hz, 1H), 1.60 (t, J=8.1Hz, 1H), 1.35 (s, 9H). (Exchangeable protons are not visible in the spectrum.) I-1d: 11H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 4.42 (d, J = 6.9 Hz, 1H), 4.22 (d, J = 6.7 Hz, 1H), 3.55 - 3.48 (m, 4H), 3.09 - 2.92 (m, 4H), 2.69 (dd, J = 12.1, 6.0 Hz, 2H), 2.06 - 2.00 (m, 2H), 1.92 (d, J = 10.1 Hz, 1H), 1.69 - 1.65 (m, 2H), 1.56 (d, J = 12.7 Hz, 1H), 1.38 (s, 9H).

[0130] 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 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-1d (3.2 g, 66% Mol.Wt I-1d) in EtOH (40 ml) was added 2M NaOH solution (10 ml, 20 mmol), and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, and the aqueous solution was neutralized to pH 7 using 1M HCl. The product was extracted with 10% MeOH in DCM (3 × 150 ml), and the combined organics were dried over MgSO4. The solvent was removed in vacuo to afford tert-butyl (±)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridazine-...

[0131] Step 5: 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), a solution of HCl in 1,4-dioxane (23 ml, 4 M, 94 mmol) was added. The reaction mixture was stirred at room temperature for 72 hours, then concentrated under vacuum to obtain the HCl salt of I-1f. 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 a 0.7 M NH3 solution in MeOH to obtain (±)-2,5,6,7,8,9-hexahydro-3H-6,9-epiminocyclohepta[c]pyridazine-3-one I-1f as an off-white solid.

[0132] Alternatively, the HCl salt was dissolved in MeOH, and MP-carbonate (3 eq.) was added. The resin was isolated by filtration after letting the mixture stand for 1 hour, and washed with MeOH. The filtrate was concentrated under vacuum to obtain (±)-2,5,6,7,8,9-hexahydro-3H-6,9-epiminocyclohepta[c]pyridazine-3-one I-1f as an off-white solid.

[0133] Step 6 A solution of (±)-2,5,6,7,8,9-hexahydro-3H-6,9-epiminocyclohepta[c]pyridazine-3-one I-1f (200 mg, 1.13 mmol) in MeOH (10 ml) was mixed with a solution of dibenzoyl-L-tartaric acid in MeOH (5 ml). The solvent was removed under vacuum, the residue was redissolved in EtOH (40 ml), heated at 60°C for 1 hour, cooled, and allowed to stand for 2 hours. The solid was filtered off, dried under vacuum, then 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 solid was filtered, and the filtrate was concentrated under vacuum to obtain (5R,8S)-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-2-one I-1 as an off-white solid. 11H NMR (400MHz, DMSO-d6) δ12.48 (s,1H), 6.56 (s,1H), 4.05~3.99 (m,1H), 3.63 (t,J=5.9Hz,1H), 2.90~2.78 (m,1H), 2.45 (t,J=1.4Hz,1H), 1.98~1.81 (m,2H), 1.65 (t,J=9.3Hz,1H), 1.53~1.39 (m,1H). (No NH detected).

[0134] Intermediate 2 (I-32) [ka] 4-bromo-5-chloro-2-fluoroaniline I-2a (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) were added to the vial. The vial was evacuated under vacuum, refilled with N2, and this process was repeated three times. 1,4-dioxane (4.00 ml) was added, followed by tripotassium phosphate aqueous solution spurged with N2 (2.11 ml, 2.00 M, 4.22 mmol). After the addition was complete, the vial was again evacuated and refilled with N2. The reaction mixture was heated at 95°C for 2 hours, then cooled to room temperature, filtered through a Celite pad, 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 organic matter was dried over MgSO4, filtered, and concentrated under vacuum. The product was purified by chromatography on silica gel (0-30% ELISA / isohexane) to obtain 4-(benzo[c][1,2,5]oxadiazole-5-yl)-5-chloro-2-fluoroaniline I-2 as a bright 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).

[0135] Intermediate 3(I-3) [ka] Step 1: Pd(dppf)Cl2 (2.73 g, 3.34 mmol) was added to a solution of 4-bromo-5-chloro-2-fluoroaniline I-2a (10.0 g, 44.6 mmol), potassium acetate (13.1 g, 134 mmol), and bis(pinacolato)diborone (17.0 g, 66.8 mmol) in 1,4-dioxane (100 mL). The reaction mixture was heated at 100 °C for 4 hours, then cooled to room temperature and stirred for 20 hours. The resulting mixture was diluted with HCl (200 mL) and filtered. The precipitate was washed with an additional HCl (200 mL), and the filtrate was concentrated under vacuum. The precipitate was separated between DCM (150 mL) and saturated aqueous NaHCO3 (150 mL), the organic matter was washed with saturated aqueous NaHCO3 (150 mL) and brine (150 mL), and the mixture was concentrated under vacuum. The residue was suspended in pentane (300 mL), stirred for 45 minutes, then cooled to 0°C and filtered. The precipitate was washed with additional pentane (2 × 50 mL) and dried under vacuum to obtain 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzeneamine I-3a as a black powder. 1 H NMR(400MHz,DMSO-d6)δ7.14(d,J=11.9Hz,1H), 6.73(d,J=7.7Hz,1H), 5.89(s,2H), 1.16(s,12H)

[0136] Step 2: To a solution of 2,2,2-trifluoroethylamine (674 μL, 8.52 mmol) and 5-bromo-2-fluoropyridine I-3b (585 μL, 5.68 mmol) in THF (3 mL), a KHMDS solution in THF (8.5 mL, 1 M, 8.52 mmol) was gradually added. The reaction mixture was stirred at room temperature for 1 hour, then quenched with MeOH (10 mL), and the mixture was concentrated under vacuum. The product was purified by silica gel chromatography (0-30% Â / isohexane) to obtain 5-bromo-N-(2,2,2-trifluoroethyl)pyridine-2-amine I-3c as a sticky white solid. 1 H NMR (400MHz, DMSO-d6) δ8.09(d,J=2.5Hz,1H), 7.62(dd,J=8.9,2.5Hz,1H), 7.38(t,J=6.6Hz,1H), 6.62(d,J=8.8Hz,1H), 4.13(qd,J=9.8,6.6Hz,2H).

[0137] Step 3: Under an N2 atmosphere, a suspension of 5-bromo-N-(2,2,2-trifluoroethyl)pyridine-2-amine I-3c (250 mg, 980 μmol), 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-3a (505 mg, 1.08 mmol), and Pd-118 (32 mg, 49.0 μmol) in MeCN (4 mL) was combined with a pre-degassed aqueous solution of tribasic potassium phosphate (1.47 mL, 2 M, 2.94 mmol). The reaction mixture was heated at 77 °C for 2 hours, then cooled to room temperature and poured into brine (40 mL), followed by extraction with RINKAN (2 × 40 mL). The combined organic matter was washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. The material was purified by silica gel chromatography (0-30% siRNA / isohexane) to obtain 5-(4-amino-2-chloro-5-fluorophenyl)-N-(2,2,2-trifluoroethyl)pyridine-2-amine I-3 as a yellowish-brown solid. 1H NMR(400MHz,DMSO-d6)δ8.01(dd,J=2.4,0.8Hz,1H), 7.49(dd,J=8.6,2.4Hz,1H), 7.25(t,J=6.6Hz,1H), 7.05( d,J=12.0Hz,1H), 6.88(d,J=8.4Hz,1H), 6.65(dd,J=8.7,0.8Hz,1H), 5.50(s,2H), 4.18(qd,J=9.8,6.5Hz,2H).

[0138] Intermediate 4(I-4) [ka] Step 1: To a solution of 5-bromo-N-(2,2,2-trifluoroethyl)pyridine-2-amine I-3c (200 mg, 784 μmol) in DMF (1.00 mL) at 0°C, NaH (38 mg, 60% Wt, 941 μmol) was added all at once. MeI (98 μL, 1.57 mmol) was added, and stirring was continued at 0°C for 30 minutes. The reaction was quenched with water (1 mL), and the product was extracted in ethyl acetate (3 × 5 mL). The combined organic matter was dried over MgSO4, filtered, and concentrated under vacuum. The product was purified by silica gel chromatography (0-15% ethyl acetate / isohexane) to obtain 5-bromo-N-methyl-N-(2,2,2-trifluoroethyl)pyridine-2-amine I-4a as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ8.20(dd,J=2.6,0.7Hz,1H), 7.76(dd,J=9.0,2.6Hz,1H), 6.79(dd,J=9.1,0.7Hz,1H), 4.45(q,J=9.6Hz,2H), 3.07(d,J=1.1Hz,3H).

[0139] Step 2: 5-(4-amino-2-chloro-5-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)pyridine-2-amine I-4 was synthesized from 5-bromo-N-methyl-N-(2,2,2-trifluoroethyl)pyridine-2-amine I-4a and 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-3a using substantially the same procedure as for I-3. 1 H NMR(400MHz,DMSO-d6)δ8.13(dd,J=2.4,0.8Hz,1H), 7.63(dd,J=8.8,2.5Hz,1H), 7.08(d,J=12.0Hz,1H),6. 89(d,J=8.4Hz,1H), 6.82(dd,J=8.9,0.9Hz,1H), 5.52(d,J=3.3Hz,2H), 4.50(q,J=9.6Hz,2H), 3.11(s,3H).

[0140] Intermediate 5 (I-5) [ka] A flask containing 4-bromo-5-chloro-2-fluoroaniline I-2a (50.0 g, 222.8 mmol) and (6-fluoropyridine-3-yl)boronic acid (31.4 g, 222.8 mmol) was purged with N2 for 5 minutes, then MeCN (500 mL) was added, and N2 was bubbled into the reaction mixture. Pd-118 (3.63 g, 5.57 mmol) was added, followed by the addition of tripotassium phosphate aqueous solution (334 mL, 2 M, 668.3 mmol). The resulting mixture was purged with N2 for 5 minutes, heated to 90°C, stirred for 2 hours, then cooled to room temperature, and left to stand with stirring for 16 hours, at which point a precipitate formed. This was filtered off, washed with acetonitrile (50 mL), water (50 mL), and DCM (200 mL), and dried in a vacuum to obtain 5-chloro-2-fluoro-4-(6-fluoropyridine-3-yl)aniline I-5 as a brown solid. 1H NMR (400MHz, DMSO-d6) δ8.23(d,J=2.6Hz,1H), 8.02(td,J=8.2,2.6Hz,1H), 7.27~7.16(m,2H), 6.93(d,J=8.3Hz,1H), 5.69(s,2H).

[0141] Intermediate 6 [ka] To a solution of cyclopentanol (107 mg, 1.25 mmol) in THF (3 mL) at 0°C, sodium hydride (53 mg, 60% wt., 1.33 mmol) was added. The resulting mixture was stirred at room temperature for 30 minutes, and then a solution of 5-chloro-2-fluoro-4-(6-fluoropyridine-3-yl)aniline I-5 (200 mg, 831 μmol) in THF (3 mL) was added. The resulting mixture was heated to 60°C for 2.5 hours, then cooled to room temperature, and water (0.1 mL), brine (25 mL), and DCM (25 mL) were added. The layers were separated, the aqueous solutions were extracted with DCM (25 mL), and the combined organic matter was dried over MgSO4 and concentrated under vacuum. The product was purified by silica gel chromatography (0-20% siRNA / isohexane) to obtain 5-chloro-4-(6-(cyclopentyloxy)pyridine-3-yl)-2-fluoroaniline I-6 as a viscous yellow oily substance. 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).

[0142] Intermediate 7(I-7) [ka] Step 1: N2 was passed through a vial containing 4-bromo-5-chloro-2-fluoroaniline I-2a (424 mg, 1.89 mmol), (5,6-difluoropyridine-3-yl)boronic acid (250 mg, 1.57 mmol), and Pd-118 (29 mg, 44.9 μmol), followed by the addition of 1,4-dioxane (3 mL), and then degassed potassium phosphate aqueous solution (2.36 mL, 2 M, 4.72 mmol). The reaction mixture was heated at 95°C for 24 hours, cooled to room temperature, water (15 mL) was added, and the product was extracted in DCM (3 × 10 mL). The combined organic matter was passed through a hydrophobic frit, and the filtrate was concentrated under vacuum. The product was purified by silica gel chromatography (30-100% DCM / heptane), and then 5-chloro-4-(5,6-difluoropyridine-3-yl)-2-fluoroaniline I-7a was obtained as a pale yellow solid by triturating the material from n-pentane. 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)

[0143] Step 2: Add KO in THF (2.66 mL, 20% Wt, 4.41 mmol) to a mixture of 5-chloro-4-(5,6-difluoropyridine-3-yl)-2-fluoroaniline I-7a (300 mg, 1.10 mmol) and trifluoroethanol (320 μL, 4.41 mmol) in THF (10 mL) at 0°C. tA solution of Bu was added, and the resulting substance was heated at room temperature for 20 hours. The reaction mixture was separated between brine (20 mL) and DCM (20 mL), and the layers were separated. The aqueous solution was extracted into DCM (20 mL), combined with the organic matter, and concentrated under vacuum. The product was purified by silica gel chromatography (0-20% (0.7 M ammonia / MeOH) / DCM) to obtain 5-chloro-2-fluoro-4-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)aniline I-7 as a pale yellow oil. 1H NMR(400MHz,DMSO-d6)δ8.04(d,J=1.9Hz,1H), 7.89(dd,J=11.3,2.0Hz,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).

[0144] Intermediate 8 (I-8) [ka] Step 1: To a solution of trifluoroethanol (305 μL, 4.24 mmol) in DMF (10 mL), NaH (339 mg, 8.48 mmol) was added at 0°C. After stirring at 0°C for 30 minutes, 3,6-dibromopyridazine I-8a (1 g, 4.24 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into an aqueous solution of NH4Cl (5 mL) and extracted in HCl (3 × 30 mL). The combined organic matter was washed with brine (80 mL), dried over Na2SO4, and concentrated under vacuum. The product was purified by silica gel chromatography (10% HCl / petroleum ether) to obtain 3-bromo-6-(2,2,2-trifluoroethoxy)pyridazine I-8b as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.00 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 9.2 Hz, 1H), 5.15 (q, J = 8.8 Hz, 2H).

[0145] Step 2: A mixture of 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-3a (300 mg, 1.10 mmol), 3-bromo-6-(2,2,2-trifluoroethoxy)pyridazine I-8b (284 mg, 1.1 mmol), Na2CO3 (352 mg, 3.30 mmol), and Pd(PPh3)4 (128 mg, 0.11 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was heated at 100°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The product was purified by silica gel chromatography (10% siRNA / petroleum ether) to obtain 5-chloro-2-fluoro-4-(6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)aniline I-8 as a white solid. LC-MS (Method 3) at 1.39 min yielded m / z 322.0 (M+H). + (ES + ).

[0146] Intermediate 9 (I-9) [ka] 5-Chloro-4-(6-((2,2-difluorocyclopropyl)methoxy)pyridine-3-yl)-2-fluoroaniline I-9 was synthesized from 5-chloro-2-fluoro-4-(6-fluoropyridine-3-yl)aniline I-5 and (2,2-difluorocyclopropyl)methanol using substantially the same procedure as for I-6. 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).

[0147] Intermediate 12 (I-12) [ka] 5-Chloro-4-(6-(cyclobutylmethoxy)pyridine-3-yl)-2-fluoroaniline I-12 was synthesized from 5-chloro-2-fluoro-4-(6-fluoropyridine-3-yl)aniline I-5 and cyclobutylmethanol I-12a using substantially the same procedure as for I-10. 1 H NMR(400MHz,DMSO-d6)δ8.12(dd,J=2.5,0.7Hz,1H), 7.71(dd,J=8.6,2.5Hz,1H), 7.12(d,J=11.9Hz,1H), 6.90(d,J=8.4Hz,1H), 6.83(dd,J=8.6,0.7Hz,1H), 5.63~5.57(m,2H), 4.25(d,J=7.0Hz,2H), 2.81~2.67(m,1H), 2.13~2.01(m,2H), 1.96~1.79(m,4H).

[0148] Intermediate 14 (I-14) [ka] Step 1: 5-chloro-2-fluoro-4-(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)aniline I-14 was synthesized from 5-chloro-2-fluoro-4-(6-fluoropyridine-3-yl)aniline I-5 using substantially the same procedure as for I-10. 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=8.5,0.7Hz,1H), 6.92(d,J=8.3Hz,1H), 5.63(s,2H), 5.02(q,J=9.1Hz,2H).

[0149] Intermediate 15 (I-15) [ka] To a vial containing cataCXium® A Pd G3 (3.2 mg, 4.5 μmol), (1H-pyrazole-4-yl)boronic acid (29.9 mg, 267 μmol) and 4-bromo-5-chloro-2-fluoroaniline I-2a (20.0 mg, 89.1 μmol) in 1,4-dioxane (1.00 ml), and a solution of K2CO3 in water (208 μl, 1.5 M, 312 μmol) were added. The mixture was stirred at 95°C for 2 hours, then loaded onto SCX (1 g), washed with MeOH, and the product was eluted with 0.7 M ammonia in MeOH to obtain 5-chloro-2-fluoro-4-(1H-pyrazole-4-yl)aniline I-15. LC-MS (Method 1) showed m / z 212.2, 214.2 (M+H) at 0.85 min. + (ES + ).

[0150] Intermediate 16 (I-16) [ka] 5-Chloro-2-fluoro-4-(1-methyl-1H-indazole-4-yl)aniline I-16 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-2a using essentially the same procedure as for I-15. LC-MS (Method 1) at 1.40 min, m / z 275.8 (M+H) + (ES + )

[0151] Intermediate 17 (I-17) [ka] 6-(4-amino-2-chloro-5-fluorophenyl)-1-methylindorin-2-one I-17 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-2a and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indorin-2-one using essentially the same procedure as for I-7a. 1H 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).

[0152] Intermediate 18 (I-18) [ka] 5-Chloro-2-fluoro-4-(1-methyl-1H-indazole-5-yl)aniline I-18 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-2a and (1-methyl-1H-indazole-5-yl)boronic acid using essentially the same procedure as for I-7a. 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).

[0153] Intermediate 19 (I-19) [ka] 4-([1,2,5]oxadiazolo[3,4-b]pyridine-6-yl)-5-chloro-2-fluoroaniline I-19 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-2a 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-7a. 1H 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).

[0154] Intermediate 20 (I-20) [ka] 5-Chloro-2-fluoro-4-(pyridazin-4-yl)aniline I-20 was synthesized from 4-bromo-5-chloro-2-fluoroaniline I-2a and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine using substantially the same procedure as for I-7a. 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).

[0155] Intermediate 21 (I-21) [ka] 6-Bromo-2-methyl-3,4-dihydroisoquinoline-1-one (141 mg, 589 μmol), 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-3a (160 mg, 589 μmol), and Pd-118 (10.0 mg, 15.3 μmol) were added to a scintillation vial. N2 was passed through the vial, then 1,4-dioxane (3.00 ml) was added, followed by the addition of degassed potassium phosphate aqueous solution (884 μl, 2 M, 1.77 mmol). The reaction mixture was heated at 95°C for 2 hours, then cooled to room temperature, water (15 ml) was added, and then extracted with DCM (3 × 10 ml). The combined organic matter was passed through hydrophobic frit and concentrated under vacuum. The product was purified by chromatography (10-30% siRNA / DCM) on silica gel to obtain 6-(4-amino-2-chloro-5-fluorophenyl)-2-methyl-3,4-dihydroisoquinoline-1(2H)-one I-21 as a pale gray 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).

[0156] Intermediate 22 (I-22) [ka] 5-Chloro-2-fluoro-4-(imidazo[1,5-a]pyridine-6-yl)aniline I-22 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-3a and 6-bromoimidazo[1,5-a]pyridine using substantially the same procedure as for I-21. 1H 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).

[0157] Intermediate 23 (I-23) [ka] 4-(benzo[c][1,2,5]oxadiazole-4-yl)-5-chloro-2-fluoroaniline I-23 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-3a and 4-bromobenzo[c][1,2,5]oxadiazole using essentially the same procedure as for I-21. 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).

[0158] Intermediate 24 (I-24) [ka] Step 1: 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline I-24b was synthesized from 4-bromo-2-fluoro-5-(trifluoromethyl)aniline I-24a using substantially the same procedure as for I-3a. 1 H 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).

[0159] Step 2: 4-([1,2,5]oxadiazolo[3,4-b]pyridine-6-yl)-2-fluoro-5-(trifluoromethyl)aniline I-24 was synthesized from 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline I-24b and 6-bromo-[1,2,5]oxadiazolo[3,4-b]pyridine using essentially the same procedure as for I-21. 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)

[0160] Intermediate 25 (I-25) [ka] Step 1: PIDA (4.64 g, 14.4 mmol) was added to a solution of 6-chloro-3-nitropyridine-2-ylamine I-25a (1.00 g, 5.76 mmol) in acetone (60 ml). The reaction mixture was heated at 80°C for 6 hours and then concentrated under vacuum. The product was purified by chromatography (0-100% siRNA / DCM) on silica gel to obtain 5-chloro-[1,2,5]oxadiazolo[3,4-b]pyridine 1-oxide I-25b as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.77(d,J=9.1Hz,1H), 7.16(d,J=9.2Hz,1H).

[0161] Step 2: A solution of 5-chloro-[1,2,5]oxadiazolo[3,4-b]pyridine 1-oxide I-25b (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 heated to room temperature and stirred for 16 hours, then 1 M NaOH aqueous solution (30 ml) was added, and the mixture was vigorously stirred for 15 minutes. The product was extracted into DCM (3 × 50 ml), the combined organic matter was dried over sodium sulfate, and concentrated under vacuum. The product was purified by silica gel chromatography (0-50% ethyl acetate / isohexane), and then further purified by silica gel chromatography (0-30% ethyl acetate / isohexane) to obtain 5-chloro-[1,2,5]oxadiazolo[3,4-b]pyridine I-25c as a yellow oily substance, which solidified upon standing. 1 H NMR(400MHz,CDCl3)δ8.22(d,J=9.2Hz,1H), 7.40(d,J=9.2Hz,1H)

[0162] Step 3: 4-([1,2,5]oxadiazolo[3,4-b]pyridine-5-yl)-5-chloro-2-fluoroaniline I-25 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-3a and 5-chloro-[1,2,5]oxadiazolo[3,4-b]pyridine I-25c using essentially the same procedure as for I-21. 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).

[0163] Intermediate 26 (I-26) [ka]

[0164] Step 1: 5-bromo-4-fluorobenzo[c][1,2,5]oxadiazole 1-oxide I-26b was synthesized from 4-bromo-3-fluoro-2-nitroaniline I-26a and PIDA using essentially the same procedure as for I-25b. 1 H NMR (400MHz, CDCl3) δ7.28~7.22 (m, 1H), 7.14 (d, J = 9.5Hz, 1H).

[0165] Step 2: To a solution of 5-bromo-4-fluorobenzo[c][1,2,5]oxadiazole 1-oxide I-26b (584 mg, 2.51 mmol) in EtOH (3 mL), triethyl phosphite (646 μL, 3.76 mmol) was added, and the reaction mixture was heated at 77 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with DCM (15 mL), and vigorously stirred for 20 minutes. Then, diluted 10% v / v sodium hypochlorite aqueous solution (10 mL) was added, the layers were separated, and the organic matter was passed through a hydrophobic frit. The filtrate was concentrated under vacuum, and the product was purified by silica gel chromatography (0-40% siRNA / isohexane) to obtain 5-bromo-4-fluorobenzo[c][1,2,5]oxadiazole I-26c as an orange solid. 1 H NMR (400MHz, DMSO-d6) δ7.95 (d,J=9.5Hz,1H), 7.82 (dd,J=9.4,6.0Hz,1H).

[0166] Step 3: 5-chloro-2-fluoro-4-(4-fluorobenzo[c][1,2,5]oxadiazole-5-yl)aniline I-26 was synthesized from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I-3a and 5-bromo-4-fluorobenzo[c][1,2,5]oxadiazole I-26c using essentially the same procedure as for I-21. 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).

[0167] Intermediate 52 (I-52) [ka]

[0168] Step 1: To a solution of 4,6-dichloronicotinaldehyde I-52a (17.3 g, 88.5 mmol) and (S)-2-methylpropane-2-sulfinamide (10.7 g, 88.5 mmol) in DCM (150 ml), cesium carbonate (28.8 g, 88.5 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The substance was filtered, and the solid residue was washed with DCM (150 ml). The solvent was evaporated to obtain (S)-N-((4,6-dichloropyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide I-52b 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).

[0169] Step 2: A solution of butyl-3-en-1-ylmagnesium bromide (0.5 M in THF) (60.9 ml, 30.4 mmol) was slowly added at -78°C to a solution of (S)-N-((4,6-dichloropyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide I-52b (5.00 g, 17.9 mmol) in THF (100 mL). The reaction mixture was slowly warmed to room temperature over 16 hours. The reaction mixture was cooled to 0-10°C, saturated NH4Cl aqueous solution (100 ml) was added, and the mixture was stirred for 5 minutes. The layers were separated, and the aqueous phase was extracted with ELISA (2 × 250 ml). The combined organic matter was washed with brine (50 ml), dried over Na2SO4, and concentrated under vacuum. The product was purified by chromatography on silica gel (0-30% MTBE in DCM) to obtain (S)-N-((R)-1-(4,6-dichloropyridine-3-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-52c as a clear yellow oil. 1H 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).

[0170] Step 3: Prepare a solution of HCl (4M in dioxane) (41 ml, 0.16 mol), t The mixture was added to a solution of (S)-N-((R)-1-(4,6-dichloropyridine-3-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-52c (11 g, 33 mmol) in BuOH (50 ml), and the reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was cooled in an ice bath, water (220 ml) was added, and the mixture was stirred for 10 minutes. The aqueous solution was extracted with MTBE (3 × 30 ml). The organic layer was extracted with water (2 × 30 ml). The aqueous solution was basicized using saturated NaHCO3 aqueous solution and further solid NaHCO3, and the mixture was stirred for 15 minutes. The product was extracted with MTBE (3 × 100 ml). The combined organic matter was washed with water (500 ml), dried with Na2SO4, and concentrated in a vacuum to obtain (R)-1-(4,6-dichloropyridine-3-yl)penta-4-en-1-amine I-52d as an orange oily substance. 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).

[0171] Step 4: To a solution of (R)-1-(4,6-dichloropyridine-3-yl)penta-4-en-1-amine I-52d (7.04 g, 30.5 mmol) in DCM (70 ml), (4-methoxyphenyl)boronic acid (13.9 g, 91.4 mmol), copper(II) acetate (6.09 g, 33.5 mmol), and Et3N (21.2 ml, 152 mmol) were added. The resulting mixture was stirred at room temperature for 20 hours. Further amounts of copper(II) acetate (2.21 g, 12.2 mmol), (4-methoxyphenyl)boronic acid (5.55 g, 36.6 mmol), and Et3N (5.09 ml, 36.6 mmol) were added, and the mixture was stirred for another 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 layer and the aqueous layer, respectively. The layers were separated, and the aqueous product was extracted with DCM (100 ml). The combined organic product was washed with water (100 ml) and dried over MgSO4. The product was purified by chromatography on silica gel (0-50% siRNA / isohexane) to obtain (R)-N-(1-(4,6-dichloropyridine-3-yl)penta-4-en-1-yl)-4-methoxyaniline I-52e as a concentrated 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).

[0172] Step 5: To a solution of (R)-N-(1-(4,6-dichloropyridine-3-yl)penta-4-en-1-yl)-4-methoxyaniline I-52e (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 Celite pad, and the filtrate was concentrated under vacuum. The product was purified by chromatography on silica gel (0-30% MTBE in isohexane) to obtain (R)-N-(1-(4-chloro-6-methoxypyridine-3-yl)penta-4-en-1-yl)-4-methoxyaniline I-52f 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).

[0173] Step 6: Pd-161 (763.6 mg, 1.65 mmol) and NaO tBu (2.38 g, 24.8 mmol) was placed in a three-necked round-bottom flask, purged under vacuum, and refilled with N2 (3 times). (R)-N-(1-(4-chloro-6-methoxypyridine-3-yl)penta-4-en-1-yl)-4-methoxyaniline I-52f (5.79 g, 16.52 mmol) was purged under vacuum and refilled with N2 (3 times). Toluene (180 ml) was added to the amine, and the resulting solution was transferred to a three-necked round-bottom flask. The round-bottom flask was purged under vacuum and refilled with N2 (3 times). The resulting mixture was heated at 95°C for 2 hours. The reaction mixture was cooled and filtered through a Celite pad. The filtrate was washed with ELISA. The filtrate was concentrated under vacuum. The product was purified by chromatography on silica gel (0-50% ethyl acetate / isohexane) to obtain (6S,9R)-3-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-52g 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).

[0174] 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-52g (2.00g, 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 organic matter was extracted with water (50 ml). The aqueous layer was basicized with KOH (3.6 ml, 5 M) and extracted with 10% MeOH (300 ml) in DCM. Further KOH (1.8 ml, 5 M) was added, and the aqueous layer was extracted with 10% MeOH (100 ml) in DCM. Further KOH (1.8 ml, 5 M) was added, and the aqueous layer was extracted with 10% MeOH (150 ml) in DCM. The combined organic matter was dried over Na2SO4 and concentrated in vacuum to obtain (6S,9R)-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-52h as a brown oily substance. 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).

[0175] Step 8: A solution of (6S,9R)-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-52h (0.99 g, 5.2 mmol) in HBr (48% in water) (8.8 ml, 78 mmol) was heated under reflux for 16 hours. The mixture was concentrated under vacuum, 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 NH3 solution in MeOH (0.7 M) to obtain (6S,9R)-2,5,6,7,8,9-hexahydro-3H-6,9-epiminocyclohepta[c]pyridine-3-one I-52 as a brown solid. 1 ¹H NMR (400MHz, DMSO-d6): δ 11.11 (s, 1H), 7.03 (s, 1H), 6.01 (s, 1H), 4.04 (d, J=5.4Hz, 1H), 3.62 (t, J=5.9Hz, 1H), 2.83 (dd, J=17.7, 5.1Hz, 1H), 2.40 (dt, J=17.7, 1.3Hz, 1H), 1.92~1.78 (m, 2H), 1.68~1.56 (m, 1H), 1.45 (dt, J=9.3, 4.8Hz, 1H). No replaceable NH was observed.

[0176] The following intermediates may be prepared using appropriate starting materials and following a procedure similar to that used in the preparation of 1a described in Experimental Scheme 1. [Table 10] TIFF2026516783000066.tif250170 TIFF2026516783000067.tif241170 TIFF2026516783000068.tif227170 TIFF2026516783000069.tif230170 TIFF2026516783000070.tif60170

[0177] Various modifications and variations of the described aspects of the present invention will not deviate from the scope and spirit of the invention and will be apparent to those skilled in the art. Although the present invention is described in relation to certain preferred embodiments, it should be understood that the present invention as described in the claims should not be excessively limited to such specific embodiments. In fact, various modifications of the described style for carrying out the present invention, which will be apparent to those skilled in the art, are intended to be within the scope of the following claims.

[0178] (References) Bohn, T. et al. (2018). Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nature Immunology, 1319-1326. Damaghi, M. et al. (2013). pH Sensing and Regulation in Cancer. Frontiers in Physiology. Gaublomme, J. et al. (2015). Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell, 1400-1412. Hernandez, J. (2018). GPR65, a critical regulator of Th17 cell pathogenicity, is regulated by the CRTC2 / CREB pathway. The Journal of Immunology, 200 (Supplement). Korn, T. et al. (2009). IL-17 and Th17 Cells. Annual Reviews in Immunology, 485-517. Wang, J. et al. (2004). TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor. Journal of Biological Chemistry, 45626-45633. Yoshida, N. et al. (2016). ICER is requisite for Th17 differentiation. Nature Communications, 12993.

Claims

1. Compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof 【Chemistry 1】 (In the formula, Ring B is a monocyclic aromatic group 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, 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 group, CONH-aryl group, aryloxy-alkyl group, O-aralkyl group and O-aryl group are each independently further optionally substituted with one or more groups selected from 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, and in the latter groups, the cycloalkyl may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups. m is an integer between 0 and 3. p and q are independently between 0 and 3. Y is CR １０ R １０ ' and R １０ and R １０ Each of these is independently selected from H, F, alkyl, and haloalkyl. R ａ and R ｂ Each is independently selected from H and alkyl, R ６ The is selected from H, alkyl, cycloalkyl and hydroxyalkyl, R １３ , R １３ ', R １４ , R １４ ', R １５ , R １５ 'and R １６ A method for preparing (each independently selected from H, alkyl, haloalkyl and alkoxyalkyl), (i) Compound of formula (IV) (wherein B is as defined above) to compound of formula (V) (wherein R ２１ The steps include treating with a phenyl compound (which may be substituted with 1 to 5 fluorine atoms) to form the compound of formula (III), (ii) The compound of formula (III) above is the compound of formula (II) or a pharmaceutically acceptable salt thereof (wherein Y, R ａ , R ｂ and R ６ The steps are to treat with the above-mentioned method to form the compound of formula (I) and 【Chemistry 2】 The method, including the method described above.

2. R ａ and R ｂ The method according to claim 1, wherein both are H.

3. Y is CH ２ The method according to claim 1 or 2.

4. R ６ The method according to any one of claims 1 to 3, wherein is selected from H, methyl and hydroxymethyl, and more preferably H.

5. Ring B is 【Transformation 3】 (In the formula, R １ , R ４ and R ５ Each of these is independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, and halo. R ２ and R ３ These are, 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, aryloxyalkyl, O-aralkyl and CO ２ - Selected from alkyl groups, including 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 and O-aryl group are respectively halo, haloalkyl, alkyl, alkoxy, NHCO-alkyl, and 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 - The cycloalkyl group may be further substituted with one or more groups independently selected from the cycloalkyl group, and in the latter group, the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups, or alkoxy groups. The method according to any one of claims 1 to 4.

6. R ２ and R ３ However, each is 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 The method according to claim 5, wherein the aryl group, heteroaryl group, heterocycloalkyl group, O-cycloalkyl group and O-aryl group are selected from alkyl groups, and each of these groups may be further substituted with one or more groups independently selected from halo, alkyl, alkoxy, and haloalkoxyl groups.

7. R ３ The group is an aryl group or a heteroaryl group, and each of them is a halo, haloalkyl, alkyl, alkoxy, NHCO-alkyl, or 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 The method according to claim 5, wherein the cycloalkyl group may be further substituted with one or more groups independently selected from the cycloalkyl group, and in the latter group, the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups.

8. R ３ is phenyl, pyridyl, pyrimidinyl, pyrazolyl, pyrazinyl, [1,2,5]thiadiazolo[3,4-b]pyridinyl, indazolyl, triazolyl, benzotriazolyl, oxoisoindolinyl, oxindolinyl, imidazolyl, benzoxazinyl, pyrrolopyridinyl, oxotetrahydroisoquinolinyl, 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 selected from pyridyl groups, each of which is 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, heteroaryl and O-(CH ２ ) ｐ -cycloalkyl, and may be further substituted with one or more groups independently selected from, in the latter groups, the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups, The method according to claim 5.

9. R ３ but, 【Chemistry 4】 【change】 Selected from, each of them is 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, -(CH ２ ) ｑ -O-heteroaryl and O-(CH ２ ) ｐ The method according to claim 5, wherein the cycloalkyl group may be further substituted with one or more groups independently selected from the cycloalkyl group, and in the latter group, the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups.

10. R ３ but 【Transformation 5】 (In the formula, R １７ However, 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, dialkylaminoalkoxy and O-(CH ２ ) ｐ - Selected from cycloalkyl groups, the cycloalkyl group may be substituted with one or more halo groups, alkyl groups, or alkoxy groups. R １８ H and Halo are selected, R １９ is selected from H, alkoxy, and alkoxy-alkyl, R ２０ H, halo and CO ２ R １６ The method according to claim 5, wherein the selected is from the following.

11. R １７ H, OMe, OEt, O ｉ Pr, F, SO ２ Me, Halo, O-Cyclobutyl, O-Oxetanyl, O-CH ２ CF ３ ,CH ２ CF ３ O-CH ２ -Cyclobutyl, O-cyclopentyl, NHCH ２ CF ３ , N(Me)CH ２ CF ３ O-CH ２ - (difluorocyclopropyl) and O-CH ２ - Selected from cyclopropyl, R １８ The is selected from H and F, R １９ H and MeOCH ２ - Selected from, R ２０ H, F and CO ２ Selected from Me, R １ F is, R ２ H is, R ４ is Cl or CF ３ And, R ５ The method according to claim 10, wherein is H.

12. R ２ and R ５ The method according to any one of claims 5 to 11, wherein both are H.

13. R １ The method according to any one of claims 5 to 12, wherein is selected from H, F, Me, MeO, Cl, OH, and CN, and preferably H or F.

14. R ４ Cl, Br and CF ３ The method according to any one of claims 5 to 13, wherein the material is selected from, and more preferably Cl.

15. R １ F is R ２ H is R ４ Cl is and R ５ The method according to any one of claims 5 to 14, wherein is H.

16. The method according to any one of claims 1 to 15, wherein the compound of formula (V) is selected from phenylchloroformate and pentafluorophenylchloroformate.

17. The method according to any one of claims 1 to 16, wherein the compound of formula (V) is phenylchloroformate.

18. The method according to any one of claims 1 to 17, wherein step (i) is carried out in the absence of a base.

19. The method according to any one of claims 1 to 18, wherein step (i) is carried out in an organic solvent, preferably an organic solvent selected from tetrahydrofuran, dichloromethane, dimethyl sulfoxide (DMSO), and 2-methyltetrahydrofuran, and mixtures thereof.

20. The method according to any one of claims 1 to 19, wherein the ratio of compound (V) to compound (IV) in step (i) is about 3:1 to about 1:1, more preferably about 2:1 to about 1:

1.

21. The method according to any one of claims 1 to 20, wherein step (i) is performed at a temperature of about 0°C to about 45°C, preferably about 10°C to about 40°C, more preferably about 20°C to about 40°C, and more preferably about 25°C to about 35°C.

22. The method according to any one of claims 1 to 21, wherein step (ii) is carried out in the presence of a base, more preferably a tertiary aliphatic amine base.

23. The bases are N,N-diisopropylethylamine (DIEA), triethylamine, tri- ｎ Propylamine, triisopropylamine and tri ｎ The method according to claim 22, wherein the agent is selected from butylamine, N-methylmorpholine, and N-methylpiperidine, and more preferably triethylamine.

24. The method according to any one of claims 1 to 23, wherein step (ii) is carried out in an organic solvent, preferably an organic solvent selected from tetrahydrofuran, dichloromethane, dimethyl sulfoxide (DMSO), and 2-methyltetrahydrofuran, and mixtures thereof.

25. The method according to any one of claims 1 to 24, wherein step (ii) is carried out at a temperature of about 35°C to about 65°C, more preferably about 40°C to about 60°C, and more preferably about 40°C to about 50°C.

26. The method according to any one of claims 1 to 25, wherein steps (i) and (ii) are carried out without isolating or purifying the compound of formula (III).

27. The method according to any one of claims 1 to 25, further comprising isolating the reaction mixture of the compound of formula (III) obtained in step (i) before performing step (ii).

28. The method according to claim 27, wherein the compound of formula (III) is isolated and purified from the reaction mixture before performing step (ii).

29. The method according to any one of claims 1 to 28, wherein the compound of formula (II) is in the form of a pharmaceutically acceptable salt, more preferably in the form of a hydrochloride salt.

30. The method according to any one of claims 1 to 29, wherein the ratio of compound (II) or a pharmaceutically acceptable salt thereof to compound (III) in step (ii) is about 1:

1.

31. The compounds of formula (I) are as follows: Table 1 The method according to any one of claims 1 to 30, selected from and its enantiomers, and mixtures of its enantiomers including racemic mixtures, and pharmaceutically acceptable salts and solvates thereof.

32. Compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof 【Transformation 6】 (In the formula, Ring B is a 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, aryloxyalkyl, O-aralkyl and CO ２ - A monocyclic aromatic group which may be substituted with one or more substituents selected from alkyl groups, 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 and O-aryl group are respectively halo, alkyl, haloalkyl, alkoxy, NHCO-alkyl, and 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 -The cycloalkyl group may be further substituted with one or more groups independently selected from the cycloalkyl group, and in the latter group, the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups. m is an integer between 0 and 3. p and q are independently between 0 and 3. R １３ , R １３ ', R １４ , R １４ ', R １５ , R １５ 'and R １６ Each of these is independently selected from H, alkyl, haloalkyl, and alkoxyalkyl. R ２１ (This is a phenyl compound that may be substituted with 1 to 5 fluorine atoms.)

33. Ring B is 【Transformation 7】 (In the formula, R １ , R ４ and R ５ Each of these is independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, and halo. R ２ and R ３ These are, 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, aryloxyalkyl, O-aralkyl and CO ２ - Selected from alkyl groups, including 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 and O-aryl group are respectively halo, haloalkyl, alkyl, alkoxy, NHCO-alkyl, and 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 - The cycloalkyl group may be further substituted with one or more groups independently selected from the cycloalkyl group, and in the latter group, the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups, or alkoxy groups. The compound according to claim 32.

34. R ２ and R ３ However, each is 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 The compound according to claim 33, wherein the aryl group, heteroaryl group, heterocycloalkyl group, O-cycloalkyl group and O-aryl group are each further substituted with one or more groups independently selected from halo, alkyl, alkoxy and haloalkoxyl.

35. R ３ The group is an aryl group or a heteroaryl group, and each of them is a halo, haloalkyl, alkyl, alkoxy, NHCO-alkyl, or 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 The compound according to claim 33, which may be further substituted with one or more groups independently selected from the cycloalkyl group, wherein the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups.

36. R ３ Phenyl, pyridyl, pyrimidinyl, pyrazolyl, pyrazinyl, [1,2,5]thiadiazolo[3,4-b]pyridinyl, indazolyl, triazolyl, benzotriazolyl, oxoisoindlinyl, oxoindlinyl, imidazolyl, benzooxazinyl, pyrrolopyridinyl, oxotetrohydroisoquinolinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazolyl, pyridadinyl, oxazolyl, isothiazolyl, benzo[d]isoxazolyl, benzo[c]isothiazolyl, imidazo[1,5-a]pyridinyl, O-pyridinyl, CONHPh, NHCOPh, OCH ２ Ph, CH ２ OPh, selected from [1,2,5]oxadiazolo[3,4-b]pyridinyl, benzo[c]isoxazolyl, or 2H-benzo[b][1,4]oxazine-3(4H)-onyl, more preferably a pyridinyl group, each of which may be halo, alkyl, alkoxy, NHCO-alkyl, or 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, heteroaryl and O-(CH ２ ) ｐ The compound according to claim 33, which may be further substituted with one or more groups independently selected from the cycloalkyl group, wherein the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups.

37. R ３ but 【Transformation 8】 【change】 Selected from, each of them is 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, -(CH ２ ) ｑ -O-heteroaryl and O-(CH ２ ) ｐ The compound according to claim 33, which may be further substituted with one or more groups independently selected from the cycloalkyl group, wherein the cycloalkyl group may be further substituted with one or more halo groups, haloalkyl groups, alkyl groups or alkoxy groups.

38. R ３ but 【Chemistry 9】 (In the formula, R １７ 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, dialkylaminoalkoxy and O-(CH ２ ) ｐ - Selected from cycloalkyl groups, the cycloalkyl group may be substituted with one or more halo groups, alkyl groups, or alkoxy groups; R １８ It is selected from H and Halo, R １９ is selected from H, alkoxy, and alkoxy-alkyl, R ２０ H, halo and CO ２ R １６ (Selected from) The compound according to claim 33.

39. R １７ H, OMe, OEt, O ｉ Pr, F, SO ２ Me, Halo, O-Cyclobutyl, O-Oxetanyl, O-CH ２ CF ３ ,CH ２ CF ３ O-CH ２ -Cyclobutyl, O-cyclopentyl, NHCH ２ CF ３ , N(Me)CH ２ CF ３ O-CH ２ - (difluorocyclopropyl) and O-CH ２ - Selected from cyclopropyl, R １８ The is selected from H and F, R １９ H and MeOCH ２ - Selected from, R ２０ H, F, and CO ２ Selected from Me, R １ F is, R ２ H is, R ４ is Cl or CF ３ And, R ５ The compound according to claim 38, wherein is H.

40. R ２ and R ５ The compound according to any one of claims 33 to 39, wherein both are H.

41. R １ The compound according to any one of claims 33 to 40, wherein is selected from H, F, Me, MeO, Cl, OH, and CN, and preferably H or F.

42. R ４ Cl, Br and CF ３ A compound according to any one of claims 33 to 41, selected from, and more preferably Cl.

43. R １ F is R ２ H is R ４ Cl is and R ５ A compound according to any one of claims 33 to 42, wherein is H.

44. R ２１ The compound according to any one of claims 33 to 43, wherein is phenyl or pentafluorophenyl, and more preferably phenyl.

45. A compound according to any one of claims 32 to 44, selected from the following and its enantiomers, as well as mixtures of its enantiomers including racemic mixtures, and pharmaceutically acceptable salts and solvates thereof. Table 2

46. Use of the compound according to any one of claims 32 to 45 in the preparation of the compound of formula (I) as defined in claim 1.

47. Compounds selected from the following, as well as their pharmaceutically acceptable salts and solvates. Table 3

48. Use of the compound according to claim 47 in the preparation of a compound of formula (I) as defined in claim 1.

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