Tetrahydropyrazolopyridine derivative

Abstract

The present invention relates to tetrahydropyrazolopyridine derivatives having AAK1 inhibitory activity.

Description

TETRAHYDROPYRAZOLOPYRIDINE DERIVATIVE

[0001] The present invention relates to tetrahydropyrazolopyridine derivatives having AAK1 inhibitory activity.

[0002] Adaptor-associated kinase 1 (AAK1), also known as AP2-associated protein kinase 1, is a member of Ark1 / Prk1 family of serine / threonine kinase, which is an enzyme involved in clathrin-mediated endocytosis. Recently, AAK1 has attracted attention as a promising target for the treatment of various neurological and psychiatric disorders, including schizophrenia, Parkinson's disease, bipolar disorder, Alzheimer's disease, and neuropathic pain, as well as viral infection (Non-Patent Literatures 1 - 12), and the research on its inhibitors has been progressing.

[0003] [NPL 1] Henderson DM, et al. Mol Biol Cell. 2007; 18(7): 2698-2706. [NPL 2] Mettlen M, et al. Annu Rev Biochem. 2018: 87: 871-896. [NPL 3] Kuai L, et al. Chem Biol. 2011; 18(7): 891-906. [NPL 4] Mei L, et al. Nat Rev Neurosci. 2008; 9(6): 437-452. [NPL 5] Buonanno A. Brain Res Bull. 2010; 83(3-4): 122-131. [NPL 6] Jaaro-Peled H, et al. Schizophr Bull. 2010; 36(2): 301-313. [NPL 7] Wen L, et al. Proc Natl Acad Sci U S A. 2010; 107(3): 1211-1216. [NPL 8] Latourelle JC, et al. BMC Med Genet. 2009: 10: 98. [NPL 9] Zhang Y, et al. Am J Med Genet B Neuropsychiatr Genet. 2005; 137B(1): 5-16. [NPL 10] Kostich W, et al. J Pharmacol Exp Ther. 2016; 358(3): 371-386. [NPL 11] Karim M, et al. Antiviral Res. 2022: 204: 105367. [NPL 12] Neveu G, et al. J Virol. 2015; 89(8): 4387-4404.

[0004] The purpose of the present invention is to provide a new pharmaceutical compound having a potent AAK1 inhibitory activity, which is expected to have therapeutic effect for schizophrenia, Parkinson's disease, neuropathic pain, bipolar disorder, Alzheimer's disease, viral infection, etc.

[0005] The present inventors have extensively studied to reach the above purpose, and then have found that a new compound of formula (1) below has a potent AAK1 inhibitory activity. Based upon the findings, the present invention has been achieved.

[0006] (Item 1) A compound of a general formula [1]: wherein L1is -C(=O)-, -C(=S)-, -S(=O)-, or -SO2-, R is H, C1-6alkyl, or halogen, R1is C1-6alkyl, C3-10cycloalkyl, 4- to 12-membered saturated or aromatic heterocyclyl, -O-R11, or -N(R11a)(R11b), wherein the heterocyclyl may be substituted with oxo to give an oxide or dioxide form, and any one or more hydrogen atoms in R1may be substituted with the same or different R12, R11, R11a, and R11bare each independently H, C1-6alkyl, C3-8cycloalkyl, or 4- to 10-membered saturated heterocyclyl, wherein C1-6alkyl may be substituted with halogen, cyano, C1-6alkoxy, or C3-8cycloalkyl, and 4- to 10-membered saturated heterocyclyl may be substituted with C1-6alkyl, R12is each independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy-C1-6alkyl, C6-10aryl, C3-10cycloalkyl, 4- to 12-membered saturated or aromatic heterocyclyl, -C(=O)-R13, -O-R13, -S-R13, or -N(R13a)(R13b), R13, R13a, and R13bare each independently H, C1-6alkyl, -C(=O)-C1-6alkyl, or C1-6alkoxy-C1-6alkyl, wherein the alkyl and alkoxy in R13, R13a, and R13bmay be substituted with halogen or cyano, R2is each independently C1-6alkyl, m is 0, 1, or 2, wherein when m is 2 and two R2bind to the same carbon, the two R2may be taken together to form 3- to 6-membered spiro-ring, and Ring A is an optionally-substituted thieno[3,2-b]pyridine or [1,2]thiazolo[4,5-b]pyridine, or an N-oxide thereof, or a salt thereof or a co-crystal thereof.

[0007] (Item 2) The compound of Item 1, wherein Ring A is optionally substituted with 1 - 3 the same or different R3, wherein R3is selected from halogen, C1-6haloalkyl, C1-6hydroxyalkyl, -CHO, -C(=O)-C1-6alkyl, C6-10aryl, or 4- to 7-membered saturated or aromatic heterocyclyl, wherein the heterocyclyl may be substituted with oxo to give an oxide or dioxide form, and the aryl or the heterocyclyl may be substituted with C1-6alkyl, cyano, or C1-6haloalkyl, or a salt thereof or a co-crystal thereof.

[0008] (Item 3) The compound of Item 1 or 2, wherein the binding position of the thieno[3,2-b]pyridine or [1,2]thiazolo[4,5-b]pyridine in Ring A is the following or a salt thereof or a co-crystal thereof.

[0009] (Item 4) The compound of Item 2, wherein the optionally-substituted thieno[3,2-b]pyridine or [1,2]thiazolo[4,5-b]pyridine in Ring A is the following wherein * indicates the binding site to the pyrazole ring, or a salt thereof or a co-crystal thereof.

[0010] (Item 5) The compound of any one of Items 1 - 4, wherein R is H.

[0011] (Item 6) The compound of any one of Items 1 - 5, wherein R2is methyl.

[0012] (Item 7) The compound of any one of Items 1 - 6, wherein the general formula [1] is the following formula: or a salt thereof or a co-crystal thereof.

[0013] (Item 8) The compound of any one of Items 1 - 6, wherein the general formula [1] is the following formula: or a salt thereof or a co-crystal thereof.

[0014] (Item 9) The compound of any one of Items 1 - 6, wherein the general formula [1] is the following formula: or a salt thereof or a co-crystal thereof.

[0015] (Item 10) The compound of any one of Items 1 - 6, wherein the general formula [1] is the following formula: or a salt thereof or a co-crystal thereof.

[0016] (Item 11) The compound of any one of Items 1 - 6, wherein the general formula [1] is the following formula: or a salt thereof or a co-crystal thereof.

[0017] (Item 12) The compound of any one of Items 1 - 11, wherein R1or R12is a 4- to 7-membered monocyclic or 7- to 10-membered bicyclic saturated heterocyclyl which includes 1 - 4 the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom as a ring heteroatom, or a salt thereof or a co-crystal thereof.

[0018] (Item 13) The compound of any one of Items 1 - 11, wherein R1or R12is a 5- or 6-membered monocyclic or 8- to 10-membered bicyclic aromatic heterocyclyl which includes 1 - 4 the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom as a ring heteroatom, or a salt thereof or a co-crystal thereof.

[0019] (Item 14) The compound of any one of Items 1 - 11, wherein R1or R12is an 8- to 10-membered bicyclic bridged heterocyclyl which includes 1 - 4 the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom as a ring heteroatom, or a salt thereof or a co-crystal thereof.

[0020] (Item 15) The compound of any one of Items 1 - 11, wherein R1or R12is an 8- to 12-membered bicyclic spiro heterocyclyl which includes 1 - 4 the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom as a ring heteroatom, or a salt thereof or a co-crystal thereof.

[0021] (Item 16) The compound of any one of Items 12 - 15, wherein R1or R12includes only 1 - 4 nitrogen atoms as a ring heteroatom, or a salt thereof or a co-crystal thereof.

[0022] (Item 17) The compound of any one of Items 12 - 15, wherein R1or R12includes only 1 or 2 oxygen atoms as a ring heteroatom, or a salt thereof or a co-crystal thereof.

[0023] (Item 18) The compound of any one of Items 12 - 15, wherein R1or R12includes only one sulfur atom as a ring heteroatom, or a salt thereof or a co-crystal thereof.

[0024] (Item 19) The compound of any one of Items 12 - 15, wherein R1or R12includes 1 or 2 oxygen atoms and 1 - 3 nitrogen atoms as a ring heteroatom, or a salt thereof or a co-crystal thereof.

[0025] (Item 20) The compound of any one of Items 12 - 15, wherein R1or R12includes 1 or 2 sulfur atoms and 1 - 3 nitrogen atoms as a ring heteroatom, or a salt thereof or a co-crystal thereof.

[0026] (Item 21) The compound of any one of Items 1 - 20, wherein R1or R12is (i) azetidinyl, pyrrolidinyl, or piperidinyl, (ii) oxetanyl, oxolanyl, oxanyl, or dioxanyl, (iii) pyrazolyl, imidazolyl, 1,3-oxazolyl, thiazolyl, pyridinyl, pyrazinyl, or 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazinyl, (iv) 8-oxa-3-azabicyclo[3.2.1]octanyl, 7-oxabicyclo[2.2.1]heptanyl, or 2-oxa-5-azabicyclo[2.2.1]heptanyl, (v) 5-azaspiro[2.4]heptanyl, or (vi) morpholinyl, 1,4-oxazepanyl, or hexahydrofuro[3,4-c]pyrrolyl, or a salt thereof or a co-crystal thereof.

[0027] (Item 22) The compound of any one of Items 1 - 11, wherein R1is (i) C1-6alkyl optionally-substituted with halogen, cyano, C1-6alkoxy, phenyl, 4- to 12-membered saturated or aromatic heterocyclyl, -OH, -O-C1-6alkyl, -S-C1-6alkyl, NH2, N(CH3)2, N(CH3)C(=O)CH3, or N(CH3)CH2CH2OH, (ii) -O-C1-6alkyl optionally-substituted with fluoro, C1-6alkoxy (methoxy), or 4- to 12-membered saturated or aromatic heterocyclyl, (iii) -N(R11a)(R11b), wherein R11aand R11bis independently H, C1-6alkyl, C1-6alkoxy, C3-8cycloalkyl, oxanyl, or C1-6alkyl substituted with halogen, cyano, or cyclopropyl, (iv) -O-4- to 10-membered saturated heterocyclyl, optionally-substituted with methyl, (v) C3-10cycloalkyl optionally-substituted with cyano, fluoro, or methoxy-methyl, or (vi) 4- to 12-membered saturated or aromatic heterocyclyl optionally-substituted with oxo, halogen, cyano, C1-6alkyl, C1-6haloalkyl, -C(=O)-C1-6alkyl, -O-C1-6alkyl, or C1-6alkoxy-C1-6alkyl, or a salt thereof or a co-crystal thereof.

[0028] (Item 23) The compound of any one of Items 1 - 11, wherein R1is (i) C1-6alkyl optionally-substituted with 1 to 4 the same or different substituents selected from the group consisting of fluoro, cyano, -CF3, -O-CH3, phenyl, oxolanyl, morpholinyl, pyrazolyl, -OH, -O-t-Bu, -S-CH3, NH2, N(CH3)2, N(CH3)C(=O)CH3, and N(CH3)CH2CH2OH, (ii) -O-C1-6alkyl optionally-substituted with 1 to 4 the same or different substituents selected from the group consisting of fluoro, methoxy, 1,3-oxazolyl, and oxolanyl, (iii) -N(CH3)2, -NHCH3, -NH-ethyl, -N(CH3)CH2CN, -N(CH3)-oxanyl, -NH-C(=O)-CH3, -NH-CH2-cyclopropyl, -NH-CH2CH2CN, -NH-CH2CHF2, or -N(CH3)CH2-cycloprpyl, (iv) -O-oxetanyl which is optionally-substituted with 1 to 4 methyl, (v) cyclopropyl, cyclobutyl, cyclopentyl, or bicyclo[1.1.1]pentanyl, which is optionally-substituted with 1 to 4 the same or different substituents selected from the group consisting of cyano, fluoro, and methoxy-methyl, or (vi) azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxanyl, dioxanyl, pyrazolyl, imidazolyl, 1,3-oxazolyl, thiazolyl, pyridinyl, pyrazinyl, 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazinyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 5-azaspiro[2.4]heptanyl, morpholinyl, 1,4-oxazepanyl, or hexahydrofuro[3,4-c]pyrrolyl, which is optionally-substituted with 1 to 4 the same or different substituents selected from the group consisting of fluoro, methyl, ethyl, cyano, CF3, CHF2, oxo, C(=O)CH3, OCH3, and CH2OCH3, or a salt thereof or a co-crystal thereof.

[0029] (Item 24) The compound of any one of Items 1 - 23, wherein L1is -C(=O)-, -C(=S)-, or -SO2-, or a salt thereof or a co-crystal thereof.

[0030] (Item 25) The compound of any one of Items 1 - 23, wherein L1is -C(=O)- or -C(=S)-, or a salt thereof or a co-crystal thereof.

[0031] (Item 26) The compound of any one of Items 2 - 25, wherein R3is F, Cl, difluoromethyl, hydroxymethyl, -CHO, phenyl, 4-cyanophenyl, 2-methyl-1,3-thiazol-5-yl, 1,3-thiazol-2-yl, 1,3-thiazol-5-yl, 1,2-thiazol-3-yl, 1-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl, 1-trifluoromethyl-1H-pyrazol-4-yl, pyrrolidin-2-on-1-yl, 3,4-dihydro-2H-pyridin-1-yl, pyridin-2-yl, 2-methylpyridin-4-yl, 3-fluoropyrrolidin-1-yl, 1,3-oxazol-2-yl, 1,3-oxazol-5-yl, 2,3-dihydro-1,4-oxazin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, 1-methyl-1H-imidazol-2-yl, or 1-methyl-1H-imidazol-5-yl, or a salt thereof or a co-crystal thereof.

[0032] (Item 27) The compound of Item 10 or 11, wherein L1is -C(=O)-, R1is (i) C1-6alkyl optionally-substituted with -OH or NH2, (ii)-O-oxetanyl, or (iii) oxetanyl, oxolanyl, oxanyl, dioxanyl, pyrrolidinyl, pyrazolyl, imidazolyl, or morpholinyl, which is optionally-substituted with 1 to 4 the same or different substituents selected from the group consisting of fluoro, cyano, methyl, and CF3, and Ring A is wherein R3is fluoro, chloro, methylpyrazolyl, or trifluoromehylpyrazolyl and * indicates the binding site to the pyrazole ring, or a salt thereof or a co-crystal thereof.

[0033] (Item 28) The compound of Item 1, or a salt thereof or a co-crystal thereof, wherein the compound is selected from Examples 1 to 207.

[0034] (Item 29) The compound of Item 1, which is selected from the following compounds: or a salt thereof or a co-crystal thereof.

[0035] (Item 30) The compound of Item 1, which is selected from the following compounds:

[0036] (Item 31) A pharmaceutical composition comprising the compound of any one of Items 1 - 30, or a salt thereof or a co-crystal thereof.

[0037] (Item 32) An inhibitor of AAK1 activity, comprising the compound of any one of Items 1 - 30, or a salt thereof or a co-crystal thereof.

[0038] (Item 33) A pharmaceutical composition for treating or preventing Alzheimer's disease, bipolar disorder, Parkinson disease, schizophrenia, cognitive impairment in schizophrenia, acute pain, chronic pain, neuropathic pain, muscular dystrophy, or a disease associated with viral infection, comprising the compound of any one of Items 1 - 30, or a salt thereof or a co-crystal thereof.

[0039] (Item 34) The pharmaceutical composition of Item 33, wherein the acute pain and chronic pain are pain associated with rheumatoid arthritis, or wherein the neuropathic pain is pain associated with fibromyalgia, central nervus neuropathy (such as spinal cord injury related pain), or peripheral neuropathy (such as diabetic neuropathy and postherpetic neuralgia, chemotherapy induced peripheral neuropathy) wherein the muscular dystrophy includes Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy, Limb-Girdle muscular dystrophies, von Graefe-Fuchs muscular dystrophy, oculopharyngeal muscular dystrophy, Mytonic dystrophy, congenital muscular dystrophy.

[0040] (Item 35) The compound of any one of Items 1 - 30, or a salt thereof or a co-crystal thereof, for use in treating or preventing Alzheimer's disease, bipolar disorder, Parkinson disease, schizophrenia, cognitive impairment in schizophrenia, acute pain, chronic pain, neuropathic pain, muscular dystrophy, or a disease associated with viral infection.

[0041] (Item 36) The compound of any one of Item 35, or a salt thereof or a co-crystal thereof, wherein the acute pain and chronic pain are pain associated with rheumatoid arthritis, or wherein the neuropathic pain is pain associated with fibromyalgia, central nervus neuropathy (such as spinal cord injury related pain), or peripheral neuropathy (such as diabetic neuropathy and postherpetic neuralgia, chemotherapy induced peripheral neuropathy) wherein the muscular dystrophy includes Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy, Limb-Girdle muscular dystrophies, von Graefe-Fuchs muscular dystrophy, oculopharyngeal muscular dystrophy, Mytonic dystrophy, congenital muscular dystrophy.

[0042] (Item 37) Use of the compound of any one of Items 1 - 30, or a salt thereof or a co-crystal thereof in the manufacture of a medicament for treating or preventing Alzheimer's disease, bipolar disorder, Parkinson disease, schizophrenia, cognitive impairment in schizophrenia, acute pain, chronic pain, neuropathic pain, muscular dystrophy, or a disease associated with viral infection.

[0043] (Item 38) The use of Item 37, wherein the acute pain and chronic pain are pain associated with rheumatoid arthritis, or wherein the neuropathic pain is pain associated with fibromyalgia, central nervus neuropathy (such as spinal cord injury related pain), or peripheral neuropathy (such as diabetic neuropathy and postherpetic neuralgia, chemotherapy induced peripheral neuropathy) wherein the muscular dystrophy includes Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy, Limb-Girdle muscular dystrophies, von Graefe-Fuchs muscular dystrophy, oculopharyngeal muscular dystrophy, Mytonic dystrophy, congenital muscular dystrophy.

[0044] (Item 39) A method for treating or preventing Alzheimer's disease, bipolar disorder, Parkinson disease, schizophrenia, cognitive impairment in schizophrenia, acute pain, chronic pain, neuropathic pain, muscular dystrophy, or a disease associated with viral infection, comprising administering a therapeutically effective amount of the compound of any one of Items 1 - 30, or a salt thereof or a co-crystal thereof to a patient in need thereof.

[0045] (Item 40) The method of Item 39, wherein the acute pain and chronic pain are pain associated with rheumatoid arthritis, or wherein the neuropathic pain is pain associated with fibromyalgia, central nervus neuropathy (such as spinal cord injury related pain), or peripheral neuropathy (such as diabetic neuropathy and postherpetic neuralgia, chemotherapy induced peripheral neuropathy) wherein the muscular dystrophy includes Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy, Limb-Girdle muscular dystrophies, von Graefe-Fuchs muscular dystrophy, oculopharyngeal muscular dystrophy, Mytonic dystrophy, congenital muscular dystrophy.

[0046] (Item 41) A process for the preparation of a compound of formula [I] according to any one of Items 1 - 30, or a salt thereof, as described herein.

[0047] (Item 42) An intermediate compound in the process for preparing a compound of formula [I], or a salt thereof, as described herein.

[0048] (Item 43) The compound according to Item 42, represented by any one of the compounds of formulae [P1], [P6], [P7], and [P10]: wherein L1, R, R1, R2, m, and Ring A are as defined above, or a salt thereof.

[0049] (Item 44) The compound according to Item 42, or a salt thereof, wherein the compound is selected from the compounds of Reference Examples 1 to 56, or a salt thereof.

[0050] Another embodiment of the present invention includes a method of treating or controlling a disease or disorder, comprising administering a therapeutically or prophylactically effective amount of the AAK1 inhibitor of the present invention to a patient in need thereof, wherein the disease or disorder is Alzheimer's disease, bipolar disorder, Parkinson disease, schizophrenia (including cognitive impairment in schizophrenia), pain, muscular dystrophy,　or viral infection. Specific types of pain include chronic pain, acute pain, and neuropathic pain. Specific types of acute pain and chronic pain include pain associated with rheumatoid arthritis. Specific types of muscular dystrophy include Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy, Limb-Girdle muscular dystrophies, von Graefe-Fuchs muscular dystrophy, oculopharyngeal muscular dystrophy, Mytonic dystrophy, congenital muscular dystrophy. Specific types of neuropathic pain include pain associated with fibromyalgia, central nervus neuropathy, and peripheral neuropathy (such as diabetic neuropathy, postherpetic neuralgia, chemotherapy induced peripheral neuropathy).

[0051] The "halogen" used herein includes, for example, fluorine, chlorine, bromine, and iodine, and preferably, fluorine and chlorine.

[0052] The "C1-6alkyl" used herein means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, which includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, and their structural isomers.

[0053] The "C1-6alkoxy" used herein means an oxy group substituted with the above "C1-6alkyl", which includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0054] The "C3-10cycloalkyl" used herein means a cyclic non-aromatic hydrocarbon group having 3 to 10 carbon atoms. The "C3-10cycloalkyl" includes preferably "C3-6cycloalkyl". The "C3-10cycloalkyl" includes a bridged one. The "C3-10cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cycloheptyl, and bicyclo[1.1.1]pentyl.

[0055] The "C1-6haloalkyl" used herein means a C1-6alkyl group substituted with one or more the same or different halogen atoms. The "C1-6haloalkyl" includes preferably a C1-6alkyl group substituted with 1 to 5 the same or different halogen atoms. The "C1-6haloalkyl" includes, for example, mono-, di-, or tri-fluoromethyl; mono-, di-, or tri-chloromethyl; mono-, di-, tri-, tetra-, or penta-fluoroethyl; mono-, di-, tri-, tetra-, or penta-chloroethyl; and 1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl. The typical C1-6haloalkyl includes trifluoromethyl and difluoromethyl.

[0056] The "C1-6hydroxyalkyl" means a C1-6alkyl group substituted with one or more hydroxy groups. The "C1-6hydroxyalkyl" includes preferably a C1-6alkyl group substituted with 1 to 3 hydroxy groups. The "C1-6hydroxyalkyl" includes, for example, hydroxymethyl, 2-hydroxyethyl, and 3-hydroxypropyl.

[0057] The "4- to 12-membered saturated or aromatic heterocyclyl" includes a monocyclic one and a polycyclic one such as bicyclic one, and preferably mono-cyclic and bicyclic ones. For example, such bicyclic ring includes a bicyclic ring in which one ring is a saturated hetero ring and the other is an aromatic hetero ring, and a bicyclic ring in which one ring is a saturated or aromatic hetero ring and the other is a cycloalkyl or benzene ring.

[0058] The "4- to 12-membered saturated heterocyclyl" used herein means a 4- to 12-membered saturated ring group containing heteroatom(s), which includes the ring group having partially unsaturated bond(s). It includes 4- to 7-membered mono-cyclic or 7- to 12-membered bi-cyclic saturated hetero ring group containing, as ring-constituting heteroatoms, 1 to 4 the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom; and 4- to 7-membered mono-cyclic or 7- to 10-membered bi-cyclic saturated hetero ring group containing, as ring-constituting heteroatoms, 1 to 4 the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom. It includes, preferably, 4- to 7-membered mono-cyclic saturated hetero ring group containing 1 or 2 the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, and 7- to 10-membered bi-cyclic saturated hetero ring group containing 1 to 3 the same or different heteroatoms, and more preferably, 4- to 6-membered mono-cyclic or 7- to 8-membered bi-cyclic saturated hetero ring group containing 1 or 2 the same or different heteroatoms selected from the group consisting of nitrogen atom and oxygen atom.

[0059] The "4- to 12-membered aromatic heterocyclyl" includes 4- to 8-membered mono-cyclic or 7- to 10-membered bi-cyclic aromatic heterocyclyl containing, as ring-constituting heteroatoms, 1 to 4 the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, preferably 5- to 6-membered mono-cyclic aromatic heterocyclyl containing only 1 - 4 nitrogen atoms, or only one oxygen or sulfur atom, or one or two nitrogen atoms and one oxygen atom or sulfur atom, more preferably 5- to 6-membered mono-cyclic aromatic heterocyclyl containing only one or two nitrogen atoms, or one or two nitrogen atoms and one oxygen or sulfur atom.

[0060] In the present specification, the "4- to 12-membered saturated or aromatic heterocyclyl" is a saturated, partially-unsaturated, or unsaturated, monocyclic or polycyclic heterocyclic ring group containing, as ring-constituting heteroatoms, 1 to 4 heteroatoms independently-selected from the group consisting of nitrogen, oxygen, and sulfur (preferably nitrogen and oxygen), which includes, for example, (a) a saturated, partially-unsaturated, or unsaturated 4- to 8-membered, preferably 4- to 7-membered, more preferably a saturated 5- or 6-membered mono-cyclic heterocyclic ring group containing 1 to 4 nitrogen atoms alone as ring-constituting heteroatoms; specifically including a group containing a ring selected from the group consisting of pyrrole, imidazole, pyrazole, pyridine, tetrahydropyridine, pyrimidine, pyrazine, pyridazine, triazole, tetrazole, dihydrotriazine, azetidine, pyrrolidine, imidazolidine, piperidine, pyrazolidine, piperazine, azepane and 1,4-diazepane, and oxides and dioxides thereof, (b) a saturated, partially-unsaturated, or unsaturated 6- to 12-membered, bi-cyclic, tri-cyclic, bridged-cyclic, or spiro-cyclic heterocyclic ring group containing 1 to 5 nitrogen atoms alone as ring-constituting atoms, preferably a saturated, partially-unsaturated, or unsaturated 6- to 12-membered bi-cyclic, tri-cyclic, bridged-cyclic, or spiro-cyclic heterocyclic ring containing 1 to 3 nitrogen atoms alone as ring-constituting heteroatoms; specifically including a group containing a ring selected from the group consisting of indole, indoline (dihydroindole), isoindole, isoindoline (dihydroisoindole), benzoimidazole, dihydrobenzoimidazole, indazole, indazoline (dihydroindazole), quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, benzotriazole, tetrazolopyridine, tetrazolopyridazine, dihydrotriazolopyridazine, imidazopyridine, naphthyridine, tetrahydronaphthyridine, hexahydronaphthyridine, cinnoline, quinoxaline, dihydroquinoxaline, tetrahydroquinoxaline, quinazoline, dihydroquinazoline, tetrahydroquinazoline, pentahydropyrazolo[3,4-c]pyridine, octahydro-2H-pyrazino[1,2-a]pyrazine, octahydropyrrolo[2,3-c]pyrrole, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole, tetrahydropyridoindole, benzoazepine, tetrahydrobenzoazepine, carbazole, phenanthridine, dihydrophenanthridine, diazabicyclo[2.2.1]heptane, diazabicyclo[3.1.1]heptane, diazabicyclo[3.2.0]heptane, diazabicyclo[3.4]octane, diazaspiro[3.3]heptane, diazaspiro[2.5]octane, octahydro-1H-pyrido[3,4-b][1,4]oxazine, azabicyclo[3.1.0]hexane, hexahydropyrrolo[1,2-a]pyrazine, 2,5-diazabicyclo[2.2.1]heptane, and oxides and dioxides thereof, (c) a saturated, partially-unsaturated, or unsaturated 4- to 8-membered (preferably 5- or 6-membered) monocyclic heterocyclic ring containing 1 or 2 oxygen atoms alone as ring-constituting heteroatoms; specifically including a group containing a ring selected from the group consisting of oxetane, furan, tetrahydropyran, tetrahydrofuran and dioxane, oxepane, and oxides and dioxides thereof, (d) a saturated, partially-unsaturated, or unsaturated 6- to 12-membered bi-cyclic, tri-cyclic, bridged-cyclic, or spiro-cyclic heterocyclic ring group containing 1 to 3 oxygen atoms alone as ring-constituting heteroatoms; specifically including a group containing a ring selected from the group consisting of benzofuran, dihydrobenzofuran, chroman, benzodioxole, benzodioxane, 2-oxabicyclo[2.2.1]hexane, 3-oxabicyclo[3.1.0]hexane, 2-oxaspiro[3.3]heptane, 5-oxaspiro[2.4]heptane, 8-oxaspiro[4.5]decane, 2-oxabicyclo[2.2.1]heptane, 3-oxabicyclo[4.1.0]heptane, 2-oxabicyclo[3.1.1]heptane, 5-oxaspiro[2.3]hexane and oxides and dioxides thereof, (e) a saturated, partially-unsaturated, or unsaturated 4- to 8-membered (preferably 5- or 6-membered) monocyclic heterocyclic ring containing, as ring-constituting heteroatoms, 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms; specifically including a group containing a ring selected from the group consisting of oxazole, isoxazole, oxadiazole and morpholine, and oxides and dioxides thereof, (f) a saturated, partially-unsaturated, bridged-cyclic, or unsaturated 6- to 12-membered bi-cyclic, tri-cyclic, bridged-cyclic, or spiro-cyclic heterocyclic ring containing, as ring-constituting heteroatoms, 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms; specifically including a group containing a ring selected from the group consisting of benzoxazole, dihydrobenzoxazole, benzoxadiazole, benzoisoxazole, benzoxazine, dihydrobenzoxazine, furopyridine, furopyrrole, benzoxazepine, tetrahydrobenzoxazepine, oxaazabicycloheptane,oxadiazabicyclononane, octahydropyrrolo[3,4-b][1.4]oxazine, octahydropyrazino[2,1-c][1.4]oxazine, pyridooxazine, 2-oxa-5-azabicyclo[4.1.0]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-oxa-6-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, 3-oxa-7,9-diazabicyclo[3.3.1]nonane, 9-oxa-3,7-diazabicyclo[3.3.1]nonane, hexahydrofuro[3,4-c]pyrrole, 1-oxa-6-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.4]octane, 2-oxa-5,8-diazaspiro[3.5]nonane, 5-oxa-2,8-diazaspiro[3.5]nonane, and oxides and dioxides thereof, (g) a saturated, partially-unsaturated, or unsaturated 4- to 8-membered mono-cyclic heterocyclic ring or a saturated, partially-unsaturated, bridged-cyclic, or unsaturated 6- to 15-membered bi-cyclic, tri-cyclic, bridged-cyclic, or spiro-cyclic heterocyclic ring containing, 1 or 2 sulfur atoms as ring-constituting heteroatoms; specifically including a group containing a ring selected from the group consisting of tetrahydrothiophene, tetrahydrothiopyran, thiepane, thiophen, thiopyran, benzothiophene, and oxides and dioxides thereof, and (h) a saturated, partially-unsaturated, or unsaturated 4- to 8-membered mono-cyclic heterocyclic ring or a saturated, partially-unsaturated, bridged-cyclic, or unsaturated 6- to 15-membered bi-cyclic, tri-cyclic, bridged-cyclic, or spiro-cyclic heterocyclic ring containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms as ring-constituting heteroatoms; specifically including a group containing a ring selected from the group consisting of thiazolidine, thiomorpholine, thiazole, thiadiazole, thiazine, and thiazepane, benzoisothiazole, benzothiazole, and oxides and dioxides thereof.

[0061] The polycyclic saturated or aromatic heterocyclyl may be a bridged ring or a spiro ring. When R1is 4- to 12-membered saturated or aromatic heterocyclyl, preferably R12is not a 4- to 12-membered saturated or aromatic heterocyclyl.

[0062] The "4- to 10-membered saturated heterocyclyl" in R11means a 4- to 10-membered saturated ring group containing heteroatom(s), which may include partially unsaturated bond(s). It includes 4- to 7-membered mono-cyclic or 7- to 10-membered bi-cyclic saturated heterocyclyl containing, as ring-constituting heteroatoms, 1 to 4 the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, preferably 4- to 7-membered mono-cyclic saturated heterocyclyl containing one or two the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom.

[0063] The substituent "4- to 7-membered saturated or aromatic heterocyclyl" with which Ring A is substituted means 4- to 7-membered saturated ring group containing heteroatom(s), which may include partially unsaturated bond(s). It includes 4- to 7-membered mono-cyclic saturated or aromatic heterocyclyl containing, as ring-constituting heteroatoms, 1 to 4 the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, preferably 4- to 6-membered mono-cyclic saturated or aromatic heterocyclyl containing one or two the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom.

[0064] The "heterocyclyl substituted with oxo to give oxide or dioxide form" used herein means a heterocyclyl wherein the carbon atom of "-CH2-" in the ring is oxidized to "-C=O-". The "oxide" has one "-C=O-", and the "dioxide" has two "-C=O-". For example, it includes the following groups.

[0065] The "C6-10aryl" used herein means an aromatic hydrocarbon group having 6 - 10 carbon atoms, which includes, more preferably, phenyl. The "C6-10aromatic hydrocarbon group" includes, for example, phenyl, 1-naphthyl, and 2-naphthyl.

[0066] The "thieno[3,2-b]pyridine" or "[1,2]thiazolo[4,5-b]pyridine" has the structures shown below, and the binding position is bondable carbon atom or nitrogen atom in the ring. And, "an N-oxide thereof" means a N-oxide form of the nitrogen atom which constitutes the ring. Preferably, the binding position is as shown below.

[0067] The "salt" used herein means a pharmaceutically acceptable acid addition salt or base addition salt. The pharmaceutically acceptable salt includes, but not to be limited thereto, acid addition salts such as acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citrate, stearate, succinate, ethylsuccinate, malonate, lactate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, benzenesulfonate, para-toluenesulfonate (tosylate), laurylsulfate, malate, ascorbate, mandelate, saccharin, xinafoate, pamoate, cinnamate, adipate, cysteine salt, N-acetylcysteine salt, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nitrate, nicotinate, oxalate, picrate, thiocyanate, undecanoate, acrylic acid polymer salt, and carboxy vinyl polymer salt; inorganic base addition salts such as lithium salt, sodium salt, potassium salt, and calcium salt; organic base addition salts such as morpholine and piperidine; and addition salts with amino acid such as aspartate and glutamate.

[0068] The "co-crystal" used herein means a complex crystal composed of the present compound and an ingredient (coformer) that exist in the same crystal lattice interacting nonionically each other in a molar ratio. The co-crystal can exist as multiple crystal forms (also referred to herein as "crystalline polymorphs"). The present compound forming a co-crystal may be in any crystal form or a mixture thereof, and may be amorphous. The coformer includes, for example, the compounds listed below, but not to be limited thereto. And, Examples 12, 30, 41, etc. shown below are exemplified as co-crystals. The present compound or a salt thereof and the coformer may coexist in various proportions, for example, 1 / 10, 1 / 5, 1 / 4, 1 / 3, 1 / 2, 2 / 3, 3 / 4, 1, 1.5, 2, 3, etc.

[0069] The compound of the present invention encompasses various hydrates, solvates, and crystalline polymorphs of Compound [1] or a salt thereof or a co-crystal thereof. The hydrates or solvates of Compound [1] or a salt thereof or a co-crystal thereof may be present in various proportions, for example, 1 / 10, 1 / 5, 1 / 4, 1 / 3, 1 / 2, 2 / 3, 3 / 4, 1, 1.5, 2, 3, etc.

[0070] The compound of the present invention or a salt thereof or a co-crystal thereof also includes compounds in which one or more atoms are replaced by one or more isotope atoms. Examples of isotope atoms include deuterium (2H or D), tritium (3H),11C,13C,14C,13N,15N,15O,17O,18O,32P,35S,36Cl,37Cl,18F,123I,125I, and the like.

[0071] In one embodiment, Compound [I], or a salt thereof or a co-crystal thereof, may be useful as a Positron Emission Topography (PET) tracer, preferably a PET imaging agent, that may be useful for in vitro, exo vivo, in vivo, or clinical trial tests and diagnostic imaging in humans and / or non-humans. Substitution with positron emitting isotopes, such as11C,18F,15O, and13N, can be useful in PET studies for examining target occupancy. For example, compounds labeled with11C or18F may be used for a PET tracer.

[0072] The compound [1] of the present invention includes pharmaceutically acceptable prodrugs. Examples of substituents that can be modified to make prodrugs include reactive functional groups such as -OH, -COOH, and amino. The modifying groups of these functional groups can be selected appropriately from the "substituents" in the present specification. The functional groups may be modified with any group(s) selected appropriately from the protecting groups of hydroxy, carboxy, and amino.

[0073] Preferred L1, R1, R2, R11, R11a, R11b, R12, R13, R13a, R13b, and m in the present compound of formula (1) are shown below, but the technical scope of the present invention is not limited to the scope of compounds listed below.

[0074] In an embodiment, L1includes -C(=O)-, -C(=S)-, and -SO2-, preferably -C(=O)- and -C(=S)-, and more preferably -C(=O)-.

[0075] In an embodiment, R includes H, C1-6alkyl, and halogen, preferably H, methyl, F, and Cl, and more preferably H.

[0076] In an embodiment, R1includes C1-6alkyl, C3-10cycloalkyl, 4- to 12-membered saturated heterocyclyl, 4- to 12-membered aromatic heterocyclyl, -O-R11, and -N(R11a)(R11b), wherein the saturated and aromatic heterocyclyls may be substituted with oxo to give an oxide or dioxide form, and any one or more hydrogen atoms in R1may be substituted with the same or different R12. The above C1-6alkyl includes, preferably methyl, ethyl, propyl, isopropyl, 2-methylpropyl, tert-butyl, 2-methylbutyl, 3-methylbutyl, and hexyl, more preferably methyl, ethyl, propyl, 2-methylpropyl, 2-methylbutyl, and 3-methylbutyl. The above C3-10cycloalkyl includes, preferably cyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1.1.1]pentyl. The above 4- to 12-membered saturated heterocyclyl includes, preferably azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, morpholinyl, oxazepanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, hexahydrofuro[3,4-c]pyrrolyl, dihydro-4H-pyrazolo[1,5-a]pyrazinyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, and azaspiro[2.4]heptanyl. The above 4- to 12-membered aromatic heterocyclyl includes, preferably pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, and pyrazinyl, and the above aromatic heterocyclyl substituted with oxo includes pyridin-2(1H)-one.

[0077] In an embodiment, R11, R11a, and R11binclude H, C1-6alkyl, C3-8cycloalkyl, and 4- to 10-membered saturated heterocyclyl. The above C1-6alkyl includes methyl, ethyl, propyl, butyl, pentyl, hexyl, and their structural isomers, preferably methyl, ethyl, propyl, and tert-butyl, more preferably methyl, ethyl, and tert-butyl. The above C3-8cycloalkyl includes, preferably cyclopropyl, cyclobutyl, and cyclopentyl. The above 4- to 10-membered saturated heterocyclyl includes, preferably oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.

[0078] In an embodiment, R12includes halogen, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy-C1-6alkyl, C6-10aryl, C3-10cycloalkyl, 4- to 12-membered saturated or aromatic heterocyclyl, -C(=O)-R13, -O-R13, -S-R13, and -N(R13a)(R13b). The above halogen includes, preferably fluoro and chloro, more preferably fluoro. The above C1-6alkyl includes, preferably methyl and ethyl. The above C1-6haloalkyl includes, preferably trifluoromethyl, difluoromethyl, and 2,2,2-trifluoroethyl, more preferably trifluoromethyl. The above C1-6alkoxy-C1-6alkyl includes, preferably methoxymethyl, ethoxymethyl, and methoxyethyl, more preferably methoxymethyl. The above C6-10aryl includes, preferably phenyl and naphthyl, more preferably phenyl. The above C3-10cycloalkyl includes, preferably cyclopropyl, cyclobutyl, and cyclopentyl, more preferably cyclopropyl. The above 4- to 12-membered saturated or aromatic heterocyclyl includes, preferably oxazolyl, tetrahydrofuranyl, morpholinyl, and pyrazolyl.

[0079] In an embodiment, R13, R13aand R13bincludes H, C1-6alkyl, -C(=O)-C1-6alkyl, and C1-6alkoxy-C1-6alkyl, wherein R13, R13aand R13bmay be substituted with halogen or cyano. The above C1-6alkyl includes, preferably methyl and ethyl, more preferably methyl. The above -C(=O)-C1-6alkyl includes, preferably acetyl. The above C1-6alkoxy-C1-6alkyl includes, preferably 2-methoxyethyl.

[0080] In an embodiment, R2includes C1-6alkyl, preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, and their structural isomers, and more preferably methyl.

[0081] In an embodiment, R3includes halogen, C1-6haloalkyl, C1-6hydroxyalkyl, -CHO, -C(=O)-C1-6alkyl, C6-10aryl, or 4- to 7-membered saturated or aromatic heterocyclyl, wherein the heterocyclyl may be substituted with oxo to give an oxide or dioxide form, and the aryl or the heterocyclyl may be substituted with C1-6alkyl, cyano, or C1-6haloalkyl. Preferably, R3includes F, Cl, difluoromethyl, hydroxymethyl, -CHO, phenyl, 4-cyanophenyl, 2-methyl-1,3-thiazol-5-yl, 1,3-thiazol-2-yl, 1,3-thiazol-5-yl, 1,2-thiazol-3-yl, 1-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl, 1-trifluoromethyl-1H-pyrazol-4-yl, pyrrolidin-2-on-1-yl, 3,4-dihydro-2H-pyridin-1-yl, pyridin-2-yl, 2-methylpyridin-4-yl, 3-fluoropyrrolidin-1-yl, 1,3-oxazol-2-yl, 1,3-oxazol-5-yl, 2,3-dihydro-1,4-oxazin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, 1-methyl-1H-imidazol-2-yl, and 1-methyl-1H-imidazol-5-yl.

[0082] In an embodiment, m includes 0, 1, and 2, and preferably 1.

[0083] General process The compound of formula [1] can be prepared, for example, based on the general processes shown below, but is not limited thereto. As starting material compounds, a commercially available one may be used, or it may be synthesized according to a known method or a method analogous thereto. The solvents, acids, bases, protecting groups, and leaving groups which are used as needed in the production of the compound of formula [1] are not particularly limited as long as they are commonly used in the field of organic synthetic chemistry. In the process of the compound of formula [1], each product can be used in the next reaction as a reaction solution including it or as its crude product, or it can be also isolated from the reaction mixture according to a conventional method, or can be also easily purified by conventional separation means. Conventional separation means include, for example, filtration, extraction, concentration, solvent removal, crystallization, recrystallization, reprecipitation, distillation, chromatography, and optical resolution. In the preparation of Compound [1], when performing an alkylation reaction, hydrolysis reaction, amination reaction, esterification reaction, amidation reaction, etherification reaction, oxidation reaction, reduction reaction, or the like, these reactions are themselves performed by known methods. The above conventionally-used methods and reagents are disclosed, for example, in ORGANIC FUNCTIONAL GROUP PREPARATIONS Second Edition, ACADEMIC PRESS, INC. 1989; Comprehensive Organic Transformations VCH Publishers Inc., 1989, P. G. M. Wuts; T. W. Greene "Greene's Protective Groups in Organic Synthesis" (Fourth Edition, 2006); and John Wiley & Sons; New York, 1991, P. 309. In the general process of the compound of formula [1], starting compounds, intermediate compounds, and compounds of formula [1], and their intermediate compounds including compounds of [P1] to [P12] may be in a salt form thereof, and each desired compounds prepared in each reaction may be also in a salt form thereof. When the above compound is a free compound, it can be converted into a desired salt thereof by a known method; or when the above compound is a salt compound, it can be converted into its free form or another desired salt thereof by a known method.

[0084] In the present specification, the options and preferred embodiments for the different features of the compound, method and composition of the present invention as presented include all possible combinations of the options and preferred embodiments for these different features as long as they are consistent combinations.

[0085] Methods of manufacture Methods of manufacturing Compound [1] are explained below. Compound [1] may be manufactured, but is not limited thereto, based on the methods described in the General syntheses and Examples below. Unless otherwise specified, reaction temperatures may be optionally adjusted depending on reactants, solvents, and other conditions used in each reaction herein.

[0086] An alkylation reaction, hydrolysis reaction, amination reaction, esterification reaction, amidation reaction etherification reaction, nucleophilic substitution reaction, addition reaction, oxidation reaction, reduction reaction, and the like in the General syntheses may be performed in accordance with any known methods. Examples of such methods include the methods described in Experimental Chemistry (Fifth Edition, edited by The Chemical Society of Japan, Maruzen Co., Ltd.); Organic Functional Group Preparations Second Edition, Academic Press, Inc., 1989; Comprehensive Organic Transformations, VCH Publishers, Inc., 1989; and P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis (Fourth Edition, 2006), and the like.

[0087] As used herein, the term "C1-18alkanesulfonyl" is a linear or branched alkanesulfonyl having 1 to 18 carbon atoms (C1-18), and examples thereof include methanesulfonyl, 1-propanesulfonyl, 2-propanesulfonyl, butanesulfonyl, cyclohexanesulfonyl, dodecanesulfonyl, octadecanesulfonyl, and the like.

[0088] As used herein, the term "lower alkanesulfonyloxy" is a linear or branched alkanesulfonyloxy having 1 to 6 carbon atoms (C1-6), and examples thereof include methanesulfonyloxy, ethanesulfonyloxy, 1-propanesulfonyloxy, 2-propanesulfonyloxy, 1-butanesulfonyloxy, 3-butanesulfonyloxy, 1-pentanesulfonyloxy, 1-hexanesulfonyloxy, and the like.

[0089] As used herein, the term "arylsulfonyloxy" is phenylsulfonyloxy, naphthylsulfonyloxy, and the like, that is optionally substituted with 1 to 3 groups selected from the group consisting of a linear or branched alkyl having 1 to 6 carbon atoms (C1-6), a linear or branched alkoxy having 1 to 6 carbon atoms (C1-6), nitro, and halogen, on the benzene or naphthalene ring. Examples of phenylsulfonyloxy optionally having substituent(s) include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 2-nitrophenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and the like. Specific examples of naphthylsulfonyloxy include α-naphthylsulfonyloxy, β-naphthylsulfonyloxy, and the like.

[0090] As used herein, the term "aralkylsulfonyloxy" is a linear or branched alkanesulfonyloxy having 1 to 6 carbon atoms (C1-6) that is substituted with phenyl optionally substituted with 1 to 3 groups selected from the group consisting of a linear or branched alkyl having 1 to 6 carbon atoms (C1-6), a linear or branched alkoxy having 1 to 6 carbon atoms (C1-6), nitro, and halogen on the benzene ring; or a linear or branched alkanesulfonyloxy having 1 to 6 carbon atoms (C1-6) that is substituted with naphthyl, and the like. Examples of alkanesulfonyloxy substituted with phenyl include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, and the like. Specific examples of alkanesulfonyloxy substituted with naphthyl include α-naphthylmethylsulfonyloxy, β-naphthylmethylsulfonyloxy, and the like.

[0091] Examples of the term "perhaloalkanesulfonyloxy" used herein include trifluoromethanesulfonyloxy and the like.

[0092] Examples of the term "sulfonio" used herein include dimethylsulfonio, diethylsulfonio, dipropylsulfonio, di-(2-cyanoethyl)sulfonio, di-(2-nitroethyl)sulfonio, di-(aminoethyl)sulfonio, di-(2-methylaminoethyl)sulfonio, di-(2-dimethylaminoethyl)sulfonio, di-(2-hydroxyethyl)sulfonio, di-(3-hydroxypropyl)sulfonio, di-(2-methoxyethyl)sulfonio, di-(2-carbamoylethyl)sulfonio, di-(2-carbamoylethyl)sulfonio, di-(2-carboxyethyl)sulfonio, di-(2-methoxycarbonylethyl)sulfonio, diphenylsulfonio, and the like.

[0093] As used herein, the term "solvent" may be an inert solvent in a reaction described herein, and examples thereof include water, ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether), hydrocarbons, halogenated hydrocarbons (e.g., methylene chloride, chloroform, 1,2-dichloroethane, and carbon tetrachloride), aromatic hydrocarbons (e.g., benzene, toluene, and xylene), alcohols (e.g., methanol, ethanol, and isopropanol), esters, ketones, amides, nitriles, sulfoxides, and polar solvents (e.g., N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile). These solvents may be used alone or as a mixture of any two or more of them with optional ratios. Examples of "hydrocarbons" herein include, for example, aliphatic hydrocarbons such as hexane and pentane; alicyclic hydrocarbons such as cyclopentane and cyclohexane; and aromatic hydrocarbons such as benzene and toluene. Examples of "alcohols" herein include, for example, methanol, ethanol, 2-propanol, propanol, and tert-butanol. Examples of "ethers" herein include, for example, chained ethers such as diethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, and diphenyl ether; and circular ethers such as 1,4-dioxane and tetrahydrofuran. Examples of "esters" herein include, for example, ethyl acetate and ethyl propionate. Examples of "ketones" herein include, for example, acetone, methyl ethyl ketone, and methyl isobutyl ketone. Examples of "amides" herein include, for example, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-2-pyrrolidone. Examples of "nitriles" herein include, for example, acetonitrile and propionitrile. Examples of "sulfoxides" herein include, for example, dimethyl sulfoxide.

[0094] As used herein, the term "catalyst" to be used in reduction reactions is not particularly limited to examples used herein, but examples thereof include palladium on carbon (Pd / C), platinum on carbon (Pt / C), platinum oxide (PtO2), and the like.

[0095] As used herein, the term "halogenating agent" is not particularly limited to examples used herein, but examples thereof include fluorinating agents, chlorinating agents, brominating agents, and iodinating agents, such as potassium fluoride, tetrabutylammonium fluoride, (diethylamino)sulfur trifluoride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, oxalyl chloride, trichlorophosphoric acid, bromine, phosphorus oxybromide, phosphorus tribromide, iodine, sodium iodide, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, and the like.

[0096] As used herein, the term "acid" is not particularly limited to examples used herein, but includes an inorganic acid, an organic acid, and the like. Examples of the “inorganic acid” include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, and the like. Examples of the “organic acid” include acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, and the like. These acids may be used alone or as a mixture of any two or more of them.

[0097] As used herein, the term "base" is not particularly limited to examples used herein, but includes an inorganic base, an organic base, and the like. Examples of the “inorganic base” include alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, and barium hydroxide), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate, and barium carbonate), alkali metal carboxylates (e.g., sodium acetate, potassium acetate, and sodium butyrate), alkali metal hydrogen carbonates (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, and cesium hydrogen carbonate), alkali metal phosphates (e.g., sodium phosphate, potassium phosphate, and cerium phosphate), alkaline earth metal phosphates (e.g., magnesium phosphate and calcium phosphate), alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide), alkali metal hydride (e.g., sodium hydride, potassium hydride, and cesium hydride), and the like. Examples of the "organic base" include aromatic amines (e.g., pyridine and lutidine), trialkylamines (e.g., trimethylamine, triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine (DIPEA)), cyclohexyldimethylamine, 4-dimethylaminopyridine (DMAP), N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorphiline, tetramethylethylenediamine, tetramethylpropylenediamine, picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), dialkylamine (e.g., diethylamine and diisopropylamine), metal amides (e.g., lithium diisopropylamide and lithium hexamethyldisilazide), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and sodium phenoxide), and the like. These bases may be used alone or as a mixture of any two or more of them. The organic base herein is preferably DMAP or TEA.

[0098] As used herein, the term "palladium catalyst" is not particularly limited to examples used herein, and examples thereof include tetravalent palladium catalysts such as sodium hexachloropalladium (IV) acid tetrahydrate and potassium hexachloropalladium (IV) acid; divalent palladium catalysts such as [1,1’-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane adduct (PdCl2(dppf).DCM), (2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium (II) methanesulfonate (XPhos Pd G3), palladium (II) chloride, palladium (II) bromide, palladium (II) acetate, palladium (II) acetylacetonate, dichlorobis(benzonitrile)palladium (II), dichlorobis(acetonitrile)palladium (II), dichlorobis(triphenylphosphine)palladium (II), dichlorotetraammine palladium (II), dichloro(cycloocta-1,5-diene)palladium (II), and palladium (II) trifluoroacetate; and zerovalent palladium catalysts such as tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3), tris(dibenzylideneacetone)dipalladium (0)-chloroform complex, and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh3)4). These palladium compounds may be used alone or as a mixture of any two or more of them.

[0099] As used herein, the term "leaving group" is not particularly limited to examples used herein, and examples thereof include halogen (e.g., fluorine, chlorine, bromine, and iodine), C1-18alkylsulfonyl, alkylsulfonyloxy (e.g., methylsulfonyloxy, ethylsulfonyloxy, and trifluoromethylsulfonyloxy), phenyloxy (e.g., 4-nitrophenyloxy), arylsulfonyloxy (e.g., benzenesulfonyloxy, p-toluenesulfonyloxy, 2,4,6-trimethylbenzenesulfonyloxy, 2-nitrobenzenesulfonyloxy, and 4-nitrobenzenesulfonyloxy), aralkylsulfonyloxy, perhaloalkanesulfonyloxy, sulfonio, toluenesulfoxy, nitrophenylcarbonate, imidazolecarbonate, and the like.

[0100] Examples of a condensation agent used herein include, but not limited to: T3P; PyBOP; DMT-MM; COMU; HBTU; HATU; DCC; N-cyclohexyl-N’-morpholinoethylcarbodiimide; N-cyclohexyl-N’-(4-diethylaminocyclohexyl)carbodiimide; N,N’-diethylcarbodiimide; N,N’-diisopropylcarbodiimide; N,N-diisopropylethylamine; WSC or a hydrochloride salt thereof; N,N’-carbonylbis(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene, 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphoryl chloride; phosphorus trichloride; diphenylphosphoryl azide; thionyl chloride; oxalyl chloride; alkyl haloformate such as ethyl chloroformate and isopropyl chloroformate; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide inner salt; benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; and so-called Vilsmeier agents prepared by reactions of DMF with thionyl chloride, phosgene, trichloromethyl chloroformate, or phosphorus oxychloride.

[0101] In addition to a condensation agent, a condensation accelerator may be added. Examples of a condensation accelerator used herein include, but not limited to, 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), 1-hydroxy-7-azabenzotriazole (HOAt), and hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine (HOOBt).

[0102] Examples of a reducing agent used herein include, but not limited to, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium triethylborohydride, lithium triethylborohydride, lithium aluminum hydride, sodium dihydridobis(2-methoxyethoxy)aluminate, borane-tetrahydrofuran complex, diisobutylaluminium hydride, and hydrosilane such as triethylsilane and phenylsilane.

[0103] Examples of a reducing agent for the reductive amination reaction herein include, but not limited to: sodium borohydride (NaBH4), lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride (NaBH(OAc)3), sodium triethylborohydride, lithium triethylborohydride, lithium aluminum hydride, sodium dihydridobis(2-methoxyethoxy)-aluminate, borane-tetrahydrofuran complex, diisobutylaluminium hydride, formic acid, sodium formate, ammonium formate, and phenylsilane. Examples of a catalyst for the reductive amination reaction herein include, but not limited to: Iridium catalysts such as chloro(pentamethylcyclopentadienyl)(8-quinolinolato)iridium (III), chlorido(8-quinolinolato-κ2N,O)(η5-pentamethylcyclopentadienyl)iridium (III), [5,5'-bis(trifluoromethyl)-2,2'-bipyridine-κN,κN]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl] iridium hexafluorophosphate and (4,4'-Di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-kappaN)phenyl-kappaC] iridium (III) hexafluorophosphate.

[0104] Examples of a "protecting group of hydroxy" used herein include, but not limited to, any protecting groups of hydroxy used in the field of synthetic organic chemistry, and include, for example, alkyl groups (e.g., methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, acetylmethyl); alkenyl groups (e.g., ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl); alkynyl groups (e.g., ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2-propynyl); formyl; alkyl (alkenyl) carbonyl groups (e.g., acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, (E)-2-methyl-2-butenoyl); arylcarbonyl groups (e.g., benzoyl, α-naphthoyl, β-naphthoyl, 2-bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, 4-toluoyl, 4-anisoyl, 4-nitrobenzoyl, 2-nitrobenzoyl, 2-(methoxycarbonyl)benzoyl, 4-phenylbenzoyl); alkoxycarbonyl groups (e.g., methoxycarbonyl, tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, 9-fluorenylmethyloxycarbonyl); tetrahydro (thio) pyranyl (furanyl) groups (e.g., tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl, tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl); silyl groups (e.g., trimethylsilyl, triethylsilyl, isopropyl dimethylsilyl, tert-butyldimethyl silyl, methyldiisopropyl silyl, methyl di-tert-butylsilyl, triisopropylsilyl, diphenylmethyl silyl, diphenylbutyl silyl, diphenylisopropyl silyl, phenyldiisopropyl silyl); alkoxymethyl groups (e.g., methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, tert-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl); alkoxyethyl groups (e.g., 1-ethoxyethyl, 1-(isopropoxy)ethyl); halogenated ethyl groups (e.g., 2,2,2-trichloroethyl); aralkyl groups (e.g., benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl); alkenyloxycarbonyl groups (e.g., vinyloxycarbonyl, allyloxycarbonyl); and aralkyloxycarbonyl groups (e.g., benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl).

[0105] Examples of a "protecting group of carboxy" used herein include, but not limited to, any protecting groups of carboxy used in the field of synthetic organic chemistry, and include, for example, the "alkyl groups", "alkenyl groups", "alkynyl groups", "aralkyl groups", and "silyl groups" as above listed in the examples of the "protecting group of hydroxy" and similar groups thereof.

[0106] Examples of a "protecting group of amino" used herein include, but not limited to, any protecting groups of amino used in the field of synthetic organic chemistry, and include, for example, the "alkyl (alkenyl) carbonyl groups", "arylcarbonyl groups", "alkoxycarbonyl groups", "silyl groups", "aralkyl groups", "alkenyloxycarbonyl groups", and "aralkyloxycarbonyl groups" as above listed in the "protecting group of hydroxy" and similar groups thereof.

[0107] The reaction temperature in each step in the General syntheses herein typically ranges from -80 to 150°C. The reaction time in each step typically ranges from 0.1 to 200 hours.

[0108] General syntheses In general, the compounds of the invention and intermediates of use in the synthesis of such compounds may be made according to synthesis techniques known to those skilled in this field, as well as by the representative methods set forth below, those in the Examples and the Reference Examples, and any modifications thereof. In the following schemes, reactive groups can, as appropriate, be protected with protecting groups and deprotected according to established techniques well known to the skilled person. The processes of the invention include any individual step of a multi-step scheme.

[0109] General synthesis 1: Condensation reaction In the scheme, R, R1, R2, m, and Ring A are as defined above.

[0110] The compound [1a] may be prepared by the reaction of compound [P1] with compound [P2] in the presence of a condensation reagent and a base in an inert solvent.

[0111] General synthesis 2: N-alkylation In the scheme, R, R1, R2, L1, m, and Ring A are as defined above.

[0112] (Step 1) The compound [P3] may be prepared by the reaction of compound [P2'] with SOCl2in an inert solvent. (Step 2) The compound [1] may be prepared by the reaction of compound [P1] with compound [P3] in the presence of a base in an inert solvent.

[0113] General synthesis 3: Urea formulation 1 In the scheme, R, R2, L1, m and Ring A are as defined above.

[0114] The compound [1a] may be prepared by the reaction of compound [P1] and compound [P4] with a C=O source (e.g. CDI, triphosgene) in the presence of a base in an inert solvent.

[0115] General synthesis 4: Urea formulation 2 In the scheme, R, R2, m and Ring A are as defined above.

[0116] The compound [1a] may be prepared by the reaction of compound [P1] with compound [P5] in an inert solvent. The compound [1a] may be also prepared by the reaction of compound [P6] with compound [P4] in the presence of MeI or MsOH in an inert solvent.

[0117] General synthesis 4: Urea formulation 3 In the scheme, R, R2, R11a, R11b, m and Ring A are as defined above.

[0118] The compound [1b] may be prepared by the reaction of compound [P7] with compound [P8] in the presence of base in an inert solvent.

[0119] General synthesis 5: Thiourea formulation In the scheme, R, R2, m and Ring A are as defined above.

[0120] The compound (1d) may be prepared by the reaction of compound [P1] and compound [P4] with a C=S source (e.g. 1,1’-thiocarbonylimidazole) in the presence of a base in an inert solvent.

[0121] General synthesis 6: Carbamate formulation In the scheme, R, R2, R11, m and Ring A are as defined above.

[0122] The compound [1e] may be prepared by the reaction of compound (P1) with compound [P9] in the presence of a base in an inert solvent.

[0123] General synthesis 7: Pd-coupling In the scheme, R, R2, R1, m and Ring A are as defined above, and X is a suitable leaving group.

[0124] The compound [1] may be prepared by the reaction of compound [P10] with compound [P11] in the presence of a palladium catalyst (e.g. Xphos-Pd-G3) and a fluoride ion (e.g. CsF) in an inert solvent.

[0125] General synthesis 7: Deprotection In the scheme, R, R1, R2, L1, m, and Ring A are as defined above, and Q1'is a suitable protecting group.

[0126] The compound [1] may be prepared by the deprotection reaction of compound (P12) When R1is amine, Q1is an "protecting group of amino" described herein. The deprotection herein comprises any suitable deprotection reactions, the conditions of which depend upon the nature of a protecting group used. For example, when Q1is a tert-butoxycarbonyl, the tert-butoxycarbonyl may be deprotected to the corresponding amine by hydrolysis with a suitable aqueous inorganic acid (e.g. hydrochloric acid). Any solvents may be used in this reaction, and the solvent preferably used herein includes water, an organic solvent, and a mixed solvent of water and any of the organic co-solvents herein.

[0127] In each of the reactions in the above synthetic schemes, the reaction product may be used in the next reaction either as is in the form dissolved in the reaction solution or as a crude product, but it may also be isolated from the reaction mixture by ordinary methods and easily purified by ordinary separation techniques. Examples of ordinary separation techniques include recrystallization, distillation, and chromatography.

[0128] Any starting compounds, intermediate compounds, and product compounds in each of the above steps and Compound [1] include geometric isomers, stereoisomers, optical isomers, and tautomers thereof. Respective isomers may be separated by ordinary optical resolution methods. They may also be manufactured from raw material compounds having suitable optical activity.

[0129] Compound [1] may be manufactured according to any of the above synthetic schemes, or analogous methods thereof.

[0130] Unless otherwise specified, any starting compounds used in the manufacture of Compound [1] are commercially available, or may be produced by known methods or analogous methods thereof.

[0131] Any starting compounds and product compounds in each step above may be used in the form of appropriate salts thereof. Examples of such salts include salts similar to those listed for salts of Compound [1].

[0132] When any compounds obtained in each step or commercially available compounds used herein are in the free form, they may be converted to corresponding salts by known methods. When any compounds obtained in each step or commercially available compounds used herein are in the salt form, they may be converted to corresponding free forms or into other salts by known methods.

[0133] The pharmaceutical composition comprising the compound [1] or a salt thereof or a co-crystal thereof as an active ingredient is a general formulation of pharmaceutical compositions, which can be formed with the compound [1] or a salt thereof or a co-crystal thereof, as well as a generally-used carrier, diluent and / or excipient, such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and lubricants (also referred to as "pharmaceutically acceptable carrier").

[0134] Such a pharmaceutical composition can be selected from various forms according to the therapeutic objective, and examples thereof include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (liquids, emulsions, suspensions, etc.), and the like.

[0135] A wide range of known carriers may be used when molding the preparation in the form of a tablet, and examples thereof include excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone; disintegrants such as dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose; disintegration inhibitors such as white sugar, stearin, cocoa butter, and hydrogenated oil; absorption aids such as quaternary ammonium salt and sodium lauryl sulfate; humectants such as glycerin and starch; absorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. Furthermore, coloring agents, preservatives, fragrances, flavoring agents, sweeteners, etc., and / or other pharmaceuticals may be contained as necessary.

[0136] Moreover, the tablet may as necessary be made into a tablet with an ordinary coating, such as a sugar-coated tablet, gelatin-coated tablet, enteric coated tablet, film-coated tablet, double tablet or multilayer tablet.

[0137] A wide range of known carriers may be used when molding the preparation in the form of a pill, and examples thereof include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc; binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol; and disintegrants such as laminaran, and agar.

[0138] A wide range of known carriers may be used when forming the preparation as a suppository, and examples thereof include polyethylene glycol, cocoa butter, higher alcohol, ester of higher alcohol, gelatin, and semi-synthetic glyceride.

[0139] When the preparation is an injection, the liquid, the emulsion or the suspension is preferably sterilized, and is also preferably isotonic with blood. A wide variety of known diluents can be used for forming these liquid, emulsion, and suspension, such as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, sufficient amounts of sodium chloride, glucose, or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and a conventional solubilizing agent, buffer, soothing agent, etc. may be included, and further a coloring agent, preservative, etc., and / or one or more other pharmaceuticals may be also included as necessary.

[0140] The amount of Compound [1] or a salt thereof or a co-crystal thereof that is contained in the pharmaceutical composition is not particularly limited and may be selected appropriately from a wide range, but generally Compound [1] or a salt thereof or a co-crystal thereof is preferably contained in the amount of 1% to 70% of the pharmaceutical composition.

[0141] The method for administering the pharmaceutical composition of the present invention is not particularly limited, and it can be administered by a method suited to the dosage form, the age and sex of the patient (in particular, human), the disease status and other conditions. For example, it can be administered orally when it is in the form of a tablet, pill, liquid, suspension, emulsion, granules or capsules. When it is an injection, it can be administered intravenously either alone or in a mixture with an ordinary replacement fluid such as glucose or amino acids, or else it can be administered by itself intramuscularly, intradermally, subcutaneously or intraperitoneally as necessary. In the case of a suppository, it can be administered in the rectum.

[0142] The dose of the pharmaceutical composition may be selected according to the administration method, the age and sex of the patient (in particular, human), the severity of the disease and other conditions, but generally 0.001 to 100 mg or preferably 0.001 to 50 mg of Compound [1] per 1 kg of body weight can be administered per day in one to several administrations. The dose herein is also referred to as effective amount. This dose is affected by various conditions, and in some cases a dose below the aforementioned range may be sufficient, while in others a dose above the aforementioned range may be necessary.

[0143] The compound [1] or a salt thereof or a co-crystal thereof has a potent AAK1 inhibitory activity, which is expected to have therapeutic and / or prophylactical effect for a disease / disorder associated with AAK1. Specifically, it is expected to have therapeutic and / or prophylactical effect for Alzheimer's disease, bipolar disorder, Parkinson disease, schizophrenia, cognitive impairment in schizophrenia, acute pain, chronic pain, neuropathic pain, muscular dystrophy, or a disease associated with viral infection, and the like. Specific types of pain include chronic pain, acute pain, and neuropathic pain. Specific types of acute pain and chronic pain include pain associated with rheumatoid arthritis. Specific types of neuropathic pain include pain associated with fibromyalgia, central nervus neuropathy (such as spinal cord injury related pain), and peripheral neuropathy (such as diabetic neuropathy, postherpetic neuralgia, chemotherapy induced peripheral neuropathy). Specific types of muscular dystrophy include Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy, Limb-Girdle muscular dystrophies, von Graefe-Fuchs muscular dystrophy, oculopharyngeal muscular dystrophy, Mytonic dystrophy, congenital muscular dystrophy. Another embodiment of the invention includes a method of treating or controlling a disease or disorder, comprising administering a therapeutically or prophylactically effective amount of the AAK1 inhibitor of the invention to a patient in need thereof, wherein the disease or disorder is Alzheimer's disease, bipolar disorder, pain, Parkinson disease, schizophrenia (including cognitive impairment in schizophrenia), or viral infection. Specific types of pain include chronic pain, acute pain, and neuropathic pain. Specific types of acute pain and chronic pain include pain associated with rheumatoid arthritis. Specific types of neuropathic pain include pain associated with fibromyalgia, central nervus neuropathy (such as spinal cord injury related pain), and peripheral neuropathy (such as diabetic neuropathy, postherpetic neuralgia, chemotherapy induced peripheral neuropathy).

[0144] The present invention is explained in further detail below through the following Reference example, Examples, and Test examples, but these do not limit the present invention.

[0145] The following abbreviations are used in this Description.

[0146] In the examples below, "room temperature" generally indicates from about 10°C to about 35°C. The ratios indicated for mixed solvents are volume ratios unless otherwise specified. Percentages indicate weight% unless otherwise specified. The1H-NMR (proton nuclear magnetic resonance spectrum) was measured by Fourier-transform type NMR (any one of Bruker AVANCE III 400 (400 MHz), Bruker AVANCE III HD (500 MHz), RUKER AVANCE 400 (400 MHz), and BRUKER AVANCE III 300N (300 MHz)). The spectra were analyzed with MestReNova version:14.1.2 (Mestrelab Research) or ACD / Spectrus ProcessorTM(ACD). Mass spectrum (MS) was measured by LC / MS (either of ACQUITY UPLC H-Class and Shimadzu LCMS-2020). As an ionization method, ESI method was used. The data indicate actual measured values (found). Generally, molecular ion peaks ([M+H]+, [M-H]-, etc.) were observed. In the case of a salt, a molecular ion peak or fragment ion peak of free form was generally observed. In silica gel column chromatography, when denoted as basic, aminopropylsilane-bonded silica gel was used. The absolute configuration of the compound was determined by known X-ray crystal structure analysis methods (for example, Shigeru Oba and Shigenobu Yano, "Basic Course for Chemists 12, X-ray Crystal Structure Analysis" (First Edition, 1999)), or estimated from empirical rules of Shi asymmetric epoxidation (Waldemar Adam, Rainer T. Fell, Chantu R. Saha-Moller and Cong-Gui Zhao: Tetrahedron: Asymmetry 1998, 9, 397-401. Yuanming Zhu, Yong Tu, Hongwu Yu, Yian Shi: Tetrahedron Lett. 1988, 29, 2437-2440).

[0147] (Reference example 1) tert-Butyl N-[(2S)-1-[(7S)-7-methyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-1-oxopropan-2-yl]carbamate To a solution of (S)-7-(7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)thieno[3,2-b]pyridine (100 mg), (tert-butoxycarbonyl)-L-alanine (74.0 mg), HOBt (74.9 mg), and DIPEA (0.285 ml) in DCM (5 ml) was added WSC (94 mg) at 0°C. The reaction solution was warmed to room temperature, and stirred for 18 hours. Water was added to the reaction solution, and the organic layer was separated. The organic layer was concentrated, and then the residue was purified by silica gel column chromatography (AcOEt / hexane) to give the title compound (135 mg).

[0148] (Reference example 8) (S)-7-(7-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)thieno[3,2-b]pyridine To a solution of LAH (0.54 g) in THF (50 mL) was added (S)-7-methyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (1.35 g) at 0°C under nitrogen atmosphere. The mixture was stirred at 60°C for 3 hours. To the reaction mixture were added acetone (1.5 ml) and sodium sulfate decahydrate (3 g) at 0°C, and the mixture was stirred at room temperature. The insoluble matter was removed with a filter and the filtrate was concentrated. 4M HCl / AcOEt was added to the residue, and the solution was concentrated. The obtained solid was washed with AcOEt to give the title compound (1.28 g).

[0149] (Reference example 9) (S)-7-Methyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one A mixture of a solution of (S)-ethyl 1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-3-(thieno[3,2-b]pyridin-7-yl)-1H-pyrazole-5-carboxylate (10.0 g) in dichloromethane (70 mL) and a solution of 4M hydrogen chloride / dioxane (70 mL) was stirred at 25°C for one hour. The resulting precipitate was collected on a filter. To the obtained precipitate were added water (50 mL) and aqueous saturated sodium bicarbonate (300 mL), and the mixture was stirred at 25°C for one hour. The resulting precipitate was collected on a filter and dried in vacuo. The residue was triturated in methanol, and the precipitate was collected on a filter and dried in vacuo to give the title compound (5.90 g).

[0150] (Reference example 10) (S)-Ethyl 1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-3-(thieno[3,2-b]pyridin-7-yl)-1H-pyrazole-5-carboxylate A mixture of (S)-ethyl 3-bromo-1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-1H-pyrazole-5-carboxylate (20.0 g), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-b]pyridine (27.8 g), Pd(dppf)Cl2(3.89 g), potassium phosphate (33.9 g), and 1,4-dioxane (400 mL) was stirred at 100°C under nitrogen atmosphere for 16 hours. The mixture was diluted with water (300 mL), and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrated was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the title compound (15.0 g).

[0151] (Reference example 12) tert-Butyl (S)-(2-(3-bromo-5-(hydroxymethyl)-1H-pyrazol-1-yl)propyl)carbamate To a mixture of ethyl (S)-3-bromo-1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-1H-pyrazole-5-carboxylate (20.0 g) and THF (200 mL) was added dropwise a solution of lithium borohydride in THF (2 M, 79.7 mL) at 0°C under nitrogen atmosphere. The mixture was warmed to 20°C and stirred for 2 hours. The reaction mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrated was concentrated to give the title compound (17.6 g).

[0152] (Reference example 13) tert-Butyl (S)-(2-(3-bromo-5-(bromomethyl)-1H-pyrazol-1-yl)propyl)carbamate To a mixture of the compound of Reference example 12 (20.0 g) and THF (250 mL) was added dropwise phosphorus tribromide (19.4 g) at 0°C under nitrogen atmosphere. The mixture was warmed to 20°C and stirred for 2 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrated was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to givethe title compound (10.7 g). To the aqueous layer obtained in the above extraction was added 2M aqueous sodium hydroxide to adjust the pH to 9, and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrated was concentrated to give (7S)-2-bromo-7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (salt-free form of Reference example 28) (2.50 g).

[0153] (Reference example 14) tert-Butyl (7S)-2-bromo-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate To a mixture of tert-butyl (S)-(2-(3-bromo-5-(bromomethyl)-1H-pyrazol-1-yl)propyl)carbamate (10.7 g) of the above Reference example 13 and DMF (150 mL) was slowly added sodium hydride (2.16 g, 60% in oil) at 20°C under nitrogen atmosphere, and the mixture was stirred at 20°C for 2 hours. The reaction mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrated was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to givethe title compound as a crude product (part 1). To a mixture of (7S)-2-bromo-7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (salt-free form of Reference example 28) (2.50 g) and THF (40 mL) was added di-tert-butyl dicarbonate (5.05 g) at 20°C. The mixture was stirred at 20°C for 2 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrated was concentrated to give the title compound as a crude product (part 2). The crude products part 1 and part 2 were mixed, and the mixture was purified by silica gel column chromatography (petroleum ether, and petroleum ether / ethyl acetate) to give the title compound (11.0 g).

[0154] (Reference example 15) tert-Butyl (7S)-7-methyl-2-(tributylstannyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate A mixture of the compound of Reference example 14 (11.0 g), bis(tributyltin) (24.2 g), Cy3P-Pd-G3 (1.13 g), and dioxane (150 mL) was stirred at 100°C under nitrogen atmosphere for 14 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrated was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the title compound (13.5 g).

[0155] (Reference example 16) 7-Chloro-2-fluorothieno[3,2-b]pyridine To a solution of 7-chlorothieno[3,2-b]pyridine (25 g) in THF (500 mL) was gradually added n-butyllithium (110 mL) at -78°C under argon atmosphere, and the mixture was stirred at -78°C for one hour. To the reaction mixture was gradually added a solution of N-fluorobenzenesulfonimide (56 g) in THF (200 mL). The mixture was stirred at -78°C for one hour, and then at room temperature for further one hour. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride and brine, dried over anhydrous sodium sulfate, and filtered. The filtrated was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the title compound (5 g).

[0156] (Reference example 17) tert-Butyl (7S)-2-(2-fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate A mixture of the compound of Reference example 16 (3.00 g), the compound of Reference example 15 (8.42 g), XPhos-Pd-G3 (0.95 g), and 1,4-dioxane (80 mL) was stirred at 100°C under nitrogen atmosphere for 14 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give the title compound (5.58 g).

[0157] (Reference example 18) (7S)-2-Fluoro-7-(7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)thieno[3,2-b]pyridine dihydrochloride A mixture of the compound of Reference example 17 (5.58 g), dichloromethane (40 mL), and 4M hydrogen chloride / 1,4-dioxane (20 mL) was stirred at 20°C for 3 hours. The precipitate was collected on a filter, washed with ethyl acetate, and dried in vacuo to give the title compound (4.60 g).

[0158] (Reference example 19) tert-Butyl (7S)-2-(isothiazolo[4,5-b]pyridin-7-yl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate A mixture of the compound of Reference example 15 (1.3 g), 7-bromoisothiazolo[4,5-b]pyridine (0.584 g), Xphos-Pd-G3 (0.105 g), cesium fluoride (0.825 g), and dioxane (7 ml) was stirred at 90°C under nitrogen atmosphere for 1.5 hours. The reaction mixture was cooled to room temperature, and concentrated. The residue was purified by silica gel (NH) chromatography (ethyl acetate / hexane) to give the title compound (874 mg).

[0159] (Reference example 20) (7S)-7-(7-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)isothiazolo[4,5-b]pyridine dihydrochloride The compound of Reference example 19 (874 mg) was suspended in 10 % hydrochloric acid-methanol (10 ml), and the suspension was stirred at room temperature overnight. The reaction solution was concentrated to give the title compound (804 mg).

[0160] (Reference example 21) (4-Nitrophenyl) 1,3-oxazol-4-ylmethyl carbonate To a solution of 4-oxazolylmethanol (232 mg) in DCM (20 ml) were added TEA (0.5 ml) and bis(4-nitrophenyl)carbonate (795 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with AcOEt. The organic layer was dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (522 mg).

[0161] (Reference example 26) [(7S)-2-Bromo-7-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[cis-2,6-dimethylmorpholin-4-yl]methanone To (7S)-2-bromo-7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine hydrochloride (hydrochloride of Reference example 28) (2.283 g) were added DMF (10 mL), then DIPEA (6.32 ml) and DMAP (0.110 g). The mixture was cooled in ice bath, and a solution of (3-methylimidazol-3-ium-1-yl)-[cis-2,6-dimethylmorpholin-4-yl]methanone iodide (Reference example 27)(6.0 g) in DMF (5 ml) was added to the cooled mixture. The reaction mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture. The mixture was extracted with AcOEt, dried over sodium sulfate, and concentrated. The residue was purified by silica gel (amino silica) chromatography (hexane / AcOEt) to give the title compound (2.9 g).

[0162] (Reference example 27) (3-Methylimidazol-3-ium-1-yl)-[cis-2,6-dimethylmorpholin-4-yl]methanone iodide To a solution of cis-(2,6-dimethylmorpholino)(1H-imidazol-1-yl)methanone (355 mg) in MeCN (1.3 ml) was added MeI (0.344 ml), and the solution was stirred at 50°C for 2 hours. The reaction solution was concentrated to give the title compound (538 mg).

[0163] (Reference example 29) 7-Chloro-2-(difluoromethyl)thieno[3,2-b]pyridine To a solution of 7-chlorothieno[3,2-b]pyridine-2-carbaldehyde (100 mg) in DCM (1.5 mL) was added dropwise (diethylamino)sulfur trifluoride (245 mg) at 0°C under nitrogen atmosphere. The reaction mixture was warmed to 20°C, and stirred for 2 hours. The reaction mixture was diluted with aqueous saturated sodium bicarbonate, and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (100 mg).

[0164] (Reference example 30) 1-(7-Chlorothieno[3,2-b]pyridin-2-yl)pyrrolidin-2-one A suspension of 7-chloro-2-iodothieno[3,2-b]pyridine (111 mg), 2-pyrrolidone (38 mg), CuI (11 mg), (1S,2S)-(+)-1,2-diaminocyclohexane (13 mg), and K3PO4(159 mg) in dioxane (2 ml) was refluxed for 22 hours. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (hexane / AcOEt) to give the title compound (78 mg).

[0165] (Reference example 31) 7-Chloro-2-(piperidin-1-yl)thieno[3,2-b]pyridine(Reference example 32) 7-Chloro-2-(3,4-dihydropyridin-1(2H)-yl)thieno[3,2-b]pyridine The titled compounds, Reference examples 31 and 32, were prepared from piperidine and 7-chloro-2-iodothieno[3,2-b]pyridine as starting materials and then isolated, in the same manner as Reference example 36 below.

[0166] (Reference example 36) 4-(7-Chlorothieno[3,2-b]pyridin-2-yl)-2,3-dihydro-1,4-oxazine A suspension of 7-chloro-2-iodothieno[3,2-b]pyridine (335 mg), morpholine (128 mg), BINAP (42 mg), Pd(OAc)2(13 mg), and NaOtBu (163 mg) in toluene (5 ml) was refluxed for 19 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane / AcOEt) to give the title compound (26 mg).

[0167] (Reference example 37) 7-Chloro-2-(1,3-thiazol-5-yl)thieno[3,2-b]pyridine A mixture of 5-bromothiazole (271 mg), 7-chloro-2-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-b]pyridine (291 mg), Pd(dppf)Cl2(68 mg), potassium phosphate (527 mg), 1,4-dioxane (3 mL), and water (0.3 ml) was refluxed under nitrogen atmosphere for 5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane / AcOEt) to give the title compound (38 mg).

[0168] (Reference example 38) rac-(3-Methylimidazol-3-ium-1-yl)-(trans-2,6-dimethylmorpholin-4-yl)methanone iodide To a solution of rac-imidazol-1-yl-[trans-2,6-dimethylmorpholin-4-yl]methanone (550 mg) in CH3CN (2.6 ml) was added MeI (0.657 ml), and the solution was stirred at 50°C for 2 hours. The reaction solution was concentrated, and the residue was used without purification in the next step.

[0169] (Reference example 39) rac-Imidazol-1-yl-(trans-2,6-dimethylmorpholin-4-yl)methanone To a solution of CDI (443 mg) in DCM (4 mL) was added a solution of rac-trans-2,6-dimethylmorpholine (300 mg) in DCM (1 mL) at 0°C. The reaction solution was warmed to room temperature, and stirred for 2 hours. Water was added to the reaction solution, and the organic layer was washed with brine, dried over sodium sulfate, concentrated, and dried to give the title compound (552 mg).

[0170] (Reference example 40) 7-Chloro-2-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-b]pyridine 4,4,5,5-Tetraethyl-2-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.46 g), 2-bromo-7-chlorothieno[3,2-b]pyridine (3.53 g), and KOAc (2.79 g) were suspended in dioxane (70 ml), and Pd(dppf)Cl2 / DCM (580 mg) was added to the suspension, and the suspension was refluxed for 4 hours. The reaction mixture was filtered through Celite, and concentrated. The residue was purified by silica gel chromatography (hexane / AcOEt) to give the title compound (3.74 g).

[0171] (Reference example 41) (NE)-N-[(4-Chloro-3-dodecylsulfanyl-2-pyridinyl)methylidene]hydroxylamine To a solution of 4-chloro-3-fluoropicolinaldehyde (12.1 g) in DMF (240 ml) were added K2CO3(12.6 g) and n-dodecanethiol (20 ml) at 0°C, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The obtained residue was dissolved in EtOH (260 ml), and NaOAc (9.35 g) and hydroxyl amine hydrochloride (7.92 g) were added the solution. The solution was stirred at room temperature for 2 hours. Water (260 ml) was added to the reaction solution, and the resulting crystal was collected on a filter and washed with water and AcOEt to give the title compound (21.3 g).

[0172] (Reference example 42) 7-Chloro-[1,2]thiazolo[4,5-b]pyridine A suspension of the compound of Reference example 41 (20 g) in THF (200 ml) was cooled to -10°C, and thionyl chloride (33.3 g) was added dropwise to the suspension while the internal temperature was not beyond 0°C. Then, the suspension was stirred for further one hour. To the reaction solution was added saturated sodium bicarbonate solution, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was washed with hexane to give the title compound (7.6 g).

[0173] (Reference example 43) 1-([1,2]Thiazolo[4,5-b]pyridin-7-yl)ethanone To 1,4-butanediol (8 ml) were added 1,4-butanediol vinyl ether (16 ml), Na2CO3(5.0 g), 1,3-bis(diphenylphosphino)propane (483 mg), silver trifluoromethanesulfonate (602 mg), and palladium acetate (263 mg), and the mixture was stirred at 80°C under nitrogen atmosphere. A solution of the compound of Reference example 42 (4 g) in CPME (20 ml) was added dropwise to the reaction mixture while the internal temperature was not lowered. The temperature of the oil bath was set to 135°C, and the reaction mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature, and water (20 ml) and conc. hydrochloric acid (9.8 ml) were added to the reaction mixture. The mixture was stirred at 50°C for 30 minutes. The mixture was extracted with AcOEt, concentrated, and re-crystalized with heptane-EtOH to give the title compound (2.2 g).

[0174] (Reference example 44) Ethyl 5-([1,2]thiazolo[4,5-b]pyridin-7-yl)-1H-pyrazole-3-carboxylate To a solution of the compound of Reference example 43 (5.2 g) and diethyl oxalate (6.3 g) in THF (200 ml) was added LiHMDS (28.6 ml, 1.11 M) at 0°C. The reaction solution was stirred at 0°C for 3 hours, and AcOH (50 ml) and hydrazine monohydrate (2.9 g) were added to the reaction solution. The mixture was stirred at 80°C for one hour. The THF was removed under reduced pressure, and water (150 ml) was added to the residue. The precipitated crystal was washed with AcOEt / hexane to give the title compound (7.1 g).

[0175] (Reference example 45) Ethyl 2-[(2S)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]-5-([1,2]thiazolo[4,5-b]pyridin-7-yl)pyrazole-3-carboxylate To a suspension of the compound of Reference example 44 (4.34 g) in THF (86 ml) were added N-t-BOC-(R)-1-amino-2-propanol (3.05 g) and PPh3(8.30 g), and further di-tert-butyl azodicarboxylate (7.29 g) at 0°C. The reaction solution was stirred at room temperature for 4 hours, and the solvent was removed. The residue was dispersed in AcOEt, and the precipitated solid was collected on a filter and washed to give the title compound (5.41 g).

[0176] (Reference example 46) tert-Butyl N-[(2S)-2-[5-(hydroxymethyl)-3-([1,2]thiazolo[4,5-b]pyridin-7-yl)pyrazol-1-yl]propyl]carbamate To suspension of calcium chloride (2.14 g) in EtOH (84 ml) was added sodium borohydride (1.46 g) at room temperature. The mixture was stirred for 20 minutes, and then cooled in ice bath. The compound of Reference example 45 (4.17 g) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice water (200 ml) carefully, and stirred for a while. To the reaction mixture were added aqueous saturated NH4Cl (200 mL) and AcOEt (200 mL). The organic layer was separated, and further the aqueous layer was extracted with AcOEt (200 ml). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (3.76 g).

[0177] (Reference example 47) tert-Butyl (7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate To a solution of the compound of Reference example 46 (3.76 g) in DCM (70 ml) in ice bath were added Et3N (2.018 ml) and MsCl (0.903 ml), and the mixture was stirred for one hour and further stirred at room temperature for 2 hours. The reaction mixture was cooled, water was added thereto, and the organic layer was separated. The aqueous layer was extracted with AcOEt. The combined organic layer was washed with brine, dried over Na2SO4, filtrated, and concentrated. The residue was dissolved in DMF (70 ml), and cooled in ice bath. NaH (0.5 g) was added thereto, and the reaction mixture was stirred at room temperature overnight. Further NaH (0.5 g) was added thereto, and the reaction mixture was stirred at 60°C for 6 hours. After cooling the reaction mixture, H2O was added to the reaction mixture, and the organic layer was extracted with AcOEt. The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (AcOEt / hexane) to give the title compound (972 mg).

[0178] (Reference example 48) 7-Chloro-2-[1-(trifluoromethyl)pyrazol-4-yl]thieno[3,2-b]pyridine A mixture of 2-bromo-7-chlorothieno[3,2-b]pyridine (304 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-pyrazole (353 mg), Pd(dppf)Cl2(50 mg), K3PO4(519 mg), 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 70°C under argon atmosphere for 15 hours. To the reaction medium was added aqueous saturated NaHCO3, and the mixture was extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (AcOEt / hexane) to give the title compound (266 mg).

[0179] (Reference example 49) 7-Chloro-2-(pyridazin-3-yl)thieno[3,2-b]pyridine A mixture of 3-bromopyridazine (271 mg), 7-chloro-2-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-b]pyridine (300 mg), Pd(dppf)Cl2(56 mg), K3PO4(543 mg), 1,4-dioxane (6 mL) and water (0.3 mL) was stirred at rt under argon atmosphere for 4 hours. To the reaction medium was added water. The resulting solid was filtered to give the title compound (249 mg).

[0180] (Reference example 52) tert-Butyl (7S)-7-methyl-2-[2-[1-(trifluoromethyl)pyrazol-4-yl]thieno[3,2-b]pyridin-7-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate A mixture of 7-chloro-2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)thieno[3,2-b]pyridine (100 mg), tert-butyl (S)-7-methyl-2-(tributylstannyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (520 mg), Xphos-Pd-G3 (56 mg), cesium fluoride (150 mg), and dioxane (5 mL) was stirred at 100°C under nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, and concentrated. The residue was purified by silica gel (amino silica) chromatography (AcOEt / hexane) to give the title compound (147 mg).

[0181] (Reference example 53) 7-[(7S)-7-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-2-[1-(trifluoromethyl)pyrazol-4-yl]thieno[3,2-b]pyridine; dihydrochloride A mixture of the compound of Reference example 52(147 mg) and 10% HCl / methanol (5 mL) was stirred at 50°C for 3 hours. The precipitate was collected by filtration, washed with AcOEt, and dried under reduced pressure to obtain the title compound (133 mg).

[0182] The chemical structures, preparing methods, and spectral data of Reference examples 1 - 56 are shown in the following table.

[0183] (Example 1) (2S)-2-Amino-1-[(7S)-7-methyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]propan-1-one; dihydrochloride To a solution of the compound of Reference example 1 (129 mg) in DCM (2 ml) was added 4M HCl / dioxane (10 ml) at room temperature, and the mixture was stirred for 2 hours. The reaction solution was concentrated, and the resulting solid was washed with AcOEt to give the title compound (107 mg).

[0184] (Example 8) [(7S)-7-Methyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[(2R)-oxolan-2-yl]methanone A mixture of hydrochloride of Reference example 8 (60 mg), HATU (89 mg), (R)-(+)-tetrahydrofuran-2-carboxylic acid (34 mg), DIPEA (0.10 g), and DMF (2 mL) was stirred at room temperature overnight. The mixture was filtered and the filtrate was purified with a preparative HPLC (YMCTriartC18, eluted with MeCN / 10 mM NH4HCO3aq) to give the title compound (60 mg).

[0185] (Example 9) [(7S)-7-Methyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[(2R*)-piperidin-2-yl]methanone dihydrochloride The titled compound was prepared from the corresponding starting material in the same manner as Example 1. The purification was carried out by SFC preparative separation (CHIRALPAK IH, CO2: MeOH + 0.1 % DEA), and the compound that came out later was designated as Example 9.

[0186] (Example 10) (2S)-2-Hydroxy-4-methyl-1-[(7S)-7-methyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]pentan-1-one A mixture of the compound of Reference example 8 (88 mg), (2S)-2-hydroxy-4-methyl-pentanoic acid (88 mg), HOBt (127 mg), DIPEA (0.485 ml), EDC (160 mg), and DCM (8 mL) was stirred at room temperature overnight. Water was added to the reaction solution, and the organic layer was separated. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (90 mg).

[0187] (Example 12) (4-Fluorooxan-4-yl)-[(7S)-2-(2-fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone; fumaric acid (2:1) A mixture of (S)-2-fluoro-7-(7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)thieno[3,2-b]pyridine hydrochloride (137 mg), 4-fluorotetrahydro-2H-pyran-4-carboxylic acid (75 mg), HOBt (97 mg), DIPEA (0.369 ml), EDC (121 mg), and DCM (6 mL) was stirred at room temperature for 42 hours. Water was added to the reaction solution, and the organic layer was separated. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (AcOEt / hexane) to give (4-fluorooxan-4-yl)-[(7S)-2-(2-fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone (109 mg). NMR2: δ 1.56-2.06 (m, 5H), 2.33-2.37 (m, 2H), 3.57-3.93 (m, 5H), 4.31-5.02 (m, 3H), 5.22 (d, J = 16.2 Hz, 1H), 6.63 (s, 1H), 6.95 (d, J = 2.8 Hz, 1H), 7.45 (d, J = 5.1 Hz, 1H), 8.63 (d, J = 5.1 Hz, 1H). melting point: 176°C (4-Fluorooxan-4-yl)-[(7S)-2-(2-fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone (100 mg) and fumaric acid (28 mg) were dissolved in acetone (2 ml) with heating, and the solution was stirred at room temperature overnight. The precipitate was washed with acetone and water to give a co-crystal of (4-fluorooxan-4-yl)-[(7S)-2-(2-fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone and fumaric acid (2: 1)(31 mg).

[0188] (Example 13) [(2R*)-2-Methyloxolan-2-yl]-[(7S)-7-methyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone(Example 14) [(2S*)-2-Methyloxolan-2-yl]-[(7S)-7-methyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone To a solution of 2-methyltetrahydrofuran-2-carboxylic acid (130 mg) in THF (8 ml) were added SOCl2(0.083 ml) and DMF (1 drop) at 0°C. The solution was warmed to room temperature and then stirred for one hour. The reaction solution was concentrated, and the residue was dissolved again in THF (8 ml). To the solution were added hydrochloride of Reference example 8 (204 mg) and TEA (0.278 ml) at room temperature, and the solution was stirred for 18 hours. The reaction solution was quenched with MeOH, and DCM and water were added thereto. The organic layer was separated, and concentrated. The residue was purified by silica gel column chromatography (amino silica) (AcOEt / hexane) to give a mixture of the diastereomers (153 mg). Further, the mixture was separated by SFC preparative separation (CHIRALPAK IH, CO2: MeOH + 0.1 % DEA), and the compound that came out first was designated as Example 13 (62.7 mg), and the compound that came out later was designated as Example 14 (61.8 mg).

[0189] (Example 15) [(7S)-2-(2-Fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[(2R*)-2-methyloxolan-2-yl]methanone(Example 16) [(7S)-2-(2-Fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[(2S*)-2-methyloxolan-2-yl]methanone The titled compound was prepared from Reference example 18 and the corresponding starting material in the same manner as Example 13. The purification was carried out by SFC preparative separation (CHIRALPAK IH, CO2: MeOH + 0.1 %DEA), and the compound that came out first was designated as Example 15, and the compound that came out later was designated as Example 16.

[0190] (Example 17) [(7S)-2-(2-Fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[(3S)-oxan-3-yl]methanone(Example 18) [(7S)-2-(2-Fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[(3R)-oxan-3-yl]methanone The titled compound was prepared from Reference example 18 and the corresponding starting material in the same manner as Example 10. The purification was carried out by SFC preparative separation (CHIRALPAK IB N-5, CO2: MeOH + 0.1 %DEA), and the compound that came out first was designated as Example 17, and the compound that came out later was designated as Example 18.

[0191] (Example 20) [cis-2,6-Dimethylmorpholin-4-yl]-[(7S)-2-(2-fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone A mixture of cis-2,6-dimethylmorpholine (71 mg), DIPEA (119 mg), CDI (65 mg), and THF (1 mL) was stirred at 0°C for 30 minutes. To the mixture was added the compound of Reference example 18 (100 mg), and the mixture was stirred at room temperature overnight. cis-2,6-Dimethylmorpholine (18 mg) was added thereto again, and the mixture was stirred at 60°C for 2 hours. To the reaction solution was added aqueous saturated sodium bicarbonate, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane / AcOEt, AcOEt / MeOH) to give the title compound (28 mg).

[0192] (Example 25) [(7S)-2-(2-Fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[(3R)-oxolan-3-yl]methanone; hydrochloride A mixture of the compound of Reference example 18 (70 mg), (R)-tetrahydrofuran-3-carboxylic acid (50 mg), HATU (0.11 g), DIPEA (0.11 g), and DMF (2 mL) was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (YMC-TriartC18, eluted with 10 mM aqueous sodium ammonium bicarbonate / acetonitrile) to give a free form of the title compound. To a solution of the free form in AcOEt (1 mL) was added 4M hydrogen chloride / AcOEt (0.11 mL), and the mixture was concentrated. The residue was suspended in diethyl ether, and the title compound (50 mg) was collected on a filter.

[0193] (Example 26) tert-Butyl (7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate A mixture of the compound of Reference example 15 (1.3 g), 7-bromoisothiazolo[4,5-b]pyridine (0.584 g), Xphos-Pd-G3 (0.105 g), cesium fluoride (0.825 g), and dioxane (7 ml) was stirred at 90°C under nitrogen atmosphere for 1.5 hours. The reaction mixture was cooled to room temperature, and concentrated. The residue was purified by silica gel (amino silica) chromatography (ethyl acetate / hexane) to give the title compound (874 mg).

[0194] (Example 30) [cis-2,6-Dimethylmorpholin-4-yl]-[(7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone; fumaric acid (2:1) To a suspension of the compound of Reference example 20 (700 mg) in THF (10 ml) were added DIEA (1.19 ml) and CDI (479 mg), and the mixture was stirred at room temperature for one hour. To the reaction solution were added cis-2,6-dimethylmorpholine (2.82 ml) and DMAP (27.8 mg), and the mixture was refluxed overnight. The reaction mixture was diluted with aqueous saturated sodium bicarbonate, and extracted with AcOEt. The organic layer was dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated, and the residue was purified by silica gel chromatography (hexane / AcOEt). The obtained product was re-crystalized (EtOH / water) to give [cis-2,6-dimethylmorpholin-4-yl]-[(7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone (723 mg). NMR1: δ 1.09 (dd, J = 6.1, 3.2 Hz, 6H), 1.62 (d, J = 6.4 Hz, 3H), 2.45-2.67 (m, 2H), 3.25-3.43 (m, 1H), 3.47-3.66 (m, 4H), 3.87-3.98 (m, 1H), 4.39-4.74 (m, 3H), 7.03 (s, 1H), 7.97 (d, J = 4.7 Hz, 1H), 8.89 (d, J = 4.7 Hz, 1H), 9.30 (s, 1H). melting point: 112°C [cis-2,6-Dimethylmorpholin-4-yl]-[(7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone (100 mg) and fumaric acid (14 mg) were suspended in acetone (1 ml), and the suspension was stirred under light-shielding overnight. The precipitate was washed with acetone to give a co-crystal of [cis-2,6-dimethylmorpholin-4-yl]-[(7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone and fumaric acid (2: 1) (90 mg).

[0195] (Example 32) (2-Methylpyrazol-3-yl)-[(7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone A solution of the compound of Reference example 20 (60 mg), 1-methylpyrazole-5-carboxylic acid (30 mg), HATU (89 mg), and TEA (59 mg) in DMF (1 ml) was stirred at room temperature for 2 hours. Water and AcOEt were added to the rection solution, and the obtained solid was collected on a filter and washed with AcOEt to give the title compound (49 mg).

[0196] (Example 38) [(7S)-7-Methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[(3R)-oxolan-3-yl]methanone A solution of the compound of Reference example 20 (30 mg), (3R)-tetrahydrofuran-3-carboxylic acid (14 mg), HATU (45 mg), and TEA (30 mg) in DCM (2 ml) was stirred at room temperature for 2 hours. To the reaction solution was added aqueous saturated sodium bicarbonate, and the mixture was extracted with a AcOEt-MeOH mixture. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtrated, and concentrated. The residue was purified by silica gel (amino silica) chromatography (hexane / AcOEt) to give the title compound (23 mg).

[0197] (Example 41) (3,3-Difluoropyrrolidin-1-yl)-[(7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone: succinic acid (1:1) A mixture of (S)-7-(7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)isothiazolo[4,5-b]pyridine hydrochloride (70 mg), DIPEA (88 mg), CDI (48 mg), and THF (1 mL) was stirred at room temperature for one hour. To the mixture was added 3,3-difluoropyrrolidine (97 mg), and the mixture was refluxed overnight. The reaction solution was concentrated, and the residue was purified by silica gel (amino silica) column chromatography (hexane / AcOEt) to give (3,3-difluoropyrrolidin-1-yl)-[(7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone (73 mg). NMR2: δ 1.76 (d, J = 6.4 Hz, 3H), 2.28-2.51 (m, 2H), 3.28 (dd, J = 13.8, 8.9 Hz, 1H), 3.59-3.80 (m, 3H), 3.80-3.95 (m, 1H), 4.04 (ddd, J = 13.9, 4.2, 1.5 Hz, 1H), 4.50 (d, J = 16.1 Hz, 1H), 4.54-4.62 (m, 1H), 4.73 (d, J = 16.1 Hz, 1H), 6.67 (s, 1H), 7.61 (d, J = 4.7 Hz, 1H), 8.82 (d, J = 4.7 Hz, 1H), 9.17 (s, 1H). melting point: 182°C (3,3-Difluoropyrrolidin-1-yl)-[(7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone (100 mg) and succinic acid (29 mg) were dissolved in acetone (2 ml) under heating, and the solution was stirred at room temperature overnight. The precipitate was washed with acetone and water to give a co-crystal of (3,3-difluoropyrrolidin-1-yl)-[(7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone and succinic acid (1:1) (12 mg).

[0198] (Example 45) (1,1,1-Trifluoro-2-methylpropan-2-yl)(7S)-2-(2-fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate To a suspension of the compound of Reference example 18 (100 mg) and 4-nitrophenyl (1,1,1-trifluoro-2-methylpropan-2-yl)carbonate (122 mg) in DMF (4 ml) was added DIPEA (0.242 ml) at room temperature, and the mixture was stirred at 50°C for 2 hours. To the reaction medium was added aqueous saturated NaHCO3, and the mixture was extracted with AcOEt. The organic layer was washed with water, and concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt, AcOEt / MeOH) to give the title compound (115 mg).

[0199] (Example 49) (2-Ethylpyrazol-3-yl)-[(7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone A solution of the compound of Reference example 20 (50 mg), 1-ethylpyrazole-5-carboxylic acid (22 mg), COMU (68 mg), and TEA (44 mg) in DCM (1 ml) was stirred at room temperature for 2 hours. Aqueous saturated sodium carbonate and DCM were added to the reaction solution. The organic layer was dried over sodium sulfate, and concentrated. The residue was purified by silica gel (amino silica) chromatography (ethyl acetate / hexane) to give the title compound (38 mg).

[0200] (Example 69) [cis-2,6-Dimethylmorpholin-4-yl]-[(7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanethione 1,1’-Thiocarbonylimidazole (797 mg) was dissolved in DCM (14 ml), and cis-2,6-dimethylmorpholine (0.538 ml) was added to the solution under ice cooling. The mixture was stirred at room temperature for one hour. The reaction solution was washed with brine, dried over sodium sulfate, and concentrated to give a residue (772 mg). The residue (772 mg) was dissolved in MeCN (4 ml), and MeI (1.086 ml) was added to the solution. The mixture was stirred at 50°C for one hour. The reaction solution was concentrated (crude product 1.28 g). The crude product (406 mg) and DMAP (9.00 mg) were dissolved in DMF (2 ml), and DIPEA (0.257 ml) and the salt-free form of Reference example 20 (200 mg) were added to the solution at ice cooling. The mixture was stirred at 70°C for 19 hours. To the reaction solution was added H2O, and the mixture was extracted with AcOEt, dried over sodium sulfate, and concentrated. To the residue was added IPA / H2O to give the title compound (51 mg).

[0201] (Example 70) (3,3-Difluoropyrrolidin-1-yl)-[(7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanethione 1,1’-Thiocarbonylimidazole (69 mg) was dissolved in DMF (1 ml), and a solution of the salt-free form of Reference example 20 (100 mg) in DMF (1 ml) was added to the solution at room temperature. 20 minutes later, 3,3-difluoropyrrolidine hydrochloride (63.5 mg) was added to the reaction solution, and the mixture was stirred at 70°C overnight. H2O was added to the reaction mixture, and the mixture was extracted with DCM, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt), and the obtained solid was triturated with IPE to give the title compound (65 mg).

[0202] (Example 71) [(7S)-7-Methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-(pyrrolidin-1-yl)methanethione 1,1’-Thiocarbonylimidazole (69 mg) was dissolved in DMA (1 ml), and a solution of a salt-free form of Reference example 20 (100 mg) in DMA (1 ml) was added to the solution at room temperature. 50 minutes later, pyrrolidine (79 mg) was added to the reaction solution, and the mixture was stirred at 100°C under microwave irradiation for 15 minutes. H2O was added to the reaction solution. The precipitation was washed with water and dried to give the title compound (101 mg).

[0203] (Example 79) [(7S)-2-[2-(Difluoromethyl)thieno[3,2-b]pyridin-7-yl]-7-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[cis-2,6-dimethylmorpholin-4-yl]methanone A suspension of the compound of Reference example 25 (95 mg), the compound of Reference example 29 (44 mg), cesium fluoride (56 mg), and XPhos Pd G3 (14 mg) in dioxane (2 ml) was stirred at 100°C under argon atmosphere for 4 hours. The reaction solution was concentrated, and the residue was purified by silica gel (amino silica) chromatography (AcOEt / hexane) to give the title compound (65 mg).

[0204] (Example 82) [7-Methyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl](morpholin-4-yl)methanone To a solution of triphosgene (96.7 mg) in DCM (4 mL) was added a solution of 7-(7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)thieno[3,2-b]pyridine hydrochloride (200 mg) and TEA (330 mg) in DCM (4 mL) at 0°C. The mixture was stirred at 0°C for one hour, and morpholine (62.5 mg) was added to the reaction mixture. The reaction mixture was stirred at 25°C under nitrogen atmosphere for one hour. Aqueous sodium bicarbonate (10 mL) was added to the reaction mixture, and the mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated, and the residue was purified by preparative HPLC (Waters Xbridge, water (10 mM ammonium bicarbonate)-acetonitrile) to give a racemic mixture (100 mg). The racemic mixture (100 mg) was purified by chiral SFC (DAICEL CHIRALPAK AS-H, 0.1 % NH3H2O MeOH, CO2) to give the title compound (compound with longer retention time, 23.0 mg).

[0205] (Example 116) (7S)-N,N,7-Trimethyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxamide To a mixture of (S)-7-(7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)thieno[3,2-b]pyridine (680 mg) and Et3N (1.05 mL) in THF (15 mL) was added p-nitrophenol chloroformate (608 mg) at room temperature. The mixture was stirred at room temperature overnight. The reaction was quenched with brine and extracted with AcOEt. The extract was washed with water and dried over MgSO4. The solvent was evaporated in vacuo to give 4-nitrophenyl (S)-7-methyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate which was divided into portions and used in the next step without further purification. A mixture of 4-nitrophenyl (S)-7-methyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (30 mg), DIPEA (18 mg), a solution of dimethylamine in THF (2 M, 69 μL), and THF (2 mL) was stirred at 40°C for 2 hours. To the reaction mixture was added a solution of dimethylamine in THF (2 M, 0.34 mL), and the mixture was stirred at 50°C overnight. The reaction mixture was filtrated and the filtrate was purified by preparative HPLC (YMC-Triart C18, eluted with 10 mM aqueous ammonium bicarbonate / acetonitrile) to give the title compound (10 mg).

[0206] (Example 149) and (Example 150) (3-Fluorooxolan-3-yl)[(7S)-7-methyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]methanone The titled compound was prepared from the corresponding starting material in the same manner as Example 8. The purification was carried out by HPLC (CHIRALPAK IA, Hexane / Ethanol=20 / 80 (v / v)) to give two single isomers, and the compound that came out first was designated as Example 149, and the compound that came out later was designated as Example 150 (the absolute structures at the fluorooxolane moiety are undetermined).

[0207] (Example 152) and (Example 153) 2-Methoxy-1-[(7S)-7-methyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]propan-1-one The titled compound was prepared from the corresponding starting material in the same manner as Example 8. The purification was carried out by HPLC (CHIRALPAK IG, Hexane / Ethanol=25 / 75 (v / v)) to give two single isomers, and the compound that came out first was designated as Example 152, and the compound that came out later was designated as Example 153 (the absolute structures at the methoxypropanone moiety are undetermined).

[0208] (Example 157) and (Example 158) 1-[(7S)-2-(2-Fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-2-(oxolan-3-yl)ethan-1-one The titled compound was prepared from the corresponding starting material in the same manner as Example 8. The purification was carried out by HPLC (CHIRALPAK IC, Ethanol) to give two single isomers, and the compound that came out first was designated as Example 157, and the compound that came out later was designated as Example 158 (the absolute structures at the oxolanylethane moiety are undetermined).

[0209] (Example 159) and (Example 160) [(7S)-7-Methyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl](oxetan-2-yl)methanone The titled compound was prepared from the corresponding starting material in the same manner as Example 8. The purification was carried out by HPLC (CHIRALPAK IG, Ethanol) to give two single isomers, and the compound that came out first was designated as Example 159, and the compound that came out later was designated as Example 160 (the absolute structures at the oxetanylmethanone moiety are undetermined).

[0210] (Example 164) and (Example 165) (3-Fluorooxolan-3-yl)[(7S)-2-(2-fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]methanone The titled compound was prepared from the corresponding starting material in the same manner as Example 8. The purification was carried out with HPLC (CHIRALPAK IA, Ethanol) to give two single isomers, and the compound that came out first was designated as Example 164, and the compound that came out later was designated as Example 165 (the absolute structures at the fluorooxolane moiety are undetermined).

[0211] (Example 178) [(2R,6R)-2,6-Dimethylmorpholin-4-yl]-[(7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone A solution of the compound of Reference example 20 (300 mg), the compound of Reference example 38 (924 mg), DIPEA (0.761 ml), and DMAP (11 mg) in DMF (10 ml) was stirred at room temperature for 18 hours. H2O was added to the reaction solution, and the mixture was extracted with AcOEt, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (amino silica) (hexane / AcOEt), and the obtained compounds were separated by SFC preparative separation (CHIRALPAK-IH, CO2-iPrOH + 0.1% DEA) to give the title compound (121 mg) and a stereoisomer of the title compound (Example 179) (107 mg). The structure of the morpholine moiety of the compound that came out later (Example 179) was determined as (S,S) through single crystal X-ray structure analysis.

[0212] (Example 184) (7S)-5-(Difluoromethanesulfonyl)-7-methyl-2-(thieno[3,2-b]pyridin-7-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine A mixture of the compound of Reference example 8 (17 mg), difluoromethanesulfonyl chloride (16 mg), triethylamine (19 mg), and THF (1 mL) was stirred at room temperature overnight. The mixture was concentrated by blowing air at 60°C, and the residue was purified by preparative HPLC (YMCTriart C18, eluted with MeCN / 10 mM NH4HCO3aq) to give the title compound.

[0213] (Example 185) (7S)-N,7-Dimethyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-sulfonamide A solution of the compound of Reference example 20 (85 mg), N-methylsulfamoyl chloride (38 mg), and TEA (0.172 ml) in DCM (2 ml) was stirred at 0°C for 30 minutes. H2O was added to the reaction solution, and the precipitated crystal was collected on a filter and washed with AcOEt to give the title compound (28 mg).

[0214] (Example 186) [(cis)-2,6-Dimethylmorpholin-4-yl]-[(7S)-7-methyl-2-[2-[1-(trifluoromethyl)pyrazol-4-yl]thieno[3,2-b]pyridin-7-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone A mixture of the compound of Reference example 25 (102 mg), 7-chloro-2-(1-(trifluoromethyl)pyrazol-4-yl)thieno[3,2-b]pyridine (66 mg), XPhos Pd G3 (15 mg), cesium fluoride (60 mg) and dioxane (2 mL) was stirred at 100°C for 6 hours under argon atmosphere. The reaction mixture was cooled to room temperature, concentrated, and then the residue was purified by silica gel column chromatography (amino silica) (AcOEt / hexane) to give the title compound (119 mg).

[0215] (Example 193) [(7S)-7-Methyl-2-[2-[1-(trifluoromethyl)pyrazol-4-yl]thieno[3,2-b]pyridin-7-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[(3R)-oxolan-3-yl]methanone A mixture of the compound of Reference example 53 (60 mg), (R)-tetrahydrofuran-3-carboxylic acid (18 mg), HATU (57 mg), TEA (38 mg) and DMF (3 mL) was stirred at room temperature overnight. To the reaction mixture was added aqueous saturated NaHCO3, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (amino silica) (AcOEt / hexane) to give the solid. The solid was triturated in IPE to give the title compound (48 mg).

[0216] (Example 199) [2-(Difluoromethyl)morpholin-4-yl]-[(7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone To a suspension of the compound of Example 202 (154 mg) in CH3CN (4 mL) was added methyl iodide (0.083 mL). The mixture was stirred at 50°C for 21 hours. To the reaction mixture was added (2-difluoromethyl)morpholine (146 mg). The mixture was refluxed for 8 hours. To reaction mixture was added aqueous saturated NaHCO3, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (amino silica) (AcOEt / hexane) to give the solid. The solid was triturated in IPE to give the title compound (42 mg).

[0217] (Example 200) [(7S)-7-Methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[2-(trifluoromethyl)morpholin-4-yl]methanone In a microwave tube, to a suspension of the compound of Example 202 (100 mg) in acetonitrile (2 mL) was added methanesulfonic acid (0.036 mL). The mixture was stirred at room temperature for 30 minutes. 2-(Trifluoromethyl)morpholine hydrochloride (105 mg) was added thereto, and the mixture was stirred under microwave irradiation at 150°C for 1 hour. To the reaction solution was added saturated sodium bicarbonate solution, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (amino silica) (hexane / AcOEt), and the resulting solid was washed with IPE to give the title compound (71 mg).

[0218] (Example 202) Imidazol-1-yl-[(7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone To a solution of (7S)-7-(7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)isothiazolo[4,5-b]pyridine (150 mg) in acetonitrile (2 mL) was added CDI (90 mg), and the mixture was stirred at room temperature for one hour. To the mixture was added CDI (90 mg), and the mixture was stirred at room temperature for one hour. The precipitate was collected on a filter to give the title compound (154 mg).

[0219] (Example 203) [(7S)-7-Methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[3-(trifluoromethyl)morpholin-4-yl]methanone To a solution of CDI (94 mg) was added 3-(trifluoromethyl)morpholine hydrochloride (111 mg), and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added methanesulfonic acid (0.075 mL), and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added the compound of Reference Example 20 (200 mg), and the mixture was stirred under microwave irradiation at 130°C for 30 minutes. The reaction mixture was diluted with water, and extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (amino silica) (hexane / AcOEt), and the resulting solid was washed with IPE to give the title compound (28 mg).

[0220] (Example 204) (5,5-Dimethyloxolan-3-yl)-[(7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone To a solution of the compound of Reference Example 20 (220 mg) and 5,5-dimethyltetrahydrofuran-3-carboxylic acid (101 mg) in DMF (4 mL) were added HATU (67 mg) and DIPEA (0.45 mL), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. AcOEt was added to the residue, and the insoluble material was removed by filtration. The filtrate was concentrated and purified by silica gel column chromatography (hexane / AcOEt then AcOEt / MeOH), and the resulting solid was washed with AcOEt to give the title compound (37 mg).

[0221] The chemical structures, preparing methods, and spectral data of Examples 1 - 207 are shown in the following table.

[0222] Tests The pharmacological actions of the present compounds are explained here showing the results of pharmacological tests of the representative compounds of the present invention, but the present invention should not be limited thereto.

[0223] Test example 1. in vitro AAK1 inhibitory activity (1) Preparation of AAK1-His protein Sf9 cells (Thermo, Catalog No. 514002) were infected with baculovirus into which AAK1 gene sequence had been introduced with Entry clone pENTR-D-TOPO / hAAK1-His, and cultured in 2L of medium [PSFM-J1 Medium, 5% FBS, 100 units / mL Penicillin, 100 μg / mL Streptomycin (PSFM-J1 Medium; FUJIFILM Wako Pure Chemical Corporation, Catalog No. 160-25851, FBS; Biowest, Catalog No. S1560, 100 × Penicillin-Streptomycin Solution; FUJIFILM Wako Pure Chemical Corporation, Catalog No. 168-23191)] at 27°C for 72 hours. Then, the Sf9 cells were collected by centrifugation [Beckman Coulter, Avanti J-26S XP, Rotor JLA-8.1000, 6,000 rpm (9,000 x g), 4°C, 10 min)], and the cells were dissolved by freeze-thawing. A dissolution buffer having the following composition was used: 50 mM Tris-HCl (pH 8.0), 150 mM NaCl, 1 mM DTT, 5 U / mL Benzonase Nuclease (Tris; FUJIFILM Wako Pure Chemical Corporation, Catalog No. 201-06273, HCl; FUJIFILM Wako Pure Chemical Corporation, Catalog No. 081-05435, NaCl; FUJIFILM Wako Pure Chemical Corporation, Catalog No. 195-01663, DTT; FUJIFILM Wako Pure Chemical Corporation, Catalog No. 049-08972, Benzonase Nuclease; Merck, Catalog No. 71205). The purification was carried out using Ni-NTA affinity column (FUJIFILM Wako Pure Chemical Corporation, Catalog No. 141-09764), and HiLoadTM26 / 600 SuperdexTM200 pg (Cytiva, Catalog No. 28989336). The final buffer for AAK1 protein had the following composition: 1 x TBS, 5%(w / v) Glycerol, 1 mM DTT (TBS; Takara Bio, Catalog No. T9141, Glycerol; FUJIFILM Wako Pure Chemical Corporation, Catalog No. 075-00611, DTT; FUJIFILM Wako Pure Chemical Corporation, Catalog No. 049-08972).

[0224] (2) Enzyme assay As enzyme assay buffer, 25 mM Tris-HCl (pH 7.5), 10 mM MgCl2, 0.01% Tween20, and 1 mM DTT (Tris-HCl; NIPPON GENE, Catalog No. 318-90225, MgCl2; SIGMA, Catalog No. M1028-100 ML, Tween20; Bio-Rad, Catalog No. 1610781, DTT; FUJIFILM Wako Pure Chemical Corporation, Catalog No. 049-08972) were used. The hAAK1-His protein (AAK1 full length, derived from insect cells, final concentration: 6 nM) prepared above was added to a plate (Greiner, Catalog No. 784075) containing the test compound dissolved in DMSO (FUJIFILM Wako Pure Chemical Corporation, Catalog No. 043-07216) at a final concentration of 1% DMSO, and the plate was allowed to stand at room temperature for 60 minutes. ATP (SIGMA, Catalog No. A7699-1G, final concentration: 1 mM) and biotin-peptide [QHQTKEEQSQITSQVT*GQIGWRREGIKYRR-K (biotin), custom synthesis at Scrum Inc., final concentration: 100 nM] were added thereto to start the enzyme reaction, and the mixture was allowed to stand at room temperature for 60 minutes. SA-Xlent (Cisbio, Catalog No. 611SAXLB, final concentration: 25 nM) diluted with HTRF KinEASE detection buffer (Cisbio, Catalog No. 62SDBRDF) and Eu-labeled anti-AP2M1 pThr156 antibody (antibody of CST Inc., Catalog No. 7399S which was labeled by Cisbio, final concentration: 0.5 nM) were added thereto, and the mixture was allowed to stand at room temperature overnight. TR-FRET signal was detected (Ex 337 nm, Em 665 / 620 nm) using EnVision plate reader (PerkinElmer, Catalog No. 2104-0020) and IC50was calculated. <Measurement parameters> TR-FRET ratio is used for values of Sample, High control, and Low control. TR-FRET ratio = Em 665 nm / Em 620 nm × 10000 Inhibition rate = (1-(Sample - Low control) / (High control - Low control)) × 100 Low control is a well without AAK1, High control is a well with enzyme without inhibitor. IC50is calculated with XLfit (fit model 204 : 4 Parameter Logistic Model, IDBS Ltd.). y = (A+((B-A) / (1+(10^((C-x)×D))))) y: Inhibition rate (%) x: Compound concentration for test (common logarithm) A: y min B: y max C: IC50(common logarithm) D: hill slope A and B are fixed at 0% and 100%, respectively.

[0225] (3) Result

[0226] Test example 2. in vitro Cell activity (1) Cell assay T-REx-293 cells (Thermo, Catalog No. R71007) were seeded to CorningTMBioCoatTMCollagen I Coat Flask (Corning, Catalog No. 356485), and cultured at 37°C overnightin 5 % CO2. The culture medium had the following composition. DMEM, 10% FBS, 100 units / mL Penicillin, 100 μg / mL Streptomycin, 10 μg / mL Blasticidin S HCl [DMEM (high glucose); FUJIFILM Wako Pure Chemical Corporation, Catalog No. 043-30085, FBS; Corning, Catalog No. 35-010-CV, 100 × Penicillin-Streptomycin Solution; FUJIFILM Wako Pure Chemical Corporation, Catalog No. 168-23191, Blasticidin S HCl; Invitrogen, Catalog No. A1113903]. The transfection medium used during seeding was only DMEM and 10% FBS. The day after seeding, Tet-on AAK1 expression plasmid (pcDNA5TO / hAAK1) and AP2M1 expression plasmid (pcDNA3.1 / hAP2M1-HAtag) were transfected using Lipofectamine LTX Reagent with PLUS Reagent (Thermo, Catalog No. 15338100), and cultured at 37°C for 6 hours in 5 % CO2. Then, the culture medium was treated with TrypLE Express Enzyme (1X) and no phenol red (Thermo, Catalog No. 12604013) at room temperature for 5 minutes, and the cells were collected from the culture medium and seeded to a 96-well plate. The next day, the compound solution dissolved in Doxycycline (Takara-Bio, Catalog No. 631311, final concentration: 1 μg / mL) and DMSO (FUJIFILM Wako Pure Chemical Corporation, Catalog No. 043-07216, final concentration: 0.1%) was diluted with the culture medium and added to the well plate. Further next day, Cell lysate was prepared with Lysis buffer [1 × Lysis buffer, 1 / 1000 × Protease inhibitor cocktail, 1 / 1000 × Phosphatase inhibitor cocktail (10 × Lysis buffer; CST, Catalog No. 9803S, Protease inhibitor cocktail; Sigma, Catalog No. P8340-1ML, Phosphatase inhibitor cocktail; Sigma, Catalog No. P5726-1ML)]. Then, the phosphorylation state of the substrate AP2M1 was detected by ELISA. A plate washer (Biotek, Catalog No. 405TSUVSQ) was used to wash the plates. A coating antibody (Anti-HA Rat IgG, Roche, Catalog No. 11867423001) was diluted 3000 times with PBS (FUJIFILM Wako Pure Chemical Corporation, Catalog No. 045-29795) and added to a plate (Maxisorp 96 plate, Nunc, Catalog No. 437111). The plate was left standing at 4°C overnight, and the coating antibody was removed. Then, a blocking solution [0.5 × Block Ace (Megmilk Snow Brand, Catalog No. UKB40), 1 / 2000 × ProClin 300 (Sigma, Catalog No. 48912-U)] was added to the plate. The plate was left standing at 4°C overnight, and washed with TBST three times. Immuno-enhancer Reagent A solution (FUJIFILM Wako Pure Chemical Corporation, Catalog No. 298-68604) and the Cell lysate were added to the plate, and the plate was allowed to stand at room temperature for 1.5 hours. The plate was washed with TBST three times. A primary antibody [Anti-Phospho-AP2M1 (Thr156) rabbit IgG, CST, Catalog No. 7399S] which was diluted 1000 times with the Immuno-enhancer Reagent A was added to the plate, and the plate was allowed to stand at room temperature for one hour. The plate was washed with TBST three times. A secondary antibody (Anti-rabbit IgG HRP conjugate, CST, Catalog No. 7074S) which was diluted 2000 times with the Immuno-enhancer Reagent B was added to the plate, and the plate was allowed to stand at room temperature for one hour. The plate was washed three times with TBST, a luminescent substance, ELISA-Star Chemiluminescent Peroxidase Substrate (FUJIFILM Wako Pure Chemical Corporation, Catalog No. 295-78803) was added thereto, and the luminescent signal was detected using EnVision Plate Reader (PerkinElmer, Catalog No. 2104-0020) and IC50was calculated. <Measurement parameters> Inhibition rate = (1 - (Sample-Low control) / (High control - Low control)) × 100 Low control is a well without Doxycycline, High control is a well with Doxycycline. IC50is calculated with XLfit (fit model 204 : 4 Parameter Logistic Model, IDBS Ltd.). y = (A+((B-A) / (1+(10^((C-x)×D))))) A: y min B: y max C: IC50(common logarithm) D: hill slope y: Inhibition rate (%) x: Compound concentration for test (common logarithm) A and B are fixed at 0% and 100%, respectively. (2) Result

[0227] Test example 3. PD assay An administration solution of the test substance was orally administered to C57BL / 6J mice (CLEA Japan) at a dose of 0.1 to 3 mg / 10 mL / kg. 0.5% Methylcellulose (FUJIFILM Wako Pure Chemical Corporation, Catalog No. 133-17815) was used as the solvent for the administration solution. 0.5 to 4 hours after the administration, the mice were decapitated without anesthesia. The cerebral cortex was cut out from the brain tissue. The weight of the cerebral cortex was measured, and it was placed in an Eppendorf tube (Eppendorf, catalog No. 0030120094). Five times the weight (μL) of Cell Lysis Buffer (Cell Signaling Technology, Catalog No. 9803) and 5 mm zirconia balls (Nikkato Corporation, Catalog No. 17111050, YTZ ball 5 mm) were added to the tube, and the tissue was disrupted using TissueLyzer II (QIAGEN, Catalog No. 85300, speed 27 Hz / s, 30 min × 2). The supernatant after centrifugation was collected, and the amount of the protein therein was measured using Pierce BCA Protein Assay Kit (ThermoFisher Scientific, Catalog No. 23227). 4 × Laemmli sample buffer (Bio-Rad, Catalog No. 1610747) and (±)-dithiothreitol solution (WAKO, Catalog No. 048-29224, final concentration: 50 mM) were added to the supernatant, and the mixture was heated at 95°C for 5 minutes. Western blotting was performed using the above samples. The protein solution per sample was adjusted to 5 μg / 15 μL, added to a 7.5% Criterion TGX precast gel (Bio-Rad, Catalog No. 5671025), and electrophoresed using CriterionTMcell (Bio-Rad, Catalog No. 1656001) [200 V (constant voltage), for 40 minutes]. After the electrophoresis, the 7.5% Criterion TGX precast gel was taken out, and transferred using Transblot Turbo Transfer System (BIO-RAD, Catalog No. 1704150) and Trans-Blot Turbo Transfer Pack PVDF (Midi, Bio-Rad, Catalog No. 1704157). AP2M1 was detected on the membrane after the transcription, using Anti-AP2M1 (phospho T156) antibody (Cell Signaling Technology, Catalog No. 7399S), Anti-AP2M1 antibody (OriGene, Catalog No. AP50202PU-N), ECL rabbit IgG, and HRP-linked F(ab')2 Fragment (from Donkey) (Cytiva, Catalog No. NA9340-1ML). Anti-AP2M1 (phospho T156) antibody and Anti-AP2M1 antibody were diluted 1,000 times with Can Get Signal Solution 1 (TOYOBO, Catalog No. NKB-201), and reacted at 4°C overnight. And, ECL rabbit IgG, HRP-linked F(ab')2 Fragment (from Donkey) was diluted 20,000 times with Can Get Signal Solution 2 (TOYOBO, Catalog No. NKB-301), and reacted at room temperature for one hour. ECL Prime Western Blotting Detection Reagent (Cytiva, Catalog No. RPN2236) was used as a detection reagent. The luminescence due to the antibody and the detection reagent was detected using LAS-4000 mini (GE healthcare). The relative protein amount was estimated from the density of the band detected using ImageQuant TL (Cytiva, ver. 7.0), and the AP2M1 phosphorylation status between the samples was compared. EXSUS 10.0 statistical software package (CAC Croit Corporation) was used for statistical analysis. As a significant difference test, Student’s t-test, Wilcoxon test, or one-tailed Shirley Williams test was used. For example, in the above test, it was confirmed that the following Example compounds inhibited AP2M1 phosphorylation with a significant difference at doses of 0.3 to 3 mg / kg: Examples 8, 12, 18, 19, 20, 25, 30, 32, 34, 38, 47, 81, 135, 141, and 156.

Claims

1. A compound of a general formula [1]: wherein L1is -C(=O)-, -C(=S)-, -S(=O)-, or -SO2-, R is H, C1-6alkyl, or halogen, R1is C1-6alkyl, C3-10cycloalkyl, 4- to 12-membered saturated or aromatic heterocyclyl, -O-R11, or -N(R11a)(R11b), wherein the heterocyclyl may be substituted with oxo to give an oxide or dioxide form, and any one or more hydrogen atoms in R1may be substituted with the same or different R12, R11, R11a, and R11bare each independently H, C1-6alkyl, C3-8cycloalkyl, or 4- to 10-membered saturated heterocyclyl, wherein C1-6alkyl may be substituted with halogen, cyano, C1-6alkoxy, or C3-8cycloalkyl, and 4- to 10-membered saturated heterocyclyl may be substituted with C1-6alkyl, R12is each independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy-C1-6alkyl, C6-10aryl, C3-10cycloalkyl, 4- to 12-membered saturated or aromatic heterocyclyl, -C(=O)-R13, -O-R13, -S-R13, or -N(R13a)(R13b), R13, R13a, and R13bare each independently H, C1-6alkyl, -C(=O)-C1-6alkyl, or C1-6alkoxy-C1-6alkyl, wherein the alkyl and alkoxy in R13, R13a, and R13bmay be substituted with halogen or cyano, R2is each independently C1-6alkyl, m is 0, 1, or 2, wherein when m is 2 and two R2bind to the same carbon, the two R2may be taken together to form 3- to 6-membered spiro-ring, and Ring A is an optionally-substituted thieno[3,2-b]pyridine or [1,2]thiazolo[4,5-b]pyridine, or an N-oxide thereof, or a salt thereof or a co-crystal thereof.

2. The compound of claim 1, wherein Ring A is optionally substituted with 1 - 3 the same or different R3, wherein R3is selected from halogen, C1-6haloalkyl, C1-6hydroxyalkyl, -CHO, -C(=O)-C1-6alkyl, C6-10aryl, or 4- to 7-membered saturated or aromatic heterocyclyl, wherein the heterocyclyl may be substituted with oxo to give an oxide or dioxide form, and the aryl or the heterocyclyl may be substituted with C1-6alkyl, cyano, or C1-6haloalkyl, or a salt thereof or a co-crystal thereof.

3. The compound of claim 1 or 2, wherein the binding position of the thieno[3,2-b]pyridine or [1,2]thiazolo[4,5-b]pyridine in Ring A is the following or a salt thereof or a co-crystal thereof.

4. The compound of any one of claims 1 - 3, wherein the general formula [1] is the following formula: or a salt thereof or a co-crystal thereof.

5. The compound of any one of claims 1 - 4, wherein R1is (i) C1-6alkyl optionally-substituted with halogen, cyano, C1-6alkoxy, phenyl, 4- to 12-membered saturated or aromatic heterocyclyl, -OH, -O-C1-6alkyl, -S-C1-6alkyl, NH2, N(CH3)2, N(CH3)C(=O)CH3, or N(CH3)CH2CH2OH, (ii) -O-C1-6alkyl optionally-substituted with fluoro, C1-6alkoxy (methoxy), or 4- to 12-membered saturated or aromatic heterocyclyl, (iii) -N(R11a)(R11b), wherein R11aand R11bis independently H, C1-6alkyl, C1-6alkoxy, C3-8cycloalkyl, oxanyl, or C1-6alkyl substituted with halogen, cyano, or cyclopropyl, (iv) -O-4- to 10-membered saturated heterocyclyl, optionally-substituted with methyl, (v) C3-10cycloalkyl optionally-substituted with cyano, fluoro, or methoxy-methyl, or (vi) 4- to 12-membered saturated or aromatic heterocyclyl optionally-substituted with oxo, halogen, cyano, C1-6alkyl, C1-6haloalkyl, -C(=O)-C1-6alkyl, -O-C1-6alkyl, or C1-6alkoxy-C1-6alkyl, or a salt thereof or a co-crystal thereof.

6. The compound of any one of claims 1 - 4, wherein R1is (i) C1-6alkyl optionally-substituted with 1 to 4 the same or different substituents selected from the group consisting of fluoro, cyano, -CF3, -O-CH3, phenyl, oxolanyl, morpholinyl, pyrazolyl, -OH, -O-t-Bu, -S-CH3, NH2, N(CH3)2, N(CH3)C(=O)CH3, and N(CH3)CH2CH2OH, (ii) -O-C1-6alkyl optionally-substituted with 1 to 4 the same or different substituents selected from the group consisting of fluoro, methoxy, 1,3-oxazolyl, and oxolanyl, (iii) -N(CH3)2, -NHCH3, -NH-ethyl, -N(CH3)CH2CN, -N(CH3)-oxanyl, -NH-C(=O)-CH3, -NH-CH2-cyclopropyl, -NH-CH2CH2CN, -NH-CH2CHF2, or -N(CH3)CH2-cycloprpyl, (iv) -O-oxetanyl which is optionally-substituted with 1 to 4 methyl, (v) cyclopropyl, cyclobutyl, cyclopentyl, or bicyclo[1.1.1]pentanyl, which is optionally-substituted with 1 to 4 the same or different substituents selected from the group consisting of cyano, fluoro, and methoxy-methyl, or (vi) azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxanyl, dioxanyl, pyrazolyl, imidazolyl, 1,3-oxazolyl, thiazolyl, pyridinyl, pyrazinyl, 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazinyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 5-azaspiro[2.4]heptanyl, morpholinyl, 1,4-oxazepanyl, or hexahydrofuro[3,4-c]pyrrolyl, which is optionally-substituted with 1 to 4 the same or different substituents selected from the group consisting of fluoro, methyl, ethyl, cyano, CF3, CHF2, oxo, COCH3, OCH3, and CH2OCH3, or a salt thereof or a co-crystal thereof.

7. The compound of claim 4, wherein R is H, L1is -C(=O)-, R1is (i) C1-6alkyl optionally-substituted with -OH or NH2, (ii) -O-oxetanyl, or (iii) oxetanyl, oxolanyl, oxanyl, dioxanyl, pyrrolidinyl, pyrazolyl, imidazolyl, or morpholinyl, which is optionally-substituted with 1 to 4 the same or different substituents selected from the group consisting of fluoro, cyano, methyl, and CF3, R2is methyl, and Ring A is wherein R3is fluoro, chloro, methylpyrazolyl, or trifluoromehylpyrazolyl and * indicates the binding site to the pyrazole ring, or a salt thereof or a co-crystal thereof.

8. The compound of claim 1, or a salt thereof or a co-crystal thereof, wherein the compound is selected from Examples 1 to 207.

9. The compound of claim 1, which is selected from the following compounds: or a salt thereof or a co-crystal thereof.

10. The compound of claim 1, which is selected from the following compounds:

11. A pharmaceutical composition comprising the compound of any one of claims 1 - 10, or a salt thereof or a co-crystal thereof.

12. The compound of any one of claims 1 - 10, or a salt thereof or a co-crystal thereof, for use in treating or preventing Alzheimer's disease, bipolar disorder, Parkinson disease, schizophrenia, cognitive impairment in schizophrenia, acute pain, chronic pain, neuropathic pain, muscular dystrophy, or a disease associated with viral infection, or a disease associated with viral infection.

13. Use of the compound of any one of claims 1 - 10, or a salt thereof or a co-crystal thereof in the manufacture of a medicament for treating or preventing Alzheimer's disease, bipolar disorder, Parkinson disease, schizophrenia, cognitive impairment in schizophrenia, acute pain, chronic pain, neuropathic pain, muscular dystrophy, or a disease associated with viral infection.

14. A method for treating or preventing Alzheimer's disease, bipolar disorder, Parkinson disease, schizophrenia, cognitive impairment in schizophrenia, acute pain, chronic pain, neuropathic pain, muscular dystrophy, or a disease associated with viral infection, comprising administering a therapeutically effective amount of the compound of any one of claims 1 - 10, or a salt thereof or a co-crystal thereof to a patient in need thereof.

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