1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine derivatives and related compounds as LRRK2, NUAK1 and / or TYK2 kinase modulators for treatment of e.g. autoimmune disease

Abstract

To provide compounds useful as LRRK2, NUAK1 and / or TYK2 kinase modulators for the treatment of autoimmune diseases or the like.SOLUTION: The present invention provides compounds of formula (I) that are capable of modulating one or more kinases, especially LRRK2 and / or NUAK1 and / or TYK2 or mutants thereof, e.g., inhibiting or activating. The compounds are useful for treating diseases, e.g., autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, and Alzheimer's disease. Preferred compounds are, e.g., 1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine derivatives and related compounds.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 899,908, filed on September 13, 2019, the content of which is incorporated herein by reference.

[0002] Field of the Invention The present invention generally relates to compounds, as well as pharmacological compositions for the treatment of conditions, and their use as radiolabeled tracers in positron emission tomography (PET) for diagnostic use.

Background Art

[0003] Background Various medical conditions that affect millions of people are caused or exacerbated by the unregulated activity of protein kinases. For example, abnormal kinase activity is associated with autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, Alzheimer's disease, Parkinson's disease, skin disorders, eye diseases, infectious diseases, and hormone - related diseases. However, in many such disorders, there are no effective inhibitors or activators for the specific kinases that cause the disorder or its symptoms. As a result, patients continue to suffer from many disorders due to the lack of suitable drugs for their conditions.

Summary of the Invention

Means for Solving the Problems

[0004] Summary The present invention provides pharmacological compositions for the treatment of conditions, and compounds useful as radiolabeled tracers in positron emission tomography (PET) for diagnostic use. In certain embodiments, the compounds of the invention modulate, e.g., inhibit or activate, the protein kinase activities associated with human diseases, disorders and conditions, such as leucine rich repeat kinase 2 (LRRK2), SNF1-like kinase 1 (NUAK1), also known as AMPK-related protein kinase 5 and also known as ARK5, and non-receptor tyrosine-protein kinase 2 (TYK2). The compounds exhibit improved pharmacological properties, such as tissue delivery, specificity, efficacy and stability. For example, the present invention includes compounds that can cross the blood-brain barrier and bind to kinase targets with high affinity. Furthermore, radiolabeled forms of the compounds of the invention are useful as PET tracers for identifying the anatomical location of abnormal kinase activity. Accordingly, the compounds of the invention are useful as therapeutic and diagnostic agents for a variety of conditions such as Parkinson's disease and autoimmune diseases.

[0005] Accordingly, the present invention provides compositions containing the compounds described herein, including pharmacological compositions and compositions for diagnostic use. The present invention further provides methods of using such compositions for diagnosing and / or treating disorders in a subject.

[0006] In one aspect, the present invention is directed to a compound of formula (I):

Chemical formula

[0007] The compound of formula (I) is of formula (II):

Chemical formula

[0008] One of U, V, W, and X may be N.

[0009] U may be N. V may be CR 4 and W may be CR 5 and X may be CR 6 and each of R 4 and R 5 and R 6 is H. V may be CR 4 and W may be CR 5 and X may be CR 6 and each of R 6 is H and each of R 4 and R 5 is independently F, Cl, CF 3 and C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR', where each of R and R' is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl or C 2~8 heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form C 2~8 heterocycloalkyl. V may be CR 4 and W may be CR 5 and X may be CR 6 where each of R 4 and R 6 is H, R 5 is F, Cl, CF 3 C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR', where each of R and R' is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, or C 2~8 heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form C 2~8 heterocycloalkyl.

[0010] V may be N. U may be CR 3 and W may be CR 5 and X may be CR 6 where each of R 3 R 5 and R 6 is H. U may be CR 3 and W may be CR 5 and X may be CR 6 where R 6 is H and each of R 3 and R 5 is independently F, Cl, CF 3 C 1~6 alkyl, C2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR', where each of R and R' is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, or C 2~8 heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2~8 heterocycloalkyl. U may be CR 3 and W may be CR 5 and X may be CR 6 and each of R 3 and R 6 is H, and R 5 is F, Cl, CF 3 , C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8 heterocyclo alkenyl, -OR, -C(O)OR, or -C(O)NRR', where each of R and R' is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, or C 2~8 heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2~8 heterocycloalkyl.

[0011] U may be N, V may be CR 4 and W may be CR 5 and X may be CR 6 and each of R 6 is H, and each of R 4 and R 5 is independently F, Cl, CF 3 , C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR', wherein each of R and R' is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, or C 2~8 heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2~8 heterocycloalkyl.

[0012] U may be CR 3 V may be N, W may be CR 5 X may be CR 6 R 6 is H, and each of R 3 and R 5 is independently F, Cl, CF 3 C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR', wherein each of R and R' is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, or C 2~8 heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2~8 heterocycloalkyl.

[0013] U may be N, V may be CR 4 W may be CR 5 X may be CR 6 R 4 and R 6 are each H, and R 5 is F, Cl, CF 3 C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR', and each of R and R' is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, or C 2~8 heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2~8 heterocycloalkyl.

[0014] U may be CR 3 and V may be N, and W may be CR 5 and X may be CR 6 and each of R 3 and R 6 is H, and R 5 is F, Cl, CF 3 , C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR', and each of R and R' is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, or C 2~8 heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2~8 heterocycloalkyl.

[0015] R 1 may be aryl. R 1 is [Chemical Formula] (wherein each of R a ~R e is independently H, halo, OH, CN, CF 3 , CHF 2 , CH 2 F, NH 2 , NO 2 , C 1~6 alkyl, C1~6 Haloalkyl, C 2~6 Alkenyl, C 3~8 Cycloalkyl, C 2~8 Heterocycloalkyl, C 2~8 Heterocyclo Alkenyl, aryl, heteroaryl, -C(O)R, -C(O)OR, -C(O)NRR’, -C(O)NRS(O) 2 R’, -C(O)NRS(O) 2 NR’R”, -OR, -OC(O)NRR’, -NRR’, -NRC(O)R’, -NRC(O)NR’R”, -NRS(O) 2 R’, -NRS(O) 2 NR’R”, -S(O) 2 R, or -S(O) 2 NRR’, and each of R, R’, and R” is independently H, halo, OH, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 3~8 cycloalkyl, C 2~8 heterocycloalkyl, aryl, or heteroaryl, or R and R’, or R’ and R” together with the nitrogen to which they are attached form a C 2~8 heterocycloalkyl) may be.

[0016] R b , R c and R d at least two of which may each be H. R b , R c and R d each may be H. R a and R e each is independently may be halo or C 1~6 alkyl. R a and R e each may be halo. R a and R e each may be F or Cl. R a and Re Each of them may be F, R b , R c , and R d Each of them may be H. R a and R e Each of them may be Cl, R b , R c , and R d Each of them may be H.

[0017] R 1 may be a 5- or 6-membered heteroaryl. R 1 may be a 5-membered heteroaryl. R 1 may be a 5-membered heteroaryl containing at least one N. R 1 may be a 5-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, indolyl, indazolyl, and azaindazolyl. R 1 may be a 5-membered heteroaryl containing O or S. R 1 may be a 5-membered heteroaryl selected from the group consisting of furanyl, thienyl, benzofuranyl, and benzothienyl. R 1 may be a 6-membered heteroaryl containing at least one N. R 1 may be optionally substituted pyridine.

[0018] R 2 may be H, halo, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 thioalkyl, or C 3~8 cycloalkyl. R 2 may be H, halo, -CH 3 , -SCH 3 , or cyclopropyl. R 2 may be H, Cl, -CH 3 , or -SCH 3 .

[0019] The compound of formula (I) is of formula (III): [Chemical formula] (wherein, R 1 is aryl or heteroaryl, R 2 is H, halo, OH, CN, CF 3 , C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 thioalkyl, or C 3~8 cycloalkyl, R 3 ~R 6 each of which is independently H, halo, OH, CN, CF 3 , CHF 2 , CH 2 F, NH 2 , NO 2 , C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 3~8 cycloalkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, aryl, heteroaryl, -C(O)R, -C(O)OR, -C(O)NRR’, -C(O)NRS(O) 2 R’, -C(O)NRS(O) 2 NR’R”, -OR, -OC(O)NRR’, -NRR’, -NRC(O)R’, -NRC(O)NR’R”, -NRS(O) 2 R’, -NRS(O) 2 NR’R”, -S(O) 2 R, or -S(O) 2 NRR’ or R 4 and R 5 together with the atoms to which they are attached form a ring having 5 to 10 members, each of R, R’, and R” is independently H, halo, OH, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 3~8 cycloalkyl, C 2~8is heterocycloalkyl, aryl, or heteroaryl, or R and R’, or R’ and R” together with the nitrogen to which they are attached form a C 2~8 heterocycloalkyl) and may be represented by

[0020] R 3 ~R 6 each is independently H, halo, OH, CN, CF 3 , NH 2 , NO 2 , C 1~6 alkyl, C 3~8 cycloalkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, aryl, heteroaryl, -C(O)OR, -C(O)NRR’, -OR, -OC(O)NRR’, -NRR’, or -NRC(O)R’. At least three of R 3 ~R 6 may be H. Each of R 3 , R 4 , and R 6 may be H. All of R 3 ~R 6 may be H. R 3 and R 6 are each H, and each of R 4 and R 5 is independently halo, OH, CN, CF 3 , NH 2 , NO 2 , C 1~6 alkyl, C 3~8 cycloalkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, aryl, heteroaryl, -C(O)OR, -C(O)NRR’, -OR, -OC(O)NRR’, -NRR’, or -NRC(O)R’. Each of R 3 , R 4 , and R 6 may be H, and R 5 is halo, OH, CN, CF 3 , NH2 、 NO 2 、 C 1~6 alkyl, C 3~8 cycloalkyl, C 2~8 heterocycloalkyl, C 2~8 It may also be heterocycloalkenyl, aryl, heteroaryl, -C(O)OR, -C(O)NRR’, -OR, -OC(O)NRR’, -NRR’, or -NRC(O)R’. R 3 ~ R 6 Each of them may independently be H, halo, CF 3 、 C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8 It may also be heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR’. R 3 and R 6 Each of them may be H, R 4 and R 5 Each of them may independently be halo, CF 3 、 C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8 It may also be heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR’. R 4 and R 5 Each of them may independently be F, Cl, CF 3 、 C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8 It may also be heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR’, and each of R and R’ may independently be H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, or C 2~8 heterocycloalkyl, or R and R’ together with the nitrogen to which they are attached form C 2~8 heterocycloalkyl. R 3 、 R 4 、 and R 6 Each of them may be H, R 5 is halo, CF 3 、 C1~6 Alkyl, C 2~8 Heterocycloalkyl, C 2~8 Heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR’ may also be used. R 5 is F, Cl, CF 3 , C 1~6 Alkyl, C 2~8 Heterocycloalkyl, C 2~8 Heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR’ may also be used, and each of R and R’ is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, or C 2~8 Heterocycloalkyl, or R and R’ together with the nitrogen to which they are attached form C 2~8 Heterocycloalkyl.

[0021] The compound of formula (I) is of formula (III):

Chemical formula

Chemical formula

[0022] The compound of formula (I) is of formula (II):

Chemical formula

Chemical formula

[0023] A may be a 5-membered heteroaryl containing at least one N. A may be a 5-membered heteroaryl selected from the group consisting of pyrazolyl, indazolyl, and azaindazolyl.

[0024] In another aspect, the present invention provides a pharmaceutical composition containing a compound such as any of those described above, or a pharmaceutically acceptable salt of such a compound, and a pharmaceutically acceptable carrier.

[0025] In another aspect, the present invention provides a compound such as any of those described above for use in the manufacture of a medicament for treating a medical condition characterized by abnormal activity or expression of a kinase. The kinase may be overexpressed or underexpressed. The kinase may have increased activity or decreased activity. The kinase may be LRRK2, NUAK1, or TYK2.

[0026] In another aspect, the present invention provides a method of modulating a kinase by contacting a cell containing the kinase with a compound such as any of those described above or a pharmaceutically acceptable salt of such a compound. The method may include inhibiting the kinase. The method may include activating the kinase. The kinase may be LRRK2, NUAK1 or TYK2. In another aspect, the present invention provides a method of treating a medical condition characterized by overexpression of a kinase, the method comprising administering to a subject in need thereof an effective amount of a compound such as any of those described above or a pharmaceutically acceptable salt of such a compound. The kinase may be LRRK2, NUAK1 or TYK2. The condition may be an autoimmune disease, an inflammatory disease, a bone disease, a metabolic disease, a neurological or neurodegenerative disease, cancer, a cardiovascular disease, an allergy, asthma, Alzheimer's disease, Parkinson's disease, a skin disorder, an eye disease, an infectious disease, or a hormone-related disease.

[0027] In another aspect, the present invention provides a method of preparing a compound such as any of those described above by reacting a bisamino compound with an aldehyde to form the compound.

[0028] DETAILED DESCRIPTION Chemical Definitions

[0029] The expression "cycloalkyl" refers to a saturated or partially unsaturated (e.g., cycloalkenyl group) cyclic group containing one or more rings and containing 3 to 14 ring carbon atoms such as 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring carbon atoms. Further, the expression "cycloalkyl" means that one or more hydrogen atoms are fluorine, chlorine, bromine or iodine atoms, or OH, =O, SH, =S, NH 2 3 2 ​​​​Groups replaced by a radical, and thus refers to, for example, cyclic ketones such as cyclohexanone, 2-cyclohexenone or cyclopentanone. Further specific examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetralin, cyclopentylcyclohexyl, fluorocyclohexyl, or cyclohex-2-enyl groups.

[0030] The expression heterocycloalkyl refers to cycloalkyl groups as defined above, in which one or more (e.g., 1, 2 or 3) ring carbon atoms are replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom, or an SO or SO 2 group. The heterocycloalkyl group preferably has one or two rings containing 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring atoms (e.g., C, O, N or S). Further, the expression heterocycloalkyl refers to a group substituted by a fluorine, chlorine, bromine or iodine atom, or an OH, =O, SH, =S, NH 2 , =NH, N 3 or NO 2 group. Examples are piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl, or 2-pyrazolinyl groups, and also lactams, lactones, cyclic imides and cyclic anhydrides.

[0031] The expression "alkylcycloalkyl" refers to a cycloalkyl group as defined above, further containing both an alkyl, alkenyl or alkynyl group, such as an alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl, and alkynylcycloalkyl group. The alkylcycloalkyl group preferably contains one or two rings having 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring carbon atoms, and one or two alkyl, alken yl or alkynyl groups having 1 to 6 carbon atoms.

[0032] The expression "heteroalkylcycloalkyl" refers to an alkylcycloalkyl group as defined above, in which one or more (e.g., 1, 2 or 3) carbon atoms are replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom, or an SO group or an SO 2 group. The heteroalkylcycloalkyl group preferably contains one or two rings having 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups having 1 to 6 carbon atoms. Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl, and heteroalkylheterocycloalkenyl, and the cyclic groups are saturated or mono-, di- or tri-unsaturated.

[0033] The expression "aryl" refers to an aromatic group containing one or more rings containing 6 to 14 ring carbon atoms, such as 6 to 10 ring carbon atoms. Further, the expression "aryl" refers to a fluorine, chlorine, bromine or iodine atom, or an OH, SH, NH 2 , N 3 or NO 2Refers to a group substituted by a group. Examples are phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl groups.

[0034] The expression heteroaryl refers to an aromatic group containing one or more rings containing 5 to 14 ring atoms, for example 5 to 10 ring atoms, and containing one or more (for example 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms. Further, the expression heteroaryl also refers to a fluorine, chlorine, bromine or iodine atom, or an OH, SH, N 3 , NH 2 or NO 2 Refers to a group substituted by a group. Examples are pyridyl (e.g., 4-pyridyl), imidazolyl (e.g., 2-imidazolyl), phenylpyrrolyl (e.g., 3-phenylpyrrolyl), thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, pyridazinyl, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3'-bifuryl, pyrazolyl (e.g., 3-pyrazolyl), and isoquinolinyl groups.

[0035] The term "aralkyl" refers to a group containing both aryl as defined above, and also alkyl, alkenyl, alkynyl, and / or cycloalkyl groups, such as arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl, and alkylarylcycloalkenyl groups. Specific examples of aralkyl are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene, and indane. The aralkyl group preferably contains one or two aromatic ring systems having 6 to 10 carbon atoms, and one or two alkyl, alkenyl, and / or alkynyl groups having 1 to 2 to 6 carbon atoms, and / or a cycloalkyl group having 5 or 6 ring carbon atoms.

[0036] The term "heteroaralkyl" refers to an aralkyl group as defined above in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by oxygen, nitrogen, silicon, selenium, phosphorus, boron, or sulfur atoms, i.e., a group containing both aryl or heteroaryl as defined above, and also alkyl, alkenyl, alkynyl, and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups. The heteroaralkyl group preferably contains one or two aromatic ring systems having 5 or 6 to 10 ring carbon atoms, and one or two alkyl, alkenyl, and / or alkynyl groups having 1 to 2 to 6 carbon atoms, and / or a cycloalkyl group having 5 or 6 ring carbon atoms, with 1, 2, 3, or 4 of these carbon atoms replaced by oxygen, sulfur, or nitrogen atoms.

[0037] ​Examples include aryl heteroalkyl, aryl heterocycloalkyl, aryl heterocycloalkenyl, arylalkyl heterocycloalkyl, arylalkenyl heterocycloalkyl, arylalkynyl heterocycloalkyl, arylalkyl heterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroaryl heteroalkyl, heteroaryl cycloalkyl, heteroaryl cycloalkenyl, heteroaryl heterocycloalkyl, heteroaryl heterocycloalkenyl, heteroarylalkyl cycloalkyl, heteroarylalkyl heterocycloalkenyl, heteroaryl heteroalkyl cycloalkyl, heteroaryl heteroalkyl cycloalkenyl, and heteroaryl heteroalkyl heterocycloalkyl groups, and the cyclic groups are saturated or mono-, di-, or tri-unsaturated. Specific examples include tetrahydroisoquinolinyl, benzoyl, 2- or 3-ethylindolyl, 4-methylpyridino, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxyphenylalkyl groups.

[0038] As described above, the expressions cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl also refer to groups substituted by a fluorine, chlorine, bromine, or iodine atom, or an OH, =O, SH, =S, NH 2 , =NH, N 3 , or NO 2 group.

[0039] The expression "optionally substituted" particularly refers to a group optionally substituted by a fluorine, chlorine, bromine, or iodine atom, or an OH, =O, SH, =S, NH 2 , =NH, N 3 , or NO 2 group. This expression further includes a group optionally substituted by 1, 2, 3 or more unsubstituted C 1 ~C 10 alkyl, C 2 ~C 10 alkenyl, C2 ~C 10 Alkynyl, C1 - C 10 Heteroalkyl, C 3 ~C 16 Cycloalkyl, C 2 ~C 17 Heterocycloalkyl, C 4 ~C 20 Alkylcycloalkyl, C 2 ~C 19 Heteroalkylcycloalkyl, C 6 ~C 18 Aryl, C 1 ~ 17 Heteroaryl, C 7 ~C 20 Aralkyl or C 2 ~C 19 Groups that may be substituted by a heteroaralkyl group. Further, this expression particularly refers to 1, 2, 3 or more unsubstituted C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Heteroalkyl, C 3 ~C 10 Cycloalkyl, C 2 ~C 9 Heterocycloalkyl, C 7 ~C 12 Alkylcycloalkyl, C 2 ~C 11 Heteroalkylcycloalkyl, C 6 ~C 10 Aryl, C 1 ~C 9 Heteroaryl, C 7 ~C 12 Aralkyl or C 2 ~C 11 Groups that may be substituted by a heteroaralkyl group.

[0040] Exemplary substituents are F, Cl, Br, OH, SH, =O, NH 2 、C 1 ~ 4 Alkyl, C1 ~ 4 Heteroalkyl cyclopropyl, SF 5 , NO and NO 2 is.

[0041] Other exemplary substituents are F, Cl, Br, OH, SH, =O, NH 2 , C 1~4 alkyl (e.g., methyl, ethyl, t-butyl), NMe 2 , CONH 2 , CH 2 NMe 2 , NHSO 2 Me, C(CH 3 )2CN, COMe, OMe, SMe, COOMe, COO Et, CH 2 COOH, OCH 2 COOH, COOH, SOMe, SO 2 Me, cyclopropyl, SO 2 NH 2 , SO 2 NHMe, SO 2 CH 2 CH 2 OH, NHCH 2 CH 2 OH, CH 2 CH 2 OCH 3 , SF 5 , SO 2 NMe 2 , NO, NO 2 , OCF 3 , SO 2 CF 3 , CN or CF 3 is.

[0042] Other exemplary substituents are F, Cl, Br, Me, OMe, CN or CF 3 is.

[0043] The term halogen preferably refers to F, Cl, Br or I.

[0044] According to certain embodiments, all alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl and heteroaralkyl groups described herein may be optionally substituted.

[0045] When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl, or heteroaralkyl group contains more than one ring, these rings may be joined to each other by single or double bonds, or these rings may be fused. Compound

[0046] In one aspect, the present invention provides a compound of formula (I):

Chemical formula

[0047] R 1 is one of the following groups:

Chemical formula

[0048] The compound of formula (I) is of formula (II):

Chemical formula

[0049] One of U, V, W, and X may be N.

[0050] U may be N. V may be CR 4 and may be, W may be CR 5 and may be, X may be CR 6 and may be, R 4 R 5 and R 6 each is H. V may be CR 4 and may be, W may be CR 5 and may be, X may be CR6 may also be, R 6 is H, R 4 and R 5 each of which is independently F, Cl, CF 3 , C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR’, and each of R and R’ is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl or C 2~8 heterocycloalkyl, or R and R’ together with the nitrogen to which they are attached form C 2~8 heterocycloalkyl. V may be CR 4 and W may be CR 5 and X may be CR 6 , R 4 and R 6 each of which is H, R 5 is F, Cl, CF 3 , C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR’, and each of R and R’ is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, or C 2~8 heterocycloalkyl, or R and R’ together with the nitrogen to which they are attached form C 2~8 heterocycloalkyl.

[0051] V may be N. U may be CR 3 and W may be CR 5 and X may be CR 6 , R 3 , R 5 , and R 6 each of which is H. U is CR 3It may also be that W is CR 5 It may also be that X is CR 6 It may also be that R 6 is H, and each of R 3 and R 5 is independently F, Cl, CF 3 , C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR’, and each of R and R’ is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, or C 2~8 heterocycloalkyl, or R and R’ together with the nitrogen to which they are attached form C 2~8 heterocycloalkyl. U may also be CR 3 It may also be that W is CR 5 It may also be that X is CR 6 It may also be that R 3 and R 6 are each H, and R 5 is F, Cl, CF 3 , C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR’, and each of R and R’ is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, or C 2~8 heterocycloalkyl, or R and R’ together with the nitrogen to which they are attached form C 2~8 heterocycloalkyl.

[0052] U may be N, V may be CR 4 It may also be that W is CR 5 It may also be that X is CR 6 It may also be that R 6 is H, and each of R 4 and R5 Each of them is independently F, Cl, CF 3 , C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR’, and each of R and R’ is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, or C 2~8 heterocycloalkyl, or R and R’ together with the nitrogen to which they are attached form C 2~8 heterocycloalkyl.

[0053] U may be CR 3 and V may be N, W may be CR 5 and X may be CR 6 , R 6 is H, and each of R 3 and R 5 is independently F, C l, CF 3 , C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR’, and each of R and R’ is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, or C 2~8 heterocycloalkyl, or R and R’ together with the nitrogen to which they are attached form C 2~8 heterocycloalkyl.

[0054] U may be N, V may be CR 4 and W may be CR 5 and X may be CR 6 , R 4 and R 6 are each H, and R 5 is F, Cl, CF3 , C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR', and each of R and R' is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, or C 2~8 heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form C 2~8 heterocycloalkyl.

[0055] U may be CR 3 and V may be N, and W may be CR 5 and X may be CR 6 and each of R 3 and R 6 is H, and R 5 is F, Cl, CF 3 , C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR', and each of R and R' is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, or C 2~8 heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form C 2~8 heterocycloalkyl.

[0056] R 1 may be aryl. R 1 is [Chemical formula] (wherein each of R a ~R e is independently H, halo, OH, CN, CF 3 , CHF 2 , CH2 F, NH 2 , NO 2 , C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 3~8 cycloalkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, aryl, heteroaryl, -C(O)R, -C(O)OR, -C(O)NRR’, -C(O)NRS(O) 2 R’, -C(O)NRS(O) 2 NR’R”, -OR, -OC(O)NRR’, -NRR’, -NRC(O)R’, -NRC(O)NR’R”, -NRS(O) 2 R’, -NRS(O) 2 NR’R”, -S(O) 2 R, or -S(O) 2 NRR’ and each of R, R’, and R” is independently H, halo, OH, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 3~8 cycloalkyl, C 2~8 heterocycloalkyl, aryl, or heteroaryl, or R and R’, or R’ and R” together with the nitrogen to which they are attached form a C 2~8 heterocycloalkyl) it may be.

[0057] R b , R c and R d at least two of which may each be H. R b , R c and R d each may be H. R a and R e each may independently be halo or C 1~6 alkyl. R a and R e each may be halo it may be. Ra and R e each of which may be F or Cl. R a and R e each of which may be F, and R b , R c , and R d each of which may be H. R a and R e each of which may be Cl, and R b , R c , and R d each of which may be H.

[0058] R 1 may be a 5- or 6-membered heteroaryl. R 1 may be a 5-membered heteroaryl. R 1 may be a 5-membered heteroaryl containing at least one N. R 1 may be a 5-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, indolyl, indazolyl, and azaindazolyl. R 1 may be a 5-membered heteroaryl containing O or S. R 1 may be a 5-membered heteroaryl selected from the group consisting of furanyl, thienyl, benzofuranyl, and benzothienyl. R 1 may be a 6-membered heteroaryl containing at least one N. R 1 may be an optionally substituted pyridine.

[0059] R 2 may be H, halo, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 thioalkyl, or C 3~8 cycloalkyl. R 2 may be H, halo, -CH 3 , -SCH 3 , or cyclopropyl. R 2 may be H, Cl, -CH 3 , or -SCH 3 .

[0060] The compound of formula (I) is of formula (III):

Chemical formula

[0061] R 3 ~R 6 each is independently H, halo, OH, CN, CF 3 , NH 2 , NO 2 , C 1~6 alkyl, C 3~8 cycloalkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, aryl, heteroaryl, -C(O)OR, -C(O)NRR’, -OR, -OC(O)NRR’, -NRR’, or -NRC(O)R’. R 3 ~R 6 at least three of which may be H. R 3 , R 4 , and R 6 each may be H. R 3 ~R 6 all may be H. R 3 and R 6 are each H, and R 4 and R 5 each is independently halo, OH, CN, CF 3 , NH 2 , NO 2 , C 1~6 alkyl, C 3~8 cycloalkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, aryl, heteroaryl, -C(O)OR, -C(O)NRR’, -OR, -OC(O)NRR’, -NRR’, or -NRC(O)R’. R 3 , R 4 , and R 6 each may be H, and R 5 is halo, OH, CN, CF 3 , NH2 、 NO 2 、 C 1~6 alkyl, C 3~8 cycloalkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, aryl, heteroaryl, -C(O)OR, -C(O)NRR’, -OR, -OC(O)NRR’, -NRR’, or -NRC(O)R’ may be. R 3 ~R 6 Each of them may independently be H, halo, CF 3 、 C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR’ may be. R 3 and R 6 Each of them may be H, R 4 and R 5 Each of them may independently be halo, CF 3 、 C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR’ may be. R 4 and R 5 Each of them may independently be F, Cl, CF 3 、 C 1~6 alkyl, C 2~8 heterocycloalkyl, C 2~8 heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR’ may be, and each of R and R’ may independently be H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, or C 2~8 heterocycloalkyl, or R and R’ together with the nitrogen to which they are attached form C 2~8 heterocycloalkyl. R 3 、 R 4 、 and R 6 Each of them may be H, R 5 is halo, CF 3 、 C1~6 Alkyl, C 2~8 Heterocycloalkyl, C 2~8 Heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR' may also be. R 5 is F, Cl, CF 3 , C 1~6 Alkyl, C 2~8 Heterocycloalkyl, C 2~8 Heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR' may also be, and each of R and R' is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, or C 2~8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form C 2~8 Heterocycloalkyl.

[0062] The compound of formula (I) is of formula (III):

Chemical formula

Chemical formula

[0063] The compound of formula (I) is of formula (II):

Chemical formula

Chemical formula

[0064] A may be a 5-membered heteroaryl containing at least one N. A may be a 5-membered heteroaryl selected from the group consisting of pyrazolyl, indazolyl, and azaindazolyl.

[0065] The compound of formula (I) has the following structure:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0066] The present invention provides a pharmaceutical composition comprising the above-described one or more compounds, or a pharmaceutically acceptable ester, prodrug, hydrate, solvate or salt thereof, in combination with a pharmaceutically acceptable carrier as required. The present invention further provides such a compound for the preparation of a medicament for the treatment of one or more diseases referred to herein.

[0067] The pharmaceutical composition may contain a therapeutically effective amount of one or more compounds of the present invention. The therapeutically effective amount of the compound according to the present invention means an amount of the compound effective to prevent, alleviate or improve the symptoms of the disease or to prolong the survival of the subject being treated. The determination of the therapeutically effective amount is within the scope of the art.

[0068] The therapeutically effective amount or dosage of the compound according to the present invention may vary within a wide range and may be determined by methods known in the art. Such dosage may be adjusted according to the individual requirements in each particular case, including the specific compound being administered, the route of administration, the condition being treated, and the patient being treated.

[0069] The composition of the present invention may include a vehicle for delivering one or more compounds of the present invention. For example, the composition may contain particles such as nanoparticles, microparticles, liposomes, micelles and virus particles.

[0070] Examples of pharmaceutically acceptable salts of the sufficiently basic compounds of the present invention are salts of physiologically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, or salts of organic acids such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid. Further, the sufficiently acidic The compounds of the invention may form alkali metal salts or alkaline earth metal salts, such as sodium, potassium, lithium, calcium or magnesium salts, ammonium salts or organic base salts, such as methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumine, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine or arginine salts, and all of these are also further examples of the salts of the invention. The compounds of the invention may be solvated, particularly hydrated. Hydratization / hydration may occur during the production process or as a result of the hygroscopicity of the compounds of the invention which are initially water-free. Solvates and / or hydrates may exist, for example, in solid or liquid form.

[0071] It should be understood that certain compounds of the invention may have tautomeric forms, various geometric isomers (usually shown as cis / trans isomers or more generally as (E) and (Z) isomers), or various optical isomers (usually named according to the Cahn-Ingold-Prelog or R / S system) as a result of one or more chiral carbon atoms, where only one is detailed or shown in the following description. All of these tautomeric forms, geometric or optical isomers (as well as racemates and diastereomers), and polymorphic forms are included in the invention. Since the compounds of the invention may contain asymmetric C atoms, they may exist as achiral compounds, mixtures of diastereomers, mixtures of enantiomers, or as optically pure compounds. The invention includes all pure enantiomers and all pure diastereomers, as well as mixtures thereof in any mixing ratio.

[0072] According to a further embodiment of the invention, one or more hydrogen atoms of the compounds of the invention may be replaced by deuterium. Deuterium modification improves the metabolic properties of the drug without substantially or entirely changing its inherent pharmacological action. Deuterium substitution at specific molecular positions improves metabolic stability, reduces the formation of toxic metabolites and / or increases the formation of desired active metabolites. Accordingly, the invention also encompasses partially and fully deuterated compounds of the invention. The term hydrogen also encompasses deuterium.

[0073] The therapeutic use of the compounds according to the invention, their pharmacologically acceptable salts, solvates and hydrates respectively, as well as formulations and pharmaceutical compositions, is also within the scope of the invention. The pharmaceutical compositions according to the invention may contain at least one compound of the invention as active ingredient, as well as, if desired, carrier substances and / or adjuvants.

[0074] The invention also relates to prodrugs composed of the compounds of the invention and at least one pharmacologically acceptable protecting group which is cleaved under physiological conditions, for example alkoxy, arylalkyloxy, acyl, acyloxymethyl groups (e.g. pivaloyloxymethyl) as defined herein, 2-alkyl, 2-aryl or 2-arylalkyloxycarbonyl-2-alkylideneethyl groups or acyloxy groups such as ethoxy, benzyloxy, acetyl or acetyloxy, or in the case of compounds of the invention having in particular a hydroxy group (-OH): sulfate, phosphate (-OPO 3 or -OCH 2 OPO 3 ), or esters of amino acids. For example, the composition may contain a prodrug of the hydroxy group of the compound of the invention.

[0075] As used herein, the term pharmaceutically acceptable ester refers to esters including those which are hydrolyzed in vivo and readily disintegrate in the human body to leave the parent compound or its salt. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic acids, alkenoic acids, cycloalkanoic acids and alkane diacids, and each alkyl or alkenyl moiety preferably has up to 6 carbon atoms. Ex Examples of specific esters include, but are not limited to, formate esters, acetate esters, propionate esters, butyrate esters, acrylate esters and ethyl succinate esters.

[0076] The present invention also relates to prodrugs, biodegradable esters, biodegradable amides, polymorphs, tautomers, stereoisomers, metabolites, N-oxides, biodegradable carbamates, biodegradable ethers, physiologically functional derivatives, atropisomers, or in vivo hydrolyzable precursors, diastereomers or mixtures of diastereomers, chemically protected forms, affinity reagents, complexes, chelates and stereoisomers of the compounds of the present invention.

[0077] As described above, therapeutically useful agents containing the compounds of the present invention, their solvates, salts or formulations are also included within the scope of the present invention. Generally, the compounds of the present invention are administered alone or in combination with any other therapeutic agent, using acceptable modes known and known in the art.

[0078] For oral administration, such therapeutically useful agents can be administered by the following routes: orally, for example, as tablets, dragees, coated tablets, pills, semi-solids, soft or hard capsules, for example, soft and hard gelatin capsules, aqueous or oily solutions, emulsions, suspensions or syrups; parenterally, including intravenous, intramuscular and subcutaneous injections, for example, as injectable solutions or suspensions; rectally as suppositories; by inhalation or insufflation, for example, as powder formulations, as microcrystals, or as sprays (for example, liquid aerosols); transdermally, for example, via a transdermal delivery system (TDS) such as a plaster containing the active ingredient, or by one of the nasal passages. For the production of such tablets, pills, semi-solids, coated tablets, dragees and hard, for example, gelatin capsules, the therapeutically useful product can be mixed with pharmaceutically inert inorganic or organic excipients such as lactose, sucrose, glucose, gelatin, malt, silica gel, starch or their derivatives, talc, stearic acid or its salts, dried skim milk. For the production of soft capsules, excipients such as, for example, vegetable oils, petroleum, animal oils or synthetic oils, waxes, fats, polyols can be used. For the production of liquid solutions, emulsions or suspensions or syrups, excipients such as, for example, water, alcohol, physiological saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrin, vegetable oils, petroleum, animal oils or synthetic oils can be used. Particularly useful are lipids such as phospholipids (for example, of natural origin and / or having a particle size between 300 and 350 nm) in phosphate buffered saline (pH = 7 - 8, for example 7.4). In the case of suppositories, excipients such as, for example, vegetable oils, petroleum, animal oils or synthetic oils, waxes, fats and polyols can be used. In the case of aerosol formulations, compressed gases suitable for this purpose such as, for example, oxygen, nitrogen and carbon dioxide can be used. Pharmaceutically useful agents can also contain additives for preservation, stabilization, for example, UV stabilizers, emulsifiers, sweeteners, fragrances, salts for changing the osmotic pressure, buffers, coating additives and antioxidants.

[0079] Generally, for oral or parenteral administration to an adult human of approximately 80 kg body weight, a daily dosage of about 10 mg to about 10,000 mg, or about 20 mg to about 1,000 mg should be appropriate, but may exceed the upper limit if so indicated. The daily dosage may be administered as a single dose or in divided doses, or, in the case of parenteral administration, by continuous infusion or subcutaneous injection. Method for preparing the compound

[0080] The present invention also provides a method for preparing the compounds of the present invention such as those described above. A synthetic scheme for preparing a specific compound of formula (I) is provided in the following examples. Method for treating diseases, disorders and conditions

[0081] The compounds and compositions of the present invention may be used for diagnosing, treating or preventing a disease, disorder or condition. The present invention further provides a method for diagnosing or treating a disease, disorder or condition using a compound or composition of the present invention.

[0082] Diseases, disorders and conditions that can be diagnosed and / or treated using the compositions and methods of the present invention include those related to abnormal activity of one or more kinases, e.g., increased activity or decreased activity. The kinase may be a serine-threonine kinase or a tyrosine kinase, e.g., a receptor tyrosine kinase or a non-receptor tyrosine kinase. For example, and without limitation, the kinase may be leucine-rich repeat kinase 2 (LRRK2), NUAK family SNF1-like kinase 1 (NUAK1, also known as AMPK-related protein kinase 5 or ARK5), or non-receptor tyrosine-protein kinase TYK2 (TYK2), including variants of any of the foregoing kinases.

[0083] The disease, disorder or condition may be associated with abnormal LRRK2 activity, such as Alzheimer's disease, Crohn's disease, inflammatory bowel disease, inflammatory disease, Hansen's disease, neurodegenerative disease, non-skin cancer, or Parkinson's disease including familial Parkinson's disease, sporadic Parkinson's disease, late-onset Parkinson's disease (PD), and Parkinson's disease type 8.

[0084] The disease, disorder or condition may be associated with abnormal NUAK1 activity, such as cancer, e.g., colorectal cancer, gastric cancer, endometrial cancer, or multiple myeloma, diabetes, fibrosis, neurodegenerative disease, or umbilical hernia.

[0085] The disease, disorder or condition may be associated with abnormal TYK2 activity, such as autoimmune disorder, Crohn's disease, hyperimmunoglobulin E syndrome, inflammatory bowel disease, multiple sclerosis (MS), psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE), type 1 diabetes (T1D), or ulcerative colitis.

[0086] The disease, disorder or condition is a respiratory / obstructive airway disease or disorder, such as rhinorrhea, tracheal stenosis, airway constriction, acute allergy, atrophic rhinitis or chronic rhinitis (e.g., caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, dry rhinitis), drug-induced rhinitis, membranous rhinitis (including croupous, fibrinous, and pseudomembranous rhinitis), adenopathic rhinitis, perennial allergic rhinitis, seasonal rhinitis (including vasomotor rhinitis and allergic rhinitis (hay fever)), hay fever, asthma (e.g., bronchial, atopic, allergic, intrinsic, extrinsic, exercise-induced, cold-induced, occupational, bacterial infection-induced, and dust asthma, particularly chronic or refractory asthma (e.g., late-onset asthma and airway hyperresponsiveness)), bronchitis (including chronic, acute, arachidonic acid-induced, catarrhal, croupous, debilitating, and eosinophilic bronchitis), cardiac bronchitis, pneumoconiosis, chronic inflammatory diseases of the lung leading to interstitial fibrosis such as interstitial lung disease (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, or other autoimmune conditions), acute lung injury (ALI), adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airway or lung disease (CORD, COAD, COLD or COPD, e.g., irreversible COPD), chronic rhinosinusitis, conjunctivitis (e.g., allergic conjunctivitis), cystic fibrosis, extrinsic allergic alveolitis (farmer's lung and related diseases), pulmonary fibrosis, hypersensitivity lung disease, hypersensitivity pneumonitis, idiopathic interstitial pneumonia, nasal congestion, nasal polyposis, otitis media and cough (inflammatory or iatrogenic chronic cough), pleurisy, pulmonary congestion, pulmonary emphysema, bronchiectasis, sarcoidosis, cryptogenic fibrosing alveolitis, pulmonary fibrosis including fibrosis associated with antineoplastic therapy, chronic infections including tuberculosis and aspergillosis and other fungal infections, vasculitis and thrombotic disorders of the pulmonary vasculature, as well as pulmonary hypertension, acute viral infections including the common cold, respiratory syncytial virus, influenza, coronavirus (including SARS) and Or it may be or include an infectious disease caused by adenovirus, allergic bronchopulmonary mycosis, emphysema, diffuse panbronchiolitis, systemic anaphylaxis or hypersensitivity response, drug allergy (e.g., to penicillin, cephalosporin), insect sting allergy, and food-related allergies (such as migraine, rhinitis and eczema) that may affect remotely from the intestine, anaphylactic shock, or vasospasm.

[0087] The disease, disorder or condition is a disease or disorder related to bones and joints, such as osteoporosis, arthritis (including rheumatoid, infectious, autoimmune, chronic, malignant), seronegative spondyloarthropathies (such as ankylosing spondylitis, rheumatoid spondylitis, psoriatic arthritis, enthesitis, Behcet's disease, Marie-Strümpell arthritis, arthritis associated with inflammatory bowel disease and Reiter's disease, etc.), systemic sclerosis, osteoarthritis, primary osteoarthritis, and both osteoarthritis secondary to, for example, congenital hip dysplasia, spondylitis of the cervical and lumbar spine, and pain in the lower back and neck, Still's disease, reactive arthritis and undifferentiated spondylitis, septic arthritis, and other infection-related arthropathies and bone disorders including tuberculosis such as Pott's disease and Poncet's syndrome, acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and inflammation of tendons, bursae and synovium associated with calcium apatite, primary and secondary Sjögren's syndrome, systemic sclerosis and localized systemic scleroderma, mixed connective tissue disease and undifferentiated connective tissue disease, inflammatory muscle diseases including polymyalgia rheumatica, juvenile arthritis including idiopathic inflammatory arthritis and syndromes associated therewith regardless of joint distribution, other joint diseases (such as intervertebral disc degeneration or temporomandibular bone degeneration), rheumatic fever and its systemic complications, giant cell arteritis, Takayasu arteritis, polyarteritis nodosa, microscopic polyangiitis and vasculitis including vasculitis associated with viral infection, allergic reactions, cryoglobulins, abnormal proteinemia, low back pain, familial Mediterranean fever, Muckle-Wells syndrome and familial Hibernian fever, Kikuchi disease, drug-induced arthralgia, tendonititides, polychondritis, and muscle diseases, osteoporosis, osteomalacia-like osteoporosis, osteopenia, osteogenesis imperfecta, osteopetrosis, fibrous dysplasia, osteonecrosis, Paget's disease of bone, hypophosphatemia, Felty's syndrome, Still's disease, loosening of artificial joint implants, sprains or strains of muscles or joints, tendinitis, myositis, periarthritis humeroscapularis, cervical-shoulder-arm syndrome, or tendoperiostitis, or may include them.

[0088] The disease, disorder or condition is a disease or disorder related to the skin or eyes, such as glaucoma, ocular hypertension, cataract, retinal detachment, psoriasis (including plaque psoriasis, pustular psoriasis, psoriatic arthritis, erythrodermic psoriasis), palmoplantar pustulosis, xeroderma, eczematous diseases (e.g., atopic dermatitis, ultraviolet irradiation dermatitis, contact dermatitis and seborrheic dermatitis), phytodermatitis, photodermatitis, cutaneous eosinophilia, chronic skin ulcer, cutaneous erythematosus, contact hypersensitivity / allergic contact dermatitis (including hypersensitivity to poison ivy, poison oak, or oak), as well as eosinophilic cystic folliculitis (Tokura disease), pruritus, drug eruption, urticaria (acute or chronic, allergic or non-allergic), acne, erythema, herpes dermatitis, scleroderma, vitiligo, lichen planus, lichen sclerosus et atrophicus, pyoderma gangrenosum, cutaneous sarcoma, pemphigus, ocular pemphigus, pemphigoid, epidermolysis bullosa, angioedema, vasculitis, toxic erythema, cutaneous eosinophilia, alopecia areata, androgenetic alopecia, Sweet syndrome, Stevens-Johnson syndrome, Weber-Christian syndrome, erythema multiforme, infectious and non-infectious cellulitis, panniculitis, cutaneous lymphoma, non-melanoma skin cancer and other dysplastic lesions, blepharitis, iritis, anterior and posterior uveitis, choroiditis, autoimmune, degenerative or inflammatory disorders affecting the retina, uveitis including sympathetic ophthalmia, sarcoidosis, dry infections including viral, fungal and bacterial, allergic conjunctivitis, increased fibrosis, keloid, keloid-forming surgical wound, postoperative scar, bullous epidermal detachment, dry eye, eye inflammation, allergic conjunctivitis, vernal catarrh, vernal keratoconjunctivitis and giant papillary conjunctivitis, ocular angiogenesis, corneal injury and scar, all forms of macular degeneration, macular edema, macular dystrophy, abnormal wound healing, episcleritis, scleritis, scleroderma, marginal ulcerative keratitis, fungal keratitis, herpes keratitis, invasive aspergillosis; keratoconus, corneal epithelial dysplasia, or severe intraocular inflammation may be or may include.

[0089] The disease, disorder or condition may be or include a disease or disorder related to the gastrointestinal tract and abdomen, such as celiac disease (e.g., celiac sprue), cholecystitis, enteritis (including infectious, ischemic, radiation, drug-induced, and eosinophilic gastroenteritis), eosinophilic esophagitis, eosinophilic gastrointestinal inflammation, allergen-induced diarrhea, bowel diseases associated with seronegative arthropathies, gastritis, autoimmune atrophic gastritis, ischemic bowel disease, inflammatory bowel disease (Crohn's disease and ulcerative colitis), colitis, Mooren ulcer, irritable bowel syndrome, necrotizing enteritis, gastrointestinal ischemia, glossitis, gingivitis, periodontitis, esophagitis including reflux, proctitis, fibrosis and cirrhosis of the liver, pancreatitis, acute and chronic, pancreatic fibrosis, pancreatic sclerosis, pancreatic lithiasis, cirrhosis, hepatitis (congestive, autoimmune, acute, fulminant, chronic, drug-induced, alcohol-induced, lupoid, fatty liver type, and chronic viral), fatty liver, primary biliary sclerosis, hepatic porphyria, and allergic disorders related to the gastrointestinal tract, spastic colon, diverticulitis, gastrointestinal bleeding, Behcet's disease, partial hepatectomy, acute liver necrosis (e.g., necrosis caused by toxins, viral hepatitis, shock or hypoxia), or hemolytic uremic syndrome.

[0090] The disease, disorder or condition may be or include a hematological disease or disorder, such as anemia, coagulation, myeloproliferative disorders, hemorrhagic disorders, leukopenia, eosinophilic disorders, leukemia (e.g., myeloid, lymphoma, plasma cell dyscrasias, pancreatic disorders, von Willebrand disease, hemophilia, purpura (including idiopathic thrombocytopenic purpura), or Wiskott-Aldrich syndrome.

[0091] The disease, disorder or condition may be or may include a metabolic disease or disorder such as obesity, amyloidosis, abnormalities of amino and acid metabolism such as branched-chain disease, aminoacidemia, aminoaciduria, abnormalities of urea metabolism, hyperammonemia, mucopolysaccharidosis such as Morquio - Brailsford syndrome, storage diseases such as glycogen storage disease and lipid storage disease, type I glycogenosis such as Cori's disease, malabsorption diseases such as intestinal carbohydrate malabsorption disease, oligosaccharide deficiencies such as maltase, lactase, sucrase deficiencies, fructose metabolism disorders, galactose metabolism disorders, galactosemia, carbohydrate utilization abnormalities such as diabetes, hypoglycemia, pyruvate metabolism abnormalities, fat deficiency anemia, hypolipoproteinemia, lipid disorders, hyperlipoproteinemia, carnitine or carnitine acyltransferase deficiency, porphyrin metabolism, porphyrin abnormalities, purine metabolism abnormalities, lysosomal diseases, gangliosidosis, sphingolipidosis, sulfatide lipidosis, cerebral leukodystrophy, or metabolic diseases of the nerves and nervous system such as Lesch - Nyhan syndrome.

[0092] The disease, disorder or condition is a state associated with cerebellar dysfunction or abnormal brain metabolism, such as dementia, Alzheimer's disease, Huntington's chorea, Parkinson's disease, Pick's disease, toxic encephalopathy, inflammatory neuropathy, a demyelinating neuropathy such as Guillain - Barré syndrome; Meniere's disease and nerve root disorders, any disorder resulting from hyperfunction or hypofunction of an endocrine gland secreting certain hormones and any combination thereof, primary and secondary metabolic disorders associated with hormone deficiency, such as Shipple's syndrome, pituitary gland dysfunction and its effects on other endocrine glands, such as the thyroid, adrenal glands, ovaries and testes, acromegaly, hyperthyroidism and hypothyroidism, goiter, euthyroid syndrome, thyroiditis, and thyroid cancer, overproduction or underproduction of adrenal steroid hormones, adrenogenital syndrome, Cushing's syndrome, Addison's disease of the adrenal cortex, Addison's pernicious anemia, primary and secondary aldosteronism, diabetes insipidus, true diabetes, carcinoid syndrome, parathyroid gland dysfunction, islet cell dysfunction, abnormalities caused by diabetes, estrogen deficiency, female endocrine system abnormalities such as resistant ovary syndrome; muscle weakness, myotonia, Duchenne and other muscular dystrophies, Steinert type myotonic dystrophy, mitochondrial myopathies such as abnormal catabolism of muscle, carbohydrate and lipid storage myopathies, glycogenosis, myoglobinuria, malignant hyperthermia, polymyalgia rheumatica, dermatomyositis, polymyositis, primary myocardial diseases, cardiomyopathy; ectodermal disorders, neurofibromatosis, scleroderma and polyarteritis, Louis - Barré syndrome, von Hippel - Lindau disease, Sturge - Weber syndrome Group, tuberous sclerosis, amyloidosis, porphyria; sexual dysfunction in both men and women; states of confusion and seizures resulting from abnormal secretion of antidiuretic hormone from the pituitary gland, Riddle's syndrome, Bartter's syndrome, Fanconi type I syndrome, or renal electrolyte depletion, which may or may not be present or included.

[0093] The disease, disorder or condition is a state associated with transplant rejection, such as acute and chronic allograft rejection after solid organ transplantation, such as kidney, heart, liver, lung and corneal transplantation, chronic graft - versus - host disease, skin graft rejection, and bone marrow transplant rejection, or immunosuppression, which may or may not be present or included.

[0094] The disease, disorder or condition may be or may include a urogenital-related condition such as nephritis (interstitial, acute interstitial (allergic), and glomerulonephritis), nephrotic syndrome, cystitis including acute and chronic (interstitial) cystitis, and Hunner's ulcer, acute and chronic urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvovaginitis, vulvovaginal candidiasis, Peyronie's disease and erectile dysfunction, kidney disease, renal fibrosis, pyelonephritis, secondary atrophic kidney, steroid-dependent and anti-steroid nephrosis, or Goodpasture's syndrome.

[0095] The disease, disorder or condition may be or include a disease or disorder associated with the CNS, such as a neurodegenerative disease, Alzheimer's disease, and other cognitive disorders including CJD and nvCJD, amyloidosis, and other demyelinating syndromes, cerebral atherosclerotic arteriosclerosis and vasculitis, temporal arteritis, myasthenia gravis, postoperative visceral pain, headache, migraine, neuralgia (including trigeminal neuralgia), atypical facial pain, acute and chronic pain including joint and bone pain (whether central or peripheral, acute, intermittent or persistent), pain due to cancer and tumor infiltration, neuropathic pain syndromes including diabetic, postherpetic and HIV-related neuropathy, neurosarcoidosis, brain injury, for cerebrovascular diseases, and their sequelae, Parkinson's disease, corticobasal degeneration, motor neuron disease, ALS (amyotrophic lateral sclerosis), multiple sclerosis, traumatic brain injury, stroke, post-stroke, post-traumatic brain injury, and cerebral small vessel disease, dementia, vascular dementia, Lewy body dementia, frontotemporal dementia linked to chromosomes 1 to 17 with parkinsonism, frontotemporal dementia including Pick's disease, progressive supranuclear palsy, corticobasal degeneration, Huntington's disease, thalamic degeneration, HIV dementia, dementia including schizophrenia with dementia, and Korsakoff psychosis are also considered CNS disorders within the meaning of the definition, central and peripheral nervous system complications of malignant, infectious or autoimmune processes, pain sensation, cerebral infarction, seizure, cerebral ischemia, head injury, spinal cord injury, spinal muscular atrophy, Shy-Drager syndrome, Reye's syndrome, progressive multifocal leukoencephalopathy, normal pressure hydrocephalus, sclerosing panencephalitis, frontal lobe dementia, acute poliomyelitis (poliomyelitis), poliomyelitic neuropathy, viral encephalitis, allergic encephalomyelitis, epileptic encephalopathy, Creutzfeldt-Jakob disease, kuru, bovine spongiform encephalopathy (mad cow disease), scrapie, epilepsy, cerebral amyloid angiopathy, depression, mania, bipolar disorder, hereditary cerebellar ataxia, peripheral neuropathy, Nasu-Hakola syndrome, or Machado-Joseph disease, or may contain them.

[0096] The disease, disorder or condition is an inflammatory or immunological disease or disorder, such as general inflammation (of the eyes, nose, lungs and gastrointestinal tract), mastocytosis / mast cell disorder (skin, systemic, mast cell activation syndrome and pediatric mast cell disease), mastitis (breast), vaginitis, vasculitis (e.g., necrotizing, cutaneous, and allergic vasculitis), Wegener's granulomatosis, myositis (including polymyositis, dermatomyositis), basophil-related diseases including basophilic leukemia and basophilia, and eosinophil-related diseases such as Churg-Strauss syndrome, eosinophilic granuloma, erythematosus (e.g., systemic erythematosus, subacute cutaneous erythematosus, and discoid erythematosus), chronic thyroiditis, Hashimoto's thyroiditis, Graves' disease, type I diabetes, complications resulting from true diabetes, other immune disorders, eosinophilic fasciitis, hyper IgE syndrome, Addison's disease, antiphospholipid syndrome, immunodeficiency diseases, acquired immunodeficiency syndrome (AIDS), Hansen's disease, Sézary syndrome, paraneoplastic syndrome, and polymyositis, synovitis, Evans syndrome, leukotri Other autoimmune disorders, fevers, myositis, or neurological diseases, which may be or may include those selected from B4-mediated diseases, idiopathic hypoparathyroidism, nephrotic syndrome, lupus, or immunosuppression.

[0097] The disease, disorder or condition is a cardiovascular disease or disorder, such as congestive heart failure, myocardial infarction, ischemic heart disease, any type of atrial and ventricular arrhythmia, hypertension, traumatic brain injury, vascular occlusion, stroke, cerebrovascular disorder, atherosclerosis, restenosis affecting coronary and peripheral vascular circulation, pericarditis, cardiomyopathy, myocardial sarcoid, endocarditis, inflammatory and autoimmune cardiomyopathies including valvulitis, and aortic arteritis including infectious (e.g., syphilitic), hypertensive vascular disease, peripheral vascular disease, and disorders of the proximal and peripheral veins including atherosclerosis, vasculitis, phlebitis, and thrombosis including deep vein thrombosis, and complications of venous aneurysm, aortic aneurysm, periarteritis nodosa, cardiac fibrosis, idiopathic cardiomyopathy after myocardial infarction, or angiogenesis, which may be or may include those.

[0098] The disease, disorder or condition may be or include an oncological disease or disorder, such as common cancers (prostate, breast, lung, ovary, pancreas, intestinal and colorectal, abdominal, stomach (and any other gastrointestinal cancer), liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testis, ovary, thymus, thyroid), eye, head, neck, nervous system (central and peripheral), lymphatic system, blood, pelvis, skin, bone, soft tissue, spleen, chest, urogenital and brain tumors), breast cancer, urogenital cancer, lung cancer, gastrointestinal cancer, epidermoid cancer, melanoma, ovarian cancer, pancreatic cancer, neuroblastoma, malignant tumors affecting the bone marrow (including leukemia), as well as lymphoproliferative systems such as Hodgkin and non-Hodgkin lymphomas, B-cell lymphoma, follicular lymphoma, metastatic disease and tumor recurrence, as well as tumor-associated syndromes and hypergammaglobulinemia, lymphoproliferative diseases, disorders and / or conditions, paraproteinemia, purpura (including idiopathic thrombocytopenic purpura), Waldenström macroglobulinemia, Gaucher's disease, histiocytosis, retinoblastoma and any other hyperproliferative disease, sarcoma, cachexia, tumor growth, tumor invasion, metastasis, AIDS-related lymphoma, malignant immunoproliferative disease, multiple myeloma and malignant plasmacytoma, lymphocytic leukemia, acute or chronic myelogenous leukemia, acute or chronic lymphocytic leukemia, monocytic leukemia, other leukemias of certain cell types, leukemias of unspecified cell types, other unspecified malignant tumors of the lymphatic, hematopoietic cells and related tissues, such as diffuse large cell type lymphoma, T-cell lymphoma or cutaneous T-cell lymphoma). Myeloid cancer includes, for example, acute or chronic myelogenous leukemia or corneal leukemia.

[0099] The disease, disorder or condition may be or may include other diseases or disorders such as pain, migraine, sleep disorder, fever, sepsis, idiopathic thrombocytopenic purpura, postoperative adhesion, facial flushing, ischemic / reperfusion injury in the heart, brain, and peripheral extremities, bacterial infection, viral infection, fungal infection, thrombosis, endotoxin shock, septic shock, temperature regulation including fever, Raynaud's disease, gangrene, diseases requiring anticoagulant treatment, congestive heart failure, mucus secretion disorder, pulmonary hypotension, dysmenorrhea and prostaglandin-induced smooth muscle contraction associated with preterm labor, premature birth, reperfusion injury, burns, heat injury, bleeding or traumatic shock, menstrual pain, menstrual cramps, dysmenorrhea, periodontal disease, rickettsial infection disease, protozoal disease, reproductive disease, toothache, pain after tooth extraction, herpes zoster, herpes simplex, retroperitoneal fibrosis, or various radiation injuries.

[0100] In certain embodiments, the disease is selected from the group consisting of inflammatory diseases, autoimmune diseases, allergic disorders, and eye disorders. In certain embodiments, the disease is selected from the group consisting of itching, eczema, asthma, rhinitis, dry eye, eye inflammation, allergic conjunctivitis, vernal catarrh, vernal keratoconjunctivitis, giant papillary conjunctivitis, fungal keratitis and uveitis.

[0101] The method may include modulating the activity of one or more kinases in a subject, such as any of the kinases described above. The method may include inhibiting a kinase. The method may include activating a kinase, for example, stimulating or enhancing the activity of a kinase. The method may include modulating a single kinase or preferentially modulating a particular kinase over other kinases. The method may include modulating multiple kinases or preferentially modulating two more particular kinases over other kinases.

[0102] The method may include providing a compound of the present invention. The method may include providing a plurality of compounds of the present invention.

[0103] The method may include contacting a cell containing a kinase with one or more compounds of the present invention. For example, and without limitation, the step of contacting the cell with the compound may include exposing the cell to the compound in a formulation such as any of those described above; delivering the compound into the cell; providing the compound to a subject and exposing the subject's cells to the compound. The contacting step may be carried out in vivo or in vitro. The in vitro contacting may include exposing cells or tissues isolated from a subject. The method may include contacting the cell with a single compound of the present invention. The method may include contacting the cell with a plurality of compounds of the present invention.

[0104] The method may include administering a composition to a subject. The composition may be provided by any suitable route of administration. For example, and without limitation, the composition may be administered buccally, by injection, dermally, enterally, intraarterially, intravenously, intranasally, e.g., by inhalation, intraocularly, orally, parenterally, to the lung, rectally, subcutaneously, systemically, topically, e.g., to the skin or eye, transdermally, or with or on an implantable medical device (e.g., a stent or drug-eluting stent, or something equivalent to a balloon).

[0105] The method may include using a composition of the present invention to diagnose a disease, disorder or condition in a subject. For example, a radiolabeled form of the compound can be used as a tracer in positron emission tomography (PET) to identify the anatomical location of abnormal kinase activity. PET is known in the art, e.g., Wadsak Wolfgang, Mitterhauser Markus (2010), 「Basics and principles of radiopharmaceuticals for PET / CT」, European Journal of Radiology, 73 (3):461-469. doi:10.1016 / j.ejrad.2009.12.022; Bailey, D.L; D.W. Townsend; P.E.Valk; M.N. Maisey (2005), Positron Emission Tomography: Basic Sciences. Secaucus, NJ: Springer-Verlag, ISBN 1-85233-798-2; and Carlson, Neil (January 22, 2012). Physiology of Behavior. Methods and Strategies of Research, 11th edition, Pearson, p. 151, ISBN 0205239390, the contents of each of which are incorporated herein by reference. The present invention may include administering one or more compositions of the present invention for both diagnostic and therapeutic purposes. The content is incorporated herein by reference. The present invention may include administering one or more compositions of the present invention for both diagnostic and therapeutic purposes.

Examples

[0106] (Example 1) The following methods were used for the synthesis of the compounds described herein.

[0107] Flash chromatography: Use a SNAP silica cartridge and an ethyl acetate / cyclohexane / methanol or dichloromethane / methanol gradient as the eluent, and perform flash chromatography on a Biotage Isolera® system.

[0108] Microwave conditions: Reactions under microwave conditions are carried out on a Biotage initiator® microwave system.

[0109] SEMIprep Reversed-Phase Chromatography: The following instruments were used for SEMIprep reversed-phase chromatography: 2 x Varian PrepStar SD-1, 1 x Dionex P580 Pump 1 Channel (MakeUP I), 1 x Dionex AXP-MS (MakeUP II), 1 x Dionex MSQ, 1 x Dionex UVD 340V-Prep Flow Cell, and Gilson 215 Liquid Handler. A SunFire Prep C18 OBD 5μm, 19×50mm column was used.

[0110] In a typical experiment, the column flow rate was 30 mL / min, solvent A was methanol containing 0.3% acetic acid, and solvent B was water containing 0.3% acetic acid. The typical times, as well as the relative volumes of solvents A and B, were as follows: [Table 4] A mass spectrometry detector (API-ES, positive) at UV254nm was used for detection. (Example 2)

[0111] The terms and abbreviations used in the examples are shown in Table 1. [Table 1] (Example 3)

[0112] The synthetic methods of the specific molecules used as reagents in the synthetic schemes described herein are known in the art and are described in the references shown in Table 2. [Table 2] (Example 4) [Chemical Formula]

[0113] 1.1 equivalents of intermediate 3,5-dibromo-4-nitropyrazole was suspended in dichloromethane, and THF was added until it was completely dissolved. Next, 1.3 equivalents of dihydropyran and a catalytic amount of p-toluenesulfonic acid monohydrate were added. The mixture was stirred overnight, diluted with DCM, and washed with saturated NaHCO 3 aqueous solution and water. The combined organic matter was dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure to obtain the desired product as a white solid. The product was used without further purification. See J.P. H. Juffermans and Clarisse L. Habraken, The Journal of OrganicChemistry1986, 51, 24, 4656-4660, Nov. 1, 1986. (Example 5) [Chemical formula]

[0114] Intermediate 2, 3-chloro-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole. 5-chloro-4-nitro-1H-pyrazole was dissolved in DCM and cooled to 0 °C. 1.2 equivalents of 3,4-dihydro-2H-pyran and 0.1 equivalent of p-toluenesulfonic acid were slowly added. The mixture was stirred at room temperature overnight. The mixture was extracted with saturated NaHCO 3 aqueous solution and water. The aqueous layer was extracted with DCM, and the organic layer was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography. (Example 6) [Chemical formula]

[0115] Intermediate 3, 3-bromo-5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-amine. Dissolve 3-bromo-5-iodopyridin-2-amine in dioxane and water. Add 1 equivalent of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 3 equivalents of Na 2 CO 3 to it. After degassing the mixture with N 2 , add 0.05 equivalent of Pd(PPh 3 ) 4 . Degas the mixture again and stir it at 80 °C overnight. Further add 0.02 equivalent of Pd(PPh 3 ) 4 and stir the mixture at 80 °C for 4 hours. Cool the mixture to room temperature and filter it through celite. Wash the solid with MeOH and water. Concentrate the filtrate under reduced pressure, dilute it with water and extract it with DCM. Dry the organic layer with Na 2 SO 4 , filter and evaporate it. Purify the crude material by flash chromatography. (Example 7) [Chemical formula]

[0116] Intermediate 4, 2-bromo-4-(3,6-dihydro-2H-pyran-4-yl)aniline. Using 2-bromo-4-iodoaniline as the starting material, it was synthesized as described for Intermediate 3. (Example 8) [Chemical formula]

[0117] Intermediate 5, tert-butyl 6-amino-5-bromo-5’,6’-dihydro-[3,4’-dipyridine]-1’(2’H)-carboxylate. Using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate as the starting material, it was synthesized as described for Intermediate 3. (Example 9) [Chemistry]

[0118] Intermediate 6, 6 - Amino - pyridine - 2 - carboxylic acid (tetrahydro - pyran - 4 - yl) - amide. 1 equivalent of 6 - amino - pyridine - 2 - carboxylic acid and tetrahydro - pyran - 4 - ylamine were dissolved in dry DMF. 1.05 equivalents of PYBOP and 2.1 equivalents of DIPEA were added. The mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate and washed with saturated NaHCO 3 aqueous solution and water. The combined organic matter was dried over Na 2 SO 4 and filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography. (Example 10) [Chemistry]

[0119] Intermediate 7. 6 - Amino - pyridine - 2 - carboxylic acid (tetrahydro - pyran - 4 - yl) - amide was dissolved in 3 / 1 chloroform / DCM. The mixture was cooled to 0 °C. 1.3 equivalents of bromine were added dropwise and the mixture was stirred at room temperature for 3 days. The mixture was quenched with a 5% w / v aqueous solution of Na 2 S 2 O 3 and basified with aqueous NaOH solution and extracted with DCM. The combined organic matter was dried over Na 2 SO 4 and filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography. (Example 11) [Chemistry]

[0120] Intermediate 8, 2-(3-amino-4-bromophenyl)propan-2-ol. Ethyl 3-amino-4-bromobenzoate was dissolved in dry THF and cooled to 0 °C. 6 equivalents of 1.4 M methylmagnesium bromide in THF / toluene (1 / 3) was added, and the mixture was stirred at 0 °C for 30 minutes. NH 4 The reaction mixture was quenched by adding a saturated aqueous solution of NH 2 SO 4 Cl and extracted with ethyl acetate. The organic layer was dried over Na (Example 12) [Chemical formula]

[0121] Intermediate 9, 4-(3-bromo-4-nitrophenoxy)tetrahydro-2H-pyran. Tetrahydro-2H-pyran-4-ol was dissolved in dry DMF and cooled to 0 °C. 1.8 equivalents of a 60% NaH dispersion in oil was added, and then 2-bromo-4-fluoro-1-nitrobenzene was added dropwise. The mixture was heated to reflux for 45 minutes, cooled to room temperature, and quenched by adding water. The precipitate was collected by filtration. The filtrate was extracted with ethyl acetate, and the organic layer was washed with brine and dried over Na 2 SO 4 and filtered and concentrated under reduced pressure. The combined crude products were purified by flash chromatography. (Example 13)

[0122] General procedure for iron reduction: The aryl nitro compound is dissolved in ethanol / water 4 / 1, 10 equivalents of iron and 10 equivalents of NH 4 Cl, and a few drops of 2 M HCl are added. The mixture is heated at 50 °C for 1 hour. The mixture is filtered through celite, and the solid is washed with MeOH and water. The filtrate is concentrated and basified with 15% w / v NaOH. The aqueous layer is extracted with ethyl acetate, and the combined organic layers are dried over Na 2 SO 4 and filtered and concentrated under reduced pressure. The product is used without further purification. (Example 14)

Chem.

[0123] Intermediate 10, 4-(3-bromo-4-aminophenoxy)tetrahydro-2H-pyran (a representative example of an iron reduction reaction). 4-(3-bromo-4-nitrophenoxy)tetrahydro-2H-pyran was dissolved in 4 / 1 ethanol / water, and 10 equivalents of iron and 10 equivalents of NH 4 Cl, and a few drops of 2M HCl were added. The mixture was heated at 50 °C for 1 hour. The mixture was filtered through celite, and the solid was washed with MeOH and water. The filtrate was concentrated and basified with 15% w / v NaOH. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The product was used without further purification. (Example 15)

Chem.

[0124] Intermediate 11, 3-bromo-N-(2-fluoroethyl)-4-nitroaniline. 2-bromo-4-fluoro-1-nitrobenzene and 1.5 equivalents of 2-fluoroethan-1-amine hydrochloride were dissolved in dry DMF, and then 2 equivalents of K 2 CO 3 was added. The mixture was stirred at 120 °C for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography. (Example 16)

Chem.

[0125] Intermediate 12, 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-amine. Using 4-bromo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole as a starting material, the title compound was synthesized according to the general protocol of iron reduction. (Example 17)

Chemical formula

[0126] Intermediate 13, 3-bromo-N1-(2-fluoroethyl)benzene-1,4-diamine. Using 3-bromo-N-(2-fluoroethyl)-4-nitroaniline as a starting material, the title compound was synthesized according to the general protocol of iron reduction. (Example 18)

Chemical formula

[0127] Intermediate 14, 4-bromo-1-(difluoromethyl)-3-nitro-1H-pyrazole and 4-bromo-1-(difluoromethyl)-5-nitro-1H-pyrazole. 4-Bromo-3-nitro-1H-pyrazole was dissolved in DMF and water (4 / 1 v / v). 6 equivalents of K 2 CO 3 and 1.2 equivalents of 2-chloro-2,2-difluoroacetic acid were added. . The mixture was stirred at 120 °C overnight. An additional 1.2 equivalents of 2-chloro-2,2-difluoroacetic acid was added and the mixture was stirred at 120 °C for 3 days. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with 1 M aqueous NaOH, water and brine, dried over Na 2 SO 4 and filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography. The isomers were used as a mixture in the next step. (Example 19)

Chemical formula

[0128] Intermediates 15, 4-bromo-1-(difluoromethyl)-1H-pyrazol-3-amine and 4-bromo-1-(difluoromethyl)-1H-pyrazol-5-amine. A mixture of 4-bromo-1-(difluoromethyl)-3-nitro-1H-pyrazole and 4-bromo-1-(difluoromethyl)-5-nitro-1H-pyrazole was used as the starting material, and the title compound was synthesized according to the general protocol for iron reduction. The material was used as a mixture of isomers. (Example 20)

Chemical formula

[0129] Intermediate 16, 4-(4-bromo-3-nitrophenoxy)tetrahydro-2H-pyran. 1 equivalent of tetrahydro-2H-pyran-4-ol, 4-bromo-3-nitrophenol and 2.6 equivalents of PPh 3 were dissolved in dry THF. The mixture was cooled to 0 °C, and 2.3 equivalents of DBAD dissolved in dry THF was slowly added. The mixture was warmed to room temperature and stirred overnight. An additional 0.3 equivalent of tetrahydro-2H-pyran-4-ol, 0.3 equivalent of PPh 3 , and DBAD were added, and the mixture was stirred at room temperature for 4 hours. TFA (20% v / v) was added, and the mixture was partitioned between water and ethyl acetate. The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography. (Example 21)

Chemical formula

[0130] Intermediate 17, 2-Bromo-5-((tetrahydro-2H-pyran-4-yl)oxy)aniline. Using 4-(4-Bromo-3-nitrophenoxy)tetrahydro-2H-pyran as a starting material, the title compound was synthesized according to the general protocol for iron reduction. (Example 22)

[0131] General protocol for reduction using H2 / Pd / C: Dissolve the aromatic nitro compound in ethanol. Add 0.05 equivalent of 10% w / w / Pd carbon, and stir the mixture overnight under a hydrogen atmosphere. Filter the mixture through celite, and concentrate the filtrate under reduced pressure. Use the product without further purification. (Example 23)

Chemical formula

[0132] Intermediate 18, 3-(Dimethoxymethyl)-2,4-difluoroaniline (representative example of H2 / Pd / C reduction reaction). Dissolve 2-(Dimethoxymethyl)-1,3-difluoro-4-nitrobenzene in ethanol, add 0.05 equivalent of Pd / C (10% w / w), and stir the mixture at room temperature overnight. Filter the mixture through celite, and concentrate the filtrate under reduced pressure. Use the mixture without further purification. (Example 24)

Chemical formula

[0133] Intermediate 19, 3-(Dimethoxymethyl)-2,4-difluoro-N-(2-fluoroethyl)aniline. 3-(Dimethoxymethyl)-2,4-difluoroaniline, 1.2 equivalents of 1-bromo-2-fluoroethane, 2 equivalents of Cs 2 CO 3, and 1.5 equivalents of DIPEA were dissolved in dry DMF. The mixture was heated at 140 °C for 30 minutes under microwave conditions, then at 160 °C for 30 minutes, then 1 equivalent of 1-bromo-2-fluoroethane was added, and the mixture was heated again at 160 °C for 30 minutes. The mixture was diluted with ethyl acetate, washed with water and brine, and dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography. (Example 25) [Chemical formula]

[0134] Intermediate 20, 2,6-difluoro-3-((2-fluoroethyl)amino)benzaldehyde. 3-(Dimethoxymethyl)-2,4-difluoro-N-(2-fluoroethyl)aniline was dissolved in THF, 10% v / v of 6M HCl was added, and the mixture was stirred overnight. The mixture was basified with 6M aqueous NaOH and extracted with ethyl acetate. The organic layer was washed with brine and dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography. (Example 26) [Chemical formula]

[0135] Intermediate 21, 3-bromo-4-nitro-N-(2,4,4-trimethylpentan-2-yl)aniline. 1.5 equivalents of 2-bromo-4-fluoro-1-nitrobenzene, 2,4,4-trimethylpentan-2-amine, and 2 equivalents of K 2 CO 3 were dissolved in DMF. The mixture was heated at 120 °C overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by flash chromatography. (Example 27)

Chem.

[0136] Intermediate 22, 3-bromo-N1-(2,4,4-trimethylpentan-2-yl)benzene-1,4-diamine. Using 3-bromo-4-nitro-N-(2,4,4-trimethylpentan-2-yl)aniline as the starting material, the title compound was synthesized according to the general protocol of iron reduction. (Example 28)

Chem.

[0137] Intermediate 23, 4-bromo-6-chloropyridin-3-amine. Using 4-bromo-2-chloro-5-nitropyridine as the starting material, the title compound was synthesized according to the general protocol of iron reduction. (Example 29)

Chem.

[0138] Intermediate 24, 2-bromo-4-ethyl-6-fluoroaniline 1-bromo-5-ethyl-3-fluoro-2-nitrobenzene. Using 1-bromo-5-ethyl-3-fluoro-2-nitrobenzene as the starting material, the title compound was synthesized according to the general protocol of iron reduction. trobenzene as the starting material, the title compound was synthesized according to the general protocol of iron reduction. (Example 30)

Chem.

[0139] Intermediate 25, 3-bromo-4-nitrophenyldimethylcarbamate. 3-Bromo-4-nitrophenol was dissolved in dry acetonitrile. 1.5 equivalents of solid K 2 CO 3And 1.2 equivalents of dimethylcarbamyl chloride were added. The mixture was stirred overnight at room temperature and then stirred at 100 °C for 2 hours. The mixture was diluted with DCM, washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography. (Example 31) [Chemical formula]

[0140] Intermediate 26, 4-amino-3-bromophenyl dimethylcarbamate. Using 3-bromo-4-nitrophenyl dimethylcarbamate as the starting material, the title compound was synthesized according to the general protocol for iron reduction. (Example 32) [Chemical formula]

[0141] Intermediate 27, 2,6-difluoro-4-(2-fluoroethoxy)benzaldehyde. 2,6-difluoro-4-hydroxybenzaldehyde, 1.1 equivalents of 1-bromo-2-fluoroethane and 1.5 equivalents of K 2 CO 3 were dissolved in dry DMF. The reaction was heated at 140 °C for 5 minutes under microwave conditions. After adding an additional 0.5 equivalent of 1-bromo-2-fluoroethane, the heating was repeated. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 2M HCl and water, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography. (Example 33) [Chemical formula]

[0142] Intermediate 28, 4-bromo-2-chloro-6-trifluoromethyl-pyridin-3-ylamine. 2-Chloro-6-trifluoromethyl-pyridin-3-ylamine was dissolved in MeCN, and 1 equivalent of NBS was added. The mixture was heated to 80 °C for 2 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and triturated with diethyl ether. The crude reaction mixture was purified by gradient flash chromatography. (Example 34) [Chemical formula]

[0143] Intermediate 29, 4-(3-bromo-4-nitro-phenyl)-morpholine. 2-Bromo-4-fluoro-1-nitro-benzene was dissolved in DMF, and 1.3 equivalents of morpholine and 2 equivalents of K 2 CO 3 were added. The mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted with ethyl acetate and DCM. The combined organics were dried and filtered, and concentrated under reduced pressure. The crude product was used without further purification. (Example 35) [Chemical formula]

[0144] Intermediate 30, 4-(3-bromo-4-nitro-phenyl)-morpholine. Using 4-(3-bromo-4-nitro-phenyl)-morpholine as the starting material, the title compound was synthesized according to the general protocol for iron reduction. (Example 36) [Chemical formula]

[0145] Intermediate 31, N-(3'-amino-4'-chloro-[1,1'-biphenyl]-3-yl)acetamide. 2-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 1 equivalent of N-(3-bromophenyl)acetamide were dissolved in dioxane, and 0.1 equivalent of Pd dppf and 4 equivalents of 2M Na 2 CO 3 in water were added. The mixture was heated at 135 °C for 10 minutes under microwave conditions. The mixture was filtered through celite, washed with MeOH and water, and concentrated under reduced pressure. The mixture was redissolved in DCM, washed with water, dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The crude material was purified by gradient flash chromatography. (Example 37) [Chemical formula]

[0146] Intermediate 32, 2-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)aniline. 1-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 1 equivalent of 5-bromo-2-chloroaniline were dissolved in dioxane, and 0.1 equivalent of Pd dppf and 4 equivalents of 2M Na 2 CO 3 in water were added. The mixture was heated at 135 °C for 10 minutes under microwave conditions. The mixture was filtered through celite, washed with MeOH and water, and concentrated under reduced pressure. The mixture was redissolved in DCM, washed with water, dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The crude material was purified by gradient flash chromatography. (Example 38) [Chemical formula]

[0147] Intermediate 33, 4-(4-bromo-3-nitrophenoxy)tetrahydro-2H-pyran. Tetrahydro-2H-pyran-4-ylmethanesulfonate and 1 equivalent of 4-bromo-3-nitrophenol were dissolved in dry DMF. 1.5 equivalents of K 2 CO 3 was added. The mixture was heated at 150 °C for 30 minutes while being stimulated with microwave. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 2M HCl, saturated NaHCO 3 aqueous solution and brine. The combined organic phases were dried over Na 2 SO 4 and filtered and concentrated under reduced pressure. The crude mixture was purified by gradient flash chromatography. (Example 39)

Chemical Structure

[0148] Intermediate 34, 2-bromo-5-((tetrahydro-2H-pyran-4-yl)oxy)aniline. Using 4-(4-bromo-3-nitrophenoxy)tetrahydro-2H-pyran as the starting material, the title compound was synthesized according to the general protocol for iron reduction. (Example 40)

Chemical Structure

Chemical Structure

[0149] General route to the class of 1H-[1,2]diazepine compounds. (Example 41) Route A: Formation of aryl-aryl bond.

Chem.

[0150] 2-[4-Nitro-2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-phenylamine (Representative example of Suzuki coupling from acid from commercially available boron ester or commercially available boron pinacol ester in Route A). 1 equivalent of 5-chloro-4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole was dissolved in dioxane, then 1.2 equivalents of 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine, 0.1 equivalent of Pd dppf and 3 equivalents of 2M Na 2 CO 3 was dissolved. The mixture was degassed with N 2 and heated at 80 °C overnight. The mixture was filtered through Celite and washed with MeOH. The filtrate was extracted with DCM (3 times). The combined organic phases were dried over Na 2 SO 4 and filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography. (Example 42) Route B: Formation of aryl-aryl bond.

Chem.

[0151] 2-Methoxy-6-[4-nitro-2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-phenylamine (Representative example of sequential borylation / Suzuki coupling using 4,4,5,5,4’,4’,5’,5’-octamethyl-[2,2’]bi[[1,3,2]dioxaborolanyl]. The two steps were carried out in a "2-step-1-pot" reaction). 1 equivalent of 2-bromo-6-methoxy-phenylamine and 4 equivalents of potassium acetate were dissolved in dry dioxane, and the mixture was N2 After degassing with, 0.1 equivalent of Pd dppf, N 2 After further degassing with, 2 equivalents of diborolane were added. The mixture was heated at 80 °C overnight. 0.8 equivalent of 5-chloro-4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole and 3 equivalents of 2M Na 2 CO 3 were added to this mixture. The mixture was flashed again with N 2 , and then 0.05 equivalent of Pd dppf was added. The mixture was stirred at 80 °C overnight. The reaction mixture was filtered through celite and the solid was washed with MeOH. The filtrate was concentrated under reduced pressure, diluted with water and extracted 3 times with ethyl acetate. The combined organics were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography. (Example 43) Route C: Formation of aryl-aryl bond. [Chemical formula]

[0152] 3-Methoxy-2-[4-nitro-2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-phenylamine (representative example of Stille coupling using 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane in Route C). 1 equivalent of 2-bromo-3-methoxy-phenylamine and 3 equivalents of triethylamine were dissolved in dry dioxane. The mixture was flashed with N 2 , and after further degassing with, 3 equivalents of pinacol borane were added. The mixture was heated at 140 °C for 2 hours under microwave conditions. 0.8 equivalent of 5-chloro-4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole and 3 equivalents of 2M Na 2 CO 2 solution were added to this mixture. The mixture was flashed with N 3 , and then 2After flash again, 0.1 equivalent of Pd dppf was further added. The mixture was stirred at 80 °C overnight. The reaction mixture was filtered through celite and the solid was washed with MeOH. The filtrate was concentrated under reduced pressure, diluted with water and extracted three times with DCM. The combined organic matters were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography. (Example 44) Route D: Formation of aryl-aryl bond.

Chemical formula

[0153] 6-Methoxy-2-[2-(4-methoxy-benzyl)-4-nitro-2H-pyrazol-3-yl]-pyridin-3-ylamine (representative example of direct arylation in Route D). 4-Nitro-1-(4-methoxy-benzyl)-1H-pyrazole, 1 equivalent of 2-bromo-6-methoxy-pyridin-3-ylamine, 0 .3 equivalent of pivalic acid, and 3 equivalents of K 2 CO 3 were dissolved in dry DMF. The mixture was degassed with N 2 , then 0.15 equivalent of catacxiumA and Pd(OAc) 2 were added. The mixture was degassed and stirred at 115 °C overnight. The mixture was filtered through celite and the solid was washed with methanol. After concentration under reduced pressure, the mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine and dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography. (Example 45) Route E. Hydrogenation.

Chemical formula

[0154] 5-(2-Amino-5-methyl-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-ylamine (Route E: Representative example of hydrogenation). 4-Methyl-2-[4-nitro-2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-phenylamine was dissolved in methanol, and 0.07 equivalent of Pd / C, 10% w / w was added. The mixture was stirred for 5 hours at room temperature under a hydrogen atmosphere (balloon). The mixture was filtered through celite, and the solid was washed with MeOH. The filtrate was concentrated under reduced pressure to obtain the title product. This was used without further purification. (Example 46) Route F: Basic hydrogenation.

[0155] 4-(4-Amino-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-6-(trifluoromethyl)pyridin-3-amine (Route F: Representative example of basic hydrogenation). 2-Chloro-4-(1-(4-methoxybenzyl)-4-nitro-1H-pyrazol-5-yl)-6-(trifluoromethyl)pyridin-3-amine was dissolved in 32 mL of dry iPrOH. The system was evacuated and refilled with N 2 three times. Next, 1.2 equivalents of triethylamine and 1 equivalent of Pd carbon (10% w) were quickly added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere (balloon). The mixture was filtered through celite and washed thoroughly with MeOH. Next, the filtrate was concentrated under reduced pressure. The material was used without further purification. (Example 47) Route G: Reduction with iron.

[0156] 5-(2-Amino-6-methoxy-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-ylamine (Method G: Representative example of reduction with iron). 3-Methoxy-2-[4-nitro-2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-phenylamine was dissolved in 10 / 4 v / v ethanol / water, and 10 equivalents of iron and NH 4Cl and a few drops of 2M HCl were added. The mixture was heated at 50 °C for 1 hour. The mixture was filtered through celite and the solid was washed with MeOH and water. The mixture was concentrated, basified to pH 10 with 15% w / v aqueous NaOH, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2 SO 4 and filtered and concentrated under reduced pressure. The crude product was used without further purification. (Example 48) The cyclization / deprotection procedure using the aryl-aryldiamine and corresponding aldehyde described. [Chemical formula] (Example 49) [Chemical formula]

[0157] 5-(2,6-Difluorophenyl)-8-methoxy-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine from 5-(2,6-difluorophenyl)-8-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine. 5-(2-Amino-4-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-amine and 1 equivalent of 2,6-difluoro-benzaldehyde were dissolved in tert.-butanol. 3 equivalents of iodine and 3 equivalents of K 2 CO 3 were added. The mixture was stirred at room temperature overnight. 5% w / v aqueous Na 2 S 2 O 3 solution was added. After stirring for 30 minutes, the solution was diluted with water and extracted with DCM. The organic layer was evaporated. The product was used in the next step without further purification. The product of the above step was dissolved in TFA. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and purified by SEMIprep reverse phase chromatography. (Example 50)

[0158] The following HPLC methods were used: Method: HPLC-MS A Column: "Waters ACQUITY UPLC HSS T3 50×2.1 1.8μm PN:186003538" Gradient: "2% - 4.0 min → 95% - 1.0 min → 95% - 0.1 min → 2% - 2.9 min → 2%; ACN / H2O + 0.1% HCOOH" Flow rate: "0.6 mL / min" ms: "ESI positive & negative" Method: HPLC-MS B Column: "Waters ACQUITY UPLC CSH C18 50×2.1 1.7μm PN:186005296" Gradient: "5% - 4.0 min → 95% - 1.0 min → 95% - 0.1 min → 5% - 2.9 min → 5%; ACN / H2O + 0.1% HCOOH" Flow rate: "0.6 mL / min" ms: "ESI positive and negative" Method: HPLC-MS C Column: "Waters ACQUITY UPLC CSH C18 50×2.1 1.7μm PN:186005296" Gradient: "4% - 4.0 min → 96% - 1.0 min → 96% - 0.1 min → 4% - 2.9 min → 4%; ACN / H2O + 1mM NH 4 Ac - buffer pH9.2" Method: HPLC-MS D Column: "Waters CORTECS UPLC C18+50×2.1 1.6μm PN:186007114" Gradient: "5% - 4.0 min → 95% - 1.0 min → 95% - 0.1 min → 5% - 2.9 min → 5%; ACN / H2O + 0.1% HCOOH" Flow rate: "0.6 mL / min" ms: "ESI positive & negative" Method: HPLC-MS E Column: "Waters ACQUITY UPLC CSH C18 50×2.1 1.7μm PN:186005296" Gradient: "5% - 0.75 min → 95% - 0.5 min → 95% - 0.05 min → 5% - 1.2 min → 5%; ACN / H2O + 0.1% HCOOH" Flow rate: "1.2 mL / min" ms: "ESI positive"

[0159] The products listed in Table 3 were synthesized by a cyclization / deprotection method.

Table 3 - 1

Table 3 - 2

Table 3 - 3

Table 3 - 4

Table 3 - 5

Table 3 - 6

Table 3 - 7

Table 3 - 8

Table 3 - 9

Table 3 - 10

Table 3 - 11

Table 3 - 12

Table 3 - 13

Table 3-14

Table 3-15

Table 3-16

Table 3-17

Table 3-18

Table 3-19

Table 3-20

Table 3-21

Table 3-22

Table 3-23

Table 3-24

Table 3-25

Table 3-26

Table 3-27

Table 3-28

Table 3-29

Table 3-30

Table 3-31

Table 3-32

Table 3-33

Table 3-34

Table 3-35

Table 3-36

Table 3-37

Table 3-38

Table 3-39

Table 3-40

Table 3-41

Table 3-42

Table 3-43

Table 3-44

Table 3-45

Table 3-46

Table 3-47

Table 3-48

Table 3-49

Table 3-50

Table 3-51

Table 3-52

Table 3-53

Table 3-54

Table 3-55

Table 3-56

Table 3-57

Table 3-58

Table 3-59

Table 3-60

Table 3-61

Table 3-62

Table 3-63

Table 3-64

Table 3-65

Table 3-66

Table 3-67

Table 3-68

Chem.

[0160] Intermediate 35, 5-(2,6-difluorophenyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine. 3-Bromo-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine purified by flash chromatography was dissolved in dioxane. 1 equivalent of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane, 2 equivalents of Cs 2 CO 3 , and 0.2 equivalent of Pd(PPh 3 ) 4 were added. The mixture was degassed and heated at 140 °C for 20 minutes under microwave conditions. The mixture was filtered and the solid was washed with MeOH. After concentration under reduced pressure, the mixture was used without further purification. The additional step, deprotection, followed the corresponding procedure described above. (Example 53)

Chem.

[0161] Compound 81, 5-(2,6-difluorophenyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-8-carboxamide. The crude 5-(2,6-difluorophenyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-8-carboxylic acid after deprotection was dissolved in dry DMF. 1.5 equivalents of EDCI, 1.8 equivalents of HOBT, 2 equivalents of NH 4 Cl and 6 equivalents of triethylamine were added, and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined organic matter was washed with brine, dried over Na 2 SO 4 and filtered and concentrated under reduced pressure. The crude product was purified by SEMIprep chromatography. (Example 54)

Chemical Structure

[0162] Compound 93, 5-(2,6-difluorophenyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxamide. 5-(2,6-difluorophenyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxamide was synthesized according to this procedure using 5-(2,6-difluorophenyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxylic acid as the starting material. (Example 55)

Chemical Structure

[0163] Compound 95, 5-(2,6-difluorophenyl)-N-(tetrahydro-2H-pyran-4-yl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-8-carboxamide. 5-(2,6-Difluorophenyl)-N-(tetrahydro-2H-pyran-4-yl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-8-carboxamide was synthesized according to this procedure using tetrahydro-2H-pyran-4-amine and 5-(2,6-difluorophenyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-8-carboxylic acid as starting materials. (Example 56)

Chemical Structure

[0164] Compound 97, 5-(2-chloro-6-fluorophenyl)-N-(2-fluoroethyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxamide. 5-(2-Chloro-6-fluorophenyl)-N-(2-fluoroethyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxamide was synthesized according to this procedure using 2-fluoroethane-1-amine hydrochloride and 5-(2-chloro-6-fluorophenyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxylic acid as starting materials. (Example 57)

Chemical Structure

[0165] Compound 110, (5-(2,6-difluorophenyl)-1,4-dihydrobenzo[d (Pyrazolo[3,4-f][1,3]diazepin-9-yl)(3-fluoroazetidin-1-yl)methanone. (5-(2,6-Difluorophenyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepin-9-yl)(3-fluoroazetidin-1-yl)methanone was synthesized according to this procedure using 3-fluoroazetidine hydrochloride and 5-(2,6-difluorophenyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxylic acid as starting materials. (Example 58) [Chemical formula] Compound 112

[0166] Step 1: 5-(2,6-Difluorophenyl)-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine-9-carboxylic acid. Methyl 5-(2,6-difluorophenyl)-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine-9-carboxylate was dissolved in a saturated aqueous solution of THF. LiOH was added and the mixture was stirred at 60 °C for 3 hours. The mixture was acidified and extracted with ethyl acetate. The combined organics were dried over Na 2 SO 4 and filtered and concentrated under reduced pressure. The product was used without further purification.

[0167] Step 2: 5-(2,6-Difluorophenyl)-N-(2-fluoroethyl)-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine-9-carboxamide. 5-(2,6-Difluorophenyl)-N-(2-fluoroethyl)-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine-9-carboxamide was synthesized according to this procedure using 5-(2,6-difluorophenyl)-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine-9-carboxylic acid and 2-fluoroethan-1-amine as starting materials. (Example 59) [Chemical formula]

[0168] Compound 113, 5-(2,6-difluorophenyl)-N-(2-fluoroethyl)- N-methyl-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxamide. 5-(2,6-Difluorophenyl)-N-(2-fluoroethyl)-N-methyl-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxamide was synthesized according to this procedure using (2-fluoroethyl)-methyl-amine hydrochloride of 5-(2,6-difluorophenyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxylic acid as the starting material. (Example 60) [Chemical formula] Compound 128

[0169] Step 1: 5-(2,6-Difluorophenyl)-1-(4-methoxybenzyl)-9-(1,2,3,6-tetrahydropyridin-4-yl)-1,6-dihydropyrazolo[4,3-d]pyrido[3,2-f][1,3]diazepine. tert-Butyl 4-(5-(2,6-difluorophenyl)-1-(4-methoxybenzyl)-1,6-dihydropyrazolo[4,3-d]pyrido[3,2-f][1,3]diazepine-9-yl)-5,6-dihydropyridine-1(2H)-carboxylate was dissolved in 4M HCl in dioxane. The mixture was stirred at room temperature overnight. The solid was collected by filtration and used without further purification. [Chemical formula]

[0170] Step 2: 5-(2,6-Difluorophenyl)-9-(1-(2-fluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-(4-methoxybenzyl)-1,6-dihydropyrazolo[4,3-d]pyrido[3,2-f][1,3]diazepine. 1-Bromo-2-fluoroethane and hydrogen chloride, and hydrogen chloride and 5-(2,6-difluorophenyl)-1-(4-methoxybenzyl)-9-(1,2,3,6-tetrahydropyridin-4-yl)-1,6-dihydropyrazolo[4,3-d]pyrido[3,2-f][1,3]diazepine were dissolved in dry DMF, and 2 equivalents of 1-bromo-2-fluoroethane and 4 equivalents of DIPEA were added. The mixture was stirred at 12 0 °C for 15 minutes under microwave conditions. After adding 2 equivalents of 1-bromo-2-fluoroethane, heating was repeated. The mixture was diluted with water and extracted with ethyl acetate. The combined organic materials were dried over Na 2 SO 4 and filtered and concentrated under reduced pressure. The crude product was used without further purification for the deprotection described above. (Example 61) [Chemical formula]

[0171] Compound 132, 2-(4-(5-(2,6-Difluorophenyl)-1,6-dihydropyrazolo[4,3-d]pyrido[3,2-f][1,3]diazepin-9-yl)-5,6-dihydropyridin-1(2H)-yl)ethan-1-ol. 5-(2,6-Difluorophenyl)-9-(1,2,3,6-tetrahydropyridin-4-yl)-1,6-dihydropyrazolo[4,3-d]pyrido[3,2-f][1,3]diazepine was dissolved in dry DMF. 4 equivalents of DIPEA and 1 equivalent of 2-bromoethan-1-ol were added. The mixture was stirred at room temperature overnight. An additional 3 equivalents of DIPEA and 2 equivalents of 2-bromoethan-1-ol were added, and the mixture was stirred at room temperature again overnight. The mixture was concentrated under reduced pressure and purified by flash chromatography. (Example 62) [Chemistry]

[0172] Intermediate 36, tert-butyl 2-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyrazolo[4,3-d]pyrido[3,2-f][1,3]diazepin-9-yl)-1H-pyrrole-1-carboxylate. 9-Chloro-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyrazolo[4,3-d]pyrido[3,2-f][1,3]diazepine was dissolved in dioxane. 1.5 equivalents of (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid and 12 equivalents of 2M Na 2 CO 3 solution was added. The mixture was degassed with N 2 and then 0.2 equivalent of Pd dppf was added. The mixture was heated at 140 °C for 30 minutes under microwave conditions. Additionally, 1.5 equivalents of (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid and 0.2 equivalent of Pd dppf 0.2 equivalent were added, and the mixture was heated at 140 °C for 3 0 minutes again under microwave conditions. This addition and heating were repeated twice. The mixture was filtered through celite and concentrated under reduced pressure. The next step, deprotection, was carried out under the above conditions. (Example 63) [Chemistry]

[0173] Compound 90, N-(5-(2,6-difluorophenyl)-1,6-dihydropyrazolo[4,3-d]pyrido[3,2-f][1,3]diazepin-9-yl)acetamide and N-(1-acetyl-5-(2,6-difluorophenyl)-1,6-dihydropyrazolo[4,3-d]pyrido[3,2-f][1,3]diazepin-9-yl)acetamide. 5-(2,6-Difluorophenyl)-1,6-dihydropyrazolo[4,3-d]pyrido[3,2-f][1,3]diazepin-9-amine was dissolved in DCM, and 4 equivalents of acetyl chloride and 2 equivalents of triethylamine were added. The mixture was stirred overnight at room temperature. The mixture was diluted with methanol and saturated NaHCO 3 aqueous solution, basified with solid NaOH, and stirred at 40 °C for 12 hours. The mixture was neutralized with 2M HCl, concentrated under reduced pressure, and purified by SEMIprep chromatography. (Example 64)

[0174] The compounds in Table 3 were tested for their inhibitory effects on a series of kinases according to the following procedure. Biochemical assay:

[0175] The basic protocol of the TR-FRET LanthaScreen Eu Kinase Binding Assay inhibitor test was carried out as follows. The LanthaScreen Kinase Binding Assay (ThermoFisher / USA) for evaluating inhibitors was performed by adding 5 μl of the test compound, 5 μl of the tracer to a 384-well low-volume plate in the corresponding DMSO dilution / 5 μl of kinase / antibody mixture. After incubation at room temperature for 1 hour, the plate was read. The data analysis of the luminescence ratio was according to the LanthaScreen Eu Kinase Binding Assay protocol.

[0176] The kinases and assay components were adjusted to the final concentrations according to the kit protocol. For LRRK2: 5 nM wt human LRRK2, catalytic domain, or G2019S human LRRK2, catalytic domain (ThermoFisher / USA), 2 nM Eu-Anti-GST Antibody, 10 nM Kinase Tracer 236 in 1X Kinase Buffer A. For NUAK1: 8 nM wt human NUAK1, full length (ThermoFisher / USA), 2 nM Eu-Anti-His Antibody, 5 nM Kinase Tracer 236 in 1X Kinase Buffer A. The basic protocol for the inhibitor test of the HTRF KinEASE assay (Cisbio / France) included two steps:

[0177] Enzyme step: Add 4 μl of the test compound in the corresponding DMSO dilution, 4 μl of the kinase / substrate mixture, and 2 μl of ATP to a 384-well low-volume plate. Incubate at room temperature for at least 30 minutes.

[0178] Detection step: Add 5 μl of the antibody and 5 μl of streptavidin-XL665, and read the plate after 60 minutes. Data analysis of the luminescence ratio follows the protocol of the KinEASE assay.

[0179] The kinases and assay components were adjusted to the final concentrations according to the kit protocol. For TYK2: 2 nM wt human TYK2, catalytic domain (SignalChem / Canada), 1 μM HTRF KinEASE-TK substrate-biotin, 1 μM ATP in 1×Kinase Buffer The results of the biochemical tests were as follows: Inhibitory activity against LRRK2 (wt) and LRRK2 (G2019)

[0180] The following compounds had an IC below 10 nM 50Having: Compound 93; Compound 200; Compound 248; Compound 143; Compound 247; Compound 35; Compound 183; Compound 135; Compound 97; Compound 101; Compound 67; Compound 187; Compound 36; Compound 117; Compound 94; Compound 202; Compound 103; Compound 138; Compound 171; Compound 147; Compound 211; Compound 95; Compound 162; Compound 71; Compound 207; Compound 81; Compound 201; Compound 197; Compound 225; Compound 141; Compound 69; Compound 73; Compound 166; Compound 64; Compound 61; Compound 226; Compound 88; Compound 167; Compound 152; Compound 50; Compound 76; Compound 190; Compound 25; Compound 102; Compound 165; Compound 72; Compound 220; Compound 182; Compound 128; Compound 168; Compound 161; Compound 184; Compound 53; Compound 120; Compound 209; Compound 231; Compound 49; Compound 188; Compound 127; Compound 196; Compound 178; Compound 169; Compound 79; Compound 149; Compound 151; Compound 45; Compound 133; Compound 115; Compound 44; Compound 157; Compound 210; Compound 126; Compound 156; Compound 125; Compound 33; Compound 51; Compound 164; Compound 40; Compound 140; Compound 78; Compound 195; Compound 242; Compound 27; Compound 132; Compound 47; Compound 237; Compound 173; Compound 218; Compound 145; Compound 180; Compound 46; Compound 42; Compound 38; Compound 158; Compound 86; Compound 77; Compound 216; Compound 206; Compound 236; Compound 68; Compound 217; Compound 43; Compound 139; Compound 90; Compound 41; Compound 239; Compound 194; Compound 238; Compound 34; Compound 112; Compound 175; Compound 63; Compound 18; Compound 98; Compound 136; Compound 146; Compound 8; Compound 172; Compound 176; Compound 179; Compound 205; Compound 241; Compound 240; Compound 222; Compound 87; Compound 204; Compound 123; Compound 191; Compound 52; Compound 192; Compound 163; Compound 159; Compound 212; Compound 39; Compound 215; Compound 223; Compound 228; Compound 37; Compound 186; and Compound 198.

[0181] The following compounds had an IC between 10 nM and 100 nM: 50 Compound 234; Compound 150; Compound 124; Compound 32; Compound 99; Compound 160; Compound 219; Compound 177; Compound 185; Compound 221; Compound 131; Compound 189; Compound 105; Compound 110; Compound 100; Compound 130; Compound 137; Compound 230; Compound 232; Compound 233; Compound 208; Compound 235; Compound 203; Compound 243; Compound 245; Compound 11; Compound 199; Compound 30; Compound 214; Compound 148; Compound 13; Compound 244; Compound 193; Compound 229; Compound 224; Compound 113; Compound 107; Compound 170; Compound 142; Compound 213; Compound 181; Compound 111; Compound 122; Compound 31; Compound 129; Compound 82; Compound 155; Compound 14; Compound 84; Compound 29; Compound 104; Compound 83; Compound 227; and Compound 66.

[0182] The following compounds had an IC between 100 nM and 1000 nM: 50 Compound 56; Compound 108; Compound 114; Compound 75; Compound 144; Compound 119; Compound 59; Compound 57; Compound 118; Compound 48; Compound 60; Compound 62; Compound 1; Compound 134; Compound 174; Compound 106; Compound 3; Compound 21; Compound 89; Compound 24; Compound 17; Compound 91; Compound 92; Compound 80; Compound 116; Compound 12; and Compound 9. Inhibitory activity against TYK2

[0183] The following compounds had an IC of less than 10 nM: 50 Compound 73; Compound 242; Compound 226; Compound 229; Compound 95; Compound 230; Compound 162; Compound 222; Compound 241; Compound 157; Compound 236; Compound 81; Compound 228; and Compound 221.

[0184] The following compounds had an IC between 10 nM and 100 nM: 50Having: Compound 225; Compound 156; Compound 247; Compound 231; Compound 216; Compound 72; Compound 237; Compound 160; Compound 88; Compound 239; Compound 155; Compound 105; Compound 220; Compound 227; Compound 243; Compound 159; Compound 198; Compound 211; Compound 235; Compound 71; Compound 224; Compound 49; Compound 52; Compound 197; Compound 248; Compound 232; Compound 238; Compound 245; Compound 223; Compound 240; Compound 98; Compound 69; Compound 218; Compound 127; Compound 34; Compound 164; Compound 135; Compound 158; Compound 99; Compound 200; Compound 76; Compound 190; Compound 27; Compound 171; Compound 219; Compound 68; Compound 8; Compound 66; Compound 30; Compound 147; Compound 169; Compound 33; Compound 201; Compound 210; Compound 53; Compound 234; Compound 233; Compound 202; and Compound 89.

[0185] The following compounds have an IC between 100 nM and 1000 nM 50 Having: Compound 42; Compound 11; Compound 90; Compound 64; Compound 43; Compound 143; Compound 152; Compound 111; Compound 35; Compound 25; Compound 39; Compound 32; Compound 79; Compound 61; Compound 165; Compound 78; Compound 37; Compound 203; Compound 119; Compound 18; Compound 161; Compound 215; Compound 36; Compound 94; Compound 114; Compound 50; Compound 125; Compound 103; Compound 107; Compound 150; Compound 108; Compound 146; Compound 194; Compound 93; Compound 199; Compound 183; Compound 172; Compound 163; Compound 184; Compound 166; Compound 244; Compound 217; Compound 186; Compound 38; Compound 56; Compound 182; Compound 45; Compound 115; Compound 170; Compound 138; Compound 126; Compound 214; Compound 106; Compound 60; and Compound 168.

[0186] Inhibitory activity against NUAK1 The following compounds have an IC of less than 10 nM 50 Having: Compound 71; Compound 165; Compound 234; Compound 237; and Compound 226

[0187] The following compounds had an IC 50 between 10 nM and 100 nM: Compound 72; Compound 36; Compound 143; Compound 53; Compound 225; Compound 171; Compound 155; Compound 164; Compound 233; Compound 127; Compound 35; Compound 135; Compound 168; Compound 126; Compound 175; Compound 231; Compound 241; Compound 211; Compound 160; Compound 228; Compound 68; Compound 218; Compound 166; Compound 69; Compound 73; Compound 125; Compound 202; Compound 115; Compound 44; Compound 76; Compound 216; Compound 235; Compound 99; Compound 42; Compound 183; Compound 27; Compound 93; Compound 158; Compound 215; Compound 162; Compound 230; Compound 194; Compound 200; Compound 147; Compound 88; Compound 207; Compound 103; Compound 238; Compound 61; Compound 159; Compound 180; Compound 186; Compound 182; Compound 34; Compound 33; Compound 184; Compound 25; Compound 64; Compound 173; Compound 138; Compound 203; Compound 197; Compound 95; Compound 98; Compound 179; Compound 240; Compound 169; Compound 210; Compound 247; Compound 94; Compound 161; Compound 209; Compound 43; Compound 178; Compound 46; Compound 190; Compound 50; Compound 11; and Compound 242

[0188] The following compounds had an IC 50having: Compound 150; Compound 32; Compound 188; Compound 201; Compound 167; Compound 8; Compound 105; Compound 78; Compound 204; Compound 157; Compound 37; Compound 219; Compound 146; Compound 221; Compound 177; Compound 217; Compound 18; Compound 172; Compound 220; Compound 208; Compound 163; Compound 214; Compound 206; Compound 176; Compound 45; Compound 152; Compound 156; Compound 100; Compound 87; Compound 51; Compound 151; Compound 243; Compound 39; Compound 40; Compound 212; Compound 47; Compound 59; Compound 222; Compound 229; Compound 198; Compound 239; Compound 49; Compound 38; Compound 145; Compound 102; Compound 236; Compound 90; Compound 245; Compound 185; Compound 41; Compound 223; Compound 136; Compound 227; Compound 137; Compound 114; Compound 140; and Compound 205. Incorporation by reference

[0189] References and citations to other documents such as patents, patent applications, published patent applications, journals, books, papers, web content, etc. have been made throughout this disclosure. All such documents are hereby incorporated by reference in their entirety for all purposes. Equivalents

[0190] In addition to what is shown and described herein, various modifications of the present invention and many of its further embodiments will become apparent to those skilled in the art from the entire contents of this document, including references to scientific and patent literature cited herein. The subject matter of this document includes important information, exemplification, and guidance applicable to the practice of the present invention in various embodiments of the present invention and their equivalents. The present invention provides, for example, the following items. (Item 1) The following formula (I):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Claims

[Claim 1] The invention described in the specification.

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