1,4-Dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine Derivatives and Related Compounds as LRRK2, NUAK1 and / or TYK2 Kinase Modulators, for example, for the Treatment of Autoimmune Diseases

Abstract

The present invention relates to compounds of formula (I) that can modulate, e.g., inhibit or activate, one or more kinases, particularly LRRK2 and / or NUAK1 and / or TYK2, or mutants thereof. The compounds are useful for treating diseases such as 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. The present description discloses the synthesis and characterization of exemplary compounds and their pharmacological data (e.g., pages 40-146; Examples 1-63; Compounds 1-248; Tables 1-3). Preferred compounds are, for example, 1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine derivatives and related compounds. TIFF2022548246000158.tif64120

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 899,908, filed September 13, 2019, the contents of which are incorporated by reference.

[0002] FIELD OF THE INVENTION The present invention relates generally to compounds and their use in pharmacological compositions for the treatment of conditions and as radiolabeled tracers in positron emission tomography (PET) for diagnostic use. [Background technology]

[0003] background Various medical conditions that affect millions of people are caused or aggravated by the unregulated activity of protein kinase.For example, abnormal kinase activity is related to autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological and neurodegenerative disease, cancer, cardiovascular disease, allergy, asthma, Alzheimer's disease, Parkinson's disease, skin disorder, eye disease, infectious disease and hormone-related disease.However, in many such disorders, there is no effective inhibitor or activator for the specific kinase that causes the disorder or its symptoms.As a result, patients continue to suffer from many disorders due to the lack of suitable drugs for these conditions. Summary of the Invention [Means for solving the problem]

[0004] overview The present invention provides compounds useful in pharmacological compositions for the treatment of conditions and as radiolabeled tracers in positron emission tomography (PET) for diagnostic use. In certain embodiments, the compounds of the present invention modulate, e.g., inhibit or activate, protein kinase activity 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 (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 capable of penetrating the blood-brain barrier and binding to kinase targets with high affinity. Furthermore, radiolabeled forms of the compounds of the present invention are useful as PET tracers for identifying the anatomical location of abnormal kinase activity. Thus, the compounds of the present invention are useful as therapeutic and diagnostic agents for a wide variety of conditions, such as Parkinson's disease and autoimmune diseases.

[0005] Thus, 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 to diagnose and / or treat disorders in a subject.

[0006] In one aspect, the present invention provides a compound of formula (I): [ka] or a tautomer thereof, or a pharmaceutically acceptable salt thereof (In the formula, R 1 is aryl or heteroaryl, R 2 H, halo, OH, CN, CF3, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Thioalkyl, C 3~8 Cycloalkyl, C2~8 heterocycloalkyl, aryl, or heteroaryl; A is aryl or 5- or 6-membered heteroaryl; C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Thioalkyl, C 3~8 Cycloalkyl, C 2~8 Each of heterocycloalkyl, aryl, and heteroaryl may optionally be selected from halo, OH, CN, CF, NH, NO, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Thioalkyl, C 3~8 Cycloalkyl, C 2~8 Heterocycloalkyl, C 2~8 Heterocycloalkenyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylamino, C 2~6 Dialkylamino, C 7~12 Aralkyl, C 1~12 substituted with one or more moieties selected from the group consisting of heteroaralkyl, aryl, heteroaryl, -C(O)R, -C(O)OR, -C(O)NRR', -C(O)NRS(O)R', -C(O)NRS(O)NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)R', -NRS(O)NR'R", -S(O)R, and -S(O)NRR'; Each of R, R', and R" independently represents 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" taken together with the nitrogen to which they are attached, are C 2~8forming a heterocycloalkyl) to provide.

[0007] The compound of formula (I) may be a compound of formula (II): [ka] (In the formula, R 1 is aryl or heteroaryl, R 2 H, halo, OH, CN, CF3, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Thioalkyl or C 3~8 is cycloalkyl, U is N or CR 3 and V is N or CR 4 and W is N or CR 5 and X is N or CR 6 and R 3 ~R 6 each independently represents H, halo, OH, CN, CF3, CHF2, CH2F, NH2, NO2, 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)R', -C(O)NRS(O)NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)R', -NRS(O)NR'R", -S(O)R, or -S(O)NRR'; Each of R, R' and R" independently represents H, halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C3~8 Cycloalkyl, C 2~8 heterocycloalkyl, aryl, or heteroaryl; R and R', or R' and R" together with the nitrogen to which they are attached, form C 2~8 forming a heterocycloalkyl, At most one N is assigned to U, V, W, and X) It may be represented by:

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

[0009] U can be N. V can be CR 4 W may be CR 5 X may be CR 6 R may be 4 , R 5 , and R 6 Each of these is H. V is CR 4 W may be CR 5 X may be CR 6 R may be 6 is H and R 4 and R 5 Each of the is independently F, Cl, CF3, 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 are C 2~8 Forms a heterocycloalkyl. V is CR 4 W may be CR 5 X may be CR 6 R may be 4 and R 6 Each of is H and R5 are F, Cl, CF3, 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 are C 2~8 Forms a heterocycloalkyl.

[0010] V can be N. U can be CR 3 W may be CR 5 X may be CR 6 R may be 3 , R 5 , and R 6 Each of these is H. U is CR 3 W may be CR 5 X may be CR 6 R may be 6 is H and R 3 and R 5 Each of the is independently F, Cl, CF3, 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 are C 2~8 Forms a heterocycloalkyl. U is CR 3 W may be CR 5 X may be CR 6 R may be 3 and R 6Each of is H and R 5 are F, Cl, CF3, 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 are C 2~8 Forms a heterocycloalkyl.

[0011] U can be N and V can be CR 4 W may be CR 5 X may be CR 6 R may be 6 is H and R 4 and R 5 Each of the is independently F, Cl, CF3, 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 are C 2~8 Forms a heterocycloalkyl.

[0012] U is CR 3 V may be N and W may be CR 5 X may be CR 6 R may be 6 is H and R 3 and R 5 Each of the is independently F, Cl, CF3, C 1~6 Alkyl, C 2~8Heterocycloalkyl, 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 are C 2~8 Forms a heterocycloalkyl.

[0013] U can be N and V can be CR 4 W may be CR 5 X may be CR 6 R may be 4 and R 6 Each of is H and R 5 are F, Cl, CF3, 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 are C 2~8 Forms a heterocycloalkyl.

[0014] U is CR 3 V may be N and W may be CR 5 X may be CR 6 R may be 3 and R 6 Each of is H and R 5 are F, Cl, CF3, 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 are C 2~8 Forms a heterocycloalkyl.

[0015] R 1 R may be aryl. 1 teeth, [ka] (In the formula, R a ~R e each independently represents H, halo, OH, CN, CF3, CHF2, CH2F, NH2, NO2, 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)R', -C(O)NRS(O)NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)R', -NRS(O)NR'R", -S(O)R, or -S(O)NRR'; Each of R, R', and R" independently represents 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 C 2~8 forming a heterocycloalkyl) may be.

[0016] R b , R c and R d At least two of R may each be H. b , R c and R d Each of R may be H. a and R e each independently represents a halo or C 1~6 It may be alkyl. a and R e Each of R may be a halo. a and R e Each of R may be F or Cl. a and R e may be F, and R b , R c , and R d Each of R may be H. a and R e may each be Cl, and R b , R c , and R d may each be H.

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

[0018] R 2 H, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Thioalkyl, or C 3~8 It may also be cycloalkyl. R 2 R may be H, halo, -CH, -SCH, or cyclopropyl. 2 may be H, Cl, —CH3, or —SCH3.

[0019] The compound of formula (I) may be represented by formula (III): [ka] (In the formula, R 1 is aryl or heteroaryl, R 2 H, halo, OH, CN, CF3, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Thioalkyl, or C 3~8 is cycloalkyl, R 3 ~R 6 each independently represents H, halo, OH, CN, CF3, CHF2, CH2F, NH2, NO2, 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)R', -C(O)NRS(O)NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)R', -NRS(O)NR'R", -S(O)R, or -S(O)NRR', or R 4and R 5 form a ring having 5 to 10 members together with the atoms to which they are attached, Each of R, R', and R" independently represents 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" taken together with the nitrogen to which they are attached, are C 2~8 forming a heterocycloalkyl) It may be represented by:

[0020] R 3 ~R 6 Each of the is independently H, halo, OH, CN, CF3, NH2, NO2, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~8 Heterocycloalkyl, C 2~8 It may be heterocycloalkenyl, aryl, heteroaryl, -C(O)OR, -C(O)NRR', -OR, -OC(O)NRR', -NRR', or -NRC(O)R'. 3 ~R 6 At least three of R may be H. 3 , R 4 , and R 6 Each of R may be H. 3 ~R 6 All of R may be H. 3 and R 6 are H and R 4 and R 5 Each of the is independently halo, OH, CN, CF3, NH2, NO2, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~8 Heterocycloalkyl, C 2~8It may be heterocycloalkenyl, aryl, heteroaryl, -C(O)OR, -C(O)NRR', -OR, -OC(O)NRR', -NRR', or -NRC(O)R'. 3 , R 4 , and R 6 may be H, and R 5 Halo, OH, CN, CF3, NH2, NO2, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~8 Heterocycloalkyl, C 2~8 It may be heterocycloalkenyl, aryl, heteroaryl, -C(O)OR, -C(O)NRR', -OR, -OC(O)NRR', -NRR', or -NRC(O)R'. 3 ~R 6 each independently represents H, halo, CF, C 1~6 Alkyl, C 2~8 Heterocycloalkyl, C 2~8 R may be heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR'. 3 and R 6 may be H, and R 4 and R 5 Each of these independently represents a halo, CF3, C 1~6 Alkyl, C 2~8 Heterocycloalkyl, C 2~8 R may be heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR'. 4 and R 5 Each of the is independently F, Cl, CF3, 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 are C2~8 Form a heterocycloalkyl. R 3 , R 4 , and R 6 may be H, and R 5 Halo, CF3, C 1~6 Alkyl, C 2~8 Heterocycloalkyl, C 2~8 R may be heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR'. 5 are F, Cl, CF3, 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 are C 2~8 Forms a heterocycloalkyl.

[0021] The compound of formula (I) may be represented by formula (III): [ka] [In the formula, R 1 teeth, [ka] (In the formula, R a , R b , R c , R d , and R e each of is H, Br, F or Cl; R 2 is H, Cl, -CH3 or -SCH3, R 3 and R 6 Each of is H and R 4 and R 5each independently represents halo, OH, CN, CF3, CHF2, CH2F, NH2, NO2, 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′, or R 4 and R 5 together with the atoms to which they are attached form a ring having 5 to 10 members, 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" taken together with the nitrogen to which they are attached, are C 2~8 forming a heterocycloalkyl) represents] It may be represented by:

[0022] The compound of formula (I) may be a compound of formula (II): [ka] [In the formula, R 1 teeth, [ka] (In the formula, R a , R b , R c , R d , and R e each of is H, Br, F or Cl; R 2 is H, Cl, -CH3 or -SCH3, U is N and V is CR 4 and W is CR 5 and X is CR6 and R 4 and R 6 Each of is H and R 5 are F, Cl, CF3, CHF2, CH2F, C 1~6 Alkyl, C 2~8 Heterocycloalkyl, C 2~8 heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR', where 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" taken together with the nitrogen to which they are attached, are C 2~8 forming a heterocycloalkyl) represents] It may be represented by:

[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 azaidazolyl.

[0024] In another aspect, the invention provides a pharmaceutical composition comprising 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 kinase activity or expression. The kinase may be overexpressed or underexpressed. The kinase may have increased or decreased activity. The kinase may be LRRK2, NUAK1, or TYK2.

[0026] In another aspect, the present invention provides a method for 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.

[0027] In another aspect, the present invention provides a method of treating a medical condition characterized by overexpression of a kinase by 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.

[0028] In another aspect, the present invention provides a method for preparing a compound such as any of those described above by reacting a bisamino compound with an aldehyde to form the compound. DETAILED DESCRIPTION OF THE INVENTION

[0029] Detailed Description Chemical Definition The term cycloalkyl refers to saturated or partially unsaturated (e.g., cycloalkenyl) cyclic groups 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. Furthermore, the term cycloalkyl refers to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine, or iodine atoms, or by OH, ═O, SH, ═S, NH, ═NH, N, or NO groups, thus, for example, cyclic ketones such as cyclohexanone, 2-cyclohexenone, or cyclopentanone. Further particular examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbomyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetralin, cyclopentylcyclohexyl, fluorocyclohexyl, or cyclohex-2-enyl groups.

[0030] The term heterocycloalkyl refers to a cycloalkyl group, as defined above, in which one or more (e.g., one, two, or three) ring carbon atoms are replaced by oxygen, nitrogen, silicon, selenium, phosphorus, or sulfur atoms, or by an SO or SO group. Heterocycloalkyl groups preferably have one or two rings containing 3 to 10 (e.g., three, four, five, six, or seven) ring atoms (e.g., C, O, N, or S). Furthermore, the term heterocycloalkyl refers to groups substituted by fluorine, chlorine, bromine, or iodine atoms, or by OH, ═O, SH, ═S, NH, ═NH, N, or NO groups. Examples are piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl, or 2-pyrazolinyl groups, as well as lactams, lactones, cyclic imides, and cyclic anhydrides.

[0031] The term alkylcycloalkyl refers to cycloalkyl as defined above, as well as groups containing both alkyl, alkenyl or alkynyl groups, such as alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl, and alkynylcycloalkyl groups. Preferably, alkylcycloalkyl groups contain one or two rings with 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring carbon atoms and one or two alkyl, alkenyl or alkynyl groups with 1 or 2 to 6 carbon atoms.

[0032] The term "heteroalkylcycloalkyl" refers to an alkylcycloalkyl group as defined above in which one or more (e.g., one, two, or three) carbon atoms have been replaced by oxygen, nitrogen, silicon, selenium, phosphorus, or sulfur atoms, or by an SO or SO group. Heteroalkylcycloalkyl groups preferably contain one or two rings with 3 to 10 (e.g., three, four, five, six, or seven) ring atoms and one or two alkyl, alkenyl, alkynyl, or heteroalkyl groups with one or two to six carbon atoms. Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl, and heteroalkylheterocycloalkenyl, where the cyclic groups are saturated or mono-, di-, or tri-unsaturated.

[0033] The term "aryl" refers to an aromatic group containing one or more rings, each containing 6 to 14 ring carbon atoms, for example 6 to 10 ring carbon atoms. Furthermore, the term "aryl" refers to a group substituted with a fluorine, chlorine, bromine, or iodine atom, or an OH, SH, NH, N, or NO group. Examples are phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl, or 4-hydroxyphenyl group.

[0034] The term heteroaryl refers to an aromatic group containing one or more rings containing 5 to 14 ring atoms, e.g., 5 to 10 ring atoms, and containing one or more (e.g., 1, 2, 3, or 4) oxygen, nitrogen, phosphorus, or sulfur ring atoms. Additionally, the term heteroaryl refers to groups substituted with fluorine, chlorine, bromine, or iodine atoms, or OH, SH, N3, NH2, or NO2 groups. 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, benzisoxazolyl, 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 groups containing both aryl, as defined above, and alkyl, alkenyl, alkynyl, and / or cycloalkyl groups, such as arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl, and alkylarylcycloalkenyl groups. Specific examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene, and indane. Aralkyl groups preferably contain one or two aromatic ring systems containing 6 to 10 carbon atoms and one or two alkyl, alkenyl, and / or alkynyl groups containing 1, 2, or 6 carbon atoms, and / or a cycloalkyl group containing 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, each as defined above, and also alkyl, alkenyl, alkynyl, and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups. Heteroaralkyl groups preferably contain one or two aromatic ring systems containing 5 or 6 to 10 ring carbon atoms, and one or two alkyl, alkenyl, and / or alkynyl groups containing 1 or 2 to 6 carbon atoms, and / or cycloalkyl groups containing 5 or 6 ring carbon atoms, in which one, two, three, or four of these carbon atoms are replaced by oxygen, sulfur, or nitrogen atoms.

[0037] Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroarylheterocycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroarylalkylheterocycloalkenyl, heteroarylheterocycloalkyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl, and heteroarylheteroalkylheterocycloalkyl groups, where the cyclic groups are saturated or mono-, di-, or tri-unsaturated. Specific examples are tetrahydroisoquinolinyl, benzoyl, 2- or 3-ethylindolyl, 4-methylpyridino, 2-, 3-, or 4-methoxyphenyl, 4-ethoxyphenyl, and 2-, 3-, or 4-carboxyphenylalkyl groups.

[0038] As noted above, the terms cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl also refer to groups substituted with fluorine, chlorine, bromine, or iodine atoms, or with OH, ═O, SH, ═S, NH, ═NH, N, or NO groups.

[0039] The term "optionally substituted" refers in particular to groups optionally substituted by fluorine, chlorine, bromine or iodine atoms, or by OH, ═O, SH, ═S, NH, ═NH, N or NO groups. This term also refers to groups optionally substituted by one, two, three or more unsubstituted C-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Heteroalkyl, C3-C 16 Cycloalkyl, C2-C 17Heterocycloalkyl, C4-C 20 Alkylcycloalkyl, C2-C 19 Heteroalkylcycloalkyl, C6-C 18 Aryl, C1~ 17 Heteroaryl, C7-C 20 Aralkyl or C2-C 19 Furthermore, this expression particularly refers to groups that may be substituted by one, two, three or more unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C6 aryl ... 10 Cycloalkyl, C2-C9 heterocycloalkyl, C7-C 12 Alkylcycloalkyl, C2-C 11 Heteroalkylcycloalkyl, C6-C 10 Aryl, C1-C9 heteroaryl, C7-C 12 Aralkyl or C2-C 11 It refers to a group that may be substituted by a heteroaralkyl group.

[0040] Exemplary substituents are F, Cl, Br, OH, SH, ═O, NH 2 , C 1-4 alkyl, C 1-4 heteroalkyl cyclopropyl, SF 5 , NO, and NO 2 .

[0041] Other exemplary substituents are F, Cl, Br, OH, SH, ═O, NH, C 1~4 alkyl (e.g., methyl, ethyl, t-butyl), NMe2, CONH2, CH2NMe2, NHSO2Me, C(CH3)2CN, COMe, OMe, SMe, COOMe, COOEt, CH2COOH, OCH2COOH, COOH, SOMe, SO2Me, cyclopropyl, SO2NH2, SO2NHMe, SO2CH2CH2OH, NHCH2CH2OH, CH2CH2OCH3, SF5, SO2NMe2, NO, NO2, OCF3, SO2CF3, CN or CF3.

[0042] Other exemplary substituents are F, Cl, Br, Me, OMe, CN, or CF3.

[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, the rings may be joined to each other by single or double bonds, or the rings may be annulated. compound

[0046] In one aspect, the present invention provides a compound of formula (I): [ka] or a tautomer thereof, or a pharmaceutically acceptable salt thereof (In the formula, R 1 is aryl or heteroaryl, R 2 H, halo, OH, CN, CF3, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Thioalkyl, C 3~8 Cycloalkyl, C 2~8 heterocycloalkyl, aryl, or heteroaryl; A is aryl or 5- or 6-membered heteroaryl; C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Thioalkyl, C 3~8 Cycloalkyl, C 2~8Each of heterocycloalkyl, aryl, and heteroaryl may optionally be selected from halo, OH, CN, CF, NH, NO, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Thioalkyl, C 3~8 Cycloalkyl, C 2~8 Heterocycloalkyl, C 2~8 Heterocycloalkenyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylamino, C 2~6 Dialkylamino, C 7~12 Aralkyl, C 1~12 substituted with one or more moieties selected from the group consisting of heteroaralkyl, aryl, heteroaryl, -C(O)R, -C(O)OR, -C(O)NRR', -C(O)NRS(O)R', -C(O)NRS(O)NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)R', -NRS(O)NR'R", -S(O)R, and -S(O)NRR'; Each of R, R', and R" independently represents 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" taken together with the nitrogen to which they are attached, are C 2~8 forming a heterocycloalkyl) to provide. R 1 is the formula X 1 -L 1 -Y 1 or a group of formula X 1 -L 1 -Y 1 -LA-Z 1 may be a group X 1is an optionally substituted phenyl group or an optionally substituted heteroaryl group containing 5 or 6 ring atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N, and L 1 is a bond or a group of formula -CH2-, -C(=O)-, -SO-, -SO2-, -NH-C(=O)-, -C(=O)-NH-, -C(=O)-O-, -OC(=O)-, -NH-C(=O)-O-, -OC(=O)-NH-, -NH-SO2-NH-, -CH2-NH-CH2-, -NHSO2-, -SO2-NH- or -NH-C(=O)-NH-, Y 1 is an optionally substituted phenyl group, an optionally substituted heteroaryl group containing 5 or 6 ring atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N, an optionally substituted C3-C7 cycloalkyl group, or an optionally substituted heterocycloalkyl group containing 3, 4, 5, 6 or 7 ring atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N; L 2 is a bond or a group of formula -CH2-, -C(=O)-, -SO-, -SO2-, -NH-C(=O)-, -C(=O)-NH-, -C(=O)-O-, -OC(=O)-, -NH-C(=O)-O-, -OC(=O)-NH-, -NH-SO2-NH-, -CH2-NH-CH2-, -NHSO2-, -SO2-NH- or -NH-C(=O)-NH-, Z 1 is an optionally substituted phenyl group, an optionally substituted heteroaryl group containing 5 or 6 ring atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N, an optionally substituted C3-C7 cycloalkyl group, or an optionally substituted heterocycloalkyl group containing 3, 4, 5, 6 or 7 ring atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N.

[0047] R 1 is the following group: [ka] may be selected from:

[0048] The compound of formula (I) may be a compound of formula (II): [ka] (In the formula, R 1 is aryl or heteroaryl, R 2 H, halo, OH, CN, CF3, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Thioalkyl or C 3~8 is cycloalkyl, U is N or CR 3 and V is N or CR 4 and W is N or CR 5 and X is N or CR 6 and R 3 ~R 6 each independently represents H, halo, OH, CN, CF3, CHF2, CH2F, NH2, NO2, 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)R', -C(O)NRS(O)NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)R', -NRS(O)NR'R", -S(O)R, or -S(O)NRR'; Each of R, R' and R" independently represents H, halo, OH, C 1~6 Alkyl, C 1~6Haloalkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl, C 2~8 heterocycloalkyl, aryl, or heteroaryl; R and R', or R' and R" together with the nitrogen to which they are attached, form C 2~8 forming a heterocycloalkyl, At most one N is assigned to U, V, W, and X) It may be represented by:

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

[0050] U can be N. V can be CR 4 W may be CR 5 X may be CR 6 R may be 4 , R 5 , and R 6 Each of these is H. V is CR 4 W may be CR 5 X may be CR 6 R may be 6 is H and R 4 and R 5 Each of the is independently F, Cl, CF3, 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 are C 2~8 Forms a heterocycloalkyl. V is CR 4 W may be CR 5 X may be CR 6 R may be 4 and R6 Each of is H and R 5 are F, Cl, CF3, 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 are C 2~8 Forms a heterocycloalkyl.

[0051] V can be N. U can be CR 3 W may be CR 5 X may be CR 6 R may be 3 , R 5 , and R 6 Each of these is H. U is CR 3 W may be CR 5 X may be CR 6 R may be 6 is H and R 3 and R 5 Each of the is independently F, Cl, CF3, 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 are C 2~8 Forms a heterocycloalkyl. U is CR 3 W may be CR 5 X may be CR 6 R may be3 and R 6 Each of is H and R 5 are F, Cl, CF3, 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 are C 2~8 Forms a heterocycloalkyl.

[0052] U can be N and V can be CR 4 W may be CR 5 X may be CR 6 R may be 6 is H and R 4 and R 5 Each of the is independently F, Cl, CF3, 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 are C 2~8 Forms a heterocycloalkyl.

[0053] U is CR 3 V may be N and W may be CR 5 X may be CR 6 R may be 6 is H and R 3 and R 5 Each of the is independently F, Cl, CF3, C1~6 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 are C 2~8 Forms a heterocycloalkyl.

[0054] U can be N and V can be CR 4 W may be CR 5 X may be CR 6 R may be 4 and R 6 Each of is H and R 5 are F, Cl, CF3, 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 are C 2~8 Forms a heterocycloalkyl.

[0055] U is CR 3 V may be N and W may be CR 5 X may be CR 6 R may be 3 and R 6 Each of is H and R 5 are F, Cl, CF3, 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 are C 2~8 Forms a heterocycloalkyl.

[0056] R 1 R may be aryl. 1 teeth, [ka] (In the formula, R a ~R e each independently represents H, halo, OH, CN, CF3, CHF2, CH2F, NH2, NO2, 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)R', -C(O)NRS(O)NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)R', -NRS(O)NR'R", -S(O)R, or -S(O)NRR'; Each of R, R', and R" independently represents 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 C 2~8 forming a heterocycloalkyl) may be.

[0057] R b , R c and R d At least two of R may each be H. b , R c and R d Each of R may be H. a and R e each independently represents a halo or C 1~6 It may be alkyl. a and R e Each of R may be a halo. a and R e Each of R may be F or Cl. a and R e may be F, and R b , R c , and R d Each of R may be H. a and R e may each be Cl, and R b , R c , and R d may each be H.

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

[0059] R 2 H, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Thioalkyl, or C 3~8 It may also be cycloalkyl. R 2 R may be H, halo, -CH, -SCH, or cyclopropyl. 2 may be H, Cl, —CH3, or —SCH3.

[0060] The compound of formula (I) may be represented by formula (III): [ka] (In the formula, R 1 is aryl or heteroaryl, R 2 H, halo, OH, CN, CF3, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Thioalkyl, or C 3~8 is cycloalkyl, R 3 ~R 6 each independently represents H, halo, OH, CN, CF3, CHF2, CH2F, NH2, NO2, 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)R', -C(O)NRS(O)NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)R', -NRS(O)NR'R", -S(O)R, or -S(O)NRR'; Each of R, R', and R" independently represents 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" taken together with the nitrogen to which they are attached, are C 2~8 forming a heterocycloalkyl) It may be represented by:

[0061] R 3 ~R 6 Each of the is independently H, halo, OH, CN, CF3, NH2, NO2, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~8 Heterocycloalkyl, C 2~8 It may be heterocycloalkenyl, aryl, heteroaryl, -C(O)OR, -C(O)NRR', -OR, -OC(O)NRR', -NRR', or -NRC(O)R'. 3 ~R 6 At least three of R may be H. 3 , R 4 , and R 6 Each of R may be H. 3 ~R 6 All of R may be H. 3 and R 6 are H and R 4 and R 5 Each of the is independently halo, OH, CN, CF3, NH2, NO2, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~8 Heterocycloalkyl, C 2~8 It may be heterocycloalkenyl, aryl, heteroaryl, -C(O)OR, -C(O)NRR', -OR, -OC(O)NRR', -NRR', or -NRC(O)R'. 3 , R 4 , and R 6may be H, and R 5 Halo, OH, CN, CF3, NH2, NO2, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~8 Heterocycloalkyl, C 2~8 It may be heterocycloalkenyl, aryl, heteroaryl, -C(O)OR, -C(O)NRR', -OR, -OC(O)NRR', -NRR', or -NRC(O)R'. 3 ~R 6 each independently represents H, halo, CF, C 1~6 Alkyl, C 2~8 Heterocycloalkyl, C 2~8 R may be heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR'. 3 and R 6 may be H, and R 4 and R 5 Each of these independently represents a halo, CF3, C 1~6 Alkyl, C 2~8 Heterocycloalkyl, C 2~8 R may be heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR'. 4 and R 5 Each of the is independently F, Cl, CF3, 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 are C 2~8 Form a heterocycloalkyl. R 3 , R 4 , and R 6 may be H, and R 5 Halo, CF3, C 1~6 Alkyl, C2~8 Heterocycloalkyl, C 2~8 R may be heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR'. 5 are F, Cl, CF3, 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 are C 2~8 Forms a heterocycloalkyl.

[0062] The compound of formula (I) may be represented by formula (III): [ka] [In the formula, R 1 teeth, [ka] (In the formula, R a , R b , R c , R d , and R e each of is H, Br, F or Cl; R 2 is H, Cl, -CH3 or -SCH3, R 3 and R 6 Each of is H and R 4 and R 5 each independently represents halo, OH, CN, CF3, CHF2, CH2F, NH2, NO2, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~8 Heterocycloalkyl, C 2~8heterocycloalkenyl, aryl, heteroaryl, —C(O)OR, —C(O)NRR′, —OR, —OC(O)NRR′, —NRR′, or —NRC(O)R′, or R 4 and R 5 together with the atoms to which they are attached form a ring having 5 to 10 members, 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" taken together with the nitrogen to which they are attached, are C 2~8 forming a heterocycloalkyl) represents] It may be represented by:

[0063] The compound of formula (I) may be a compound of formula (II): [ka] [In the formula, R 1 teeth, [ka] (In the formula, R a , R b , R c , R d , and R e each of is H, Br, F or Cl; R 2 is H, Cl, -CH3 or -SCH3, U is N and V is CR 4 and W is CR 5 and X is CR 6 and R 4 and R 6 Each of is H and R 5 are F, Cl, CF3, CHF2, CH2F, C 1~6 Alkyl, C 2~8Heterocycloalkyl, C 2~8 heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR', where 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" taken together with the nitrogen to which they are attached, are C 2~8 forming a heterocycloalkyl) represents] It may be represented by:

[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 azaidazolyl.

[0065] Compounds of formula (I) have the following structure: [ka] [ka] [ka] [ka] It may be represented by one of: Pharmaceutical Composition

[0066] The present invention provides pharmaceutical compositions comprising one or more of the compounds described above, or pharmaceutically acceptable esters, prodrugs, hydrates, solvates, or salts thereof, optionally in combination with a pharmaceutically acceptable carrier. The present invention further provides such compounds for the preparation of medicaments for the treatment of one or more of the diseases mentioned herein.

[0067] Pharmaceutical compositions may contain one or more compounds of the present invention in therapeutically effective amounts.The therapeutically effective amount of the compound according to the present invention means the amount of compound that is effective for preventing, alleviating or ameliorating the symptoms of disease or prolonging the life of the subject being treated.Determining therapeutically effective amount is within the skill of the art.

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

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

[0070] Examples of pharmacologically acceptable salts of the sufficiently basic compounds of the present invention include 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.In addition, the sufficiently acidic compounds of the present 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, all of which are also further examples of salts of the present invention.The compounds of the present invention may be solvated, particularly hydrated.Hydration may occur during the production process or as a result of the hygroscopic nature of the compounds of the present invention that do not initially contain water. The solvates and / or hydrates may exist, for example, in solid or liquid form.

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

[0072] According to a further embodiment of the present invention, one or more hydrogen atoms of the compounds of the present invention may be replaced by deuterium. Deuterium modification improves the metabolic properties of a drug with little or no change in 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. Therefore, the present invention also encompasses partially and fully deuterated compounds of the present 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, are also within the scope of the present invention. Pharmaceutical compositions according to the present invention may comprise at least one compound of the present invention as an active ingredient, and, if necessary, carrier substances and / or adjuvants.

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

[0075] As used herein, the term "pharmaceutically acceptable ester" refers to esters, including those that are hydrolyzed in vivo and easily decompose in the human body, leaving 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 alkanedioic acids, where each alkyl or alkenyl moiety advantageously has 6 or less carbon atoms. Specific examples of esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates.

[0076] The invention also relates to prodrugs, biohydrolyzable esters, biohydrolyzable amides, polymorphs, tautomers, stereoisomers, metabolites, N-oxides, biohydrolyzable carbamates, biohydrolyzable 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 invention.

[0077] As mentioned 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, alone or in combination with any other therapeutic agent, are administered by using known and accepted modes known in the art.

[0078] For oral administration, such therapeutically useful agents can be administered by one of the following routes: orally, for example, as tablets, sugar-coated tablets, coated tablets, pills, semisolids, 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 a powder formulation, as microcrystals, or as a spray (for example, liquid aerosol); transdermally, for example, via a transdermal delivery system (TDS) such as a plaster containing the active ingredient, or intranasally. For the production of such tablets, pills, semisolids, coated tablets, sugar-coated tablets, and hard, for example, gelatin capsules, the therapeutically useful products can be mixed with pharmaceutically inert inorganic or organic excipients, such as lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof, talc, stearic acid or a salt thereof, dried skim milk, etc. For the production of soft capsules, excipients such as vegetable oils, petroleum oils, animal or synthetic oils, waxes, fats, and polyols can be used. For the production of liquid solutions, emulsions, suspensions, or syrups, excipients such as water, alcohol, saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable oils, petroleum oils, animal oils, or synthetic oils can be used. Particularly useful are lipids such as phospholipids (e.g., of natural origin and / or with a particle size between 300 and 350 nm) in phosphate-buffered saline (pH = 7-8, e.g., 7.4). For suppositories, excipients such as vegetable oils, petroleum oils, animal or synthetic oils, waxes, fats, and polyols can be used. For aerosol formulations, compressed gases suitable for this purpose, such as oxygen, nitrogen, and carbon dioxide, can be used. Pharmaceutically useful agents may also contain additives for preservation and stabilization, such as UV stabilizers, emulsifiers, sweeteners, flavoring agents, salts for varying osmotic pressure, buffers, coating additives, and antioxidants.

[0079] Generally, for oral or parenteral administration to an adult human weighing approximately 80 kg, a daily dosage of about 10 mg to about 10,000 mg, or about 20 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded if indicated. The daily dosage may be administered as a single dose or in divided doses, or, for parenteral administration, as continuous infusion or subcutaneous injection. Compound preparation method

[0080] The present invention also provides methods of making the compounds of the invention, such as those described above. Synthetic schemes for making certain compounds of formula (I) are provided in the Examples below. Methods of Treating Diseases, Disorders, and Conditions

[0081] The compounds and compositions of the invention may be used to diagnose, treat, or prevent a disease, disorder, or condition. The invention further provides methods of diagnosing or treating a disease, disorder, or condition using a compound or composition of the invention.

[0082] The diseases, disorders, and conditions that can be diagnosed and / or treated using the compositions and methods of the present invention include those associated with the abnormal activity, for example, increased activity or decreased activity, of one or more kinases.The kinase may be a serine-threonine kinase or a tyrosine kinase, for example, 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 mutants of any of the aforementioned 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, leprosy, 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 type 8 Parkinson's disease.

[0084] The disease, disorder or condition may be associated with aberrant NUAK1 activity, such as cancer, eg, colorectal cancer, gastric cancer, endometrial cancer, or multiple myeloma, diabetes, fibrosis, neurodegenerative disease, or omphalocele.

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

[0086] The disease, disorder, or condition may be a respiratory / obstructive airway disease or disorder, such as rhinorrhea, tracheal stenosis, airway constriction, acute allergy, atrophic or chronic rhinitis (e.g., caseous rhinitis, hypertrophic rhinitis, suppurative rhinitis, rhinitis sicca), rhinitis medicamentosa, membranous rhinitis (including croupus, fibrinous, and pseudomembranous rhinitis), scrofulous rhinitis, perennial allergic rhinitis, seasonal rhinitis (including neurogenic rhinitis (hay fever) and vasomotor rhinitis), hay fever, asthma (e.g., bronchial, atopic, allergic, endogenous, extrinsic, exercise-induced, cold-induced, occupational, bacterial infection-induced, and dust asthma). chronic inflammatory diseases of the lungs leading to interstitial fibrosis, such as bronchitis (including chronic, acute, arachidic acid-induced, catarrhal, croupy, debilitating, and eosinophilic bronchitis), cardiac bronchitis, pneumoconiosis, 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 disease (CORD, COAD, COLD, or COPD, e.g., uncontrolled lung injury, uncontrolled lung disease ... inverse COPD), chronic sinusitis, 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-related or iatrogenic chronic cough), pleuritis, pulmonary congestion, emphysema, bronchiectasis, sarcoidosis, fibrosing alveolitis of unknown cause, pulmonary fibrosis including fibrosis complicated by antineoplastic therapy, chronic infections including tuberculosis and aspergillosis and other fungal infections, vasculitis and thrombotic disorders of the pulmonary vasculature, and pulmonary It may be or include hypertension, acute viral infections including the common cold, infections caused by respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus, allergic bronchopulmonary mycosis, emphysema, diffuse panbronchiolitis, systemic anaphylaxis or hypersensitivity reactions, drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies, and food-related allergies that may affect remotely from the gut (such as migraines, rhinitis, and eczema), anaphylactic shock, or vasospasm.

[0087] The disease, disorder or condition may be any disease or disorder related to the bones and joints, such as osteoporosis, arthritis (including rheumatic, infectious, autoimmune, chronic, malignant), seronegative spondyloarthropathy (such as ankylosing spondylitis, rheumatoid spondylitis, psoriatic arthritis, enthesitis, Behcet's disease, Marie-Strümpel arthritis, arthritis associated with inflammatory bowel disease and Reiter's disease), systemic sclerosis, osteoarthritis, both primary osteoarthritis and osteoarthritis secondary to, for example, congenital hip dysplasia, cervical and Lumbar spondylitis and other infection-related arthropathies and bone disorders such as lower back and neck pain, Still's disease, reactive arthritis and undifferentiated spondylitis, septic arthritis, and tuberculosis including Pott's disease and Ponce syndrome, acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite-related inflammation of tendons, bursae, and synovium, primary and secondary Sjogren's syndrome, systemic sclerosis and limited systemic sclerosis, mixed connective tissue disease and undifferentiated connective tissue inflammatory myopathies including polymyalgia rheumatica; juvenile arthritis including idiopathic inflammatory arthritis of any joint distribution and associated syndromes; other joint diseases (e.g., disc degeneration or temporomandibular degeneration); rheumatic fever and its systemic complications; vasculitis including giant cell arteritis, Takayasu's arteritis, polyarteritis nodosa, microscopic polyarteritis and vasculitis associated with viral infections; hypersensitivity reactions; cryoglobulins; dysproteinemia; low back pain; familial Mediterranean fever; Muckle-Wells syndrome; and familial haemorrhage. The condition may be or may include Iburnian fever, Kikuchi's disease, drug-induced arthralgia, tendonitis, polychondritis, and muscle diseases, osteoporosis, osteoporotic osteomalacia, osteopenia, osteogenesis imperfecta, osteopetrosis, osteofibrosis, osteonecrosis, Paget's disease of bone, hypophosphatemia, Felty's syndrome, Still's disease, loosening of artificial joint implants, muscle or joint sprains or strains, tendinitis, fasciitis, glenohumeral periarthritis, cervicobrachial syndrome, or tenoperiostitis.

[0088] The disease, disorder or condition may be a disease or disorder related to the skin or eyes, such as glaucoma, ocular hypertension, cataracts, retinal detachment, psoriasis (including plaque psoriasis, pustular psoriasis, psoriatic arthritis, and erythrodermic psoriasis), palmoplantar pustulosis, xerodoma, eczematous diseases (e.g., atopic dermatitis, photodermatitis, contact dermatitis, and seborrheic dermatitis), phytodermatitis, photodermatitis, cutaneous eosinophilia, chronic skin ulcers, cutaneous lupus erythematosus, contact hypersensitivity / allergic contact dermatitis ( (including hypersensitivity to poison ivy, sumac, or oak), as well as eosinophilic cystic folliculitis (Oto's disease), pruritus, drug eruption, hives (acute or chronic, allergic or non-allergic), acne, erythema, dermatitis herpetiformis, scleroderma, vitiligo, lichen planus, scleroatrophic lichen, pyoderma gangrenosum, dermatosarcoma, pemphigus, ocular pemphigoid, epidermolysis bullosa, angioedema, vasculitis, erythema toxicum, cutaneous eosinophilia, alopecia areata, male pattern baldness, Sweet's syndrome, and Buns-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, ophthalmia including sympathetic ophthalmia, sarcoidosis, dry eye infections including viral, fungal and bacterial, allergic conjunctivitis, increased fibrosis, keloids, keloid formation It may be or include surgical wounds, post-surgical scars, bullous excoriation, dry eye, ocular inflammation, allergic conjunctivitis, vernal keratoconjunctivitis, vernal keratoconjunctivitis and giant papillary conjunctivitis, ocular angiogenesis, corneal injury and scarring, any form of macular degeneration, macular edema, macular dystrophy, abnormal healing of injury, scleritis, episcleritis, scleroderma, marginal ulcerative keratitis, fungal keratitis, herpetic keratitis, invasive aspergillosis; keratoconus, corneal epithelial dysplasia, or severe intraocular inflammation.

[0089] The disease, disorder, or condition is 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, enteropathy associated with seronegative arthropathy, gastritis, autoimmune atrophic gastritis, ischemic bowel disease, inflammatory bowel disease (Crohn's disease and ulcerative colitis), colitis, Mooren's ulcer, irritable bowel syndrome, necrotizing enterocolitis, 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 of the liver, hepatitis (congestive, autoimmune, acute, fulminant, chronic, drug-induced, alcohol-induced, lupus, fatty liver, and chronic viral), fatty liver, primary biliary sclerosis, hepatic porphyria, and gastrointestinal-related allergic disorders, spastic colon, diverticulitis, gastrointestinal bleeding, Behcet's disease, partial liver resection, acute liver necrosis (e.g., necrosis caused by toxins, viral hepatitis, shock, or oxygen deprivation), or hemolytic uremic syndrome.

[0090] The disease, disorder, or condition may be or may include a hematological disease or disorder, such as anemia, coagulation, myeloproliferative disorder, bleeding disorder, leukopenia, eosinophilic disorder, leukemia (e.g., myeloid, lymphoma, dysplasmocytosis), pancreatic disorder, Banti's disease, hemophilia, purpura (including idiopathic thrombocytopenic purpura), or Wiskott-Aldrich syndrome.

[0091] The disease, disorder or condition may be a metabolic disease or disorder, e.g., obesity, amyloidosis, disorders of amino and acid metabolism such as branched chain disease, hyperaminoacidemia, hyperaminoaciduria, disorders of urea metabolism, hyperammonemia, mucopolysaccharidoses, e.g., Maroteaux-Lamy syndrome, storage diseases such as glycogen storage disease and lipid storage disease, type I glycogen storage diseases such as Cori's disease, malabsorption diseases such as intestinal carbohydrate malabsorption, oligosaccharide deficiencies such as maltase, lactase, sucrase deficiency, disorders of fructose metabolism, disorders of galactose metabolism, galactose metabolism disorders, The condition may be or may include a metabolic disorder of the nervous system and nervous system, such as lectosemia, carbohydrate utilization disorders such as diabetes mellitus, hypoglycemia, pyruvate metabolism disorders, hypolipidemia, hypolipidemia, hyperlipidemia, carnitine or carnitine acyltransferase deficiency, porphyrin metabolism, porphyrin disorders, purine metabolism disorders, lysosomal diseases, gangliosidoses, sphingolipidoses, sulfatidolipidosis, cerebral leukodystrophy, or Lesch-Nyhan syndrome.

[0092] The disease, disorder or condition may be a disorder of cerebellar dysfunction or abnormalities of cerebral metabolism, e.g., dementia, Alzheimer's disease, Huntington's chorea, Parkinson's disease, Pick's disease, toxic encephalopathy, inflammatory neuropathies, demyelinating neuropathies such as Guillain-Barre syndrome; Meniere's disease and radiculopathy; primary and secondary metabolic disorders associated with hormone deficiency, such as any disorder resulting from hyperfunction or hypofunction of endocrine glands that secrete certain hormones, and any combination thereof; Sipple's syndrome; dysfunction of the pituitary gland and its effects on other endocrine glands, e.g., the thyroid gland, adrenal glands, ovaries and testes; acromegaly; hyper- and hypothyroidism; goiter; euthyroid syndrome; thyroiditis; and thyroid cancer; over- 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; diabetes mellitus; The disorder may be or may include: female endocrine system disorders such as Noid syndrome, parathyroid dysfunction, pancreatic islet cell dysfunction, disorders caused by diabetes, estrogen deficiency, resistant ovarian syndrome; muscle weakness, myotonia, Duchenne and other muscular dystrophies, Steinert myotonic dystrophy, mitochondrial myopathies such as disorders of muscle catabolism, carbohydrate and lipid storage myopathies, glycogen storage diseases, myoglobinuria, malignant hyperthermia, polymyalgia rheumatica, dermatomyositis, polymyositis, primary cardiac myopathy, cardiomyopathies; ectodermal disorders, neurofibromatosis, scleroderma and polyarteritis nodosa, Lewis-Barr syndrome, von Hippel-Lindau disease, Sturge-Weber syndrome, tuberculous sclerosis, amyloidosis, porphyria; male and female sexual dysfunction; confusion and seizures due to abnormal secretion of antidiuretic hormone from the pituitary gland, Liddle syndrome, Bartter syndrome, Fanconi type I syndrome, or renal electrolyte wasting.

[0093] The disease, disorder or condition may be or may include a condition associated with transplant rejection, such as acute and chronic allograft rejection after solid organ transplants, e.g., kidney, heart, liver, lung and corneal transplants, chronic graft-versus-host disease, skin graft rejection, and bone marrow transplant rejection, or immunosuppression.

[0094] The disease, disorder or condition may be or include a genitourinary condition such as nephritis (interstitial, acute interstitial (allergic), and glomerulonephritis), nephrotic syndrome, cystitis including acute and chronic (interstitial) cystitis, as well as 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 antisteroid nephrosis, or Goodpasture's syndrome.

[0095] The disease, disorder or condition may be a disease or disorder associated with the CNS, such as neurodegenerative diseases, Alzheimer's disease and other cognitive disorders including CJD and nvCJD, amyloidosis and other demyelinating syndromes, cerebral atherosclerosis and vasculitis, temporal arteritis, myasthenia gravis, postoperative visceral pain, headache, migraine, neuralgia (including trigeminal neuralgia), atypical facial pain, acute and chronic pain (whether central or peripheral, acute, intermittent or persistent), including joint and bone pain. Pain due to cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic and HIV-associated neuropathy, neurosarcoidosis, brain injury, cerebrovascular disease and their consequences, 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, dementia with Lewy bodies, and genes linked to chromosomes 1-17. Frontotemporal dementia including frontotemporal dementia with Parkinsonism, frontotemporal dementia including Pick's disease, progressive supranuclear spasms, 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, as are central and peripheral nervous system complications of malignant, infectious, or autoimmune processes, pain, cerebral infarction, seizures, cerebral ischemia, head injury, spinal cord injury, myelopathic muscular atrophy, Shy-Drager syndrome, and Reye's syndrome. , progressive multifocal leukoencephalopathy, normal pressure cerebral edema, 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.

[0096] The disease, disorder, or condition may be an inflammatory or immunological disease or disorder, such as general inflammation (of the eye, nose, lungs, and gastrointestinal tract), mastocytosis / mast cell disorders (skin, systemic, mast cell activation syndrome, and pediatric mast cell disease), mastitis (breast), vaginitis, vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis), Wegener's granulomatosis, myositis (including polymyositis, dermatomyositis), basophil-related disorders including basophilic leukemia and basophilic leukocytosis, and Churg-Strauss syndrome, eosinophil-related disorders such as eosinophilic granulomatosis, lupus erythematosus (e.g., systemic lupus erythematosus, subacute cutaneous lupus erythematosus, The condition may be or may include other autoimmune disorders selected from polymyositis, bursitis, Evans syndrome, leukotriene B4-mediated disease, idiopathic hypoparathyroidism, nephrotic syndrome, lupus erythematosus, and discoid lupus erythematosus, chronic thyroiditis, Hashimoto's thyroiditis, Graves' disease, type 1 diabetes, complications due to diabetes mellitus, other immune disorders, eosinophilic fasciitis, hyper-IgE syndrome, Addison's disease, antiphospholipid syndrome, immunodeficiency disease, acquired immunodeficiency syndrome (AIDS), leprosy, Sézary syndrome, paraneoplastic syndromes, and other autoimmune disorders selected from polymyositis, bursitis, Evans syndrome, leukotriene B4-mediated disease, idiopathic hypoparathyroidism, nephrotic syndrome, lupus, or immunosuppression, fever, myositis, neurological disorders.

[0097] The disease, disorder or condition may be or may include cardiovascular diseases or disorders such as congestive heart failure, myocardial infarction, ischemic heart disease, atrial and ventricular arrhythmias of all kinds, hypertension, cerebral trauma, vascular occlusive disease, stroke, cerebrovascular accidents, atherosclerosis, restenosis affecting the coronary and peripheral circulation, inflammatory and autoimmune cardiomyopathies including pericarditis, cardiomyopathy, myocardial sarcoid, endocarditis, valvulitis, and aortitis, 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, as well as varicose veins, complications of aortic aneurysms, periarteritis nodosa, cardiac fibrosis, idiopathic cardiomyopathy after myocardial infarction, or angiogenesis.

[0098] The disease, disorder or condition may be an oncological disease or disorder, such as common cancers (prostate, breast, lung, ovary, pancreas, intestine and colon, abdomen, stomach (and any other digestive system cancer), liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testes, ovaries, thymus, thyroid), eye, head, neck, nervous system (central and peripheral), lymphatic system, blood, pelvis, skin, bone, soft tissue, spleen, breast, genitourinary and brain tumors), breast cancer, genitourinary cancer, lung cancer, gastrointestinal cancer, epidermoid carcinoma, melanoma, ovarian cancer, pancreatic cancer, neuroblastoma, malignancies affecting the bone marrow (including leukemia) and lymphoproliferative system such as Hodgkin's and non-Hodgkin's lymphoma, B-cell lymphoma, follicular lymphoma, metastatic disease and tumor recurrence, as well as paraneoplastic syndromes and high-grade cancers. The cancer may be or include macroglobulinemia, lymphoproliferative diseases, disorders and / or conditions, paraproteinemia, purpura (including idiopathic thrombocytopenic purpura), Waldenstrom's macroglobulinemia, Gaucher's disease, histiocytic proliferation, 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 myeloid leukemia, acute or chronic lymphocytic leukemia, monocytic leukemia, other leukemias of specific cell tumors, leukemias of unspecified cell tumors, other unspecified malignancies of lymphoid system, hematopoietic cells and related tissues, e.g., diffuse large cell lymphoma, T-cell lymphoma, or cutaneous T-cell lymphoma. Bone marrow cancers include, for example, acute or chronic myeloid leukemia or corneal leukemia.

[0099] The disease, disorder or condition may be or include other diseases or disorders such as pain, migraine, sleep disorders, fever, sepsis, idiopathic thrombocytopenic purpura, postoperative adhesions, facial hot flashes, ischemic / reperfusion injury in the heart, brain, peripheral limbs, bacterial infection, viral infection, fungal infection, thrombosis, endotoxic shock, septic shock, thermoregulation including fever, Raynaud's disease, gangrene, diseases requiring anticoagulant therapy, congestive heart failure, impaired mucus secretion, pulmonary hypotension, prostanoid-induced smooth muscle contraction with dysmenorrhea and preterm labor, premature labor, reperfusion injury, burns, scalds, hemorrhagic or traumatic shock, menstrual pain, menstrual cramps, dysmenorrhea, periodontal disease, rickettsial infectious diseases, protozoal diseases, reproductive diseases, toothache, pain after tooth extraction, shingles, 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 ocular disorders, hi certain embodiments, the disease is selected from the group consisting of pruritus, eczema, asthma, rhinitis, dry eye, ocular inflammation, allergic conjunctivitis, vernal keratoconjunctivitis, 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, e.g., 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 specific kinases over other kinases.

[0102] The method may include providing a compound of the invention.The method may include providing a plurality of compounds of the 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, contacting a cell with a 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; or providing the compound to a subject and exposing the subject's cells to the compound. The contacting step may be performed in vivo or in vitro. In vitro contacting may include exposing cells or tissues isolated from a subject. The method may include contacting a cell with a single compound of the present invention. The method may include contacting a cell with multiple 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 bucally, by injection, skin, enterally, intra-arterially, intravenously, intranasally, e.g., by inhalation, intraocularly, orally, parenterally, pulmonary, rectally, subcutaneously, systemically, topically, e.g., to the skin or eye, transdermally, or with or onto an implantable medical device (e.g., a stent or drug-eluting stent, or balloon equivalent).

[0105] The method may include using a composition of the invention to diagnose a disease, disorder, or condition in a subject. For example, radiolabeled forms of the compounds can be used as tracers in positron emission tomography (PET) to identify the anatomical location of aberrant kinase activity. PET is known in the art and is described, for example, in 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, DL; DW Townsend; PE Valk; MN 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 involve administering one or more compositions of the present invention for both diagnostic and therapeutic purposes. [Example]

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

[0107] Flash chromatography: Flash chromatography is performed on a Biotage Isolera® system using a SNAP silica cartridge and an ethyl acetate / cyclohexane / methanol or dichloromethane / methanol gradient as eluent.

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

[0109] SEMIprep reversed-phase chromatography: The following equipment was used for SEMIprep reversed-phase chromatography: 2x Varian PrepStar SD-1, 1x Dionex P580 Pump 1 Channel (MakeUP I), 1x Dionex AXP-MS (MakeUP II), 1x Dionex MSQ, 1x Dionex UVD 340V-Prep Flow Cell, and Gilson 215 Liquid Handler. A SunFire Prep C18 OBD 5 μm, 19 x 50 mm 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. Typical times and relative volumes of solvents and solvent B were as follows: [Table 4] A mass spectrometric detector (API-ES, positive) at UV 254 nm was used for detection. Example 2

[0111] Terms and abbreviations used in the examples are listed in Table 1. [Table 1] Example 3

[0112] Methods for the synthesis of certain molecules used as reagents in the synthetic schemes described herein are known in the art and are described in the references set forth in Table 2. [Table 2] Example 4 [ka]

[0113] The intermediate, 1.1 equivalents of 3,5-dibromo-4-nitropyrazole, was suspended in dichloromethane and THF was added until complete dissolution. Next, 1.3 equivalents of dihydropyran and a catalytic amount of toluenesulfonic acid monohydrate were added. The mixture was stirred overnight, diluted with DCM, and washed with saturated aqueous NaHCO3 and water. The combined organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure to give 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 Organic Chemistry 1986, 51, 24, 4656-4660, November 1, 1986. Example 5 [ka]

[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 equivalents of toluenesulfonic acid were slowly added. The mixture was stirred at room temperature overnight. The mixture was extracted with saturated aqueous NaHCO3 and water. The aqueous layer was extracted with DCM, and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography. Example 6 [ka]

[0115] Intermediate 3, 3-bromo-5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-amine. 3-Bromo-5-iodopyridin-2-amine was dissolved in dioxane and water. 1 equivalent of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 3 equivalents of Na2CO3 were added. The mixture was degassed with N2, and then 0.05 equivalents of Pd(PPh3)4 were added. The mixture was degassed again and stirred at 80 °C overnight. An additional 0.02 equivalents of Pd(PPh3)4 were added, and the mixture was stirred at 80 °C for 4 hours. The mixture was cooled to room temperature and filtered through Celite. The solid was washed with MeOH and water. The filtrate was concentrated under reduced pressure, diluted with water, and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and evaporated. The crude material was purified by flash chromatography. Example 7 [ka]

[0116] Intermediate 4, 2-bromo-4-(3,6-dihydro-2H-pyran-4-yl)aniline. Synthesized as described in Intermediate 3 using 2-bromo-4-iodoaniline as the starting material. Example 8 [ka]

[0117] Intermediate 5, tert-butyl 6-amino-5-bromo-5',6'-dihydro-[3,4'-dipyridine]-1'(2'H)-carboxylate. Synthesized as described in Intermediate 3 using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate as the starting material. Example 9 [ka]

[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 aqueous NaHCO3 and water. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography. Example 10 [ka]

[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 NaSO, basified with aqueous NaOH, and extracted with DCM. The combined organics were dried over NaSO, filtered, and concentrated under reduced pressure. The crude mixture was purified by flash chromatography. Example 11 [ka]

[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) were added, and the mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched by adding saturated aqueous NH Cl and extracted with ethyl acetate. The organic layer was dried over Na SO , filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography. Example 12 [ka]

[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 were added, followed by the dropwise addition of 2-bromo-4-fluoro-1-nitrobenzene. The mixture was heated to reflux for 45 minutes, cooled to room temperature, and quenched by the addition of water. The precipitate was collected by filtration. The filtrate was extracted with ethyl acetate, and the organic layer was washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The combined crude products were purified by flash chromatography. Example 13

[0122] General procedure for iron reduction: Dissolve the aryl nitro compound in 4 / 1 ethanol / water and add 10 equivalents of iron and 10 equivalents of NH4Cl, as well as a few drops of 2M HCl. Heat the mixture at 50°C for 1 hour. Filter the mixture through Celite and wash the solid with MeOH and water. Concentrate the filtrate and basify with 15% w / v NaOH. Extract the aqueous layer with ethyl acetate, dry the combined organic layers over Na2SO4, filter, and concentrate under reduced pressure. Use the product without further purification. Example 14 [ka]

[0123] Intermediate 10, 4-(3-bromo-4-aminophenoxy)tetrahydro-2H-pyran (representative of iron reduction reactions). 4-(3-Bromo-4-nitrophenoxy)tetrahydro-2H-pyran was dissolved in 4 / 1 ethanol / water, and 10 equivalents of iron and 10 equivalents of NH4Cl 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 Na2SO4, filtered, and concentrated under reduced pressure. The product was used without further purification. Example 15 [ka]

[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 K2CO3 were 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 [ka]

[0125] Intermediate 12, 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-amine. The title compound was synthesized using 4-bromo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole as the starting material following the general protocol for iron reduction. Example 17 [ka]

[0126] Intermediate 13, 3-bromo-N1-(2-fluoroethyl)benzene-1,4-diamine. The title compound was synthesized using 3-bromo-N-(2-fluoroethyl)-4-nitroaniline as the starting material following the general protocol for iron reduction. Example 18 [ka]

[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 K2CO3 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 Na2SO4, 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 [ka]

[0128] Intermediate 15, 4-bromo-1-(difluoromethyl)-1H-pyrazol-3-amine and 4-bromo-1-(difluoromethyl)-1H-pyrazol-5-amine. Using a mixture of 4-bromo-1-(difluoromethyl)-3-nitro-1H-pyrazole and 4-bromo-1-(difluoromethyl)-5-nitro-1H-pyrazole as starting materials, the title compound was synthesized according to the general protocol for iron reduction. The materials were used as isomer mixtures. Example 20 [ka]

[0129] Intermediate 16, 4-(4-bromo-3-nitrophenoxy)tetrahydro-2H-pyran. One equivalent of tetrahydro-2H-pyran-4-ol, 4-bromo-3-nitrophenol, and 2.6 equivalents of PPh3 were dissolved in dry THF. The mixture was cooled to 0 °C, and 2.3 equivalents of DBAD dissolved in dry THF were slowly added. The mixture was allowed to warm to room temperature and stirred overnight. An additional 0.3 equivalents of tetrahydro-2H-pyran-4-ol, 0.3 equivalents of PPh3, 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 Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography. Example 21 [ka]

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

[0131] General protocol for reduction using H2 / Pd / C: The aromatic nitro compound is dissolved in ethanol. 0.05 equivalents of 10% w / w Pd on charcoal are added and the mixture is stirred overnight under a hydrogen atmosphere. The mixture is filtered through Celite and the filtrate is concentrated under reduced pressure. The product is used without further purification. Example 23 [ka]

[0132] Intermediate 18, 3-(dimethoxymethyl)-2,4-difluoroaniline (representative of the H2 / Pd / C reduction reaction). 2-(Dimethoxymethyl)-1,3-difluoro-4-nitrobenzene was dissolved in ethanol, 0.05 equivalents of Pd / C (10% w / w) was added, and the mixture was stirred at room temperature overnight. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The mixture was used without further purification. Example 24 [ka]

[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 CsCO, and 1.5 equivalents of DIPEA were dissolved in dry DMF. The mixture was heated under microwave conditions at 140°C for 30 minutes, then at 160°C for 30 minutes. After adding 1 equivalent of 1-bromo-2-fluoroethane, the mixture was again heated at 160°C for 30 minutes. The mixture was diluted with ethyl acetate, washed with water and brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography. Example 25 [ka]

[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, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography. Example 26 [ka]

[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 K2CO3 are dissolved in DMF. The mixture is heated at 120 °C overnight. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction mixture is purified by flash chromatography. Example 27 [ka]

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

[0137] Intermediate 23, 4-bromo-6-chloropyridin-3-amine. The title compound was synthesized using 4-bromo-2-chloro-5-nitropyridine as the starting material following the general protocol for iron reduction. Example 29 [ka]

[0138] Intermediate 24, 2-Bromo-4-ethyl-6-fluoroaniline 1-Bromo-5-ethyl-3-fluoro-2-nitrobenzene. The title compound was synthesized using 1-Bromo-5-ethyl-3-fluoro-2-nitrobenzene as the starting material and following the general protocol for iron reduction. Example 30 [ka]

[0139] Intermediate 25, 3-bromo-4-nitrophenyl dimethylcarbamate. 3-Bromo-4-nitrophenol was dissolved in dry acetonitrile. 1.5 equivalents of solid K2CO3 and 1.2 equivalents of dimethylcarbamic chloride were added. The mixture was stirred overnight at room temperature and then at 100 °C for 2 hours. The mixture was diluted with DCM, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography. Example 31 [ka]

[0140] Intermediate 26, 4-amino-3-bromophenyldimethylcarbamate. The title compound was synthesized using 3-bromo-4-nitrophenyldimethylcarbamate as the starting material following the general protocol for iron reduction. Example 32 [ka]

[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 K2CO3 were dissolved in dry DMF. The reaction was heated at 140 °C for 5 minutes under microwave conditions. After adding an additional 0.5 equivalents of 1-bromo-2-fluoroethane, 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 Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography. Example 33 [ka]

[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 [ka]

[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 K2CO3 were added. The mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate and DCM. The combined organics were dried, filtered, and concentrated under reduced pressure. The crude product was used without further purification. Example 35 [ka]

[0144] Intermediate 30, 4-(3-Bromo-4-nitro-phenyl)-morpholine. The title compound was synthesized using 4-(3-bromo-4-nitro-phenyl)-morpholine as the starting material following the general protocol for iron reduction. Example 36 [ka]

[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 Na2CO3 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 Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by gradient flash chromatography. Example 37 [ka]

[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 NaCO in water were added. The mixture was heated at 135° C. under microwave conditions for 10 minutes. 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 NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by gradient flash chromatography. Example 38 [ka]

[0147] Intermediate 33, 4-(4-bromo-3-nitrophenoxy)tetrahydro-2H-pyran. Tetrahydro-2H-pyran-4-yl methanesulfonate and 1 equivalent of 4-bromo-3-nitrophenol were dissolved in dry DMF. 1.5 equivalents of K2CO3 were added. The mixture was heated at 150 °C for 30 minutes under microwave irradiation. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 2M HCl, saturated aqueous NaHCO3, and brine. The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by gradient flash chromatography. Example 39 [ka]

[0148] Intermediate 34, 2-bromo-5-((tetrahydro-2H-pyran-4-yl)oxy)aniline. The title compound was synthesized using 4-(4-bromo-3-nitrophenoxy)tetrahydro-2H-pyran as the starting material following the general protocol for iron reduction. Example 40 [ka] [ka] Optionally substituted 5- or 6-membered aryl or heteroaryl R: H, Hal, Ar, Alk PG:PMB, 2-THP "B": B(OH)2, Bpin X+:C2Cl6, C2Cl2Br2, I2, ICl

[0149] A general route to the 1H-[1,2]diazepine compound class. Example 41 Pathway A: Aryl-aryl bond formation. [ka]

[0150] 2-[4-Nitro-2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-phenylamine (Route A: Representative of Suzuki coupling from commercially available boron esters or acids from commercially available boron pinacol esters). 1 equivalent of 5-chloro-4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole was dissolved in dioxane, followed by 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 Na2CO3. The mixture was degassed with N2 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 Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography. Example 42 Pathway B: Aryl-aryl bond formation. [ka]

[0151] Representative example of sequential boronation / Suzuki coupling using 2-methoxy-6-[4-nitro-2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-phenylamine (Route B: 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl]. The two steps were carried out in a "two-step-one-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 degassed with N. After that, 0.1 equivalent of Pd-dppf and, after further degassing with N, 2 equivalents of diborolane were added. The mixture was heated at 80 °C overnight. 0.8 equivalents of 5-chloro-4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole and 3 equivalents of 2M Na.sub.2CO. were added to the mixture. The mixture was flushed with N2 again, and then another 0.05 equivalents 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 three times with ethyl acetate. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography. Example 43 Pathway C: Aryl-aryl bond formation. [ka]

[0152] 3-Methoxy-2-[4-nitro-2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-phenylamine (Route C: Representative example of Stille coupling using 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane). 1 equivalent of 2-bromo-3-methoxy-phenylamine and 3 equivalents of triethylamine were dissolved in dry dioxane. The mixture was flushed with N2, followed by the addition of 0.1 equivalent of Pd dppf and, after further degassing with N2, 3 equivalents of pinacolborane. The mixture was heated at 140 °C for 2 hours under microwave conditions. 0.8 equivalents of 5-chloro-4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole and 3 equivalents of 2 M Na2CO3 solution were added to the mixture. The mixture was again flushed with N2, followed by the addition of another 0.1 equivalent of Pd dppf. 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 organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography. Example 44 Pathway D: Aryl-aryl bond formation. [ka]

[0153] 6-Methoxy-2-[2-(4-methoxybenzyl)-4-nitro-2H-pyrazol-3-yl]-pyridin-3-ylamine (Representative of Route D: Direct Arylation). 4-Nitro-1-(4-methoxybenzyl)-1H-pyrazole, 1 equivalent of 2-bromo-6-methoxy-pyridin-3-ylamine, 0.3 equivalents of pivalic acid, and 3 equivalents of K2CO3 were dissolved in dry DMF. The mixture was degassed with N2, and then 0.15 equivalents of catacxium A 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, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography. Example 45 Route E. Hydrogenation. [ka]

[0154] 5-(2-Amino-5-methyl-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-ylamine (representative of Route E: hydrogenation). 4-Methyl-2-[4-nitro-2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-phenylamine was dissolved in methanol and 0.07 equivalents of Pd / C, 10% w / w, was added. The mixture was stirred at room temperature under a hydrogen atmosphere (balloon) for 5 hours. The mixture was filtered through Celite and the solid was washed with MeOH. The filtrate was concentrated under reduced pressure to give the title product, which 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 (representative of Route F: 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 backfilled with N three times. Then, 1.2 equivalents of triethylamine and 1 equivalent of Pd on charcoal (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. The filtrate was then concentrated under reduced pressure. The material was used without further purification. Example 47 Pathway G: Reduction by iron.

[0156] 5-(2-Amino-6-methoxy-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-ylamine (representative of Method G: 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 NH4Cl and a few drops of 2 M HCl were added. The mixture was heated at 50 °C for 1 h. 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 Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used without further purification. Example 48 Cyclization / deprotection procedures using the described aryl-aryldiamines and corresponding aldehydes. [ka] Example 49 [ka]

[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-pyrazol-4-amine and 1 equivalent of 2,6-difluorobenzaldehyde were dissolved in tert-butanol. 3 equivalents of iodine and 3 equivalents of K2CO3 were added. The mixture was stirred overnight at room temperature. 5% w / v aqueous Na2SO3 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 method was used: Method: HPLC-MS A Column: "Waters ACQUITY UPLC HSS T3 50 x 2.1 1.8 μm 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: "0.6mL / min" ms: "ESI Positive & Negative" Method: HPLC-MS B Column: "Waters ACQUITY UPLC CSH C18 50 x 2.1 1.7 μm 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: "0.6mL / min" ms: "ESI Positive and Negative" Method: HPLC-MS C Column: "Waters ACQUITY UPLC CSH C18 50 x 2.1 1.7 μm PN: 186005296" Gradient: 4% - 4.0 min → 96% - 1.0 min → 96% - 0.1 min → 4% - 2.9 min → 4% ACN / H2O + 1 mM NH4Ac buffer pH 9.2 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: "0.6mL / min" ms: "ESI Positive & Negative" Method: HPLC-MS E Column: "Waters ACQUITY UPLC CSH C18 50 x 2.1 1.7 μm 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: "1.2mL / min" ms: "ESI positive"

[0159] The products listed in Table 3 were synthesized by the 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] The following compounds from Table 3 were synthesized using additional steps: Example 52 [ka]

[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 CsCO, and 0.2 equivalents of Pd(PPh) 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 further step, deprotection, followed the corresponding procedure described above. Example 53 [ka]

[0161] Compound 81, 5-(2,6-difluorophenyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-8-carboxamide. 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 NH4Cl, 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 organics were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by SEMIprep chromatography. Example 54 [ka]

[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 [ka]

[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 the following 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 [ka]

[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-fluoroethan-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 [ka]

[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 [ka] 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 saturated aqueous THF. LiOH was added, and the mixture was stirred at 60 °C for 3 h. The mixture was acidified and extracted with ethyl acetate. The combined organics were dried over Na2SO4, 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 [ka]

[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 the following procedure using 5-(2,6-difluorophenyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxylic acid (2-fluoroethyl)-methylamine hydrochloride as the starting material. Example 60 [ka] 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]diazepin-9-yl)-5,6-dihydropyridine-1(2H)-carboxylate was dissolved in 4 M HCl in dioxane. The mixture was stirred at room temperature overnight. The solid was collected by filtration and used without further purification. [ka]

[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 120 °C under microwave conditions for 15 minutes. 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 organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used without further purification for deprotection as described above. Example 61 [ka]

[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. 3 more equivalents of DIPEA and 2 equivalents of 2-bromoethan-1-ol were added, and the mixture was stirred at room temperature overnight again. The mixture was concentrated under reduced pressure and purified by flash chromatography. Example 62 [ka]

[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 a 2M Na2CO3 solution were added. The mixture was degassed with N2, and then 0.2 equivalents of Pd dppf was added. The mixture was heated under microwave conditions at 140° C. for 30 minutes. An additional 1.5 equivalents of (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid and 0.2 equivalents of Pd dppf were added, and the mixture was again heated under microwave conditions at 140° C. for 30 minutes. This addition and heating was repeated twice. The mixture was filtered through Celite and concentrated under reduced pressure. The next step, deprotection, was carried out under the conditions described above. Example 63 [ka]

[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 at room temperature overnight. The mixture was diluted with methanol and saturated aqueous NaHCO3, then 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 activity against a range of kinases according to the following procedure. Biochemical assays:

[0175] The basic protocol for TR-FRET LanthaScreen Eu Kinase Binding Assay inhibitor testing was as follows. The LanthaScreen Kinase Binding Assay (ThermoFisher, USA) for inhibitor evaluation was performed by adding 5 μl of test compound and 5 μl of tracer in the corresponding DMSO dilution / 5 μl of kinase / antibody mixture to a 384-well small-volume plate. After 1 hour of incubation at room temperature, the plate was read. Data analysis of the emission ratio followed the LanthaScreen Eu Kinase Binding Assay protocol.

[0176] Kinase and assay components were adjusted to the final concentrations specified in the kit protocol: for LRRK2: 5 nM wt human LRRK2 catalytic site or G2019S human LRRK2 catalytic site (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 HTRF KinEASE assay (Cisbio / France) inhibitor testing included two steps:

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

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

[0179] Kinase and assay components were adjusted to final concentrations according to the kit protocol: for TYK2: 2 nM wt human TYK2, catalytic site (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 have an IC of less than 10 nM 50Compound 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 6 1; 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 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; 7; 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 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; 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 have IC values ​​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 have IC values ​​between 100nM and 1000nM: 50 Compounds included: 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 have 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 have IC values ​​between 10 nM and 100 nM: 50Compound 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 22 3; 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 IC values ​​between 100nM and 1000nM: 50 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 2 17; 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 Compound 71; Compound 165; Compound 234; Compound 237; and Compound 226

[0187] The following compounds have IC values ​​between 10 nM and 100 nM: 50 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 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 have IC values ​​between 100nM and 1000nM: 50Compound 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, patent application publications, journals, books, articles, web content, etc. have been made throughout this disclosure. All such documents are hereby incorporated by reference herein in their entirety for all purposes. equivalent

[0190] Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the entire contents of this document, including references to the scientific and patent literature cited herein. The subject matter of this specification contains important information, exemplification, and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof. The present invention provides, for example, the following items. (Item 1) Formula (I): [ka] or a tautomer thereof, or a pharmaceutically acceptable salt thereof [In the formula, R1 is aryl or heteroaryl, each of which is optionally substituted; R 2 H, halo, OH, CN, CF 3 、C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Thioalkyl, C 3~8 Cycloalkyl, C 2~8 heterocycloalkyl, aryl, or heteroaryl; A is aryl or 5- or 6-membered heteroaryl; Said C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Thioalkyl, C 3~8 Cycloalkyl, C 2~8 Each of heterocycloalkyl, aryl, and heteroaryl may optionally include halo, OH, CN, CF 3 , N.H. 2 , NO 2 、C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Thioalkyl, C 3~8 Cycloalkyl, C 2~8 Heterocycloalkyl, C 2~8 Heterocycloalkenyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylamino, C 2~6 Dialkylamino, C 7~12 Aralkyl, C 1~12 Heteroaralkyl, 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, and -S(O) 2 NRR′, Each of R, R', and R" independently represents H, halo, OH, C 1~6 Alkyl, C1~6 Haloalkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl, C 2~8 heterocycloalkyl, aryl, or heteroaryl, or R and R', or R' and R" taken together with the nitrogen to which they are attached, are C 2~8 forming a heterocycloalkyl]. (Item 2) Formula (II) shown below:

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Claims

1. Formula (II): 【Transformation 79】 or a tautomer thereof, or a pharmaceutically acceptable salt thereof [In the formula, R １ is aryl or heteroaryl, each of which is optionally substituted; R ２ 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 is cycloalkyl, U is N or CR ３ and V is N or CR ４ and W is N or CR ５ and X is N or CR ６ and R ３ ~R ６ each independently represents H, halo, OH, CN, CF ３ , CHF ２ , C.H. ２ F, N.H. 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′, 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; R and R', or R' and R", together with the nitrogen to which they are attached, form C ２～８ forming a heterocycloalkyl, At most one N is assigned to U, V, W, and X].

2. Formula (III): 【Chemistry 80】 [In the formula, R １ is aryl or heteroaryl, each of which is optionally substituted; R ２ H, halo, OH, CN, CF ３ , CHF ２ , C.H. ２ F, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkyl, C １～６ thioalkyl, or C ３～８ is cycloalkyl, R ３ ~R ６ each independently represents H, halo, OH, CN, CF ３ , CHF ２ , C.H. ２ F, N.H. 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 ２～８ heterocycloalkyl, aryl, or heteroaryl, or R and R′, or R′ and R″ together with the nitrogen to which they are attached, are C ２～８ forming a heterocycloalkyl] 2. The compound of claim 1, wherein:

3. 2. The compound of claim 1, wherein one of U, V, W, and X is N, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

4. R １ 2. The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein is aryl.

5. R １ 2. The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein is 5- or 6-membered heteroaryl.

6. R ２ H, halo, C １～６ Alkyl, C １～６ Alkoxy, C １～６ thioalkyl, or C ３～８ 2. The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R is cycloalkyl.

7. R ３ ~R ６ each independently represents H, halo, OH, CN, CF ３ , CHF ２ , C.H. ２ F, N.H. ２ , NO ２ , C １～６ Alkyl, C ３～８ Cycloalkyl, C ２～８ Heterocycloalkyl, C ２～８ 3. The compound of claim 2, wherein the compound is heterocycloalkenyl, aryl, heteroaryl, -C(O)OR, -C(O)NRR', -OR, -OC(O)NRR', -NRR', or -NRC(O)R', or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

8. R ３ ~R ６ 3. The compound of claim 2, wherein at least three of are each H, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

9. R ３ , R ４ , and R ６ is H, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

10. R ３ ~R ６ is H, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

11. R ３ and R ６ is H, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

12. R ３ and R ６ each of which is H, and R ４ and R ５ each independently represents halo, OH, CN, CF ３ , CHF ２ , C.H. ２ F, N.H. ２ , NO ２ , C １～６ Alkyl, C ３～８ Cycloalkyl, C ２～８ Heterocycloalkyl, C ２～８ 3. The compound of claim 2, wherein the compound is heterocycloalkenyl, aryl, heteroaryl, -C(O)OR, -C(O)NRR', -OR, -OC(O)NRR', -NRR', or -NRC(O)R', or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

13. R ３ , R ４ , and R ６ each of which is H, and R ５ Halo, OH, CN, CF ３ , N.H. ２ , NO ２ , C １～６ Alkyl, C ３～８ Cycloalkyl, C ２～８ Heterocycloalkyl, C ２～８ 3. The compound of claim 2, wherein the compound is heterocycloalkenyl, aryl, heteroaryl, -C(O)OR, -C(O)NRR', -OR, -OC(O)NRR', -NRR', or -NRC(O)R', or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

14. R ３ ~R ６ each independently represents H, halo, CF ３ , C １～６ Alkyl, C ２～８ Heterocycloalkyl, C ２～８ 8. The compound of claim 7, which is heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR', or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

15. R ３ and R ６ each of which is H, and R ４ and R ５ Each of these independently represents halo, CF ３ , CHF ２ , C.H. ２ F, C １～６ Alkyl, C ２～８ Heterocycloalkyl, C ２～８ 8. The compound of claim 7, which is heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR', or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

16. R ４ and R ５ each independently represents F, Cl, CF ３ , CHF ２ , C.H. ２ F, 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 are C ２～８ 16. The compound of claim 15, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, which forms a heterocycloalkyl.

17. R ３ , R ４ , and R ６ each of which is H, and R ５ Halo, CF ３ , CHF ２ , C.H. ２ F, C １～６ Alkyl, C ２～８ Heterocycloalkyl, C ２～８ 8. The compound of claim 7, which is heterocycloalkenyl, -OR, -C(O)OR, or -C(O)NRR', or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

18. R ５ is F, Cl, CF ３ , CHF ２ , C.H. ２ F, 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 are C ２～８ 18. The compound of claim 17, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, which forms a heterocycloalkyl.

19. 4. The compound of claim 3, wherein U is N, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

20. V is CR ４ and W is CR ５ and X is CR ６ and R ４ , R ５ and R ６ is H, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

21. V is CR ４ and W is CR ５ and X is CR ６ and R ６ is H and R ４ and R ５ each independently represents F, Cl, CF ３ , CHF ２ , C.H. ２ F, 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 are C ２～８ 20. The compound of claim 19, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, which forms a heterocycloalkyl.

22. V is CR ４ and W is CR ５ and X is CR ６ and R ４ and R ６ each of which is H, and R ５ is F, Cl, CF ３ , CHF ２ , C.H. ２ F, 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 are C ２～８ 20. The compound of claim 19, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, which forms a heterocycloalkyl.

23. 4. The compound of claim 3, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein V is N.

24. U is CR ３ and W is CR ５ and X is CR ６ and R ３ , R ５ , and R ６ is H, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

25. U is CR ３ and W is CR ５ and X is CR ６ and R ６ is H and R ３ and R ５ each independently represents F, Cl, CF ３ , CHF ２ , C.H. ２ F, 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 are C ２～８ 24. The compound of claim 23, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, which forms a heterocycloalkyl.

26. U is CR ３ and W is CR ５ and X is CR ６ and R ３ and R ６ each of which is H, and R ５ is F, Cl, CF ３ , CHF ２ , C.H. ２ F, 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 are C ２～８ 24. The compound of claim 23, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, which forms a heterocycloalkyl.

27. U is N and V is CR ４ and W is CR ５ and X is CR ６ and R ６ is H and R ４ and R ５ each independently represents F, Cl, CF ３ , CHF ２ , C.H. ２ F, C １～６ Alkyl, C ２～８ Heterocycloalkyl, C ２～８ heterocycloalkenyl, —OR, —C(O)OR, or —C(O)NRR′; or U is CR ３ , V is N, and W is CR ５ and X is CR ６ and R ６ is H and R ３ and R ５ each independently represents F, Cl, CF ３ , CHF ２ , C.H. ２ F, C １～６ Alkyl, C ２～８ Heterocycloalkyl, C ２～８ heterocycloalkenyl, —OR, —C(O)OR, or —C(O)NRR′; 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 are C ２～８ 4. The compound of claim 3, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, which forms a heterocycloalkyl.

28. U is N and V is CR ４ and W is CR ５ and X is CR ６ and R ４ and R ６ each of which is H, and R ５ is F, Cl, CF ３ , CHF ２ , C.H. ２ F, C １～６ Alkyl, C ２～８ Heterocycloalkyl, C ２～８ heterocycloalkenyl, —OR, —C(O)OR, or —C(O)NRR′; or U is CR ３ , V is N, and W is CR ５ and X is CR ６ and R ３ and R ６ each of which 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′; 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 are C ２～８ 4. The compound of claim 3, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, which forms a heterocycloalkyl.

29. R １ but, 【Chemistry 81】 [In the formula, R ａ ~R ｅ each independently represents H, halo, OH, CN, CF ３ , CHF ２ , C.H. ２ F, N.H. 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′, 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 C ２～８ forming a heterocycloalkyl] 5. The compound of claim 4, wherein:

30. R ｂ , R ｃ and R ｄ 30. The compound of claim 29, wherein at least two of are each H, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

31. R ｂ , R ｃ and R ｄ is H, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

32. R ａ and R ｅ each independently is halo or C １～６ 30. The compound of claim 29, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

33. R ａ and R ｅ 30. The compound of claim 29, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein each of is halo.

34. R ａ and R ｅ is F or Cl, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

35. R ａ and R ｅ Each of the is F and R ｂ , R ｃ , and R ｄ is H, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

36. R ａ and R ｅ each of R ｂ , R ｃ , and R ｄ is H, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

37. R １ 6. The compound of claim 5, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein is a 5-membered heteroaryl.

38. R １ 38. The compound of claim 37, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein is a 5-membered heteroaryl containing at least one N.

39. R １ 39. The compound of claim 38, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein is a 5-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, indolyl, indazolyl, and azaidazolyl.

40. R １ 38. The compound of claim 37, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein is an O- or S-containing 5-membered heteroaryl.

41. R １ 41. The compound of claim 40, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein is a 5-membered heteroaryl selected from the group consisting of furanyl, thienyl, benzofuranyl, and benzothienyl.

42. R １ 6. The compound of claim 5, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein is a 6-membered heteroaryl containing at least one N.

43. R １ 43. The compound of claim 42, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein is optionally substituted pyridine.

44. R ２ H, halo, -CH ３ , -SCH ３ or cyclopropyl, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

45. R ２ H, Cl, -CH ３ , or -SCH ３ 45. The compound of claim 44, wherein:

46. Formula (III): 【Chemistry 82】 [In the formula, R １ teeth, 【Chemistry 83】 [In the formula, R ａ , R ｂ , R ｃ , R ｄ , and R ｅ each of which is H, Br, F or Cl; R ２ is H, Cl, -CH ３ or -SCH ３ and R ３ and R ６ Each of is H, and R ４ and R ５ each independently represents halo, OH, CN, CF ３ , N.H. 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′, wherein 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, are C ２～８ forming a heterocycloalkyl] 2. The compound of claim 1, wherein:

47. Formula (II): 【Chemical 84】 [In the formula, R １ teeth, 【Chemical 85】 [In the formula, R ａ , R ｂ , R ｃ , R ｄ , and R ｅ each of which is H, Br, F or Cl; R ２ is H, Cl, -CH ３ or -SCH ３ and U is N and V is CR ４ and W is CR ５ and X is CR ６ and R ４ and R ６ Each of is H, and R ５ are F, Cl, and 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, 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, are C ２～８ forming a heterocycloalkyl] 2. The compound of claim 1, wherein:

48. 10. A pharmaceutical composition comprising a compound of claim 1 or a tautomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

49. 10. A composition comprising the compound of claim 1 or a tautomer thereof or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating a medical condition characterized by overexpression or overactivity of a kinase.

50. 50. The composition of claim 49, wherein the kinase is leucine-rich repeat kinase 2 (LRRK2), AMPK-related protein kinase 5 (NUAK1), or non-receptor tyrosine-protein kinase 2 (TYK2).

51. 10. A composition comprising the compound of claim 1 or a tautomer thereof or a pharmaceutically acceptable salt thereof for use in a method of modulating the activity of a kinase, the method comprising contacting a cell containing the kinase with the compound or the pharmaceutically acceptable salt thereof.

52. 52. The composition of claim 51, wherein the compound inhibits the activity of the kinase.

53. 52. The composition of claim 51, wherein the kinase is leucine-rich repeat kinase 2 (LRRK2), AMPK-related protein kinase 5 (NUAK1), or non-receptor tyrosine-protein kinase 2 (TYK2).

54. 10. A composition comprising the compound of claim 1 or a tautomer thereof or a pharmaceutically acceptable salt thereof for treating a medical condition characterized by overexpression of a kinase in a subject in need of such treatment.

55. 55. The composition of claim 54, wherein the kinase is leucine-rich repeat kinase 2 (LRRK2), AMPK-related protein kinase 5 (NUAK1), or non-receptor tyrosine-protein kinase 2 (TYK2).

56. 55. The composition of claim 54, wherein the medical condition is 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.

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