Compounds as LRRK2, NUAK1 and / or TYK2 kinase modulators for treatment of e.g. Autoimmune diseases

Abstract

The present invention relates to compounds of formula (I) capable of modulating, e.g. Inhibiting or activating, one or more kinases, in particular LRRK2 and / or NUAK1 and / or TYK2 or mutants thereof. The compounds are useful in the treatment of diseases such as autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergy, asthma, Alzheimer's disease, Parkinson's disease, skin disorders, eye diseases, infectious diseases and hormone-related diseases. The present specification discloses synthesis and characterization of exemplary compounds and pharmacological data of the compounds (e.g., Page 40th to Page 146; examples 1 to 63; compounds 1 to 248; tables 1 to 3). Preferred compounds are, for example, l, 4-dihydrobenzo [d] pyrazolo [3, 4-f] [l, 3] diazepine derivatives and related compounds. Exemplary compounds are, for example, 5-(2, 6-difluorophenyl)-8-methoxy-1, 4-dihydrobenzo [d] pyrazolo [3, 4-f] [1, 3] diazepine (example 49). (Formula (II)). # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 899,908, filed on September 13, 2019, the contents of which are incorporated by reference. Technical Field

[0003] The present invention generally relates to compounds and their use in pharmacological compositions for treating disease states and to radiolabeled tracers in positron emission tomography (PET) for diagnostic use. Background Art

[0004] A wide variety of medical conditions that affect millions of people are caused or exacerbated by the unregulated activity of protein kinases. For example, aberrant kinase activity is associated with autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, Alzheimer's disease, Parkinson's disease, skin disorders, eye diseases, infectious diseases, and hormone-related diseases. However, for many of these diseases, there are no effective inhibitors or activators for the specific kinases that cause the condition or its symptoms. As a result, patients continue to suffer from a range of diseases due to a lack of appropriate drugs for their conditions. Summary of the invention

[0005] The present invention provides compounds of pharmacological compositions useful for treating pathologies and radiolabeled tracers for use in positron emission tomography (PET) for diagnostic purposes. In certain embodiments, the compounds of the present invention modulate, e.g., inhibit or activate, inhibit protein kinase activity, such as leucine-rich repeat kinase 2 (LRRK2), SNF1-like kinase 1 (also known as AMPK-associated protein kinase 5 (NUAK1), also known as (ARK5)) and non-receptor tyrosine protein kinase 2 (TYK2) activity, which are associated with human diseases, disorders and pathologies. These compounds exhibit improved pharmacological properties, such as tissue delivery, specificity, efficacy and stability. For example, the present invention comprises compounds that are able to penetrate the blood-brain barrier and bind to kinase targets with high affinity. In addition, radiolabeled forms of the compounds of the present invention can be used as PET tracers to identify anatomical locations of abnormal kinase activity. Therefore, the compounds of the present invention can be used as therapeutic and diagnostic agents for a variety of pathologies, such as Parkinson's disease and autoimmune diseases.

[0006] Thus, the present invention provides compositions containing the compounds described herein, including pharmacological compositions and compositions for diagnostic applications. The present invention further provides methods of using such compositions to diagnose and / or treat a condition in a subject.

[0007] In one aspect, the present invention provides a compound of formula (I):

[0008]

[0009] or a tautomer thereof or a pharmaceutically acceptable salt thereof,

[0010] in:

[0011] R 1 is aryl or heteroaryl;

[0012] R 2 H, halogen, 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; and

[0013] A is an aryl group or a 5-membered or 6-membered heteroaryl group;

[0014] Among them, C 1-6 Alkyl, the C 1-6 Alkoxy, the C 1-6 Haloalkyl, the C 1-6 Thioalkyl, the C 3-8 Cycloalkyl, the C 2-8 Each of the heterocycloalkyl, the aryl and the heteroaryl is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, CF3, NH2, NO2, 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 Halogenated alkoxy, C 1-6 Alkylamino, C 2-6 Dialkylamino, C 7-12 Aralkyl, C 1-12heteroaralkyl, aryl, heteroaryl, -C(O)R, -C(O)OR, -C(O)NRR', -C(O)NRS(O)2R', -C(O)NRS(O)2NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)2R', -NRS(O)2NR'R", -S(O)2R and -S(O)2NRR',

[0015] 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 form a C 2-8 Heterocycloalkyl.

[0016] The compound of formula (I) can be represented by formula (II):

[0017]

[0018] in

[0019] R 1 is aryl or heteroaryl;

[0020] R 2 H, halogen, OH, CN, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Thioalkyl or C 3-8 Cycloalkyl;

[0021] U is N or CR 3 ;

[0022] V is N or CR 4 ;

[0023] W is N or CR 5 ;

[0024] X is N or CR 6 ;and

[0025] R 3 to R 6 Each of which is independently H, halogen, OH, CN, CF3, CHF2, CH2F, NH2, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C3-8 Cycloalkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocycloalkenyl, aryl, heteroaryl, -C(O)R, -C(O)OR, -C(O)NRR', -C(O)NRS(O)2R', -C(O)NRS(O)2NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)2R', -NRS(O)2NR'R", -S(O)2R or -S(O)2NRR',

[0026] in

[0027] 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

[0028] R and R' or R' and R" together with the nitrogen to which they are attached form a C 2-8 heterocycloalkyl; and

[0029] At most one N is assigned to U, V, W, and X.

[0030] One of U, V, W and X may be N.

[0031] U can be N. V can be CR 4 , W can be CR 5 , and X can be CR 6 , where R 4 , R 5 and R 6 Each of them is H. V can be CR 4 , W can be CR 5 , and X can be CR 6 , R 6 H and R 4 and R 5 Each of which is independently F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocyclohetero ... 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C2-8 Heterocycloalkyl. V can be CR 4 , W can be CR 5 , and X can be CR 6 , R 4 and R 6 Each of them is H, and R 5 For F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocyclohetero ... 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0032] V can be N. V can be CR 3 , W can be CR 5 , and X can be CR 6 , where R 3 , R 5 and R 6 Each of them is H. U can be CR 3 , W can be CR 5 , and X can be CR 6 , R 6 H and R 3 and R 5 Each of which is independently F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocyclohetero ... 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl. U can be CR 3 , W can be CR 5 , and X can be CR 6 , R 3 and R 6 Each of is H, and R5 is F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8heterocyclohetero ... 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0033] U can be N, V ​​can be CR 4 , W can be CR 5 , and X can be CR 6 , R 6 is H, and R 4 and R 5 Each of which is independently F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocyclohetero ... 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0034] U can be CR 3 , V can be N, W can be CR 5 , and X can be CR 6 , R 6 is H, and R 3 and R 5 Each of which is independently F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocyclohetero ... 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0035] U can be N, V ​​can be CR 4 , W can be CR 5 , and X can be CR 6 , R 4 and R 6Each of them is H, and R 5 For F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocycloheterocycloalkenyl, -OR, -C(O)OR or -C(O)NRR'; wherein each of R and R' is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0036] U can be CR 3 , V can be N, W can be CR 5 , and X can be CR 6 , R 3 and R 6 Each of them is H, and R 5 For F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocycloheterocycloalkenyl, -OR, -C(O)OR or -C(O)NRR'; wherein each of R and R' is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0037] R 1 R may be an aryl group. 1 Can be

[0038]

[0039] Where R a to R e Each of which is independently H, halogen, 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 2-8heterocycloalkenyl, aryl, heteroaryl, -C(O)R, -C(O)OR, -C(O)NRR', -C(O)NRS(O)2R', -C(O)NRS(O)2NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)2R', -NRS(O)2NR'R", -S(O)2R or -S(O)2NRR',

[0040] in

[0041] 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

[0042] R and R' or R' and R" together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0043] R b , R c and R d At least two of them can each be H. b , R c and R d Each of them can be H. R a and R e Each of which is independently halogen or C 1-6 Alkyl. a and R e Each of R may be a halogen group. a and R e Each of R can be F or Cl. a and R e Each of them can be F, and R b , R c and R d Each of them can be H. R a and R e Each of them can be Cl, and R b , R c and R d Each of can be H.

[0044] R 1 It may be a 5-membered or 6-membered heteroaryl group. 1 It may be a 5-membered heteroaryl group. 1 It may be a 5-membered heteroaryl group containing at least one N. 1R may be a 5-membered heteroaryl group selected from the group consisting of pyrrolyl, pyrazolyl, indolyl, indazolyl and azaindazolyl. 1 It may be a 5-membered heteroaryl group containing O or S. 1 R may be a 5-membered heteroaryl group selected from the group consisting of a furyl group, a thienyl group, a benzofuranyl group, and a benzothienyl group. 1 It may be a 6-membered heteroaryl group containing at least one N. 1 It may be an optionally substituted pyridine.

[0045] R 2 Can be H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Thioalkyl or C 3-8 Cycloalkyl. 2 It can be H, halogen, -CH3, -SCH3 or cyclopropyl. 2 It can be H, Cl, -CH3 or -SCH3.

[0046] The compound of formula (I) can be represented by formula (III):

[0047]

[0048] in

[0049] R 1 is aryl or heteroaryl;

[0050] R 2 H, halogen, OH, CN, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Thioalkyl or C 3-8 cycloalkyl; and

[0051] R 3 to R 6 Each of which is independently H, halogen, 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 2-8heterocycloalkenyl, aryl, heteroaryl, -C(O)R, -C(O)OR, -C(O)NRR', -C(O)NRS(O)2R', -C(O)NRS(O)2NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)2R', -NRS(O)2NR'R", -S(O)2R or -S(O)2NRR', or R 4 and R 5 Together with the atoms to which it is attached, it forms a ring having between 5 and 10 members,

[0052] in

[0053] Each of R, R' and R" is independently H, halo, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 2-8 heterocycloalkyl, aryl or heteroaryl, or R and R' or R' and R" together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0054] R 3 to R 6 Each of which can be independently H, halogen, OH, CN, CF3, 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'. 3 to R 6 At least three of them may be H. 3 , R 4 and R 6 Each of the R 3 to R 6 They can all be H. 3 and R 6 Each of them is H, and R 4 and R 5 Each of which can be independently halogen, OH, CN, CF3, 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'. 3 , R 4 and R 6 Each of them can be H, and R 5 Can be halogen, OH, CN, CF3, 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'. 3 to R 6 Each of which can be independently H, halogen, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocycloalkenyl, -OR, -C(O)OR or -C(O)NRR'. 3 and R 6 Each of them can be H, and R 4 and R 5 Each of which can be independently halogen, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocycloalkenyl, -OR, -C(O)OR or -C(O)NRR'. 4 and R 5 Each of which can be independently F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocyclohetero ... 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl. 3 , R 4 and R 6 Each of them can be H, and R 5 Can be halogen, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocycloalkenyl, -OR, -C(O)OR or -C(O)NRR'. 5Can be F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocyclohetero ... 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0055] The compound of formula (I) can be represented by formula (III):

[0056]

[0057] in:

[0058] R 1 express

[0059]

[0060] in:

[0061] R a , R b , R c , R d and R e Each of is H, Br, F or Cl;

[0062] R 2 is H, Cl, -CH3 or -SCH3; and

[0063] R 3 and R 6 Each of H, R 4 and R 5 Each of which is independently halogen, 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, they form a ring having between 5 and 10 members, wherein each of R, R' and R" is independently H, halogen, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 3-8 Cycloalkyl, C 2-8 heterocycloalkyl, aryl or heteroaryl, or R and R' or R' and R" together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0064] The compound of formula (I) can be represented by formula (II):

[0065]

[0066] in:

[0067] R 1 express

[0068]

[0069] in:

[0070] R a , R b , R c , R d and R e Each of is H, Br, F or Cl;

[0071] R 2 is H, Cl, -CH3 or -SCH3; and

[0072] U is N, V ​​is CR 4 , W is CR 5 , and X is CR 6 , R 4 and R 6 Each of them is H, and R 5 For 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', 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 form a C 2-8 Heterocycloalkyl.

[0073] A may be a 5-membered heteroaryl group containing at least one N. A may be a 5-membered heteroaryl group selected from the group consisting of a pyrazolyl group, an indazolyl group, and an azaindazolyl group.

[0074] In another aspect, the present invention provides pharmaceutical compositions comprising a compound, such as any of those described above or a pharmaceutically acceptable salt of such a compound and a pharmaceutically acceptable carrier.

[0075] In another aspect, the invention provides a compound, such as any of those described above, for use in the manufacture of a medicament for treating a medical condition characterized by abnormal activity or expression of a kinase. The kinase may be overexpressed or underexpressed. The activity of the kinase may be increased or the activity may be decreased. The kinase may be LRRK2, NUAK1 or TYK2.

[0076] In another aspect, the invention provides a method of regulating 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 comprise inhibiting the kinase. The method may comprise activating the kinase. The kinase may be LRRK2, NUAK1 or TYK2.

[0077] In another aspect, the invention provides methods 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 thereof. 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.

[0078] In another aspect, the invention provides a method of preparing a compound, such as any of those described above, by reacting a bisamino compound with an aldehyde to form the compound. DETAILED DESCRIPTION

[0079] Chemical Definition

[0080] The expression cycloalkyl refers to a saturated or partially unsaturated (e.g., cycloalkenyl) cyclic group containing one or more rings and containing 3 to 14 ring carbon atoms, such as 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring carbon atoms. The expression cycloalkyl also refers to a group in which one or more hydrogen atoms have been replaced by fluorine atoms, chlorine atoms, bromine atoms or iodine atoms or by OH, =O, SH, =S, NH2, =NH, N3 or NO2 groups, thus, for example, cyclic ketones, such as cyclohexanone, 2-cyclohexenone or cyclopentanone. Other specific examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, spiro [4,5] decyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decahydronaphthyl, bicyclo [4.3.0] nonyl, tetralin, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl.

[0081] The expression heterocycloalkyl refers to a cycloalkyl as defined above, wherein one or more (e.g., 1, 2 or 3) ring carbon atoms have been replaced by oxygen atoms, nitrogen atoms, silicon atoms, selenium atoms, phosphorus atoms or sulfur atoms or SO groups or SO2 groups. Heterocycloalkyl preferably has 1 or 2 rings containing 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring atoms (e.g., C, O, N or S). The expression heterocycloalkyl also refers to a group substituted by a fluorine atom, a chlorine atom, a bromine atom or an iodine atom or by an OH, =O, SH, =S, NH2, =NH, N3 or NO2 group. Examples are piperidinyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrofuranyl or 2-pyrazolinyl as well as lactams, lactones, cyclic imides and cyclic anhydrides.

[0082] The expression alkylcycloalkyl refers to a group containing both a cycloalkyl group and an alkyl, alkenyl or alkynyl group according to the above definition, for example, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl. Alkylcycloalkyl preferably contains a cycloalkyl group containing one or two rings having 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring carbon atoms and one or two alkyl, alkenyl or alkynyl groups having 1 or 2 to 6 carbon atoms.

[0083] The statement heteroalkylcycloalkyl refers to an alkylcycloalkyl as defined above, wherein one or more (for example, 1, 2 or 3) carbon atoms have been replaced by an oxygen atom, a nitrogen atom, a silicon atom, a selenium atom, a phosphorus atom or a sulfur atom or an SO group or SO2 group. The heteroalkylcycloalkyl preferably contains 1 or 2 rings with 3 to 10 (for example, 3, 4, 5, 6 or 7) ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups with 1 or 2 to 6 carbon atoms. Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl, and these cyclic groups are saturated or monounsaturated, diunsaturated or triunsaturated.

[0084] The expression aryl refers to an aromatic group containing one or more rings containing 6 to 14 ring carbon atoms, such as 6 to 10 ring carbon atoms. The expression aryl also refers to groups substituted by fluorine atoms, chlorine atoms, bromine atoms or iodine atoms or by OH, SH, NH2, N3 or NO2 groups. Examples are phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilino, 3-nitrophenyl or 4-hydroxyphenyl.

[0085] The expression heteroaryl refers to an aromatic group containing one or more rings, which contain 5 to 14 ring atoms, such as 5 to 10 ring atoms, and contain one or more (for example, 1, 2, 3 or 4) oxygen ring atoms, nitrogen ring atoms, phosphorus ring atoms or sulfur ring atoms. The expression heteroaryl also refers to a group substituted by a fluorine atom, a chlorine atom, a bromine atom or an iodine atom or by an OH, SH, N3, NH2 or NO2 group. Examples are pyridinyl (e.g., 4-pyridinyl), 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, quinolyl, isoquinolyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidinyl, 2,3'-bifuranyl, pyrazolyl (e.g., 3-pyrazolyl), and isoquinolyl.

[0086] Aralkyl is meant to contain aryl and also contain the group according to the above-mentioned definition of alkyl, alkenyl, alkynyl and / or cycloalkyl, for example, aryl-alkyl, aryl alkenyl, aryl alkynyl, aryl cycloalkyl, aryl cycloalkenyl, alkyl aryl cycloalkyl and alkyl aryl cycloalkenyl.The specific example of aralkyl is toluene, dimethylbenzene, mesitylene, vinylbenzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indane.Aralkyl preferably contains one or two aromatic ring systems containing 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl containing 1 or 2 to 6 carbon atoms and / or the cycloalkyl containing 5 or 6 ring carbon atoms.

[0087] The expression heteroaralkyl refers to an aralkyl group as defined above, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms have been replaced by oxygen atoms, nitrogen atoms, silicon atoms, selenium atoms, phosphorus atoms, boron atoms or sulfur atoms, i.e. a group containing an aryl or heteroaryl group and an alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl group according to the above definitions, respectively. The heteroaralkyl group preferably contains 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 a cycloalkyl group containing 5 or 6 ring carbon atoms, wherein 1, 2, 3 or 4 of these carbon atoms have been replaced by oxygen atoms, sulfur atoms or nitrogen atoms.

[0088] Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroarylheterocycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroarylalkylheterocycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroarylalkylheterocycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl and heteroarylheteroalkylheterocycloalkyl, these cyclic groups are saturated or mono-unsaturated, di-unsaturated or tri-unsaturated. Specific examples are tetrahydroisoquinolinyl, benzoyl, 2-ethylindolyl or 3-ethylindolyl, 4-methylpyridyl, 2-methoxyphenyl, 3-methoxyphenyl or 4-methoxyphenyl, 4-ethoxyphenyl, 2-carboxyphenylalkyl, 3-carboxyphenylalkyl or 4-carboxyphenylalkyl.

[0089] As mentioned above, the expressions cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to radicals which are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, =O, SH, =S, NH2, =NH, N3 or NO2 groups.

[0090] The expression "optionally substituted" refers in particular to radicals which are optionally substituted by fluorine, chlorine, bromine or iodine atoms or by OH, =O, SH, =S, NH2, =NH, N3 or NO2 groups. This expression also refers to radicals which may be substituted by one, two, three or more unsubstituted C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Heteroalkyl, C3-C 16 Cycloalkyl, C2-C 17 Heterocycloalkyl, C4-C 20 Alkylcycloalkyl, C2-C 19 Heteroalkylcycloalkyl, C6-C 18 Aryl, C 1-17 Heteroaryl, C7-C 20 Arylalkyl or C2-C 19 This expression also refers in particular to a group which may be substituted by one, two, three or more unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl, C7-C 12 Alkylcycloalkyl, C2-C 11 Heteroalkylcycloalkyl, C6-C 10 Aryl, C1-C9 heteroaryl, C7-C 12 Arylalkyl or C2-C 11 Heteroaralkyl substituted groups.

[0091] Exemplary substituents are F, Cl, Br, OH, SH, =O, NH2, C 1-4 Alkyl, C 1-4 Heteroalkylcyclopropyl, SF5, NO and NO2.

[0092] Other exemplary substituents are F, Cl, Br, OH, SH, =O, NH2, C 1-4 Alkyl (e.g., methyl, ethyl, tert-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.

[0093] Other exemplary substituents are F, Cl, Br, Me, OMe, CN or CF3.

[0094] The term halo preferably refers to F, Cl, Br or I.

[0095] According to certain embodiments, all alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl, and heteroaralkyl groups described herein can be optionally substituted.

[0096] When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl group contains more than one ring, the rings may be bonded to each other by single or double bonds, or the rings may be cyclic.

[0097] Compound

[0098] In one aspect, the present invention provides a compound of formula (I):

[0099]

[0100] or a tautomer thereof or a pharmaceutically acceptable salt thereof,

[0101] in:

[0102] R 1 is aryl or heteroaryl;

[0103] R 2 H, halogen, 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; and

[0104] A is an aryl group or a 5-membered or 6-membered heteroaryl group;

[0105] Among them, C 1-6 Alkyl, the C 1-6 Alkoxy, the C 1-6 Haloalkyl, the C 1-6 Thioalkyl, the C 3-8 Cycloalkyl, the C 2-8 Each of the heterocycloalkyl, the aryl and the heteroaryl is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, CF3, NH2, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Thioalkyl, C 3-8 Cycloalkyl, C 2-8 Heterocycloalkyl, C 2-8Heterocycloalkenyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, 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)2R', -C(O)NRS(O)2NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)2R', -NRS(O)2NR'R", -S(O)2R and -S(O)2NRR',

[0106] 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 form a C 2-8 Heterocycloalkyl.

[0107] R 1 It can be expressed as 1 -L 1 -Y 1 A group or formula X 1 -L 1 -Y 1 -LA-Z 1 of groups, among which

[0108] X 1 L is optionally substituted phenyl or optionally substituted heteroaryl containing 5 or 6 ring atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N; 1 a bond or group of the 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-;

[0109] Y 1is optionally substituted phenyl, optionally substituted heteroaryl containing 5 or 6 ring atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N, optionally substituted C3-C7 cycloalkyl or optionally substituted heterocycloalkyl containing 3, 4, 5, 6 or 7 ring atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N;

[0110] L 2 is a bond or group of the 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-, -NH SO2-, -SO2-NH-, or -NH-C(=O)-NH-; and

[0111] Z 1 is optionally substituted phenyl, optionally substituted heteroaryl having 5 or 6 ring atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N, optionally substituted C3-C7 cycloalkyl or optionally substituted heterocycloalkyl having 3, 4, 5, 6 or 7 ring atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N.

[0112] R 1 Can be selected from the following groups:

[0113]

[0114] The compound of formula (I) can be represented by formula (II):

[0115]

[0116] in

[0117] R 1 is aryl or heteroaryl;

[0118] R 2 H, halogen, OH, CN, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Thioalkyl or C 3-8 Cycloalkyl;

[0119] U is N or CR 3 ;

[0120] V is N or CR 4 ;

[0121] W is N or CR 5 ;

[0122] X is N or CR 6 ;and

[0123] R 3 to R 6 Each of which is independently H, halogen, 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)2R', -C(O)NRS(O)2NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)2R', -NRS(O)2NR'R", -S(O)2R or -S(O)2NRR',

[0124] in

[0125] 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

[0126] R and R' or R' and R" together with the nitrogen to which they are attached form a C 2-8 heterocycloalkyl; and

[0127] At most one N is assigned to U, V, W, and X.

[0128] One of U, V, W and X may be N.

[0129] U can be N. V can be CR 4 , W can be CR 5 , and X can be CR 6 , where R 4 , R 5 and R 6 Each of them is H. V can be CR 4 , W can be CR 5 , and X can be CR 6 , R 6 H and R 4 and R 5 Each of which is independently F, Cl, CF3, C1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocyclohetero ... 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl. V can be CR 4 , W can be CR 5 , and X can be CR 6 , R 4 and R 6 Each of them is H, and R 5 For F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocyclohetero ... 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0130] V can be N. V can be CR 3 , W can be CR 5 , and X can be CR 6 , where R 3 , R 5 and R 6 Each of them is H. U can be CR 3 , W can be CR 5 , and X can be CR 6 , R 6 H and R 3 and R 5 Each of which is independently F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocyclohetero ... 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8Heterocycloalkyl. U can be CR 3 , W can be CR 5 , and X can be CR 6 , R 3 and R 6 Each of is H, and R5 is F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocyclohetero ... 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0131] U can be N, V ​​can be CR 4 , W can be CR 5 , and X can be CR 6 , R 6 is H, and R 4 and R 5 Each of which is independently F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocyclohetero ... 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0132] U can be CR 3 , V can be N, W can be CR 5 , and X can be CR 6 , R6 is H, and R 3 and R5 are each independently F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocyclohetero ... 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0133] U can be N, V ​​can be CR 4 , W can be CR 5 , and X can be CR 6 , R 4 and R 6 Each of them is H, and R 5 For F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocycloheterocycloalkenyl, -OR, -C(O)OR or -C(O)NRR'; wherein each of R and R' is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0134] U can be CR 3 , V can be N, W can be CR 5 , and X can be CR 6 , R 3 and R 6 Each of them is H, and R 5 For F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocycloheterocycloalkenyl, -OR, -C(O)OR or -C(O)NRR'; wherein each of R and R' is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0135] R 1 R may be an aryl group. 1 Can be

[0136]

[0137] Where R a to R e Each of which is independently H, halogen, OH, CN, CF3, CHF2, CH2F, NH2, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-6 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)2R', -C(O)NRS(O)2NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)2R', -NRS(O)2NR'R", -S(O)2R or -S(O)2NRR',

[0138] in

[0139] 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

[0140] R and R' or R' and R" together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0141] R b , R c and R d At least two of them can each be H. b , R c and R d Each of them can be H. R a and R e Each of which is independently halogen or C 1-6 Alkyl. a and R e Each of R may be a halogen group. a and R e Each of R can be F or Cl. a and R e Each of them can be F, and R b , R c and R d Each of them can be H. R a and R e Each of them can be Cl, and R b , R c and R d Each of can be H.

[0142] R 1 It may be a 5-membered or 6-membered heteroaryl group.1 It may be a 5-membered heteroaryl group. 1 It may be a 5-membered heteroaryl group containing at least one N. 1 R may be a 5-membered heteroaryl group selected from the group consisting of pyrrolyl, pyrazolyl, indolyl, indazolyl and azaindazolyl. 1 It may be a 5-membered heteroaryl group containing O or S. 1 R may be a 5-membered heteroaryl group selected from the group consisting of a furyl group, a thienyl group, a benzofuranyl group, and a benzothienyl group. 1 It may be a 6-membered heteroaryl group containing at least one N. 1 It may be an optionally substituted pyridine.

[0143] R 2 Can be H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Thioalkyl or C 3-8 Cycloalkyl. 2 It can be H, halogen, -CH3, -SCH3 or cyclopropyl. 2 It can be H, Cl, -CH3 or -SCH3.

[0144] The compound of formula (I) can be represented by formula (III):

[0145]

[0146] in

[0147] R 1 is aryl or heteroaryl;

[0148] R 2 H, halogen, OH, CN, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Thioalkyl or C 3-8 cycloalkyl; and

[0149] R 3 to R 6 Each of which is independently H, halogen, 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 2-8heterocycloalkenyl, aryl, heteroaryl, -C(O)R, -C(O)OR, -C(O)NRR', -C(O)NRS(O)2R', -C(O)NRS(O)2NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)2R', -NRS(O)2NR'R", -S(O)2R or -S(O)2NRR',

[0150] in

[0151] Each of R, R' and R" is independently H, halo, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 2-8 heterocycloalkyl, aryl or heteroaryl, or R and R' or R' and R" together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0152] R 3 to R 6 Each of which can be independently H, halogen, OH, CN, CF3, 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'. 3 to R 6 At least three of them may be H. 3 , R 4 and R 6 Each of the R 3 to R 6 They can all be H. 3 and R 6 Each of them is H, and R 4 and R 5 Each of which can be independently halogen, OH, CN, CF3, 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'. 3 , R 4 and R 6Each of them can be H, and R 5 Can be halogen, OH, CN, CF3, 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'. 3 to R 6 Each of which can be independently H, halogen, CF3, C 1-6 R is alkyl, C2-8 heterocycloalkyl, C2-8 heterocycloalkenyl, -OR, -C(O)OR or -C(O)NRR'. 3 and R 6 Each of them can be H, and R 4 and R 5 Each of which can be independently halogen, CF3, C 1-6 R is alkyl, C2-8 heterocycloalkyl, C2-8 heterocycloalkenyl, -OR, -C(O)OR or -C(O)NRR'. 4 and R 5 Each of which can be independently F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocyclohetero ... 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C 2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl. 3 , R 4 and R 6 Each of them can be H, and R 5 Can be halogen, CF3, C 1-6 R is alkyl, C2-8 heterocycloalkyl, C2-8 heterocycloalkenyl, -OR, -C(O)OR or -C(O)NRR'. 5 Can be F, Cl, CF3, C 1-6 Alkyl, C 2-8 Heterocycloalkyl, C 2-8 heterocyclohetero ... 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or C2-8 Heterocycloalkyl, or R and R' together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0153] The compound of formula (I) can be represented by formula (III):

[0154]

[0155] in:

[0156] R 1 express

[0157]

[0158] in:

[0159] R a , R b , R c , R d and R e Each of is H, Br, F or Cl;

[0160] R 2 is H, Cl, -CH3 or -SCH3; and

[0161] R 3 and R 6 Each of H, R 4 and R 5 Each of which is independently halogen, 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, they form a ring having between 5 and 10 members, wherein each of R, R' and R" is independently H, halogen, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 2-8 heterocycloalkyl, aryl or heteroaryl, or R and R' or R' and R" together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl.

[0162] The compound of formula (I) can be represented by formula (II):

[0163]

[0164] in:

[0165] R 1 express

[0166]

[0167] in:

[0168] R a , R b , R c , R d and R e Each of is H, Br, F or Cl;

[0169] R 2 is H, Cl, -CH3 or -SCH3; and

[0170] U is N, V ​​is CR 4 , W is CR 5 , and X is CR 6 , R 4 and R 6 Each of them is H, and R 5 For 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', 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 form a C 2-8 Heterocycloalkyl.

[0171] A may be a 5-membered heteroaryl group containing at least one N. A may be a 5-membered heteroaryl group selected from the group consisting of a pyrazolyl group, an indazolyl group, and an azaindazolyl group.

[0172] The compound of formula (I) can be represented by one of the following structures:

[0173]

[0174]

[0175]

[0176] Pharmaceutical composition

[0177] The present invention provides pharmaceutical compositions comprising one or more of the above compounds or pharmaceutically acceptable esters, prodrugs, hydrates, solvates or salts thereof, optionally in combination with a pharmaceutically acceptable carrier. The present invention further provides a method for preparing

[0178] Such compounds are useful as medicaments for the treatment of one or more of the diseases mentioned herein.

[0179] The pharmaceutical composition may contain one or more therapeutically effective amounts of the compounds of the present invention. The therapeutically effective amount of the compounds according to the present invention means the amount of the compound that effectively prevents, alleviates or improves the symptoms of the disease or prolongs the survival of the subject being treated. The determination of the therapeutically effective amount is within the technical scope of the art.

[0180] The therapeutically effective amount or dosage of the compounds according to the invention may vary within wide limits and may be determined in a manner known in the art. Such dosage may be adjusted to the individual needs of each particular case, including the specific compound being administered, the route of administration, the condition being treated, and the patient being treated.

[0181] The compositions of the invention may include a vehicle for delivering one or more compounds of the invention. For example, the composition may contain particles, such as nanoparticles, microparticles, liposomes, micelles, and viral particles.

[0182] Examples of pharmacologically acceptable salts of sufficiently basic compounds of the present invention are physiologically acceptable inorganic acids, such as salts of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; or organic acids, such as salts of methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid. Further, sufficiently acidic compounds of the present invention can form alkali metal salts or alkaline earth metal salts, such as sodium salts, potassium salts, lithium salts, calcium salts or magnesium salts; ammonium salts; or organic base salts, such as methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumine, piperidine, morpholine, tri-(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, especially hydrated. Hydration (hydratization / hydration) may occur during the production process, or due to the hygroscopic properties of the initially anhydrous compounds of the present invention. Solvates and / or hydrates may exist, for example, in solid or liquid form.

[0183] It should be understood that some compounds of the present invention may have tautomeric forms, only one of which may be specifically mentioned or depicted in the following description, different geometric isomers (which are usually represented as cis / trans isomers or more generally as (E) and (Z) isomers) or different optical isomers (usually named under the Cahn-Ingold-Prelog or R / S system) arising from one or more chiral carbon atoms. All such 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 non-chiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds. The present invention includes both all pure enantiomers and all pure diastereomers, as well as mixtures thereof in any mixing ratio.

[0184] According to other embodiments of the present invention, one or more hydrogen atoms of the compound of the present invention can be replaced by deuterium. Deuterium modification improves the metabolic characteristics of the drug, and its intrinsic pharmacology has almost no or no change. Deuterium substitution at a specific molecular position improves metabolic stability, reduces the formation of toxic metabolites and / or increases the formation of desired active metabolites. Therefore, the present invention also encompasses partial and complete deuterated compounds of the present invention. The term hydrogen also encompasses deuterium.

[0185] The therapeutic use of the compounds according to the invention, their pharmacologically acceptable salts, solvates and hydrates, as well as formulations and pharmaceutical compositions are also within the scope of the invention. The pharmaceutical composition according to the invention may comprise at least one compound of the invention as an active ingredient and optionally a carrier substance and / or an adjuvant.

[0186] The present invention also relates to prodrugs consisting of a compound of the invention and at least one pharmacologically acceptable protecting group which will be cleaved under physiological conditions, such as alkoxy-, arylalkoxy-, acyl-, acyloxymethyl (e.g., pivaloyloxymethyl), 2-alkyl-, 2-aryl- or 2-arylalkyloxycarbonyl-2-alkyleneethyl or acyloxy groups as defined herein, such as, for example, ethoxy, benzyloxy, acetyl or acetoxy, or, in particular for the compounds of the invention, esters with a hydroxyl group (-OH): sulfate, phosphate (-OPO3 or -OCH2OPO3) or an amino acid. For example, the composition may contain a prodrug of a hydroxyl group of a compound of the invention.

[0187] As used herein, the term pharmaceutically acceptable ester refers in particular to those esters that hydrolyze in vivo and include those that readily 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, specifically alkanoic acids, alkenoic acids, cycloalkyl acids and alkandioic acids, wherein each alkyl or alkenyl moiety advantageously has no more than 6 carbon atoms. Examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinate.

[0188] The present 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 present invention.

[0189] As mentioned above, therapeutically useful agents containing 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 will be administered alone or in combination with any other therapeutic agent by using means known and acceptable in the art.

[0190] For oral administration, such therapeutically useful agents can be administered by one of the following routes: oral administration, for example, as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, such as soft and hard gelatin capsules, aqueous or oily solutions, emulsions, suspensions or syrups; parenteral administration, including intravenous, intramuscular and subcutaneous injections, for example, as injectable solutions or suspensions; rectal administration, as suppositories; by inhalation or insufflation, for example, as powder formulations, as microcrystals or as sprays (e.g., liquid aerosols); transdermal administration, for example, by transdermal delivery systems (TDS), such as plasters containing active ingredients; or intranasal administration. For the production of such tablets, pills, semisolids, coated tablets, dragees and hard capsules, for example, gelatin, the therapeutically useful product can be mixed with a pharmaceutically inert inorganic or organic excipient, such as lactose, sucrose, glucose, gelatin, malt, silica gel, starch or its derivatives, talc, stearic acid or its salts, skimmed milk powder, etc. For the production of soft capsules, for example, vegetable oil, petroleum, animal oil or synthetic oil, wax, fat, polyol can be used as excipient. For the production of liquid solutions, emulsions or suspensions or syrups, for example, water, alcohol, saline, glucose aqueous solution, polyol, glycerol, lipid, phospholipid, cyclodextrin, vegetable oil, petroleum, animal oil or synthetic oil can be used as excipient. Particularly useful are lipids, such as phospholipids (e.g., natural origin and / or particle size between 300 and 350nm) in phosphate buffered saline (pH=7 to 8, e.g., 7.4). For suppositories, for example, vegetable oil, petroleum, animal oil or synthetic oil, wax, fat and polyol can be used as excipients. For aerosol formulations, compressed gases suitable for this purpose can be used, for example, oxygen, nitrogen and carbon dioxide. Pharmaceutically useful agents can also contain additives for preservation and stability, for example, UV stabilizers, emulsifiers, sweeteners, aromatics, salts that change osmotic pressure, buffers, coating additives and antioxidants.

[0191] Generally, in the case of oral or parenteral administration to an adult weighing about 80 kg, a daily dose of about 10 mg to about 10,000 mg or about 20 mg to about 1,000 mg should be appropriate, but the upper limit may be exceeded when indicated. The daily dose may be administered as a single dose or in divided doses, or for parenteral administration, it may be administered as a continuous infusion or subcutaneous injection.

[0192] Methods for preparing compounds

[0193] The present invention also provides methods for preparing the compounds of the present invention, such as those described above.Synthetic schemes for preparing specific compounds of formula (I) are provided in the following examples.

[0194] Methods of treating diseases, disorders and conditions

[0195] The compounds and compositions of the invention can 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 the compounds or compositions of the invention.

[0196] Diseases, disorders and conditions that can be diagnosed and / or treated using the compositions and methods of the invention include those associated with abnormal activity, such as increased activity or decreased activity, of one or more kinases. The kinase can be a serine-threonine kinase or a tyrosine kinase, such as a receptor tyrosine kinase or a non-receptor tyrosine kinase. For example, but not limited to, the kinase can be a leucine-rich repeat kinase 2 (LRRK2), a NUAK family SNF1-like kinase 1 (NUAK1, also known as AMPK-associated protein kinase 5 or ARK5), or a non-receptor tyrosine protein kinase TYK2 (TYK2), including mutants of any of the above kinases.

[0197] The disease, disorder or condition may be associated with aberrant 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 Parkinson's disease type VIII.

[0198] The disease, disorder or condition may be associated with aberrant NUAK1 activity, such as cancer, for example colorectal cancer, gastric cancer, endometrial cancer or multiple myeloma, diabetes, fibrosis, a neurodegenerative disease or omphalocele.

[0199] The disease, disorder or condition may be associated with aberrant TYK2 activity, such as an autoimmune disease, 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.

[0200] The disease, disorder or condition may be or include a respiratory / obstructive airway disease or disorder such as rhinorrhoea, tracheoconstriction, airway constriction, acute rhinitis, allergic rhinitis, atrophic rhinitis or chronic rhinitis (such as caseous rhinitis, hypertrophic rhinitis, suppurative rhinitis, sicca rhinitis), medicamentous rhinitis, membranous rhinitis (including croup, fibrinous rhinitis and pseudomembranous rhinitis), scrofulous rhinitis, perennial allergic rhinitis, seasonal rhinitis (including neurogenic rhinitis (hay fever) and vasomotor rhinitis), hay fever, asthma (such as bronchial, atopic, allergic, intrinsic, extrinsic, exercise-induced, cold air-induced, Occupational, bacterial infection-induced and dust asthma, especially chronic asthma or refractory asthma (e.g., delayed asthma and airway hyperresponsiveness), bronchitis (including chronic bronchitis, acute bronchitis, arachidonic bronchitis, catarrhal bronchitis, croup, tuberculous bronchitis and eosinophilic bronchitis), cardiogenic bronchitis, pneumoconiosis, chronic inflammatory diseases of the lungs leading to interstitial fibrosis, such as interstitial lung disease (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis or other autoimmune conditions), acute lung injury (ALI), adult respiratory Acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airway or lung disease (CORD, COAD, COLD or COPD, such as irreversible COPD), chronic sinusitis, conjunctivitis (e.g., allergic conjunctivitis), cystic fibrosis, extrinsic allergic alveolitis (such as farmer's lung and related diseases), fibrotic lung, allergic lung disease, hypersensitivity pneumonitis, idiopathic interstitial pneumonia, nasal congestion, nasal polyps, otitis media and cough (chronic cough related to inflammation or iatrogenically induced), pleurisy, pulmonary congestion, emphysema, bronchiectasis, sarcoidosis, pulmonary fibrosis, including cryptogenic fibrosing alveolitis, antineoplastic therapy Concurrent fibrotic and chronic infections, including tuberculosis and aspergillosis and other fungal infections, vasculitic and thrombotic disorders of the pulmonary vasculature, and pulmonary hypertension, acute viral infections including the common cold, and infections caused by respiratory syncytial virus, influenza, coronaviruses (including SARS), and adenovirus, allergic bronchopulmonary fungal disease, emphysema, diffuse panbronchiolitis, systemic anaphylaxis or hypersensitivity reactions, drug allergies (e.g., to penicillins, cephalosporins), allergic reactions to insect bites and stings, and food-related allergies that may not be related to the intestine (such as migraines, rhinitis, and eczema), anaphylactic shock, or vasospasm.

[0201] The disease, disorder or condition may be or include a bone and joint related disease or disorder such as osteoporosis, arthritis (including rheumatic, infectious, autoimmune, chronic, malignant), seronegative spondyloarthropathies (such as ankylosing spondylitis, rheumatoid spondylitis, psoriatic arthritis, enthesopathy, Bechet's disease, Marie-Strumpell arthritis, inflammatory bowel arthritis and Reiter's disease), systemic sclerosis, osteoarthritis, osteoarthropathy, both primary and secondary, such as congenital hip dysplasia, cervical and lumbar spondylitis and lower back and neck pain, Still's disease, reactive arthritis and undifferentiated spondylopathy, septic arthritis and other infection related arthropathy and bone disorders such as tuberculosis, including Pott's disease and Poncet's syndrome. 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 localized scleroderma, mixed connective tissue disease and undifferentiated connective tissue disease, inflammatory myopathies including polymyalgia rheumatica, juvenile arthritis including idiopathic inflammatory arthritis of any joint distribution and related syndromes, other joint diseases (such as intervertebral disc degeneration or temporomandibular joint 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, allergic reactions, cryoglobulins, paraproteins, low back pain, familial Mediterranean fever, Muckle-Wells syndrome and familial Hibenian fever, Kikuchi disease, disease), drug-induced arthralgia, tendinitis, polychondritis and muscle disease, osteoporosis, osteomalacia such as osteoporosis, osteopenia, osteogenesis imperfecta, osteosclerosis, 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, frozen shoulder, cervical brachial syndrome or tenosynovitis.

[0202] The disease, disorder or condition may be or include a skin or eye-related disease or condition such as glaucoma, ocular hypertension, cataract, retinal detachment, psoriasis (including psoriasis vulgaris, pustular psoriasis, arthritic psoriasis, psoriatic erythroderma), palmoplantar pustulosis, xeroderma, eczematous diseases (such as atopic dermatitis, ultraviolet radiation dermatitis, contact dermatitis and seborrheic dermatitis), phytodermatitis, photodermatitis, cutaneous eosinophilia, chronic skin ulcers, cutaneous lupus erythematosus, contact allergy / allergic contact dermatitis (including allergy to poison ivy, sumac or oak), and eosinophilic folliculitis (Ofuji's disease). disease), pruritus, drug eruption, urticaria (acute or chronic, allergic or nonallergic), acne, erythema, dermatitis herpetiformis, scleroderma, vitiligo, lichen planus, lichen sclerosus atrophicus, pyoderma gangrenosum, sarcoidosis of the skin, pemphigus, pemphigus ocular, pemphigoid, epidermolysis bullosa, angioedema, vasculitis, toxic erythema, cutaneous eosinophilia, alopecia areata, male pattern baldness, Sweet's syndrome, Stevens-Johnson syndrome, Weber-Christian syndrome syndrome), erythema multiforme, cellulitis, infectious and noninfectious panniculitis, cutaneous lymphoma, non-melanoma skin cancer and other dysplastic lesions, blepharitis, iritis, anterior and posterior uveitis, choroiditis, autoimmune, degenerative or inflammatory conditions affecting the retina, eye inflammation (including sympathetic eye inflammation), sarcoidosis, xerosis infections (including viral, fungal and bacterial), allergic conjunctivitis, increased fibrosis, keloids, scar formation, surgery Posterior scarring, epidermolysis bullosa, dry eyes, ocular inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis and giant papillary conjunctivitis, ocular angiogenesis, corneal damage and scarring, various forms of macular degeneration, macular edema, macular dystrophy, abnormal wound healing, scleritis, episcleritis, pachydermia, peripheral ulcerative keratitis, fungal keratitis, herpetic keratitis, invasive aspergillosis; keratoconus, corneal epithelial dystrophy, or severe intraocular inflammation.

[0203] The disease, disorder or condition can be or include a gastrointestinal and abdominal related disease or disorder, such as celiac / coeliac disease (e.g., 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 (Mooren's ulcer), irritable bowel syndrome, necrotizing enterocolitis, intestinal ischemia, glossitis, gingivitis, periodontitis, esophagitis, including reflexes, proctitis, liver fibrosis and cirrhosis, acute and chronic pancreatitis, pancreatic fibrosis, pancreatic sclerosis, pancreatic stones, cirrhosis, hepatitis (congestive, autoimmune, acute, fulminant, chronic, drug-induced, alcoholic, lupus, steatohepatitis, and chronic viral hepatitis), fatty liver, primary biliary cirrhosis, hepatic porphyria and gastrointestinal related allergic disorders, spastic colon, diverticulitis, gastrointestinal bleeding, Behcet's disease; partial hepatectomy, acute hepatic necrosis (e.g., caused by toxins, viral hepatitis, shock, or hypoxia), or hemolytic uremic syndrome.

[0204] The disease, disorder or condition can be or comprise a blood disease or disorder, such as anemia, coagulation, a myeloproliferative disorder, a bleeding disorder, leukopenia, an eosinophilic disorder, a leukemia (e.g., myeloid, lymphoma, plasma cell dyscrasia, a splenic disorder, Band's disease, hemophilia, purpura (including idiopathic thrombocytopenic purpura), or Wiskott-Aldrich syndrome.

[0205] The disease, disorder or condition can be or include a metabolic disease or disorder, such as obesity, amyloidosis, amino and acid metabolism disorders, such as branched chain disease, hyperaminoacidemia, hyperaminoaciduria, urea metabolism disorders, hyperammonemia, mucopolysaccharidosis, such as Maroteaux-Lamy syndrome, storage diseases such as glycogen storage disease and lipid storage disease, glycogen storage disease type I disease, such as Cori's disease, disease), malabsorption diseases such as intestinal carbohydrate malabsorption, oligosaccharidase deficiency such as maltase, lactase, sucrase deficiency, fructose metabolism disorders, galactose metabolism disorders, galactosemia, carbohydrate utilization disorders such as diabetes, hypoglycemia, pyruvate metabolism disorders, hypolipidemia, hypolipoproteinemia, hyperlipidemia, hyperlipoproteinemia, carnitine or carnitine acyltransferase deficiency, porphyrin metabolism disorders, porphyrin, purine metabolism disorders, lysosomal diseases, metabolic diseases of the nerves and nervous system such as gangliosidosis, sphingolipidosis, cerebral sulfatide deposition disease, leukodystrophy or Lesch Nyhan Syndrome.

[0206] The disease, disorder or condition may be or comprise cerebellar dysfunction or a disorder of brain metabolism, such as dementia, Alzheimer's disease, Huntington's chores, Parkinson's disease, Pick's disease, toxic encephalopathy, demyelinating neuropathies, such as inflammatory neuropathies, Guillain-Barre syndrome; Meniere's disease and radiculopathy, primary and secondary metabolic disorders associated with hormone deficiencies, such as any disorder resulting from hyperfunction or hypofunction of certain hormone-secreting endocrine glands, and any combination thereof. Sipple's syndrome, pituitary dysfunction and its effects on other endocrine glands such as thyroid, adrenal glands, ovaries and testicles, acromegaly, hyperthyroidism and hypothyroidism, euthyroid goiter, euthyroid sick syndrome, thyroiditis and thyroid cancer, excessive or insufficient secretion of adrenal steroid hormones, adrenal allergic syndrome, Cushing's syndrome, Addison's disease of the adrenal cortex, Addison's pernicious anemia, primary and secondary aldosteronism, diabetes insipidus, diabetes mellitus, carcinoid syndrome, disorders caused by parathyroid dysfunction, islet cell dysfunction, diabetes, estrogen deficiency, anti-ovarian syndrome and other female endocrine system disorders; muscle weakness and myotonia.Duchenne's and other muscular dystrophies, dystrophia myotonica of Steinert, mitochondrial myopathies, such as catabolic disorders in muscle, carbohydrate and lipid storage myopathies, glycogenosis, myoglobinuria, malignant hyperthermia, polymyalgia rheumatica, dermatomyositis, polymyositis, primary cardiomyopathy, cardiomyopathy; ectodermal disorders, neurofibromatosis, scleroderma and polyarteritis, Louis-Bar syndrome, von Hippel-Lindau disease, Sturge-Weber syndrome, tuberous sclerosis, amyloidosis, porphyria; sexual dysfunction in men and women; confusional states and epileptic seizures caused by inappropriate secretion of antidiuretic hormone by the pituitary gland, Liddle's syndrome, Bartter's syndrome, Fanconi's I syndrome, syndrome) or renal electrolyte depletion.

[0207] The disease, disorder or condition may be or comprise a transplant rejection-related condition, such as acute and chronic allograft rejection following solid organ transplantation, e.g., transplantation of kidney, heart, liver, lung and cornea, chronic graft-versus-host disease, skin transplant rejection and bone marrow transplant rejection or immunosuppression.

[0208] The disease, disorder or condition may be or include a urogenital related condition such as nephritis (interstitial, acute interstitial (allergic) and glomerulonephritis), nephrotic syndrome, cystitis, including acute and chronic (interstitial) cystitis and Hunner's ulcer, acute and chronic urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvovaginitis, vulvovaginal candidiasis, Peyronie's disease and erectile dysfunction, nephropathy, renal fibrosis, pyelitis, secondary renal atrophy, steroid-dependent and steroid-resistant nephropathy or Goodpasture's syndrome.

[0209] The disease, disorder or condition may be or include a CNS-related disease or disorder such as neurodegenerative diseases, Alzheimer's disease and other zygotic disorders, including CJD and nvCJD, amyloidosis and other demyelinating syndromes, cerebral atherosclerosis and vasculitis, temporal arteritis, myasthenia gravis, acute and chronic pain (acute, intermittent or persistent, whether central or peripheral in origin), including postoperative visceral pain, headache, migraine, neuralgia (including trigeminal neuralgia), atypical facial pain, joint and bone pain, pain due to cancer and tumor invasion, neuropathic pain syndromes, including diabetic, post-herpetic and HIV-related neuropathic pain syndromes. disease, neurosarcoidosis, brain injury, cerebrovascular disease and its consequences, Parkinson's disease, corticobasal degeneration, motor neurone disease, dementias including ALS (amyotrophic lateral sclerosis), multiple sclerosis, traumatic brain injury, stroke, sequelae of stroke, post-traumatic brain injury and small vessel cerebrovascular disease, dementias, vascular dementia, dementia with Lewy bodies, frontotemporal dementia and Parkinson's disease linking chromosomes 1 to 17, frontotemporal dementias including Pick's disease, progressive supranuclear palsy, corticobasal degeneration, Huntington's disease, thalamic degeneration, HIV dementia, schizophrenia with dementia and Korsakoff's psychosis, which within the meaning of the definition are also considered to be complications of malignant, infectious or autoimmune processes of the central and peripheral nervous systems, pain, cerebral infarction, seizure, cerebral ischemia, head injury, spinal cord injury, spinal muscular atrophy, Shy-Drager syndrome, Reye's syndrome, progressive multifocal leukoencephalopathy, normal pressure hydrocephalus, sclerosing panencephalitis, frontal lobe dementia, acute anterior horn poliomyelitis (poliomyelitis), poliomyelitis neurosis, viral encephalitis, allergic encephalomyelitis, epileptic optic encephalopathy, Creutzfeldt-Jakob disease, kurudisease, bovine spongiform encephalopathy (mad cow disease), scrapie, epilepsy, cerebral amyloid angiopathy, depression, mania, manic-depressive disorder, hereditary cerebellar ataxia, peripheral neuropathy, Nasu-Hakola syndrome syndrome or Machado-Joseph disease.

[0210] The disease, disorder or condition can be or include an inflammatory or immune disease or disorder, such as systemic inflammation (ocular, nasal, pulmonary and gastrointestinal), mastocytosis / mast cell disorders (cutaneous, systemic, mast cell activation syndrome and pediatric mast cell disease), mastitis (breast), vaginitis, vasculitis (e.g., necrotizing, cutaneous and allergic vasculitis), Wegener granulamatosis, myositis (including polymyositis, dermatomyositis), basophil-related diseases, including basophilic leukemia and basophilic leukocytosis and eosinophil-related diseases, such as Churg-Strauss syndrome, eosinophilic granuloma, lupus erythematosus (such as systemic lupus erythematosus, subacute cutaneous lupus erythematosus and discoid lupus erythematosus), chronic thyroiditis, Hashimoto's thyroiditis, Grave's disease, disease), type I diabetes, complications caused by diabetes, other immune disorders, eosinophilic fasciitis, hyper-IgE syndrome, Addison's disease, antiphospholipid syndrome, immunodeficiency diseases, acquired immunodeficiency syndrome (AIDS), leprosy, Sezary syndrome, paraneoplastic syndromes and other autoimmune diseases, fever, myositis, a neurological disease selected from polymyositis, bursitis, Evans syndrome, leukotriene B4-mediated disease, idiopathic hypoparathyroidism, nephrotic syndrome, lupus, or immunosuppression.

[0211] The disease, disorder or condition may be or include a cardiovascular disease or disorder such as congestive heart failure, myocardial infarction, ischemic heart disease, various atrial and ventricular arrhythmias, hypertension, brain trauma, occlusive vascular disease, stroke, cerebrovascular disorders, atherosclerosis, restenosis affecting the coronary arteries and peripheral blood circulation, pericarditis, myocarditis, inflammatory and autoimmune cardiomyopathy, including cardiomyosacral tumours, endocarditis, valvulitis, and aortitis, including infectious (e.g. syphilis), hypertensive vascular disease, peripheral vascular disease and atherosclerosis, vasculitis, proximal and peripheral venous disorders, including phlebitis and thrombosis, including deep vein thrombosis and varicose vein complications, aortic aneurysm, periarteritis nodosa, cardiac fibrosis, sequelae of myocardial infarction, idiopathic cardiomyopathy or angioplasty.

[0212] The disease, disorder or condition may be or include a neoplastic 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, testis, ovary, thymus, thyroid), eye, head, neck, nervous system (central and peripheral), lymphatic system, blood, pelvis, skin, bone, soft tissue, spleen, chest, genitourinary and brain tumors), breast cancer, genitourinary cancer, lung cancer, gastrointestinal cancer, epidermoid carcinoma, melanoma, ovarian cancer, pancreatic cancer, neuroblastoma, cancers affecting the bone marrow (including leukemias) and lymphoproliferative system (such as Hodgkin's lymphoma and non-Hodgkin's lymphoma) malignancies of the leukemia, lymphoma, B-cell lymphoma, follicular lymphoma, metastatic disease and tumor recurrence and paraneoplastic syndromes, as well as hypergammaglobulinemia, lymphoproliferative diseases, disorders and / or conditions, paraproteinemias, purpura (including idiopathic thrombocytopenic purpura), Waldenstron's Macroglobulinemia, Gaucher's disease), histiocytosis, retinoblastoma and any other hyperproliferative disease, malignant neoplasm, cachexia, tumor growth, tumor invasion, metastasis, AIDS-related lymphoma, malignant immunoproliferative disease, multiple myeloma and malignant plasma cell neoplasms, lymphoid leukemias, acute or chronic myeloid leukemias, acute or chronic lymphocytic leukemias, monocytic leukemias, leukemias of other specified cell types, leukemias of unspecified cell types, other and unspecified malignancies of lymphoid, hematopoietic and related tissues, such as 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 leukoma.

[0213] The disease, disorder or condition may be or include another disease or disorder, such as pain, migraine, sleep disorder, fever, sepsis, idiopathic thrombocytopenic purpura, postoperative adhesions, flushing, ischemic / reperfusion injury in the heart, brain, peripheral limbs, bacterial infection, viral infection, fungal infection, thrombosis, endotoxin shock, septic shock, heat regulation, including fever, Raynaud's disease, gangrene, diseases requiring anticoagulant therapy, congestive heart failure, mucus secretion disorders, pulmonary hypotension, prostaglandin-induced smooth muscle contraction associated with dysmenorrhea and premature labor, premature labor, reperfusion injury, burns, thermal injury, hemorrhagic or traumatic shock, dysmenorrhea, menstrual cramp, dysmenorrhea, periodontal degeneration, rickettsial infections, protozoal diseases, reproductive diseases, toothache, post-extraction pain, herpes zoster, herpes simplex, retroperitoneal fibrosis, or various radiation injuries.

[0214] In certain embodiments, the disease is selected from the group consisting of: inflammatory diseases, autoimmune diseases, allergic disorders, and ocular disorders. In certain embodiments, the disease is selected from the group consisting of: pruritus, eczema, asthma, rhinitis, dry eyes, ocular inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, giant papillary conjunctivitis, fungal keratitis, and uveitis.

[0215] The method may comprise modulating the activity of one or more kinases in a subject, such as any of the kinases described above. The method may comprise inhibiting a kinase. The method may comprise activating, such as stimulating or enhancing the activity of a kinase. The method may comprise modulating a single kinase or preferentially modulating a specific kinase over other kinases. The method may comprise modulating multiple kinases or preferentially modulating two more specific kinases over other kinases.

[0216] The method may comprise providing a compound of the invention. The method may comprise providing a plurality of compounds of the invention.

[0217] The method may comprise contacting a cell containing a kinase with one or more compounds of the invention. For example, but not limited to, contacting a cell with a compound may comprise exposing the cell to the compound, for example in a formulation such as any of those described above; delivering the compound inside a cell; providing the compound to a subject and allowing cells in the subject to be exposed to the compound. The contacting may be performed in vivo or in vitro. In vitro contacting may comprise exposing cells or tissues isolated from a subject. The method may comprise contacting a cell with a single compound of the invention. The method may comprise contacting a cell with multiple compounds of the invention.

[0218] The method may include administering the composition to the subject. The composition may be provided by any suitable route of administration. For example, but not limited to, the composition may be administered orally, by injection, to the skin, enterally, intra-arterially, intravenously, intranasally, such as by inhalation, intraocularly, orally, parenterally, pulmonary, rectal, subcutaneously, systemically, topically, such as to the skin or eye, transdermally, or with or on an implantable medical device (e.g., a stent or drug eluting stent or balloon equivalent). The method may include using the composition of the invention to diagnose a disease, disorder or condition in a subject. For example, a radiolabeled form of the compound may be used as a tracer in positron emission tomography (PET) to identify the anatomical location of abnormal kinase activity. PET is known in the art 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 349261-1. 1-85233-798-2; and Carlson, Neil (January 22, 2012). "Physiology of Behavior Methods and Strategies of Research", 11th edition, Pearson Publishing House (Pearson, p. 151, ISBN 0205239390, the contents of each of which are incorporated herein by reference. The present invention may include the use of one or more compositions of the present invention for diagnostic and therapeutic purposes.

[0219] Examples

[0220] Example 1:

[0221] The following methods were used for the synthesis of the compounds described herein.

[0222] Flash chromatography: Flash chromatography was performed on a Biotage Isolera(R) system using a SNAP silica column and either ethyl acetate / cyclohexane / methanol or dichloromethane / methanol gradients as eluents.

[0223] Microwave conditions: Reactions under microwave conditions were performed in a Biotage initiator(R) microwave system.

[0224] SEMIprep reversed phase chromatography: The following equipment was used for SEMIprep reversed phase chromatography: 2x Varian PrepStar SD-1, 1x Dionex P580 Pump 1Channel (MakeUP I), 1x Dionex AXP-MS (MakeUP II), 1x Dionex MSQ, 1x Dionex UVD 340V-preparative flow cell, and Gilson 215 liquid handler. A SunFirePrep C18 OBD 5 μm, 19×50 mm column was used.

[0225] 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 solvent A and solvent B are as follows:

[0226] Time (minutes) Solvent A Solvent B 0.0 30.00 70.00 10.0 100.00 0.00 14.0 100.00 0.00 14.4 30.00 70.00 16.4 30.00 70.00

[0227] Detection was performed using a mass spectrometer detector (API-ES, positive) at UV 254 nm.

[0228] Example 2:

[0229] Table 1 provides the terms and abbreviations used in the examples.

[0230] Table 1.

[0231]

[0232] Example 3:

[0233] 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 provided in Table 2.

[0234] Table 2.

[0235]

[0236]

[0237] Example 4:

[0238]

[0239] Intermediate 1. 1 eq. of 3,5-dibromo-4-nitropyrazole was suspended in dichloromethane and THF was added until completely dissolved. Then 1.3 eq. of dihydropyran and a catalytic amount of toluenesulfonic acid monohydrate were added. The mixture was stirred on, then diluted with DCM, washed with a saturated aqueous solution of NaHCO3 and water. The combined organics were dried over Na2SO4, filtered and evaporated under reduced pressure to give the desired product as a white solid. The product can be used without further purification. See JPH Juffermans and Clarisse L. Habraken, Journal of Organic Chemistry 1986, 51, 24, 4656-4660, November 1, 1986.

[0240] Example 5:

[0241]

[0242] 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 eq. of 3,4-dihydro-2H-pyran and 0.1 eq. of toluenesulfonic acid were slowly added. The mixture was stirred on at rt. The mixture was extracted with a saturated aqueous solution of 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.

[0243] Example 6:

[0244]

[0245] 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 eq. of 2-(3,6-dihydro-2H-pyridin-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 3 eq. of Na2CO3 were added. The mixture was degassed with N2, and then 0.05 eq. of Pd(PPh3)4 was added. The mixture was degassed again and stirred at 80°C for 4 h. Another 0.02 eq. of Pd(PPh3)4 was added, and the mixture was stirred at 80°C for 4 h. The mixture was cooled to rt 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.

[0246] Example 7:

[0247]

[0248] Intermediate 4. 2-Bromo-4-(3,6-dihydro-2H-pyridin-4-yl)aniline. Synthesized as described for Intermediate 3 using 2-bromo-4-iodoaniline as starting material.

[0249] Example 8:

[0250]

[0251] Intermediate 5. tert-Butyl 6-amino-5-bromo-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate. Synthesized as described for Intermediate 3 using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate as starting material.

[0252] Example 9:

[0253]

[0254] Intermediate 6. 6-Amino-pyridine-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide. 1 eq. of 6-amino-pyridine-2-carboxylic acid and tetrahydro-pyran-4-ylamine were dissolved in dry DMF. 1.05 eq. of PYBOP and 2.1 eq. of DIPEA were added. The mixture was stirred at rt for 3 h. 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.

[0255] Example 10:

[0256]

[0257] Intermediate 7. 6-amino-pyridine-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide was dissolved in chloroform / DCM 3 / 1. The mixture was cooled to 0°C. 1.3 eq. of bromine was added dropwise and the mixture was stirred at rt for 3 days. The mixture was quenched with 5% w / v aqueous Na2S2O3, basified with aqueous NaOH solution and extracted with DCM. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography.

[0258] Example 11:

[0259]

[0260] Intermediate 8.2-(3-amino-4-bromophenyl)propane-2-ol. Ethyl 3-amino-4-bromobenzoate was dissolved in dry THF and cooled to 0°C. 6 eq. of 1.4 M methylmagnesium bromide was added to THF / toluene (1 / 3) and the mixture was stirred at 0°C for 30 minutes. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography.

[0261] Example 12:

[0262]

[0263] 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 eq. of NaH (60% dispersion in oil) was added, followed by dropwise addition of 2-bromo-4-fluoro-1-nitrobenzene. The mixture was heated to reflux for 45 minutes, then cooled to rt and quenched by addition of water. The precipitate was collected by filtration. The filtrate was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The combined crude product was purified by flash chromatography.

[0264] Example 13:

[0265] General procedure for iron reduction: The aryl nitro compound was dissolved in 4 / 1 ethanol / water, 10 eq. of iron and 10 eq. of NH4Cl and a few drops of 2M 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 filtrate was concentrated and then 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.

[0266] Example 14:

[0267]

[0268] Intermediate 10. 4-(3-Bromo-4-aminophenoxy)tetrahydro-2H-pyran (representative example of iron reduction). 4-(3-Bromo-4-nitrophenoxy)tetrahydro-2H-pyran was dissolved in 4 / 1 ethanol / water, 10 eq. of iron and 10 eq. of NH4Cl and a few drops of 2M 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 filtrate was concentrated and then 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.

[0269] Example 15:

[0270]

[0271] Intermediate 11.3-Bromo-N-(2-fluoroethyl)-4-nitroaniline. 2-Bromo-4-fluoro-1-nitrobenzene and 1.5 eq. of 2-fluoroethane-1-amine hydrochloride were dissolved in dry DMF, and then 2 eq. of K2CO3 were added. The mixture was stirred at 120°C for 2 h. 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.

[0272] Example 16:

[0273]

[0274] Intermediate 12. 4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-amine The title compound was synthesized according to the general protocol for iron reduction using 4-bromo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole as starting material.

[0275] Example 17:

[0276]

[0277] Intermediate 13. 3-Bromo-N1-(2-fluoroethyl)benzene-1,4-diamine The title compound was synthesized according to the general protocol for iron reduction using 3-bromo-N-(2-fluoroethyl)-4-nitroaniline as the starting material.

[0278] Example 18:

[0279]

[0280] 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 eq. of K2CO3 and 1.2 eq. of 2-chloro-2,2-difluoroacetic acid were added. The mixture was stirred at 120°C for 1 h. Another 1.2 eq. 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 rt, diluted with water and extracted with ethyl acetate. The organic layer was washed with 1M NaOH aqueous solution, 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 for the next step.

[0281] Example 19:

[0282]

[0283] Intermediate 15.4-bromo-1-(difluoromethyl)-1H-pyrazole-3-amine and 4-bromo-1-(difluoromethyl)-1H-pyrazole-5-amine. A mixture of 4-bromo-1-(difluoromethyl)-3-nitro-1H-pyrazole and 4-bromo-1-(difluoromethyl)-5-nitro-1H-pyrazole was used as starting material to synthesize the title compound according to the general scheme of iron reduction. The material was used as an isomeric mixture.

[0284] Example 20:

[0285]

[0286] Intermediate 16.4-(4-bromo-3-nitrophenoxy)tetrahydro-2H-pyran. 1 eq. of tetrahydro-2H-pyran-4-ol, 4-bromo-3-nitrophenol and 2.6 eq. of PPh3 were dissolved in dry THF. The mixture was cooled to 0°C and 2.3 eq. of DBAD dissolved in dry THF was slowly added. The mixture was warmed to rt and stirred on. Another 0.3 eq. of tetrahydro-2H-pyran-4-ol, 0.3 eq. of PPh3 and DBAD were added and the mixture was stirred at rt for 4 h. 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.

[0287] Example 21:

[0288]

[0289] Intermediate 17. 2-Bromo-5-((tetrahydro-2H-pyran-4-yl)oxy)aniline. The title compound was synthesized according to the general protocol for iron reduction using 4-(4-bromo-3-nitrophenoxy)tetrahydro-2H-pyran as starting material.

[0290] Example 22:

[0291] General protocol for reduction using H2 / Pd / C: The aromatic nitro compound was dissolved in ethanol. 0.05 eq. of Pd (10% w / w on charcoal) was added and the mixture was stirred on under a hydrogen atmosphere. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The product was used without further purification.

[0292] Example 23:

[0293]

[0294] Intermediate 18. 3-(Dimethoxymethyl)-2,4-difluoroaniline (representative example of H2 / Pd / C reduction). 2-(Dimethoxymethyl)-1,3-difluoro-4-nitrobenzene was dissolved in ethanol, 0.05 eq. of Pd / C (10% w / w) was added, and the mixture was stirred on at rt. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The mixture was used without further purification.

[0295] Example 24:

[0296]

[0297] Intermediate 19.3-(dimethoxymethyl)-2,4-difluoro-N-(2-fluoroethyl)aniline. 3-(dimethoxymethyl)-2,4-difluoroaniline, 1.2 eq. of 1-bromo-2-fluoroethane, 2 eq. of Cs2CO3 and 1.5 eq. of DIPEA were dissolved in dry DMF. The mixture was heated at 140°C for 30 minutes under microwave conditions, then at 160°C for 30 minutes, and then after adding 1 eq. of 1-bromo-2-fluoroethane again, heated at 160°C for 30 minutes. The mixture was diluted with ethyl acetate, washed with water and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography.

[0298] Example 25:

[0299]

[0300] 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 on. 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.

[0301] Example 26:

[0302]

[0303] Intermediate 21. 3-Bromo-4-nitro-N-(2,4,4-trimethylpentane-2-yl)aniline. 1.5 eq. of 2-bromo-4-fluoro-1-nitrobenzene, 2,4,4-trimethylpentane-2-amine and 2 eq. of K2CO3 were dissolved in DMF. The mixture was heated on at 120°C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by flash chromatography.

[0304] Example 27:

[0305]

[0306] Intermediate 22. 3-Bromo-N1-(2,4,4-trimethylpentan-2-yl)benzene-1,4-diamine The title compound was synthesized according to the general protocol for iron reduction using 3-bromo-4-nitro-N-(2,4,4-trimethylpentan-2-yl) as starting material.

[0307] Example 28:

[0308]

[0309] Intermediate 23. 4-Bromo-6-chloropyridin-3-amine The title compound was synthesized according to the general protocol for iron reduction using 4-bromo-2-chloro-5-nitropyridine as starting material.

[0310] Example 29:

[0311]

[0312] Intermediate 24. 2-Bromo-4-ethyl-6-fluoroaniline, 1-bromo-5-ethyl-3-fluoro-2-nitrobenzene The title compound was synthesized according to the general protocol for iron reduction using 1-bromo-5-ethyl-3-fluoro-2-nitrobenzene as starting material.

[0313] Example 30:

[0314]

[0315] Intermediate 25. 3-Bromo-4-nitrophenyl dimethylcarbamate. 3-Bromo-4-nitrophenol was dissolved in dry acetonitrile, 1.5 eq. of K2CO3 solid and 1.2 eq. of dimethylcarbamoyl chloride were added. The mixture was stirred at rt for 1 h and then placed at 100°C for 2 h. 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.

[0316] Example 31:

[0317]

[0318] Intermediate 26. 4-Amino-3-bromophenyl dimethylcarbamate The title compound was synthesized according to the general protocol for iron reduction using 3-bromo-4-nitrophenyl dimethylcarbamate as starting material.

[0319] Example 32:

[0320]

[0321] Intermediate 27.2,6-difluoro-4-(2-fluoroethoxy)benzaldehyde. 2,6-difluoro-4-hydroxybenzaldehyde, 1.1 eq. of 1-bromo-2-fluoroethane and 1.5 eq. of K2CO3 were dissolved in dry DMF. The reaction was heated at 140 °C for 5 minutes under microwave conditions. The heating was repeated after adding an additional 0.5 eq. of 1-bromo-2-fluoroethane. 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.

[0322] Example 33:

[0323]

[0324] Intermediate 28.4-bromo-2-chloro-6-trifluoromethyl-pyridin-3-ylamine. 2-Chloro-6-trifluoromethyl-pyridin-3-ylamine was dissolved in MeCN and 1 eq. of NBS was added. The mixture was heated to 80 ° C for two hours. The mixture was cooled to rt, then concentrated under reduced pressure and ground with diethyl ether. The crude reaction mixture was purified by gradient flash chromatography.

[0325] Example 34:

[0326]

[0327] Intermediate 29.4-(3-bromo-4-nitro-phenyl)-morpholine. 2-bromo-4-fluoro-1-nitro-benzene was dissolved in DMF and 1.3 eq. of morpholine and 2 eq. of KCO were added. The mixture was stirred overnight at rt. 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 can be used without further purification.

[0328] Example 35:

[0329]

[0330] Intermediate 30. 4-(3-Bromo-4-nitro-phenyl)-morpholine The title compound was synthesized according to the general protocol for iron reduction using 4-(3-bromo-4-nitro-phenyl)-morpholine as starting material.

[0331] Example 36:

[0332]

[0333] 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 eq. of N-(3-bromophenyl)acetamide were dissolved in dioxane, 0.1 eq. of Pd dppf and 4 eq. of 2M Na2CO3 aqueous solution 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.

[0334] Example 37:

[0335]

[0336] 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 eq. of 5-bromo-2-chloroaniline were dissolved in dioxane, 0.1 eq. of Pd dppf and 4 eq. of 2M aqueous Na2CO3 were added. The mixture was heated at 135°C under microwave conditions for 10 min. 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.

[0337] Example 38:

[0338]

[0339] Intermediate 33.4-(4-bromo-3-nitrophenoxy)tetrahydro-2H-pyran. Tetrahydro-2H-pyran-4-yl methanesulfonate and 1 eq. of 4-bromo-3-nitrophenol were dissolved in dry DMF. 1.5 eq. of K2CO3 were added. The mixture was heated at 150°C for 30 minutes under microwave stimulation. 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.

[0340] Example 39:

[0341]

[0342] Intermediate 34. 2-Bromo-5-((tetrahydro-2H-pyran-4-yl)oxy)aniline. The title compound was synthesized according to the general protocol for iron reduction using 4-(4-bromo-3-nitrophenoxy)tetrahydro-2H-pyran as starting material.

[0343] Example 40:

[0344] General route to 1H-[1,3]diazepine compounds (7 rings)

[0345]

[0346] Optionally substituted 5-membered or 6-membered aryl or heteroaryl

[0347] R:H、Hal、Ar、Alk

[0348] PG: PMB, 2-THP

[0349] "B": B(OH)2, Bpin

[0350] X+: C2Cl6, C2Cl2Br2, I2, ICl

[0351] General route to 1H-[1,2]diazepines.

[0352] Example 41:

[0353] Route A: Aryl-aryl bond formation.

[0354]

[0355] 2-[4-Nitro-2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-aniline (Representative example of route A: Suzuki coupling from commercial boronic esters or acid from commercial boropinacol esters). 1 eq. of 5-chloro-4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole was dissolved in dioxane, then 1.2 eq. of 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-aniline, 0.1 eq. of Pd dppf and 3 eq. of 2M Na2CO3 were added. The mixture was degassed with N2 and heated on at 80°C. 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.

[0356] Example 42:

[0357] Route B: Aryl-aryl bond formation.

[0358]

[0359] 2-Methoxy-6-[4-nitro-2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-aniline (Representative example of route B: Sequential borylation / Suzuki coupling using 4,4,5,5,4',4',5',5'-octamethyl-[2,2']di[[1,3,2]dioxaborolanyl]). These two steps are carried out in a "one pot two steps" reaction. 1 eq. of 2-bromo-6-methoxy-aniline and 4 eq. of potassium acetate are dissolved in dry dioxane, the mixture is degassed with N2, then 0.1 eq. of Pd dppf is added, and after further degassing with N2, 2 eq. of diborolan is added. This mixture is heated at 80°C on. 0.8 eq. of 5-chloro-4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole and 3 eq. of 2M Na2CO3 was added to the mixture. The mixture was flushed with N2 again, and then an additional 0.05eq. of Pd dppf was added. The mixture was stirred on at 80°C. The reaction mixture was filtered through celite and the solid was washed with MeOH. The filtrate was concentrated under reduced pressure, diluted with water and extracted 3 times with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography.

[0360] Example 43:

[0361] Route C: Aryl-aryl bond formation.

[0362]

[0363] 3-Methoxy-2-[4-nitro-2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-aniline (Representative example of route C: Stille coupling using 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane). 1 eq. of 2-bromo-3-methoxy-aniline and 3 eq. of triethylamine are dissolved in dry dioxane. The mixture is flushed with N2, then 0.1 eq. of Pd dppf is added, and after further degassing with N2, 3 eq. of pinacolboran is added. This mixture is heated under microwave conditions at 140°C for 2 h. 0.8 eq. of 5-chloro-4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole and 3 eq. of 2M Na2CO3 solution are added to this mixture. The mixture was flushed with N2 again, and then an additional 0.1 eq. of Pd dppf was added. The mixture was stirred on at 80 °C. The reaction mixture was filtered through celite and the solid was washed with MeOH. The filtrate was concentrated under reduced pressure, diluted with water, and extracted 3 times with DCM. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography.

[0364] Example 44:

[0365] Route D: Aryl-aryl bond formation.

[0366]

[0367] 6-Methoxy-2-[2-(4-methoxy-benzyl)-4-nitro-2H-pyrazol-3-yl]-pyridin-3-ylamine (representative example of route D: direct arylation). 4-Nitro-1-(4-methoxy-benzyl)-1H-pyrazole, 1 eq. of 2-bromo-6-methoxy-pyridin-3-ylamine, 0.3 eq. of pivalic acid and 3 eq. of K2CO3 were dissolved in dry DMF. The mixture was degassed with N2, then 0.15 eq. of catacxium A and Pd(OAc)2 were added. The mixture was degassed and stirred at 115°C on. 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.

[0368] Example 45:

[0369] Route E: Hydrogenation.

[0370]

[0371] 5-(2-Amino-5-methyl-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-ylamine (Representative example of Route E: hydrogenation). 4-Methyl-2-[4-nitro-2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-aniline was dissolved in methanol and 0.07 eq. of Pd / C (10% w / w) was added. The mixture was stirred at rt. Placed under a hydrogen atmosphere (balloon) for 5 h. 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. It was used without further purification.

[0372] Example 46:

[0373] Route F: basic hydrogenation.

[0374] 4-(4-amino-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-6-(trifluoromethyl)pyridin-3-amine (Representative example 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 N2 three times. Then 1.2 eq. of triethylamine and 1 eq. of Pd on charcoal (10% w) were added quickly. Under a hydrogen atmosphere (balloon), the mixture was stirred at rt on. 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.

[0375] Example 47:

[0376] Route G: Reduction with iron.

[0377] 5-(2-Amino-6-methoxy-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-ylamine (Representative example of Method G: reduction with iron). 3-Methoxy-2-[4-nitro-2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-aniline was dissolved in 10 / 4 v / v ethanol / water, 10 eq. of iron and NH4Cl and a few drops of 2M HCl were added. The mixture was heated at 50°C for 1 h.

[0378] 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 NaOH saturated aqueous solution and extracted 3 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.

[0379] Example 48:

[0380] The cyclization / deprotection procedure was performed using the described aryl-aryl diamine and the corresponding aldehyde.

[0381]

[0382] Example 49:

[0383]

[0384] 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 eq. of 2,6-difluoro-benzaldehyde were dissolved in tert-butanol. 3 eq. of iodine and 3 eq. of K2CO3 were added. The mixture was stirred at rt for 1 hr. 5% w / v aqueous Na2S2O3 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 rt for 3 h. The mixture was concentrated under reduced pressure and purified by SEMIprep reverse phase chromatography.

[0385] Example 50:

[0386] The following HPLC method was used:

[0387] Method: HPLC-MS A

[0388] Column: "Waters ACQUITY UPLC HSS T3 50x2.1 1.8μm PN:186003538"

[0389] Gradient: "2%-4.0 min->95%-1.0 min->95%-0.1 min->2%-2.9 min->2%; ACN / H2O+0.1% HCOOH"

[0390] Flow rate: "0.6 ml / min"

[0391] ms: "ESI positive and negative"

[0392] Method: HPLC-MS B

[0393] Column: "Waters ACQUITY UPLC CSH C18 50x2.1 1.7μm PN:186005296"

[0394] Gradient: "5%-4.0 min->95%-1.0 min->95%-0.1 min->5%-2.9 min->5%; ACN / H2O+0.1% HCOOH"

[0395] Flow rate: "0.6 ml / min"

[0396] ms: "ESI positive and negative"

[0397] Method: HPLC-MS C

[0398] Column: "Waters ACQUITY UPLC CSH C18 50x2.1 1.7μm PN:186005296"

[0399] 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"

[0400] Method: HPLC-MSD

[0401] Column: "Waters CORTECS UPLC C18+50x2.1 1.6μm PN:186007114"

[0402] Gradient: "5%-4.0 min->95%-1.0 min->95%-0.1 min->5%-2.9 min->5%; ACN / H2O+0.1% HCOOH"

[0403] Flow rate: "0.6 ml / min"

[0404] ms: "ESI positive and negative"

[0405] Method: HPLC-MS E

[0406] Column: "Waters ACQUITY UPLC CSH C18 50x2.1 1.7μm PN:186005296"

[0407] Gradient: "5%-0.75 min -> 95%-0.5 min -> 95%-0.05 min -> 5%-1.2 min -> 5%; ACN / H2O+0.1% HCOOH"

[0408] Flow rate: "1.2 ml / min"

[0409] ms: "ESI positive"

[0410] The products listed in Table 3 were synthesized according to the cyclization / deprotection method.

[0411] Table 3.

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426] The following compounds in Table 3 were synthesized using additional procedures.

[0427] Example 52:

[0428]

[0429] 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 dioxan. 1 eq. of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane, 2 eq. of Cs2CO3 and 0.2 eq. of Pd(PPh3)4 were added. The mixture was degassed and heated at 140°C for 20 minutes under microwave conditions. The mixture was filtered and the solid was washed with MeOH. After concentration under reduced pressure, the mixture was used without further purification. Additional deprotection steps were performed according to the corresponding procedures above.

[0430] Example 53:

[0431]

[0432] Compound 81.5-(2,6-Difluorophenyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-8-carboxamide. The deprotected crude 5-(2,6-difluorophenyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-8-carboxamide was dissolved in dry DMF. 1.5 eq. of EDCI, 1.8 eq. of HOBT, 2 eq. of NH4Cl and 6 eq. of triethylamine were added and the mixture was stirred on at rt. 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.

[0433] Example 54:

[0434]

[0435] 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.

[0436] Example 55:

[0437]

[0438] Compound 95. 5-(2,6-Difluorophenyl)-N-(tetrahydro-2H-pyran-4-yl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-8-carboxamide. 5-(2,6-Difluorophenyl)-N-(tetrahydro-2H-pyran-4-yl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-8-carboxamide was synthesized according to this procedure using tetrahydro-2H-pyran-4-amine and 5-(2,6-difluorophenyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-8-carboxylic acid as starting materials.

[0439] Example 56:

[0440]

[0441] Compound 97. 5-(2-Chloro-6-fluorophenyl)-N-(2-fluoroethyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxamide. 5-(2-Chloro-6-fluorophenyl)-N-(2-fluoroethyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxamide was synthesized according to this procedure using 2-fluoroethane-1-amine hydrochloride and 5-(2-chloro-6-fluorophenyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxylic acid as starting materials.

[0442] Example 57:

[0443]

[0444] 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]diazepin-9-carboxylic acid as starting materials.

[0445] Example 58:

[0446]

[0447] Compound 112

[0448] 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.

[0449] Step 2: 5-(2,6-Difluorophenyl)-N-(2-fluoroethyl)-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine-9-carboxamide. According to this procedure, 5-(2,6-difluorophenyl)-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine-9-carboxamide was synthesized using 5-(2,6-difluorophenyl)-1,6-dihydropyrazolo[4,3-d]pyrido[4,3-f][1,3]diazepine-9-carboxylic acid and 2-fluoroethane-1-amine as starting materials.

[0450] Example 59:

[0451]

[0452] Compound 113. 5-(2,6-Difluorophenyl)-N-(2-fluoroethyl)-N-methyl-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxamide. 5-(2,6-Difluorophenyl)-N-(2-fluoroethyl)-N-methyl-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxamide was synthesized according to this procedure using 5-(2,6-difluorophenyl)-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine-9-carboxylic acid (2-fluoro-ethyl)-methyl-amine hydrochloride as the starting material.

[0453] Example 60:

[0454]

[0455] Compound 128

[0456] 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 4M HCl in dioxane. The mixture was stirred at rt on. The solid was collected by filtration and used without further purification.

[0457]

[0458] 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, 2 eq. of 1-bromo-2-fluoroethane and 4 eq. of DIPEA were added. The mixture was stirred at 120° C. for 15 minutes under microwave conditions. After adding 2 eq. of 1-bromo-2-fluoroethane, the 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 can be used for deprotection as described above without further purification.

[0459] Example 61:

[0460]

[0461] Compound 132. 2-(4-(5-(2,6-Difluorophenyl)-1,6-dihydropyrazolo[4,3-d]pyrido[3,2-f][1,3]diazepine-9-yl)-5,6-dihydropyridin-1(2H)-yl)ethane-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 eq. of DIPEA and 1 eq. of 2-bromoethane-1-ol were added. The mixture was stirred at rt for 1 h. Another 3 eq. of DIPEA and 2 eq. of 2-bromoethane-1-ol were added and the mixture was stirred again at rt for 1 h. The mixture was concentrated under reduced pressure and purified by flash chromatography.

[0462] Example 62:

[0463]

[0464] 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]diazepine-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 eq. of (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid, 12 eq. of 2M Na2CO3 solution were added. The mixture was degassed with N2 and then 0.2 eq. of Pd dppf was added. The mixture was heated at 140°C for 30 minutes under microwave conditions. Another 1.5 eq. of (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid and 0.2 eq. of Pd dppf 0.2 eq were added, and the mixture was heated again at 140°C for 30 minutes under microwave conditions. This addition and heating were repeated twice. The mixture was filtered through celite and concentrated under reduced pressure. The next step of deprotection was carried out under the above conditions.

[0465] Example 63:

[0466]

[0467] 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, 4 eq. of acetyl chloride and 2 eq. of triethylamine were added. The mixture was stirred at rt for 12 h. The mixture was diluted with methanol and saturated aqueous NaHCO3, then basified with solid NaOH and stirred at 40°C for 12 h. The mixture was neutralized with 2M HCl, then concentrated under reduced pressure and purified by SEMIprep chromatography.

[0468] Example 64:

[0469] The compounds in Table 3 were tested for their inhibitory effects on a panel of kinases according to the following procedure.

[0470] Biochemical assays:

[0471] The basic protocol for the TR-FRET LanthaScreen Eu kinase binding assay inhibitor study is as follows. The LanthaScreen kinase binding assay (ThermoFisher / USA) evaluates inhibitors by adding 5 μl of test compound / 5 μl kinase / antibody mixture, 5 μl of tracer in the corresponding DMSO dilution to a 384-well small volume plate. After incubation for 1 hour at room temperature, the plate is read. The data analysis of the emission rate is performed according to the LanthaScreen Eu kinase binding assay protocol.

[0472] Kinases and assay components were adjusted to final concentrations according to the kit protocol. For LRRK2: 5 nM wt human LRRK2, catalytic site, or G2019S human LRRK2, catalytic site (Thermo Fisher / 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 (Thermo Fisher / USA), 2 nM Eu anti-His antibody, 5 nM Kinase Tracer 236 in 1X Kinase Buffer A.

[0473] The basic protocol for inhibitor studies in the HTRF kinase assay (Cisbio / FRA) involves the following two steps:

[0474] Enzymatic step: Add 4 μl of test compound in corresponding DMSO dilution, 4 μl of kinase / substrate mix, 2 μl of ATP to a 384-well small volume plate. Incubate at room temperature for at least 30 minutes.

[0475] Detection step: Add 5 μl antibody and 5 μl streptavidin-XL665 and read the plate after 60 min. Emission data analysis was performed according to the kinase assay protocol.

[0476] Kinase and assay components were adjusted to final concentrations according to the kit protocol. For TYK2: 2 nM wt human TYK2, catalytic site (SignalChem / CAN), 1 μM HTRF Kinase-TK Substrate-Biotin, 1 μM ATP (in 1x Kinase Buffer)

[0477] The biochemical test results are as follows:

[0478] Inhibitory activity against LRRK2(wt) and LRRK2(G2019)

[0479] IC of the following compounds 50Below 10 nM: Compound 93; Compound 200; Compound 248; Compound 143; Compound 247; Compound 35; Compound 183; Compound 135; Compound 97; Compound 101; Compound 67; Compound 187; Compound 36; Compound 117; Compound 94; Compound 202; Compound 103; Compound 138; Compound 171; Compound 147; Compound 211; Compound 95; Compound 162; Compound 71; Compound 207; Compound 81; Compound 201; Compound 197; Compound 225; Compound 141; Compound 69; Compound 73; Compound 166; Compound 64; Compound 61; Compound 226; Compound 88; Compound 167; Compound 152; Compound 50; Compound 76; Compound 190; Compound 25; Compound 102; Compound 165; Compound 72; Compound 220; Compound 182; Compound 128; Compound 168; Compound 161; Compound 184; Compound 53; Compound 120; Compound 209; Compound 231; Compound 49; Compound 188; Compound 127; Compound 196; Compound 178; Compound 169; Compound 79; Compound 149; Compound 151; Compound 45; Compound 133; Compound 115; Compound 44; Compound 157; Compound 210; Compound 126; Compound 156; Compound 125; Compound 33; Compound 51; Compound 164; Compound 40; Compound 140; Compound 78; Compound 195; Compound 242; Compound 27; Compound 132; Compound 47; Compound 237; Compound 173; Compound 218; Compound 145; Compound 180; Compound 46; Compound 42; Compound 38; Compound 158; Compound 86; Compound 77; Compound 216; Compound 206; Compound 236; Compound 68; Compound 217; Compound 43; Compound 139; Compound 90; Compound 41; Compound Compound 239; Compound 194; Compound 238; Compound 34; Compound 112; Compound 175; Compound 63; Compound 18; Compound 98; Compound 136; Compound 146; Compound 8; Compound 172; Compound 176; Compound 179; Compound 205; Compound 241; Compound 240; Compound 222; Compound 87; Compound 204; Compound 123; Compound 191; Compound 52; Compound 192; Compound 163; Compound 159; Compound 212; Compound 39; Compound 215; Compound 223; Compound 228; Compound 37; Compound 186; and Compound 198.

[0480] IC of the following compounds 50Between 10 nM and 100 nM: 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.

[0481] IC of the following compounds 50 Between 100 nM and 1000 nM: 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.

[0482] Inhibitory activity against TYK2

[0483] IC of the following compounds 50 Below 10 nM: 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.

[0484] IC of the following compounds 50Between 10 nM and 100 nM: Compound 225; Compound 156; Compound 247; Compound 231; Compound 216; Compound 72; Compound 237; Compound 160; Compound 88; Compound 239; Compound 155; Compound 105; Compound 220; Compound 227; Compound 243; Compound 159; Compound 198; Compound 211; Compound 235; Compound 71; Compound 224; Compound 49; Compound 52; Compound 197; Compound 248; Compound 232; Compound 238; Compound 245 ; Compound 223; Compound 240; Compound 98; Compound 69; Compound 218; Compound 127; Compound 34; Compound 164; Compound 135; Compound 158; Compound 99; Compound 200; Compound 76; Compound 190; Compound 27; Compound 171; Compound 219; Compound 68; Compound 8; Compound 66; Compound 30; Compound 147; Compound 169; Compound 33; Compound 201; Compound 210; Compound 53; Compound 234; Compound 233; Compound 202; and Compound 89.

[0485] IC of the following compounds 50 Between 100 nM and 1000 nM: 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 Compound 103; Compound 107; Compound 150; Compound 108; Compound 146; Compound 194; Compound 93; Compound 199; Compound 183; Compound 172; Compound 163; Compound 184; Compound 166; Compound 244; Compound 217; Compound 186; Compound 38; Compound 56; Compound 182; Compound 45; Compound 115; Compound 170; Compound 138; Compound 126; Compound 214; Compound 106; Compound 60; and Compound 168.

[0486] Inhibitory activity against NUAK1

[0487] IC of the following compounds 50 Below 10 nM: Compound 71; Compound 165; Compound 234; Compound 237; and Compound 226.

[0488] IC of the following compounds 50 Between 10 nM and 100 nM: Compound 72; Compound 36; Compound 143; Compound 53; Compound 225; Compound 171; Compound 155; Compound 164; Compound 233; Compound 127; Compound 35; Compound 135; Compound 168; Compound 126; Compound 175; Compound 231; Compound 241; Compound 211; Compound 160; Compound 228; Compound 68; Compound 218; Compound 166; Compound 69; Compound 73; Compound 125; Compound 202; Compound 115; Compound 44; Compound 76; Compound 216; Compound 235; Compound 99; Compound 42; Compound 183; Compound 27; Compound 93; Compound 158; Compound 2 Compound 15; 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.

[0489] IC of the following compounds 50Between 100 nM and 1000 nM: Compound 150; Compound 32; Compound 188; Compound 201; Compound 167; Compound 8; Compound 105; Compound 78; Compound 204; Compound 157; Compound 37; Compound 219; Compound 146; Compound 221; Compound 177; Compound 217; Compound 18; Compound 172; Compound 220; Compound 208; Compound 163; Compound 214; Compound 206; Compound 176; Compound 45; Compound 152; Compound 156; Compound 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.

[0490] Incorporated by Reference

[0491] Other documents, such as patents, patent applications, patent publications, journals, books, papers, and web content, have been referenced and cited throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes.

[0492] Equivalent

[0493] Various modifications of the present invention and many additional embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the entire content of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, illustrations, and guidance that may be suitable for practicing the present invention in its various embodiments and their equivalents.

Claims

1. A compound of the following formula (I): or a tautomer thereof or a pharmaceutically acceptable salt thereof, in: R 1 is aryl or heteroaryl, each of which is optionally substituted; R 2 H, halogen, 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; and A is an aryl group or a 5-membered or 6-membered heteroaryl group; Wherein C 1-6 Alkyl, the C 1-6 Alkoxy, the C 1-6 haloalkyl, the C 1-6 Thioalkyl, the C 3-8 Cycloalkyl, the C 2-8 Each of the heterocycloalkyl, aryl and heteroaryl groups is optionally substituted with one or more moieties selected from the group consisting of halogen, OH, CN, CF3, NH2, NO2, 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 Halogenated alkoxy, 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)2R', -C(O)NRS(O)2NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)2R', -NRS(O)2NR'R", -S(O)2R and -S(O)2NRR', 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 form a C 2-8 Heterocycloalkyl.

2. The compound according to claim 1, which has the formula (II) shown below: in R 1 is aryl or heteroaryl, each of which is optionally substituted; R 2 H, halogen, OH, CN, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Thioalkyl or C 3-8 Cycloalkyl; U is N or CR 3 ; V is N or CR 4 ; W is N or CR 5 ; X is N or CR 6 ;and R 3 to R 6 Each of which is independently H, halogen, 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)2R', -C(O)NRS(O)2NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)2R', -NRS(O)2NR'R", -S(O)2R or -S(O)2NRR', in Each of R, R' and R" is independently H, halo, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 2-8 heterocycloalkyl, aryl or heteroaryl, or R and R' or R' and R" together with the nitrogen to which they are attached form a C 2-8 heterocycloalkyl; and At most one N is assigned to U, V, W, and X.

3. The compound according to claim 2, which has the formula (III) shown below: in R 1 is aryl or heteroaryl, each of which is optionally substituted; R 2 H, halogen, OH, CN, CF3, CHF2, CH2F, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Thioalkyl or C 3-8 cycloalkyl; and R 3 to R 6 Each of which is independently H, halogen, 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)2R', -C(O)NRS(O)2NR'R", -OR, -OC(O)NRR', -NRR', -NRC(O)R', -NRC(O)NR'R", -NRS(O)2R', -NRS(O)2NR'R", -S(O)2R or -S(O)2NRR', or R 4 and R 5 Together with the atoms to which it is attached, it forms a ring having between 5 and 10 members, in Each of R, R' and R" is independently H, halo, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 2-8 heterocycloalkyl, aryl or heteroaryl, or R and R' or R' and R" together with the nitrogen to which they are attached form a C 2-8 Heterocycloalkyl. The compound according to claim 2 , wherein one of U, V, W and X is N.

5. The compound according to claim 2, wherein R 1 It is an aromatic group.

6. The compound according to claim 2, wherein R 1 It is a 5-membered or 6-membered heteroaryl group.

7. The compound according to claim 2, wherein R 2 H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Thioalkyl or C 3-8 Cycloalkyl.

8. The compound according to claim 3, wherein R 3 to R 6 Each of which is independently H, halogen, 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'.

9. The compound according to claim 3, wherein R 3 to R 6 At least three of them are each H.

10. The compound according to claim 3, wherein R 3 , R 4 and R 6 Each of them is H.

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