CN119019402A

CN119019402A - Polycyclic compounds as LRRK2 kinase inhibitors and preparation methods and uses thereof

Info

Publication number: CN119019402A
Application number: CN202310592800.6A
Authority: CN
Inventors: 王召印; 杨帅龙
Original assignee: Shanghai Institute of Organic Chemistry of CAS
Current assignee: Shanghai Institute of Organic Chemistry of CAS
Priority date: 2023-05-24
Filing date: 2023-05-24
Publication date: 2024-11-26
Also published as: WO2024240256A1

Abstract

本文涉及一种作为LRRK2激酶抑制剂的环状化合物及其制备方法和用途。具体地，本文提供了如通式I所示的LRRK2抑制剂，其中，环A和环B如说明书和权利要求书中所定义。本文还公开了通式I化合物的制备方法以及其抑制LRRK2的活性的效果。本发明所述的通式I化合物可用于制备用于治疗诸如帕金森和癌症等疾病的药物。 The present invention relates to a cyclic compound as an LRRK2 kinase inhibitor, and its preparation method and use. Specifically, the present invention provides an LRRK2 inhibitor as shown in the general formula I, wherein ring A and ring B are as defined in the specification and claims. The present invention also discloses a method for preparing the compound of the general formula I and its effect of inhibiting the activity of LRRK2. The compound of the general formula I described in the present invention can be used to prepare a drug for treating diseases such as Parkinson's disease and cancer.

Description

Polycyclic compounds as LRRK2 kinase inhibitors, methods of preparation and uses thereof

Technical Field

The application belongs to the field of medicines, and in particular relates to a polycyclic compound serving as an LRRK2 kinase inhibitor, a preparation method and application thereof, such as application in treating and preventing LRRK2 mediated inflammatory diseases, cancers and neurodegenerative diseases (such as Parkinson's disease and senile dementia).

Background

Leucine-rich repeat kinase 2 (LRRK 2) is the most common mutant gene in familial Parkinson's Disease (PD), LRRK2 gene mutations are also associated with primary PD, and therefore LRRK2 kinase inhibitors may be effective therapeutic agents for PD. In addition, mutations in LRRK2 are also associated with immune related diseases, such as Inflammatory Bowel Disease (IBD), and are potential targets for the treatment of such diseases.

In view of the foregoing, there is a strong need in the art to develop a new class of leucine-rich repeat kinase 2 (LRRK 2) inhibitors.

Disclosure of Invention

The invention aims to provide polycyclic compounds capable of inhibiting LRRK2 with high efficiency, a preparation method thereof and application thereof in treating and preventing LRRK2 mediated diseases such as inflammatory diseases, cancers and neurodegenerative diseases such as Parkinson's disease and senile dementia.

In a first aspect of the present invention, there is provided a compound of formula I, or various isomers and pharmaceutically acceptable salts thereof:

Wherein:

selected from the following ring structures:

Selected from the following bicyclic group structures:

Wherein: wherein:

X is selected from N or CR ⁵;

R ¹、R²、R⁴、R⁵ and R ⁶ are each independently optionally substituted with one or more (e.g., 12, 3, 4 or 5) R ^s1 is substituted with a group selected from the group consisting of: hydrogen, halogen, amino, cyano, SF ₅、-C_1-12 alkyl, -C _2-12 alkenyl, -C _2-12 alkynyl, -C _0-6 alkylene-OC _1-12 alkyl (including C _1-12 alkoxy), -C _1-12 alkylthio (-SC _1-12 alkyl), -C _0-6 alkylene-C _3-10 cycloalkyl, -C _0-6 alkylene-4 to 10 membered heterocyclyl, -C _0-6 alkylene-C _6-10 aryl, -C _0-6 alkylene-5 to 10 membered heteroaryl, -C _0-6 alkylene-C (O) R ^a、-C_0-6 alkylene-C (O) OR ^a、-C_0-6 alkylene-C (O) NR ^aR^b、-C_0-6 alkylene-SO ₂C_1-6 alkyl, -C _0-6 alkylene-SO ₂C_6-10 aryl, -C _0-6 alkylene-SO ₂ to 10 membered heteroaryl, -C _0-6 alkylene-SO ₂C_3-6 cycloalkyl, -C _1-13 alkylene-OH (e.g. -C (C _1-6 alkyl) ₂-OH)、-C_3-12 cycloalkyl-OH;

Each R ^s1 is independently selected from the group consisting of: halo, hydroxy, amino, cyano, C _1-6 alkyl, -SO ₂NR^aR^b、-SO₂C_1-6 alkyl, -SO ₂C_3-6 cycloalkyl, -SO ₂C_6-10 aryl, -SO ₂ -5 to 10 membered heteroaryl, -CONR ^aR^b、-CONRa-C_6-10 aryl, -CONR ^a -5 to 10 membered heteroaryl, -COC _1-6 alkyl, -COC _3-6 cycloalkyl, -COC _6-10 aryl, -CO-5 to 10 membered heteroaryl, C _1-6 alkoxy and oxo (=o);

r ³ is optionally substituted with one or more (e.g., 1,2, 34 or 5) R ^s2 is substituted with a group selected from the group consisting of: hydrogen, -C _1-12 alkyl, -C _2-12 alkenyl, -C _2-12 alkynyl, -4 to 15 membered heterocyclyl, -C _0-6 alkylene-OC _1-12 alkyl (e.g. -C _1-12 alkoxy), -C _1-12 alkylthio, -C _0-6 alkylene-C _3-10 cycloalkyl, -C _0-6 alkylene-3 to 10 membered heterocyclyl, -C _0-6 alkylene-C _6-10 aryl, -C _0-6 alkylene-5 to 10 membered heteroaryl, -C _0-6 alkylene-C (O) R ^a、-C_0-6 alkylene-C (O) OR ^a、-C_0-6 alkylene-C (O) NR ^aR^b、-C_0-6 alkylene-SO ₂C_1-6 alkyl, -C _0-6 alkylene-SO ₂C_6-10 aryl, -C _0-6 alkylene-SO ₂ to 10 membered heteroaryl, -C _0-6 alkylene-SO ₂C_3-6 cycloalkyl, -C _1-13 alkylene-OH (e.g. -C (C _1-6 alkyl) ₂-OH)-C_3-12 cycloalkyl-OH;

Each R ^s2 is independently optionally substituted with one or more (e.g., 1, 2, 34 or 5) R ^c or R ^3a are substituted with a group selected from the group consisting of: halo, hydroxy, C _1-6 alkyl, -OC _1-6 alkyl, C _1-6 haloalkyl, -C _0-6 alkylene-C _3-10 cycloalkyl, -C _0-6 alkylene-3 to 10 membered heterocyclyl, OC _3-6 cycloalkyl, amino, cyano 、-SO₂NR^aR^b、-SO₂R⁸、-CONR^aR^b、-CONR^a-C_6-10 aryl, -CONR ^a 5 to 10 membered heteroaryl, -C (O) R ⁸ and oxo (=o) groups; or when two R ^s2 are located on adjacent atoms, they optionally together form a ring selected from the group consisting of optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) R ^c: c _3-10 cycloalkyl, 3 to 10 membered heterocyclyl, C _6-10 aryl, and 5 to 10 membered heteroaryl;

R ^3a is optionally substituted with one or more (e.g., 1, 2, 34 or 5) R ^s3 is substituted with a group selected from the group consisting of: hydrogen, -C _1-12 alkyl, -C _2-12 alkenyl, -C _2-12 alkynyl, -4 to 15 membered heterocyclyl, -C _0-6 alkylene-OC _1-12 alkyl (e.g. -C _1-12 alkoxy), -C _1-12 alkylthio, -C _0-6 alkylene-C _3-10 cycloalkyl, -C _0-6 alkylene-3 to 10 membered heterocyclyl, -C _0-6 alkylene-C _6-10 aryl, -C _0-6 alkylene-5 to 10 membered heteroaryl, -C _0-6 alkylene-C (O) R ^a、-C_0-6 alkylene-C (O) OR ^a、-C_0-6 alkylene-C (O) NR ^aR^b、-C_0-6 alkylene-SO ₂C_1-6 alkyl, -C _0-6 alkylene-SO ₂C_6-10 aryl, -C _0-6 alkylene-SO ₂ to 10 membered heteroaryl, -C _0-6 alkylene-SO ₂C_3-6 cycloalkyl, -C _1-12 alkylene-OH (e.g. -C (C _1-6 alkyl) ₂-OH)-C_3-12 cycloalkyl-OH;

Each R ^s3 is independently selected from the group consisting of: halogen, hydroxy, C _1-6 alkyl, -OC _1-6 alkyl, C _1-6 haloalkyl, -C _0-6 alkylene-C _3-10 cycloalkyl, -C _0-6 alkylene-3 to 10 membered heterocyclyl, OC _3-6 cycloalkyl, Amino, cyano, -SO ₂NR^aR^b、-SO₂R⁸ (e.g., -SO ₂C_1-6 alkyl, -SO ₂C_3-6 cycloalkyl, -SO ₂C_6-10 aryl, -SO ₂ -to 10-membered heteroaryl), -CONR ^aR^b、-CONR^a-C_6-10 aryl, -CONR ^a 5-to 10-membered heteroaryl, -C (O) R ⁸ (preferably, -C (O) R ⁸ is selected from the group consisting of-COC _1-6 alkyl, -COC _3-6 cycloalkyl, -COC _6-10 aryl, -CO5 to 10 membered heteroaryl) and oxo (=o);

or when R ¹ and R ²、R¹ and R ³ or R ² and R ³ are located on adjacent atoms, R ¹ and R ²、R¹ and R ³ or R ² and R ³ optionally together form a ring selected from the group consisting of optionally substituted with one or more (e.g. 1,2, 3,4 or 5) R ^c: c _3-10 cycloalkyl, 3 to 10 membered heterocyclyl, C _6-10 aryl, and 5 to 10 membered heteroaryl;

R ⁷ is selected from the group consisting of: hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, NR ^aR^b、OR^a;

R ⁸ is optionally substituted with one or more (e.g., 1, 2, 34 or 5) R ^c is substituted with a group selected from the group consisting of: c _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 to 10 membered heteroaryl;

R ^a and R ^b are independently selected from the group consisting of: hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, or R ^a and R ^b together with the nitrogen atom to which they are attached optionally form a 3 to 6 membered heterocyclic ring in which the heterocyclic ring atom is selected from N, O and S;

R ^c are each independently selected from the group consisting of: halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, -NH ₂、-CN、-NH(C_1-4 alkyl), -N (C _1-4 alkyl) ₂、-OH、-OC_1-6 alkyl; or when two R ^c are located on the same atom they optionally together form a C _3-6 cycloalkyl group which is unsubstituted or substituted by one or more (e.g. 1,2,3,4 or 5) substituents selected from halogen, -CN and C _1-4 alkyl.

In another preferred embodiment, "R ¹、R²、R⁴、R⁵ and R ⁶ are each independently a group selected from the group consisting of substituted with one or more R ^s1" means that each of the alkyl, amino, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl groups in the optional groups defined in R ¹、R²、R⁴、R⁵ and R ⁶ are each optionally and independently substituted with one or more R ^s1.

In another preferred embodiment, "R ³ is a group selected from the group consisting of optionally substituted with one or more R ^s2" means that each of the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups in the optional groups defined in R ³ are optionally and independently substituted with one or more R ^s2.

In another preferred embodiment, "each R ^s2 is independently a group selected from the group consisting of optionally substituted with one or more R ^c or R ^3a" means that each of the alkyl, alkylene, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups in the optional groups defined in R ^s2 are optionally and independently substituted with one or more R ^c or R ^3a.

In another preferred embodiment, each R ^s2 is independently a group as defined previously optionally substituted with one or more R ^c.

In another preferred embodiment, R ⁸ is selected from the group consisting of: c _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, C _6-10 aryl, 5 to 10 membered heteroaryl.

In another preferred embodiment, -SO ₂R⁸ is a group selected from the group consisting of: -SO ₂-C_1-6 alkyl, -SO ₂-C_3-6 cycloalkyl, -SO ₂-C_6-10 aryl, -SO ₂ -5 to 10 membered heteroaryl.

In another preferred embodiment, -COR ⁸ is a group selected from the group consisting of: -CO-C _1-6 alkyl, -CO-C _3-6 cycloalkyl, -CO-C _6-10 aryl, -CO-5 to 10 membered heteroaryl.

In another preferred embodiment, the compound is a compound of formula II:

Wherein R ¹、R²、R³、R⁴、R⁵、R⁶ and R ⁷ are as defined in formula I. In another preferred embodiment, the compound is of formula III:

Wherein R ¹、R²、R³、R⁴、R⁶ and R ⁷ are as defined in formula I.

In another preferred embodiment, the compound is of formula IV:

Wherein R ¹、R²、R³、R⁴、R⁵、R⁶ and R ⁷ are as defined in formula I. In another preferred embodiment, the compound is of formula V:

Wherein R ¹、R²、R³、R⁴、R⁶ and R ⁷ are as defined in formula I.

In another preferred embodiment, the compound is of formula VI:

wherein X is selected from N or CR ⁵;

R ¹、R²、R³、R⁴、R⁵、R⁶ and R ⁷ are as defined for formula I.

In another preferred embodiment, the compound is of formula VII:

wherein X is selected from N or CR ⁵;

R ¹、R²、R³、R⁴、R⁵、R⁶ and R ⁷ are as defined for formula I.

In another preferred embodiment, the compound is of formula VIII:

wherein X is selected from N or CR ⁵;

Y is selected from S, O, NR ²;

R ¹、R²、R³、R⁴、R⁵、R⁶ and R ⁷ are as defined for formula I.

In another preferred embodiment, the compound is of formula IX:

Wherein R ¹、R²、R³、R⁴、R⁵ and R ⁷ are as defined in formula I.

In another preferred embodiment, R ¹ is a group selected from the group consisting of: hydrogen, cyano, halogen, -C _1-12 alkyl, -C _2-12 alkenyl, -C _2-12 alkynyl, C _3-10 cycloalkyl.

In another preferred embodiment, R ¹ is a group selected from the group consisting of: hydrogen, cyano, halogen, -C _1-12 alkyl, -C _2-12 alkenyl, -C _2-12 alkynyl, C _3-10 cycloalkyl; wherein each R ^s1 is independently selected from the group consisting of: halogen, C _1-6 alkyl.

In another preferred embodiment, R ¹ is selected from the group consisting of: hydrogen, cyano, halogen, -C _1-12 alkyl, -C _2-12 alkenyl, -C _2-12 alkynyl, C _3-10 cycloalkyl.

In another preferred embodiment, R ¹ is selected from the group consisting of: -C _1-12 alkyl, C _3-10 cycloalkyl.

In another preferred embodiment, R ¹ is selected from the group consisting of: methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl.

In another preferred embodiment, R ² is selected from the group consisting of: hydrogen, -C _1-12 alkyl.

In another preferred embodiment, R ² is hydrogen.

In another preferred embodiment, R ² is a group selected from the group consisting of: hydrogen, cyano, halogen, -C _1-12 alkyl, -C _2-12 alkenyl, -C _2-12 alkynyl, C _3-10 cycloalkyl.

In another preferred embodiment, R ² is a group selected from the group consisting of: hydrogen, cyano, halogen, -C _1-12 alkyl, -C _2-12 alkenyl, -C _2-12 alkynyl, C _3-10 cycloalkyl; wherein each R ^s1 is independently selected from the group consisting of: halogen, C _1-6 alkyl.

In another preferred embodiment, R ² is selected from the group consisting of: hydrogen, cyano, halogen, -C _1-12 alkyl, -C _2-12 alkenyl, -C _2-12 alkynyl, C _3-10 cycloalkyl.

In another preferred embodiment, R ² is selected from the group consisting of: -C _1-12 alkyl, C _3-10 cycloalkyl.

In another preferred embodiment, R ² is selected from the group consisting of: methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl.

In another preferred embodiment, R ¹ is selected from the group consisting of: hydrogen, -C _1-12 alkyl.

In another preferred embodiment, R ¹ is hydrogen.

In another preferred embodiment, R ⁴、R⁵ and R ⁶ are each independently a group selected from the group consisting of: hydrogen, halogen, -C _1-12 alkyl, -C _0-6 alkylene-C _3-10 cycloalkyl.

In another preferred embodiment, R ⁵ is selected from the group consisting of: hydrogen, halogen, -C _1-12 alkyl, -C _0-6 alkylene-C _3-10 cycloalkyl.

In another preferred embodiment, R ⁵ is selected from the group consisting of: hydrogen, halogen, -C _1-6 alkyl.

In another preferred embodiment, R ⁴ and R ⁶ are each independently a group selected from the group consisting of: hydrogen, halogen, -C _1-12 alkyl, -C _0-6 alkylene-C _3-10 cycloalkyl.

In another preferred embodiment, each R ^s1 is independently selected from the group consisting of: halogen, C _1-6 alkyl.

In another preferred embodiment, R ⁷ is selected from the group consisting of: hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halo. An alkyl group.

In another preferred embodiment, R ⁷ is selected from the group consisting of: hydrogen, C _1-6 alkyl.

In another preferred embodiment, R ³ is a group selected from the group consisting of: hydrogen, -C _1-12 alkyl, -3 to 15 membered heterocyclyl, -C _0-6 alkylene-C _3-10 cycloalkyl, -C _0-6 alkylene-3 to 10 membered heterocyclyl, -C _0-6 alkylene-5 to 10 membered heteroaryl, -C _0-6 alkylene-C (O) R ^a、-C_0-6 alkylene-SO ₂C_1-6 alkyl.

In another preferred embodiment, R ³ is a group selected from the group consisting of: c _3-10 cycloalkyl, 3 to 10 membered heterocyclyl.

In another preferred embodiment, R ³ is selected from the group consisting of:

-C (C _1-6 alkyl) ₂-R^s2,

Wherein,

Y ¹ is selected from the group consisting of: CH ₂、CHR^s2、C(R^s2)₂、O、S、SO、SO₂、NH、NR^s2;

n3 and n6 are each independently 0, 1, 2 or 3;

n1 and n2 are each independently 0, 1, 2 or 3, and n1 and n2 are not both 0 or 3;

n4 and n5 are each independently 0, 1 or 2, and n4 and n5 are not simultaneously 0.

N7 and n8 are each independently 1 or 2;

n9 and n10 are each independently 0 or 1;

r ^s2 is as defined in formula I.

In another preferred embodiment, Y ¹ is selected from the group consisting of ：CH、CHR^s2、C(R^s2)₂、O、S、NR^a、NC(O)R⁸、NSO₂R⁸、NSO₂NR^aR^b.

In another preferred embodiment, each R ^s2 is independently selected from the group consisting of: halo, hydroxy, C _1-6 alkyl, OC _1-6 alkyl, C _1-6 haloalkyl, -C _0-6 alkylene-C _3-10 cycloalkyl, -C _0-6 alkylene-3 to 10 membered heterocyclyl, -C _0-6 alkylene-C _6-10 aryl, -C _0-6 alkylene-5 to 10 membered heteroaryl, -OC _3-6 cycloalkyl, amino, cyano 、-SO₂NR^aR^b、-SO₂R⁸-CONR^aR^b、-CONR^a-C_6-10 aryl, -CONR ^a -5 to 10 membered heteroaryl, -C (O) R ⁸、C_1-6 alkoxy and oxo (=o).

In another preferred embodiment, ring A and ring B are each independently a corresponding group in Table A or in the specific compounds shown in the preparation examples.

In another preferred embodiment, R ¹、R²、R³、R⁴、R⁵、R⁶ and R ⁷ are each independently of the other a corresponding group in table a or in the specific compounds shown in the preparation examples.

In another preferred embodiment, the pass through compound is selected from Table A below

Table A

In another preferred embodiment, the compounds (e.g., compounds of formulas I through IX) include all stereoisomers.

In another preferred embodiment, the compounds (e.g., compounds of formulas I through IX) include all atropisomers.

In another preferred embodiment, the stereoisomers of the compounds (e.g., compounds of formulas I through IX) are cis-trans isomers.

In another preferred embodiment, the compounds (e.g., compounds of formulas I through IX) are optically pure isomers.

In another preferred embodiment, the compound (e.g., compounds of formulas I through IX) is a racemate.

In another preferred embodiment, the compounds (e.g., compounds of formulas I through IX) are enantiomers.

In another preferred embodiment, any one or more hydrogen atoms of the compounds (e.g., compounds represented by formulas I to IX) may be replaced with deuterium atoms.

In another preferred embodiment, the compounds (e.g., compounds of formulas I through IX) include prodrugs thereof.

In another preferred embodiment, the pharmaceutically acceptable salt of the compound of formulas I through IX is selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, mesylate, triflate, besylate, tosylate (tosylate), 1-naphthalenesulfonate, 2-naphthalenesulfonate, acetate, trifluoroacetate, malate, tartrate, citrate, lactate, oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate, mandelate.

In a second aspect of the present invention there is provided a pharmaceutical composition comprising (a) a safe and effective amount of a compound active ingredient as described in the first aspect or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug thereof, (b) a pharmaceutically acceptable carrier or excipient.

In another preferred embodiment, the pharmaceutical composition further comprises an additional therapeutic agent.

In another preferred embodiment, the additional therapeutic agent is an immune checkpoint protein inhibitor.

In another preferred embodiment, the immune checkpoint protein inhibitor is an antibody.

In a third aspect of the present invention there is provided the use of a compound according to the first aspect or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug thereof, wherein the use is selected from one or more of the following:

(i) Preparing an LRRK2 inhibitor;

(ii) Preparing a medicament for treating or preventing LRRK2 mediated diseases;

(iii) Preparing a medicament for treating or preventing parkinson's disease and/or cancer;

(iv) Preparing a medicament for use in combination with an immune checkpoint protein inhibitor (e.g. an antibody) to treat or prevent cancer;

(v) Preparing a medicament for treating or preventing inflammatory diseases, tumors and/or neurodegenerative diseases;

(vi) A medicament for the treatment or prevention of a tumor (e.g., cancer) for use in combination with a tumor medicament or therapy is prepared.

In another preferred embodiment, the inflammatory disease is Inflammatory Bowel Disease (IBD).

In another preferred embodiment, the tumor is a cancer.

In another preferred embodiment, the neurodegenerative disease is selected from the group consisting of: parkinson's disease and senile dementia.

In another preferred embodiment, the oncology drug or therapy comprises: PD-1 antibodies, CTLA-4 antibodies, PD-L1 antibodies, PD-L2 antibodies, adoptive cell transplantation therapy, cancer vaccines, IDO (indoleamine 2, 3-dioxygenase) inhibitors, TDO (tryptophan dioxygenase) inhibitors, IDO/TDO dual inhibitors, EP4 antagonists, HDAC (histone deacetylase) inhibitors, STING (interferon gene stimulatory protein) activators, kinase inhibitors, any other chemotherapeutic or targeted therapeutic or radiotherapeutic agents.

In another preferred example, the tumor (e.g. cancer), a neurodegenerative disease (e.g. parkinson's disease, senile dementia, i.e. alzheimer's disease), an inflammatory disease (e.g. Inflammatory Bowel Disease (IBD)).

In another preferred embodiment, the LRRK2 mediated disease is selected from the group consisting of: cancer, parkinson's disease, alzheimer's disease, senile dementia, inflammatory Bowel Disease (IBD), tuberculosis, leprosy, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthropathies, gout, systemic lupus erythematosus, sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, autoimmune hepatitis, autoimmune liver and gall disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, huntington's disease, allergic diseases, asthma, multiple sclerosis, type diabetes, wegener's granulomatosis, pulmonary sarcoidosis, behcet's disease, interleukin-I invertase-related fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-related periodonitis.

In a fourth aspect of the present invention, there is provided a pharmaceutical combination, wherein the pharmaceutical composition comprises:

(a) A first active ingredient which is a compound according to the first aspect or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug thereof; and

(B) A second active ingredient that is an immune checkpoint protein inhibitor.

In another preferred embodiment, the immune checkpoint protein inhibitor is selected from the group consisting of: PD-1 antibody, CTLA-4 antibody, PD-L1 antibody, PD-L2 antibody, IDO (indoleamine 2, 3-dioxygenase) inhibitor, TDO (tryptophan dioxygenase) inhibitor, IDO/TDO dual inhibitor, EP4 antagonist, HDAC (histone deacetylase) inhibitor, STING (interferon gene stimulatory protein) activator, and kinase inhibitor.

In a fifth aspect of the invention, there is provided a method of inhibiting LRRK2 kinase activity comprising the steps of: contacting LRRK2 kinase with a compound as described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a prodrug thereof, thereby inhibiting the activity of LRRK2 kinase.

In another preferred embodiment, the method is non-therapeutic in vitro.

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. Is limited to a space and will not be described in detail herein.

Detailed Description

The present inventors have conducted extensive and intensive studies and have unexpectedly found that a class of compounds having a novel structure, such as the compounds represented by formula I, have excellent leucine-rich repeat kinase 2 (LRRK 2) inhibitory activity. Based on this, the present inventors completed the present invention.

Definition of the definition

As used herein, the term "alkyl", as a whole or as part of a group, refers to monovalent saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms, e.g., C _1-12(C_1-6) alkyl refers to monovalent saturated aliphatic hydrocarbon groups having 1 to 12 (1 to 6) carbon atoms, which term includes straight and branched chain hydrocarbon groups. In this context, preferred alkyl groups have 1 to 6 carbon atoms (i.e., C _1-6 alkyl groups), more preferably alkyl groups have 1 to 4 carbon atoms (i.e., C _1-4 alkyl groups). Examples of alkyl groups include, but are not limited to: methyl (i.e., CH ₃ -), ethyl (i.e., CH ₃CH₂ -), n-propyl (i.e., CH ₃CH₂CH₂ -), isopropyl (i.e., (CH ₃)₂ CH-), n-butyl (i.e., CH ₃CH₂CH₂CH₂ -), isobutyl (i.e., (CH ₃)₂CHCH₂ -), sec-butyl (i.e., (CH ₃)(CH₃CH₂) CH-), tert-butyl (i.e., (CH ₃)₃ C-), n-pentyl (i.e., CH ₃CH₂CH₂CH₂CH₂ -), neopentyl (i.e., (CH ₃)₃CCH₂ -).

As used herein, the term "aryl", as a whole or as part of a group, refers to a monovalent aromatic carbocyclic group having the indicated number of carbon atoms, e.g., 6 to 20, i.e., C _6-20 aryl (preferably 6-14C _6-14 aryl, more preferably 6-10C _6-10 aryl) carbon atoms as ring atoms, which may be monocyclic (e.g., phenyl) or fused (e.g., naphthyl or anthracenyl). When the aryl group is a fused ring city, so long as the point of attachment is on an aromatic carbon atom, other rings in the fused ring may be non-aromatic, and examples of such fused rings include, for example, 2-benzoxazolone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl and the like. Preferred aryl groups include phenyl and naphthyl.

As used herein, the term "alkenyl", as a whole or as part of a group, refers to an unsaturated hydrocarbon group having the indicated number of carbon atoms and having at least 1 (e.g., 1 to 2) unsaturated olefinic bonds (> c=c <). Typically, alkenyl has 2 to 12 carbon atoms, i.e., C _2-12 alkenyl, preferably alkenyl has 2 to 6 carbon atoms, i.e., C _2-6 alkenyl, more preferably alkenyl has 2 to 4 carbon atoms, i.e., C _2-4 alkenyl. Examples of such groups include, for example, vinyl, allyl, but-3-enyl. Similarly, the term "alkynyl" refers to an unsaturated hydrocarbon group having the indicated number of carbon atoms and having at least 1 (e.g., 1 or 2) unsaturated carbon-carbon triple bonds. Typically, alkynyl has 2-12 carbon atoms, i.e., C _2-12 alkynyl, preferably alkynyl has 2-6 carbon atoms, i.e., C _2-6 alkynyl, more preferably alkynyl has 2-4 carbon atoms, i.e., C _2-4 alkynyl. Examples of such groups include, for example, ethynyl, 1-and 3-propynyl, 3-butynyl.

As used herein, the term "cycloalkyl", as a whole or as part of a group, refers to a cyclic alkyl (preferably saturated cyclic alkyl) group having a single or multiple ring system of the specified number of carbon ring atoms (including fused systems, bridged ring systems and spiro ring systems). When cycloalkylalkyl is a fused ring system, the other ring or rings fused may be cycloalkyl, heterocyclic, aryl or heteroaryl, provided the attachment site is through the ring of the cycloalkyl. Preferably, cycloalkyl has 3 to 10 ring carbon atoms, i.e., C _3-10 cycloalkyl, more preferably, cycloalkyl has 3 to 6 ring carbon atoms, i.e., C _3-6 cycloalkyl. Examples of suitable cycloalkyl groups include: for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine. The term "halo" refers to the substitution of one or more or all of the hydrogens of the group with halogen atoms (e.g., F, cl, br, and I). For example, as used herein, the term "haloalkyl" refers to an alkyl group as defined herein substituted with one or more halogen atoms, examples of haloalkyl include, for example, -CF ₃、-CH₂CF₃.

As used herein, the term "heteroaryl", as a whole or as part of a group, refers to an aromatic group having the specified number of ring atoms and having 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur. Generally, heteroaryl refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms within the ring. Preferably, the heteroaryl has 5 to 10 ring atoms (i.e., a 5 to 10 membered heteroaryl), more preferably, the heteroaryl has 5 to 6 ring atoms (i.e., a 5 to 6 membered heteroaryl or a 5 or 6 membered heteroaryl) and contains 1,2, 3, or 4 heteroatoms. Herein, such heteroaryl groups may be monocyclic (e.g., pyridinyl or furanyl) or fused (e.g., indolizinyl (indolizinyl) or benzothienyl). When heteroaryl is a fused ring, the fused ring or rings may also be non-aromatic and/or contain one heteroatom, so long as the point of attachment is through an atom of the aromatic heteroaryl (which may be a heteroatom such as N or may be a carbon atom in the ring). In some embodiments, the ring atoms nitrogen and/or sulfur of the heteroaryl group are optionally oxidized to an N-oxide (N-O), sulfinyl or sulfonyl. Preferably, examples of heteroaryl groups include pyridyl, pyrrolyl, indolyl, thienyl and furyl.

As used herein, the term "substituted heteroaryl" refers to heteroaryl substituted with 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from the same substituents as defined for substituted aryl.

As used herein, the term "heterocyclyl" (also referred to herein as "heterocycle" or "heterocyclic" or "heterocycloalkyl") as a whole or as part of a group refers to a saturated, partially saturated, or unsaturated cyclic group (but not aromatic) having the indicated number of ring atoms and containing 1 to 5 (e.g., 1,2, 3, or 4, preferably 1 or 2) heteroatoms selected from nitrogen, sulfur, or oxygen in the ring. Heterocyclic groups may have a single ring system or a fused ring system (including bridged and spiro ring systems). Typically, the ring of the heterocyclyl has 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen. When the heterocyclic group is a fused ring system, the fused ring or rings may be cycloalkyl, aryl or heteroaryl, provided that the point of attachment is through a non-aromatic ring. The heterocyclic group may be attached to the rest of the compound through a carbon atom on the ring or a heteroatom (e.g., nitrogen atom) on the ring. In some embodiments, the nitrogen and/or sulfur atoms of the heterocyclic group are optionally oxidized to provide N-oxide, sulfinyl, and sulfonyl moieties. Preferably, the heterocyclyl includes 3 to 10 ring atoms (i.e., 3 to 10 membered heterocyclyl), more preferably, 4 to 6 ring atoms (i.e., 4 to 6 membered heterocyclyl), and contains 1,2, 3, or 4 heteroatoms.

As used herein, the term "substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to a heterocyclic group substituted with 1 to 5 (e.g., 1 to 3) substituents, which are the same as substituents defined for substituted cycloalkyl.

In some embodiments, the above terms (e.g., "alkyl," "cycloalkyl," "heterocyclyl," "aryl," "heteroaryl," etc.) will include both substituted and unsubstituted forms of the indicated group. Preferably, when in a substituted form, substituted means 1 to 5 (e.g., 1 to 3, or 1 or 2) substituents are substituted as defined herein.

The term "one or more" as used herein is preferably 1, 2,3, 4 or 5, more preferably 1, 2 or 3.

Unless otherwise indicated, herein each cycloalkyl is a C _3-6 cycloalkyl, each heterocyclyl is a 3 to 10 membered heterocyclyl, each aryl is a C _6-10 aryl, and each heteroaryl is a 5 to 10 membered heteroaryl.

In some embodiments, substituents for groups such as "alkyl", "cycloalkyl", "heterocyclyl", "aryl", "heteroaryl", and the like are selected from, but are not limited to, the following chemical groups: halogen, -C _1-6 alkyl, -C _3-8 cycloalkyl, -C _1-6 haloalkyl, -C _3-8 halocycloalkyl, -C _1-6 alkoxy, -C _3-8 cycloalkoxy, -C _1-6 alkylthio, -C _0-6 alkylene-OH, nitro, aldehyde, -SF ₅、-C_0-6 alkylene-NR ^aR^b、-C_0-6 alkylene-carboxyl, -C _0-6 alkylene-COR ^a、-C_0-6 alkylene-CO ₂R^a、-C_0-6 alkylene-CONR ^dR^e、-C_0-6 alkylene-SO ₂R^a、-C_0-6 alkylene-SO ₂NR^dR^e, Carbonyl, -C _0-6 alkylene-CN, -C _3-8 cycloalkyl-OH, -C _2-6 alkenyl, C _2-6 alkynyl, -C _0-6 alkylene-S (O) (NH) C _1-6alkyl、-C_0-6 alkylene-S (O) (NCN) C _1- ₆alkyl、-C_0-6 alkylene-NR ^cS(O)₂R^b、-C_0-6 alkylene-NR ^cS(O)₂NR^cR^b、-C_0-6 alkylene-NR ^cC(O)NH₂、-C_0-6 alkylene-NR ^cC(O)R^b、-C_0-6 alkylene-NR ^cC(O)NR^dR^e、-C_0-6 alkylene-NR ^cC(O)OR^b、-C_0-6 alkylene-NRSO ₂R^bC(O)-R^b、-C_0-6 alkylene-P (O) R ^cR^b、-C_0-6 alkylene-P (O) (OR ^c)(OR^b)、-C_0-6 alkylene-C (O) C _1-6 alkylene amino, C _1-6 heteroalkyl, C _3-10 carbocycle (group), C _5-10 aryl (ring), 4 to 10 membered heteroaryl (ring), 5 to 10 membered heteroaryl (ring). Preferably, R ^a、R^b and R ^c are each independently hydrogen, unsubstituted C _1-8 alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C _1-8 alkyl, C _1-8 alkoxy or C _1-8 thioalkoxy, or unsubstituted aryl-C _1-4 alkyl.

As used herein, C _0-6 alkylene means having no alkylene group or having a C _1-6 alkylene group at that position, i.e., C _0-6 alkylene represents absent (single bond) or C _1-6 alkylene.

For the compounds provided herein, a bond from a substituent (typically an R group) to the center of a ring (e.g., heterocyclyl, cycloalkyl, aryl, and heteroaryl) will be understood to refer to a bond that provides a connection at any available vertex of the ring. As used herein, the terms "comprising," "including," or "comprising" mean that the various ingredients can be used together in a mixture or composition of the invention. Thus, the terms "consisting essentially of and" consisting of are encompassed by the term "containing.

As used herein, the term "stereoisomer" refers to a compound of differing chirality at one or more stereocenters. Stereoisomers include enantiomers isomers and diastereomers.

As used herein, the term "tautomer" refers to alternative forms of compounds having different proton positions, such as enol-ketone and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms attached to the-NH-portion of the ring and the = N-portion of the ring, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

Compounds of the invention

As used herein, the term "compound of the present invention" refers to a compound as described in the first aspect of the present invention, such as the compounds of formulae I to ix. The term also includes and includes various crystalline forms, various isomers, pharmaceutically acceptable salts, hydrates or solvates or prodrugs of the compounds of the present invention.

As used herein, the term "pharmaceutically acceptable salt" refers to the non-toxic acid or alkaline earth metal salts of the compounds of the present invention as shown in formulas I to ix. These salts may be prepared in situ upon final isolation and purification of the compounds of formulae I to IX, or by reaction of a suitable organic or inorganic acid or base with a basic or acidic functional group, respectively. Representative salts include, but are not limited to: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorsulfonate, digluconate, cyclopentane propionate, dodecyl sulfate, ethane sulfonate, glucose heptanoate, glycerophosphate, hemisulfate, heptanoate, caproate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphtyl sulfonate, oxalate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, and undecanoate. In addition, the basic nitrogen-containing groups may be quaternized with the following agents: alkyl halides, such as methyl, ethyl, propyl, butyl chloride, bromide and iodide; dialkyl sulfates such as dimethyl, diethyl, dibutyl and dipentyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides, and the like. Thus obtaining a water-soluble or oil-soluble or dispersible product. Examples of acids that may be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, citric acid. The base addition salts may be prepared in situ upon final isolation and purification of the compounds of formulae I to ix, or by reacting the carboxylic acid moiety with a suitable base (such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation) or ammonia, or an organic primary, secondary or tertiary amine, respectively. Pharmaceutically acceptable salts include, but are not limited to, alkali and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, aluminum salts, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to: ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful in forming base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

As used herein, the term "solvate" refers to a compound of the invention that coordinates to a solvent molecule to form a complex in a specific ratio. "hydrate" refers to a complex of the compound of the present invention coordinated to water.

As used herein, "prodrug" refers to any derivative of a compound of the invention that, when administered to a subject, is capable of providing, directly or indirectly, a compound of the invention or an active metabolite or residue thereof. Particularly preferred derivatives and prodrugs are those that, when administered to a subject, increase the bioavailability of the compounds of the examples (e.g., orally administered compounds are more readily absorbed into the blood) or enhance the transport of the parent compound to a biological compartment (e.g., brain or lymphatic system) relative to the parent species. Prodrugs include ester forms of the compounds of the present invention.

Where stereoisomers of the compounds of the invention are present, the invention includes all stereoisomers of the compounds.

Where a tautomer exists for a compound of the present invention, the present invention includes all tautomers of the compound.

Where a tautomer exists in a compound of the present invention, the present invention includes all atropisomers of the compound.

The invention also includes deuterated compounds produced by substitution of any one or more hydrogen atoms of the compounds with deuterium, a stable isotope thereof.

Pharmaceutical compositions and methods of administration

Because the compounds of the present invention have excellent inhibitory activity against leucine-rich repeat kinase 2 (LRRK 2), the compounds of the present invention and various crystal forms, various isomers, pharmaceutically acceptable salts, hydrates or solvates or prodrugs thereof, and pharmaceutical compositions containing the compounds of the present invention as a main active ingredient are useful for treating, preventing and alleviating diseases mediated by LRRK2 protein kinase. According to the prior art, the compounds of the present invention are useful in therapy, prophylaxis and alleviation. According to the prior art, the compounds of the invention are useful for the treatment of: degenerative diseases (including parkinson's disease), inflammatory diseases (such as IBD), and tumors (such as cancer), or LRRK2 mediated diseases as described elsewhere herein.

The invention also provides active ingredients within the safe and effective amount range of the compounds of the general formulas I to IX, and pharmaceutically acceptable carriers.

The "active ingredient" of the present invention refers to the compounds of the general formulae I to IX of the present invention.

The "active ingredients" and pharmaceutical compositions of the present invention are useful as treatments for neurodegenerative diseases (including parkinson's disease) and cancer.

"Safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of active ingredient per dose, more preferably 10-200mg of active ingredient per dose. Preferably, the "one dose" is a tablet or capsule.

"Pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatibility" as used herein means that the components of the composition are capable of blending with and between the active ingredients of the present invention without significantly reducing the efficacy of the active ingredients.

Generally, the compounds of the preferred embodiments will be administered in a therapeutically effective amount by any one of the acceptable modes of administration of agents having similar effects. The actual amount of the compound (i.e., active ingredient) of the preferred embodiment is determined by a number of factors, such as the severity of the disease to be treated, the age and relative health of the patient, the efficacy of the compound being used, the route and form of administration, and other factors. The medicament may be administered a plurality of times a day, preferably once or twice a day. All of these factors are within the contemplation of the attending physician.

Purpose of the preferred embodiment: the therapeutically effective dose may generally be the total daily dose administered to the patient either in one go or in divided doses, for example, from about 0.001 to about 1000 mg/kg body weight per day, preferably from about 1.0 to about 30 mg/kg body weight per day. The unit dose composition (Dosage unit composition) may contain its dose factor to form a daily dose. The choice of dosage form depends on various factors such as the mode of administration and the bioavailability of the drug substance. In general, the compounds of the preferred embodiments may be administered as pharmaceutical compositions by any of the routes: oral, systemic (e.g., transdermal, intranasal, or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous). The preferred mode of administration is oral, and the convenient daily dosage can be adjusted according to the degree of bitterness. The compositions may take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols or any other suitable compositions. Another preferred means of administering the preferred embodiment compounds is inhalation. This is an effective method of delivering therapeutic agents directly to the respiratory tract (see, e.g., U.S. patent No. 5,607,915).

Suitable pharmaceutically acceptable carriers or excipients include: such as treatments and drug delivery modifiers and accelerators, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starches, gelatin, cellulose, sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting waxes, ion exchange resins and the like, and combinations of any two or more thereof. The liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including petroleum, animal, vegetable or synthetic sources such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose and glycols. Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, mack pub.co., new jersey (1991), incorporated herein by reference.

Process for the preparation of the compounds of the invention

The compounds of the present invention may be prepared, isolated or obtained by any method apparent to those skilled in the art. The compounds of the present invention may also be prepared according to the exemplary preparation schemes provided below (as in the examples). The reaction conditions, steps and reactants not provided in the exemplary preparation schemes are obvious and known to those skilled in the art. As used herein, the symbols and conventions used in these processes, schemes and examples, whether or not a particular abbreviation is specifically defined, have the meanings well known to those skilled in the art.

For example, the compounds of the present invention may be obtained synthetically from known or commercially available starting materials according to schemes one, two or three as shown below.

In the scheme I, 2, 4-dichloropyrrolo [2,1-f ] [1,2,4] triazine is taken as a raw material, reduced by sodium borohydride, and then oxidized by DDQ to obtain an intermediate I-1. Then coupling with proper substituted amino pyrazole by Buchwald coupling to obtain an intermediate I-2, performing trifluoromethylation by using reagents such as CF ₃SO₂ Na and the like, and finally performing chlorination by using NCS to obtain a target product I-4. In the formulae, R ¹、R² and R ³ are as defined elsewhere herein.

In the scheme II, the intermediate II-2 is obtained by brominating the I-1 as a raw material, then different substituents are introduced by adopting Suzuki or still coupling according to the used reagent, and then Buchwald coupling is carried out on the intermediate II-4 with proper substituted aminopyrazole. And then chloridizing to obtain the final product II-5. In the formulae, R ¹、R²、R³ and R ⁴ are as defined elsewhere herein

III-1 is oxidized with a peroxide such as mCPBA to give III-2, which is then reacted with an appropriately substituted aminopyrazole under the catalysis of p-toluenesulfonic acid monohydrate to give III-3. After removal of the protecting group, condensation with a suitable carboxylic acid gives III-5, followed by catalytic ring closure to III-6 using POCl ₃. And carrying out bromination and coupling reaction on III-6 to obtain a product III-8. In the formulae, R ¹、R²、R³、R⁴ and R ⁵ are as defined elsewhere herein.

The use herein also provides the use of a compound of the invention as shown in formulae I to IX for:

(i) Preparing an LRRK2 inhibitor for the treatment of neurodegenerative diseases, inflammatory diseases (such as IBD) and cancer; and/or

(Ii) Preparing a medicament for preventing and/or treating LRRK2 mediated diseases, particularly parkinson's disease; and/or

(Iii) Preparation of combination drugs for tumor treatment including LRRK2 inhibitors with other tumor drugs: PD-1 antibodies, CTLA-4 antibodies, PD-L1 antibodies, PD-L2 antibodies, adoptive cell transplantation therapy, cancer vaccines, IDO (indoleamine 2, 3-dioxygenase) inhibitors, TDO (tryptophan dioxygenase) inhibitors, IDO/TDO dual inhibitors, EP4 antagonists, HDAC (histone deacetylase) inhibitors, STING (interferon gene stimulatory protein) activators, kinase inhibitors, any other chemotherapeutic or targeted therapeutic or radiotherapeutic agents.

The main advantages of the invention include:

(a) The compounds of the present invention have excellent inhibitory ability against LRRK2 activity.

Abbreviations and test conditions:

Abbreviations used in the examples of the present invention have the conventional meaning understood by those skilled in the art, unless otherwise indicated, for example, the following abbreviations have the indicated meanings: EA: ethyl acetate; DCM: dichloromethane; DIEA: diisopropylethylamine; naBH ₄: sodium borohydride; DMF: n, N-dimethylformamide; DMSO: dimethyl sulfoxide; DPPF (DPPF): 1,1' -bis (diphenylphosphine) ferrocene; DIAD: diisopropyl azodicarboxylate; EDCI:1- (3-dimethylaminopropyl) -3-ethylcarbodiimide; HATU: o- (7-azobenzotriazol) -1, 3-tetramethylurea hexafluorophosphate; HOAT N-hydroxy-7-azobenzotriazole; IPA: isopropyl alcohol; LDA: lithium diisopropylamide; liHMDS: lithium bis (hexamethyldisilyl) amide; NCS: n-chlorosuccinimide; NBS: n-bromosuccinimide; NIS: n-iodosuccinimide; PE: petroleum ether; EA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; PPh ₃: triphenylphosphine; RT: room temperature; DDQ:2, 3-dichloro-5, 6-dicyanobenzoquinone; +/-BINAP: and (+ -) -1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine.

Reversed phase HPLC purification conditions: HPLC-MS analysis was performed on a Vortight HPLC 2790 using Vortight micromass ZQ 4000 (MAA 050 type) as the mass detector and Vortight 2487UV as the detector. The column used was a Feinomei OOB-4605-E0 (5U-XB-C18-100A, 50X 4.6 mm). The mobile phases were eluent A (water, 0.05% TFA) and eluent B (CH ₃ CN, 0.05% TFA) at an elution rate of 1 ml/min. The starting conditions were 90% a for 1 minute, then 90% a was linearly decreased to 10% a in 5 minutes, and then back up from 10% a to 90% a in 1 minute, with a total run time of 7 minutes. The mobile phase gradient and the run time can be appropriately adjusted according to the nature of the compound.

Chiral HPLC resolution conditions: using Agilent Technologies-1200 affinity liquid chromatography, chiral columns were used with cellophane CHIRALPAK IG (cat# IG00EE-AT 002), CHIRALPAK IG (cat# IG00CE-AQ 017), CHIRALPAK AD-H (cat# ADH0CE-EL 100). The mobile phase is eluent A (n-hexane) and eluent B (ethanol), the elution speed is 0.8 or 3ml/min, and the elution condition adopts ethanol with constant proportion. Depending on the nature of the compound, the chiral chromatography column type, the mobile phase ethanol ratio and the run time can be adjusted appropriately.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are by weight, units are parts by weight.

Materials and reagents used in the examples of the present invention are commercially available products unless otherwise indicated.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.

Example 1: t-1

2-Methyl-2- (3-methyl-4- (pyrrolo [2,1-f ] [1,2,4] triazin-2-ylamino) -1H-pyrazol-1-yl) propionitrile

First step, M-1 preparation

2, 4-Dichloropyrrolo [2,1-f ] [1,2,4] triazine (4 g) was dissolved in ultra-dry THF (60 ml) and iPrOH (10 ml), followed by the addition of NaBH ₄ (1287 mg). After stirring at room temperature for 6h, the mixture was filtered and dried. The resulting solid was dissolved in DCM (70 ml) and DDQ (5796 mg) was added. After stirring at room temperature for 2h, quenching with saturated NaHCO ₃ solution, extraction with DCM, and flash column chromatography of the organic phase to give 2.96g of pale yellow green solid.

MS ESI:m/z＝154,[M+1]⁺。

Second step, M-2 preparation

M-1 (2000 mg) was dissolved in ultra-dry 1,4-dioxane (50 ml), then methyl 2- (4-amino-3-methyl-1H-pyrazol-1-yl) -2-methylpropionate (2524 mg), pd (OAc) ₂ (177.8 mg), + BINAP (1329.7 mg) and Cs ₂CO₃ (6937.2 mg) were added, and then air was replaced with nitrogen, and heated at 100 ℃. After 3h the reaction was completed, saturated solution of NH ₄ Cl was quenched, extracted with EA, and the organic phase was spun dry and purified by flash column chromatography to give 3.27g of solid.

MS ESI:m/z＝315,[M+1]⁺。

Third step, M-3 preparation

M-2 (1000 mg) and NH ₃ in MeOH (7N) were added to the tube, heated at 100deg.C for 2 days, and flash column chromatography on silica gel afforded 900mg of a pale yellow solid.

MS ESI:m/z＝300,[M+1]⁺。

Fourth step, T-1 preparation

M-3 (900 mg) was dissolved in ultra-dry THF (25 ml), followed by the addition of Burgess reagent (1470 mg). After stirring at room temperature for 3h, quenching with saturated NH ₄ Cl solution, EA extraction, and flash column chromatography on silica gel after spin-drying the organic phase to give 440mg of product.

MS ESI:m/z＝282,[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.67(s,1H),8.21(s,1H),7.57(s,1H),6.76(m,1H),6.73(d,J＝2.0Hz,1H),2.31(s,3H),2.02(s,6H).

Example 2: t-2

2-Methyl-2- (3-methyl-4- ((7- (trifluoromethyl) pyrrolo [2,1-f ] [1,2,4] triazin-2-yl) amino) -1H-pyrazol-1-yl) propionitrile

T-1 (50 mg) was dissolved in DCM (4 ml) and ultrapure water (0.2 ml) under ice bath, and then CF ₃SO₂ Na (136.6 mg), T-butyl hydroperoxide (0.27ml,5.5N in decane) and DMSO (0.8 ml) were added. After stirring at 40℃for 6h, the reaction was completed, quenched by addition of saturated NH ₄ Cl solution, extracted by EA, and the organic phase was dried by flash column chromatography and C ₁₈ reversed phase preparative chromatography to give 25mg of solid T-2.

MS ESI:m/z＝350,[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.79(s,1H),8.40(s,1H),6.98(d,J＝4.7Hz,1H),6.74(d,J＝4.7Hz,1H),6.71(s,1H),2.33(s,3H),2.02(s,6H).

Example 3: t-3

2- (4- ((5-Chloro-7- (trifluoromethyl) pyrrolo [2,1-f ] [1,2,4] triazin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) -2-methylpropanenitrile

T-2 (16 mg) was dissolved in ultra-dry DMF (3 ml), NCS (5 mg) was added, after stirring for 3h NCS (3 mg) was added, after stirring overnight, quenched with saturated NH ₄ Cl solution, extracted with EA, and the organic phase was dried by flash column chromatography and C ₁₈ reverse phase preparative chromatography to give 3mg of solid T-3.

MS ESI:m/z＝384,[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.85(s,1H),8.34(s,1H),6.92(s,1H),6.59(s,1H),2.34(s,1H),2.01(s,3H).

Example 4: t-4

2- (4- ((5-Chloro-7-methylpyrrolo [2,1-f ] [1,2,4] triazin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) -2-methylpropanenitrile

First step, preparation of M-4

M-1 (1 g) was dissolved in acetonitrile (32 ml), and NBS (1159 mg) was added under ice bath. After stirring in ice bath for 2h, quenching with saturated NH ₄ Cl solution, EA extraction, and flash column chromatography on silica gel after spin-drying the organic phase gave 1.2g of solid M-4.

MS ESI:m/z＝232,[M+1]⁺。

Second step, M-5 preparation

M-4 (100 mg) was dissolved in 1,4-dioxane (4 ml) and water (0.4 ml), followed by addition of potassium methyltrifluoroborate (105 mg), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (70 mg) and cesium carbonate (421 mg). After air was replaced with nitrogen, stirred overnight at 100 ℃, quenched with saturated NH ₄ Cl, extracted with EA, and the organic phase was dried by flash column chromatography to give 30mg of solid M-5.

MS ESI:m/z＝168,[M+1]⁺。

Third step, M-6 preparation

M-5 (30 mg) was dissolved in ultra-dry 1,4-dioxane (2 ml), followed by addition of 2- (4-amino-3-methyl-1H-pyrazol-1-yl) -2-methylpropanenitrile (29 mg), pd (OAc) ₂ (12.2 mg), +BINAP (45.7 mg) and Cs ₂CO₃ (95.6 mg). Air was then replaced with nitrogen, heated at 100 ℃ overnight, quenched with NH ₄ Cl saturated solution, extracted with EA, and the organic phase was dried by flash column chromatography to give 19mg of solid.

MS ESI:m/z＝296,[M+1]⁺。

Fourth step, T-4 preparation

M-6 (19 mg) was dissolved in DMF (2 ml), NCS (8.5 mg) was added, stirred at room temperature for 2 days, quenched with saturated NH ₄ Cl solution, extracted with EA, and the organic phase was dried by flash column chromatography and C ₁₈ reversed phase preparative chromatography to give 3.4mg of solid T-4.

MS ESI:m/z＝330,[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.60(s,1H),8.33(s,1H),6.61(bs,1H),6.50(s,1H),2.53(s,3H),2.32(s,3H),2.00(s,6H).

Example 5: t-5

2- (4- ((5-Chloro-7-cyclopropylpyrrolo [2,1-f ] [1,2,4] triazin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) -2-methylpropanenitrile

First step, M-7 preparation

M-4 (100 mg) was dissolved in1, 4-dioxane (4 ml) and water (0.2 ml), followed by addition of cyclopropylboronic acid (92 mg), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (70 mg) and potassium carbonate (178 mg). After air was replaced with nitrogen, stirred at 100℃for 3h, quenched with saturated NH ₄ Cl solution, extracted with EA, and the organic phase was dried by flash column chromatography to give 30mg of solid M-5.

MS ESI:m/z＝194,[M+1]⁺。

Second step, M-8 preparation

Using M-7 (30 mg) as a raw material, 17mg of M-8 was produced under the same conditions as in the third step of example 4.

MS ESI:m/z＝322,[M+1]⁺。

Third step, T-5 preparation

M-8 (17 mg) was dissolved in THF (1 ml) and MeOH (0.2 ml), NCS (7 mg) was added, after stirring overnight, NCS (10 mg) was added, after stirring for 5h, the reaction was quenched with saturated NaHCO ₃, extracted with EA, and the organic phase was dried by flash column chromatography and C ₁₈ reversed phase preparative chromatography to give 5.4mg of solid T-5.

MS ESI:m/z＝356,[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.56(s,1H),8.40(s,1H),6.71(bs,1H),6.32(s,1H),2.33(s,3H),2.31–2.19(m,1H),1.99(s,6H),1.16(m,2H),0.89(m,2H).

Example 6: t-6

(±) -5-Chloro-N- (3-chloro-1- (1- (methylsulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7-cyclopropylpyrrolo [2,1-f ] [1,2,4] triazin-2-amine

First step, M-9 preparation

M-7 (50 mg) was dissolved in ultra-dry 1,4-dioxane (2 ml), followed by addition of 3-chloro-1- (1- (methylsulfonyl) piperidin-4-yl) -1H-pyrazol-4-amine (76.75 mg), pd (OAc) ₂ (17.6 mg), + BINAP (65.9 mg) and Cs ₂CO₃ (207 mg). Then air was replaced with nitrogen, heated at 100 ℃ overnight, quenched with saturated NH ₄ Cl, extracted with EA, and the organic phase was dried by flash column chromatography to give 63mg M-9.

MS ESI:m/z＝436,[M+1]⁺。

Second step, T-6 preparation

M-9 (63 mg) was dissolved in THF (1.5 ml) and MeOH (0.5 ml), NCS (17.4 mg) was added, after stirring for 6h, the reaction was quenched with saturated NaHCO ₃, extracted with EA, and the organic phase was dried by flash column chromatography and C ₁₈ reversed phase preparative chromatography to give 25.7mg of solid T-6.

MS ESI:m/z＝470,[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.56(s,1H),8.28(s,1H),6.63(bs,1H),6.26(s,1H),4.37(m,1H),3.96(m,2H),2.99(m,2H),2.86(s,3H),2.39–2.24(m,3H),2.10(m,2H),1.17–1.06(m,2H),0.84(m,2H).

Example 7: t-7 and T-8

(+ -) -Trans-5-chloro-N- (3-chloro-1- (3-fluoro-1- (methylsulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7-cyclopropylpyrrolo [2,1-f ] [1,2,4] triazin-2-amine (T-7)

1-Fluoro-1- (3-fluoro-1- (methylsulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7-cyclopropylpyrrolo [2,1-f ] [1,2,4] triazin-2-amine (T-8)

First step, M-10 preparation

Cis-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (4 g) and 4-nitropyrazole were dissolved in THF (90 ml), followed by addition of PPh ₃ (7.17 g) and DIAD (5.39 ml). After heating at 30 ℃ for 7 hours, the reaction solution is filtered and dried, and then light yellow oily matter is obtained through flash silica gel column chromatography. It was dissolved in HCl 1, 4-dioxane (40 ml, 4N) and stirred for 2h, followed by spin-drying to give M-10.

MS ESI:m/z＝215,[M+1]⁺。

Second step, M-11 preparation

To the hydrochloride salt of M-10 (500 mg) was added DCM (10 ml), NEt ₃ (0.49 ml) and MsCl (0.27 ml). After stirring for 1h, spin-drying gave 350mg of M-11 by flash column chromatography.

MS ESI:m/z＝293,[M+1]⁺。

Third step, M-12 preparation

M-11 (350 mg) was dissolved in ethanol (5 ml), followed by addition of alumina-supported palladium (70 mg, 5%), concentrated hydrochloric acid (0.86 ml) and triethylsilane (1.65 ml). After stirring at room temperature for 1 day, triethylsilane (1.65 ml) was added, and after stirring overnight, naHCO ₃ solution was neutralized, EA was extracted, and after spin-drying through the column 120mg M-12 was obtained.

MS ESI:m/z＝297,[M+1]⁺。

Fourth step, M-13 preparation

Using M-7 (50 mg) and M-12 (81.7 mg) as raw materials, 41mg of M-13 was produced under the same conditions as in the first step of example 6.

MS ESI:m/z＝454,[M+1]⁺。

Fifth step, T-7 and T-8 are prepared

M-13 (41 mg) was dissolved in THF (1.5 ml) and MeOH (0.5 ml), NCS (12 mg) was added, after stirring overnight NCS (7 mg) was added, stirring was continued for 10h, the reaction was quenched with NaHCO ₃ saturated solution, EA was extracted, and the organic phase was dried by flash column chromatography and C ₁₈ reversed phase preparative chromatography to give 18mg T-7 and 12mg T-8.

MS ESI:m/z＝488,[M+1]⁺(T-7)。

¹H NMR(400MHz,CDCl₃)δ8.52(s,1H),8.30(s,1H),6.31(s,1H),5.10(m,1H),4.98(m,1H),4.45(m,1H),4.24(m,1H),3.94(m,1H),3.03(m,2H),2.91(s,3H),2.48–2.26(m,1H),2.22–2.11(m,1H),1.18(m,2H),0.87(m,2H).(T-7)

MS ESI:m/z＝522,[M+1]⁺(T-8)。

¹H NMR(400MHz,CDCl₃)δ8.57(s,1H),8.28(s,1H),6.54(s,1H),5.11(m,1H),5.05–4.94(m,1H),4.45(m,1H),4.36–4.18(m,1H),3.95(m,1H),3.11–2.95(m,2H),2.92(s,3H),2.41(m,1H),2.13(m,1H),1.31(m,2H),1.19–1.01(m,2H).(T-8)

Examples 7A and 7B: chiral resolution of T-7-1 and T-7-2: t-7 was resolved into example 7A (T-7-1, 11.2 min) and example 7B (T-7-2, 13.81 min) using CHIRALPAK IG (cat# IG00CE-AQ 017) column at a flow rate of 0.8ml/min with 50% ethanol/n-hexane as eluent.

Examples 7C and 7D: t-8-1 and T-8-2

Chiral resolution: t-8 was resolved into example 7C (T-8-1, 11.17 min) and example 7D (T-8-2, 13.79 min) using CHIRALPAK IG (cat# IG00CE-AQ 017) column at a flow rate of 0.8ml/min with 50% ethanol/n-hexane as eluent.

Example 8: t-9

(±) -3- (4- ((5-Chloro-7-cyclopropylpyrrolo [2,1-f ] [1,2,4] triazin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) cyclobutane-1-carbonitrile

Using M-7 (50 mg) and (+ -) -3- (4-amino-3-methyl-1H-pyrazol-1-yl) cyclobutane-1-carbonitrile (55 mg) as starting materials, 47mg of T-9 was prepared under the same conditions as in example 6.

MS ESI:m/z＝368,[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.56(s,1H),8.09(s,1H),6.51(s,1H),6.28(s,1H),4.68(m,1H),2.93(m,4H),2.85(m,1H),2.31(s,3H),2.25(m,1H),1.15(m,2H),0.91m,2H).

Examples 8A and 8B: resolution of the cis-trans isomers of T-9-1 and T-9-2: t-9 was resolved into example 8A (T-9-1, 15.4 min) and example 8B (T-9-2, 19.15 min) using CHIRALPAK AD-H (cat# ADH0CE-EL 100) column at a flow rate of 0.8ml/min with 50% ethanol/n-hexane as eluent.

Example 9: t-10

(±) -3- (4- ((5-Chloro-7-cyclopropylpyrrolo [2,1-f ] [1,2,4] triazin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) -3-methyldihydrofuran-2 (3H) -one

Using M-7 (50 mg) and 3- (4-amino-3-methyl-1H-pyrazol-1-yl) -3-methyldihydrofuran-2 (3H) -one (61 mg) as starting materials, 35mg of T-10 was produced under the same conditions as in example 6.

MS ESI:m/z＝387,[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.44(s,1H),8.31(s,1H),6.40(s,1H),4.55–4.34(m,2H),3.40–3.23(m,1H),2.48(m,1H),2.35(s,3H),2.33–2.28(m,1H),1.79(s,3H),1.35–1.11(m,2H),0.95(s,2H).

Examples 9A and 9B: t-10-1 and T-10-2

Chiral resolution: t-10 was resolved into example 9A (T-10-1, 11.27 min) and example 9B (T-10-2, 14.95 min) using CHIRALPAK AD-H (cat# ADH0CE-EL 100) column at a flow rate of 0.8ml/min with 50% ethanol/n-hexane as eluent.

Example 10: t-11

2- ((1- (2-Cyanopropan-2-yl) -3-methyl-1H-pyrazol-4-yl) amino) -4- (methylamino) pyrrolo [2,1-f ] [1,2,4] triazine-5-carbonitrile

First step, preparation of M-16

2, 4-Dichloropyrrolo [2,1-f ] [1,2,4] triazine (500 mg) was dissolved in iPrOH (20 ml), and methylamine hydrochloride (161.9 mg) and DIEA (0.76 ml) were added. After stirring for 2h, water was added to quench, followed by extraction with EA and the organic phase was dried by spinning to give 487mg M-16.

MS ESI:m/z＝183,[M+1]⁺。

Second step, M-18 preparation

M-16 (487 mg) was dissolved in DMF (10 ml), and NIS (493.65 mg) was added. After stirring for 3h, quenching with saturated NH ₄ Cl solution, extraction with EA and flash column chromatography of the organic phase over silica gel gave 33mg M-18 and 656mg M-17.

MS ESI:m/z＝309,[M+1]⁺。

Third step, M-19 preparation

M-18 (33 mg) was dissolved in DMF (2 ml), and zinc cyanide (5.15 mg), pd ₂dba₃ (8 mg) and dppf (4.86 mg) were added. After replacing air with nitrogen, heating at 100deg.C for 4h, adding zinc cyanide (6 mg), heating for 1h, quenching with saturated NH ₄ Cl solution, extracting with EA, and performing flash column chromatography on the organic phase to obtain 22mg M-19.

MS ESI:m/z＝208,[M+1]⁺。

Fourth step, T-11 preparation

Starting from M-19 (22 mg) and 2- (4-amino-3-methyl-1H-pyrazol-1-yl) -2-methylpropanenitrile (22 mg), 14.1mg of T-11 was obtained under the same conditions as in the case of the sixth step

MS ESI:m/z＝336,[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.11(s,1H),7.32(d,J＝2.8Hz,1H),6.80(d,J＝2.8Hz,1H),6.39(s,1H),6.17(s,1H),3.24(d,J＝4.8Hz,3H),2.31(s,3H),2.00(s,6H).

Example 11: t-12

2- ((1- (2-Cyanopropan-2-yl) -3-methyl-1H-pyrazol-4-yl) amino) -7-cyclopropyl-4- (methylamino) pyrrolo [2,1-f ] [1,2,4] triazine-5-carbonitrile

First step, preparation of M-20

Using M-16 (1.3 g) as a raw material, 1.74g M-20 was obtained under the same conditions as in the first step of example 4.

MS ESI:m/z＝261,[M+1]⁺。

Second step, M-21 preparation

Using M-20 (1740 mg) as a raw material, 926mg of M-21 was obtained under the same conditions as in the first step of example 5.

MS ESI:m/z＝223,[M+1]⁺。

Third step, M-22 preparation

Using M-21 (200 mg) and 2- (4-amino-3-methyl-1H-pyrazol-1-yl) -2-methylpropanenitrile (163 mg) as starting materials, 182mg of M-22 was produced under the same conditions as in the case of the sixth step.

MS ESI:m/z＝336,[M+1]⁺。

Fourth step, M-23 preparation

Using M-22 (40 mg) as a raw material, 45mg of M-23 was produced under the same conditions as in the second step of example 10.

MS ESI:m/z＝477,[M+1]⁺。

Fifth step, T-12 preparation

M-23 (45 mg) was dissolved in DMF (2 ml), and zinc cyanide (13.6 mg), pd ₂dba₃ (7 mg) and dppf (4 mg) were added. After replacing air with nitrogen, heating at 100deg.C for 4h, quenching with saturated NH ₄ Cl solution, EA extraction, spin-drying the organic phase, and subjecting to flash column chromatography and C ₁₈ reversed phase preparative chromatography to obtain T-12.

MS ESI:m/z＝376,[M+1]⁺。

¹H NMR (400MHz,CDCl₃)δ8.37(s,1H),6.42(s,1H),6.11(s,1H),3.24(d,,3H),2.34(s,3H),2.14(m,1H),1.98(s,6H),1.10(m,2H),0.79(m,2H).

Example 12: t-13

2- (4- ((5-Chloro-7-cyclopropyl-4- (methylamino) pyrrolo [2,1-f ] [1,2,4] triazin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) -2-methylpropanenitrile

Using M-22 (40 mg) as a raw material, 18mg of T-13 was produced under the same conditions as in the second step of example 6.

MS ESI:m/z＝385,[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.38(s,1H),6.17(s,1H),6.01(s,1H),5.96(s,1H),3.13(s,3H),2.32(s,3H),2.16(m,1H),1.98(s,6H),1.04(m,2H),0.76(m,2H).

Example 13: t-14

(±) - (4- (4- ((5-Chloro-7-cyclopropylpyrrolo [2,1-f ] [1,2,4] triazin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) piperidin-1-yl) (cyclopropyl) methanone

72Mg of T-14 was prepared from M-7 (40 mg) and (4- (4-amino-3-methyl-1H-pyrazol-1-yl) piperidin-1-yl) (cyclopropyl) methanone (64 mg) using the same conditions as in example six.

MS ESI:m/z＝440,[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.58(s,1H),8.02(s,1H),6.37(s,1H),6.26(s,1H),4.74(m,1H),4.30(m,2H),3.29(m,1H),2.80(m,1H),2.30(s,3H),2.21(m,3H),1.98(m,2H),1.78(m,1H),1.13–1.04(m,2H),1.03–0.96(m,2H),0.92–0.84(m,2H),0.78(m,2H).

Example 14: t-15

(±) -1- (4- (4- ((5-Chloro-7-cyclopropylpyrrolo [2,1-f ] [1,2,4] triazin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) piperidin-1-yl) -2, 2-difluoropropan-1-one

First step, preparation of M-24

4- (3-Methyl-4-nitro-1H-pyrazol-1-yl) piperidine hydrochloride (202 mg) was dissolved in DCM (5 ml), followed by the addition of HATU (501 mg), 2-difluoropropionic acid (190 mg) and DIEA (1.56 ml). After 3h at room temperature, the reaction mixture was concentrated, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration to give crude M-24 (276 mg) by column chromatography.

MS ESI:m/z＝303,[M+1]⁺。

Second step, M-25 preparation

M-24 (276 mg) was dissolved in methanol (10 ml), then Pd/C (50 mg) was added thereto, stirred overnight under hydrogen atmosphere, filtered, and after spin-drying, 148mg of M-25 was prepared by flash column chromatography.

MS ESI:m/z＝273,[M+1]⁺。

Third step, M-26 preparation

Using M-7 (97 mg) and M-25 (148 mg) as raw materials, 25mg of M-26 was produced under the same conditions as in the first step of example six.

MS ESI:m/z＝430,[M+1]⁺。

Fourth step, T-15 preparation

Using M-26 (25 mg) as a raw material, 12mg of T-15 was produced under the same conditions as in the second step of example six.

MS ESI:m/z＝464,[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.57(s,1H),8.03(s,1H),6.37(s,1H),6.26(s,1H),4.62(m,1H),4.43(m,1H),4.37–4.26(m,1H),3.26(m,1H),2.92(m,1H),2.28(s,3H),2.25(m,1H),2.24–2.18(m,2H),2.04–1.97(m,2H),1.85(t,J＝20.0Hz,3H),1.12–1.02(m,2H),0.92–0.82(m,2H).

LRRK2 activity inhibition assay

1. Kinase reaction reagent formula

1.1. Kinase reaction buffer (1X)

TABLE 1.1-1 ADP-Glo buffer (LRRK 2)

Name of the name	Storage concentration	Working concentration.
			Hepes	1M	50mM
MgCl₂	1M	10mM
			Brij35	30％	0.01％
DTT	1M	2mM
			H₂O	N/A	N/A
EGTA	N/A	1mM

2MM DTT, ready-to-use.

1.2. Kinase formulations

TABLE 1.2-1 kinase formulations

1.3. Substrate mixture formulation

TABLE 1.3-1 substrate mixture formulations

Kinase enzymes	ATP concentration [ mu M ]	LRRK substrate
			LRRK2	20	0.1mg/mL

2. Experimental procedure

ADP-Glo method

1) A kinase reaction buffer was used to prepare a2 XATP/substrate solution and a2 Xkinase/metal ion solution.

2) Transferring the compound dilutions 20nL to 384 assay plates with Echo 655; after centrifugation, 2. Mu.L of 2 Xkinase and metal ion solution were added to 384 assay plates, centrifuged at 1000rpm for 1 min and incubated at 25℃for 10 min;

3) mu.L of the 2 Xsubstrate and ATP solution were added to 384 assay plates, centrifuged at 1000rpm for 1 min and incubated at 25℃for 60 min.

4) Transfer 4. Mu.L ADP-Glo to 384 assay plates, centrifuge at 1000rpm for 1 min, incubate at 25℃for 40 min.

5) Transfer 8. Mu.L of the detection solution to 384 detection plates, centrifuge at 1000rpm for 1 min, incubate at 25℃for 40min.

6) The luminescence signal was read using a multifunctional microplate reader.

3. Data processing method

The inhibition ratio of each test solution was calculated by setting the reading value of the negative control to 0% inhibition ratio and the reading value of the positive control to 100% inhibition ratio.

: Average value of positive control well ratio

: Average value of the ratio of negative control wells

IC ₅₀ (half inhibition concentration) of the compound was obtained using the following nonlinear fitting formula:

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC₅₀-X)*HillSlope))

Log of compound concentration

Inhibition of the compounds (% inh)

The Z' factor calculation equation:

Z’＝1-3(SDmin+SDmax)/(AVEmax-AVEmin)

Wherein:

min is positive control Data value, max is negative control DMSO Data value.

SD is standard error and AVE is average.

TABLE 2 LRRK2 Activity inhibition assay results

All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug thereof:

Where:

Select from the following ring structures:

Selected from the following bicyclic structures:

in:

X is selected from N or CR ⁵ ;

^R1 , ^R2 , ^R4 , ^R5 and ^R6 are each independently a ^group selected from the group consisting of hydrogen, halogen, amino, cyano, _SF5 , _-C1-12 alkyl, -C2-12 alkenyl, _-C2-12 alkynyl, -C0-6 alkylene- _OC1-12 alkyl, _-C1-12 alkylthio, _-C0-6 alkylene- _C3-10 cycloalkyl, _-C0-6 alkylene- ₄ to ₁₀ membered heterocyclyl, _-C0-6 alkylene- _C6-10 aryl, _-C0-6 alkylene-5 to 10 membered heteroaryl, _-C0-6 alkylene-C(O)R ^a , _-C0-6 alkylene-C(O)OR ^a , _-C0-6 alkylene-C(O)NR ^a R ^b , -C0-6 _{-C 0-6} alkylene-SO ₂ C _1-6 alkyl, -C _0-6 alkylene-SO ₂ C _6-10 aryl, -C _0-6 alkylene-SO ₂ 5- to 10-membered heteroaryl, -C _0-6 alkylene-SO ₂ C _3-6 cycloalkyl, -C _1-13 alkylene-OH, -C _3-12 cycloalkylene-OH;

each R ^s1 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, C _1-6 alkyl, -SO ₂ NR ^a R ^b , -SO ₂ C _1-6 alkyl, -SO ₂ C _3-6 cycloalkyl, -SO ₂ C _6-10 aryl, -SO ₂ -5 to 10 membered heteroaryl, -CONR ^a R ^b , -CONR ^a -C _6-10 aryl, -CONR ^a -5 to 10 membered heteroaryl, -COC _1-6 alkyl, -COC _3-6 cycloalkyl, -COC _6-10 aryl, -CO-5 to 10 membered heteroaryl, C _1-6 alkoxy, and oxo (=O) substitution;

^R3 is a group selected from the following group optionally substituted by one or more ^Rs2 : hydrogen, _-C1-12 alkyl, _-C2-12 alkenyl, _-C2-12 alkynyl, -4 to 15-membered heterocyclyl, _-C0-6 alkylene- _OC1-12 alkyl, _-C1-12 alkylthio, _-C0-6 alkylene- _C3-10 cycloalkyl, _-C0-6 alkylene-3 to 10-membered heterocyclyl, _-C0-6 alkylene- _C6-10 aryl, _-C0-6 alkylene-5 to 10-membered heteroaryl, _-C0-6 alkylene-C(O)R ^a , _-C0-6 alkylene-C(O)OR ^a , _-C0-6 alkylene-C(O)NR ^a R ^b , _-C0-6 alkylene-SO ₂ _C1-6 alkyl, _-C0-6 alkylene-SO ₂ C _6-10 aryl, -C _0-6 alkylene-SO ₂ 5- to 10-membered heteroaryl, -C _0-6 alkylene-SO ₂ C _3-6 cycloalkyl, -C _1-13 alkylene-OH, -C _3-12 cycloalkylene-OH;

Each ^R ^s2 is independently a group selected from the group ^consisting of halogen, hydroxy, C _1-6 alkyl, -OC _{1-6 alkyl, C 1-6} haloalkyl, -C _0-6 alkylene-C _3-10 cycloalkyl, -C _0-6 alkylene- ₃ to 10 membered heterocyclyl, OC _3-6 cycloalkyl, amino, cyano, -SO ₂ NR ^a R ^b , -SO ₂ R ⁸ , -CONR ^a R ^b , -CONR ^a -C _6-10 aryl, -CONR ^a 5 to 10 membered heteroaryl, -C(O)R ⁸ and oxo, which is optionally substituted by one or more R ^{c or R 3a} ; or, when two R ^s2 are located on adjacent atoms, they are optionally formed together to form a ring selected from the group consisting of C _3-10 cycloalkyl, 3 to 10 membered heterocyclyl, C 3-6 _6-10 membered aryl and 5- to 10-membered heteroaryl;

R ^3a is a group selected from the following group optionally substituted by one or more R ^s3 : hydrogen, -C _1-12 alkyl, -C _2-12 alkenyl, -C _2-12 alkynyl, -4 to 15-membered heterocyclyl, -C _0-6 alkylene-OC _1-12 alkyl, -C _1-12 alkylthio, -C _0-6 alkylene-C _3-10 cycloalkyl, -C _0-6 alkylene-3 to 10-membered heterocyclyl, -C _0-6 alkylene-C _6-10 aryl, -C _0-6 alkylene-5 to 10-membered heteroaryl, -C _0-6 alkylene-C (O) R ^a , -C _0-6 alkylene-C (O) OR ^a , -C _0-6 alkylene-C (O) NR ^a R ^b , -C _0-6 alkylene-SO ₂ C _1-6 alkyl, -C _0-6 alkylene-SO ₂ C _6-10 aryl, -C _0-6 alkylene-SO ₂ 5- to 10-membered heteroaryl, -C _0-6 alkylene-SO ₂ C _3-6 cycloalkyl, -C _1-12 alkylene-OH, -C _3-12 cycloalkylene-OH;

each R ^s3 is independently selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, -OC _1-6 alkyl, C _1-6 haloalkyl, -C _0-6 alkylene-C _3-10 cycloalkyl, -C _0-6 alkylene-3 to 10 membered heterocyclyl, OC _3-6 cycloalkyl, amino, cyano, -SO ₂ NR ^a R ^b , -SO ₂ R ⁸ , -CONR ^a R ^b , -CONR ^a -C _6-10 aryl, -CONR ^a 5 to 10 membered heteroaryl, -C(O)R ⁸ and oxo;

Alternatively, when R ¹ and R ² , R ¹ and R ³ or R ² and R ³ are located on adjacent atoms, R ¹ and R ² , R ¹ and R ³ or R ² and R ³ optionally together form a ring optionally substituted with one or more R ^c selected from the group consisting of C _3-10 cycloalkyl, 3 to 10 membered heterocyclyl, C _6-10 aryl and 5 to 10 membered heteroaryl;

^R7 is selected from the group consisting of hydrogen, _C1-6 alkyl, _C1-6 haloalkyl ^, _C3-6 cycloalkyl, _C3-6 halocycloalkyl, ^NRaRb , ^ORa ;

R ⁸ is a group selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 to 10 membered heteroaryl, optionally substituted by one or more R ^c ;

^Ra and ^Rb are independently selected from the group consisting of hydrogen, _C1-6 alkyl, _C1-6 haloalkyl, _C3-6 cycloalkyl, _C3-6 halocycloalkyl, or ^Ra and ^Rb together with the nitrogen atom to which they are attached optionally form a 3- to 6-membered heterocyclic ring in which the heterocyclic atom is selected from N, O and S;

R ^c is each independently selected from the following group: halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, -NH ₂ , -CN, -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -OH, -OC _1-6 alkyl; or, when two R ^c are located on the same atom, they optionally together form a C _3-6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from halogen, -CN and C _1-4 alkyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, a stereoisomer or a tautomer thereof, or a prodrug thereof, wherein the compound has a structure represented by a general formula selected from the group consisting of:

Wherein, Y is selected from S, O, and NR ² ; and the definitions of other groups are as described in claim 1 .

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug thereof, characterized in that it has one or more of the following characteristics:

(a) R ¹ is selected from the group consisting of hydrogen, cyano, halogen, -C _1-12 alkyl, -C _2-12 alkenyl, -C _2-12 alkynyl, C _3-10 cycloalkyl;

(b) R ² is selected from the group consisting of hydrogen, -C _1-12 alkyl;

(c) R ⁴ , R ⁵ and R ⁶ are each independently a group selected from the group consisting of hydrogen, halogen, -C _1-12 alkyl, -C _0-6 alkylene, -C _3-10 cycloalkyl substituted by one or more R ^s1 ; wherein each R ^s1 is independently selected from the group consisting of halogen, C _1-6 alkyl;

(d) ^R7 is selected from the group consisting of hydrogen, _C1-6 alkyl, _C1-6 haloalkyl, _C3-6 cycloalkyl, _C3-6 halocycloalkyl.

4. The compound according to claim 1, or a pharmaceutically acceptable salt, a stereoisomer or a tautomer thereof, or a prodrug thereof, wherein R ³ is selected from the group consisting of:

-C(C _1-6 alkyl) ₂ -R ^s2 ,

in,

Y ¹ is selected from the group consisting of CH ₂ , CHR ^s2 , C(R ^s2 ) ₂ , O, S, SO, SO ₂ , NH, NR ^s2 ;

n3 and n6 are each independently 0, 1, 2 or 3;

n1 and n2 are each independently 0, 1, 2 or 3, and n1 and n2 are not 0 or 3 at the same time;

n4 and n5 are each independently 0, 1 or 2, and n4 and n5 are not 0 at the same time;

n7 and n8 are each independently 1 or 2;

n9 and n10 are each independently 0 or 1;

R ^s2 is as defined in Formula I.

5. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, or a prodrug thereof, characterized in that the compound is selected from Table A or selected from Example Compounds T-1, T-2, T-3, T-4, T-5, T-6, T-7, T-8, T-9, T-10, T-11, T-12, T-13 and T-14.

6. A pharmaceutical composition, characterized in that it comprises (a) a safe and effective amount of the active ingredient of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, a stereoisomer or a tautomer thereof, or a prodrug thereof, and (b) a pharmaceutically acceptable carrier or excipient.

7. The use of the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug thereof, characterized in that the use is one or more uses selected from the group consisting of:

(i) preparing LRRK2 inhibitors;

(ii) preparing a drug for treating or preventing a disease mediated by LRRK2;

(iii) preparing drugs for treating or preventing Parkinson's disease and cancer;

(iv) preparing a drug for treating or preventing cancer in combination with an immune checkpoint protein inhibitor;

(v) preparing drugs for treating or preventing inflammatory diseases, tumors and/or neurodegenerative diseases;

(vi) preparing a drug for treating or preventing tumors for use in combination with a tumor drug or therapy.

8. The use according to claim 7, characterized in that the LRRK2-mediated disease is selected from the group consisting of tumors, neurodegenerative diseases, and inflammatory diseases.

9. The method of claim 7, wherein the LRRK2-mediated disease is selected from the group consisting of cancer, Alzheimer's disease, Parkinson's disease, inflammatory bowel disease (IBD), tuberculosis, leprosy, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic fatty liver hepatitis, autoimmune inflammatory cytokine secretion, inflammatory bowel disease ... Autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, allergic diseases, asthma, multiple sclerosis, type 2 diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme-associated febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, and periodontitis.

10. A pharmaceutical combination, characterized in that the pharmaceutical composition comprises:

(a) a first active ingredient, wherein the first active ingredient is a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, a stereoisomer or a tautomer thereof, or a prodrug thereof; and

(b) a second active ingredient, wherein the second active ingredient is an immune checkpoint protein inhibitor.