Heterocyclic compound as LRRK2 inhibitor

Abstract

The present disclosure relates to a novel heterocyclic compound as an LRRK2 inhibitor, which is useful for the manufacture of a medicament for treating diseases associated therewith. The medicament is particularly useful for the prevention and treatment of cancer.

Description

Heterocyclic compounds as LRRK2 inhibitors

[0001] The present invention relates to a novel heterocyclic compound useful for the manufacture of a medicament for treating diseases associated with LRRK2 inhibitors. The medicament is particularly useful for the prevention and treatment of cancer.

[0002] Protein kinases are intracellular enzymes that regulate cell growth and proliferation, as well as the induction of immune responses. Dysregulation of a wide range of protein kinases has been linked to the development and growth of cancer cells. Furthermore, protein kinases play a crucial role in signaling mechanisms that induce malignant cell characteristics, making them important targets in cancer. Therapies that selectively inhibit protein kinases have shown significant efficacy in the treatment of advanced cancer.

[0003] LRRK2 (leucine-rich repeat kinase-2) protein is a member of the leucine-rich repeat kinase family and has been reported to have various cellular functions and signaling pathways (FEBS J. 2015; 282: 2806-26), and the LRRK2 activating mutation G2019S is known to be associated with the pathogenesis of Parkinson's disease (N. Engl. J. Med. 2006; 354: 424-5). In addition, LRRK2 has been reported to be involved in regulating cancer cell growth through various pathways and may be useful as a biomarker in breast cancer patients with LRRK2 expression (Cancer Res. Treat, 2021; 53(1):9-24).

[0004] Existing immunotherapy monotherapy has a response rate of only about 20%, and the low response rates of current immune checkpoint inhibitors still limit their effectiveness in certain cancer types (e.g., ovarian cancer and triple-negative breast cancer). To address the approximately 80% of patients who do not respond to existing immunotherapy and to develop treatments targeting a wider range of cancer types, the identification of novel target mechanisms and the development of novel small-molecule drugs that inhibit these mechanisms are essential.

[0005] The present invention targets cancers that exhibit resistance / refractory to current immune checkpoint inhibitors with high unmet needs, and research and development are underway with the goal of developing an innovative new drug that inhibits the function of gMDSC (granulocytic MDSC), known as the main cell responsible for immune checkpoint inhibitor refractoriness in such cancers. In addition, development is also underway for a combination anticancer agent that overcomes the refractoriness of triple-negative breast cancer and metastatic ovarian cancer that exhibit resistance to PARP inhibitors and dramatically improves their responsiveness.

[0006] In patients with triple-negative breast cancer and ovarian cancer, patients with high LRRK2 expression are less responsive to standard therapies (PARP inhibitors) than those with low LRRK2 expression, resulting in shorter overall survival. In patients resistant to PARP inhibitors, LRRK2 inhibitors are expected to have a priming effect that overcomes PARP inhibitor refractoriness and directly induce immunogenic cell death in cancer cells. Therefore, co-administration of the inhibitor of the present invention with a PARP inhibitor in patients with high LRRK2 expression is expected to not only convert non-responders to PARP inhibitors but also extend the duration of response, thereby reducing the recurrence rate. It is expected that PARP inhibitors will have a synergistic effect in ovarian cancer and triple-negative breast cancer with high LRRK2 expression, and it has great potential to expand to various cancers that are poorly responsive to existing immunotherapies through combination therapy with immunotherapies.

[0007] In particular, the present invention aims to develop a LRRK2-targeting small molecule anticancer agent that dramatically improves the low responsiveness and refractoriness of immune checkpoint inhibitors and standard treatments, PARP inhibitors, for triple-negative breast cancer and ovarian cancer patients.

[0008] Currently, drugs targeting LRRK2 are primarily being developed for the treatment of Parkinson's disease. Parkinson's disease results from chronic, progressive neuronal degeneration, the cause of which remains unclear. While the primary cause remains unknown, it is known that dopamine deficiency in the brain due to neuronal loss causes observable symptoms. These mechanisms are reported to be key trends in LRRK2-associated Parkinson's disease, and the development of drugs targeting LRRK2 is actively underway.

[0009] The LRRK2 protein has been reported to be associated with the transmission of mild cognitive impairment associated with Alzheimer's disease, L-dopa-induced dyskinesia, and central nervous system (CNS) disorders related to neuronal progenitor differentiation. Furthermore, the G2019S mutation in the LRRK2 protein has been reported to be associated with an increased incidence of acute myeloid leukemia (AML), as well as non-cutaneous cancers such as renal, lung, and prostate cancers. Specifically, the G2019S mutation in the LRRK2 protein increases the catalytic activity of the LRRK2 kinase domain. Furthermore, mutant LRRK2 proteins have also been reported to be associated with amyotrophic lateral sclerosis, rheumatoid arthritis, and ankylosing spondylitis (International Patent Publication No. WO 2011 / 038572).

[0010] Meanwhile, treatment methods for tumors include surgery, radiation therapy, anticancer drug therapy (chemotherapy), and hormone therapy. Of these, surgery and radiation therapy have been primarily used, but radiation therapy, in particular, is associated with side effects such as neurotoxicity and dementia. Therefore, anticancer drug therapy (chemotherapy) has been attracting attention to address these issues, but cancer resistance to anticancer drugs remains a concern. Therefore, the inventors of the present invention have discovered that a compound used as an inhibitor of the LRRK2 protein can be useful for cancer prevention and treatment, thereby completing the present invention.

[0011] The purpose of the present invention is to provide a novel heterocyclic compound represented by chemical formula 1 that exhibits LRRK2 (leucine-rich repeat kinase-2) inhibitory activity.

[0012] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease associated with the activation of LRRK2, comprising a heterocyclic compound of the above chemical formula 1 as an active ingredient.

[0013] According to one aspect of the present invention, a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof is provided:

[0014] [Chemical Formula 1]

[0015]

[0016]

[0017] In the above chemical formula 1,

[0018] R1 and R3 are each independently -H, alkyl or alkoxy, provided that at least one of R1 and R3 is alkoxy;

[0019] R2 is -EG, wherein E is a direct bond, heterocycloalkylene, -O-, -C(=O)- or -S(=O)2-; G is a 4 to 12 membered heterocycloalkyl; wherein the heterocycloalkyl may be optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, dialkylamino and dialkylaminoalkylcarbonyl;

[0020] R4 is -H, alkyl, cycloalkyl or alkoxy;

[0021] R5 is -H, halo, cyano (-CN), alkyl, haloalkyl or alkoxy;

[0022] R4 and R5 may be linked together to form an unsubstituted or alkyl substituted saturated or unsaturated 5 to 11 membered carbocycle or heterocycle;

[0023] R6 is and;

[0024] X is CH or N;

[0025] R7 and R8 are each independently alkoxy, or are linked together to form a saturated or unsaturated 5 to 8 membered carbocycle or heterocycle; wherein the carbocycle and heterocycle may be optionally substituted with one or more substituents selected from hydroxy, halo, oxo (=O), alkyl, and alkoxy;

[0026] The above heterocycloalkyl and heterocycle contain one or more heteroatoms selected from N, O and S,

[0027] However, if R5 is -H, R2 is , and is selected from.

[0028]

[0029] In defining the compound of the above chemical formula 1 through this specification, the following concepts defined for substituents are used.

[0030]

[0031] In the present invention, the term “hydroxy” group means -OH.

[0032] In the present invention, the term “halo”, when used alone or in combination with other additional terms (e.g., haloalkyl), represents a radical which is fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0033] In the present invention, the term “oxo” group means =O (i.e., oxygen having a double bond).

[0034] In the present invention, the term “carbonyl” group means -C(=O)-.

[0035] In the present invention, the term “sulfonyl” group means -S(=O)2-.

[0036] In the present invention, the term “cyano” group means -CN.

[0037] In the present invention, the term “amino” group may mean a primary, secondary or tertiary amino group bonded through a nitrogen atom, alone or in combination.

[0038] In the present invention, the term “alkyl”, when used alone or in combination with other additional terms, means a radical of a saturated aliphatic hydrocarbon group having, for example, 1 to 5 carbon atoms, which is straight-chain or branched.

[0039] In the present invention, the term “alkoxy” means alkyloxy (-O-alkyl group), for example, alkyloxy having 1 to 5 carbon atoms.

[0040] In the present invention, the term “heterocycloalkyl” or “heterocycloalkylene” means a saturated aliphatic hydrocarbon having a ring shape, for example, 4 to 12 members or 4 to 10 members, containing one or more heteroatoms selected from N, O and S as a reducing group.

[0041] In the present invention, the term “carbocycle” means a radical of a saturated or unsaturated aliphatic hydrocarbon group having, for example, 3 to 10 carbon atoms or 5 to 8 carbon atoms in a ring shape.

[0042] In the present invention, the term “heterocycle” means a cyclic, for example, 5 to 11-membered or 5 to 8-membered, saturated, partially or fully unsaturated hydrocarbon containing one or more heteroatoms selected from N, O and S as a reducing group.

[0043]

[0044] The compound of the above chemical formula 1 according to the present invention can form a pharmaceutically acceptable salt. Such pharmaceutically acceptable salts include acid addition salts formed by acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid; organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, or trifluoroacetic acid; gluconic acid, benzoic acid, lactic acid, fumaric acid, and maleic acid; and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalsulfonic acid; and also include salts with alkali metals such as sodium and potassium. In addition, the salts may include salts with other acids or bases known and used in the technical field to which aromatic amidine derivatives or lactam derivatives belong. The pyrimidine derivative compound of the above chemical formula I according to the present invention can be converted into its salt by a conventional method.

[0045]

[0046] According to one specific example of the present invention, in the chemical formula 1

[0047] R1 and R3 are each independently -H, C1-C5 alkyl or C1-C5 alkoxy, provided that at least one of R1 and R3 is C1-C5 alkoxy;

[0048] R2 is -EG, wherein E is a direct bond, heterocycloalkylene, -O-, -C(=O)- or -S(=O)2-; G is a 4 to 12 membered heterocycloalkyl; wherein the heterocycloalkyl may be optionally substituted with 1 to 3 substituents selected from hydroxy, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C1-C5 alkylsulfonyl, di(C1-C5 alkyl)amino and di(C1-C5 alkyl)aminoalkylcarbonyl;

[0049] R4 is -H, C1-C5 alkyl, C3-C8 cycloalkyl or C1-C5 alkoxy;

[0050] R5 is -H, halo, cyano, C1-C5 alkyl, halo-C1-C5 alkyl or C1-C5 alkoxy;

[0051] R4 and R5 may be linked together to form a saturated or unsaturated 5 to 8 membered carbocycle or heterocycle which is unsubstituted or substituted with C1-C5 alkyl;

[0052] R6 is and;

[0053] X is CH or N;

[0054] R7 and R8 are each independently alkoxy or are linked together to form a saturated or unsaturated 5 to 8 membered heterocycle; wherein the heterocycle may be optionally substituted with 1 to 3 substituents selected from hydroxy, halo, oxo, C1-C5 alkyl and C1-C5 alkoxy;

[0055] The above heterocycloalkylene, heterocycloalkyl and heterocycle contain 1 to 4 heteroatoms selected from N, O and S,

[0056] However, if R5 is -H, R2 is , and is selected from.

[0057]

[0058] According to another specific example of the present invention, in the above chemical formula 1, R1 and R3 are each independently -H or C1-C5 alkoxy, and at least one of R1 and R3 is C1-C5 alkoxy.

[0059] According to another specific example of the present invention, in the above formula 1, R2 is -EG, wherein E is a direct bond, heterocycloalkylene, -O-, -C(=O)- or -S(=O)2-; G is a 4 to 10 membered heterocycloalkyl; and the heterocycloalkyl may be optionally substituted with one or two substituents selected from hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylcarbonyl, C1-C5 alkoxycarbonyl, C1-C3 alkylsulfonyl, di(C1-C3 alkyl)amino and di(C1-C3 alkyl)aminoalkylcarbonyl.

[0060] According to another specific example of the present invention, in the above formula 1, R4 is -H, C1-C3 alkyl, C3-C6 cycloalkyl or C1-C3 alkoxy; R5 is -H, F, Cl, Br, cyano, C1-C3 alkyl, halo-C1-C3 alkyl or C1-C3 alkoxy; R4 and R5 may be linked together to form an unsubstituted or C1-C3 alkyl substituted saturated or unsaturated 5 to 8 membered carbocycle or heterocycle.

[0061] According to another specific example of the present invention, in the chemical formula 1, R6 is and;

[0062] X is CH or N;

[0063] R7 and R8 are each independently C1-C2 alkoxy, or are linked together to form a saturated or unsaturated 5 to 8 membered heterocycle; and the heterocycle may be optionally substituted with one substituent selected from hydroxy, halo, oxo, C1-C2 alkyl, and C1-C2 alkoxy.

[0064]

[0065] Representative compounds of the chemical formula 1 according to the present invention may include, but are not limited to, the following compounds:

[0066] 1-(4-(4-((5-chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 1);

[0067] 5-Chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(2,5-dimethoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine (Compound 2);

[0068] 5-chloro-4-(3,4-dimethoxyphenyl)-N-(3-isopropoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine (Compound 3);

[0069] 1-(4-(4-((5-chloro-4-(quinolin-3-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 4);

[0070] 1-(4-(2,5-dimethoxy-4-((4-(quinolin-3-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 5);

[0071] 5-Chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine (Compound 6);

[0072] 1-(1-(4-((5-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperidin-4-yl)pyrrolidin-3-ol (Compound 7);

[0073] 5-Chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(2-methoxy-4-((1-methylpiperidin-4-yl)oxy)phenyl)pyrimidin-2-amine (Compound 8);

[0074] 1-(4-(4-((5-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 9);

[0075] 1-(4-(4-((5-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperidin-1-yl)-2-(dimethylamino)ethan-1-one (Compound 10);

[0076] 5-Chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(2,5-dimethoxy-4-(1-methylpiperidin-4-yl)phenyl)pyrimidin-2-amine (Compound 11);

[0077] 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 12);

[0078] 1-(4-(1-(4-((5-chloro-4-(quinolin-3-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperidin-4-yl)piperazin-1 -yl)ethan-1-one (Compound 13);

[0079] 1-(4-(1-(4-((5-chloro-4-(quinolin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one (Compound 14);

[0080] 1-(4-(4-((5-chloro-4-(1-methyl-1H-indazol-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 15);

[0081] 6-(2-((4-(4-acetylpiperazin-1-yl)-2,5-dimethoxyphenyl)amino)-5-chloropyrimidin-4-yl)-2-methylisoindolin-1-one (Compound 16);

[0082] 1-(4-(4-((5-chloro-4-(1-methyl-1H-indol-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 17);

[0083] 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 18);

[0084] 1-(4-(4-((5-chloro-4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 19);

[0085] 1-(4-(2,5-dimethoxy-4-((4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 20);

[0086] 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-indol-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 21);

[0087] 1-(4-(1-(4-((5-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-2-yl)amino)-2, 5-dimethoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one (Compound 22);

[0088] 1-(4-(1-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one (Compound 23);

[0089] 4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(2,5-dimethoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)pyrimidin-2-amine (Compound 24);

[0090] 1-(4-(4-((5-chloro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 25);

[0091] 1-(4-(2,5-Dimethoxy-4-((4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 26);

[0092] 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 27);

[0093] 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 28);

[0094] 1-(4-(2,5-dimethoxy-4-((5-methoxy-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperidin-1-yl)ethan-1-one (Compound 29);

[0095] 1-(3-(4-((5-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-1H-pyrazol-1-yl)ethan-1-one (Compound 30);

[0096] 1-(4-(4-((5-Fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 31);

[0097] 1-(4-(4-((5-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 32);

[0098] 1-(4-(2,5-Dimethoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 33);

[0099] 1-(4-(2,5-dimethoxy-4-((5-methyl-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 34);

[0100] 1-(4-(2,5-dimethoxy-4-((5-methoxy-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 35);

[0101] 1-(4-(4-((5-Bromo-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 36);

[0102] 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-fluoropyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 37);

[0103] 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 38);

[0104] 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylpyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 39);

[0105] 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methoxypyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 40);

[0106] 1-(4-(4-((5-Fluoro-4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 41);

[0107] N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 42);

[0108] N-(4-(3-(dimethylamino)azetidin-1-yl)-2-methoxyphenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 43);

[0109] N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 44);

[0110] 1-(4-((4-((5-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)sulfonyl)piperazin-1-yl)ethan-1-one (Compound 45);

[0111] 1-(4-(4-((5-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)piperazin-1-yl)ethan-1-one (Compound 46);

[0112] 1-(4-(4-((4-(1-Ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-fluoropyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 47);

[0113] (3-Methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (Compound 48);

[0114] (4-((5-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (Compound 49);

[0115] 5-Fluoro-N-(2-methoxy-4-morpholinosulfonyl)phenyl)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 50);

[0116] N-(2,5-Dimethoxy-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 51);

[0117] 1-(4-(4-((5-Fluoro-4-(thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 52);

[0118] tert-Butyl 5-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,5-diazaspiro[3.4]octane-2-carboxylate (Compound 53);

[0119] N-(2,5-Dimethoxy-4-(2,5-diazaspiro[3.4]octan-5-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 54);

[0120] 2-((4-(4-acetylpiperazin-1-yl)-2,5-dimethoxyphenyl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidine-5-carbonitrile (Compound 55);

[0121] 6-(2-((4-(4-acetylpiperazin-1-yl)-2,5-dimethoxyphenyl)amino)-5-methylpyrimidin-4-yl)quinolin-2(1H)-one (Compound 56-1);

[0122] 1-(4-(4-((4-(2-hydroxyquinolin-6-yl)-5-methylpyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 56-2);

[0123] 1-(4-(4-((5-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 57);

[0124] 1-(4-(2,5-Dimethoxy-4-((5-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 58);

[0125] 1-(4-(4-((5-Fluoro-4-(1,5-naphthyridin-3-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 59);

[0126] 1-(4-(4-((5-Fluoro-4-(8-fluoroquinolin-3-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 60);

[0127] 1-(4-(4-((5-Fluoro-4-(pyrido[2,3-b]pyrazin-7-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 61);

[0128] 1-(4-(2,5-dimethoxy-4-((5-methyl-4-(quinoxalin-6-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 62);

[0129] 1-(4-(4-((4-(Benzo[c][1,2,5]oxadiazol-5-yl)-5-methylpyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 63);

[0130] tert-Butyl 6-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Compound 64);

[0131] 1-(5-(4-((5-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,5-diazaspiro[3.4]octan-2-yl)ethan-1-one (Compound 65);

[0132] N-(2,5-Dimethoxy-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 66);

[0133] 1-(6-(4-((5-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one (Compound 67);

[0134] N-(2,5-Dimethoxy-4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 68);

[0135] (3-Methoxy-4-((4-thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (Compound 69);

[0136] (4-((5-Fluoro-4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (Compound 70);

[0137] (4-((5-Fluoro-4-thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (Compound 71);

[0138] (3-Methoxy-4-((4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (Compound 72);

[0139] (4-((5-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (Compound 73);

[0140] N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine (Compound 74);

[0141] N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine (Compound 75);

[0142] N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine (Compound 76);

[0143] N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-4-(thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-amine (Compound 77);

[0144] N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-amine (Compound 78);

[0145] N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(8-fluoroquinolin-3-yl)pyrimidin-2-amine (Compound 79);

[0146] N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-4-(quinoxalin-6-yl)pyrimidin-2-amine (Compound 80);

[0147] N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-methyl-4-(quinoxalin-6-yl)pyrimidin-2-amine (Compound 81);

[0148] 1-(4-(4-((5-Fluoro-4-methyl-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 82);

[0149] 1-(4-(2,5-Dimethoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)furo[3,2-d]pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 83);

[0150] 1-(4-(2,5-Dimethoxy-4-((9-methyl-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-9H-purin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 84);

[0151] 1-(4-(4-((4-Cyclopropyl-5-fluoro-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 85);

[0152] 1-(4-(4-((5-Fluoro-4-methoxy-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 86); and

[0153] 1-(4-(4-((5-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2-methoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 87).

[0154]

[0155] The names of the compounds described above were written according to the nomenclature using structures provided by CS ChemDraw Ultra software of CambridgeSoft.

[0156]

[0157] The present invention also includes a hydrate or solvate form of the compound of the above chemical formula 1. Such a hydrate or solvate can be prepared by a known method, and is preferably non-toxic and water-soluble, and is particularly preferably a hydrate or solvate in which 1 to 5 molecules of water or an alcohol-based solvent are combined.

[0158]

[0159] According to another aspect of the present invention, a pharmaceutical composition for preventing or treating a disease associated with LRRK2 is provided, comprising a compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.

[0160] In addition, the present invention provides a use of the compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of a disease associated with LRRK2.

[0161] In addition, the present invention provides a method for preventing or treating a disease associated with LRRK2, comprising administering a compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0162]

[0163] In another specific embodiment according to the present invention, the disease associated with LRRK2 may be selected from the group consisting of solid cancer, hematological cancer, radiation or drug resistant cancer, and metastatic cancer. In another specific example according to the present invention, the disease associated with the LRRK2 is triple-negative breast cancer, breast cancer, male breast cancer, ovarian cancer, cervical cancer, endometrial cancer, uterine sarcoma, vaginal cancer, female genital tumor, female external genital cancer, female urethral cancer, prostate cancer, penile cancer, male genital tumor, stomach cancer, liver cancer, gallbladder cancer, ductal cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, thyroid cancer, oral cancer, thoracic tumor, small cell lung cancer, non-small cell lung cancer, thymic cancer, mediastinal tumor, esophageal cancer, laryngeal cancer, oropharyngeal cancer, nasal cavity / paranasal sinus cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, brain cancer, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, craniopharyngioma, ependymoma, It can be selected from the group consisting of brainstem tumors, head and neck tumors, and skin cancers.

[0164]

[0165] The pharmaceutical composition of the present invention may be formulated according to a conventional method by additionally including, as an active ingredient, a compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof, a conventional non-toxic pharmaceutically acceptable additive, such as a carrier, an excipient, a diluent, and an adjuvant.

[0166] The pharmaceutical composition of the present invention can be prepared in various oral dosage forms such as tablets, pills, powders, capsules, syrups or emulsions, or parenteral dosage forms such as intramuscular, intravenous or subcutaneous administration.

[0167] Examples of additives that can be used in the pharmaceutical composition of the present invention include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, etc. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, gum tragacanth, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, etc.

[0168] The pharmaceutical composition of the present invention can be formulated into an oral dosage form by mixing an additive with an active ingredient. Examples of the additive include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc.

[0169] The pharmaceutical composition of the present invention can be formulated in an injection form by mixing an additive with an active ingredient. Examples of the additive include water, saline solution, glucose solution, a similar sugar solution, alcohol, glycol, ether, oil, fatty acid, fatty acid ester, glyceride, surfactant, suspending agent, emulsifier, etc.

[0170] The compound of chemical formula 1 according to the present invention or a pharmaceutically acceptable salt thereof can effectively prevent or treat a disease associated with LRRK2.

[0171] Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, these examples and experimental examples are merely illustrative and the scope of the present invention is not limited thereto.

[0172]

[0173] Example 1: Synthesis of 1-(4-(4-((5-chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 1)

[0174]

[0175]

[0176] (a) Synthesis of 1-bromo-2,5-dimethoxy-4-nitrobenzene

[0177] 2-Bromo-1,4-dimethoxybenzene (18.55 g, 85.46 mmol) was dissolved in acetic acid (185.5 mL), and nitric acid (23.08 g, 256.38 mmol, 15.28 mL, 70% purity) was slowly added at room temperature. The reaction mixture was stirred at 25°C for 2 hours, and the solid product obtained from the reaction was filtered through a paper filter, washed with H2O, and dried under reduced pressure to obtain 1-bromo-2,5-dimethoxy-4-nitrobenzene (20.14 g, 99%) as a yellow solid.

[0178] 1H-NMR (500 MHz, CHLOROFORM-D) δ 7.46 (s, 1H), 7.33 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H)

[0179]

[0180] (b) Synthesis of 1-(4-(2,5-dimethoxy-4-nitrophenyl)piperazin-1-yl)ethan-1-one

[0181] 1-Bromo-2,5-dimethoxy-4-nitrobenzene (12 g, 45.79 mmol) and 1-(piperazin-1-yl)ethan-1-one (7.04 g, 54.95 mmol) were dissolved in toluene (457.92 mL), and tris(dibenzylideneacetone)dipalladium (1.68 g, 1.83 mmol), (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) (2.28 g, 3.66 mmol), and cesium carbonate (44.76 g, 137.37 mmol) were added, and the reaction mixture was stirred at 110°C for 16 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, 0.1% formic acid in acetonitrile: 0.1% formic acid in H2O (ultrapure)) to give 1-(4-(2,5-dimethoxy-4-nitrophenyl)piperazin-1-yl)ethan-1-one (14.16 g, 70%) as a brown solid.

[0182] 1H-NMR (500 MHz, CHLOROFORM-D) δ 7.57 (s, 1H), 6.50 (s, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.73 (dt, J = 77.2, 4.9 Hz, 4H), 3.22 (dt, J = 28.4, 4.9 Hz, 4H), 2.15 (s, 3H)

[0183]

[0184] (c) Synthesis of 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0185] 1-(4-(2,5-Dimethoxy-4-nitrophenyl)piperazin-1-yl)ethan-1-one (10.06 g, 32.52 mmol) was dissolved in ethanol (163.44 mL) / H2O (ultrapure water, 40.86 mL), and iron (9.08 g, 162.62 mmol) and ammonium chloride (17.40 g, 325.23 mmol) were added at room temperature. The reaction mixture was stirred at 70°C for 6 h, cooled to room temperature, neutralized with 1 N sodium hydroxide, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel, hexane:ethyl acetate) to obtain 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (9.08 g, 77%) as a brown solid.

[0186] LC / MS ESI (+): 280 (M+1)

[0187] 1H-NMR (500 MHz, DMSO-D6) δ 6.47 (s, 1H), 6.35 (s, 1H), 4.43 (s, 2H), 3.68 (s, 3H), 3.67 (s, 3H), 3.53-3.50 (m, 4H), 2.80 (dt, J = 33.5, 5.0 Hz, 4H), 2.01 (s, 3H)

[0188]

[0189] (d) Synthesis of 5-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine

[0190] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (5.13 g, 19.87 mmol) and 2,4,5-trichloropyrimidine (3.65 g, 19.87 mmol) were dissolved in tetrahydrofuran (51.48 mL) / H2O (ultrapure water, 25.74 mL). Tetrakis(triphenylphosphine)palladium(0) (1.15 g, 993.71 μmol) and potassium carbonate (5.49 g, 39.75 mmol) were added, and the reaction mixture was stirred at 110°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silicic acid (SiO2) silica gel, dichloromethane:methanol) to obtain 5-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (3.98 g, 72%) as a yellow solid.

[0191] LC / MS ESI (+): 279 / 281 (M+1)

[0192] 1H-NMR (500 MHz, DMSO-D6) δ 8.99 (s, 1H), 8.75 (d, J = 2.1 Hz, 1H), 8.51 (d, J = 2.1 Hz, 1H), 7.67 (d, J = 3.4 Hz, 1H), 6.65 (d, J = 3.4 Hz, 1H), 3.89 (s, 3H)

[0193]

[0194] (e) Synthesis of 1-(4-(4-((5-chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0195] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (3.98 g, 14.25 mmol) and 5-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (3.98 g, 14.25 mmol) were dissolved in toluene (141.41 mL), and palladium(II) acetate (159.94 mg, 712.41 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (824.43 mg, 1.42 mmol), and potassium carbonate (3.94 g, 28.50 mmol) were added, and the reaction mixture was stirred at 130°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel, dichloromethane:methanol) to obtain 1-(4-(4-((5-chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (3.94 g, 83%) as a yellow solid.

[0196] LC / MS ESI (+): 522 / 524 (M+1)

[0197] 1H-NMR (600 MHz, CHLOROFORM-D) δ 8.96 (d, J = 2.1 Hz, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.43 (s, 1H), 8.40 (s, 1H), 7.76 (s, 1H), 6.57 (s, 1H), 6.54 (d, J = 3.4 Hz, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 3.81 (t, J = 4.8 Hz, 2H), 3.64 (t, J = 4.8 Hz, 2H), 3.04 (t, J = 4.8 Hz, 2H), 3.00 (t, J = 4.8 Hz, 2H), 2.14 (s, 3H)

[0198]

[0199] Compounds of Examples 2 to 24 were synthesized in a similar manner to Example 1, and the data of Examples 2 to 24 are shown in Table 1 below.

[0200] [Table 1]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212] Example 25: Synthesis of 1-(4-(4-((5-chloro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 25)

[0213]

[0214]

[0215] (a) Synthesis of 5-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine

[0216] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (51 mg, 0.2 mmol) and 2,4,5-trichloropyrimidine (25 μL, 0.22 mmol) were dissolved in 1,4-dioxane (1.27 mL) / H2O (ultrapure water, 656.09 μL). Tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.01 mmol) and potassium carbonate (55 mg, 0.4 mmol) were added, and the reaction mixture was stirred at 120°C for 1.5 h under a nitrogen stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silicon dioxide (SiO2) silica gel) to obtain 5-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (31.6 mg, 56%) as a white solid.

[0217] 1H-NMR (600 MHz, CDCl3) δ 9.13 (d, J = 2.1 Hz, 1H), 8.69-8.70 (m, 2H), 8.14 (s, 1H), 4.22 (s, 3H)

[0218]

[0219] (b) Synthesis of 1-(4-(4-((5-chloro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0220] 1-(4-(4-Amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (13 mg, 0.046 mmol) was dissolved in isopropanol (1.5 ml), and 5-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (13 mg, 0.046 mmol) and 4 M hydrogen chloride solution (3 μL, 0.092 mmol) were added dropwise, and the reaction mixture was stirred at 160°C for 2 h using a microwave reactor. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silicon dioxide (SiO2) silica gel) to obtain 1-(4-(4-((5-chloro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (4 mg, 16%) as a yellow solid.

[0221] 1H-NMR (600 MHz, CDCl3) δ 9.15 (d, J = 1.4 Hz, 1H), 8.68 (d, J = 1.4 Hz, 1H), 8.47 (s, 1H), 8.31 (d, J = 6.9 Hz, 1H), 8.10 (s, 1H), 7.77 (s, 1H), 6.58 (s, 1H), 4.22 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.81 (t, J = 5.2 Hz, 2H), 3.64 (t, J = 4.8 Hz, 2H), 3.03 (dt, J = 21.3, 5.2 Hz, 4H), 2.14 (s, 3H)

[0222]

[0223] Example 26: Synthesis of 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 26)

[0224]

[0225]

[0226] (a) Synthesis of 5-(2-chloropyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine

[0227] (1-Methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (35 mg, 197.78 μmol) and 2,4-dichloropyrimidine (32.41 mg, 217.55 μmol) were dissolved in tetrahydrofuran (659.29 μL) / H2O (ultrapure water, 329.59 μL). Tetrakis(triphenylphosphine)palladium(0) (11.43 mg, 9.89 μmol) and potassium carbonate (54.67 mg, 395.55 μmol) were added, and the reaction mixture was stirred at 110°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel) to obtain 5-(2-chloropyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (40 mg, 82.33%) as a white solid.

[0228] LC / MS ESI (+): 246 / 248 (M+1)

[0229] 1H-NMR (500 MHz, DMSO-D6) δ 9.35 (d, J = 2.0 Hz, 1H), 9.08 (d, J = 2.0 Hz, 1H), 8.85 (d, J = 5.2 Hz, 1H), 8.34 (s, 1H), 8.29 (d, J = 5.3 Hz, 1H), 4.12 (s, 3H)

[0230]

[0231] (b) Synthesis of 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one

[0232] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (17 mg, 60.86 μmol) and 5-(2-chloropyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (14.95 mg, 60.86 μmol) were dissolved in toluene (398.38 μL), palladium(II) acetate (1.37 mg, 6.09 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.04 mg, 12.17 μmol), and potassium carbonate (16.82 mg, 121.72 μmol) were added, and the reaction mixture was stirred at 120°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel) to obtain 1-(4-(4-((5-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (13 mg, 42.93%) as a yellow solid.

[0233] LC / MS ESI (+): 489 (M+1)

[0234] 1H-NMR (500 MHz, DMSO-D6) δ9.35 (d, J = 2.0 Hz, 1H), 9.00 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 5.2 Hz, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.52 (d, J = 5.3 Hz, 1H), 6.68 (s, 1H), 4.11 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.58 (dd, J = 10.2, 6.5 Hz, 4H), 2.96 (dt, J = 32.7, 4.9 Hz, 4H), 2.04 (s, 3H)

[0235]

[0236] Example 27: Synthesis of 1-(4-(2,5-dimethoxy-4-((4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 27)

[0237]

[0238]

[0239] (a) Synthesis of 6-(2-chloropyrimidin-4-yl)-3-methyl-3H-imidazo[4,5-b]pyridine

[0240] 3-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine (50 mg, 192.97 μmol) and 2,4-dichloropyrimidine (28.75 mg, 192.97 μmol) were dissolved in tetrahydrofuran (1.27 mL) / H2O (ultrapure water, 656.09 μL). Tetrakis(triphenylphosphine)palladium(0) (11.15 mg, 9.65 μmol) and potassium carbonate (53.34 mg, 385.93 μmol) were added, and the reaction mixture was stirred at 110°C for 3 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure water)) to obtain 6-(2-chloropyrimidin-4-yl)-3-methyl-3H-imidazo[4,5-b]pyridine (37.00 mg, 75.77%) as a white solid.

[0241] LC / MS ESI (+): 246 (M+1) / 248

[0242] 1H-NMR (500 MHz, DMSO-D6) δ9.22 (d, J = 2.0 Hz, 1H), 8.87-8.83 (m, 2H), 8.58 (s, 1H), 8.32 (d, J = 5.4 Hz, 1H), 3.90 (s, 3H)

[0243]

[0244] (b) Synthesis of 1-(4-(2,5-dimethoxy-4-((4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one

[0245] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (11.37 mg, 40.71 μmol) and 6-(2-chloropyrimidin-4-yl)-3-methyl-3H-imidazo[4,5-b]pyridine (10 mg, 40.71 μmol) were dissolved in toluene (400 μL), and palladium(II) acetate (182.78 μg, 0.81 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (942.11 μg, 1.63 μmol), and cesium carbonate (26.53 mg, 81.41 μmol) were added, and the reaction mixture was stirred at 120°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure)) to obtain 1-(4-(2,5-dimethoxy-4-((4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (5.8 mg, 29.00%) as a yellow solid.

[0246] LC / MS ESI (+): 245 / 489 (M+1)

[0247] 1H-NMR (500 MHz, DMSO-D6) δ9.21 (d, J = 2.0 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.53-8.51 (m, 2H), 8.13 (s, 1H), 7.94 (s, 1H), 7.55 (d, J = 5.2 Hz, 1H), 6.68 (s, 1H), 3.89 (s, 3H), 3.83 (d, J = 6.7 Hz, 6H), 3.59 (dd, J = 10.2, 6.3 Hz, 4H), 2.97 (dt, J = 33.0, 4.9 Hz, 4H), 2.04 (s, 3H)

[0248]

[0249] Example 28: Synthesis of 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 28)

[0250]

[0251]

[0252] (a) Synthesis of 6-(2-chloropyrimidin-4-yl)-1-methyl-1H-benzo[d]imidazole

[0253] (1-Methyl-1H-benzo[d]imidazol-6-yl)boronic acid (35 mg, 0.2 mmol) and 2,4-dichloropyrimidine (35.8 mg, 0.24 mmol) were dissolved in 1,4-dioxane (1.0 mL) / H2O (ultrapure water, 0.5 mL). Tetrakis(triphenylphosphine)palladium(0) (5.8 mg, 0.025 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, and the reaction mixture was stirred at 100°C for 5 min using a microwave reactor. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silicon dioxide (SiO2) silica gel) to obtain 6-(2-chloropyrimidin-4-yl)-1-methyl-1H-benzo[d]imidazole (34 mg, 70%) as a white solid.

[0254] 1H-NMR (600 MHz, CDCl3) δ8.61 (d, J = 5.5 Hz, 1H), 8.32 (s, 1H), 7.98 (s, 1H), 7.86-7.91 (m, 2H), 7.71 (d, J = 5.5 Hz, 1H), 3.94 (s, 3H)

[0255]

[0256] (b) Synthesis of 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one

[0257] 1-(4-(4-Amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (21 mg, 0.075 mmol) was dissolved in isopropanol (2.0 ml), and 6-(2-chloropyrimidin-4-yl)-1-methyl-1H-benzo[d]imidazole (34 mg, 0.14 mmol) and 4 M hydrogen chloride solution (5.2 μL, 0.15 mmol) were added dropwise, and the reaction mixture was stirred at 160°C for 2 h using a microwave reactor. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silicon dioxide (SiO2) silica gel) to obtain 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (16 mg, 41%) as a yellow solid.

[0258] 1H-NMR (600 MHz, CDCl3) δ 8.48 (t, J = 5.5 Hz, 2H), 8.20 (s, 1H), 8.04 (dd, J = 8.3, 1.4 Hz, 1H), 7.97 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.74 (s, 1H), 7.21 (d, J = 4.8 Hz, 1H), 6.60 (s, 1H), 3.94 (d, J = 4.8 Hz, 6H), 3.90 (s, 3H), 3.81-3.83 (m, 2H), 3.66 (t, J = 4.8 Hz, 2H), 3.04 (dt, J = 21.3, 5.2 Hz, 4H), 2.15 (s, 3H)

[0259]

[0260] Example 29: Synthesis of 1-(4-(2,5-dimethoxy-4-((5-methoxy-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperidin-1-yl)ethan-1-one (Compound 29)

[0261]

[0262]

[0263] (a) Synthesis of 5-(2-chloro-5-methoxypyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine

[0264] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (60 mg, 232.45 μmol) and 2,4-dichloro-5-methoxypyrimidine (41.61 mg, 232.45 μmol) were dissolved in tetrahydrofuran (781.83 μL) / H2O (ultrapure water, 390.91 μL), tetrakis(triphenylphosphine)palladium(0) (13.43 mg, 11.62 μmol) and potassium carbonate (64.25 mg, 464.89 μmol) were added, and the reaction mixture was stirred at 100°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel) to obtain 5-(2-chloro-5-methoxypyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (41 mg, 64.21%) as a white solid.

[0265] LC / MS ESI (+): 275 / 277 (M+1)

[0266] 1H-NMR (500 MHz, DMSO-D6) δ 8.97 (d, J = 2.1 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.65 (s, 1H), 7.62 (d, J = 3.4 Hz, 1H), 6.63 (d, J = 3.6 Hz, 1H), 4.04 (s, 3H), 3.87 (s, 3H)

[0267]

[0268] (b) Synthesis of 1-(4-(2,5-dimethoxy-4-((5-methoxy-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperidin-1-yl)ethan-1-one

[0269] 1-(4-(4-Amino-2,5-dimethoxyphenyl)piperidin-1-yl)ethan-1-one (12.8 mg, 0.046 mmol) was dissolved in isopropanol (2.0 ml), and 5-(2-chloro-5-methoxypyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (14.6 mg, 0.06 mmol) and 4 M hydrogen chloride solution (11.3 μL, 0.092 mmol) were added dropwise, and the reaction mixture was stirred at 160°C for 3 h using a microwave reactor. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silicon dioxide (SiO2) silica gel) to obtain 1-(4-(2,5-dimethoxy-4-((5-methoxy-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperidin-1-yl)ethan-1-one (10.2 mg, 46%) as a yellow solid.

[0270] 1H-NMR (500 MHz, DMSO-D6) δ 9.02 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.44 (s, 1H), 8.12 (s, 1H), 7.75 (s, 1H), 7.60 (d, J = 3.4 Hz, 1H), 6.66 (s, 1H), 6.58 (d, J = 3.4 Hz, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H), 3.49-3.59 (m, 4H), 2.73(m, 1H), 2.04 (s, 3H), 1.89-1.64 (m, 4H)

[0271]

[0272] Example 30: Synthesis of 1-(3-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-1H-pyrazol-1-yl)ethan-1-one (Compound 30)

[0273]

[0274]

[0275] (a) Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine

[0276] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 387.41 μmol) and 2,4-dichloro-5-fluoropyrimidine (64.69 mg, 387.41 μmol) were dissolved in tetrahydrofuran (787.53 μL) / H2O (ultrapure water, 393.77 μL), tetrakis(triphenylphosphine)palladium(0) (22.38 mg, 19.37 μmol), potassium carbonate (107.08 g, 774.82 μmol) were added, and the reaction mixture was stirred at 110°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silicic acid (SiO2) silica gel) to obtain 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (101.76 mg, 86.48%) as a white solid.

[0277] LC / MS ESI (+): 263 / 265 (M+1)

[0278] 1H-NMR (500 MHz, DMSO-D6) δ 8.94-8.93 (m, 2H), 8.66 (t, J = 1.0 Hz, 1H), 7.67 (d, J = 3.5 Hz, 1H), 6.69 (d, J = 3.5 Hz, 1H), 3.87 (d, J = 12.4 Hz, 3H)

[0279]

[0280] (b) Synthesis of 1-(3-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-1H-pyrazol-1-yl)ethan-1-one

[0281] 1-(3-(4-Amino-2,5-dimethoxyphenyl)-1H-pyrazol-1-yl)ethan-1-one (3 mg, 0.1 mmol) and 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (42 mg, 0.16 mmol) were dissolved in 1,4-dioxane (2.0 mL), and tris(dibenzylideneacetone)dipalladium (11.0 mg, 0.012 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (13.9 mg, 0.024 mmol), and cesium carbonate (117.3 mg, 0.36 mmol) were added, and the reaction mixture was stirred at 120°C for 5 hours under a nitrogen stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silicic acid (SiO2) silica gel) to obtain 1-(3-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-1H-pyrazol-1-yl)ethan-1-one (3.4 mg, 5.8%) as a yellow solid.

[0282] 1H-NMR (600 MHz, CDCl3) δ 9.26 (d, J = 1.4 Hz, 1H), 8.81 (d, J = 1.4 Hz, 1H), 8.69 (d, J = 2.8 Hz, 1H), 8.67 (d, J = 2.8 Hz, 1H), 8.29 (s, 1H), 7.91 (s, 1H), 7.74 (s, 1H), 7.29 (d, J = 3.4 Hz, 1H), 7.13 (d, J = 2.8 Hz, 1H), 6.63 (d, J = 3.4 Hz, 1H), 3.98 (d, J = 10.3 Hz, 6H), 3.93 (s, 3H), 2.24 (s, 3H)

[0283]

[0284] Example 31: Synthesis of 1-(4-(4-((5-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 31)

[0285]

[0286]

[0287] (a) Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-benzo[d]imidazole

[0288] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (516.2 mg, 2 mmol) and 2,4-dichloro-5-fluoropyrimidine (500 mg, 3 mmol) were dissolved in 1,4-dioxane (7.0 mL) / H2O (ultrapure water, 3.5 mL). (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (146.4 mg, 0.2 mmol) and sodium carbonate (700 mg, 6.6 mmol) were added, and the reaction mixture was stirred at 90°C for 3.5 hours under a nitrogen stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silicic acid (SiO2) silica gel) to obtain 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-benzo[d]imidazole (453 mg, 86%) as a white solid.

[0289] 1H-NMR (600 MHz, CDCl3) δ 8.64 (s, 1H), 8.51 (d, J = 2.8 Hz, 1H), 8.21-8.23 (m, 1H), 7.98 (s, 1H), 7.53 (d, J = 8.3 Hz, 1H), 3.92 (s, 3H)

[0290]

[0291] (b) Synthesis of 1-(4-(4-((5-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0292] 1-(4-(4-Amino-2,5-dimethoxyphenyl)piperidin-1-yl)ethan-1-one (21.5 mg, 0.077 mmol) and 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-benzo[d]imidazole (26.3 mg, 0.1 mmol) were dissolved in 1,4-dioxane (2.5 mL), and tris(dibenzylideneacetone)dipalladium (7.0 mg, 0.0077 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (8.9 mg, 0.015 mmol), and cesium carbonate (75.2 mg, 0.23 mmol) were added, and the reaction mixture was stirred at 120°C for 4 hours under a nitrogen stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silicic acid (SiO2) silica gel) to obtain 1-(4-(4-((5-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (34 mg, 87.3%) as a yellow solid.

[0293] 1H-NMR (600 MHz, CDCl3) δ 8.65 (s, 1H), 8.42 (s, 1H), 8.34 (d, J = 3.4 Hz, 1H), 8.20 (d, J = 9.0 Hz, 1H), 7.96 (s, 1H), 7.70 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 6.59 (s, 1H), 3.95 (s, 3H), 3.91 (d, J = 6.2 Hz, 3H), 3.89 (s, 3H), 3.82 (t, J = 4.8 Hz, 2H), 3.65 (t, J = 4.8 Hz, 2H), 3.04 (dt, J = 21.1, 5.0 Hz, 4H), 2.15 (s, 3H)

[0294]

[0295] Example 32: Synthesis of 1-(4-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 32)

[0296]

[0297]

[0298] (a) Synthesis of bromo-2,5-dimethoxy-4-nitrobenzene

[0299] 2-Bromo-1,4-dimethoxybenzene (18.55 g, 85.46 mmol) was dissolved in acetic acid (185.5 mL), and nitric acid (23.08 g, 256.38 mmol, 15.28 mL, 70% purity) was slowly added at room temperature. The reaction mixture was stirred at 25°C for 2 hours, and the solid product obtained from the reaction was filtered through a paper filter, washed with H2O, and dried under reduced pressure to obtain 1-bromo-2,5-dimethoxy-4-nitrobenzene (20.14 g, 99%) as a yellow solid.

[0300] LC / MS ESI (+): 262 / 264 (M+1)

[0301] 1H-NMR (500 MHz, CHLOROFORM-D) δ 7.46 (s, 1H), 7.33 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H)

[0302]

[0303] (b) Synthesis of 1-(4-(2,5-dimethoxy-4-nitrophenyl)piperazin-1-yl)ethan-1-one

[0304] 1-Bromo-2,5-dimethoxy-4-nitrobenzene (12 g, 45.79 mmol) and 1-(piperazin-1-yl)ethan-1-one (7.04 g, 54.95 mmol) were dissolved in toluene (457.92 mL), and tris(dibenzylideneacetone)dipalladium (1.68 g, 1.83 mmol), (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) (2.28 g, 3.66 mmol), and cesium carbonate (44.76 g, 137.37 mmol) were added, and the reaction mixture was stirred at 110°C for 16 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and then extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel) to obtain 1-(4-(2,5-dimethoxy-4-nitrophenyl)piperazin-1-yl)ethan-1-one (14.16 g, 70%) as a brown solid.

[0305] LC / MS ESI (+): 310 (M+1)

[0306] 1H-NMR (500 MHz, CHLOROFORM-D) δ 7.57 (s, 1H), 6.50 (s, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.73 (dt, J = 77.2, 4.9 Hz, 4H), 3.22 (dt, J = 28.4, 4.9 Hz, 4H), 2.15 (s, 3H)

[0307]

[0308] (c) Synthesis of 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0309] 1-(4-(2,5-Dimethoxy-4-nitrophenyl)piperazin-1-yl)ethan-1-one (10.06 g, 32.52 mmol) was dissolved in ethanol (163.44 mL) / H2O (ultrapure water, 40.86 mL), and iron (9.08 g, 162.62 mmol) and ammonium chloride (17.40 g, 325.23 mmol) were added at room temperature. The reaction mixture was stirred at 70°C for 6 h, cooled to room temperature, neutralized with 1 N sodium hydroxide, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2)) to obtain 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (9.08 g, 77%) as a brown solid.

[0310] LC / MS ESI (+): 280 (M+1)

[0311] 1H-NMR (500 MHz, DMSO-D6) δ 6.47 (s, 1H), 6.35 (s, 1H), 4.43 (s, 2H), 3.68 (s, 3H), 3.67 (s, 3H), 3.53-3.50 (m, 4H), 2.80 (dt, J = 33.5, 5.0 Hz, 4H), 2.01 (s, 3H)

[0312]

[0313] (d) Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine

[0314] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 387.41 μmol) and 2,4-dichloro-5-fluoropyrimidine (64.69 mg, 387.41 μmol) were dissolved in tetrahydrofuran (787.53 μL) / H2O (ultrapure water, 393.77 μL), tetrakis(triphenylphosphine)palladium(0) (22.38 mg, 19.37 μmol), potassium carbonate (107.08 g, 774.82 μmol) were added, and the reaction mixture was stirred at 110°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2 silica gel) to obtain 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (101.76 mg, 86.48%) as a white solid.

[0315] LC / MS ESI (+): 263 / 265 (M+1)

[0316] 1H-NMR (500 MHz, DMSO-D6) δ 8.94-8.93 (m, 2H), 8.66 (t, J = 1.0 Hz, 1H), 7.67 (d, J = 3.5 Hz, 1H), 6.69 (d, J = 3.5 Hz, 1H), 3.87 (d, J = 12.4 Hz, 3H)

[0317]

[0318] (e) Synthesis of 1-(4-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0319] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (15 mg, 53.70 μmol) and 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (14.11 mg, 53.70 μmol) were dissolved in toluene (540 μL), palladium(II) acetate (1.21 mg, 5.37 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.21 mg, 10.74 μmol), and cesium carbonate (34.99 mg, 107.40 μmol) were added, and the reaction mixture was stirred at 120°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine(NH2) silica gel) to obtain 1-(4-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (8.9 mg, 17.37%) as a yellow solid.

[0320] LC / MS ESI (+): 506 (M+1)

[0321] 1H-NMR (500 MHz, DMSO-D6) δ 8.95 (s, 1H), 8.65 (s, 1H), 8.57 (d, J = 3.7 Hz, 1H), 8.19 (s, 1H), 7.86 (s, 1H), 7.65 (d, J = 3.4 Hz, 1H), 6.67 (s, 1H), 6.63 (d, J = 3.5 Hz, 1H), 3.88 (s, 3H), 3.81 (m, 6H), 3.58 (dd, J = 10.2, 6.4 Hz, 4H), 2.95 (dt, J = 32.9, 5.0 Hz, 4H), 2.04 (s, 3H)

[0322]

[0323] Example 33: Synthesis of 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 33)

[0324]

[0325]

[0326] (a) Synthesis of 5-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine

[0327] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 387.41 μmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (84.06 mg, 387.41 μmol) were dissolved in tetrahydrofuran (773.60 μL) / H2O (ultrapure water, 386.80 μL), tetrakis(triphenylphosphine)palladium(0) (22.38 mg, 19.37 μmol), potassium carbonate (107.08 mg, 774.82 μmol) were added, and the reaction mixture was stirred at 100°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel) to obtain 5-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (121.13 mg, 28.07%) as a white solid.

[0328] LC / MS ESI (+): 313 / 315 (M+1)

[0329] 1H-NMR (500 MHz, DMSO-D6) δ 9.29 (s, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 3.4 Hz, 1H), 6.65 (d, J = 3.4 Hz, 1H), 3.89 (s, 3H)

[0330]

[0331] (b) Synthesis of 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one

[0332] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (15 mg, 53.70 μmol) and 5-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (16.79 mg, 53.70 μmol) were dissolved in toluene (540 μL), palladium(II) acetate (1.21 mg, 5.37 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.21 mg, 10.74 μmol), and cesium carbonate (34.99 mg, 107.40 μmol) were added, and the reaction mixture was stirred at 120°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine(NH2) silica gel) to obtain 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (13.1 mg, 43%) as a yellow solid.

[0333] LC / MS ESI (+): 556 (M+1)

[0334] 1H-NMR (500 MHz, DMSO-D6) δ 9.14 (d, J = 5.3 Hz, 1H), 8.78 (s, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 1.9 Hz, 1H), 7.64 (d, J = 3.4 Hz, 1H), 7.49 (s, 1H), 6.63 (s, 1H), 6.58 (d, J = 3.4 Hz, 1H), 3.87 (s, 3H), 3.77 (s, 3H), 3.71 (d, J = 13.3 Hz, 3H), 3.56 (d, J = 3.6) Hz, 4H), 2.95 (d, J = 32.5 Hz, 4H), 2.47 (s, 3H)

[0335]

[0336] Example 34: Synthesis of 1-(4-(2,5-dimethoxy-4-((5-methyl-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 34)

[0337]

[0338]

[0339] (a) Synthesis of 5-(2-chloro-5-methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine

[0340] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (60 mg, 232.45 μmol) and 2,4-dichloro-5-methylpyrimidine (37.89 mg, 232.45 μmol) were dissolved in tetrahydrofuran (781.83 μL) / H2O (ultrapure water, 390.91 μL), tetrakis(triphenylphosphine)palladium(0) (13.43 mg, 11.62 μmol) and potassium carbonate (64.25 mg, 464.89 μmol) were added, and the reaction mixture was stirred at 100°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel) to obtain 5-(2-chloro-5-methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (52 mg, 86.47%) as a white solid.

[0341] LC / MS ESI (+): 259 / 261 (M+1)

[0342] 1H-NMR (500 MHz, DMSO-D6) δ 8.71 (d, J = 0.6 Hz, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.35 (d, J = 2.1 Hz, 1H), 7.65 (d, J = 3.4 Hz, 1H), 6.61 (d, J = 3.4 Hz, 1H), 3.88 (s, 3H), 2.42 (s, 3H)

[0343]

[0344] (b) Synthesis of 1-(4-(2,5-dimethoxy-4-((5-methyl-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one

[0345] 1-(4-(4-Amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (15 mg, 53.70 μmol) and 5-(2-chloro-5-methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (13.89 mg, 53.70 μmol) were dissolved in toluene (540 μL), palladium(II) acetate (1.21 mg, 5.37 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.21 mg, 10.74 μmol), and cesium carbonate (34.99 mg, 107.40 μmol) were added, and the reaction mixture was stirred at 120°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine(NH2) silica gel) to obtain 1-(4-(2,5-dimethoxy-4-((5-methyl-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (11.4 mg, 42.05%) as a yellow solid.

[0346] LC / MS ESI (+): 502 (M+1)

[0347] 1H-NMR (500 MHz, DMSO-D6) δ 8.65 (d, J = 2.0 Hz, 1H), 8.39 (s, 1H), 8.36 (d, J = 2.1 Hz, 1H), 8.11 (s, 1H), 7.85 (s, 1H), 7.62 (d, J = 3.4 Hz, 1H), 6.65 (s, 1H), 6.57 (d, J = 3.4 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.74 (s, 3H), 3.56-3.54 (m, 4H), 2.92 (dt, J = 32.8, 4.5 Hz, 4H), 2.31 (s, 3H), 2.03 (s, 3H)

[0348]

[0349] Example 35: Synthesis of 1-(4-(2,5-dimethoxy-4-((5-methoxy-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 35)

[0350]

[0351]

[0352] (a) Synthesis of 5-(2-chloro-5-methoxypyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine

[0353] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (60 mg, 232.45 μmol) and 2,4-dichloro-5-methoxypyrimidine (41.61 mg, 232.45 μmol) were dissolved in tetrahydrofuran (781.83 μL) / H2O (ultrapure water, 390.91 μL), tetrakis(triphenylphosphine)palladium(0) (13.43 mg, 11.62 μmol) and potassium carbonate (64.25 mg, 464.89 μmol) were added, and the reaction mixture was stirred at 100°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel) to obtain 5-(2-chloro-5-methoxypyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (41 mg, 64.21%) as a white solid.

[0354] LC / MS ESI (+): 275 / 277 (M+1)

[0355] 1H-NMR (500 MHz, DMSO-D6) δ 8.97 (d, J = 2.1 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.65 (s, 1H), 7.62 (d, J = 3.4 Hz, 1H), 6.63 (d, J = 3.6 Hz, 1H), 4.04 (s, 3H), 3.87 (s, 3H)

[0356]

[0357] (b) Synthesis of 1-(4-(2,5-dimethoxy-4-((5-methoxy-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one

[0358] 1-(4-(4-Amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (15 mg, 53.70 μmol) and 5-(2-chloro-5-methoxypyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (14.75 mg, 53.70 μmol) were dissolved in toluene (540 μL), palladium(II) acetate (1.21 mg, 5.37 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.21 mg, 10.74 μmol), and cesium carbonate (34.99 mg, 107.40 μmol) were added, and the reaction mixture was stirred at 120°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine(NH2) silica gel) to obtain 1-(4-(2,5-dimethoxy-4-((5-methoxy-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (12.3 mg, 43.99%) as a yellow solid.

[0359] LC / MS ESI (+): 518 (M+1)

[0360] 1H-NMR (500 MHz, DMSO-D6) δ 9.02 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.44 (s, 1H), 8.12 (s, 1H), 7.75 (s, 1H), 7.60 (d, J = 3.4 Hz, 1H), 6.66 (s, 1H), 6.58 (d, J = 3.4 Hz, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H), 3.57 (dd, J = 10.1, 6.4 Hz, 4H), 2.98-2.89 (m, 4H), 2.04 (s, 3H)

[0361]

[0362] Example 36: Synthesis of 1-(4-(4-((5-bromo-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 36)

[0363]

[0364]

[0365] (a) Synthesis of 5-(5-bromo-2-chloropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine

[0366] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (60 mg, 232.45 μmol) and 5-bromo-2,4-dichloropyrimidine (52.97 mg, 232.45 μmol) were dissolved in tetrahydrofuran (781.83 μL) / H2O (ultrapure water, 390.91 μL), tetrakis(triphenylphosphine)palladium(0) (13.43 mg, 11.62 μmol) and potassium carbonate (64.25 mg, 464.89 μmol) were added, and the reaction mixture was stirred at 100°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel) to obtain 5-(5-bromo-2-chloropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (27 mg, 35.90%) as a brown solid.

[0367] LC / MS ESI (+): 325 / 327 / 328 (M+1)

[0368] 1H-NMR (500 MHz, DMSO-D6) δ 9.08 (s, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 3.4 Hz, 1H), 6.65 (d, J = 3.4 Hz, 1H), 3.89 (s, 3H)

[0369]

[0370] (b) Synthesis of 1-(4-(4-((5-bromo-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0371] 1-(4-(4-Amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (10 mg, 35.80 μmol) and 5-(5-bromo-2-chloropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (11.58 mg, 35.80 μmol) were dissolved in toluene (357.99 μL), palladium(II) acetate (803.73 μg, 3.58 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.14 mg, 7.16 μmol), and potassium carbonate (9.90 mg, 71.60 μmol) were added, and the reaction mixture was stirred at 110°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine(NH2) silica gel) to obtain 1-(4-(4-((5-bromo-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (2 mg, 9.44%) as a brown solid.

[0372] LC / MS ESI (+): 566 / 568 (M+1)

[0373] 1H-NMR (500 MHz, DMSO-D6) δ 8.69 (d, J = 2.0 Hz, 1H), 8.63 (s, 1H), 8.44 (s, 1H), 8.42 (d, J = 2.0 Hz, 1H), 7.70 (s, 1H), 7.63 (d, J = 3.4 Hz, 1H), 6.64 (s, 1H), 6.59 (d, J = 3.4 Hz, 1H), 3.87 (s, 3H), 3.79 (s, 3H), 3.73 (s, 3H), 3.56 (dd, J = 10.0, 5.9 Hz, 4H), 2.94 (dt, J = 32.8, 4.9 Hz, 4H), 2.03 (s, 3H)

[0374]

[0375] Example 37: Synthesis of 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-fluoropyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 37)

[0376]

[0377]

[0378] (a) Synthesis of 2-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-fluoropyrimidine

[0379] 2,3-Dihydro-1,4-benzodioxin-6-ylboronic acid (83.50 mg, 500.10 μmol) and 2,4-dichloro-5-fluoropyrimidine (83.5 mg, 500.10 μmol) were dissolved in tetrahydrofuran (1.2 mL) / H2O (ultrapure water, 0.6 mL). Tetrakis(triphenylphosphine)palladium(0) (46.23 mg, 40.01 μmol) and potassium carbonate (138.23 mg, 1.00 mmol) were added, and the reaction mixture was stirred at 100°C for 4 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure water)) to obtain 2-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-fluoropyrimidine (117 mg, 87.74%) as a white solid.

[0380] LC / MS ESI (+): 267 (M+1) / 269

[0381] 1H-NMR (500 MHz, DMSO-D6) δ 8.88 (d, J = 3.6 Hz, 1H), 7.60 (dq, J = 8.6, 1.1 Hz, 1H), 7.56 (dd, J = 2.1, 0.7 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 4.36-4.31 (m, 4H)

[0382]

[0383] (b) Synthesis of 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-fluoropyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0384] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (30 mg, 107.40 μmol) and 2-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-fluoropyrimidine (28.64 mg, 107.40 μmol) were dissolved in toluene (1.07 mL), palladium(II) acetate (1.45 mg, 6.44 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.46 mg, 12.89 μmol), and cesium carbonate (104.98 mg, 322.19 μmol) were added, and the reaction mixture was stirred at 110°C for 12 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure)) to obtain 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-fluoropyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (24.1 mg, 44.04%) as a yellow solid.

[0385] LC / MS ESI (+): 255, 510 (M+1)

[0386] 1H-NMR (500 MHz, DMSO-D6) δ 8.48 (d, J = 3.9 Hz, 1H), 8.06 (s, 1H), 7.80 (s, 1H), 7.58-7.55 (m, 2H), 6.99 (d, J = 8.4 Hz, 1H), 6.62 (s, 1H), 4.30-4.26 (m, 4H), 3.76 (d, J = 3.0 Hz, 6H), 3.54 (dd, J = 10.3, 6.6 Hz, 4H), 2.91 (dt, J = 32.8, 4.9 Hz, 4H), 2.00 (s, 3H)

[0387]

[0388] Example 38: Synthesis of 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 38)

[0389]

[0390]

[0391]

[0392] (a) Synthesis of 2-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-(trifluoromethyl)pyrimidine

[0393] 2,3-Dihydro-1,4-benzodioxin-6-ylboronic acid (108.51 mg, 500.10 μmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (90 mg, 500.10 μmol) were dissolved in tetrahydrofuran (1.2 mL) / H2O (ultrapure water, 0.6 mL). Tetrakis(triphenylphosphine)palladium(0) (46.23 mg, 40.01 μmol) and potassium carbonate (138.23 mg, 1.00 mmol) were added, and the reaction mixture was stirred at 100°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure water)) to obtain 2-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-(trifluoromethyl)pyrimidine (34 mg, 21.47%) as a brown solid.

[0394] LC / MS ESI (+): 317 (M+1) / 319

[0395] 1H-NMR (500 MHz, DMSO-D6) δ 9.22 (s, 1H), 7.14-7.10 (m, 2H), 7.04-7.01 (m, 1H), 4.35-4.30 (m, 4H)

[0396]

[0397] (b) Synthesis of 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0398] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (29.99 mg, 107.37 μmol) and 2-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-(trifluoromethyl)pyrimidine (34 mg, 107.37 μmol) were dissolved in toluene (1.07 mL), palladium(II) acetate (1.45 mg, 6.44 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.46 mg, 12.88 μmol), and cesium carbonate (104.95 mg, 322.11 μmol) were added, and the reaction mixture was stirred at 110°C for 12 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure)) to obtain 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (21.6 mg, 35.95%) as a yellow solid.

[0399] LC / MS ESI (+): 280, 560 (M+1)

[0400] 1H-NMR (500 MHz, DMSO-D6) δ 8.78-9.24 (1H), 8.68 (s, 1H), 7.07-7.01 (m, 2H), 6.93 (d, J = 8.4 Hz, 1H), 6.59 (s, 1H), 4.26 (q, J = 5.3) Hz, 4H), 3.71 (d, J = 12.6 Hz, 6H), 3.53 (dd, J = 10.0, 5.9 Hz, 4H), 2.92 (dt, J = 32.8, 4.7 Hz, 4H), 2.00 (s, 3H)

[0401]

[0402] Example 39: Synthesis of 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylpyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 39)

[0403]

[0404]

[0405] (a) Synthesis of 2-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylpyrimidine

[0406] (2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid (90 mg, 500.10 μmol) and 2,4-dichloro-5-methylpyrimidine (81.52 mg, 500.10 μmol) were dissolved in tetrahydrofuran (1.2 mL) / H2O (ultrapure water, 0.6 mL). Tetrakis(triphenylphosphine)palladium(0) (46.23 mg, 40.01 μmol) and potassium carbonate (138.23 mg, 1.00 mmol) were added, and the reaction mixture was stirred at 100°C for 4 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure water)) to obtain 2-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylpyrimidine (111 mg, 84.49%) as a white solid.

[0407] LC / MS ESI (+): 263 (M+1) / 265

[0408] 1H-NMR (500 MHz, DMSO-D6) δ 8.65 (d, J = 0.6 Hz, 1H), 7.24-7.21 (m, 2H), 7.00 (d, J = 8.3 Hz, 1H), 4.31 (dtd, J = 14.1, 3.5, 1.6 Hz, 4H), 2.36 (s, 3H)

[0409]

[0410] (b) Synthesis of 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylpyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0411] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (30 mg, 107.40 μmol) and 2-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylpyrimidine (28.21 mg, 107.40 μmol) were dissolved in toluene (1.07 mL), palladium(II) acetate (1.45 mg, 6.44 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.46 mg, 12.88 μmol), and cesium carbonate (104.98 mg, 322.19 μmol) were added, and the reaction mixture was stirred at 110°C for 12 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure)) to obtain 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylpyrimidin-2-yl)amino)-2,5-dimethoxyphenyl]piperazin-1-yl)ethan-1-one (25.0 mg, 46.04%) as a yellow solid.

[0412] LC / MS ESI (+): 254, 506 (M+1)

[0413] 1H-NMR (500 MHz, DMSO-D6) δ 8.30 (s, 1H), 8.08 (s, 1H), 7.73 (s, 1H), 7.26-7.20 (m, 2H), 6.93 (d, J = 8.3 Hz, 1H), 6.60 (s, 1H), 4.26 (dd, J = 9.2, 4.9 Hz, 4H), 3.75 (d, J = 28.2 Hz, 6H), 3.53-3.51 (m, 4H), 2.88 (dt, J = 32.8, 4.6 Hz, 4H), 2.22 (s, 3H), 1.99 (s, 3H)

[0414]

[0415] Example 40: Synthesis of 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methoxypyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 40)

[0416]

[0417]

[0418] (a) Synthesis of 2-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methoxypyrimidine

[0419] (2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid (90 mg, 500.10 μmol) and 2,4-dichloro-5-methoxypyrimidine (89.52 mg, 500.10 μmol) were dissolved in tetrahydrofuran (1.2 mL) / H2O (ultrapure water, 0.6 mL). Tetrakis(triphenylphosphine)palladium(0) (46.23 mg, 40.01 μmol) and potassium carbonate (138.23 mg, 1.00 mmol) were added, and the reaction mixture was stirred at 100°C for 4 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure water)) to obtain 2-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methoxypyrimidine (73 mg, 52.38%) as a white solid.

[0420] LC / MS ESI (+): 279 (M+1) / 281

[0421] 1H-NMR (500 MHz, DMSO-D6) δ 8.55-8.63 (1H), 7.60-7.69 (2H), 6.92-7.05 (1H), 4.21-4.40 (4H), 3.28-3.35 (1H)

[0422]

[0423] (b) Synthesis of 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methoxypyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0424] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (30 mg, 107.40 μmol) and 2-chlorolanyl-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-methoxy-pyrimidine (29.93 mg, 107.40 μmol) were dissolved in toluene (1.07 mL), palladium(II) acetate (1.45 mg, 6.44 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.46 mg, 12.88 μmol), and cesium carbonate (104.98 mg, 322.19 μmol) were added, and the reaction mixture was stirred at 110°C for 12 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure)) to obtain 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methoxypyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (25.0 mg, 46.04%) as a yellow solid.

[0425] LC / MS ESI (+): 262, 522 (M+1)

[0426] 1H-NMR (500 MHz, DMSO-D6) δ 8.35 (s, 1H), 8.06 (s, 1H), 7.68-7.63 (m, 3H), 6.93-6.91 (m, 1H), 6.61 (s, 1H), 4.28-4.24 (m, 4H), 3.84 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.53 (dd, J = 9.9, 7.9 Hz, 4H), 2.89 (dt, J = 32.6, 4.9 Hz, 4H), 2.00 (s, 3H)

[0427]

[0428] Example 41: Synthesis of 1-(4-(4-((5-fluoro-4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 41)

[0429]

[0430]

[0431] (a) Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-3-methyl-3H-imidazo[4,5-b]pyridine

[0432] 3-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine (50 mg, 192.97 μmol) and 2,4-dichloro-5-fluoropyrimidine (35.44 mg, 212.26 μmol) were dissolved in tetrahydrofuran (627.73 μL) / H2O (ultrapure water, 313.82 μL), tetrakis(triphenylphosphine)palladium(0) (11.15 mg, 9.65 μmol) and potassium carbonate (53.34 mg, 385.93 μmol) were added, and the reaction mixture was stirred at 110°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel) to obtain 6-(2-chloro-5-fluoropyrimidin-4-yl)-3-methyl-3H-imidazo[4,5-b]pyridine (44 mg, 86.48%) as a white solid.

[0433] LC / MS ESI (+): 264 / 266 (M+1)

[0434] 1H-NMR (500 MHz, DMSO-D6) δ 9.02 (t, J = 1.5 Hz, 1H), 9.00 (d, J = 3.1 Hz, 1H), 8.64 (t, J = 1.5 Hz, 1H), 8.62 (s, 1H), 3.91 (s, 3H)

[0435]

[0436] (b) Synthesis of 1-(4-(4-((5-fluoro-4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0437] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (16 mg, 57.28 μmol) and 6-(2-chloro-5-fluoropyrimidin-4-yl)-3-methyl-3H-imidazo[4,5-b]pyridine (15.10 mg, 57.28 μmol) were dissolved in toluene (381.86 μL), palladium(II) acetate (1.29 mg, 5.73 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.63 mg, 11.46 μmol), and potassium carbonate (15.83 mg, 114.56 μmol) were added, and the reaction mixture was stirred at 120°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine(NH2) silica gel) to obtain 1-(4-(4-((5-fluoro-4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (23 mg, 79.00%) as a yellow solid.

[0438] LC / MS ESI (+): 507 (M+1)

[0439] 1H-NMR (500 MHz, DMSO-D6) δ 9.04 (s, 1H), 8.66 (s, 1H), 8.61 (d, J = 3.4 Hz, 1H), 8.57 (s, 1H), 8.30 (s, 1H), 7.77 (s, 1H), 6.66 (s, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.79 (s, 3H), 3.58 (dd, J = 10.2, 6.2 Hz, 4H), 2.96 (dt, J = 33.1, 4.9 Hz, 4H), 2.04 (s, 3H)

[0440]

[0441] Example 42: Synthesis of N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 42)

[0442]

[0443]

[0444] (a) Synthesis of 1-(2,5-dimethoxy-4-nitrophenyl)-N,N-dimethylazetidin-3-amine

[0445] 1-Bromanyl-2,5-di(methoxy)-4-nitro-benzene (300 mg, 1.14 mmol) and N,N-di(methyl)azetidin-3-amine (187.68 mg, 1.37 mmol, CL) were dissolved in toluene (7.63 mL), tris(dibenzylideneacetone)dipalladium(0) (52.42 mg, 57.24 μmol), ((1,1'-binaphthalene)-2,2'-diyl)bis(diphenylphosphane) (71.28 mg, 114.48 μmol), cesium carbonate (1.12 g, 3.43 mmol), and N,N-diisopropylethylamine (443.87 mg, 3.43 mmol, 598.20 μL) were added, and the reaction mixture was stirred under an argon stream. The mixture was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature, H2O was added, and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel, ethyl acetate:hexane) to obtain 1-(2,5-dimethoxy-4-nitro-phenyl)-N,N-dimethylazetidin-3-amine (260 mg, 80.74%) as a yellow solid.

[0446] LC / MS ESI (+): 282 (M+1)

[0447] 1H-NMR (500 MHz, DMSO-D6) δ 7.43 (s, 1H), 5.95 (s, 1H), 4.20 (t, J = 8.2 Hz, 2H), 3.92 (dd, J = 9.5, 5.3 Hz, 2H), 3.86 (s, 3H), 3.73 (s, 3H), 3.15-3.10 (m, 1H), 2.10 (s, 6H)

[0448]

[0449] (b) Synthesis of 1-(4-amino-2,5-dimethoxyphenyl)-N,N-dimethylazetidin-3-amine

[0450] 1-(2,5-Dimethoxy-4-nitro-phenyl)-N,N-dimethylazetidin-3-amine (258 mg, 917.15 μmol) was dissolved in ethanol (7.36 mL) and water (1.84 mL). Iron (256.09 mg, 4.59 mmol) and ammonium chloride (245.30 mg, 4.59 mmol) were added, and the reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and saturated sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel, dichloromethane:methanol) to obtain 1-(4-azanyl-2,5-dimethoxyphenyl)-N,N-dimethylazetidin-3-amine (195 mg, 84.60%) as a black solid.

[0451] LC / MS ESI (+): 252 (M+1)

[0452]

[0453] (c) Synthesis of N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine

[0454] 1-(4-Azanyl-2,5-dimethoxyphenyl)-N,N-dimethylazetidin-3-amine (20 mg, 79.58 μmol) and 5-(2-chlorolanyl-5-fluoranyl-pyrimidin-4-yl)-1-methyl-pyrrolo[2,3-b]pyridine (22.99 mg, 87.54 μmol) were dissolved in toluene (0.80 mL), palladium(II) acetate (1.79 mg, 7.96 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9.21 mg, 15.92 μmol), and cesium carbonate (51.86 mg, 159.16 μmol) were added, and the reaction mixture was stirred at 120°C for 4 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:water) to obtain N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoranyl-4-(1-methylpyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (14.5 mg, 38.16%) as a yellow solid.

[0455] LC / MS ESI (+): 478 (M+1)

[0456] 1H-NMR (500 MHz, DMSO-D6) δ 8.93 (s, 1H), 8.62 (s, 1H), 8.51 (d, J = 3.7 Hz, 1H), 8.13 (s, 1H), 7.64 (d, J = 3.5 Hz, 1H), 7.57 (s, 1H), 6.62 (d, J = 3.4 Hz, 1H), 6.16 (s, 1H), 3.97-3.95 (m, 2H), 3.87 (s, 3H), 3.77 (s, 3H), 3.71 (s, 3H), 3.54-3.51 (m, 2H), 3.07-3.02 (m, 1H), 2.11-2.08 (m, 6H)

[0457]

[0458] Example 43: Synthesis of N-(4-(3-(dimethylamino)azetidin-1-yl)-2-methoxyphenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 43)

[0459]

[0460]

[0461] (a) Synthesis of 1-(3-methoxy-4-nitrophenyl)-N,N-dimethylazetidin-3-amine

[0462] 4-Bromanyl-2-methoxy-1-nitro-benzene (300 mg, 1.29 mmol) and N,N-dimethylazetidin-3-amine (211.49 mg, 1.55 mmol, CL) were dissolved in toluene (8.6 mL), and tris(dibenzylideneacetone)dipalladium(0) (59.06 mg, 64.50 μmol), ((1,1'-binaphthalene)-2,2'-diyl)bis(diphenylphosphane) (80.32 mg, 129.00 μmol), cesium carbonate (1.26 g, 3.87 mmol), and N,N-diisopropylethylamine (500.16 mg, 3.87 mmol, 674.07 μL) were added, and the reaction mixture was stirred at 100°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel, ethyl acetate:hexane) to obtain 1-(3-methoxy-4-nitro-phenyl)-N,N-dimethylazetidin-3-amine (260 mg, 80.74%) as an orange solid.

[0463] LC / MS ESI (+): 252 (M+1)

[0464] 1H-NMR (500 MHz, DMSO-D6) δ 7.90 (d, J = 9.2 Hz, 1H), 6.03 (dd, J = 9.0, 2.3 Hz, 1H), 6.00 (d, J = 2.1 Hz, 1H), 4.06 (t, J = 8.2 Hz, 2H), 3.88 (s, 3H), 3.81 (dd, J = 9.2, 5.1 Hz, 2H), 3.25-3.20 (m, 1H), 2.12 (s, 6H)

[0465]

[0466] (b) Synthesis of 1-(4-amino-3-methoxyphenyl)-N,N-dimethylazetidin-3-amine

[0467] 1-(3-Methoxy-4-nitro-phenyl)-N,N-dimethylazetidin-3-amine (223 mg, 887.45 μmol) was dissolved in ethanol (7.1 mL) and water (1.78 mL). Iron (247.80 mg, 4.44 mmol) and ammonium chloride (237.36 mg, 4.44 mmol, 155.13 μL) were added, and the reaction mixture was stirred at 70°C for 1 hour. The reaction mixture was cooled to room temperature, filtered through Celite, and saturated sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel, dichloromethane:methanol) to obtain 1-(4-azanyl-3-methoxyphenyl)-N,N-dimethylazetidin-3-amine (163 mg, 83.00%) as a black solid.

[0468] LC / MS ESI (+): 222 (M+1)

[0469] 1H-NMR (500 MHz, DMSO-D6) δ 6.49 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 2.3 Hz, 1H), 5.83 (dd, J = 8.2, 2.4 Hz, 1H), 4.02 (s, 2H), 3.79 (t, J = 6.8 Hz, 2H), 3.72 (s, 3H), 3.34 (t, J = 6.3 Hz, 2H), 3.07 (q, J = 6.2 Hz, 1H), 2.06 (d, J = 10.7 Hz, 6H)

[0470]

[0471] (c) Synthesis of N-(4-(3-(dimethylamino)azetidin-1-yl)-2-methoxyphenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine

[0472] 1-(4-Azanyl-3-methoxy-phenyl)-N,N-dimethylazetidin-3-amine (20 mg, 90.38 μmol) and 5-(2-chlorolanyl-5-fluoranyl-pyrimidin-4-yl)-1-methyl-pyrrolo[2,3-b]pyridine (26.11 mg, 99.41 μmol) were dissolved in toluene (0.90 mL), palladium(II) acetate (2.03 mg, 9.04 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10.46 mg, 18.08 μmol), and cesium carbonate (58.89 mg, 180.75 μmol) were added, and the reaction mixture was stirred at 120°C for 4 hours under an argon stream. The reaction mixture was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:water) to give N-(4-(3-(dimethylamino)azetidin-1-yl)-2-methoxy-phenyl)-5-fluoranyl-4-(1-methylpyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (8.2 mg, 20.28%) as a yellow solid.

[0473] LC / MS ESI (+): 448 (M+1)

[0474] 1H-NMR (500 MHz, DMSO-D6) δ 8.89 (s, 1H), 8.56-8.56 (m, 1H), 8.46 (d, J = 3.7 Hz, 1H), 8.15 (s, 1H), 7.63 (d, J = 3.5 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 3.5 Hz, 1H), 6.14 (d, J = 2.3 Hz, 1H), 6.04 (dd, J = 8.5, 2.4 Hz, 1H), 3.92 (t, J = 7.1 Hz, 2H), 3.87 (s, 3H), 3.77 (d, J = 4.7 Hz, 3H), 3.54 (dd, J = 7.3, 5.8 Hz, 2H), 3.15 (t, J = 6.5 Hz, 1H), 2.13-2.08 (m, 6H)

[0475]

[0476] Example 44: Synthesis of N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 44)

[0477]

[0478]

[0479] 1-(4-Azanyl-2,5-dimethoxyphenyl)-N,N-dimethylazetidin-3-amine (20 mg, 79.58 μmol) and 5-(2-chloropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (21.42 mg, 87.54 μmol) were dissolved in toluene (0.80 mL), palladium(II) acetate (1.79 mg, 7.96 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9.21 mg, 15.92 μmol), and cesium carbonate (51.86 mg, 159.16 μmol) were added, and the reaction mixture was stirred at 120°C for 4 hours under an argon stream. The reaction mixture was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:water) to obtain N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-4-(1-methylpyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (6.7 mg, 18.32%) as a yellow solid.

[0480] LC / MS ESI (+): 460 (M+1)

[0481] 1H-NMR (500 MHz, DMSO-D6) δ 9.06 (d, J = 2.1 Hz, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.43 (d, J = 5.2 Hz, 1H), 7.96 (s, 1H), 7.75 (s, 1H), 7.61 (d, J = 3.4 Hz, 1H), 7.41 (d, J = 5.3 Hz, 1H), 6.58 (d, J = 3.5 Hz, 1H), 6.18 (s, 1H), 3.98-3.95 (m, 2H), 3.87 (s, 3H), 3.80 (s, 3H), 3.74 (s, 3H), 3.53 (t, J = 6.9 Hz, 2H), 3.05 (t, J = 6.3 Hz, 1H), 2.09 (s, 6H)

[0482]

[0483] Example 45: Synthesis of 1-(4-((4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)sulfonyl)piperazin-1-yl)ethan-1-one (Compound 45)

[0484]

[0485]

[0486] (a) Synthesis of 1-(4-((3-methoxy-4-nitrophenyl)sulfonyl)piperazin-1-yl)ethan-1-one

[0487] 3-Methoxy-4-nitrobenzenesulfonyl chloride (200 mg, 794.77 μmol) was dissolved in dichloromethane (1.86 mL), and 1-acetylpiperazine (112.05 mg, 874.25 μmol) and N,N-diisopropylethylamine (415.30 μL, 2.38 mmol) were sequentially added at 0°C. The reaction mixture was stirred at 25°C for 2 h under a stream of argon, H2O was added, and the mixture was extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2 silica gel) to obtain 1-(4-((3-methoxy-4-nitrophenyl)sulfonyl)piperazin-1-yl)ethan-1-one (225 mg, 82.45%) as a brown solid.

[0488] LC / MS ESI (+): 344 (M+1)

[0489] 1H-NMR (500 MHz, CHLOROFORM-D) δ 7.92 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H), 7.39 (dd, J = 8.3, 1.7 Hz, 1H), 4.03 (s, 3H), 3.73 (t, J = 5.0 Hz, 2H), 3.58 (t, J = 5.0 Hz, 2H), 3.09-3.06 (m, 4H), 2.06 (s, 3H)

[0490]

[0491] (b) Synthesis of 1-(4-((4-amino-3-methoxyphenyl)sulfonyl)piperazin-1-yl)ethan-1-one

[0492] 1-(4-(3-Methoxy-4-nitro-phenyl)sulfonylpiperazin-1-yl)ethanone (222 mg, 646.56 μmol) was dissolved in ethanol (4.97 mL) / H2O (ultrapure water, 1.24 mL), and iron (180.55 mg, 3.23 mmol) and ammonium chloride (345.85 mg, 6.47 mmol) were added at room temperature. The reaction mixture was stirred at 70°C for 2 h, cooled to room temperature, neutralized with 1 N sodium hydroxide, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2)) to obtain 1-(4-((4-amino-3-methoxyphenyl)sulfonyl)piperazin-1-yl)ethan-1-one (164.6 mg, 80.67%) as a brown solid.

[0493] LC / MS ESI (+): 314 (M+1)

[0494] 1H-NMR (500 MHz, DMSO-D6) δ 7.03 (dd, J = 8.3, 1.9 Hz, 1H), 6.92 (d, J = 1.8 Hz, 1H), 6.68 (d, J = 8.3 Hz, 1H), 5.71 (s, 2H), 3.79 (s, 3H), 3.46-3.42 (m, 4H), 2.76 (dt, J = 28.8, 5.0 Hz, 4H), 1.90 (s, 3H)

[0495]

[0496] (c) Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine

[0497] 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine was obtained as a white solid by the same method as in (d) of Example 1.

[0498] LC / MS ESI (+): 263 / 265 (M+1)

[0499] 1H-NMR (500 MHz, DMSO-D6) δ 8.94-8.93 (m, 2H), 8.66 (t, J = 1.0 Hz, 1H), 7.67 (d, J = 3.5 Hz, 1H), 6.69 (d, J = 3.5 Hz, 1H), 3.87 (d, J = 12.4 Hz, 3H)

[0500]

[0501] (d) Synthesis of 1-(4-((4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)sulfonyl)piperazin-1-yl)ethan-1-one

[0502] 1-(4-((4-amino-3-methoxyphenyl)sulfonyl)piperazin-1-yl)ethan-1-one (20 mg, 63.82 μmol) and 5-(2-chlorolanyl-5-fluoranyl-pyrimidin-4-yl)-1-methyl-pyrrolo[2,3-b]pyridine (18.44 mg, 70.20 μmol) were dissolved in toluene (638.22 μL), palladium(II) acetate (1.43 mg, 6.38 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.39 mg, 12.76 μmol), and cesium carbonate (41.59 mg, 127.64 μmol) were added, and the reaction mixture was stirred at 110°C for 8 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure)) to obtain 1-(4-((4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)sulfonyl)piperazin-1-yl)ethan-1-one (20.4 mg, 58.86%) as a yellow solid.

[0503] LC / MS ESI (+): 540 (M+1)

[0504] 1H-NMR (500 MHz, CHLOROFORM-D) δ 9.16 (t, J = 1.0 Hz, 1H), 8.84 (d, J = 8.6 Hz, 1H), 8.68 (d, J = 1.1 Hz, 1H), 8.41 (d, J = 3.5 Hz, 1H), 8.08 (s, 1H), 7.43 (dd, J = 8.6, 1.8 Hz, 1H), 7.28 (d, J = 3.4 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 6.60 (d, J = 3.5 Hz, 1H), 4.00 (s, 3H), 3.96 (s, 3H), 3.72-3.70 (m, 2H), 3.56-3.54 (m, 2H), 3.04-3.01 (m, 4H), 2.03 (s, 3H)

[0505]

[0506] Example 46: Synthesis of 1-(4-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)piperazin-1-yl)ethan-1-one (Compound 46)

[0507]

[0508]

[0509] (a) Synthesis of 1-(4-(3-methoxy-4-nitrobenzoyl)piperazin-1-yl)ethan-1-one

[0510] 3-Methoxy-4-nitrobenzoic acid (200 mg, 1.01 mmol) was dissolved in N,N-dimethylformamide (2.01 mL), and 1-acetylpiperazine (143.03 mg, 1.12 mmol), HATU (578.60 mg, 1.52 mmol), and N,N-diisopropylethylamine (530.11 μL, 3.04 mmol) were sequentially added at room temperature. The reaction mixture was stirred at 70°C for 1 h under a stream of argon, cooled to room temperature, added H2O, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel) to obtain 1-(4-(3-methoxy-4-nitrobenzoyl)piperazin-1-yl)ethan-1-one (274 mg, 87.89%) as a brown solid.

[0511] LC / MS ESI (+): 308 (M+1)

[0512] 1H-NMR (500 MHz, CHLOROFORM-D) δ 7.88 (d, J = 8.3 Hz, 1H), 7.16 (s, 1H), 7.01 (dd, J = 8.1, 1.5 Hz, 1H), 3.99 (s, 3H), 3.84-3.41 (m, 8H), 2.15 (s, 3H)

[0513]

[0514] (b) Synthesis of 1-(4-(4-amino-3-methoxybenzoyl)piperazin-1-yl)ethan-1-one

[0515] 1-(4-(3-Methoxy-4-nitro-phenyl)sulfonylpiperazin-1-yl)ethanone (270 mg, 878.62 μmol) was dissolved in ethanol (6.76 mL) / H2O (ultrapure water, 1.69 mL), and iron (245.35 mg, 4.39 mmol) and ammonium chloride (469.97 mg, 8.79 mmol, 307.17 μL) were added at room temperature. The reaction mixture was stirred at 70 °C for 2 h, cooled to room temperature, neutralized with 1 N sodium hydroxide, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2)) to obtain 1-(4-(4-amino-3-methoxybenzoyl)piperazin-1-yl)ethan-1-one (162.5 mg, 66.45%) as a brown solid.

[0516] LC / MS ESI (+): 278 (M+1)

[0517] 1H-NMR (500 MHz, DMSO-D6) δ 6.86 (d, J = 1.7 Hz, 1H), 6.82 (dd, J = 8.0, 1.8 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 5.17 (s, 2H), 3.78 (s, 3H), 3.53-3.46 (m, 8H), 2.02 (s, 3H)

[0518]

[0519] (c) Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine

[0520] 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine was obtained as a white solid by the same method as in (d) of Example 1.

[0521] LC / MS ESI (+): 263 / 265 (M+1)

[0522] 1H-NMR (500 MHz, DMSO-D6) δ 8.94-8.93 (m, 2H), 8.66 (t, J = 1.0 Hz, 1H), 7.67 (d, J = 3.5 Hz, 1H), 6.69 (d, J = 3.5 Hz, 1H), 3.87 (d, J = 12.4 Hz, 3H)

[0523]

[0524] (d) Synthesis of 1-(4-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)piperazin-1-yl)ethan-1-one

[0525] 1-(4-(4-Amino-3-methoxybenzoyl)piperazin-1-yl)ethan-1-one (20 mg, 72.12 μmol) and 5-(2-chlorolanyl-5-fluoranyl-pyrimidin-4-yl)-1-methyl-pyrrolo[2,3-b]pyridine (20.84 mg, 79.33 μmol) were dissolved in toluene (638.22 μL), palladium(II) acetate (1.62 mg, 7.21 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.35 mg, 14.42 μmol), and cesium carbonate (47.00 mg, 144.24 μmol) were added, and the reaction mixture was stirred at 110°C for 8 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure)) to obtain 1-(4-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)piperazin-1-yl)ethan-1-one (36.31 mg, 77.81%) as a yellow solid.

[0526] LC / MS ESI (+): 504 (M+1)

[0527] 1H-NMR (500 MHz, DMSO-D6) δ 8.97 (s, 1H), 8.66 (t, J = 3.7 Hz, 2H), 8.40 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.66 (d, J = 3.4 Hz, 1H), 7.12-7.08 (m, 2H), 6.66 (d, J = 3.5 Hz, 1H), 3.90 (d, J = 15.6 Hz, 6H), 3.50 (s, 8H), 2.03 (s, 3H)

[0528]

[0529] Example 47: Synthesis of 1-(4-(4-((4-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-fluoropyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 47)

[0530]

[0531]

[0532] (a) Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-ethyl-1H-pyrrolo[2,3-b]pyridine

[0533] (1-Ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (40 mg, 210.52 μmol) and 2,4-dichloro-5-fluoropyrimidine (42.18 mg, 252.62 μmol) were dissolved in tetrahydrofuran (701.77 μL) / H2O (ultrapure water, 350.83 μL). Tetrakis(triphenylphosphine)palladium(0) (12.16 mg, 10.53 μmol) and potassium carbonate (58.19 mg, 421.04 μmol) were added, and the reaction mixture was stirred at 110°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and the mixture was extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel) to obtain 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-ethyl-1H-pyrrolo[2,3-b]pyridine (35 mg, 60.09%) as a white solid.

[0534] LC / MS ESI (+): 277 / 279 (M+1)

[0535] 1H-NMR (500 MHz, DMSO-D6) δ 8.94 (d, J = 3.4 Hz, 1H), 8.92 (t, J = 1.7 Hz, 1H), 8.66 (q, J = 1.0 Hz, 1H), 7.75 (d, J = 3.5 Hz, 1H), 6.69 (d, J = 3.5 Hz, 1H), 4.36 (q, J = 7.3 Hz, 2H), 1.41 (t, J = 7.3 Hz, 3H)

[0536]

[0537] (b) Synthesis of 1-(4-(4-((4-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-fluoropyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0538] 1-(4-(4-Amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (16 mg, 57.28 μmol) and 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-ethyl-1H-pyrrolo[2,3-b]pyridine (15.85 mg, 57.28 μmol) were dissolved in toluene (381.85 μL), palladium(II) acetate (1.29 mg, 5.73 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.63 mg, 11.46 μmol), and potassium carbonate (15.83 mg, 114.56 μmol) were added, and the reaction mixture was stirred at 120°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine(NH2) silica gel) to obtain 1-(4-(4-((4-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-fluoropyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (10 mg, 32.71%) as a yellow solid.

[0539] LC / MS ESI (+): 520 (M+1)

[0540] 1H-NMR (500 MHz, DMSO-D6) δ 8.93 (s, 1H), 8.64 (d, J = 0.9 Hz, 1H), 8.57 (d, J = 3.7 Hz, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.72 (d, J = 3.5 Hz, 1H), 6.67 (s, 1H), 6.63 (d, J = 3.4 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.58 (dd, J = 10.2, 6.3 Hz, 4H), 2.95 (dt, J = 32.7, 4.9 Hz, 4H), 2.04 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H)

[0541]

[0542] Example 48: Synthesis of (3-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (Compound 48)

[0543]

[0544]

[0545] (a) Synthesis of (3-methoxy-4-nitrophenyl)(morpholino)methanone

[0546] 3-Methoxy-4-nitrobenzoic acid (200 mg, 1.01 mmol) was dissolved in N,N-dimethylformamide (1.09 mL), and morpholine (106.48 μL, 1.22 mmol), HATU (578.60 mg, 1.52 mmol), and N,N-diisopropylethylamine (530.11 μL, 3.04 mmol) were sequentially added at room temperature. The reaction mixture was stirred at 70°C for 1 h under a stream of argon, cooled to room temperature, added H2O, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel) to obtain (248 mg, 91.82%) of (3-methoxy-4-nitrophenyl)(morpholino)methanone as a brown solid.

[0547] LC / MS ESI (+): 267 (M+1)

[0548] 1H-NMR (500 MHz, CHLOROFORM-D) δ 7.87 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 1.4 Hz, 1H), 7.02-7.00 (m, 1H), 3.99 (s, 3H), 3.80-3.42 (m, 8H)

[0549]

[0550] (b) Synthesis of (4-amino-3-methoxyphenyl)(morpholino)methanone

[0551] (3-Methoxy-4-nitro-phenyl)-morpholin-4-yl-methanone (245 mg, 920.19 μmol) was dissolved in ethanol (7.08 mL) / H2O (ultrapure water, 1.77 mL), and iron (256.96 mg, 4.60 mmol) and ammonium chloride (492.21 mg, 9.20 mmol) were added at room temperature. The reaction mixture was stirred at 70°C for 2 h, cooled to room temperature, neutralized with 1 N sodium hydroxide, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2)) to obtain (4-amino-3-methoxyphenyl)(morpholino)methanone (204.7 mg, 94.12%) as a yellow solid.

[0552] LC / MS ESI (+): 237 (M+1)

[0553] 1H-NMR (500 MHz, DMSO-D6) δ 6.85 (d, J = 1.7 Hz, 1H), 6.80 (dd, J = 7.9, 1.7 Hz, 1H), 6.61 (d, J = 7.9 Hz, 1H), 5.15 (s, 2H), 3.77 (s, 3H), 3.59-3.49 (m, 8H)

[0554]

[0555] (c) Synthesis of 5-(2-chloroylpyrimidin-4-yl)-1-methyl-pyrrolo[2,3-b]pyridine

[0556] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (200 mg, 774.82 μmol) and 2,4-bis(chloranyl)pyrimidine (115.43 mg, 774.82 μmol) were dissolved in tetrahydrofuran (2.6 mL) / H2O (ultrapure water, 1.3 mL). Tetrakis(triphenylphosphine)palladium(0) (44.77 mg, 38.74 μmol) and potassium carbonate (214.18 mg, 1.55 mmol) were added, and the reaction mixture was stirred at 100°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure water)) to obtain 5-(2-chloroylpyrimidin-4-yl)-1-methyl-pyrrolo[2,3-b]pyridine (186 mg, 98.11%) as a white solid.

[0557] LC / MS ESI (+): 245 (M+1) / 247

[0558] 1H-NMR (500 MHz, DMSO-D6) δ 9.06-9.14 (1H), 8.71-8.85 (2H), 8.17-8.28 (1H), 7.61-7.71 (1H), 6.57-6.72 (1H), 3.83-3.90 (3H)

[0559]

[0560] (d) Synthesis of (3-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone

[0561] (4-Amino-3-methoxyphenyl)(morpholino)methanone (30 mg, 126.98 μmol) and 5-(2-chloronylpyrimidin-4-yl)-1-methyl-pyrrolo[2,3-b]pyridine (34.18 mg, 139.67 μmol) were dissolved in toluene (619.55 μL), palladium(II) acetate (2.85 mg, 12.70 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (14.69 mg, 25.40 μmol), and potassium carbonate (35.10 mg, 253.95 μmol) were added, and the reaction mixture was stirred at 120°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure)) to obtain (3-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (26.30 mg, 46.49%) as a yellow solid.

[0562] LC / MS ESI (+): 445 (M+1), 889

[0563] 1H-NMR (500 MHz, DMSO-D6) δ 9.11 (d, J = 2.0 Hz, 1H), 8.76 (d, J = 2.1 Hz, 1H), 8.56 (d, J = 5.3 Hz, 1H), 8.45 (d, J = 8.7 Hz, 1H), 8.23 ​​(s, 1H), 7.63 (d, J = 3.4 Hz, 1H), 7.59 (d, J = 5.2 Hz, 1H), 7.12-7.10 (m, 2H), 6.63 (d, J = 3.5 Hz, 1H), 3.91 (d, J = 27.5 Hz, 6H), 3.58 (d, J = 38.7 Hz, 8H)

[0564]

[0565] Example 49: Synthesis of (4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (Compound 49)

[0566]

[0567]

[0568] (4-Amino-3-methoxyphenyl)(morpholino)methanone (30 mg, 126.98 μmol) and 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (36.69 mg, 139.67 μmol) were dissolved in toluene (619.55 μL), palladium(II) acetate (2.85 mg, 12.70 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (14.69 mg, 25.40 μmol), and potassium carbonate (35.10 mg, 253.95 μmol) were added, and the reaction mixture was stirred at 120°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure)) to obtain (4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (49.20 mg, 83.65%) as a yellow solid.

[0569] LC / MS ESI (+): 463 (M+1), 925

[0570] 1H-NMR (500 MHz, DMSO-D6) δ 8.97 (t, J = 1.5 Hz, 1H), 8.66-8.64 (m, 2H), 8.39 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 3.5 Hz, 1H), 7.11-7.07 (m, 2H), 6.66 (d, J = 3.4 Hz, 1H), 3.90 (d, J = 14.4 Hz, 6H), 3.57 (d, J = 41.0 Hz, 8H)

[0571]

[0572] Example 50: Synthesis of 5-fluoro-N-(2-methoxy-4-(morpholinosulfonyl)phenyl)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 50)

[0573]

[0574]

[0575] (a) Synthesis of 4-((3-methoxy-4-nitrophenyl)sulfonyl)morpholine

[0576] 3-Methoxy-4-nitrobenzenesulfonyl chloride (200 mg, 794.77 μmol) was dissolved in dichloromethane (1.75 mL), and morpholine (104.28 μL, 1.19 mmol) and N,N-diisopropylethylamine (415.30 μL, 2.38 mmol) were sequentially added at 0°C. The reaction mixture was stirred at 25°C for 15 h under a stream of argon, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2 silica gel) to obtain 4-((3-methoxy-4-nitrophenyl)sulfonyl)morpholine (190 mg, 79.08%) as a brown solid.

[0577] LC / MS ESI (+): 303 (M+1)

[0578] 1H-NMR (500 MHz, CHLOROFORM-D) δ 7.94 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 1.7 Hz, 1H), 7.41 (dd, J = 8.3, 1.7 Hz, 1H), 4.03 (s, 3H), 3.77 (t, J = 4.8 Hz, 4H), 3.07 (t, J = 4.7 Hz, 4H)

[0579]

[0580] (b) Synthesis of 2-methoxy-4-morpholin-4-ylsulfonyl-aniline

[0581] 4-((3-Methoxy-4-nitrophenyl)sulfonyl)morpholine (190 mg, 628.51 μmol) was dissolved in ethanol (4.83 mL) / H2O (ultrapure water, 1.21 mL), and iron (175.51 mg, 3.14 mmol) and ammonium chloride (336.19 mg, 6.29 mmol) were added at room temperature. The reaction mixture was stirred at 70°C for 2 h, cooled to room temperature, neutralized with 1 N sodium hydroxide, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2)) to obtain 2-methoxy-4-morpholin-4-ylsulfonyl-aniline (168.9 mg, 98.48%) as a yellow solid.

[0582] LC / MS ESI (+): 273 (M+1)

[0583] 1H-NMR (500 MHz, DMSO-D6) δ 7.08 (dd, J = 8.3, 2.0 Hz, 1H), 6.96 (d, J = 1.8 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 5.76 (s, 2H), 3.83 (s, 3H), 3.61 (t, J = 4.7 Hz, 4H), 2.79 (t, J = 4.6 Hz, 4H)

[0584]

[0585] (c) Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine

[0586] 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine was obtained as a white solid by the same method as in (d) of Example 1.

[0587] LC / MS ESI (+): 263 / 265 (M+1)

[0588] 1H-NMR (500 MHz, DMSO-D6) δ 8.94-8.93 (m, 2H), 8.66 (t, J = 1.0 Hz, 1H), 7.67 (d, J = 3.5 Hz, 1H), 6.69 (d, J = 3.5 Hz, 1H), 3.87 (d, J = 12.4 Hz, 3H)

[0589]

[0590] (d) Synthesis of 5-fluoro-N-(2-methoxy-4-(morpholinosulfonyl)phenyl)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine

[0591] 2-Methoxy-4-morpholin-4-ylsulfonyl-aniline (30 mg, 110.16 μmol) and 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (31.83 mg, 121.18 μmol) were dissolved in toluene (537.53 μL), palladium(II) acetate (2.47 mg, 11.02 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12.75 mg, 22.03 μmol), and potassium carbonate (30.45 mg, 220.33 μmol) were added, and the reaction mixture was stirred at 120°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure)) to obtain 5-fluoro-N-(2-methoxy-4-(morpholinosulfonyl)phenyl)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (49.20 mg, 83.65%) as a yellow solid.

[0592] LC / MS ESI (+): 499 (M+1), 997

[0593] 1H-NMR (500 MHz, DMSO-D6) δ 9.00-8.99 (m, 1H), 8.73 (d, J = 3.7 Hz, 1H), 8.68 (q, J = 1.0 Hz, 1H), 8.62-8.59 (m, 2H), 8.17-8.23 (0H), 7.66 (d, J = 3.5 Hz, 1H), 7.43 (dd, J = 8.4, 2.0 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 6.68 (d, J = 3.4 Hz, 1H), 4.00 (s, 3H), 3.89 (s, 3H), 3.64 (t, J = 4.7 Hz, 4H), 2.90 (t, J = 4.6 Hz, 4H)

[0594]

[0595] Example 51: Synthesis of N-(2,5-dimethoxy-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 51)

[0596]

[0597]

[0598] (a) Synthesis of 1-(2,5-dimethoxy-4-nitrophenyl)-4-(methylsulfonyl)piperazine

[0599] 1-Bromo-2,5-dimethoxy-4-nitrobenzene (100 mg, 381.60 μmol) and 1-methylsulfonylpiperazine (94.00 mg, 572.39 μmol) were dissolved in toluene (2.54 mL), and tris(dibenzylideneacetone)dipalladium(0) (17.47 mg, 19.08 μmol), ([1,1'-binaphthalene]-2,2'-diyl)bis(diphenylphosphane) (23.76 mg, 38.16 μmol), and cesium carbonate (373.00 mg, 1.14 mmol) were added. The reaction mixture was stirred at 110°C for 15 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel, ethyl acetate:dichloromethane) to obtain 1-(2,5-dimethoxy-4-nitrophenyl)-4-(methylsulfonyl)piperazine (113 mg) as a yellow solid.

[0600] LC / MS ESI (+): 346 (M+1)

[0601] 1H-NMR (500 MHz, DMSO-D6) δ 7.52 (s, 1H), 6.68 (s, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 3.33 (s, 4H), 3.26 (dd, J = 9.4, 4.4 Hz, 4H), 2.94 (s, 3H)

[0602]

[0603] (b) Synthesis of 2,5-dimethoxy-4-(4-(methylsulfonyl)piperazin-1-yl)aniline

[0604] 1-[2,5-Di(methoxy)-4-nitro-phenyl]-4-methylsulfonyl-piperazine (111 mg, 321.39 μmol) was dissolved in ethanol (2.57 mL) and water (0.64 mL). Iron (89.74 mg, 1.61 mmol) and ammonium chloride (85.96 mg, 1.61 mmol) were added, and the reaction mixture was stirred at 70°C for 1 hour. The reaction mixture was cooled to room temperature, filtered through Celite, and saturated sodium bicarbonate was added to the reaction mixture, followed by extraction with dichloromethane. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel, ethyl acetate:dichloromethane:hexane) to obtain 2,5-dimethoxy-4-(4-(methylsulfonyl)piperazin-1-yl)aniline (77 mg, 64%) as a yellow solid.

[0605] LC / MS ESI (+): 316 (M+1)

[0606] 1H-NMR (500 MHz, DMSO-D6) δ 6.51 (s, 1H), 6.36 (s, 1H), 4.45 (s, 2H), 3.69 (s, 3H), 3.66 (s, 3H), 3.20 (t, J = 4.8 Hz, 4H), 2.92 (dd, J = 9.8, 5.1 Hz, 7H)

[0607]

[0608] (c) Synthesis of N-(2,5-dimethoxy-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine

[0609] 2,5-Dimethoxy-4-(4-(methylsulfonyl)piperazin-1-yl)aniline (14 mg, 44.39 μmol) and 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (12.83 mg, 48.83 μmol) were dissolved in toluene (0.44 mL), palladium(II) acetate (996.59 μg, 4.44 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.14 mg, 8.88 μmol), and cesium carbonate (28.93 mg, 88.78 μmol) were added, and the reaction mixture was stirred at 120°C for 5 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel, acetonitrile:water) to obtain N-(2,5-dimethoxy-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (6.5 mg, 27.04%) as a yellow solid.

[0610] LC / MS ESI (+): 542 (M+1)

[0611] 1H-NMR (500 MHz, DMSO-D6) δ 8.95 (s, 1H), 8.65 (d, J = 0.8 Hz, 1H), 8.58 (d, J = 3.7 Hz, 1H), 8.20 (s, 1H), 7.88 (s, 1H), 7.65 (d, J = 3.5 Hz, 1H), 6.71 (s, 1H), 6.63 (d, J = 3.4 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H), 3.26 (t, J = 4.7 Hz, 4H), 3.09 (t, J = 4.7 Hz, 4H), 2.94 (s, 3H)

[0612]

[0613] Example 52: Synthesis of 1-(4-(4-((5-fluoro-4-(thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 52)

[0614]

[0615]

[0616] (a) Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)thiazolo[5,4-b]pyridine

[0617] 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)thiazolo[5,4-b]pyridine (50 mg, 190.74 μmol) and 2,4-dichloro-5-fluoropyrimidine (35.03 mg, 209.82 μmol) were dissolved in tetrahydrofuran (620.49 μL) / H2O (ultrapure water, 310.20 μL). Tetrakis(triphenylphosphine)palladium(0) (11.02 mg, 9.54 μmol) and potassium carbonate (52.72 mg, 381.48 μmol) were added, and the reaction mixture was stirred at 110°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and the mixture was extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel) to obtain 6-(2-chloro-5-fluoropyrimidin-4-yl)thiazolo[5,4-b]pyridine (45 mg, 88.47%) as a white solid.

[0618] LC / MS ESI (+): 267 / 269 (M+1)

[0619] 1H-NMR (500 MHz, DMSO-D6) δ 9.72 (s, 1H), 9.23 (d, J = 1.0 Hz, 1H), 9.09 (d, J = 2.9 Hz, 1H), 8.99 (t, J = 0.9 Hz, 1H)

[0620]

[0621] (b) Synthesis of 1-(4-(4-((5-fluoro-4-(thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0622] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (16 mg, 57.28 μmol) and 6-(2-chloro-5-fluoropyrimidin-4-yl)thiazolo[5,4-b]pyridine (16.80 mg, 63.01 μmol) were dissolved in toluene (374.95 μL), palladium(II) acetate (1.29 mg, 5.73 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.63 mg, 11.46 μmol), and potassium carbonate (15.83 mg, 114.56 μmol) were added, and the reaction mixture was stirred at 120°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine(NH2) silica gel) to obtain 1-(4-(4-((5-fluoro-4-(thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (5 mg, 17.03%) as a yellow solid.

[0623] LC / MS ESI (+): 510 (M+1)

[0624] 1H-NMR (500 MHz, DMSO-D6) δ 9.69 (s, 1H), 9.28 (s, 1H), 9.00 (d, J = 1.7 Hz, 1H), 8.68 (d, J = 3.2 Hz, 1H), 8.41 (s, 1H), 7.74 (s, 1H), 6.67 (s, 1H), 3.80 (s, 6H), 3.58 (dd, J = 10.2, 6.2 Hz, 4H), 2.96 (dt, J = 33.0, 4.7 Hz, 4H), 2.04 (s, 3H)

[0625]

[0626] Example 53: Synthesis of tert-butyl 5-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,5-diazaspiro[3.4]octane-2-carboxylate (Compound 53)

[0627]

[0628]

[0629] (a) Synthesis of tert-butyl 5-(2,5-dimethoxy-4-nitrophenyl)-2,5-diazaspiro[3.4]octane-2-carboxylate

[0630] 1-Bromanyl-2,5-di(methoxy)-4-nitro-benzene (298.75 mg, 1.14 mmol) and 1,1-di(methyl)ethyl 2,5-diazaspiro[3.4]octane-2-carboxylate (290.41 mg, 1.37 mmol) were dissolved in toluene (7.60 mL), and tris(dibenzylideneacetone)dipalladium(0) (52.20 mg, 57.00 μmol), ([1,1'-binaphthalene]-2,2'-diyl)bis(diphenylphosphane) (70.98 mg, 114.00 μmol), and cesium carbonate (1.11 g, 3.42 mmol) were added, and the reaction mixture was stirred at 100°C for 48 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel, ethyl acetate:hexane) to obtain tert-butyl 5-(2,5-dimethoxy-4-nitrophenyl)-2,5-diazaspiro[3.4]octane-2-carboxylate (255 mg, 56.85%) as a yellow solid.

[0631] LC / MS ESI (+): 394 (M+1)

[0632] 1H-NMR (500 MHz, DMSO-D6) δ 7.56 (s, 1H), 6.67 (s, 1H), 4.30 (d, J = 8.9 Hz, 2H), 3.83 (s, 3H), 3.77 (d, J = 10.4 Hz, 5H), 3.60 (s, 2H), 2.19 (s, 2H), 1.81 (q, J = 6.5 Hz, 2H), 1.39 (s, 9H)

[0633]

[0634] (b) Synthesis of tert-butyl 5-(4-amino-2,5-dimethoxyphenyl)-2,5-diazaspiro[3.4]octane-2-carboxylate

[0635] 1,1-Di(methyl)ethyl 5-(2,5-di(methoxy)-4-nitro-phenyl)-2,5-diazaspiro[3.4]octane-2-carboxylate (253 mg, 643.06 μmol) was dissolved in ethanol (5.05 mL) and water (1.26 mL). Iron (179.56 mg, 3.22 mmol) and ammonium chloride (171.99 mg, 3.22 mmol, 112.41 μL) were added, and the reaction mixture was stirred at 70°C for 1 hour. The reaction mixture was cooled to room temperature, filtered through Celite, and saturated sodium bicarbonate was added to the reaction mixture, followed by extraction with dichloromethane. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel, dichloromethane) to obtain tert-butyl 5-(4-amino-2,5-dimethoxyphenyl)-2,5-diazaspiro[3.4]octane-2-carboxylate (195 mg, 83.43%) as an off-white solid.

[0636] LC / MS ESI (+): 394 (M+1)

[0637] 1H-NMR (500 MHz, DMSO-D6) δ 7.56 (s, 1H), 6.67 (s, 1H), 4.30 (d, J = 8.9 Hz, 2H), 3.83 (s, 3H), 3.77 (d, J = 10.4 Hz, 5H), 3.60 (s, 2H), 2.19 (s, 2H), 1.81 (q, J = 6.5 Hz, 2H), 1.39 (s, 9H)

[0638]

[0639] (c) Synthesis of tert-butyl 5-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,5-diazaspiro[3.4]octane-2-carboxylate

[0640] 1,1-Di(methyl)ethyl 5-(4-azanyl-2,5-di(methoxy)phenyl)-2,5-diazaspiro[3.4]octane-2-carboxylate (150 mg, 412.71 μmol) and 5-(2-chlorolanyl-5-fluoranyl-pyrimidin-4-yl)-1-methyl-pyrrolo[2,3-b]pyridine (119.25 mg, 453.98 μmol) were dissolved in toluene (4.13 mL), and palladium(II) acetate (9.27 mg, 41.27 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (47.76 mg, 82.54 μmol), potassium carbonate (114.08 mg, 825.42 μmol, 49.82 μL) was added, and the reaction mixture was stirred at 120°C for 15 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:water) to obtain tert-butyl 5-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,5-diazaspiro[3.4]octane-2-carboxylate (82 mg, 33.70%) as a yellow solid.

[0641] LC / MS ESI (+): 590 (M+1)

[0642] 1H-NMR (500 MHz, DMSO-D6) δ 8.98 (s, 1H), 8.67 (d, J = 0.9 Hz, 1H), 8.61 (d, J = 3.7 Hz, 1H), 8.19 (s, 1H), 8.04 (s, 1H), 7.65 (d, J = 3.4 Hz, 1H), 6.85 (s, 1H), 6.62 (d, J = 3.5 Hz, 1H), 3.92 (d, J = 8.6 Hz, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H), 3.63 (d, J = 7.3 Hz, 2H), 3.28 (t, J = 6.5 Hz, 2H), 2.17 (t, J = 7.0 Hz, 2H), 1.82 (q, J = 6.7 Hz, 2H), 1.32 (d, J = 14.8 Hz, 9H)

[0643]

[0644] Example 54: Synthesis of N-(2,5-dimethoxy-4-(2,5-diazaspiro[3.4]octan-5-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 54)

[0645]

[0646]

[0647] tert-Butyl 5-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,5-diazaspiro[3.4]octane-2-carboxylate (78 mg, 132.28 μmol) was dissolved in 1,4-dioxane (1.32 mL), 4 M hydrogen chloride solution (48.23 mg, 1.32 mmol, 0.33 mL) was added dropwise, and the reaction mixture was stirred at 25°C for 15 h under an argon stream. The reaction mixture was neutralized with 1 N sodium hydroxide solution and extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel, dichloromethane:methanol) to obtain N-(2,5-dimethoxy-4-(2,5-diazaspiro[3.4]octan-5-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (47 mg, 72.58%) as a yellow solid.

[0648] LC / MS ESI (+): 490 (M+1)

[0649] 1H-NMR (500 MHz, DMSO-D6) δ 8.98 (d, J = 1.7 Hz, 1H), 8.67 (d, J = 1.1 Hz, 1H), 8.61 (d, J = 3.5 Hz, 1H), 8.20 (s, 1H), 8.02 (s, 1H), 7.65 (d, J = 3.4 Hz, 1H), 6.91 (s, 1H), 6.63 (d, J = 3.5 Hz, 1H), 5.76 (s, 1H), 3.88-3.85 (m, 3H), 3.82 (s, 3H), 3.76 (d, J = 6.9 Hz, 3H), 3.55 (d, J = 8.4 Hz, 2H), 3.23 (t, J = 6.6 Hz, 2H), 3.13 (d, J = 8.3 Hz, 2H), 2.21 (t, J = 7.1 Hz, 2H), 1.83-1.78 (m, 2H)

[0650]

[0651] Example 55: Synthesis of 2-((4-(4-acetylpiperazin-1-yl)-2,5-dimethoxyphenyl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidine-5-carbonitrile (Compound 55)

[0652]

[0653]

[0654] (a) Synthesis of 2-chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidine-5-carbonitrile

[0655] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (30 mg, 116.22 μmol) and 2,4-dichloropyrimidine-5-carbonitrile (40.44 mg, 232.45 μmol) were dissolved in 1,4-dioxane (570.94 μL) / H2O (ultrapure water, 190.31 μL), tetrakis(triphenylphosphine)palladium(0) (6.72 mg, 5.81 μmol) and sodium bicarbonate (19.53 mg, 232.45 μmol) were added, and the reaction mixture was stirred at 90°C for 3 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel) to obtain 2-chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidine-5-carbonitrile (3 mg, 9.57%) as a gray solid.

[0656] LC / MS ESI (+): 270 / 272 (M+1)

[0657]

[0658] (b) Synthesis of 2-((4-(4-acetylpiperazin-1-yl)-2,5-dimethoxyphenyl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidine-5-carbonitrile

[0659] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (4.66 mg, 16.69 μmol) and 2-chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidine-5-carbonitrile (3.0 mg, 11.12 μmol) were dissolved in toluene (109.90 μL), palladium(II) acetate (249.74 μg, 1.11 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.29 mg, 2.22 μmol), and potassium carbonate (3.07 mg, 22.25 μmol) were added, and the reaction mixture was stirred at 120°C for 30 minutes under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel) to give 2-((4-(4-acetylpiperazin-1-yl)-2,5-dimethoxyphenyl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidine-5-carbonitrile (4 mg, 69.89%) as a yellow solid.

[0660] LC / MS ESI (+): 513 (M+1)

[0661] 1H-NMR (500 MHz, DMSO-D6) δ 8.83 (s, 2H), 8.56 (d, J = 1.7 Hz, 1H), 7.67 (d, J = 3.4 Hz, 1H), 7.64-7.60 (m, 1H), 7.56 (dd, J = 7.2, 3.1 Hz, 1H), 6.66 (s, 2H), 3.88 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 3.58 (d, J = 4.1 Hz, 4H), 2.98 (dt, J = 32.6, 4.6 Hz, 4H), 2.04 (s, 3H)

[0662]

[0663] Examples 56-1 and 56-2: Synthesis of 6-(2-((4-(4-acetylpiperazin-1-yl)-2,5-dimethoxyphenyl)amino)-5-methylpyrimidin-4-yl)quinolin-2(1H)-one and 1-(4-(4-((4-(2-hydroxyquinolin-6-yl)-5-methylpyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compounds 56-1 and 56-2)

[0664]

[0665]

[0666] (a) Synthesis of 6-(2-chloro-5-methylpyrimidin-4-yl)quinolin-2(1H)-one

[0667] 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2(1H)-one (20 mg, 73.77 μmol) and 2,4-dichloro-5-methylpyrimidine (14.43 mg, 88.52 μmol) were dissolved in 1,4-dioxane (354.60 μL) / H2O (ultrapure water, 118.20 μL). Tetrakis(triphenylphosphine)palladium(0) (4.26 mg, 3.69 μmol) and sodium bicarbonate (18.59 mg, 221.31 μmol) were added, and the reaction mixture was stirred at 100°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel) to obtain 6-(2-chloro-5-methylpyrimidin-4-yl)quinolin-2(1H)-one (15 mg, 74.84%) as a white solid.

[0668] LC / MS ESI (+): 272 / 274 (M+1)

[0669]

[0670] (b) Synthesis of 6-(2-((4-(4-acetylpiperazin-1-yl)-2,5-dimethoxyphenyl)amino)-5-methylpyrimidin-4-yl)quinolin-2(1H)-one and 1-(4-(4-((4-(2-hydroxyquinolin-6-yl)-5-methylpyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0671] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (14 mg, 50.12 μmol) and 6-(2-chloro-5-methylpyrimidin-4-yl)quinolin-2(1H)-one (13.62 mg, 50.12 μmol) were dissolved in toluene (501.19 μL), palladium(II) acetate (1.13 mg, 5.01 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.80 mg, 10.02 μmol), and potassium carbonate (13.85 mg, 100.24 μmol) were added, and the reaction mixture was stirred at 120°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel) to obtain 6-(2-((4-(4-acetylpiperazin-1-yl)-2,5-dimethoxyphenyl)amino)-5-methylpyrimidin-4-yl)quinolin-2(1H)-one and 1-(4-(4-((4-(2-hydroxyquinolin-6-yl)-5-methylpyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (15 mg, 56.17%) as a yellow solid.

[0672] LC / MS ESI (+): 515 (M+1)

[0673] 1H-NMR (500 MHz, DMSO-D6) δ 11.93 (s, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 8.08 (d, J = 1.8 Hz, 1H), 8.00 (d, J = 9.6 Hz, 1H), 7.90 (dd, J = 8.6, 2.0 Hz, 1H), 7.82 (s, 1H), 7.40 (d, J = 8.6 Hz, 1H), 6.64 (s, 1H), 6.56 (d, J = 9.6 Hz, 1H), 3.82 (d, J = 5.8 Hz, 3H), 3.73 (s, 3H), 3.56 (dd, J = 10.2, 6.8 Hz, 4H), 2.92 (dt, J = 32.5, 4.9 Hz, 4H), 2.29 (s, 3H), 2.03 (s, 3H)

[0674]

[0675] Example 57: Synthesis of 1-(4-(4-((5-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 57)

[0676]

[0677]

[0678] (a) Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine

[0679] (1-Methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (30 mg, 197.78 μmol) and 2,4-dichloro-5-fluoropyrimidine (36.32 mg, 217.55 μmol) were dissolved in tetrahydrofuran (659.29 μL) / H2O (ultrapure water, 329.59 μL), tetrakis(triphenylphosphine)palladium(0) (11.43 mg, 9.89 μmol) and potassium carbonate (54.67 mg, 395.55 μmol) were added, and the reaction mixture was stirred at 110°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and the mixture was extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel) to obtain 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (48 mg, 92.05%) as a white solid.

[0680] LC / MS ESI (+): 264 / 266 (M+1)

[0681] 1H-NMR (500 MHz, DMSO-D6) δ 9.17 (t, J = 1.0 Hz, 1H), 9.01 (d, J = 3.2 Hz, 1H), 8.94-8.94 (m, 1H), 8.37 (s, 1H), 4.13 (s, 3H)

[0682]

[0683] (b) Synthesis of 1-(4-(4-((5-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0684] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (17 mg, 60.86 μmol) and 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (16.05 mg, 60.86 μmol) were dissolved in toluene (398.38 μL), palladium(II) acetate (1.37 mg, 6.09 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.04 mg, 12.17 μmol), and potassium carbonate (16.82 mg, 121.72 μmol) were added, and the reaction mixture was stirred at 120°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine(NH2) silica gel) to obtain 1-(4-(4-((5-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (26 mg, 83.72%) as a yellow solid.

[0685] LC / MS ESI (+): 507 (M+1)

[0686] 1H-NMR (500 MHz, DMSO-D6) δ 9.20 (t, J = 1.0 Hz, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 3.4 Hz, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 7.77 (s, 1H), 6.66 (s, 1H), 4.12 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.58 (dd, J = 10.2, 6.4 Hz, 4H), 2.96 (dt, J = 32.8, 4.9 Hz, 4H), 2.04 (s, 3H)

[0687]

[0688] Example 58: Synthesis of 1-(4-(2,5-dimethoxy-4-((5-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 58)

[0689]

[0690]

[0691] 1-(4-(4-Amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (10.8 mg, 38.66 μmol) and 5-(2-chloro-5-methylpyrimidin-4-yl)-1-methyl-1H-benzo[d]imidazole (10.0 mg, 38.66 μmol) were dissolved in toluene (257.76 μL), palladium(II) acetate (868.03 μg, 3.87 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.47 mg, 7.73 μmol), and potassium carbonate (10.69 mg, 77.33 μmol) were added, and the reaction mixture was stirred at 120°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine(NH2) silica gel) to obtain 1-(4-(2,5-dimethoxy-4-((5-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (16 mg, 81.00%) as a yellow solid.

[0692] LC / MS ESI (+): 502 (M+1)

[0693] 1H-NMR (500 MHz, DMSO-D6) δ 8.38 (s, 1H), 8.28 (s, 1H), 8.18 (s, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 7.80 (s, 1H), 7.68 (s, 1H), 6.65 (s, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 3.74 (s, 3H), 3.56 (dd, J = 10.2, 6.9 Hz, 4H), 2.92 (dt, J = 32.8, 4.9 Hz, 4H), 2.30 (s, 3H), 2.03 (s, 3H)

[0694]

[0695] Example 59: Synthesis of 1-(4-(4-((5-fluoro-4-(1,5-naphthyridin-3-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 59)

[0696]

[0697]

[0698] (a) Synthesis of 3-(2-chloro-5-fluoropyrimidin-4-yl)-1,5-naphthyridine

[0699] 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,5-naphthyridine (30 mg, 117.14 μmol) and 2,4-dichloro-5-fluoropyrimidine (21.51 mg, 128.85 μmol) were dissolved in tetrahydrofuran (381.23 μL) / H2O (ultrapure water, 190.33 μL), tetrakis(triphenylphosphine)palladium(0) (6.77 mg, 5.86 μmol) and potassium carbonate (32.38 mg, 234.28 μmol) were added, and the reaction mixture was stirred at 110°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and the mixture was extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure water)) to obtain 3-(2-chloro-5-fluoropyrimidin-4-yl)-1,5-naphthyridine (21.6 mg, 69.92%) as a white solid.

[0700] LC / MS ESI (+): 261 (M+1) / 263

[0701] 1H-NMR (500 MHz, DMSO-D6) δ 9.48-9.59 (1H), 9.10-9.20 (2H), 8.96-9.03 (1H), 8.53-8.62 (1H), 7.91-8.00 (1H)

[0702]

[0703] (b) Synthesis of 1-(4-(4-((5-fluoro-4-(1,5-naphthyridin-3-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0704] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (17.04 mg, 61.00 μmol) and 3-(2-chloro-5-fluoropyrimidin-4-yl)-1,5-naphthyridine (15.9 mg, 61.00 μmol) were dissolved in toluene (297.64 μL), palladium(II) acetate (1.37 mg, 6.10 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.06 mg, 12.20 μmol), and potassium carbonate (16.86 mg, 122.00 μmol) were added, and the reaction mixture was stirred at 120°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure)) to obtain 1-(4-(4-((5-fluoro-4-(1,5-naphthyridin-3-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (22.10 mg, 71.87%) as an orange solid.

[0705] LC / MS ESI (+): 252, 504 (M+1)

[0706] 1H-NMR (500 MHz, DMSO-D6) δ 9.58 (d, J = 2.0 Hz, 1H), 9.12 (dd, J = 4.1, 1.7 Hz, 1H), 8.98 (d, J = 1.1 Hz, 1H), 8.71 (d, J = 3.2 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.46 (s, 1H), 7.90 (q, J = 4.2 Hz, 1H), 7.74 (s, 1H), 6.67 (s, 1H), 3.81 (d, J = 2.3 Hz, 6H), 3.58 (dd, J = 10.2, 6.4 Hz, 4H), 2.96 (dt, J = 33.0, 4.9 Hz, 4H), 2.04 (s, 3H)

[0707]

[0708] Example 60: Synthesis of 1-(4-(4-((5-fluoro-4-(8-fluoroquinolin-3-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 60)

[0709]

[0710]

[0711] (a) Synthesis of 3-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoroquinoline

[0712] (8-Fluoroquinolin-3-yl)boronic acid (50 mg, 261.83 μmol) and 2,4-dichloro-5-fluoropyrimidine (48.09 mg, 288.01 μmol) were dissolved in tetrahydrofuran (852.11 μL) / H2O (ultrapure water, 425.42 μL). Tetrakis(triphenylphosphine)palladium(0) (15.13 mg, 13.09 μmol) and potassium carbonate (72.37 mg, 523.65 μmol) were added, and the reaction mixture was stirred at 100°C for 4 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure water)) to obtain 3-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoroquinoline (35.3 mg, 48.56%) as a white solid.

[0713] LC / MS ESI (+): 278 (M+1) / 280

[0714]

[0715] (b) Synthesis of 1-(4-(4-((5-fluoro-4-(8-fluoroquinolin-3-3yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0716] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (30 mg, 107.40 μmol) and 3-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoroquinoline (30.18 mg, 108.05 μmol) were dissolved in toluene (527.19 μL), palladium(II) acetate (2.43 mg, 10.80 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12.50 mg, 21.61 μmol), and potassium carbonate (29.87 mg, 216.09 μmol) were added, and the reaction mixture was stirred at 120°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure)) to obtain 1-(4-(4-((5-fluoro-4-(8-fluoroquinolin-3-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (42.90 mg, 76.02%) as an orange solid.

[0717] LC / MS ESI (+): 261, 521 (M+1)

[0718] 1H-NMR (500 MHz, DMSO-D6) δ 9.51 (d, J = 1.2 Hz, 1H), 9.07 (s, 1H), 8.70 (d, J = 3.1 Hz, 1H), 8.42 (s, 1H), 8.02-8.00 (m, 1H), 7.75-7.70 (m, 3H), 6.67 (s, 1H), 3.80 (d, J = 7.0 Hz, 6H), 3.58 (dd, J = 10.3, 6.5 Hz, 4H), 2.96 (dt, J = 32.8, 4.9 Hz, 4H), 2.04 (s, 3H)

[0719]

[0720] Example 61: Synthesis of 1-(4-(4-((5-fluoro-4-(pyrido[2,3-b]pyrazin-7-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 61)

[0721]

[0722]

[0723] (a) Synthesis of 7-(2-chloro-5-fluoropyrimidin-4-yl)pyrido[2,3-b]pyrazine

[0724] 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrido[2,3-b]pyrazine (50 mg, 194.48 μmol) and 2,4-dichloro-5-fluoropyrimidine (35.72 mg, 213.93 μmol) were dissolved in tetrahydrofuran (632.93 μL) / H2O (ultrapure water, 315.99 μL), tetrakis(triphenylphosphine)palladium(0) ((11.24 mg, 9.72 μmol) and potassium carbonate (53.76 mg, 388.96 μmol) were added, and the reaction mixture was stirred at 100°C for 4 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract Washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure water)) to obtain 7-(2-chloro-5-fluoropyrimidin-4-yl)pyrido[2,3-b]pyrazine (34.00 mg, 63.36%) as a white solid.

[0725] LC / MS ESI (+): 262 (M+1) / 264

[0726] 1H-NMR (500 MHz, DMSO-D6) δ 9.68 (d, J = 2.3 Hz, 1H), 9.28 (d, J = 1.7 Hz, 1H), 9.21 (d, J = 1.7 Hz, 1H), 9.16 (d, J = 2.8 Hz, 1H), 9.09 (q, J = 1.1 Hz, 1H)

[0727]

[0728] (b) Synthesis of 1-(4-(4-((5-fluoro-4-(pyrido[2,3-b]pyrazin-7-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0729] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (30.53 mg, 109.31 μmol) and 7-(2-chloro-5-fluoropyrimidin-4-yl)pyrido[2,3-b]pyrazine (28.6 mg, 109.31 μmol) were dissolved in toluene (1.07 mL), palladium(II) acetate (2.45 mg, 10.93 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12.65 mg, 21.86 μmol), and potassium carbonate (30.22 mg, 218.62 μmol) were added, and the reaction mixture was stirred at 120°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure)) to obtain 1-(4-(4-((5-fluoro-4-(pyrido[2,3-b]pyrazin-7-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (39.10 mg, 70.75%) as a yellow solid.

[0730] LC / MS ESI (+): 505 (M+1)

[0731] 1H-NMR (500 MHz, DMSO-D6) δ 9.74 (d, J = 2.3 Hz, 1H), 9.24 (d, J = 1.8 Hz, 1H), 9.17 (d, J = 1.8 Hz, 1H), 9.08 (d, J = 2.3 Hz, 1H), 8.74 (d, J = 3.1 Hz, 1H), 8.51 (s, 1H), 7.72 (s, 1H), 6.67 (s, 1H), 3.81 (d, J = 1.8 Hz, 6H), 3.58 (dd, J = 10.2, 6.2 Hz, 4H), 2.96 (dt, J = 33.1, 4.9 Hz, 4H), 2.04 (s, 3H)

[0732]

[0733] Example 62: Synthesis of 1-(4-(2,5-dimethoxy-4-((5-methyl-4-(quinoxalin-6-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 62)

[0734]

[0735]

[0736] (a) Synthesis of 6-(2-chloro-5-methylpyrimidin-4-yl)quinoxaline

[0737] 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline (50 mg, 195.23 μmol, 44.52 μL) and 2,4-dichloro-5-methylpyrimidine (35.01 mg, 214.75 μmol) were dissolved in tetrahydrofuran (588.88 μL) / H2O (ultrapure water, 294.00 μL), tetrakis(triphenylphosphine)palladium(0) (11.28 mg, 9.76 μmol) and potassium carbonate (53.97 mg, 390.46 μmol) were added, and the reaction mixture was stirred at 110°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and the mixture was extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure water)) to obtain 6-(2-chloro-5-methylpyrimidin-4-yl)quinoxaline (34.50 mg, 67.42%) as a yellow solid.

[0738] LC / MS ESI (+): 257 (M+1) / 259

[0739] 1H-NMR (500 MHz, DMSO-D6) δ 9.06 (s, 2H), 8.82 (s, 1H), 8.42 (d, J = 1.8 Hz, 1H), 8.26 (d, J = 8.6 Hz, 1H), 8.15 (dd, J = 8.7, 2.0 Hz, 1H), 2.44 (s, 3H)

[0740]

[0741] (b) Synthesis of 1-(4-(2,5-dimethoxy-4-((5-methyl-4-(quinoxalin-6-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one

[0742] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (21.76 mg, 77.91 μmol) and 6-(2-chloro-5-methylpyrimidin-4-yl)quinoxaline (20 mg, 77.91 μmol) were dissolved in toluene (380.17 μL), palladium(II) acetate (1.75 mg, 7.79 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9.02 mg, 15.58 μmol), and potassium carbonate (21.54 mg, 155.83 μmol) were added, and the reaction mixture was stirred at 120°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure)) to obtain 1-(4-(2,5-dimethoxy-4-((5-methyl-4-(quinoxalin-6-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (24.1 mg, 44.04%) as a yellow solid.

[0743] LC / MS ESI (+): 500 (M+1)

[0744] 1H-NMR (500 MHz, DMSO-D6) δ 9.03 (t, J = 2.1 Hz, 2H), 8.48 (s, 1H), 8.43 (d, J = 1.2 Hz, 1H), 8.23 ​​(s, 2H), 8.01 (d, J = 30.0 Hz, 2H), 6.65 (s, 1H), 3.82 (s, 3H), 3.73 (s, 3H), 3.56 (dd, J = 10.4, 6.6 Hz, 4H), 2.92 (dt, J = 32.7, 4.9 Hz, 4H), 2.33 (s, 3H), 2.03 (s, 3H)

[0745]

[0746] Example 63: Synthesis of 1-(4-(4-((4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-methylpyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 63)

[0747]

[0748]

[0749] (a) Synthesis of 5-(2-chloro-5-methylpyrimidin-4-yl)benzo[c][1,2,5]oxadiazole

[0750] 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole (50 mg, 202.38 μmol) and 2,4-dichloro-5-methylpyrimidine (36.29 mg, 222.62 μmol) were dissolved in tetrahydrofuran (641.24 μL) / H2O (ultrapure water, 320.14 μL). Tetrakis(triphenylphosphine)palladium(0) (11.69 mg, 10.12 μmol) and potassium carbonate (55.94 mg, 404.76 μmol) were added, and the reaction mixture was stirred at 110°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and the mixture was extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure water)) to obtain 5-(2-chloro-5-methylpyrimidin-4-yl)benzo[c][1,2,5]oxadiazole (39.10 mg, 73.43%) as a yellow solid.

[0751] LC / MS ESI (+): 247 (M+1) / 249

[0752] 11H-NMR (500 MHz, DMSO-D6) δ 8.85 (s, 1H), 8.45-8.44 (m, 1H), 8.23 ​​(dd, J = 9.4, 1.0 Hz, 1H), 7.83 (dd, J = 9.3, 1.4 Hz, 1H), 2.42 (s, 3H)

[0753]

[0754] (b) Synthesis of 1-(4-(4-((4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-methylpyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0755] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (11.33 mg, 40.54 μmol) and 5-(2-chloro-5-methylpyrimidin-4-yl)benzo[c][1,2,5]oxadiazole (10 mg, 40.54 μmol) were dissolved in toluene (400.54 μL), palladium(II) acetate (910.23 μg, 4.05 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.69 mg, 8.11 μmol), and potassium carbonate (11.21 mg, 81.09 μmol) were added, and the reaction mixture was stirred at 120°C for 1 hour under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure)) to obtain 1-(4-(4-((4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-methylpyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (6.4 mg, 31.71%) as a red solid.

[0756] LC / MS ESI (+): 245 / 490 (M+1)

[0757] 1H-NMR (500 MHz, DMSO-D6) δ 8.49 (s, 1H), 8.39 (t, J = 1.1 Hz, 1H), 8.19 (dd, J = 9.3, 1.1 Hz, 1H), 8.04 (s, 1H), 7.94-7.92 (m, 2H), 6.64 (s, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 3.56 (dd, J = 10.3, 6.3 Hz, 4H), 2.92 (dt, J = 32.7, 4.9 Hz, 4H), 2.30 (s, 3H), 2.03 (s, 3H)

[0758]

[0759] Example 64: Synthesis of tert-butyl 6-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Compound 64)

[0760]

[0761]

[0762] (a) Synthesis of tert-butyl 6-(2,5-dimethoxy-4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0763] 1-Bromo-2,5-dimethoxy-4-nitrobenzene (300 mg, 1.14 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (272.36 mg, 1.37 mmol) were dissolved in toluene (7.63 mL), and tris(dibenzylideneacetone)dipalladium(0) (52.42 mg, 57.24 μmol), ([1,1'-binaphthalene]-2,2'-diyl)bis(diphenylphosphane) (71.28 mg, 114.48 μmol), and cesium carbonate (1.12 g, 3.43 mmol) were added, and the reaction mixture was stirred at 100°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel, ethyl acetate:hexane) to obtain tert-butyl 6-(2,5-dimethoxy-4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (430 mg, 99.00%) as a yellow solid.

[0764] LC / MS ESI (+): 380 (M+1)

[0765] 1H-NMR (500 MHz, DMSO-D6) δ 7.43 (s, 1H), 5.93 (s, 1H), 4.28 (s, 4H), 4.02 (s, 4H), 3.85 (s, 3H), 3.73 (s, 3H), 1.37 (d, J = 8.4 Hz, 9H)

[0766]

[0767] (b) Synthesis of tert-butyl 6-(4-amino-2,5-dimethoxyphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0768] tert-Butyl 6-(2,5-dimethoxy-4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (428 mg, 1.13 mmol) was dissolved in ethanol (9.02 mL) and water (2.26 mL). Iron (314.99 mg, 5.64 mmol) and ammonium chloride (301.71 mg, 5.64 mmol, 197.20 μL) were added, and the reaction mixture was stirred at 70°C for 1 hour. The reaction mixture was cooled to room temperature, filtered through Celite, and saturated sodium bicarbonate was added to the reaction mixture, followed by extraction with dichloromethane. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel, ethyl acetate:hexane) to obtain tert-butyl 6-(4-amino-2,5-dimethoxyphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (342 mg, 86.76%) as a gray solid.

[0769] LC / MS ESI (+): 350 (M+1)

[0770] 1H-NMR (500 MHz, DMSO-D6) δ 6.31 (s, 1H), 5.98 (s, 1H), 4.15 (s, 2H), 3.96 (s, 4H), 3.76-3.59 (m, 10H), 1.37 (s, 9H)

[0771]

[0772] (c) Synthesis of tert-butyl 6-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0773] tert-Butyl 6-(4-amino-2,5-dimethoxyphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (180 mg, 515.13 μmol) and 5-(2-chlorolanyl-5-fluoranyl-pyrimidin-4-yl)-1-methyl-pyrrolo[2,3-b]pyridine (148.84 mg, 566.65 μmol) were dissolved in toluene (2.58 mL), and palladium(II) acetate (11.57 mg, 51.51 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (59.61 mg, 103.03 μmol) and potassium carbonate (142.39 mg, 1.03 mmol) were added, and the reaction was carried out under an argon stream. The mixture was stirred at 120°C for 4 hours. The reaction mixture was cooled to room temperature, H2O was added, and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:water) to obtain tert-butyl 6-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (150 mg, 50.59%) as a yellow solid.

[0774] LC / MS ESI (+): 576 (M+1)

[0775] 1H-NMR (500 MHz, DMSO-D6) δ 8.92 (s, 1H), 8.61 (s, 1H), 8.51 (d, J = 3.5 Hz, 1H), 8.13 (s, 1H), 7.64 (d, J = 3.5 Hz, 1H), 7.59 (s, 1H), 6.62 (d, J = 3.4 Hz, 1H), 6.13 (s, 1H), 3.98 (d, J = 27.1 Hz, 8H), 3.87 (s, 3H), 3.77 (s, 3H), 3.71 (s, 3H), 1.38 (s, 9H)

[0776]

[0777] Example 65: Synthesis of 1-(5-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,5-diazaspiro[3.4]octan-2-yl)ethan-1-one (Compound 65)

[0778]

[0779]

[0780] N-(2,5-dimethoxy-4-(2,5-diazaspiro[3.4]octan-5-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (7 mg, 14.30 μmol) was dissolved in dichloromethane (0.14 mL), and acetic acid (1.72 mg, 28.60 μmol, 1.64 μL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (10.87 mg, 28.60 μmol) and N,N-diisopropylethylamine (5.54 mg, 42.90 μmol, 7.47 μL) were added. The reaction mixture was stirred at 25°C for 1 hour under an argon stream. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:water) to obtain 1-(5-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino]-2,5-dimethoxyphenyl)-2,5-diazaspiro[3.4]octan-2-yl)ethan-1-one (5.9 mg, 77.62% yield) as a yellow solid.

[0781] LC / MS ESI (+): 532 (M+1)

[0782] 1H-NMR (500 MHz, DMSO-D6) δ 8.97 (t, J = 1.6 Hz, 1H), 8.67 (d, J = 1.1 Hz, 1H), 8.61 (d, J = 3.7 Hz, 1H), 8.21 (s, 1H), 8.03 (s, 1H), 7.65 (d, J = 3.5 Hz, 1H), 6.84 (s, 1H), 6.63 (d, J = 3.4 Hz, 1H), 4.14 (d, J = 8.7 Hz, 1H), 3.92 (d, J = 8.7 Hz, 1H), 3.88-3.85 (m, 4H), 3.80 (d, J = 5.8 Hz, 3H), 3.77 (s, 3H), 3.65 (d, J = 9.9 Hz, 1H), 3.32-3.29 (m, 2H), 2.23-2.14 (m, 2H), 1.86-1.81 (m, 2H), 1.70 (s, 3H)

[0783]

[0784] Example 66: Synthesis of N-(2,5-dimethoxy-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 66)

[0785]

[0786]

[0787] tert-Butyl 6-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (113 mg, 196.31 μmol) was dissolved in formic acid (1.31 mL), and the reaction mixture was stirred at 80°C for 30 min. The reaction mixture was cooled to room temperature, neutralized with 1 N sodium hydroxide solution, and filtered. The residue was purified by column chromatography (amine (NH2) silica gel, dichloromethane:methanol) to obtain N-(2,5-dimethoxy-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (40 mg, 42.85%) as a yellow solid.

[0788] LC / MS ESI (+): 476 (M+1)

[0789] 1H-NMR (500 MHz, DMSO-D6) δ 8.92 (s, 1H), 8.61 (s, 1H), 8.51 (d, J = 3.7 Hz, 1H), 8.12 (s, 1H), 7.64 (t, J = 3.5 Hz, 1H), 7.58 (d, J = 11.3 Hz, 1H), 6.62 (d, J = 3.5 Hz, 1H), 6.14 (s, 1H), 3.89-3.84 (m, 7H), 3.76 (d, J = 3.5 Hz, 3H), 3.71 (s, 3H), 3.66-3.59 (m, 4H)

[0790]

[0791] Example 67: Synthesis of 1-(6-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one (Compound 67)

[0792]

[0793]

[0794] N-(2,5-Dimethoxy-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (10 mg, 21.03 μmol) was dissolved in dichloromethane (0.21 mL), acetic acid (2.53 mg, 42.06 μmol, 2.41 μL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (15.99 mg, 42.06 μmol) and N,N-diisopropylethylamine (8.15 mg, 63.09 μmol, 10.99 μL) were added and the reaction mixture was stirred at 25°C for 30 minutes under an argon stream. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:water) to obtain 1-(6-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one (8.5 mg, 78.10%) as a yellow solid.

[0795] LC / MS ESI (+): 518 (M+1)

[0796] 1H-NMR (500 MHz, DMSO-D6) δ 8.92 (s, 1H), 8.61 (s, 1H), 8.52 (d, J = 3.7 Hz, 1H), 8.16-8.12 (m, 1H), 7.66-7.60 (m, 2H), 6.64-6.61 (m, 1H), 6.15 (s, 1H), 4.28 (d, J = 12.8 Hz, 2H), 4.01-3.94 (m, 6H), 3.89-3.86 (m, 3H), 3.79-3.75 (m, 3H), 3.71 (s, 3H), 1.77-1.73 (m, 3H)

[0797]

[0798] Example 68: Synthesis of N-(2,5-dimethoxy-4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 68)

[0799]

[0800]

[0801] N-(2,5-Dimethoxy-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (15 mg, 31.54 μmol) was dissolved in methanol (0.16 mL) and tetrahydrofuran (0.16 mL), paraformaldehyde (9.47 mg, 315.45 μmol, 8.75 μL) and acetic acid (18.94 mg, 315.45 μmol, 18.06 μL) were added, and the reaction mixture was stirred at 60°C for 50 minutes under an argon stream. Sodium triacetoxyborohydride (33.43 mg, 157.72 μmol) was added, and the reaction mixture was stirred at 25°C for 10 minutes. After completion of the reaction, the reaction mixture was purified by reverse-phase column chromatography (C18-silica gel, acetonitrile:water) to obtain N-(2,5-dimethoxy-4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (6.7 mg, 43.39%) as a yellow solid.

[0802] LC / MS ESI (+): 490 (M+1)

[0803] 1H-NMR (500 MHz, DMSO-D6) δ 8.92 (s, 1H), 8.61 (s, 1H), 8.51 (d, J = 3.7 Hz, 1H), 8.12 (s, 1H), 7.64 (d, J = 3.4 Hz, 1H), 7.58 (d, J = 11.9 Hz, 1H), 6.62 (d, J = 3.5 Hz, 1H), 6.13 (s, 1H), 3.91-3.84 (m, 8H), 3.76 (d, J = 9.0 Hz, 3H), 3.72-3.69 (m, 3H), 3.27 (s, 3H), 2.20 (s, 3H)

[0804]

[0805] Example 69: Synthesis of (3-methoxy-4-((4-thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (Compound 69)

[0806]

[0807]

[0808] (4-Amino-3-methoxyphenyl)(morpholino)methanone (9.54 mg, 40.37 μmol) and 6-(2-chloropyrimidin-4-yl)thiazolo[5,4-b]pyridine (10.04 mg, 40.37 μmol) were dissolved in toluene (398.83 μL), and palladium(II) acetate (906.37 μg, 4.04 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.67 mg, 8.07 μmol), and potassium carbonate (11.16 mg, 80.74 μmol) were added. The reaction mixture was stirred at 120°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure water)) to obtain (3-methoxy-4-((4-thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (4.9 mg, 26.86%) as a yellow solid.

[0809] LC / MS ESI (+): 449 (M+1), 897

[0810] 1H-NMR (500 MHz, DMSO-D6) δ 9.67 (s, 1H), 9.47 (d, J = 2.0 Hz, 1H), 9.19 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 5.2 Hz, 1H), 8.46 (s, 1H), 8.34 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 5.2 Hz, 1H), 7.12-7.08 (m, 2H), 3.92 (s, 3H), 3.62-3.54 (m, 8H)

[0811]

[0812] Example 70: Synthesis of (4-((5-fluoro-4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (Compound 70)

[0813]

[0814]

[0815] (4-Amino-3-methoxyphenyl)(morpholino)methanone (10.75 mg, 45.51 μmol) and 6-(2-chloro-5-fluoropyrimidin-4-yl)-3-methyl-3H-imidazo[4,5-b]pyridine (12 mg, 45.51 μmol) were dissolved in toluene (449.64 μL), palladium(II) acetate (1.02 mg, 4.55 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.27 mg, 9.10 μmol), and potassium carbonate (12.58 mg, 91.03 μmol) were added, and the reaction mixture was stirred at 120°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure)) to obtain (4-((5-fluoro-4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (17.5 mg, 81.47%) as a yellow solid.

[0816] LC / MS ESI (+): 464 (M+1)

[0817] 1H-NMR (500 MHz, DMSO-D6) δ 9.05 (s, 1H), 8.69-8.66 (m, 2H), 8.58 (s, 1H), 8.48 (s, 1H), 8.24 (d, J = 8.3 Hz, 1H), 7.11-7.06 (m, 2H), 3.91 (d, J = 1.2 Hz, 6H), 3.57 (d, J = 42.2 Hz, 8H)

[0818]

[0819] Example 71: Synthesis of (4-((5-fluoro-4-thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (Compound 71)

[0820]

[0821]

[0822] (4-Amino-3-methoxyphenyl)(morpholino)methanone (11.52 mg, 48.75 μmol) and 6-(2-chloro-5-fluoropyrimidin-4-yl)thiazolo[5,4-b]pyridine (13 mg, 48.75 μmol) were dissolved in toluene (481.59 μL), and palladium(II) acetate (1.09 mg, 4.87 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.64 mg, 9.75 μmol), and potassium carbonate (13.47 mg, 97.49 μmol) were added. The reaction mixture was stirred at 120°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure water)) to obtain (4-((5-fluoro-4-thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (8.4 mg, 36.55%) as a yellow solid.

[0823] LC / MS ESI (+): 467 (M+1), 934

[0824] 1H-NMR (500 MHz, DMSO-D6) δ 9.70 (s, 1H), 9.28 (d, J = 1.1 Hz, 1H), 9.00 (d, J = 1.4 Hz, 1H), 8.76 (d, J = 3.1 Hz, 1H), 8.61 (s, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.11-7.05 (m, 2H), 3.91 (s, 3H), 3.57 (d, J = 41.6 Hz, 8H)

[0825]

[0826] Example 72: Synthesis of (3-methoxy-4-((4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (Compound 72)

[0827]

[0828]

[0829] (4-Amino-3-methoxyphenyl)(morpholino)methanone (7.69 mg, 32.56 μmol) and 5-(2-chloropyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (8 mg, 32.56 μmol) were dissolved in toluene (321.71 μL), and palladium(II) acetate (731.10 μg, 3.26 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.77 mg, 6.51 μmol), and potassium carbonate (9.00 mg, 65.13 μmol) were added. The reaction mixture was stirred at 120°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure water)) to obtain (3-methoxy-4-((4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (12.9 mg, 88.03%) as a white solid.

[0830] LC / MS ESI (+): 446 (M+1), 891

[0831] 1H-NMR (500 MHz, DMSO-D6) δ 9.37 (d, J = 2.0 Hz, 1H), 9.02 (d, J = 2.0 Hz, 1H), 8.61 (d, J = 5.2 Hz, 1H), 8.40 (d, J = 8.1 Hz, 1H), 8.32 (d, J = 1.7 Hz, 2H), 7.63 (d, J = 5.2 Hz, 1H), 7.12-7.09 (m, 2H), 4.12 (s, 3H), 3.93 (s, 3H), 3.58 (d, J = 40.0 Hz, 8H)

[0832]

[0833] Example 73: Synthesis of (4-((5-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (Compound 73)

[0834]

[0835]

[0836] (4-Amino-3-methoxyphenyl)(morpholino)methanone (13.89 mg, 58.79 μmol) and 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (15.5 mg, 58.79 μmol) were dissolved in toluene (580.79 μL), palladium(II) acetate (1.32 mg, 5.88 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.80 mg, 11.76 μmol), and potassium carbonate (16.25 mg, 117.58 μmol) were added, and the reaction mixture was stirred at 120°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel, acetonitrile:H2O (ultrapure)) to obtain (4-((5-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (12.9 mg, 88.03%) as a yellow solid.

[0837] LC / MS ESI (+): 464 (M+1), 927

[0838] 1H-NMR (500 MHz, DMSO-D6) δ 9.22 (d, J = 1.8 Hz, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 3.4 Hz, 1H), 8.47 (s, 1H), 8.35 (s, 1H), 8.25 (d, J = 8.1 Hz, 1H), 7.11-7.06 (m, 2H), 4.12 (s, 3H), 3.91 (s, 3H), 3.57 (d, J = 41.9 Hz, 8H)

[0839]

[0840] Example 74: Synthesis of N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine (Compound 74)

[0841]

[0842]

[0843] 1-(4-Amino-2,5-dimethoxyphenyl)-N,N-dimethylazetidin-3-amine (10.0 mg, 39.79 μmol) and 6-(2-chloro-5-fluoropyrimidin-4-yl)-3-methyl-3H-imidazo[4,5-b]pyridine (10.49 mg, 39.79 μmol) were dissolved in toluene (301.27 μL), palladium(II) acetate (893.31 μg, 3.98 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.60 mg, 7.96 μmol), and potassium carbonate (11.00 mg, 79.58 μmol) were added, and the reaction mixture was stirred at 120°C for 3 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel) to obtain N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine (11 mg, 56.21%) as a yellow solid.

[0844] LC / MS ESI (+): 479 (M+1)

[0845] 1H-NMR (500 MHz, DMSO-D6) δ 9.02 (s, 1H), 8.63 (s, 1H), 8.56 (s, 1H), 8.55 (d, J = 3.5 Hz, 1H), 8.22 (s, 1H), 7.50 (s, 1H), 6.16 (s, 1H), 3.98-3.95 (m, 2H), 3.89 (s, 3H), 3.77 (s, 3H), 3.70 (s, 3H), 3.54-3.52 (m, 2H), 3.05 (t, J = 6.3 Hz, 1H), 2.08 (s, 6H)

[0846]

[0847] Example 75: Synthesis of N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine (Compound 75)

[0848]

[0849]

[0850] 1-(4-Amino-2,5-dimethoxyphenyl)-N,N-dimethylazetidin-3-amine (10.0 mg, 39.79 μmol) and 5-(2-chloropyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (9.77 mg, 39.79 μmol) were dissolved in toluene (301.26 μL), palladium(II) acetate (893.31 μg, 3.98 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.60 mg, 7.96 μmol), and potassium carbonate (11.00 mg, 79.58 μmol) were added, and the reaction mixture was stirred at 120°C for 3 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel) to give N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine (8 mg, 42.43%) as a yellow solid.

[0851] LC / MS ESI (+): 461 (M+1)

[0852] 1H-NMR (500 MHz, DMSO-D6) δ 9.32 (d, J = 2.0 Hz, 1H), 8.96 (d, J = 2.1 Hz, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.65 (s, 1H), 7.45 (d, J = 5.2 Hz, 1H), 6.18 (s, 1H), 4.11 (s, 3H), 3.99-3.96 (m, 2H), 3.79 (d, J = 6.7 Hz, 3H), 3.73 (s, 3H), 3.54 (t, J = 7.0 Hz, 2H), 3.06 (t, J = 6.3 Hz, 1H), 2.09 (s, 6H)

[0853]

[0854] Example 76: Synthesis of N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine (Compound 76)

[0855]

[0856]

[0857] 1-(4-Amino-2,5-dimethoxyphenyl)-N,N-dimethylazetidin-3-amine (10.0 mg, 39.79 μmol) and 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (10.49 mg, 39.79 μmol) were dissolved in toluene (301.27 μL), palladium(II) acetate (893.31 μg, 3.98 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.60 mg, 7.96 μmol), and potassium carbonate (11.00 mg, 79.58 μmol) were added, and the reaction mixture was stirred at 120°C for 3 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel) to obtain N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine (6 mg, 29.84%) as a yellow solid.

[0858] LC / MS ESI (+): 479 (M+1)

[0859] 1H-NMR (500 MHz, DMSO-D6) δ 9.17 (d, J = 2.0 Hz, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 3.5 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.23 ​​(s, 1H), 7.49 (s, 1H), 6.16 (s, 1H), 4.11 (s, 3H), 3.96 (t, J = 7.1 Hz, 2H), 3.77 (s, 3H), 3.70 (s, 3H), 3.55-3.52 (m, 2H), 3.05 (t, J = 6.3 Hz, 1H), 2.09 (s, 6H)

[0860]

[0861] Example 77: Synthesis of N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-4-(thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-amine (Compound 77)

[0862]

[0863]

[0864] 1-(4-Amino-2,5-dimethoxyphenyl)-N,N-dimethylazetidin-3-amine (10.0 mg, 39.79 μmol) and 6-(2-chloropyrimidin-4-yl)thiazolo[5,4-b]pyridine (9.90 mg, 39.79 μmol) were dissolved in toluene (301.26 μL), palladium(II) acetate (893.31 μg, 3.98 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.60 mg, 7.96 μmol), and potassium carbonate (11.00 mg, 79.58 μmol) were added, and the reaction mixture was stirred at 120°C for 3 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel) to give N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-4-(thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-amine (8 mg, 43.13%) as a yellow solid.

[0865] LC / MS ESI (+): 464 (M+1)

[0866] 1H-NMR (500 MHz, DMSO-D6) δ 9.65 (s, 1H), 9.43 (d, J = 2.0 Hz, 1H), 9.15 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 5.0 Hz, 1H), 8.20 (s, 1H), 7.62 (s, 1H), 7.58 (d, J = 5.2 Hz, 1H), 6.18 (s, 1H), 3.99-3.96 (m, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 3.55-3.53 (m, 2H), 3.08-3.03 (m, 1H), 2.09 (s, 6H)

[0867]

[0868] Example 78: Synthesis of N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-amine (Compound 78)

[0869]

[0870]

[0871] 1-(4-Amino-2,5-dimethoxyphenyl)-N,N-dimethylazetidin-3-amine (10.0 mg, 39.79 μmol) and 6-(2-chloro-5-fluoropyrimidin-4-yl)thiazolo[5,4-b]pyridine (10.61 mg, 39.79 μmol) were dissolved in toluene (301.27 μL), palladium(II) acetate (893.31 μg, 3.98 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.60 mg, 7.96 μmol), and potassium carbonate (11.00 mg, 79.58 μmol) were added, and the reaction mixture was stirred at 120°C for 3 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine(NH2) silica gel) to give N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-amine (4 mg, 20.43%) as a yellow solid.

[0872] LC / MS ESI (+): 482 (M+1)

[0873] 1H-NMR (500 MHz, DMSO-D6) δ 9.68 (s, 1H), 9.25 (d, J = 1.7 Hz, 1H), 8.97 (d, J = 1.8 Hz, 1H), 8.62 (d, J = 3.2 Hz, 1H), 8.35 (s, 1H), 7.46 (s, 1H), 6.16 (s, 1H), 3.98-3.95 (m, 2H), 3.77 (s, 3H), 3.70 (s, 3H), 3.53 (t, J = 7.0 Hz, 2H), 3.08-3.03 (m, 1H), 2.09 (s, 6H)

[0874]

[0875] Example 79: Synthesis of N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(8-fluoroquinolin-3-yl)pyrimidin-2-amine (Compound 79)

[0876]

[0877]

[0878] 1-(4-Amino-2,5-dimethoxyphenyl)-N,N-dimethylazetidin-3-amine (10.0 mg, 39.79 μmol) and 3-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoroquinoline (11.05 mg, 39.79 μmol) were dissolved in toluene (301.26 μL), palladium(II) acetate (893.31 μg, 3.98 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.60 mg, 7.96 μmol), and potassium carbonate (11.00 mg, 79.58 μmol) were added, and the reaction mixture was stirred at 120°C for 3 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel) to give N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(8-fluoroquinolin-3-yl)pyrimidin-2-amine (7 mg, 35.30%) as a yellow solid.

[0879] LC / MS ESI (+): 493 (M+1)

[0880] 1H-NMR (500 MHz, DMSO-D6) δ 9.49 (d, J = 1.4 Hz, 1H), 9.04 (s, 1H), 8.64 (d, J = 3.2 Hz, 1H), 8.36 (s, 1H), 8.01-7.99 (m, 1H), 7.74-7.68 (m, 2H), 7.47 (s, 1H), 6.17 (s, 1H), 3.98-3.95 (m, 2H), 3.77 (s, 3H), 3.70 (s, 3H), 3.54 (t, J = 7.0 Hz, 2H), 3.06 (q, J = 6.3 Hz, 1H), 2.09 (s, 6H)

[0881]

[0882] Example 80: Synthesis of N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-4-(quinoxalin-6-yl)pyrimidin-2-amine (Compound 80)

[0883]

[0884]

[0885] 1-(4-Amino-2,5-dimethoxyphenyl)-N,N-dimethylazetidin-3-amine (10.0 mg, 39.79 μmol) and 6-(2-chloropyrimidin-4-yl)quinoxaline (9.66 mg, 39.79 μmol) were dissolved in toluene (301.26 μL), palladium(II) acetate (893.31 μg, 3.98 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.60 mg, 7.96 μmol), and potassium carbonate (11.00 mg, 79.58 μmol) were added, and the reaction mixture was stirred at 120°C for 3 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel) to give N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-4-(quinoxalin-6-yl)pyrimidin-2-amine (7 mg, 38.09%) as a yellow solid.

[0886] LC / MS ESI (+): 458 (M+1)

[0887] 1H-NMR (500 MHz, DMSO-D6) δ 9.03 (d, J = 1.7 Hz, 1H), 9.01 (d, J = 1.7 Hz, 1H), 8.89 (d, J = 1.8 Hz, 1H), 8.60 (dd, J = 8.8, 1.9 Hz, 1H), 8.55 (d, J = 5.0 Hz, 1H), 8.23 ​​(d, J = 8.9 Hz, 1H), 8.16 (s, 1H), 7.70 (s, 1H), 7.60 (d, J = 5.2 Hz, 1H), 6.19 (s, 1H), 3.99-3.96 (m, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.56-3.53 (m, 2H), 3.06 (t, J = 6.3 Hz, 1H), 2.09 (s, 6H)

[0888]

[0889] Example 81: Synthesis of N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-methyl-4-(quinoxalin-6-yl)pyrimidin-2-amine (Compound 81)

[0890]

[0891]

[0892] 1-(4-Amino-2,5-dimethoxyphenyl)-N,N-dimethylazetidin-3-amine (10.0 mg, 39.79 μmol) and 6-(2-chloro-5-methylpyrimidin-4-yl)quinoxaline (10.21 mg, 39.79 μmol) were dissolved in toluene (301.25 μL), palladium(II) acetate (893.31 μg, 3.98 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.60 mg, 7.96 μmol), and potassium carbonate (11.00 mg, 79.58 μmol) were added, and the reaction mixture was stirred at 120°C for 3 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2) silica gel) to give N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-methyl-4-(quinoxalin-6-yl)pyrimidin-2-amine (9 mg, 47.65%) as a yellow solid.

[0893] LC / MS ESI (+): 472 (M+1)

[0894] 1H-NMR (500 MHz, DMSO-D6) δ 9.03 (t, J = 2.2 Hz, 2H), 8.42 (s, 1H), 8.39 (d, J = 1.7 Hz, 1H), 8.23-8.18 (m, 2H), 7.91 (s, 1H), 7.75 (s, 1H), 6.15 (s, 1H), 3.93 (t, J = 7.1 Hz, 2H), 3.79 (s, 3H), 3.65 (s, 3H), 3.49 (t, J = 6.9 Hz, 2H), 3.04 (q, J = 6.3 Hz, 1H), 2.31 (s, 3H), 2.07 (s, 6H)

[0895]

[0896] Example 82: Synthesis of 1-(4-(4-((5-fluoro-4-methyl-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 82)

[0897]

[0898]

[0899] (a) Synthesis of 5-(2-chloro-5-fluoro-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine

[0900] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (28.52 mg, 110.50 μmol) and 2,4-dichloro-5-fluoro-6-methylpyrimidine (20 mg, 110.50 μmol) were dissolved in tetrahydrofuran (387.43 μL) / H2O (ultrapure water, 193.69 μL), tetrakis(triphenylphosphine)palladium(0) (12.77 mg, 11.05 μmol) and potassium carbonate (30.54 mg, 221.00 μmol) were added, and the reaction mixture was stirred at 80°C for 3 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel) to obtain 5-(2-chloro-5-fluoro-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (20.4 mg, 63.23%) as a yellow solid.

[0901] LC / MS ESI (+): 277 (M+1) / 279

[0902] 1H-NMR (500 MHz, DMSO-D6) δ 8.90 (t, J = 1.7 Hz, 1H), 8.63 (q, J = 1.0 Hz, 1H), 7.67 (d, J = 3.5 Hz, 1H), 6.67 (d, J = 3.5 Hz, 1H), 3.88 (s, 3H), 2.54 (d, J = 3.1 Hz, 3H)

[0903]

[0904] (b) Synthesis of 1-(4-(4-((5-fluoro-4-methyl-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0905] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (20 mg, 71.60 μmol) and 5-(2-chloro-5-fluoro-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (19.81 mg, 71.60 μmol) were dissolved in toluene (715.25 μL), palladium(II) acetate (1.61 mg, 7.16 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.29 mg, 14.32 μmol), and potassium carbonate (19.79 mg, 143.20 μmol) were added, and the reaction mixture was stirred at 120°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine(NH2) silica gel) to obtain 1-(4-(4-((5-fluoro-4-methyl-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (21.3 mg, 57.16%) as a yellow solid.

[0906] LC / MS ESI (+): 260 / 520 (M+1)

[0907] 1H-NMR (500 MHz, DMSO-D6) δ 8.93 (t, J = 1.6 Hz, 1H), 8.63 (t, J = 1.0 Hz, 1H), 8.04 (s, 1H), 7.96 (s, 1H), 7.64 (d, J = 3.4 Hz, 1H), 6.66 (s, 1H), 6.61 (d, J = 3.4 Hz, 1H), 3.88 (s, 3H), 3.82 (d, J = 5.0 Hz, 6H), 3.57 (dd, J = 10.3, 6.6 Hz, 4H), 2.94 (dt, J = 32.7, 4.9 Hz, 4H), 2.44 (d, J = 2.8 Hz, 3H), 2.04 (s, 3H)

[0908]

[0909] Example 83: Synthesis of 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)furo[3,2-d]pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 83)

[0910]

[0911]

[0912] (a) Synthesis of 2-chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)furo[3,2-d]pyrimidine

[0913] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (27.31 mg, 105.82 μmol) and 2,4-dichlorofuro[3,2-d]pyrimidine (20 mg, 105.82 μmol) were dissolved in tetrahydrofuran (352.75 μL) / H2O (ultrapure water, 176.35 μL), tetrakis(triphenylphosphine)palladium(0) (12.23 mg, 10.58 μmol) and potassium carbonate (29.25 mg, 211.64 μmol) were added, and the reaction mixture was stirred at 80°C for 3 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel) to obtain 2-chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)furo[3,2-d]pyrimidine (31.8 mg, 96.47%) as a white solid.

[0914] LC / MS ESI (+): 285 (M+1) / 287

[0915] 1H-NMR (500 MHz, DMSO-D6) δ 9.29 (d, J = 2.1 Hz, 1H), 8.97 (d, J = 2.1 Hz, 1H), 8.75 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 3.5 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 6.73 (d, J = 3.5 Hz, 1H), 3.92 (d, J = 14.7 Hz, 3H)

[0916]

[0917] (b) Synthesis of 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)furo[3,2-d]pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one

[0918] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (20 mg, 71.60 μmol) and 2-chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)furo[3,2-d]pyrimidine (20.38 mg, 71.60 μmol) were dissolved in toluene (715.25 μL), palladium(II) acetate (1.61 mg, 7.16 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.29 mg, 14.32 μmol), and potassium carbonate (19.79 mg, 143.20 μmol) were added, and the reaction mixture was stirred at 120°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine(NH2) silica gel) to obtain 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)furo[3,2-d]pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (25.7 mg, 67.95%) as a yellow solid.

[0919] LC / MS ESI (+): 264 / 528 (M+1)

[0920] 1H-NMR (500 MHz, DMSO-D6) δ 9.32 (d, J = 2.1 Hz, 1H), 8.98 (d, J = 2.1 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 8.15 (s, 1H), 7.94 (s, 1H), 7.67 (d, J = 3.5 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 6.68-6.68 (m, 2H), 3.90 (s, 3H), 3.85 (d, J = 7.2 Hz, 6H), 3.59 (dd, J = 10.2, 6.7) Hz, 4H), 2.96 (dt, J = 32.8, 5.0 Hz, 4H), 2.03 (d, J = 16.2 Hz, 3H)

[0921]

[0922] Example 84: Synthesis of 1-(4-(2,5-dimethoxy-4-((9-methyl-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-9H-purin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 84)

[0923]

[0924]

[0925] (a) Synthesis of 2-chloro-9-methyl-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-9H-purine

[0926] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (25.43 mg, 98.51 μmol) and 2,6-dichloro-9-methyl-9H-purine (20 mg, 98.51 μmol) were dissolved in tetrahydrofuran (328.38 μL) / H2O (ultrapure water, 164.16 μL), tetrakis(triphenylphosphine)palladium(0) (11.38 mg, 9.85 μmol) and potassium carbonate (27.23 mg, 197.02 μmol) were added, and the reaction mixture was stirred at 80°C for 3 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel) to obtain 2-chloro-9-methyl-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-9H-purine (20.2 mg, 67.67%) as a white solid.

[0927] LC / MS ESI (+): 299 (M+1) / 301

[0928] 1H-NMR (500 MHz, DMSO-D6) δ 9.67 (d, J = 2.0 Hz, 1H), 9.37 (d, J = 2.1 Hz, 1H), 8.67 (s, 1H), 7.65 (d, J = 3.4 Hz, 1H), 6.71 (d, J = 3.5 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H)

[0929]

[0930] (b) Synthesis of 1-(4-(2,5-dimethoxy-4-((9-methyl-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-9H-purin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one

[0931] 1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (20 mg, 71.60 μmol) and 2-chloro-9-methyl-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-9H-purine (21.39 mg, 71.60 μmol) were dissolved in toluene (715.25 μL), palladium(II) acetate (1.61 mg, 7.16 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.29 mg, 14.32 μmol), and potassium carbonate (19.79 mg, 143.20 μmol) were added, and the reaction mixture was stirred at 120°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine(NH2) silica gel) to obtain 1-(4-(2,5-dimethoxy-4-((9-methyl-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-9H-purin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (24.1 mg, 62.15%) as a yellow solid.

[0932] LC / MS ESI (+): 271 / 542 (M+1)

[0933] 1H-NMR (500 MHz, DMSO-D6) δ 9.71 (d, J = 2.0 Hz, 1H), 9.39 (d, J = 2.0 Hz, 1H), 8.38 (s, 1H), 8.30 (s, 1H), 7.92 (s, 1H), 7.62 (d, J = 3.5 Hz, 1H), 6.69-6.65 (m, 2H), 3.88 (d, J = 9.0 Hz, 9H), 3.78 (s, 3H), 3.59 (dd, J = 10.1, 7.0 Hz, 4H), 2.96 (dt, J = 32.8, 4.9 Hz, 4H), 2.05 (s, 3H)

[0934]

[0935] Example 85: Synthesis of 1-(4-(4-((4-cyclopropyl-5-fluoro-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 85)

[0936]

[0937]

[0938] (a) Synthesis of 5-(2-chloro-6-cyclopropyl-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine

[0939] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (24.94 mg, 96.60 μmol) and 2,4-dichloro-6-cyclopropyl-5-fluoropyrimidine (20 mg, 96.60 μmol) were dissolved in tetrahydrofuran (322.03 μL) / H2O (ultrapure water, 160.99 μL), tetrakis(triphenylphosphine)palladium(0) (11.16 mg, 9.66 μmol) and potassium carbonate (26.70 mg, 193.21 μmol) were added, and the reaction mixture was stirred at 80°C for 6 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18-silica gel) to obtain 5-(2-chloro-6-cyclopropyl-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (20.3 mg, 69.41%) as a yellow solid.

[0940] LC / MS ESI (+): 303 (M+1) / 305

[0941] 1H-NMR (500 MHz, DMSO-D6) δ 8.90 (t, J = 1.6 Hz, 1H), 8.62 (q, J = 1.0 Hz, 1H), 7.66 (d, J = 3.4 Hz, 1H), 6.67 (d, J = 3.5 Hz, 1H), 3.88 (s, 3H), 2.47-2.43 (m, 1H), 1.29-1.25 (m, 2H), 1.17-1.14 (m, 2H)

[0942]

[0943] (b) Synthesis of 1-(4-(4-((4-cyclopropyl-5-fluoro-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0944] 1-(4-(4-Amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (13.84 mg, 49.55 μmol) and 5-(2-chloro-6-cyclopropyl-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (15 mg, 49.55 μmol) were dissolved in toluene (494.98 μL), palladium(II) acetate (1.11 mg, 4.95 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.73 mg, 9.91 μmol), and potassium carbonate (13.70 mg, 99.10 μmol) were added, and the reaction mixture was stirred at 120°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine(NH2) silica gel) to obtain 1-(4-(4-((4-cyclopropyl-5-fluoro-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (14.3 mg, 52.90%) as a yellow solid.

[0945] LC / MS ESI (+): 273 / 546 (M+1)

[0946] 1H-NMR (500 MHz, DMSO-D6) δ 8.93 (t, J = 1.7 Hz, 1H), 8.63 (q, J = 1.0 Hz, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.64 (d, J = 3.5 Hz, 1H), 6.65 (s, 1H), 6.62 (d, J = 3.5 Hz, 1H), 3.88-3.82 (m, 9H), 3.57 (dd, J = 10.2, 6.8 Hz, 4H), 2.97-2.89 (m, 4H), 2.33-2.42 (1H), 2.03 (s, 3H), 1.18-1.16 (m, 4H)

[0947]

[0948] Example 86: Synthesis of 1-(4-(4-((5-fluoro-4-methoxy-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 86)

[0949]

[0950]

[0951] (a) Synthesis of 2,4-dichloro-5-fluoro-6-methoxypyrimidine

[0952] 2,4,6-Trichloro-5-fluoropyrimidine (100 mg, 496.49 μmol) was dissolved in tetrahydrofuran (4.87 mL) and cooled to 0°C. A 30% solution of sodium methoxide (89.41 mg, 496.49 μmol) was added and stirred at 0°C for 2 hours. H2O was added to the reaction mixture and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel) to obtain 2,4-dichloro-5-fluoro-6-methoxypyrimidine (20.3 mg, 69.41%) as a yellow solid.

[0953] LC / MS ESI (+): ND

[0954] 1H-NMR (500 MHz, DMSO-D6) δ 4.06 (s, 3H)

[0955]

[0956] (b) Synthesis of 5-(2-chloro-5-fluoro-6-methoxypyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine

[0957] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (26.21 mg, 101.53 μmol) and 2,4-dichloro-5-fluoro-6-methoxypyrimidine (20 mg, 101.53 μmol) were dissolved in tetrahydrofuran (338.44 μL) / H2O (ultrapure water, 169.19 μL), tetrakis(triphenylphosphine)palladium(0) (11.73 mg, 10.15 μmol) and potassium carbonate (28.06 mg, 203.05 μmol) were added, and the reaction mixture was stirred at 80°C for 10 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel) to obtain 5-(2-chloro-5-fluoro-6-methoxypyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (15.2 mg, 49.95%) as a yellow solid.

[0958] LC / MS ESI (+): 293 (M+1) / 295

[0959] 1H-NMR (500 MHz, DMSO-D6) δ 8.86 (t, J = 1.6 Hz, 1H), 8.57 (q, J = 1.0 Hz, 1H), 7.66 (d, J = 3.5 Hz, 1H), 6.66 (d, J = 3.4 Hz, 1H), 4.08 (s, 3H), 3.88 (s, 3H)

[0960]

[0961] (c) Synthesis of 1-(4-(4-((5-fluoro-4-methoxy-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one

[0962] 1-(4-(4-Amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (9.54 mg, 34.17 μmol) and 5-(2-chloro-5-fluoro-6-methoxypyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (10 mg, 34.17 μmol) were dissolved in toluene (341.30 μL), palladium(II) acetate (767.03 μg, 3.42 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.95 mg, 6.83 μmol), and potassium carbonate (9.44 mg, 68.33 μmol) were added, and the reaction mixture was stirred at 120°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine(NH2) silica gel) to obtain 1-(4-(4-((5-fluoro-4-methoxy-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (13.1 mg, 71.59%) as a yellow solid.

[0963] LC / MS ESI (+): 268 / 536 (M+1)

[0964] 1H-NMR (500 MHz, DMSO-D6) δ 8.90 (t, J = 1.5 Hz, 1H), 8.59 (d, J = 1.4 Hz, 1H), 8.05 (s, 1H), 7.90 (s, 1H), 7.63 (d, J = 3.5 Hz, 1H), 6.67 (s, 1H), 6.61 (d, J = 3.5 Hz, 1H), 4.04 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H), 3.57 (dd, J = 10.2, 6.6 Hz, 4H), 2.94 (dt, J = 32.8, 4.9 Hz, 4H), 2.04 (s, 3H)

[0965]

[0966] Example 87: Synthesis of 1-(4-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2-methoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 87)

[0967]

[0968]

[0969] (a) Synthesis of 1-(4-(2-methoxy-4-nitrophenyl)piperazin-1-yl)ethan-1-one

[0970] 1-Bromo-2-methoxy-4-nitrobenzene (100 mg, 430.98 μmol) and 1-(piperazin-1-yl)ethan-1-one (66.29 mg, 517.17 μmol) were dissolved in toluene (4.31 mL), and tris(dibenzylideneacetone)dipalladium (39.47 mg, 43.10 μmol), (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) (53.67 mg, 86.20 μmol), and cesium carbonate (280.84 mg, 861.95 μmol) were added, and the reaction mixture was stirred at 120°C for 15 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18-silica gel) to obtain 1-(4-(2-methoxy-4-nitrophenyl)piperazin-1-yl)ethan-1-one (144.3 mg, 92.59%) as a brown solid.

[0971] LC / MS ESI (+): 280 (M+1)

[0972] 1H-NMR (500 MHz, DMSO-D6) δ 7.84 (dd, J = 8.9, 2.6 Hz, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1H), 3.92 (s, 3H), 3.58 (t, J = 3.9 Hz, 4H), 3.17 (dt, J = 32.5, 5.1 Hz, 4H), 2.04 (s, 3H)

[0973]

[0974] (b) Synthesis of 1-(4-(4-amino-2-methoxyphenyl)piperazin-1-yl)ethan-1-one

[0975] 1-(4-(2-Methoxy-4-nitrophenyl)piperazin-1-yl)ethan-1-one (120.00 mg, 429.66 μmol) was dissolved in ethanol (3.36 mL) / H2O (ultrapure water, 841.24 μL), and iron (119.97 mg, 2.15 mmol) and ammonium chloride (114.92 mg, 2.15 mmol) were added at room temperature. The reaction mixture was stirred at 70°C for 2 h, cooled to room temperature, neutralized with 1 N sodium hydroxide, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine (NH2)) to obtain 1-(4-(4-amino-2-methoxyphenyl)piperazin-1-yl)ethan-1-one (70.7 mg, 66.00%) as a brown solid.

[0976] LC / MS ESI (+): 250 (M+1)

[0977] 1H-NMR (500 MHz, DMSO-D6) δ 6.60 (d, J = 8.3 Hz, 1H), 6.23 (d, J = 2.4 Hz, 1H), 6.07 (dd, J = 8.3, 2.4 Hz, 1H), 4.75 (s, 2H), 3.69 (s, 3H), 3.52-3.48 (m, 4H), 2.74 (dt, J = 32.7, 5.0 Hz, 4H), 2.00 (d, J = 8.7 Hz, 3H)

[0978]

[0979] (c) Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine

[0980] 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine was obtained as a white solid by the same method as in (d) of Example 1.

[0981] LC / MS ESI (+): 263 / 265 (M+1)

[0982] 1H-NMR (500 MHz, DMSO-D6) δ 8.94-8.93 (m, 2H), 8.66 (t, J = 1.0 Hz, 1H), 7.67 (d, J = 3.5 Hz, 1H), 6.69 (d, J = 3.5 Hz, 1H), 3.87 (d, J = 12.4 Hz, 3H)

[0983]

[0984] (d) Synthesis of 1-(4-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2-methoxyphenyl)piperazin-1-yl)ethan-1-one

[0985] 1-(4-(4-Amino-2-methoxyphenyl)piperazin-1-yl)ethan-1-one (20 mg, 80.22 μmol) and 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (21.07 mg, 80.22 μmol) were dissolved in toluene (801.40 μL), palladium(II) acetate (1.80 mg, 8.02 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9.28 mg, 16.04 μmol), and potassium carbonate (22.17 mg, 160.44 μmol) were added, and the reaction mixture was stirred at 120°C for 2 hours under an argon stream. The reaction mixture was cooled to room temperature, H2O was added, and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (amine(NH2) silica gel) to obtain 1-(4-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2-methoxyphenyl)piperazin-1-yl)ethan-1-one (19.5 mg, 51.12%) as a yellow solid.

[0986] LC / MS ESI (+): 238, 476 (M+1)

[0987] 1H-NMR (500 MHz, DMSO-D6) δ 9.63 (s, 1H), 8.98 (t, J = 1.5 Hz, 1H), 8.65 (q, J = 1.0 Hz, 1H), 8.60 (d, J = 3.7 Hz, 1H), 7.66-7.62 (m, 2H), 7.26 (dd, J = 8.6, 2.3 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 6.65 (d, J = 3.5 Hz, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.55 (dd, J = 10.2, 6.7 Hz, 4H), 2.88 (dt, J = 32.2, 5.0 Hz, 4H), 2.03 (s, 3H)

[0988]

[0989] Experimental Example: Evaluation of LRRK2 Enzyme Inhibitory Activity

[0990] The LRRK2 kinase inhibitory effect of the above compounds was measured using the ADP-GloTM + LRRK2 Kinase Enzyme System (Promega, Cat: V4475) and was performed according to the assay method provided by the manufacturer.

[0991] Test compounds were prepared at various concentrations in 5% DMSO, and the compounds were diluted in a reaction solution (40 nM Tris (pH 7.5), 20 mM MgCl , 0.1 mg / ml BSA, 50 μM DTT), and the enzyme activity was measured at a final concentration of 1% DMSO. A total of 5 μL of the compound and reaction solution at various concentrations, 20 mg (13.3 nM) LRRK2 enzyme, 10 μM ATP, and 0.2 μg / ml substrate (LRRKtide) were mixed and reacted at room temperature for 2 hours. After adding 5 μL of ADP-Glo ​​reagent, a total of 10 μL was further reacted at room temperature for 40 minutes. After adding 10 μL of kinase detection reagent, the reaction was performed at room temperature for 30 minutes, and the degree of inhibition of LRRK2 enzyme activity was confirmed by analyzing the luminescence measured using a Synergy HTX multireader (Agilent) device.

[0992] The results of evaluating the inhibitory activity of the example compounds on the LRRK2 enzyme are shown in Tables 2 and 3 (IC 50 : Inhibitory concentration 50%).

[0993] [Table 2]

[0994]

[0995] [Table 3]

[0996]

[0997]

[0998] As shown in Tables 2 and 3 above, it was found that the compound of the present invention has inhibitory activity against the LRRK2 enzyme. Therefore, the compound of formula I according to the present invention can be usefully used in the treatment of diseases related to LRRK2.

Claims

A compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, R1 and R3 are each independently -H, alkyl or alkoxy, provided that at least one of R1 and R3 is alkoxy; R2 is -EG, wherein E is a direct bond, heterocycloalkylene, -O-, -C(=O)- or -S(=O)2-; G is a 4 to 12 membered heterocycloalkyl; wherein the heterocycloalkyl may be optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, dialkylamino and dialkylaminoalkylcarbonyl; R4 is -H, alkyl, cycloalkyl or alkoxy; R5 is -H, halo, cyano (-CN), alkyl, haloalkyl or alkoxy; R4 and R5 may be linked together to form an unsubstituted or alkyl substituted saturated or unsaturated 5 to 11 membered carbocycle or heterocycle; R6 is and; X is CH or N; R7 and R8 are each independently alkoxy, or are linked together to form a saturated or unsaturated 5 to 8 membered carbocycle or heterocycle; wherein the carbocycle and heterocycle may be optionally substituted with one or more substituents selected from hydroxy, halo, oxo (=O), alkyl, and alkoxy; The above heterocycloalkyl and heterocycle contain one or more heteroatoms selected from N, O and S, However, if R5 is -H, R2 is , and is selected from. In the first paragraph, R1 and R3 are each independently -H, C1-C5 alkyl or C1-C5 alkoxy, provided that at least one of R1 and R3 is C1-C5 alkoxy; R2 is -EG, wherein E is a direct bond, a 4- to 12-membered heterocycloalkylene, -O-, -C(=O)-, or -S(=O)2-; G is a 4- to 12-membered heterocycloalkyl; wherein the heterocycloalkyl may be optionally substituted with 1 to 3 substituents selected from hydroxy, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C1-C5 alkylsulfonyl, di(C1-C5 alkyl)amino, and di(C1-C5 alkyl)aminoalkylcarbonyl; R4 is -H, C1-C5 alkyl, C3-C8 cycloalkyl or C1-C5 alkoxy; R5 is -H, halo, cyano, C1-C5 alkyl, halo-C1-C5 alkyl or C1-C5 alkoxy; R4 and R5 may be linked together to form a saturated or unsaturated 5 to 8 membered carbocycle or heterocycle which is unsubstituted or substituted with C1-C5 alkyl; R6 is and; X is CH or N; R7 and R8 are each independently alkoxy or are linked together to form a saturated or unsaturated 5 to 8 membered heterocycle; wherein the heterocycle may be optionally substituted with 1 to 3 substituents selected from hydroxy, halo, oxo, C1-C5 alkyl and C1-C5 alkoxy; The above heterocycloalkylene, heterocycloalkyl and heterocycle contain 1 to 4 heteroatoms selected from N, O and S, However, if R5 is -H, R2 is , and A compound characterized by being selected from or a pharmaceutically acceptable salt thereof. A compound or a pharmaceutically acceptable salt thereof, characterized in that in claim 1, R1 and R3 are each independently -H or C1-C5 alkoxy, and at least one of R1 and R3 is C1-C5 alkoxy. A compound or a pharmaceutically acceptable salt thereof, characterized in that in claim 1, R2 is -EG, wherein E is a direct bond, a 4 to 10 membered heterocycloalkylene, -O-, -C(=O)-, or -S(=O)2-; G is a 4 to 10 membered heterocycloalkyl; and wherein the heterocycloalkyl may be optionally substituted with one or two substituents selected from hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylcarbonyl, C1-C5 alkoxycarbonyl, C1-C3 alkylsulfonyl, di(C1-C3 alkyl)amino, and di(C1-C3 alkyl)aminoalkylcarbonyl. A compound or a pharmaceutically acceptable salt thereof, characterized in that in claim 1, R4 is -H, C1-C3 alkyl, C3-C6 cycloalkyl or C1-C3 alkoxy; R5 is -H, F, Cl, Br, cyano, C1-C3 alkyl, halo-C1-C3 alkyl or C1-C3 alkoxy; and R4 and R5 can be linked together to form an unsubstituted or C1-C3 alkyl substituted saturated or unsaturated 5 to 8 membered carbocycle or heterocycle. In the first paragraph, R6 is and; X is CH or N; A compound or a pharmaceutically acceptable salt thereof, wherein R7 and R8 are each independently C1-C2 alkoxy or are linked together to form a saturated or unsaturated 5-8 membered heterocycle; and wherein the heterocycle can be optionally substituted with one substituent selected from hydroxy, halo, oxo, C1-C2 alkyl, and C1-C2 alkoxy. In claim 1, a compound or a pharmaceutically acceptable salt thereof, characterized in that the compound of formula 1 is selected from the following group: 1-(4-(4-((5-chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 1); 5-Chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(2,5-dimethoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine (Compound 2); 5-chloro-4-(3,4-dimethoxyphenyl)-N-(3-isopropoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine (Compound 3); 1-(4-(4-((5-chloro-4-(quinolin-3-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 4); 1-(4-(2,5-dimethoxy-4-((4-(quinolin-3-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 5); 5-Chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine (Compound 6); 1-(1-(4-((5-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperidin-4-yl)pyrrolidin-3-ol (Compound 7); 5-Chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(2-methoxy-4-((1-methylpiperidin-4-yl)oxy)phenyl)pyrimidin-2-amine (Compound 8); 1-(4-(4-((5-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 9); 1-(4-(4-((5-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperidin-1-yl)-2-(dimethylamino)ethan-1-one (Compound 10); 5-Chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(2,5-dimethoxy-4-(1-methylpiperidin-4-yl)phenyl)pyrimidin-2-amine (Compound 11); 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 12); 1-(4-(1-(4-((5-chloro-4-(quinolin-3-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperidin-4-yl)piperazin-1 -yl)ethan-1-one (Compound 13); 1-(4-(1-(4-((5-chloro-4-(quinolin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one (Compound 14); 1-(4-(4-((5-chloro-4-(1-methyl-1H-indazol-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 15); 6-(2-((4-(4-acetylpiperazin-1-yl)-2,5-dimethoxyphenyl)amino)-5-chloropyrimidin-4-yl)-2-methylisoindolin-1-one (Compound 16); 1-(4-(4-((5-chloro-4-(1-methyl-1H-indol-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 17); 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 18); 1-(4-(4-((5-chloro-4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 19); 1-(4-(2,5-dimethoxy-4-((4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 20); 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-indol-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 21); 1-(4-(1-(4-((5-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-2-yl)amino)-2, 5-dimethoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one (Compound 22); 1-(4-(1-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one (Compound 23); 4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(2,5-dimethoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)pyrimidin-2-amine (Compound 24); 1-(4-(4-((5-chloro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 25); 1-(4-(2,5-Dimethoxy-4-((4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 26); 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 27); 1-(4-(2,5-dimethoxy-4-((4-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 28); 1-(4-(2,5-dimethoxy-4-((5-methoxy-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperidin-1-yl)ethan-1-one (Compound 29); 1-(3-(4-((5-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-1H-pyrazol-1-yl)ethan-1-one (Compound 30); 1-(4-(4-((5-Fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 31); 1-(4-(4-((5-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 32); 1-(4-(2,5-Dimethoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 33); 1-(4-(2,5-dimethoxy-4-((5-methyl-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 34); 1-(4-(2,5-dimethoxy-4-((5-methoxy-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 35); 1-(4-(4-((5-Bromo-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 36); 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-fluoropyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 37); 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 38); 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylpyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 39); 1-(4-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methoxypyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 40); 1-(4-(4-((5-Fluoro-4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 41); N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 42); N-(4-(3-(dimethylamino)azetidin-1-yl)-2-methoxyphenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 43); N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 44); 1-(4-((4-((5-Fluoro-4-(1-methyl1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)sulfonyl)piperazin-1-yl)ethan-1-one (Compound 45); 1-(4-(4-((5-Fluoro-4-(1-methyl1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)piperazin-1-yl)ethan-1-one (Compound 46); 1-(4-(4-((4-(1-Ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-fluoropyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 47); (3-Methoxy-4-((4-(1-methyl1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (Compound 48); (4-((5-Fluoro-4-(1-methyl1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (Compound 49); 5-Fluoro-N-(2-methoxy-4-(morpholinosulfonyl)phenyl)-4-(1-methyl1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 50); N-(2,5-Dimethoxy-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 51); 1-(4-(4-((5-Fluoro-4-(thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 52); tert-Butyl 5-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,5-diazaspiro[3.4]octane-2-carboxylate (Compound 53); N-(2,5-Dimethoxy-4-(2,5-diazaspiro[3.4]octan-5-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 54); 2-((4-(4-acetylpiperazin-1-yl)-2,5-dimethoxyphenyl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidine-5-carbonitrile (Compound 55); 6-(2-((4-(4-acetylpiperazin-1-yl)-2,5-dimethoxyphenyl)amino)-5-methylpyrimidin-4-yl)quinolin-2(1H)-one (Compound 56-1); 1-(4-(4-((4-(2-hydroxyquinolin-6-yl)-5-methylpyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 56-2); 1-(4-(4-((5-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 57); 1-(4-(2,5-Dimethoxy-4-((5-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 58); 1-(4-(4-((5-Fluoro-4-(1,5-naphthyridin-3-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 59); 1-(4-(4-((5-Fluoro-4-(8-fluoroquinolin-3-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 60); 1-(4-(4-((5-Fluoro-4-(pyrido[2,3-b]pyrazin-7-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 61); 1-(4-(2,5-dimethoxy-4-((5-methyl-4-quinoxalin-6-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 62); 1-(4-(4-((4-(Benzo[c][1,2,5]oxadiazol-5-yl)-5-methylpyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 63); tert-Butyl 6-(4-((5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Compound 64); 1-(5-(4-((5-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,5-diazaspiro[3.4]octan-2-yl)ethan-1-one (Compound 65); N-(2,5-Dimethoxy-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 66); 1-(6-(4-((5-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one (Compound 67); N-(2,5-Dimethoxy-4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-5-fluoro-4-(1-methyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)pyrimidin-2-amine (Compound 68); (3-Methoxy-4-((4-thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (Compound 69); (4-((5-Fluoro-4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (Compound 70); (4-((5-Fluoro-4-thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (Compound 71); (3-Methoxy-4-((4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (Compound 72); (4-((5-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (Compound 73); N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine (Compound 74); N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine (Compound 75); N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine (Compound 76); N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-4-(thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-amine (Compound 77); N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(thiazolo[5,4-b]pyridin-6-yl)pyrimidin-2-amine (Compound 78); N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-fluoro-4-(8-fluoroquinolin-3-yl)pyrimidin-2-amine (Compound 79); N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-4-(quinoxalin-6-yl)pyrimidin-2-amine (Compound 80); N-(4-(3-(dimethylamino)azetidin-1-yl)-2,5-dimethoxyphenyl)-5-methyl-4-(quinoxalin-6-yl)pyrimidin-2-amine (Compound 81); 1-(4-(4-((5-Fluoro-4-methyl-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 82); 1-(4-(2,5-Dimethoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)furo[3,2-d]pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 83); 1-(4-(2,5-Dimethoxy-4-((9-methyl-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-9H-purin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-one (Compound 84); 1-(4-(4-((4-Cyclopropyl-5-fluoro-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 85); 1-(4-(4-((5-Fluoro-4-methoxy-6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2,5-dimethoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 86); and 1-(4-(4-((5-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2-methoxyphenyl)piperazin-1-yl)ethan-1-one (Compound 87). A pharmaceutical composition for preventing or treating a disease associated with LRRK2, comprising a compound of formula 1 defined in any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient, together with a pharmaceutically acceptable carrier. A pharmaceutical composition according to claim 8, characterized in that the disease associated with LRRK2 is selected from the group consisting of solid cancer, blood cancer, radiation or drug resistant cancer, and metastatic cancer. In claim 8, the disease related to the LRRK2 is triple-negative breast cancer, breast cancer, male breast cancer, ovarian cancer, cervical cancer, endometrial cancer, uterine sarcoma, vaginal cancer, female genital tumor, female external genital cancer, female urethral cancer, prostate cancer, penile cancer, male genital tumor, stomach cancer, liver cancer, gallbladder cancer, ductal cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, thyroid cancer, oral cancer, thoracic tumor, small cell lung cancer, non-small cell lung cancer, thymic cancer, mediastinal tumor, esophageal cancer, laryngeal cancer, oropharyngeal cancer, nasal cavity / paranasal sinus cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, brain cancer, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, craniopharyngioma, ependymoma, brainstem tumor, head and neck A pharmaceutical composition characterized in that it is selected from the group consisting of tumors and skin cancers.

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