ULK1 / 2 INHIBITORS AND USES THEREOF

Abstract

Described herein are compounds that are ULK1 / 2 inhibitors, and the use of such compounds in the treatment of disorders such as cancer.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 171,763, filed April 7, 2021, which is incorporated by reference in its entirety.

[0002] The present disclosure relates to ULK1 / 2 inhibitors and their use in the treatment of cancers sensitive to ULK1 / 2 inhibition. [Background technology]

[0003] Autophagy, the process of cellular self-digestion, plays a role in maintaining energy homeostasis and protein synthesis, and is recognized to play a role in cancer by both preventing and promoting cell death, as it results in the degradation of long-lived proteins and damaged organelles. The autophagy-related gene (Atg) family has more than 35 members and regulates multiple steps of the process. UNC-51-like kinase 1 (ULK1) has been demonstrated to mediate autophagy. Studies have shown that inhibition of ULK1 promotes apoptosis and suppresses tumor growth and metastasis in cancer. Mol. Cancer Ther by Dower et al.; 17(11), 2018, pp. 2366-2376; iScience by Martin et al.; 8, 2018, pp. 74-84; Yale Journal of Biology and Medicine by Tompkins et al.; 92, 2019, pp. 707-718; Cell Death and Disease by Lin et al.; 10, 2019, pp. 139.

[0004] Therefore, there is an urgent need to develop ULK1 inhibitors for the treatment of cancer in subjects, including humans. Summary of the Invention

[0005] The present disclosure provides novel ULK1 / 2 inhibitors and the use of the inhibitors in the treatment of cancers sensitive to ULK1 / 2 inhibition (eg, CML).

[0006] As used herein, the compound of formula (I):

[0007] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, R 1 is C1-C6 haloalkyl or cycloalkyl; R 2 is hydrogen, halogen, deuterium, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl; R 4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl; R 5 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)ORb , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same carbon 5 come together to form oxo, Ring A is a 6- to 12-membered bicyclic ring optionally containing 1-4 heteroatoms selected from the group consisting of O, S, N, P, and B; R A are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -O(C2-C6 alkylene) OR a , -O(C2-C6 alkylene)NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b C(=O)NR c R d , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently selected from 1, 2, or 3 R Aa is replaced by Alternatively, two R on the same carbon A come together to form oxo, R Aa are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b C(=O)NR c R d , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same carbon Aa come together to form oxo, L 1 can have 1, 2, or 3 R L1 is a C3-C4 alkylene optionally substituted with R L1 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , or -NR c R d and Alternatively, two R on the same carbon L1 come together to form oxo, n is 1 to 4; m is 0 to 4; p is 1 or 2; R a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); alkyl, alkenyl, alkynyl, cycloalkyl , heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R bare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); alkyl, alkenyl, alkynyl, cycloalkoxy, alkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); alkyl, alkenyl, alkynyl, cycloalkoxy, alkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; Or, R c and R d taken together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one, two, or three deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; Disclosed are compounds, or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof.

[0008] As used herein, the compound of formula (IIa) or (IIb):

[0009] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, R 1 is C1-C6 haloalkyl or cycloalkyl; R 2 is hydrogen, halogen, deuterium, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 3is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl; R 4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl; R B are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -O(C2-C6 alkylene) OR a , -O(C2-C6 alkylene)NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b C(=O)NR c R d , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently selected from 1, 2, or 3 R Ba is replaced by Alternatively, two R on the same carbon B come together to form oxo, R Ba are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b C(=O)NR c R d , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same carbon Ba come together to form oxo, R B1 is hydrogen, -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R C are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same carbon C come together to form oxo, L 2 can have 1, 2, or 3 R L2 is a C1-C4 alkylene optionally substituted with R L2are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , or -NR c R d and Alternatively, two R on the same carbon L2 come together to form oxo, q is 0 to 4; r is 0 to 4; R a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); alkyl, alkenyl, alkynyl, cycloalkyl , heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R bare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); alkyl, alkenyl, alkynyl, cycloalkoxy, alkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); alkyl, alkenyl, alkynyl, cycloalkoxy, alkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; Or, R c and R d taken together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one, two, or three deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; Disclosed are compounds, or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof.

[0010] As used herein, the compound of formula (IIa):

[0011] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof is disclosed.

[0012] As used herein, the compound of formula (IIb):

[0013] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof is disclosed.

[0014] According to a third aspect of the present disclosure, there is provided a method of treating a cancer sensitive to ULK1 / 2 inhibition in a subject in need of such treatment, the method comprising administering to the subject an effective amount of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0015] Additional embodiments of the present disclosure further include a method for treating abnormal cell growth in a subject, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. In certain such embodiments, the abnormal cell growth is cancer, and in some of these embodiments, the cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal axis tumor, brain stem glioma, or pituitary adenoma.Such cancer can be KRAS-related cancer.Specific examples include lung cancer, colon cancer, pancreatic cancer, and ovarian cancer. In some embodiments, the method of treating cancer is a method of treating chronic myelogenous leukemia. In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer comprises a liquid tumor. In some embodiments, the cancer is chronic myelogenous leukemia.

[0016] According to a fourth aspect of the present disclosure, there is provided the use of a compound of formula (I), (IIa) or (IIb) as defined above, or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof, in the manufacture of a medicament for use in the treatment of cancer sensitive to ULK1 / 2 inhibition.

[0017] In some embodiments, the subject's cancer comprises a cancer with one or more alterations in the MAPK pathway. The one or more alterations in the MAPK pathway comprise a cancer with an alteration in one or more of the RAS, RAF, MEK, and ERK pathways. In some embodiments, the subject's cancer comprises one or more alterations in the RAS pathway. In some embodiments, the subject's cancer comprises one or more alterations in the RAF pathway. In some embodiments, the subject's cancer comprises one or more alterations in the MEK pathway. In some embodiments, the subject's cancer comprises one or more alterations in the ERK pathway. In some embodiments, the subject is a mammalian subject. In a preferred embodiment, the subject is a human subject. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] "Abnormal cell growth", as used herein, unless otherwise specified, refers to cell growth that is not dependent on normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth can be benign (non-cancerous) or malignant (cancerous). Abnormal cell growth includes, as abnormal growth, (1) tumor cells (tumors) that show increased expression of ULK1 or ULK2, (2) tumors that grow due to abnormal ULK1 or ULK2 activation, and / or (3) tumors that are characterized by amplification or overexpression of genes that express ULK1 or ULK2.

[0019] The term "additional anti-cancer agent" as used herein means any one or more therapeutic agents, other than the compounds of the present disclosure, that are or can be used to treat cancer. In some embodiments, such additional anti-cancer agents include compounds from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors such as protein tyrosine kinase inhibitors and / or serine / threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, tumor immunotherapeutics, and the like.

[0020] As used herein, "cancer" refers to any malignant and / or aggressive growth or tumor resulting from abnormal cell growth. Cancer includes solid tumors, blood cancers, bone marrow cancers, or lymphatic cancers, named after the type of cells that form the cancer. Examples of solid tumors include sarcomas and carcinomas. Blood cancers include, but are not limited to, leukemia, lymphoma, and myeloma. Cancer also includes primary cancers that arise in a specific site of the body, metastatic cancers that start in one place in the body and spread further to other sites, recurrence from the primary cancer of origin after remission, and another primary cancer that is a new primary cancer in an individual with a history of a different cancer.

[0021] As used herein, the term "combination therapy" refers to the administration of a compound of the present disclosure together with at least one additional pharmaceutical agent or agent (e.g., one or more additional anti-cancer agents), either sequentially or simultaneously.

[0022] As used herein, "subject" refers to a human or animal subject. In certain preferred embodiments, the subject is a human subject.

[0023] The term "treat" or "treating" cancer, as used herein, refers to administering a compound of the present invention to a subject suffering from or diagnosed with cancer to achieve at least one positive therapeutic effect, such as reducing the number of cancer cells, reducing tumor size, slowing the rate of cancer cell invasion into surrounding organs, or slowing the rate of tumor metastasis or tumor growth, reversing, alleviating, inhibiting the progression of, or preventing the disorder or disease to which such term applies, or one or more symptoms of such disorder or disease. The term "treatment", as used herein, unless otherwise specified, refers to the act of administering a treatment, as "treating" is defined immediately above. The term "treating" also includes adjuvant and neoadjuvant treatment of a subject.

[0024] As used herein, "pharmacologically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0025] As used herein, the following terms have the following meanings unless otherwise specified.

[0026] "Oxo" refers to the =O radical.

[0027] "Carboxyl" refers to --COOH.

[0028] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monoradical having from 1 to about 10 carbon atoms, more preferably from 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl. "C1-C6 alkyl" and "C1-C6 alkyl" are examples of alkyl groups. 1-6 Whenever a numerical range such as "alkyl" appears herein, it means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C 1-10 In some embodiments, alkyl is C 1-6 In some embodiments, alkyl is C1-5 In some embodiments, alkyl is C 1-4 In some embodiments, alkyl is C 1-3 Alkyl. Unless otherwise specifically stated herein, alkyl groups may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkyl is optionally substituted with halogen.

[0029] "Alkenyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans conformation about the double bond and is to be understood as including both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. "C2-C6 alkenyl" and "C 2-6Numerical ranges such as "alkenyl", whenever they appear herein, mean that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. Unless specifically stated herein, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkenyl is optionally substituted with halogen.

[0030] "Alkynyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. "C2-C6 alkynyl" and "C 2-6Numerical ranges such as "alkynyl", whenever they appear herein, mean that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. Unless specifically stated herein, alkynyl groups may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0031] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless specifically stated otherwise in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkylene is optionally substituted with halogen.

[0032] "Alkoxy" is R a is an alkyl radical as defined by the formula -OR aUnless specifically stated herein, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0033] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems and may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6-10 membered aromatic ring and may be monocyclic or bicyclic (e.g., phenyl or naphthyl). In some embodiments, the aryl is a 6 membered aromatic ring (phenyl). Aryl radicals include, but are not limited to, anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Aryl radicals include, but are not limited to, 1,2,3,5,6,7-hexahydro-s-indacene, 2,3-dihydro-1H-indene, 1,2,3,4-tetrahydronaphthalene, 2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalene, and 1,2,3,4,5,6,7,8-octahydroanthracene.Unless otherwise specifically stated herein, aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0034] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. In some embodiments, cycloalkyls are fully saturated. Representative cycloalkyls include those having 3 to 15 carbon atoms (C3-C4). 15 Cycloalkyl or C3-C 15 Cycloalkenyl, 3 to 10 carbon atoms (C3-C 10 Cycloalkyl or C3-C 10Cycloalkyls include, but are not limited to, cycloalkyls having 3 to 8 carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), 3 to 6 carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkenyl), 3 to 5 carbon atoms (C3-C5 cycloalkyl or C3-C5 cycloalkenyl), or 3 to 4 carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, cycloalkyls are 3 to 10 membered cycloalkyl or 3 to 10 membered cycloalkenyl. In some embodiments, cycloalkyls are 3 to 6 membered cycloalkyl or 3 to 6 membered cycloalkenyl. In some embodiments, cycloalkyls are 5 to 6 membered cycloalkyl or 5 to 6 membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl include adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless specifically stated otherwise in the specification, cycloalkyl may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0035] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0036] "Haloalkyl" refers to an alkyl radical as defined above that is substituted by one or more halo radicals as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0037] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0038] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0039] "Deuteroalkyl" refers to an alkyl radical, as defined above, substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyls include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0040] "Heterocycloalkyl" refers to a 3-24 membered partially or fully saturated ring radical containing 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1-3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless specifically stated otherwise in the specification, a heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems, the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include those having 2 to 15 carbon atoms (C2-C4). 15 Heterocycloalkyl or C2-C 15Heterocycloalkenyl, 2 to 10 carbon atoms (C2-C 10 Heterocycloalkyl or C2-C 10heterocycloalkenyl), heterocycloalkyl having 2 to 8 carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (C2-C6 heterocycloalkyl or C2-C6 heterocycloalkenyl), 2 to 5 carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyls include aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, and the like. Examples of heterocycloalkyl include, but are not limited to, zolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise noted, heterocycloalkyls have 2 to 10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3-8 membered heterocycloalkyl or a 3-8 membered heterocycloalkenyl.In some embodiments, the heterocycloalkyl is a 3-7 membered heterocycloalkyl or a 3-7 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkyl or a 3-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-6 membered heterocycloalkyl or a 4-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-6 membered heterocycloalkyl or a 5-6 membered heterocycloalkenyl. Unless specifically stated otherwise herein, the heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0041] "Heteroaryl" refers to a 5-14 membered ring system radical containing 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1-3 nitrogens. In some embodiments, the heteroaryl contains 1 or 2 nitrogens. In some embodiments, the heteroaryl contains 1 nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl may be optionally oxidized and the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a 5-6 membered heteroaryl. In some embodiments, the heteroaryl is a 6 membered heteroaryl. In some embodiments, the heteroaryl is a 5 membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indophenyl, and phenyl. These include, but are not limited to, linyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless specifically stated otherwise herein, a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with halogen.

[0042] The term "optionally" or "optionally" means that the event or circumstance described below may or may not occur, and that the description includes examples in which the event or circumstance occurs and examples in which the event or circumstance does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl group" as appropriate above. Furthermore, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at a level between fully and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that with respect to any group that contains one or more substituents, such groups are not intended to introduce any substitutions or substitution patterns that are sterically impractical and / or synthetically unfeasible (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which are defined to include optionally substituted alkyl groups, possibly without limitation).Thus, any described substituents will be understood to have, in their entirety, a maximum molecular weight of about 1000 daltons, more typically up to about 500 daltons.

[0043] As used herein, a dashed bond in a portion of a chemical structure

[0044] [ka] represents the point of attachment of a portion of a chemical structure to the remainder of a compound of Formula (I), (IIa), or (IIb).

[0045] compound As used herein, the compound of formula (I):

[0046] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, R 1 is C1-C6 haloalkyl or cycloalkyl; R 2 is hydrogen, halogen, deuterium, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl; R 4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl; R 5 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same carbon 5 come together to form oxo, Ring A is a 6- to 12-membered bicyclic ring optionally containing 1 to 4 heteroatoms selected from the group consisting of O, S, N, P, and B; R A are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -O(C2-C6 alkylene) OR a , -O(C2-C6 alkylene)NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b C(=O)NR c R d , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently selected from 1, 2, or 3 R Aais replaced by Alternatively, two R on the same carbon A come together to form oxo, R Aa are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b C(=O)NR c R d , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same carbon Aa come together to form oxo, L 1 can have 1, 2, or 3 R L1 is a C3-C4 alkylene optionally substituted with R L1 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , or -NR c R d and Alternatively, two R on the same carbon L1come together to form oxo, n is 1 to 4; m is 0 to 4; p is 1 or 2; R a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); alkyl, alkenyl, alkynyl, cycloalkyl , heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R bare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); alkyl, alkenyl, alkynyl, cycloalkoxy, alkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); alkyl, alkenyl, alkynyl, cycloalkoxy, alkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; Or, R c and R d taken together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one, two, or three deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; Disclosed are compounds, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0047] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the compound of formula (I) is

[0048] [ka] isn't it.

[0049] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen, halogen, deuterium, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen, halogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 2is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen.

[0050] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is C1-C6 alkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is hydrogen.

[0051] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 4 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 4 is C1-C6 alkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 4 is hydrogen.

[0052] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1is C1-C6 haloalkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cyclopropyl.

[0053] In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, L 1 can have 1, 2, or 3 R L1 In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, L is a C alkylene optionally substituted with 1 can have 1, 2, or 3 R L1 is a C4 alkylene optionally substituted with

[0054] In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, L 1 is C3-C4 alkylene. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, L 1 is C alkylene. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, L 1 is a C4 alkylene.

[0055] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R L1 are each independently deuterium, halogen, -OH, -OR a , or -NR c R d or two R on the same carbon L1In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R L1 are each independently deuterium or halogen, or two R L1 together form oxo.

[0056] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, p is 1. In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, p is 2.

[0057] In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, m is 0. In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, m is 1 or 2. In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, m is 1. In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, m is 2.

[0058] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl, or two R on the same carbon. 5 In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5are each independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; or two R 5 In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5 are each independently deuterium, halogen, or C1-C6 alkyl, or two R 5 together form oxo.

[0059] In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is a 6-12 membered bicyclic ring, optionally containing 1-4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is a 6-12 membered bicyclic ring, optionally containing 1-4 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is a 6-12 membered bicyclic ring, optionally containing 1-4 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is a 6-12 membered bicyclic ring optionally containing one or two heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is a 6-10 membered bicyclic ring containing one heteroatom that is O. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is a 6-10 membered bicyclic ring containing one heteroatom that is N.

[0060] In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is

[0061] [ka] In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is:

[0062] [ka] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof,

[0063] [ka] teeth,

[0064] [ka] and R A’ is hydrogen or C1-C6 alkyl.

[0065] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R A are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -O(C2-C6 alkylene) OR a , -O(C2-C6 alkylene)NR c R d , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c Rd , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently selected from 1, 2, or 3 R Aa or two R on the same carbon A together form oxo.

[0066] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R A are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -O(C2-C6 alkylene) OR a , -O(C2-C6 alkylene)NR c R d , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); or two R on the same carbon. A together form oxo.

[0067] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R A are each independently a halogen, -OH, or -OR a , -O(C2-C6 alkylene)NR c R d , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each independently selected from 1, 2, or 3 R Aa or two R on the same carbon A together form oxo.

[0068] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R A are each independently a halogen, -OH, or -OR a , -O(C2-C6 alkylene)NR c R d , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl, or two R on the same carbon. A together form oxo.

[0069] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R Aare each independently a halogen, -OH, or -OR a , -NR c R d , -C(=O)R a , C1-C6 alkyl, or C1-C6 haloalkyl, each alkyl being independently selected from 1, 2, or 3 R Aa or two R on the same carbon A together form oxo.

[0070] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R A are each independently a halogen, -OH, or -OR a , -NR c R d , -C(=O)R a or C1-C6 alkyl; or two R A together form oxo.

[0071] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R A are each independently a halogen, -OH, or -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl, each alkyl being independently selected from 1, 2, or 3 R Aa is replaced by.

[0072] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R A are each independently halogen or C1-C6 alkyl.

[0073] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R A are each independently a halogen.

[0074] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R Aa are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl, or two R on the same carbon. Aa together form oxo.

[0075] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R Aa are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; or two R Aa together form oxo.

[0076] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R Aa are each independently a halogen, -OH, or -OR a , -NR c R d or C1-C6 alkyl.

[0077] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 1 to 3. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 1. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 1 or 2. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 2.

[0078] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof,

[0079] [ka] teeth,

[0080] [ka] is selected from.

[0081] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof,

[0082] [ka] teeth,

[0083] [ka] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof,

[0084] [ka] teeth,

[0085] [ka] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof,

[0086] [ka] teeth,

[0087] [ka] It is.

[0088] Also provided herein are compounds of formula (IIa) or (IIb):

[0089] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, R 1 is C1-C6 haloalkyl or cycloalkyl; R 2 is hydrogen, halogen, deuterium, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl; R 4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl; R B are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -O(C2-C6 alkylene) OR a , -O(C2-C6 alkylene)NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b C(=O)NR c R d , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently selected from 1, 2, or 3 R Bais replaced by Alternatively, two R on the same carbon B come together to form oxo, R Ba are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b C(=O)NR c R d , -NHS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same carbon Ba come together to form oxo, R B1 is hydrogen, -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R C are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same carbon C come together to form oxo, L 2 but 1, 2, or 3 R L2 is a C1-C4 alkylene optionally substituted with R L2 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , or -NR c R d and Alternatively, two R on the same carbon L2 come together to form oxo, q is 0 to 4; r is 0 to 4; R aare each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); alkyl, alkenyl, alkynyl, cycloalkyl , heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); alkyl, alkenyl, alkynyl, cycloalkoxy, alkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R cand R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); alkyl, alkenyl, alkynyl, cycloalkoxy, alkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; Or, R c and R d taken together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one, two, or three deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; Disclosed are compounds, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0090] In some embodiments, the compound has formula (IIa):

[0091] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0092] In some embodiments, the compound has formula (IIb):

[0093] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0094] In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen, halogen, deuterium, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen, halogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen.

[0095] In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 3is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is C1-C6 alkyl. In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is hydrogen.

[0096] In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 4 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 4 is C1-C6 alkyl. In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 4 is hydrogen.

[0097] In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C1-C6 haloalkyl. In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cyclopropyl.

[0098] In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, L 2 can have 1, 2, or 3 R L2 In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, L is a C alkylene optionally substituted with 2 can have 1, 2, or 3 R L2 is a C4 alkylene optionally substituted with

[0099] In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, L 2 is C3-C4 alkylene. In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, L 2 is C alkylene. In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, L 2 is a C4 alkylene.

[0100] In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R L2 are each independently deuterium, halogen, -OH, -OR a , or -NR c R d or two R on the same carbonL2 In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R L2 are each independently deuterium or halogen, or two R L2 In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, two R on the same carbon are taken together to form oxo. L2 together form oxo.

[0101] In some embodiments of a compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof,

[0102] [ka] teeth,

[0103] [ka] In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof,

[0104] [ka] teeth,

[0105] [ka] It is.

[0106] In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, q is 0 to 2. In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, q is 0 or 1. In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, q is 1 or 2. In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, q is 1.

[0107] In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R B1 is hydrogen, -C(=O)R a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl). In some embodiments of a compound of formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R B1 is hydrogen, -C(=O)R a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R B1 is hydrogen, -C(=O)R a, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R B1 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R B1 is hydrogen.

[0108] In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R B are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently selected from 1, 2, or 3 R Ba In some embodiments of the compounds of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R B are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently selected from 1, 2, or 3 R Ba In some embodiments of the compounds of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R B are each independently a halogen, -OH, or -OR a , -NR c R d , -C(=O)R a , C1-C6 alkyl, or C1-C6 haloalkyl, each of which is independently selected from 1, 2, or 3 R Ba or two R on the same carbon B In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R B are each independently a halogen, -OH, or -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl, each alkyl being independently selected from 1, 2, or 3 R Ba In some embodiments of the compounds of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R B is each independently halogen or C1-C6 alkyl. In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R B are each independently a halogen.

[0109] In some embodiments of the compound of formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring C is cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring C is aryl or heteroaryl. In some embodiments of the compound of formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring C is heteroaryl. In some embodiments of the compound of formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring C is heterocycloalkyl.

[0110] In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R C are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl, or two R on the same carbon. C In some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R C are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl; or two R CIn some embodiments of the compound of Formula (IIa) or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, two R on the same carbon are taken together to form oxo. C together form oxo.

[0111] In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, where each alkyl is optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, or -C(=O)OCH3. In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R ais each independently C1-C6 alkyl or C1-C6 haloalkyl, each alkyl being optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, or -C(=O)OCH3. In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R a is each independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R a are each independently C1-C6 alkyl.

[0112] In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R bare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, where each alkyl is optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, or -C(=O)OCH3. In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R b are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, where each alkyl is optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, or -C(=O)OCH3. In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R b is each independently hydrogen, C-C alkyl, or C-C haloalkyl. In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R b is each independently hydrogen or C-C alkyl. In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R b In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R b are each independently C1-C6 alkyl.

[0113] In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, where each alkyl is optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, or -C(=O)OCH3. In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R c and R dare each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, where each alkyl is optionally substituted with 1, 2, or 3 deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, or -C(=O)OCH3. In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R c and R d is each independently hydrogen, C-C alkyl, or C-C haloalkyl. In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R c and R d is each independently hydrogen or C-C alkyl. In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R c and R d In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R c and R d are each independently C1-C6 alkyl.

[0114] In some embodiments of a compound of Formula (I), (IIa), or (IIb), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R c and R dtogether with the atom to which they are attached form a heterocycloalkyl optionally substituted with one, two, or three deuterium, oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -S(=O)2NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl.

[0115] In this specification,

[0116] [ka]

[0117] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0118] In this specification,

[0119] [ka]

[0120] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0121] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as their corresponding mixtures. In some circumstances, the compounds described herein have one or more chiral centers, with each center being present in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers obtained by a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, separable complexes are preferred. In some embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by exploiting these dissimilarities. In some embodiments, diastereomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers are subsequently recovered along with the resolving agent by any practical means that do not result in racemization.

[0122] labeled compound In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those listed herein, but in which one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, respectively. 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Cl, etc. Compounds described herein and pharma- ceutically acceptable salts, solvates, or stereoisomers thereof that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds, e.g., 3 H and 14 Incorporating radioactive isotopes such as C are useful for drug and / or substrate tissue distribution assays. Tritiated isotopes, i.e. 3 H, and the carbon-14 isotope, i.e. 14 C are particularly preferred for their ease of preparation and detectability. In addition, deuterium, i.e. 2 Substitution with heavier isotopes, such as 3H, offers certain therapeutic advantages due to greater metabolic stability, including increased half-life in vivo and reduced dosage requirements.

[0123] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0124] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0125] In some embodiments, the compounds described herein contain acidic or basic groups and thus react with any of a number of inorganic or organic bases, as well as inorganic and organic bases, to form pharma- ceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or solvates or stereoisomers thereof, or by separately reacting the purified compounds in free form with a suitable acid or base and isolating the salt formed.

[0126] Examples of pharma- ceutically acceptable salts include salts prepared by reacting the compounds described herein with a mineral, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, asparaginate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chloroate, chloroform ... dibenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, chloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undeconate, and xylenesulfonate.

[0127] Additionally, the compounds described herein can be prepared as pharma- ceutically acceptable salts formed by reacting the free base form of the compound with a pharma- ceutically acceptable inorganic or organic acid, such as inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, as well as inorganic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, Included are organic acids such as cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiarybutylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, which are not themselves pharmaceutically acceptable, are utilized in the preparation of salts useful as intermediates to obtain the compounds disclosed herein, or solvates or stereoisomers thereof, and pharmaceutically acceptable acid addition salts thereof.

[0128] In some embodiments, compounds described herein that contain free acid groups are reacted with a suitable base, such as hydroxides, carbonates, bicarbonates, sulfates, of pharma- ceutically acceptable acid cations, with ammonia, or with pharma-ceutically acceptable organic primary, secondary, tertiary, or quaternary amines. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, and aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl)4.

[0129] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It will be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, such quaternization results in water or oil-soluble or dispersible products.

[0130] solvate In some embodiments, the compounds described herein exist as solvates. The invention provides methods of treating diseases by administration of such solvates. The invention further provides methods of treating diseases by administration of such solvates as pharmaceutical compositions.

[0131] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments are formed during the crystallization process with pharma- ceutically acceptable solvents, such as water or ethanol. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from aqueous / organic solvent mixtures using organic solvents, including but not limited to dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can optionally exist in solvated as well as unsolvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0132] Tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers in the formulas described herein. Tautomers are compounds that are interchangeable by migration of hydrogen atoms with switching of single bonds and adjacent double bonds. In bond configurations where tautomerization is possible, chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on various factors, including temperature, solvent, and pH.

[0133] Treatment Disclosed herein is a method for treating a cancer sensitive to ULK1 / 2 inhibition in a subject in need of such treatment. Some embodiments of the present disclosure include a method for treating abnormal cell growth in a subject, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. In certain such embodiments, the abnormal cell growth is cancer, and in some of these embodiments, the cancer is lung cancer, pancreatic cancer, skin cancer including melanoma, head and neck cancer, ovarian cancer, rectal cancer, colon cancer, breast cancer, thyroid cancer, chronic or acute leukemia, and renal cell carcinoma. Such cancer may be a KRAS-associated cancer. In some embodiments, the cancer comprises a solid tumor. Specifically, the cancer includes lung cancer, colon cancer, pancreatic cancer, and ovarian cancer. In some embodiments, the method for treating cancer is a method for treating chronic myeloid leukemia. In some embodiments, the cancer comprises a liquid tumor. In some embodiments, the cancer is chronic myeloid leukemia.

[0134] In one embodiment, the compound for use described above is administered in combination with one or more additional anti-cancer agents. Such additional anti-cancer agents include compounds from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors such as protein tyrosine kinase inhibitors and / or serine / threonine kinases and / or phosphatases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, tumor immunotherapy agents, etc. In some embodiments, the additional anti-cancer agent is a tyrosine kinase inhibitor. In a more preferred embodiment, the tyrosine kinase inhibitor is selected from imatinib and nilotinib. In several embodiments, the additional anti-cancer agent is administered simultaneously, sequentially, or separately with the compound or its pharma- ceutically acceptable salt. In one embodiment, the additional cancer treatment is radiation therapy.

[0135] In some embodiments, one or more compounds disclosed herein are administered to a subject suffering from a cancer with an alteration in one or more of the MAPK pathways, including cancer with an alteration in one or more of the RAS, SHP2, RAF, MEK, and ERK pathways. In some embodiments, the subject's cancer has one or more alterations in the RAS pathway. In some embodiments, the subject's cancer has one or more alterations in the RAF pathway. In some embodiments, the subject's cancer has one or more alterations in the MEK pathway. In some embodiments, the subject's cancer has one or more alterations in the ERK pathway. In some embodiments, one or more compounds disclosed herein are administered to a subject suffering from a cancer induced by cell signaling in the MAPK pathway.

[0136] In some embodiments, one or more compounds disclosed herein are administered to a subject suffering from a cancer that has one or more alterations in the PI3K-AKT pathway, including cancer that has one or more alterations in the PI3K, PTEN, and AKT pathways. In some embodiments, the subject's cancer has one or more alterations in the PI3K pathway. In some embodiments, the subject's cancer has one or more alterations in the PTEN pathway. In some embodiments, the subject's cancer has one or more alterations in the AKT pathway. In some embodiments, one or more compounds disclosed herein are administered to a subject suffering from a cancer that includes one or more alterations in the mTOR pathway.

[0137] In some embodiments, the cancer of interest has one or more alterations in the RAS pathway, including mutations in KRAS, such as G12C, G12D and G12V mutations.The KRAS inhibitors that can be used in combination with the compounds disclosed herein include, but are not limited to, one or more of AMG510, MRTX849 and GDC-6036.

[0138] In some embodiments, the cancer of the subject has one or more changes in RAF, including mutations to BRAF, including BRAF V600E.BRAF inhibitors that can be used in combination with the compounds disclosed herein include, but are not limited to, one or more of encorafenib, dabrafenib, and vemurafenib.

[0139] In some embodiments, the cancer of interest has one or more changes in ERK pathway.The ERK inhibitor that can be used in combination with the compounds disclosed herein includes but is not limited to one or more of ulixertinib, ASN007, LY3214996, AZ13767370, MK-8353, and LTT462.

[0140] In some embodiments, the cancer of the subject has one or more changes in MEK pathway.MEK inhibitors that can be used in combination with the compounds disclosed herein include, but are not limited to, one or more of trametinib, binimetinib, cobimetinib, and selumetinib.In some embodiments, the cancer of the subject can be treated by administering the compounds disclosed herein in combination with an inhibitor of mammalian target of rapamycin (mTOR).The mTOR inhibitors that can be used include, but are not limited to, sirolimus, everolimus, temsirolimus, and ridaforolimus (AP23573 and MK-8669).

[0141] The present disclosure also provides a method for treating cancers sensitive to ULK1 / 2 inhibition by simultaneously, separately, or sequentially administering (i) a compound as defined in any of the above embodiments or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and (ii) an additional anti-cancer agent. In some embodiments, the cancer is lung cancer, pancreatic cancer, skin cancer including melanoma, head and neck cancer, ovarian cancer, rectal cancer, colon cancer, breast cancer, thyroid cancer, chronic or acute leukemia, and renal cell carcinoma. Such cancers may be KRAS-associated cancers. In some embodiments, the cancer comprises a solid tumor. Specifically, the cancers include lung cancer, colon cancer, pancreatic cancer, and ovarian cancer. In some embodiments, the method for treating cancer is a method for treating chronic myeloid leukemia. In some embodiments, the cancer comprises a liquid tumor. In some embodiments, the cancer is chronic myeloid leukemia.

[0142] In some embodiments, the additional anti-cancer agent is an anti-angiogenic agent, including, for example, VEGF inhibitors, VEGFR inhibitors, PDGFR inhibitors, sunitinib, bevacizumab, axitinib, SU14813 (Pfizer), and AG13958 (Pfizer). Additional anti-angiogenic agents include sorafenib.

[0143] In other embodiments, the additional anticancer agent is a so-called signal transduction inhibitor (e.g., inhibits the means by which regulatory molecules that govern the processes fundamental to cell growth, differentiation, and survival communicate intracellularly). Signal transduction inhibitors include small molecules, antibodies, and antisense molecules. Signal transduction inhibitors include, for example, kinase inhibitors (e.g., tyrosine kinase inhibitors or serine / threonine kinase inhibitors) and cell cycle inhibitors. More specifically, signal transduction inhibitors include, for example, farnesyl protein transferase inhibitors, EGF inhibitors, ErbB-1 (EGFR), ErbB-2, pan erb, ERBB family inhibitors, IGF1R inhibitors, MEK, c-Kit inhibitors, Erk1 / 2 inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitors, P70S6 kinase inhibitors, WNT pathway inhibitors, and so-called multi-targeted kinase inhibitors.

[0144] In some embodiments, the additional anti-cancer agent is a tyrosine kinase inhibitor, hi some embodiments, the tyrosine kinase inhibitor is selected from imatinib and nilotinib.

[0145] As mentioned above, the compounds of the present disclosure may be used in combination with one or more additional anti-cancer agents. The effectiveness of the compounds of the present disclosure against a particular tumor may be enhanced by combination with other approved or experimental cancer treatments, such as radiation, surgery, chemotherapy agents, targeted therapy, agents that inhibit other signaling pathways that are dysregulated in tumors, and other immune enhancing agents, such as PD-1 antagonists.

[0146] When combination therapy is used, one or more additional anti-cancer agents may be administered sequentially or simultaneously with the compound of the present disclosure. In one embodiment, the additional anti-cancer agent is administered to the mammal (e.g., human) prior to administration of the compound of the present disclosure. In another embodiment, the additional anti-cancer agent is administered to the mammal after administration of the compound of the present disclosure. In another embodiment, the additional anti-cancer agent is administered to the mammal (e.g., human) simultaneously with administration of the compound of the present disclosure.

[0147] The present disclosure also relates to a pharmaceutical composition for treating abnormal cell growth in a mammal, including a human, comprising an amount of a compound of the present disclosure as defined above (including hydrates, solvates, and polymorphs of the compound or a pharma- ceutically acceptable salt thereof) in combination with one or more (preferably 1-3) additional anti-cancer therapeutic agents.

[0148] Within the scope of this disclosure, beneficial or desired clinical outcomes for a subject to which the compounds of this disclosure are administered alone or in the form of a pharma- ceutically acceptable composition include, but are not limited to, one or more of the following: reduced proliferation (or destruction) of neoplastic or cancer cells, inhibition of metastasis or neoplastic cells, reduction or decrease in tumor size, remission of cancer, reduction of symptoms caused by cancer, improvement of the quality of life of a person suffering from cancer, reduction of the dose of other drugs required for the treatment of cancer, delay of cancer progression, cure of cancer, overcoming one or more resistance mechanisms of cancer, and / or prolongation of the time a subject survives from cancer. Positive therapeutic effects on cancer can be measured in a number of ways (see, for example, WA Weber, Assessing tumor response to therapy, J.Nucl.Med.50 Suppl.1:1S-10S (2009)). For example, according to the National Cancer Institute (NCI) criteria for tumor growth inhibition (T / C), a T / C of 42% or less is the minimum level of antitumor activity. A T / C of less than 10% was considered a high level of antitumor activity, where T / C (%) = median tumor volume after treatment / median tumor volume in controls x 100.

[0149] In some embodiments, the treatment achieved by the treatments disclosed herein is defined by reference to any of partial response (PR), complete response (CR), overall response (OR), progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). PFS, also referred to as "time to tumor progression," refers to the time during and after treatment during which the cancer does not grow, and includes the amount of time during which the subject experiences CR or PR, as well as the amount of time during which the subject experiences stable disease (SD). DFS refers to the time during and after treatment during which the subject remains disease-free. OS refers to an increase in life expectancy compared to naive or untreated subjects. In some embodiments, the response to the combinations disclosed herein is any of PR, CR, PFS, DFS, OR, or OS, as assessed using the response criteria of Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

[0150] Treatment regimens for the compounds of the present disclosure, or pharmaceutical compositions comprising the compounds of the present disclosure, that are effective in treating cancer in a subject may vary depending on factors such as the disease state, age, and weight of the subject, and the ability of the treatment to induce an anti-cancer response in the subject. Any embodiment of the aspects of the present disclosure may not be effective in achieving a positive therapeutic effect in all subjects, but should be achieved in a statistically significant number of subjects, as determined by any statistical test known in the art, such as Student's t-test, chi2 test, Mann-Whitney U test, Kruskal-Wallis test (H test), Jonkheel-Tapstra test, and Wilcoxon test.

[0151] Dosage forms and regimens Administration of the compounds disclosed herein may be affected by any method that allows delivery of the compound to the site of action, including oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular, or infusion), topical, and rectal administration.

[0152] Dosage regimens can be adjusted to provide the desired optimal response. For example, a single bolus may be administered, multiple divided doses may be administered over time, or a single bolus may be dosed down or up in proportion to the exigencies of treatment. For ease of administration and uniformity of dosage, it is particularly convenient to formulate parenteral compositions as unit dosage forms. Unit dosage form, as used herein, refers to physically discrete units suitable as single dosages for the mammalian subject to be treated, each unit containing a predetermined amount of active compound calculated to provide the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for unit dosage forms disclosed herein are determined by and directly depend on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the technical limitations inherent in compounding such active compounds for treatment sensitivity in individuals.

[0153] Therefore, those skilled in the art will recognize that, based on the disclosure provided herein, the dose and administration regimen will be adjusted according to methods well known in the art of treatment. That is, the maximum tolerated dose can be easily established, and the effective amount that provides a detectable therapeutic benefit to the subject can be determined, as well as the time requirement for administration of each agent to provide a detectable therapeutic benefit to the subject. Thus, although specific doses and administration regimens are illustrated herein, these examples are in no way intended to limit the doses and administration regimens that can be provided to a subject in the practice of the present invention.

[0154] It should be noted that dosage values ​​vary depending on the type and severity of the disease to be alleviated and may include single or multiple doses. It should be further understood that for any particular subject, specific dosage regimens will need to be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the composition, and that the dosage ranges set forth herein are merely examples and are not intended to limit the scope or practice of the claimed compositions. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present invention encompasses dose escalation within a subject as determined by one of skill in the art. It will be understood that the determination of appropriate dosages and regimens for administration of chemotherapeutic agents is well known in the relevant art and is encompassed by one of skill in the art upon reading the teachings disclosed herein.

[0155] The dosage of the compounds disclosed herein will depend on the subject being treated, the severity of the disease or illness, the rate of administration, the deposition of the compound, and the discretion of the prescribing physician. However, effective amounts range from about 0.001 to about 100 mg per kg of body weight per day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this amount would be about 0.05 to about 7 g / day, preferably about 0.1 to about 2.5 g / day. In some instances, dosage levels below the lower end of the aforementioned range may be more than sufficient, while in other cases, larger doses may be utilized without causing any adverse side effects, provided that the dose is first divided into several smaller doses for administration throughout the day.

[0156] Formulation and route of administration The compound disclosed herein may be administered to a subject that requires administration in the form of a pharma- ceutically acceptable composition, which comprises one or more compounds disclosed herein and a pharma- ceutically acceptable carrier or excipient.Pharmaceutically acceptable carrier can comprise any conventional pharmaceutical carrier or excipient.The selection of carrier and / or excipient will depend to a greater extent on factors such as specific administration form, the effect of carrier or excipient on solubility and stability, and the nature of dosage form.

[0157] Suitable pharma- ceutically acceptable carriers include inert diluents or fillers, water, and various organic solvents, such as hydrates and solvates. Pharmaceutical compositions may contain additional ingredients, such as flavorings, binders, excipients, etc., if desired. Thus, for oral administration, tablets containing various excipients, such as citric acid, may be used with starch, alginic acid, and certain silicate complexes, as well as with binders, such as sucrose, gelatin, acacia, etc. Non-limiting examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. In addition, lubricants, such as magnesium stearate, sodium lauryl sulfate, and talc, are often useful for targeting purposes. Similar types of solid compositions may also be used in soft and hard-filled gelatin capsules. Thus, non-limiting examples of materials include lactose or milk sugar, and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with a diluent, such as water, ethanol, propylene glycol, glycerin, or combinations thereof, along with various sweeteners or flavorings, colorants or dyes, and, if desired, emulsifying or suspending agents. The pharmaceutical compositions may be in a form suitable for oral administration, for example, as tablets, capsules, pills, powders, sustained release formulations, suspensions, for parenteral injection as sterile solutions, suspensions, or emulsions, for topical administration as ointments or creams, or for rectal administration as suppositories.

[0158] Exemplary parenteral dosage forms include solutions or suspensions of the active compound in sterile solutions, such as aqueous propylene glycol or dextrose solutions. If desired, such dosage forms can be suitably buffered. Pharmaceutical compositions may be in unit dosage forms suitable for single administration of precise dosage amounts.

[0159] Pharmaceutical compositions suitable for delivery of the compounds disclosed herein, and methods for their preparation, will be readily apparent to those skilled in the art. Such compositions, and methods for their preparation, can be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995), which is incorporated herein by reference in its entirety.

[0160] The compounds disclosed herein can be administered orally.Oral administration may require swallowing so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used, where the compound enters the bloodstream directly from the mouth.Preparations suitable for oral administration include tablets, capsules containing microparticles, liquids, or pieces, lozenges (including those filled with liquid), chewable tablets, microparticles and nanoparticles, gels, solid solutions, liposomes, films (including mucoadhesives), ovules, sprays, and liquid preparations.

[0161] Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations can be used as fillers in soft or hard capsules, and typically include carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils, and one or more emulsifiers and / or suspending agents.Liquid formulations can also be prepared by reconstitution of solids, for example from sachets.

[0162] The compounds disclosed herein may also be used in fast-dissolving and fast-disintegrating dosage forms, such as those described in Expert Opinion in Therapeutic Patents, 11(6), 981-986 by Liang and Chen (2001), which is incorporated herein by reference in its entirety.

[0163] In tablet dosage forms, the drug may comprise 1 wt% to 80 wt% of the dosage form, more typically 5 wt% to 60 wt% of the dosage form, depending on the dosage. The tablet as a whole also contains a disintegrant in addition to the drug. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant will comprise 1 wt% to 25 wt%, preferably 5 wt% to 20 wt% of the dosage form.

[0164] Binders are generally used to provide cohesive properties to tablet formulations.Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.Tablets can also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dicalcium phosphate dihydrate.

[0165] Tablets may also optionally contain surface active agents such as sodium lauryl sulfate and polysorbate 80, and lubricants such as silicon dioxide and talc. Surface active agents, if present, are typically present in an amount of 0.2 wt% to 5 wt% of the tablet, and lubricants are typically present in an amount of 0.2 wt% to 1 wt% of the tablet.

[0166] Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Lubricants are generally present in an amount of 0.25 wt% to 10 wt%, preferably 0.5 wt% to 3 wt% of the tablet. Other conventional ingredients include antioxidants, colorants, flavorings, preservatives, and flavoring agents. An exemplary tablet contains up to about 80 wt% of drug, about 10 wt% to about 90 wt% of binder, about 0 wt% to about 85 wt% of diluent, about 2 wt% to about 10 wt% of disintegrant, and about 0.25 wt% to about 10 wt% of lubricant. Tablet formulations can be compressed directly or by roller to form tablets. Alternatively, the tablet formulation, or a portion thereof, can be wet-, dry-, or melt-granulated, melt-congealed, or extruded prior to tableting. The final formulation can include one or more layers, be coated or uncoated, or be encapsulated. Tablet formulation is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1," by H. Lieberman and L. Lachman, Marcel Dekker, NY, NY, 1980 (ISBN 0-8247-6918-X), which is incorporated herein by reference in its entirety.

[0167] Solid formulations for oral administration can be formulated to be immediate release and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release. Suitable modified release formulations are described in U.S. Pat. No. 6,106,864. Details of other suitable release techniques, such as high energy dispersions and osmotic coated particles, can be found in Verma et al., Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00 / 35298. The disclosures of these references are incorporated herein by reference in their entirety.

[0168] Compounds disclosed herein can also be administered directly into bloodstream, muscle or internal organs.Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular and subcutaneous.Suitable devices for parenteral administration include needle (including microneedle) syringe, needleless syringe and infusion technology product.

[0169] Parenteral formulations may typically contain excipients such as salts, carbohydrates, and buffers (preferably up to pH 3-9), although for some applications they may be more suitably formulated as non-sterile aqueous solutions or as dry forms used in combination with a suitable vehicle, such as sterile pyrogen-free water. Preparation of parenteral formulations under sterile conditions, for example by lyophilization, may be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of the compounds disclosed herein used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility enhancers. Formulations for parenteral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release. Thus, the compounds disclosed herein may be formulated as solids, semi-solids, or thixotropic liquids for administration as implanted depots that provide modified release of the active compound. Examples of such formulations include drug-coated stents, and PGLA microspheres.

[0170] The compounds disclosed herein may also be administered topically to the skin or mucosa, i.e., dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated. See, for example, J Pharm Sci, 88(10), 955-958 by Finnin and Morgan (October 1999). Other local administration means include electroporation, iontophoresis, phonophoresis, sonophoresis, and injection with or without microneedles (e.g., Powderject.TM, Bioject.TM, etc.). The disclosures of these references are incorporated herein by reference in their entirety. Formulations for topical administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release.

[0171] The compounds disclosed herein can also be administered intranasally or by inhalation, typically in the form of a dry powder (alone, in admixture, e.g., dry blend with lactose, or in admixture with mixed particle components, e.g., phospholipids such as phosphatidylcholine), with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, from a dry powder inhaler, or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer. For intranasal use, the powder can include a bioadhesive agent, such as chitosan or cyclodextrin. The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound disclosed herein, including, for example, ethanol, aqueous ethanol, or alternative suitable agents for dispersion, solubilization, or sustained release of the active propellant as a solvent and optional surfactant, such as sorbitan trioleate, oleic acid, or oligolactic acid. Prior to use in a dry powder or suspension formulation, the pharmaceutical agent may be micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be accomplished by any suitable fine powder method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying. Capsules (e.g., made of gelatin or HPMC), blisters, and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mixture of the compound disclosed herein, a suitable powder base, such as lactose or starch, and a performance modifier, such as I-leucine, mannitol, or magnesium stearate. The lactose can be anhydrous or in the form of lactose monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.A suitable solution formulation for use in an atomizer that uses electrohydrodynamics to produce a fine mist contains 1 μg-20 mg of a compound disclosed herein per actuation, and actuation volumes can vary from 1 μL to 100 μL. A typical formulation includes a compound disclosed herein, propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol. For inhalation / intranasal administration, suitable flavors such as menthol or levomenthol, or sweeteners such as saccharin or sodium saccharin, may be added to the formulations disclosed herein. Formulations for inhalation / intranasal administration are formulated to be immediate and / or modified release, for example using glycolic / lactic acid copolymers (PGLA). Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release. For dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a metered amount. Units according to the invention are typically arranged to administer a metered dose or "puff" containing a desired amount of a compound disclosed herein. The total daily dose may be administered in a single dose, or, more usually, in divided doses throughout the day.

[0172] The compounds disclosed herein may be administered rectally or vaginally, for example in the form of suppository, pessary, or enema.Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.Formulations for rectal / vaginal administration may be formulated to be immediate release and / or modified release.Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

[0173] The compounds disclosed herein may also be administered directly to the eye or ear, typically in the form of drops of finely divided suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for administration to the eye and ear include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses, and microparticulate or vesicular systems such as niosomes or liposomes. Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gellan gum may be incorporated with preservatives such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. Formulations for topical administration to the eye / ear may be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, or programmed release.

[0174] The compounds disclosed herein may be combined with soluble macromolecular entities such as cyclodextrin and its suitable derivatives, or polyethylene glycol-containing polymers, to improve solubility, dissolution rate, taste masking, bioavailability, and / or stability in any of the above-mentioned dosage forms. Complexes of drugs with cyclodextrins, for example, have been found to be useful in most dosage forms and routes of administration overall. Both non-inclusion and inclusion complexes may be used. Instead of direct complexation with the drug, cyclodextrins may be used as auxiliary additives, i.e., carriers, diluents, or solubilizers. The most commonly used for these purposes are α, β, and γ cyclodextrins, examples of which can be found in WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148, which are incorporated herein by reference in their entirety.

[0175] Kit-of-Parts Within the scope of the present disclosure, two or more pharmaceutical compositions, at least one of which contains a compound according to the present disclosure, may be conveniently combined in the form of a kit suitable for simultaneous administration of the compositions. Thus, the kits disclosed herein comprise two or more separate pharmaceutical compositions, at least one of which contains a compound disclosed herein, and a means for separately holding the aforementioned pharmaceutical compositions, such as a container, a divided bottle, or a divided foil packet. An example of such a kit is the familiar blister pack used for packaging tablets, capsules, and the like. The kits disclosed herein are particularly suitable for administering different dosage forms, for example oral and parenteral, administering separate compositions at different dosage intervals, or titrating separate compositions against each other. To aid compliance, the kits typically include instructions for administration, and may be provided with a memory aid. EXAMPLES

[0176] material and method General Procedure for the Synthesis of Compounds Chromatography Preparative high pressure liquid chromatography was performed using an Agilent instrument. The instrument was configured to monitor the chromatography with a multi-wavelength UV detector (Agilent G1365B) and a MM-ES+APCI mass spectrometer (Agilent G-1956A) connected in series, and to collect samples with an automatic fraction collector (Agilent G1364B) when appropriate criteria were met. Collection could be guided by any combination of UV spectrometer or mass spectrometer, or based on time. Typical conditions for the separation process were as follows: The chromatography column was an Xbridge C-18 (19×100 mm). The gradient was run for 7 minutes at a flow rate of 40 mL / min (starting gradient: 10% methanol and 90% water, ending gradient: 100% methanol and 0% water, with either 0.1% formic acid, 0.1% ammonium hydroxide or 0.1% trifluoroacetic acid added to the water as buffer). One of skill in the art will appreciate that it may be necessary or desirable to modify conditions for each particular compound, for example, by changing the starting or ending solvent composition, modifying solvents or buffers, changing run times, flow rates and / or changing chromatographic columns.

[0177] Flash chromatography refers to silica gel chromatography and was performed using an SP4 or Isolara 4 MPLC system (Biotage), prepackaged silica gel cartridges (provided by Biotage), or using conventional glass column chromatography.

[0178] Analysis method 1H nuclear magnetic resonance (NMR) spectroscopy was performed near room temperature in the solvents stated, using an ECX400 spectrometer (JEOL) unless otherwise stated. In all cases, the NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million using conventional abbreviations for the designation of major peaks; e.g., s for singlet, d for doublet, t for triplet, q for quartet, dd for doublet of doublets, and br for broadened term. Analytical LCMS was typically performed using an Agilent HPLC instrument equipped with a C-18 Xbridge column (3.5 μm, 4.6 × 30 mm, starting gradient: 10% organic and 90% water, ending gradient: organic and 0% water, with either 0.1% ammonium hydroxide or 0.1% trifluoroacetic acid added to the water as buffer). The organic solvent was either acetonitrile or methanol. A flow rate of 3 mL / min was used with UV detection at 254 and 210 nm.

[0179] Mass spectra were recorded using a MM-ES+APCI mass spectrometer (Agilent G-1956A). When thin layer chromatography (TLC) was used, this refers to silica gel TLC using silica gel MK6F 60 Å plates; f is the distance traveled by the compound divided by the distance traveled by the solvent on the TLC plate.

[0180] Preparation of compounds If the preparation of starting materials is not described, they are commercially available, known in the literature, or easily accessible by those skilled in the art using standard procedures. Where compounds are shown to have been prepared similarly to previous examples or intermediates, those skilled in the art will understand that reaction times, equivalents of reagents, solvents, concentrations, and temperatures can be modified for each particular reaction, and that it may be necessary or desirable to employ different work-up or purification techniques.

[0181] When reactions are carried out using microwave irradiation, the microwave used is an Initiator 60 from Biotage. The actual power supplied is varied during the course of the reaction to maintain a constant temperature.

[0182] Some hydrogenation processes were carried out using a ThalesNano H-Cube® continuous flow hydrogenation reactor. The catalysts were provided by ThalesNano as cartridges, "CatCarts". Pressures, flow rates, temperatures and cartridges are indicated in the experimental section. The equipment was used according to the manufacturer's operating procedures. Those skilled in the art will appreciate that it may be necessary or desirable to repeatedly cycle the reaction mixture, possibly replacing cartridges between cycles, to improve the yield of the reaction.

[0183] Abbreviation Some common abbreviations are listed below, other abbreviations not listed may be used and will be understood by those skilled in the art. DCM = dichloromethane DMF = N,N-dimethylformamide THF = tetrahydrofuran MeOH = methanol TFA = trifluoroacetic acid Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene HATU = N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate EDCI = 1,3-propanediamine, N3-(ethylcarbonimidoyl)-N1,N1-dimethyl-, hydrochloride DCC = 1,3-dicyclohexylcarbodiimide Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0) TEA = triethylamine rm = reaction mixture rt=room temperature AcOH = acetic acid IPA = Isopropanol DIPEA = N,N-diisopropylethylamine TBSMSCl = tertiary butyl dimethyl silyl chloride MeCN = acetonitrile NH3 = Ammonia EtOH = ethanol EtOAc = ethyl acetate LCMS = High Pressure Liquid Chromatography Directed to Mass Spectrometry UV=ultraviolet light SCX = strong cation exchange TPAP = Tetrapropylammonium perruthenate DMSO = dimethyl sulfoxide BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl TPAP = Tetrapropylammonium perruthenate DIAD = diisopropyl azodicarboxylate NMO = N-methylmorpholine N-oxide

[0184] Compound synthesis Intermediate 1: 1-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one

[0185] [ka]

[0186] Step 1: Synthesis of 3-(2-oxopiperidin-1-yl)propanenitrile To a stirred solution of piperidin-2-one (10.0 g, 101 mmol) in THF (250 mL) was added 60% NaH (4.8 g, 202 mmol) at 0°C, warmed to room temperature and stirred for 30 min. The reaction mixture was cooled to 0°C and 2-bromopropionitrile (10.5 mL, 121 mmol) was added dropwise over 20 min, warmed to room temperature and stirred for 2 h. After completion of the reaction (TLC), the reaction mass was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh, 20% ethyl acetate in petroleum ether) to give a pale yellow liquid (8.0 g, 52%). 1 H NMR (400MHz, CDCl3): δ3.58(t,J=6.8Hz,2H),3.48(t,J=5.2Hz,2H),2.69(t,J =6.4Hz,2H),2.40(t,J=6.8Hz,2H),1.80-1.88(m,4H);LCMS(m / z)=153.1[M+H] +

[0187] Step 2: Synthesis of 1-(3-aminopropyl)piperidin-2-one To a stirred solution of 3-(2-oxopiperidin-1-yl)propanenitrile (10.0 g, 65 mmol) in MeOH (200 mL) was added NH4OH (25 mL) and Ra-Ni (wet) (6.0 g) at room temperature under nitrogen atmosphere, and the resulting reaction mixture was stirred under H2 (balloon) pressure for 16 h. After completion of the reaction (TLC), the reaction mixture was filtered through a Celite pad and washed with methanol. The filtrates were combined and concentrated to give a colorless liquid (8.0 g, 78%). 1 H NMR(400MHz,DMSO-d6):δ3.10-3.31(m,5H),2.44(q,J=15.2Hz,1H),2.32(t,J =4.8Hz,1H),2.18(t,J=6.0Hz,2H),1.83-1.49(m,7H);LCMS(m / z)=157.1[M+H] +

[0188] Step 3: Synthesis of 1-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one DIPEA (33.4mL, 192mmol) was added to a solution of 1-(3-aminopropyl)piperidin-2-one (30g, 192mmol) in IPA (300mL) at 0°C and stirred for 10 minutes. The resulting solution was cooled to -78°C and a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (50.0g, 230mmol) in IPA (50mL) was added and stirred at room temperature for 16 hours. After completion of the reaction (TLC), the reaction mixture was concentrated, diluted with cold water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude compound was purified by column chromatography (SiO2, 100-200 mesh, 50% ethyl acetate in petroleum ether) to give intermediate 1 (18g, 28%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6):δ8.39(d,J=0.8Hz,1H),8.01(t,J=5.2Hz,1H),3.41-3.36(m,2H ),3.31-3.25(m,4H),2.23(t,J=6.4Hz,2H),1.75-1.69(m,6H);LCMS(m / z)=337.0[M+H] +

[0189] Intermediate 2: 1-(6-amino-7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone

[0190] [ka]

[0191] Step 1: Synthesis of N-[2-(4-chlorophenyl)ethyl]-2,2,2-trifluoro-acetamide To a solution of 2-(4-chlorophenyl)ethanamine (50.0 g, 321 mmol) in DCM (600 mL) was added triethylamine (44.7 mL, 323 mmol) followed by trifluoroacetic anhydride (67.7 g, 322.5 mmol) at 0° C. and the mixture was stirred at 0° C. for 4 h. After completion of the reaction (by TLC), the mixture was diluted with DCM and washed with water and brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give an off-white solid (60.0 g, 75%). 1 H NMR(400MHz,DMSO-d6):δ9.47(s,1H),7.24(d,J=8.4Hz,2H),7.24(d,J=8.0Hz,2H),3.38-3.43(q,J=13.2&7.2Hz,2H),2.79(t,J=7.2Hz,2H)

[0192] Step 2: Synthesis of 1-(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone To a solution of N-[2-(4-chlorophenyl)ethyl]-2,2,2-trifluoro-acetamide (50 g, 198 mmol) in acetic acid (107 mL) was added concentrated sulfuric acid (71.5 mL) followed by p-formaldehyde (15.8 g, 397.4 mmol) at 0° C., warmed to room temperature and stirred for 4 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution and brine solution, dried over anhydrous Na2SO4, filtered and concentrated to give the compound as a viscous oil (45 g, 86%), which was used in the next step without further purification.

[0193] Step 3: Synthesis of 1-(7-chloro-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone To a solution of 1-(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (50 g, 190 mmol) in concentrated sulfuric acid (500 mL) was added nitric acid (23.9 g, 379 mmol) at -10°C and stirring was continued for 4 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh, 10% ethyl acetate in petroleum ether) to give a pale yellow solid (35 g, 60%). LCMS (m / z) = 307.0 [MH] +

[0194] Step 4: Synthesis of 1-(6-amino-7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone To a solution of 1-(7-chloro-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (14 g, 45.4 mmol) in ethyl acetate (140 mL) was added SnCl2.2H2O (51.2 g, 227 mmol) followed by water (3.5 mL) at room temperature and stirred for 16 h. The reaction mixture was concentrated and purified by flash column chromatography (SiO2, 100-200 mesh, 10% ethyl acetate in petroleum ether) to give intermediate 2 as a brown solid (5.0 g, 40%). 1 H NMR(400MHz,DMSO-d6):δ7.14(d,J=12.8Hz,1H),6.59(d,J=3.2Hz,1H),5.27(d,J=10.4Hz ,2H),4.57(d,J=8.4Hz,2H),3.75-3.70(m,2H),2.78-2.73(m,2H);LCMS(m / z)=279.4[M+H] +

[0195] Intermediate 3: 1-(6-amino-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one

[0196] [ka]

[0197] Step 1: Synthesis of 2,2,2-trifluoro-N-(4-methoxyphenethyl)acetamide To a solution of 2-(4-methoxyphenyl)ethan-1-amine (5.0 g, 33 mmol) in DCM (150 mL) was added triethylamine (11.5 mL, 80 mmol) followed by trifluoroacetic anhydride (7.5 g, 35.2 mmol) at 0° C. and stirring was continued at the same temperature for 4 h. The reaction mixture was diluted with DCM and washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give an off-white solid (7.1 g, 87%). 1 H NMR (400MHz, CDCl3): δ7.12-7.09(m,2H),6.89-6.85(m,2H),6.27(brs,1H),3.80( s,3H),3.59(q,J=13.6&6.8Hz,2H),2.83(t,J=7.2Hz,2H);LCMS(m / z):248.3[M+H] +

[0198] Step 2: Synthesis of 2,2,2-trifluoro-N-(4-methoxy-3-nitrophenethyl)acetamide To a solution of 2,2,2-trifluoro-N-(4-methoxyphenethyl)acetamide (4.0 g, 16.2 mmol) in TFA (50 mL) was added nitric acid (3.3 mL, 36.1 mmol) at -10°C and stirring was continued at the same temperature for 2 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude compound was purified by column chromatography (SiO2, 100-200 mesh, 1% methanol in dichloromethane) to give a pale yellow solid (3.1 g, 65%). 1H NMR (400MHz, CDCl3): δ7.70(d,J=2.4Hz,1H),7.38(dd,J=2.0Hz&8.4Hz,1H),7.06(d,J=8.8Hz,1H),6 .35(brs,1H),3.96(s,3H),3.62(q,J=13.6&6.8Hz,2H),2.91(t,J=7.Hz,2H);LCMS(m / z):293.3[M+H] +

[0199] Step 3: Synthesis of 2,2,2-trifluoro-1-(7-methoxy-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one To a solution of 2,2,2-trifluoro-N-(4-methoxy-3-nitrophenethyl)acetamide (2.0 g, 6.85 mmol) in acetic acid (13.2 mL) was added concentrated sulfuric acid (20 mL) followed by p-formaldehyde (10.3 g, 34.2 mmol) at 50° C. and stirred at room temperature for 3.5 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution followed by brine solution. The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude compound was purified by preparative HPLC to give a pale yellow solid (1.5 g, 72%). 1 H NMR(400MHz,DMSO-d6):δ7.71(s,1H),7.30(s,1H),4.82(s,2H),3.90(s,3H),3.82(t,J=5.6Hz,2H),2.91(s,2H);LCMS(m / z):305.3[M+H] +

[0200] Step 4: Synthesis of 1-(6-amino-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one To a solution of 2,2,2-trifluoro-1-(7-methoxy-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (1.5 g, 4.93 mmol) in methanol (200 mL), Pd / C (0.3 g) was added at room temperature and stirred under hydrogen (balloon pressure) for 2 h. The reaction mixture was filtered through Celite, washed with methanol, and the filtrate was concentrated. Purification by column chromatography (SiO2, 100-200 mesh, 10% ethyl acetate in petroleum ether) gave a brown solid (0.580 g, 43%), which was used in the next step without further purification. LCMS (m / z): 275.1 [M+H] +

[0201] Intermediate 4: 2-Methyl-1,2,3,4-tetrahydroisoquinolin-6-amine

[0202] [ka]

[0203] Step 1: Synthesis of 2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-4-nitrobenzoic acid Sodium methoxide (12.9 g, 238 mmol) was added slowly to a slurry of 2-chloro-4-nitrobenzoic acid (10 g, 49.6 mmol) and copper(I) bromide (0.712 g, 4.96 mmol) in dimethyl malonate (113 mL, 992.2 mmol). The resulting reaction mixture was stirred at room temperature for 15 minutes and then heated at 70 °C with vigorous stirring for 24 hours. The reaction mixture was cooled to room temperature and diluted with water (100 mL) and hexanes (100 mL). The aqueous layer was separated and toluene (100 mL) was added. The mixture was filtered through Celite and washed with hexanes (100 mL) and toluene (100 mL). The resulting biphasic mixture was acidified to pH 1 with 6N HCl solution and the precipitate was filtered, washed with toluene (150 mL) and hexanes (150 mL) and dried under vacuum to give a white solid (3 g, 20%). 1H NMR(300MHz,DMSO-d6):δ13.8(br s,1H),8.32(dd,J1=2.4Hz,J2=8.7Hz,1H),8.22-8.15(m,2H),5.81(s,1H),3.69(s,6H);LCMS(m / z):298.30(M+H) +

[0204] Step 2: Synthesis of 2-(carboxymethyl)-4-nitrobenzoic acid A solution of sodium hydroxide (16.1 g, 403 mmol) in water (120 mL) was added to a solution of 2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-4-nitrobenzoic acid (24 g, 80.74 mmol) in methanol (120 mL) at room temperature over 90 min, and the mixture was stirred for 3 h. The mixture was concentrated under reduced pressure, and the residue was acidified with concentrated HCl (22.4 mL) at room temperature. The resulting white aqueous suspension was extracted twice with 250 mL of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate volume reduced to 100 mL. The resulting solution was heated to 70° C. for 6 h, and the precipitated solid was filtered, washed with ethyl acetate, and dried under vacuum to give a white solid (13 g, 71%). 1 H NMR (300MHz, DMSO-d6): δ13.8-12.4 (br s, 2H), 8.27 (d, J = 2.1 Hz, 1 H), 8.22-8.19 (m, 1 H), 8.09 (d, J = 9.0 Hz, 1 H), 4.09 (s, 2 H).

[0205] Step 3: Synthesis of 2-(2-(hydroxymethyl)-5-nitrophenyl)ethan-1-ol To a solution of 2-(carboxymethyl)-4-nitrobenzoic acid (13 g, 57.7 mmol) in THF (60 mL) was added 1 M borane in THF (289 mL, 289 mmol) at 0° C. The resulting reaction mixture was allowed to warm to room temperature and then heated at 70° C. for 3 h. The reaction mixture was cooled to room temperature and then to 0° C., quenched with methanol, and the resulting reaction mixture was heated to reflux for 2 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate (300 mL) and water (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give an off-white solid (9 g, 79%). 1 H NMR(400MHz,D2O):δ8.07-8.06(m,2H),7.68(d,J=8.4Hz,1H),4.65(s,2H),3.67-3.63(m,2H),2.83(t,J=6.4Hz,2H)

[0206] Step 4: Synthesis of 2-(2-((methylsulfonyl)oxy)ethyl)-4-nitrobenzyl methanesulfonate To a solution of 2-(2-(hydroxymethyl)-5-nitrophenyl)ethan-1-ol (4 g, 20.3 mmol) in dry DCM (40 mL) was added triethylamine (8.4 mL, 60.8 mmol) and methanesulfonyl chloride (5.8 g, 50.7 mmol) at 0° C. and stirring was continued at the same temperature for 30 min. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (50 mL) and saturated aqueous NaHCO3 (40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give an off-white solid (4 g, 56%). (m / z): 376.25 (M+Na) +

[0207] Step 5: Synthesis of 2-methyl-6-nitro-1,2,3,4-tetrahydroisoquinoline To a solution of 2-(2-((methylsulfonyl)oxy)ethyl)-4-nitrobenzyl methanesulfonate (4 g, 11.31 mmol) in THF (20 mL) was added methylamine (2 M in THF) (40 mL) at 0° C., the mixture was allowed to warm to room temperature and then heated at 100° C. in a sealed tube for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by flash column chromatography on silica gel 100-200 mesh (gradient elution from 40-50% EtOAc / petroleum ether) to give a white solid (1.5 g, 69%). 1 H NMR (400MHz, CDCl3): δ7.99-7.95(m,2H),7.16(d,J=8.4Hz,1H),3.65(s,2H),3.01(t,J=6.0H,2H),2.72(t,J=6.0Hz,2H),2.48(s,3H).

[0208] Step 6: Synthesis of 2-methyl-1,2,3,4-tetrahydroisoquinolin-6-amine A Parshaker vessel was charged with a solution of 2-methyl-6-nitro-1,2,3,4-tetrahydroisoquinoline (1.5 g, 7.80 mmol) in methanol (45 mL) and 10% Pd / C (200 mg). The mixture was hydrogenated at 50 psi for 2 h. The reaction mixture was filtered through a pad of Celite, washed with methanol, and the filtrate was concentrated to give a brown gel (1.2 g, 95%). 1 H NMR (400MHz, CDCl3): δ6.80(d,J=8.4Hz,1H),6.49-6.44(m,2H),3.51(brs,2H),3.46(s, 2H),2.82(t,J=6.0Hz,2H),2.63(t,J=6.0Hz,2H),2.42(s,3H);LCMS(m / z):163.40(M+H) +

[0209] Intermediate 5: 2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-amine

[0210] [ka]

[0211] Step 1: Synthesis of 7-nitro-1,2,3,4-tetrahydroisoquinoline 1,2,3,4-Tetrahydroisoquinoline (10 g, 75.08 mmol) was added dropwise to a stirred ice-cold solution of concentrated H2SO4 (37.5 mL). KNO3 (8.34 g, 82.58 mmol) was then added portion wise while maintaining the temperature below 5°C. The resulting reaction mixture was stirred at room temperature for an additional 16 hours. The reaction mixture was carefully poured into an ice-cold solution of concentrated ammonium hydroxide and then extracted with chloroform. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting dark brown oil was taken up in ethanol, cooled in an ice bath and treated with concentrated HCl. The yellow precipitate was collected by filtration and recrystallized from methanol to give a yellow solid (4 g, 30%). 1 H NMR(400MHz,DMSO-d6):δ9.69(brs,1H),8.21(d,J=2.0Hz,1H),8.11(dd,J1=2.4,J2=8.4Hz,1H),7.52 (d,J=8.8Hz,1H),4.38(s,2H),3.39(t,J=6.4Hz,2H),3.14(t,J=6.4Hz,2H);LCMS(m / z):179.34(M+H) +

[0212] Step 2: Synthesis of 2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline To a mixture of formaldehyde (8.2 mL) and formic acid (5 mL) was added 7-nitro-1,2,3,4-tetrahydroisoquinoline (2 g, 11.22 mmol) and the mixture was heated at 100 °C for 4 h. The reaction was cooled to room temperature, poured into ice, basified to pH 11 with aqueous ammonia, and the precipitated gummy residue was extracted twice with 150 mL of dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography using fluorosil (eluent: 0-5% HCl-DCM) gave a black solid (900 mg, 42%). 1H NMR(400MHz,DMSO-d6):δ7.99-7.97(m,2H),7.39(d,J=9.2Hz,1H),3.59(s,2H),2 .93(t,J=6.0Hz,2H),2.62(t,J=6.0Hz,2H),2.35(s,3H);LCMS(m / z):193.45(M+H) +

[0213] Step 3: Synthesis of 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine A Parshaker vessel was charged with a solution of 2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (1 g, 5.20 mmol) in methanol (45 mL) and 10% Pd / C (100 mg) was added at room temperature under nitrogen. The mixture was hydrogenated at 50 psi for 3 h. The reaction mixture was filtered through a pad of Celite, washed with methanol, and the filtrate was concentrated to give a pale yellow solid (600 mg, 71%). 1 H NMR(300MHz,DMSO-d6):δ6.72(d,J=8.1Hz,1H),6.35(dd,J1=2.1Hz,J2=8.1Hz,1H),6.21(d,J=1.8Hz,1H), 4.75(s,2H),3.30(s,2H),2.61(t,J=6.0Hz,2H),2.50-2.46(m,2H),2.28(s,3H);LCMS(m / z):163.26(M+H) +

[0214] Intermediate 6: 2-chloro-N-(3-(pyrrolidin-1-yl)propyl)-5-(trifluoromethyl)pyrimidin-4-amine

[0215] [ka]

[0216] To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1 g, 4.60 mmol) in IPA (20 mL) was added DIPEA (2.4 mL, 13.82 mmol) and 3-(pyrrolidin-1-yl)propan-1-amine (0.88 g, 6.91 mmol) at 0° C., the mixture was stirred at room temperature and then heated at 50° C. for 16 h. The reaction mixture was evaporated, the residue was taken up in ethyl acetate (40 mL), washed with water (40 mL), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 50% ethyl acetate / petroleum ether) to give an off-white solid (250 mg, 18%). 1 H NMR (400MHz, CDCl3): δ8.99(brs,1H),8.17(s,1H),3.23(q,J=5.6Hz,2H),2.7 0(t,J=5.6Hz,2H),2.55(brs,4H),1.80-1.76(m,6H);LCMS(m / z):309.39(M+H) +

[0217] Intermediate 7: 1-(3-(2-chloro-5-cyclopropylpyrimidin-4-ylamino)propyl)pyrrolidin-2-one

[0218] [ka]

[0219] To a stirred solution of 2,4-dichloro-5-cyclopropylpyrimidine (400 mg, 2.11 mmol) in IPA (5 mL) was added DIPEA (0.55 mL, 3.16 mmol) and 1-(3-aminopropyl)pyrrolidin-2-one (0.33 mL, 2.32 mmol) at 0° C., and the reaction mixture was heated at 50° C. for 16 h. The mixture was concentrated under reduced pressure, and the residue was partitioned between water (20 mL) and ethyl acetate (30 mL). The aqueous layer was extracted twice with 30 mL of ethyl acetate, and the combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude compound was purified by automated flash chromatography (gradient elution from 0-5% MeOH / DCM) to give a white solid (350 mg, 56%). 1 H NMR (300MHz, CDCl3): δ7.73(s,1H),6.95-6.86(m,1H),3.53-3.37(m,6H),2.46(t,J=8.1Hz,2H),2.14-2.04( m,2H),1.81-1.73(m,2H),1.53-1.49(m,1H),1.05-0.98(m,2H),0.58-0.52(m,2H);LCMS(m / z):295.47[M+H] + .

[0220] Intermediate 8: 1-(3-((2-chloro-5-cyclopropylpyrimidin-4-yl)amino)propyl)piperidin-2-one

[0221] [ka]

[0222] To a stirred solution of 2,4-dichloro-5-cyclopropylpyrimidine (300 mg, 1.58 mmol) in IPA (5 mL) was added DIPEA (0.83 mL, 4.74 mmol) and 1-(3-aminopropyl)piperidin-2-one at 0° C. TFA salt (602 mg, 2.37 mmol) was added and stirring was continued at room temperature for 5 h. The reaction mixture was evaporated and the residue was taken up in ethyl acetate (20 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash column chromatography (silica gel, 100-200 mesh, eluted with 20% ethyl acetate / petroleum ether) gave an off-white solid (200 mg, 41%). 1 H NMR (400MHz, CDCl3): δ7.72(s,1H),7.10(brs,1H),3.51-3.46(m,4H),3.30(t,J=5.6Hz,2H),2.43(t,J=5.6H z,2H),1.87-1.73(m,6H),1.57-1.50(m,1H),1.04-0.99(m,2H),0.58-0.52(m,2H);LCMS(m / z):309.43(M+H) +

[0223] Intermediate 9: 4-(4-aminophenyl)-1-methylpiperidin-4-ol

[0224] [ka]

[0225] Step 1: Synthesis of 4-(4-bromophenyl)-1-methylpiperidin-4-ol To a solution of 1,4-dibromobenzene (15 g, 63.58 mmol) in dry tetrahydrofuran (150 mL), n-BuLi (2.5 M in n-hexane, 28 mL, 69.93 mmol) was added at −78° C. under nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 min. N-Methyl 4-piperidone 19 (7.91 g, 69.93 mmol) was added at −78° C., and the resulting reaction mixture was stirred at −78° C. for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution (30 mL) and diluted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give an off-white solid (6 g, 35%). 1 H NMR(300MHz,DMSO-d6):δ7.50-740(m,4H),4.86(s,1H),2.56-2.48(m,2H),2.37- 2.28(m,2H),2.19(s,3H),1.90(dt,J1=4.2,12.6Hz,2H),1.54(d,J=11.4Hz,2H).

[0226] Step 2: Synthesis of 4-(4-((diphenylmethylene)amino)phenyl)-1-methylpiperidin-4-ol A mixture of 4-(4-bromophenyl)-1-methylpiperidin-4-ol (3 g, 11.10 mmol), benzophenone imine (2.41 g, 13.3 mmol), cesium carbonate (10.8 g, 33.3 mmol) in 1,4-dioxane (60 mL) was degassed with argon for 5 min, followed by the addition of Xantphos (0.81 g, 0.88 mmol) and Pd2(dba)3 (0.60 g, 0.66 mmol). The resulting reaction mixture was heated at 100 °C for 16 h, cooled to room temperature, filtered through a pad of Celite and washed with ethyl acetate. The filtrate was concentrated and the residue was purified by flash column chromatography (gradient elution from 2-5% MeOH in DCM) to give an off-white solid. 1H NMR(300MHz,DMSO-d6):δ7.62(dd,J1=1.8,J2=8.4Hz,1H),7.52-7.42(m,4H),7.33-7.31(m,3H),7.23(d,J=8.4Hz,2H),7.16-7.13(m,2H),6.63(d ,J=8.7Hz,2H),4.61(s,1H),2.49-2.48(m,2H),2.32-2.25(m,2H),2.16( s,3H),1.88-1.78(m,2H),1.48(d,J=11.7Hz,2H);LCMS(m / z):371.4(M+H) +

[0227] Step 3: Synthesis of 4-(4-aminophenyl)-1-methylpiperidin-4-ol A mixture of 4-(4-((diphenylmethylene)amino)phenyl)-1-methylpiperidin-4-ol 22 (1.5 g, 4.05 mmol), sodium acetate (0.83 g, 10.13 mmol) and hydroxylamine hydrochloride (0.5 g, 7.47 mmol) in methanol (30 mL) was stirred at room temperature for 2 h. The mixture was concentrated and diluted with dichloromethane and 0.1 M NaOH solution. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (gradient elution from 2-5% MeOH in DCM) gave a pale yellow solid (0.3 g, 36%). LCMS (m / z): 207.42 (M+H). +

[0228] Intermediate 10: 2-Chloro-N,5-dicyclopropylpyrimidin-4-amine

[0229] [ka] To a solution of 2,4-dichloro-5-cyclopropylpyrimidine (0.5 g, 2.65 mmol) in IPA (5 mL) was added DIPEA (0.68 mL, 3.98 mmol) and cyclopropylamine (0.18 g, 3.19 mmol) and the mixture was stirred at 50° C. for 16 h. The reaction mixture was evaporated, the residue was taken up in ethyl acetate (20 mL), washed with water (20 mL) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash column chromatography (eluent: 20% ethyl acetate / petroleum ether) gave a white solid (0.4 g, 72%). 1 H NMR(300MHz,DMSO-d6):δppm7.68(d,J=0.9Hz,1H),7.41(d,J=2.7Hz,1H),2.86-2.80(m,1H),1.5 7-1.51(m,1H),0.88-0.82(m,2H),0.78-0.72(m,2H),0.63-0.52(m,4H).LCMS(m / z):210.39[M+H] + .

[0230] Intermediate 11: tert-Butyl 7-amino-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0231] [ka]

[0232] Step 1: Ethyl N-[2-(3-fluorophenyl)ethyl]carbamate To 3-fluorophenethylamine (1.0 g, 7.19 mmol) in EtN (2.08 mL, 1.43 mmol) was added ethyl chloroformate (0.82 mL, 8.63 mmol) dropwise and the solution was stirred and allowed to warm to room temperature over 2.5 h. The reaction mixture was concentrated in vacuo to give a white solid. This was triturated with EtOAc, the solids removed by vacuum filtration, and the filtrate concentrated in vacuo to give the product, ethyl N-[2-(3-fluorophenyl)ethyl]carbamate, as a yellow oil (1.45 g, 68.7 mmol, 96%). 1H NMR (400 MHz, chloroform-d) d 7.23-7.30 (m, 1H), 6.97 (d, J = 7.33 Hz, 1H), 6.87-6.95 (m, 2H), 4.53-4.78 (m, 1H), 4.11 (q, J = 7.02 Hz, 2H), 3.43 (q, J = 6.87 Hz, 2H), 2.81 (t, J = 7.10 Hz, 2H), 1.18-1.28 (m, 3H).

[0233] Step 2: 6-Fluoro-3,4-dihydro-2H-isoquinolin-1-one Ethyl N-[2-(3-fluorophenyl)ethyl]carbamate (1.45 g, 68.7 mmol) and polyphosphoric acid (10 mL) were combined and stirred at 120° C. for 2 h. The reaction mixture was cooled to 70° C. and added to stirring water. EtOAc was added and the organic layer was extracted, dried and concentrated under vacuum onto silica. The compound was purified by column chromatography (40-80% EtOAc in PE). Fractions containing the product were combined and concentrated to give a colorless oil (0.367 g, 33%). 1 H NMR (400MHz, chloroform-d) d8.07 (dd, J = 5.95, 8.70Hz, 1H), 6.99-7.10 (m, 2H), 6.91 (dd, J = 2.52, 8.93Hz, 1H), 3.58 (dt, J = 2.75, 6.64Hz, 2H), 2.99 (t, J = 6.64Hz, 2H); LCMS (m / z): 166.0 [M+H] + .

[0234] Step 3: 6-Fluoro-7-nitro-3,4-dihydro-2H-isoquinolin-1-one To a solution of 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (0.367 g, 2.22 mmol) in H2SO4 at 0°C, HNO3 (0.11 mL, 2.67 mmol) was added dropwise and left to stir at 0°C for 45 min. The reaction mixture was added to water and extracted with EtOAc. The organic layer was washed with aqueous NaHCO3, dried and concentrated in vacuo to give a yellow solid (0.334 g, 72%). 1H NMR (400 MHz, chloroform-d) d 8.80 (d, J = 7.50 Hz, 1H), 7.15-7.21 (m, 1H), 6.25-6.39 (m, 1H), 3.66 (dt, J = 2.70, 6.70 Hz, 2H), 3.12 (t, J = 6.40 Hz, 2H).

[0235] Step 4: 6-Methoxy-7-nitro-3,4-dihydro-2H-isoquinolin-1-one To a solution of 6-fluoro-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (0.100 g, 0.48 mmol) in MeOH (15 mL), NaOMe (0.027 g, 0.50 mmol) was added, heated to reflux overnight, cooled, and concentrated by vacuum filtration to give a dark yellow solid (0.110 g). 1 H NMR (400 MHz, chloroform-d) d 8.57 (s, 1H), 6.90 (s, 1H), 6.25-6.33 (m, 1H), 4.02 (s, 3H), 3.60-3.65 (m, 2H), 3.05-3.10 (m, 2H).

[0236] Step 5: 6-Methoxy-7-nitro-1,2,3,4-tetrahydroisoquinoline To a solution of 6-methoxy-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (0.110 g, 0.50 mmol) in THF (10 mL) was added 1M BH3 in THF (0.99 μL, 0.99 mmol) and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled, concentrated, extracted with EtOAc and washed with saturated NaHCO3. The organic layer was separated, dried and concentrated in vacuo. The residue was taken up in DCM / MeOH and passed through an SCX cartridge and the product was eluted with 2M NH3 in MeOH. The eluent was concentrated in vacuo to give the product 6-methoxy-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.027 g, 26%). 1 H NMR (400MHz, chloroform-d) d7.60(s,1H), 6.79(s,1H), 4.00(s,2H), 3.94(s,3H), 3.14-3.18(m,2H), 2.83-2.89(m,2H); LCMS(m / z):209.0[M+H] +.

[0237] Step 6: tert-Butyl 6-methoxy-7-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylate To a solution of 6-methoxy-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.027 g, 0.13 mmol) and Et3N (28 μL, 0.20 mmol) in DCM (50 mL) was added BOCO (1.91 g, 8.77 mmol) followed by DMAP (4 mg, 0.033 mmol) and the resulting mixture was left stirring overnight. DCM and HO were added and the organic layer was separated, dried and concentrated under vacuum onto silica. The compound was purified by column chromatography (5-30% EtOAc in PE). The fractions containing the product were combined and concentrated under vacuum to give a yellow gum (0.029 g, 72%). 1 H NMR (400MHz, chloroform-d) 7.68(s,1H), 6.84(s,1H), 4.55(s,2H), 3.94(s,3H), 3.63-3.71(m,2H), 2.84-2.92(m,2H), 1.50(s,9H); LCMS (m / z): 208.9[M-CO2 t Bu+H] + .

[0238] Step 7: tert-Butyl 7-amino-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate A solution of tert-butyl 6-methoxy-7-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylate (0.029 g, 0.094 mmol) in EtOAc (50 mL) and MeOH (50 mL) was passed through an H-Cube reactor fitted with a 10% Pd / C cartridge at 1 mL / min under "full H2" at 25°C. The product was obtained by evaporation of the solvent (0.014 g, 54%). 1 H NMR (400MHz, chloroform-d) d6.52-6.59 (m, 2H), 4.44 (s, 2H), 3.84 (s, 3H), 3.57-3.66 (m, 2H), 2.69-2.78 (m, 2H), 1.48 (s, 9H); LCMS (m / z): 177.0 [M-CO2t Bu+H] + .

[0239] Intermediate 12: tert-Butyl 7-amino-6-ethoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0240] [ka]

[0241] Prepared similarly to Intermediate 11, except sodium ethoxide was used instead of sodium methoxide in step 4.

[0242] Intermediate 13: Isochroman-7-amine

[0243] [ka]

[0244] Step 1: 2-(Carboxymethyl)-5-nitro-benzoic acid To a suspension of homophthalic acid (1.0 g, 5.55 mmol) in H2SO4 (2.5 mL) was added HNO3 (0.28 mL, 6.66 mmol) at 0 °C and the mixture was left to stir for 2 h. The reaction mixture was added to water and extracted with EtOAc, the organic layer was separated, dried and concentrated in vacuo to give a yellow solid. Trituration with Et2O gave a white solid (0.605 g, 48%). 1 H NMR(400MHz,DMSO-d6)d8.61(d,J=2.75Hz,1H),8.36(dd,J=2.40,8.40Hz,1H),7.67(d,J=8.40Hz,1H),4.10(s,2H).

[0245] Step 2: 7-Nitroisochroman To a solution of 2-(carboxymethyl)-5-nitro-benzoic acid (0.610 g, 2.70 mmol) in THF (20 mL) was added 1M BH3 in THF (8.1 mL, 8.10 mmol) and the reaction mixture was refluxed at 70 °C for 2 h. The reaction mixture was cooled and 1M BH3 in THF (5.4 mL, 5.40 mmol) was added and then refluxed for 24 h. The reaction mixture was cooled and then 2M aqueous HCl (6 mL) was added and heated at 70 °C for 30 min. The reaction mixture was cooled, diluted with EtOAC and neutralized with saturated aqueous NaHCO3. The organic layer was separated, dried and concentrated under vacuum onto silica. The compound was purified by column chromatography (10-100% EtOAc in petroleum ether) to give 7-nitro-isochroman (0.060 g, 12%). 1 H NMR(400MHz,DMSO-d6)d8.03(dd,J=2.30,8.47Hz,1H),7.99(d,J=2.29Hz,1H),7. 43(d,J=8.40Hz,1H),4.78(s,2H),3.90(t,J=5.72Hz,2H),2.91(t,J=5.72Hz,2H).

[0246] Step 3: Isochroman-7-amine A solution of 7-nitroisochroman (0.040 g, 0.279 mmol) in EtOAc (2 mL) and MeOH (8 mL) was passed through an H-Cube reactor fitted with a PtO2 cartridge at 1 mL / min at 25 °C under "full H2". To ensure maximum conversion to the product, the reaction mixture was passed a second time under the same conditions. The resulting solution was concentrated under vacuum to give a white solid (0.030 g, 0.201 mmol, 71% yield). 1 H NMR(400MHz,DMSO-d6)d6.76(d,J=8.10Hz,1H),6.38(dd,J=2.40,8.00Hz,1H),6.18(d,J=2.40Hz,1H),4.86(br. s,2H),4.51(s,2H),3.79(t,J=5.60Hz,2H),2.58(t,J=5.50Hz,2H);LCMS(m / z):150.1[M+H] + .

[0247] Intermediate 14: 1-(4-amino-3-methoxy-pyrazol-1-yl)-2-methyl-propan-2-ol

[0248] [ka]

[0249] Step 1: 1-(3-Methoxy-4-nitro-pyrazol-1-yl)-2-methyl-propan-2-ol To 3-methoxy-4-nitro-1H-pyrazole (1.0 g, 7.87 mmol) and CS2CO3 (7.67 g, 23.6 mmol) in DMF (40 mL) was added isobutylene oxide (1.4 mL, 15.7 mmol) and the reaction was heated at 100 °C for 3 h. The reaction mixture was cooled, diluted with EtOAc and HO, the organic layer was separated, washed twice with HO / LiCI, separated, dried and concentrated in vacuo to give a pale yellow solid. The solid was absorbed onto silica and purified by column chromatography (40-60% EtOAc in PE). Fractions containing the desired product were combined and concentrated to give a pale yellow solid (0.800 g, 47%).

[0250] Step 2: 1-(4-amino-3-methoxy-pyrazol-1-yl)-2-methyl-propan-2-ol A solution of 1-(3-methoxy-4-nitro-pyrazol-1-yl)-2-methyl-propan-2-ol (0.100 g, 0.436 mmol) in IPA (2 mL) was passed through an H-Cube reactor fitted with a Pd / C cartridge at 1 mL / min at 25° C. under “full H2”. The solution was concentrated under vacuum to give the product 1-(4-amino-3-methoxy-pyrazol-1-yl)-2-methyl-propan-2-ol (0.076 g, 0.411 mmol, 94% yield). LCMS (m / z): 186.1 [M+H] +

[0251] Intermediate 15: 7-Amino-6-methoxy-3,4-dihydro-2H-isoquinolin-1-one

[0252] [ka]

[0253] A solution of 6-methoxy-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (0.133 g, 0.599 mmol) in IPA (2 mL) was passed twice through an H-Cube reactor fitted with a Pd / C cartridge at 1 mL / min at 25° C. under “full H2”. The solution was concentrated under vacuum to give 7-amino-6-methoxy-3,4-dihydro-2H-isoquinolin-1-one (0.093 g, 81%). 1 H NMR (400MHz, chloroform-d) d7.40 (s, 1H), 6.58 (s, 1H), 6.32 (br. s, 1H), 3.90 (s, 3H), 3.53 (dt, J = 2.75, 6.64Hz, 2H), 2.89 (t, J = 6.60Hz, 2H); LCMS (m / z): 193.0 [M+H] + .

[0254] Intermediate 16: 6-Amino-5-methoxy-2-methyl-isoindolin-1-one

[0255] [ka]

[0256] Step 1: Methyl 4-fluoro-2-methyl-benzoate To a solution of 4-fluoro-2-methylbenzoic acid (2.5 g, 16.2 mmol) in MeOH (100 mL) was added H2SO4 (5 mL) and the reaction mixture was heated at 70° C. overnight. The reaction mixture was cooled, diluted with DCM and H2O, and the organic layer was separated, washed with aqueous NaHCO3, dried, and concentrated in vacuo to give a brown oil (1.0 g, 37%). 1 H NMR (400 MHz, chloroform-d) d 7.96 (dd, J = 6.18, 8.47 Hz, 1H), 6.89-6.97 (m, 2H), 3.89 (s, 3H), 2.61 (s, 3H).

[0257] Step 2: Methyl 4-fluoro-2-methyl-5-nitro-benzoate To methyl 4-fluoro-2-methyl-benzoate (1.0 g, 6.49 mmol) in H2SO4 (10 mL) was added HNO3 (0.30 mL, 7.14 mmol) dropwise at 5° C. and left to stir for 45 min. The reaction mixture was poured into H2O and extracted with EtOAc. The organic layer was separated, dried and concentrated in vacuo to give a yellow oil (1.22 g, 95% yield). 1 H NMR (400 MHz, chloroform-d) d 8.71 (d, J = 8.00 Hz, 1H), 7.20 (d, J = 11.70 Hz, 1H), 3.95 (s, 3H), 2.71 (s, 3H).

[0258] Step 3: Methyl 4-methoxy-2-methyl-5-nitro-benzoate To methyl 4-fluoro-2-methyl-5-nitro-benzoate (1.22 g, 6.12 mmol) in MeOH (50 mL) was added NaOMe (0.347 g, 6.43 mmol) and the reaction mixture was heated to reflux for 4 h. The reaction mixture was cooled, water and EtOAc were added, and the organic layer was separated, dried, and concentrated under vacuum onto silica. The compound was purified by column chromatography (5-10% EtOAc in PE) to give a white solid (0.741 g, 57%). 1 H NMR (400 MHz, chloroform-d) d 8.58 (s, 1H), 6.93 (s, 1H), 4.02 (s, 3H), 3.91 (s, 3H), 2.72 (s, 3H).

[0259] Step 4: Methyl 2-(bromomethyl)-4-methoxy-5-nitro-benzoate To methyl 4-methoxy-2-methyl-5-nitro-benzoate (0.741 g, 3.51 mmol) in MeCN (20 mL) was added NBS (0.750 g, 4.21 mmol) followed by 75% benzoyl peroxide (0.849 g, 2.51 mmol) and the reaction mixture was heated to 70° C. overnight. Water and DCM were added to the reaction mixture and the organic layer was separated, dried and concentrated under vacuum onto silica. Purification by column chromatography (0-15% EtOAc in petroleum ether) gave a yellow solid (0.725 g, 71%). 1 H NMR (400MHz, chloroform-d) d8.57(s,1H), 7.19-7.20(m,1H), 5.02(s,2H), 4.06(s,3H), 3.91(s,3H)

[0260] Step 5: 5-Methoxy-2-methyl-6-nitro-isoindolin-1-one To methyl 2-(bromomethyl)-5-methoxy-4-nitro-benzoate (0.725 g, 2.5 mmol) in Et3N (0.43 mL, 3.0 mmol) and MeOH (30 mL) was added methylamine (1.25 mL, 2.5 mmol) and the reaction mixture was heated to reflux for 4 h. The reaction mixture was cooled, concentrated under vacuum onto silica and purified by column chromatography to give a yellow solid (0.150 g, 27%). 1 H NMR (400MHz, chloroform-d) d8.25(s,1H), 7.14(s,1H), 4.43(s,2H), 4.03(s,3H), 3.20(s,3H); LCMS (m / z): 223.0[M+H] + .

[0261] Step 6: 6-Amino-5-methoxy-2-methyl-isoindolin-1-one A solution of 5-methoxy-2-methyl-6-nitro-isoindolin-1-one (0.030 g, 0.135 mmol) in IPA (2 mL) was passed twice through an H-Cube reactor fitted with a Pd / C cartridge at 1 mL / min, 25° C., under “full H2”. The solution was concentrated in vacuo to give the product 6-amino-5-methoxy-2-methyl-isoindolin-1-one (0.025 g, 0.130 mmol, 96% yield). LCMS (m / z): 193.0 [M+H] + .

[0262] Intermediate 17: tert-Butyl 7-amino-6-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0263] [ka]

[0264] Step 1: 6-Amino-7-nitro-3,4-dihydro-2H-isoquinolin-1-one To a 20 mL microwave vial was added 6-fluoro-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (0.5 g, 2.38 mmol) and ammonium hydroxide (10 mL). The vial was sealed and heated at 50° C. for 1 h, then concentrated in vacuo to give a bright yellow solid (0.525 g). 1 H NMR(400MHz,DMSO-d6)d ppm8.43(s,1H),7.87(s,1H),7.73-7.81(m,2H),6.79-6.83(m,1H),3.31-3.34(m,2H),2.79-2.85(m,2H);LCMS(m / z):208.0[M+H + ].

[0265] Step 2: 6-Chloro-7-nitro-3,4-dihydro-2H-isoquinolin-1-one A suspension of 6-amino-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (0.25 g, 1.20 mmol) in MeCN (20 mL) was added at 0 °C with CuCl (0.179 g, 1.81 mmol) andt BuONO (0.21 mL, 1.81 mmol) was added. The reaction mixture was stirred and allowed to warm to room temperature over 2 h. Further CuCl (0.179 g, 1.81 mmol) and t BuONO (0.21 mL, 1.81 mmol) was added and the reaction mixture was heated to reflux for 1 h. The reaction mixture was allowed to cool. 2M aqueous HCl was added until no further effervescence was observed. The reaction mixture was poured into EtOAc and the organic layer was separated, washed with 2M aqueous HCl, dried and concentrated in vacuo to give a yellow solid (0.226 g, 83%). 1 H NMR (400MHz, DMSO-d6)d ppm 8.37 (s, 1H), 8.34 (br. s., 1H), 7.83 (s, 1H), 3.39-3.45 (m, 1H), 2.99-3.04 (m, 1H).

[0266] Step 3: 6-Chloro-7-nitro-1,2,3,4-tetrahydroisoquinoline To a solution of 6-chloro-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (0.226 g, 1 mmol) in THF (10 mL) was added BH3 (1 M in THF, 3 mL, 3 mmol). The reaction mixture was refluxed overnight and then cooled. 2 M aqueous HCl (5 mL) was added. The reaction mixture was neutralized with saturated aqueous NaHCO3 and the organic phase was extracted with EtOAc, separated, dried and concentrated in vacuo. The crude was absorbed onto silica and purified by column chromatography (20-100% EtOAc in PE, 0-20% MeOH in EtOAc) to give a yellow residue (0.054 g). 1 H NMR (400MHz, chloroform-d) ppm 7.63 (s, 1H), 7.30 (s, 1H), 4.06 (s, 2H), 3.18 (t, J = 5.72Hz, 2H), 2.88 (t, J = 5.72Hz, 2H); LCMS (m / z): 213 [M+H + ],

[0267] Step 4: tert-Butyl 6-chloro-7-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylate To a solution of 6-chloro-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.054 g, 0.25 mmol) in DCM (5 mL) was added Et3N (74 ul, 0.51 mmol), BOCO (0.067 g, 0.030 mmol), and DMAP (3 mg, 0.025 mmol). The reaction mixture was left stirring at room temperature overnight and then diluted with DCM and water. The organic layer was separated, dried, and concentrated under vacuum onto silica. Purification by column chromatography (5-20% EtOAC in PE) gave a yellow gum (0.05 g, 63% yield). 1 H NMR (400MHz, chloroform-d) ppm 7.70 (s, 1H), 7.34 (s, 1H), 4.60 (s, 2H), 3.64-3.70 (m, 2H), 2.86-2.91 (m, 2H), 1.50 (s, 9H); LCMS (m / z): 213 [M-CO2 t Bu+H] + .

[0268] Step 5: tert-Butyl 7-amino-6-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylate A solution of tert-butyl 6-chloro-7-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylate (0.050 g, 0.16 mmol) in EtOAc (10 mL) and MeOH (10 mL) was passed twice through an H-Cube reactor fitted with a PtO2 cartridge at 1 mL / min, 25 °C, and "full H2". The final solution was concentrated in vacuo to give the product (0.045 g). LCMS (m / z): 183 / 185 [M-CO2 t Bu+H] + .

[0269] Intermediate 18: tert-Butyl 4-(3-amino-4-chloro-phenoxy)piperidine-1-carboxylate

[0270] [ka]

[0271] Step 1: tert-Butyl 4-(4-chloro-3-nitro-phenoxy)piperidine-1-carboxylate To a solution of 4-chloro-3-nitrophenol (0.500 g, 2.88 mmol) and K2CO3 (0.795 g, 5.76 mmol) in DMF, tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (0.881 g, 3.17 mmol) was added and the reaction mixture was heated at 70 °C overnight. EtOAc and water were added to the reaction mixture and the organic layer was extracted and washed with water. The organic layer was concentrated in vacuo onto silica and purified by column chromatography (5-15% EtOAc in PE). The product-containing fractions were combined to give a yellow oil which was then taken up in DCM and washed with 2M aqueous Na2CO3, the organic layer was separated, dried and concentrated in vacuo to give the product as a yellow solid (0.649 g, 1.82 mmol, 63% yield). 1 H NMR(chloroform-d)d:7.44(d,J=8.7Hz,1H),7.40(s,1H),7.05-7.09(m,1H),4.43-4.60(m,1H),3.63-3. 73(m,2H),3.27-3.45(m,2H),1.89-2.02(m,2H),1.76(s,2H),1.48(s,9H).LCMS(m / z):257.0[M-CO2 t Bu+H] + .

[0272] Step 2: tert-Butyl 4-(3-amino-4-chloro-phenoxy)piperidine-1-carboxylate To a solution of tert-butyl 4-(4-chloro-3-nitro-phenoxy)piperidine-1-carboxylate (0.649 g, 1.82 mmol) in EtOAc (30 mL) was added SnCl2.2H2O (2.06 g, 9.11 mmol) and the reaction mixture was left to stir overnight. The reaction mixture was poured into saturated aqueous NaHCO3 and the organic layer was separated, dried and concentrated in vacuo to give the product tert-butyl 4-(3-amino-4-chloro-phenoxy)piperidine-1-carboxylate (0.330 g, 1.01 mmol, 56% yield) as a white solid. 1H NMR(chloroform-d)d:7.12(d,J=8.7Hz,1H),6.34(d,J=2.7Hz,1H),6.28(dd,J=8.7,2.7Hz,1H),4.33-4.42(m,1H),4.11(br. s,2H),3.61-3.73(m,2H),3.27-3.38(m,2H),1.84-1.94(m,2H),1.65-1.78(m,2H),1.47(s,9H).LCMS(m / z):227.0[M-CO2 t Bu+H] + .

[0273] Intermediate 19: 7-Amino-N,N-dimethyl-2,3-dihydrobenzofuran-5-sulfonamide

[0274] [ka]

[0275] Step 1: N,N-Dimethyl-7-nitro-2,3-dihydrobenzofuran-5-sulfonamide

[0276] [ka] To a solution of 7-nitro-2,3-dihydrobenzofuran-5-sulfonyl chloride (0.100 g, 0.380 mmol) in DCM, dimethylamine (0.021 g, 0.760 mmol) was added and the reaction mixture was left stirring at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography (40-100% EtOAc in PE) to give a white solid (0.078 g, 76%). 1 H NMR (chloroform-d) 8.35-8.39 (m, 1H), 7.82 (d, J = 1.4 Hz, 1H), 4.99 (t, J = 8.9 Hz, 2H), 3.43 (t, J = 8.9 Hz, 2H), 2.77 (s, 6H).

[0277] Step 2: 7-Amino-N,N-dimethyl-2,3-dihydrobenzofuran-5-sulfonamide A solution of N,N-dimethyl-7-nitro-2,3-dihydrobenzofuran-5-sulfonamide (0.078 g, 0.286 mmol) in EtOAc (10 mL) and MeOH (10 mL) was passed through an H-Cube reactor fitted with a 10% Pd / C cartridge at 1 mL / min continuous flow at 25° C. under “full H2”. Removal of the solvent afforded the product as a white solid (0.043 g, 62%). 1 H NMR (chloroform-d): 7.05-7.08 (m, 1H), 6.98 (d, J = 1.8 Hz, 1H), 4.69 (t, J = 8.9 Hz, 2H), 3.23-3.32 (m, 2H), 2.66-2.72 (m, 6H). LCMS (m / z): 243 [M+H] + .

[0278] Intermediate 20: 5-Morpholinosulfonyl-2,3-dihydrobenzofuran-7-amine

[0279] [ka]

[0280] Prepared similarly to Intermediate 19 except morpholine was used in step 1. 1 H NMR(chloroform-d)d:6.99-7.09(m,1H),6.95(d,J=1.8Hz,1H),4.70(t,J=8.9Hz,2H),3.69-3.7 7(m,4H),3.37-3.64(m,2H),3.27(t,J=8.9Hz,2H),2.90-3.06(m,4H);LCMS(m / z):285[M+H] + .

[0281] Intermediate 21: tert-Butyl 4-[(7-amino-2,3-dihydrobenzofuran-5-yl)sulfonyl]piperazine-1-carboxylate

[0282] [ka]

[0283] Prepared similarly to Intermediate 19, except N-BOC-piperazine was used in step 1. 1 H NMR (chloroform-d): 6.99-7.07 (m, 1H), 6.94 (d, J = 1.8 Hz, 1H), 4.70 (t, J = 8.7 Hz, 2H), 3.48-3.56 (m, 4H), 3.27 (t, J = 8.7 Hz, 2H), 2.91-3.01 (m, 4H), 1.42 (s, 9H)

[0284] Intermediate 22: 3-Methoxy-1-(2-morpholinoethyl)pyrazol-4-amine

[0285] [ka]

[0286] Step 1: 4-[2-(3-methoxy-4-nitro-pyrazol-1-yl)ethyl]morpholine To a mixture of 3-methoxy-4-nitro-1H-pyrazole (0.250 g, 1.75 mmol) and K2CO3 (0.483 g, 3.50 mmol) in DMF (5 mL) was added 4-(2-chloroethyl)morpholine hydrochloride (0.390 g, 2.10 mmol) and the reaction mixture was heated at 70 °C overnight. After cooling, the mixture was concentrated onto silica gel and purified by column chromatography (70-100% EtOAc in PE, 0-20% MeOH in EtOAc) to give the product (0.280 g, 63%). 1 H NMR (chloroform-d) Shift: 8.12 (s, 1H), 3.97-4.17 (m, 5H), 3.65-3.79 (m, 4H), 2.79 (t, J = 6.0 Hz, 2H), 2.24-2.55 (m, 4H). LCMS (m / z): 257.1 [M+H] + .

[0287] Step 2: 3-Methoxy-1-(2-morpholinoethyl)pyrazol-4-amine A solution of 4-[2-(3-methoxy-4-nitro-pyrazol-1-yl)ethyl]morpholine (0.140 g, 0.547 mmol) in EtOAc (30 mL) and MeOH (10 mL) was passed through an H-Cube reactor fitted with a 10% Pd / C cartridge at 1 mL / min at 25 °C under "full H2" and then concentrated in vacuo to give the product (0.104 g, 84%). 1 H NMR (chloroform-d) Shift: 6.95 (s, 1H), 3.96 (t, J = 6.6 Hz, 2H), 3.90 (s, 3H), 3.66-3.71 (m, 4H), 2.70 (t, J = 6.6 Hz, 2H), 2.47-2.62 (m, 2H), 2.42-2.47 (m, 4H). LCMS (m / z): 227.1 [M+H] + .

[0288] Intermediate 23: 2-Chloro-5-(morpholinomethyl)aniline

[0289] [ka]

[0290] Step 1: 4-Chloro-3-nitro-benzaldehyde To a solution of (4-chloro-3-nitro-phenyl)methanol (0.500 g, 2.67 mmol) in THF (10 mL) was added Dess-Martin periodinane (0.752 g, 4.011 mmol) and the reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was concentrated in vacuo directly onto silica and purified by column chromatography (10-30% EtOAc in PE) to give a yellow solid (0.302 g, 61% yield). 1 H NMR (chloroform-d): 10.05 (s, 1H), 8.38 (d, J = 1.8 Hz, 1H), 8.05 (dd, J = 8.2, 1.8 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H).

[0291] Step 2: 4-[(4-chloro-3-nitro-phenyl)methyl]morpholine To a solution of 4-chloro-3-nitro-benzaldehyde (0.100 g, 0.541 mmol) in DCM was added morpholine (0.049 g, 0.568 mmol) and Na(OAc)3BH (0.172 g, 0.811 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo directly onto silica gel and purified by column chromatography (30-100% EtOAc in PE) to give a yellow gum (0.132 g, 95%). 1 H NMR (chloroform-d) Shift: 7.85-7.90 (m, 1H), 7.49-7.52 (m, 2H), 3.68-3.76 (m, 4H), 3.53 (s, 2H), 2.38-2.53 (m, 4H). LCMS (m / z): 257.0 [M+H] + .

[0292] Step 3: 2-Chloro-5-(morpholinomethyl)aniline To a solution of 4-[(4-chloro-3-nitro-phenyl)methyl]morpholine (0.132 g, 0.516 mmol) in EtOAc was added SnCl2.2H2O (0.582 g, 2.58 mmol) and the reaction mixture was left to stir overnight. Saturated aqueous NaHCO3 was added to the reaction mixture and the organic layer was separated, dried and concentrated in vacuo to give the desired product (0.110 g, 94% yield). 1 H NMR(chloroform-d)d:7.18(d,J=7.8Hz,1H),6.82(d,J=1.8Hz,1H),6.59-6.73(m,1H),4.05(br. s.,2H),3.67-3.80(m,4H),3.42(s,2H),2.36-2.54(m,4H).LCMS(m / z):227.0[M+H] + .

[0293] Intermediate 24: 6-Chloro-1,2,3,4-tetrahydroisoquinolin-7-amine

[0294] [ka]

[0295] Step 1: Ethyl N-[2-(3-chlorophenyl)ethyl]carbamate To a solution of 2-(3-chlorophenyl)ethanamine (5.1 g, 33.0 mmol) and Et3N (7.12 mL, 49.4 mmol) in DCM (50 mL) was added ethyl chloroformate (3.77 mL, 39.6 mmol) dropwise and the reaction mixture was left stirring at room temperature for 3 h. The reaction mixture was concentrated in vacuo and triturated with EtOAc. The mixture was filtered to remove a white solid and the filtrate was concentrated to give a yellow oil. The oil was concentrated onto silica and purified by column chromatography (15-100% EtOAc in PE) to give the product (2.26 g, 9.95 mmol, 30% yield). 1 H NMR (400 MHz, chloroform-d) d 7.16-7.25 (m, 3H), 7.04-7.09 (m, 1H), 4.58-4.76 (m, 1H), 4.10 (q, J = 7.10 Hz, 2H), 3.41 (q, J = 7.00 Hz, 2H), 2.78 (t, J = 7.00 Hz, 2H), 1.22 (t, J = 7.10 Hz, 3H).

[0296] Step 2: 6-Chloro-3,4-dihydro-2H-isoquinolin-1-one Ethyl N-[2-(3-chlorophenyl)ethyl]carbamate (2.26 g, 9.95 mmol) and polyphosphoric acid (15 mL) were heated at 120° C. for 5 h. The reaction mixture was cooled to 70° C., poured into water, and extracted with EtOAc. The organic layer was separated, washed with aqueous NaHCO3, dried, and concentrated in vacuo to give the product 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (0.632 g, 3.49 mmol, 35% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d): d 8.01 (d, J = 8.24 Hz, 1H), 7.32-7.35 (m, 1H), 7.24 (d, J = 2.29 Hz, 1H), 6.18-6.32 (m, 1H), 3.55-3.61 (m, 2H), 2.97-3.02 (m, 2H).

[0297] Step 3: 6-Chloro-7-nitro-3,4-dihydro-2H-isoquinolin-1-one To a solution of 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (0.434 g, 2.40 mmol) in H2SO4 (5 mL) was added HNO3 (0.31 mL, 2.88 mmol) dropwise at 0 °C and the reaction mixture was left to stir for 15 min. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with aqueous NaHCO3, dried and concentrated in vacuo to give a yellow solid. The solid was triturated with DCM / MeOH and the yellow solid was collected and dried by vacuum filtration to give the product 6-chloro-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (0.354 g, 1.57 mmol, 65% yield). 1 H NMR (400MHz, DMSO-d6)d8.28-8.38(m,2H),7.81-7.85(m,1H),3.39-3.45(m,2H),2.98-3.05(m,2H).

[0298] Step 4: 7-Amino-6-chloro-3,4-dihydro-2H-isoquinolin-1-one To a solution of 6-chloro-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (0.327 g, 1.45 mmol) in EtOAc (30 mL) was added SnCl2.2H2O (1.64 g, 7.23 mmol) and the reaction mixture was left to stir at room temperature overnight. Aqueous NaHCO3 was added to the reaction mixture to give a white precipitate which was then removed by filtration. The organic layer of the filtrate was separated, dried and concentrated under vacuum to give the product 7-amino-6-chloro-3,4-dihydro-2H-isoquinolin-1-one (0.230 g, 1.17 mmol, 81% yield) as a pale yellow solid. 1 H NMR (400 MHz, chloroform-d) d 7.48 (s, 1H), 7.13 (s, 1H), 6.00-6.11 (m, 1H), 3.50-3.56 (m, 2H), 2.86-2.91 (m, 2H).

[0299] Step 5: 6-Chloro-1,2,3,4-tetrahydroisoquinolin-7-amine To 7-amino-6-chloro-3,4-dihydro-2H-isoquinolin-1-one (0.050 g, 0.255 mmol) in THF (3 mL) was added LiAlH4 (2M in THF) (0.65 mL, 1.78 mmol) dropwise and the reaction was heated to reflux for 30 min. NMR showed incomplete conversion so an additional equivalent of LiAlH4 was added and the reaction mixture was stirred at reflux for 4.5 h. The reaction mixture was cooled, H2O, 15% NaOH+H2O were added and the mixture was filtered and passed through a phase separator. The eluent was concentrated under vacuum to give the product 6-chloro-1,2,3,4-tetrahydroisoquinolin-7-amine (0.046 g, 0.247 mmol, 94% yield) as a cream solid. 1 H NMR (400 MHz, chloroform-d) d 6.98 (s, 1H), 6.43 (s, 1H), 3.87-3.96 (m, 4H), 3.04-3.09 (m, 2H), 2.64-2.69 (m, 2H).

[0300] Intermediate 25: 6-Amino-5-methoxy-2-methyl-isoindolin-1-one

[0301] [ka]

[0302] Step 1: Methyl 4-fluoro-2-methyl-benzoate To a solution of 4-fluoro-2-methylbenzoic acid (2.5 g, 16.2 mmol) in MeOH (100 mL) was added H2SO4 (5 mL) and the reaction mixture was heated at 70° C. overnight. The reaction mixture was cooled, diluted with DCM and H2O, and the organic layer was separated, washed with NaHCO3 (aq), dried, and concentrated in vacuo to give the product, methyl 4-fluoro-2-methyl-benzoate (1.0 g, 6.49 mmol, 37% yield) as a brown oil. 1 H NMR (400 MHz, chloroform-d) d 7.96 (dd, J = 6.18, 8.47 Hz, 1H), 6.89-6.97 (m, 2H), 3.89 (s, 3H), 2.61 (s, 3H).

[0303] Step 2: Methyl 4-fluoro-2-methyl-5-nitro-benzoate To methyl 4-fluoro-2-methyl-benzoate (1.0 g, 6.49 mmol) in H2SO4 (10 mL) was added HNO3 (0.30 mL, 7.14 mmol) dropwise at 5° C. and left to stir for 45 min. The reaction mixture was poured into H2O and extracted with EtOAc. The organic layer was separated, dried, and concentrated in vacuo to give the product methyl 4-fluoro-2-methyl-5-nitro-benzoate (1.22 g, 6.12 mmol, 95% yield) as a yellow oil that solidified upon standing. 1 H NMR (400 MHz, chloroform-d) d 8.71 (d, J = 8.00 Hz, 1H), 7.20 (d, J = 11.70 Hz, 1H), 3.95 (s, 3H), 2.71 (s, 3H).

[0304] Step 3: Methyl 4-methoxy-2-methyl-5-nitro-benzoate To methyl 4-fluoro-2-methyl-5-nitro-benzoate (1.22 g, 6.12 mmol) in MeOH (50 mL) was added NaOMe (0.347 g, 6.43 mmol) and the reaction mixture was heated to reflux for 4 h. The reaction mixture was cooled, HO and EtOAc were added, and the organic layer was separated, dried, and concentrated under vacuum onto silica. The compound was purified by column chromatography (5-10% EtOAc in PE) and the product-containing fractions were combined and concentrated under vacuum to give the product, methyl 4-methoxy-2-methyl-5-nitro-benzoate (0.741 g, 3.51 mmol, 57% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) d 8.58 (s, 1H), 6.93 (s, 1H), 4.02 (s, 3H), 3.91 (s, 3H), 2.72 (s, 3H).

[0305] Step 4: Methyl 2-(bromomethyl)-4-methoxy-5-nitro-benzoate To methyl 4-methoxy-2-methyl-5-nitro-benzoate (0.741 g, 3.51 mmol) in MeCN (20 mL) was added NBS (0.750 g, 4.21 mmol) followed by benzoyl peroxide (75%) (0.849 g, 2.51 mmol) and the reaction mixture was heated to 70 °C overnight. HO and DCM were added to the reaction mixture and the organic layer was separated, dried and concentrated under vacuum onto silica. Attempted purification by column chromatography (0-15% EtOAc in PE) gave the product methyl 2-(bromomethyl)-4-methoxy-5-nitro-benzoate (0.725 g, 2.51 mmol, 71% yield) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) d 8.57 (s, 1H), 7.19-7.20 (m, 1H), 5.02 (s, 2H), 4.06 (s, 3H), 3.91 (s, 3H).

[0306] Step 5: 5-Methoxy-2-methyl-6-nitro-isoindolin-1-one To methyl 2-(bromomethyl)-5-methoxy-4-nitro-benzoate (0.725 g, 2.5 mmol) in Et3N (0.43 mL, 3.0 mmol) and MeOH (30 mL) was added methylamine (1.25 mL, 2.5 mmol) and the reaction mixture was heated to reflux for 4 h. The reaction mixture was cooled, concentrated under vacuum onto silica and purified by column chromatography to give the product 5-methoxy-2-methyl-6-nitro-isoindolin-1-one (0.150 g, 0.676 mmol, 27% yield) as a yellow solid. 1 H NMR (400MHz, chloroform-d) d 8.25(s,1H), 7.14(s,1H), 4.43(s,2H), 4.03(s,3H), 3.20(s,3H); LCMS (m / z): 223.0[M+H] + .

[0307] Step 6: 6-Amino-5-methoxy-2-methyl-isoindolin-1-one A solution of 5-methoxy-2-methyl-6-nitro-isoindolin-1-one (0.030 g, 0.135 mmol) in IPA (2 mL) was passed through an H-Cube reactor fitted with a Pd / C cartridge at 1 mL / min, 25° C., under “full H2” twice. The solution was concentrated under vacuum to give the product 6-amino-5-methoxy-2-methyl-isoindolin-1-one (0.025 g, 0.130 mmol, 96% yield). LCMS (m / z) 193.0 [M+H] + .

[0308] Intermediate 26: 2-Chloro-5-(trifluoromethyl)-N-[(1-tritylpyrazol-3-yl)methyl]pyrimidin-4-amine

[0309] [ka]

[0310] Step 1: (3E)-1-tritylpyrazole-3-carbaldehyde oxime 1-Tritylpyrazole-3-carbaldehyde (9.2 g, 2.72 mmol), hydroxylamine hydrochloride (3.8 g, 5.44 mmol), sodium acetate (4.5 g, 5.44 mmol) were combined in methanol (100 mL) and water (10 mL) and the reaction mixture was heated to reflux for 1.5 h. The reaction mixture was cooled, concentrated in vacuo, DCM was added, the organic phase was separated, dried and concentrated in vacuo to give the product (3E)-1-tritylpyrazole-3-carbaldehyde oxime (9.4 g, 98%) as a white solid. 1 H NMR(400MHz,DMSO-d6)d 11.18(s,1H),11.12-11.31(m,1H),7.93-8.09(m,1H),7.34-7.39(m,9H),7.31-7.44(m,10H),7.02-7.12(m,6H),6.45-6.60(m,1H).

[0311] Step 2: (1-tritylpyrazol-3-yl)methanamine A solution of (3E)-1-tritylpyrazole-3-carbaldehyde oxime (9.37 g, 27 mmol) in THF (100 mL) was added dropwise to lithium aluminum hydroxide in THF (53.1 mL, 53 mmol) at 0° C. The reaction mixture was heated at 65° C. for 1.5 h. The reaction mixture was cooled, ice was added, and the reaction mixture was quenched by careful addition of methanol. The resulting solution / gel was filtered and washed with methanol. The filtrate was concentrated under vacuum onto silica, the silica was split between 50 g SNAP cartridges, and the compound was purified by column chromatography (5-10% MeOH in DCM). The product-containing fractions were combined and concentrated under vacuum to give (1-tritylpyrazol-3-yl)methanamine as a yellow solid (4.55 g, 55%). 1 H NMR (400MHz, DMSO-d6)7.35-7.47(m,10H),7.03-7.16(m,6H),6.26-6.39(m,1H),3.66-3.73(m,2H),1.69(t,J=7.10Hz,2H).

[0312] Step 3: 2-Chloro-5-(trifluoromethyl)-N-[(1-tritylpyrazol-3-yl)methyl]pyrimidin-4-amine To a suspension of (1-tritylpyrazol-3-yl)methanamine (3.3 g, 9.65 mmol) and triethylamine (2.8 mL, 1.93 mmol) in IPA (80 mL) was added 2,4-dichloro-5-trifluoromethylpyrimidine (2.1 g, 9.65 mmol) and stirred at 50 °C overnight. The reaction mixture was cooled, diluted with DCM and water, and the organic layer was separated, dried, and concentrated under vacuum onto silica. The compound was purified by column chromatography (5-20% ethyl acetate in petroleum ether). Fractions containing the first peak were combined under vacuum to give 2-chloro-5-(trifluoromethyl)-N-[(1-tritylpyrazol-3-yl)methyl]pyrimidin-4-amine (1.57 g, 32%) as a white solid. 1H NMR(400MHz,chloroform-d)d 8.19-8.29(m,1H),7.31-7.34(m,8H),7.05-7.17(m,7H),6.35(br.s.,1H),6.20(d,J=2.29Hz,1H),4.67-4.75(m,2H)HPLC Rt=2.41 min (MeCN, pH10).

[0313] Example 1: 1-(3-(2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5(trifluoromethyl)pyrimidin-4-ylamino)propyl)piperidin-2-one

[0314] [ka]

[0315] Step 1: Synthesis of 1-(3-(2-(7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)propyl)piperidin-2-one To a solution of intermediate 1 (10 g, 29.8 mmol) in IPA (100 mL) was added intermediate 2 (9.9 g, 35.7 mmol) and the reaction mixture was heated to 80° C. for 16 h. The reaction mixture was concentrated and the crude compound was purified by column chromatography (SiO2, 100-200 mesh, 50% ethyl acetate in petroleum ether) to give a light brown solid (9.5 g, 55%), which was used in the next step without purification.

[0316] Step 2: 1-(3-(2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5(trifluoromethyl)pyrimidin-4-ylamino)propyl)piperidin-2-one To a solution of 1-(3-(2-(7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)propyl)piperidin-2-one (10 g, 17.2 mmol) in a mixture of ethanol (120 mL) and water (60 mL) was added potassium carbonate (9.5 g, 68.8 mmol) at room temperature. The mixture was heated to 70° C. for 3 h, cooled to room temperature and concentrated. Column chromatography (SiO2, 6% MeOH in DCM) followed by purification by preparative HPLC afforded the title compound as an off-white solid (3.5 g, 42%). 1 H NMR(400MHz,CDCl3)δ 8.22(s,1H),8.17(s,1H),7.37(s,1H),7.05(s,1H),6.80(s,1H),3.97(s,2H),3.44-3.51(m,4H),3.28(d,J=5.8Hz,2H), 3.16(t,J=6.0Hz,2H),2.81(t,J=5.8Hz,2H),2.44(t,J=5.8Hz,2H),1.83-1.78(m,J=4.9Hz,6H);LCMS(m / z)=483.56[M+H] +

[0317] Example 2: (S)-3-(2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)propanamide

[0318] [ka]

[0319] Step 1: Synthesis of ethyl 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)propanoate To a solution of ethyl 3-aminopropanoate hydrochloride (500 mg, 3.25 mmol) in IPA (5 mL) was added N,N-diisopropylethylamine (0.93 g, 7.16 mmol) at 0° C., and the reaction mixture was stirred at the same temperature for 30 min. The reaction mixture was cooled to −78° C., and a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.85 g, 3.91 mmol) in IPA (5 mL) was added, and the reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated, diluted with ethyl acetate, and washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by reverse phase column chromatography [C18, 0.1% aqueous HCOOH in MeCN] to give ethyl 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)propanoate (400 mg, 41%). 1 H NMR(400MHz,CDCl3):δ ppm 8.27(d,J=0.8Hz,1H),6.31(brs,1H),4.21(q,J=14.4Hz & 7.2Hz,2H),3.88(q,J=11.6Hz & 6.0Hz,2H),2.68(t,J=6.0Hz,2H),1.29(t,J=7.2Hz,3H).LCMS(m / z):298.0[M+H] +

[0320] Step 2: Synthesis of 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)propanoic acid To a solution of ethyl 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)propanoate (0.35 g, 1.17 mmol) in THF:water (2:1, 10 mL) was added lithium hydroxide monohydrate (0.15 g, 3.57 mmol) at room temperature and stirred for 1 h. The reaction mixture was quenched with saturated aqueous citric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)propanoic acid (300 mg), which was carried on to the next step without purification. LCMS (m / z): 270.0 [M+H] + .

[0321] Step 3: Synthesis of (S)-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)propanamide To a solution of 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)propanoic acid (300 mg, crude) in THF (5 mL) was added N,N-diisopropylethylamine (360 mg, 2.78 mmol), (S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride (180 mg, 1.02 mmol), and 1-propanephosphonic anhydride (50% in ethyl acetate, 1.5 mL, 2.33 mmol) at room temperature, and the reaction mixture was stirred for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give (S)-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)propanamide (450 mg), which was used directly in the next step without purification. LCMS(m / z):391.0[M+H] +

[0322] Step 4: Synthesis of (S)-3-(2-(7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-propanamide To a solution of (S)-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)propanamide (450 mg) from step 3 in IPA (10 mL) was added intermediate 2 (380 mg, 1.38 mmol) at room temperature and the reaction mixture was heated to 80° C. for 16 h. The reaction mixture was concentrated under reduced pressure and the crude product was triturated with Et2O to give an off-white solid (350 mg). The crude product was used directly in the next step. LCMS (m / z): 633.0 [M+H] +

[0323] Step 5: Synthesis of (S)-3-(2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)propanamide To a solution of (S)-3-(2-(7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)propanamide (350 mg, crude) in ethanol:water (2:1, 7.5 mL) was added K2CO3 (230 mg, 1.66 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the crude product was suspended in MeCN and methanol, filtered through a pad of Celite, and the filtrate was concentrated. Purification by preparative HPLC afforded the title compound as an off-white solid (90 mg, 14% over steps 2-4). 1 H NMR (400MHz, DMSO-d6): δ ppm 8.68(s,1H),8.50(d,J=9.2Hz,1H),8.13(s,1H),7.52(s,1H),7.12(s,1H),6.8 8(t,J=5.2Hz,1H),4.01-3.99(m,1H),3.78(s,2H),3.58(q,J=6.0Hz,2H),2.89( t,J=5.6Hz,2H),2.62(t,J=5.6Hz,2H),2.51-2.49(m,2H),1.04-1.00(m,1H),0 .62-0.57(m,1H),0.47-0.43(m,2H),0.22-0.26(m,1H).LCMS(m / z):537.0[M+H] +

[0324] Example 3: 1-(3-((2-((1-(2-(dimethylamino)ethyl)-3-methoxy-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one

[0325] [ka]

[0326] Step 1: Synthesis of 2-(3-methoxy-4-nitro-1H-pyrazol-1-yl)-N,N-dimethylethan-1-amine To a stirred solution of 3-methoxy-4-nitro-1H-pyrazole (0.5 g, 3.49 mmol) in DMF (5 mL) at room temperature was added K2CO3 (1.44 g, 10.5 mmol) at room temperature followed by 2-chloro-N,N-dimethylethan-1-amine. HCl (0.6 g, 4.19 mmol) and the reaction mixture was heated to 70 °C for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography using silica 100-200 gel (elution: 10% MeOH:DCM) gave a pale yellow solid (0.55 g, 73%). 1 H NMR(400MHz,CDCl3):δ 8.12(s,1H)4.05-4.02(m,5H),2.72(t,J=6Hz,2H),2.27(s,6H);LCMS(m / z):215.30[M+H] +

[0327] Step 2: Synthesis of 1-(2-(dimethylamino)ethyl)-3-methoxy-1H-pyrazol-4-amine To a stirred solution of 2-(3-methoxy-4-nitro-1H-pyrazol-1-yl)-N,N-dimethylethan-1-amine (0.55 g, 2.57 mmol) in MeOH (15 mL) was added 10% Pd / C (0.5 g) at room temperature and stirred under H2 pressure (balloon pressure) for 4 h. The reaction mixture was filtered through Celite and washed with MeOH. Concentration of the filtrate gave crude 1-(2-(dimethylamino)ethyl)-3-methoxy-1H-pyrazol-4-amine (0.47 g, quantitative), which was used in the next step. 1H NMR(400MHz,CDCl3):δ 6.95(s,1H)3.95(t,J=6.4Hz,2H)3.91(s,3H),2.65(t,J=6.8Hz,2H),2.27(s,6H);LCMS(m / z):185.27[M+H] +

[0328] Step 3: 1-(3-((2-((1-(2-(dimethylamino)ethyl)-3-methoxy-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one To a solution of 1-(2-(dimethylamino)ethyl)-3-methoxy-1H-pyrazol-4-amine (0.45 g, 2.44 mmol) in IPA (20 mL) was added Intermediate 1 (0.66 g, 1.96 mmol) and the mixture was heated in a sealed tube at 80° C. for 12 h. The reaction mixture was concentrated and purified by preparative HPLC to give the title compound as an off-white solid (0.098 g, 10%). 1 H NMR(400MHz,DMSO-d6):δ 8.48(brs,1H),8.05(s,1H),7.68(brs,1H),7.03(brs,1H),3.99(brs,2H),3.77(s,3H),3.27- 3.20(m,6H),2.58(t,J=6.4Hz,2H),2.21-2.16(m,8H),1.69(brs,6H);LCMS(m / z):485.28[M+H] +

[0329] Example 4: 1-(3-((2-((7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one

[0330] [ka]

[0331] Step 1: Synthesis of 1-(3-((2-((7-methoxy-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one To a solution of intermediate 3 (0.30 g, 1.09 mmol) in IPA (6.0 mL) was added intermediate 1 (0.366 g, 1.09 mmol) at room temperature and heated to 80 °C for 16 h. After concentration under reduced pressure, the crude compound was purified by column chromatography (SiO2, 100-200 mesh, 6% methanol in dichloromethane) to give an off-white solid (0.30 g, 48%). 1 H NMR(400MHz,DMSO-d6):δ 8.19(s,2H),7.93(s,1H),7.25(brs,1H),6.97(brs,1H),4.72(s,2H),3.85(s,3H),3.81(t,J=6Hz,2H)3.43(q,J=12.4 & 10.4Hz,2H),3.31(t,J=6.8Hz,2H),3.21(m,2H),2.87(s,2H),2.21(t,J=6.4Hz,2H),1.80-1.69(m,6H);LCMS(m / z):575.6[M+H] +

[0332] Step 2: Synthesis of 1-(3-((2-((7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one To a solution of 1-(3-((2-((7-methoxy-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (0.30 g, 0.52 mmol) in a mixture of ethanol (12 mL) and water (6 mL) was added potassium carbonate (0.36 g, 2.60 mmol) and the mixture was stirred at 70° C. for 3 h. The mixture was concentrated under reduced pressure and partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic layers were dried (Na2SO4) and concentrated. Purification by preparative HPLC afforded an off-white solid (0.054 g, 21%). 1 H NMR(400MHz,DMSO-d6):δ 8.14(s,1H),7.93(s,1H),7.80(s,1H),7.23(brs,1H),6.67(s,1H),3.79(s,5H),3.38-3.32(m,4H),3.2 1(s,2H),2.91-2.90(m,2H),2.60(s,2H),2.24-2.22(m,2H),1.72-1.71(m,6H);LCMS(m / z):479.3[M+H] +

[0333] Example 5: N2-(3-fluorophenyl)-N4-(3-(pyrrolidin-1-yl)propyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0334] [ka]

[0335] To a solution of intermediate 6 (120 mg, 0.38 mmol) in tert-butanol (6 mL) were added trifluoroacetic acid (174 mg, 1.52 mmol) and 3-fluoroaniline (34 mg, 0.30 mmol) at room temperature, and the mixture was stirred at 100° C. for 3 h. The reaction mixture was evaporated, the residue was basified with 1N NaOH solution, and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude solid was purified by trituration with diethyl ether to give an off-white solid (60 mg, 40%). 1 H NMR(400MHz,DMSO-d6):δ 9.81(s,1H),8.20(s,1H),7.85-7.79(m,2H),7.46(dd,J1=0.8Hz,J2=9.2Hz,1H),7.31-7.25(m,1H),6.76(td,J1=2.4,J2=8.4H z,1H),3.51(q,J=6.4Hz,2H),2.54(t,J=6.4Hz,2H),2.43(brs,4H),1.80-1.74(m,2H),1.68(brs,4H);LCMS(m / z):384.47(M+H) +

[0336] Example 6: N2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-N4-(3-(pyrrolidin-1-yl)propyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0337] [ka]

[0338] To a solution of intermediate 6 (120 mg, 0.38 mmol) in tert-butanol (6 mL) were added trifluoroacetic acid (174 mg, 2.2 mmol) and intermediate 4 (50 mg, 0.30 mmol) and the mixture was stirred at 100° C. for 3 h. The reaction mixture was evaporated and the residue was basified with 1N NaOH solution and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude solid was purified by trituration with diethyl ether to give an off-white solid (70 mg, 41.4%). 1 H NMR(400MHz,DMSO-d6):δ 9.45(br s,1H),8.14(s,1H),7.63(t,J=4.4Hz,1H)7.55(s,1H),7.43(dd,J1=2.0,J2=8.4Hz,1H),6.92(d,J=8.4Hz,1H),3.51(t,J=6.4Hz,2H),3.40 (s,2H),2.77(t,J=6.0Hz,2H),2.57-2.53(m,4H),2.42(brs,4H),2.31(s,3H),1.79-1.72(m,2H),1.67(brs,4H);LCMS(m / z):435.52(M+H) +

[0339] Example 7: 1-(3-((2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one

[0340] [ka]

[0341] To a solution of Intermediate 1 (170 mg, 0.50 mmol) in n-butanol (8 mL) were added trifluoroacetic acid (228 mg, 2.0 mmol) and Intermediate 6 (65 mg, 0.40 mmol) and the mixture was stirred at 100° C. for 5 h. The reaction mixture was evaporated and the residue was basified with 1N NaOH solution and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude solid was purified by trituration with diethyl ether to give an off-white solid (53 mg, 22%). 1 H NMR(400MHz,DMSO-d6):δ 9.48(br s,1H),8.15(s,1H),7.55(s,1H),7.40(d,J=8.0Hz,1H),7.19(brs,1H),6.94(d,J=8.0Hz,1H),3.40(brs,4H),3.31(brs,2H),3.14 -3.18(m,2H),2.82-2.76(m,2H),2.56(t,J=4.8Hz,2H),2.32(s,3H),2.24-2.18(m,2H),1.76-1.68(m,6H);LCMS(m / z):463.5(M+H) +

[0342] Example 8: 1-[3-[[2-[3-[(1-methyl-4-piperidyl)oxy]anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0343] [ka]

[0344] Step 1: Synthesis of 1-methyl-4-(3-nitrophenoxy)piperidine To a solution of 1-fluoro-3-nitrobenzene (5 g, 35.4 mmol) in dimethyl sulfoxide (25 mL), sodium tert-butoxide (3.74 g, 39.0 mmol) was added and the mixture was stirred at 10° C. for 10 min, then 1-methylpiperidin-4-ol (6.1 g, 53.1 mmol) was added and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oil (4.0 g, 48%) which was used in step 2 without further purification.

[0345] Step 2: Synthesis of 3-((1-methylpiperidin-4-yl)oxy)aniline A Parshaker vessel was charged with a solution of 1-methyl-4-(3-nitrophenoxy)piperidine (4 g, 16.9 mmol) in methanol (50 mL) and 10% Pd / C (0.40 g) was added under a nitrogen atmosphere. The mixture was hydrogenated at 30 psi for 5 h. The reaction mixture was filtered through Celite and washed with methanol. The filtrate was concentrated to give a yellow solid (3.0 g, 86%) which was used in the next step without purification.

[0346] Step 3: Synthesis of 1-(3-((2-((3-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-5-(trifluoromethyl)-pyrimidin-4-yl)amino)propyl)piperidin-2-one To a solution of intermediate 1 (100 mg, 0.297 mmol) in t-butanol (5 mL) was added TFA (0.9 mL, 1.19 mmol) and 3-((1-methylpiperidin-4-yl)oxy)aniline (50 mg, 0.238 mmol) and the mixture was stirred at 100 °C for 4 h. The mixture was concentrated under reduced pressure and the residue was suspended in water (20 mL), basified with 1N aqueous NaOH and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. Purification by flash column chromatography (100-200 mesh silica gel using 4% MeOH / DCM as eluent) followed by further purification by preparative HPLC afforded a white solid (40 mg, 26%). 1 H NMR(300MHz,DMSO-d6):δ 9.55(s,1H),8.18(s,1H),7.41(s,1H),7.33(d,J=8.1Hz,1H),7.23(t,J=5.7Hz,1H),7.13(d,J=8.1Hz, 1H),6.56(dd,J=1.8,7.8Hz,1H),4.33-4.27(m,1H),3.42(q,J=5.7Hz,2H),3.36-3.32(m,2H),3.22(br s,2H),2.87(d,J=10.2Hz,1H),2.56-2.50(m,1H),2.22(t,J=6.0Hz,2H),2.17(s,3H),2.03-1 .94(m,3H),1.78-1.69(m,7H),1.53-1.50(m,1H),1.33-1.29(m,1H);LCMS(m / z):507.5[M+H] + .

[0347] Example 9: 1-[3-[[5-cyclopropyl-2-[(2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)amino]pyrimidin-4-yl]amino]propyl]pyrrolidin-2-one

[0348] [ka]

[0349] To a stirred solution of intermediate 7 (160 mg, 0.54 mmol) in n-butanol (5 mL) was added intermediate 4 (70.5 mg, 0.43 mmol) followed by TFA (0.17 mL, 2.18 mmol) at room temperature. The reaction mixture was heated at 100° C. for 5 h and then evaporated under reduced pressure. The residue was suspended in water (20 mL), basified with 1N aqueous NaOH, and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. Purification by automated flash chromatography (gradient elution from 0–10% MeOH in DCM) afforded a yellow solid (70 mg, 30%). 1 H NMR(400MHz,CDCl3):δ 7.67(s,1H),7.46(s,1H),7.30-7.27(m,1H),6.92(d,J=8.4Hz,2H),6.38-6.44( m,1H),3.53-3.48(m,4H),3.43-3.39(m,4H),2.90(t,J=6.0Hz,2H),2.67(t,J=5. 6Hz,2H),2.45(s,3H),2.44-2.42(m,2H),2.10-2.03(m,2H),1.84-1.78(m,2H),1 .51-1.48(m,1H),0.94-0.89(m,2H),0.51-0.47(m,2H);LCMS(m / z):421.60[M+H] + .

[0350] Example 10: 1-(3-((5-cyclopropyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one

[0351] [ka]

[0352] To a stirred solution of intermediate 7 (160 mg, 0.54 mmol) in n-butanol (5 mL) was added intermediate 5 (70.5 mg, 0.43 mmol) followed by TFA (0.17 mL, 2.18 mmol) at room temperature. The reaction mixture was heated at 100° C. for 5 h and then evaporated under reduced pressure. The residue was suspended in water (20 mL), basified with 1N aqueous NaOH, and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. Purification by automated flash chromatography (gradient elution from 0–10% MeOH in DCM) afforded a yellow solid (75 mg, 33%). 1 H NMR(400MHz,CDCl3):δ 7.67(s,1H),7.38(s,1H),7.30-7.28(m,1H),7.01(d,J=8.0Hz,1H),6.85(br s,1H),6.45-6.35(m,1H),3.56(s,2H),3.52-3.48(m,2H),3.43-3.39(m,4H), 2.86(t,J=5.6Hz,2H),2.68(t,J=5.6Hz,2H),2.45-2.42(m,5H),2.10- 2.03(m,2H),1.83-1.78(m,2H),1.51-1.48(m,1H),0.93-0.89(m,2H),0.51- 0.49(m,2H);LCMS(m / z):421.60[M+H] + .

[0353] Example 11: 1-(3-((5-cyclopropyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one

[0354] [ka]

[0355] To a solution of intermediate 8 (170 mg, 0.55 mmol) in n-butanol (6 mL) were added trifluoroacetic acid (251 mg, 2.2 mmol) and intermediate 4 (71.4 mg, 0.44 mmol) and the mixture was stirred at 100° C. for 3 h. The reaction mixture was evaporated and the residue was made basic with 1N NaOH solution and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Trituration with diethyl ether gave an off-white solid (70 mg, 29%). 1 H NMR(400MHz,CDCl3):δ 7.67(s,1H),7.46(s,1H),7.29-7.25(m,1H),6.92(d,J=8.4Hz,1H),6.72( brs,1H),6.48(brs,1H),3.52-3.47(m,6H),3.29(brs,2H),2.90(t,J=6.0H z,2H),2.66(t,J=6.0Hz,2H),2.44-2.41(m,5H),1.86-1.79(m,6H),1.51- 1.48(m,1H),0.93-0.88(m,2H),0.50-0.47(m,2H);LCMS(m / z):435.5(M+H) +

[0356] Example 12: 1-(3-((5-cyclopropyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one

[0357] [ka]

[0358] Prepared similarly to Example 11, but using 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (71.4 mg, 0.44 mmol) for intermediate 5. The product was isolated as a white solid (25 mg, 11%). 1H NMR(300MHz,DMSO-d6):δ 8.71(s,1H),7.59(s,1H),7.53(brs,1H),7.41(d,J=8.4Hz,1H),6.92(d,J=8.4 Hz,1H),6.86-6.82(m,1H),3.43-3.37(m,6H),3.25-3.20(m,2H),2.75-2.70(m ,2H),2.60-2.55(m,2H),2.33(s,3H),2.28-2.21(m,2H),1.78-1.68(m,6H),1. 48-1.42(m,1H),0.84-0.79(m,2H),0.48-0.42(m,2H);LCMS(m / z):435.52(M+H) +

[0359] Example 13: 1-(3-(5-cyclopropyl-2-(3-((dimethylamino)methyl)phenyl amino)pyrimidin-4-ylamino)propyl)piperidin-2-one

[0360] [ka]

[0361] To a stirred solution of intermediate 8 (0.23 g, 0.74 mmol) in n-butanol (5 mL) was added 3-((dimethylamino)methyl)aniline (0.11 g, 0.74 mmol) and TFA (0.31 g, 2.96 mmol) and the resulting solution was stirred at 100° C. for 5 h. The reaction mixture was concentrated and the residue was basified with saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (2×20 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative HPLC afforded a white solid (50 mg, 16%). 1H NMR(300MHz,DMSO-d6):δ 8.82(s,1H),7.80(s,1H),7.60(s,1H),7.56(d,J=8.7Hz,1H),7.13(t,J=7. 8Hz,1H),6.86(t,J=5.7Hz,1H),6.76(d,J=7.2Hz,1H),3.46-3.35(m,5H),3. 24-3.22(m,2H),2.22(t,J=6.0Hz,2H),2.14(s,6H),1.81-1.70(m,6H),1.48 -1.43(m,1H),0.85-0.79(m,2H),0.49-0.44(m,2H);LCMS(m / z):423.5[M+H] + .

[0362] Example 14: 1-(3-((5-cyclopropyl-2-((4-(4-hydroxy-1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one

[0363] [ka]

[0364] A mixture of 4-(4-aminophenyl)-1-methylpiperidin-4-ol (Intermediate 9) (78.4 mg, 0.38 mmol), Intermediate 8 (150 mg, 0.48 mmol), sodium tert-butoxide (139 mg, 1.44 mmol) in 1,4-dioxane (10 mL) was degassed with argon for 5 min before adding Xantphos (22.2 mg, 0.038 mmol) and Pd2(dba)3 (26.4 mg, 0.028 mmol). The resulting reaction mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through Celite, washing with ethyl acetate. The filtrate was concentrated and the residue was purified by flash column chromatography (gradient elution from 2-5% MeOH in DCM) to give an off-white solid (60 mg, 26%). 1H NMR(400MHz,DMSO-d6):δ 8.77(s,1H),7.67(d,J=8.8Hz,2H),7.59(s,1H),7.29(d,J=8.8Hz,2H),6.83(t,J=5.6Hz,1H) ,4.55(s,1H),3.39(q,J=6.8Hz,4H),3.23(t,J=5.6Hz,2H),2.50-2.49(m,2H),2.32(t,J=11.2 Hz,2H),2.23(t,J=6.4Hz,2H),2.18(s,3H),1.92-1.86(m,2H),1.79-1.69(m,6H),1.55(d,J=1 2.4Hz,2H),1.46-1.44(m,1H),0.84-0.79(m,2H),0.47-0.43(m,2H);LCMS(m / z):479.52(M+H) +

[0365] Example 15: 5-Cyclopropyl-N2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-N4-(3-(pyrrolidin-1-yl)propyl)pyrimidine-2,4-diamine

[0366] [ka]

[0367] Step 1: Synthesis of 2-chloro-5-cyclopropyl-N-(3-(pyrrolidin-1-yl)propyl)pyrimidin-4-amine To a solution of 2,4-dichloro-5-cyclopropylpyrimidine (500 mg, 2.64 mmol) in IPA (10 mL) was added DIPEA (1.38 mL, 7.92 mmol) and 3-(pyrrolidin-1-yl)propan-1-amine (508 mg, 3.96 mmol) at 0 °C, then the mixture was heated to 50 °C for 16 h. The reaction mixture was evaporated, the residue was taken up in ethyl acetate (30 mL), washed with water (30 mL), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude material was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 50% ethyl acetate / petroleum ether) to give a white solid (400 mg, 53.8%).

[0368] Step 2: Synthesis of 5-cyclopropyl-N2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-N4-(3-(pyrrolidin-1-yl)propyl)pyrimidine-2,4-diamine To a solution of 2-chloro-5-cyclopropyl-N-(3-(pyrrolidin-1-yl)propyl)pyrimidin-4-amine (200 mg, 0.71 mmol) in tert-butanol (6 mL) was added TFA (324 mg, 2.84 mmol) and intermediate 4 (91 mg, 0.56 mmol) at room temperature. The reaction mixture was evaporated, the residue was basified with 1N NaOH solution, extracted with ethyl acetate (2 x 20 mL), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude solid was purified by trituration with diethyl ether to give an off-white solid (70 mg, 27.6%). 1 H NMR(400MHz,DMSO-d6):δ 8.68(s,1H),7.61(s,1H),7.57(s,1H),7.41(dd,J1=1.6,J2 =8.0Hz,1H),6.88(t,J=5.2Hz,1H),6.84(d,J=8.0Hz,1H),3.48(q,J=6.8Hz,2H),3.37(s,2H),2.75(t,J=6.0Hz,2H),2.54(t,J=6.0Hz,2H),2. 43(brs,6H),2.30(s,3H),1.80-1.76(m,2H),1.66(brs,4H),1.43-1.40(m,1H),0.81-0.76(m,2H),0.46-0.42(m,2H);LCMS(m / z):407.5(M+H) +

[0369] Example 16: 1-(3-((5-cyclopropyl-2-((3-((1-methylpiperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one

[0370] [ka]

[0371] To a stirred solution of intermediate 8 (0.17 g, 0.55 mmol) in n-butanol (5 mL) was added 3-((1-methylpiperidin-4-yl)oxy)aniline (0.1 g, 0.55 mmol) and TFA (0.23 g, 2.2 mmol) at room temperature, and the resulting solution was stirred at 100° C. for 5 h. The reaction mixture was cooled to room temperature and concentrated, and the residue was basified with saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The crude was purified by preparative HPLC to give a white solid (90 mg, 37%). 1 H NMR(300MHz,CDCl3):δ 7.69(s,1H),7.32(d,J=1.8Hz,1H),7.15-7.11(m,2H),6.80(br s,1H),6.56-6.44(m,2H),4.40-4.34(m,1H),3.53-3.49(m,4H),3.29(br s,2H),2.96(d,J=8.4Hz,1H),2.63-2.59(m,1H),2.43(br s,2H),2.29(s,3H),2.18-1.99(m,3H),1.84-1.79(m,7H),1.60-1.44(m,3H),0.95-0.89(m,2H),0.52-0.47(m,2H);LCMS(m / z):479.58[M+H] +

[0372] Example 17: N4,5-Dicyclopropyl-N2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidine-2,4-diamine

[0373] [ka]

[0374] To a solution of intermediate 10 (0.2 g, 0.95 mmol) in t-butanol (4 mL) was added TFA (0.43 g, 3.82 mmol) and intermediate 4 (0.12 g, 0.76 mmol) at room temperature and stirred at 100° C. for 3 h. The reaction mixture was evaporated and the residue was basified with 1N NaOH solution and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude solid was purified by trituration with diethyl ether to give an off-white solid (0.05 g, 16%). 1 H NMR(300MHz,DMSO-d6):δ 8.75(s,1H),7.79(s,1H),7.57(s,1H),7.49(dd,J1=1.8Hz,J2=8.4Hz,1H),6 .84(d,J=8.4Hz,1H),6.74(d,J=2.7Hz,1H),3.37(s,2H),2.85-2.82(m,1H), 2.76-2.72(m,2H),2.56-2.49(m,2H),2.30(s,3H),1.49-1.44(m,1H),0.80- 0.76(m,4H),0.64-0.59(m,2H),0.46-0.41(m,2H);LCMS(m / z):336.19[M+H] +

[0375] Example 18: N4,5-Dicyclopropyl-N2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine

[0376] [ka]

[0377] To a solution of intermediate 10 (0.2 g, 0.95 mmol) in t-butanol (4 mL) were added TFA (0.43 g, 3.82 mmol) and 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (0.12 g, 0.76 mmol) at room temperature, and the mixture was stirred at 100° C. for 3 h. The reaction mixture was evaporated, the residue was basified with 1N NaOH solution, and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude solid was purified by trituration with diethyl ether to give the product as an off-white solid (0.06 g, 18.7%). 1 H NMR(300MHz,DMSO-d6):δ ppm 8.79(s,1H),7.72(s,1H),7.57-7.51(m,2H),6.93(d,J=8.4Hz,1H),6.76(d,J=2.4Hz,1H),3.52(s,2H),2.86-2.82(m,1H),2.81 -2.68(m,4H),2.40(s,3H),1.49-1.42(m,1H),0.80-0.74(m,4H),0.69-0.59(m,2H),0.46-0.41(m,2H);LCMS(m / z):336.19[M+H] + .

[0378] Example 19: 1-[3-[[2-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0379] [ka]

[0380] Intermediate 1 (0.050 g, 0.149 mmol) and tert-butyl 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylate (0.039 g, 0.156 mmol) were combined in IPA (2 mL) and heated at 80° C. for 3 h. The reaction mixture was cooled, concentrated in vacuo onto silica and purified by column chromatography (10-100% EtOAc in PE). Fractions containing the product were combined and concentrated in vacuo. The product was dissolved in DCM and TFA was added and the resulting solution was stirred for 15 min. The reaction mixture was passed through an SCX cartridge and the product was eluted with 2M NH3 in MeOH. The eluent was concentrated to give the product 1-[3-[[2-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one (0.044 g, 0.098 mmol, 66% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.50(s,1H),8.17(s,1H),7.51-7.58(m,1H),7.38-7.44(m,J=1.00,1.0 0Hz,1H),7.21-7.23(m,1H),7.19-7.26(m,1H),6.95(d,J=8.70Hz,1H),3 .85(s,2H),3.40-3.44(m,2H),3.23(s,3H),2.96-3.03(m,2H),2.66-2. 73(m,2H),2.19-2.25(m,2H),1.67-1.77(m,6H);LCMS(m / z):449.1[M+H] + .

[0381] Examples 20 to 23

[0382] [ka]

[0383] Examples 20-23 were prepared similarly to Example 19 from Intermediate 1 and the appropriate amine.

[0384] [Table 1]

[0385] Example 24: 1-[3-[[2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0386] [ka]

[0387] To a solution of 1-[3-[[2-[(6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]-5-(trifluoromethyl)-pyrimidin-4-yl]amino]propyl]piperidin-2-one (0.110 g, 0.230 mmol) in DCM was added formaldehyde (22 mL, 0.276 mmol) followed by sodium triacetoxyborohydride (0.098 g, 0.460 mmol) and the reaction mixture was left to stir for 1 h. The reaction mixture was diluted with DCM and saturated NaHCO3 (aq) and the organic layer was separated, dried and concentrated in vacuo to give a brown gum. This gum was taken up in MeOH and subjected to preparative HPLC to give the product (0.033 g, 29%). 1 H NMR(400MHz,DMSO-d6)d 8.14(s,1H),7.97(s,1H),7.76(s,1H),7.20-7.31(m,1H),6.76(s,1H) ,3.80(s,3H),3.42(s,2H),3.35-3.39(m,2H),3.30(t,J=6.64Hz,2H), 3.21(t,J=5.50Hz,2H),2.78(s,2H),2.57(t,J=5.95Hz,2H),2.33(s,3H),2.22(t,J=6.18Hz,2H),1.65-1.76(m,6H);LCMS(m / z):493.1[M+H] + .

[0388] Example 25: 1-[3-[[2-(isochroman-7-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0389] [ka]

[0390] Intermediate 1 (0.050 g, 0.149 mmol) and isochroman-7-amine (0.022 g, 0.149 mmol) were combined in IPA, sealed in a microwave vial and heated at 80 °C for 2 h. The reaction mixture was cooled, concentrated under vacuum onto silica and purified by column chromatography (10-100% EtOAc in PE). Fractions containing the product were combined and concentrated to give the product 1-[3-[[2-(isochroman-7-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one (0.011 g, 0.024 mmol, 16% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)d 9.57(br.s,1H),8.16(s,1H),7.48-7.53(m,1H),7.39-7.45(m,1H),7.17-7.25(m,1H),7.01-7.07(m,1H),4.65(s,2H),3.82-3.89(m,2H) ,3.40(q,J=6.11Hz,2H),3.29-3.33(m,2H),3.22(s,2H),2.68-2.74(m,2H),2.18-2.27(m,2H),1.63-1.78(m,6H).LCMS(m / z):450.0[M+H] + .

[0391] Examples 26 to 37 Examples 26-37 were prepared similarly to Example 25 from Intermediate 1 and the appropriate amine.

[0392] [ka]

[0393] [Table 2-1]

[0394] [Table 2-2]

[0395] [Table 2-3]

[0396] Example 38: 1-[3-[[2-[2-methoxy-4-(morpholine-4-carbonyl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0397] [ka]

[0398] To 3-methoxy-4-[[4-[3-(2-oxo-1-piperidyl)propylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzoic acid (0.050 g, 0.107 mmol) in DMF (1 mL) was added HATU (0.049 g, 0.128 mmol), DIPEA (0.039 mL, 0.214 mmol), and morpholine (0.010 g, 0.118 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and water, the organic layer was separated, washed with water, and concentrated under vacuum. The residue was taken up in MeOH and subjected to preparative HPLC to give the product (0.022 g, 38%). 1H NMR(400MHz,DMSO-d6)d 8.23(d,J=8.24Hz,1H),8.19(s,1H),8.12(s,1H),7.30-7.36(m,1H),7.07-7.09(m,1H),7.02-7.06(m,1H),3.89(s,3H),3.44-3 .67(m,8H),3.35-3.41(m,2H),3.28-3.32(m,2H),3.19-3.24(m,2H),2.19-2.25(m,2H),1.65-1.77(m,6H);LCMS(m / z):537[M+H] + .

[0399] Examples 39 to 41

[0400] [ka]

[0401] Examples 39-41 were prepared analogously to Example 38 from 3-methoxy-4-[[4-[3-(2-oxo-1-piperidyl)propylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzoic acid and the appropriate amine.

[0402] [Table 3]

[0403] Example 42: 3-Methoxy-4-[[4-[3-(2-oxo-1-piperidyl)propylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-(4-piperidyl)benzamide

[0404] [ka]

[0405] Prepared from 3-methoxy-4-[[4-[3-(2-oxo-1-piperidyl)-propylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzoic acid and tert-butyl 4-aminopiperidine-1-carboxylate as in Example 38, except removal of the BOC group was accomplished by stirring the crude product in 1:1 DCM-TFA (2 mL) for 30 min. The reaction mixture was concentrated in vacuo and purified by preparative HPLC. 1 H NMR(400MHz,DMSO-d6)d 8.23(d,J=8.24Hz,1H),8.18(d,J=0.92Hz,1H),8.13-8.17(m,1H),8.09(s,1H),7.46 -7.50(m,1H),7.45(d,J=1.83Hz,1H),7.30-7.35(m,1H),3.89(s,3H),3.80-3.86(m,1 H),3.33-3.40(m,2H),3.25-3.29(m,2H),3.15-3.21(m,2H),2.96-3.04(m,2H),2.54- 2.62(m,2H),2.19(s,2H),1.61-1.78(m,8H),1.38-1.51(m,2H);LCMS(m / z):550[M+H] +

[0406] Example 43: 1-[3-[[2-[(6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0407] [ka]

[0408] Prepared analogously to Example 19 from Intermediate 1 and Intermediate 17. 1H NMR(400MHz,DMSO-d6)dppm 8.74(s,1H),8.10(s,1H),7.40(s,1H),7.15-7.23(m,2H),3.83(s,2H),3.21-3.29(m,4H),3.15-3.20( LCMS(m / z):483 / 485[M+H + ].

[0409] Example 44: 1-[3-[[2-[2-chloro-5-(4-piperidyloxy)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0410] [ka]

[0411] Intermediate 1 (0.07 g, 0.208 mmol) and tert-butyl 4-(3-amino-4-chloro-phenoxy)piperidine-1-carboxylate (0.075 g, 0.230 mmol) were combined in IPA (3 mL) and heated at 85° C. overnight. The reaction mixture was concentrated in vacuo, dissolved in DCM (2 mL) and TFA (0.5 mL) was added. The reaction mixture was stirred for 15 min and passed through an SCX cartridge, eluting with 2M NH3 in MeOH. Purification by preparative HPLC afforded the product (0.012 g, 11%). 1 H NMR(chloroform-d)d:8.26(d,J=2.7Hz,1H),8.19(s,1H),7.49(s,1H),7.25(d,J=8 .7Hz,1H),6.84-6.94(m,1H),6.54(s,1H),4.28-4.46(m,1H),3.43-3.59(m,4H) ,3.25-3.33(m,2H),3.09-3.22(m,2H),2.69-2.83(m,2H),2.39-2.50(m,2H),1 .97-2.09(m,2H),1.79-1.87(m,6H),1.70-1.76(m,2H).LCMS(m / z):527.0[M+H] +

[0412] Example 45: 1-[3-[[5-(trifluoromethyl)-2-[[6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]amino]pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0413] [ka]

[0414] Prepared analogously to example 19 from intermediate 1 and 6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-7-amine. 1 H NMR(chloroform-d)d:8.15(d,J=0.9Hz,1H),7.95(s,1H),7.35(s,1H),7.12(s,1H),6.70-6.88(m,1H),3.97-4.15(m,2H), 3.41-3.50(m,4H),3.25-3.33(m,2H),3.14-3.22(m,2H),2.72-2.89(m,2H),2.33-2.53(m,2H),1.76-1.84(m,6H);m / z 517(M+H) +

[0415] Example 46: 1-[3-[[2-[(3-ethoxy-1-methyl-pyrazol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0416] [ka]

[0417] Intermediate 1 (0.050 g, 0.149 mmol), 3-ethoxy-1-methyl-pyrazol-4-amine hydrochloride (0.029 g, 0.164 mmol), and IPA (2 mL) were combined in a microwave vial and heated at 80° C. overnight. The reaction mixture was cooled, dissolved in MeOH, and purified by preparative HPLC. The product was passed through an SCX cartridge to give the product (0.042 g, 64%). 1 H NMR(chloroform-d)d:8.04-8.22(m,1H),7.63-7.80(m,1H),6.37-6.92(m,2H),4.22-4.33(m,2H),3.75(s,3H),3.45-3 .53(m,4H),3.20-3.37(m,2H),2.37-2.51(m,2H),1.78-1.87(m,6H),1.40(t,J=7.1Hz,3H).LCMS(m / z):442.0[M+H] +

[0418] Examples 47 to 52

[0419] [ka]

[0420] [Table 4]

[0421] Example 52: 1-[3-[[2-[(5-piperazin-1-ylsulfonyl-2,3-dihydrobenzofuran-7-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0422] [ka]

[0423] Prepared analogously to example 19 from intermediate 1 and tert-butyl 4-[(7-amino-2,3-dihydrobenzofuran-5-yl)sulfonyl]piperazine-1-carboxylate. 1 H NMR(chloroform-d)d:8.83(d,J=1.4Hz,1H),8.14(d,J=0.9Hz,1H),7.46(br.s,1H),7.23(d,J=1.8Hz,1H),7.10-7.20(m,1H),4.74(t,J=8.9Hz, 2H),3.52-3.63(m,2H),3.41-3.51(m,2H),3.25-3.37(m,4H),2.84-3. 04(m,8H),2.38-2.48(m,2H),1.70-1.88(m,7H);LCMS(m / z):584[M+H] +

[0424] Example 53: 1-[3-[[2-[[3-methoxy-1-(2-morpholinoethyl)pyrazol-4-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0425] [ka]

[0426] Intermediate 1 (0.050 g, 0.149 mmol), 3-methoxy-1-(2-morpholinoethyl)pyrazol-4-amine (0.037 g, 0.164 mmol), and IPA (2 mL) were combined and heated at 120° C. under microwave. The reaction mixture was cooled, concentrated, and purified by preparative HPLC (low pH buffer). The product was passed through an SCX cartridge to give the final product (0.046 g, 53% yield). 1H NMR(chloroform-d)d:8.10-8.17(m,1H),7.76(br.s.,1H),6.78-6.94(m,1H),6.58(br.s.,1H),4.01-4.13(m,2H),3.95(s,3 H),3.66-3.73(m,4H),3.40-3.52(m,4H),3.22-3.33(m,2H),2.78(t,J=6.9Hz,2H),2.40-2.53(m,6H),1.77-1.89(m,6H). LCMS(m / z):527.1[M+H] + .

[0427] Examples 54 to 55

[0428] [ka]

[0429] Prepared analogously to Example 53 from Intermediate 1 and the appropriate amine.

[0430] [Table 5]

[0431] Example 56: 1-[3-[[2-[(2-acetyl-6-chloro-3,4-dihydro-1H-isoquinolin-7-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0432] [ka]

[0433] To a solution of 1-[3-[[2-[(6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]-5-(trifluoromethyl)-pyrimidin-4-yl]amino]propyl]piperidin-2-one (0.030 g, 0.062 mmol) in Et3N (18 μL, 0.124 mmol) and DCM, acetyl chloride (5.5 μL, 0.77 mmol) was added and the reaction mixture was left stirring at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give the product (0.011 g, 34%). 1 H NMR (chloroform-d) shifts: 8.37 (s, 1H), 8.16 (s, 1H), 7.53 (s, 1H), 7.17-7.22 (m, 1H), 6.88-7.04 (m, 1H), 4.60-4.74 (m, 2H), 3.65-3.86 (m, 2H), 3.45-3.56 (m, 4H), 3.27-3.36 (m, 2H), 2.74-2.92 (m, 2H), 2.41-2.50 (m, 2H), 2.16-2.35 (m, 3H), 1.78-1.89 (m, 6H). LCMS (m / z): 525.0 [M+H] + .

[0434] Example 57: 1-[3-[[2-(2-chloro-5-hydroxy-anilino)-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0435] [ka]

[0436] Step 1: tert-Butyl-(4-chloro-3-nitro-phenoxy)-dimethyl-silane To a solution of 4-chloro-3-nitrophenol (0.500 g, 0.289 mmol) and Et3N (0.843 g, 0.578 mmol) in DCM (20 mL) was added tert-butyldimethylsilyl chloride (0.528 g, 0.318 mmol) and the reaction mixture was left to stir at room temperature for 1 h. The reaction mixture was diluted with DCM and water and the organic layer was separated, dried and concentrated directly onto SiO2. Purification by column chromatography (0-10% EtOAc in PE) afforded the desired product tert-butyl-(4-chloro-3-nitro-phenoxy)-dimethyl-silane (0.637 g, 73% yield) as a pale yellow oil. 1 H NMR (chloroform-d): 7.39 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 2.7 Hz, 1H), 6.99 (dd, J = 8.7, 2.7 Hz, 1H), 0.99 (s, 9H), 0.24 (s, 6H).

[0437] Step 2: 5-[tert-Butyl(dimethyl)silyl]oxy-2-chloro-aniline To a solution of tert-butyl-(4-chloro-3-nitro-phenoxy)-dimethyl-silane (0.637 g, 2.10 mmol) in EtOAc (30 mL) was added SnCl2.2H2O (2.37 g, 10.5 mmol) and the reaction mixture was left to stir overnight. The reaction mixture was poured into saturated NaHCO3 (aq) and the organic layer was separated, dried and concentrated in vacuo to give the product 5-[tert-butyl(dimethyl)silyl]oxy-2-chloro-aniline (536 mg, 94%). 1 H NMR (chloroform-d): 7.07 (d, J = 8.7 Hz, 1H), 6.30 (d, J = 2.7 Hz, 1H), 6.21 (dd, J = 8.7, 2.7 Hz, 1H), 0.97 (s, 9H), 0.18 (s, 6H).

[0438] Step 3: 1-[3-[[2-[5-[tert-butyl(dimethyl)silyl]oxy-2-chloro-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one Intermediate 1 (0.100 g, 0.298 mmol), 5-[tert-Butyl(dimethyl)silyl]oxy-2-chloro-aniline (0.089 g, 0.327 mmol), and IPA (2 mL) were combined in a microwave vial and heated at 80° C. overnight. The reaction mixture was cooled and concentrated under vacuum onto silica. The compound was purified by column chromatography (10-100% EtOAc in PE) to give a yellow oil (0.114 g, 65%). 1 H NMR (chloroform-d) shifts: 8.16-8.19 (m, 1H), 8.14 (s, 1H), 7.43-7.59 (m, 1H), 7.20 (d, J = 8.7 Hz, 1H), 6.86-6.98 (m, 1H), 6.46 (dd, J = 8.7, 2.7 Hz, 1H), 3.45-3.55 (m, 4H), 3.25-3.30 (m, 2H), 2.40-2.51 (m, 2H), 1.79-1.86 (m, 6H), 0.99 (s, 9H), 0.22 (s, 6H). LCMS (m / z): 558.0 [M+H] + .

[0439] Step 4: 1-[3-[[2-(2-chloro-5-hydroxy-anilino)-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one 1-[3-[[2-[5-[tert-Butyl(dimethyl)silyl]oxy-2-chloro-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]-propyl]piperidin-2-one (0.114 g, 0.205 mmol) in THF (5 mL) was added to TBAF (1 M in THF, 0.31 mL, 0.307 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum onto silica and purified by column chromatography to give a white solid (0.090 g, 99%). 1H NMR (chloroform-d) shifts: 10.10 (br.s., 1H), 8.02 (s, 1H), 7.42 (d, J = 2.7 Hz, 1H), 7.19 (d, J = 8.7 Hz, 1H), 7.03-7.12 (m, 1H), 6.46-6.74 (m, 1H), 3.43-3.53 (m, 4H), 3.30-3.37 (m, 2H), 2.39-2.52 (m, 2H), 1.80-1.89 (m, 6H). LCMS (m / z): 443.9 [M+H] + .

[0440] Example 58: 1-[3-[[2-[2-chloro-5-[2-(dimethylamino)ethoxy]anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0441] [ka]

[0442] To a mixture of 1-[3-[[2-(2-chloro-5-hydroxy-anilino)-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one (0.030 g, 0.068 mmol) and K2CO3 (0.019 g, 0.135 mmol) in DMF (1 mL) was added 2-chloro-N,N-dimethyl-ethanamine hydrochloride (0.011 g, 0.080 mmol). The reaction mixture was heated at 70 °C overnight, concentrated in vacuo, and purified by preparative HPLC to give the product (3 mg, 9%). 1 H NMR(chloroform-d)d:8.25(d,J=2.7Hz,1H),8.19(d,J=0.9Hz,1H),7.49(s,1H),7.25(d,J=8.7Hz,1H),6.85-6.93(m,1H),6.55(dd,J=8.7,2.7Hz,1H),4. 05-4.14(m,2H),3.44-3.57(m,4H),3.25-3.33(m,2H),2.74-2.83(m,2H), 2.41-2.50(m,2H),2.38(s,6H),1.77-1.86(m,6H).LCMS(m / z):515.0[M+H] + .

[0443] Example 59: 1-[3-[[2-[2-chloro-5-(2-morpholinoethoxy)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0444] [ka]

[0445] Prepared analogously to example 58 from 1-[3-[[2-(2-chloro-5-hydroxy-anilino)-5-(trifluoromethyl)-pyrimidin-4-yl]amino]propyl]piperidin-2-one and 2-morpholinoethanamine hydrochloride to give the product (0.010 g, 27%). 1 H NMR(chloroform-d)d:8.24(d,J=3.2Hz,1H),8.19(d,J=0.9Hz,1H),7.49(s,1H),7.2 6(d,J=8.7Hz,1H),6.86-7.01(m,1H),6.47-6.58(m,1H),4.12(t,J=5.7Hz,2H), 3.70-3.77(m,4H),3.44-3.57(m,4H),3.26-3.33(m,2H),2.82(t,J=5.7Hz,2H), 2.56-2.63(m,4H),2.41-2.50(m,2H),1.78-1.87(m,6H).LCMS(m / z):557.0[M+H] + .

[0446] Example 60: 1-[3-[[2-[2-methoxy-5-(methylaminomethyl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0447] [ka]

[0448] Step 1: 4-Methoxy-3-[[4-[3-(2-oxo-1-piperidyl)propylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzaldehyde To a solution of 1-[3-[[2-[5-(hydroxymethyl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one (0.140 g, 0.309 mmol) in THF (10 mL) was added Dess-Martin periodinane (0.087 g, 0.464 mmol) and the reaction mixture was left stirring at room temperature for 2 h. The reaction mixture was concentrated under vacuum onto silica and purified by column chromatography (40-80% EtOAc in PE) to give a light brown solid (0.083 g, 60% yield). 1 H NMR(chloroform-d)d:9.90(s,1H),9.18(d,J=2.3Hz,1H),8.17(d,J=0.9Hz,1H),7 .77(s,1H),7.51(dd,J=8.2,2.3Hz,1H),7.03-7.13(m,1H),7.00(d,J=8.2Hz, 1H),4.00(s,3H),3.59-3.69(m,2H),3.45-3.55(m,2H),3.24-3.36(m,2H),2. 41-2.52(m,2H),1.90-1.97(m,2H),1.80-1.86(m,4H).LCMS(m / z):452.0[M+H] + .

[0449] Step 2: 1-[3-[[2-[2-methoxy-5-(methylaminomethyl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one To a solution of 4-methoxy-3-[[4-[3-(2-oxo-1-piperidyl)propylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzaldehyde (0.027 g, 0.060 mmol) in DCM / MeOH (5 mL) was added methylamine (0.7 μL, 0.072 mmol) followed by Na(OAc)3BH (0.019 g, 0.090 mmol) and the reaction mixture was left stirring at room temperature overnight. The reaction mixture was concentrated under vacuum, taken up in MeOH and subjected to preparative HPLC (pH 1) which was then passed through an SCX cartridge to give the desired product (7 mg, 20%). 1 H NMR (chloroform-d):8.48(d,J=2.3Hz,1H),8.16(s,1H),7.68(s,1H),6.95(dd,J=8.2,2.3Hz,1H),6.76-6.86(m,2H),3.88(s,3H),3.72-3.76(m,2 H),3.53-3.60(m,2H),3.49-3.50(m,1H),3.45-3.47(m,2H),3.24-3.3 3(m,2H),2.43-2.47(m,5H),1.78-1.86(m,6H).LCMS(m / z):467.1[M+H] + .

[0450] Example 61: 1-[3-[[2-[2-methoxy-5-(morpholinomethyl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0451] [ka]

[0452] Prepared as in Example 60 using morpholine in step 2. 1H NMR (chloroform-d) shifts: 8.49 (d, J = 1.8 Hz, 1H), 8.16 (s, 1H), 7.67-7.74 (m, 1H), 6.97 (dd, J = 8.2, 1.8 Hz, 1H), 6.82-6.88 (m, 2H), 3.90 (s, 3H), 3.71-3.79 (m, 4H), 3.46-3.68 (m, 6H), 3.26-3.34 (m, 2H), 2.40-2.75 (m, 6H), 1.78-1.91 (m, 6H); LCMS (m / z): 523 [M+H] + .

[0453] Example 62: N-(3-((2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide

[0454] [ka]

[0455] Step 1: tert-Butyl 6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0456] [ka]

[0457] Zinc chloride (3.04 mL, 1 M in EtO, 3.04 mmol) was dissolved in 2,4-dichloro-5-trifluoromethylpyrimidine (0.300 g, 1.38 mmol) in 1:1 DCE: t To a stirred solution of BuOH (12 mL) was added dropwise at 0° C. The reaction mixture was stirred for 1 h and then treated with 6-amino-2-N-1,2,3,4-tetrahydroisoquinoline (341 mg, 1.38 mmol) followed by triethylamine (0.21 mL, 1.52 mmol) in 1:1 DCE: tThe mixture was stirred for 2 h, concentrated in vacuo, then taken up in DCM and concentrated in vacuo onto silica. The crude reaction mixture was purified by column chromatography (10 g column, 60-70% EA in PE) to give a white solid (370 mg, 75%). 1 H NMR(400MHz,chloroform-d)δ ppm 8.59(s,1H),7.36(m,2H),7.11(d,J=8.24Hz,1H),4.55(s,2H),3.65(t,J=5.04Hz,2H),2.84(t,J=5.50Hz,2H),1.48(s,9H).

[0458] Step 2: N-(3-((2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide N-(3-aminopropyl)cyclobutanecarboxamide (12 mg, 0.079 mmol) and triethylamine (0.02 mL, 0.119 mmol) were added to a suspension of tert-butyl 6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (34 mg, 0.079 mmol) in IPA (2 mL). The reaction mixture was stirred at 70° C. for 2 h, then cooled to room temperature and concentrated in vacuo. This was taken up in DCM (5 mL) and TFA (1 mL) was added and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated and the resulting residue was purified by preparative HPLC (pH 1) and then desalted (SCX cartridge). The solvent was concentrated in vacuo to give a white solid (2.1 mg, 6%). 1H NMR (400MHz, DMSO-d6) δ ppm 9.45(s,1H),8.12(s,1H),7.63(t,J=5.50Hz,1H),7.51(s,1H),7.36(dd,J=9 .62,2.29Hz,1H),7.12(t,J=4.58Hz,1H),6.88(d,J=8.70Hz,1H),3.77(s,2H) ),3.40(q,J=6.00Hz,2H),3.04(m,2H),2.92(m,2H),2.63(t,J=5.50Hz,2H), 2.07(m,2H),1.95(m,2H),1.82(m,1H),1.67(m,4H);LCMS(m / z):449.1[M+H] + .

[0459] Examples 63 to 67 Prepared analogously to Example 62 in step 1 from tert-butyl 6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate and the appropriate amine.

[0460] [ka]

[0461] [Table 6-1]

[0462] [Table 6-2]

[0463] Example 68: 1-[4-[[2-[(6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]-1-piperidyl]ethanone

[0464] [ka]

[0465] Step 1: tert-Butyl 7-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0466] [ka]

[0467] 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.390 g, 1.79 mmol) in DCE (15 mL) and t To the BuOH (15 mL) solution, ZnCl2 (1 M in Et2O) (3.96 mL, 3.96 mmol) was added dropwise at 0 °C and left to stir for 1 h. Then, tert-butyl 7-amino-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (0.500 g, 1.79 mmol) and Et3N (0.52 mL, 3.58 mmol) were added in a 1:1 ratio of DCE and 1:1 ratio of Et3N to DCE. t The BuOH solution was added dropwise and the reaction mixture was allowed to stir and warm over the weekend. The reaction mixture was concentrated in vacuo, taken up in DCM and absorbed onto silica. The compound was purified by column chromatography (0-15% EtOAc in PE) and the product-containing fractions were combined and concentrated in vacuo to give the product tert-butyl 7-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (0.760 g, 1.66 mmol, 92% yield) as a colorless oil that solidified upon standing. 1 H NMR (400MHz, chloroform-d) d 8.57-8.63 (m, 1H), 8.10-8.14 (m, 1H), 6.66-6.69 (m, 1H), 4.54-4.59 (m, 2H), 3.89-3.90 (m, 3H), 3.63-3.69 (m, 2H), 2.78-2.85 (m, 2H), 1.50-1.52 (m, 9H); LCMS (m / z): 358.9 [M-CO2 t Bu+H] + .

[0468] Step 2: 1-[4-[[2-[(6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]-1-piperidyl]ethenone tert-Butyl 7-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (0.045 g, 0.098 mmol), 1-(4-amino-1-piperidyl)ethanone (0.015 g, 0.108 mmol), and IPA (2 mL) were combined in a microwave vial and heated overnight at 80° C. The reaction mixture was concentrated and TFA was added (1 mL), then the residue was taken up in MeOH and subjected to preparative HPLC (pH 10) to give the product (9 mg, 20%). 1 H NMR(400MHz,DMSO-d6)d 8.16(s,1H),8.02(s,1H),7.69(s,1H),6.73(s,1H),6.55-6.64(m,1H),4.38-4 .46(m,1H),4.23-4.34(m,1H),3.84-3.90(m,1H),3.80(s,5H),3.00-3.08(m,1H) ),2.87-2.95(m,2H),2.60-2.68(m,2H),2.51-2.57(m,1H),1.98-2.03(m,3H),1 .75-1.86(m,2H),1.56-1.68(m,1H),1.43-1.56(m,1H);LCMS(m / z):465.0[M+H] + .

[0469] Examples 69 to 73 Prepared analogously to Example 68 in step 2 from tert-butyl 7-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate and the appropriate amine.

[0470] [ka]

[0471] [Table 7]

[0472] Example 74: N-[3-[[5-cyclopropyl-2-[(6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide

[0473] [ka]

[0474] Step 1: N-[3-[(2-chloro-5-cyclopropyl-pyrimidin-4-yl)amino]propyl]cyclobutanecarboxamide

[0475] [ka]

[0476] 2,4-Dichloro-5-cyclopropyl-pyrimidine (0.294 g, 1.08 mmol), N-(3-aminopropyl)cyclobutanecarboxamide (0.170 g, 0.899 mmol), DIPEA (0.33 mL, 1.70 mmol), and IPA (10 mL) were combined and heated at 50° C. for 3 h. The reaction mixture was cooled, concentrated onto silica, and the compound was purified by column chromatography (10-100% EtOAc in PE). Fractions were combined and concentrated to give a yellow oil (0.037 g, 13%). LCMS (m / z): 309.1 [M+H] + .

[0477] Step 2: N-[3-[[5-cyclopropyl-2-[(6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide N-[3-[(2-chloro-5-cyclopropyl-pyrimidin-4-yl)amino]propyl]cyclobutanecarboxamide (0.037 g, 0.120 mmol), tert-butyl 7-amino-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (0.037 g, 0.132 mmol), and IPA (2 mL) were combined in a microwave vial and heated at 80° C. overnight. The reaction mixture was concentrated, dissolved in DCM (2 mL), TFA was added (0.5 mL), and the residue was then passed through an SCX cartridge and the product was eluted with 2M NH3 in MeOH. The eluent was concentrated, taken up in MeOH, and purified by preparative HPLC (pH 10) to give a white solid (0.013 g, 23% yield). 1 H NMR (400MHz, chloroform-d) d 8.20(s,1H), 7.74(s,1H), 7.34(br.s,1H), 6.57(s,1H), 5.90-5.96(m,1H), 5.82-5.89(m,1H), 3.98(s,2H), 3.83-3.89(m,3H), 3.57-3.64(m,2H), 3.29-3.35(m,2H), 3.11-3.19(m,2H), 3.28-3.36(m,2H), 3.29-3.35(m,2H), 3.33-3.28(m,2H), 3.28-3.36 ... H),2.80-2.92(m,1H),2.72-2.78(m,2H),2.21-2.30(m,2H),2.02-2.12(m,2H),1.74-1.9 7(m,4H),1.42-1.52(m,1H),0.88-0.96(m,2H),0.47-0.54(m,2H).LCMS(m / z):451.1[M+H] + .

[0478] Example 75: 1-[3-[[5-cyclopropyl-2-[(6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0479] [ka]

[0480] Prepared similarly to Example 74, except in step 2, 1-(3-aminopropyl)piperidin-2-one was used.

[0481] 1 H NMR(400MHz,chloroform-d)d 8.26(s,1H),7.69(s,1H),7.49(br.s,1H),6.52-6.59(m,2H),4.07(s,2H),3.86(s,3H),3.45-3.56(m,5H),3.28-3.34(m,2H),3.2 1-3.26(m,2H),2.79-2.86(m,2H),2.41-2.44(m,2H),1.79-1.87(m,6H),1.48-1.56(m,1H),0.90-0.97(m,2H),0.46-0.56(m,2H).

[0482] Example 76: 1-[3-[[2-[(2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]pyrrolidin-2-one

[0483] [ka]

[0484] 1-[3-[[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]pyrrolidin-2-one (0.045 g, 0.140 mmol), 2-methyl-3,4-dihydro-1H-isoquinolin-6-amine (0.027 g, 0.168 mmol), and IPA (2 mL) were combined, sealed in a microwave vial, and heated at 80° C. for 18 hours. The reaction mixture was cooled, concentrated, and purified by HPLC to give the product (9 mg, 14%). 1H NMR(400MHz,chloroform-d)d 8.12(s,1H),7.37-7.45(m,1H),7.25-7.29(m,1H),7.06-7.15(m,1H),6.92-6.98(m,1H),6.44-6.55(m,1H),3.46-3.55(m,4H),3.32 -3.43(m,4H),2.85-2.94(m,2H),2.64-2.71(m,2H),2.39-2.47(m,5H),1.99-2.12(m,2H),1.77-1.80(m,2H);LCMS(m / z):449.1[M+H] + .

[0485] Example 77: 1-[3-[[2-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]pyrrolidin-2-one

[0486] [ka]

[0487] Prepared analogously to example 19 from 1-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one and tert-butyl 7-amino-3,4-dihydro-1H-isoquinoline-2-carboxylate. 1 H NMR(400MHz,chloroform-d)d 8.12(s,1H),6.91-7.00(m,1H),6.50-6.57(m,2H),6.03-6.13(m,1H),4.82(s,2H),4.01(t,J=5.95Hz,2H),3.4 9-3.55(m,2H),3.33-3.44(m,4H),2.76-2.84(m,2H),2.38-2.47(m,2H),2.01-2.11(m,2H),1.77-1.86(m,2H). LCMS(m / z):435.1[M+H] + .

[0488] Example 78: N2-(6-Methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-N4-(morpholin-2-ylmethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0489] [ka]

[0490] Step 1: tert-Butyl 7-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0491] [ka]

[0492] 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.185 g, 0.853 mmol) in DCE (8 mL) and t To a solution of BuOH (8 mL) ZnCl2 was added dropwise at 5° C. and the reaction mixture was left to stir for 1 h. To this was added tert-butyl 7-amino-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (0.237 g, 0.853 mmol) and Et3N (0.14 mL, 0.938 mmol) and the reaction mixture was left to stir at room temperature overnight. The reaction mixture was concentrated under vacuum onto silica and purified by column chromatography (0-10% EtOAc in PE) to give the product (0.160 g, 41%). 1 H NMR (400MHz, chloroform-d) d 8.57-8.63 (m, 1H), 8.10-8.14 (m, 1H), 6.66-6.69 (m, 1H), 4.54-4.59 (m, 2H), 3.89-3.90 (m, 3H), 3.63-3.69 (m, 2H), 2.78-2.85 (m, 2H), 1.50-1.52 (m, 9H); MS (m / z): 458.9 [M+H] + .

[0493] Step 2: N2-(6-Methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-N4-(morpholin-2-ylmethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine tert-Butyl-7-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (0.050 g, 0.109 mmol), tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (0.023 g, 0.109 mmol), Et3N (24 mL, 0.164 mmol), and IPA (2 mL) were combined, sealed in a microwave vial, and heated at 80 °C for 18 h. The compound was purified by column chromatography (10-40% EtOAc in PE). The fractions containing the product were combined and concentrated under vacuum. The residue was taken up in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was passed through an SCX cartridge and the product was eluted with 2M NH3 in MeOH. The eluate was concentrated in vacuo and triturated with Et2O to give the product (0.030 g, 58% yield). 1 H NMR(400MHz,DMSO-d6)d 8.14(s,1H),7.99(s,1H),7.75(br.s,1H),6.98-7.10(m,1H),6.73(s,1H),3.78-3.86(m,5H),3.69-3.75(m,1H),3.55-3.64( m,1H),3.45-3.50(m,1H),3.36-3.40(m,2H),2.92-2.99(m,2H),2.60-2.73(m,5H),2.31-2.39(m,1H);LCMS(m / z):439.0[M+H] + .

[0494] Example 79: 3-[[2-[(6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]-1-morpholino-propan-1-one

[0495] [ka]

[0496] Step 1: 3-[[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]-1-morpholino-propan-1-one To 3-amino-1-morpholino-propan-1-one (0.732 g, 4.63 mmol) and Et3N (1.34 mL, 9.26 mmol) in IPA was added 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.0 g, 4.67 mmol) and the reaction mixture was heated at 50 °C overnight. The reaction mixture was cooled, concentrated under vacuum onto silica and purified by column chromatography (0-100% EtOAc in PE). Fractions containing the product were combined and concentrated under vacuum to give the product 3-[[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]-1-morpholino-propan-1-one (0.419 g, 1.24 mmol, 27% yield) as a white solid. 1 H NMR (400MHz, chloroform-d) d 8.22 (s, 1H), 6.68-6.79 (m, 1H), 3.86-3.92 (m, 2H), 3.65-3.69 (m, 4H), 3.60-3.64 (m, 2H), 3.42-3.46 (m, 2H), 2.59-2.63 (m, 2H); LCMS (m / z): 339.0 [M+H] + .

[0497] Step 2: 3-[[2-[(6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]-1-morpholino-propan-1-one 3-[[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]-1-morpholino-propan-1-one (0.050 g, 0.148 mmol), tert-butyl 7-amino-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (0.045 g, 0.163 mmol), and IPA (2 mL) were combined and heated at 80° C. for 3 hours. The reaction mixture was cooled, concentrated in vacuo, taken up in DCM, then TFA (1 mL) was added and the reaction mixture was left to stir for 30 minutes. The reaction mixture was concentrated in vacuo, taken up in MeOH, and concentrated to give the product (0.011 g, 0.023 mmol, 15% yield). 1 H NMR(400MHz,DMSO-d6)d 8.15(s,1H),7.97(s,1H),7.68(s,1H),7.01-7.13(m,1H),6.70(s,1H),3.79(s,3H),3.71(s,2H),3.58-3.67(m,2H),3 .48-3.54(m,4H),3.42-3.46(m,2H),3.35-3.39(m,2H),2.86-2.93(m,2H),2.58-2.66(m,4H);LCMS(m / z):481.0[M+H] + .

[0498] Example 80: 1-Morpholino-3-[[2-[3-(4-piperidyloxy)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propan-1-one

[0499] [ka]

[0500] The preparation was carried out similarly. 1H NMR(400MHz,DMSO-d6)d 9.51-9.59(m,1H),8.20(s,1H),7.35-7.40(m,1H),7.26-7.33(m,1H),7.03-7.1 5(m,2H),6.51-6.61(m,1H),4.24-4.34(m,1H),3.64-3.73(m,2H),3.51-3.54(m ,2H),3.43-3.50(m,4H),3.35-3.38(m,2H),2.90-2.97(m,2H),2.63-2.70(m,2H ),2.51-2.57(m,2H),1.85-1.96(m,2H),1.36-1.49(m,2H);LCMS(m / z):495[M+H] + .

[0501] Example 81: 1-[3-[[2-[(6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]pyrrolidin-2-one

[0502] [ka]

[0503] tert-Butyl-7-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (0.040 g, 0.087 mmol), 1-(3-aminopropyl)pyrrolidin-2-one (0.015 g, 0.105 mmol), and IPA (2 mL) were combined and heated at 80° C. for 3 hours. The reaction mixture was cooled, concentrated in vacuo, taken up in DCM, then TFA (1 mL) was added and the reaction mixture was left to stir for 30 minutes. The reaction mixture was concentrated in vacuo, taken up in MeOH, and concentrated to give the product (3 mg, 0.006 mmol, 7.4% yield). 1H NMR(400MHz,DMSO-d6)d 8.15(s,1H),7.97(s,1H),7.74(s,1H),7.10-7.23(m,1H),6.73(s,1H),3.77-3.84(m,5H),3.29-3.35(m,4H),3.17-3.23(m, 2H),2.91-3.01(m,2H),2.62-2.71(m,2H),2.18-2.26(m,2H),1.85-1.97(m,2H),1.65-1.76(m,2H);LCMS(m / z):465.0[M+H] + .

[0504] Example 82: N-[3-[[2-[(6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide

[0505] [ka]

[0506] Prepared analogously to example 81 from tert-butyl-7-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate and N-(3-aminopropyl)cyclobutene-carboxamide. 1 H NMR (400MHz, DMSO-d6) 8.10(s,1H),7.90(s,1H),7.75(br.s,1H),7.60-7.66(m,1H),7.13-7.22(m, 1H),6.69(s,1H),3.72-3.78(m,5H),3.33-3.39(m,2H),2.99-3.06(m,2H),2. 87-2.94(m,3H),2.58-2.65(m,2H),2.03-2.12(m,2H),1.91-1.99(m,2H),1.7 7-1.89(m,1H),1.66-1.74(m,1H),1.56-1.64(m,2H);LCMS(m / z):479.0[M+H] + .

[0507] Example 83: 1-[3-[[2-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl]amino]propyl]piperidin-2-one

[0508] [ka]

[0509] Prepared analogously to example 19 from intermediate 1 and tert-butyl 7-amino-3,4-dihydro-1H-isoquinoline-2-carboxylate. 1 H NMR(400MHz,chloroform-d)d 8.12(s,1H),6.95(d,J=8.70Hz,1H),6.51-6.58(m,2H),6.21-6.33(m,1H),4.83(s,2H),3.95-4.08(m,2H),3.43 -3.53(m,4H),3.25-3.32(m,2H),2.80(s,2H),2.44(t,J=5.95Hz,2H),1.78-1.86(m,6H);LCMS(m / z):449.1[M+H] + .

[0510] Example 84: 5-Cyclopropyl-N4-(3-(dimethylamino)propyl)-N2-(3-(1-methylpiperidin-4-yloxy)phenyl)pyrimidine-2,4-diamine

[0511] [ka]

[0512] Step 1: N1-(2-chloro-5-cyclopropylpyrimidin-4-yl)-N3,N3-dimethylpropane-1,3-diamine To a solution of 2,4-dichloro-5-cyclopropylpyrimidine (0.25 g, 1.32 mmol) in IPA (5 mL) was added DIPEA (0.34 mL, 1.99 mmol) followed by N1,N1-dimethylpropane-1,3-diamine (0.16 g, 1.59 mmol) at room temperature and stirred at 60 °C for 16 h. The reaction mixture was evaporated and the resulting residue was taken up in 10% methanol / DCM (30 mL), washed with water (10 mL) and the separated organic layer was dried over sodium sulfate and concentrated under vacuum. The crude compound was purified by column chromatography (silica gel, 100-200 mesh, eluted with 1% methanol / chloroform) to give an off-white solid (0.15 g, 45%). 1 H NMR(400MHz,CDCl3):δ 7.8(s,1H),7.71(s,1H),3.62-3.58(m,2H),2.52-2.49(m,2H),2.27(s,6H),1.81-1.75 (m,2H),1.37-1.34(m,1H),0.89-0.85(m,2H),0.56-0.52(m,2H);LCMS(m / z):255[M+H] + .

[0513] Step 2: 5-Cyclopropyl-N4-(3-(dimethylamino)propyl)-N2-(3-(1-methylpiperidin-4-yloxy)phenyl)-pyrimidine-2,4-diamine To a solution of N1-(2-chloro-5-cyclopropylpyrimidin-4-yl)-N3,N3-dimethylpropane-1,3-diamine (0.15 g, 0.59 mmol) in t-butanol (4 mL), TFA (0.27 g, 2.36 mmol) was added followed by 3-[(1-methyl-4-piperidyl)oxy]aniline (0.097 g, 0.47 mmol) at room temperature and stirred at 100° C. for 4 h. The reaction mixture was evaporated and the resulting residue was basified with 1N NaOH solution and extracted with ethyl acetate (2×20 mL), the combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under vacuum. The crude solid was purified by trituration with diethyl ether and n-pentane to give the product as an off-white solid (0.06 g, 24%). 1H NMR(400MHz,CDCl3):δ 7.68(s,1H),7.37.38(m,1H),7.15-7.12(m,2H),6.88-6.81(m,2H),6.56-6.53(m ,1H),4.40-4.35(m,1H),3.63-3.59(m,2H),2.95(d,J=10.8Hz,2H),2.60(d,J=10 .8Hz,1H),2.49-2.46(m,2H),2.29-2.16(m,8H),2.1-1.8(m,3H),1.79-1.64(m,3 H),1.63-1.35(m,3H),0.83-0.78(m,2H),0.51-0.47(m,2H);LCMS(m / z):425[M+H] + .

[0514] Example 85: N4-(1H-pyrazol-3-ylmethyl)-N2-(1-pyrrolidin-3-ylpyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0515] [ka]

[0516] 2-Chloro-5-(trifluoromethyl)-N-[(1-tritylpyrazol-3-yl)methyl]pyrimidin-4-amine (50 mg, 0.09 mmol) and tert-butyl 3-(4-aminopyrazol-1-yl)pyrrolidine-1-carboxylate (27 mg, 0.11 mmol) were combined in butanol in a microwave vial and heated at 100° C. overnight. The reaction mixture was cooled and TFA was added. The reaction mixture was passed through an SCX cartridge and the product was eluted with 2M NH3 in MeOH. The eluent was concentrated in vacuo, taken up in MeOH and purified by preparative HPLC. 1H NMR (400MHz, methanol-D3)8.09(br.s.,1H),7.82(br.s.,1H),7.55(br.s.,1H),7.47(br.s.,1H),6.21(br.s.,1H),4. 63-4.88(m,3H),3.23(br.s.,1H),2.95-3.13(m,1H),2.30(d,J=7.79Hz,1H),1.97-2.22(m,1H).LCMS(m / z)394[M+H] + .

[0517] Example 86: N4-(1H-pyrazol-3-ylmethyl)-N2-[4-(2-pyrrolidin-1-ylethyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0518] [ka]

[0519] 2-Chloro-5-(trifluoromethyl)-N-[(1-tritylpyrazol-3-yl)methyl]pyrimidin-4-amine (50 mg, 0.09 mmol) and 4-(ethylenepyrrolidine)aniline (19 mg, 0.10 mmol) were combined in a sealed tube in butanol (3 mL) and heated at 110° C. for 18 hours. The reaction mixture was cooled, concentrated in vacuo, TFA was added and stirred for 30 minutes. Et3SiH was added and the reaction mixture was concentrated in vacuo. The residue was taken up in MeOH, passed through an SCX cartridge and the product was eluted with 2M NH3 in MeOH. The product was purified by preparative HPLC. 1 H NMR(DMSO-d6)d:9.51(br.s.,1H),8.18(s,1H),7.32-7.66(m,4H),7.06(d,J=8.2Hz,2H),6.04-6.16(m,1H),4.62( d,J=5.5Hz,2H),2.62-2.68(m,2H),2.53-2.61(m,2H),2.43-2.47(m,4H),1.56-1.73(m,5H);LCMS(m / z):432[M+H] + .

[0520] Example 87: N2-(4-morpholinophenyl)-N4-(pyrrolidin-3-ylmethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0521] [ka]

[0522] Step 1: 4-Chloro-N-(4-morpholinophenyl)-5-(trifluoromethyl)pyrimidin-2-amine A 1M solution of zinc chloride in diethyl ether (3 mL, 3 mmol) was dissolved in 1:1 DCE of pyridine: t BuOH (12 mL) solution was added dropwise with ice cooling. Stirred for 1 hour. 4-Morpholinoaniline (246 mg, 1.4 mmol) was added. 1:1 DCE of triethylamine: t A solution of BuOH (4 mL) was added dropwise. The solution was allowed to warm to room temperature with continued cooling. After 3 h the reaction was complete. The reaction mixture was concentrated to dryness and the residue was preloaded onto silica and purified with 2:1 PE / EA to give 4-chloro-N-(4-morpholinophenyl)-5-(trifluoromethyl)pyrimidin-2-amine as a yellow solid (270 mg, 55%). 1 H NMR (400MHz, DMSO-d6) 10.44 (s, 1H), 8.70 (s, 1H), 7.40-7.60 (m, 2H), 6.87-7.05 (m, 2H), 3.61-3.84 (m, 4H), 2.96-3.11 (m, 4H). LCMS(m / z):358[M+H] + .

[0523] Step 2: N2-(4-morpholinophenyl)-N4-(pyrrolidin-3-ylmethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine 4-Chloro-N-(4-morpholinophenyl)-5-(trifluoromethyl)pyrimidin-2-amine (50 mg, 0.14 mmol), 3-aminopyrrolidine (28 mg, 0.14 mmol), and triethylamine (30 μL, 0.21 mmol) were combined in butanol in a sealed chromacol vial and heated overnight at 105° C. The reaction mixture was concentrated in vacuo, passed through SCX, and subjected to HPLC purification (pH 10) to give the product N2-(4-morpholinophenyl)-N4-(pyrrolidin-3-ylmethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (10.8 mg, 18%). 1 H NMR (400MHz, chloroform-d) 8.13(d,J=0.92Hz,1H),7.43-7.50(m,2H),7.16(s,1H),6.85-6.94(m,2H),5. 77(br.s.,1H),3.87(dd,J=3.89,5.72Hz,4H),3.41-3.56(m,2H),3.10-3.16( m,4H),2.99-3.08(m,2H),2.87-2.96(m,1H),2.78(dd,J=4.81,10.76Hz,1H), 2.44-2.54(m,1H),1.97(dtd,J=5.04,8.30,13.17Hz,1H),1.46-1.57(m,1H). LCMS(m / z):423[M+H] + . Examples 88-92 were prepared similarly to Example 87.

[0524] Example 88: N4-(4-aminocyclohexyl)-N2-(4-morpholinophenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0525] [ka]

[0526] 1H NMR(400MHz,chloroform-d)d 8.12(s,1H),7.43-7.53(m,2H),7.05(br.s.,1H),6.87-6.94(m,2H),4. 91(d,J=6.41Hz,1H),3.95-4.05(m,1H),3.95-4.05(m,J=3.90,6.60Hz,1 H),3.84-3.92(m,4H),3.09-3.18(m,4H),2.75-2.85(m,1H),2.18(d,J= 8.70Hz,2H),1.93-2.02(m,2H),1.22-1.40(m,4H).LCMS(m / z):437[M+H] + .

[0527] Example 89: N2-(4-morpholinophenyl)-N4-[2-(4-piperidyl)ethyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0528] [ka]

[0529] 1 H NMR(400MHz,chloroform-d)d 8.12(s,1H),7.43-7.53(m,2H),7.05(br.s.,1H),6.87-6.94(m,2H),4.91(d,J=6.41Hz,1H),3.95-4.05(m,1H),3.95-4.05,(m,J=3.9 0,6.60Hz,1H),3.84-3.92(m,4H),3.09-3.18(m,4H),2.75-2.85(m,1H),2.18(d,J=8.70Hz,2H),1.93-2.02(m,2H),1.22-1.40(m,4H). LCMS(m / z):451[M+H] + .

[0530] Example 90: N2-(4-morpholinophenyl)-N4-(morpholin-2-ylmethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0531] [ka]

[0532] 1 H NMR(400MHz,chloroform-d)d 8.14(d,J=0.92Hz,1H),7.40-7.48(m,2H),6.99-7.06(m,1H),6.87-6.94(m,2H),5.56(br.s.,1H),3.90-3.96(m,1H),3.83 -3.90(m,4H),3.59-3.75(m,3H),3.37-3.48(m,1H),3.07-3.18(m,4H),2.82-2.97(m,3H),2.65(dd,J=9.85,12.14Hz,1H). LCMS(m / z):439[M+H] + .

[0533] Example 91: N4-[2-(1H-imidazol-4-yl)ethyl]-N2-(4-morpholinophenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0534] [ka]

[0535] 1 H NMR(400MHz,chloroform-d)d 8.11(s,1H),7.66(s,1H),7.45-7.52(m,2H),6.87-6.94(m,2H),6.84(d,J=0.92Hz,1H),5.91(br.s.,1H) ,3.86-3.89(m,4H),3.88(d,J=4.58Hz,4H),3.75-3.83(m,2H),3.11-3.14(m,4H),2.94(t,J=6.41Hz,2H). LCMS(m / z):434[M+H] + .

[0536] Example 92: N2-(4-morpholinophenyl)-N4-(1H-pyrazol-4-ylmethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0537] [ka]

[0538] 1 H NMR(400MHz,chloroform-d)d 8.12-8.20(m,1H),7.55-7.60(m,2H),7.45-7.50(m,2H),6.88-6.94(m,2H),4.60-4.64(m,2H),3.85-3.91(m,4H),3.10-3.16(m,4H). LCMS(m / z):420[M+H] + .

[0539] Example A A radiometric assay was used to measure ULK activity, and a glass fiber capture filter method was used to detect radiolabeled binding to MBP substrates. 33 P incorporation was measured. Reaction conditions were 0.2mg / mL MBP, 20uM ATP (0.25μCi / well), 50mM Tris HCl, pH7.5, 10mM MgCl2, 0.1% beta-mercaptoethanol, 0.1mM EGTA, 0.01% BSA. Ten point Half log Compound dilution series were prepared in 100% DMSO and added to the reactions to give a final assay concentration of 10% DMSO. Compounds were tested in duplicate and values ​​were normalized to a 10% DMSO only control. Data were fitted with a four parameter fit equation and IC50 values ​​shown are the average of at least two independent experiments.

[0540] [Table 8-1]

[0541] [Table 8-2]

Claims

1. The following: 【Chemistry 1-1】 【Chemistry 1-2】 or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

2. The following: 【Chemistry 2】 2. The compound of claim 1, wherein:

3. The following: 【Chemistry 3】 2. The compound of claim 1, wherein:

4. The following: 【Chemistry 4】 2. The compound of claim 1, wherein:

5. The following: 【Chemistry 5】 2. The compound of claim 1, wherein:

6. The following: 【Chemistry 6】 2. The compound of claim 1, wherein:

7. The following: 【Chemistry 7】 2. The compound of claim 1, wherein:

8. The following: 【Chemistry 8】 2. The compound of claim 1, wherein:

9. The following: 【Chemistry 9】 2. The compound of claim 1, wherein:

10. The following: 【Chemistry 10】 2. The compound of claim 1, wherein:

11. The following: 【Chemistry 11】 2. The compound of claim 1, wherein:

12. The following: 【Chemistry 12】 2. The compound of claim 1, wherein:

13. The following: 【Chemistry 13】 2. The compound of claim 1, wherein:

14. A pharmaceutical composition comprising the compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a pharma- ceutically acceptable excipient.

15. Use of a compound according to claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a pharmaceutical for use in a method of treating cancer in a subject in need thereof, the method comprising administering the compound, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

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