MEK inhibitors and their therapeutic uses

Abstract

The present disclosure provides compounds, compositions containing such compounds, and methods for designing, developing, producing and preparing compounds represented by general formula (I), including pharmaceutically acceptable salts thereof or synthetic intermediates thereof: #imgabs0# The compounds act as MEK inhibitors and can exhibit one or more beneficial therapeutic effects, including the treatment of cancer.

Description

Background Art

[0001] field

[0002] The present invention relates to the fields of chemistry and medicine. More specifically, the present invention relates to MEK inhibitors, techniques for designing and synthesizing such MEK inhibitors, compositions comprising MEK inhibitors, and methods of treating diseases comprising administering MEK inhibitors.

[0003] Related technical description

[0004] Cancer is one of the most common causes of death in the United States. In the United States, cancer accounts for approximately one-quarter of deaths. The 5-year relative survival rate for cancer patients diagnosed between 1996 and 2003 was approximately two-thirds, higher than the approximately one-half between 1975 and 1977 (Cancer Facts & Figures, American Cancer Society: Atlanta, Ga. (2008)). Between 2000 and 2009, the incidence of new cancer cases in men decreased by an average of 0.6% per year, but remained unchanged in women. From 2000 to 2009, the mortality rate for all cancers combined decreased by an average of 1.8% per year in men and by 1.4% per year in women. This improvement in survival reflects advances in early diagnosis and improvements in treatment, which are still needed. Discovering highly effective anticancer agents with low toxicity is a major goal of cancer research.

[0005] Furthermore, cancer-related cachexia is a debilitating condition associated with muscle loss, fatigue, weakness, and loss of appetite in cancer patients. Cachexia is also associated with serious clinical consequences, including muscle weakness that can lead to difficulty walking and pulmonary complications. Cachexia is a significant contributing factor to mortality in cancer patients.

[0006] Cachexia is characterized in part by a loss of skeletal muscle mass that cannot be reversed by conventional nutritional support, resulting in significant weight loss that seriously affects patient morbidity and mortality. Cachexia has been identified in more than 80% of patients with gastric, pancreatic, and esophageal cancer; approximately 70% of patients with head and neck cancer; and approximately 60% of patients with lung, colorectal, and prostate cancer. See Muscle (2012) 3, 245-51. Despite the impact of cachexia on mortality in cancer patients, no effective therapy has been developed to prevent or halt the progression of cachexia. For example, it is estimated that more than 85% of pancreatic cancer patients (including those in the early stages) lose an average of 14% of their pre-disease weight. See, BMC Cancer, 2010 Jul 8;10:363. Cachectic pancreatic cancer patients are often weak and fatigued, have lower tolerance to therapy, and have more adverse consequences for surgery. Therefore, cachexia is a major driver of mortality in pancreatic cancer. Unfortunately, the 5-year survival rate for pancreatic cancer has not exceeded 6% in the past 40 years, making it the lowest survival rate among all malignancies.

[0007] A lot of effort has been invested in designing treatments for cachexia syndrome, but unfortunately, there is no single, completely satisfactory treatment for reversing the weight loss associated with cancer cachexia. The development of different treatment strategies has focused on two goals: counteracting anorexia and neutralizing metabolic disorders. However, providing complete nutritional requirements through total parenteral nutrition does not eliminate weight loss. On the contrary, many drugs have been proposed and used in clinical trials, while others are still being studied using experimental animals to restore metabolic changes. See, Toledo et al., 2014 PloS One. In one study, the MEK inhibitor selumetinib was found to promote muscle growth in patients with bile duct cancer. See British Journal of Cancer, (2012), 106, 1583-1586. In another study, the MEK inhibitor binimetinib was found to promote muscle growth in patients with BTC. See, Inv New Drugs (2018) 36, 1037-1043.

[0008] In addition to its potential role in cachexia, MEK is a key signaling intermediate in the MAPK / ERK pathway that is inappropriately activated in a wide range of human tumors, including those originating from the lung, pancreas, ovary, skin, and colon. Although several MEK inhibitors have received regulatory approval to date, these MEK inhibitors have not met expectations for clinical efficacy. Identifying a new class of MEK inhibitors that can maximize the reversal of pathology in the MAPK / ERK pathway while limiting drug-related toxicities would have a significant impact on the morbidity and mortality of cancer patients. Summary of the Invention

[0009] The compounds disclosed in this application have been found to exhibit surprising and unexpected biological effects. These compounds are MEK inhibitors that maximally reverse pathological changes in the MAPK / ERK pathway and are effective anticancer and anticancer cachexia agents suitable for use in anticancer and anticancer cachexia pharmaceutical formulations.

[0010] Some embodiments provide compounds having the structure of Formula (I):

[0011]

[0012] Including pharmaceutically acceptable salts thereof, wherein:

[0013] Ring A is

[0014] R 1 、R 2 、R 3 、R 4 and R 6 each independently selected from the group consisting of H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-acylamino, optionally substituted N-acylamino, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamoyl, optionally substituted N-thiocarbamoyl, optionally substituted N-carbamoyl, optionally substituted O-carbamoyl, optionally substituted urea, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, or L;

[0015] X is C(R 5 )2、CH(R 5 )、CH2、-O-、

[0016] L is -Z1-Z2 or -Z1-Z2-Z3;

[0017] Z1, Z2 and Z3 are independently –CH2–, –O–, –S–, S=O, –SO2–, C=O, –CO2–, –NO2, –NH–, –CH2CCH, –CH2CN, –NR 5 R 5 , –NH(CO)–, –(CO)NH–, –(CO)NR 5 R5 –, –NH-SO2–, –SO2-NH–, –R 5 CH2–, –R 5 O–,–R 5 S–, R 5 -S=O、–R 5 SO2–, R 5 -C=O、–R 5 CO2–,–R 5 NH–,–R 5 NH(CO)–,–R 5 (CO)NH–、–R 5 NH-SO2–,–R 5 SO2-NH–, –CH2R 5 –, –OR 5 –, –SR 5 –、S=OR 5 ,–SO2R 5 –、C=OR 5 , –CO2R 5 –, –NHR 5 –, –NH(CO)R 5 –,–(CO)NHR 5 –, –NH-SO2R 5 –, –SO2-NHR 5 -, optionally substituted C1 to C6 alkyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 heteroaryl);

[0018] Each R 5 are independently H, deuterium, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 carbocyclyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclyl, or optionally substituted C3 to C10 heteroaryl; and

[0019] Y is CH2, NH or O,

[0020] Provided that R1 is not pyrimidinyl.

[0021] In some embodiments of Formula (I), Ring A is In some embodiments, R2 is -CH3. In some embodiments, R 2 is L. In some embodiments, L is -Z1-Z2. In some embodiments, Z1 is -CH2-. In some embodiments, Z2 is selected from optionally substituted C3 to C8 cycloalkyl, optionally substituted C3 to C8 heterocyclyl, optionally substituted C3 to C8 heteroaryl, -NR 5 R 5 , -CH2CH or -CH2CN. In some embodiments, R 5 In some embodiments, L is -Z1-Z2-Z3. In some embodiments, Z1 is -CH2- and Z2 is an optionally substituted C3 to C8 heterocyclyl, and Z3 is -CH2-(optionally substituted aryl). In some embodiments, Z1 is -CH2- and Z2 is an optionally substituted wherein n is 1, 2, 3 or 4. In some embodiments, Z1 is -CH2- and Z2 is optionally substituted

[0022] Some embodiments provide compounds of formula (Ia):

[0023]

[0024] Including pharmaceutically acceptable salts thereof, wherein:

[0025] Ring A is

[0026] R 2 、R 3 、R 4 and R 6 each independently selected from the group consisting of H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-acylamino, optionally substituted N-acylamino, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamoyl, optionally substituted N-thiocarbamoyl, optionally substituted N-carbamoyl, optionally substituted O-carbamoyl, optionally substituted urea, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, or L;

[0027] X is C(R 5)2、CH(R 5 )、CH2、-O-、

[0028] L is -Z1-Z2 or -Z1-Z2-Z3;

[0029] Z1, Z2 and Z3 are independently –CH2–, –O–, –S–, S=O, –SO2–, C=O, –CO2–, –NO2, –NH–, –CH2CCH, –CH2CN, –NR 5 R 5 , –NH(CO)–, –(CO)NH–, –(CO)NR 5 R 5 –, –NH-SO2–, –SO2-NH–, –R 5 CH2–, –R 5 O–,–R 5 S–, R 5 -S=O、–R 5 SO2–, R 5 -C=O、–R 5 CO2–,–R 5 NH–,–R 5 NH(CO)–,–R 5 (CO)NH–、–R 5 NH-SO2–,–R 5 SO2-NH–, –CH2R 5 –, –OR 5 –, –SR 5 –、S=OR 5 ,–SO2R 5 –、C=OR 5 , –CO2R 5 –, –NHR 5 –, –NH(CO)R 5 –,–(CO)NHR 5 –, –NH-SO2R 5 –, –SO2-NHR 5 -, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 heteroaryl);

[0030] Each R 5are independently H, deuterium, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 carbocyclyl, optionally substituted C6 to C 10 aryl, an optionally substituted C3 to C8 heterocyclic group, or an optionally substituted C3 to C 10 heteroaryl; and

[0031] Y is CH2, NH or O,

[0032] The condition is R 1 Not a pyrimidinyl.

[0033] In some embodiments of Formula (Ia), Ring A is In some embodiments, R 2 is -CH3. In some embodiments, R 2 is L. In some embodiments, L is -Z1-Z2. In some embodiments, Z1 is -CH2-. In some embodiments, Z2 is selected from optionally substituted C3 to C8 cycloalkyl, optionally substituted C3 to C8 heterocyclyl, optionally substituted C3 to C8 heteroaryl, -NR 5 R 5 , -CH2CH or -CH2CN. In some embodiments, R 5 In some embodiments, L is -Z1-Z2-Z3. In some embodiments, Z1 is -CH2-, Z2 is an optionally substituted C3 to C8 heterocyclyl, and Z3 is -CH2-(optionally substituted aryl). In some embodiments, Z1 is -CH2- and Z2 is an optionally substituted wherein n is 1, 2, 3 or 4. In some embodiments, Z1 is -CH2- and Z2 is optionally substituted

[0034] Some embodiments provide compounds of Formula (Ib):

[0035]

[0036] Including pharmaceutically acceptable salts thereof, wherein:

[0037] Ring A is

[0038] R 2 、R 3 、R 4 and R 6each independently selected from the group consisting of H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-acylamino, optionally substituted N-acylamino, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamoyl, optionally substituted N-thiocarbamoyl, optionally substituted N-carbamoyl, optionally substituted O-carbamoyl, optionally substituted urea, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, or L;

[0039] L is -Z1-Z2 or -Z1-Z2-Z3;

[0040] Z1, Z2 and Z3 are independently –CH2–, –O–, –S–, S=O, –SO2–, C=O, –CO2–, –NO2, –NH–, –CH2CCH, –CH2CN, –NR 5 R 5 , –NH(CO)–, –(CO)NH–, –(CO)NR 5 R 5 –, –NH-SO2–, –SO2-NH–, –R 5 CH2–, –R 5 O–,–R 5 S–, R 5 -S=O、–R 5 SO2–, R 5 -C=O、–R 5 CO2–,–R 5 NH–,–R 5 NH(CO)–,–R 5 (CO)NH–、–R 5 NH-SO2–,–R 5 SO2-NH–, –CH2R 5 –, –OR 5 –, –SR 5 –、S=OR 5 ,–SO2R 5 –、C=OR 5 , –CO2R 5 –, –NHR 5 –, –NH(CO)R 5 –, –(CO)NHR 5–, –NH-SO2R 5 –, –SO2-NHR 5 -, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 heteroaryl);

[0041] Each R 5 are independently H, deuterium, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 carbocyclyl, optionally substituted C6 to C 10 aryl, an optionally substituted C3 to C8 heterocyclic group, or an optionally substituted C3 to C 10 heteroaryl; and

[0042] The condition is R 1 Not a pyrimidinyl.

[0043] In some embodiments of Formula (Ib), Ring A is In some embodiments, R 2 is -CH3. In some embodiments, R 2 is L. In some embodiments, L is -Z1-Z2. In some embodiments, Z1 is -CH2-. In some embodiments, Z2 is selected from optionally substituted C3 to C8 cycloalkyl, optionally substituted C3 to C8 heterocyclyl, optionally substituted C3 to C8 heteroaryl, -NR 5 R 5 , -CH2CH or -CH2CN. In some embodiments, R 5 is selected from H or CH3. In some embodiments, L is -Z1-Z2-Z3. In some embodiments, Z1 is -CH2-, Z2 is an optionally substituted C3 to C8 heterocyclyl, and Z3 is -CH2-(optionally substituted aryl).

[0044] Some embodiments provide compounds of formula (Ic):

[0045]

[0046] Including pharmaceutically acceptable salts thereof, wherein:

[0047] Ring A is

[0048] R1 、R 2 、R 3 、R 4 , and R 6 each independently selected from the group consisting of H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-acylamino, optionally substituted N-acylamino, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamoyl, optionally substituted N-thiocarbamoyl, optionally substituted N-carbamoyl, optionally substituted O-carbamoyl, optionally substituted urea, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, or L;

[0049] X is C(R 5 )2、CH(R 5 )、CH2、-O-、

[0050] L is -Z1-Z2 or -Z1-Z2-Z3;

[0051] Z1, Z2 and Z3 are independently –CH2–, –O–, –S–, S=O, –SO2–, C=O, –CO2–, –NO2, –NH–, –CH2CCH, –CH2CN, –NR 5 R 5 , –NH(CO)–, –(CO)NH–, –(CO)NR 5 R 5 –, –NH-SO2–, –SO2-NH–, –R 5 CH2–, –R 5 O–,–R 5 S–, R 5 -S=O、–R 5 SO2–, R 5 -C=O、–R 5 CO2–,–R 5 NH–,–R 5 NH(CO)–,–R 5 (CO)NH–、–R 5 NH-SO2–,–R 5 SO2-NH–, –CH2R 5 –, –OR 5 –, –SR5 –、S=OR 5 ,–SO2R 5 –、C=OR 5 , –CO2R 5 –, –NHR 5 –, –NH(CO)R 5 –, –(CO)NHR 5 –, –NH-SO2R 5 –, –SO2-NHR 5 -, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 heteroaryl);

[0052] Each R 5 are independently H, deuterium, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 carbocyclyl, optionally substituted C6 to C 10 aryl, an optionally substituted C3 to C8 heterocyclic group, or an optionally substituted C3 to C 10 heteroaryl; and

[0053] Y is CH2, NH or O,

[0054] The condition is R 1 Not a pyrimidinyl.

[0055] In some embodiments of Formula (Ic), Ring A is In some embodiments, R 2 is -CH3. In some embodiments, R 2 is L. In some embodiments, L is -Z1-Z2. In some embodiments, Z1 is -CH2-. In some embodiments, Z2 is selected from optionally substituted C3 to C8 cycloalkyl, optionally substituted C3 to C8 heterocyclyl, optionally substituted C3 to C8 heteroaryl, -NR 5 R 5 , -CH2CH or -CH2CN. In some embodiments, R 5 is selected from H or CH3. In some embodiments, L is -Z1-Z2-Z3. In some embodiments, Z1 is -CH2-, Z2 is an optionally substituted C3 to C8 heterocyclyl, and Z3 is -CH2-(optionally substituted aryl).

[0056] In some embodiments, Z1 is -CH2- and Z2 is optionally substituted wherein n is an integer selected from 1, 2, 3, and 4. In some embodiments, Z1 is -CH2- and Z2 is optionally substituted

[0057] A compound of formula (I) having the structure depicted by formula (Id):

[0058]

[0059] Including pharmaceutically acceptable salts thereof, wherein:

[0060] Ring A is

[0061] R 3 and R 4 each independently selected from the group consisting of H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-acylamino, optionally substituted N-acylamino, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamoyl, optionally substituted N-thiocarbamoyl, optionally substituted N-carbamoyl, optionally substituted O-carbamoyl, optionally substituted urea, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, and L;

[0062] R 6 selected from the group consisting of H, deuterium, hydroxy, halogen, cyano, nitro, optionally substituted amino, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, and optionally substituted C2 to C6 alkynyl;

[0063] R 9 and R 10 are each independently selected from hydrogen, deuterium, an optionally substituted C1 to C6 alkyl group, an optionally substituted C3 to C8 cycloalkyl group, an optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10heteroaryl);

[0064] X 1 Selected from the group consisting of CH, B, N or PO4;

[0065] n is selected from 1, 2, 3 or 4;

[0066] Each R 5 and R 5′ independently selected from H, deuterium, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 carbocyclyl, optionally substituted C6 to C 10 aryl, an optionally substituted C3 to C8 heterocyclic group, and an optionally substituted C3 to C8 10 heteroaryl; and

[0067] Y is CH2, NH or O,

[0068] The condition is R 1 Not a pyrimidinyl.

[0069] In some embodiments, n is 1 or 2. In some embodiments, wherein X 1 is CH or N. In some embodiments, R 9 is selected from optionally substituted C1 to C6 alkyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 Aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 In some embodiments, R 10 is selected from the group consisting of an optionally substituted C1 to C6 alkyl group, an optionally substituted C3 to C8 cycloalkyl group, an optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 Heteroaryl.

[0070] Some embodiments provide compounds of formula (II):

[0071]

[0072] Including pharmaceutically acceptable salts thereof, wherein:

[0073] Q A , Q B , Q C independently C or N;

[0074] R 1 、R 2 、R 3 、R 6 , and R 7each independently selected from the group consisting of H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-acylamino, optionally substituted N-acylamino, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamoyl, optionally substituted N-thiocarbamoyl, optionally substituted N-carbamoyl, optionally substituted O-carbamoyl, optionally substituted urea, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, or L;

[0075] X is C(R 5 )2、CH(R 5 )、CH2、-O-、

[0076] L is -Z1-Z2 or -Z1-Z2-Z3;

[0077] Z1, Z2 and Z3 are independently –CH2–, –O–, –S–, S=O, –SO2–, C=O, –CO2–, –NO2, –NH–, –CH2CCH, –CH2CN, –NR 5 R 5 , –NH(CO)–, –(CO)NH–, –(CO)NR 5 R 5 –, –NH-SO2–, –SO2-NH–, –R 5 CH2–, –R 5 O–,–R 5 S–, R 5 -S=O、–R 5 SO2–, R 5 -C=O、–R 5 CO2–,–R 5 NH–,–R 5 NH(CO)–,–R 5 (CO)NH–、–R 5 NH-SO2–,–R 5 SO2-NH–, –CH2R 5 –, –OR 5 –, –SR 5 –、S=OR 5 ,–SO2R 5 –、C=OR 5, –CO2R 5 –, –NHR 5 –, –NH(CO)R 5 –, –(CO)NHR 5 –, –NH-SO2R 5 –, –SO2-NHR 5 -, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 heteroaryl);

[0078] Each R 5 are independently H, deuterium, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 carbocyclyl, optionally substituted C6 to C 10 aryl, an optionally substituted C3 to C8 heterocyclic group, or an optionally substituted C3 to C 10 heteroaryl;

[0079] Y is CH2, NH or O; and

[0080] Z is C or N,

[0081] The condition is R 1 Not a pyrimidinyl.

[0082] In some embodiments of Formula (II), R 2 is -CH3. In some embodiments, R 2 is L. In some embodiments, L is -Z1-Z2. In some embodiments, Z1 is -CH2-. In some embodiments, Z2 is selected from optionally substituted C3 to C8 cycloalkyl, optionally substituted C3 to C8 heterocyclyl, optionally substituted C3 to C8 heteroaryl, -NR 5 R 5 , -CH2CH or -CH2CN. In some embodiments, R 5 In some embodiments, L is -Z1-Z2-Z3. In some embodiments, Z1 is -CH2-, Z2 is an optionally substituted C3 to C8 heterocyclyl, and Z3 is -CH2-(optionally substituted aryl). In some embodiments, Z1 is -CH2- and Z2 is an optionally substituted wherein n is an integer selected from 1, 2, 3, and 4. In some embodiments, Z1 is -CH2- and Z2 is optionally substituted

[0083] Some embodiments provide compounds of formula (IIa):

[0084]

[0085] Including pharmaceutically acceptable salts thereof, wherein:

[0086] R 2 、R 3 、R 6 and R 8 each independently selected from the group consisting of H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-acylamino, optionally substituted N-acylamino, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamoyl, optionally substituted N-thiocarbamoyl, optionally substituted N-carbamoyl, optionally substituted O-carbamoyl, optionally substituted urea, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, or L;

[0087] X is C(R 5 )2、CH(R 5 )、CH2、-O-、

[0088] L is -Z1-Z2 or -Z1-Z2-Z3;

[0089] Z1, Z2 and Z3 are independently selected from halogen, -CH2-, -O-, -S-, S=O, -SO2-, C=O, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR 5 R 5′ , –NH(CO)–, –(CO)NH–, –(CO)NR 5 R 5′ –, –NH-SO2–, –SO2-NH–, –R 5 CH2–, –R 5 O–,–R 5 S–, R 5 -S=O、–R 5 SO2–, R 5 -C=O、–R 5 CO2–,–R 5NH–,–R 5 NH(CO)–,–R 5 (CO)NH–、–R 5 NH-SO2–,–R 5 SO2-NH–, –CH2R 5 –, –OR 5 –, –SR 5 –、S=OR 5 ,–SO2R 5 –、C=OR 5 , –CO2R 5 –, –NHR 5 –, –NH(CO)R 5 –,–(CO)NHR 5 –, –NH-SO2R 5 –, –SO2-NHR 5 -, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 heteroaryl);

[0090] R 5 and R 5′ Each of the above is independently selected from H, deuterium, an optionally substituted C1 to C6 alkyl, an optionally substituted C2 to C6 alkenyl, an optionally substituted C2 to C6 alkynyl, an optionally substituted C3 to C8 carbocyclyl, an optionally substituted C6 to C 10 aryl, an optionally substituted C3 to C8 heterocyclic group, or an optionally substituted C3 to C 10 heteroaryl;

[0091] Y is CH2, NH or O; and

[0092] Z is C or N.

[0093] In some embodiments of Formula (IIa), R 2 is -CH3. In some embodiments, R 2 is L. In some embodiments, L is -Z1-Z2. In some embodiments, Z1 is -CH2-. In some embodiments, Z2 is selected from optionally substituted C3 to C8 cycloalkyl, optionally substituted C3 to C8 heterocyclyl, optionally substituted C3 to C8 heteroaryl, -NR 5 R 5 , -CH2CCH or -CH2CN. In some embodiments, R 5In some embodiments, L is -Z1-Z2-Z3. In some embodiments, Z1 is -CH2-, Z2 is an optionally substituted C3 to C8 heterocyclyl, and Z3 is -CH2-(optionally substituted aryl). In some embodiments, Z1 is -CH2- and Z2 is an optionally substituted wherein n is selected from 1, 2, 3, and 4. In some embodiments, Z1 is -CH2- and Z2 is optionally substituted

[0094] Some embodiments provide the structure depicted in Formula (IIb):

[0095]

[0096] Including pharmaceutically acceptable salts thereof, wherein:

[0097] R 2 It is L;

[0098] R 6 is H, deuterium, halo or optionally substituted C1 to C6 alkyl;

[0099] L is -Z1-Z2 or -Z1-Z2-Z3;

[0100] Z1, Z2 and Z3 are independently –CH2–, –O–, –S–, S=O, –SO2–, C=O, –CO2–, –NO2, –NH–, –CH2CCH, –CH2CN, –NR 5 R 5 , –NH(CO)–, –(CO)NH–, –(CO)NR 5 R 5 –, –NH-SO2–, –SO2-NH–, –R 5 CH2–, –R 5 O–,–R 5 S–, R 5 -S=O、–R 5 SO2–, R 5 -C=O、–R 5 CO2–,–R 5 NH–,–R 5 NH(CO)–,–R 5 (CO)NH–、–R 5 NH-SO2–,–R 5 SO2-NH–, –CH2R 5 –, –OR 5 –, –SR 5 –、S=OR 5 ,–SO2R 5 –、C=OR5 , –CO2R 5 –, –NHR 5 –, –NH(CO)R 5 –, –(CO)NHR 5 –, –NH-SO2R 5 –, –SO2-NHR 5 -, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 heteroaryl);

[0101] Each R 5 are independently H, deuterium, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 carbocyclyl, optionally substituted C6 to C 10 aryl, an optionally substituted C3 to C8 heterocyclic group, or an optionally substituted C3 to C 10 heteroaryl;

[0102] Z is C or N.

[0103] In some embodiments of Formula (IIb), L is -Z1-Z2. In some embodiments, Z1 is -CH2-. In some embodiments, Z2 is selected from optionally substituted C3 to C8 cycloalkyl, optionally substituted C3 to C8 heterocyclyl, optionally substituted C3 to C8 heteroaryl, -NR 5 R 5 , -CH2CCH or -CH2CN. In some embodiments, R 5 In some embodiments, L is -Z1-Z2-Z3. In some embodiments, Z1 is -CH2-, Z2 is an optionally substituted C3 to C8 heterocyclyl, and Z3 is -CH2-(optionally substituted aryl). In some embodiments, Z1 is -CH2- and Z2 is an optionally substituted wherein n is 1, 2, 3 or 4. In some embodiments, Z1 is -CH2- and Z2 is optionally substituted

[0104] In some embodiments, the compound of formula (II) is represented by the structure of formula (IIc):

[0105]

[0106] Including pharmaceutically acceptable salts thereof, wherein:

[0107] R 1 and R 2 each independently selected from the group consisting of H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-acylamino, optionally substituted N-acylamino, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamoyl, optionally substituted N-thiocarbamoyl, optionally substituted N-carbamoyl, optionally substituted O-carbamoyl, optionally substituted urea, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, or L;

[0108] L is -Z1-Z2 or -Z1-Z2-Z3;

[0109] Z1, Z2 and Z3 are independently –CH2–, –O–, –S–, S=O, –SO2–, C=O, –CO2–, –NO2, –NH–, –CH2CCH, –CH2CN, –NR 5 R 5’ , –NH(CO)–, –(CO)NH–, –(CO)NR 5 R 5’ –, –NH-SO2–, –SO2-NH–, –R 5 CH2–, –R 5 O–,–R 5 S–, R 5 -S=O、–R 5 SO2–, R 5 -C=O、–R 5 CO2–,–R 5 NH–,–R 5 NH(CO)–,–R 5 (CO)NH–、-NHCH2CO-、–R 5 NH-SO2–,–R 5 SO2-NH–, –CH2R 5 –, –OR 5 –, –SR 5 –、S=OR 5 ,–SO2R 5 –、C=OR 5 , –CO2R 5 –, –NHR5 –, –NH(CO)R 5 –, –(CO)NHR 5 –, –NH-SO2R 5 –, –SO2-NHR 5 -, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 heteroaryl);

[0110] Each R 5 and R 5’ are independently H, deuterium, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 carbocyclyl, optionally substituted C6 to C 10 aryl, an optionally substituted C3 to C8 heterocyclic group, or an optionally substituted C3 to C 10 heteroaryl; and

[0111] Z is C or N,

[0112] The condition is R 1 Not a pyrimidinyl.

[0113] In some embodiments, R 2 is not -CH3. In some embodiments, R 2 is L. In some embodiments, L is -Z1-Z2. In some embodiments, Z1 is -CH2-. In some embodiments, Z2 is selected from optionally substituted C3 to C8 cycloalkyl, optionally substituted C3 to C8 heterocyclyl, optionally substituted C3 to C8 heteroaryl, -NR 5 R 5 ', -CH2CCH or -CH2CN. In some embodiments, R 5 and R 5 ' are each selected from H or CH3. In some embodiments, L is -Z1-Z2-Z3. In some embodiments, Z1 is -CH2-, Z2 is selected from N or an optionally substituted C3 to C8 heterocyclyl, and Z3 is selected from an optionally substituted C1 to C6 alkyl, an optionally substituted C2 to C6 alkenyl, an optionally substituted C2 to C6 alkynyl, an optionally substituted C3 to C8 cycloalkyl, an optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 Heteroaryl.

[0114] In some embodiments, the compound of formula (II) is represented by the structure of formula (IId):

[0115]

[0116] Including pharmaceutically acceptable salts thereof, wherein:

[0117] R 3 selected from the group consisting of H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-acylamino, optionally substituted N-acylamino, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamoyl, optionally substituted N-thiocarbamoyl, optionally substituted N-carbamoyl, optionally substituted O-carbamoyl, optionally substituted urea, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl;

[0118] R 6 selected from the group consisting of H, deuterium, hydroxy, halogen, cyano, nitro, optionally substituted amino, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, and optionally substituted C2 to C6 alkynyl;

[0119] R 8 is selected from H, deuterium, an optionally substituted C1 to C6 alkyl, an optionally substituted C2 to C6 alkenyl, an optionally substituted C2 to C6 alkynyl, an optionally substituted C3 to C8 carbocyclyl, an optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl;

[0120] R 9 and R 10 are each independently selected from hydrogen, deuterium, an optionally substituted C1 to C6 alkyl group, an optionally substituted C3 to C8 cycloalkyl group, an optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 heteroaryl); and

[0121] X1 Selected from the group consisting of CH, B, N.

[0122] In some embodiments, R 3 selected from H, deuterium, halogen, C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 Heteroaryl.

[0123] In some embodiments, R 6 is selected from H, deuterium, hydroxy, halogen, cyano, nitro, optionally substituted amino, optionally substituted C1 to C6 alkoxy, and optionally substituted C1 to C6 alkyl.

[0124] In some embodiments, R 8 is selected from hydrogen, deuterium, hydroxy, halogen, cyano, nitro, optionally substituted amino, optionally substituted C1 to C6 alkoxy, and optionally substituted C1 to C6 alkyl.

[0125] In some embodiments, R 9 selected from H, deuterium, halogen, C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 Heteroaryl.

[0126] In some embodiments, R 10 selected from H, deuterium, halogen, C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 Heteroaryl.

[0127] In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), or (IId) is selected from the compounds of Table A. In some embodiments, the compound of Formula (I) or Formula (II) is selected from the group consisting of:

[0128]

[0129]

[0130] and pharmaceutically acceptable salts thereof.

[0131] In some embodiments, the pharmaceutically acceptable salt is an alkali metal salt or an ammonium salt.

[0132] Some embodiments provide pharmaceutical compositions comprising a therapeutically effective amount of at least one compound having the structure of Formula (I):

[0133] 1.

[0134] Including pharmaceutically acceptable salts thereof, wherein:

[0135] Ring A is

[0136] R 1 、R 2 、R 3 、R 4 , and R 6 each independently selected from the group consisting of H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-acylamino, optionally substituted N-acylamino, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamoyl, optionally substituted N-thiocarbamoyl, optionally substituted N-carbamoyl, optionally substituted O-carbamoyl, optionally substituted urea, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, or L;

[0137] X is C(R 5 )2、CH(R 5 )、CH2、-O-、

[0138] L is -Z1-Z2 or -Z1-Z2-Z3;

[0139] Z1, Z2 and Z3 are independently –CH2–, –O–, –S–, S=O, –SO2–, C=O, –CO2–, –NO2, –NH–, –CH2CCH, –CH2CN, –NR 5 R 5 , –NH(CO)–, –(CO)NH–, –(CO)NR 5 R 5 –, –NH-SO2–, –SO2-NH–, –R5 CH2–, –R 5 O–,–R 5 S–, R 5 -S=O、–R 5 SO2–, R 5 -C=O、–R 5 CO2–,–R 5 NH–,–R 5 NH(CO)–,–R 5 (CO)NH–、–R 5 NH-SO2–,–R 5 SO2-NH–, –CH2R 5 –, –OR 5 –, –SR 5 –、S=OR 5 ,–SO2R 5 –、C=OR 5 , –CO2R 5 –, –NHR 5 –, –NH(CO)R 5 –,–(CO)NHR 5 –, –NH-SO2R 5 –, –SO2-NHR 5 -, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 heteroaryl);

[0140] Each R 5 are independently H, deuterium, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 carbocyclyl, optionally substituted C6 to C 10 aryl, an optionally substituted C3 to C8 heterocyclic group, or an optionally substituted C3 to C 10 heteroaryl; and

[0141] Y is CH2, NH or O,

[0142] The condition is R 1 Not a pyrimidinyl.

[0143] Some embodiments provide pharmaceutical compositions comprising a therapeutically effective amount of at least one compound having the structure of Formula (II):

[0144] 2.

[0145] Including pharmaceutically acceptable salts thereof, wherein:

[0146] Q A , Q B , Q C independently C or N;

[0147] R 1 、R 2 、R 3 、R 6 , and R 7 each independently selected from the group consisting of H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-acylamino, optionally substituted N-acylamino, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamoyl, optionally substituted N-thiocarbamoyl, optionally substituted N-carbamoyl, optionally substituted O-carbamoyl, optionally substituted urea, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, or L;

[0148] X is C(R 5 )2、CH(R 5 )、CH2、-O-、

[0149] L is -Z1-Z2 or -Z1-Z2-Z3;

[0150] Z1, Z2 and Z3 are independently –CH2–, –O–, –S–, S=O, –SO2–, C=O, –CO2–, –NO2, –NH–, –CH2CCH, –CH2CN, –NR 5 R 5 , –NH(CO)–, –(CO)NH–, –(CO)NR 5 R 5 –, –NH-SO2–, –SO2-NH–, –R 5 CH2–, –R 5 O–,–R 5 S–, R 5 -S=O、–R 5 SO2–, R 5 -C=O、–R 5 CO2–,–R5 NH–,–R 5 NH(CO)–,–R 5 (CO)NH–、–R 5 NH-SO2–,–R 5 SO2-NH–, –CH2R 5 –, –OR 5 –, –SR 5 –、S=OR 5 ,–SO2R 5 –、C=OR 5 , –CO2R 5 –, –NHR 5 –, –NH(CO)R 5 –,–(CO)NHR 5 –, –NH-SO2R 5 –, –SO2-NHR 5 -, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 heteroaryl);

[0151] Each R 5 are independently H, deuterium, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 carbocyclyl, optionally substituted C6 to C 10 aryl, an optionally substituted C3 to C8 heterocyclic group, or an optionally substituted C3 to C 10 heteroaryl;

[0152] Y is CH2, NH or O; and

[0153] Z is C or N,

[0154] The condition is R 1 Not a pyrimidinyl.

[0155] Some embodiments relate to methods of treating a mammal having a disease or condition. In some embodiments, the method comprises administering to the mammal a therapeutically effective amount of a compound as described herein. Some embodiments relate to methods of treating a mammal having a disease or condition. In some embodiments, the method comprises administering to the mammal a therapeutically effective amount of a pharmaceutical composition as described herein. In some embodiments, the mammal is a human. In some embodiments, the method further comprises administering to the mammal an additional drug. In some embodiments, the method comprises administering to a subject having the disease or condition an effective amount of any one of the compounds as described herein or a pharmaceutically acceptable salt thereof.

[0156] Some embodiments relate to a method of treating a disease. In some embodiments, the method comprises administering an effective amount of a pharmaceutical composition as described herein to a subject suffering from the disease. In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, lung cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, gastric cancer, prostate cancer, kidney cancer, colorectal cancer, or leukemia. In further or additional embodiments, the fibrogenic disorder is scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, cirrhosis of the liver, keloid formation, interstitial nephritis, or pulmonary fibrosis. In some embodiments, the cancer is associated with a RAS mutation. In some embodiments, the RAS mutation is a KRAS mutation selected from the group consisting of G12C, G12S, G12R, G12F, G12L, G12N, G12A, G12D, G12V, G13C, G13S, G13D, G13V, G13P, S17G, P34S, A59E, A59G, A59T, Q61K, Q61L, Q61R, and Q61H. In some embodiments, the disease is cancer cachexia.

[0157] Some embodiments relate to methods of inhibiting cell proliferation. In some embodiments, the method comprises contacting a cell with an effective amount of a compound as described herein or a pharmaceutical composition as described herein. In some embodiments, the cell has a RAS mutation.

[0158] Some embodiments relate to methods of inducing apoptosis in a cell. In some embodiments, the method comprises contacting the cell with an effective amount of a compound as described herein or a pharmaceutical composition as described herein.

[0159] Some embodiments relate to methods of treating a subject having a cancer that is resistant to treatment with a MEK protein kinase inhibitor. In some embodiments, the method comprises contacting a cell with an effective amount of a compound as described herein or a pharmaceutical composition as described herein.

[0160] Some embodiments relate to methods of treating a subject having a cancer that is resistant to treatment with a RAF protein kinase inhibitor. In some embodiments, the method comprises contacting a cell with an effective amount of a compound as described herein or a pharmaceutical composition as described herein.

[0161] Some embodiments relate to methods of treating cancer cachexia in a mammal having cancer. In some embodiments, the method comprises administering an effective amount of a compound as described herein or a pharmaceutical composition as described herein.

[0162] In some embodiments, a compound as described herein or a pharmaceutical composition as described herein can be administered in a single dose. In some embodiments, a compound as described herein or a pharmaceutical composition as described herein can be administered in a single dose once daily.

[0163] In some embodiments, the compound as described herein or the pharmaceutical composition as described herein can be administered more than once a day in multiple doses. In some embodiments, the compound as described herein or the pharmaceutical composition as described herein can be administered twice a day. In some embodiments, the compound as described herein or the pharmaceutical composition as described herein can be administered three times a day. In some embodiments, the compound as described herein or the pharmaceutical composition as described herein can be administered at a dose between 0.1 mg and 2000 mg. In some embodiments, the compound as described herein or the pharmaceutical composition as described herein can be administered at a dose of about 0.001 mg / kg body weight / day to about 1000 mg / kg body weight / day.

[0164] In some embodiments, the compounds as described herein possess the pharmaceutical characteristics of RAF resistance, BID dosing, balanced metabolism, and activity between about 3 and about 6 hours.

[0165] In some embodiments, the compounds as described herein interact with the first region of MEK kinase comprising L115, L118, V127, and M143.

[0166] In some embodiments, the compound interacts with a second region of MEK kinase that includes K97.

[0167] In some embodiments, the compounds as described herein interact with a third region of MEK kinase comprising S212, 1215, and M219.

[0168] In some embodiments, described herein are methods for developing molecules based on the evaluation and balance of two downstream molecular targets.

[0169] In some embodiments, the methods may include administering a compound that targets pERK (T202 / Y204) and pSTAT3 (S727).

[0170] In some embodiments, described herein are methods for preventing the CRAF-bypass pathway from reactivating MEK.

[0171] In some embodiments, the method may include administering an effective amount of any of the compounds or pharmaceutical compositions described herein.

[0172] In some embodiments, described herein are methods for designing drug therapeutic windows for dual RAF / MEK inhibitors.

[0173] In some embodiments, the method may comprise administering a therapeutic agent that has a plasma half-life of less than 12 hours, is dosed QD or BID, is resistant to MEK reactivation by the CRAF-bypass, and achieves an optimal metabolic balance between pERK and pSTAT3 (S727) inhibition. BRIEF DESCRIPTION OF THE DRAWINGS

[0174] Figure 1 The pERK(T202 / Y204):Total ERK to pSTAT3(S727):Total-STAT3 ratios of Reference-1, Reference-2, Compound (Cmpd)-7, Compound-10, Compound-9, Compound-11, Compound-12, Compound-13, Compound-14, Compound-15, and Compound-16 in A549 KRAS mutant lung cancer are illustrated.

[0175] Figure 2 Demonstrated is CRAF-bypass in A549 KRAS-mutant lung cancer by elevated pMEK:total MEK ratio following treatment with selected reference MEK inhibitors.

[0176] Figure 3 The gastrocnemius pharmacokinetic (PK) results of Reference-1, Reference-2, Compound-7, Compound-10, Compound-9, Compound-11, Compound-12, Compound-13, Compound-14, Compound-15 and Compound-16 at a single 2-hour time point in the C26 tumor model are illustrated.

[0177] Figure 4 Tumor pharmacokinetic (PK) results for Reference-1, Reference-2, Compound-7, Compound-10, Compound-9, Compound-11, Compound-12, Compound-13, Compound-14, Compound-15, and Compound-16 at a single 2-hour time point in the C26 tumor model are illustrated.

[0178] Figure 5The plasma pharmacokinetic (PK) results of Reference-1, Reference-2, Compound-7, Compound-10, Compound-9, Compound-11, Compound-12, Compound-13, Compound-14, Compound-15 and Compound-16 in the C26 tumor model at a single 2-hour time point are illustrated.

[0179] Figure 6 The hepatic pharmacokinetic (PK) results of Reference-1, Reference-2, Compound-7, Compound-10, Compound-9, Compound-11, Compound-12, Compound-13, Compound-14, Compound-15 and Compound-16 in the C26 tumor model at a single 2-hour time point are illustrated.

[0180] Figure 7A Illustrated is a comparison of the MTD study in C26 tumor bearing tumors between Reference-1 and Compound-9 at 100 mg / kg QD.

[0181] Figure 7B Illustrated is a comparison of the MTD study in C26 tumor bearing tumors between Compound 13 and Compound 14 at 100 mg / kg QD.

[0182] Figure 8A Illustrated is a comparison of the MTD study in C26 tumor bearing patients between Reference-1 and Compound-9 at 100 mg / kg BID.

[0183] Figure 8B Illustrated is a comparison of the MTD study in C26 tumor bearing mice between Compound-13 and Compound-14 at 100 mg / kg BID.

[0184] Figure 9 A549 (KRAS-G12S) pERK dose response is exemplified.

[0185] Figure 10 Diagram illustrating the colon-26 model of efficacy and safety in KRAS G12D CRC.

[0186] Figure 11A Graph illustrating C-26 pharmacology study of KRAS G12D CRC tumor growth; Figure 11B Graph illustrating C-26 pharmacology study of KRAS G12D CRC weight loss.

[0187] Figure 12 Graph illustrating activity in the Colon-26 KRAS mutant CRC model.

[0188] Figure 13 Graph illustrating dual RAF / MEK resistance to CRAF-bypass.

[0189] Figure 14A Graph illustrating the dual RAF / MEK:CRAF-bypass time course of A459 KRAS pERK:total ERK; Figure 14B Exemplified is pMEK:total MEK in the NSCLC model A549 KRAS(G12S).

[0190] Figure 15A Graph illustrating pERK:total ERK (activated) in the BRAF V600E mutant A375 melanoma model; Figure 15B Demonstrates pERK:total ERK and paradoxical activation by RAF inhibitors in the KRAS G12S mutant A549 model.

[0191] Figure 16 Graph illustrating single-dose pharmacokinetic profile in plasma.

[0192] Figure 17 Graph illustrating single-dose pharmacokinetic profiles in the CRC model Colon-26 tumor.

[0193] Figure 18 Illustrated is a graph of relative body weight corrected for tumor volume of the NSCLC model A549. DETAILED DESCRIPTION

[0194] In some embodiments, MEK inhibitors are provided. Various embodiments of these compounds include compounds having a structure of Formula I as described herein or a pharmaceutically acceptable salt thereof. In some embodiments, prodrugs, metabolites, stereoisomers, hydrates, solvates, polymorphs, and pharmaceutically acceptable salts of the compounds disclosed herein are provided.

[0195] In certain aspects, provided herein are methods or uses for treating, preventing, or ameliorating a disease or condition in a subject, comprising administering to the subject at least one compound disclosed herein. In some embodiments, provided are methods or uses for treating, preventing, or ameliorating cancer, comprising administering a compound having a structure of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), or (IId) as described herein. In some embodiments, provided are methods or uses for treating cancer cachexia, comprising administering a compound having a structure of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), or (IId) as described herein.

[0196] definition

[0197] Unless otherwise expressly defined, the technical and / or scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. If a term is defined in multiple ways herein, the definition in this section shall prevail unless otherwise indicated. As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, and pharmacology are employed unless otherwise indicated. Unless otherwise indicated, the conjunction "or" or "and" is used to mean "and / or." In addition, the use of the term "including," as well as other forms such as "includes" and "included," is not limited. As used in this specification, whether in transitional phrases or in the body of the claims, the terms "comprise(s)" and "comprising" should be interpreted as having an open-ended meaning. That is, the term should be interpreted synonymously with the phrases "having at least" or "including at least." When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

[0198] Although the present disclosure has been described and illustrated in detail in the foregoing description, such description is to be considered illustrative or exemplary rather than restrictive. The present disclosure is not limited to the disclosed embodiments. Variations of the disclosed embodiments can be understood and implemented by those skilled in the art in practicing the claimed disclosure, based on a study of the present disclosure and the appended claims.

[0199] With respect to the use of substantially any plural and / or singular terms herein, those skilled in the art can translate from the plural to the singular and / or from the singular to the plural depending on the context and / or application. For the sake of clarity, various singular / plural permutations may be explicitly set forth herein. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

[0200] All references cited herein are hereby incorporated by reference in their entirety. If publications and patents or patent applications incorporated by reference contradict the disclosure contained in this specification, this specification is intended to supersede and / or take precedence over any such contradictory material.

[0201] Unless otherwise defined, all terms (including technical and scientific terms) should be given their ordinary and customary meanings as given to those skilled in the art and should not be limited to special or customary meanings unless expressly defined as such herein. It should be noted that the use of a particular term in describing certain features or aspects of the present disclosure should not be construed as implying that the term is redefined herein to include any particular feature associated with the term in connection with the feature or aspect of the present disclosure.

[0202] Where a range of values is provided, it is understood that the upper and lower limits, and every intervening value between the upper and lower limits of that range, are encompassed within the embodiments.

[0203] As used herein, the term "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in certain circumstances, they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug is not. The solubility of the prodrug in the form of a pharmaceutical composition may also be improved compared to the parent drug. An example (but not limiting) of a prodrug is a compound that is administered as an ester ("prodrug") to facilitate transport across cell membranes where water solubility is not conducive to migration, but then, once the compound enters the cell where water solubility is beneficial, it is metabolically hydrolyzed to a carboxylic acid, the active entity. A further example of a prodrug may be a short peptide (polyamino acid) bonded to an acid group, wherein the peptide is metabolized to reveal the active moiety. Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs (ed. H. Bundgaard, Elsevier, 1985), which is incorporated herein by reference in its entirety.

[0204] Metabolites of the compounds disclosed herein include active species produced when the compounds are introduced into the biological milieu.

[0205] The compounds disclosed herein with at least one chiral center can exist as racemates or as each enantiomer, and can exist as enantiomer-enriched mixtures of enantiomers. It should be noted that all such isomers and mixtures thereof are included within the scope of the present invention. In addition, the crystalline forms of the compounds disclosed herein can exist as alternative polymorphs. Such polymorphs are included in one embodiment of the present invention. In addition, some compounds in the compounds of the present invention can, for example, form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are included in one embodiment of the present invention.

[0206] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that does not significantly stimulate the organism to which it is applied and does not eliminate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting the compound with an inorganic acid such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, etc. Pharmaceutical salts can also be obtained by reacting the compound with an organic acid such as an aliphatic or aromatic carboxylic acid or sulfonic acid, such as acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or naphthalenesulfonic acid. Pharmaceutically acceptable salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., calcium or magnesium salt), a salt with an organic base (e.g., dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine), and a salt containing an amino acid (e.g., arginine, lysine, etc.).

[0207] If the manufacture of a pharmaceutical formulation involves intimate mixing of a pharmaceutical excipient with the active ingredient in salt form, it may be necessary to use a non-basic pharmaceutical excipient, ie, an acidic or neutral excipient.

[0208] In various embodiments, the compounds disclosed herein can be used alone, in combination with other compounds disclosed herein, or in combination with one or more other agents active in the therapeutic areas described herein.

[0209] The term "halogen atom" as used herein refers to any radioactive stable atom of column 7 of the periodic table of elements, such as fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred.

[0210] As used herein, the term "ester" refers to a ester having the formula -(R) n The chemical moiety -COOR', wherein R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon), wherein n is 0 or 1.

[0211] As used herein, the term "amide" refers to a compound having the formula -(R) n- C(O)NHR' or -(R) n- The chemical moiety NHC(O)R', wherein R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon), wherein n is 0 or 1. The amide can be an amino acid or peptide molecule attached to a molecule of the present invention to form a prodrug.

[0212] Any amine, hydroxyl, or carboxyl side chain on the compounds disclosed herein can be esterified or amidated. The procedures and specific groups used to achieve this are known to those skilled in the art and can be readily found in reference materials such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York, NY, 1999 (incorporated herein in its entirety).

[0213] As used herein, the term "aromatic" refers to an aromatic group having at least one ring with a conjugated π electron system and includes both carbocyclic aromatic groups (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups. The term "carbocycle" refers to a compound containing one or more covalently closed ring structures and the atoms forming the main chain of the ring are all carbon atoms. Thus, the term distinguishes carbocycle from heterocycle, in which the ring main chain contains at least one atom that is different from carbon. The term "heteroaromatic" refers to an aromatic group containing at least one heterocycle.

[0214] As used herein, "C" wherein "a" and "b" are integers a to C b" refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in a cycloalkyl, aryl, heteroaryl, or heterocyclyl ring. That is, an alkyl, alkenyl, alkynyl, cycloalkyl ring, aryl ring, heteroaryl ring, or heterocyclyl ring can contain from "a" to "b" (inclusive) carbon atoms. Thus, for example, "C1 to C4 alkyl" or "C1-C4 alkyl" refers to all alkyl groups having from 1 to 4 carbon atoms, i.e., CH3-, CH3CH2-, CH3CH2C H2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. Likewise, for example, a cycloalkyl group may contain from "a" to "b" (inclusive) total atoms, such as a C3-C8 cycloalkyl group having from 3 to 8 carbon atoms in the ring. If "a" and "b" are not specified with respect to an alkyl, cycloalkyl, or cycloalkenyl group, the broadest range described in those definitions is assumed. Similarly, a "4- to 7-membered heteroaryl" group may contain from "a" to "b" (inclusive) total atoms, such as a C3-C8 cycloalkyl group having from 3 to 8 carbon atoms in the ring. "Cycyl" refers to all heterocyclic groups having 4 to 7 total ring atoms, such as azetidine, oxetane, oxazoline, pyrrolidine, piperidine, piperazine, morpholine, etc. As used herein, the term "C1-C6" includes C1, C2, C3, C4, C5 and C6, as well as ranges defined by any one of the two preceding numbers. For example, C1-C6 alkyl includes C1, C2, C3, C4, C5 and C6 alkyl, C2-C6 alkyl, C1-C3 alkyl Etc. Similarly, C3-C8 carbocyclyl or cycloalkyl each include hydrocarbon rings containing 3, 4, 5, 6, 7 and 8 carbon atoms, or a range defined by either of the two numbers, such as C3-C7 cycloalkyl or C5-C6 cycloalkyl. As another example, 3 to 10 membered heterocyclyl includes 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, or a range defined by either of the two aforementioned numbers, such as 4 to 6 membered or 5 to 7 membered heterocyclyl.

[0215] As used herein, "alkyl" refers to a fully saturated (no double or triple bonds) straight or branched hydrocarbon chain hydrocarbon group. An alkyl group may have 1 to 20 carbon atoms (whenever a numerical range such as "1 to 20" appears in this document, it refers to each integer within the given range; for example, "1 to 20 carbon atoms" means that the alkyl group may be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to 20 carbon atoms (including 20 carbon atoms), although this definition also encompasses the occurrence of the term "alkyl" without specifying a numerical range). An alkyl group may also be a medium-sized alkyl group having 1 to 10 carbon atoms. An alkyl group may also be a low-sized alkyl group having 1 to 5 carbon atoms. The alkyl group of a compound may be designated as "C1-C4 alkyl" or similar designations. By way of example only, "C1-C4 alkyl" indicates that the alkyl chain has one to four carbon atoms, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like.

[0216] The alkyl group may be substituted or unsubstituted. When substituted, the one or more substituent groups are one or more groups individually and independently selected from the group consisting of alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic)alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, ester, sulfhydryl, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-acyl The invention also includes amine, S-sulfonamido, N-sulfonamido, C-carboxyl, protected C-carboxyl, O-carboxyl, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido and amino (including mono- and di-substituted amino), and protected derivatives thereof. When a substituent is described as "optionally substituted", the substituent may be substituted by one of the above substituents.

[0217] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. An alkenyl group may be unsubstituted or substituted. When substituted, one or more substituents may be selected from the same groups disclosed above for alkyl substitution. An alkenyl group may have from 2 to 20 carbon atoms, although this definition also encompasses occurrences of the term "alkenyl" without specifying a numerical range. An alkenyl group may also be a medium-sized alkenyl group having from 2 to 9 carbon atoms. An alkenyl group may also be a lower alkenyl group having from 2 to 4 carbon atoms. The alkenyl group of the compound may be designated as "C 2-4 "C-alkenyl" or similar designations. By way of example only, "C 2-4 “Alkenyl” means that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl, buta-1,2-dienyl, and buta-1,2-dien-4-yl. Typical alkenyl groups include, but are by no means limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0218] As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight or branched hydrocarbon chain. The alkynyl group may be substituted or unsubstituted. When substituted, one or more substituents may be selected from the same groups disclosed above for alkyl substitution. An alkynyl group may have from 2 to 20 carbon atoms, although this definition also encompasses occurrences of the term "alkynyl" without specifying a numerical range. An alkynyl group may also be a medium-sized alkynyl group having from 2 to 9 carbon atoms. An alkynyl group may also be a lower alkynyl group having from 2 to 4 carbon atoms. The alkynyl group of the compound may be designated as "C 2-4 Alkynyl" or similar designations. By way of example only, "C 2-4 "Alkynyl" means that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl and 2-butynyl. Typical alkynyl groups include, but are by no means limited to, ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0219] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur) in the backbone of the chain. A heteroalkyl group may have from 1 to 20 carbon atoms, although this definition also encompasses occurrences of the term "heteroalkyl" without specifying a numerical range. A heteroalkyl group may also be a medium-sized heteroalkyl group having from 1 to 9 carbon atoms. A heteroalkyl group may also be a low-sized heteroalkyl group having from 1 to 4 carbon atoms. The heteroalkyl group of the compound may be designated as "C 1-4Heteroalkyl" or similar designations. A heteroalkyl group may contain one or more heteroatoms. By way of example only, "C 1-4 "Heteroalkyl" means a heteroalkyl group having 1 to 4 carbon atoms in the chain and additionally having one or more heteroatoms in the backbone of the chain.

[0220] As used herein, "aryl" refers to a carbocyclic (all-carbon) ring or two or more fused rings (rings sharing two adjacent carbon atoms) with a completely delocalized π electron system. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. Aryl groups can be substituted or unsubstituted. When substituted, a hydrogen atom is replaced by one or more substituent groups, which are one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic)alkyl, hydroxyl, protected hydroxyl, alkoxy, aryloxy, acyl, ester, sulfhydryl, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl substituted aryl, arylsulfonyl ...

[0221] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system with a completely delocalized π electron system), one or two or more fused rings containing one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur). Examples of heteroaryl rings include but are not limited to furan, thiophene, phthalazine, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Heteroaryl groups can be substituted or unsubstituted. When substituted, the hydrogen atom is replaced by one or more substituent groups, which are one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic)alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, ester, thiol, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl The invention also includes alkyl, ...

[0222] As used herein, "aralkyl" or "arylalkyl" refers to an aryl group attached as a substituent through an alkylene group. The alkylene and aryl groups of the aralkyl group may also be substituted or unsubstituted. Examples include, but are not limited to, benzyl, substituted benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group.

[0223] As used herein, "heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group attached as a substituent through an alkylene group. The alkylene and heteroaryl groups of the heteroaralkyl group may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furanylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, as well as substituted and benzo-fused analogs thereof. In some cases, the alkylene group is a lower alkylene group.

[0224] As used herein, "alkylene" refers to a branched or straight-chain fully saturated diradical chemical group containing only carbon and hydrogen, which is connected to the rest of the molecule through two points of attachment (i.e., alkanediyl). Alkylene can have from 1 to 20 carbon atoms, although this definition also covers occurrences of the term alkylene without specifying a numerical range. Alkylene can also be a medium-sized alkylene having from 1 to 9 carbon atoms. Alkylene can also be a lower alkylene having from 1 to 4 carbon atoms. Alkylene can be designated as "C 1-4 Alkylene" or similar designations. By way of example only, "C 1-4 “Alkylene” means an alkylene chain having 1 to 4 carbon atoms, i.e., the alkylene chain is selected from the group consisting of methylene, ethylene, ethane-1,1-diyl, propylene, propane-1,1-diyl, propane-2,2-diyl, 1-methyl-ethylene, butylene, butane-1,1-diyl, butane-2,2-diyl, 2-methyl-propane-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1-ethyl-ethylene.

[0225] As used herein, "alkenylene" refers to a straight or branched diradical chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, which is connected to the rest of the molecule through two points of attachment. An alkenylene group can have from 2 to 20 carbon atoms, although this definition also encompasses occurrences of the term alkenylene without specifying a numerical range. An alkenylene group can also be a medium-sized alkenylene group having from 2 to 9 carbon atoms. An alkenylene group can also be a lower alkenylene group having from 2 to 4 carbon atoms. An alkenylene group can be designated as "C 2-4 "C 2-4 The term "alkenylene" refers to an alkenylene chain having 2 to 4 carbon atoms, i.e., an alkenylene chain selected from the group consisting of vinylene, ethylene-1,1-diyl, propenylene, propen-1,1-diyl, prop-2-ene-1,1-diyl, 1-methyl-vinylene, but-1-enylene, but-2-enylene, but-1,3-dienylene, butene-1,1-diyl, but-1,3-diene-1,1-diyl, but- 2-ene-1,1-diyl, but-3-ene-1,1-diyl, 1-methyl-prop-2-ene-1,1-diyl, 2-methylprop-2-ene-1,1-diyl, 1-ethyl-vinylene, 1,2-dimethylvinylene, 1-methyl-propenylene, 2-methyl-propenylene, 3-methyl-propenylene, 2-methyl-propenylene-1,1-diyl and 2,2-dimethyl-ethylene-1,1-diyl.

[0226] As used herein, "alkylidene" refers to a divalent group (such as =CR'R") that is attached to one carbon of another group to form a double bond, including, but not limited to, methine (=CH2) and ethylene (=CHCH3). As used herein, "arylalkylidene" refers to an alkylidene group in which R' and R" are aryl groups. Alkylidene groups may also be substituted or unsubstituted.

[0227] As used herein, "alkoxy" refers to a group of the formula -OR (wherein R is an alkyl group as defined above), for example, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, tert-pentoxy, etc. The alkoxy group can be substituted or unsubstituted.

[0228] As used herein, "alkylthio" refers to a group of the formula -SR (wherein R is an alkyl group as defined above), for example, methylthio, ethylthio, n-propylthio, 1-methylethylthio (isopropylthio), n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, etc. Alkylthio groups may also be substituted or unsubstituted.

[0229] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, respectively, where R is an aryl group, such as, but not limited to, phenyl. Both aryloxy and arylthio groups can be substituted or unsubstituted.

[0230] As used herein, "acyl" refers to -C(=O)R, wherein R is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclyl, aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein. Non-limiting examples include formyl, acetyl, propionyl, benzoyl and acryloyl.

[0231] As used herein, "cycloalkyl" refers to a fully saturated (no double bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, these rings can be joined together in a fused, bridged or spirocyclic manner. Cycloalkyl can be C3 to C 10 In some embodiments, the cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. If substituted, unless otherwise indicated, one or more substituents may be alkyl or selected from those indicated above for alkyl substitution. When substituted, the substituents on the cycloalkyl group may form an aromatic ring fused to the cycloalkyl group, including aryl and heteroaryl groups.

[0232] As used herein, "cycloalkenyl" refers to a cycloalkyl group containing one or more double bonds in the ring, but if there are more than one double bond, they cannot form a completely delocalized π electron system in the ring (otherwise the group will be an "aryl" as defined herein). When consisting of two or more rings, these rings can be linked together in a fused, bridged or spirocyclic manner. Cycloalkenyl groups can be unsubstituted or substituted. When substituted, unless otherwise indicated, one or more substituents can be alkyl or selected from the groups disclosed above for alkyl substitution. When substituted, the substituents on the cycloalkenyl group can form an aromatic ring fused to the cycloalkenyl group, including aryl and heteroaryl.

[0233] As used herein, "cycloalkynyl" refers to a cycloalkyl group containing one or more triple bonds in the ring. When composed of two or more rings, these rings can be joined together in a fused, bridged, or spirocyclic manner. A cycloalkynyl group can be unsubstituted or substituted. When substituted, unless otherwise indicated, one or more substituents can be an alkyl group or a group selected from the groups disclosed above for alkyl substitution. When substituted, the substituents on the cycloalkynyl group can form an aromatic ring fused to the cycloalkynyl group, including aryl and heteroaryl groups.

[0234] As used herein, "heteroalicyclic ring" or "heteroalicyclic group" refers to a stable 3- to 18-membered ring consisting of carbon atoms and 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. "Heteroalicyclic ring" or "heteroalicyclic group" can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can be joined together in a fused, bridged or spirocyclic manner; and the nitrogen, carbon and sulfur atoms in the "heteroalicyclic ring" or "heteroalicyclic group" can be optionally oxidized; the nitrogen can be optionally quaternized; and the ring can also contain one or more double bonds, provided that they do not form a completely delocalized π electron system in all rings. The heteroalicyclic group can be unsubstituted or substituted. When substituted, the one or more substituent groups may be one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic)alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, ester, thiol, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl The term "heteroalicyclic" refers to a group consisting of a C-amino, N-amino, S-sulfonamido, N-sulfonamido, C-carboxyl, protected C-carboxyl, O-carboxyl, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino (including monosubstituted and disubstituted amino groups), and protected derivatives thereof. Examples of such "heteroalicyclic" or "heteroalicyclic" groups include, but are not limited to, azepanyl, acridinyl, carbazolyl, cinnamyl, dioxolanyl, imidazolinyl, morpholinyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, 4-piperidonyl, pyrazolidinyl, 2-oxopyrrolidinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, and thiomorpholinyl sulfone. When substituted, the substituents on a heteroalicyclyl group may form an aromatic ring fused to the heteroalicyclyl group, the aromatic ring including aryl and heteroaryl groups.

[0235] As used herein, the term "(cycloalkenyl)alkyl" refers to a cycloalkenyl group attached as a substituent through an alkylene group. The alkylene and cycloalkenyl groups of the (cycloalkenyl)alkyl group may be substituted or unsubstituted. In some cases, the alkylene group is a lower alkylene group.

[0236] As used herein, the term "(cycloalkynyl)alkyl" refers to a cycloalkynyl group attached as a substituent through an alkylene group. The alkylene group and the cycloalkynyl group of the (cycloalkynyl)alkyl group may be substituted or unsubstituted. In some cases, the alkylene group is a lower alkylene group.

[0237] As used herein, the term "O-carboxyl" refers to a "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl, as defined herein. The O-carboxyl group can be substituted or unsubstituted.

[0238] As used herein, the term "C-carboxy" refers to a "-C(=O)R" group, where R may be the same as defined for O-carboxy. The C-carboxy group may be substituted or unsubstituted.

[0239] As used herein, the term "trihalomethanesulfonyl" refers to an "X3CSO2-" group, where X is a halogen.

[0240] As used herein, the term "cyano" refers to a "-CN" group.

[0241] As used herein, the term "cyano" refers to a "-OCN" group.

[0242] As used herein, the term "isocyanato" refers to a "-NCO" group.

[0243] As used herein, the term "thiocyanato" refers to a "-SCN" group.

[0244] As used herein, the term "isothiocyanato" refers to a "-NCS" group.

[0245] As used herein, the term "sulfinyl" refers to a "-S(=O)-R" group, wherein R may be the same as defined for O-carboxyl. The sulfinyl group may be substituted or unsubstituted.

[0246] As used herein, the term "sulfonyl" refers to a "-SO2R" group, where R may be the same as defined for O-carboxyl. A sulfonyl group may be substituted or unsubstituted.

[0247] As used herein, the term "S-sulfonamido" refers to "-SO2NR A R B " group, wherein R A and R B The same definition as for the O-carboxyl group may be used. The S-sulfonylamino group may be substituted or unsubstituted.

[0248] As used herein, the term "N-sulfonamido" refers to "-SO2N(R A )(R B )" group, wherein R, R A and R B The same definition as for the O-carboxyl group may be used. The sulfonyl group may be substituted or unsubstituted.

[0249] As used herein, the term "trihalomethanesulfonylamino" refers to a "X3CSO2N(R)-" group, wherein X is a halogen and R may be the same as defined for O-carboxyl. The trihalomethanesulfonylamino group may be substituted or unsubstituted.

[0250] As used herein, the term "O-carbamoyl" refers to "-OC(=O)NR A R B " group, wherein R A and R B The O-carbamoyl group may be substituted or unsubstituted.

[0251] As used herein, the term "N-carbamoyl" refers to "ROC(=O)NR A -"a group in which R and R A The same definition as for the O-carboxyl group may be used. The N-carbamoyl group may be substituted or unsubstituted.

[0252] As used herein, the term "O-thiocarbamoyl" refers to "-OC(=S)-NR A R B " group, wherein R A and R B The O-thiocarbamoyl group may be substituted or unsubstituted.

[0253] As used herein, the term "N-thiocarbamoyl" refers to "ROC(=S)NR A -"a group in which R and R A The same definition as for the O-carboxyl group may be used. The N-thiocarbamoyl group may be substituted or unsubstituted.

[0254] As used herein, the term "C-amido" refers to "-C(=O)NR A R B " group, wherein R A and R B The same definition as for the O-carboxyl group may be used. The C-amide group may be substituted or unsubstituted.

[0255] As used herein, the term "N-amido" refers to "RC(=O)NR A -"a group in which R and R A The same definition as for the O-carboxyl group may be used. The N-amide group may be substituted or unsubstituted.

[0256] As used herein, the term "amino" refers to "-NR A R B " group, wherein RA and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0257] As used herein, the term "aminoalkyl" refers to an amino group linked through an alkylene group.

[0258] As used herein, the term "ester" refers to a "-C(=O)OR" group, where R may be the same as defined for an O-carboxyl group. Esters may be substituted or unsubstituted.

[0259] As used herein, the term "lower aminoalkyl" refers to an amino group connected through a lower alkylene group. The lower aminoalkyl group may be substituted or unsubstituted.

[0260] As used herein, the term "lower alkoxyalkyl" refers to an alkoxy group connected through a lower alkylene group. The lower alkoxyalkyl group may be substituted or unsubstituted.

[0261] As used herein, the term "acetyl" refers to a -C(=O)CH3 group.

[0262] As used herein, the term "trihalomethanesulfonyl" refers to a X3CS(=O)2- group, where X is a halogen.

[0263] As used herein, the term "O-carbamoyl" refers to -OC(=O)-NR, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl, as defined herein. The O-carbamoyl group can be substituted or unsubstituted.

[0264] As used herein, the term "N-carbamoyl" refers to a ROC(=O)NH- group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl, as defined herein. The N-carbamoyl group can be substituted or unsubstituted.

[0265] As used herein, the term "O-thiocarbamoyl" refers to a -OC(=S)-NR group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl, as defined herein. The O-thiocarbamoyl group can be substituted or unsubstituted.

[0266] As used herein, the term "N-thiocarbamoyl" refers to a ROC(=S)NH- group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl, as defined herein. The N-thiocarbamoyl group can be substituted or unsubstituted.

[0267] As used herein, the term "perhaloalkyl" refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms.

[0268] As used herein, the term "halogen" or "halo" refers to any radiostable atom from column 7 of the periodic table, such as fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred.

[0269] As used herein, the term "carbocyclyl" refers to a non-aromatic cyclic ring or ring system containing only carbon atoms in the main chain of the ring system. When a carbocyclyl is a ring system, two or more rings can be joined together in a fused, bridged or spirocyclic manner. A carbocyclyl can have any degree of saturation, as long as at least one ring in the ring system is not aromatic. Thus, carbocyclyl includes cycloalkyl, cycloalkenyl and cycloalkynyl. A carbocyclyl can have 3 to 20 carbon atoms, although this definition also covers the occurrence of the term "carbocyclyl" without specifying a numerical range. A carbocyclyl can also be a medium-sized carbocyclyl having 3 to 10 carbon atoms. A carbocyclyl can also be a carbocyclyl having 3 to 6 carbon atoms. A carbocyclyl can be designated as "C 3-6 Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicyclo[2.2.2]octyl, adamantyl, and spiro[4.4]nonyl.

[0270] As used herein, the term "(cycloalkyl)alkyl" refers to a cycloalkyl group attached as a substituent through an alkylene group. The alkylene group and the cycloalkyl group of the (cycloalkyl)alkyl group may be substituted or unsubstituted. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. In some cases, the alkylene group is a lower alkylene group.

[0271] As used herein, the term "cycloalkyl" refers to a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0272] As used herein, the term "cycloalkenyl" means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. An example is cyclohexenyl.

[0273] As used herein, the term "heterocyclyl" refers to three-, four-, five-, six-, seven-, and eight- or more-membered rings in which carbon atoms, together with one to three heteroatoms, constitute the ring. However, the heterocyclyl group may optionally contain one or more unsaturated bonds positioned so that an aromatic π-electron system is not present. The heteroatoms are independently selected from oxygen, sulfur, and nitrogen.

[0274] The heterocyclic group may further contain one or more carbonyl or thiocarbonyl functional groups such that the definition includes oxo- and thio-systems, such as lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, and the like.

[0275] As used herein, "heterocyclyl" refers to a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyl groups can be joined together in a fused, bridged, or spirocyclic manner. Heterocyclyl groups can have any degree of saturation, as long as at least one ring in the ring system is not aromatic. One or more heteroatoms can be present in a non-aromatic ring or an aromatic ring in the ring system. A heterocyclyl group can have 3 to 20 ring members (i.e., the number of atoms, including carbon atoms and heteroatoms, that make up the ring backbone), although this definition also encompasses the occurrence of the term "heterocyclyl" without specifying a numerical range. A heterocyclyl group can also be a medium-sized heterocyclyl group having 3 to 10 ring members. A heterocyclyl group can also be a heterocyclyl group having 3 to 6 ring members. A heterocyclyl group can be designated as a "3-6 membered heterocyclyl" or similar designations. In preferred six-membered monocyclic heterocyclyls, the one or more heteroatoms are selected from one to a maximum of three selected from O, N or S, and in preferred five-membered monocyclic heterocyclyls, the one or more heteroatoms are selected from one or two heteroatoms selected from O, N or S. Examples of heterocyclyl rings include, but are not limited to, azepanyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidonyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl. , 1,4-oxathiinyl, 1,4-oxathiinyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinone, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0276] As used herein, the term "(heterocyclyl)alkyl" refers to a heterocyclyl group attached as a substituent through an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0277] As used herein, the terms "purified," "substantially purified," and "isolated" mean that the compounds disclosed herein are free from other, different compounds with which the compounds of the invention are normally associated in their native state, such that the compounds of the invention constitute at least 0.5%, 1%, 5%, 10%, or 20%, and most preferably at least 50% or 75%, by weight, of the mass of a given sample.

[0278] Substituted groups are based on or derived from unsubstituted parent groups in which one or more hydrogen atoms are exchanged with another atom or group. Unless otherwise stated, when a group is considered to be "substituted", the group is substituted by one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, ), 5-10 membered heterocyclyl (optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heterocyclyl-C1-C6-alkyl (optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (C1-C6) alkyl (optionally substituted by halo, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy (C1-C6) alkyl (i.e., ether), aromatic alkyl, such as -CF3, -OCF3, -C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfonamido, N-sulfonamido, C-carboxyl, O-carboxyl, acyl, cyano, isocyano, thiocyano, isothiocyano, sulfinyl, sulfonyl, and oxo (=O). When a group is described as "optionally substituted", the group may be substituted by the above substituents.

[0279] In some embodiments, the substituted group is substituted with one or more substituents individually and independently selected from the group consisting of C1-C4 alkyl, amino, hydroxy, and halogen.

[0280] It should be understood that certain radical naming conventions may include monoradicals or diradicals depending on the context. For example, when a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a diradical. For example, a substituent identified as an alkyl group requiring two points of attachment includes a diradical such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other radical naming conventions clearly indicate that the radical is a diradical such as "alkylene" or "alkenylene."

[0281] Unless otherwise indicated, when a substituent is considered to be "optionally substituted", it means that the substituent is a group that can be substituted by one or more groups individually and independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxyl, O-carboxyl, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino (including mono- and di-substituted amino groups), as well as protected derivatives thereof. Protecting groups that can form protected derivatives of the above substituents are known to those skilled in the art and can be found in references such as Greene and Wuts above.

[0282] As used herein, the term "agent" or "test agent" includes any substance, molecule, element, compound, entity, or combination thereof. It includes, but is not limited to, for example, proteins, polypeptides, peptides, or mimetics, small organic molecules, polysaccharides, polynucleotides, etc. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances. Unless otherwise indicated, the terms "agent," "substance," and "compound" are used interchangeably herein.

[0283] As used herein, the term "analog" refers to a molecule that is structurally similar to a reference molecule but has been modified in a targeted and controlled manner by replacing specific substituents of the reference molecule with alternative substituents. Analogs are expected by those skilled in the art to exhibit the same, similar, or improved utility compared to the reference molecule. The synthesis and screening of analogs to identify variants of known compounds with improved properties (such as higher binding affinity for the target molecule) is a well-known method in medicinal chemistry.

[0284] As used herein, the term "mammal" is used in its ordinary biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, and mice, but also includes many other species.

[0285] As used herein, the term "microbial infection" refers to the invasion of a host organism by pathogenic microorganisms, whether the organism is a vertebrate, invertebrate, fish, plant, bird or mammal. This includes the overgrowth of microorganisms that are normally present in or on the body of a mammal or other organism. More generally, a microbial infection can be any situation in which the presence of one or more microbial colonies causes damage to the host mammal. Thus, a mammal is "suffering from" a microbial infection when there are an excessive number of microbial colonies in or on its body, or when the effects of the presence of one or more microbial colonies are damaging the cells or other tissues of the mammal. Specifically, this description applies to bacterial infections. Note that the compounds of the preferred embodiments can also be used to treat microbial growth or contamination of cell cultures or other culture media, or inanimate surfaces or objects, and the preferred embodiments should not be limited herein to treating higher organisms unless expressly provided in the claims.

[0286] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agents are incompatible with the active ingredient, it is contemplated that they will be used in therapeutic compositions. In addition, various adjuvants commonly used in the art may be included. For example, Gilman et al. (eds.) (1990), Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th edition, Pergamon Press (which is incorporated herein by reference in its entirety) describes considerations for including various components in pharmaceutical compositions.

[0287] As used herein, the term "subject" refers to a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird, such as a chicken, as well as any other vertebrate or invertebrate.

[0288] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a therapeutic agent effective to alleviate one or more symptoms of a disease or condition to some extent or reduce the likelihood of its onset, and includes curing the disease or condition. "Cure" means eliminating the symptoms of the disease or condition; however, even after a cure is achieved, certain long-term or permanent effects may still exist (e.g., extensive tissue damage).

[0289] As used herein, the terms "treat," "treatment," or "treating" refer to the administration of a pharmaceutical composition for preventive and / or therapeutic purposes. The term "prophylactic treatment" refers to the treatment of a subject who does not yet exhibit symptoms of a disease or condition but is susceptible to or otherwise at risk for a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to the administration of a treatment to a subject.

[0290] It is understood that if a compound disclosed herein has unfilled valences, such valences will be filled with hydrogen and / or deuterium.

[0291] It should be understood that the compounds described herein can be isotopically labeled or labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels or chemiluminescent labels. Replacement of isotopes such as deuterium can provide certain therapeutic advantages (such as, for example, half-life extension in vivo or dosage reduction) produced by higher metabolic stability. Each chemical element as represented by a compound structure can include any isotope of the element. For example, in a compound structure, a hydrogen atom can be clearly disclosed or understood to be present in a compound. At any position where a hydrogen atom may be present in a compound, the hydrogen atom can be any isotope of hydrogen, including but not limited to 1-hydrogen (protium), hydrogen-2 (deuterium) and hydrogen-3 (tritium). Therefore, unless the context clearly states otherwise, the compounds mentioned herein encompass all potential isotopic forms.

[0292] As used herein, the term "about" refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by up to 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length. When a value is preceded by the word "about," the component is not intended to be strictly limited to that value, but is intended to include variations from that value.

[0293] Compound

[0294] Some embodiments provide compounds of formula (I):

[0295]

[0296] In some embodiments, Formula (I) is a pharmaceutically acceptable salt as described herein.

[0297] In some embodiments, Formula (I) is represented by Formula (Ia), Formula (Ib), Formula (Ic), or Formula (Id):

[0298]

[0299] In some embodiments, Formula (Ia), Formula (Ib), Formula (Ic), or Formula (Id) is a pharmaceutically acceptable salt as described herein.

[0300] In some embodiments, Ring A is

[0301] In some embodiments of the compound of Formula (I) or (Ic), R 1 and optionally substituted C1 to C6 alkyl, optionally substituted C1 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C6 alkyl, optionally substituted C1 to C6 alkyl ... 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 Heteroaryl, or L.

[0302] In some embodiments, R 1 In some embodiments, R 1 It is not an ether-linked pyrimidinyl group.

[0303] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 2 and optionally substituted alkyl, optionally substituted C-C6 ... 10aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, or L. In some further embodiments, R 2 is L. In some further embodiments, R 2 It is –CH3.

[0304] In some embodiments of compounds of Formula (I), (Ia), (Ib), (Ic), or (Id), R 3 The alkyl radicals may be selected from hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amide, optionally substituted N-amide, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamide, optionally substituted N-sulfonamide, optionally substituted sulfonate, optionally substituted O-thiocarbamoyl, optionally substituted N-thiocarbamoyl, optionally substituted N-carbamoyl, optionally substituted O-carbamoyl, optionally substituted urea, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 Heteroaryl, or L.

[0305] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R 4 and optionally substituted alkyl, optionally substituted C-C6 ... 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 Heteroaryl, or L.

[0306] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Ic), R 5R may be selected from H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl. In some embodiments, R 5 is H, deuterium, halo or optionally substituted C1 to C6 alkyl.

[0307] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Ic), R 5’ R may be selected from H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl. In some embodiments, R 5′ is H, deuterium, halo or optionally substituted C1 to C6 alkyl.

[0308] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Ic), R 6 R may be selected from H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl. In some embodiments, R 6 is H, deuterium, halo or optionally substituted C1 to C6 alkyl.

[0309] In some embodiments of the compound of formula (I) or (Ia), X may be selected from C(R 5 )2、CH(R 5 )、CH2、-O-、 In some further embodiments, X is CH2 or -O-. In some further embodiments, X is -O-.

[0310] In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), L can be selected from -Z1-Z2. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), L can be selected from -Z1-Z2-Z3.

[0311] In some embodiments of the compounds of Formula (I), (Ia), (Ib) or (Ic), Z1 can be selected from -CH2-, -O-, -S-, S=O, -SO2-, C=O, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR 5 R 5′ , –NH(CO)–, –(CO)NH–, –(CO)NR 5 R5′ –, –NH–SO2–, –SO2-NH–, –R 5 CH2–, –R 5 O–,–R 5 S–, R 5 -S=O、–R 5 SO2–, R 5 -C=O、–R 5 CO2–,–R 5 NH–,–R 5 NH(CO)–、-NHCH2CO-、–R 5 (CO)NH–、–R 5 NH-SO2–,–R 5 SO2-NH–, –CH2R 5 –, –OR 5 –, –SR 5 –、S=OR 5 ,–SO2R 5 –、C=OR 5 , –CO2R 5 –, –NHR 5 –, –NH(CO)R 5 –, –(CO)NHR 5 –, –NH-SO2R 5 –, –SO2-NHR 5 -, optionally substituted C1 to C6 alkyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 In some further embodiments, Z1 is -CH2-.

[0312] In some embodiments of the compounds of Formula (I), (Ia), (Ib) or (Ic), Z2 can be selected from hydrogen, deuterium, halo, -CH2-, -O-, -S-, S=O, -SO2-, C=O, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR 5 R 5′ , –NH(CO)–, –(CO)NH–, –(CO)NR 5 R 5 –, -NHCH2CO-, –NH–SO2–, –SO2-NH–, –R 5 CH2–, –R 5 O–,–R5 S–, R 5 -S=O、–R 5 SO2–, R 5 -C=O、–R 5 CO2–,–R 5 NH–,–R 5 NH(CO)–,–R 5 (CO)NH–、–R 5 NH-SO2–,–R 5 SO2-NH–, –CH2R 5 –, –OR 5 –, –SR 5 –、S=OR 5 ,–SO2R 5 –、C=OR 5 , –CO2R 5 –, –NHR 5 –, –NH(CO)R 5 –, –(CO)NHR 5 –, –NH-SO2R 5 –, –SO2-NHR 5 -, optionally substituted C1 to C6 alkyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 In some further embodiments, Z2 is C3 to C8 cycloalkyl, optionally substituted C3 to C8 heterocyclyl, optionally substituted C3 to C8 heteroaryl, -NR 5 R 5 , -CH2CH or -CH2CN. In some further embodiments, Z2 is an optionally substituted C3 to C8 heterocyclyl. In some embodiments, Z2 is -CH2- and Z2 is -NR 5 R 5′ In some embodiments, Z2 is an optionally substituted C3 to C8 heterocyclyl.

[0313] In some embodiments of the compounds of Formula (I), (Ia), (Ib), or (Ic), Z3 may be selected from hydrogen, deuterium, halo, -COH, -CO2H, -NO2, -CH2CCH, -CH2CN, -NR 5 R 5′ 、–(CO)NH2、–(CO)NR 5 R 5′、–SO2-NH2、–R 5 CH3, –R 5 -COH, –R 5 CO2H,–R 5 NH2, –R 5 NH(COH), –R 5 (CO)NH2, –R 5 NH-SO2H, –R 5 SO2-NH2, –CH2R 5 、–OR 5 ,–SO2R 5 –, –CO2R 5 ,–NHR 5 、–NH(CO)R 5 、–(CO)NHR 5 、–NH-SO2R 5 , –SO2-NHR 5 , optionally substituted amino, optionally substituted C1 to C4 alkyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 heteroaryl).

[0314] In some embodiments of compounds of Formula (Id), n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0315] In some embodiments of the compound of Formula (Id), X 1 Can be selected from -CH, B, N or PO4. In some embodiments, X 1 Is -CO2-, N or -SO2-. In some embodiments, X 1 i is N.

[0316] In some embodiments of the compound of Formula (Id), R 9 can be selected from hydrogen, deuterium, optionally substituted C1 to C6 alkyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 In some further embodiments, Z2 is C3 to C8 cycloalkyl, optionally substituted C3 to C8 heterocyclyl, optionally substituted C3 to C8 heteroaryl, -NR 5 R 5′ , -CH2CH or -CH2CN.

[0317] In some embodiments of the compound of Formula (Id), R 10 can be selected from hydrogen, deuterium, optionally substituted C1 to C6 alkyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 In some further embodiments, Z2 is C3 to C8 cycloalkyl, optionally substituted C3 to C8 heterocyclyl, optionally substituted C3 to C8 heteroaryl, -NR 5 R 5′ , -CH2CH or -CH2CN.

[0318] In some embodiments, the optionally substituted C3 to C8 heterocyclyl is In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, the optionally substituted C3 to C8 heterocyclyl is In some embodiments, the optionally substituted C3 to C8 heterocyclyl is In some embodiments, the optionally substituted C3 to C8 heterocyclyl is In some embodiments, the optionally substituted C3 to C8 heterocyclyl is In some embodiments, Z2 is In some embodiments, the optionally substituted C3 to C8 heterocyclyl is

[0319] In some embodiments, Z1 is -CH2- and Z2 is an optionally substituted C3 to C8 heterocyclyl, and Z3 is an optionally substituted aryl. In some embodiments, Z1 is -CH2- and Z2 is an optionally substituted C3 to C8 heterocyclyl, and Z3 is hydrogen. In some embodiments, Z1 is -CH2- and Z2 is an optionally substituted C3 to C8 heterocyclyl, and Z3 is an optionally substituted alkyl. In some embodiments, Z1 is -CH2- and Z2 is an optionally substituted C3 to C8 heterocyclyl, and Z3 is -CH2-(optionally substituted aryl). In some embodiments, Z1 is -CH2- and Z2 is

[0320] In some embodiments of the compound of Formula (I) or (Ia), Y is CH2, NH or O.

[0321] In some embodiments, Formula (I) is a compound of the disclosed formulae, such as Formula (A)-(Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (II), Formula (IIa), Formula (IIb), Formula (IIc), or Formula (IId), but does not include compounds: In some embodiments, Formula (I) is a compound of the disclosed formula, such as Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (II), Formula (IIa), Formula (IIb), Formula (IIc), or Formula (IId), but does not include R 2 In some embodiments, Formula (I) is a disclosed formula, such as Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (II), Formula (IIa), Formula (IIb), Formula (IIc), or Formula (IId), but does not include R 2 In some embodiments, Formula (I) is a disclosed formula, such as a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (II), Formula (IIa), Formula (IIb), Formula (IIc), or Formula (IId), but does not include R 2 For the case of ethyl.

[0322] Some embodiments provide compounds of formula (II):

[0323]

[0324] In some embodiments, Formula (II) is a pharmaceutically acceptable salt as described herein.

[0325] In some embodiments, Formula (II) is represented by Formula (IIa), Formula (IIb), or Formula (IIc):

[0326]

[0327]

[0328] In some embodiments, Formula (IIa), Formula (IIb), Formula (IIc), and Formula (IId) may be a pharmaceutically acceptable salt as described herein.

[0329] In some embodiments of Formula (II), Q A , Q B , Q C are independently C or N.

[0330] In some embodiments of the compound of Formula (II) or (IIc), R 1 and optionally substituted C1 to C6 alkyl, optionally substituted C1 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C6 alkyl, optionally substituted C1 to C6 alkyl ... 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 Heteroaryl, or L.

[0331] In some embodiments, R 1 is not O-pyrimidinyl. In some embodiments, R 1 It is not an ether-linked pyrimidinyl group.

[0332] In some embodiments of the compound of Formula (II), (IIa), or (IIb), R 2and optionally substituted alkyl, optionally substituted C-C6 ... 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, or L. In some further embodiments, R 2 is L. In some further embodiments, R 2 It is –CH3.

[0333] In some embodiments of the compound of Formula (II), (IIa), or (IId), R 3 is H, deuterium, hydroxy, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amide, optionally substituted N-amide, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamide, optionally substituted N-sulfonamide, optionally substituted sulfonate, optionally substituted O-thiocarbamoyl, optionally substituted N-thiocarbamoyl, optionally substituted N-carbamoyl, optionally substituted O-carbamoyl, optionally substituted urea, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 Heteroaryl, or L.

[0334] In some embodiments of the compound of Formula (II) or (IIa), R 4and optionally substituted alkyl, optionally substituted C-C6 ... 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 Heteroaryl, or L.

[0335] In some embodiments of the compound of Formula (II), (IIa), (IIb), or (IIc), R 5 is H, deuterium, hydroxy, halogen, cyano, nitro, optionally substituted amino, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl. In some embodiments, R 5 is H, deuterium, halo or optionally substituted C1 to C6 alkyl.

[0336] In some embodiments of the compound of Formula (II), (IIa), (IIb), or (IIc), R 5’ is H, deuterium, hydroxy, halogen, cyano, nitro, optionally substituted amino, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl. In some embodiments, R 5 is H, deuterium, halo or optionally substituted C1 to C6 alkyl.

[0337] In some embodiments of the compound of Formula (II), (IIa), (IIb), (IIc), or (IId), R 6 is H, deuterium, hydroxy, halogen, cyano, nitro, optionally substituted amino, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl. In some embodiments, R 6 is H, deuterium, halo or optionally substituted C1 to C6 alkyl.

[0338] In some embodiments of the compound of Formula (II) or (IIa), X is C(R 5 )2、CH(R 5)、CH2、-O-、 In some further embodiments, X is CH2 or -O-. In some further embodiments, X is -O-.

[0339] In some embodiments of the compound of Formula (II), (IIa), (IIb) or (IIc), L is -Z1-Z2. In some embodiments of the compound of Formula (II), (IIa) or (IIb), -Z1-Z2-Z3.

[0340] In some embodiments of the compound of Formula (II), (IIa), (IIb) or (IIc), Z1 is -CH2-, -O-, -S-, S=O, -SO2-, C=O, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR 5 R 5 , –NH(CO)–, –(CO)NH–, –(CO)NR 5 R 5 –, –NH–SO2–, –SO2-NH–, –R 5 CH2–, –R 5 O–,–R 5 S–, R 5 -S=O、–R 5 SO2–, R 5 -C=O、–R 5 CO2–,–R 5 NH–,–R 5 NH(CO)–,–R 5 (CO)NH–、–R 5 NH-SO2–,–R 5 SO2-NH–, –CH2R 5 –, –OR 5 –, –SR 5 –、S=OR 5 ,–SO2R 5 –、C=OR 5 , –CO2R 5 –, –NHR 5 –, –NH(CO)R 5 –, –(CO)NHR 5 –, –NH-SO2R 5 –, –SO2-NHR 5 -, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 In some further embodiments, Z1 is -CH2-.

[0341] In some embodiments of the compound of Formula (II), (IIa), (IIb) or (IIc), Z2 is halo, -CH2-, -O-, -S-, S=O, -SO2-, C=O, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR 5 R 5 , –NH(CO)–, –(CO)NH–, –(CO)NR 5 R 5 –, –NH–SO2–, –SO2-NH–, –R 5 CH2–, –R 5 O–,–R 5 S–, R 5 -S=O、–R 5 SO2–, R 5 -C=O、–R 5 CO2–,–R 5 NH–,–R 5 NH(CO)–,–R 5 (CO)NH–、–R 5 NH-SO2–,–R 5 SO2-NH–, –CH2R 5 –, –OR 5 –, –SR 5 –、S=OR 5 ,–SO2R 5 –、C=OR 5 , –CO2R 5 –, –NHR 5 –, –NH(CO)R 5 –, –(CO)NHR 5 –, –NH-SO2R 5 –, –SO2-NHR 5 -, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10In some further embodiments, Z2 is C3 to C8 cycloalkyl, optionally substituted C3 to C8 heterocyclyl, optionally substituted C3 to C8 heteroaryl, -NR 5 R 5 , -CH2CH or -CH2CN. In some further embodiments, Z2 is an optionally substituted C3 to C8 heterocyclyl. In some embodiments, Z1 is -CH2- and Z2 is -NR 5 R 5 In some embodiments, Z2 is an optionally substituted C3 to C7 heterocyclyl.

[0342] In some embodiments of the compound of Formula (II), (IIa), (IIb), or (IIc), Z3 is hydrogen, halo, -COH, -CO2H, -NO2, -CH2CCH, -CH2CN, -NR 5 R 5 、–(CO)NH2、–(CO)NR 5 R 5 、–SO2-NH2、–R 5 CH3, –R 5 -COH, –R 5 CO2H,–R 5 NH2, –R 5 NH(COH), –R 5 (CO)NH2, –R 5 NH-SO2H, –R 5 SO2-NH2, –CH2R 5 、–OR 5 ,–SO2R 5 –, –CO2R 5 ,–NHR 5 、–NH(CO)R 5 、–(CO)NHR 5 、–NH-SO2R 5 , –SO2-NHR 5 , optionally substituted amino, optionally substituted C1 to C4 alkyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 heteroaryl).

[0343] In some embodiments, Z1 is -CH2- and Z2 is an optionally substituted C3 to C8 heterocyclyl, and Z3 is an optionally substituted aryl. In some embodiments, Z1 is -CH2- and Z2 is an optionally substituted C3 to C8 heterocyclyl, and Z3 is hydrogen. In some embodiments, Z1 is -CH2- and Z2 is an optionally substituted C3 to C8 heterocyclyl, and Z3 is an optionally substituted alkyl. In some embodiments, Z1 is -CH2- and Z2 is an optionally substituted C3 to C8 heterocyclyl, and Z3 is -CH2-(optionally substituted aryl). In some embodiments, the optionally substituted C3 to C8 heterocyclyl is In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, the optionally substituted C3 to C8 heterocyclyl is In some embodiments, the optionally substituted C3 to C8 heterocyclyl is optionally substituted In some embodiments, the optionally substituted C3 to C8 heterocyclyl is optionally substituted In some embodiments, the optionally substituted C3 to C8 heterocyclyl is In some embodiments, the optionally substituted C3 to C8 heterocyclyl is In some embodiments, the optionally substituted C3 to C8 heterocyclyl is In some embodiments, Z2 is In some embodiments, the optionally substituted C3 to C8 heterocyclyl is

[0344] In some embodiments of the compound of Formula (II), R 7 are independently H, deuterium, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 carbocyclyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, or L. In some further embodiments, R 7 is selected from halo, H or CH3.

[0345] In some embodiments of the compound of Formula (IIa), R 8 is selected from H, deuterium, an optionally substituted C1 to C6 alkyl, an optionally substituted C2 to C6 alkenyl, an optionally substituted C2 to C6 alkynyl, an optionally substituted C3 to C8 carbocyclyl, an optionally substituted C6 to C 10aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 In some further embodiments, R 8 is selected from halo, H, deuterium or CH3.

[0346] In some embodiments of the compound of Formula (Id), X 1 Can be selected from -CH, -CO2-, N, or -SO2-. In some embodiments, X 1 Is -CO2-, N or -SO2-. In some embodiments, X 1 i is N.

[0347] In some embodiments of the compound of Formula (Id), R 9 can be selected from hydrogen, deuterium, optionally substituted C1 to C6 alkyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 In some further embodiments, Z2 is C3 to C8 cycloalkyl, optionally substituted C3 to C8 heterocyclyl, optionally substituted C3 to C8 heteroaryl, -NR 5 R 5′ , -CH2CH or -CH2CN.

[0348] In some embodiments of the compound of Formula (Id), R 10 can be selected from hydrogen, deuterium, optionally substituted C1 to C6 alkyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C 10 aryl, optionally substituted C3 to C8 heterocyclic group, optionally substituted C3 to C 10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to C8 cycloalkyl), or -CH2-(optionally substituted C3 to C8 cycloalkyl) 10 In some further embodiments, Z2 is C3 to C8 cycloalkyl, optionally substituted C3 to C8 heterocyclyl, optionally substituted C3 to C8 heteroaryl, -NR 5 R 5′ , -CH2CH or -CH2CN.

[0349] In some embodiments of the compound of Formula (II) or (IIa), Y is CH2, NH or O.

[0350] In some embodiments of the compound of Formula (II) or (IIa), X is CH2 or O.

[0351] In some embodiments of the compound of Formula (II), (IIa), or (IId), Z is C or N.

[0352] In some embodiments, formula (II) does not include In some embodiments, Formula (II), (IIa), (IIb), or (IIc) does not include R 2 For CH3.

[0353] In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), or (IIc) is selected from the compounds of Table A and pharmaceutically acceptable salts thereof.

[0354] Table A. Exemplary compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), or (IId):

[0355] Table A

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381] In some embodiments, the pharmaceutically acceptable salt may be an alkali metal salt. In some embodiments, the pharmaceutically acceptable salt may be an alkali metal salt. In some embodiments, the pharmaceutically acceptable salt may be an alkaline earth metal salt. In some embodiments, the pharmaceutically acceptable salt may be an ammonium salt.

[0382] synthesis

[0383] The compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or pharmaceutically acceptable salts thereof, as described herein, can be prepared in a variety of ways, including those known to those skilled in the art. The routes shown and described herein are illustrative only and are not intended to be construed as limiting the scope of the claims in any way. Those skilled in the art will be able to identify modifications of the disclosed syntheses and will be able to devise alternative routes based on the disclosure herein; all such modifications and alternative routes are within the scope of the claims. Examples of the methods are described in the Examples below.

[0384] Preparation method

[0385] Compounds disclosed herein can be synthesized by the following methods, or by modifying these methods to synthesize. The method of modifying the method includes, among others, temperature, solvent, reagent, etc., and will be apparent to those skilled in the art. In general, during any method for preparing compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any related molecules. This can be achieved by conventional protecting groups, such as Protective Groups in Organic Chemistry (JFWMcOmie, ed., Plenum Press, 1973); and Greene & Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 (both of which are incorporated herein by reference in their entirety). Protective groups can be removed in a convenient subsequent stage using methods known in the art. Synthetic chemical transformations that can be used to synthesize useful compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995 (both of which are herein incorporated by reference in their entirety).

[0386] When the preparation process of compound disclosed herein produces a mixture of stereoisomers, such isomers can be separated by conventional techniques such as preparative chiral chromatography. The compound can be prepared in racemic form, or a single enantiomer can be synthesized or split by stereoselectivity. The compound can be split into its component enantiomers by standard techniques (such as by forming a salt with an optically active acid such as (-)-di-p-toluoyl-d-tartaric acid and / or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of free alkali). The compound can also be split using a chiral auxiliary by forming a diastereomeric derivative such as an ester, amide or ketal and then performing chromatographic separation and removing the chiral auxiliary.

[0387] Pharmaceutical composition

[0388] On the other hand, a pharmaceutical composition is disclosed, which comprises a physiologically acceptable surfactant, carrier, diluent, excipient, smoothing agent, suspending agent, film-forming material and coating aid, or a combination thereof; and a compound disclosed herein. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field and are described in, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference in its entirety. Preservatives, stabilizers, dyes, sweeteners, spices, flavorings, etc. can be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid, and esters of p-hydroxybenzoic acid can be added as preservatives. In addition, antioxidants and suspending agents can be used. In various embodiments, alcohols, esters, sulfated aliphatic alcohols, and the like can be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicates, magnesium aluminate, magnesium aluminate methyl silicate, synthetic aluminum silicate, calcium carbonate, sodium carbonate, calcium hydrogen phosphate, carboxymethylcellulose calcium, and the like can be used as excipients; magnesium stearate, talc, hardened oil, and the like can be used as lubricants; coconut oil, olive oil, sesame oil, peanut oil, soybean oil can be used as suspending agents or lubricants; cellulose acetate phthalate, which is a derivative of carbohydrates such as cellulose or sugar, or methyl acetate-methacrylate copolymer, which is a derivative of polyethylene, can be used as a suspending agent; and plasticizers such as phthalates can be used as suspending agents.

[0389] As used herein, the term "pharmaceutical composition" refers to a mixture of a compound disclosed herein with other chemical components (such as a diluent or carrier). Pharmaceutical compositions facilitate administration of the compound to an organism. There are a variety of techniques for administering compounds in the art, including but not limited to oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting the compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0390] As used herein, the term "carrier" refers to a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier because it facilitates the absorption of many organic compounds into the cells or tissues of an organism.

[0391] As used herein, the term "diluent" refers to a chemical compound diluted in water that dissolves the compound of interest and stabilizes the biologically active form of the compound. Salts dissolved in buffered solutions are used as diluents in the art. One commonly used buffered solution is phosphate-buffered saline, as it mimics the salt conditions of human blood. Because buffer salts can control the pH of a solution at low concentrations, buffered diluents rarely alter the biological activity of a compound.

[0392] As used herein, the term "physiologically acceptable" refers to a carrier or diluent that does not abrogate the biological activity and properties of the compound.

[0393] As used herein, "excipient" refers to an inert substance added to a pharmaceutical composition to provide the composition with, but not limited to, bulk, consistency, stability, binding capacity, lubrication, disintegrating ability, etc. "Diluent" is a type of excipient.

[0394] For each compound described herein, and for each genus or subgenus of compounds described herein, a pharmaceutical composition is also described, comprising the compound alone or in admixture with other compounds of that genus or subgenus or with alternative compounds described herein or with one or more alternative pharmaceutically active compounds, and one or more pharmaceutically acceptable carriers, diluents, excipients, or combinations thereof. The pharmaceutical compositions described herein can be administered to human patients by themselves, or in admixture with other active ingredients (such as in combination therapy), or with carriers, diluents, excipients, or combinations thereof. Appropriate formulations depend on the route of administration selected. Techniques for the preparation and administration of the compounds described herein are known to those skilled in the art.

[0395] Pharmaceutical compositions disclosed herein can be prepared in any manner known per se, for example, by conventional mixing, dissolving, granulating, dragee manufacturing, grinding, emulsifying, encapsulating, embedding, or tableting processes. In addition, the active ingredient is included in an amount effective to achieve its intended purpose. Many compounds used in the pharmaceutical combinations disclosed herein can be provided in the form of salts with pharmaceutically compatible counterions.

[0396] The pharmaceutical compositions described herein can be administered to human patients as such, or in admixture with other active ingredients (e.g., in combination therapy), or with a suitable carrier or one or more excipients. Techniques for formulating and administering the compounds of the present invention are described in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.

[0397] Suitable routes of administration may, for example, include oral, rectal, transmucosal, topical or intestinal administration; parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, and intrathecal, direct intracerebroventricular, intraperitoneal, intranasal or intraocular injection. The compound may also be administered in a sustained-release or controlled-release dosage form including reservoir injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for extended and / or timed, pulsed administration at a predetermined rate.

[0398] The pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, eg, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.

[0399] Pharmaceutical compositions for use according to the present invention can therefore be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into pharmaceutically acceptable preparations. Appropriate formulation depends on the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used where appropriate and as understood in the art; for example, as described in Remington's Pharmaceutical Sciences, supra.

[0400] Injections can be prepared in conventional forms as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in liquids before injection, or emulsions. Suitable excipients are, for example, water, saline, glucose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, etc. In addition, if necessary, the injectable pharmaceutical composition may contain trace amounts of non-toxic auxiliary substances, such as wetting agents, pH buffers, etc. Physiologically compatible buffers include, but are not limited to, Hanks's solution, Ringer's solution, or physiological saline buffer. If necessary, absorption enhancement products (e.g., liposomes) can be used.

[0401] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation.

[0402] For parenteral administration, for example, pharmaceutical preparations for bolus injection or continuous infusion include aqueous solutions of active compounds in water-soluble form. In addition, the suspension of active compounds can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils (such as sesame oil), or other organic oils (such as soybean oil, grapefruit oil or almond oil), or synthetic fatty acid esters (such as ethyl oleate or triglycerides) or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension can also contain a suitable stabilizer, or increase the solubility of the compound to allow the preparation of a highly concentrated solution. Injectable preparations can be presented in unit dosage form, for example, in ampoule or multidose container with preservative. The composition can be in the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and can contain formulations such as suspending agents, stabilizers and / or dispersants. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (eg, sterile pyrogen-free water) before use.

[0403] For oral administration, the compound can be easily formulated by combining the active compound with a pharmaceutically acceptable carrier well known in the art. Such carriers can prepare the compound of the present invention into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by the patient to be treated. Pharmaceutical products for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding the resulting mixture, and processing the granular mixture after adding a suitable adjuvant (if necessary) to obtain tablets or dragee cores. Suitable excipients are especially fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose products, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If necessary, disintegrants such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof (such as sodium alginate) can be added. The dragee core has a suitable coating. For this purpose, can use concentrated sugar solution, this concentrated sugar solution can optionally contain gum arabic, talcum, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.Dye or pigment can be added in tablet or dragee coating so as to be used for identifying or in order to characterize the different combinations of active compound dosage. For this purpose, can use concentrated sugar solution, this concentrated sugar solution can optionally contain gum arabic, talcum, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.Dye or pigment can be added in tablet or dragee coating so as to be used for identifying or in order to characterize the different combinations of active compound dosage.

[0404] Pharmaceutical preparations for oral use include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain a mixture of the active ingredient with a filler (e.g., lactose), a binder (e.g., starch), and / or a lubricant (e.g., talc or magnesium stearate), and optionally, a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added. All formulations for oral administration should be in a dosage suitable for such administration.

[0405] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0406] For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base (e.g., lactose or starch).

[0407] Further disclosed herein are various pharmaceutical compositions for uses well known in the pharmaceutical art including intraocular, intranasal and intraaural delivery. Suitable penetrants for these uses are generally known in the art. Pharmaceutical compositions for intraocular delivery include aqueous ophthalmic solutions of a water-soluble form of the active compound, such as eye drops or gellan gum (Shedden et al., Clin. Ther., 23(3):440-50 (2001)) or hydrogels (Mayer et al., Ophthalmologica, 210(2):101-3 (1996)); ophthalmic ointments; ophthalmic suspensions, such as microparticles, i.e., small polymer particles containing the drug, suspended in a liquid carrier medium (Joshi, A., J. Ocul. Pharmacol., 10(1):29-45 (1994)), lipid-soluble formulations (Alm et al., Prog. Clin. Biol. Res., 312:447-58 (1989)) and microspheres (Mordenti, Toxicol. Sci., 52(1):101-6 (1999)); and ocular inserts. All of the above-mentioned references are incorporated herein by reference in their entirety. Suitable pharmaceutical preparations of this type are most often and preferably formulated as sterile, isotonic and buffered to achieve stability and comfort. Pharmaceutical compositions for intranasal delivery can also include drops and sprays, which are often prepared to simulate nasal secretions in many aspects to ensure that normal ciliary action is maintained. As disclosed in Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Co., Easton, PA (1990) (which is incorporated herein by reference in its entirety) and well known to those skilled in the art, suitable preparations are most often and preferably isotonic, slightly buffered to maintain a pH of 5.5 to 6.5, and most often and preferably contain antimicrobial preservatives and appropriate pharmaceutical stabilizers. Pharmaceutical preparations for intraauricular delivery include suspensions and ointments for external application in the ear. Common solvents for such ear preparations include glycerol and water.

[0408] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

[0409] In addition to the preparations described previously, the compound can also be formulated as a depot-type product. Such long-acting preparations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compound can be formulated with a suitable polymeric material or hydrophobic material (e.g., formulated as an emulsion in an acceptable oil) or an ion exchange resin, or formulated as a slightly soluble derivative, e.g., as a slightly soluble salt.

[0410] For hydrophobic compounds, a suitable pharmaceutical carrier may be a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. A common co-solvent system used is the VPD co-solvent system, which is 3% w / v benzyl alcohol, 8% w / v non-polar surfactant polysorbate 80, and 1% w / v PEG-100. TM and 65% w / v polyethylene glycol 300 in absolute ethanol. The proportions of the cosolvent system can be varied considerably without significantly changing its solubility and toxicity characteristics. In addition, the identity of the cosolvent components can be varied: for example, other low-toxicity nonpolar surfactants can be used in place of polysorbate 80. TM The fraction size of polyethylene glycol can be varied; other biocompatible polymers can replace polyethylene glycol, such as polyvinyl pyrrolidone; and other sugars or polysaccharides can replace glucose.

[0411] Alternatively, other delivery systems for hydrophobic drug compounds can be used. Liposomes and emulsions are examples of delivery vehicles or carriers known to hydrophobic drugs. Certain organic solvents, such as dimethyl sulfoxide, can also be used, although usually at the expense of greater toxicity. In addition, sustained-release systems such as semipermeable matrices of solid hydrophobic polymers containing therapeutic agents can be used to deliver the compound. Various sustained-release materials have been established and are well known to those skilled in the art. According to their chemical properties, sustained-release capsules may release the compound for several weeks to more than 100 days. According to the chemical properties and biostability of the therapeutic agent, other protein stabilization strategies can be adopted.

[0412] Agents intended for intracellular administration can be administered using techniques well known to those of ordinary skill in the art. For example, such agents can be encapsulated into liposomes. When the liposomes are formed, all molecules present in the aqueous solution are incorporated into the aqueous interior. The liposome contents are not affected by the external microenvironment, but because the liposomes fuse with the cell membrane, they are effectively delivered to the cytoplasm. Liposomes can be coated with tissue-specific antibodies. The liposomes will target and be selectively taken up by the desired organ. Alternatively, small hydrophobic organic molecules can be administered directly into the cell.

[0413] Additional therapeutic or diagnostic agents may be incorporated into the pharmaceutical composition.Alternatively or additionally, the pharmaceutical composition may be combined with other compositions containing other therapeutic or diagnostic agents.

[0414] Parenteral pharmaceutical compositions

[0415] To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous, etc.), 0.1 mg to 120 mg of a water-soluble salt / soluble substance itself / solubilized complex of a compound of the preferred embodiment is dissolved in sterile water and then mixed with 10 μL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.

[0416] Injectable pharmaceutical composition

[0417] To prepare an injectable formulation, 0.1 mg to 100 mg of a compound of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), or (IIc), 2.0 mL of sodium acetate buffer (0.4 M), HCl (1 N) or NaOH (1 M) (enough to a suitable pH value), and water (distilled, sterile) (enough to 20 mL) are mixed. All of the above ingredients except the water are mixed and stirred, and, if desired, can also be slightly heated. Then, enough water is added.

[0418] Oral pharmaceutical composition

[0419] To prepare a pharmaceutical composition for oral delivery, 0.1 mg to 120 mg of the compound of the embodiment is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule, or 0.1 mg to 120 mg of the compound is granulated with a binder solution (such as a starch solution) and a suitable diluent (such as microcrystalline cellulose), a disintegrant (such as croscarmellose sodium), the resulting mixture is dried and a lubricant is added and compressed into tablets suitable for oral administration.

[0420] Sublingual (hard lozenge) pharmaceutical composition

[0421] To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, 0.1 mg to 120 mg of a compound of the preferred embodiment is mixed with 420 mg of powdered sugar / mannitol / xylitol or such sugars that provide a negative heat to the solution, 1.6 mL of light corn syrup, 2.4 mL of distilled water, and 0.42 mL of peppermint extract or other flavoring. The mixture is blended and poured into a mold to form a lozenge suitable for buccal administration.

[0422] Rapidly disintegrating sublingual tablets

[0423] Fast disintegrating sublingual tablets are prepared by mixing the following: 48.5% by weight of a compound of a preferred embodiment, 20% by weight of microcrystalline cellulose (KG-802), 24.5% by weight of mannitol or modified glucose or a combination to help the compressed tablet dissolve faster in the mouth, 5% by weight of low-substituted hydroxypropyl cellulose (50 μm), and 2% by weight of magnesium stearate. Tablets are prepared by direct compression (AAPS PharmSciTech. 2006; 7(2): E41). The total weight of the compressed tablets is maintained at 150 mg. The formulation is prepared by mixing the amount of the compound of the preferred embodiment with the total amount of microcrystalline cellulose (MCC) and mannitol / modified glucose or a combination, and two-thirds of the amount of low-substituted hydroxypropyl cellulose (L-HPC) using a three-dimensional hand mixer (Inversina, Bioengineering AG, Switzerland) for 4.5 minutes. All of the magnesium stearate (MS) and the remaining one-third of the amount of L-HPC are added 30 seconds before the end of mixing.

[0424] Inhaled pharmaceutical composition

[0425] To prepare a pharmaceutical composition for inhalation delivery, 0.1 mg to 100 mg of a compound of the preferred embodiment is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit suitable for inhalation administration, such as a nebulizer.

[0426] Nebulizer suspension pharmaceutical composition

[0427] In another embodiment, a compound of the preferred embodiment (0.1 mg to 100 mg) is suspended in sterile water (100 mL); Span 85 (1 g) is added, followed by glucose (5.5 g) and ascorbic acid (10 mg). Benzalkonium chloride (3 mL of a 1:750 aqueous solution) is added and the pH is adjusted to 7 with phosphate buffer. The suspension is packaged in a sterile spray bottle.

[0428] Transdermal patch pharmaceutical composition

[0429] In order to prepare a pharmaceutical composition for transdermal delivery, 0.1 mg to 100 mg of a compound of the preferred embodiment is embedded in or deposited on a patch having a single adhesive face. The resulting patch is then attached to the skin via the adhesive face for transdermal application.

[0430] External use gel pharmaceutical composition

[0431] To prepare a pharmaceutical topical gel composition, 0.1 mg to 100 mg of a compound of the preferred embodiment is mixed with 1.75 g of hydroxypropylcellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate, and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into a container suitable for topical administration, such as a tube.

[0432] ophthalmic solution

[0433] To prepare a pharmaceutical ophthalmic solution composition, 0.1 mg to 100 mg of a compound of the preferred embodiment is mixed with 0.9 g NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into an ophthalmic delivery unit suitable for ophthalmic administration, such as an eye drop container.

[0434] nasal spray solution

[0435] To prepare the pharmaceutical nasal spray solution, 0.1 mg to 100 mg of a compound of the preferred embodiment is mixed with 30 mL of 0.05 M phosphate buffer solution (pH 4.4).The solution is placed in a nasal applicator designed to deliver 100 μl of spray per application.

[0436] Treatment methods / uses

[0437] Aspects disclosed herein relate to administering to a subject in need thereof an effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds as described herein, such as one or more compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof.

[0438] As disclosed elsewhere herein, some embodiments relate to treating a disease or condition, such as cancer, by administering a compound or composition as disclosed herein. Subjects who need to receive a compound or composition as disclosed herein to improve health do not always need to be identified before receiving the first treatment with the compound or composition. For example, a subject can be predetermined that they will suffer from a disease or condition, such as cancer, before showing any signs of the disease or condition. Alternatively, if the subject has the risk of suffering from a disease or condition such as cancer or does not suffer from a disease or condition such as cancer (for example, once the patient shows symptoms of another disease or condition associated with cancer), the subject can receive preventive treatment. Therefore, in some embodiments, the compound or composition can be administered to the subject after the subject receives an early diagnosis. In some embodiments, not every subject is a candidate for such administration, and the identification of the treatment subject may be necessary. It should be understood that the selection of the patient depends on many factors within the skill range of the general physician. Therefore, some embodiments disclosed herein further include identifying the subject as a subject who will benefit from administering an effective amount of at least one compound or composition to increase lifespan, increase survival time, or increase life span.

[0439] In other aspects, the present disclosure relates to methods for treating, preventing, or prophylactic cancer, which may comprise administering to a subject in need thereof an effective amount of one or more compounds described herein (such as a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising a compound described herein (such as a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof). In certain embodiments, the cancer may be selected from brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, gastric cancer, prostate cancer, kidney cancer, colorectal cancer, or leukemia. In further or additional embodiments, the cancer is brain cancer or ach-enocortical cancer. In further or additional embodiments, the cancer is breast cancer. In further or additional embodiments, the cancer is ovarian cancer. In further or additional embodiments, the cancer is pancreatic cancer. In further or additional embodiments, the cancer is gastric cancer. In further or additional embodiments, the cancer is prostate cancer. In further or additional embodiments, the cancer is kidney cancer. In another embodiment, the cancer is colorectal cancer. In further or additional embodiments, the cancer is myeloid leukemia. In further or additional embodiments, the cancer is glioblastoma. In further or additional embodiments, the cancer is follicular lymphoma. In further or additional embodiments, the cancer is pre-B acute leukemia. In further or additional embodiments, the cancer is chronic lymphocytic B-leukemia. In further or additional embodiments, the cancer is mesothelioma. In further or additional embodiments, the cancer is a small cell lineage cancer.

[0440] Some embodiments relate to methods of inhibiting the proliferation of cells having a RAS mutation, comprising administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer has been associated with a RAS mutation. Some embodiments relate to methods of inducing apoptosis in cells having a RAS mutation, comprising administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof. Some embodiments relate to methods of inhibiting the proliferation of cells having a KRAS mutation, comprising administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer has been associated with a KRAS mutation. Some embodiments relate to methods of inducing apoptosis in cells having a KRAS mutation, comprising administering a compound of Formula (I), (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof. Some embodiments relate to methods of inhibiting the proliferation of cells having a NRAS mutation, comprising administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is already associated with a NRAS mutation. Some embodiments relate to methods of inducing apoptosis in cells having a RAS mutation, comprising administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS mutation is located at codons 12, 13, 59, 61, and / or 146. In some embodiments, the mutant form of the KRAS protein has one or more amino acid substitutions selected from the group consisting of G12C, G12S, G12R, G12F, G12L, G12N, G12A, G12D, G12V, G13C, G13S, G13D, G13V, G13P, S17G, P34S, A59E, A59G, A59T, Q61K, Q61L, Q61R, and Q61H.In some embodiments, the mutant form of the KRAS protein has one or more amino acid substitutions selected from the group consisting of G12C, G12R, G12S, G12A, G12D, G12V, G13C, G13R, G13S, G13A, G13D, G13V, A59E, A59G, A59T, Q61K, Q61L, Q61R, Q61H, K117N, K117R, K117E, A146P, A146T, and A146V.

[0441] In certain embodiments, the cancer is resistant to treatment with a MEK protein kinase inhibitor. In other embodiments, the cancer is resistant to treatment with a RAF protein kinase inhibitor. In still further embodiments, the resistance is acquired. In other embodiments, the resistance is de novo. In further or additional embodiments, the cancer is resistant to an anticancer agent.

[0442] In some aspects, provided herein are compounds or pharmaceutical compositions and methods for treating cancer comprising a therapeutically effective amount of a dual RAF / MEK protein kinase inhibitor. In some embodiments, the administration of a dual RAF / MEK protein kinase inhibitor provides an increase in the area under the serum concentration-time curve (AUC) of the dual RAF / MEK protein kinase inhibitor. In some embodiments, the cancer is resistant to treatment with a RAF protein kinase inhibitor. In further embodiments, the cancer is resistant to RAF protein kinase inhibitors and the RAF protein kinase inhibitors include A-RAF inhibitors, B-RAF inhibitors, or C-RAF inhibitors. In further embodiments, the cancer is resistant to RAF protein kinase inhibitors, and the RAF protein kinase inhibitors include B-RAF inhibitors.

[0443] In some embodiments, the resistant cancer is pancreatic cancer, melanoma, colon cancer, lung cancer, or gastric cancer. In further embodiments, the resistant cancer is pancreatic cancer. In another embodiment, the resistant cancer is gastric cancer. In alternative embodiments, provided are drug combinations and methods for resensitizing cancer cells in a patient having or suspected of having a cancer that is resistant to an anticancer agent to treatment, comprising administering to the patient a therapeutically effective amount of a dual MEK / RAF inhibitor as disclosed herein.

[0444] Some embodiments disclosed herein relate to methods of treating a mammal having a disease, which methods may comprise administering to a subject in need thereof an effective amount of one or more compounds described herein (such as a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising a compound described herein (such as a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof). Other embodiments disclosed herein relate to methods of treating a subject having cancer cachexia, which methods can include administering to the subject an effective amount of one or more compounds described herein (such as a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof), or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound described herein (such as a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof).

[0445] Some embodiments described herein relate to the use of one or more compounds described herein (such as compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId) or pharmaceutically acceptable salts thereof) for the manufacture of a medicament for ameliorating and / or treating cancer or a cancer condition such as cancer cachexia, which can include administering to a subject an effective amount of one or more compounds described herein (such as compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId) or pharmaceutically acceptable salts thereof). Other embodiments described herein relate to one or more compounds described herein (such as compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId) or pharmaceutically acceptable salts thereof), which can be used to ameliorate and / or treat cancer or a cancer condition such as cancer cachexia by administering to a subject an effective amount of one or more compounds described herein or pharmaceutically acceptable salts thereof.

[0446] Some embodiments disclosed herein relate to methods of ameliorating and / or treating cancer, which may comprise contacting cancer cells with an effective amount of one or more compounds described herein (such as a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising one or more compounds described herein (such as a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof). In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, may act as an inhibitor of MEK. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can act as an inhibitor of ERK. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can act as a mitoSTAT3 inhibitor. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can reduce inflammatory cachexia and muscle atrophy.

[0447] In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can be administered once daily in a single dose. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can be administered more than once daily in multiple doses. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can be administered once daily. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can be administered twice daily. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can be administered three times a day. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can be administered four times a day.

[0448] In some aspects, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can inhibit abnormal cell growth. In some embodiments, abnormal cell growth occurs in a mammal. Methods for inhibiting abnormal cell growth may comprise administering an effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, wherein abnormal cell growth is inhibited. Methods for inhibiting abnormal cell growth in a mammal may comprise administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof to a mammal, wherein the amount of the compound effectively inhibits abnormal cell growth in the mammal.

[0449] In other aspects, the present invention relates to a method for degrading, inhibiting the growth of, or killing cancer cells, comprising contacting the cells with a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, effective to degrade, inhibit the growth of, or kill the cells. In some embodiments, the cancer cells comprise brain, breast, lung, ovarian, pancreatic, gastric, prostate, kidney, or colorectal cancer cells.

[0450] In some embodiments, cancer cells are degraded. In some embodiments, 1% of cancer cells are degraded. In further or additional embodiments, 2% of cancer cells are degraded. In further or additional embodiments, 3% of cancer cells are degraded. In further or additional embodiments, 4% of cancer cells are degraded. In further or additional embodiments, 5% of cancer cells are degraded. In further or additional embodiments, 10% of cancer cells are degraded. In further or additional embodiments, 20% of cancer cells are degraded. In further or additional embodiments, 25% of cancer cells are degraded. In further or additional embodiments, 30% of cancer cells are degraded. In further or additional embodiments, 40% of cancer cells are degraded. In further or additional embodiments, 50% of cancer cells are degraded. In further or additional embodiments, 60% of cancer cells are degraded. In further or additional embodiments, 70% of cancer cells are degraded. In further or additional embodiments, 75% of cancer cells are degraded. In further or additional embodiments, 80% of cancer cells are degraded. In further or additional embodiments, 90% of the cancer cells are degraded. In further or additional embodiments, 100% of the cancer cells are degraded. In further or additional embodiments, substantially all of the cancer cells are degraded.

[0451] In some embodiments, cancer cells are killed. In further or additional embodiments, 1% of cancer cells are killed. In further or additional embodiments, 2% of cancer cells are killed. In further or additional embodiments, 3% of cancer cells are killed. In further or additional embodiments, 4% of cancer cells are killed. In further or additional embodiments, 5% of cancer cells are killed. In further or additional embodiments, 1.0% of cancer cells are killed. In further or additional embodiments, 20% of cancer cells are killed. In further or additional embodiments, 25% of cancer cells are killed. In further or additional embodiments, 30% of cancer cells are killed. In further or additional embodiments, 40% of cancer cells are killed. In further or additional embodiments, 50% of cancer cells are killed. In further or additional embodiments, 60% of cancer cells are killed. In further or additional embodiments, 70% of cancer cells are killed. In further or additional embodiments, 75% of the cancer cells are killed. In further or additional embodiments, 80% of the cancer cells are killed. In further or additional embodiments, 90% of the cancer cells are killed. In further or additional embodiments, 100% of the cancer cells are killed. In further or additional embodiments, substantially all of the cancer cells are killed.

[0452] In further or additional embodiments, the growth of cancer cells is inhibited. In further or additional embodiments, the growth of cancer cells is inhibited by about 1%. In further or additional embodiments, the growth of cancer cells is inhibited by about 2%. In further or additional embodiments, the growth of cancer cells is inhibited by about 3%. In further or additional embodiments, the growth of cancer cells is inhibited by about 4%. In further or additional embodiments, the growth of cancer cells is inhibited by about 5%. In further or additional embodiments, the growth of cancer cells is inhibited by about 10%. In further or additional embodiments, the growth of cancer cells is inhibited by about 20%. In further or additional embodiments, the growth of cancer cells is inhibited by about 25%. In further or additional embodiments, the growth of cancer cells is inhibited by about 30%. In further or additional embodiments, the growth of cancer cells is inhibited by about 40%. In further or additional embodiments, the growth of cancer cells is inhibited by about 50%. In further or additional embodiments, the growth of cancer cells is inhibited by about 60%. In further or additional embodiments, the growth of cancer cells is inhibited by about 70%. In further or additional embodiments, the growth of cancer cells is inhibited by about 75%. In further or additional embodiments, the growth of cancer cells is inhibited by about 80%. In further or additional embodiments, the growth of cancer cells is inhibited by about 90%. In further or additional embodiments, the growth of cancer cells is inhibited by about 100%.

[0453] In some embodiments, the size of a tumor is reduced by administering a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof. In further or additional embodiments, the size of the tumor is reduced by at least 1%. In further or additional embodiments, the size of the tumor is reduced by at least 2%. In further or additional embodiments, the size of the tumor is reduced by at least 3%. In further or additional embodiments, the size of the tumor is reduced by at least 4%. In further or additional embodiments, the size of the tumor is reduced by at least 5%. In further or additional embodiments, the size of the tumor is reduced by at least 10%. In further or additional embodiments, the size of the tumor is reduced by at least 20%. In further or additional embodiments, the size of the tumor is reduced by at least 25%. In further or additional embodiments, the size of the tumor is reduced by at least 30%. In further or additional embodiments, the size of the tumor is reduced by at least 40%. In further or additional embodiments, the size of the tumor is reduced by at least 50%. In further or additional embodiments, the size of the tumor is reduced by at least 60%. In further or additional embodiments, the size of the tumor is reduced by at least 70%. In further or additional embodiments, the size of the tumor is reduced by at least 75%. In further or additional embodiments, the size of the tumor is reduced by at least 80%. In further or additional embodiments, the size of the tumor is reduced by at least 85%. In further or additional embodiments, the size of the tumor is reduced by at least 90%. In further or additional embodiments, the size of the tumor is reduced by at least 95%. In further or additional embodiments, the tumor is eradicated. In some embodiments, the size of the tumor does not increase.

[0454] In some embodiments, tumor proliferation is reduced by administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof. In some embodiments, tumor proliferation is reduced by at least 1%. In some embodiments, tumor proliferation is reduced by at least 2%. In some embodiments, tumor proliferation is reduced by at least 3%. In some embodiments, tumor proliferation is reduced by at least 4%. In some embodiments, tumor proliferation is reduced by at least 5%. In some embodiments, tumor proliferation is reduced by at least 10%. In some embodiments, tumor proliferation is reduced by at least 20%. In some embodiments, tumor proliferation is reduced by at least 25%. In some embodiments, tumor proliferation is reduced by at least 30%. In some embodiments, tumor proliferation is reduced by at least 40%. In some embodiments, tumor proliferation is reduced by at least 50%. In some embodiments, tumor proliferation is reduced by at least 60%. In some embodiments, tumor proliferation is reduced by at least 70%. In some embodiments, tumor proliferation is reduced by at least 75%. In some embodiments, tumor proliferation is reduced by at least 75%. In some embodiments, tumor proliferation is reduced by at least 80%. In some embodiments, tumor proliferation is reduced by at least 90%. In some embodiments, tumor proliferation is reduced by at least 95%. In some embodiments, tumor proliferation is prevented.

[0455] Application method

[0456] The compound or pharmaceutical composition can be administered to the patient in any suitable manner. Non-limiting examples of methods of administration include, in particular, (a) oral administration, including administration in the form of capsules, tablets, granules, sprays, syrups or other such forms; (b) administration by non-oral routes such as rectal, vaginal, intraurethral, intraocular, intranasal or intraaural administration, including administration in the form of aqueous suspensions, oily products or drops, sprays, suppositories, ointments, ointments, etc.; (c) administration by subcutaneous, intraperitoneal, intravenous, intramuscular, intradermal, intraorbital, intracapsular, intraspinal, intrasternal injection, including delivery by infusion pump; (d) topical administration, such as by injection directly in the kidney or heart region, for example, by reservoir implantation; and (e) topical administration; as deemed appropriate by those skilled in the art for contacting the compound of the present invention with living tissue.

[0457] The pharmaceutical composition suitable for administration includes a composition in which the active ingredient is contained in an amount effective to achieve its intended purpose. The therapeutically effective amount of the compound disclosed herein required for the dosage will depend on the route of administration, the type of animal (including humans) being treated, and the physical characteristics of the particular animal being considered. The dosage can be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, simultaneous medication, and other factors that will be recognized by those skilled in the art of medicine. More specifically, a therapeutically effective amount means the amount of the compound that effectively prevents, alleviates, or improves symptoms of the disease or prolongs the lifespan of the treated subject. Determining a therapeutically effective amount is fully within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0458] As will be apparent to those skilled in the art, useful in vivo doses to be administered and specific modes of administration will vary according to the age, body weight, and mammalian species being treated, the specific compounds employed, and the specific uses for which these compounds are employed. The determination of effective dose levels (i.e., the dose levels necessary to achieve the desired result) can be accomplished by those skilled in the art using conventional pharmacological methods. Typically, human clinical applications of a product begin with lower dose levels, increasing the dose level until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used to formulate useful doses and routes of administration of the compositions identified by the methods of the present invention using established pharmacological methods.

[0459] In non-human animal studies, the potential product is initially administered at a higher dose level and the dose is reduced until the desired effect is no longer achieved or the adverse side effects disappear. The dosage range may be wide, depending on the desired effect and the therapeutic indication. Typically, the dosage may be between about 10 micrograms / kg and 100 mg / kg body weight, preferably between about 100 micrograms / kg and 10 mg / kg body weight. Alternatively, as will be appreciated by those skilled in the art, the dosage may be based on and calculated according to the patient's surface area.

[0460] The exact formulation, route of administration, and dosage of the pharmaceutical compositions of the present invention can be selected by the individual physician based on the patient's condition. (See, e.g., Fingl et al. 1975, "The Pharmacological Basis of Therapeutics," which is incorporated herein by reference in its entirety, particularly with reference to Chapter 1, page 1). Typically, the dosage range of the composition administered to the patient can be about 0.5 mg / kg to 1000 mg / kg of the patient's body weight. The dosage can be a single dose or a series of two or more doses given over the course of one or more days, depending on the patient's needs. In cases where human dosages have been determined for at least some of the conditions, the present invention will use those same dosages, or dosages between about 0.1% and 500%, more preferably between about 25% and 250%, of the established human dosages. In cases where no human dosage has been determined, as in the case of a newly discovered drug compound, the ED may be used. 50 or ID 50 Suitable human doses, as qualified by animal toxicity studies and efficacy studies, can be extrapolated from the values or other appropriate values derived from in vitro or in vivo studies.

[0461] It should be noted that the attending physician will know how and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunction. On the contrary, if the clinical response is insufficient (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level. The magnitude of the dosage administered during the management of the condition of interest will vary with the severity of the condition to be treated and the route of administration. For example, the severity of the condition can be assessed in part by standard prognostic assessment methods. Further, dosage and possible dosage frequency will also vary according to the age, weight and response of the individual patient. Programs comparable to those discussed above can be used in veterinary medicine.

[0462] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations can be made about the dosage. The daily dosage regimen for adult patients can be, for example, between 0.1 mg and 2000 mg, preferably between 1 mg and 500 mg, for example, an oral dose of each active ingredient of 5 mg to 200 mg. In other embodiments, an intravenous, subcutaneous, or intramuscular dose of each active ingredient of between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, for example, 1 mg to 40 mg is used. In the case of administering a pharmaceutically acceptable salt, the dosage can be calculated as the free base. In some embodiments, the composition is administered 1 to 4 times a day. Alternatively, the composition of the present invention can be administered by continuous intravenous infusion, preferably with a dose of up to 1000 mg per day of each active ingredient. As will be understood by those skilled in the art, in some cases, it may be necessary to administer the compounds disclosed herein in an amount exceeding or even far exceeding the above-mentioned preferred dosage range in order to effectively and actively treat, in particular, aggressive diseases or infections. In some embodiments, the compound will be administered for a continuous treatment period, for example, a week or longer, or for months or years.

[0463] In further or additional embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can be administered in an amount ranging from about 0.001 / kg body weight / day to about 1000 mg / kg body weight / day. In further or additional embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can be administered in an amount ranging from about 0.5 mg / kg / day to about 50 mg / kg / day. In further or additional embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can be administered in an amount ranging from about 0.001 g / day to about 7 g / day. In further or additional embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can be administered in an amount of about 0.002 g / day to about 6 g / day. In further or additional embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can be administered in an amount of about 0.005 g / day to about 5 g / day. In further or additional embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can be administered in an amount of about 0.01 g / day to about 5 g / day. In further or additional embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can be administered in an amount of about 0.02 g / day to about 5 g / day. In further or additional embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can be administered in an amount of about 0.05 g / day to about 2.5 g / day. In further or additional embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, can be administered in an amount of about 0.1 g / day to about 1 g / day. In further or additional embodiments, dosage levels below the lower limit of the aforementioned range may be more than sufficient.

[0464] Dosage and interval can be adjusted individually to provide plasma levels of the active moiety sufficient to maintain the modulatory effect, or the minimum effective concentration (MEC). The MEC will vary for each compound but can be estimated based on in vitro data. The dose required to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.

[0465] Dosage intervals can also be determined using the MEC.Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10%-90% of the time, preferably 30%-90% of the time, and most preferably 50%-90% of the time.

[0466] In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0467] The amount of composition administered may depend on the subject being treated, the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

[0468] The efficacy and toxicity of the compounds disclosed herein can be assessed using known methods. For example, the toxicology of a specific compound or a subset of compounds that share certain chemical moieties can be determined by determining in vitro toxicity to a cell line (such as a mammal, preferably a human cell line). The results of such studies can often predict toxicity in animals (such as mammals, or more specifically, humans). Alternatively, the toxicity of a specific compound in an animal model (such as a mouse, rat, rabbit, or monkey) can be determined using known methods. Several generally recognized methods (such as in vitro methods, animal models, or human clinical trials) can be used to determine the efficacy of a specific compound. There are generally recognized in vitro models for almost all categories of pathologies (including but not limited to cancer, cardiovascular disease, and various immune dysfunctions). Similarly, acceptable animal models can be used to determine the efficacy of chemicals for treating such pathologies. When selecting a model to determine efficacy, technicians can select appropriate models, dosages, routes of administration, and regimens under the guidance of the prior art. Of course, human clinical trials can also be used to determine the efficacy of compounds in humans.

[0469] The composition may be present in a package or dispenser device, as needed, which may include one or more unit dosage forms containing the active ingredient. The package may, for example, include metal or plastic foil, such as a blister pack. The package or dispenser device may be accompanied by instructions for use. The package or dispenser may also be accompanied by a notice related to the container, the form of which is specified by a government agency that manages drug manufacturing, use, or sales, and the notice reflects the agency's approval or veterinary management of the form of the drug for human use. For example, such a notice may be a prescription drug label approved by the U.S. Food and Drug Administration, or an approved product instruction sheet. A composition comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in a suitable container, and labeled for the treatment of the indicated condition.

[0470] Administration and pharmaceutical compositions

[0471] The compound is administered in a therapeutically effective dose. Although human dosage levels have not yet been specifically determined for the compounds described herein, in general, a daily dose can be from about 0.25 mg / kg to about 120 mg / kg body weight or higher, from about 0.5 mg / kg or less to about 70 mg / kg, from about 1.0 mg / kg to about 50 mg / kg body weight, or from about 1.5 mg / kg to about 10 mg / kg body weight. Therefore, for administration to a 70 kg person, the dosage range will be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg per day to about 3000 mg per day. Of course, the amount of the active compound administered will depend on the subject being treated and the disease state, the severity of the ailment, the mode and schedule of administration, and the judgment of the prescribing physician.

[0472] Administration of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be carried out by any accepted mode of administration for agents with similar efficacies, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. Oral and parenteral administration are generally used to treat the indications that are the subject of the preferred embodiments.

[0473] The compounds useful as described above can be formulated into pharmaceutical compositions for treating these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins (2005) (incorporated by reference in its entirety). Thus, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereomers, tautomers, polymorphs, and solvates thereof) or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof.

[0474] In addition to the useful selected compounds as described above, some embodiments include compositions containing pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delay agents, etc. The purposes of such media and agents for pharmaceutically active substances are well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, it is expected that it will be used in therapeutic compositions. In addition, various adjuvants commonly used in this area can be included. For example, Gilman et al. (editor) (1990), Goodman and Gilman's:The Pharmacological Basis of Therapeutics, 8th edition, Pergamon Press (which is incorporated herein by reference in its entirety) describes the considerations of including various components in pharmaceutical compositions.

[0475] Some examples of substances that can be used as pharmaceutically acceptable carriers or components thereof are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa oil; polyols such as propylene glycol, glycerol, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as Tween; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffered solution.

[0476] The choice of pharmaceutically acceptable carrier for use in conjunction with the subject compounds is essentially determined by the manner in which the compound is to be administered.

[0477] The compositions described herein are preferably provided in unit dosage form. As used herein, "unit dosage form" is a composition containing a certain amount of compound, and the compound of this amount is suitable for being administered to animals, preferably mammalian subjects, in a single dose according to good medical practice. However, the preparation of a single dosage form or unit dosage form does not mean that the dosage form is administered once a day or once per course of treatment. Such dosage forms are expected to be administered once, twice, three times or more per day, and can be administered in an infusion form over a period of time (e.g., about 30 minutes to about 2-6 hours), or in a continuous infusion form, and can be given more than once during the course of treatment, but single administration is not explicitly excluded. Technicians will recognize that the preparation does not specifically consider the entire course of treatment, and such decisions are left to the technical staff of the therapeutic field rather than the field of preparations.

[0478] Useful compositions as described above can be for a variety of routes of administration, for example, for oral, nasal, rectal, topical (including transdermal), ophthalmic, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular or other parenteral administration in a variety of suitable forms. Technicians will appreciate that oral compositions and nasal compositions include compositions administered by inhalation and prepared using available methods. Depending on the specific route of administration desired, a variety of pharmaceutically acceptable carriers well known in the art can be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surfactants and encapsulating materials. Optional pharmaceutically active substances that do not substantially interfere with the inhibitory activity of the compound can be included. The amount of the carrier used in conjunction with the compound is sufficient to provide a practical amount of material for the administration of the compound per unit dose. Techniques and compositions for preparing dosage forms useful in the methods described herein are described in the following references, which are incorporated herein by reference in their entirety: Modern Pharmaceutics, 4th edition, Chapters 9 and 10 (Banker and Rhodes eds., 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th edition (2004).

[0479] Various oral dosage forms can be used, including solid forms such as tablets, capsules, granules and bulk powders. Tablets can be compressed tablets, triturated tablets, enteric-coated tablets, sugar-coated tablets, film-coated tablets or multiple compressed tablets containing suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow-inducing agents and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent products reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavorings.

[0480] Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art. Tablets typically contain the following conventional pharmaceutically compatible adjuvants: inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; binders such as starch, gelatin, and sucrose; disintegrants such as starch, alginic acid, and cross-linked carboxymethyl cellulose; lubricants such as magnesium stearate, stearic acid, and talc. Glidants such as silicon dioxide can be used to improve the flow characteristics of the powder mixture. Colorants such as FD&C dyes can be added to improve the appearance. Sweeteners and flavorings such as aspartame, saccharin, menthol, mint, and fruit flavors are useful adjuvants for chewable tablets. Capsules typically contain one or more of the solid diluents disclosed above. The selection of the carrier component depends on non-critical secondary considerations such as taste, cost, and shelf stability, and can be readily made by those skilled in the art.

[0481] Oral compositions also include liquid solutions, emulsions, suspensions, and the like. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, gum tragacanth, and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more components such as the sweeteners, flavorings, and coloring agents disclosed above.

[0482] Such compositions may also be coated by conventional methods, typically using a pH or time-dependent coating, so that the subject compound is released in the gastrointestinal tract near the desired topical application, or at various times to prolong the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethylcellulose, Eudragit coating, wax, and shellac.

[0483] The compositions described herein may optionally contain other pharmaceutical actives.

[0484] Other compositions that can be used to achieve systemic delivery of the subject compounds include sublingual, buccal, and nasal dosage forms. Such compositions typically contain one or more soluble filler materials, such as sucrose, sorbitol, and mannitol; and binders, such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Glidants, lubricants, sweeteners, colorants, antioxidants, and flavorings disclosed above may also be included.

[0485] Liquid compositions formulated for topical ophthalmic use are formulated so that they can be applied topically to the eye. Comfort should be maximized as much as possible, although sometimes formulation considerations (e.g., drug stability) may require less than optimal comfort. Where comfort cannot be maximized, the liquid should be formulated so that it can be tolerated by the patient during topical ophthalmic use. In addition, ophthalmologically acceptable liquids should be packaged for single use or contain preservatives to prevent contamination from repeated use.

[0486] For ophthalmic applications, solutions or medicines are often prepared using physiological saline solutions as the primary vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH using an appropriate buffer system. The preparations may also contain conventional pharmaceutically acceptable preservatives, stabilizers, and surfactants.

[0487] Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate, and phenylmercuric nitrate. Useful surfactants include, for example, Tween 80. Similarly, various useful vehicles can be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethyl cellulose, hydroxyethyl cellulose, and purified water.

[0488] Tonicity adjusting agents may be added as needed or convenient. These include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol, and glycerol, or any other suitable ophthalmologically acceptable tonicity adjusting agent.

[0489] Various buffers and methods for adjusting pH can be used, so long as the resulting product is ophthalmologically acceptable. For many compositions, the pH will be between 4 and 9. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. Acids or bases can be used to adjust the pH of these formulations as needed.

[0490] In a similar context, ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0491] Other excipient components that may be included in ophthalmic preparations are chelating agents. One useful chelating agent is disodium edetate, although other chelating agents may be used in place of or in combination with it.

[0492] For topical use, creams, ointments, gels, solutions or suspensions containing the compounds disclosed herein are employed. Topical formulations generally may include a pharmaceutical carrier, cosolvents, emulsifiers, penetration enhancers, preservative systems, and emollients.

[0493] For intravenous administration, the compounds and compositions described herein can be dissolved or dispersed in a pharmaceutically acceptable diluent, such as saline or glucose solution. Suitable excipients can be included to reach the required pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl and citric acid. In various embodiments, the pH range of the final composition is 2 to 8, or preferably 4 to 7. Antioxidant excipients can include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition can include sodium phosphate or potassium phosphate, citric acid, tartaric acid, gelatin and carbohydrates, such as glucose, mannitol and dextran. Further acceptable excipients are described in Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety. Antimicrobials may also be included to obtain antibacterial or antifungal solutions, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0494] The composition for intravenous administration can be provided to the caregiver in the form of one or more solids, which can be reconstituted with a suitable diluent such as sterile water, saline or water containing glucose shortly before administration. In other embodiments, the composition is provided in the form of a solution ready for parenteral administration. In yet other embodiments, the composition is provided in the form of a solution further diluted before administration. In embodiments comprising administering a combination of a compound as described herein with another agent, the combination can be provided to the caregiver as a mixture, or the caregiver can mix the two agents before administration, or the two agents can be administered separately.

[0495] The actual dosage of the active compounds described herein depends on the specific compound and the condition to be treated; selection of the appropriate dosage is well within the knowledge of the skilled artisan.

[0496] Second (or other additional) dose

[0497] In some embodiments, the second therapeutic agent is an anti-inflammatory agent. In some embodiments, the second therapeutic agent is a nonsteroidal anti-inflammatory agent. In some embodiments, the second therapeutic agent is an anti-cancer agent.

[0498] In some embodiments, the method comprises administering an effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId) or a pharmaceutically acceptable salt thereof in combination with an amount of a chemotherapeutic agent, wherein the combination and the amount of the chemotherapeutic agent together are effective to inhibit abnormal cell growth. Many chemotherapeutic agents are currently known in the art and can be used in combination. In some embodiments, the chemotherapeutic agent is selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens. Also described is a method for inhibiting abnormal cell growth in a mammal, the method comprising administering to the mammal an amount of a MEK protein kinase inhibitor and / or a Raf protein kinase inhibitor in combination with radiation therapy, wherein the amount of the MEK protein kinase inhibitor and / or the Raf protein kinase inhibitor in combination with radiation therapy is effective to inhibit abnormal cell growth in the mammal or to treat a hyperproliferative disorder in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapies described herein.

[0499] In some embodiments, the present disclosure also relates to a method for inhibiting abnormal cell growth in a mammal, which method may include a compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (IIc) or a pharmaceutically acceptable salt thereof, and an amount of one or more substances selected from anti-angiogenic agents, signal transduction inhibitors and antiproliferative agents. Anti-angiogenic agents, such as MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors and COX-11 (cyclooxygenase 11) inhibitors can be used in combination with the compounds of the present invention and the pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREX™ (alecoxib), valdecoxib and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96 / 33172 (published October 24, 1996), WO 96 / 27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No. 99308617.2 (filed October 29, 1999), WO 98 / 07697 (published February 26, 1998), WO 98 / 03516 (published January 29, 1998), WO 98 / 34918 (published August 13, 1998), WO 98 / 34915 (published August 13, 1998), WO 98 / 33768 (published on August 6, 1998), WO 98 / 30566 (published on July 16, 1998), European Patent Publication 606,046 (published on July 13, 1994), European Patent Publication 931,788 (published on July 28, 1999), WO 90 / 05719 (published on May 31, 1990), WO 99 / 52910 (published on October 21, 1999), WO 99 / 52889 (published on October 21, 1999), WO 99 / 29667 (published on June 17, 1999), PCT International Application No. PCT / IB98 / 01113 (filed on July 21, 1991), European Patent Application No. 99302232.1 (filed on March 25, 1999), UK Patent Application No. 9912961.1 (filed June 3, 1999), U.S. Provisional Application No. 60 / 148,464 (filed August 12, 1999), U.S. Patent No. 5,863,949 (issued January 26, 1999), U.S. Patent No. 5,861,510 (issued January 19, 1999) and European Patent Publication No. 780,386 (published June 25, 1997).Some MMP-2 and MMP-9 inhibitors have little or no activity against MMP-1, while some selectively inhibit MMP-2 and / or AMP-9 relative to other matrix metalloproteinases (e.g., MAP-1, NEMP-3, MMP-4, M7v1P-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, and MMP-13). Some specific examples of M1v1P inhibitors useful in the present invention are AG-3340, RU32-3555, and RS13-0830.

[0500] In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or a pharmaceutically acceptable salt thereof, is administered with at least one additional therapeutic agent. In some embodiments, the therapeutic agent is paclitaxel, bortezomib, or both. In further or additional embodiments, the therapeutic agent is selected from the group consisting of a cytotoxic agent, an anti-angiogenic agent, and an anti-tumor agent. In further or additional embodiments, the anti-tumor agent is selected from the group consisting of an alkylating agent, an antimetabolite, an epiclophyllotoxim; anti-tumor enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum coordination complexes, biological response modifiers and growth inhibitors, hormone / anti-hormonal therapeutics, and hematopoietic growth factors.

[0501] Many chemotherapeutic agents are currently known in the art and can be used in combination with the compounds and compositions of the present disclosure. In some embodiments, the chemotherapeutic agent is selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.

[0502] In some embodiments, the combination is administered in combination with another therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy, surgery, or any combination thereof. In further or additional embodiments, the combination is administered in combination with at least one additional therapeutic agent. In further or additional embodiments, the therapeutic agent is selected from the group consisting of a cytotoxic agent, an anti-angiogenic agent, and an anti-tumor agent. In further or additional embodiments, the anti-tumor agent is selected from the group consisting of an alkylating agent, an antimetabolite, an epiphyllotoxin; anti-tumor enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum coordination complexes, biological response modifiers and growth inhibitors, hormone / anti-hormonal therapeutics, and hematopoietic growth factors.

[0503] In some embodiments, the second therapeutic agent is an agent for co-regulating MEK or RAF pathways. In some embodiments, the second therapeutic agent is a MEK or RAF inhibitor. In some embodiments, RAF inhibitors are vemurafenib, dabrafenib, XL-281, LGX-818, CEP-32496, ARQ-736, MEK-162, selumetinib, refametinib, E-6201, pimasertib, WX-554, and GDC-0973.

[0504] In some embodiments, the second therapeutic agent is selected from aspirin; diflunisal; salsalate; acetaminophen; ibuprofen; dexibuprofen; naproxen; fenoprofen; ketoprofen; dexketoprofen; flurbiprofen; oxaprozin; loxoprofen; indomethacin; tolmetin; sulindac; etodolac; ketorolac; diclofenac; aceclofenac; nabumetone; enolic acid; acid; piroxicam; meloxicam; tenoxicam; droxicam; lornoxicam; isoxicam; mefenamic acid; meclofenamic acid; flufenamic acid; tolfenamic acid; sulfonanilide; clonidine; licofelone; dexamethasone; and prednisone.

[0505] In some embodiments, the second therapeutic agent is selected from chloroethylamine; cyclophosphamide; melphalan; chlorambucil; ifosfamide; busulfan; N-nitroso-N-methylurea (MNU); carmustine (BCNU); lomustine (CCNU); cimustine (MeCCNU); fotemustine; streptozotocin; dacarbazine; mitozolomide; temozolomide; thiotepa; mitomycin; diazinon (AZQ); cisplatin; carboplatin; and oxaliplatin.

[0506] In some embodiments, the second therapeutic agent is selected from vincristine; vinblastine; vinorelbine; vindesine; vinflunine; paclitaxel; docetaxel; etoposide; teniposide; tofacitinib; ixabepilone; irinotecan; topotecan; camptothecin; doxorubicin; mitoxantrone; and teniposide.

[0507] In some embodiments, the second therapeutic agent is selected from actinomycin; bleomycin; plicamycin; mitomycin; daunorubicin; epirubicin; idarubicin; pirarubicin; aclarubicin; mitoxantrone; cyclophosphamide; methotrexate; 5-fluorouracil; prednisolone; folinic acid; methotrexate; melphalan; capecitabine; chlorethylamine; uramustine; melphalan; chlorambucil; ifosfamide; bendamustine; 6-mercaptopurine; and procarbazine.

[0508] In some embodiments, the second therapeutic agent is selected from cladribine; pemetrexed; fludarabine; gemcitabine; hydroxyurea; nelarabine; cladribine; clofarabine; cytarabine; decitabine; cytarabine; liposomal cytarabine liposomal; pralatrexate; floxuridin; fludarabine; colchicine; thioguanine; cabazitaxel; larotaxel; ortataxel; tesetaxel; aminopterin; pemetrexed; pralatrexate; raltitrexed; pemetrexed; carmofur; and floxuridine.

[0509] In some embodiments, the second therapeutic agent is selected from azacitidine; decitabine; hydroxycarbamide; topotecan; irinotecan; belotecan; teniposide; aclarubicin; epirubicin; idarubicin; amrubicin; pirarubicin; valrubicin; zorubicin; rubicin; mitoxantrone; pixantrone; chloroethylamine; chlorambucil; prednimustine; uramustine; estramustine; carmustine; lomustine; fotemustine; nimustine; ranimustine; carboquone; thio-TEPA; triazone; and triethylene melamine.

[0510] In some embodiments, the second therapeutic agent is selected from nedaplatin; satraplatin; procarbazine; dacarbazine; temozolomide; altretamine; mitobronitol; pipobroman; actinomycin; bleomycin; plicamycin; aminolevulinic acid; methyl aminolevulinate; aminolevulinate; efaproxiral; talaporfin; temoporfin; verteporfin; avocidib; seliciclib; palbociclib; bortezomib; carfilzomib; anagrelide; masoprocol; olaparib; belinostat; panobinostat; romidepsin; vorinostat sta; idelalisib; atrasentan; bexarotene; testolactone; amsacrine; trabectedin; alitretinoin; tretinoin; demecolcine; elsamitrucin; etoglucid; lonidamine; lucanthone; mitoguazone; mitotane; oblimersen; omacetaxine mepesuccinate; and eribulin.

[0511] In some embodiments, the second therapeutic agent is selected from azathioprine; mycophenolic acid; leflunomide; teriflunomide; tacrolimus; cyclosporin; pimecrolimus; abetimus; gusperimus; lenalidomide; pomalidomide; thalidomide; anakinra; nakinra; sirolimus; everolimus; ridaforolimus; temsirolimus; umirolimus; zotarolimus; eculizumab; adalimumab; afelimomab; certolizumab pegol pegol; golimumab; infliximab; nerelimomab; mepolizumab; omalizumab; faralimomab; elsilimomab; lebrikizumab; ustekinumab; etanercept; otetuximab otelixizumab; teplizumab; visilizumab; clenoliximab; keliximab; zanolimumab; efalizumab; erlizumab; obinutuzumab; rituximab; and ocrelizumab.

[0512] In some embodiments, the second therapeutic agent is selected from pascolizumab; gomiliximab; lumiliximab; teneliximab; toralizumab; aselizumab; galiximab; gavilimomab; ruplizumab; belimumab umab; blisibimod; ipilimumab; tremelimumab; bertilimumab; lerdelimumab; metelimumab; natalizumab; tocilizumab; odulimomab; basiliximab; Daclizumab; inolimomab; zolimoma; torolimumab; cedelizumab; fontolizumab; maslimomab; morolimumab; pexelizumab; reslizumab; rovelizumab ab); siplizumab; talizumab; telimomab; vapaliximab; vepalimomab; abatacept; belatacept; pegsunercept; aflibercept; alefacept; and rilonacept.

[0513] Example

[0514] General Procedure

[0515] Additional embodiments are disclosed in further detail in the following examples, which are not intended to limit the scope of the claims in any way.

[0516] The materials used to prepare the compounds of formula (I), (Ia), (Ib) or (Ic) described herein can be prepared by known methods or are commercially available. In these reactions, variants known per se to those skilled in the art but not described in greater detail may also be used. The skilled artisan is fully capable of preparing any of the compounds described based on the literature and this disclosure.

[0517] It will be appreciated that those skilled in the art of organic chemistry can readily perform the operations without further instruction, that is, it is well within the skill's scope and practice to perform these operations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, electrophilic and nucleophilic reactions, etherifications, esterifications, and saponifications. These operations are discussed in standard texts such as March's Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (incorporated herein by reference in its entirety).

[0518] The technical staff will readily appreciate that when other functional groups in the molecule are masked or protected, certain reactions can be performed best, thereby avoiding any undesirable side reactions and / or increasing the productive rate of the reaction. The technical staff often utilizes protecting groups to achieve the productive rate of this type of increase or to avoid undesirable reactions. These reactions can be found in the literature and are also within the scope of the technical staff. The examples of many operations in these operations can be found in, for example, T.Greene and P.Wuts Protecting Groups in Organic Synthesis, the 4th edition, John Wiley & Sons (2007), which is incorporated herein by reference in its entirety.

[0519] The following illustrative schemes are provided to guide the reader and represent preferred methods for preparing the compounds exemplified herein. These methods are not restrictive, and it is apparent that other approaches may be employed to prepare these compounds. Such methods specifically include solid-phase-based chemistry, including combinatorial chemistry. The skilled artisan is fully capable of preparing these compounds by the methods provided in the literature and this disclosure. The compound numbers used in the synthetic schemes described below are intended only for those specific schemes and should not be construed as identically numbered in other parts of this application or confused with identically numbered in other parts of this application.

[0520] The trademarks used herein are examples only and reflect the illustrative material used in connection with the present invention. The skilled artisan will recognize that variations in batches, manufacturing processes, etc. are to be expected. Thus, the examples and the trademarks used therein are non-limiting and are not intended to be limiting, but are merely illustrative of how a skilled artisan may choose to implement one or more embodiments of the present invention.

[0521] The following example schemes are provided for the purpose of guiding the reader and collectively represent example methods for preparing the compounds provided herein. In addition, other methods for preparing the compounds described herein will be apparent to those of ordinary skill in the art based on the following reaction schemes and examples. Unless otherwise indicated, all variables are defined as above.

[0522] Example 1

[0523] General Synthesis A

[0524]

[0525] Compound 2: To a solution of 2-fluoro-3-nitrotoluene 1 (153.9 g, 268 mmol, 1.0 eq) and NBS (57.8 g, 321 mmol, 1.20 eq) in MeCN (1340 mL) was added 1,1-azobis(cyclohexanecarbonitrile) (8.0 g, 32.1 mmol, 0.12 eq) under a nitrogen atmosphere. The resulting reaction mixture was stirred at 80 ° C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain an orange suspension. Et2O was added and the resulting suspension was stirred at room temperature for 18 hours. The suspension was filtered and the residue was washed with some additional Et2O. The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a dark red oil that crystallized after standing. The product was recrystallized from heptane to obtain 1-(bromomethyl)-2-fluoro-3-nitrobenzene 2 (43.8 g, 186.7 mmol, yield: 70%, purity: 99%) as a white solid. LCMS (Method K): tR = 1.95 min; [M+H] + Calcd. m / z = 234.0, found = massless; 1H NMR (400 MHz, DMSO) δ 8.14 (td, J = 7.8, 7.3, 1.7 Hz, 1H), 8.01–7.93 (m, 1H), 7.50–7.40 (m, 1H), 4.81 (d, J = 1.4 Hz, 2H).

[0526] Compound 3: diol (1.20 equivalents) was added to a solution of 2-(2-fluoro-3-nitrobenzyl)-3-oxobutanoic acid ethyl ester 3 (1.0 equivalents) in perchloric acid (10-20 equivalents). The reaction mixture was stirred at room temperature for 1-18 hours. Water was added to the reaction mixture, the product was filtered and washed with water and Et2O. The dry residue was used to obtain a solid coumarin.

[0527] Compound 4: To a solution of coumarin (1.0 eq) in N,N-dimethylformamide (dry) (0.13–0.2 M) was added a 60% dispersion of sodium hydride on mineral oil (1.60 eq) at 0°C under an N2 atmosphere. The resulting reaction mixture was stirred for 10 min, and then dimethylcarbamoyl chloride (1.50–1.60 eq) was added. The resulting reaction mixture was allowed to warm to room temperature and stirred for 2–60 h. Water was added to quench the reaction mixture. The resulting suspension was filtered and washed with water and Et2O. The residue was dried to obtain the dimethylcarbamate as a solid.

[0528] Compound 5: Dimethylcarbamate (1.0 eq) was suspended in methanol (0.2 M) and in some cases some CH2Cl2 was added to obtain a solution. Argon was bubbled through the solution for 10 min. Then 50% -nickel slurry in water (1.0 eq) or 10% palladium on activated carbon (0.05 eq). The resulting reaction mixture was purged with hydrogen and stirred at room temperature for 2-18 h. The reaction mixture was filtered through celite and washed with MeCN, CH2Cl2 and MeOH. The filtrate was concentrated under reduced pressure to obtain the primary amine as a solid.

[0529] Compound 6: To a suspension (0.2 M) of a primary amine (1.0 equiv) and pyridine (3.00 equiv) in N,N-dimethylformamide cooled in an ice bath (0 ° C) was added dropwise a clear solution (0.2 M) of methylsulfamoyl chloride (2.50 equiv) in acetonitrile (anhydrous). After complete addition, the resulting reaction mixture was allowed to warm to room temperature and stirred for 1-16 h. Water was added to the reaction mixture and the resulting suspension was stirred for 1 hour. The suspension was filtered and washed with water and Et2O. The residue was dried to obtain the sulfamoyl group as a solid.

[0530] Compound 7: A solution (0.06-0.10 M) of sulfamoyl (1.0 equiv.) in tetrahydrofuran (dry) was cooled to -78 ° C under a nitrogen atmosphere and 1 M LiHMDS (3.00 equiv.) in THF was slowly added. After complete addition, the reaction mixture formed was diluted with some additional tetrahydrofuran (dry) in some cases and stirred for 30 min, allowing it to warm to 0 ° C. This was added dropwise to a solution (0.04 M) of NCS or NBS (1.20 equiv.) in tetrahydrofuran (dry) cooled (-78 ° C) via a cannula over 15 minutes. The reaction mixture formed was stirred at -78 ° C for 1 hour. At -78 ° C, the reaction mixture was quenched with 1 M HCl and warmed to room temperature. Some additional water was added and the product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The impure product was purified by column chromatography using the 'flash' method (heptane / EtOAc = 1 :0 → 0: 1) to afford the bromide or chloride as a solid.

[0531] Example 2

[0532] General Synthesis B

[0533]

[0534] Compound B.1: To a solution of ethyl 2-(2-fluoro-3-nitrobenzyl)-3-oxobutanoate 3 (6.54 g, 23.09 mmol, 1.0 equiv) in perchloric acid (29.8 mL, 346 mmol, 15.0 equiv) was added resorcinol (3.05 g, 27.7 mmol, 1.20 equiv). The resulting reaction mixture was stirred at room temperature for 1 h. Water was added to the reaction mixture, and the product was filtered and washed with water and Et2O. The residue was dried under reduced pressure at 40°C overnight to afford 3-(2-fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-2H-chromen-2-one (15.224 g, 45.8 mmol, 112% yield) as an off-white solid.

[0535] LCMS (Method I): t R =1.92min; [M+H] +The calculated value of m / z = 330.1, the found value = 330.0; 1HNMR (400 MHz, DMSO) δ 10.51 (s, 1H), 8.03–7.92 (m, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.60–7.51 (m, 1H), 7.32 (t, J = 8.0 Hz, 1H), 6.83 (dd, J = 8.8, 2.4 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 4.02 (s, 2H), 2.43 (s, 3H).

[0536] Compound B.2: To a suspension of 3-(2-fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-2H-chromen-2-one (3 g, 7.74 mmol, 1.0 eq) in CHCl (0.6 M) was added DIPEA (5 ml, 28.6 mmol, 3.70 eq). MEM-Cl (1.8 ml, 15.90 mmol, 2.05 eq) was added and the resulting reaction mixture was stirred at room temperature for 18 h. The reaction mixture was purified by column chromatography using the 'Flash' method (heptane / EtOAc 3:1→1:3) to afford 3-(2-fluoro-3-nitrobenzyl)-7-((2-methoxyethoxy)methoxy)-4-methyl-2H-chromen-2-one (2.71 g, 6.49 mmol, 84% yield) as a colorless oil.

[0537] LCMS (Method I): t R =2.08min; [M+H] + Calcd. m / z = 418.0, found = 418.0.

[0538] Compound B.3: A solution of 3-(2-fluoro-3-nitrobenzyl)-7-((2-methoxyethoxy)methoxy)-4-methyl-2H-chromen-2-one (2.71 g, 6.49 mmol, 1.0 equiv) in tetrahydrofuran (dry) (0.04 M) was cooled to -78°C and LiHMDS (1 M in THF, 7.79 ml, 7.79 mmol, 1.20 equiv) was slowly added. The resulting reaction mixture was stirred at -78°C for 30 min, then NBS (1.156 g, 6.49 mmol, 1.0 equiv) dissolved in tetrahydrofuran (dry) (75 ml) was slowly added. The resulting yellow solution was stirred at -78°C for 30 min. The reaction mixture was quenched with saturated aqueous NH4Cl at -78°C and allowed to warm to room temperature. The product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a yellow oil. The impure product was purified by column chromatography using the 'flash' method (heptane / EtOAc 1:0→1:3) to afford 4-(bromomethyl)-3-(2-fluoro-3-nitrobenzyl)-7-((2-methoxyethoxy)methoxy)-2H-chromen-2-one (2.1 g, 4.23 mmol, 65% yield) as an off-white fluffy solid.

[0539] LCMS (Method K): t R =1.94min; [M+H] + Calculated value of m / z = 496.0 / 498.0, found = 496.0 / 498.0

[0540] Compound B.4: 4-(Bromomethyl)-3-(2-fluoro-3-nitrobenzyl)-7-((2-methoxyethoxy)methoxy)-2H-chromen-2-one (1.5 g, 3.02 mmol, 1.0 equiv) was suspended in dimethylamine (2.0 M in MeOH, 15 ml, 30.0 mmol, 10.0 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The impure product was suspended in Et2O. The solid was filtered off and the residue was washed with Et2O and dried to give 4-((dimethylamino)methyl)-3-(2-fluoro-3-nitrobenzyl)-7-((2-methoxyethoxy)methoxy)-2H-chromen-2-one (1.27 g, 2.59 mmol, 86% yield) as an off-white solid.

[0541] LCMS (Method I): t R =2.11min; [M+H] + Calculated value of m / z = 461.1, found value = 461.1

[0542] Compound B.5: To a mixture of 4-((dimethylamino)methyl)-3-(2-fluoro-3-nitrobenzyl)-7-((2-methoxyethoxy)methoxy)-2H-chromen-2-one (1.27 g, 2.59 mmol, 1.0 equiv) in methanol (0.26 M) was added

[0148] A mixture of 4-nitro-2-nitro-1-oxadiazole (2-nitro-1-oxadiazole)-1-nitro-2 ...

[0543] LCMS (Method U): t R =2.02min; [M+H] + Calculated value of m / z = 430.8, found value = 430.8

[0544] Compound B.6: To a 1.2 M solution of 3-(3-amino-2-fluorobenzyl)-4-((dimethylamino)methyl)-7-((2-methoxyethoxy)methoxy)-2H-chromen-2-one (1.1 g, 2.56 mmol, 1.0 eq) in N,N-dimethylformamide (dry) was added a 1.2 M solution of methylsulfamoyl chloride (0.268 ml, 3.07 mmol, 1.2 eq) in acetonitrile (anhydrous) and pyridine (0.413 ml, 5.11 mmol, 2.0 eq). The resulting reaction mixture was stirred at room temperature for 1 h. A 50% aqueous NaHCO solution was added to the reaction mixture, and the product was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The impure product was purified by column chromatography using the 'flash' method (heptane / EtOAc 3:2→1:9) to afford the sulfonamide (1.35 g, 2.58 mmol, yield: 101%) as a yellow oil.

[0545] LCMS (Method U): t R =1.94min; [M+H] + Calculated value of m / z = 524.2, found = 524.1

[0546] Compound B.7: To a solution of sulfonamide (910 mg, 1.738 mmol, 1.0 equivalent) in methanol / THF (1: 1) (0.17 mL) was added sulfuric acid (1.5 ml, 28.1 mmol, 16 equivalents). The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched in a saturated aqueous NaHCO solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The impure product was purified by column chromatography using a 'fast' method (CH2Cl2 / MeOH 1: 0 → 95: 5). The desired fractions were combined and concentrated under reduced pressure. The residue was dissolved in MeCN / water and lyophilized to obtain phenol (510 mg, 1.171 mmol, yield: 67%) as a yellow solid.

[0547] LCMS (Method J): t R =2.68min; [M+H] + Calculated value of m / z = 436.1, found = 436.0

[0548] Example 3

[0549] General synthesis of C

[0550]

[0551] Compound C.2: A solution of C1 (3.0 g, 7.49 mmol) in tetrahydrofuran (dry) (100 mL) was cooled to -78 ° C under a nitrogen atmosphere and 1 M LiHMDS (9.7 mL, 9.7 mmol, 1.3 equiv.) in THF was slowly added. After complete addition, the resulting reaction mixture was stirred at -78 ° C for 30 min and then at 0 ° C for 30 min. Then, paraformaldehyde (3.4 g, 112 mmol, 15 equiv.) was added. The reaction mixture was stirred at 0 ° C for 1 hour. The reaction mixture was then quenched with 1 M HCl and warmed to room temperature, and the product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The impure product was purified by flash column chromatography (heptane / EtOAc=1:0→3:7) to obtain C.2 (1.67 g, 3.41 mmol, purity: 88%, yield: 46%) as an off-white solid.

[0552] Compound C.3: tert-Butyldimethylsilyl chloride (338 mg, 2.24 mmol) and imidazole (162 mg, 2.37 mmol) were dissolved in N, N-dimethylformamide (20 mL) and added 3-(2-fluoro-3-nitrobenzyl)-4-(2-hydroxyethyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (645 mg, 1.32 mmol), and the mixture was stirred overnight. Then, the reaction mixture was quenched with water and the product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The impure product was purified by flash column chromatography (heptane / EtOAc=1:0→1:1) to obtain C.3 (502 mg, 0.92 mmol, yield: 70%) as a colorless oil.

[0553] Compound C.4: C.3 (2.3 g, 4.22 mmol) was dissolved in 150 mL of MeOH and argon was bubbled through the solution for 10 min. Then, a slurry of 50% Raney-Ni in water (2 mL, 8.44 mmol) was added. The mixture was purged with hydrogen and stirred at room temperature for 1.5 h. The reaction was then quenched by purging with argon and the mixture was filtered through diatomaceous earth and concentrated and stripped with EtOAc and DCM to obtain C.4 (2.41 g, 4.21 mmol, purity: 90%, yield: 100%) as a brown oil.

[0554] Compound C.5: To a suspension (0.2 M) of a primary amine (1.0 equiv.) and pyridine (3.00 equiv.) in N,N-dimethylformamide cooled in an ice bath (0 ° C) was added dropwise a clear solution (0.2 M) of methylsulfamoyl chloride (2.50 equiv.) in acetonitrile (anhydrous). After complete addition, the resulting reaction mixture was allowed to warm to room temperature and stirred for 1-16 h. Water was added to the reaction mixture and the resulting suspension was stirred for 1 hour. The suspension was filtered, washed with water and Et2O. The residue was dried to obtain the sulfamoyl group as a solid. 727 mg, 5.61 mmol of C.4 produced C.5 (1.97 g, 3.24 mmol, purity: 95%, yield: 87%) as an orange foam.

[0555] Compound 100: To a stirred solution of C,5 (1.97 g, 2.92 mmol) in 5 mL of 1,4-dioxane was added 2 mL of 4N HCl in 1,4-dioxane. After 30 min, the solvent was evaporated and stripped with DCM and purified by flash column chromatography (heptane / EtOAc = 1:0 → 0:1) to afford 100 (1.45 g, 2.79 mmol, 96% yield) as an off-white foam.

[0556] analyze : LCMS (Method P): t R =1.19min; [M+H] + m / z calculated = 494.1, found = 494.1; 1 H NMR 1H NMR (400MHz, CDCl3) δ7.65(d,J=8.7Hz,1H),7.34(dt,1H),7.14–7.07(m,2H),7.02–6.90(m,2H),6.81–6.73(m,1H),4.79 (q,J=5.3Hz,1H),4.09(s,2H),3.67(t,J=7.3Hz,2H),3.17–3.08(m,5H),3.03(s,3H),2.75(d,J=5.3Hz,3H),2.27(s,1H).

[0557] Compound 101: To an ice-cooled, stirred solution of 100 (100 mg, 203 mmol) and carbon tetrabromide (161 mg, 0.487 mmol, 2.4 equiv) in 4 mL of DCM was added triphenylphosphine (117 mg, 0.446 mmol, 2.2 equiv) and the reaction was allowed to warm to room temperature and stirred for 5 h. The solvent was evaporated, and the residue was redissolved in 1 mL of DCM and purified by 'flash' column chromatography (heptane / EtOAc = 1:0 → 2:8) to obtain 101 (146 mg, 0.186 mmol, purity: 71%, yield: 92%) as a white foam.

[0558] Example 4

[0559] General Synthesis D

[0560]

[0561] Compound D.2: 2-chloro-3-fluoroisonicotinaldehyde hydrate (56.13 g, 316 mmol, 1.0 equivalent) was dissolved in methanol (630 ml), and the solution was cooled to 0 ° C. Sodium borohydride (11.96 g, 316 mmol, 1.0 equivalent) was added in batches, and the resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched in 1000 mL of ice water slurry and slowly acidified. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain (2-chloro-3-fluoropyridin-4-yl)methanol (66.25 g, 410 mmol, 98% yield) as an off-white solid.

[0562] LCMS (Method K): tR = 1.20 min; [M+H]+ Calcd. m / z = 162.0, found = 162.0.

[0563] Compound D.3: (2-Chloro-3-fluoropyridin-4-yl)methanol (30 g, 186 mmol, 1.0 equiv) was dissolved in anhydrous tetrahydrofuran (460 mL) under a nitrogen atmosphere and cooled to 0°C. Lithium tert-butoxide (2.2 M, 89 mL, 195 mmol, 1.05 equiv) in THF was added dropwise, followed by methanesulfonyl chloride (17.25 mL, 223 mmol, 1.20 equiv). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was added to a cooled (0°C) solution of sodium iodide (27.8 g, 186 mmol, 1.0 equiv), lithium tert-butoxide (93 mL, 204 mmol, 1.10 equiv), and ethyl acetoacetate (47.2 mL, 371 mmol, 2.00 equiv) in 300 mL of anhydrous THF. The resulting reaction mixture was stirred at 0°C for 30 minutes and then at 50°C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with 0.2M LiCl and once with brine. The organic phase was dried over NaSO and concentrated under reduced pressure to afford ethyl 2-((2-chloro-3-fluoropyridin-4-yl)methyl)-3-oxobutanoate (54.5 g, 199 mmol, 107% yield) as a yellow oil.

[0564] LCMS (Method K): tR = 1.91 and 2.12 min; m / z calcd for [M+H]+ = 274.1, found = 274.0.

[0565] Compound D.4: To a solution of ethyl 2-((2-chloro-3-fluoropyridin-4-yl)methyl)-3-oxobutanoate (51.2 g, 187 mmol, 1.0 equiv) in sulfuric acid (3-20 equiv) was added diol 4 (2.00 equiv). The resulting reaction mixture was stirred at room temperature for 2-18 h. Water was added to the reaction mixture, and the product was filtered and washed with water and Et2O. The residue was recrystallized from EtOH:HO 8:2 to obtain the coumarin as a solid.

[0566] Compound D.5: To a solution of coumarin (1.0 eq) in N,N-dimethylformamide (dry) (0.15–0.4 M) at 0°C under N2 atmosphere was added a 60% dispersion of sodium hydride on mineral oil (1.40–1.60 eq). The resulting reaction mixture was stirred for 10–20 min, followed by the addition of dimethylcarbamoyl chloride (1.25–1.60 eq). The resulting reaction mixture was allowed to warm to room temperature and stirred for 1–24 h. Water was added to quench the reaction mixture. The resulting suspension was stirred for 1 h, filtered, and washed with water and heptane. The residue was dried to obtain the dimethylcarbamate as a solid.

[0567] Compound D.6: To a solution of dimethylcarbamate (1.0 equiv.) and tert-butylcarbamate (1.40-10.0 equiv.) in 1,4-dioxane (0.1-0.2 M) was added Xantphos (0.10-0.20 equiv.), cesium carbonate (1.20-1.50 equiv.) and PdOAc2 (0.10 equiv.) under a nitrogen atmosphere. After purging with nitrogen for another 5 minutes, the resulting reaction mixture was stirred at 90°C for 18 hours. The reaction mixture was filtered through celite and washed with CHCl2. The filtrate was concentrated under reduced pressure, and the residue was dissolved in CHCl2 (0.3-0.5 M). TFA (0.30-10.00 equiv.) was added and the resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and co-evaporated twice with CHCl2 to give an oil. The oil was purified by reverse phase chromatography 'fast acid' method to obtain the aminopyridine as a solid.

[0568] Compound D.7: To an ice-cooled (0°C) suspension of aminopyridine (1.0 equiv) and pyridine (3.00 equiv) in N,N-dimethylformamide (0.2–0.30 M) was added dropwise a clear solution of methylsulfamoyl chloride (2.50 equiv) in acetonitrile (anhydrous) (0.2 M). After complete addition, the resulting reaction mixture was allowed to warm to room temperature and stirred for 16 h. Water was added to the reaction mixture and the resulting suspension was stirred for 1 h. The suspension was filtered and washed with water and Et2O. The residue was dried to obtain the sulfamoyl group as a solid.

[0569] Compound D.8: A solution (0.06 M) of sulfonamide (1.0 equivalent) in tetrahydrofuran (dry) was cooled to -78 ° C under a nitrogen atmosphere and 1 M LiHMDS (3.00 equivalents) in THF was slowly added. After complete addition, the reaction mixture formed was diluted with some additional tetrahydrofuran (dry) in some cases and stirred for 30 min, allowing it to warm to 0 ° C. This was added dropwise to a solution (0.04 M) of NCS or NBS (1.20 equivalents) in tetrahydrofuran (dry) cooled (-78 ° C) via a cannula over 15 minutes. The reaction mixture formed was stirred at -78 ° C for 1 hour. At -78 ° C, the reaction mixture was quenched with 1 M HCl and warmed to room temperature. Some additional water was added and the product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the bromide or chloride as a solid.

[0570] Example 5

[0571] General Synthesis E

[0572]

[0573] Compound E.2: The bromide or chloride (1.0 eq) was suspended in methanol (0.10–0.20 M). Amine (1–10 eq) was added and the resulting reaction mixture was stirred at room temperature for 2–16 h. The reaction mixture was filtered and purified by preparative HPLC (method: acid preparative or base preparative) and then freeze-dried or Genevac TM The desired amine is then obtained as a solid.

[0574] Compound E.3: Dimethylamine E.2 (1.0 equiv) and pyridine (1.1-1.5 equiv) were dissolved in CHCl (0.2-0.8 M). Sulfonyl chloride (1.2-1.7 equiv) was added and the resulting reaction mixture was stirred at room temperature for 2-18 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography using the 'flash' method (CHCl / EtOAc = 1:0→6:4) to obtain the sulfamoyl group E.3 as a solid.

[0575] Compound E.4: A solution (0.06 M) of sulfonamide E.3 (1.0 equivalent) in tetrahydrofuran (dry) was cooled to -78 ° C under a nitrogen atmosphere and 1 M LiHMDS (1-3 equivalents) in THF was slowly added. After complete addition, the reaction mixture formed was diluted with some additional tetrahydrofuran (dry) and stirred for 30 min, allowing it to warm to 0 ° C. This was added dropwise to a solution (0.04 M) of NCS or NBS (1.2 equivalents) in tetrahydrofuran (dry) cooled (-78 ° C) via a cannula over 15 minutes. The reaction mixture formed was stirred at -78 ° C for 1 hour. At -78 ° C, the reaction mixture was quenched with 1M H2SO4 and warmed to room temperature. Some additional water was added and the product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the bromide or chloride E.4 as a solid.

[0576] Compound E.5: Bromide or chloride E.4 (1.0 eq) was suspended in methanol (0.10–0.20 M). Amine (1–10 eq) was added and the resulting reaction mixture was stirred at room temperature for 2–16 h. The reaction mixture was filtered and purified by preparative HPLC (method: acid preparative or base preparative) and then freeze-dried or Genevac TM The desired amine E.5 is then obtained as a solid.

[0577] Example 6

[0578] General Synthesis F

[0579]

[0580] Phenol F.1 (1.0 eq.) and potassium carbonate (2.0 eq.) were dissolved in DMF (0.03-0.2 M). Acid chloride (1.0 eq.) was added and stirred at room temperature for 1-18 hours. The reaction mixture was purified by preparative HPLC (method: "Prepare acid" or "Prepare base") and then freeze-dried or Genevac TM The desired F.2 was then obtained as a solid.

[0581] Example 7

[0582] General synthesis G

[0583]

[0584] Compound G.2: To a solution of G.1 (1.0 eq.) in DMF (0.1-0.2 M) was added the corresponding amine (1.5 eq.) and Et3N (2-5 eq.); each in a separate vial. The reaction mixture was stirred at room temperature for 2-18 h. The reaction mixture was then filtered and purified by preparative HPLC (method: preparative acid or preparative base) to prepare the product in Geneva. TM After evaporation in vacuo at 40° C., the desired product G.2 was obtained as a solid.

[0585] Example 8

[0586] Synthesis of compound 102

[0587]

[0588] Compound 102 was prepared in 5 steps:

[0589] Step 1: Starting from ethyl 2-(2-fluoro-3-nitrobenzyl)-3-oxobutanoate 3 (48.9 g, 173 mmol) and resorcinol (1.04 equiv), the synthesis was carried out according to the procedure of General Synthesis A. After filtration, the residue was stirred in saturated aqueous NaHCO3 solution until bubbling ceased. The suspension was filtered again, washed with water, Et2O, and dried to obtain the corresponding coumarin 5 as a yellow solid (50.3 g, 153 mmol, yield: 98%).

[0590] Step 2: Following the synthetic procedure of compound 4, the corresponding dimethylcarbamate 6 (70.7 g, 166 mmol, yield: 109%) was obtained as a yellow solid.

[0591] Step 3: According to the synthetic procedure of compound 5, Pd / C and EtOH / THF 1:2 (0.05 M) were used as solvent to obtain the corresponding primary amine 7 (50.83 g, 130 mmol, yield: 77%) as a pale pink solid.

[0592] Step 4: Following the procedure for compound 6, 35 g, 90 mmol of compound 7 was used as the starting material for synthesis. Methylsulfamoyl chloride was added at 2.5 equivalents to obtain the corresponding sulfamoyl group 8 (37.8 g, 76 mmol, yield: 84%) as a beige solid.

[0593] Step 5: Synthesized according to general procedure E using NBS except using 1N H2SO4 instead of 1N HCl to obtain the title compound as a white solid (23.9 g, 40.5 mmol, 56% yield).

[0594] Yield: The title compound was isolated as a white solid (40% over 5 steps).

[0595] Analysis: LCMS (Method U): t R =1.97min; [M+H2O] + Calcd. m / z = 559.0 / 561.0, found = 559.0 / 561.0.

[0596] Example 9

[0597] Synthesis of compound 7

[0598]

[0599] Compound 7 was prepared in 4 steps:

[0600] Step 1: Starting from ethyl 2-(2-fluoro-3-nitrobenzyl)-3-oxobutanoate (48.9 g, 173 mmol) and resorcinol (1.04 equiv), the compound 4 was synthesized according to the general synthesis method. After filtration, the residue was stirred in saturated aqueous NaHCO3 solution until bubbling stopped. The suspension was filtered again, washed with water, Et2O, and dried to obtain the corresponding coumarin 5 as a yellow solid (50.3 g, 153 mmol, yield: 98%).

[0601] Step 2: Synthesized according to the general synthesis of compound 5 to obtain the corresponding dimethylcarbamate (70.7 g, 166 mmol, yield: 109%) as a yellow solid.

[0602] Step 3: According to the general synthesis of compound 6, Pd / C and EtOH / THF 1:2 (0.05 M) were used as solvent to obtain the corresponding primary amine as a pale pink solid (50.83 g, 130 mmol, yield: 77%).

[0603] Step 4: According to the general synthesis of compound 7, 35 g, 90 mmol of 7 was used as the starting material for synthesis. Methylsulfamoyl chloride was added at 2.5 equivalents to obtain the title compound (37.8 g, 76 mmol, yield: 84%) as a beige solid.

[0604] Yield: The title compound was isolated as a beige solid (69% over 4 steps).

[0605] Analysis: LCMS (Method I): t R =1.98min; [M+H] +The calculated value of m / z = 464.1, the found value = 464.1; 1H NMR (400 MHz, CDCl3) δ 7.65–7.59 (m, 1H), 7.39 (td, J = 7.8, 1.7 Hz, 1H), 7.15–7.08 (m, 2H), 7.01 (t, J = 7.8 Hz, 1H), 6.95 (td, J = 7.9, 7.4, 1.8 Hz, 1H), 6.60 (d, J = 3.0 Hz, 1H), 4.44 (q, J = 5.4 Hz, 1H), 4.06 (s, 2H), 3.13 (s, 3H), 3.03 (s, 3H), 2.75 (d, J = 5.3 Hz, 3H), 2.44 (s, 3H).

[0606] Example 10

[0607] Synthesis of compound 9

[0608]

[0609] Compound 9 was prepared in 1 step:

[0610] Step 1: Starting with 4-(bromomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (22.22 g, 34.79 mmol) and 2 M dimethylamine in MeOH, the product was synthesized according to the general synthesis of compound E.2. After complete conversion, the reaction was concentrated under reduced pressure. 1 M HCl was added to the residue, and the aqueous layer was extracted with CHCl. The aqueous layer was made basic with solid NaCO. The basic aqueous layer was extracted with CHCl. The organic layer from the basic extraction was washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to obtain the title compound as a pale yellow solid (13.23 g, 25.7 mmol, 74% yield).

[0611] Yield: Compound 9 was isolated as a light yellow solid (74% over 1 step)

[0612] Analysis: LCMS (Method T): t R =1.53min; [MH] +The calculated value of m / z = 507.2, the found value = 507.2; 1H NMR (400 MHz, DMSO) δ 9.38 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.28 (td, J = 8.0, 1.6 Hz, 1H), 7.25–7.18 (m, 2H), 7.15 (dd, J = 8.8, 2.4 Hz, 1H), 7.00 (t, J = 7.9 Hz, 1H), 6.90–6.77 (m, 1H), 4.04 (s, 2H), 3.64 (s, 2H), 3.06 (s, 3H), 2.93 (s, 3H), 2.52 (d, J = 4.9 Hz, 3H), 2.19 (s, 6H).

[0613] Example 11

[0614] Synthesis of compound 10

[0615]

[0616] Compound 10 was prepared in 2 steps:

[0617] Step 1: Starting with 4-(bromomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (0.35 g, 0.59 mmol) and N-Boc piperazine, the synthesis was carried out according to the general synthesis of compound E.2, and NEt (1.0 equiv) was additionally added. The product was purified by preparative alkali. The desired fractions were combined and concentrated under reduced pressure to afford the amine as a colorless oil (0.414 g, 0.486 mmol, 82% yield, 76% purity).

[0618] Step 2: Amine was dissolved in 1,4-dioxane (3 mL), HCl (4 M, 16.7 eq, 2.0 mL, 8.00 mmol) in dioxane was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and co-evaporated with CH2Cl2 twice. The residue was dissolved in MeCN / water and lyophilized to obtain the title compound (304 mg, 0.49 mmol, yield: 102%) as a white solid.

[0619] Yield: Compound 10 was isolated as a white solid (84% over 2 steps).

[0620] Analysis: LCMS (Method S): t R =1.00min; [MH] +The calculated value of m / z = 548.2, the found value = 548.2; 1H NMR (400 MHz, DMSO) δ 9.37 (s, 1H), 8.88 (s, 2H), 8.09 (d, J = 8.8 Hz, 1H), 7.32–7.19 (m, 3H), 7.17 (dd, J = 8.9, 2.4 Hz, 1H), 7.00 (t, J = 7.8 Hz, 1H), 6.86–6.78 (m, 1H), 4.04 (s, 2H), 3.86 (s, 2H), 3.07 (s, 3H), 2.95 (d, J = 14.4 Hz, 7H), 2.73 (s, 4H), 2.54 (d, J = 2.8 Hz, 3H).

[0621] Example 12

[0622] Synthesis of compound 103

[0623]

[0624] Compound 103 was prepared in 5 steps:

[0625] Step 1: To a solution (0.1 M) of 3-(2-fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-2H-chromen-2-one (700 mg, 2.126 mmol, 1.0 equiv) and 2-bromopyrimidine (2467 mg, 15.52 mmol, 7.3 equiv) in N,N-dimethylformamide was added potassium carbonate (588 mg, 4.25 mmol, 2.00 equiv) at room temperature, and the resulting reaction mixture was stirred at 80° C. for 1 h. The solvent was evaporated under reduced pressure. Water was added and the product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The impure product was purified by column chromatography using the 'flash' method (heptane / EtOAc 4:1→1:4) to afford 3-(2-fluoro-3-nitrobenzyl)-4-methyl-7-(pyrimidin-2-yloxy)-2H-chromen-2-one (470 mg, 1.154 mmol, 51% yield) as a light yellow solid.

[0626] Step 2: To a suspension (0.11 M) of 3-(2-fluoro-3-nitrobenzyl)-4-methyl-7-(pyrimidin-2-yloxy)-2H-chromen-2-one (470 mg, 1.154 mmol, 1.0 equiv) in N,N-dimethylformamide (dried) was added tin(II) chloride dihydrate (1302 mg, 5.77 mmol, 5.00 equiv). The resulting reaction mixture was stirred at 70° C. for 1.5 h. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford 3-(3-amino-2-fluorobenzyl)-4-methyl-7-(pyrimidin-2-yloxy)-2H-chromen-2-one (430 mg, 1.026 mmol, 84% yield) as an orange oil.

[0627] Step 3: To a solution (0.1 M) of 3-(3-amino-2-fluorobenzyl)-4-methyl-7-(pyrimidin-2-yloxy)-2H-chromen-2-one (430 mg, 1.026 mmol, 1.0 equiv) and pyridine (0.373 ml, 4.61 mmol, 4.50 equiv) in N,N-dimethylformamide (dry) was added a solution of methylsulfamoyl chloride (0.203 ml, 2.359 mmol, 2.30 equiv) in acetonitrile (3 ml) at 0°C, and the resulting reaction mixture was stirred at room temperature for 2 hours. Water was added and the product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the sulfamoyl group (493 mg, 0.912 mmol, 89% yield) as an orange solid.

[0628] Step 4: Sulfonamide (30 mg, 0.064 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (dry) (0.04 M), purged with argon and cooled to -78 ° C. Then, LiHMDS (1 M in THF, 0.191 ml, 0.191 mmol, 3.00 equiv) was added and the mixture was stirred for 30 min. A solution of N-bromosuccinimide (13.62 mg, 0.077 mmol, 1.20 equiv) in tetrahydrofuran (dry) (0.5 ml) was added dropwise. The mixture was stirred at -78 ° C for 30 min. Water was added to the reaction mixture. The product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the bromide (30 mg, 0.034 mmol, yield: 53%) as an orange solid.

[0629] Step 5: Starting from bromide (0.02 g, 0.037 mmol) and piperazine, the synthesis was carried out according to General Procedure P with preparation of base to obtain the title compound (11.1 mg, 0.02 mmol, yield: 54%) as a white solid.

[0630] Yield: The title compound was isolated as a white solid (11% over 5 steps).

[0631] Analysis: LCMS (Method P): t R =1.12min; [MH] + Calculated value of m / z = 555.2, found = 555.2.

[0632] Example 13

[0633] Synthesis of compound 104

[0634]

[0635] Compound 104 was prepared in 2 steps:

[0636] Step 1: Sulfonamide, N-[3-fluoro-4-[[4-methyl-2-oxo-7-(2-pyrimidinyloxy)-2H-1-chromen-3-yl]methyl]-2-pyridinyl]-N'-methyl- (20 mg, 0.042 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (dry) (0.02 M), purged with argon and cooled to -78°C. Then, LiHMDS (1 M in THF, 0.169 ml, 0.169 mmol, 4.00 equiv) was added and the mixture was stirred for 30 min. A solution of N-bromosuccinimide (9 mg, 0.051 mmol, 1.20 equiv) in tetrahydrofuran (dry) (0.5 ml) was added dropwise. The mixture was stirred at -78°C for 30 min. 1 M HCl was added to the reaction mixture. The product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the bromide (27 mg, 0.028 mmol, yield: 66%) as an orange oil.

[0637] Step 2: Starting from bromide (0.02 g, 0.037 mmol) and piperazine, the title compound was synthesized according to the general synthesis of compound G.2 using a preparative base to obtain the title compound as a white solid (7.8 mg, 0.0140 mmol, yield: 38%).

[0638] Yield: The title compound was isolated as a white solid (25% over 2 steps).

[0639] Analysis: LCMS (Method P): t R =0.83min; [MH] + Calculated value of m / z = 556.2, found = 556.2.

[0640] Example 14

[0641] Synthesis of compound 105

[0642]

[0643] Compound 105 was prepared in 2 steps:

[0644] Step 1: 4-(Bromomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (0.3 g, 0.553 mmol, 1.0 equiv) was dissolved in ammonia (0.5 M in THF, 20 mL, 10.0 mmol, 18 equiv) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to give 4-(aminomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate hydrobromide (331 mg, 0.592 mmol, 107% yield) as an off-white solid.

[0645] Step 2: 4-(Aminomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate hydrobromide (40 mg, 0.072 mmol, 1.0 eq) was dissolved in CHCl (0.04 M). EtN (0.08 mL, 0.572 mmol, 8.0 eq) and trimethylsilyl isocyanate (0.077 mL, 0.572 mmol, 8.0 eq) were added and the resulting reaction mixture was stirred at room temperature for 18 hours. The product was purified by preparative acid to obtain the title compound (6.5 mg, 0.012 mmol, 17% yield) as a white solid after lyophilization.

[0646] Yield: Compound 105 was isolated as a white solid (18% over 2 steps)

[0647] Analysis: LCMS (Method T): t R =1.20min; [M+H] + Calculated value of m / z = 522.2, found = 522.4.

[0648] Example 15

[0649] Synthesis of compound 106

[0650]

[0651] Compound 106 was prepared in 3 steps:

[0652] Step 1: 4-(Bromomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (0.3 g, 0.553 mmol, 1.0 equiv) was dissolved in ammonia (0.5 M in THF, 20 mL, 10.0 mmol, 18 equiv) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to give 4-(aminomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate hydrobromide (331 mg, 0.592 mmol, 107% yield) as an off-white solid.

[0653] Step 2: To a solution of 4-(aminomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate hydrobromide (40 mg, 0.072 mmol, 1.0 equiv) and 2-((tert-butyldimethylsilyl)oxy)ethyl(4-nitrophenyl)carbonate (31.7 mg, 0.093 mmol, 1.3 equiv) in N,N-dimethylformamide (dried) (2 mL) was added triethylamine (0.030 mL, 0.215 mmol, 3.0 equiv), and the resulting reaction mixture was stirred at room temperature for 3 days. The mixture was diluted with EtOAc and water, the layers were separated, and the aqueous layer was extracted once with EtOAc. The combined organic layers were washed twice with water and brine, dried over Na2SO4, and concentrated. Water was added to the reaction mixture. The product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The impure product was purified by column chromatography using the 'flash' method (heptane / EtOAc 4:1→1:4) to afford 3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-4-(8,8,9,9-tetramethyl-3-oxo-4,7-dioxa-2-aza-8-silandecyl)-2H-chromen-7-yl dimethylcarbamate (25 mg, 0.033 mmol, 46% yield) as a white solid.

[0654] Step 3: To a solution of 3-(2-fluoro-3-(N-methylsulfamoyl)amino)benzyl)-2-oxo-4-(8,8,9,9-tetramethyl-3-oxo-4,7-dioxa-2-aza-8-silandecyl)-2H-chromen-7-yl dimethylcarbamate (25 mg, 0.037 mmol, 1.0 equiv) in tetrahydrofuran (0.5 mL) was added hydrochloric acid (4 N in dioxane, 0.092 mL, 0.367 mmol, 10 equiv) and the resulting reaction mixture was stirred at room temperature for 30 minutes. The product was purified by preparative base to afford the title compound as a white solid after lyophilization (9.6 mg, 0.017 mmol, 46% yield).

[0655] Yield: The title compound was isolated as a white solid (23% over 3 steps).

[0656] Analysis: LCMS (Method T): t R =1.25min; [M+H] + The calculated value of m / z = 567.2, the found value = 567.4; 1H NMR (400 MHz, DMSO) δ 9.38 (s, 1H), 7.94 (d, J = 8.9 Hz, 1H), 7.85 (t, J = 5.7 Hz, 1H), 7.32–7.22 (m, 2H), 7.19 (dd, J = 8.8, 2.4 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 6.81 (s, 1H), 4.71 (t, J = 5.3 Hz, 1H), 4.41 (d, J = 5.6 Hz, 2H), 4.12 (s, 2H), 3.96 (t, J = 5.1 Hz, 2H), 3.50 (q, J = 5.2 Hz, 2H), 3.07 (s, 3H), 2.93 (s, 3H).

[0657] Example 16

[0658] Synthesis of compound 107

[0659]

[0660] Compound 107 was prepared in 1 step:

[0661] Step 1: Starting from 3-(3-amino-2-fluorobenzyl)-4-methyl-2-oxo-2H-chromen-7-yl dimethylcarbamate (0.1 g, 0.27 mmol) and ethanesulfonyl chloride, the product was synthesized according to the general synthesis of E.3 to obtain the title compound (46.8 mg, 0.10 mmol, yield: 37%) as a white solid.

[0662] Yield: Compound 107 was isolated as a white solid (37% over 1 step)

[0663] Analysis: LCMS (Method R): t R =1.57min; [M+H2O] + The calculated value of m / z = 480.2, the found value = 480.1; 1H NMR (400 MHz, DMSO) δ 9.60 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.29–7.22 (m, 2H), 7.19 (dd, J = 8.8, 2.3 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 6.95 (td, J = 7.9, 7.5, 1.7 Hz, 1H), 3.99 (s, 2H), 3.15–3.02 (m, 5H), 2.93 (s, 3H), 2.45 (s, 3H), 1.26 (t, J = 7.4 Hz, 3H).

[0664] Example 17

[0665] Synthesis of compound 108

[0666]

[0667] Compound 108 was prepared in 4 steps:

[0668] Step 1: Starting from ethyl 2-(2-fluoro-3-nitrobenzyl)-3-oxobutanoate (1.0 g, 3.53 mmol) and 4-methylbenzene-1,3-diol (1.20 equivalents), the corresponding coumarin (1.32 g, 3.68 mmol, yield: 104%) was obtained as an off-white solid according to the general synthesis of compound 4.

[0669] Step 2: The general synthetic procedure of compound 5 was followed to obtain the corresponding dimethylcarbamate (0.91 g, 2.06 mmol, yield: 54%) as a pale yellow solid.

[0670] Step 3: Synthesize according to the general synthesis of compound 6. After filtration, the product was purified by column chromatography using the 'flash' method (CH2Cl2 / MeOH=1:0→95:5) to obtain the corresponding primary amine (0.54 g, 0.79 mmol, purity: 56%, yield: 35%) as a light yellow solid.

[0671] Step 4: Synthesized according to the general synthesis of compound 7. After filtration, 576 mg of impure compound was obtained. 50 mg was further purified by preparative LC (basic) to obtain the title compound (13.2 mg, 0.027 mmol, yield: 66%) as a white solid after freeze-drying.

[0672] Yield: Compound 108 was isolated as a white solid (13% over 4 steps)

[0673] Analysis: LCMS (Method T): t R =1.58min; [MH] + The calculated value of m / z = 476.1, the found value = 476.2; 1H NMR (400 MHz, DMSO) δ 9.38 (s, 1H), 7.76 (s, 1H), 7.30–7.24 (m, 1H), 7.22 (s, 1H), 7.13 (s, 1H), 6.99 (t, J = 7.9 Hz, 1H), 6.82 (t, J = 7.2 Hz, 1H), 3.96 (s, 2H), 3.09 (s, 3H), 2.94 (s, 3H), 2.44 (s, 3H), 2.23 (s, 3H).

[0674] Example 18

[0675] Synthesis of compound 109

[0676]

[0677] Compound 109 was prepared in 4 steps:

[0678] Step 1: Starting from ethyl 2-(2-fluoro-3-nitrobenzyl)-3-oxobutanoate 3 (1.0 g, 3.53 mmol) and 4-chlorobenzene-1,3-diol (1.20 equiv.), the product was synthesized according to the general synthesis of compound 4 to obtain the corresponding coumarin 5 (0.95 g, 2.57 mmol, yield: 73%) as an off-white solid.

[0679] Step 2: The general synthetic procedure of compound 5 was followed to obtain the corresponding dimethylcarbamate (0.88 g, 1.95 mmol, yield: 75%) as a pale yellow solid.

[0680] Step 3: According to the general synthetic procedure of compound 6, the corresponding primary amine was obtained as a light yellow solid (0.51 g, 1.22 mmol, yield: 60%).

[0681] Step 4: The general synthetic procedure of compound 7 was followed to obtain: 588 mg of impure compound was obtained after filtration. 50 mg was further purified by preparative LC (basic) to obtain the title compound (28.9 mg, 0.027 mmol, yield: 44%) as a white solid after freeze-drying.

[0682] Yield: Compound 109 was isolated as a white solid (14% over 4 steps).

[0683] Analysis: LCMS (Method T): t R =1.63min; [MH] + The calculated value of m / z = 496.1, the found value = 496.2; 1H NMR (400 MHz, DMSO) δ 9.40 (s, 1H), 8.03 (s, 1H), 7.50 (s, 1H), 7.28 (td, J = 7.9, 1.8 Hz, 1H), 7.10 (s, 1H), 6.98 (t, J = 7.9 Hz, 1H), 6.84 (t, J = 7.0 Hz, 1H), 3.97 (s, 2H), 3.10 (s, 3H), 2.95 (s, 3H), 2.45 (s, 3H).

[0684] Example 19

[0685] Synthesis of compound 19

[0686]

[0687] Compound 19 was prepared in 1 step:

[0688] Step 1: Starting with 4-(bromomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (23.9 g, 44.1 mmol) and azetidine, the product was synthesized according to the general synthetic procedure of compound E.2, and DIPEA (2.0 equivalents) was added during the reaction. After complete conversion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography using the 'flash' method (heptane / EtOAc=1:0→0:1). The desired fractions were combined and concentrated under reduced pressure to obtain the title compound (11.8 g, 22.17 mmol, 50% yield) as an off-white solid.

[0689] Yield: Compound 19 was isolated as an off-white solid (50% over 1 step).

[0690] Analysis: LCMS (Method T): t R =1.53min; [MH] +The calculated value of m / z = 519.2, the found value = 519.2; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.8 Hz, 1H), 7.38 (td, J = 7.8, 1.6 Hz, 1H), 7.15–7.03 (m, 2H), 6.99 (t, J = 8.1 Hz, 1H), 6.86 (t, J = 7.7 Hz, 1H), 6.68 (s, 1H), 4.58 (q, J = 5.3 Hz, 1H), 4.15 (s, 2H), 3.60 (s, 2H), 3.12 (s, 3H), 3.03 (s, 3H), 2.73 (d, J = 5.3 Hz, 3H), 2.26 (s, 6H).

[0691] Example 20

[0692] Synthesis of compound 21

[0693]

[0694] Compound 21 was prepared in 1 step:

[0695] Step 1: Starting from 6-chloro-4-(chloromethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (50 mg, 0.094 mmol) and piperazine, the synthesis was carried out according to the general synthesis of compound E.2. The impure product was combined with other batches and purified by preparative base to give the title compound as a white solid after freeze-drying (22 mg, 0.037 mmol, 39% yield).

[0696] Yield: Compound 21 was isolated as a white solid (65% over 1 step).

[0697] Analysis: LCMS (Method R): t R =1.43min; [M+H] + The calculated value of m / z = 582.2, the found value = 582.2; 1H NMR (400 MHz, DMSO) δ 8.30 (s, 1H), 8.27 (s, 1H), 7.48 (s, 1H), 7.31–7.19 (m, 2H), 6.99 (t, J = 7.9 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 4.03 (s, 2H), 3.70 (s, 2H), 3.10 (s, 3H), 2.95 (s, 3H), 2.64 (t, J = 4.6 Hz, 4H), 2.53 (d, J = 2.9 Hz, 3H), 2.40 (s, 4H).

[0698] Example 21

[0699] Synthesis of compound 110

[0700]

[0701] Compound 110 was prepared in 4 steps:

[0702] Step 1: Starting from ethyl 2-((2-chloro-3-fluoropyridin-4-yl)methyl)-3-oxobutanoate (1.18 g, 4.31 mmol) and 4-methylbenzene-1,3-diol (1.20 equiv), the compound D.4 was synthesized according to the general synthetic procedure. After the reaction was completed, water was added and the resulting suspension was filtered. The residue was co-evaporated with Et2O. The residue was dried under reduced pressure at 40 ° C overnight to obtain the corresponding coumarin (1.7 g, 4.53 mmol, yield: 105%, purity: 89%) as a beige solid.

[0703] Step 2: The general synthetic procedure of compound D.5 was followed to obtain the corresponding dimethylcarbamate (1.94 g, 4.32 mmol, yield: 95%, purity: 90%) as a beige solid.

[0704] Step 3: Compound D.6 was synthesized using the general synthetic procedure of compound D.5 (0.9 g, 2.22 mmol). Deprotection with TFA was not performed. The reaction mixture was filtered and concentrated under reduced pressure. The impure product was combined with another batch and purified by column chromatography using the 'Flash' method (CHCl / MeOH 1:0→94:6) to obtain the corresponding primary amine D.6 (0.22 g, 0.303 mmol, 14% yield, 53% purity) as a brown solid.

[0705] Step 4: synthesize according to the general synthesis procedure of compound D.7. After complete conversion, the reaction mixture is quenched with water and the product is extracted with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The impure product is diluted with CH2Cl2 and purified by column chromatography with 'fast' method (CH2Cl2 / MeOH 1:0→96:4) to obtain 141mg of yellow oil. 25mg of the impure product is purified by preparing alkali to obtain the title compound (13.7mg, 0.029mmol, yield: 59%) as a white solid after lyophilization.

[0706] Yield: Compound 110 was isolated as a white solid (8% over 4 steps).

[0707] Analysis: LCMS (Method T): t R=1.58min; [MH] + The calculated value of m / z = 479.1, the found value = 479.2; 1H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 7.89 (s, 1H), 7.78 (s, 1H), 7.23 (s, 1H), 6.94 (s, 1H), 6.77 (s, 1H), 4.00 (s, 2H), 3.10 (s, 3H), 2.94 (s, 3H), 2.46 (s, 3H), 2.23 (s, 3H).

[0708] Example 22

[0709] Synthesis of compound 111

[0710]

[0711] Compound 111 was prepared in 4 steps:

[0712] Step 1: Starting from ethyl 2-((2-chloro-3-fluoropyridin-4-yl)methyl)-3-oxobutanoate (15.0 g, 46.0 mmol) and 4-chlorobenzene-1,3-diol (1.20 equivalents), the product was synthesized according to the general synthetic procedure of compound D.4. After the reaction was completed, water was added and the resulting suspension was filtered. The residue was co-evaporated with EtOH and triturated in EtOH / Et2O. The solid was filtered off to obtain the corresponding coumarin (4.8 g, 13.55 mmol, yield: 29%) as a white solid.

[0713] Step 2: The general synthetic procedure of compound D.5 was followed to obtain the corresponding dimethylcarbamate (5.48 g, 11.86 mmol, yield: 87%, purity: 92%) as a pale yellow solid.

[0714] Step 3: Compound D.6 was synthesized starting from 1.0 g, 2.35 mmol of compound D.5 according to the general synthetic procedure. Deprotection with TFA was not performed. The reaction mixture was filtered and concentrated under reduced pressure. The impure product was purified by column chromatography using the 'flash' method (heptane / EtOAc 9:1→1:4) to obtain the corresponding primary amine (0.12 g, 0.281 mmol, 12% yield) as a beige solid.

[0715] Step 4: According to the general synthetic procedure of compound D.7, 400 mg and 0.789 mmol of primary amine were used as starting materials for synthesis. After complete conversion, the reaction mixture was quenched with water. The product was extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The impure product was purified by column chromatography using a 'fast' method (CH2Cl2 / MeOH1:0→96:4). The impure product was purified with preparative base to obtain the title compound (27.5 mg, 0.054 mmol, yield: 7%) as a white solid after lyophilization.

[0716] Yield: Compound 111 was isolated as a white solid (0.2% over 4 steps).

[0717] Analysis: LCMS (Method T): t R =1.20min; [M+H] + The calculated value of m / z = 499.1, the found value = 499.2; 1H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 8.04 (s, 1H), 7.95–7.86 (m, 1H), 7.51 (s, 1H), 6.95 (s, 1H), 6.81 (s, 1H), 4.01 (s, 2H), 3.11 (s, 3H), 2.95 (s, 3H), 2.47 (s, 3H).

[0718] Example 23

[0719] Synthesis of compound 112

[0720]

[0721] Compound 112 was prepared in 3 steps:

[0722] Step 1: Starting from ethyl 2-((2-chloro-3-fluoropyridin-4-yl)methyl)-3-oxobutanoate (10.0 g, 24.12 mmol) and resorcinol (2.00 equiv), the synthesis was carried out according to the general synthesis of compound D.4. Sulfuric acid was used instead of perchloric acid. After complete conversion, the reaction mixture was cooled (0 ° C) and quenched with saturated aqueous NaHCO3 solution until alkaline pH. The white suspension formed was washed with water, Et2O and dried to obtain the corresponding coumarin (8.61 g, 23.4 mmol, yield: 97%, purity: 87%) as an off-white solid.

[0723] Step 2: The general synthetic procedure of compound D.5 was followed to obtain the corresponding dimethylcarbamate (9.33 g, 23.16 mmol, yield: 99%) as a beige solid.

[0724] Step 3: To a 0.1 M solution of dimethylcarbamate (200 mg, 0.512 mmol, 1.0 eq) and cyclopropanesulfonamide (93 mg, 0.768 mmol, 1.5 eq) in 1,4-dioxane (ultra dry) was added Xantphos (59.2 mg, 0.102 mmol, 0.2 eq), cesium carbonate (250 mg, 0.768 mmol, 1.5 eq), and PdOAc (11.49 mg, 0.051 mmol, 0.1 eq) under N2 atmosphere. The resulting reaction mixture was stirred at 100 ° C for 16 hours. The reaction mixture was filtered through a plug of celite, eluting with CHCl. The filtrate was concentrated and purified by column chromatography using the 'flash' method (CHCl / EtOAc = 1:0 → 6:4). The impure product was further purified by preparative base to afford the title compound as a white solid after lyophilization (89 mg, 0.208 mmol, yield: 41%).

[0725] Yield: Compound 112 was isolated as a white solid (39% over 3 steps).

[0726] Analysis: LCMS (Method R): t R =1.43min; [M+H] + The calculated value of m / z = 476.1, the found value = 476.2; 1H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 7.94 (d, J = 5.1 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 2.3 Hz, 1H)), 7.20 (dd, J = 8.8, 2.4 Hz, 1H), 6.88 (d, J = 6.0 Hz, 1H), 4.02 (s, 2H), 3.17 (s, 1H), 3.07 (s, 3H), 2.93 (s, 3H), 2.48 (s, 3H), 1.16–0.93 (m, 4H).

[0727] Example 24

[0728] Synthesis of compound 113

[0729]

[0730] Compound 113 was prepared in 1 step:

[0731] Step 1: Starting from 3-(3-amino-2-fluorobenzyl)-4-methyl-2-oxo-2H-chromen-7-yl dimethylcarbamate (0.1 g, 0.27 mmol) and cyclopropanesulfonyl chloride, the product was synthesized according to the general synthesis of E.3 to obtain the title compound as a white solid (71.4 mg, 0.15 mmol, yield: 56%).

[0732] Yield: Compound 113 was isolated as a white solid (56% over 1 step).

[0733] Analysis: LCMS (Method R): t R =1.58min; [M+H2O] + The calculated value of m / z = 492.4, the found value = 492.1; 1H NMR (400 MHz, DMSO) δ 9.58 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.31–7.22 (m, 2H), 7.19 (dd, J = 8.7, 2.3 Hz, 1H), 7.09–6.94 (m, 2H), 3.99 (s, 2H), 3.07 (s, 3H), 2.93 (s, 3H), 2.64 (tt, J = 7.9, 4.8 Hz, 1H), 2.45 (s, 3H)), 1.00–0.80 (m, 4H).

[0734] Example 25

[0735] Synthesis of compound 114

[0736]

[0737] Compound 114 was prepared in 3 steps:

[0738] Step 1: Starting from ethyl 2-((2-chloro-3-fluoropyridin-4-yl)methyl)-3-oxobutanoate (10.0 g, 24.12 mmol) and resorcinol (2.00 equiv), the synthesis was carried out according to the general synthesis of compound D.4. Sulfuric acid was used instead of perchloric acid. After complete conversion, the reaction mixture was cooled (0 ° C) and quenched with saturated aqueous NaHCO3 solution until alkaline pH. The white suspension formed was washed with water, Et2O and dried to obtain the corresponding coumarin (8.61 g, 23.4 mmol, yield: 97%, purity: 87%) as an off-white solid.

[0739] Step 2: The general synthetic procedure of compound D.5 was followed to obtain the corresponding dimethylcarbamate (9.33 g, 23.16 mmol, yield: 99%) as a beige solid.

[0740] Step 3: To a 0.1 M solution of dimethylcarbamate (100 mg, 0.256 mmol, 1.0 eq) and isopropylsulfonamide (47 mg, 0.384 mmol, 1.5 eq) in 1,4-dioxane (ultra-dry) was added Xantphos (29.6 mg, 0.051 mmol, 0.2 eq), cesium carbonate (125 mg, 0.384 mmol, 1.5 eq), and PdOAc (5.7 mg, 0.026 mmol, 0.1 eq) under N2 atmosphere. The resulting reaction mixture was stirred at 100 ° C for 16 hours. The reaction mixture was filtered through a plug of celite, eluting with CHCl. The filtrate was concentrated and purified by column chromatography using the 'flash' method (CHCl / EtOAc = 1:0 → 6:4). The impure product was further purified by preparative base to afford the title compound as a white solid after lyophilization (37 mg, 0.077 mmol, yield: 30%).

[0741] Yield: Compound 114 was isolated as a white solid (29% over 3 steps).

[0742] Analysis: LCMS (Method R): t R =1.47min; [M+H] + The calculated value of m / z = 478.1, the found value = 478.2; 1H NMR (400 MHz, DMSO) δ 10.49 (s, 1H), 8.05–7.82 (m, 2H), 7.27 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.8, 2.3 Hz, 1H), 6.88 (s, 1H), 4.08–3.86 (m, 3H), 3.07 (s, 3H), 2.93 (s, 3H), 2.47 (s, 3H), 1.31 (d, J = 6.8 Hz, 6H).

[0743] Example 26

[0744] Synthesis of compound 115

[0745]

[0746] Compound 115 was prepared in 1 step:

[0747] Step 1: Starting with 3-(3-amino-2-fluorobenzyl)-4-methyl-2-oxo-2H-chromen-7-yl dimethylcarbamate (0.1 g, 0.27 mmol) and 2-propanesulfonyl chloride, the product was synthesized according to the general synthesis of compound E.3. The reaction took 3 days, and the product was purified by column chromatography using the 'flash' method (CH2Cl2 / EtOAc = 1:0 → 6:4) to obtain the title compound (35.8 mg, 0.074 mmol, 27% yield) as a white solid.

[0748] Yield: Compound 115 was isolated as a white solid (27% over 1 step).

[0749] Analysis: LCMS (Method R): t R =1.62min; [M+H] + The calculated value of m / z = 477.1, the found value = 477.2; 1H NMR (400 MHz, DMSO) δ 9.58 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.31–7.22 (m, 2H), 7.19 (dd, J = 8.8, 2.3 Hz, 1H), 7.02 (t, J = 7.9 Hz, 1H), 6.97–6.88 (m, 1H), 3.98 (s, 2H), 3.22 (p, J = 6.8 Hz, 1H), 3.07 (s, 3H), 2.93 (s, 3H), 2.45 (s, 3H), 1.27 (d, J = 6.8 Hz, 6H).

[0750] Example 27

[0751] Synthesis of compound 116

[0752]

[0753] Compound 116 was prepared in 1 step:

[0754] Step 1: Starting from 4-(bromomethyl)-6-chloro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (45 mg, 0.075 mmol, purity: 40%) and N-methylbenzylamine, the product was synthesized according to the general synthesis of compound E.2, and Net3 (3.0 equivalents) was added. The product was purified by preparative base to obtain the title compound as a white solid after freeze-drying (12.8 mg, 0.021 mmol, yield: 66%).

[0755] Yield: Compound 116 was isolated as a white solid (66% over 1 step).

[0756] Analysis: LCMS (Method T): t R =1.98min; [M+H] + The calculated value of m / z = 617.2 / 619.2, the found value = 617.4 / 619.4; 1H NMR (400 MHz, DMSO) δ 9.41 (s, 1H), 8.25 (s, 1H), 7.47 (s, 1H), 7.37–7.21 (m, 6H), 7.15 (s, 1H), 6.97 (t, J = 7.9 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 4.05 (s, 2H), 3.76 (s, 2H), 3.56 (s, 2H), 3.11 (s, 3H), 2.95 (s, 3H), 2.52 (d, J = 4.0 Hz, 3H), 2.06 (s, 3H).

[0757] Example 28

[0758] Synthesis of compound 117

[0759]

[0760] Compound 117 was prepared in 1 step:

[0761] Step 1: Starting from 4-(bromomethyl)-6-chloro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (45 mg, 0.075 mmol, purity: 40%) and N-methylpropylamine, the synthesis was carried out according to the general synthesis of compound E.2, and Net3 (3.0 equivalents) was added. The product was purified by preparing the base and then the acid to obtain the title compound (3.8 mg, 0.007 mmol, yield: 21%) as a white solid after freeze-drying.

[0762] Yield : Compound 117 was isolated as a white solid (21% over 1 step).

[0763] analyze : LCMS (Method T): t R =1.94min; [M+H] +m / z calculated = 569.2 / 571.2, found = 569.4 / 571.4; 1H NMR (400MHz, DMSO) δ9.41(s,1H),8.29(s,1H),7.48(s,1H),7.28(t,J=7.7Hz,1H),7.15(s,1H),6.98(t,J=7.9Hz,1H),6.81(t,J=7.2Hz,1H),4. 04(s,2H),3.71(s,2H),3.10(s,3H),2.95(s,3H),2.52(s,3H),2.35(t, J=7.0Hz,2H),2.06(s,3H),1.44(h,J=7.3Hz,2H),0.82(t,J=7.3Hz,3H).

[0764] Example 29

[0765] Synthesis of compound 118

[0766]

[0767] Compound 117 was prepared in 1 step:

[0768] Step 1: Starting from 3-(3-amino-2-fluorobenzyl)-4-methyl-2-oxo-2H-chromen-7-yl dimethylcarbamate (0.1 g, 0.27 mmol) and cyclobutanesulfonyl chloride, the product was synthesized according to the general synthesis of compound E.3. The reaction mixture was purified by the 'preparative base' method to obtain the title compound (8.0 mg, 0.016 mmol, 6% yield) as a white solid after lyophilization.

[0769] Yield: Compound 117 was isolated as a white solid (6% over 1 step).

[0770] Analysis: LCMS (Method R): t R =1.65min; [M+H] + The calculated value of m / z = 489.1, the found value = 489.4; 1H NMR (400 MHz, DMSO) δ 9.51 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.28–7.15 (m, 3H), 7.06–6.88 (m, 2H), 3.98 (s, 2H), 3.90 (p, J = 8.2 Hz, 1H), 3.07 (s, 3H), 2.93 (s, 3H), 2.45 (s, 3H), 2.36–2.13 (m, 4H), 1.97–1.80 (m, 2H).

[0771] Example 30

[0772] Synthesis of compound 119

[0773]

[0774] Compound 119 was prepared in 1 step:

[0775] Step 1: Starting with 3-(2-amino-3-fluoropyridin-4-ylmethyl)-4-methyl-2-oxo-2H-chromen-7-yl dimethylcarbamate (0.05 g, 0.135 mmol) and ethanesulfonyl chloride, the product was synthesized according to the general synthesis of compound E.3. The reaction mixture was purified by the 'preparative base' method to give the title compound (3.6 mg, 0.007 mmol, 6% yield) as a white solid after lyophilization.

[0776] Yield: Compound 119 was isolated as a white solid (6% over 1 step).

[0777] Analysis: LCMS (Method R): t R =1.42min; [M+H] + The calculated value of m / z = 464.1, the found value = 464.2; 1H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 8.01–7.80 (m, 2H), 7.27 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.8, 2.4 Hz, 1H), 6.88 (s, 1H), 4.02 (s, 2H), 3.63–3.42 (m, 2H), 3.07 (s, 3H), 2.93 (s, 3H), 2.47 (s, 3H), 1.26 (t, J = 7.4 Hz, 3H).

[0778] Example 31

[0779] Synthesis of compound 120

[0780]

[0781] Compound 120 was prepared in 3 steps:

[0782] Step 1: Starting from 3-(3-amino-2-fluorobenzyl)-4-methyl-2-oxo-2H-chromen-7-yl dimethylcarbamate (0.516 g, 1.115 mmol) and ethanesulfonyl chloride, the product was synthesized according to the general synthesis of compound E.3 to obtain sulfamoyl as a white solid (320 mg, 0.678 mmol, yield: 61%).

[0783] Step 2: Synthesized using NBS according to the general synthetic procedure for compound E.4. After extraction, the impure product was purified by column chromatography using the 'flash' method (heptane / EtOAc = 1:0 → 0:1) to obtain the corresponding bromide compound (324 mg, 0.53 mmol, yield: 79%, purity: 89%) as a white solid.

[0784] Step 3: According to the general synthetic procedure of compound E.5, 10 mg, 0.016 mmol of bromide compound and 2M dimethylamine in MeOH were used as starting materials to synthesize. The impure product was purified by preparing a base and then by SFC CEL-2 gradient to obtain the title compound (2.8 mg, 0.005 mmol, yield: 33%) as a white solid.

[0785] Yield: Compound 120 was isolated as a white solid (16% over 3 steps).

[0786] Analysis: LCMS (Method T): t R =1.61min; [M+H] + The calculated value of m / z = 506.2, the found value = 506.4; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.8 Hz, 1H), 7.44 (td, J = 7.7, 1.2 Hz, 1H), 7.14–7.05 (m, 2H), 7.01 (t, J = 7.9 Hz, 1H), 6.90 (t, J = 7.2 Hz, 1H), 6.49–6.43 (m, 1H), 4.16 (s, 2H), 3.60 (s, 2H), 3.16 (q, J = 7.4 Hz, 3H), 3.13 (s, 2H), 3.04 (s, 3H), 2.27 (s, 6H), 1.40 (t, J = 7.4 Hz, 3H).

[0787] Example 32

[0788] Synthesis of compound 121

[0789]

[0790] Compound 121 was prepared in 1 step:

[0791] Step 1: Starting from phenol (20 mg, 0.046 mmol) and 4-morpholinecarbonyl chloride, the compound was synthesized according to the general synthesis of compound F.2. Purification was performed using the 'preparative base' method to obtain the title compound (16 mg, 0.029 mmol, 64% yield) as a white solid after lyophilization.

[0792] Yield: Compound 121 was isolated as a white solid (64% over 1 step).

[0793] Analysis: LCMS (Method P): t R =1.39min; [M+H] + The calculated value of m / z = 549.2, the found value = 549.1; 1H NMR (400MHz, CDCl3) δ8.03 (d, J=8.8Hz, 1H), 7.39 (td, J=7.9, 1.6Hz, 1H), 7.1 4–7.05(m,2H),7.00(td,J=8.0,1.2Hz,1H),6.92–6.84(m,1H),6.61(d,J=3.2 Hz,1H),4.43(t,J=5.3Hz,1H),4.15(s,2H),3.77(dd,J=5.5,4.0Hz,4H),3.70 (d, J = 7.4Hz, 2H), 3.60 (d, J = 12.2Hz, 4H), 2.76 (d, J = 5.3Hz, 3H), 2.28 (s, 6H).

[0794] Example 33

[0795] Synthesis of compound 122

[0796]

[0797] Compound 122 was prepared in 1 step:

[0798] Step 1: Starting from phenol (20 mg, 0.046 mmol) and 4-morpholinecarbonyl chloride, the compound was synthesized according to the general synthesis of compound F.2. Purification was performed using the 'preparative base' method to obtain the title compound (16 mg, 0.029 mmol, 64% yield) as a white solid after lyophilization.

[0799] Yield: Compound 122 was isolated as a white solid (64% over 1 step).

[0800] Analysis: LCMS (Method P): t R =1.39min; [M+H] +The calculated value of m / z = 549.2, the found value = 549.1; 1H NMR (400MHz, CDCl3) δ8.03 (d, J=8.8Hz, 1H), 7.39 (td, J=7.9, 1.6Hz, 1H), 7.1 4–7.05(m,2H),7.00(td,J=8.0,1.2Hz,1H),6.92–6.84(m,1H),6.61(d,J=3.2 Hz,1H),4.43(t,J=5.3Hz,1H),4.15(s,2H),3.77(dd,J=5.5,4.0Hz,4H),3.70 (d, J = 7.4Hz, 2H), 3.60 (d, J = 12.2Hz, 4H), 2.76 (d, J = 5.3Hz, 3H), 2.28 (s, 6H).

[0801] Example 34

[0802] Synthesis of compound 123

[0803]

[0804] Compound 123 was prepared in 1 step.

[0805] Step 1: Starting with the general synthesis procedure, D.4 (155 mg, 0.356 mmol) was dissolved in MeCN (1.8 mL) and DMAP (130 mg, 1.07 mmol, 3 equiv) and dimethylthiocarbamoyl chloride (66 mg, 0.53 mmol, 1.5 equiv) was added. The mixture was stirred at room temperature overnight and at 40 °C for 4 h. The reaction was purified as is using the "preparative acid" method to afford the title compound (163 mg, 0.31 mmol, 86% yield) as a white solid after lyophilization.

[0806] Analysis: LCMS (Method R): t R =0.951min; [MH] + The calculated value of m / z = 523.2, the found value = 523.4; 1H NMR (400 MHz, DMSO) δ 9.38 (s, 1H), 8.08 (d, J = 8.9 Hz, 1H), 7.33–7.16 (m, 3H), 7.11 (dd, J = 8.8, 2.4 Hz, 1H), 7.00 (t, J = 7.9 Hz, 1H), 6.84 (t, J = 7.1 Hz, 1H), 4.05 (s, 2H), 3.65 (s, 2H), 3.41–3.30 (m, 6H), 2.55–2.52 (m, 3H), 2.20 (s, 6H).

[0807] Example 35

[0808] Synthesis of compound 124

[0809]

[0810] Compound 124 was prepared in 1 step:

[0811] Step 1: Starting from 4-(chloromethyl)-3-((3-fluoro-2-((N-methylsulfamoyl)amino)pyridin-4-yl)methyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (390 mg, 0.391 mmol, purity: 50%) and 2M dimethylamine in MeOH, the synthesis was carried out according to the general synthesis of compound E.2. The product was purified by the "preparative acid" method to give the title compound as an off-white solid after lyophilization (80 g, 0.155 mmol, yield: 40%).

[0812] Yield: Compound 124 was isolated as an off-white solid (40% over 1 step).

[0813] Analysis: LCMS (Method R): t R =0.80min; [MH] + The calculated value of m / z = 508.2, the found value = 508.4; 1H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 8.09 (d, J = 8.9 Hz, 1H), 7.90 (d, J = 5.1 Hz, 1H), 7.24 (d, J = 2.3 Hz, 1H), 7.16 (dd, J = 8.8, 2.4 Hz, 1H), 6.96 (s, 1H), 6.79 (t, J = 5.1 Hz, 1H), 4.07 (s, 2H), 3.66 (s, 2H), 3.07 (s, 3H), 2.93 (s, 3H), 2.20 (s, 6H).

[0814] Example 36

[0815] Synthesis of compound 125

[0816]

[0817] Compound 125 was prepared in 3 steps:

[0818] Step 1: Starting from ethyl 2-((2-chloro-3-fluoropyridin-4-yl)methyl)-3-oxobutanoate (10.0 g, 24.12 mmol) and resorcinol (2.00 equiv), the synthesis was carried out according to the general synthesis of compound D.4. Sulfuric acid was used instead of perchloric acid. After complete conversion, the reaction mixture was cooled (0 ° C) and quenched with saturated aqueous NaHCO3 solution until alkaline pH. The white suspension formed was washed with water, Et2O and dried to obtain the corresponding coumarin (8.61 g, 23.4 mmol, yield: 97%, purity: 87%) as an off-white solid.

[0819] Step 2: The general synthetic procedure of compound D.5 was followed to obtain the corresponding dimethylcarbamate (9.33 g, 23.16 mmol, yield: 99%) as a beige solid.

[0820] Step 3: To a solution (0.1 M) of dimethylcarbamate (200 mg, 0.512 mmol, 1.0 eq) and cyclobutanesulfonamide (104 mg, 0.768 mmol, 1.5 eq) in 1,4-dioxane (ultra dry) were added Xantphos (59.2 mg, 0.102 mmol, 0.2 eq), cesium carbonate (250 mg, 0.768 mmol, 1.5 eq) and PdOAc (11.5 mg, 0.051 mmol, 0.1 eq) under N atmosphere. The resulting reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered through a plug of celite eluting with CHCl. The filtrate was concentrated and purified by preparative basic to obtain the title compound (53 mg, 0.107 mmol, 21% yield) as a white solid after lyophilization.

[0821] Yield: Compound 125 was isolated as a white solid (20% over 3 steps).

[0822] Analysis: LCMS (Method L): t R =3.71min; [M+H] + The calculated value of m / z = 490.2, the found value = 490.1; 1H NMR (400 MHz, DMSO) δ 10.53 (bs, 1H), 8.00–7.79 (m, 2H), 7.26 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.7, 2.3 Hz, 1H), 6.84 (s, 1H), 4.50 (bs, 1H), 4.00 (s, 2H), 3.07 (s, 3H), 2.93 (s, 3H), 2.48–2.34 (m, 5H), 2.29–2.17 (m, 2H), 2.01–1.83 (m, 2H).

[0823] Example 37

[0824] Synthesis of compound 126

[0825]

[0826] Compound 125 was prepared in 1 step:

[0827] Step 1: Starting from phenol (20 mg, 0.046 mmol) and diethylcarbamoyl chloride, the compound was synthesized according to the general synthesis of compound F.2. Purification was performed using the 'preparative base' method to obtain the title compound (9.7 mg, 0.018 mmol, 39% yield) as a white solid after lyophilization.

[0828] Yield: Compound 125 was isolated as a white solid (39% over 1 step)

[0829] Analysis: LCMS (Method P): t R =1.65min; [M+H] + m / z calcd = 535.2, found = 535.1; no H NMR, compound was prepared from library.

[0830] Example 38

[0831] Synthesis of compound 127

[0832]

[0833] Compound 126 was prepared in 1 step:

[0834] Step 1: Starting from phenol (20 mg, 0.046 mmol) and 4-methyl-1-piperazinecarbonyl chloride, the compound was synthesized according to the general synthesis of compound F.2. Purification was performed using the 'preparative base' method to obtain the title compound as a white solid (17.8 mg, 0.032 mmol, 70% yield) after lyophilization.

[0835] Yield: Compound 126 was isolated as a white solid (70% over 1 step).

[0836] Analysis: LCMS (Method P): t R =1.33min; [M+H] + m / z calcd = 562.2, found = 562.1; no H NMR, compound was prepared from a library.

[0837] Example 39

[0838] Synthesis of compound 128

[0839]

[0840] Compound 128 was prepared in 1 step:

[0841] Step 1: Using phenol (50 mg, 0.115 mmol) and azetidine-1-carbonyl chloride as starting materials, synthesize according to the general synthesis of compound F.2, and add DMAP (0.6 equivalents) and Et3N (1.1 equivalents), and react in CH2Cl2 (0.11 M). After complete conversion, the reaction mixture is concentrated and water is added to the residue. The product is extracted with CH2Cl2. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The impure product is purified with the 'preparative alkaline' method to obtain the title compound (6 mg, 0.012 mmol, yield: 10%) as a white solid after lyophilization.

[0842] Yield: Compound 128 was isolated as a white solid (10% over 1 step).

[0843] Analysis: LCMS (Method T): t R =1.44min; [M+H] + The calculated value of m / z = 519.2, the found value = 519.1; 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.8 Hz, 1H), 7.39 (td, J = 7.9, 1.6 Hz, 1H), 7.15–7.05 (m, 2H), 7.03–6.96 (m, 1H), 6.90–6.83 (m, 1H), 6.61 (s, 1H), 4.44 (q, J = 5.4 Hz, 1H), 4.25 (s, 2H), 4.15 (s, 4H), 3.59 (s, 2H)), 2.75 (d, J = 5.3 Hz, 3H), 2.36 (p, J = 7.7 Hz, 2H), 2.27 (s, 6H).

[0844] Example 40

[0845] Synthesis of compound 129

[0846]

[0847] Compound 129 was prepared in 1 step:

[0848] Step 1: To a solution of the phenol derivative (50 mg, 0.115 mmol, 1.0 eq) and 2-bromopyrimidine (30 mg, 0.19 mmol, 1.6 eq) in N,N-dimethylformamide (dried) (2 ml) was added potassium carbonate (26 mg, 0.19 mmol, 1.6 eq). The resulting reaction mixture was stirred at 80 ° C for 5 hours. Water was added and the product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The impure product was purified by the 'preparative base' method to obtain the title compound (8.0 mg, 0.016 mmol, yield: 14%) as a white solid after lyophilization.

[0849] Yield: The title compound was isolated as a white solid (14% over 1 step).

[0850] Analysis: LCMS (Method T): t R =1.34min; [M+H] + The calculated value of m / z = 514.2, the found value = 514.1; 1H NMR(400MHz, CDCl3)δ8.60(d,J=4.7Hz,2H),8.11(d,J=8.8Hz,1H),7.40(td, J=7.8,1.6Hz,1H),7.22(d,J=2.4Hz,1H),7.17(dd,J=8.8,2.4Hz,1H),7.12(t ,J=4.8Hz,1H),7.01(t,J=8.0Hz,1H),6.91–6.81(m,1H),6.61(s,1H),4.43(q ,J=5.4Hz,1H),4.17(s,2H),3.62(s,2H),2.77(d,J=5.2Hz,3H),2.29(s,6H).

[0851] Example 41

[0852] Synthesis of compound 130

[0853]

[0854] Compound 130 was prepared in 4 steps:

[0855] Step 1: Starting from ethyl 2-(2-fluoro-3-nitrobenzyl)-3-oxobutanoate (2.0 g, 7.06 mmol) and 4-fluorobenzene-1,3-diol (1.20 equivalents), the product was synthesized according to the general synthesis of compound 4 to obtain the corresponding coumarin compound (2.85 g, 8.13 mmol, yield: 115%) as an off-white solid.

[0856] Step 2: According to the general synthetic procedure of compound 5, the reaction time was 2.5 days to obtain the corresponding dimethylcarbamate (2.28 g, 5.01 mmol, purity: 92%, yield: 61%) as a beige solid.

[0857] Step 3: According to the general synthetic procedure of compound 6, the corresponding primary amine was obtained as a light yellow solid (1.28 g, 3.11 mmol, yield: 57%).

[0858] Step 4: Follow the general synthesis procedure of compound 7. After filtration, the impure product was purified by flash column chromatography (CH2Cl2 / MeOH=1:0→97:3) to obtain the title compound (1.043 g, 2.15 mmol, yield: 65%) as an off-white solid.

[0859] Yield: Compound 130 was isolated as an off-white solid (26% over 4 steps).

[0860] Analysis: LCMS (Method R): t R =1.55min; [MH] + The calculated value of m / z = 480.1, the found value = 480.2; 1H NMR (400 MHz, DMSO) δ 9.37 (s, 1H), 7.86 (d, J = 11.2 Hz, 1H), 7.49 (d, J = 6.8 Hz, 1H), 7.28 (td, J = 7.8, 1.6 Hz, 1H), 7.21 (q, J = 5.1 Hz, 1H), 7.01 (t, J = 7.9 Hz, 1H), 6.91–6.83 (m, 1H), 3.98 (s, 2H), 3.08 (s, 3H), 2.94 (s, 3H), 2.53 (s, 3H), 2.43 (s, 3H).

[0861] Example 42

[0862] Synthesis of compound 131

[0863]

[0864] Compound 131 was prepared in 1 step:

[0865] Step 1: Starting from 6-chloro-4-(chloromethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (20 mg, 0.038 mmol) and azetidine, the general synthetic procedure for compound E.2 was followed, and potassium carbonate (3.0 equiv) was added. The impure product was combined with other batches and purified by preparative base to give the title compound (44 mg, 0.076 mmol, 65% yield) as a white solid after freeze-drying.

[0866] Yield: The title compound was isolated as a white solid (65% over 1 step).

[0867] Analysis: LCMS (Method R): t R =0.95min; [M+H] + The calculated value of m / z = 553.1, the found value = 553.2; 1H NMR (400 MHz, DMSO) δ 9.39 (s, 1H), 8.20 (s, 1H), 7.48 (s, 1H), 7.33–7.19 (m, 2H), 7.00 (t, J = 8.0 Hz, 1H), 6.81 (t, J = 7.1 Hz, 1H), 4.09 (s, 2H), 3.82 (s, 2H), 3.16 (t, J = 6.9 Hz, 4H), 3.10 (s, 3H), 2.95 (s, 3H), 2.53 (d, J = 4.8 Hz, 3H), 1.91 (p, J = 7.0 Hz, 2H).

[0868] Example 43

[0869] Synthesis of compound 132

[0870]

[0871] Compound 132 was prepared in 3 steps:

[0872] Step 1: Starting from 3-(3-amino-2-fluorobenzyl)-6-chloro-4-methyl-2-oxo-2H-chromen-7-yl dimethylcarbamate (0.320 g, 0.585 mmol) and ethanesulfonyl chloride, the synthesis was carried out according to the general synthesis of compound E.3. During the work-up, the reaction mixture was combined with another batch to obtain the sulfamoyl group as a white solid (350 mg, 0.704 mmol, yield: 92%).

[0873] Step 2: Synthesized using NBS according to the general synthetic procedure for compound E.4. After extraction, the impure product was purified by column chromatography using the 'flash' method (heptane / EtOAc=1:0→0:1) and then by preparative acid to obtain the corresponding bromide as a beige solid (65 mg, 0.113 mmol, yield: 19%).

[0874] Step 3: Synthesize using 2M dimethylamine in MeOH according to the general synthesis procedure of compound E.5. The reaction mixture was quenched with water and the product was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative acid to obtain the title compound (39 mg, 0.073 mmol, 65% yield) as a white solid after lyophilization.

[0875] Yield: Compound 132 was isolated as a white solid (11% over 3 steps).

[0876] Analysis: LCMS (Method V): t R =3.92min; [M+H] + The calculated value of m / z = 540.1 / 542.1, the found value = 540.1 / 542.1; 1H NMR (400 MHz, DMSO) δ 9.67 (s, 1H), 8.21 (s, 1H), 7.48 (s, 1H), 7.25 (td, J = 7.8, 1.7 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.98–6.88 (m, 1H), 4.05 (s, 2H), 3.66 (s, 2H), 3.14–3.07 (m, 5H), 2.95 (s, 3H), 2.18 (s, 6H)), 1.26 (t, J = 7.3 Hz, 3H).

[0877] Example 44

[0878] Synthesis of compound 133

[0879]

[0880] Compound 133 was prepared similarly to compound 225 using chloride instead of bromide.

[0881] Step-1: 6-chloro-4-(chloromethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (300 mg, 0.564 mmol) and triethylamine (236 uL, 1.69 mmol, 3 equivalents) were stirred in DCM (7 mL) at 40° C. and glycine tert-butyl ester (308 uL, 2.25 mmol, 4 equivalents) was added. The next day, water was added and the product was extracted with DCM (2×). The combined extracts were dried over brine and sodium sulfate and evaporated. The residue was redissolved in 1 mL of DCM and purified by column chromatography using the "preparative base" method to obtain the intermediate tert-butyl ester (126 mg, 0.20 mmol, yield: 35%).

[0882] Step 2: The intermediate from the previous step (126 mg, 0.20 mmol) was stirred in 2 mL of DCM and 2 mL of 4 N HCl in dioxane (58 mmol, 287 equiv). The next day, the volatiles were evaporated, the residue was stripped with DCM, and the crude product was redissolved in MeCN and purified using the 'preparative base' method to afford the title compound as an off-white solid (94 mg, 0.16 mmol, 81% yield).

[0883] Example 45

[0884] Synthesis of compound 134

[0885]

[0886] Compound 134 was prepared in 1 step:

[0887] Step 1: Starting from 4-(chloromethyl)-6-fluoro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (30 mg, 0.058 mmol) and piperazine, the product was synthesized according to the general synthesis of compound E.2. EtN (3.0 equiv) was added. The impure product was purified by preparative base to give the title compound as a white solid after freeze-drying (17.3 mg, 0.029 mmol, 51% yield).

[0888] Yield: Compound 134 was isolated as a white solid (51% over 1 step)

[0889] Analysis: LCMS (Method T): t R =1.39min; [M+H] +The calculated value of m / z = 566.2, the found value = 566.4; 1H NMR (400 MHz, DMSO) δ 8.04 (d, J = 11.8 Hz, 1H), 7.47 (d, J = 6.9 Hz, 1H), 7.28 (td, J = 7.9, 1.7 Hz, 1H), 7.24–7.12 (m, 1H), 6.99 (t, J = 7.9 Hz, 1H), 6.82 (t, J = 7.1 Hz, 1H), 4.03 (s, 2H), 3.66 (s, 2H), 3.08 (s, 3H), 2.94 (s, 3H), 2.63–2.55 (m, 4H), 2.55–2.52 (m, 3H), 2.41–2.28 (m, 4H).

[0890] Example 46

[0891] Synthesis of compoun...

Claims

1. A compound having a structure depicted by formula (IIa): Including pharmaceutically acceptable salts thereof, wherein: R 2 is L; R 3 It is fluorine; R 6 is H, deuterium, halogen, or C1 to C6 alkyl; R 8 is a C1 to C6 alkyl group; L is -Z1-Z2; Z1 is –CH2; Z2 is selected from C3 to C8 heterocyclic group or -NR 5 R 5′ ; Each R 5 and R 5’ are each independently H, deuterium, C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C8 carbocyclyl, C6 to C 10 Aryl, C3 to C8 heterocyclic group, or C3 to C 10 heteroaryl; X is O; Y is O; and Z is C or N.

2. The compound of claim 1, wherein Z2 is -NR 5 R 5’ .

3. The compound of claim 2, wherein R 5 and R 5' Each is independently a C1 to C6 alkyl group.

4. The compound of claim 2, wherein R 5 and R 5' are each independently H or CH3.

5. The compound of claim 2, wherein R 5 and R 5' Each independently is CH3.

6. The compound of claim 1, wherein Z2 is And n is 1, 2, 3 or 4.

7. The compound of claim 6, wherein Z2 is 8. The compound of claim 1, wherein Z2 is 9. The compound of any one of claims 1 to 8, wherein R 8 It is CH3.

10. The compound of any one of claims 1 to 8, wherein R 6 It’s H.

11. The compound of any one of claims 1 to 8, wherein R 6 It's a halogen.

12. The compound of claim 11, wherein R 6 It's chlorine.

13. The compound of claim 11, wherein R 6 It's fluorine.

14. The compound of claim 10, wherein R 5 and R 5' Each independently is CH3.

15. The compound of any one of claims 1-8, wherein Z is C.

16. The compound of any one of claims 1-8, wherein Z is N.

17. The compound of claim 1, selected from: A compound selected from the group consisting of: A compound selected from the group consisting of: or A compound selected from the group consisting of: or A compound selected from the group consisting of:

18. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1, wherein The compound is or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25.

27. Use of a compound according to any one of claims 1 to 25, which has a human plasma half-life of less than 12 hours, for the preparation of a medicament for inhibiting MEK.

28. Use of a compound as described in any one of claims 1 to 25 in the preparation of a medicament for treating a patient in need thereof, wherein the compound has a human plasma half-life of less than 12 hours; wherein the patient has been diagnosed with cancer, is resistant to MEK reactivation caused by the CRAF-bypass, and inhibits pERK and pSTAT3 (S727).

29. Use of the compound according to claim 28 in the preparation of a medicament; wherein the medicament is used to treat cancer, and the cancer is selected from brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, gastric cancer, prostate cancer, kidney cancer, colorectal cancer or leukemia.

30. Use of the compound according to claim 29 in the preparation of a medicament, wherein The lung cancer is non-small cell lung cancer.

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