FIELD

Provided herein are cyclic iminopyrimidine derivatives, pharmaceutical compositions comprising such compounds, and methods of using such compounds or compositions, such as methods of treating a proliferation disorder, a cancer or a tumor, or in some embodiments disease or disorders related to the dysregulation of kinase such as, but not limited to B-Raf V600E kinase.

BACKGROUND

The present disclosure relates to the treatment of abnormal cell growth in mammals especially humans, such as cancer and, more specifically brain cancer, with novel cyclic iminopyrimidines and their bicyclic compounds described therein, and their isotopic derivatives as well as pharmaceutical compositions containing such compounds. In addition, the present disclosure relates to the methods of preparing such compounds.

A kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the substrate gains a phosphate group and the high-energy ATP molecule donates a phosphate group. This transesterification produces a phosphorylated substrate and ADP.

Kinases are classified into broad groups by the substrate they act upon: protein kinases, lipid kinases, carbohydrate kinases. Kinases can be found in a variety of species, from bacteria to mold to worms to mammals. More than five hundred different kinases have been identified in humans.

MAP kinases (MAPKs) are a family of serine/threonine kinases that respond to a variety of extracellular growth signals. For example, growth hormone, epidermal growth factor, platelet-derived growth factor, and insulin are all considered mitogenic stimuli that can engage the MAPK pathway. Activation of this pathway at the level of the receptor initiates a signaling cascade whereby the Ras GTPase exchanges GDP for GTP. Next, Ras activates Raf kinase (also known as MAPKKK), which activates MEK (MAPKK). MEK activates MAPK (also known as ERK), which can go on to regulate transcription and translation. Whereas RAF and MAPK are both serine/threonine kinases, MAPKK is a tyrosine/threonine kinase.

The carcinogenic potential of the MAPK pathway makes it clinically significant. It is implicated in cell processes that can lead to uncontrolled growth and subsequent tumor formation. Mutations within this pathway alter its regulatory effects on cell differentiation, proliferation, survival, and apoptosis, all of which are implicated in various forms of cancer.

It is known that such kinases are frequently aberrantly expressed in common human cancers such as melanoma, colorectal cancer, thyroid cancer, glioma, breast cancer and lung cancer. It has also been shown that B-Raf, which possesses kinase activity, is mutated and/or overactive in many human cancers such as brain, lung, melanoma, colorectal cancer, ovarian cancer and papillary thyroid cancer.

Inhibition of the kinase is a useful method for disrupting the growth of mammalian cancer cells, therefore, for treating certain forms of cancer. Various compounds, such as pyrrolopyridine and thiazole derivatives, have been shown to possess kinase inhibitory properties. Many patent publications refer to certain bicyclic derivatives, in particular quinazolinone derivatives.

Several compounds with diversified chemical structures have been developed into B-Raf V600E mutant inhibitors, and two of them (Vemurafenib and Dabrafenib) are very effective in clinical applications. For example, Vemurafenib and Dabrafenib are marketed drugs treating various cancers by targeting B-Raf V600E mutation. Others compounds such as Encorafenib, which also inhibits B-Raf V600E mutant kinase, are in clinical development.



However, due to their structural characteristics, many kinase inhibitors are substrates of active transporters such as P-glycoproteins (P-gp) or breast cancer resistance protein (BCRP), and have very low tendency to penetrate into cell membrane, as well as into brain. Therefore, they are not suitable to be used for the treatment of tumors or cancers in the brain, which is protected by the blood-brain barrier (BBB).

Thus, the compounds of the present disclosure, which are selective inhibitors of certain kinases, are useful in the treatment of abnormal cell growth, in particular cancers in mammals. In addition, these compounds have good penetration of cell membrane, therefore, are useful for treating tumors or cancers, including brain tumors, in humans.

SUMMARY

In one aspect, provided is a compound of Formula (I):


or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein:
X1, X2, and X3are each independently N or CRa;
Y1, Y2, and Y3are each independently N or CRb;
Z1is O, S, NRcor CRdRe;
Z2is a bond or NRf;
m is 0, 1, 2 or 3;
n is 1, 2 or 3;
R1, R2, R3, Ra, Rb, Rd, and Reare each independently selected from the group consisting of hydrogen, halogen, —CN, —NO2, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, —ORg, —SRg, —S(O)2Rg, —NRhRi, —C(O)Rg, —OC(O)Rg, —C(O)ORg, —C(O)NRhRi, —OC(O)NRhRi, —NRgC(O)Rh, —NRgC(O)ORh, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl;
R4is hydrogen or C1-C6alkyl; and
Rc, Rf, Rg, Rh, and Riare each independently H, C1-C6alkyl, or C1-C6haloalkyl.

Provided in other aspects are compounds of Formula (I-1),


wherein

X1, X2, and X3are each independently N or CRa;

Y1, Y2, and Y3are each independently N or CRb;

Z1is O, S, NRcor CRdRe;

Z2is a bond or NRf;

m is 0, 1, 2 or 3;

n is 1, 2 or 3;

R1, R2, R3, Ra, Rb, Rd, and Reare each independently selected from the group consisting of hydrogen, halogen, —CN, —NO2, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, —ORg, —SRg, —S(O)2R, —NRhRi, —C(O)Rg, —OC(O)Rg, —C(O)ORg, —C(O)NRhRi, —OC(O)NRhRi, —NRgC(O)Rh, —NRgC(O)ORh, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl; and
Rc, Rf, Rg, Rh, and Riare each independently H or C1-C6alkyl.

Provided in other aspects are compounds of Formula (I-2a), (I-2b), and (I-2c):


or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein Y1, Y2, Y3, Z1, Z2, R1, R2, R3, m, n, and Raare as defined for Formula (I).

Provided in other aspects are compounds of Formula (I-2d), (I-2e), or (I-2f):


or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein X1, X2, X3, Z1, Z2, R1, R2, R3, m, n, and Rbare as defined for Formula (I).

Provided in other aspects are compounds of Formula (I-3a) or (I-3b):


or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein Z1, Z2, R1, R2, R3, m, and Raare as defined for Formula (I).

Provided in other aspects are compounds of Formula (I-4a), (I-4b), or (I-4c):


or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein Z1, Z2, R1, R2, R3, m, n, and Raare as defined for Formula (I).

Provided in other aspects are compounds of Formula (I-5a) or (I-5b):


or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein Z1, R1, R2, R3, m, and Raare as defined for Formula (I).

In some embodiments of any of the formulae provided herein, such as Formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), (I-2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a), or (I-5b), or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, Z1is O. In some embodiments of any of the formulae provided herein, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, Z2is a bond.

In some embodiments of any of the formulae provided herein, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, m is 0. In some embodiments, m is 1. In other embodiments, m is 2. In some embodiments of any of the formulae provided herein, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, n is 1. In some embodiments, n is 2.

In some embodiments of any of the formulae provided herein, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, each R1is independently hydrogen, —OH, —C1-C6alkyl, C1-C6alkoxy, or C1-C6dialkylamino, wherein the C1-C6alkyl is optionally substituted with halogen. Examples of C1-C6dialkylamino (i.e., —NRxRy, wherein Rxand Ryare each independently —C1-C6alkyl) include, but are not limited to —N(CH3)2, —N(CH2CH3)2, —N(CH3)CH2CH3, and —N(CH(CH3)2)2. In some embodiments, each R1is independently C1-C6alkyl substituted with halogen, —CN, —NO2, —OH, oxo, and —NR1aR1b, wherein R1aand R1bare each independently H or C1-C6alkyl. In some embodiments, R1is hydrogen. In some embodiments of any of the formulae provided herein, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, R2is hydrogen, cyano, nitro, halogen, MeSO2, C1-C6alkyl, C1-C6alkoxy, or —NRhRi, wherein the C1-C6alkyl is optionally substituted with one or more halogen, and Rhand Riare each independently C1-C6alkyl. In some embodiments, R2is CN. In some embodiments, R2is Cl. In some embodiments, R2is CF3.

In some embodiments of any of the formulae provided herein, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, R3is C1-C6alkyl, or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more groups selected from halogen and C1-C6alkyl. In some embodiments, R3is 2-fluorophenyl. In some embodiments, R3is pyrrolidinyl. In certain embodiments, R3is 3-fluoropyrrolidinyl. In some embodiments, R3is propyl. In some embodiments, R3is thiophenyl. In some embodiments, R3is C1-C6alkyl substituted with one or more groups selected from halogen, —CN, —NO2, —OH, oxo, and —NR3aR3b, wherein R3aand R3bare each independently H or C1-C6alkyl. In particular embodiments, R3is 3-fluoropropyl or 3-hydroxypropyl. In some embodiments, R3is —NRhRi, and Rhand Riare each independently H or C1-C6alkyl, or C1-C6haloalkyl. In certain embodiments, R3is —N(CH3)CH2CH3, —N(CH3)CH2CH2F, or —N(CH3)CH3.

In some embodiments of any of the formulae provided herein, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, Rais H. In some embodiments, Rais F. In some embodiments of any of the formulae provided herein, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, Rbis H. In some embodiments, Rbis F.

Provided in some embodiments are compounds of Table 1, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. Also provided are compounds of Table 2, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof.

In some aspects, provided are pharmaceutical compositions containing a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, and a pharmaceutically acceptable diluent or carrier.

In some aspects, provided are combinations containing at least one compound of Formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), (I-2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a), (I-5b), or a compound of Tables 1 or 2, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, and a second prophylactic or therapeutic agent.

In some aspects, provided are compounds of Formula (I), such as compounds of Formula (I-1), (I-2a), (I-2b), (I-2c), (I-2d), (I-2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a), (I-5b), or a compound of Tables 1 or 2, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, for use in treating and/or preventing a proliferation disorder, such as a cancer, or a tumor in a subject. In some embodiments, the proliferation disorder or cancer is selected from the group consisting of malignant or benign tumors of the liver, kidney, bladder, breast, gastric, ovarian, colorectal, prostate, pancreatic, lung, vulval, thyroid, hepatic carcinomas, sarcomas, glioblastomas, head and neck, melanoma, and other hyperplastic conditions such as benign hyperplasia of the skin and benign hyperplasia of the prostate.

Provided in some aspects are methods of treating and/or preventing a proliferation disorder, such as a cancer, or a tumor in a subject, wherein the method includes administering to the subject an effective amount of a compound of any of the formulae presented herein, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, or a pharmaceutical composition containing a compound of any of the formulae disclosed herein, or a combination containing any of the formulae disclosed herein. In some embodiments, the proliferation disorder or cancer is selected from the group consisting of malignant or benign tumors of the liver, kidney, bladder, breast, gastric, ovarian, colorectal, prostate, pancreatic, lung, vulval, thyroid, hepatic carcinomas, sarcomas, glioblastomas, head and neck, melanoma, and other hyperplastic conditions such as benign hyperplasia of the skin and benign hyperplasia of the prostate.

In some aspects, the present disclosure provides use of at least one compound of any of the formulae described herein, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, for the manufacture of a medicament.

In some aspects, the present disclosure provides a method for producing an anti-proliferative effect in a subject having a proliferation disorder, a cancer, or a tumor which is sensitive to inhibition of B-Raf V600E kinase, including administering to the subject an effective amount of a compound of any of the formulae presented herein, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, or a pharmaceutical composition containing a compound of any of the formulae disclosed herein, or a combination containing any of the formulae disclosed herein.

In some aspects, provided are compounds of Formula (I), such as compounds of Formula (I-1), (I-2a), (I-2b), (I-2c), (I-2d), (I-2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a), (I-5b), or a compound of Tables 1 or 2, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, for use in the treatment of a neurodegenerative disease. In some embodiments, the neurodegenerative disease is selected from the group consisting of Amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease.

In some aspects, the present disclosure provides a method for treating a neurodegenerative disease in a subject. In some embodiments, the method includes administering to the subject an effective amount of a compound of any of the formulae presented herein, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, or a pharmaceutical composition containing a compound of any of the formulae disclosed herein, or a combination containing any of the formulae disclosed herein. In some embodiments, the neurodegenerative disease is selected from the group consist of Amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease.

In yet another aspect, provided are methods for inhibiting an activity of a B-Raf V600E kinase in a cell, including contacting the cell with an effective amount of a compound of any of the formulae presented herein, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, or a pharmaceutical composition containing a compound of any of the formulae disclosed herein, or a combination containing any of the formulae disclosed herein, wherein the contacting is in vitro, ex vivo, or in vivo.

