WO2022015670A1 - Pyrido[2,3-d]pyrimidin-7(8h)-one derivatives as cyclin-dependent kinase 2 inhibitors - Google Patents

Abstract

The present disclosure provides certain pyrido[2,3-d]pyrimidin-7(8H)-one derivaties that are Cyclin-dependent kinase 2 (CDK2) inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of CDK2. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Description

PYRIDO [2,3-D] PYRIMIDIN-7(8H)-ONE DERIVATIVES AS CYCLIN-DEPENDENT

KINASE 2 INHIBITORS

Cross-Reference to Related Applications

This application is an International Application claiming the benefit of U.S. Provisional Application No. 63/051,818, filed on July 14, 2020 and its contents are incorporated herein by reference in their entirety.

Field of the disclosure

The present disclosure provides certain pyrido[2,3-d]pyrimidin-7(8H)-one derivaties that are Cy clin-dependent kinase 2 (CDK2) inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of CDK2. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Background

Cyclin-dependent kinases (CDKs) are cellular kinases that are critical for orchestrating signaling events such as DNA replication and protein synthesis to ensure faithful eukaryotic cell division and proliferation. To achieve activation, the cyclin-dependent kinase catalytic units of CDK often require binding with regulatory subunits known as cyclins. In addition, the activity of CDK is also controlled by its phosphorylation status, as well as by binding of inhibitory proteins. To date, at least twenty-one mammalian CDKs have been identified (see Malumbres M. Genome Biol. (2014) 15:122). Among these CDKs, at least CDKl/Cyclin B, CDK2/Cyclin E, CDK2/Cyclin A, CDK4/Cyclin D, CDK6/Cyclin D complexes are known to be important regulators of cell cycle progression; while other CDKs are important in regulating gene transcription, DNA repair, differentiation, and apoptosis (see Morgan, D. O. Annu. Rev. Cell. Dev. Biol. (1997) 13: 261-291).

Due to their key roles in regulating cell cycle and other essential cellular processes, increased activity or temporally abnormal activation of CDKs has been shown to result in the development of various types of cancer. Human tumor development is commonly associated with alterations in either the CDK proteins themselves or their regulators (see Cordon-Cardo C. Am. J. Pathol. (1995) 147:545-560; Karp JE, Broder S. Nat. Med. (1995) 1:309-320; and Hall M, Peters G. Adv. Cancer Res. (1996) 68:67-108). For example, amplifications of the regulatory subunits of CDKs and cyclins, and mutation, gene deletion, or transcriptional silencing of endogenous CDK inhibitory regulators have been reported (see Smalley et al. Cancer Res. (2008) 68: 5743-52). A large body of research has established the role of these alterations in promoting tumorigenesis and progression. Thus, there has been great interest in the development of inhibitors of CDKs for therapeutic purposes over the last two decades.

Selective CDK 4/6 inhibitors have changed the therapeutic management of hormone receptor-positive (HR+) metastatic breast cancer (MBC). Palbociclib, ribociclib, and abemaciclib, selective reversible inhibitors of CDK4 and CDK6, are approved for hormone receptor-positive (FIR+) metastatic breast cancer in combination with endocrine therapies. Additional clinical trials with these CDK4/6 inhibitors are ongoing in both breast and other cancers, either as single agents or in combination with other therapeutics, (see O'Leary et al. Nature Reviews (2016) 13:417-430). While CDK4/6 inhibitors have shown significant clinical efficacy in ER-positive metastatic breast cancer, the clinical benefit may be limited over time due to the development of primary or acquired resistance.

One important mechanism of resistance to CDK4/6 inhibitors is the abnormal activation of CDK2. It has been reported that high Cyclin E expression leads to overactivated CDK2/Cyclin E complex, which bypasses the requirement for CDK4/6 for cell cycle reentry (see Asghar, U. et al. Clin. Cancer Res. (2017) 23:5561). In addition, it has been found that when CDK4/6 is inhibited, there is a noncanonical CDK2/cyclin D1 complex formation that promotes pRb phosphorylation recovery and drives cell cycle progression (see Herrera-Abreu MT et al, Cancer Res. (2006) 15: 2301).

The CDK2/Cyclin E complex plays an important role in regulation of the Gl/S transition, histone biosynthesis and centrosome duphcation. Following the initial phosphorylation of Rb by Cdk4/6/cyclin D, Cdk2/Cyclin E further hyper-phosphoiylates p-RB, releases E2F to transcribe genes required for S-phase entry. During S-phase, Cyclin E is degraded and CDK2 forms a complex with Cyclin A to promote phosphorylation of substrates that permit DNA replication and inactivation of E2F, for S-phase completion. ( see Asghar et al. Nat. Rev. Drug. Discov. (2015) 14: 130-146). In addition to cyclin bindings, the activity of CDK2 is also tightly regulated through its interaction with negative regulators, such as p21 and p27. In response to mitogenic stimulation, which signals optimal environment for cell cycle, p21 and p27 are phosphorylated and degraded, releasing the break on CDK2/Cyclin activation.

Cyclin E, the regulatory cyclin for CDK2, is frequently overexpressed in cancer, and its overexpression correlates with poor prognosis. For example, Cyclin E amplification or overexpression has been shown to associate with poor outcomes in breast cancer (see Keyomarsi et al., N Engl JMed. (2002) 347:1566-75). Cyclin E2 (CCNE2) overexpression is associated with endocrine resistance in breast cancer cells and CDK2 inhibition has been reported to restore sensitivity to tamoxifen or CDK4/6 inhibitors in tamoxifen resistant and CCNE2 overexpressing cells, (see Caldon et al., Mol Cancer Ther. (2012) 11:1488-99; and Herrera-Abreu et al., Cancer Res. (2016)76:2301-2313). Cyclin E amplification also reportedly contributes to trastuzumab resistance in HER2+ breast cancer, (see Scaltriti et al. Proc Natl Acad Sci. (2011) 108:3761-6). Cyclin E overexpression has also been reported to play a role in basal-like and triple negative breast cancer (TNBC), as well as inflammatory breast cancer (see Elsawaf Z. et al. Breast Care (2011) 6:273-278; and Alexander A. et al. Oncotarget (2017) 8:14897-14911.)

Amplification or overexpression of cyclin E1 (CCNE1) is also frequently found in ovarian, gastric, endometrial, uterus, bladder, esophagus, prostate, lung and other types of cancers (see Nakayama et al. Cancer (2010) 116:2621-34; Etemadmoghadam et al. Clin Cancer Res (2013) 19: 5960-71; Au- Yeung et al. Clin. Cancer Res. (2017) 23:1862-1874; Ayhan et al. Modern Pathology (2017) 30: 297-303; Ooi et al. Hum Pathol. (2017) 61 :58-67; and Noske et al. Oncotarget (2017) 8: 14794-14805) and often correlates with poor clinical outcomes.

In some cancers, loss-of-function mutations in FBXW7, a component of SCF^Fbw7ubiquitin E3 ligase responsible for cyclin E degradation, also leads to cyclin E overexpression and CDK2 activation. Alternatively, certain cancer cells express a hyperactive, truncated form of cyclin E. In addition, cyclin A amplification and overexpression have also been reported in various cancers such as hepatocellular carcinomas, colorectal and breast cancers.

In contrast to the frequent upregulation of Cyclin E, the inhibitory regulators of CDK2, p21 and p27 are often abnormally downregulated in cancers. It is postulated that the loss or decrease of these key endogenous inhibitors leads to high and/or abnormal temporal activation of CDK2, thereby promoting oncogenic growth.

In addition, CDC25A and CDC25B, protein phosphatases responsible for the dephosphorylations that activate the CDK2, are overexpressed in various tumors. These various mechanisms of CDK2 activation have been validated using mouse cancer models. Furthermore, CDK2/cyclin E phosphorylates oncogenic Myc to oppose ras-induced senescence, highlighting the importance of CDK2 in myc/ras-induced tumorigenesis. Inactivation of CDK2 has been shown to be synthetically lethal to myc over-expressing cancer cells.

Recently, pharmacologic inhibition or genetic deletion of CDK2 preserved hearing function in animal models treated with cisplatin or noise (see Teitz T et al. J Exp Med. 2018 Apr 2;215(4): 1187-1203). Mechanistically, inhibition of CDK2 kinase activity reduces cisplatin- induced mitochondrial production of reactive oxygen species, thereby enhancing survival of inner ear cells. Therefore, in addition to anti-tumor therapies, CDK2 inhibition can also be used as a promising preventive treatment for noise-, cisplatin-, or antibiotic-induced or age-related hearing loss, for which no Food and Drug Administration approved drugs are currently available.

Currently, there are a few CDK2 inhibitors in early phase of clinical trials. For example, Dinaciclib (MK-7965) which inhibits CDK1, CDK2, CDK5 and CDK9 is in clinical development for solid tumors and hematological cancers in combination with other agents; CYC065, which potently inhibits CDK2, CDK3, CDK4, CDK9 and moderately inhibits CDK1, CDK5 and CDK7, is being investigated for the treatment of refractory CLL and other cancers; and PF-06873600, a CDK2 inhibitor with activities against other CDKs, is in clinical trial for the treatment of breast cancer either as single agent or in combination with endocrine therapies.

Therefore, small molecules that inhibit CDK2 activity are desirable. The present disclosure fulfills this and related needs.

Summary

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

wherein:

Hy is a ring according to formula (i):

where:

A is C=(O), S(O), S(O)₂, or S(O)(=NR) where R is hydrogen or alkyl; X is CH orN; Y is CH, CMe, or N; provided that at least one of X and Y is N; z is 0, 1, or 2; z’ and z” are independently 0 or 1; provided that at least one of z’ and z” is 1; and R⁵ is hydrogen, alkyl, cycloalkyl, or heterocyclyl, wherein alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, cyano, alkoxy, haloalkyl, haloalkoxy, alkylsulfonyl, NR^aR^b, C(O)NR^cR^d, and NR^eCOR^f [where R^a, R^b, R^c, R^d, R^e, and R^f are independently hydrogen, alkyl, cycloalkyl, or heterocyclyl (wherein alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, cyano, alkoxy, haloalkyl, alkylsulfonyl, and haloalkoxy) or R^a and R^b, and/or R^c and R^d, together with the nitrogen atom to which they are attached form heterocyclyl which can be optionally substituted with one or two substituents independently selected from alkyl, hydroxy, halo, cyano, alkoxy, haloalkyl, and haloalkoxy]; and further wherein Hy is substituted with R⁶, R⁷, and/or R⁸ where R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and NR^gR^h (wherein R^g and R^h are independently hydrogen, alkyl, or cycloalkyl); or R⁶ and R⁷, when attached to the same carbon of Hy, can cyclize to form a cycloalkylene or heterocyclylene; and

R⁸ is hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, halo, -C(O)NR^jR^k, -NR^wCOR^m, or heterocyclyl wherein alkyl, cycloalkyl, and heterocyclyl of R⁸ are optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, cyano, alkoxy, haloalkyl, haloalkoxy, NRⁿR^o, S(O)₂R^p, C(O)NR^qR^r, SO₂NR^sR^t, and NR^uCOR^v [where R·, R^k, R^w, R^m, Rⁿ,

R^o, R^p, R^q, R^r, R^s- R¹, R^u, and R^v are independently hydrogen, alkyl, cycloalkyl, and heterocyclyl (where alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, hydroxy, cyano, alkoxy, haloalkyl, and haloalkoxy) or independently of each other, Rⁿ and R^o, R^q and R^r, and R^s and R^t together with the nitrogen atom to which they are attached form heterocyclyl which can be optionally substituted with one or two substituents independently selected from alkyl, hydroxy, halo, cyano, alkoxy, alkylsulfonyl, and haloalkoxy]

R¹ is hydrogen, NH₂, alkyl, halo, or haloalkyl;

R² is hydrogen, halo, alkyl, haloalkyl, or cycloalkyl, where alkyl and cycloalkyl are optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, cyano, alkoxy, and haloalkoxy; R³ is hydrogen, halo, NH₂, alkyl, haloalkyl, cycloalkyl, aryl, or heterocyclyl, where alkyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, cyano, alkoxy, haloalkyl, haloalkoxy, C(O)NH₂, and C(O)OH; and

R⁴ is alkyl, cycloalkyl, or heterocyclyl, where alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, cyano, halo, and hydroxy; or a pharmaceutically acceptable salt thereof

In a second aspect, provided is a method of treating a disease treatable by inhibition of CDK2 in a patient, preferably the patient is in need of such treatment, which method comprises administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof. In a first embodiment of the second aspect, the disease is cancer. In a second subembodiment of the second aspect, the disease is cancer selected from lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, parvicellular and non-parvicellular carcinoma, bronchial carcinoma, bronchial adenoma, pleuropulmonary blastoma), skin cancer (e.g. melanoma, squamous cell carcinoma, Kaposi sarcoma, Merkel cell skin cancer), bladder cancer, breast cancer, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, head and neck cancer (e.g., cancers of the larynx, hypopharynx, nasopharynx, oropharynx, lips, and mouth), liver cancer (e.g., hepatocellular carcinoma, cholangiocellular carcinoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer (e.g. exocrine pancreatic carcinoma), stomach cancer, thyroid cancer, and parathyroid cancer. In a third subembodiment of of the second aspect, the cancers are those that are resistant to CDK4/6 inhibitors through CDK2- mediated mechanisms.

Also, in the second aspect, provided is a method of treating noise-, cisplatin-, antibiotic- induced- or age-related hearing loss, which method comprises administering to the patient, preferably a patient in need of such treatment, a a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of hearing loss is reduced when compared to an age-matched control. In some embodiments, the hearing loss is prevented when compared to an age-matched control. In a third aspect, provided is a pharmaceutical composition comprising a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

In a fourth aspect, provided is a compound of Formula (I) (or any embodiments thereof described herein), or a pharmaceutically acceptable salt thereof for use as a medicament. In one embodiment of the fourth aspect, the compound Formula (I) (and any embodiments thereof described herein), or a pharmaceutically acceptable salt thereof is useful for the treatment of one or more of diseases disclosed in the second aspect above.

In a fifth aspect, provided is the use of a compound of Formula (I (and any embodiments thereof disclosed herein)), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease in a patient in which the activity of CDK2 contributes to the pathology and/or symptoms of the disease. In one embodiment of the fifth aspect, the disease is one or more of diseases disclosed in the second aspect above.

In a sixth aspect, provided is a method of inhibiting CDK2 which method comprises contacting CDK2 with a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof; or contacting CDK2 with a pharmaceutical composition comprising a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In any of the aforementioned aspects involving the treatment of cancer, are further embodiments comprising administering the compound of Formula (I) (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof in combination with at least one additional anti cancer agent. When combination therapy is used, the agents can be administered simultaneously or sequentially.

Detailed Description

Definitions:

Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meaning:

“Alkyl” means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like. It will be recognized by a person skilled in the art that the term “alkyl” may include “alkylene” groups. “Alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated; e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

“Alkylsulfonyl” means a -SO₂R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.

“Alkoxy” means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert- butoxy, and the like.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.

“Cycloalkyl” means a monocyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

“Cycloalkylene” means a divalent saturated hydrocarbon radical of three to six carbon atoms, otherwise.g., 1,1 -cyclopropylene, and the like.

“Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.

“Haloalkyl” means alkyl radical as defined above, which is substituted with one or more halogen atoms, e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH₂CI, -CF₃, -CHF₂, -CH₂CF₃, -CF₂CF₃, -CF(CH₃)₂, and the like. When the alkyl is substituted with only fluoro, it can be referred to in this

Application as fluoroalkyl.

“Haloalkoxy” means a -OR radical where R is haloalkyl as defined above e.g., -OCF₃, -OCHF₂, and the like. When R is haloalkyl where the alkyl is substituted with only fluoro, it is referred to in this Application as fluoroalkoxy.

“Heterocyclyl” means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S(O)_n, where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a -CO- group. More specifically the term heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydro-pyranyl, thiomorpholino, and the like. When the heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic. When the heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino and is a subset of the heterocyclyl group.

“Heterocyclylene” means a saturated divalent group of 4 to 6 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S(O)_n, where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a -CO- group. More specifically the term heterocyclyl includes, but is not limited to,

and the like.

The term “oxo,” as used herein, alone or in combination, refers to =(O).

The present disclosure also includes protected derivatives of compounds of Formula (I). For example, when compounds of Formula (I) contain groups such as hydroxy, carboxy, or any group containing a nitrogen atom(s), these groups can be protected with suitable protecting groups. A comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, 5^th Ed., John Wiley & Sons, Inc. (2014), the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art.

The present disclosure also includes polymorphic forms and deuterated forms of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

The term “prodrug” refers to a compound that is made more active in vivo. Certain compounds Formula (I) may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology ( see Testa, Bernard and Mayer, Joachim M. Wiley -VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug”), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound. A “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,

4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy- 2-ene-1-carboxylic acid), 3 -pheny lpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington ’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety.

The compounds of Formula (I) may have asymmetric centers. Compounds of Formula (I) containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. All chiral, diastereomeric, all mixtures of chiral or diasteromeric forms, and racemic forms are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated. It will also be understood by a person of ordinary skill in the art that when a compound is denoted as (R) stereoisomer, it may contain the corresponding (S) stereoisomer as an impurity and vice versa. Certain compounds of Formula (I) can exist as tautomers and/or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure. Additionally, as used herein the term alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Furthermore, when the cyclic groups such as aryl is substituted, itincludes all the positional isomers albeit only a few examples are set forth. Furthermore, all hydrates of a compound of Formula (I) are within the scope of this disclosure.

The compounds of Formula (I) may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds. Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100% of the atom in question, that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present invention, such as a compound of Formula (I) (and any embodiments thereof disclosed herein including specific compounds) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵ l, respectively. Isotopically labeled compounds (e.g., those labeled with ³H and ¹⁴C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in compounds of Formula (I), including in Table I below one or more hydrogen atoms are replaced by ²H or ³H, or one or more carbon atoms are replaced by ¹³C- or ¹⁴C -enriched carbon. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁵F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

A “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient. The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass ± 10%, preferably ± 5%, the recited value and the range is included.

The phrase “... wherein Hy is optionally substituted with R⁶, R⁷, and/or R⁸ independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, and ... ,” in the definition of Hy in Formula (I) (and similar phrases used to define other groups in Formula (I)) is intended to cover Hy that is unsubstituted and Hy that is substituted with any one, or two, or all three, of R⁶, R⁷, and R⁸.

The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

The term “combination therapy” means the administration of two or more therapeutic agents to treat a disease or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

“Treating” or “treatment” of a disease includes:

(1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease;

(2) inhibiting the disease, i.e., delaying, arresting or reducing the development or severity of the disease or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

In one embodiment, treating or treatment of a disease includes inhibiting the disease, i.e., delaying, arresting or reducing the development or severity of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

A “therapeutically effective amount” means the amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

The terms "inhibiting" and "reducing," or any variation of these terms in relation to CDK2, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of CDK2activity compared to itsnormal activity.

Representative compounds of the disclosure made are disclosed in Table I and II below:

Table I

Additional representative compounds of Formula (I) that can be prepared are shown in Table II below:

Embodiments:

In further embodiments 1-12 below, the present disclosure includes:

1. In embodiment 1, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is as described in the first aspect of the Summary above.

2. In embodiment 2, the compound of embodiment 1 or a pharmaceutically acceptable salt thereof, is wherein R¹ and R² are hydrogen.

3. In embodiment 3, the compound of embodiment 1 or a pharmaceutically acceptable salt thereof, is wherein R⁴ is cycloalkyl optionally substituted with one or two substituents independently selected from alkyl, alkoxy, cyano, halo, and hydroxy. In a first subembodiment of embodiment 3, R⁴ is unsubstituted cycloalkyl. In a second subembodiment of embodiment 3, R⁴ is cycloalkyl substituted with hydroxy or alkyl, or with both hydroxyl and alkyl. In a third subembodiment of embodiment 3, R⁴ is cyclopentyl optionally substituted with one or two substituents independently selected from alkyl, alkoxy, cyano, halo, and hydroxy. In a subembodiment of the third subembodiment of embodiment 3, R⁴ is unsubstituted cyclopentyl. In a fourth subembodiment of embodiment 3, R⁴ is a group of structure:

4. In embodiment 4, the compound of any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, is wherein R³ is hydrogen, halo, haloalkyl, or alkyl optionally substituted with hydroxy. In a first subembodiment of embodiment 4, the compound or a pharmaceutically acceptable salt thereof, is wherein R³ is hydrogen. In a second subembodiment of embodiment 4, the compound or a pharmaceutically acceptable salt thereof, is wherein R³ is haloalkyl, preferably R³ is difluoromethyl. In a second subembodiment of embodiment 4, the compound or a pharmaceutically acceptable salt thereof, is wherein R³ is alkyl substituted with hydroxy, preferably R³ is 2-hydroxyethyl.

5. In embodiment 5, the compound of any one of embodiments 1 to 4 or a pharmaceutically acceptable salt thereof is wherein Hy is a ring of formula:

where Hy is substituted with R⁶, R⁷, and/or R⁸ as defined in the Summary. In a first subembodiment, Hy is a ring of formula:

where z is 1 or 2 and Hy is substituted with R⁶, R⁷, and/or R⁸ as defined in the Summary. In a second subembodiment, Hy is a ring of formula:

where Hy is substituted with R⁶, R⁷, and/or R⁸ as defined in the Summary. Within first and second subembodiments, in one group of compounds, X and Y are N. Within first and second subembodiments, in a second group of compounds, X is N and Y is CH. Within first and second subembodiments, in a third group of compounds, Y is N and X is CH.

6. In embodiment 6, the compound of any one of embodiments 1 to 5 or a pharmaceutically acceptable salt thereof, is wherein R⁵ is hydrogen.

7. In embodiment 7, the compound of any one of embodiments 1 to 5 or a pharmaceutically acceptable salt thereof, is wherein R⁵ is alkyl optionally substituted with one or two substituents independently selected from hydroxy, alkoxy, halo, and alkylsulfonyl. In a first subembodiment, R⁵ is methyl, ethyl, 2-methoxy ethyl, or 2-hydroxyethyl.

8. In embodiment 8, the compound of any one of embodiments 1 to 5 or a pharmaceutically acceptable salt thereof, is wherein R⁵ is heterocyclyl optionally substituted with one or two substituents independently selected from hydroxy, alkoxy, halo, and alkylsulfonyl. In a first subembodiment, R⁵ is oxetane, tetrahydrofuran, or tetrahydropyranyl.

9. In embodiment 9, the compound of any one of embodiments 1 to 5 or a pharmaceutically acceptable salt thereof, is wherein R⁵ is cycloalkyl optionally substituted with one or two substituents independently selected from hydroxy, alkoxy, and halo.

10. In embodiment 10, the compound of any one of embodiments 1 to 9 or a pharmaceutically acceptable salt thereof is wherein R⁶, R⁷, and R⁸ are hydrogen.

11. In embodiment 11, the compound of any one of embodiments 1 to 9 or a pharmaceutically acceptable salt thereof, is wherein Hy is substituted with R⁷ and R⁸, optionally where one or both of R⁷ and R⁸ are not hydrogen. In a first subembodiment of embodiment 11, R⁸ is alkyl, alkoxy, hydroxy, or halo wherein alkyl of R⁸ is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, NRⁿR^o, and S(O)₂R^p [where Rⁿ, R^o, and R^p are independently hydrogen, alkyl, cycloalkyl, and heterocyclyl (where alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, hydroxy, cyano, alkoxy, haloalkyl, and haloalkoxy) or Rⁿ and R^o together with the nitrogen atom to which they are attached form heterocyclyl which can be optionally substituted with one or two substituents independently selected from alkyl, hydroxy, halo, cyano, alkoxy, and haloalkoxy]. In a second subembodiment of embodiment 11, and the first subembodiment therein, R⁸ is attached to carbon that is adjacent to -X(R⁵)- group in Hy.

12. In embodiment 12, the compound of any one of embodiments 1 to 9 or a pharmaceutically acceptable salt thereof, is wherein Hy is substituted with R⁸, where R⁸ is not hydrogen. In a first subembodiment of embodiment 12, R⁸ is alkyl, alkoxy, hydroxy, or halo wherein alkyl of R⁸ is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, NRⁿ R^o, and S(O)₂R^P [where Rⁿ, R^o, and R^p are independently hydrogen, alkyl, cycloalkyl, and heterocyclyl (where alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, hydroxy, cyano, alkoxy, haloalkyl, and haloalkoxy) or Rⁿ and R^o together with the nitrogen atom to which they are attached form heterocyclyl which can be optionally substituted with one or two substituents independently selected from alkyl, hydroxy, halo, cyano, alkoxy, and haloalkoxy]. In a second subembodiment 12 and the first subembodiment therein, R⁸ is attached to carbon that is adjacent to -X(R⁵)- group in Hy.

It is understood that the embodiments and subembodiments set forth above include all combination of embodiments and subembodiments listed therein. For example, R⁸ listed in the second sub-embodiment of embodiment 12, can independently be combined with one or more of the embodiments 1-11 and/or subembodiments contained therein.

General Synthetic Scheme

Compounds Formula (I) can be made by the methods depicted in the reaction schemes shown below.

The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions,

Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (V CH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds Formula (I) can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art reading this disclosure. The starting materials and the intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about -78 °C to about 150 °C, such as from about 0 °C to about 125 °C and further such as at about room (or ambient) temperature, e.g., about 20 °C.

Compounds of Formula (I) where R¹, R², R³, R⁴ and

are as defined in summary can be synthesized as illustrated and described in Scheme 1 shown below.

Scheme 1

Compounds of Formula (I) where R¹, R², R³, R⁴ and

are as defined in Summary can be synthesized by condensation of primary amine of formula 1-a where Hy is as described in the Summary and pyridopyrimidinone of formula 1-b where LG is a suitable leaving group such as Cl or SO₂Me under suitable conditions such as acidic, basic or transition metal catalyzed reaction conditions well known in the art.

For example, compounds of formula 1-a where A is SO₂, X and Y are N, R⁵ is H, z is 0, 1, or 2 and z’ and z” are each 1, and wherein 1-a can be further optionally substituted with R⁶, R⁷ and/or R⁸, where R⁶, R⁷ and/or R⁸ is as defined in the Summary, can be prepared as illustrated and described in Method (a) below. Method (a):

Coupling reaction between a compound of formula 1-c, where z is 0, 1, or 2, and a compound of formula 1-d under acid condition such as phosphomolybdic acid provides a compound of formula 1-e. In compounds in formula 1-c and 1-d the alkylene and/or alkenylene chain can be optionally substituted with R⁶, R⁷ and/or R⁸, where R⁶, R⁷ and/or R⁸ is as defined in the Summary. Compounds of formula 1-c and 1-d are commercially available or they can be prepared by methods well known the art. For example, 3-(N-phthaloyl)propionaldehyde is commercially available and N-(but-3-en-1-yl)-4-methylbenzenesulfonamide can be synthesized by reaction between TsCl and homoallylamine in the presence of a base such as pyridine or TEA. Protection of the hydroxyl group in compound of formula 1-e with a suitable protecting group such as a TBS group provides a compound of formula 1-f. Treatment of compound 1-f with hydrazine, followed by reacting the resulting primary amine 1-g with sodium and naphthalene in DME provides a diamine compound of formula 1-h. Treatment of 1-h with sulfuric diamide in pyridine provides a compound of formula 1-i. Removal of the TBS protecting group in 1-i under acidic reaction conditions such as HC1 in dioxane provides an alcohol of formula 1-j, which can be oxidized with a suitable oxidizing reagent such as Dess-Martin reagent to provide a compound of formula 1-k Ketone 1-k can be converted to compound of formula 1-a under reductive amination conditions such as NH₄OAc and NaBH₃CN in MeOH solvent.

Compounds of Formula 1-a where R⁵ is hydrogen can be converted to other compounds with formula 1-a where R⁵ is as defined in Summary as illustrated and described in Method (b) below. Method (b):

Compounds of formula 1-a where R⁵ is other than hydrogen can be prepared from corresponding compounds of formula 1-a where R⁵ is hydrogen by first protecting the primary amine of 1-a with a suitable protecting group such as Boc, followed by treatment of the resulting amino protected derivative of formula 1-m with R⁵LG where R⁵ is other than hydrogen and LG is a leaving group such as halo, tosylate, mesylate, triflate, and the like, under alkylating reaction conditions well known in the art. Removal of the amino protecting group under conditions well known in the art provides a compound of formula 1-a.

Compounds of formula 2-a where R¹, R² and R³ are hydrogen, LG is -SO₂Me, and R⁴ is as defined in Summary can be synthesized by method illustrated in Method (c) below.

Method (c):

Displacement of the chloride in compound 2-b with an amine of formula 2-c where R⁴ is as defined in the Summary, under basic condition as such TEA provides a compound of formula 2-d. Compound 2b and amine 2-c are commercially available, or they can be prepared by methods well known the art. For example, cyclopentanamine is commercially available.

Reduction of the ester group in 2-d with a suitable reducing reagent such LiA1H₄ provides a hydroxy compound of formula 2-e, which can be converted to corresponding aldehyde of formula 2-f with an oxidizing agent such as MnO₂. Olefmation of 2-f with ethyl 2-(triphenyl-λ⁵- phosphanylidene)acetate provides a compound of formula 2g, which can undergo cyclization in the presence of a base such as DBU under heating condition to provide a compound of formula 2-h. Compound 2-h can then be converted to a compound of formula 2-a where LG is SO₂Me by treatment with an oxidant such as m-CPBA.

Utility

Increasing evidence suggests that overactivated CDK2 leads to abnormal cell cycle regulation and proliferation in cancer cells. While CDK2 mutations are rarely found, the kinase activity of CDK2/Cylin E or CDK2/Cyclin A complexes is elevated via several mechanisms in human cancers. Cyclin E has been found to be frequently amplified in human malignancies, for example, in ovarian cancer and breast cancer. In some cancer types, loss-of-function mutations in FBXW7, a component of SCF^Fbw7ubiquitin E3 ligase responsible for cyclin E degradation, also leads to cyclin E overexpression and CDK2 activation. Alternatively, certain cancer cells express a hyperactive, truncated form of cyclin E. In addition, cyclin A amplification and overexpression have also been reported in various cancers such as hepatocellular carcinomas, colorectal and breast cancers. In some tumors, catalytic activity of CDK2 is increased following loss of the expression or alteration of the location of the endogenous CDK2 inhibitor p27 or p21. In addition, CDC25A and CDC25B, protein phosphatases responsible for the dephosphorylations that activate the CDK2, are overexpressed in various tumors. These various mechanisms of CDK2 activation have been validated using mouse cancer models. Furthermore, CDK2/cyclin E phosphorylates oncogenic Myc to oppose ras-induced senescence, highlighting the importance of CDK2 in myc/ras-induced tumorigenesis. Inactivation of CDK2 has been shown to be synthetically lethal to myc over-expressing cancer cells. Therefore, a compound of the invention may be useful for treating tumors characterized by 1) overexpression of CDK2, 2) amplification of cyclin E or cyclin A, 3) loss-of-function of mutation in FBXW7, 4) expression of truncated cylclin E, 5) dysregulation of p21 or p27, and 6) hyperactive MYC/RAS.

CDK2 activation, as a result of cyclin E amplification or overexpression has also been identified as a key primary or acquired resistance pathway to tumors treated by CDK4/6 inhibitors or trastuzumab.

In some embodiments, the cancer is hepatocellular carcinomas, colorectal and breast cancers. In some embodiments, the cancer is ovarian cancer. In some such embodiments, the ovarian cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2. In other embodiments, the cancer is breast cancer, including, e.g., ER-positiive/HR-positive breast cancer, HER2-negative breast cancer; ER-positiive/HR-positive breast cancer, HER2-positive breast cancer; triple negative breast cancer (TNBC); or inflammatory breast cancer. In some embodiments, the breast cancer is endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments of each of the foregoing, the breast cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.

Testing

The CDK2 inhibitory activity of the compounds of the present disclosure can be tested using the in vitro assay described in Biological Examples 1 below.

Pharmaceutical Compositions

In general, the compounds Formula (I) (unless stated otherwise, reference to compound/compounds of Formula (I) herein includes any embodiments thereof described herein or a pharmaceutically acceptable salt thereof) will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of compounds Formula (I) may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. A suitable dosage level may be from about 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. For oral administration, the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound Formula (I), i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.

In general, compounds Formula (I) will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.

The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred) and the bioavailability of the drug substance.

The compositions are comprised of in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are generally nontoxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I). Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

The compounds of Formula (I) may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

In addition to the formulations described previously, the compounds of Formula (I) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

The compounds of Formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

Certain compounds of Formula (I) may be administered topically, that is by non- systemic administration. This includes the application of a compound of Formula (I) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, from 0.001% to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w/w. In other embodiments, it may comprise less than 5% w/w. In certain embodiments, the active ingredient may comprise from 2% w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/w of the formulation. For administration by inhalation, compounds of Formula (I) may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as 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. Alternatively, for administration by inhalation or insufflation, the compounds of Formula (I) may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000).

The level of the compound of Formula (I) in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. % of a compound of Formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1-80 wt. %.

Combinations and Combination Therapies

The compounds of Formula (I) may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of Formula (I) or the other drugs may have utility. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I). When a compound of Formula (I) is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula (I) is preferred. However, the combination therapy may also include therapies in which the compound of Formula (I) and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of Formula (I) and the other active ingredients may be used in lower doses than when each is used singly.

Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other drugs, in addition to a compound of of Formula (I). The above combinations include combinations of a compound of Formula (I) not only with one other drug, but also with two or more other active drugs. Likewise, a compound of Formula (I) may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which a compound of Formula (I) is useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I). When a compound of Formula (I) is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula (I) can be used. Accordingly, the pharmaceutical compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to a compound of Formula (I). The weight ratio of the compound of this disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.

Where the subject in need is suffering from or at risk of suffering from cancer, the subject can be treated with a compound of of Formula (I) in any combination with one or more other anti- cancer agents including but not limited to: MAP kinase pathway (RAS/RAF/MEK/ERK) inhibitors including but not limited to: Vemurafanib (PLX4032), Dabrafenib, Encorafenib (LGX818), TQ-B3233, XL-518 (Cas No. 1029872- 29-4, available from ACC Corp); trametinib, selumetinib (AZD6244), TQ-B3234, PD184352, PD325901, TAK-733, pimasertinib, binimetinib, refametinib, cobimetinib (GDC-0973), AZD8330, BVD-523, LTT462, Ulixertinib, AMG510, ARS853, and any RAS inhibitors disclosed in patents WO2016049565,

WO2016164675, WO2016168540, WO2017015562, WO2017058728, WO2017058768,

WO2017058792, WO2017058805,WO2017058807, WO2017058902, WO2017058915,

WO2017070256, WO2017087528, WO2017100546, WO2017172979, WO2017201161, WO2018064510,WO2018068017, WO2018119183;

CSF1R inhibitors (PLX3397, LY3022855, etc.) and CSF1R antibodies (IMC-054, RG7155) TGF beta receptor kinase inhibitor such as LY2157299;

BTK inhibitor such as ibrutinib;BCR-ABL inhibitors: Imatinib (Gleevec®); Inilotinib hydrochloride; Nilotinib (Tasigna®); Dasatinib (BMS-345825); Bosutinib (SKI-606); Ponatinib (AP24534); Bafetinib (INNO406); Danusertib (PHA-739358), AT9283 (CAS 1133385-83-7);

Saracatinib (AZD0530); and N-[2-[(15,4R)-6-[[4-(cyclobutylarmno)-5-(trifluoromethyl)-2 - pyrimidinyl] amino] -1, 2,3,4- tetrahy dronaphthalen-1,4-imin-9-yl]-2-oxoethyl]-acetamide (PF- 03814735, CAS 942487-16-3); ALK inhibitors: PF-2341066 (XALKOPJ ® ; crizotinib); 5-chloro-N4-(2- (isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiper azin-1-yl)piperidin-1- yl)phenyl)pyrimidine-2,4-diamine; GSK1838705 A; CH5424802; Ceritinib (ZYKADIA); TQ- B3139, TQ-B3101 PI3K inhibitors: 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1- yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941 and described in PCT Publication Nos. WO 09/036082 and WO 09/055730), 2-methyl-2-[4-[3-methyl-2-oxo-8- (quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl ]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in PCT Publication No. WO 06/122806);

Vascular Endothelial Growth Factor (VEGF) receptor inhibitors: Bevacizumab (sold under the trademark Avastin® by Genentech/Roche), axitinib, (N-methy 1-2- [ [3 - [(E)-2-pyridin-2- y letheny 1] -1H-indazol-6-yl] sulfany 1] benzamide, also known as AG013736, and described in PCT Publication No. WO 01/002369), Brivanib Alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol- 5-yloxy)-5-methylpyrrolo[2,1-f] [1,2,4]triazin-6-yloxy)propan -2-yl)2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4- pyridinylmethyl)amino]-3-pyridinecarboxamide, and described in PCT Publication No. WO 02/066470), pasireotide (also known as SOM230, and described in PCT Publication No. WO 02/010192), sorafenib (sold under the tradename Nexavar®); AL-2846 MET inhibitor such as foretinib, carbozantinib, or crizotinib;

FLT3 inhibitors - sunitinib malate (sold under the tradename Sutent® by Pfizer); PKC412 (midostaurin); tanutinib, sorafenib, lestaurtinib, KW-2449, quizartinib (AC220) and crenolanib;

Epidermal growth factor receptor (EGFR) inhibitors: Gefitnib (sold under the tradename Iressa®), N-[4- [(3 -chloro-4-fluorophenyl)amino] -7- [[(3 S)-tetrahy dro- 3-furanyl]oxy]-6- quinazolinyl]-4(dimethylamino)-2-butenamide, sold under the tradename Tovok® by Boehringer Ingelheim), cetuximab (sold under the tradename Erbitux® by Bristol-Myers Squibb), panitumumab (sold under the tradename Vectibix® by Amgen);

HER2 receptor inhibitors: Trastuzumab (sold under the trademark Herceptin® by Genentech/Roche), neratinib (also known as HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridin-2- yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide, and described PCT Publication No. WO 05/028443), lapatinib or lapatinib ditosylate (sold under the trademark Tykerb® by GlaxoSmithKline); Trastuzumab emtansine (in the United States, ado- trastuzumab emtansine, trade name Kadcyla) - an antibody -drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent mertansine (DM1); HER dimerization inhibitors: Pertuzumab (sold under the trademark Omnitarg®, by

Genentech);

CD20 antibodies: Rituximab (sold under the trademarks Riuxan® and MabThera® by Genentech/Roche), tositumomab (sold under the trademarks Bexxar® by GlaxoSmithKline), ofatumumab (sold under the trademark Arzerra® by GlaxoSmithKline);

Tyrosine kinase inhibitors: Erlotinib hydrochloride (sold under the trademark Tarceva® by Genentech/Roche), Linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5- methylphenyl)urea, also known as ABT-869, available from Genentech), sunitinib malate (sold under the tradename Sutent® by Pfizer), bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6- methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy] quinoline-3 -carbonitrile, also known as SKI-606, and described in US Patent No. 6,780,996), dasatinib (sold under the tradename Sprycel® by Bristol-Myers Squibb), armala (also known as pazopanib, sold under the tradename Votrient® by GlaxoSmithKline), imatinib and imatinib mesylate (sold under the tradenames Gilvec® and Gleevec® by Novartis).

DNA Synthesis inhibitors: Capecitabine (sold under the trademark Xeloda® by Roche), gemcitabine hydrochloride (sold under the trademark Gemzar® by Eli Lilly and Company), nelarabine ((2R3S,4R,5R)-2-(2-amino-6-methoxy-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4- diol, sold under the tradenames Arranon® and Atriance® by GlaxoSmithKline);

Antineoplastic agents: oxaliplatin (sold under the tradename Eloxatin® ay Sanofi- Aventis and described in US Patent No. 4,169,846);

Human Granulocyte colony-stimulating factor (G-CSF) modulators: Filgrastim (sold under the tradename Neupogen® by Amgen).

Immunomodulators: Afutuzumab (available from Roche®), pegfilgrastim (sold under the tradename Neulasta® by Amgen), lenalidomide (also known as CC-5013, sold under the tradename Revlimid®), thalidomide (sold under the tradename Thalomid®);

CD40 inhibitors: Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc); Pro-apoptotic receptor agonists (PARAs): Dulanermin (also known as AMG-951, available from Amgen/Genentech);

Hedgehog antagonists: 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)- benzamide (also known as GDC-0449, and described in PCT Publication No. WO 06/028958);

Phospholipase A2 inhibitors: Anagrelide (sold under the tradename Agrylin®);

BCL-2 inhibitors: 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1- piperazinyl]-N-[[4-[[(lR)-3-(4-morpholinyl)-1-[(phenylthio)m ethyl] propyl] amino] -3 - [(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No. WO 09/155386);

MCl-1 inhibitors: MIK665, S64315, AMG 397, and AZD5991;

Aromatase inhibitors: Exemestane (sold under the trademark Aromasin® by Pfizer), letrozole (sold under the tradename Femara® by Novartis), anastrozole (sold under the tradename Arimidex®);

Topoisomerase I inhibitors: Irinotecan (sold under the trademark Camptosar® by Pfizer), topotecan hydrochloride (sold under the tradename Hycamtin® by GlaxoSmithKline);

Topoisomerase II inhibitors: etoposide (also known as VP- 16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®), teniposide (also known as VM-26, sold under the tradename Vumon®); mTOR inhibitors: Temsirolimus (sold under the tradename Torisel® by Pfizer), ridaforolimus (formally known as deferolimus, (lR,2R,4S)-4-[(2R)-2- [(1R,9S,12S,15R,16E,18R,19R,21R, 23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30- dimethoxy-15,17,21,23, 29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4- azatricyclo[30.3.1.04 ' 9 ]hexatriaconta- 16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethylphosphinate, also known as AP23573 and MK8669, and described in PCT Publication No. WO 03/064383), everolimus (sold under the tradename Afinitor® by Novartis);

Proteasome inhibitor such as carfilzomib, MLN9708, delanzomib, or bortezomib;

BET inhibitors such as INCB054329, OTX015, and CPI-0610;

ESDI inhibitors such as GSK2979552, and INCB059872;

HIF-2α inhibitors such as PT2977 and PT2385;

Osteoclastic bone resorption inhibitors: l-hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate (sold under the tradename Zometa® by Novartis); CD33 Antibody Drug Conjugates: Gemtuzumab ozogamicin (sold under the tradename Mylotarg® by Pfizer/Wyeth);

CD22 Antibody Drug Conjugates: Inotuzumab ozogamicin (also referred to as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.);

CD20 Antibody Drug Conjugates: Ibritumomab tiuxetan (sold under the tradename Zevalin®);

Somatostain analogs: octreotide (also known as octreotide acetate, sold under the tradenames Sandostatin® and Sandostatin LAR®); Synthetic Interleukin- 11 (IL-11): oprelvekin (sold under the tradename Neumega® by

Pfizer/Wyeth);

Synthetic erythropoietin: Darbepoetin alfa (sold under the tradename Aranesp® by

Amgen);

Receptor Activator for Nuclear Factor κ B (RANK) inhibitors: Denosumab (sold under the tradename Prolia® by Amgen);

Thrombopoietin mimetic peptibodies: Romiplostim (sold under the tradename Nplate® by

Amgen;

Cell growth stimulators: Palifermin (sold under the tradename Kepivance® by Amgen); Anti-insulin-like Growth Factor- 1 receptor (IGF-1R) antibodies: Figitumumab (also known as CP-751,871, available from ACC Corp), robatumumab (CAS No. 934235-44-6); Anti-CSl antibodies: Elotuzumab (HuLuc63, CAS No. 915296-00-3);

CD52 antibodies: Alemtuzumab (sold under the tradename Campath®);

Histone deacetylase inhibitors (HDI): Voninostat (sold under the tradename Zolinza® by Merck);

Alkylating agents: Temozolomide (sold under the tradenames Temodar® and Temodal® by Schering-Plough/Merck), dactinomycin (also known as actinomycin-D and sold under the tradename Cosmegen®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename Alkeran®), altretamine (also known as hexamethylmelamine (HMM), sold under the tradename Hexalen®), carmustine (sold under the tradename BiCNU®), bendamustine (sold under the tradename Treanda®), busulfan (sold under the tradenames Busulfex® and Myleran®), carboplatin (sold under the tradename Paraplatin®), lomustine (also known as CCNU, sold under the tradename CeeNU®), cisplatin (also known as CDDP, sold under the tradenames Platinol® and Platinol®-AQ), chlorambucil (sold under the tradename Leukeran®), cyclophosphamide (sold under the tradenames Cytoxan® and Neosar®), dacarbazine (also known as DTIC, DIC and imidazole carboxamide, sold under the tradename DTIC-Dome®), altretamine (also known as hexamethylmelamine (HMM) sold under the tradename Hexalen®), ifosfamide (sold under the tradename Ifex®), procarbazine (sold under the tradename Matulane®), mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, sold under the tradename Mustargen®), streptozocin (sold under the tradename Zanosar®), thiotepa (also known as thiophosphoamide, TESPA and TSPA, sold under the tradename Thioplex®; Biologic response modifiers: bacillus calmette-guerin (sold under the tradenames theraCys® and TICE® BCG), denileukin diftitox (sold under the tradename Ontak®); Anti-tumor antibiotics: doxorubicin (sold under the tradenames Adriamycin® and Rubex®), bleomycin (sold under the tradename lenoxane®), daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename Cerubidine®), daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename DaunoXome®), mitoxantrone (also known as DHAD, sold under the tradename Novantrone®), epirubicin (sold under the tradename Ellence^TM), idarubicin (sold under the tradenames Idamycin®, Idamycin PFS®), mitomycin C (sold under the tradename Mutamycin®);

Anti-microtubule agents: Estramustine (sold under the tradename Emcyl®);

Cathepsin K inhibitors: Odanacatib (also know as MK-0822, N-(1-cyanocyclopropyl)-4- fluoro-N2-{ ( 1 S)-2,2,2-trifluoro-1 - [4'-(methy lsulfonyl)biphenyl-4-yl]ethyl} -L-leucinamide, available from Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, and described in PCT Publication no. WO 03/075836); Epothilone B analogs: Ixabepilone (sold under the tradename Lxempra® by Bristol- Myers Squibb);

Heat Shock Protein (HSP) inhibitors: Tanespimycin (17-allylamino-17- demethoxygeldanamycin, also known as KOS-953 and 17-AAG, available from SIGMA, and described in US Patent No. 4,261,989), NVP-HSP990, AUY922, AT13387, STA-9090, Debio 0932, KW-2478, XL888, CNF2024, TAS-116

TpoR agonists: Eltrombopag (sold under the tradenames Promacta® and Revolade® by GlaxoSmithKline);

Anti-mitotic agents: Docetaxel (sold under the tradename Taxotere® by Sanofi- Aventis); Adrenal steroid inhibitors: aminoglutethimide (sold under the tradename Cytadren®);

Anti-androgens: Nilutamide (sold under the tradenames Nilandron® and Anandron®), bicalutamide (sold under tradename Casodex®), flutamide (sold under the tradename Fulexin^TM); Androgens: Fluoxymesterone (sold under the tradename Halotestin®);

CDK (CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, CDKll/12, or CDK16) inhibitors including but not limited to Alvocidib (pan-CDK inhibitor, also known as flovopirdol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4- chromenone, and described in US Patent No. 5,621,002);

CDK4/6 inhibitors pabociclib, ribociclib, abemaciclib, and Trilaciclib; CDK9 inhibtiors AZD 4573, P276-00, AT7519M, TP-1287; CDK2/4/6 inhibitor such as PF-06873600;

SHP-2 inhibitor such as TN0155;

MDM2/MDMX, MDM2/p53 and/or MDMX/p53 modulators; Gonadotropin-releasing hormone (GnRH) receptor agonists: Leuprolide or leuprolide acetate (sold under the tradenames Viadure® by Bayer AG, Eligard® by Sanofi-Aventis and Lupron® by Abbott Lab);

Taxane anti-neoplastic agents: Cabazitaxel (l-hydroxy-7,10 -dimethoxy-9-oxo-5,20- epoxytax-11-ene-2a,4,13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{ [(tert-butoxy)carbonyl] - amino}-2-hydroxy-3-phenylpropanoate), larotaxel ((2α,3ξ,4α,5β,7α,10β,13α)- 4,10- bis(acetyloxy)- 13 -( { (2R,3S)-3- [(tert-butoxycarbonyl) amino] -2-hydroxy-3- phenylpropanoyl } - oxy)-1- hydroxy-9-oxo-5,20-epoxy-7,19-cyclotax-11-en-2-yl benzoate);

5HT1a receptor agonists: Xaliproden (also known as SR57746, 1- [2-(2-naphthyl)ethyl] -4- [3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine, and described in US Patent No.

5,266,573); HPC vaccines: Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck; Iron Chelating agents: Deferasinox (sold under the tradename Exjade® by Novartis);

Anti-metabolites: Claribine (2-chlorodeoxy adenosine, sold under the tradename leustatin®), 5-fluorouracil (sold under the tradename Adrucil®), 6-thioguanine (sold under the tradename Purinethol®), pemetrexed (sold under the tradename Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename Cytosar-U®), cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCyt^TM), decitabine (sold under the tradename Dacogen®), hydroxyurea (sold under the tradenames Hydrea®, Droxia^TM and Mylocel^TM), fludarabine (sold under the tradename Fludara®), floxuridine (sold under the tradename FUDR®), cladribine (also known as 2-chlorodeoxy adenosine (2-CdA) sold under the tradename Leustatin^TM), methotrexate (also known as amethopterin, methotrexate sodim (MTX), sold under the tradenames Rheumatrex® and Trexall^TM), pentostatin (sold under the tradename Nipent®);

Bisphosphonates: Pamidronate (sold under the tradename Aredia®), zoledronic acid (sold under the tradename Zometa®); Demethylating agents: 5-azacitidine (sold under the tradename Vidaza®), decitabine (sold under the tradename Dacogen®);

Plant Alkaloids: Paclitaxel protein-bound (sold under the tradename Abraxane®), vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, sold under the tradenames Alkaban-AQ® and Velban®), vincristine (also known as vincristine sulfate, LCR, and VCR, sold under the tradenames Oncovin® and Vincas ar Pfs®), vinorelbine (sold under the tradename Navelbine®), paclitaxel (sold under the tradenames Taxol and Onxal^TM);

Retinoids: Alitretinoin (sold under the tradename Panretin®), tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®), Isotretinoin (13-cis-retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravis®, Claras®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (sold under the tradename Targretin®);

Glucocorticosteroids : Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala-Cort®,

Hydrocortisone Phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), dexamethazone ((8S,9R,10S,11S, 13S, 14S, 16R, 17R)-9-fluoro-11, 17 -dihydroxy- 17 -(2-hydroxyacetyl)- 10,13,16- trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one), prednisolone (sold under the tradenames Delta-Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (sold under the tradenames Deltasone®, Liquid Red®, Meticorten® and Orasone®), methylprednisolone (also known as 6-Methylprednisolone, Methylprednisolone Acetate, Methylprednisolone Sodium Succinate, sold under the tradenames Duralone®, Medralone®, Medrol®, M-Prednisol® and Solu-Medrol®);

Cytokines: interleukin-2 (also known as aldesleukin and IL-2, sold under the tradename Proleukin®), interleukin- 11 (also known as oprevelkin, sold under the tradename Neumega®), alpha interferon alfa (also known as IFN-alpha, sold under the tradenames Intron® A, and Roferon-A®); [00209] Estrogen receptor downregulators: Fulvestrant (sold under the tradename Faslodex®);

Anti-estrogens: tamoxifen (sold under the tradename Novaldex®); Toremifene (sold under the tradename Fareston®);

Selective estrogen receptor modulators (SERMs): Raloxifene (sold under the tradename

Evista®);

Leutinizing hormone releasing hormone (LHRH) agonists: Goserelin (sold under the tradename Zoladex®); Progesterones: megestrol (also known as megestrol acetate, sold under the tradename Megace®);

Miscellaneous cytotoxic agents: Arsenic trioxide (sold under the tradename Trisenox®), asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the tradenames Elspar® and Kidrolase®);

One or more immune checkpoint inhibitors CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, 0X40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM kinase, arginase,

CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, HIF-2a, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, CD137 and STING. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, Arginase, KIR, LAG3, PD-1, TIM3, CD96, TIGIT and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD 160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, or pembrolizumab or PDR001. In some embodiments, the anti-PD1 antibody is pembrolizumab.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A

(atezolizumab) or MEDI4736 (durvalumab).

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti- LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or, MK-4166, INCAGN01876 or MK-1248. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of 0X40, e.g., an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562 or, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525. In some embodiments, the OX40L fusion protein is MEDI6383.

Compounds of the invention can also be used to increase or enhance an immune response, including increasing the immune response to an antigen; to improve immunization, including increasing vaccine efficacy; and to increase inflammation. In some embodiments, the compounds of the invention can be sued to enhance the immune response to vaccines including, but not limited, Listeria vaccines, oncolytic viral vaccines, and cancer vaccines such as GVAX® (granulocyte-macrophage colony -stimulating factor (GM-CF) gene-transfected tumor cell vaccine). Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses. Other immune-modulatory agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4; Sting agonists and Toll receptor agonists.

Other anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer. Compounds of this application may be effective in combination with CAR (Chimeric antigen receptor) T cell treatment as a booster for T cell activation.

A compound of Formula (I) can also be used in combination with the following adjunct therapies: anti-nausea drugs: NK-1 receptor antagonists: Casopitant (sold under the tradenames Rezonic® and Zunrisa® by GlaxoSmithKline); and

Cytoprotective agents: Amifostine (sold under the tradename Ethyol®), leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid).

Examples

The following preparations of compounds of Formula (I) are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof.

Example 1

Synthesis of rac-8-cyclopentyl-2-(((4aR,6R)-1,1-dioxidooctahy dropyrido[1,2-b] [1,2,6] -thiadiazin- 6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one [1] and rac-8-cyclopentyl-2-(((4aR,6S)-1,1- dioxidooctahydropyrido[1,2-b][1,2,6]thiadiazin-6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one [2]

Step 1: 3-(1,3-dioxoisoindol-2-yl)propanal

To a stirred solution of oxalyl chloride (9.28 g, 73 mmol, 1.50 equiv) in DCM (80 mL) was added DMSO (6.09 g, 78 mmol, 1.60 equiv) in DCM (10 mL) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 10 min at -78 °C under nitrogen atmosphere and 2-(3-hydroxypropyl)isoindole-1,3-dione (10.0 g, 49 mmol, 1.00 equiv) in DCM (10 mL) was added dropwise at -78 °C. The resulting mixture was stirred for additional 1 h at -78 °C. TEA (37.0 g, 365 mmol, 7.50 equiv) was added and the cold bath was removed. After stirring at room temperature for 30 min, the reaction mixture was quenched with saturated NH₄C1(aq.). The organic layer was washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (0-30%), to afford the title compound (5.10 g, 51.5%) as a white solid. MS(ES, m/z): [M+1]⁺ = 204.0.

Step 2: N-(but-3-en-1-yl)-4-methylbenzenesulfonamide

To a stirred solution of 3 -buten-1-amine hydrochloride (5 g, 46.477 mmol, 1.00 equiv), DMAP (1.7 g, 13.943 mmol, 0.3 equiv) and TEA (5.64 g, 55.772 mmol, 1.2 equiv) in DCM (40 mL) was added TsCI (10.6 g, 55.772 mmol, 1.2 equiv) in portions at 0 °C. The resulting mixture was stirred for 3 h at room temperature and then quenched with water and extracted with CH₂CI₂. The combined organic layers were washed with washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE(0-20%), to afford the title compound (8.8 g, 84.0%) as a yellow oil. MS(ES, m/z): [M+1]⁺ = 226.0.

Step 3: 2-(2-(4-hydroxy-1-tosylpiperidin-2-yl)ethyl)isoindoline-1,3-dione

A mixture of N-(but-3-en- 1 -yl)-4-methylbenzenesulfonamide (6.21 g, 27.559 mmol, 1.00 equiv), phosphomolybdic acid (2.0 g, 9.843 mmol, 0.35 equiv) and 3-(l,3-dioxoisoindol-2- yl)propanal (5.60 g, 27.559 mmol, 1.00 equiv) in DCM (50 mL) was stirred overnight at 40 °C. The resulting mixture was diluted with DCM. The organic layers were washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE(0-100%), to afford the title compound (3.3 g, 27.9%) as a yellow solid. MS(ES, m/z): [M+1]⁺ = 429.1. Step 4: 2-(2-(4-((tert-butyldimethylsilyl)oxy)-1-tosylpiperidin-2-yl)ethyl)isoindoline-1,3-dione

To a stirred mixture of 2-(2-(4-hydroxy-1-tosylpiperidin-2-yl)ethyl)isoindoline-1,3-dione (3.30 g, 7.701 mmol, 1.00 equiv) and imidazole (0.79 g, 11.552 mmol, 1.50 equiv) in DCM (35 mL) was added TBSCI (2.32 g, 15.403 mmol, 2.00 equiv) in portions at 0 °C. After stirring for 4 h at room temperature, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (0-30%), to afford the title compound (1.9 g, 45.4%) as an off-white solid. MS(ES, m/z): [M+1]⁺ = 543.2.

Step 5 : 2-(4-((tert-butyldimethylsilyl)oxy)-1-tosylpiperidin-2-yl)ethan-1-amine

A solution of 2-(2-(4-((tert-butyldimethylsilyl)oxy)-1-tosylpiperidin-2-yl)ethyl)isoindoline- 1,3-dione (1.90 g, 3.501 mmol, 1.00 equiv) and NH₂NH₂.H₂O (0.53 g, 10.587 mmol, 3.02 equiv, 98%) in THF (20 mL) was stirred overnight at 60 °C under nitrogen atmosphere. The mixture was cooled to room temperature and diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH/CH₂Cl₂ (0-10%), to afford the title compound (1.1 g, 76.15%) as a yellow oil. MS(ES, m/z): [M+1]⁺ = 413.1.

Step 6: 2-(4-((tert-buty ldimethy lsily l)oxy)piperidin-2-yl)ethan-1-amine

To a stirred solution of naphthalene (3.42 g, 26.656 mmol, 10.00 equiv) in DME (11 mL) was added metallic sodium (0.61 g, 26.656 mmol, 10.00 equiv) in portions at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature until Na and naphthalene completely dissolved. A solution 2-(4-((tert-butyldimethylsilyl)oxy)-1-tosylpiperidin- 2-yl)ethan-1-amine (260 mg, 0.630 mmol, 1.00 equiv) in THF (11 mL) was added at -78 °C. The reaction temperature was allowed to warm to 0 °C slowly in 2 h. The resulting solution was stirred at 0 °C until the reaction was completed. The reaction mixture was added to sat. aq. NH₄CI solution at -10°C and then extracted with EtOAc. The combined organic layer was diluted with water and then filtered. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated to give the title compound (600 mg, crude). The crude product was used in the next step directly without further purification. MS(ES, m/z): [M+1]⁺ = 259.1.

Step 7: 6-((tert-butyldimethylsilyl)oxy)octahydropyrido[1,2-b][1,2,6]thiadiazine 1,1 -dioxide

A solution of 2-(4-((tert-butyldimethylsilyl)oxy)piperidin-2-yl)ethan-1-amine (600 mg, 2.321 mmol, 1.00 equiv.) and sulfamide (446 mg, 4.643 mmol, 2.00 equiv) in pyridine (6 mL) was stirred overnight at 120 °C. After cooling to rt, the reaction mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography, eluted with EtOAc/PE(0-50%), to afford the title compound (320 mg, 43.0%) as a yellow solid. MS(ES, m/z): [M+1]⁺ = 321.1.

Step 8: 6-hydroxyoctahydropyrido[1,2-b][1,2,6]thiadiazine 1,1 -dioxide

To a stirred mixture of 6-((tert-butyldimethylsilyl)oxy)octahydropyrido[1,2-b][1,2,6]- thiadiazine 1,1-dioxide (320 mg, 0.998 mmol, 1.00 equiv) was added a solution of HCI in dioxane (4.0 M, 4 mL, 16 mmol, 16 equiv) dropwise at 0 °C. After stirred at room temperature for 24 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtO Ac/PE(0- 100%), to afford the title compound (170 mg, 82.5%) as a yellow solid. MS(ES, m/z): [M+1]⁺ = 207.0.

Step 9: hexahy dropyrido[1,2-b] [1,2,6]thiadiazin-6(2H)-one 1,1 -dioxide

A solution of 6-hydroxyoctahydropyrido[1,2-b][1,2,6]thiadiazine 1,1 -dioxide (40 mg, 0.194 mmol, 1.00 equiv) and Dess-Martin reagent (123 mg, 0.291 mmol, 1.50 equiv) in DCM (0.5 mL) was stirred overnight at room temperature. The resulting mixture was diluted with water and extracted with EtO Ac. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (0-50%), to afford the title compound (20 mg, 50.49%) as a yellow oil. MS(ES, m/z): [M+1]⁺ = 205.0.

Step 10: 6-aminooctahydropyrido[1,2-b] [1,2,6]thiadiazine 1,1 -dioxide

To a stirred solution of hexahy dropyrido[ 1 ,2-b] [1,2,6]thiadiazin-6(2H)-one 1,1 -dioxide (80 mg, 0.390 mmol, 1.00 equiv) and NH₄OAc (300 mg, 3.897 mmol, 10.00 equiv) in MeOH (2 mL) was added NaBH₃CN (49 mg, 0.779 mmol, 2 equiv) in portions and the resulting mixture was stirred for 2 h at 70 °C. After cooling to rt, the reaction mixture was concentrated under reduced pressure and then diluted with water, extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give the title compound (120 mg). The crude product was used in the next step directly without further purification. MS(ES, m/z): [M+1]⁺ = 206.1.

Step 11: tert-butyl (1,1 -dioxidooctahy dropyrido[1 ,2-b] [1,2,6]thiadiazin-6-yl)carbamate

A solution of 6-aminooctahydropyrido[1,2-b] [1 ,2,6]thiadiazine 1,1 -dioxide (120 mg, 0.386 mmol, 1.00 equiv), Boc₂O (126 mg, 0.579 mmol, 1.50 equiv) and DIEA (149 mg, 1.157 mmol, 3.00 equiv) in DCM (2 mL) was stirred for 2 h at room temperature. The resulting mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluted with EtO Ac/PE (0-90%), to afford the compound (50 mg, 28.01%) as a white solid. MS(ES, m/z): [M+1]⁺ = 306.0.

Step 12: 6-aminooctahydropyrido[1,2-b] [1 ,2,6]thiadiazine 1,1-dioxide

A flask was charged with tert-butyl (1,1 -dioxidooctahy dropyrido [1,2-b] [1,2,6]thiadiazin-6- yl)carbamate (40 mg, 0.035 mmol, 1.00 equiv) and a solution of HC1 in dioxane (4.0 M, 0.1 mL, 0.4 mmol, 11.4 equiv) was added dropwise at 0 °C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under vacuum and washed with Et20 to give the title compound (40 mg). The crude product was used in the next step directly without further purification. MS(ES, m/z): [M+1]⁺= 206.0.

Step 13 : rac-8-cyclopentyl-2-(((4aR,6R)-1,1-dioxidooctahydropyrido[1,2-b] [1,2,6]thiadiazin-6- yl)amino)pyrido[2,3-d]pyrimidin-7 (8H)-one [1] and rac-8-cyclopentyl-2-(((4aR,6S)-1,1- dioxidooctahydropyrido[1,2-b][1,2,6]thiadiazin-6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one [2]

A solution of 8-cyclopentyl-2-methanesulfonylpyrido[2,3-d]pyrimidin-7-one (330 mg, 1.125 mmol, 1.10 equiv), DIEA (107 mg, 0.827 mmol, 5.00 equiv) and 6-aminooctahy dropyrido[ 1 ,2- b] [ 1 ,2,6]thiadiazine 1,1 -dioxide hydrochloride (210 mg, 1.02 mmol, 1.00 equiv) in IP A (3.50 mL) was stirred for 16 h at 80 °C under nitrogen atmosphere. The mixture was then purified by Prep- HPLC to give two diastereomers in racemic form rac 1 and rac 2. MS(ES, m/z): [M+1]⁺ = 419.2. One of 1 and 2 has t_R4.17 min, the other of 1 and 2 has t_R4.19 min.

HPLC Analysis Conditions: Column: Ascentis Express C18, 3.0*100 mm, 2.7 μm, Column temperature: 40 °C Mobile Phase: A: water/0.05%TFA; B : Acetonitrile/THF=50: 50; Flow Mode: Time/Solv.B(%)

0.0/10.0

6.0/95.0

8.0/95.0

8.1/10.0

Flow rate: 1.2 ml/min

Example 2

Synthesis of 8-cy clopentyl-2-(((4aR,6R)-1,1-dioxidooctahy dropyrido[1,2-b] [ 1 ,2,6]thiadiazin- 6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one [3] and 8-cyclopentyl-2-(((4aS,6S)-1,1- dioxidooctahydropyrido[1,2-b][1,2,6]thiadiazin-6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one [4] or 8-cyclopentyl-2-(((4aR,6S)-1,1-dioxidooctahydropyrido[1,2-b] [1,2,6]thiadiazin-6- yl)amino)pyrido[2,3-d] pyrimidin-7 (8H)-one [5] and 8-cyclopentyl-2-(((4aS,6R)-1,1- dioxidooctahydropyrido[1,2-b][1,2,6]thiadiazin-6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one [6]

The racemic mixture with t_R4.19 min was further separated by CHIRAL_ HPLC (Mobile phase: A: n-Hexane/DCM=3/l; Mobile phase B: Ethanol; Flow rate: 18mL/min; Column: CHIRALPAK IC, 250*20mm, 5 μm Gradient: 50%B in 20min; 220nm) to give two enantiomerically pure compounds. The compounds are either enantiomers 3 and 4 or 5 and 6.

Biological Examples Example 1

CDK2/Cyclin E1 Enzyme Assay

The ability of the disclosed compounds to inhibit CDK2 was determined as follows. The kinase reactions were carried out in 384- well white polystyrene plates (Greiner Bio-One, Cat #784075) using assay buffer containing 50 mM HEPES (pH7.5), 10 mM MgCl₂, 1 mM EGTA, 0.01% Tween-20 and 2 mM DTT. 0.05 nM full-length CDK2/Cyclin E complex (Cama Biosciences, Cat # 04-165) was co-incubated with various concentrations of test compounds in 8 ul of assay buffer for 2 hours at room temperature. The reaction was initiated by addition of 4 ul substrate mixture containing 3 mM ATP and 150 nM of Ulight-MBP peptide (Perkin Emler, TRF0109) in assay buffer. After incubation at room temperature for 1 hour, the reaction was terminated by adding 4 ul detection solution containing 50 mM Tris (pH7.8), 150 mM NaCl, 0.05% BSA, 40 mM EDTA, and 4 nM Europium-conjugated anti-phospho-MBP antibody (Perkin Elmer, TRF0201). Fluorescence signals were measured on ClarioSTAR plate reader (BMG Labtech) using the TR-FRET (time-resolved fluorescence resonance energy transfer) mode (Ex 332 nm, Em 620/665 nm). The TR-FRET ratio was plotted against the inhibitor concentration and normalized to enzyme/no enzyme controls. Half maximal inhibitory concentration (IC₅₀) values were calculated with a four-parameter logistic fit using GraphPad Prism (version 8; La Jolla, CA).

CDK IC₅₀ data for selected compounds are provided in Table 2.

Table 2

* If the compound with a CDK2 IC₅₀ of 0.068 is 3, then the compound with a CDK2 IC₅₀ of 5.9 is 4 or vice versa. Similarly, if the compound with a CDK2 IC₅₀ of 0.068 is 5, then the compound with a CDK2 IC₅₀ of 5.9 is 6.

Formulation Examples

The following are representative pharmaceutical formulations containing a compound of the present disclosure.

Tablet Formulation

The following ingredients are mixed intimately and pressed into single scored tablets.

Capsule Formulation

The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.

Injectable Formulation

Compound of the disclosure (e.g., compound 1) in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL

Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound disclosed herein 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, such as a nebulizer, which is suitable for inhalation administration. Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxypropyl cellulose, 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 containers, such as tubes, which are suitable for topical administration.

Ophthalmic Solution Composition

To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound disclosed herein is mixed with 0.9 g of N aCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.

Nasal spray solution

To prepare a pharmaceutical nasal spray solution, 10 g of a compound disclosed herein is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 ul of spray for each application.

Claims

What is Claimed:

1. A compound of Formula (I):

wherein:

Hy is a a ring according to formula (i):

where:

A is C=(O), S(O), S(O)₂, or S(O)(=NR) where R is hydrogen or alkyl;

X is CH or N;

Y is CH, CMe, or N; provided that at least one of X and Y is N; z is 0, 1, or 2; z’ and z” are independently 0 or 1; provided that at least one of z’ and z” is 1; and R⁵ is hydrogen, alkyl, cycloalkyl, or heterocyclyl, wherein alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, cyano, alkoxy, haloalkyl, haloalkoxy, alkylsulfonyl, NR^aR^b, C(O)NR^cR^d, and NR^eCOR^f [where R^a, R^b, R^c, R^d, R^e, and R^f are independently hydrogen, alkyl, cycloalkyl, or heterocyclyl (wherein alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, cyano, alkoxy, haloalkyl, alkylsulfonyl, and haloalkoxy) or R^aand R^b, and R^c and R^d together with the nitrogen atom to which they are attached form heterocyclyl which can be optionally substituted with one or two substituents independently selected from alkyl, hydroxy, halo, cyano, alkoxy, haloalkyl, and haloalkoxy]; and further wherein Hy is substituted with R⁶, R⁷, and/or R⁸ where R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and NR^gR^h (wherein R^g and R^h are independently hydrogen, alkyl, and cycloalkyl); or R⁶ and R⁷, when attached to the same carbon of Hy, can cyclize to form a cycloalkylene or heterocyclylene; and

R⁸ is hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, halo, -C(O)NR^jR^k, -NR^wCOR^m, or heterocyclyl wherein alkyl, cycloalkyl, and heterocyclyl of R⁸ are optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, cyano, alkoxy, haloalkyl, haloalkoxy, NRⁿR^o, S(O)₂R^p, C(O)NR^qR^r, SO₂NR^sR^t, and NR^uCOR^v [where R^j, R^k, R^w, R^m, Rⁿ, R^o, R^p, R^q, R^r, R^s, R^t, R^u, and R^v are independently hydrogen, alkyl, cycloalkyl, or heterocyclyl

(where alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, hydroxy, cyano, alkoxy, haloalkyl, and haloalkoxy) or independent of each other, Rⁿ and R^o, R^q and R^r, and R^s and R^t, together with the nitrogen atom to which they are attached, form heterocyclyl which can be optionally substituted with one or two substituents independently selected from alkyl, hydroxy, halo, cyano, alkoxy, alkylsulfonyl, and haloalkoxy];

R¹ is H, NH₂, alkyl, halo, or haloalkyl;

R² is hydrogen, halo, alkyl, haloalkyl, or cycloalkyl where alkyl and cycloalkyl are optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, cyano, alkoxy, and haloalkoxy;

R³ is hydrogen, halo, NH₂, alkyl, haloalkyl, cycloalkyl, aryl, or heterocyclyl where alkyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, cyano, alkoxy, haloalkyl, haloalkoxy, C(O)NH₂, and C(O)OH; and

R⁴ is alkyl, cycloalkyl, or heterocyclyl where alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, cyano, halo, and hydroxy; or a pharmaceutically acceptable salt thereof

2. The compound of claim 1, or a pharmaceutical salt thereof, wherein R¹ and R² are hydrogen.

3. The compound of claim 1 or 2, or a pharmaceutical salt thereof, wherein R⁴ is cycloalkyl optionally substituted with one or two substituents independently selected from alkyl, alkoxy, cyano, halo, and hydroxy.

4. The compound of claim lor 2, or a pharmaceutical salt thereof, wherein R⁴ is unsubstituted cycloalkyl.

5. The compound of claim lor 2, or a pharmaceutical salt thereof, wherein R⁴ is cycloalkyl substituted with hydroxy or alkyl, or with both hydroxyl and alkyl.

6. The compound of claim 1 or 2, or a pharmaceutical salt thereof, wherein R⁴ is a group of structure

7. The compound of any one of claims 1 to 6, or a pharmaceutical salt thereof, wherein R³ is hydrogen, halo, haloalkyl, or alkyl optionally substituted with hydroxy.

8. The compound of any one of claims 1 to 6, or a pharmaceutical salt thereof, wherein R³ is hydrogen.

9. The compound of any one of claims 1 to 7, or a pharmaceutical salt thereof, wherein R³ is haloalkyl.

10. The compound of any one of claims 1 to 7 and 9, or a pharmaceutical salt thereof, wherein R³ is difluoromethyl.

11. The compound of any one of claims 1 to 7, or a pharmaceutical salt thereof, wherein R³ is alkyl substituted with hydroxy.

12. The compound of any one of claims 1 to 7 and 11, or a pharmaceutical salt thereof, wherein R³ is 2-hydroxymethyl.

13. The compound of any one of claims 1 to 12, or a pharmaceutical salt thereof, wherein Hy is a ring of formula:

where Hy is substituted with R⁶, R⁷, and/or R⁸.

14. The compound of any one of claims 1 to 12, or a pharmaceutical salt thereof, wherein Hy is a ring of formula: where z is 1 or 2 and Hy is substituted with R⁶, R⁷, and/or R⁸.

15. The compound of any one of claims 1 to 12, or a pharmaceutical salt thereof, wherein Hy is a ring of formula:

where Hy is substituted with R⁶, R⁷, and/or R⁸.

16. The compound of any one of claims 1 to 15, or a pharmaceutical salt thereof, wherein X and Y are N.

17. The compound of any one of claims 1 to 15, or a pharmaceutical salt thereof, wherein X is N and Y is CH.

18. The compound of any one of claims 1 to 15, or a pharmaceutical salt thereof, wherein Y is N and X is CH.

19. The compound of any one of claims 1 to 18, or a pharmaceutical salt thereof, wherein R⁵ is hydrogen.

20. The compound of any one of claims 1 to 18, or a pharmaceutical salt thereof, wherein R⁵ is alkyl optionally substituted with one or two substituents independently selected from hydroxy, alkoxy, halo, and alkylsulfonyl.

21. The compound of any one of claims 1 to 18, or a pharmaceutical salt thereof, wherein R⁵ is methyl, ethyl, 2-methoxy ethyl, or 2-hydroxy ethyl.

22. The compound of any one of claims 1 to 18, or a pharmaceutical salt thereof, wherein R⁵ is heterocyclyl optionally substituted with one or two substituents independently selected from hydroxy, alkoxy, halo, and alkylsulfonyl.

23. The compound of any one of claims 1 to 18, or a pharmaceutical salt thereof, wherein R⁵ is oxetane, tetrahydrofuran, or tetrahydropyranyl.

24. The compound of any one of claims 1 to 18, or a pharmaceutical salt thereof, wherein R⁵ is cycloalkyl optionally substituted with one or two substituents independently selected from hydroxy, alkoxy, and halo.

25. The compound of any one of claims 1 to 24, or a pharmaceutical salt thereof, wherein R⁶, R⁷, and R⁸ are hydrogen.

26. The compound of any one of claims 1 to 24, or a pharmaceutical salt thereof, wherein Hy is substituted with R⁷ and R⁸.

27. The compound of claim 26, or a pharmaceutical salt thereof, wherein R⁸ is alkyl, alkoxy, hydroxy, or halo wherein alkyl of R⁸ is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, NRⁿR^o, and S(O)₂R^p [where Rⁿ, R^o, and R^p are independently hydrogen, alkyl, cycloalkyl, and heterocyclyl (where alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, hydroxy, cyano, alkoxy, haloalkyl, and haloalkoxy) or Rⁿ and R^o together with the nitrogen atom to which they are attached form heterocyclyl which can be optionally substituted with one or two substituents independently selected from alkyl, hydroxy, halo, cyano, alkoxy, and haloalkoxy].

28. The compound of claim 26 or 27, or a pharmaceutical salt thereof, wherein R⁸ is attached to the carbon that is adjacent to -X(R⁵)- group in Hy.

29. The compound of any one of claims 1 to 24, or a pharmaceutical salt thereof, wherein Hy is substituted with R⁸ where R⁸ is not hydrogen.

30. The compound of claim 29, or a pharmaceutical salt thereof, wherein R⁸ is alkyl, alkoxy, hydroxy, or halo wherein alkyl of R⁸ is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, NRⁿR^o, and S(O)₂R^P [where Rⁿ, R^o, and R^p are independently hydrogen, alkyl, cycloalkyl, and heterocyclyl (where alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, hydroxy, cyano, alkoxy, haloalkyl, and haloalkoxy) or Rⁿ and R^o together with the nitrogen atom to which they are attached form heterocyclyl which can be optionally substituted with one or two substituents independently selected from alkyl, hydroxy, halo, cyano, alkoxy, and haloalkoxy].

31. The compound of claim 30, or a pharmaceutical salt thereof, wherein R⁸ is attached to carbon that is adjacent to -X(R⁵)- group in Hy.

32. A pharmaceutical composition comprising a compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

33. A method of inhibiting CDK2 which method comprises contacting CDK2 with a compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, or with a pharmaceutical composition of claim 32.

34. A method of treating a disease mediated by CDK2 in a patient which method comprises administering to the patient in recognized need thereof, a therapeutically effective amount of a pharmaceutical composition comprising a compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

35. A method of treating cancer in a patient which method comprises administering to the patient in recognized need thereof, a therapeutically effective amount of a pharmaceutical composition comprising a compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

36. The method of claim 35, wherein the the compound of claim 1 to 31, or a pharmaceutically acceptable salt thereof, is administered in combination with at least one other anticancer agent.

37. The method of claim 35 or 36, wherein the cancer is lung cancer, skin cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, head and neck cancer, liver cancer, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach cancer, thyroid cancer, or parathyroid cancer.