WO2015135094A1

WO2015135094A1 - Therapeutic compounds and uses thereof

Info

Publication number: WO2015135094A1
Application number: PCT/CN2014/000261
Authority: WO
Inventors: Brian K. Albrecht; Victor S. Gehling; Jean-Christophe Harmange; Tommy Lai; Jun Liang; Peter Dragovich; Dan ORTWINE; Sharada Labadie; Birong Zhang; Jim KIEFER
Original assignee: Genentech Inc; Constellation Pharmaceuticals Inc
Current assignee: Genentech Inc; Constellation Pharmaceuticals Inc
Priority date: 2014-03-13
Filing date: 2014-03-13
Publication date: 2015-09-17
Anticipated expiration: 2016-09-13

Abstract

The present invention relates to compounds useful as inhibitors of one or more histone demethylses, such as KDM5. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.

Description

THERAPEUTIC COMPOUNDS AND USES THEREOF

TECHNICAL FIELD

Compounds useful as inhibitors of histone demethylases, such as KDM5 are provided.

BACKGROUND

Packaging the 3 billion nucleotides of the human genome into the nucleus of a cell requires tremendous compaction. To accomplish this feat, DNA in our chromosomes is wrapped around spools of proteins called histones to form dense repeating protein/DNA polymers known as chromatin. Far from serving as mere packaging modules, chromatin templates form the basis of a newly appreciated and fundamentally important set of gene control mechanisms termed epigenetic regulation. By conferring a wide range of specific chemical modifications to histones and DNA, epigenetic regulators modulate the structure, function, and accessibility of our genome, thereby exerting a tremendous impact on gene expression. Hundreds of epigenetic effectors have recently been identified, many of which are chromatin-binding or chromatin-modifying enzymes. Significantly, an increasing number of these enzymes have been associated with a variety of disorders such as cancer. Thus, therapeutic agents directed against this emerging class of gene regulatory enzymes promise new approaches to the treatment of human diseases.

Additionally, the relatively rapid acquisition of resistance to cancer drugs remains a key obstacle to successful cancer therapy. Substantial efforts to elucidate the molecular basis for such drug resistance have revealed a variety of mechanisms, including drug efflux, acquisition of drug binding-deficient mutants of the target, engagement of alternative survival pathways and epigenetic alterations. Rare, stochastic, resistance-conferring genetic alterations have been found within a tumor cell population selected during drug treatment. See Sharma et al, Cell 141(l):69-80 (2010). The KDM5/JARID1 family of histone demethylases was found to play a role in cancer resistance. The KDM5/JARID1 family of demethylases in humans contains four members, KDM5A, KDM5B, KDM5C and KDM5D. KDM5 family members contain five conserved domains: JmjN, ARID, JmjC, PHD and a C₅HC₂ zinc finger. Amino acid sequences of KDM5A, KDM5B, KDM5C and KDM5D are known and are publicly available, e.g., see UniProtKB/Swiss-Prot {see e.g., KDM5A {e.g., P29375-1 and P29375-2), KDM5B {e.g., Q9UGL1-1 and Q9UGL 1-2), KDM5C {e.g., P41229-1, P41229-2, P41229-3 and P41229-4) and KDM5D {e.g., Q9BY66-1, Q9BY66-2 and Q9BY66-3). There is currently a need for compounds that inhibit of KDM5 demethylases for treating

hyperproliferative diseases, preventing drug resistance, and/or for improving the efficacy of other cancer treatments (e.g. targeted therapies, chemotherapies, and radiotherapies. SUMMARY OF THE INVENTION

One aspect provides a compound as described in any one of Examples 1-432 or a salt thereof.

Another aspect provides a compound of formula (I):

I

or a salt thereof, wherein:

R¹ is H, Ci_₆alkyl, trifluoromethyl, 3-6 membered carbocyclyl, 6 membered aryl, 3-6 f f f

membered heterocyclyl, 5-6 membered heteroaryl, halo, -OR , -SR , -N(R )₂, -CN, or -N0₂, wherein said alkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more groups independently selected from oxo, halo, Ci_3alkoxy and Ci_3alkyl;

R² is H, Ci_i₂alkyl, C₂_i₂alkenyl, C₂_i₂alkynyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, halo, -OR^a, -SR^a, -N(R^a)₂, -CN, -N0₂, -C(0)R^a, -C0₂R^a, -C(0)N(R^a)₂, -C(0)SR^a, -C(0)C(0)R^a, -C(0)CH₂C(0)R^a, -C(S)N(R^a)₂, -C(S)OR^a, -S(0)R^a, -S0₂R^a, -S0₂N(R^a)₂, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, -N(R^a)S0₂

R^a, -N(R^a)S0₂N(R^a)₂, -N(R^a)N(R^a)₂, -N(R^a)C(=N(R^a))N(R^a)₂, -C(=N)N(R^a)₂, - C=NOR^a, -C(=N(R^a))N(R^a)₂, -OC(0)R^a, or -OC(0)N(R^a)₂, wherein each Ci i₂alkyl, C₂ i₂alkenyl, C₂_i₂alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl of R² and R³ is independently optionally substituted with one or more groups R^x; and wherein R² and R³ are not each H; or R² and R³ taken together with the atoms to which they are attached form a 4, 5, 6, 7, or 8 membered carbocyclyl or aryl, which carbocyclyl or aryl is optionally substituted with one or more groups R^x;

R³ is aryl or heteroaryl, wherein each aryl and heteroaryl is optionally substituted with one or more groups R^x;

R⁴ is H, Ci_i₂alkyl, C₂_i₂alkenyl, C₂_i₂alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl, wherein each Ci_i₂alkyl, C₂_i₂alkenyl, C₂_i₂alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, Ci_i₂ alkyl, Ci_i₂haloalkyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, halo, -CN, -N0₂, -NR^mR^m, -OR^m, -C(=0)OR^m, and -OC(=0)R^m; or R⁴ and R³ taken together with the atoms to which they are attached form a heterocyclyl; each R^a is independently selected from H, Ci_6alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl, wherein each Ci_₆alkyl, C₃_₆alkenyl,

C₃_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups R^x;

each R is independently selected from H, Ci_₃ alkyl, trifluoromethyl, 3-6 membered carbocyclyl, 6 membered aryl, 3-6 membered heterocyclyl, and 5-6 membered heteroaryl, or two R groups together with the nitrogen to which they are attached form a 3-6 membered heterocyle;

each R^m is independently selected from H, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, Ci_₆haloalkyl, carbocyclyl, Ci_₆ alkanoyl, phenyl, and benzyl, wherein any Ci_₆alkyl,

C₂_₆alkenyl, C₂_₆alkynyl,Ci_₆ haloalkyl, carbocyclyl, Ci_₆ alkanoyl, phenyl, or benzyl is optionally substituted with one or more groups independently selected from halo, - CN, -N0₂, -NR^yR^z, and -OR^w; or two R^m groups together with the nitrogen to which they are attached form a 3-6 membered heterocyle;

each R^v is independently hydrogen, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl,wherein each Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, aryl, carbocyclyl, and Ci-C₆ alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^v are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and Ci_₃alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^w is independently selected from H, C_halky 1,

phenyl, benzyl, and phenethyl;

each R^x is independently selected from oxo, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, heterocycle, -F, -CI, -Br, -I, -N0₂, -N(R^V)₂, -CN, -C(O)- N(R^V)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -0-C(0)-0-R^v, -C(O)- R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -0-C(0)-N(R^v)₂, -N(R^v)-C(0)-OR^v, -N(R^v)-C(0)- N(R^V)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-S(0)-R^v, -N(R^v)-S(0)₂-R^v, -N(R^v)-S(0)- N(R^V)₂, and -N(R^v)-S(0)₂-N(R^v)₂,wherein any Ci_₆alkyl, C₂^alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocycle is optionally substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(O)- N(R^V)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂- R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)-

R^v, -N(R^v)-S(0)₂-R^v, and Ci_₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^y and R^z is independently selected from H, Ci_₄alkyl, Ci_₄alkanoyl,

Ci_₄alkoxycarbonyl, phenyl, benzyl, and phenethyl, or R^y and R^z together with the nitrogen to which they are attached form a heterocyclyl;

each R^xa is independently selected from aryl, heteroaryl, heterocycle, and carbocycle, wherein any aryl, heteroaryl, heterocycle, and carbocycle is optionally substituted with one or more groups independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, -F, -CI, -Br, -I, -N0₂, -N(R^V)₂, -CN, carbocycle, aryl, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S- R^v, -0-C(0)-R^v, -0-C(0)-0-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -O-C(O)- N(R^V)₂, -N(R^v)-C(0)-OR^v, -N(R^v)-C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R S(0)-R^v, -N(R^v)-S(0)₂-R^v, and -N(R^v)-S(0)-N(R^v)₂, wherein any

C₂_₆alkenyl, and C₂_₆alkynyl is optionally substituted with one or more groups independently selected from oxo, halo, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -O- C(0)-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R C(0)-R^v, -N(R^v)-S(0)-R^v, and -N(R^v)-S(0)₂-R^v.

Another aspect includes a composition, comprising a compound as described in any one of Examples 1-432, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

Another aspect includes compounds and compositions for treating diseases, disorders or conditions associated with KDM5 activity. Such diseases, disorders, or conditions include those described herein.

Another aspect includes a method of treating a disease associated with KDM5 activity, comprising administering a therapeutically effective amount of a compound as described in any one of Examples 1-432, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

Another aspect includes the use of a compound as described in any one of Examples 1-432, or a pharmaceutically acceptable salt thereof, in therapy.

Another aspect includes the use of a compound as described in any one of Examples

1-432, or a pharmaceutically acceptable salt thereof, in treating a disease associated with KDM5 activity. Another aspect includes the use of a compound as described in any one of Examples 1-432, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with KDM5 activity.

Another aspect includes a method of increasing the efficacy of a cancer treatment comprising a cancer therapy agent, comprising administering to a patient (a) an effective amount of a compound as described in any one of Examples 1-432, or a pharmaceutically acceptable salt thereof, and (b) an effective amount of the cancer therapy agent.

Another aspect includes a method of treating an individual with cancer who has an increased likelihood of developing resistance to a cancer therapy agent comprising

administering to the individual (a) an effective amount of a compound as described in any one of Examples 1-432, or a pharmaceutically acceptable salt thereof, and (b) an effective amount of the cancer therapy agent.

Another aspect includes processes and synthetic intermediates that are useful for preparing a compound as described in any one of Examples 1-432, or a salt thereof.

Another aspect includes a composition, comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

Another aspect includes a method of treating a disease associated with KDM5 activity, comprising administering an therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

Another aspect includes the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in therapy.

Another aspect includes the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in treating a disease associated with KDM5 activity.

Another aspect includes the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with KDM5 activity.

Another aspect includes a method of increasing the efficacy of a cancer treatment comprising a cancer therapy agent, comprising administering to a patient (a) an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) an effective amount of the cancer therapy agent.

Another aspect includes a method of treating an individual with cancer who has an increased likelihood of developing resistance to a cancer therapy agent comprising administering to the individual (a) an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) an effective amount of the cancer therapy agent.

Another aspect includes a processes and synthetic intermediates that are useful for preparing a compound of formula (I), or a salt thereof.

Another aspect includes compounds for the study of histone demethylases, such as KDM5, the study of intracellular signal transduction pathways mediated by such histone demethylases, and the comparative evaluation of modulators of these demethylases.

DETAILED DESCRIPTION

Definitions

Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5 ^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are included. Unless otherwise stated, all tautomeric forms of the compounds are included. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are included. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents. Where a particular enantiomer is preferred, it may, in some embodiments be provided substantially free of the corresponding enantiomer, and may also be referred to as "optically enriched." "Optically-enriched," as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%>, or 99% by weight of a preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, et al, Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

The term "a compound as described herein" includes the compounds described in

Examples 1-432 and salts thereof, as well as compounds of formula (I) and salts thereof.

The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), ΝΗ (as in pyrrolidinyl) or NR⁺ (as in N- substituted pyrrolidinyl)).

As used herein a "direct bond" or "covalent bond" refers to a single, double or triple bond. In certain embodiments, a "direct bond" or "covalent bond" refers to a single bond.

The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), and iodine (iodo, -I).

The term "aliphatic" or "aliphatic group", as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spiro-fused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-6 carbon atoms. In some embodiments, aliphatic groups contain 1-4 carbon atoms, and in yet other embodiments aliphatic groups contain 1-3 carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The term "unsaturated", as used herein, means that a moiety has one or more units of unsaturation.

The terms "cycloaliphatic", "carbocycle", "carbocyclyl", "carbocyclo", or "carbocyclic", used alone or as part of a larger moiety, refer to a saturated or partially unsaturated cyclic aliphatic monocyclic or bicyclic ring systems, as described herein, having from 3 to 10 members, wherein the aliphatic ring system is optionally substituted as defined above and described herein. Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In some embodiments, the cycloalkyl has 3-6 carbons. The terms "cycloaliphatic", "carbocycle", "carbocyclyl", "carbocyclo", or "carbocyclic" also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl, tetrahydronaphthyl, decalin, or bicyclo[2.2.2]octane, where the radical or point of attachment is on an aliphatic ring.

As used herein, the term "cycloalkylene" refers to a bivalent cycloalkyl group. In certain embodiments, a cycloalkylene group is a 1,1 -cycloalkylene group (i.e., a spiro-fused

Exemplary 1,1 -cycloalkylene groups include

In other embodiments, a cycloalkylene group is a 1 ,2-cycloalkylene group or a 1,3-cycloalkylene group. Exemplary

1 ,2-cycloalkylene groups include

The term "alkyl," as used herein, refers to a monovalent saturated, straight- or branched-chain hydrocarbon radical derived from an aliphatic moiety containing between one and six carbon atoms by removal of a single hydrogen atom. In some embodiments, alkyl contains 1-5 carbon atoms. In another embodiment, alkyl contains 1-4 carbon atoms. In still other embodiments, alkyl contains 1-3 carbon atoms. In yet another embodiment, alkyl contains 1-2 carbons. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, sec-pentyl, iso-pentyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, and the like.

The term "alkenyl," as used herein, denotes a monovalent group derived from a straight- or branched-chain aliphatic moiety having at least one carbon-carbon double bond by the removal of a single hydrogen atom. In certain embodiments, alkenyl contains 2-6 carbon atoms. In certain embodiments, alkenyl contains 2-5 carbon atoms. In some embodiments, alkenyl contains 2-4 carbon atoms. In another embodiment, alkenyl contains 2-3 carbon atoms. Alkenyl groups include, for example, ethenyl ("vinyl"), propenyl ("allyl"), butenyl, l-methyl-2-buten-l-yl, and the like.

The term "alkynyl," as used herein, refers to a monovalent group derived from a straight- or branched-chain aliphatic moiety having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. In certain embodiments, alkynyl contains 2-6 carbon atoms. In certain embodiments, alkynyl contains 2-5 carbon atoms. In some embodiments, alkynyl contains 2-4 carbon atoms. In another embodiment, alkynyl contains 2-3 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 2- propynyl ("propargyl"), 1-propynyl, and the like.

The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic and bicyclic ring systems having a total of five to 10 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments, "aryl" refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term aryl", as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenantriidinyl, or tetrahydronaphthyl, and the like.

The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, e.g., "heteroaralkyl", or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l ,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 4- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), ΝΗ (as in pyrrolidinyl), or (as in N- substituted pyrrolidinyl) .

A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical", are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, 2- azabicyclo[2.2.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond between ring atoms but is not aromatic. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined. The term "alkylene" refers to a bivalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH₂)_n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

As used herein, the term "inhibitor" refers to a compound that binds to and inhibits a KDM5 enzyme with measurable affinity and activity. In certain embodiments, an inhibitor has an IC₅₀ and/or binding constant of less about 50 μΜ, less than about 1 μΜ, less than about 500 nM, less than about 100 nM, or less than about 10 nM.

The terms "measurable affinity" and "measurably inhibit," as used herein, refer to a measurable reduction in activity of a KDM5 enzyme between: (i) a sample comprising a compound a compound as described herein and such KDM5 enzyme, and (ii) an equivalent sample comprising such KDM5 enzyme, in the absence of said compound.

"Pharmaceutically acceptable salts" include both acid and base addition salts.

"Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, salicyclic acid and the like.

"Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from

pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include

interconversions by reorganization of some of the bonding electrons.

A "solvate" refers to an association or complex of one or more solvent molecules and a compound or pharmaceutically acceptable salt thereof as described herein. Examples of solvents include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine. The term "hydrate" refers to the complex where the solvent molecule is water.

"Therapeutically effective amount" refers to an amount of a a compound or pharmaceutically acceptable salt thereof as described herein that (i) treats the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer. For cancer therapy, efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR). In the case of immunological disorders, the therapeutic effective amount is an amount sufficient to decrease or alleviate an allergic disorder, the symptoms of an autoimmune and/or inflammatory disease, or the symptoms of an acute inflammatory reaction (e.g. asthma). In some embodiments, a therapeutically effective amount is an amount of a chemical entity described herein sufficient to significantly decrease the activity or number of drug tolerant or drug tolerant persisting cancer cells.

"Treatment" (and variations such as "treat" or "treating") refers to clinical

intervention in an attempt to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include one or more of preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, stabilized (i.e., not worsening) state of disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, prolonging survival as compared to expected survival if not receiving treatment and remission or improved prognosis. In certain embodiments, a compound as described herein is used to delay development of a disease or disorder or to slow the progression of a disease or disorder. Those individuals in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder, (for example, through a genetic mutation or abberent expression of a gene or protein) or those in which the condition or disorder is to be prevented.

Examylar Values

In one embodiment a compound as described in any one of Examples 1-432 or a salt thereof is provided.

In another embodiment, a compound of formula (I):

I

or a salt thereof is provided, wherein:

R⁴ is H, Ci_i₂alkyl, C₂_i₂alkenyl, C₂_i₂alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl, wherein each Ci_i₂alkyl, C₂_i₂alkenyl, C₂_i₂alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, C_1-12 alkyl, Ci_i₂haloalkyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, halo, -CN, -N0₂, -NR^mR^m, -OR^m, -C(=0)OR^m, and -OC(=0)R^m; or R⁴ and R³ taken together with the atoms to which they are attached form a heterocyclyl;

each R^a is independently selected from H, Ci_6alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl, wherein each Ci_₆alkyl, C₃_₆alkenyl,

each R^m is independently selected from H, Ci_₆alkyl, C₂_₆alkenyl, C₂_6alkynyl,

Ci_₆haloalkyl, carbocyclyl, Ci_₆ alkanoyl, phenyl, and benzyl, wherein any Ci_₆alkyl,

each R^v is independently hydrogen, Ci_6alkyl, C₂_6alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl,wherein each Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, aryl, carbocyclyl, and Ci-C₆ alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^v are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and Ci_₃alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each R^w is independently selected from H, C_halky 1,

phenyl, benzyl, and phenethyl;

each R^x is independently selected from oxo, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, heterocycle, -F, -CI, -Br, -I, -N0₂, -N(R^V)₂, -CN, -C(O)- N(R^V)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -0-C(0)-0-R^v, -C(O)- R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -0-C(0)-N(R^v)₂, -N(R^v)-C(0)-OR^v, -N(R^v)-C(0)- N(R^V)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-S(0)-R^v, -N(R^v)-S(0)₂-R^v, -N(R^v)-S(0)- N(R^V)₂, and

-N(R^v)-S(0)₂-N(R^v)₂,wherein any Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocycle is optionally substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂- N(R^V)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)-R^v, -N(R^v)-S(0)₂-R^v, and Ci_₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^y and R^z is independently selected from H, Ci_₄alkyl, Ci_₄alkanoyl,

each R^xa is independently selected from aryl, heteroaryl, heterocycle, and carbocycle, wherein any aryl, heteroaryl, heterocycle, and carbocycle is optionally substituted with one or more groups independently selected from Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, -F, -CI, -Br, -I, -N0₂, -N(R^V)₂, -CN, carbocycle, aryl, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S- R^v, -0-C(0)-R^v, -0-C(0)-0-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -O-C(O)- N(R^V)₂, -N(R^v)-C(0)-OR^v, -N(R^v)-C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R

S(0)-R^v, -N(R^v)-S(0)₂-R^v, and -N(R^v)-S(0)-N(R^v)₂, wherein any

In one embodiment R¹ is H, Ci_₆alkyl, trifluoromethyl, 3-6 membered carbocyclyl, 6 membered aryl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, halo, -OR , -

SR f , -N(R f )₂, -CN, or -N0₂, wherein said alkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more groups independently selected from oxo, halo, Ci_ ₃alkoxy and Ci_₃alkyl; In another embodiment R¹ is H, methyl, or ethyl.

In another embodiment R¹ is H.

In another embodiment R² is H.

In another embodiment R² is Ci_i₂alkyl, C₂_i₂alkenyl, C₂_i₂alkynyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, halo, -OR^a, -SR^a, -N(R^a)₂, -CN, -

N0₂, -C(0)R^a, -C0₂R^a, -C(0)N(R^a)₂, -C(0)SR^a, -C(0)C(0)R^a, - C(0)CH₂C(0)R^a, -C(S)N(R^a)₂, -C(S)OR^a, -S(0)R^a, -S0₂R^a, -S0₂N(R^a)₂, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, -N(R^a)S0₂

R^a, -N(R^a)S0₂N(R^a)₂, -N(R^a)N(R^a)₂, -N(R^a)C(=N(R^a))N(R^a)₂, -C(=N)N(R^a)₂, - C=NOR^a, -C(=N(R^a))N(R^a)₂, -OC(0)R^a, or -OC(0)N(R^a)₂, wherein each Ci_i₂alkyl, C₂ i₂alkenyl, C₂_i₂alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl of R² is independently optionally substituted with one or more groups R^x.

In another embodiment R² is H, Ci_6alkyl, C₂_i₂alkenyl, C₂_i₂alkynyl, carbocyclyl, aryl, heteroaryl, halo, -CN, -SR^a, -N(R^V)₂, and -C0₂R^a, wherein any Ci_6alkyl, carbocyclyl and aryl is optionally substituted with one or more groups independently selected from Ci_

₃alkyl, carbocyclyl, halo, -CN, -N(R^v)-C(0)-R^v, and -0-R^v.

In another embodiment R² is H, isopropyl, ethyl, iert-butyl, 2,2-difluoroethyl, cyclobutyl, 2-propyn-l-yl, bromo, chloro, 2-furyl, vinyl, phenyl, 2-chlorophenylthio, 2- fluoroethyl, 2-propenyl, 1-methylvinylcyclopropyl, 4-pyridyl, 2-buten-l-yl, iodo, l-methyl-2- propyn-l-yl, 1-methylprop-l-yl, l-(cyclopropyl)ethyl, methoxycarbonyl, 2-butynyl, 2- hydroxy-l-methylethyl, 4-(methylcarbonylamino)butyl, 3-(methylcarbonylamino)propyl, 4- aminobutyl, l-methyl-2-propenyl, 1-methylcyclobutyl, propyl, 2-methoxyethyl, and 2- methylpropyl.

In another embodiment R³ is lH-pyrazol-4-yl, 1 -(cyclopropylmethyl)- lH-pyrazol-4- yl, l-(l-methylcyclopropyl)-lH-pyrazol-4-yl, 5-fluoro-lH-pyrazol-4-yl, l-(2-phenylpropan- 2-yl)-lH-pyrazol-4-yl, l-(pyridin-3-yl)-lH-pyrazol-4-yl, l-(pyridin-4-yl)-lH-pyrazol-4-yl, 1- (pyridin-2-yl)- 1 H-pyrazol-4-yl, 1 - [ 1 -(N-methylaminocarbonyl)- 1 , 1 -dimethylmethyl] - 1 H- pyrazol-4-yl, 5-fluoro- 1 -isopropyl- lH-pyrazol-4-yl, 1 -(cyclopropylmethyl)- lH-pyrazol-5-yl, 1 -(cyclopropylmethyl)- 1 H-pyrazol-3 -yl, 1 -(tetrahydro-2H-thiopyran-4-yl)- 1 H-pyrazol-4-yl, 1 -(1 , 1 -dioxidotetrahydro-2H-thiopyran-4-yl)- lH-pyrazol-4-yl, 1 -((6-(3-oxobut- 1 -en-1 - yl)pyridin-2-yl)methyl)-lH-pyrazol-4-yl, 3-iodophenyl, 3-methyl-l ,2,4-oxadiazol-5-yl, 5- methyl-l ,3,4-oxadiazol-2-yl, lH-imidazol-2-yl, 5-phenyloxazol-2-yl, l-cyclohexylpyrazol-4- yl, l-isopropylpyrazol-4-yl, biphenyl-3-yl, 3-((4-fluorophenyl)amino)phenyl, 3-(2- oxopyrrolidin-l-yl)phenyl, 3-(methylcarbonylamino)-5-phenylphenyl, 3-furyl, benzofuran-3- yl,l -phenyl- lH-pyrazol-3-yl, 5-cyclopropylfuran-2-yl, 2-methylfuran-3-yl, 1 -phenyl- 1H- pyrazol-4-yl, 1 -ethyl- lH-pyrazol-4-yl, l-methyl-6-oxo-l ,6-dihydropyridin-3-yl, furan-2-yl, 5-phenylfuran-2-yl, l-isopropyl-lH-pyrazol-4-yl, pyrimidin-5-yl, 5-methylpyridin-3-yl, 1- methyl-lH-pyrazol-3-yl, 4-phenylfuran-2-yl, 2-fluorophenyl, 4-cyanophenyl, 4- methoxyphenyl, 4-(trifluoromethyl)-phenyl, 4-fluorophenyl, 1 -benzyl- lH-pyrazol-4-yl, 5- chloropyridin-3-yl, 5-fluoropyridin-3-yl, 1 -methyl- lH-pyrazol-5-yl, 4-(hydroxymethyl)furan-

2- yl, 3-cyanophenyl, 2,5-dihydrofuran-3-yl, thiophen-3-yl, thiophen-2-yl, 1 -methyl- 1H- pyrazol-4-yl, 5-methylfuran-2-yl, 5-(hydroxymethyl)furan-2-yl, 3-(trifluoromethyl)-phenyl,

3 - methoxyphenyl, 3 -fluorophenyl, pyridin-3-yl , l-(methylsulfonyl)-lH-pyrazol-4-yl, 1- cyclopentyl-lH-pyrazol-4-yl, l-(thiophen-3-ylmethyl)-lH-pyrazol-4-yl, 4-chloro-3-

(morpholine-4-carbonyl)phenyl, 3-chloro-4-(cyclopropylaminocarbonyl)phenyl, 1-(1- hydroxy-2-methylpropan-2-yl)- 1 H-pyrazol-4-yl, 1 -(3 -methoxybenzyl)- 1 H-pyrazol-4-yl, 1 - (pyridin-4-ylmethyl)- lH-pyrazol-4-yl, 1 -(2-chlorobenzyl)- lH-pyrazol-4-yl, 1 -(3- phenoxybenzyl)- lH-pyrazol-4-yl, 1 -(4-phenoxybenzyl)- lH-pyrazol-4-yl, 1 -cyclohexyl- 1H- pyrazol-4-yl, l-(l-phenylethyl)-lH-pyrazol-4-yl, l-cyclobutyl-lH-pyrazol-4-yl, 1 -(sec- butyl)- lH-pyrazol-4-yl, 4-fluoro-3 -(pyrrolidine- l-carbonyl)phenyl, l-(cyclopropylsulfonyl)- iH-pyrazol-3-yl, 1 -(cyclopropanecarbonyl)- lH-pyrazol-3-yl, 1 -(2-cyclopropylethyl)-lH- pyrazol-4-yl, l-([l ,l'-biphenyl]-3-ylmethyl)-lH- pyrazol-4-yl, l-phenethyl-lH-pyrazol-4-yl, 1 -(2 -methoxybenzyl)- lH-pyrazol-4-yl, 1 -(4-methoxybenzyl)- lH-pyrazol-4-yl, 1 -(tert-butyl)- lH-pyrazol-4-yl, 3,4-dimethylphenyl, 3-chloro-4-ethoxyphenyl, 4-methoxy-3-methylphenyl, 2-methylbenzo[d]thiazol-5-yl, 1 -(2-phenoxybenzyl)- lH-pyrazol-4-yl, 1 -(phenylsulfonyl)- 1Η- pyrazol-4-yl, 1 -benzoyl- lH-pyrazol-4-yl, l-benzhydryl-lH-pyrazol-4-yl, l-([l ,l'-biphenyl]- 2-ylmethyl)- 1 H-pyrazol-4-yl, 1 -(cyclohexylmethyl)- 1 H-pyrazol-4-yl, 1 -(pyridin-3 -ylmethyl)- lH-pyrazol-4-yl, benzofuran-2-yl, 5-ethylfuran-2-yl, l-(2-methoxyethyl)-lH-pyrazol-4-yl, 1- (naphthalen-1 -ylmethyl)- lH-pyrazol-4-yl, l-([l ,l'-biphenyl]-4-ylmethyl)-lH-pyrazol-4-yl, 3- phenoxyphenyl, 3,4-dichlorophenyl, 3-chloro-4-methoxyphenyl, 3-methoxy-4-methylphenyl, l-(thiazol-4-ylmethyl)-lH-pyrazol-4-yl, lH-indazol-5-yl, 3,4-dimethoxyphenyl, 4-methoxy- 3,5-dimethylphenyl, l-(oxetan-3-yl)-lH-pyrazol-4-yl, l-(2-fluorobenzyl)-lH-pyrazol-4-yl, 1- (4-fiuorobenzyl)- 1 H-pyrazol-4-yl, 1 -(methoxycarbonylmethyl)- 1 H-pyrazol-4-yl, 1 -(2- (dimethylamino)ethyl)-lH-pyrazol-4-yl, 3-cyano-4-methylphenyl, benzo[d][l ,3]dioxol-5-yl, 2,3-dihydrobenzofuran-5-yl, 1 -(3-fluorobenzyl)- lH-pyrazol-4-yl, 1 -(thiophen-2-ylmethyl)- lH-pyrazol-4-yl, 1 -(2,2,2-trifiuoroethyl)- lH-pyrazol-4-yl, 1 -(3-chlorobenzyl)-lH-pyrazol-4- yl, l-isobutyl-lH-pyrazol-4-yl, l-(3,3,3-trifluoropropyl)-lH-pyrazol-4-yl, l-(difiuoromethyl)- lH-pyrazol-4-yl, l-(2-cyanoethyl)-lH-pyrazol-4-yl, 4-cyclopropylfuran-2-yl, 2,2- difluorobenzo[d][l ,3]dioxol-5-yl, 3-fluoro-4-(aminocarbonyl)phenyl, 3-fluoro-4- (methylsulfonyl)pheny 1, 3 -chloro-4-(trifluoromethoxy)phenyl, 5 -fluoro-3 - (aminocarbonyl)phenyl, 3 -(hydroxymethyl)-4-methoxyphenyl, 1 -(methy lsulfonyl)- 1 H-pyrrol- 3-yl, 1 -methyl- 1 H-pyrrol-3 -yl, 3-bromophenyl, 3-(l-methylpyrazol-4-yl)phenyl, 3-(l- isopropylpyrazol-4-yl)phenyl, 4-phenylphenyl, 4-(4-fluoroanilino)phenyl, 3-(tert- butoxycarbonylamino)phenyl, 1 -acetyl- 1 ,2,3 ,6-tetrahydropyridin-4-yl, 1 -propionyl-

1 ,2,3 ,6-tetrahydropyridin-4-yl, 1 -acryloyl- 1 ,2,3 ,6-tetrahydropyridin-4-yl, 1 -methyl- 1 ,2,3,6- tetrahydropyridin-4-yl, 1 -((2-methylthiazol-4-yl)methyl)- 1 H-pyrazol-4-yl, 1 -(2- (acetylamino)ethyl)-lH-pyrazol-4-yl, 3,5-dichlorophenyl, 2-fluoro-4-(methylsulfonyl)phenyl, l-(tert-pentyl)-lH-pyrazol-4-yl, 3-(2-morpholinoethyl)phenyl, 3-(2-

(dimethylamino)ethyl)phenyl, 1 -( 1 -(thiazol-4-yl)ethyl)- 1 H-pyrazol-4-yl, 1 -(tetrahydro-2H- pyran-4-yl)- 1 H-pyrazol-4-yl, 3 -methoxy-4-(trifluoromethyl)phenyl, 3 -methoxycarbonyl-4- chlorophenyl, 4-(trifluoromethoxy)phenyl, 3-methyl-4-(trifluoromethoxy)phenyl, 4- cyclopropyl-3-(trifluoromethyl)phenyl, 2,2-dimethyl-2,3-dihydrobenzofuran-5-yl, 3,5- dimethoxyphenyl, 3,4-difluorophenyl, 4-biphenyl, 3 -chloro-5 -fluorophenyl, 3,5- bis(trifluoromethyl)phenyl, 3-fluoro-5-methoxyphenyl, 3-(aminocarbonyl)phenyl, 4- (cyclopropylmethoxy)phenyl, 2-fluoro-5-(benzyloxycarbonyl)phenyl, 3-(lH-pyrazol-l- yl)phenyl, l-(2-hydroxycyclopentyl)-lH-pyrazol-4-yl, 3-(N-methylaminosulfonyl)phenyl, 4- (2-hydroxypropan-2-yl)phenyl, 2-(trifluoromethyl)pyridin-4-yl, 6-phenoxypyridin-3-yl, 2- methoxypyridin-4-yl, 4-methyl-2-phenylthiazol-5-yl, 3-amino-5-cyanophenyl, 1-

(tetrahydrofuran-3-yl, 3-(N-ethylaminocarbonyl)phenyl, 3-(aminocarbonylmethyl)phenyl, 6- phenylpyridin-3 -yl, 1 -(tetrahydro-2H-pyran-3 -yl)- 1 H-pyrazol-4-yl, 1 -( 1 -methoxypropan-2- yl)- 1 H-pyrazol-4-yl, 1 -(2-ethoxy ethyl)- 1 H-pyrazol-4-yl, 1 -acetyl-2,5 -dihydro- 1 H-pyrrol-3 -yl, 1 -acetyl- 1 ,2,5 ,6-tetrahydropyridin-3-yl, 1 -propionyl- 1 ,2,5 ,6-tetrahydropyridin-3-yl, 1 - propionyl-2,5-dihydro-lH-pyrrol-3-yl, l-((l S,3S)-3-hydroxycyclobutyl)-lH-pyrazol-4-yl, 2,5-dihydro- 1 H-pyrrol-3 -yl, 1 ,2,5 ,6-tetrahydropyridin-3-yl, 1 -methyl- 1 ,2,5,6- tetrahydropyridin-3-yl, l-acryloyl-l ,2,5,6-tetrahydropyridin-3-yl, l-acryloyl-2,5-dihydro-lH- pyrrol-3-yl, 4-chloro-3,5-dimethylphenyl, 4-cyano-3-methylphenyl, l-oxo-2,3-dihydro-lH- inden-5-yl, 3,4-bis(trifluoromethyl)phenyl, 3-methyl-4-(trifluoromethyl)phenyl, 1- (benzo[b]thiophen-7-ylmethyl)-lH-pyrazol-4-yl, 4-fluoro-3-(N- cyclohexylaminocarbonyl)phenyl, 4-morpholinophenyl, 4-(4-(iert-butoxycarbonyl)piperazin- l-yl)phenyl, 3 -chloro-5 -methylphenyl, 3-(methylsulfonyl)phenyl, 4-(methylsulfonylamino)- phenyl, 4-(morpholinomethyl)phenyl, 3-morpholinophenyl, l-(2-(vinylcarbonylamino)ethyl)- lH-pyrazol-4-yl, l-(2-aminoethyl)-lH-pyrazol-4-yl, 3-cyclopropyl-4-methylphenyl, 3- ethoxyphenyl, 3 -(hydroxymethyl)phenyl, 1 -(2-(iert-butoxycarbonylamino)ethyl)- 1 H-pyrazol- 4-yl, 3-phenethoxyphenyl, l ,2,3,6-tetrahydropyridin-4-yl, l-(2-(vinylsulfonylamino)ethyl)- lH-pyrazol-4-yl, 4-(phenylamino)phenyl, 3 -methyl- lH-pyrazol-4-yl, 4-(benzyloxy)phenyl, 3,5-difluorophenyl, 3-fluoro-5-trifluoromethylphenyl, 3-(ethylsulfonyl)phenyl, 3- (trifluoromethoxy)-phenyl, l-(thiazol-5-ylmethyl)-lH-pyrazol-4-yl, p-tolyl, 4- cyclopropylphenyl, 4-(ethylsulfonyl)-phenyl, 1 -(6-vinylpyridin-2-yl)methyl)- 1 H-pyrazol-4-yl, 6-(benzyloxy)pyridin-3-yl, 1 -(iert-butoxycarbonyl)-2,5-dihydro- lH-pyrrol-3-yl, 1 -(2- hydroxy- 1 -phenylethyl)- 1 H-pyrazol-4-yl, 1 -(2-cyano- 1 -phenylethyl)- 1 H-pyrazol-4-yl, 6- cyclopropylpyridin-3-yl, 4-cyano-3-methoxyphenyl, 4-methoxy-3-(trifluoromethyl)phenyl, 4- chlorophenyl, l-(3,4-difluorobenzyl)-lH-pyrazol-4-yl, 4-methyl-3-(trifluoromethyl)phenyl, 4-(pyrrolidine- 1 -carbonyl)phenyl, 4-(isopropylamino-carbonyl)phenyl, 4-(4-methylpiperazin-

1- yl)phenyl, 3-chloro-5-cyanophenyl, 3 -(pyrrolidine- l-carbonyl)phenyl, 3- (methylsulfonylaminomethyl)phenyl, 3 -( 1 H-pyrazol-5 -yl)phenyl, 4-(methylsulfonyl)phenyl, 4-(cyclopropylaminocarbonyl)phenyl, l-(2-fluoroethyl)-lH-pyrazol-4-yl, 3- (cyclopropylmethoxy)phenyl, 3-(benzyloxy)phenyl, 3-(morpholinomethyl)phenyl, 3- (phenoxymethyl)phenyl, 1 -(3 -fluorophenyl)- lH-pyrazol-4-yl, 2-cyclopropylvinyl, 6- (trifluoromethyl)pyridin-3-yl, l-(4-fluorophenyl)-lH-pyrazol-4-yl, 2,4-dimethylthiazol-5-yl, 1 -propyl- 1 H-pyrazol-4-yl, 1 -butyl- 1 H-pyrazol-4-yl, 1 -(2-(phenylamino)ethyl)- 1 H-pyrazol-4- yl, 4-(aminocarbonyl)phenyl, 4-(N-methylaminocarbonyl)phenyl, 3-fluoro-4-(N- methylamino-carbonyl)phenyl, l-(2-(3,3-difluoroazetidin-l-yl)ethyl)-lH-pyrazol-4-yl, l-(2- (3 ,3-difluoropyrrolidin- 1 -yl)ethyl)- 1 H-pyrazol-4-yl, 1 -(2-((2,2,2-trif uoroethyl)amino)ethyl)- lH-pyrazol-4-yl, 1-propenyl, 3-(methylcarbonylamino)phenyl, 4-

(methylsulfonylamino)phenyl, 4-(morpholine-4-carbonyl)phenyl, 4-(4-acetylpiperazin- 1 - yl)phenyl, l-(2,2-dif uoroethyl)-lH-pyrazol-4-yl, 5-isopropylfuran-2-yl, l-(3,3- dif uorocyclopentyl)-lH-pyrazol-4-yl, l-((l S,3R)-3-hydroxycyclopentyl)-lH-pyrazol-4-yl, 1- ((l S,3S)-3-hydroxycyclopentyl)-lH-pyrazol-4-yl, 3-(lH-pyrazol-4-yl)phenyl, 5-bromofuran-

2- yl, 3-(phenylamino)phenyl, 2-methylthiazol-5-yl, 3-(phenylethynyl)phenyl, 3- phenethylphenyl, 1 -(3 -fluorocyclopentyl)- 1 H-pyrazol-4-yl, 1 -( 1 -methoxy-2-methylpropan-2- yl)- 1 H-pyrazol-4-yl, 1 -( 1 -acryloylazetidin-3 -yl)- 1 H-pyrazol-4-yl, 1 -( 1 -propionylazetidin-3 - yl)-lH-pyrazol-4-yl, 6-oxo-l ,6-dihydropyridin-3-yl, 4-(piperazin-l-yl)phenyl, l-(l-fluoro-2- methylpropan-2-yl)-lH-pyrazol-4-yl, 3-(trifluoromethyl)-lH-pyrazol-4-yl, 3,5- dimethylphenyl, 4-(morpholinosulfonyl)phenyl, 3-(4-methylpiperazine-l-carbonyl)phenyl, 3- (2-hydroxypropan-2-yl)phenyl, l-isopropyl-3 -methyl- lH-pyrazol-4-yl, l-isopropyl-5-methyl- lH-pyrazol-4-yl, 3 -cyclopropyl-1 H-pyrazol-5 -yl, 5-methoxycarbonylpyrrol-3-yl, 3- cyclopropyl- 1 -isopropyl- 1 H-pyrazol-5 -yl, 5 -cyclopropyl- 1 -isopropyl- 1 H-pyrazol-3 -yl, 1 - isopropyl-5 -(methoxycarbonyl)pyrrol-3 -yl, 1 -methyl-3 -(trifluoromethyl)- 1 H-pyrazol-5 -yl, 1 - isopropyl- 1 H-pyrazol-3 -yl, 1 -cyclopentyl-5 -cyclopropyl- 1 H-pyrazol-3 -yl, 1 -cyclopentyl-3 - cyclopropyl- 1 H-pyrazol-5 -yl, 1-cyclopentyl-lH -pyrazol-3-yl, 1-isopropyl-l H-pyrazol-5 -yl, 1 -isopropyl-5 -(N-methylaminocarbonyl)pyrrol-3 -yl, 1 -isopropyl-5 -(N,N- dimethylaminocarbonyl)-pyrrol-3-yl, 1 -(2-cyclopropylethyl)- 1 H-pyrazol-3 -yl, 1 -(2- cyclopropylethyl)- 1 H-pyrazol-5 -yl, 1 -ethyl- 1 H-pyrazol-3 -yl, 3-(3,3-dimethyl-2- oxopyrrolidin-l-yl)phenyl, 3-(2-oxo-3-phenylpyrrolidin-l-yl)phenyl, 3-((E)-styryl)phenyl, 3- (3 -cyanophenyl)phenyl, 3 -(3 -(methylsulfonylamino)phenyl)phenyl, 3 -(4- (methylsulfonylamino)phenyl)phenyl, or 3-(4-(N-methylaminosulfonyl)phenyl)phenyl.

In another embodiment, R³ is pyrazol-4-yl, substituted with R^x.

In another embodiment, R³ is phenyl, substituted with R^x.

In another embodiment R^x is Ci_₆alkyl, that is substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-

R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)-R^v, and -N(R^v)-S(0)₂-R^v.

In another embodiment R^x is Ci_6alkyl that is substituted with R^xa.

In another embodiment R^x is C₂_6alkenyl or C₂_6alkynyl, wherein any C₂_6alkenyl and C₂_₆alkynyl is optionally substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -O- C(0)-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R C(0)-R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)-R^v, and -N(R^v)-S(0)₂-R^v

In another embodiment R^x is selected from C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, aryl, heteroaryl, heterocycle, -F, -CI, -Br, -I, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, - S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -0-C(0)-0-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, - S(0)₂-R^v, -0-C(0)-N(R^v)₂, -N(R^v)-C(0)-OR^v, -N(R^v)-C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R C(0)-R^v, -N(R^v)-S(0)-R^v, -N(R^v)-S(0)₂-R^v, -N(R^v)-S(0)-N(R^v)₂, and -N(R^v)-S(0)₂- N(R^v)₂,wherein any C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocycle is optionally substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -O- C(0)-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R C(0)-R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)-R^v, -N(R^v)-S(0)₂-R^v, and

that is optionally substituted with one or more groups independently selected from oxo and halo. In another embodiment R³ is heteroaryl that is substituted with oxo, Ci_6alkyl, C₂_ ₆alkenyl, C₂_6alkynyl, carbocyclyl, aryl, heteroaryl, heterocycle, -F, -CI, -Br, -I, -N0₂, - N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -O- C(0)-0-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -0-C(0)-N(R^v)₂, -N(R^v)-C(0)-OR^v, -N(R^v)-C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-S(0)-R^v, -N(R^v)-S(0)₂-

R^v, -N(R^v)-S(0)-N(R^v)₂, or -N(R^v)-S(0)₂-N(R^v)₂; wherein any

is substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, -N(R^V)₂, -CN, -C(O)- N(R^V)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -C(0)-R^v, -C(0)-0-R^v, - S(0)-R^v, -S(0)₂-R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-C(0)- OR^v, -N(R^v)-S(0)-R^v, and -N(R^v)-S(0)₂-R^v; and wherein any C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocycle is optionally substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(O)- N(R^V)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂- R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)- R^v, -N(R^v)-S(0)₂-R^v, and Ci_₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo.

In another embodiment R³ is a 5-membered heteroaryl that is substituted with oxo, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, heterocycle, -F, -CI, -Br, -I, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, - 0-C(0)-0-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -0-C(0)-N(R^v)₂, -N(R^v)-C(0)- OR^v, -N(R^v)-C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-S(0)-R^v, -N(R^v)-S(0)₂- R^v, -N(R^v)-S(0)-N(R^v)₂, or -N(R^v)-S(0)₂-N(R^v)₂; wherein any

is substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, -N(R^V)₂, -CN, -C(O)- N(R^V)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -C(0)-R^v, -C(0)-0-R^v, - S(0)-R^v, -S(0)₂-R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-C(0)-

OR^v, -N(R^v)-S(0)-R^v, and -N(R^v)-S(0)₂-R^v; and wherein any C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocycle is optionally substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(O)- N(R^V)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂- R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)-

R^v, -N(R^v)-S(0)₂-R^v, and Ci_₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo.

In another embodiment R³ is phenyl that is substituted with oxo, Ci_₆alkyl, C₂_ ₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, heterocycle, -N(R^V)₂, -CN, -C(O)- N(R^V)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -0-C(0)-0-R^v, -C(O)- R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -0-C(0)-N(R^v)₂, -N(R^v)-C(0)-OR^v, -N(R^v)-C(0)- N(R^V)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-S(0)-R^v, -N(R^v)-S(0)₂-R^v, -N(R^v)-S(0)- N(R^V)₂, or -N(R^v)-S(0)₂-N(R^v)₂; wherein any Ci_6alkyl, is substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(O)- N(R^V)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂- R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)-R^v, and -N(R^v)-S(0)₂-R^v; and wherein any C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocycle is optionally substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -O- R^v, -S-R^v, -0-C(0)-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -C(0)-N(R^v)₂, -S(0)₂- N(R^V)₂, -N(R^v)-C(0)-R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)-R^v, -N(R^v)-S(0)₂-R^v, and Ci ₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo.

In another embodiment R⁴ is H, methyl, ethyl, propyl, cyclopropylmethyl, 2- hydroxyethyl, 2-(dimethylmino)ethyl, phenyl, benzyl, or 2-methoxyethyl.

In another embodiment R³ is not phenyl, fluorophenyl, chlorophenyl, pyridyl, nitrophenyl, or propylisoxazole. Uses, Formulation and Administration

Pharmaceutically acceptable compositions

Another aspect includes a pharmaceutical composition comprising a a compound as described herein or a pharmaceutically acceptable salt thereof. In one embodiment, the composition further comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle. In another embodiment, the composition further comprises an amount of the compound effective to measurably inhibit KDM5. In certain embodiments, the composition is

formulated for administration to a patient in need thereofcertain embodiments.

The term "patient" or "individual" as used herein, refers to an animal, such as a mammal, such as a human. In one embodiment, patient or individual refers to a human.

The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

Compositions comprising a compound as described herein may be administered orally, parenterally, by inhalation spray, topically, transdermally, rectally, nasally, buccally, sublingually, vaginally, intraperitoneal, intrapulmonary, intradermal, epidural or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic,

intralesional and intracranial injection or infusion techniques.

In one embodiment, the composition comprising a compound as described herein is formulated as a solid dosage form for oral administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In certain embodiments, the solid oral dosage form comprising a compound as described herein further comprises one or more of (i) an inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and (ii) filler or extender such as starches, lactose, sucrose, glucose, mannitol, or silicic acid, (iii) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose or acacia, (iv) humectants such as glycerol, (v) disintegrating agent such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates or sodium carbonate, (vi) solution retarding agents such as paraffin, (vii) absorption accelerators such as quaternary ammonium salts, (viii) a wetting agent such as cetyl alcohol or glycerol monostearate, (ix) absorbent such as kaolin or bentonite clay, and (x) lubricant such as talc, calcium stearate, magnesium stearate, polyethylene glycols or sodium lauryl sulfate. In certain embodiments, the solid oral dosage form is formulated as capsules, tablets or pills. In certain embodiments, the solid oral dosage form further comprises buffering agents. In certain embodiments, such compositions for solid oral dosage forms may be formulated as fillers in soft and hard- filled gelatin capsules comprising one or more excipients such as lactose or milk sugar, polyethylene glycols and the like.

In certain embodiments, tablets, dragees, capsules, pills and granules of the

compositions comprising a compound as described herein optionally comprise coatings or shells such as enteric coatings. They may optionally comprise opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions include polymeric substances and waxes, which may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

In another embodiment, a composition comprises micro-encapsulated compound as described herein, and optionally, further comprises one or more excipients.

In another embodiment, compositions comprise liquid dosage formulations comprising a compound as described herein for oral administration, and optionally further comprise one or more of pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In certain embodiments, the liquid dosage form optionally, further comprise one or more of an inert diluent such as water or other solvent, a solubilizing agent, and an emulsifier such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,

dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols or fatty acid esters of sorbitan, and mixtures thereof. In certain embodiments, liquid oral compositions optionally further comprise one or more adjuvant, such as a wetting agent, a suspending agent, a sweetening agent, a flavoring agent and a perfuming agent.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a compound as described herein, it may be desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form.

Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

In certain embodiments, the composition for rectal or vaginal administration are formulated as suppositories which can be prepared by mixing a compound as described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, for example those which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound.

Example dosage forms for topical or transdermal administration of a compound as described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The compound as described herein is admixed under sterile conditions with a pharmaceutically acceptable carrier, and optionally preservatives or buffers.

Additional formulation examples include an ophthalmic formulation, ear drops, eye drops,. transdermal patches. Transdermal dosage forms can be made by dissolving or dispensing the compound as described herein in medium, for example ethanol or dimethylsulfoxide.

Absorption enhancers can also be used to increase the flux of the compound across the skin.

The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Nasal aerosol or inhalation formulations of a compound as described herein may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promotors to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

In certain embodiments, pharmaceutical compositions may be administered with or without food. In certain embodiments, pharmaceutically acceptable compositions are administered without food. In certain embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

Specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a compound as described herein in the composition will also depend upon the particular compound in the composition.

In one embodiment, the therapeutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01-100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosage forms, such as tablets and capsules, contain from about 5 to about 100 mg of the compound of the invention.

An example tablet oral dosage form comprises about 2 mg, 5 mg, 25 mg, 50 mg, 100 mg, 250 mg or 500 mg of a compound as described herein, and further comprises about 95-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mg

polyvinylpyrrolidone (PVP) K30 and about 1-10 mg magnesium stearate. The process of formulating the tablet comprises mixing the powdered ingredients together and further mixing with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving about 2-500 mg of a compound as described herein, in a suitable buffer solution, e.g. a phosphate buffer, and adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g. using a 0.2 micron filter, to remove impurities and contaminants.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Another aspect includes the use of a compound as described herein for the inhibition of KDM5. Ccompounds as described herein may also be used to inhibit the removal of methyl marks on histone lysine residues, including inhibiting the removal of methyl marks from mono-, di- or tri-methylation of histones HI, H2A, H2B, H3 and H4, such as H3K4 (including for example the KDM5 substrate H3K4me3), thereby altering interactions of these histone proteins with DNA and/or other proteins, and altering certain subsequent genetic or protein expression. Compounds as described herein may also be used to inhibit KDM5 and reduce drug-tolerant cells, thereby treating or preventing drug-resistant diseases, such as drug-resistant cancer. In certain embodiments, the disease can be treated using a compound as described herein to prevent resistance from forming, for example before targets of chemotherapies become mutated to confer resistance to such chemotherapies.

In certain embodiments, the binding or inhibition activity of a compound as described herein may be determined by running a competition experiment where the is incubated with the KDM5 enzyme bound to known radioligands. Detailed conditions for assaying a compound as an inhibitor of KDM5 or a mutant thereof are set forth in the Examples below.

In certain embodiments, detection of KDM5 activity is achieved with in vitro assays, which can be either direct binding (non-catalytic) or enzymatic (catalytic) asssays. Types of substrates that are used in such assays may include: short synthetic peptides corresponding to a number of residues from the N-terminus of histone sequences comprising the target lysine residue, single recombinant histone polypeptides, histone octamers reconstituted with recombinant histone proteins, and reconstituted nucleosomes (using reconstituted octamers and specific recombinant DNA fragments). The reconstituted nucleosomes may be mononucleosomes or oligonucleosomes.

Another aspect includes a method of treating or preventing a disease responsive to the inhibition of KDM5 activity in a patient. The method includes administering a

therapeutically effective amount of a compound as described hereinto a patient in need thereof.

Another aspect includes the use of a compound as described herein, in therapy.

Another aspect includes the use of a pharmaceutical composition comprising a compound as described herein, in therapy.

Another aspect includes the use of a compound as described herein, in treating a disease associated with KDM5 activity. Another aspect includes the use of a pharmaceutical composition comprising a compound as described herein, in treating a disease associated with KDM5 activity.

Another aspect includes the use of a compound as described herein, in the

manufacture of a medicament for the treatment of a disease associated with KDM5 activity. Another aspect includes the use of a pharmaceutical composition comprising a compound as described herein, in the manufacture of a medicament for the treatment of a disease associated with KDM5 activity.

In certain embodiments, the disease or condition is a hyperproliferative disease, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, multiple sclerosis,

Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, asthma, allergic disorders, inflammation, neurological disorders, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, CNS disorders or a myeloproliferative disorder.

In certain embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

Another aspect includes a method for treating, ameliorating or preventing cancer, drug-resistant cancer or another proliferative disorder by administration of an effective amount of a compound as described herein to a mammal, for example a human, in need of such treatment. In certain embodiments, the disease to be treated is cancer or drug resistant cancer.

Examples of cancers that may be treated using the compounds and methods described herein include, but are not limited to, adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, androgen dependent cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma,

chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer,

hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma,

neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma,

oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer,

paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, preimary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia,

Warthin's tumor and Wilms' tumor.

Another embodiment includes a method for the treatment of benign proliferative disorders. Examples of benign proliferative disorders include, but are not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman disease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic

granuloma and juvenile polyposis syndrome.

Another embodiment includes a therapeutic method useful for modulating protein methylation, gene expression, cell proliferation, cell differentiation and/or apoptosis in vivo in diseases mentioned above, in particular cancer, comprising administering to a patient in need of such therapy a pharmacologically active and therapeutically effective amount of one or more of the compounds as described herein.

Another embodiment includes a method for regulating endogenous or heterologous promotor activity by contacting a cell with a compound as described herein.

Another embodiment includes the use of a compound as described herein for the production of pharmaceutical compositions which are employed for the treatment and/or prophylaxis and/or amelioration of the diseases, disorders, illnesses and/or conditions as mentioned herein.

Another embodiment includes the use of a compound as described herein for the production of pharmaceutical compositions which are employed for the treatment and/or prophylaxis of diseases and/or disorders responsive or sensitive to the inhibition of histone demethylases, particularly those diseases mentioned above, such as e.g. cancer.

Compounds as described herein may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorder. The exact amount required will vary from patient to patient, depending on the species, age, and general condition of the patient, for example the severity of the disorder, the particular compound, its mode of administration, and the like. The total daily usage of a compound as described herein by a given patient will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.

Another embodiment includes a method of inhibiting KDM5 activity in a biological sample comprising contacting said biological sample with a compound as described herein.

The term "biological sample", as used herein, includes, without limitation, a cell, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Co-Administration of Compounds and Other Agents

The compound as described herein may be employed alone or in combination with other agents for treatment. For example, the second agent of the pharmaceutical combination formulation or dosing regimen may have complementary activities to the compound as described herein such that they do not adversely affect each other. The compounds may be administered together in a unitary pharmaceutical composition or separately. In one embodiment a compound or a pharmaceutically acceptable salt can be co-administered with a cytotoxic agent to treat proliferative diseases and cancer.

The term "co-administering" refers to either simultaneous administration, or any manner of separate sequential administration, of a compound as described herein, and a further active pharmaceutical ingredient or ingredients, including cytotoxic agents and radiation treatment. If the administration is not simultaneous, the compounds are

administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.

Typically, any agent that has activity against a disease or condition being treated may be co-administered. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6^th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved.

In one embodiment, the treatment method includes the co-administration of a compound as described herein and at least one cytotoxic agent. The term "cytotoxic agent" as used herein refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive . , , . ,21 1 _τ131 _τ125 _ν90 _D 186 _D 188 _c 153 „.212 _η32 _η, 212 , , .

isotopes (e.g., At , I , I , Υ , Re , Re , Sm , Βι , Ρ , Pb and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or

enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.

Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, nhibitors of LDH-A; inhibitors of fatty acid biosynthesis; cell cycle signaling inhibitors; HDAC inhibitors, proteasome inhibitors; and inhibitors of cancer metabolism.

"Chemotherapeutic agent" includes chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA^®, Genentech/OSI Pharm.), bortezomib (VELCADE^®, Millennium Pharm.), disulfiram , epigallocatechin gallate , salinosporamide A, carfilzomib, 17-AAG(geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX^®, AstraZeneca), sunitib (SUTENT^®, Pfizer/Sugen), letrozole (FEMARA^®, Novartis), imatinib mesylate (GLEEVEC^®., Novartis), finasunate (VATALANIB^®, Novartis), oxaliplatin (ELOXATIN^®, Sanofi), 5-FU (5- fluorouracil), leucovorin, Rapamycin (Sirolimus, RAPAMUNE^®, Wyeth), Lapatinib

(TYKERB^®, GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib

(NEXAVAR^®, Bayer Labs), gefitinib (IRESSA^®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN^® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine;

acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5a- reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,

novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γΐΐ and calicheamicin coll (Angew Chem. Intl. Ed. Engl. 1994 33: 183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as

neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, ADRIAMYCIN^® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin,

methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti- adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;

amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone;

elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea;

lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK^® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine;

mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE^® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE^® (docetaxel, doxetaxel; Sanofi-Aventis); chloranmbucil; GEMZAR (gemcitabine); 6- thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine;

NAVELBINE^® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA^®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;

difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX^®;

tamoxifen citrate), raloxifene, droloxifene, iodoxyfene , 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON^® (toremifme citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE^® (megestrol acetate), AROMASIN^® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR^® (vorozole), FEMARA^® (letrozole; Novartis), and ARIMIDEX^® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin,

fluoxymesterone, all transretionic acid, fenretinide, as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME^®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN^®, LEUVECTIN^®, and VAXID^®; PROLEUKIN^®, rIL-2; a topoisomerase 1 inhibitor such as LURTOTECAN^®; ABARELIX^® rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.

Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idee), pertuzumab

(OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin

(MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and the anti-interleukin-12 (ABT- 874/J695, Wyeth Research and Abbott Laboratories) which is a recombinant exclusively human-sequence, full-length IgGi λ antibody genetically modified to recognize interleukin- 12 p40 protein.

Chemotherapeutic agent also includes "EGFR inhibitors," which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an "EGFR antagonist." Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, US Patent No. 4,943, 533, Mendelsohn et al) and variants thereof, such as chimerized 225 (C225 or Cetuximab;

ERBUTIX^®) and reshaped human 225 (H225) (see, WO 96/40210, Imclone Systems Inc.); IMC-11F8, a fully human, EGFR-targeted antibody (Imclone); antibodies that bind type II mutant EGFR (US Patent No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in US Patent No. 5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (see WO98/50433, Abgenix/Amgen); EMD 55900

(Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known as El .l, E2.4, E2.5, E6.2, E6.4, E2.11, E6. 3 and E7.6. 3 and described in US 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al, J. Biol. Chem. 279(29):30375-30384 (2004)). The anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g.,

EP659,439A2, Merck Patent GmbH). EGFR antagonists include small molecules such as compounds described in US Patent Nos: 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, as well as the following PCT publications: W098/14451,

WO98/50038, WO99/09016, and WO99/24037. Particular small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA^® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fiuorophenyl)amino]-7-[3-(4- morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD 1839, gefitinib (IRES S A®) 4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(l-methyl-piperidin-4-yl)-pyrimido[5,4- d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(l- phenylethyl)amino]-lH-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4- [(l-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3- bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4- fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR/HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3

fluorophenyl)methoxy]phenyl] -6 [5 [ [ [2methylsulfonyl)ethyl] amino]methyl] -2-furanyl] -4- quinazo linamine) .

Chemotherapeutic agents also include "tyrosine kinase inhibitors" including the

EGFR-targeted drugs noted in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan- HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1 signaling; non- HER targeted TK inhibitors such as imatinib mesylate (GLEEVEC®, available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib

(PTK787/ZK222584, available from Novartis/Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines, such as PD 153035,4- (3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H- pyrrolo[2,3-d] pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4- fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; PD-0183805 (Warner-Lamber); antisense molecules ( e.g. those that bind to HER-encoding nucleic acid); quinoxalines (US Patent No. 5,804,396); tryphostins (US Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI- 1033 (Pfizer); Affmitac (ISIS 3521 ; Isis/Lilly); imatinib mesylate (GLEEVEC®); PKI 166

(Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-lCl l (Imclone), rapamycin (sirolimus, RAPAMUNE®); or as described in any of the following patent publications: US Patent No. 5,804,396; WO 1999/09016 (American Cyanamid); WO

1998/43960 (American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).

Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and

pharmaceutically acceptable salts thereof.

Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone- 17-butyrate, hydrocortisone- 17-valerate,

aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate,

prednicarbate, clobetasone- 17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; immune selective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG) (IMULAN Bio Therapeutics, LLC); anti-rheumatic drugs such as azathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, lefiunomideminocycline, sulfasalazine, tumor necrosis factor alpha (TNF ) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), Interleukin 1 (IL-1) blockers such as anakinra (Kineret), T cell costimulation blockers such as abatacept (Orencia), Interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); Interleukin 13 (IL-13) blockers such as lebrikizumab;

Interferon alpha (IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-Mi prime; Secreted homotrimeric LTa3 and membrane bound heterotrimer LTal/p2 blockers such as Anti-lymphotoxin alpha (LTa); radioactive isotopes (e.g., At²¹¹, 1¹³¹, 1¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactive isotopes of Lu); miscellaneous investigational agents such as thioplatin, PS-341 , phenylbutyrate, ET-18- OCH₃, or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, fiavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; acetylcamptothecin, scopolectin, and

9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL®); bexarotene

(TARGRETIN®); bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate

(ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate

(SKELID®), or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine; perifosine, COX-2 inhibitor (e.g. celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341); CCI-779; tipifarnib (Rl 1577); orafenib, ABT510; Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®); pixantrone;

farnesyltransferase inhibitors such as lonafarnib (SCH 6636, SARASAR™); and

pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATIN™) combined with 5-FU and leucovorin.

Chemotherapeutic agents also include non-steroidal anti-inflammatory drugswith analgesic, antipyretic and anti-inflammatory effects. NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib. NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to- moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.

Chemotherapeutic agents also include treatments for Alzheimer's Disease such as donepezil hydrochloride and rivastigmine; treatments for Parkinson's Disease such as L- DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide,

trihexephendyl, and amantadine; agents for treating multiple sclerosis (MS) such as beta interferon (e.g., Avonex^® and Rebif^®), glatiramer acetate, and mitoxantrone; treatments for asthma such as albuterol and montelukast sodium; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as

corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and antiparkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.

Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any of chemotherapeutic agents, described herein, as well as combinations of two or more of them.

The amount of both the compound as described herein and additional agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. In certain embodiments, compositions of this invention are formulated such that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive can be administered.

The additional therapeutic agent and the compound as described herein may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent, or there may be fewer side effects for the patient given that a lower dose is used. In certain embodiments, in such compositions a dosage of between 0.01 - 1 ,000 μg/kg body weight/day of the additional therapeutic agent can be administered.

Another aspect includes treating or preventing drug resistance in a patient using a compound as described herein. For example, a method of treating or preventing drug resistant cancer in a patient comprises administering a therapeutically effective amount of a compound as described herein to the patient alone or in combination with a cytotoxic agent. In certain embodiments, the individual is selected for treatment with a cytotoxic agent (e.g. , targeted therapies, chemotherapies, and/or radiotherapies). In certain embodiments, the individual starts treatment comprising administration of a compound as described herein prior to treatment with the cytotoxic agent. In certain embodiments, the individual concurrently receives treatment comprising the compound as described herein and the cytotoxic agent. In certain embodiments, the compound as described herein increases the period of cancer sensitivity and/or delays development of cancer resistance.

In particular, provided herein are methods of treating cancer in an individual comprising administering to the individual (a) a compound as described herein and (b) a cytotoxic agent (e.g. , targeted therapy, chemotherapy, and/or radiotherapy). In certain embodiments, the respective amounts of the compound as described herein and the cytotoxic agent are effective to increase the period of cancer sensitivity and/or delay the development of cancer cell resistance to the cancer therapy agent. In certain embodiments, the respective amounts of the compound as described herein and the cytotoxic agent are effective to increase efficacy of a cancer treatment comprising the cancer therapy agent. For example, in certain embodiments, the respective amounts of the compound as described herein and the cytotoxic agent are effective to increase efficacy compared to a treatment (e.g., standard of care treatment) (e.g., standard of care treatment) comprising administering an effective amount of the cancer therapy agent without (in the absence of) the compound as described herein. In certain embodiments, the respective amounts of the compound as described herein and cytotoxic agent agent are effective to increase response (e.g., complete response) compared to a treatment (e.g., standard of care treatment) comprising administering an effective amount of cytotoxic agent without (in the absence of) the compound as described herein.

Also provided herein are methods of increasing efficacy of a cancer treatment comprising a cytotoxic agent in an individual comprising administering to the individual (a) an effective amount of a compound as described herein and (b) an effective amount of the cytotoxic agent.

Provided herein are methods of treating cancer in an individual wherein cancer treatment comprising administering to the individual (a) an effective amount of a compound as described herein and (b) an effective amount of a cytotoxic agent, wherein the cancer treatment has increased efficacy compared to a treatment (e.g., standard of care treatment) comprising administering an effective amount of cytotoxic agent without (in the absence of) the compound as described herein.

In addition, provided herein are methods of delaying and/or preventing development of cancer resistant to a cancer therapy agent in an individual, comprising administering to the individual (a) an effective amount of a compound as described herein and (b) an effective amount of the cytotoxic agent.

Provided herein are methods of treating an individual with cancer who has an increased likelihood of developing resistance to a cancer therapy agent comprising

administering to the individual (a) an effective amount of a compound as described herein and (b) an effective amount of the cytotoxic agent.

Further provided herein are methods of increasing sensitivity to a cancer therapy agent in an individual with cancer comprising administering to the individual (a) an effective amount of a compound as described herein and (b) an effective amount of the cytotoxic agent.

Provided herein are also methods of extending the period of a cancer therapy agent sensitivity in an individual with cancer comprising administering to the individual (a) an effective amount of a compound as described herein and (b) an effective amount of the cytotoxic agent.

Provided herein are methods of extending the duration of response to a cytotoxic agent in an individual with cancer comprising administering to the individual (a) an effective amount of a compound as described herein and (b) an effective amount of the cytotoxic agent. In certain embodiments of any of the methods, the cytotoxic agent is a targeted therapy. In certain embodiments, the targeted therapy is one or more of an EGFR antagonist, RAF inhibitor, and/or PI3K inhibitor.

In certain embodiments of any of the methods, the targeted therapy is an EGFR antagonist. In certain embodiments of any of the methods, the EGFR antagonist is N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine and/or a pharmaceutical acceptable salt thereof. In certain embodiments, the EGFR antagonist is N-(3-ethynylphenyl)- 6,7-bis(2-methoxyethoxy)-4-quinazolinamine. In certain embodiments, the EGFR antagonist is N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2- (methylsulfonyl)ethylamino)methyl)furan-2-yl)quinazolin-4-amine,di4- methylbenzenesulfonate or a pharmaceutically acceptable salt thereof (e.g. , lapatinib).

In certain embodiments of any of the methods, targeted therapy is a RAF inhibitor. In certain embodiments, the RAF inhibitor is a BRAF inhibitor. In certain embodiments, the RAF inhibitor is a CRAF inhibitor. In certain embodiments, the BRAF inhibitor is

vemurafenib. In certain embodiments, the RAF inhibitor is 3-(2-cyanopropan-2-yl)-N-(4- methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide or a pharmaceutically acceptable salt thereof (e.g. , AZ628 (CAS# 878739-06-1)).

In certain embodiments of any of the methods, the targeted therapy is a PI3K inhibitor.

In certain embodiments of any of the methods, the cytotoxic agent is chemotherapy. In certain embodiments of any of the methods, the chemotherapy is a taxane. In certain embodiments, the taxane is paclitaxel. In certain embodiments, the taxane is docetaxel.

In certain embodiments of any of the methods, the cytotoxic agent is a platinum agent. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin. In certain embodiments of any of the methods, the cytotoxic agent is a taxane and a platinum agent. In certain embodiments, the taxane is paclitaxel. In certain embodiments, the taxane is docetaxel. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin.

In certain embodiments of any of the methods, the cytotoxic agent is a vinca alkyloid. In certain embodiments, the vinca alkyloid is vinorelbine. In certain embodiments of any of the methods, the chemotherapy is a nucleoside analog. In certain embodiments, the

nucleoside analog is gemcitabine.

In certain embodiments of any of the methods, the cytotoxic agent is radiotherapy. In certain embodiments of any of the methods, the compound as described herein is concomitantly administered with the cytotoxic agent (e.g. , targeted therapy, chemotherapy, and/or radiotherapy). In certain embodiments, the compound as described herein is

administered prior to and/or concurrently with the cytotoxic agent (e.g. , targeted therapy, chemotherapy, and/or radiotherapy).

In certain embodiments of any of the methods, the cancer is lung cancer, breast cancer, pancreatic cancer, colorectal cancer, and/or melanoma. In certain embodiments, the cancer is lung. In certain embodiments, the lung cancer is NSCLC. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is melanoma.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds, the following general methods, and other methods known to one of ordinary skill in the art, can typically be applied to all compounds and subclasses and species of each of these compounds, as described herein.

The general synthetic methods illustrateds in Schemes 1-4 and the general LCMS isolations procedures identified as LCMS Method A-LCMS Method F were used to prepare the compounds of Examples 1-432 as detailed below.

General Synthetic Methods

Scheme 1 (Method A)

1

Boronic Acid

5 6 7

The general synthesis of compounds 6 and 7 is illustrated in Scheme 1. 5-Amino-lH- pyrazole-4-carbonitrile (1) is condensed with alkyl malonate in refluxing EtOH using NaOEt as base to give intermediate 3. This is followed by reaction with phosphorous oxy chloride that leads to dichloro intermediate 4, which was selectively hydrolysed using sodium hydroxide to afford the common chloride intermediate 5. Subsequent Suzuki cross-coupling with bronic acid or boronate ester resulted in compound 6, which could be further N- alkylated with a halide R³X to afford compound 7. Scheme 2 (Met

An alternative synthesis (Method B) of compound 6 is outlined in Scheme 2. 5-Amino-lH- pyrazole-4-carbonitrile (1) was condensed with ketoester 8 in in the presence of acetic acid or titanium tetrachloride to afford compound 6. Scheme 3 (Method C)

9 10 6

X=CI, or Br, or I

An alternative synthesis of compound 6 (Method C) is shown in Scheme 3. Compound 9 was treated with N-halogen succinamde in DMF to give halide 10. Subsequent Suzuki coupling of compound 10 with a boronic acid or boronate ester also provided compound 6.

Scheme 4 (Method D)

11

TMSBr

EtCN

°C

DMSO

150 °C, MW

Under Pd-catalyzed conditions, chloride 5 could also be coupled with an amine to give compound 11. The chloride in compound 5 could be further transformed to bromide 12, in the presence of TMSBr. Subsequent coupling reaction of bromide 12 with an alcohol provided compound 13.

General LCMS Procedures

LCMS Method A (Agilent 10-80 AB, ELSD, 2 min)

Experiments were performed on an Agilent 1200 HPLC (with a PDA detector) with Agilent 6110 MSD mass spectrometer using ESI as ionization source using an Xtimate CI 8, 3 um, 30 x 2.1 mm and a 1.2 mL/min flow rate. Solvent A was water containing 0.038% TFA, and solvent B was acetonitrile containing 0.02% TFA. A gradient was run: starting with 10% A and 90% B, going to 20% A and 80% B within 0.9 min, then holding at 20% A and 80% B for 0.6 min. Total run time was 2 min.

LCMS Method B (Agilent 0-30 AB, ELSD, 2 min)

Experiments were performed on an Agilent 1200 HPLC (with a PDA detector) with Agilent 6110 MSD mass spectrometer using ESI as ionization source using an Xtimate CI 8, 3 um, 30 x 2.1 mm and a 1.2 mL/min flow rate. Solvent A was water containing 0.038% TFA, and solvent B was acetonitrile containing 0.02% TFA. A gradient was run: starting at 100% A, going to 30% A and 70% B within 0.9 min, then holding at 30% A and 70% B for 0.6 min. Total run time was 2 min.

LCMS Method C (Agilent 0-60 AB, ELSD, 2 min)

Experiments were performed on an Agilent 1200 HPLC (with a PDA detector) with Agilent 6110 MSD mass spectrometer using ESI as ionization source using an Xtimate CI 8, 3 um, 30 x 2.1 mm and a 1.2 mL/min flow rate. Solvent A was water containing 0.038% TFA, and solvent B was acetonitrile containing 0.02% TFA. A gradient was run: starting with 100%A and going to 40% A and 60% B within 0.9 min, then holding at 40% A and 60% B for 0.6 min. Total run time was 2 min.

LCMS Method D (Agilent 30-90 AB, ELSD, 2 min)

Experiments were performed on an Agilent 1200 HPLC (with a PDA detector) with Agilent 6110 MSD mass spectrometer using ESI as ionization source using an Xtimate CI 8, 3 um, 30 x 2.1 mm and a 1.2 mL/min flow rate. Solvent A was water containing 0.038% TFA, and solvent B was acetonitrile containing 0.02% TFA. A gradient was run: starting with 30% A and 70% B, going to 10% A and 90% B within 0.9 min, then holding at 10% A and 90% B for 0.6 min. Total run time was 2 min. LCMS Method E (SHIMADZU, 5-95 AB, ELSD, 1.5 min)

Experiments were performed on a SHIMADZU 20A HPLC (with a PDA detector) with SHIMADZU 2010EV MSD mass spectrometer using ESI as ionization source using an Merk RP-18e 2 x 25mm column and a 1.5mL/min flow rate. Solvent A was water containing 0.038% TFA, and solvent B was acetonitrile containing 0.02% TFA. A gradient was run: starting with 95% A and 5% B, going to 5% A and 95% B over the next 0.7 min. This solvent ratio was maintained for 0.4 min before returning to 95% A and 5% B over the next 0.4 min. Total run time was 1.5 min. LCMS Method F (Agilent 5-95 AB, ELSD, 10 min)

Experiments were performed on an Agilent 6140 quadrupole LC/MS system linked to a HPLC Agilent 1200 system with a UV detector monitoring at 254 nm, and mass spectrometry scanning 90-1300 amu in ESI+ ionization mode. This system uses an Agilent SB C18 (1.8 um 30 x 2.1 mm) column, maintained at 25 °C and a 0.4 mL/min flow rate. Solvent A was water containing 0.05% TFA, and solvent B was acetonitrile containing 0.05% TFA. A gradient was run: starting with 95% A and 5% B for the first 0.3 min, going to 5% A and 95% B over the next 6.5 min. This solvent ratio was maintained for 1.5 min before returning to 95% A and 5% B over the next 0.1 min. Total run time was 10 min.

Examples

Example 1 (Method A)

Step 1

6-isopropyl-5,7-dioxo-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-3-carbonitrile

Sodium (9.0 g, 391 mmol) was added slowly to EtOH (400 mL), and the mixture was stirred at 26 °C for 1.5 hours until sodium was consumed completely. To the resultant NaOEt solution was added 5-amino-lH-pyrazole-4-carbonitrile (20 g, 185 mmol), followed by diethyl 2-isopropylmalonate (37.5 g, 185 mmol). The reaction mixture was refluxed for 16 hours. Then the reaction mixture was cooled to room temperature and diluted with MTBE (200 mL). The precipitate was collected by filtration and dissovled in water. The solution was acidified with concentrated HC1 to pH 2-3 to afford an off-white precipitate, which was filtered and dried under reduced pressure to afford the desired product as a white solid (30 g, 74% yield). 1H NMR (400MHz, DMSO- ) δ 8.23 (s, 1H), 3.23 (q, / = 6.8 Hz, 1H), 1.20 (d, J = 6.8 Hz, 6H).

Step 2

5,7-dichloro-6-isopro yl yrazolo[l,5-a]pyrimidine-3-carbonitrile

6-Isopropyl-5,7-dioxo-4,5,6,7-tetrahydropyrazolo[l ,5-a]pyrimidine-3-carbonitrile (30 g, 137 mmol) was added to POCl₃ (100 mL) in five portions, followed by N,N-dimethylaniline (17 g, 137 mmol). The reaction mixture was heated to 110 °C and stirred for 16 hours. After being cooled to room temperature, POCI₃ was removed under reduced pressure and the residue was diluted with water (200 mL), extracted with EtOAc (200 mL x 3). Combined organics were dried over anhydrous Na₂S0₄, and concentrated. The crude residue was re-crystallized from EtOAc and hexanes (1 :5) to afford the desired product as a white solid (25 g, 71% yield). 1H NMR (400MHz, DMSO- ) δ 8.86 (s, 1H), 3.73 - 3.68 (m, 1H), 1.41 (d, / = 7.2 Hz, 6H). LCMS (ESI) m/z 255.1 [M+H]⁺, RT = 1.12 min (LCMS Method A).

Step 3

5-chloro-6-isopro yl-7-oxo-4,7-dihydro yrazolo[l,5-a]pyrimidine-3-carbonitrile

To a solution of 5,7-dichloro-6-isopropylpyrazolo[l ,5-a]pyrimidine-3-carbonitrile (10 g, 39.2 mmol) in THF (100 mL) was added aqueous NaOH solution (100 mL, 2 M). The mixture was stirred at 26 °C for 16 hours when reaction went to completion. After acidification with 1M aqueous HC1 to pH = 1 , the mixture was extracted with EtOAc (500 mL x 3). The combined organic layers were dried over anhydrous Na₂S0₄, and concentrated via rotavap. The crude residue was recrystallized from EtOAc/hexanes (1 :5) to afford the desired product as a white solid (6.8 g, 73% yield). 1H NMR (400MHz, DMSO-d₆) δ 8.29 (s, 1H), 3.30-3.23 (m, 1H), 1.30 (d, / = 7.2 Hz, 6H). LCMS (ESI) m/z 237.2 [M+H]⁺, RT = 1.11 min (LCMS Method C).

Example 2

5-chloro-6-ethyl-7-oxo-4,7-dihydro yrazolo[l,5-a]pyrimidine-3-carbonitrile

In a similar procedure as shown in Example 1 , the title compound was prepared in 36% yield from 5-amino-lH-pyrazole-4-carbonitrile and diethyl 2-ethylmalonate. 1H NMR (400MHz, MeOH-d₄) δ 8.09 (s, 1H), 2.70 (q, / = 7.6 Hz, 2H), 1.12 (t, / = 7.6 Hz, 3H); LCMS (ESI) m/z 223.1 [M+H]⁺, RT = 1.02 min (LCMS method C). Example 3

5-(furan-3-yl)-6-isopro yl-7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidine-3-carbonitrile

To a solution of 5-chloro-6-isopropyl-7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidine-3- carbonitrile (200 mg, 0.845 mmol), furan-3-ylboronic acid (104 mg, 0.93 mmol) and K₂CO₃ (233 mg, 1.69 mmol) in dioxane: H₂0 (5: 1, 3 mL) was added Pd(dppf)Cl₂ (70 mg, 0.085 mmol). The reaction vessel was sealed and heated in microware at 110 °C for 30 minutes. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel eluting with 0 - 10% MeOH in DCM to give crude product, which was further purified by preparative HPLC to afford the desired product as white solid (40 mg, 18% yield). 1H NMR (400 MHz, DMSO- ) δ 13.26 (s, 8.35 (s, 1H), 8.09 (s, 1H), 7.88 (s, 1H), 6.74 (s, 1H), 2.90 - 2.85 (m, 1H), 1.26 (d, / = 6.4 6H). LCMS (ESI) m/z 269.1 [M+H]⁺, RT = 0.95 min (LCMS Method A).

Example 4

5-(furan-3-yl)-6-isopro yl-4-methyl-7-oxo-4,7-dihydro yrazolo[l,5-a]pyrimidine-3- carbonitrile

To a solution of 5-(furan-3-yl)-6-isopropyl-7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidine-3- carbonitrile (320 mg, 1.19 mmol) and K₂CO₃ (330 mg, 2.39 mmol) in DMF (3 mL) was added Mel (0.12 mL, 1.79 mmol). After being stirred at room temperature for 6 hours, the mixture was partitioned between EtOAc (30 mL) and H₂0 (30 mL) and the two layers were separated. The aqueous layer was extracted with EtOAc (30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂S0₄, filtered and concentrated, and the residue was purified by preparative HPLC to give the desired product as white solid (15 mg, 4% yield). 1H NMR (400 MHz, DMSO- ) δ 8.47 (s, 1H), 8.00 (s, 1H), 7.98 (s, 1H), 6.71 (s, 1H), 3.60 (s, 1H), 2.65 - 2.60 (m, 1H), 1.22 (d, / = 7.2 Hz, 6H). LCMS (ESI) m/z 283.1 [M+H]⁺, RT = 1.01 min (LCMS Method A). Example 5

6-Isopropyl-7-oxo-5-(lH-pyrazol-4-yl)-4,7-dihydropyrazolo[l,5-a]pyrimidine-3-carbonit rile

To a solution of 5-chloro-6-ethyl-7-oxo-4,7-dihydropyrazolo[l ,5-a]pyrimidine-3-carbonitrile (10 g, 42.26 mmol), 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (10.66 mg, 54.93 mmol) and Na₂C0₃ (8.96 g, 84.51 mmol) in DME: H₂0 (2 : 1 , 150 mL) was added Pd(dppf)Cl₂ (3.1 g, 4.23 mmol) under nitrogen atmosphere. The reaction mixture was heated at 110 °C for 16 hours. After being cooled to room temperature, the reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM to provide the desired prouct as a brown solid (7.0 g, 62% yield). 1H NMR (400 MHz, DMSO-d₆) δ 13.42 (s, 1H), 13.09 (s, 1H), 8.36 (s, 1H), 8.17 (s, 1H), 7.78 (s, 1H), 2.97 (m, 1H), 1.29 (d, / = 7.2 Hz, 6H). LCMS (ESI): m/z 269.2 [M+H]⁺, RT = 1.02 min (LCMS Method C). Example 6

5-(l-(Cyclopropylmethyl)-lH-pyrazol-4-yl)-6-isopropyl-7-oxo-4,7-dihydropyrazolo[l,5- o]pyrimidine-3-carbonitrile

To the mixture of 6-isopropyl-7-oxo-5-(lH-pyrazol-4-yl)-4,7-dihydropyrazolo[l ,5- fl]pyrimidine-3-carbonitrile (100 mg, 0.372 mmol) and (bromomethyl)cyclopropane (50 mg ,0.372 mmol) in DMF (2 mL) was added Cs₂C0₃ (364 mg, 1.12 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was purified by preparative HPLC to afford the desired product (20 mg, 17% yield) as an off-white solid. 1H NMR (400 MHz, CD₃OD) δ 8.20 (s, 1H), 8.12 (s, 1H), 7.76 (s, 1H), 4.1 1 (d, / = 7.2 Hz, 2H), 3.10-3.03 (m, 1H), 1.37 (d, / = 7.2 Hz, 6H), 1.37 (m, 1H), 0.68-0.63 (m, 2H), 0.47-0.43 (m, 2H); LCMS (ESI) m/z 269.1 [M+H]⁺, RT = 0.73 min (LCMS Method E).

Example 7

Step 1

4-Br omo- 1 - (pr op - 1 -en -2-yl)- lH-p yr azole

A solution of Cu(OAc)₂ (6.18 g, 34.02 mmol) and 2,2'-bipyridine (5.31 g, 68.04 mmol) in DCE (30 mL) was heated to 70 °C for 15 min. Then this mixture was transferred to a suspension of 4-bromo-lH-pyrazole (5 g, 34.02 mmol), potassium trifluoro(prop-l-en-2- yl)borate (10.07 g, 68.04 mmol), and Na₂C0₃ (7.21 g, 68.04 mmol) in DCE (20 mL). The mixture was stirred at 70 °C for 8 hours before being partitioned between EtOAc and 1 N HC1. The aqueous layer was extracted with EtOAc (20 mL x 2) and the combined organic layers were washed with brine, dried over Na₂S0₄ and concentrated to afford crude product which was purified by flash column chromatography on silica gel (hexanes/EA = 200/1) to give the desired product (4.0 g, 66% yield) as colorless oil. 1H NMR (400 MHz, CDC1₃) δ 7.70 (s, 1H), 7.54 (s, 1H), 5.28 (d, / = 4.4 Hz, 1H), 4.72 (s, 1H), 2.45 (s, 3H).

Step 2

4-Br omo- 1 - ( 1 -methylcyclopr op yl)-l H-p yr azole

A solution of TFA (2.38 mL, 32.08 mmol) in DCM (10 mL) was added dropwise to Et₂Zn (1 M toluene solution, 32 mmol) in DCM (30 mL) under N₂ atmosphere in ice bath. After 20 min, a solution of CH₂I₂ (8.5 g, 32.08 mmol) in DCM (10 mL) was added dropwise and stirred for another 20 min. Then a solution of 4-bromo-l-(prop-l-en-2-yl)-lH-pyrazole in DCM (5 mL) was added and the ice bath was removed. After stirring at room temperature for 24 hours, the mixture was quenched with saturated NH₄C1 solution and extracted by DCM (20 mL x 2). Combined organics were dried over anhydrous Na₂S0₄, filtered and concentrated to give the crude product which was purified by flash column chromatography on silica gel (hexanes/EA = 100/1) to give the desired product (490 mg, 15% yield) as yellow oil. 1H NMR (400 MHz, DMSO-d₆) δ 7.50 (s, 1H), 7.43 (s, 1H), 1.59 (s, 3H) 1.24 (t, / = 6.0 Hz, 2H), 0.91 (t, / = 6.8 Hz, 2H).

Step 3

l-(l-Methylcyclopro yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole

A mixture of 4-bromo-l-(l -methylcyclopropyl)-lH-pyrazole (650 mg, 3.23 mmol), 4,4,4*,4*,5,5,5*,5*-octamethyl-2,2^,-bi(l ,3,2-dioxaborolane) (820 mg, 3.23 mmol), Pd(PPh₃)₂Cl₂ (210 mg, 0.3 mmol) and CH₃COOK (792 mg, 8.07 mmol) in dioxane (10 mL) was heated at 100 °C for 5 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was evaporated and the residue was purified by flash column chromatography on silical gel eluting with 0 - 10% EtOAc in hexanes to give the desired product (160 mg, 20%> yield) as a white solid. 1H NMR (400 MHz, CDC1₃): δ 7.80 (s, 1H), 7.77 (s, 1H), 1.32 (s, 12H), 1.27 - 1.23 (m, 2H), 0.92 - 0.89 (m, 2H).

Step 4

6-Isopropyl-5-(l-(l-methylcyclopro yl)-lH-pyrazol-4-yl)-7-oxo-4,7- dihydro yrazolo[l,5-a]pyrimidine-3-carbonitrile

To a solution of 5-chloro-6-isopropyl-7-oxo-4,7-dihydropyrazolo[l ,5-a]pyrimidine-3- carbonitrile (160 mg, 0.64 mmol), l-(l-methylcyclopropyl)-4-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)-lH-pyrazole (151 mg, 0.64 mmol) and Na₂C0₃ (136 mg, 1.28 mmol) in DME/H₂0 (2/1, 3 mL) was added Pd(dppf)Cl₂ (44 mg, 0.06 mmol) under nitrogen atmosphere. The reaction mixture was heated at 110 °C for 30 min under microwave condition. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel eluting with 50-100% EtOAc in hexanes to give crude product which was further purified by rpHPLC (Gemini C₁₈ 150 x 25 mm x 10 urn, 35-65% MeCN/H₂0) to give the desired product (62 mg, 30% yield) as a white solid. 1H NMR (400 MHz, DMSO-d₆) δ 13.01 (s, 1H), 8.37 (s, 1H), 8.23 (s, 1H), 7.71 (s, 1H), 2.98-2.92 (m, 1H), 1.64 (s, 6H), 1.29 (d, / = 7.2 Hz, 6H), 1.26-1.24 (m, 2H), 1.00 - 0.97 (m, 2H). LCMS (ESI) m/z 323.1 [M+H]⁺, RT = 1.18 min (LCMS Method C).

Example 8

Step 1

4-Bromo-5-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole

To a solution of 4-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole (5.0g, 18.0 mmol) in THF (50 mL) at -78 °C was added LDA (18.0 mL, 36.0 mmol, 2 M in THF) dropwise under N₂. After stirring at -78 °C for 30 min, the reaction mixture was cooled to -100 °C and N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (11.37 g, 36.0 mmol, dissolved in 50 mL of THF) was added dropwise to the reaction mixture, and the reaction mixture was stirred at -78 °C for 1 hour. The reaction was quenched with sat. NH₄C1 (100 mL) and extracted with methyl tert-butyl ether (100 mL). The organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to give the crude product which was purified by flash column chromatography on silica gel eluting with 0-2% EtOAc in hexanes to afford 4-bromo-5- fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole as colourless oil (460 mg, 9% yield). 1H NMR (400 MHz, CDC1₃) δ 7.42 (d, / = 2.4 Hz, 1H), 5.37 (s, 2H), 3.63 (d, / = 8.4 Hz, 2H), 0.93 (d, / = 8.4 Hz, 2H), 0.01 (s, 9H). Step 2

5-Fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-((2-(trimethylsilyl)ethoxy)me thyl)-lH-pyrazole

To a solution of 4-bromo-5-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole (460 mg, 1.56 mmol) in THF (10 mL) was added iPrMgBr (4.67 mL, 4.67 mmol, 1 M in THF) at 0 °C, and the reaction was allowed to stir at room temperature for 1 hour. 2-methoxy-4,4,5,5- tetramethyl-l ,3,2-dioxaborolane (985 mg, 6.23 mmol) was then added, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with sat. NH₄C1 (20 mL) and extracted with methyl iert-butyl ether (50 mL). The organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to give the crude target which was purified by flash column chromatography on silica gel eluting with 0-3% EtOAc in hexanes to afford the desired product (360 mg, 68% yield) as colorless oil. 1H NMR (400 MHz, CDC1₃) δ 7.63 (d, / = 3.2 Hz, 1H), 5.35 (s, 2H), 3.62 (d, / = 8.0 Hz, 2H), 1.33 (s, 12H), 0.91 (d, / = 8.0 Hz, 2H), 0.02 (s, 9H).

Step 3

5-(5-Fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)-6-isopropyl-7-oxo-4,7- dihydropyrazolo[l,5-a]pyrimidine-3-carbonitrile

To a solution of 5-chloro-6-isopropyl-7-oxo-4,7-dihydropyrazolo[l ,5-a]pyrimidine-3- carbonitrile (144 mg, 0.61 mmol), 5-fluoro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)- l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole (260 mg, 0.76 mmol) and Na₂C0₃ (161 mg, 1.52 mmol) in DME:H₂0 (2: 1 , 3 mL) was added Pd(dppf)Cl₂ (56 mg, 0.076 mmol) under nitrogen atmosphere. The reaction mixture was heated at 1 10 °C for 30 min under microwave condiction. After being cooled to room temperature, the reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel eluting with 0-3% MeOH in DCM to provide the desired prouct (220 mg crude) as a brown solid. LCMS m/z 417.0 [M+H]⁺.

Step 4

5-(5-Fluoro-lH-pyrazol-4-yl)-6-isopro yl-7-oxo-4,7-dihydro yrazolo[l,5-a]pyrimidine-

3-carbonitrile

To a solution of 5-(5-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)-6- isopropyl-7-oxo-4,7-dihydropyrazolo[l ,5-a]pyrimidine-3-carbonitrile (220 mg crude) in angydrous DCM (4 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was redissloved in HCl/dioxane (20 mL). The reaction mixture was stirred at room temperature for 16 hours and concentrated to give crude product (150 mg) which was used directly in next step. LCMS m/z 286.9 [M+H]⁺.

Step 5

5-(3-Fluoro-l-isopro yl-lH-pyrazol-4-yl)-6-isopro yl-7-oxo-4,7-dihydro yrazolo[l,5- o]pyrimidine-3-carbonitrile

To a solution of 5-(5-fluoro-lH-pyrazol-4-yl)-6-isopropyl-7-oxo-4,7-dihydropyrazolo[l ,5- fl]pyrimidine-3-carbonitrile (150 mg crude, 0.53 mmol) and 2-iodopropane (71 mg, 0.42 mmol) in DMF (3 mL) was added CS₂CO₃ (345 mg, 1.06 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and purified by rpHPLC (Gemini Ci₈ 150 x 25 mm x 10 urn, 33-63% MeCN/H₂0) to give the title compound (25 mg, 18% yield) as a white solid. 1H NMR (400 MHz, DMSO-d₆) δ 13.24 (s, 1H), 8.39 (s, 1H), 8.14 (s, 1H), 4.54 - 4.73 (m, 1H), 2.84 - 2.77 (m, 1H), 1.44 (d, / = 6.4 Hz, 6H), 1.28 (d, / = 7.2 Hz, 6H). LCMS (ESI): m/z 329.1 [M+H]⁺, RT = 1.23 min (LCMS Method C).

Example 9

6-Isopropyl-7-oxo-5-(l-(2-phenylpropan-2-yl)-lH-pyrazol-4-yl)-4,7- dihydropyrazolo[l,5-a]pyrimidine-3-carbonitrile

To a mixture of 6-isopropyl-7-oxo-5-(lH-pyrazol-3-yl)-4,7-dihydropyrazolo[l ,5- fl]pyrimidine-3-carbonitrile (200 mg, 0.75 mmol) and 2-phenylpropan-2-ol (2 mL) was added concentrated sulfuric acid (41 μΕ, 0.75 mmol). The reaction was heated to 100 °C for 20 min under microwave irradiation. The reaction was quenched with sat. NaHC0₃ (10 mL) and extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous Na₂S0₄, filtered and concentrated. The residue was purified by rpHPLC (Gemini C₁₈ 150 x 25 mm x 10 urn, 50 - 80% MeCN/H₂0) to give the desired product (140 mg, 49% yield) as a white solid. 1H NMR (400 MHz, DMSO-d₆) δ 13.06 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.35 - 7.31 (m, 2H), 7.28 -7.24 (m, 1H), 7.08 (d, / = 7.2 Hz, 2H), 3.02 - 2.95 (m, 1H), 1.99 (s, 6H), 1.30 (d, / = 7.2 Hz, 6H). LCMS (ESI): m/z 387.1 [M+H]⁺, RT = 1.12 min (LCMS Method A).

Example 10

6-Isopro yl-7-oxo-5-(l-(pyridin-3-yl)-lH-pyrazol-4-yl)-4,7-dihydro yrazolo[l,5- o]pyrimidine-3-carbonitrile

A mixture of 6-isopropyl-7-oxo-5-(lH-pyrazol-4-yl)-4,7-dihydropyrazolo[l ,5-a]pyrimidine- 3-carbonitrile (200 mg, 0.75 mmol), 3-iodopyridine (306 mg, 1.49 mmol), Cul (7 mg, 0.04 mmol), L-proline (9 mg, 0.075 mmol) and K₂C0₃ (103 mg, 0.75 mmol) in DMSO (5 mL) was heated at 120 °C for 16 hours under a nitrogen atmosphere. After cooling, the mixture was filtered and the filtrate was evaporated. The residue was purified by rpHPLC (ASB C₁₈ 150*25 mm, 40% MeCN/H₂0) to give the desired product as its HC1 salt (25 mg, 10% yield) as a white solid. 1H NMR (400 MHz, DMSO-d₆) δ 13.33 (s, 1H), 9.31 (s, 1H), 9.10 (s, 1H), 8.70 (s, 1H), 8.54 (d, / = 8.4 Hz, 1H), 8.42 (s, 1H), 8.16 (s, 1H), 7.80 (dd, / = 8.4, 4.8 Hz, 1H), 3.01-2.95 (m, 1H), 1.32 (d, / = 7.2 Hz, 6H). LCMS (ESI): m/z 346.0 [M+H]⁺, RT = 1.08 min (LCMS Method C).

Example 11

6-Isopropyl-7-oxo-5-(l-(pyridin-4-yl)-lH-pyrazol-4-yl)-4,7-dihydropyrazolo[l,5- o]pyrimidine-3-carbonitrile

In a similar procedure as shown in Example 10, this compound was prepared in 10% yield from 4-iodopyridine. 1H NMR (400 MHz, DMSO-d₆): δ 9.36 (s, 1H), 9.01 (brs, 2H), 8.45 - 8.43 (m, 3H), 8.33 (s, 1H), 2.94-2.90 (m, 1H), 1.32 (d, / = 6.8 Hz, 6H). LCMS (ESI): m/z 346.1 [M+H]⁺, RT = 0.95 min (LCMS Method C). Example 12

6-Isopropyl-7-oxo-5-(l-(pyridin-2-yl)-lH-pyrazol-4-yl)-4,7-dihydropyrazolo[l,5- o]pyrimidine-3-carbonitrile To a solution of 6-isopropyl-7-oxo-5-(lH-pyrazol-4-yl)-4,7-dihydropyrazolo[l ,5- fl]pyrimidine-3-carbonitrile (200 mg, 0.75 mmol) in DMF (5 mL) was added NaH (60% dispersion in mineral oil, 90 mg, 2.25 mmol) in DMF (5 mL) at 0 °C under N₂. After stirring at 0 °C for 30 min, 2-fluoropyridine (109 mg, 1.12 mmol) was added in portions. After addition, the resultant mixture was heated at 70 °C for 5 hours. The reaction was quenched with sat. NH₄C1 (20 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated. The residue was purified by rpHPLC (ASB Ci₈ 150 x 25 mm, 40-70% MeCN/H₂0) to give the desired product (35 mg, 14% yield) as a white solid. 1H NMR (400 MHz, DMSO-d₆) δ 13.29 (s, 1H ), 9.01 (s, 1H), 8.55 (d, / = 4.4 Hz, 2H), 8.41 (s, 1H), 8.1 1 - 8.07 (m, 2H), 8.02 (d, / = 8.0 Hz, 1H), 7.47 - 7.44 (m, 1H), 3.01 - 2.94 (m, 1H), 1.32 (d, / = 7.2 Hz, 6H); LCMS (ESI): m/z 346.0 [M+H]⁺, RT= 1.24 min (LCMS Method C).

Example 13

Step 1

Tert-butyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)propanoate To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (5.0 g, 25.8 mmol) and tert-butyl 2-bromo-2-methylpropanoate (6.32 g, 28.3 mmol) in DMF (50 mL) was added CS₂CO₃ (12.59 g, 38.65 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered and partitioned between methyl tert-butyl ether (100 mL) and H₂0 (100 mL). The combined organic layer was separated, washed with brine, dried over anhydrous Na₂S0₄ and concentrated to afford crude product which was purified by flash column chromatography on silica gel eluting with 0-10% EtOAc in hexanes to give the desired product (7.0 g, 81% yield) as a white solid. 1H NMR (400 MHz, CDC1₃) δ 7.87 (s, 1H), 7.84 (s, 1H), 1.81 (s, 6H), 1.39 (s, 9H), 1.37 (s, 12H).

Step 2

Tert-butyl 2-(4-(3-cyano-6-isopro yl-7-oxo-4,7-dihydro yrazolo[l,5-a]pyrimidin-5-yl)- lH-pyrazol-l-yl)-2-methylpropanoate

To a solution of 5-chloro-6-isopropyl-7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidine-3- carbonitrile (1.0 g, 4.2 mmol), tert-butyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)propanoate (2.12 g, 6.3 mmol) and Na₂C0₃ (890 mg, 8.4 mmol) in DME: H₂0 (2/1, 30 mL) was added Pd(dppf)Cl₂ (307 mg, 0.042 mmol) under nitrogen atmosphere. The reaction mixture was heated at 110 °C for 16 hours. After being cooled to room temperature, the reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel eluting with 0-3% MeOH in DCM to provide the crude product which was re-crystallizated from TBME/MeOH (5/1, 20 mL) to give the desired product (760 mg, 44% yield) as a brown solid. 1H NMR (400 MHz, DMSO- d₆) δ 13.16 (brs, 1H), 8.35 (s, 1H), 8.23 (s, 1H), 7.77 (S, 1H), 2.99 - 2.96 (m, 1H), 1.79 (s, 6H), 1.34 (s, 9H), 1.29 (d, / = 6.8 Hz, 2H). Step 3

2-(4-(3-Cyano-6-isopropyl-7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidin-5-yl)-lH-pyrazol- l-yl)-2-methylpropanoic acid

A mixture of tert-butyl 2-(4-(3-cyano-6-isopropyl-7-oxo-4,7-dihydropyrazolo[l,5- a]pyrimidin-5-yl)-lH-pyrazol-l-yl)-2-methylpropanoate (500 mg, 1.22 mmol) in HCl/dioxane (20 mL) was stirred at room temperature for 16 hours. The mixture was evaporated to give crude product as a brown solid which was used directly for next step. 1H NMR (400 MHz, DMSO-d₆) δ 13.13 (brs, 1 H), 8.37 (s, 1H), 8.28 (s, 1H), 7.77 (s, 1H), 3.01- 2.94 (m, 1H), 1.81 (s, 6H), 1.30 (d, / = 7.2 Hz, 2H).

Step 4

2-(4-(3-Cyano-6-isopropyl-7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidin-5-yl)-lH-pyrazol- l-yl)-N,2-dimethylpropanamide

To a solution of 2-(4-(3-cyano-6-isopropyl-7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidin-5-yl)- lH-pyrazol-l-yl)-2-methylpropanoic acid (100 mg, 0.24 mmol) and methanamine hydrochloride (32 mg, 0.48 mmol) in DMF (2 mL) was added HATU (137 mg, 0.36 mmol) and DIPEA (124 mg, 0.96 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by rpHPLC (Gemini C₁₈ 150 x 25 mm x 10 um, 6-36% MeCN/H₂0) to give the desired product (28 mg, 32% yield) as a white solid. 1H NMR (400 MHz, DMSO- ) δ 13.02 (brs, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 7.78 (s, 1H), 7.56 (d, / = 4.0 Hz, 1H), 3.03 - 3.00 (m, 1H), 2.61 (d, / = 4.8 Hz, 3H), 1.77 (s, 6H), 1.31 (d, / = 6.8 Hz, 6H). LCMS (ESI): m/z 368.1 [M+H]⁺, RT = 1.08 min (LCMS Method C). Example 14

Step 1

4-Iodo-l-isopropyl-lH-pyrazole

To a stirred solution of 4-iodo-lH-pyrazole (5 g, 25.8 mmol) and CS₂CO_{3 (}25.2 g, 77.3 mmol) in DMF (50 mL) was added 2-iodopropane (5.26 g, 30.9 mmol). The mixture was stirred at 10 °C for 16 hours. CS₂CO₃ was removed by filtration. The filtrate was diluted with H₂0 (50 mL) and extracted with EtOAc (50 mL). The organic layer was washed with water (20 mL X 6). The organic was dried over Na₂S0₄, concentrated to give the desired product (5.2 g, 85% yield) as colourless oil. 1H NMR (400 MHz, CD₃OD) δ 7.75 (s, 1H), 7.47 (s, 1H), 4.55 - 4.48 (m, 1H), 1.45 (d, / = 6.8 Hz, 6H).

Step 2

5-Fluoro-4-iodo-l-isopropyl-lH-pyrazole

The solution of 4-iodo-l-isopropyl-lH-pyrazole (2.0 g, 8.47 mmol) in THF (20 mL) was cooled to -78 °C. LDA (8.47 mL, 16.94 mmol, 2 M in THF) was added dropwise to the solution at -78 °C and then stirred at -78 °C for 30 min. The reaction mixture was cooled to - 100 °C and N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (10.7 g, 33.89 mmol, dissolved in 20 mL THF) was added dropwise to the reaction mixture. The reaction mixture was stirred at -78 °C for 1 hour. Saturated NH₄C1 (50 mL) was added to quench the reaction and then extracted with EtOAc (50 mL x 3). Combined organic layers were dried over Na₂S0₄, filtered and concentrated to give the crude target which was purified by flash column chromatography on silica gel eluting with 0-2% EtOAc in hexanes to afford the desired crude product as colourless oil. Step 3

5-Fluoro-l-isopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole A solution of 5-fluoro-4-iodo-l-isopropyl-lH-pyrazole (400 mg, 1.58 mmol) in THF (5 mL) was added 1 M of iPrMgBr (4.7 mL, 4.7 mmol) in THF at 0 °C, and the reaction was allowed to stir for 1 hour. 2-methoxy-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (1 g, 6.32 mmol) was then added, and the mixture was stirred at 10 °C for 2 hours. Saturated NH₄C1 (10 mL) was added to quench the reaction. Then the organic solvent was removed in vacuo. The remaining aqueous layer was extracted with DCM (10 mL x 3). Combined organic layers were dried over Na₂S0₄, filtered and concentrated to give the crude target which was purified by flash column chromatography on silica gel eluting with 0-3% EtOAc in hexanes to afford the desired crude product as colourless oil. Step 4

5-(5-Fluoro-l-isopropyl-lH-pyrazol-4-yl)-6-isopropyl-7-oxo-4,7-dihydropyrazolo[l,5- o]pyrimidine-3-carbonitrile

In a similar procedure as shown in Example 3, the title compound was prepared in 14% yield from 6-isopropyl-7-oxo-5-(lH-pyrazol-4-yl)-4,7-dihydropyrazolo[l ,5-a]pyrimidine-3- carbonitrile and 5-fluoro- 1 -isopropyl-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 Η- pyrazole as an off white solid. 1H NMR (400MHz, CD₃OD) δ 8.09 (s, 1H), 7.55 (d, / = 3.2 Hz, 1H), 4.69 - 4.55 (m, 1H), 2.99 - 2.93 (m, 1H), 1.51 (d, / = 6.8 Hz, 6H), 1.36 (d, / = 6.8 Hz, 6H). LCMS (ESI): m/z 329.1 [M+H]⁺, RT =1.01 min (LCMS method C). Example 15 and 16

5-(l-(cyclopropylmethyl)-lH-pyrazol-5-yl)-6-isopropyl-7-oxo-4,7-dihydropyrazolo[l,5- o]pyrimidine-3-carbonitrile and 5-(l-(cyclopropylmethyl)-lH-pyrazol-3-yl)-6-isopropyl- 7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidine-3-carbonitrile

A mixture of 6-isopropyl-7-oxo-5-(lH-pyrazol-3-yl)-4H-pyrazolo[l ,5-a]pyrimidine-3- carbonitrile (0.224 mmol, 60 mg), (iodomethyl)cyclopropane (0.671 mmol, 126mg) and CS₂CO₃ (0.671 mmol, 219mg) in DMF (2 mL) was stirred at room temperature for 7 hours. The reaction mixture was filtered and the filtrate was purified by preparative HPLC to afford the desired products as white solids.

1^st eluting peak: 5-[2-(cyclopropylmethyl)pyrazol-3-yl]-6-isopropyl-7-oxo-4H-pyrazolo[l ,5- a]pyrimidine-3-carbonitrile, 5.6 mg, 7.8% yield. 1H NMR (DMSO- ) δ: 13.63 (s, 1H), 8.37 (s, 1H), 7.67 - 7.60 (m, 1H), 6.59 - 6.47 (m, 1H), 3.93 (d, / = 7.0 Hz, 2H), 1.37 - 1.09 (m, 8H), 0.51 - 0.38 (m, 2H), 0.33 - 0.18 (m, 2H). LCMS (ESI): m/z 323.2 [M+H]⁺, RT = 4.52 min (LCMS Method F).

2^nd eluting peak: 5-[l-(cyclopropylmethyl)pyrazol-3-yl]-6-isopropyl-7-oxo-4H-pyrazolo[l ,5- a]pyrimidine-3-carbonitrile, 11.6 mg, 16.1% yield. 1H NMR (DMSO-d₆) δ: 13.21 (s, 1H), 8.36 (s, 1H), 8.00 (d, / = 2.3 Hz, 1H), 6.62 (d, / = 2.3 Hz, 1H), 4.10 (d, J = 7.1 Hz, 2H), 3.13 (p, / = 6.9 Hz, 1H), 1.36 - 1.29 (m, 1H), 1.28 (d, / = 7.0 Hz, 6H), 0.62 - 0.53 (m, 2H), 0.45 - 0.38 (m, 2H). LCMS (ESI): m/z 323.2 [M+H]⁺, RT = 4.83 min (LCMS Method F).

Example 17

Step 1

Tetr ahydr o-2H-thiopyr an-4-ol

To the reaction mixture of dihydro-2H-thiopyran-4(3H)-one (2.0 g, 16.92 mmol) in MeOH (20 mL) was added NaBH₄ (1.95 g, 51.64 mmol) at 0 °C. The reaction mixture was stirred at 10 °C for 1 hour. The reaction was quenched with saturated NH₄C1 (20 mL), extracted with EtOAc (20 mL x 3). Combined organic layers were dried over Na₂S0₄, filtered and concentrated to give the desired crude product as colourless oil. Step 2

Tetr ahydr o-2H-thiopyr an-4-yl methanesulfonate

To the reaction mixture of tetrahydro-2H-thiopyran-4-ol (2.0 g, 16.92 mmol) and Et₃N (3.42 g, 33.84 mmol) in DCM (20 mL) was added MsCl (2.91 g, 25.38 mmol) at 0 °C. The reaction mixture was stirred at 10 °C for 2 hours. The reaction mixture was washed with saturated NaHC0₃, extracted with EtOAc (20 mL x 3). Combined organic layers were dried over Na₂S0₄, filtered and concentrated to give the desired crude product as white solid.

Step 3

6-isopr op yl-7-oxo-5-(l-(tetr ahydr o-2H-thiopyr an-4-yl)-lH-pyr azol-4-yl)-4,7- dihydropyrazolo[l,5-a]pyrimidine-3-carbonitrile

In a similar procedure as shown in Example 6, the title compound was prepared in 12% yield as an off white solid. 1H NMR (400MHz, CD₃OD) δ 8.09 (s., 1H), 7.95 (s, 1H), 7.68 (s, 1H), 4.29 - 4.24 (m, 1H),3.16 - 3.09 (m, 1H), 2.96 - 2.85 (m, 2H), 2.82 - 2.71 (m, 2H), 2.48 - 2.35 (m, 2H), 2.26 - 2.10 (m, 2H), 1.37 (d, / = 6.8 Hz, 6H). LCMS (ESI) m/z 369.1 [M+H]⁺, RT = 1.01 min (LCMS method C).

Example 18

5-(l-(l,l-Dioxidotetr ahydr o-2H-thiopyran-4-yl)-lH-pyrazol-4-yl)-6-isopr op yl-7-oxo-4,7- dihydropyrazolo[l,5-a]pyrimidine-3-carbonitrile

To a solution of 6-isopropyl-7-oxo-5-(l-(tetrahydro-2H-thiopyran-4-yl)-lH-pyrazol-4-yl)-4,7

-dihydropyrazolo[l ,5-a]pyrimidine-3-carbonitrile (65 mg, 0.176 mmol) in MeOH (6 mL) at 0

⁰ C was added dropwise a solution of oxone (271 mg, 0.441 mmol) in water (6 mL) and the re action mixture was stirred at 10 °C for 16 hours. The solvent was removed under reduced pre ssure. The residue was purified by preparative HPLC to afford the desired product (20 mg, 2 9% yield) as an off-white solid. 1H NMR (400MHz, CD₃OD) δ 8.12 (s., 1H), 8.03 (s, 1H), 7.7 3(s, 1H), 4.70 - 4.24 (m, 1H), 3.39-3.36 (m, 4H), 3.13 - 3.09 (m, 1H), 2.70 - 2.65 (m, 2H), 2. 52 - 2.48 (m, 2H), 1.37 (d, / = 7.2 Hz, 6H). LCMS (ESI): m/z 401.1 [M+H]⁺, RT =0.85 min (LCMS Method C).

Example 19

Step 1

(6-(Hydroxymethyl)pyridin-2-yl)methyl 4-methylbenzenesulfonate

To a solution of pyridine -2, 6-diyldimethanol (1 g, 7.19 mmol) in DCM (20 mL) was added Ag₂0 (2.5 g, 10.78 mmol) and KI (119 mg, 0.72 mmol). The resulting mixture was cooled to -20 °C and was added TsCl (1.51 g, 7.19 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, and purified by flash column chromatography on silica gel (PE/EtOAc = 1/1) to give the desired product (800 mg, 40% yield) as white solid.

Step 2

(6-Formylpyridin-2-yl)methyl 4-methylbenzenesulfonate

To a solution of (6-(hydroxymethyl)pyridin-2-yl)methyl 4-methylbenzenesulfonate (800 mg, 2.73 mmol) in DCM (10 mL) was added Mn0₂ (2.37 g, 27.27 mmol). The resulting mixture was stirred at room temperature for 24 hours. The solid was removed by filtration and the filtrate was concentrated to dryness to give the desired crude product (500 mg, 63% yield) as white solid.

Step 3

(E)-(6-(3-oxobut-l-en-l-yl)pyridin-2-yl)methyl 4-methylbenzenesulfonate To a solution of (6-formylpyridin-2-yl)methyl 4-methylbenzenesulfonate (500 mg, 1.72 mmol) in toluene (20 mL) was added l-(triphenylphosphoranylidene)propan-2-one (525 mg, 1.65 mmol). The resulting mixture was stirred at 110 °C under N₂ for 16 hours, The reaction mixture was concentrated, and was purified by flash column chromatography on silica gel (PE/EtOAc = 3/1) to give the desired product (400 mg, 71% yield) as white solid. Step 4

(E)-6-isopro yl-7-oxo-5-(l-((6-(3-oxobut-l-en-l-yl)pyridin-2-yl)methyl)-lH-pyrazol-4- yl)-4,7-dihydro yrazolo[l,5-a]pyrimidine-3-carbonitrile To a solution of 6-isopropyl-7-oxo-5-(lH-pyrazol-4-yl)-4,7-dihydropyrazolo[l,5- fl]pyrimidine-3-carbonitrile (100 mg, 0.3 mmol) in DMF (5 mL) was added (E)-(6-(3-oxobut- l-en-l-yl)pyridin-2-yl)methyl 4-methylbenzenesulfonate (99 mg, 0.3 mmol), KI (5 mg, 0.03 mmol) and Cs₂C0₃ (292 mg, 0.9 mmol). The resulting mixture was stirred at room temperature for 2 hours and was purified by preparative EtPLC to afford the desired product (29 mg, 23% yield) as yellow solid. ¹HNMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H), 8.36 (2s, 2H), 7.91 (m, 1H), 7.81 (m, 1H), 7.71 - 7.59 (m, 2H), 7.21 (m, 1H), 7.05 (m, 1H), 5.60 (s, 2H), 2.99-2.95 (m, 1H), 2.36 (s, 3H), 1.30 (s, 6H). LCMS (ESI): m/z 428.1 [M+H]⁺, RT = 0.78 min (LCMS Method E).

Example 20 (Method B)

6-Ethyl-7-oxo-4,7-dihydro yrazolo[l,5-a]pyrimidine-3-carbonitrile A mixture of methyl 2-formylbutanoate (3.2 g, 24.6 mmol) and 5-amino-lH-pyrazole-4- carbonitrile (1.3 g, 12 mmol) in acetic acid (8 mL) was stirred at 80 °C for 16 hours. The reaction mixture was concentrated and the residue was triturated with methyl tert-butyl ether (20 mL) to give the desired product (1.4 g, 63% yield) as white solid; 1H NMR (400 MHz,

DMSO-de) δ 13.36 (s, 1H), 8.37 (s, 1H), 7.85 (s, 1H), 2.42 - 2.48 (q, / = 7.6 Hz, 2H), 1.13 (t,

/ = 7.6 Hz, 3H). LCMS (ESI): m/z 189.1 [M+H]⁺, RT = 0.86 min (LCMS Method C). Example 21

Step 1

Ethyl 2-formyl-3,3-dimethylbutanoate

To a solution of diethyl 2-(iert-butyl)malonate (500 mg, 2.31 mmol) in anhydrous DCM (5 mL) at - 78 °C under nitrogen atmosphere was added DIBAL-H (1.0 M in toluene, 4.62 mL, 4.62 mmol) dropwise. The resulting mixture was stirred at - 78 °C for 3 hours. The reaction mixture was quenched with saturated aqueous NH₄C1 solution (10 mL). The cold bath was removed. Aqueous HC1 solution (1.0 M, 10 mL) and Z), -tartaric acid (560 mg) were added sequentially and the mixture was warmed up to room temperature with vigorous stirring. The biphase mixture was then partitioned between aquesous HC1 solution (1.0 M, 20 mL) and DCM (20 mL). The organic phase was separated, dried over anhydrous Na₂S0₄, filtered, and concentrated to give the crude product, which was used for the next step without further purification.

Step 2

6-(ieri-Butyl)-7-oxo-4,7-dihydro yrazolo[l,5-a]pyrimidine-3-carbonitrile To a solution of ethyl 2-formyl-3,3-dimethylbutanoate (2.0 g crude, 2.31 mmol) in acetic acid (3.0 mL) was added 5-amino-lH-pyrazole-4-carbonitrile (77 mg, 0.7 mmol). The resulting mixture was heated at 90 °C for 16 hours. After being cooled to room temperature, the reaction mixture was concentrated, followed by azeotropic removal of acetic acid residue by toluene (10 mL x 2). The resultant residue was washed with methyl tert-butyl ether (10 mL x 2) to give the desired product (60 mg, 12% yield over two steps) as white solid. 1H NMR (400 MHz, DMSO- ) δ 8.36 (s, 1H), 7.63 (s, 1H), 1.33 (s, 9H). LCMS (ESI): m/z 217.1 [M+H]⁺, RT = 1.06 min (LCMS Method A). Example 22

6-Isopropyl-7-oxo-5-phenyl-4,7-dihydropyrazolo[l,5-a]pyrimidine-3-carbonitrile To a solution of ethyl 2-benzoyl-3-methylbutanoate (325 mg, 1.39 mmol, 1.5 eq) and 5- amino- lH-pyrazole-4-carbonitrile (100 mg, 0.93 mmol) in 2-methyltetrahydrofuran (2 ml) was added titanium tetrachloride (0.1 mL, 0.87 mmol). The reaction was stirred at room temperature for 20 minutes and then heated at 80 °C for 16 hours. The reaction was cooled to room temperature and diluted with saturated aqueous NaHCOs (5 mL). The reaction mixture was extracted with EtOAc (20 mL x 3) and the combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂S0₄, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting with 0-30% EtOAc in hexanes to afford the desired product (107 mg, 42% yield) as a brown solid. 1H NMR (400 MHz, CDCI₃) δ 13.46 (s, 1H), 8.41 (s, 1H), 7.59 - 7.58 (m, 3H), 7.53 - 7.52 (m, 2H), 2.63 -

2.59 (m, 1H), 1.24 (d, / = 6.8 Hz, 6H). LCMS (ESI): m/z 278.9 [M+H]⁺, RT = 1.15 min (LCMS Method A).

Example 23

Step 1

Ethyl 3-oxo-5-phenylpentanoate

To a solution of ethyl 3-oxobutanoate (8 g, 61.5 mmol) in THF (80 mL) was added NaH (60%) suspension in oil, 3 g, 73.8 mmol) protionwise at 0 °C and then stirred for 30 min. Then n-BuLi (29.6 mL, 73.8 mmol) was added via syringe. After being cooled to - 25 °C, (bromomethyl)benzene (1 1 g, 64.31 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was quenched with saturated aqueous NH₄C1 (200 mL) and extracted with EtOAc (100 mL). The organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to afford the crude product which was purified by flash column chromatography on silica gel eluted with 0 - 3 % EtOAc in hexanes to give the desired product (9.7 g, 72% yield) as yellow oil. 1H NMR (400 MHz, CDC1₃) δ 7.25 - 7.29 (m, 2H), 7.16 - 7.20 (m, 3H), 4.16 (q, / = 7.2 Hz, 2H), 3.41 (s, 2H), 2.85-2.94 (m, 4H 1.25 (t, / = 7.2 Hz, 3H).

Ethyl 2-isopro yl-3-oxo-5-phenylpentanoate

A mixture of ethyl 3-oxo-5-phenylpentanoate (3 g, 13.62 mmol), 2-iodopropane (2.32 g, 13.62 mmol) and K₂C0₃ (3 76 g, 27.24 mmol) in DMF (30 mL) was placed in an autoclave and heated to 80 °C for 16 hours. The mixture was filtered, concentrated and the residue was purified by flash column chromatography on silica gel eluting with 0 - 2% EtOAc in hexanes to give the desired product (400 mg, 11% yield) as colorless liquid. 1H NMR (400 MHz, CDC1₃) δ 7.15-7.27 (m, 5H), 4.11 (q, / = 6.8 Hz, 2H), 3.18 (d, / = 9.6 Hz, 1H), 2.78-3.19 (m, 4H), 2.40-2.78 (m, 1H), 1.21 (t, / = 6.8 Hz, 3H). 0.93 (d, / = 6.8 Hz, 3H), 0.84 (d, / = 6.8 Hz, 3H). LCMS (ESI): m/z 263.2 [M+H]⁺, RT = 1.27 min (LCMS Method A).

Step 3

6-isopro yl-7-oxo-5-phenethyl-4,7-dihydro yrazolo[l,5-a]pyrimidine-3-carbonitrile To a solution of ethyl 2-isopropyl-3-oxo-5-phenylpentanoate (700 mg, 2.67 mmol) and 3- amino-lH-pyrazole-4-carbonitrile (433 mg, 4 mmol) in toluene (7 mL) was added titanium tetrachloride (0.2 mL, 1.6 mmol) via syringe under N₂ atmosphere and then heated to 80 °C for 16 hours. The mixture was quenched with saturated aqueous NaHC0₃ (15 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂S0₄, filtered and concentrated. The residue was purified by prep HPLC to afford the desired product (15 mg, 2% yield) as white solid. 1H NMR (400 MHz, CDCls) δ 8.10 (s, 1H), 7.18 - 7.32 (m, 5H), 7.10 (s 1H), 3.01 (q, / = 6.8 Hz, 1H), 2.85- 2.90 (m, 4H), 1.25 (d, / = 6.8 Hz, 6H). LCMS (ESI): m/z 307.2 [M+H]⁺, RT = 1.11 min (LCMS Method A).

Example 24

Step 1

Ethyl 3-(3-iodophenyl)-3-oxopropanoate

To a solution of diethyl carbonate (12.0 g, 101.6 mmol) in anhydrous toluene (100 mL) was added NaH (60% suspension in mineral oil, 3.25 g, 81.3 mmol) portionwise at 0 °C under nitrogen atmosphere. After stirring at 0 °C for 5 minutes, the mixture was warmed up to room temperature and l-(3-iodophenyl)ethanone (5.0 g, 20.3 mmol) was added dropwise over 10 minutes. The resulting mixture was heated at 110 °C for 16 hours. The reaction was cooled to 0 °C and quenched with CH3COOH (10 mL). H₂0 (50 mL) was added and the mixture was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with saturated aqueous NaHC0₃ (100 mL), dried over anhydrous Na₂S0₄, filtered and concentrated. The residue was purified by flash column chromatography on silical gel (0- 5 % EtOAc/PE) to afford the desired product as a red oil (4.0 g, 62% yield). 1H NMR (400 MHz, CDC1₃) δ 8.28 (s, 1H), 7.92 (d, / = 8.8 Hz, 1H), 7.90 (d, / = 8.0 Hz, 1H), 7.25-7.21 (m, 1H), 4.22 (q, / = 7.2 Hz, 2H), 3.95 (s, 1H), 1.27 (t, / = 7.2 Hz, 3H). LCMS (ESI): m/z 318.8 [M+H]⁺, RT = 0.93 min (LCMS Method E).

Step 2

Ethyl 2-(3-iodobenzoyl)butanoate

To a solution of ethyl 3-(3-iodophenyl)-3-oxopropanoate (2.0 g, 6.29 mmol) in acetone (20 mL) in a vial was added K₂C0₃ (3.47 g, 25.16 mmol), 2-iodopropane (981 mg, 6.29 mmol). The vial was sealed and heated at 70 °C for 1 day. The reaction was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography on silical gel (0-5% EtOAc/PE) to afford the desired product as an yellow oil (1.6 g, 73% yield). 1H NMR (400 MHz, CDC1₃) δ 8.32 (s, 1H), 7.94 (d, / = 8.0 Hz, 1H), 7.92 (d, / = 8.0 Hz, 1H), 7.27-7.21 (m, 1H), 4.19-4.13 (m, 3H), 2.03 (d, / = 7.2 Hz, 2H), 1.20 (t, / = 7.2 Hz, 3H), 1.00 (t, / = 7.2 Hz, 3H). LCMS (ESI): m/z 346.7 [M+H]⁺, RT = 1.06 min (LCMS Method E).

Step 3

6-ethyl-5-(3-iodophenyl)-7-oxo-4,7-dihydro yrazolo[l,5-a]pyrimidine-3-carbonitrile To a solution of ethyl 2-(3-iodobenzoyl) butanoate (500 mg, 1.44 mmol) and 5-Amino-lH- pyrazole-4-carbonitrile (234 mg, 2.17 mmol) in anhydrous toluene (10 ml) under nitrogen atmosphere was added TiCl₄ (0.1 mL, 0.87 mmol). The reaction was stirred at room temperature for 30 minutes and then heated at 90 °C for 16 hours. The reaction was cooled to room temperature and diluted with saturated aqueous NaHC0₃ (20 mL). The reaction mixture was extracted with EtOAc (50 mL x 2) and the combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂S0₄, filtered and concentrated. The crude residue was purified by preparative HPLC (ASB C₁₈ 150 x 25 mm, 50% MeCN/H₂0) to afford the title compound (33 mg, 6% yield) as white solid. 1H NMR (400 MHz, CDC1₃) δ 8.05 (s, 1H), 7.92 (d, / = 8.0 Hz, 1H), 7.86 (s, 1H), 7.48 (d, / = 8.0 Hz, 1H), 7.32-7.28 (m, 1H), 2.52 (q, / = 7.2 Hz, 2H), 1.14 (t, / = 7.2 Hz, 3H). LCMS (ESI): m/z 390.9 [M+H]⁺, RT = 1.09 min (LCMS Method A). Example 25

3-cyano-6-ethyl-7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid To a suspension of ethyl 3-cyano-6-ethyl-7-oxo-4H-pyrazolo[l ,5-a]pyrimidine-5-carboxylate (0.38425 mmol, 100 mg) in THF (1 mL) was added a solution of LiOH (3 M, 0.76 mL). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with water, extracted with EtOAc. The aqueous layer was acidified with 1 N HCl to pH 3, extracted with EtOAc (3x). The combined organics were dried over Na₂S0₄, filtered, concentrated and dried to give the title compound (47 mg, 52.7% yield) as a white solid. 1H NMR (400 MHz, DMSO- d₆) δ 8.40 (s, 1H), 2.67 (q, / = 7.33 Hz, 2H), 1.09 (t, / = 7.31 Hz, 3H). LCMS (ESI): m/z 233.2 [M+H]⁺, RT = 0.37 min (LCMS Method F).

Example 26

3-cyano-6-ethyl-4-methyl-7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidine-5-carboxamide

The mixure of ethyl 3-cyano-6-ethyl-4-methyl-7-oxo-pyrazolo[l ,5-a]pyrimidine-5- carboxylate (55 mg, 0.20 mmol) in NH₄OH (28% in water, 10 mL) was stirred at room temperature for 48 hours. The mixture was concentrated via rptavap to dryness. The crude product was purified by prep HPLC to give the title compound (24.2 mg, 49.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-J₆) δ 8.50 (s, 1H), 8.41 (d, / = 23.40 Hz, 2H), 3.84 (s, 3H), 2.45 (q, / = 7.43 Hz, 2H), 1.10 (t, / = 7.37 Hz, 3H). LCMS (ESI): m/z 246.1 [M+H]⁺, RT = 2.31 min (LCMS Method F). Example 27

3-cyano-6-ethyl-N,4-dimethyl-7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidine-5- carboxamide

The mixture of 3-cyano-6-ethyl-4-methyl-7-oxo-pyrazolo[l ,5-a]pyrimidine-5-carboxylic acid (60 mg, 0.244 mmol), methylamine hydrochloride (49 mg, 0.731 mmol), HATU (189 mg, 0.487 mmol) and DIPEA (157 mg, 1.22 mmol) in DMF (1 mL) was stirred at room temperature for 18 hours. The crude product was purified by prep HPLC (5-50% CH₃CN/H₂O with 0.1% NH₄OH) to give the title compound (6.7 mg, 10.6% yield) as a white solid. 1H NMR (400 MHz, DMSO- d₆) δ 8.51 (s, 1H), 3.78 (s, 3H), 2.85 (d, / = 4.70 Hz, 3H), 2.80 (d, / = 4.88 Hz, 2H), 1.07 (t, / = 7.37 Hz, 3H). LCMS (ESI): m/z 260.2 [M+H]⁺, RT = 2.98 min (LCMS Method F). Example 28

6-ethyl-5-(3-methyl-l,2,4-oxadiazol-5-yl)-7-oxo-4H-pyrazolo[l,5-a]pyrimidine-3- carbonitrile

A solution of N-hydroxyacetamidine (60 mg, 0.807 mmol) in THF (1 mL) was treated with NaH (60%) suspension in mineral oil, 34 mg, 0.845 mmol) and 4 A molecular sieves (0.7 g) and heated at 50 °C for 1 hour. Then a solution of ethyl 3-cyano-6-ethyl-7-oxo-4H- pyrazolo[l ,5-a]pyrimidine-5-carboxylate (100 mg, 0.384 mmol) in THF (2 mL) was added. The mixture was heated at 50 °C for 4 hours. The mixture was filtered to remove the molecular sieves, and then concentrated to dryness. The crude product was purified by prep HPLC to give the title compound (67 mg, 64% yield) as a white solid. Ή NMR (400 MHz, DMSO- d₆) δ 8.35 (s, 1H), 2.74 (q, / = 7.30 Hz, 2H), 1.09 (t, / = 7.31 Hz, 3H). LCMS (ESI): m/z 271.2 [M+H]⁺, RT = 3.87 min (LCMS Method F). Example 29

6-ethyl-5-(5-methyl-l,3,4-oxadiazol-2-yl)-7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidine-3- carbonitrile

To a mixture of 3-cyano-6-ethyl-7-oxo-4H-pyrazolo[l,5-a]pyrimidine-5-carboxylic acid (60 mg, 0.258 mmol) and acetohydrazide (19 mg, 0.258 mmol) in dichloromethane (1 mL) was added 2-chloro-l,3-dimethylimidazolium chloride (90 mg, 0.517 mmol), followed by DIPEA (133 mg, 1.03 mmol) dropwise. The mixture was stirred at room temeperature for 18 hours. The mixture was then concentrated, and then purified by prep HPLC (5-50% CH₃CN/H₂0 with 0.1%) formic acid) to give the title compound (5.6 mg, 7.2% yield) as an off-white solid. Ή ΝΜΡν (400 MHz, DMSO-d₆) δ 8.30 (s, 1H), 2.77 (q, / = 7.30 Hz, 2H), 2.64 (s, 3H), 1.10 (t, J = 126 Hz, 3H). LCMS (ESI): m/z 271.2 [M+H]⁺, RT = 3.29 min (LCMS Method F).

Example 30

Step 1

3-cyano-6-ethyl-N-methoxy-N-methyl-7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidine-5- carboxamide

The mixture of 3-cyano-6-ethyl-7-oxo-4H-pyrazolo[l,5-a]pyrimidine-5-carboxylic acid (200 mg, 0.861 mmol), N-methoxymethanamine hydrochloride (92 mg, 0.947 mmol), DIPEA (267 mg, 2.0672 mmol) and HATU (401 mg, 4.03 mmol) in DMF (4 mL) was stirred at room temperature for 18 hours. The crude product was purified by prep HPLC (5-50%> CH₃CN/H₂0 with 0.1%) formic acid) to give the title compound (171 mg, 72% yield) as a white solid. Ή NMR (400 MHz, CDC1₃) δ 8.07 (s, 1H), 3.71 (s, 3H), 3.40 (s, 3H), 2.58 (d, / = 7.31 Hz, 2H), 1.23 (t, / = 7.38 Hz, 3H). LCMS (ESI) m/z 276 [M+H]⁺. Step 2

6-ethyl-5-formyl-7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidine-3-carbonitrile To a solution of 3-cyano-6-ethyl-N-methoxy-N-methyl-7-oxo-4H-pyrazolo[l,5-a]pyrimidine- 5-carboxamide (170 mg, 0.618 mmol) in THF (3 mL) at -78 °C was added lithiumaluminum hydride (1 M in THF, 0.678 mL) dropwise. The mixture was stirred at -78 °C for 1 hour, then warmed to 0 °C and kept at that temperature for 2 hours. The reaction was quenched with 25% aqueous solution of Na,K tartrate. The mixture was extracted with EtOAc (6x). The combined organics were dried (Na₂S0₄), filtered and concentrated. The crude prod was purified by silica gel column chromatography eluting with 20% MeOH/DCM to give the title compound (54 mg, 40.4% yield) as a yellow solid. LCMS (ESI) m/z 217 [M+H]⁺.

Step 3

6-ethyl-5-(lH-imidazol-2-yl)-7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidine-3-carbonitrile To the suspension of 6-ethyl-5-formyl-7-oxo-4H-pyrazolo[l,5-a]pyrimidine-3-carbonitrile (54 mg, 0.25 mmol,), NH₄OH (28 % in water, 228 mg, 3.75 mmol) and water (0.25 mL) was added glyoxal (40 % in water, 181 mg, 1.25 mmol). The mixture was stirred at room temperature for 16 hours. Then the mixure was concentrated to dryness, and the resulting crude product was purified by prep HPLC (5-50%> CH₃CN/H₂0 with 0.1 % formic acid) to give the title compound (36 mg, 56.7% yield) as a yellow solid. Ή NMR (400 MHz, DMSO- d₆) δ 8.24 (s, 1H), 7.68 (s, 2H), 2.54 (q, / = 7.36 Hz, 2H), 0.94 (t, / = 7.33 Hz, 3H). LCMS (ESI): m/z 255.2 [M+H]⁺, RT = 0.62 min (LCMS Method F). Example 31

3-cyano-6-ethyl-7-oxo-N-(2-oxo-2-phenylethyl)-4,7-dihydropyrazolo[l,5-a]pyrimidine-5- carboxamide

To a soutioln of 3-cyano-6-ethyl-7-oxo-4H-pyrazolo[l,5-a]pyrimidine-5-carboxylic acid (200 mg, 0.861 mmol) and triethylamine (218 mg, 2.15 mmol,) in THF (2 mL) was added isobutyl chloro formate (0.1463 mL). The mixture was stirred at room temperature for 1 hour. Then 2- aminoacetophenone hydrochloride (163 mg, 0.947 mmol) was added. The mixture was stirred at room temperature for 3 hours. The mixture was filtered through celite, washed with EtOAc and concentrated. The crude product was purified by prep HPLC (5-50% CH₃CN/H₂0 with 0.1% formic acid) to give the title compound (108 mg, 35.9% yield). 1H NMR (400 MHz, DMSO-d₆) δ 9.22 (s, 1H), 8.40 (s, 1H), 8.10 - 8.03 (m, 2H), 7.74 - 7.66 (m, 1H), 7.58 (dd, / = 7.12, 8.32 Hz, 2H), 4.86 (d, / = 5.61 Hz, 2H), 2.61 (q, / = 7.26 Hz, 2H), 1.10 (t, / = 7.30 Hz, 3H). LCMS (ESI): m/z 350.1 [M+H]⁺, RT = 4.98 min (LCMS Method F).

Example 32

6-ethyl-7-oxo-5-(5-phenyloxazol-2-yl)-4,7-dihydro yrazolo[l,5-a]pyrimidine-3- carbonitrile

To a solution of 3-cyano-6-ethyl-7-oxo-N-phenacyl-4H-pyrazolo[l,5-a]pyrimidine-5- carboxamide (180 mg, 0.515 mmol) in THF (5 mL) was added Burgess reagent (211 mg, 0.859 mmol). The miture was heated at 120 °C in a microwave for 45 min. The mixture was concentrated and purified by prep HPLC to give the title compound (25 mg, 15 > yield) as a pale yellow solid. Ή NMR (400 MHz, DMSO-d₆) δ 8.42 (s, 1H), 8.12 (s, 1H), 7.94 - 7.87 (m, 2H), 7.62 - 7.54 (m, 2H), 7.51 - 7.44 (m, 1H), 2.91 (q, / = 7.27 Hz, 2H), 1.20 (t, / = 7.29 Hz, 3H). LCMS (ESI): m/z 332.1 [M+H]⁺, RT = 6.10 min (LCMS Method F). Example 33

G02854848

6-(2,2-Difluoroethyl)-7-oxo-5-phenyl-4H-pyrazolo[l,5-a]pyrimidine-3-carbonitrile To a solution of ethyl 3-oxo-3-phenyl-propanoate (0.20 g, 1.04 mmol) in 2-methyl THF (5 ml) cooled in ice-bath was added sodium hydride (60% suspension in mineral oil, 0.05 g, 1.2 mmol) and the mixture was stirred for 20 min. To the resulting solution as added 2,2- difluoroethyl trifluoromethanesulfonate (0.24 g, 1.15 mmol). The mixture was then warmed up to room temperature and stirred for 72 hours. The reaction mixture quenched with HC1 (1 N) and extracted with ethyl acetate. Combined organics were dried over sodium sulfate, concentrated. The crude product was converted to the desired product (18 mg, 5.8%> yield for 2 steps) as described in Example 22. 1H NMR (400 MHz, DMSO-d₆) δ 8.43 (s, 1H), 7.55 (dq, J = 22.2, 3.2 Hz, 5H), 6.34 - 5.95 (m, 1H), 2.97 - 2.79 (m, 2H). LCMS (ESI): m/z 301.2 [M+H]⁺, RT = 4.21 min (LCMS Method F).

Example 34

6-Cyclobutyl-7-oxo-5-phenyl-4H-pyrazolo[l,5-a]pyrimidine-3-carbonitrile To a solution of ethyl 3-oxo-3-phenyl-propanoate (1.00 g, 5.2 mmol) and cyclobutanone (0.44 g, 6.2 mmol) in 2-MeTHF (50 mL) was added titanium(IV) chloride (11.0 mL 1M in DCM, 11 mmol), followed by pyridine (2.1 mL, 26 mmol). The resulting suspension was stirred at room temperature for 20 hours. The solids were removed by filtration and the filtrate was diluted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated. The residue obtained after purification on silica gel column chromatography (0- 50%) EtO Ac/heptane) was hydrogenated in the presence of Pd-C (0.20 g, 10%> w/w on activated carbon) at ambient temperature for 20 hours in ethyl acetate. The catalyst was removed by filtration and concentration of filtrate afforded ethyl 2-cyclobutyl-3-oxo-3- phenylpropanoate (0.05 g, 3.9% yield over 2 steps). The ketoester was treated with 3-amino- lH-pyrazole-4-carbonitrile as described in Example 22 to obtain the desired product (3 mg, 5.1% yield). 1H NMR (400 MHz, CDC1₃) δ 7.96 (s, 1H), 7.60 - 7.49 (m, 3H), 7.47 - 7.38 (m, 2H), 3.50 - 3.31 (m, 1H), 2.62 - 2.46 (m, 2H), 1.99 - 1.74 (m, 4H). LCMS: (ESI) m/z 291.1 [M+H]⁺, RT = 5.91 min (LCMS Method F).

Example 35

6-Cyclobutyl-7-oxo-5-(lH-pyrazol-4-yl)-4H-pyrazolo[l,5-a]pyrimidine-3-carbonitrile This compound was prepared similarly as shown in example 34. 1H NMR (400 MHz, DMSO- ) δ 8.36 (s, 1H), 8.12 (s, 1H), 7.82 (s, 1H), 3.65 - 3.49 (m, 1H), 2.74 - 2.55 (m, 2H), 2.08 - 1.89 (m, 2H), 1.90 - 1.69 (m, 2H). LCMS (ESI): m/z 281.2 [M+H]⁺, RT = 3.88 min (LCMS Method F).

Example 36

6-Cyclobutyl-5-(l-cyclohexylpyrazol-4-yl)-7-oxo-4H-pyrazolo[l,5-a]pyrimidine-3- carbonitrile

To a mixture of 6-cyclobutyl-7-oxo-5-(lH-pyrazol-4-yl)-4H-pyrazolo[l,5-a]pyrimidine-3- carbonitrile (40 mg, 0.14 mmol) and bromocyclohexane (46 mg, 0.28 mmol) was added NaH (60% suspension in mineral oil, 11 mg, 0.27 mmol) and the resulting mixture was heated 60 °C for 20 hours. The reaction mixture was cooled, acidified with HC1 and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification of the crude product by flash column chromatography on silica gel eluting with 0-100% EtO Ac/heptane afforded the desired product (5 mg, 10% yield). 1H NMR (400 MHz, CDCls) δ 7.96 (s, 1H), 7.77 (d, / = 0.8 Hz, 1H), 7.74 (d, / = 0.7 Hz, 1H), 4.27 - 4.12 (m, 1H), 3.72 - 3.58 (m, 1H), 2.80 - 2.64 (m, 2H), 2.23 (d, / = 12.3 Hz, 2H), 2.14 - 2.02 (m, 2H), 1.99 - 1.90 (m, 3H), 1.81 - 1.71 (m, 3H), 1.49 - 1.42 (m, 2H), 1.35 - 1.15 (m, 2H). LCMS (ESI): m/z 363.2 [M+H]⁺, RT = 5.30 min (LCMS Method F).

Example 37

7-Oxo-5-phenyl-6-(prop-2-yn-l-yl)-4,7-dihydro yrazolo[l,5-a]pyrimidine-3-carbonitrile To a solution of 3-amino-lH-pyrazole-4-carbonitrile (0.20 g, 1.8 mmol) and ethyl 2- benzoylpent-4-ynoate (0.63 g 2.7 mmol ) in dry 2-Me THF (20 mL) was added titanium tetrachloride (3 mL of 1M solution in toluene, 3 mmol) and the resulting dark orange solution was heated at 80 °C for 2 hours. The resulting reaction mixture was cooled, poured into water

(100 mL) and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. Purification by flash column chromatography on silica gel (20-100% ethyl acetate/heptane), followed by trituration of the residue with ethyl acetate/heptane afforded the desired product (0.11 g, 21.6% yield). 1H NMR (400 MHz, DMSO-d₆) δ 13.70 (s, 1H), 8.43 (s, 1H), 7.70 - 7.47 (m, 5H), 3.17 (d, / = 2.7 Hz, 2H), 2.82 (t, / = 2.6 Hz, 1H). LCMS (ESI): m/z 275.2 [M+H]⁺, RT = 4.09 min (LCMS Method F).

Step 1

1 -isopr opyl- lH-pyr azole-4-carb aldehyde

To a solution of lH-pyrazole-4-carbaldehyde (2.0 g, 21 mmol) and 2-iodopropane (5.32 g, 31.5 mmol) in DMF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 0.83 g, 20.7 mmol) in one portion. The resulting mixture was stirred at room temperature for 2 hours, before being quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-50% EtO Ac/heptane to obtain 1- isopropylpyrazole-4-carbaldehyde (1.2 g, 42% yield). 1H NMR (400 MHz, CDC1₃) δ 9.86 (s, 1H), 7.97 (s, 2H), 4.54 (p, / = 6.7 Hz, 1H), 1.55 (d, / = 6.7 Hz, 6H).

Step 2

ethyl 3-(l-isopro yl-lH-pyrazol-4-yl)-3-oxopropanoate

To a solution of ethyl acetate (1.28 g, 14.5 mmol) cooled to -78 °C was added LDA (7.24 mL, 2 M solution in THF/heptane/ethylbenzene, 14.4 mmol) and the mixture was stirred at -78 °C for 20 min. To this mixture was added a solution l-isopropylpyrazole-4-carbaldehyde (1.00 g, 7.24 mmol) in THF (3 mL) and the mixture was stirred for another 20 min. The reaction mixture was quenched with saturated ammonium chloride solution and the mixture was allowed to warm to room temperature. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was dissolved in DCM (100 mL) and Mn0₂ (5.0 g) was added in one portion. The mixture was stirred for 20 hours at room temperature. Mn0₂ was removed by filtration through a Celite pad and the filtrate was concentrated. Purification of the residue by flash column chromatography on silica gel (0-100%) EtO Ac/heptane) afforded the desired product (0.70 g,

40% yield). 1H NMR (400 MHz, CDC1₃) δ 7.99 (d, / = 0.6 Hz, 1H), 7.93 (d, / = 0.7 Hz, 1H), 4.52 (p, / = 6.7 Hz, 1H), 4.20 (q, / = 7.1 Hz, 2H), 3.75 (s, 2H), 1.53 (d, / = 6.7 Hz, 6H), 1.26 (t, / = 7.1 Hz, 3H).

Step 3

5-(l-isopropylpyrazol-4-yl)-6-(l-methylprop-2-ynyl)-7-oxo-4H-pyrazolo[l,5- a]pyrimidine-3-carbonitrile

A mixture of ethyl 3-(l-isopropylpyrazol-4-yl)-3-oxo-propanoate (0.20 g, 0.89 mmol), 3- bromobut-l-yne (0.13 g, 0.98 mmol) and potassium carbonate (0.18 g, 1.33 mmol) in acetone (20 mL) was heated at 50 °C for 20 hours. The reaction mixture was cooled and solid was removed by filtration. The resulting filtrate was concentrated and the crude product was dissolved in ethyl acetate, washed with water and then brine. The organic layer was dried over sodium sulfate and concentrated. The crude product was dissolved in 2-Me THF (10 mL) and 5-amino-lH-pyrazole-4-carbonitrile (0.050 g, 0.5 mmol) was added, followed by titanium tetrachloride (2.6 mL, 1 M solution in toluene). The mixture was heated at 80 °C for 2 hours. The reaction mixture was cooled, diluted with water and ethyl acetate. The organic layer washed with brine, dried over sodium sulfate and concentrated. Purification by flash column chromatography on silica gel (0-100% EtO Ac/heptane), followed by trituration of the residue with ethyl acetate afforded the desired product (35 mg, 12% yield for 2 steps). 1H NMR (400 MHz, DMSO- ) δ 8.07 (d, / = 19.6 Hz, 1H), 8.02 (s, 1H), 7.69 (s, 1H), 4.58 (p, / = 6.7 Hz, 1H), 4.06 (d, / = 8.0 Hz, 1H), 2.74 (d, / = 2.6 Hz, 1H), 1.51 (d, / = 7.1 Hz, 3H), 1.47 (d, / = 6.7 Hz, 6H). LCMS (ESI): m/z 321.2 [M+H]⁺, RT = 4.00 min (LCMS Method F). Example 39

Step 1

Ethyl 2-benzoyl-3-cyclopropylbutanoate

To a suspension of CuCl (20 mg) in THF (2 mL) cooled in ice-bath was added cyclopropylmagnesium bromide (15 mL, 0.5 M solution in THF) and the suspension was stirred for 10 min. A solution of ethyl 2-benzoylbut-2-enoate (0.50 g, 2.3 mmol) in 5 mL of THF was added dropwise and the reaction mixture stirred for 1 hour at 0 °C. The reaction mixture was then quenched with aq. HC1 and diluted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. Purification by flash column chromatography on silica gel (0-50% EtO Ac/heptane) afforded the desired product (0.45 g, 75% yield). 1H NMR (400 MHz, CDC1₃) δ 8.09 - 7.96 (m, 2H), 7.62 - 7.51 (m, 1H), 7.54 - 7.38 (m, 2H), 4.43 - 4.28 (m, 1H), 4.22 - 4.05 (m, 2H), 1.86 - 1.69 (m, 1H), 1.19 (t, / = 7.1 Hz, 3H), 1.09 (dd, / = 36.8, 6.7 Hz, 3H), 0.80 - 0.03 (m, 4H). Step 2

6-(l-cyclopropylethyl)-7-oxo-5-phenyl-4H-pyrazolo[l,5-a]pyrimidine-3-carbonitrile This compound was synthesized using similar procedure was shown for example 37. 1H NMR (400 MHz, DMSO-d₆) δ 13.47 (s, 1H), 8.40 (s, 1H), 7.64 - 7.39 (m, 5H), 1.54 - 1.44 (m, 2H), 1.35 - 1.31 (m, 3H), 0.43 - 0.35 (m, 1H), 0.26 - 0.24 (m, 1H), 0.18 - 0.15 (m, 1H). LCMS (ESI): m/z 305.2 [M+H]⁺, RT = 4.99 min (LCMS Method F). Example 40

5-([l,l'-Biphenyl]-3-yl)-6-ethyl-7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidine-3- carbonitrile

A mixture of 5-(3-bromophenyl)-6-ethyl-7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidine-3- carbonitrile (0.060 g, 0.19 mmol), phenylboronic acid (0.030g, 0.23 mmol), dichlorobis(triphenylphospine)palladium(II) (0.02 g) and sodium carbonate ( 0.10 g, mmol) in dioxane/water (2 mL/0.5 mL) was heated at 110 °C for 20 min in a microwave reactor. The reaction mixture was acidified with HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification by flash column chromatography on silica gel (20-100% EtO Ac/heptane) and trituration of the residue with ethyl acetate/heptane afforded the desired product (0.01 g, 4% yield). 1H NMR (400 MHz, DMSO-de) δ 8.26 (t, / = 1.8 Hz, 1H), 8.12 (s, 1H), 8.03 (dt, / = 7.9, 1.4 Hz, 1H), 7.77 - 7.65 (m, 3H), 7.59 - 7.46 (m, 3H), 7.47 - 7.37 (m, 1H), 6.29 (s, 1H). LCMS (ESI): m/z = 313.2 [M+H]⁺, RT = 5.35 min (LCMS Method F). Example 41

6-Ethyl-5-(3-((4-fluorophenyl)amino)phenyl)-7-oxo-4,7-dihydropyrazolo[l,5- a]pyrimidine-3-carbonitrile

A mixture of 5-(3-bromophenyl)-6-ethyl-7-oxo-4,7-dihydropyrazolo[l ,5-a]pyrimidine-3- carbonitrile (0.10 g, 0.29 mmol), 4-fluoroaniline (0.065 mg, 0.50 mmol), Pd₂(dba)₃ (20 mg) and iert-BuX-Phos (20 mg), cesium carbonate (0.29 g, 0.87 mmol) in dioxane (5 mL) was heated at 1 10 °C for 5 hours. Only trace amount of the desired product was observed. Therefore, to this mixture was then added (chloro { [BrettPhos] [2-(2- aminoethylphenyl]palladium(II)]}/[BrettPhos] admixture (molar PdP/P = 1 : 1 (40 mg) and heated at 1 10 °C for another 15 hours. The reaction mixture was acidified with HC1 and extracted with ethyl acetate. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated. Purification by flash column chromatography on silica gel (0-100% DCM/EtOAc) and trituration of the residue with ethyl acetate/heptane afforded the desired product (20 mg, 18.5% yield). 1H NMR (400 MHz, DMSO-J₆) δ 13.44 (s, 1H), 8.38 (d, / = 3.3 Hz, 2H), 7.39 (t, / = 7.9 Hz, 1H), 7.19 - 7.07 (m, 5H), 6.95 - 6.85 (m, 1H), 2.34 (q, / = 7.3 Hz, 2H), 1.01 (t, / = 7.3 Hz, 3H). LC/MS (ESI): m/z = 374.2 [M+H]⁺, RT = 5.16 min (LCMS Method F). Example 42

6-isopropyl-7-oxo-5-(3-(2-oxopyrrolidin-l-yl)phenyl)-4,7-dihydropyrazolo[l,5- o]pyrimidine-3-carbonitrile

The mixture of 5-(3-bromophenyl)-6-isopropyl-7-oxo-4H-pyrazolo[l ,5-a]pyrimidine-3- carbonitrile (0.168 mmol, 60 mg), 2-pyrrolidone (0.588 mmol, 50 mg), BrettPhos (0.0168 mmol, 9.2 mg), BrettPhos Pre-catalyst (0.0168 mmol, 13.7 mg), and Cs₂C0₃ (0.336 mmol, 109 mg) in 1,4-dioxane (2 mL) in a microwave tube was purged with N₂ for 2 min, then sealed and heated at 140 °C in a microwave for 40 min. The mixture was filtered through Celite, washed with EtOAc, concentrated. The crude product was purified by preparative HPLC to afford the desired products as a white solid (29 mg, 47% yield). 1H NMR (DMSO- d₆) δ: 13.43 (s, 1H), 8.37 (s, 1H), 7.88 - 7.78 (m, 2H), 7.56 (t, / = 7.9 Hz, 1H), 7.25 (d, / = 7.5 Hz, 1H), 3.88 (t, / = 7.0 Hz, 2H), 2.65 (p, / = 6.9 Hz, 1H), 2.57 - 2.52 (m, 2H), 2.16 - 2.03 (m, 2H), 1.24 (d, / = 6.9 Hz, 6H). LCMS (ESI): m/z 362.2 [M+H]⁺, RT = 4.27 min (LCMS Method F). Example 43

Step 1

ethyl 5-nitro-[l,l'-biphenyl]-3-carboxylate

A mixture of ethyl 5-bromo-3-nitrobenzoate (5.0 g, 18 mmol), phenylboronic acid (2.7 g, 21 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.63 g, 0.89 mmol) and sodium carbonate (7.6 g, 72 mmol) in a dioxane/water (50: 10 mL) was heated at 90 °C for 20 hours.

The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification of the residue by flash column chromatography on silica gel (10-50% EtO Ac/heptane) afforded the desire product (4.1 g, 85% yield). 1H NMR (400 MHz, CDC1₃) δ 8.82 (dd, / =

2.2, 1.4 Hz, 1H), 8.67 - 8.53 (m, 2H), 7.76 - 7.62 (m, 2H), 7.60 - 7.41 (m, 3H), 4.48 (q, / =

7.2 Hz, 2H), 1.46 (t, / = 7.1 Hz, 3H). Step 2

5-amino-[l,l'-biphenyl]-3-carbaldehyde

To a solution of ethyl 3-nitro-5-phenyl-benzoate (1.0 g, 2.1 mmol) in 2-Me THF (20 mL) cooled at 0 °C was added LAH (2.9 mL of 1M solution in THF, 2.9 mmol) and the mixture was allowed to warm to room temperature over 20 min. The reaction mixture was quenched with saturated ammonium chloride. The solid was removed by filtration through a Celite pad and the filtrate was dried over sodium sulfate and was concentrated. The residue was dissolved in DCM (50 ml) and Mn0₂ (2.0 g) was added in one portion. The mixture was stirred at ambient temperature for 72 hours. The reaction mixture was passed through a Celite pad and the filtrate was concentrated to afford an off-white solid (0.30 g, 34% yield). 1H NMR (400 MHz, CDC1₃) δ 10.04 (s, 1H), 7.91 (t, / = 1.9 Hz, 1H), 7.87 (s, 1H), 7.79 (t, / = 1.6 Hz, 1H), 7.65 - 7.59 (m, 2H), 7.49 - 7.44 (m, 2H), 7.42 - 7.36 (m, 1H), 6.70 (s, 1H), 1.56 (s, 9H).

Step 3

5-(3-amino-5-phenyl-phenyl)-7-oxo-4H-pyrazolo[l,5-a]pyrimidine-3-carbonitrile The compound was prepared using procedure that was shown for example 20. 1H NMR (400 MHz, DMSO-de) δ 8.43 (s, 1H), 7.77 - 7.67 (m, 2H), 7.56 - 7.45 (m, 2H), 7.44 - 7.35 (m, 2H), 7.23 (s, 1H), 7.12 (s, 1H), 6.25 (s, 1H). LCMS (ESI): m/z 328.1 [M+H]⁺, RT = 4.19 min (LCMS Method F). Example 44

N-[3-(3-Cyano-7-oxo-4H-pyrazolo[l,5-a]pyrimidin-5-yl)-5-phenyl-phenyl]acetamide To a solution of 5-(3-amino-5-phenyl-phenyl)-7-oxo-4H-pyrazolo[l,5-a]pyrimidine-3- carbonitrile (100 mg, 0.30 mmol) in DCM (5 mL) and DIPEA (0.11 mL, 0.61 mmol) was added acetyl chloride (48 mg, 0.61mmol). The reaction mixture was stirred for 1 hour. The reaction mixture was diluted with DCM and washed with HCl, followed by washing with water and then brine. The organic layre was dried over sodium sulfate and concentrated. Purification of the resulting residue by rpHPLC provided the desired product (15 mg, 13% yield). 1H NMR (400 MHz, DMSO-d₆) δ 10.28 (s, 1H), 8.35 (d, / = 17.1 Hz, 1H), 8.15 - 8.08 (m, 1H), 8.01 (s, 1H), 7.79 - 7.68 (m, 3H), 7.56 - 7.46 (m, 2H), 7.46 - 7.39 (m, 1H), 6.26 (s, 1H), 2.12 (s, 3H). LCMS (ESI): m/z 370.4 [M+H]⁺, RT = 4.44 min (LCMS Method F).

Example 45 (Method C)

6-Bromo-7-oxo-5-phenyl-4,7-dihydropyrazolo[l,5-a]pyrimidine-3-carbonitrile To a suspension of 7-oxo-5-phenyl-4,7-dihydropyrazolo[l,5-a]pyrimidine-3-carbonitrile (1.00 g, 4.2 mmol) in DMF (5 mL) was added NBS (0.75 g, 4.2 mmol). The mixture stirred at room temperature for 15 min, and then diluted with water. The precipitate was collected by filtration, washed with water and dried in vacuum oven at 50 °C for 20 hours to afford the desired product (0.70 g, 52% yield). 1H NMR (400 MHz, DMSO- ): δ 8.44 (s, 1H), 7.67 - 7.51 (m, 5H). LCMS (ESI): m/z 317.1 [M+H]⁺, RT = 3.48 min (LCMS Method F). Example 46

6-(2-Furyl)-5-methyl-7-oxo-4H-pyrazolo[l,5-a]pyrimidine-3-carbonitrile

A mixture of 6-bromo-5-methyl-7-oxo-4H-pyrazolo[l,5-a]pyrimidine-3-carbonitrile (0.10 g, 0.39 mmol), 2-furanylboronic acid (0.05 g, 0.47 mmol), dichlorobis(triphenylphospine)palladium(II) (0.014 g) and sodium carbonate (0.16 g,1.6 mmol) in a mixture of ethanol/water (2 mL/0.5 mL) was heated to 150 °C for 20 min in a microwave reactor. The reaction mixture was acidified with HCl and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. Purification by flash column chromatography on silica gel (20-100% ethyl acetate/heptane) and trituration of the residue with ethyl acetate/heptane afforded the desired product (0.01 g, 11.2% yield). 1H NMR (400 MHz, DMSO-d₆) δ 8.30 (s, 1H), 8.12 (s, 1H), 7.68 - 7.61 (m, 1H), 6.60 - 6.48 (m, 2H), 2.30 (s, 3H). LC/MS (ESI): m/z 241.2 [M+H]⁺, RT = 3.21 min (LCMS Method F).

Example 47 (Method D)

6-isopropyl-7-oxo-5-(phenylamino)-4,7-dihydropyrazolo[l,5-a]pyrimidine-3-carbonitrile The mixture of 5-chloro-6-isopropyl-7-oxo-4H-pyrazolo[l,5-a]pyrimidine-3-carbonitrile (60 mg, 0.253 mmol), aniline (71 mg, 0.76 mmol), BrettPhos (14 mg, 0.025 mmol), BrettPhos Pre-catalyst (20 mg, 0.025 mmol), and iBuONa (75 mg, 0.76 mmol) in 1,4-dioxane (2 mL) was purged with N₂ for 2 min, then heated at 140 °C in a microwave reactor for 20 min. The mixture was filtered to remove solid. The filter cake was washed with EtOAc. Combined filtrate was concentrated. The crude product was purified by prep HPLC to give the title compound as a white solid (8.2 mg, 11% yield). Ή NMR (400 MHz, DMSO-d₆) δ 12.93 (s, 1H), 8.56 (s, 1H), 8.21 (s, 1H), 7.30 (t, / = 7.76 Hz, 2H), 7.09 (d, / = 14.17 Hz, 2H), 6.98 (s, 1H), 3.18 - 3.00 (m, 1H), 1.29 (d, / = 6.87 Hz, 6H). LCMS (ESI): m/z 294.1 [M+H]⁺, RT = 5.3 min (LCMS Method F).

Example 48

6-isopropyl-7-oxo-5-(piperidin-l-yl)-4,7-dihydropyrazolo[l,5-a]pyrimidine-3- carbonitrile

The mixture of 5-chloro-6-isopropyl-7-oxo-4H-pyrazolo[l,5-a]pyrimidine-3-carbonitrile (160 mg, 0.676 mmol, 20 mg), piperidine (173 mg, 2.03 mmol), RuPhos (32 mg, 0.0676 mmol), RuPhos pre-catalyst (52 mg, 0.0676 mmol), and iBuONa (200 mg, 2.03 mmol) in THF (5 mL) was purged with N₂ for 2 min, then heated at 140 °C in a microwave reactor for 15 min. The mixture was filtered to remove solid. The filter cake was washed with EtOAc. Combined filtrate was concentrated. The resulting crude product was purified by prep HPLC to give the title compound as an off-white solid (10.1 mg, 5.2% yield). Ή NMR (400 MHz, DMSO-d₆) δ 8.10 (s, 1H), 4.22 - 4.09 (m, 1H), 3.94 (d, / = 3.29 Hz, 1H), 3.63 (m, 2H), 3.54 - 3.42 (m, 1H), 2.17 (m, 1H), 1.73 - 1.48 (m, 4H), 1.15 (d, / = 6.78 Hz, 3H), 0.66 (d, / = 6.84 Hz, 3H). LCMS (ESI): m/z 286.2 [M+H]⁺, RT = 5.76 min (LCMS Method F).

Step 1

5-bromo-6-isopropyl-7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidine-3-carbonitrile To the suspension of 5-chloro-6-isopropyl-7-oxo-4H-pyrazolo[l,5-a]pyrimidine-3- carbonitrile (200 mg, 0.845 mmol) in EtCN (4 mL) was added TMSBr (1.29 g, 8.45 mmol) drop wise. The mixture was then heated at 115 °C for 17 hours. The reaction was quenched with ice-water, extracted with EtOAc (3x). The combined organics were dried over Na₂S0₄, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (0-10% MeOH/DCM with 1% formic acid) to give the title compound (129 mg, 54.3% yield) as an off-white solid. LCMS (ESI) m/z 283.1 [M+H]⁺.

Step 2

6-isopropyl-7-oxo-5-phenoxy-4,7-dihydropyrazolo[l,5-a]pyrimidine-3-carbonitrile The mixture of 5-bromo-6-isopropyl-7-oxo-4H-pyrazolo[l,5-a]pyrimidine-3-carbonitrile (80 mg, 0.28 mmol), phenol (81 mg, 0.85 mmol), Cul (5 mg, 0.028 mmol), trans-N,N'- dimethylcyclohexane-l,2-diamine (8 mg, 0.056 mmol), and K₃PO₄ (187 mg, 0.85 mmol) in DMSO (2 mL) was purged with N₂ for 2 min, then heated at 150 °C in a microwave reactor for 20 min. The mixture was filtered. The filter cake was washed with EtOAc. Combined filtrate was concentrated. The crude product was purified by prep HPLC (5-50%> CH₃CN/H₂0 with 0.1%) NH₄OH) to give the title compound as an off-white solid (14 mg, 17% yield). Ή NMR (400 MHz, DMSO-d₆) δ 7.97 (s, 1H), 7.38 - 7.29 (m, 2H), 7.10-7.06 (m, 2H), 7.02 - 6.97 (m, 2H), 3.35-3.31 (m, 1H), 1.24 (d, 7 = 6.81 Hz, 6H). LCMS (ESI): m/z 295.2 [M+H]⁺, RT = 5.73 min (LCMS Method F).

Using the General Synthetic Method (Syn. Met.) and the General LCMS Method shown, the following compounds were also prepared.

LCMS LCMS

Syn.

Structure (ESI) Method NMR

Met. (min)

m/z

^:H NMR (400 MHz, CD₃OD) δ 8.28 (s, 1 H), 8.19 (s, 1 H), 7.68 (d, / = 8.0 Hz, 1 H), 7.61 (d, / = 7.6 Hz, 1 H), 7.48 (t,

A 319.0 A 1.08 / = 8.0 Hz, 1 H), 7.40 (t, / = 7.6 Hz, 1

H), 2.90-2.84 (m, 1 H), 1.36 (d, / = 6.8

Hz, 6 H).

0 I ^:H NMR (400 MHz, OMSO-d₆) δ

8.58 (d, = 4 Hz, 1 H), 8.55 (s, 1 H),

A 280.1 A 0.99 8.09 (s, 1 H), 7.77 (d, = 7.2 Hz, 1 H),

7.46 (t, = 6.8, Hz, 1 H), 2.64-2.56 (m,

N / ^H u 1 H), 1.23 (d, = 7.2 Hz, 6 H).

^:H NMR (400 MHz, CD₃OD) δ 8.26 (s,

A 255.1 C 0.93 1 H), 8.10-7.98 (m, 2 H), 2.66 (q, =

7.2 Hz, 2 H), 1.20 (t, / = 7.2 Hz, 3 H).

0 1 ^:H NMR (400 MHz, DMSO-rf₆) δ 13.30

(s., 1 H), 8.71 (s., 1 H), 8.41 (s, 1 H),

D 346.9 E 0.73 8.21 (s, 1 H), 3.71 (s, 3 H), 2.90 - 2.76 /// \ (m, 1 H), 1.30 (d, / = 7.2 Hz, 6 H).

^:H NMR (400 MHz, DMSO-rf₆) δ 13.06 (s, IH), 8.37 (s, IH), 8.20 (s, IH), 7.74

0

(s, IH), 4.87 - 4.79 (m, 1 H), 3.00 - 2.94 (m, 1 H), 2.20 - 2.07 (m, 2 H),

D 337.0 A 1.05

2.03 - 1.92 (m, 2 H), 1.90 - 1.78 (m, 2

N H), 1.73 - 1.61 (m, 2 H), 1.30 (d, =

6.8 Hz, 6 H).

^:H NMR (400 MHz, DMSO-rf₆) δ 13.07 (s., 1 H), 8.36 (s, 1 H), 8.25 (s, 1 H), 7.76 (s, 1 H), 7.55 (dd, = 4.8, 2.8 Hz,

D 364.9 A 1.02 1 H), 7.49 (d, / = 2.8 Hz, 1 H), 7.13 (d,

N kg/ = 4.8 Hz, 1 H), 5.44 (s, 2 H), 3.00 - 2.93 (m, 1 H), 1.29 (d, / = 7.2 Hz, 6 H).

Ή NMR (400 MHz, DMSO- ) δ 8.42 (s, 1 H), 7.76 (d, / = 8.0 Hz, 1 H), 7.60 (dd, / = 8.0, 2.0 Hz, 1 H), 7.57 (d, / = 2.0 Hz, 1 H),

A 426.0 E 0.76 3.70 - 3.60 (m, 4 H), 3.60 - 3.52 (m., 2 H),

3.25 - 3.15 (m., 2 H), 2.54 - 2.52 (m, 1 H),

1.22 (d, / = 7.2 Hz, 6 H). 'H NMR (400 MHz, DMSO-rf₆) δ 13.50

(s, 1 H), 8.55 (d, = 7.6 Hz, 1 H), 8.42 (s, 1 H), 7.71 (s, 1 H), 7.58 (d, = 8.0 Hz, 1 H), 7.50 (d, = 7.6 Hz, 1 H), 4.27

A 424.0 E 0.83 - 4.16 (m, 1 H), 2.58 - 2.55 (m, 1 H),

1.90 - 1.82 (m, 2 H), 1.72-1.66 (m, 2

H), 1.60 - 1.49 (m, 4 H), 1.25 (d, =

7.2 Hz, 6 H).

0 'H NMR (400 MHz, CD₃OD) δ 8.23 (s,

1 H), 8.19 (s, 1 H), 7.79 (s, 1 H), 3.82

A 341.1 A 0.90 (s, 2 H), 3.18 - 3.08 (m, 1 H), 1.65 (s, 6

N H), 1.40 (d, = 6.8 Hz, 6 H).

'H NMR (400 MHz, DMSO-rf₆) δ 13.12 (br s, 1 H), 8.36 (br s, 1 H), 8.30 (s, 1 H), 7.77 (s, 1 H), 7.34 - 7.23 (m, 1 H),

A 388.9 E 0.77

6.90 - 6.89 (m, 3 H), 5.41 (s, 2 H), 3.75 (s, 3 H), 3.02 - 2.95 (m, 1 H), 1.30 (d, = 6.8 Hz, 6 H).

'H NMR (400MHz, DMSO-rf₆) δ8.58 (d, / = 4.4 Hz, 2 H), 8.36 (d, / = 5.6 Hz,

A 360.1 E 0.60 2 H), 7.83 (s, 1 H), 7.23 (d, / = 4.4 Hz,

2 H), 5.54 (s, 2 H), 3.08 - 2.89 (m, 1 H), 1.30 (d, = 7.2 Hz, 6 H).

'H NMR (400MHz, DMSO-rf₆) δ 13.12 (br. s, 1 H), 8.37 (s, 1 H), 8.30 (s, 1 H), 7.82 (s, 1 H), 7.52 (d, / = 5.6 Hz, 1 H),

A 392.9 E 0.81

7.43 - 7.34 (m, 2 H), 7.17 (br. s, 1 H), 5.56 (s, 2 H), 3.03 - 2.92 (m, 1 H), 1.29 (d, = 6.4 Hz, 6 H).

'H NMR (400MHz, DMSO-rf₆) δ 8.07 (br. s., 1 H), 8.04 (br. s., 1 H), 7.62 (s, 1 H), 7.41 - 7.35 (m, 3 H), 7.16 - 7.13 (m,

A 451.0 E 0.85

1 H), 7.08 - 6.96 (m, 4 H), 6.93 - 6.91 (m, 1 H), 5.38 (s, 2 H), 3.17 - 2.97 (m, 1 H), 1.30 (d, = 7.2 Hz, 6 H).

13.08

H), Hz, (t, 2.0 1 H), 13.29 H), 1 H), 1 H), 13.39 H), 2 H), = 7.6 (d, 13.05 H), 7.26 2.96- 6 H). 13.05 H), 7.30 Hz, 1 H), 13.06 H), 2 H ), (m, 1 = 0.99

(s,

Hz, (s, 6H),

(s, 2.76 - 6H).

(s, 7.36 (d, J (s, (d, Hz, (m, =

(s, = 1.33

(s, IH),

IH),

IH), (s, (d, J IH), J = - - IH), 4.86 IH), Hz, - IH), J = 3H), J = 6.7

IH), J = Hz,

IH),

J = - 1.91 (m, IH), - 0.99 IH), 6.62 - IH), 2H), (m, (m, IH), IH), (m,

IH), (m, (d, J 6H) IH), IH), 6H), Hz,

EXAMPLE 433

Assessment of Inhibitory Effect of Test Compounds on KDM5A demethylase activity KDM5A demethylase assay (MassSpec assay - A)

Full length recombinant Flag tagged KDM5A protein is purified from Sf9 insect cells. The demethylation reaction buffer containes 50 mM TrisCl pH 7.4, 0.01% Triton X-100, 0.025 mg/mL BSA, 1 mM ascorbate (Cat# A4034, Sigma Aldrich), 2 mM TCEP (Cat# D9779, Sigma Aldrich), 2.0 μΜ α-ketoglutarate (# K2010, Sigma Aldrich) and 50 μΜ Fe₂(NH₄)₂(S0₄)₂ (Cat# F1543, Sigma Aldrich). In a 25 μΐ, demethylation reaction system, 20 uM recombinant KDM5A and is incubated with compounds for 10 minutes in the above buffer, and then 2.0 a-ketoglutarate (# K2010, Sigma Aldrich), 4.0 μΜ biotinylated

H3K9mel peptide (1-21 aa) , and Fe₂(NH₄)₂(S0₄)₂ are added to initiate the reaction. (All reagent concentrations are final reagent concentrations.) Reactions are incubated for 30 minutes at room temperature, and then quenched by addition of an equal volume of 1% formic acid. After termination, plates are sealed and frozen at -80 °C for analysis.

KDM5A demethylase assays (TR-FRET assay- )

Full length recombinant Flag tagged KDM5A protein is purified from Sf9 insect cells. The demethylation reaction buffer containes 50 mM TrisCl pH 7.4, 0.01% Triton X-100, 0.025 mg/mL BSA, 1 mM ascorbate, 2 mM TCEP, 3.0 μΜ α-ketoglutarate, and 50 μΜ

Fe₂(NH₄)₂(S0₄)₂. In a 10 μί demethylation reaction system, 2 uM recombinant KDM5A and is incubated with compounds for 15 minutes in the above buffer (V_t 5 uL) in a 384 well Proxi Plate (Perkin Elmer Corp.), and then 0.1 μΜ biotinylated H3K9mel peptide (1-21 aa, New England Peptide, V_t 5 uL) is added to initiate the reaction (V_t 10 uL). (All protein/reagent concentrations are final concentrations.) Reactions are incubated for 25 minutes at room temperature, and then quenched by addition of 5 uL of detection reagents (buffer as above with addition of 0.3 mM EDTA, 150 mM NaCl, 150 uM SA-SurelightAPC and 1.5 uM Eu(W1024)-K3K4Mel/2 antibody (TR-FRET reagents both Perkin-Elmer)). After a one hour incubation assays are read on a Perkin-Elmer Envision equipped with a laser source and appropriate filters. IC50S are calculated using standard dose-response equations and relative to a Max (no inhibition) and Min (no enzyme or quenched enzyme) controls.

KDM5A demethylase assays (TR-FRET assay- C)

Full length recombinant Flag tagged KDM5A protein ss purified from Sf9 insect cells. The demethylation reaction buffer contained 50 mM HEPES pH 7.0, 0.01% Triton X-100, 0.5 mM ascorbate, 2 mM DTT, 1 μΜ α-ketoglutarate, and 100 μΜ Fe2(NH₄)2(S0₄)2. In a 10 μΕ demethylation reaction system, 2 11M recombinant KDM5 A is added to compounds in the above buffer (V_t 5 uL) in a 384 well Proxi Plate (Perkin Elmer Corp.) and then 0.1 μΜ biotinylated H3K9mel peptide (1-21 aa, New England Peptide, V_t 5 uL) is added to initiate the reaction (V_t 10 uL). (All protein/reagent concentrations are final concentrations.)

Reactions are incubated for 30 minutes at room temperature, and then quenched by addition of 5uL stop buffer (3mM EDTA, 50 mM TrisCl pH 7.5, 0.01% Triton X-100, 0.01 mg/mL BSA) followed by addition of 5 uL of detection reagents (buffer as above without EDTA but with addition of 200 nM SA-XL665 (CisBio) and 2 nM Eu(W1024)-anti-H3K4Mel-2 antibody (PerkinElmer)). After a 30 minute incubation assays are read on a Perkin-Elmer Envision equipped with appropriate filters. IC50S are calculated using standard dose-response equations and relative to a Max (no inhibition) and Min (no enzyme or quenched enzyme) controls.

EXAMPLE 434

KDM5 En zyme Assay Procedure

Full length KDM5A enzyme was expressed and purified inhouse. Biotin-H3 4me3 peptide was purchased from New England Biolabs. HTRF reagents (containing Eu-labeied H3 4mel-2 antibody, and streptavidin-XL665) were purchased from Cis-Bio International. Plates were read on an Envision multi-label plate reader (Perkin Elmer).

The HTRF assay mixture contained 2 nM full length KDM5A enzyme, 100 nM H3K4Me3 peptide substrate, 1 uM 2-OG, 100 uM Fe²⁺, 500 uM ascorbate. 50 mM HEPES pH 7.0 buffer, 0.01% Triton - X 100, 2 mM DTT, 0.25 % DMSO at a final volume of 10 uL. The enzyme reaction was earned out at room temperature in black Proxiplate 384-Plus plate (Corning, Costar) within 30 minutes, in the presence of varying concentration of a test compound. At the end of enzyme reaction, 5 uL of 1 mM EDTA were added to quench the reaction and then the detection reagents (5 uL) were added to give final concentrations of 0.5 nM Eu-iabeled H3K4mel-2 antibody, and 50 nM streptavidin-XL665. The plates were incubated at room temperature for 60 minutes and then read in the Envision plate reader. The readouts were transformed into % inhibition, and IC50 value of a test compounds was generated by using four parameters curve fitting (Model 205 in XLF1T5, iDBS).

EXAMPLE 435

DM5 Cell Assay Procedure:

PC9 cells were seeded in a 384 well plate (2000 cells/well) with a test compound and incubated for 120 hours at 37 °C. H3K4Me3 mark level was assessed using A lpha ! .ISA reagents from Perkin Elmer. Briefly, cells were lysed in 5 xL of Histone cell lysis buffer for 30 min on ice. Then histories were extracted by addition of 10 Ε of Histone extraction buffer to each well for 20 minutes. 10 μΐ, of acceptor beads and 10 μΐ, of donor beads were added sequentially one hour apart, and the mixture was incubated at 26 °C for 30 minutes. Assay plate was read subsequently on Envision (Perkin Elmer), Each compound was mn in duplicate. Data were normalized to DMSO treated wells as the low response and ECso's were calculate using a four-parameter fit. Data for the compounds of Examples 1-432 from the assays described in Examples 434 and 435 is provided in the following table.

Compound Example 463 Assay Example 464 Assay

(Example KDM5A HTRF IC₅₀ H3K4Me3 PC9 EC₅₀

Number) (uM) (uM)

1 0.0043 22

2 0.003

3 0.0038 >15

4 0.065

5 0.0055

6 0.013 1.1

7 0.03 0.83

8 0.022

9 0.04 9.2

10 0.024 2.7

11 0.014 5.7

12 0.018 12

13 0.023

14 0.0053 1.7

15 0.047

16 0.011

17 0.041

18 0.021

19 0.055

20 0.037 >30

21 0.038

22 0.0095 5.3

23 0.0098

24 0.007 >30

25 0.22

26 4.4

27 3.9

28 0.018

29 0.016

30 0.012

31 0.025

32 0.015

33 0.0093

34 0.0095

35 0.03

36 0.0104

37 0.024

38 0.036

39 0.128

40 0.01

41 0.019

42 0.021 1.8

43 0.083

44 0.368

45 0.03 >30 2.9

0.024

0.084

0.025

0.02 4.9

0.0083 4.3

0.0058 3

0.017 7.4

0.006 3.7

0.011 1.8

0.016

0.0057

0.0073

0.034

0.019 2.1

0.01 14

0.012 5.7

0.015 >30

0.021

0.014

0.01

0.013

0.021

0.0078

0.0045

0.01

0.0073

0.004

0.01

0.006

0.012 29

0.0077 2.5

0.013 12

0.0068

0.0065

0.012

0.0083

0.012

0.0045

0.0075

0.014

0.01

0.009

0.012

0.0055

0.013

0.012 0.87

0.011 7.8

0.034 >30

0.038 98 0.037 2.2

99 0.006 2.8

100 0.008 6

101 0.0085 3.2

102 0.01 3.8

103 0.0055 3.7

104 0.021 2.7

105 0.008 0.66

106 0.018 1.9

107 0.019 1.5

108 0.028 >30

109 0.011 13

110 0.007 4.4

111 0.015 4.3

112 0.33

113 0.006 5.5

114 0.0055 2.1

115 0.006 2.6

116 0.008 2.7

117 0.014 0.18

118 0.015

119 0.019

120 0.019

121 0.01

122 0.013

123 0.008

124 0.011 1

125 0.03 0.83

126 0.008 >8.3

127 0.013 2.8

128 0.016 10

129 0.023

130 0.0045

131 0.018

132 0.0072

133 0.011 2.1

134 0.0055 5.2

135 0.0058 1.3

136 0.009

137 0.012

138 0.015 >30

139 0.013 7.1

140 0.012

141 0.0093 0.64

142 0.012

143 0.025

144 0.019

145 0.017 8.2

146 0.0075 3.9

147 0.0095 5.1

148 0.016

149 0.006 26 150 0.014

151 0.017

152 0.014

153 0.013 1.1

154 0.006 4.5

155 0.0098 0.95

156 0.022 5

157 0.007 8.3

158 0.015 0.53

159 0.035

160 0.019 3

161 0.013 3.5

162 0.064 >30

163 0.097

164 0.15

165 0.061

166 0.2

167 0.1

168 0.046

169 0.047

170 0.21

171 0.037

172 0.14

173 0.039

174 0.081

175 0.043

176 0.052

177 0.038

178 0.043

179 0.035

180 0.061

181 0.06

182 0.13

183 0.033

184 0.056

185 0.02 3.5

186 0.049

187 0.75

188 0.24

189 0.16

190 0.057

191 0.76

192 1.5

193 0.86

194 2.3

195 2.2

196 0.047

197 0.029

198 0.61

199 0.18

200 0.9

201 0.029 202 0.006 16

203 0.011

204 0.019

205 0.023

206 0.021

207 0.033

208 0.009

209 0.018

210 0.012

211 0.024 >30

212 0.008

213 0.018

214 0.026

215 0.41

216 0.02

217 2.1

218 8

219 4.3

220 21

221 25

222 0.012

223 0.009

224 0.025

225 5.4

226 0.37

227 0.013

228 0.023

229 9.6

230 0.009

231 0.17

232 0.019

233 0.02

234 0.015

235 0.014

236 0.018

237 0.078

238 0.049

239 0.021

240 0.05

241 0.013 2.7

242 0.027 20

243 0.02 6.8

244 0.021 >30

245 0.046 2.8

246 0.022 8.8

247 0.015 2.2

248 0.069 5.3

249 0.03 >30

250 5.7

251 8

252 7.63

253 0.013 254 0.033 4.4

255 0.035

256 0.015 16

257 0.037

258 0.044

259 0.043

260 0.036

261 0.031

262 0.021

263 0.028

264 0.021

265 0.04

266 0.029

267 0.0098

268 0.023 0.88

269 0.019

270 0.013

271 0.024

272 0.029

273 0.023

274 0.073

275 0.034

276 0.035

277 0.032

278 0.076

279 0.024 3.9

280 0.015 2.3

281 0.032 >30

282 0.008

283 0.037

284 0.016 10

285 0.023 2.3

286 0.03 14

287 0.022 11

288 0.012

289 0.035

290 0.039

291 0.055

292 0.009

293 0.019

294 0.062

295 0.039

296 0.047

297 0.028

298 0.024

299 0.025

300 0.018

301 0.17

302 0.052

303 0.015

304 0.052

305 0.047 0.67 306 0.2

307 0.025

308 0.017

309 0.037

310 0.019 1.9

311 0.028

312 0.028

313 0.018

314 0.0052

315 0.024

316 0.034

317 0.025

318 0.021

319 0.046

320 0.02

321 0.023

322 0.01

323 0.031 7.4

324 0.026 1.1

325 0.019 5.6

326 0.014 8.8

327 0.048

328 0.03 10

329 0.011 2.9

330 0.023 6.5

331 0.027 6.1

332 0.02 15

333 0.012 1.3

334 0.025

335 0.06

336 0.032

337 0.025

338 0.034

339 0.033 20

340 0.031 8.3

341 0.021

342 0.009 5.1

343 0.036

344 0.093

345 0.14

346 0.04 5.1

347 0.024 5.5

348 0.014

349 0.014

350 0.02

351 0.027

352 0.027

353 0.014

354 0.077

355 0.04

356 0.044

357 0.022 358 0.025

359 0.02

360 0.028

361 0.052

362 0.024

363 0.025 >30

364 0.018 11

365 0.018 1.7

366 0.018 2

367 0.025

368 0.075

369 0.085

370 0.008

371 0.011

372 0.015

373 0.024 8.7

374 0.038 3.4

375 0.019

376 0.019

377 0.022

378 0.014

379 0.011 2.2

380 0.048 3.7

381 0.03

382 0.048

383 0.031

384 0.013

385 0.021

386 0.012 3.9

387 0.13

388 0.025 >30

389 0.033 >30

390 0.055 0.54

391 0.011

392 0.02

393 0.012

394 0.02

395 0.01

396 0.034

397 0.032

398 0.041

399 0.054

400 0.035

401 0.039

402 0.058

403 0.057

404 0.018

405 0.012

406 0.015 3.9

407 0.048 >30

408 0.15

409 0.044 410 0.039

411 0.035 1.5

412 0.046 8.7

413 0.11

414 0.014

415 0.077

416 0.048

417 0.031

418 0.013

419 0.088

420 0.023

421 0.019

422 0.029

423 0.02

424 0.008

425 0.016

426 0.023

427 0.039

428 0.014

429 0.027

430 0.032

431 0.021

432 0.056

While a number of embodiments have been described, these examples may be altered to provide other embodiments that utilize the compounds and methods described herein. Therefore, the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A compound as described in any one of Examples 1-432 or a salt thereof.

2. A compound of formula (I):

or a salt thereof, wherein:

R¹ is H, Ci_₆alkyl, trifluoromethyl, 3-6 membered carbocyclyl, 6 membered aryl, 3-6

f f f

membered heterocyclyl, 5-6 membered heteroaryl, halo, -OR , -SR , -N(R )₂, -CN, or -N0₂, wherein said alkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more groups independently selected from oxo, halo, Ci_₃alkoxy and Ci_₃alkyl;

R² is H, Ci_i₂alkyl, C₂_i₂alkenyl, C₂_i₂alkynyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, halo, -OR^a, -SR^a, -N(R^a)₂, -CN, - N0₂, -C(0)R^a, -C0₂R^a, -C(0)N(R^a)₂, -C(0)SR^a, -C(0)C(0)R^a, - C(0)CH₂C(0)R^a, -C(S)N(R^a)₂, -

C(S)OR^a, -S(0)R^a, -S0₂R^a, -S0₂N(R^a)₂, -N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, -N(R^a)S0₂ R^a, -N(R^a)S0₂N(R^a)₂, -N(R^a)N(R^a)₂, -N(R^a)C(=N(R^a))N(R^a)₂, -C(=N)N(R^a)₂, -

C=NOR^a, -C(=N(R^a))N(R^a)₂, -OC(0)R^a, or -OC(0)N(R^a)₂, wherein each Ci i₂alkyl, C₂ i₂alkenyl, C₂_i₂alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl of R² and R³ is independently optionally substituted with one or more groups R^x; and wherein R² and R³ are not each H; or R² and R³ taken together with the atoms to which they are attached form a 4, 5, 6, 7, or 8 membered carbocyclyl or aryl, which carbocyclyl or aryl is optionally substituted with one or more groups R^x;

R³ is aryl or heteroaryl, wherein each aryl and heteroaryl is optionally substituted with one or more groups R^x; provided R³ is not phenyl, chlorophenyl, nitrophenyl, or

propylisoxazole; R⁴ is H, Ci_i₂alkyl, C₂_i₂alkenyl, C₂_i₂alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl, wherein each Ci_i₂alkyl, C₂_i₂alkenyl, C₂_i₂alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, C_1-12 alkyl, Ci_i₂haloalkyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, halo, -CN, -N0₂, -NR^mR^m, -OR^m, -C(=0)OR^m, and -OC(=0)R^m; or R⁴ and R³ taken together with the atoms to which they are attached form a heterocyclyl;

each R^a is independently selected from H, Ci_6alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl, wherein each Ci_₆alkyl, C₃_₆alkenyl, C₃_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups R^x;

Ci_₆haloalkyl, carbocyclyl, Ci_₆ alkanoyl, phenyl, and benzyl, wherein any Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl,Ci_₆ haloalkyl, carbocyclyl, Ci_₆ alkanoyl, phenyl, or benzyl is optionally substituted with one or more groups independently selected from halo, - CN, -N0₂, -NR^yR^z, and -OR^w; or two R^m groups together with the nitrogen to which they are attached form a 3-6 membered heterocyle;

each R^v is independently hydrogen, Ci_6alkyl, C₂_6alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl,wherein each Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, aryl, carbocyclyl, and Ci-C₆ alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^v are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and Ci_₃alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^w is independently selected from H, C_halky 1,

phenyl, benzyl, and phenethyl;

each R^x is independently selected from oxo, Ci_₆alkyl, C₂_6alkenyl, C₂_6alkynyl, carbocyclyl, aryl, heteroaryl, heterocycle, -F, -CI, -Br, -I, -N0₂, -N(R^V)₂, -CN, -C(O)- N(R^V)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -0-C(0)-0-R^v, -C(O)- R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -0-C(0)-N(R^v)₂, -N(R^v)-C(0)-OR^v, -N(R^v)-C(0)- N(R^V)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-S(0)-R^v, -N(R^v)-S(0)₂-R^v, -N(R^v)-S(0)- N(R^V)₂, and

each R^y and R^z is independently selected from H, Ci_₄alkyl, Ci_₄alkanoyl,

Ci_₄alkoxycarbonyl, phenyl, benzyl, and phenethyl, or R^y and R^z together with the nitrogen to which they are attached form a heterocyclyl; and

S(0)-R^v, -N(R^v)-S(0)₂-R^v, and -N(R^v)-S(0)-N(R^v)₂, wherein any

3. The compound of claim 2 wherein R¹ is H, Ci_₆alkyl, trifluoromethyl, 3-6 membered carbocyclyl, 6 membered aryl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, halo, -OR f , -SR f , -N(R f )₂, -CN, or -N0₂, wherein said alkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more groups independently selected from oxo, halo, Ci_3alkoxy and Ci_3alkyl.

4. The compound of claim 2 wherein R¹ is H, methyl, or ethyl.

5. The compound of claim2 wherein R¹ is H.

6. The compound of any one of claims 2-5 wherein R² is H.

7. The compound of any one of claims 2-5 wherein R² is Ci_i₂alkyl, C₂_i₂alkenyl, C₂_₁₂alkynyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, halo, -OR^a, -SR^a, -N(R^a)₂, -CN, -

8. The compound of any one of claims 2-5 wherein, R² is H, Ci_6alkyl, C₂_ i₂alkenyl, C₂_i₂alkynyl, carbocyclyl, aryl, heteroaryl, halo, -CN, -SR^a, -N(R^V)₂, and -C0₂R^a, wherein any Ci_₆alkyl, carbocyclyl and aryl is optionally substituted with one or more groups independently selected from Ci_₃alkyl, carbocyclyl, halo, -CN, -N(R^v)-C(0)-R^v, and -0-R^v.

9. The compound of any one of claims 2-5 wherein R² is H, isopropyl, ethyl, iert-butyl, 2,2-difiuoroethyl, cyclobutyl, 2-propyn-l-yl, bromo, chloro, 2-furyl, vinyl, phenyl, 2-chlorophenylthio, 2-fluoroethyl, 2-propenyl, 1-methylvinylcyclopropyl, 4-pyridyl, 2- buten-l-yl, iodo, l-methyl-2-propyn-l-yl, 1-methylprop-l-yl, l-(cyclopropyl)ethyl, methoxycarbonyl, 2-butynyl, 2-hydroxy-l-methylethyl, 4-(methylcarbonylamino)butyl, 3- (methylcarbonylamino)-propyl, 4-aminobutyl, l-methyl-2-propenyl, 1-methylcyclobutyl, propyl, 2-methoxyethyl, and 2-methylpropyl.

10. The compound of any one of claims 2-9 wherein R³ is lH-pyrazol-4-yl, 1- (cyclopropylmethyl)- 1 H-pyrazol-4-yl, 1 -( 1 -methylcyclopropyl)- 1 H-pyrazol-4-yl, 5 -fiuoro- lH-pyrazol-4-yl, l-(2-phenylpropan-2-yl)-lH-pyrazol-4-yl, l-(pyridin-3-yl)-lH-pyrazol-4-yl, l-(pyridin-4-yl)-lH-pyrazol-4-yl, l-(pyridin-2-yl)-lH-pyrazol-4-yl, 1-[1-(N- methylaminocarbonyl)- 1 , 1 -dimethylmethyl] - 1 H-pyrazol-4-yl, 5 -fluoro- 1 -isopropyl- 1 H- pyrazol-4-y 1, 1 -(cyclopropylmethyl)- 1 H-pyrazol-5 -yl, 1 -(cyclopropylmethyl)- 1 H-pyrazol-3 - yl, 1 -(tetrahydro-2H-thiopyran-4-yl)- 1 H-pyrazol-4-yl, 1 -( 1 , 1 -dioxidotetrahydro-2H- thiopyran-4-yl)- lH-pyrazol-4-yl, 1 -((6-(3-oxobut- 1 -en- 1 -yl)pyridin-2-yl)methyl)- 1 H-pyrazol- 4-yl, 3-iodophenyl, 3-methyl-l ,2,4-oxadiazol-5-yl, 5-methyl-l ,3,4-oxadiazol-2-yl, 1H- imidazol-2-yl, 5-phenyloxazol-2-yl, l-cyclohexylpyrazol-4-yl, l-isopropylpyrazol-4-yl, biphenyl-3-yl, 3-((4-fluorophenyl)amino)phenyl, 3-(2-oxopyrrolidin-l-yl)phenyl, 3- (methylcarbony lamino)-5 -phenylphenyl, 3 -furyl, benzofuran-3 -yl, 1 -phenyl- 1 H-pyrazol-3 -yl, 5-cyclopropylfuran-2-yl, 2-methylfuran-3-yl, 1 -phenyl- lH-pyrazol-4-yl, 1 -ethyl- lH-pyrazol- 4-yl, l-methyl-6-oxo-l ,6-dihydropyridin-3-yl, furan-2-yl, 5-phenylfuran-2-yl, 1-isopropyl- lH-pyrazol-4-yl, pyrimidin-5-yl, 5-methylpyridin-3-yl, 1 -methyl- 1 H-pyrazol-3 -yl, 4- phenylfuran-2-yl, 2-fluorophenyl, 4-cyanophenyl, 4-methoxyphenyl, 4-(trifluoromethyl)- phenyl, 4-fluorophenyl, 1 -benzyl- lH-pyrazol-4-yl, 5-chloropyridin-3-yl, 5-fluoropyridin-3-yl, 1 -methyl- lH-pyrazol-5-yl, 4-(hydroxymethyl)furan-2-yl, 3-cyanophenyl, 2,5-dihydrofuran-3- yl, thiophen-3-yl, thiophen-2-yl, 1 -methyl- lH-pyrazol-4-yl, 5-methylfuran-2-yl, 5- (hydroxymethyl)furan-2-yl, 3-(trifluoromethyl)-phenyl, 3-methoxyphenyl, 3 -fluorophenyl, pyridin-3-yl , l-(methylsulfonyl)-lH-pyrazol-4-yl, l-cyclopentyl-lH-pyrazol-4-yl, 1- (thiophen-3 -ylmethyl)- lH-pyrazol-4-yl, 4-chloro-3-(morpholine-4-carbonyl)phenyl, 3- chloro-4-(cyclopropylaminocarbonyl)phenyl, 1 -( 1 -hydroxy-2-methylpropan-2-yl)- 1H- pyrazol-4-yl, 1 -(3-methoxybenzyl)- lH-pyrazol-4-yl, 1 -(pyridin-4-ylmethyl)- lH-pyrazol-4-yl, 1 -(2-chlorobenzyl)- lH-pyrazol-4-yl, 1 -(3-phenoxybenzyl)- 1 H-pyrazol-4-yl, 1 -(4- phenoxybenzyl)-lH-pyrazol-4-yl, 1 -cyclohexyl- lH-pyrazol-4-yl, 1 -(1 -phenylethyl)- 1H- pyrazol-4-yl, l-cyclobutyl-lH-pyrazol-4-yl, 1 -(sec-butyl)- lH-pyrazol-4-yl, 4-fluoro-3- (pyrrolidine- l-carbonyl)phenyl, l-(cyclopropylsulfonyl)-iH-pyrazol-3-yl, 1-

(cyclopropanecarbonyl)-l H-pyrazol-3 -yl, 1 -(2-cyclopropylethyl)- lH-pyrazol-4-yl, 1 -([ 1 , Γ- biphenyl] -3 -ylmethyl)- 1H- pyrazol-4-yl, l-phenethyl-lH-pyrazol-4-yl, l-(2- methoxybenzyl)- 1 H-pyrazol-4-yl, 1 -(4-methoxybenzyl)- 1 H-pyrazol-4-yl, 1 -(tert-butyl)- 1 H- pyrazol-4-yl, 3,4-dimethylphenyl, 3-chloro-4-ethoxyphenyl, 4-methoxy-3-methylphenyl, 2- methylbenzo[d]thiazol-5-yl, l-(2-phenoxybenzyl)-lH-pyrazol-4-yl, l-(phenylsulfonyl)-lH- pyrazol-4-yl, 1 -benzoyl- lH-pyrazol-4-yl, l-benzhydryl-lH-pyrazol-4-yl, l-([l ,l'-biphenyl]- 2-ylmethyl)- 1 H-pyrazol-4-yl, 1 -(cyclohexylmethyl)- 1 H-pyrazol-4-yl, 1 -(pyridin-3 -ylmethyl)- lH-pyrazol-4-yl, benzofuran-2-yl, 5-ethylfuran-2-yl, l-(2-methoxyethyl)-lH-pyrazol-4-yl, 1- (naphthalen- 1 -ylmethyl)- 1 H-pyrazol-4-yl, 1 -([ 1 , 1 '-biphenyl] -4-ylmethyl)- 1 H-pyrazol-4-yl, 3 - phenoxyphenyl, 3,4-dichlorophenyl, 3-chloro-4-methoxyphenyl, 3-methoxy-4-methylphenyl, l-(thiazol-4-ylmethyl)-lH-pyrazol-4-yl, lH-indazol-5-yl, 3,4-dimethoxyphenyl, 4-methoxy- 3,5-dimethylphenyl, l-(oxetan-3-yl)-lH-pyrazol-4-yl, l-(2-fluorobenzyl)-lH-pyrazol-4-yl, 1- (4-fluorobenzyl)- 1 H-pyrazol-4-yl, 1 -(methoxycarbonylmethyl)- 1 H-pyrazol-4-yl, 1 -(2- (dimethylamino)ethyl)- lH-pyrazol-4-yl, 3 -cyano-4-methylphenyl, benzo [d] [ 1 ,3 ] dioxol-5 -yl, 2,3-dihydrobenzofuran-5-yl, 1 -(3-fluorobenzyl)- lH-pyrazol-4-yl, 1 -(thiophen-2-ylmethyl)- lH-pyrazol-4-yl, 1 -(2,2,2-trifluoroethyl)- lH-pyrazol-4-yl, 1 -(3-chlorobenzyl)-lH-pyrazol-4- yl, l-isobutyl-lH-pyrazol-4-yl, l-(3,3,3-trifluoropropyl)-lH-pyrazol-4-yl, l-(difiuoromethyl)- lH-pyrazol-4-yl, l-(2-cyanoethyl)-lH-pyrazol-4-yl, 4-cyclopropylfuran-2-yl, 2,2- difluorobenzo[d][l ,3]dioxol-5-yl, 3-fluoro-4-(aminocarbonyl)phenyl, 3-fluoro-4- (methylsulfonyl)pheny 1, 3 -chloro-4-(trifluoromethoxy)phenyl, 5 -fluoro-3 - (aminocarbonyl)phenyl, 3 -(hydroxymethyl)-4-methoxyphenyl, 1 -(methy lsulfonyl)- 1 H-pyrrol- 3-yl, 1 -methyl- 1 H-pyrrol-3 -yl, 3-bromophenyl, 3-(l-methylpyrazol-4-yl)phenyl, 3-(l- isopropylpyrazol-4-yl)phenyl, 4-phenylphenyl, 4-(4-fluoroanilino)phenyl, 3-(tert- butoxycarbonylamino)phenyl, 1 -acetyl- 1 ,2, 3, 6-tetrahydropyridin-4-yl, l-propionyl-1 ,2,3,6- tetrahydropyridin-4-yl, 1 -acryloyl- 1 ,2,3 ,6-tetrahydropyridin-4-yl, 1 -methyl- 1 ,2,3,6- tetrahydropyridin-4-yl, 1 -((2-methylthiazol-4-yl)methyl)- 1 H-pyrazol-4-yl, 1 -(2- (acetylamino)ethyl)-lH-pyrazol-4-yl, 3,5-dichlorophenyl, 2-fluoro-4-(methylsulfonyl)phenyl, l-(tert-pentyl)-lH-pyrazol-4-yl, 3-(2-morpholinoethyl)phenyl, 3-(2- (dimethylamino)ethyl)phenyl, l-(l-(thiazol-4-yl)ethyl)-lH-pyrazol-4-yl, l-(tetrahydro-2H- pyran-4-yl)- 1 H-pyrazol-4-yl, 3 -methoxy-4-(trifluoromethyl)phenyl, 3 -methoxycarbonyl-4- chlorophenyl, 4-(trifluoromethoxy)phenyl, 3-methyl-4-(trifluoromethoxy)phenyl, 4- cyclopropyl-3-(trifluoromethyl)phenyl, 2,2-dimethyl-2,3-dihydrobenzofuran-5-yl, 3,5- dimethoxyphenyl, 3,4-difluorophenyl, 4-biphenyl, 3 -chloro-5 -fluorophenyl, 3,5- bis(trifiuoromethyl)phenyl, 3-fiuoro-5-methoxyphenyl, 3-(aminocarbonyl)phenyl, 4- (cyclopropylmethoxy)phenyl, 2-fiuoro-5-(benzyloxycarbonyl)phenyl, 3-(lH-pyrazol-l- yl)phenyl, l-(2-hydroxycyclopentyl)-lH-pyrazol-4-yl, 3-(N-methylaminosulfonyl)phenyl, 4- (2-hydroxypropan-2-yl)phenyl, 2-(trifiuoromethyl)pyridin-4-yl, 6-phenoxypyridin-3-yl, 2- methoxypyridin-4-yl, 4-methyl-2-phenylthiazol-5-yl, 3-amino-5-cyanophenyl, 1- (tetrahydrofuran-3-yl, 3-(N-ethylaminocarbonyl)phenyl, 3-(aminocarbonylmethyl)phenyl, 6- phenylpyridin-3 -yl, 1 -(tetrahydro-2H-pyran-3 -yl)- 1 H-pyrazol-4-yl, 1 -( 1 -methoxypropan-2- yl)- 1 H-pyrazol-4-yl, 1 -(2-ethoxy ethyl)- 1 H-pyrazol-4-yl, 1 -acetyl-2,5 -dihydro- 1 H-pyrrol-3 -yl, 1 -acetyl- 1 ,2,5 ,6-tetrahydropyridin-3-yl, 1 -propionyl- 1 ,2,5 ,6-tetrahydropyridin-3-yl, 1 - propionyl-2,5-dihydro-lH-pyrrol-3-yl, l-((l S,3S)-3-hydroxycyclobutyl)-lH-pyrazol-4-yl, 2,5-dihydro-lH-pyrrol-3-yl, l ,2,5,6-tetrahydropyridin-3-yl, 1 -methyl- 1 ,2,5, 6- tetrahydropyridin-3-yl, l-acryloyl-l ,2,5,6-tetrahydropyridin-3-yl, l-acryloyl-2,5-dihydro-lH- pyrrol-3-yl, 4-chloro-3,5-dimethylphenyl, 4-cyano-3-methylphenyl, l-oxo-2,3-dihydro-lH- inden-5-yl, 3,4-bis(trifiuoromethyl)phenyl, 3-methyl-4-(trifiuoromethyl)phenyl, 1- (benzo[b]thiophen-7-ylmethyl)-lH-pyrazol-4-yl, 4-fluoro-3-(N- cyclohexylaminocarbonyl)phenyl, 4-morpholinophenyl, 4-(4-(iert-butoxycarbonyl)piperazin- l-yl)phenyl, 3-chloro-5-methylphenyl, 3-(methylsulfonyl)phenyl, 4-(methylsulfonylamino)- phenyl, 4-(morpholinomethyl)phenyl, 3-morpholinophenyl, l-(2-(vinylcarbonylamino)ethyl)- lH-pyrazol-4-yl, l-(2-aminoethyl)-lH-pyrazol-4-yl, 3-cyclopropyl-4-methylphenyl, 3- ethoxyphenyl, 3-(hydroxymethyl)phenyl, l-(2-(iert-butoxycarbonylamino)ethyl)-lH-pyrazol- 4-yl, 3-phenethoxyphenyl, l ,2,3,6-tetrahydropyridin-4-yl, l-(2-(vinylsulfonylamino)ethyl)- lH-pyrazol-4-yl, 4-(phenylamino)phenyl, 3 -methyl- lH-pyrazol-4-yl, 4-(benzyloxy)phenyl, 3,5-difluorophenyl, 3-fluoro-5-trifluoromethylphenyl, 3-(ethylsulfonyl)phenyl, 3- (trifluoromethoxy)-phenyl, l-(thiazol-5-ylmethyl)-lH-pyrazol-4-yl, p-tolyl, 4- cyclopropylphenyl, 4-(ethylsulfonyl)-phenyl, 1 -(6-vinylpyridin-2-yl)methyl)- 1 H-pyrazol-4-yl, 6-(benzyloxy)pyridin-3-yl, 1 -(iert-butoxycarbonyl)-2,5-dihydro- lH-pyrrol-3-yl, 1 -(2- hydroxy- 1 -phenylethyl)- 1 H-pyrazol-4-yl, 1 -(2-cyano- 1 -phenylethyl)- 1 H-pyrazol-4-yl, 6- cyclopropylpyridin-3-yl, 4-cyano-3-methoxyphenyl, 4-methoxy-3-(trifluoromethyl)phenyl, 4- chlorophenyl, 1 -(3 ,4-difluorobenzyl)- 1 H-pyrazol-4-yl, 4-methyl-3 -(trifluoromethyl)phenyl, 4-(pyrrolidine-l-carbonyl)phenyl, 4-(isopropylamino-carbonyl)phenyl, 4-(4-methylpiperazin-

1- yl)phenyl, 3-chloro-5-cyanophenyl, 3 -(pyrrolidine- l-carbonyl)phenyl, 3- (methylsulfonylaminomethyl)phenyl, 3 -( 1 H-pyrazol-5 -yl)phenyl, 4-(methylsulfonyl)phenyl, 4-(cyclopropylaminocarbonyl)phenyl, l-(2-fluoroethyl)-lH-pyrazol-4-yl, 3- (cyclopropylmethoxy)phenyl, 3-(benzyloxy)phenyl, 3-(morpholinomethyl)phenyl, 3- (phenoxymethyl)phenyl, 1 -(3 -fluorophenyl)- lH-pyrazol-4-yl, 2-cyclopropylvinyl, 6-

(trif uoromethyl)pyridin-3-yl, l-(4-f uorophenyl)-lH-pyrazol-4-yl, 2,4-dimethylthiazol-5-yl, 1 -propyl- 1 H-pyrazol-4-yl, 1 -butyl- 1 H-pyrazol-4-yl, 1 -(2-(phenylamino)ethyl)- 1 H-pyrazol-4- yl, 4-(aminocarbonyl)phenyl, 4-(N-methylaminocarbonyl)phenyl, 3-f uoro-4-(N- methylamino-carbonyl)phenyl, 1 -(2-(3 ,3 -difluoroazetidin- 1 -yl)ethyl)- 1 H-pyrazol-4-yl, 1 -(2- (3 ,3-difluoropyrrolidin- 1 -yl)ethyl)- 1 H-pyrazol-4-yl, 1 -(2-((2,2,2-trif uoroethyl)amino)ethyl)- lH-pyrazol-4-yl, 1-propenyl, 3-(methylcarbonylamino)phenyl, 4-

(methylsulfonylamino)phenyl, 4-(morpholine-4-carbonyl)phenyl, 4-(4-acetylpiperazin- 1 - yl)phenyl, l-(2,2-dif uoroethyl)-lH-pyrazol-4-yl, 5-isopropylfuran-2-yl, l-(3,3- dif uorocyclopentyl)- 1 H-pyrazol-4-yl, 1 -(( 1 S ,3R)-3 -hydroxy cyclopentyl)- 1 H-pyrazol-4-yl, 1 - ((l S,3S)-3-hydroxycyclopentyl)-lH-pyrazol-4-yl, 3-(lH-pyrazol-4-yl)phenyl, 5-bromofuran-

2- yl, 3-(phenylamino)phenyl, 2-methylthiazol-5-yl, 3-(phenylethynyl)phenyl, 3- phenethylphenyl, 1 -(3 -fluorocyclopentyl)- 1 H-pyrazol-4-yl, 1 -( 1 -methoxy-2-methylpropan-2- yl)- 1 H-pyrazol-4-yl, 1 -( 1 -acryloylazetidin-3 -yl)- 1 H-pyrazol-4-yl, 1 -( 1 -propionylazetidin-3 - yl)-lH-pyrazol-4-yl, 6-oxo-l ,6-dihydropyridin-3-yl, 4-(piperazin-l-yl)phenyl, l-(l-fluoro-2- methylpropan-2-yl)-lH-pyrazol-4-yl, 3 -(trifluoromethyl)- lH-pyrazol-4-yl, 3,5- dimethylphenyl, 4-(morpholinosulfonyl)phenyl, 3-(4-methylpiperazine-l-carbonyl)phenyl, 3- (2-hydroxypropan-2-yl)phenyl, l-isopropyl-3 -methyl- lH-pyrazol-4-yl, 1 -isopropyl-5 -methyl- lH-pyrazol-4-yl, 3 -cyclopropyl- 1 H-pyrazol-5 -yl, 5-methoxycarbonylpyrrol-3-yl, 3- cyclopropyl- 1 -isopropyl- 1 H-pyrazol-5 -yl, 5 -cyclopropyl- 1 -isopropyl- 1 H-pyrazol-3 -yl, 1 - isopropyl-5 -(methoxycarbonyl)pyrrol-3 -yl, 1 -methyl-3 -(trifluoromethyl)- 1 H-pyrazol-5 -yl, 1 - isopropyl- 1 H-pyrazol-3 -yl, 1 -cyclopentyl-5 -cyclopropyl- 1 H-pyrazol-3 -yl, 1 -cyclopentyl-3 - cyclopropyl- 1 H-pyrazol-5 -yl, 1-cyclopentyl-lH -pyrazol-3-yl, 1-isopropyl-l H-pyrazol-5 -yl, 1 -isopropyl-5 -(N-methylaminocarbonyl)pyrrol-3 -yl, 1 -isopropyl-5 -(N,N- dimethylaminocarbonyl)-pyrrol-3-yl, l-(2-cyclopropylethyl)-l H-pyrazol-3 -yl, l-(2- cyclopropylethyl)- 1 H-pyrazol-5 -yl, 1 -ethyl- 1 H-pyrazol-3 -yl, 3-(3,3-dimethyl-2- oxopyrrolidin-l-yl)phenyl, 3-(2-oxo-3-phenylpyrrolidin-l-yl)phenyl, 3-((E)-styryl)phenyl, 3- (3 -cyanophenyl)phenyl, 3 -(3 -(methylsulfonylamino)phenyl)phenyl, 3 -(4- (methylsulfonylamino)phenyl)phenyl, or 3-(4-(N-methylaminosulfonyl)phenyl)phenyl.

1 1. The compound of any one of claims 2-9 wherein R³ is pyrazol-4-yl, substituted with R^x.

12. The compound of any one of claims 2-9 wherein R³ is phenyl that is substituted with oxo, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, heterocycle, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -O- C(0)-R^v, -0-C(0)-0-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -0-C(0)-N(R^v)₂, - N(R^v)-C(0)-OR^v, -N(R^v)-C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-S(0)- R^v, -N(R^v)-S(0)₂-R^v, -N(R^v)-S(0)-N(R^v)₂, or -N(R^v)-S(0)₂-N(R^v)₂,wherein any Ci_₆alkyl, C₂ ₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocycle is optionally substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, - N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -O-C(O)- R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)- R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)-R^v, -N(R^v)-S(0)₂-R^v, or C_halky, that is optionally substituted with one or more groups independently selected from oxo and halo.

13. The compound of any one of claims 2-9 and 1 1-12 wherein R^x is Ci_6alkyl, that is substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -O-C(O)- R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)- R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)-R^v, and -N(R^v)-S(0)₂-R^v.

14. The compound of any one of claims 2-9 and 11-12 wherein R^x is Ci_6alkyl that is substituted with R^xa.

15. The compound of any one of claims 2-9 and 11-12 wherein R^x is C₂_6alkenyl or C₂_₆alkynyl, wherein any C₂_₆alkenyl and C₂_₆alkynyl is optionally substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, - S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, - S(0)₂-R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)-R^v, and -N(R^v)-S(0)₂-R^v .

16. The compound of any one of claims 2-9 and 11-12 wherein R^x is selected from C₂_₆alkenyl, C₂_6alkynyl, carbocyclyl, aryl, heteroaryl, heterocycle, -F, -CI, -Br, -I, -N0₂, -

N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -O- C(0)-0-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -0-C(0)-N(R^v)₂, -N(R^v)-C(0)-OR^v, -N(R^v)-C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-S(0)-R^v, -N(R^v)-S(0)₂- R^v, -N(R^v)-S(0)-N(R^v)₂, and -N(R^v)-S(0)₂-N(R^v)₂,wherein any C₂^alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocycle is optionally substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(O)- N(R^V)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂- R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)- R^v, -N(R^v)-S(0)₂-R^v, and Ci_₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo.

17. The compound of any one of claims 2-9 wherein R³ is heteroaryl that is substituted with oxo, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, heterocycle, -F, -CI, -Br, -I, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -0-C(0)-0-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -O- C(0)-N(R^v)₂, -N(R^v)-C(0)-OR^v, -N(R^v)-C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)- R^v, -N(R^v)-S(0)-R^v, -N(R^v)-S(0)₂-R^v, -N(R^v)-S(0)-N(R^v)₂, or -N(R^v)-S(0)₂-N(R^v)₂; wherein any Ci_₆alkyl is substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -O- C(0)-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R C(0)-R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)-R^v, and -N(R^v)-S(0)₂-R^v; and wherein any C₂ ₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocycle is optionally substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, - N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -O-C(O)-

R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)- R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)-R^v, -N(R^v)-S(0)₂-R^v, and Ci_₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo.

18. The compound of any one of claims 2-9 wherein R³ is a 5-membered heteroaryl that is substituted with oxo, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, heterocycle, -F, -CI, -Br, -I, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, - S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -0-C(0)-0-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, - S(0)₂-R^v, -0-C(0)-N(R^v)₂, -N(R^v)-C(0)-OR^v, -N(R^v)-C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R C(0)-R^v, -N(R^v)-S(0)-R^v, -N(R^v)-S(0)₂-R^v, -N(R^v)-S(0)-N(R^v)₂, or -N(R^v)-S(0)₂-N(R^v)₂; wherein any Ci_₆alkyl, is substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -0-C(0)-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -C(0)-N(R^v)₂, -S(0)₂- N(R^V)₂, -N(R^v)-C(0)-R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)-R^v, and -N(R^v)-S(0)₂-R^v; and wherein any C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocycle is optionally substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -O- C(0)-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R C(0)-R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)-R^v, -N(R^v)-S(0)₂-R^v, and

that is optionally substituted with one or more groups independently selected from oxo and halo.

19. The compound of any one of claims 2-9 wherein R³ is phenyl that is substituted with oxo, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, heterocycle, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -O- C(0)-R^v, -0-C(0)-0-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -0-C(0)-N(R^v)₂, - N(R^v)-C(0)-OR^v, -N(R^v)-C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)-R^v, -N(R^v)-S(0)- R^v, -N(R^v)-S(0)₂-R^v, -N(R^v)-S(0)-N(R^v)₂, or -N(R^v)-S(0)₂-N(R^v)₂; wherein any Ci_₆alkyl, is substituted with one or more groups independently selected from R^xa, oxo,

halo, -N0₂, -N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -O- C(0)-R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R C(0)-R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)-R^v, and -N(R^v)-S(0)₂-R^v; and wherein any C₂ ₆alkenyl, C₂_₆alkynyl, carbocyclyl, aryl, heteroaryl, and heterocycle is optionally substituted with one or more groups independently selected from R^xa, oxo, halo, -N0₂, - N(R^V)₂, -CN, -C(0)-N(R^v)₂, -S(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -0-R^v, -S-R^v, -O-C(O)- R^v, -C(0)-R^v, -C(0)-0-R^v, -S(0)-R^v, -S(0)₂-R^v, -C(0)-N(R^v)₂, -S(0)₂-N(R^v)₂, -N(R^v)-C(0)- R^v, -N(R^v)-C(0)-OR^v, -N(R^v)-S(0)-R^v, -N(R^v)-S(0)₂-R^v, and Ci_₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo.

20. The compound of any one of claims 2-19 wherein R⁴ is H, methyl, ethyl, propyl, cyclopropylmethyl, 2-hydroxyethyl, 2-(dimethylmino)ethyl, phenyl, benzyl, or 2- methoxy ethyl.

21. The compound of any one of claims 2-20 wherein R³ is not phenyl, fluorophenyl, chlorophenyl, pyridyl, nitrophenyl, or propylisoxazole.

22. A composition comprising a compound as described in any one of claims 1-21 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

23. The composition according to claim 22, in combination with an additional therapeutic agent.

24. The composition according to claim 23, wherein the additional therapeutic agent is a chemotherapeutic agent.

25. A method of increasing efficacy of a cancer treatment comprising a cytotoxic agent in an individual comprising administering to the individual (a) an effective amount of a compound as described in any one of claims 1-21 or a pharmaceutically acceptable salt thereof, and (b) an effective amount of the cytotoxic agent.

26. A method of treating an individual with cancer who has an increased likelihood of developing resistance to a cytotoxic agent comprising administering to the individual (a) an effective amount of a compound as described in any one of claims 1-21 or a pharmaceutically acceptable salt thereof, and (b) an effective amount of the cytotoxic agent.

27. A method of treating cancer in an individual comprising administering to the individual (a) a a compound as described in any one of claims 1-21 or a pharmaceutically acceptable salt thereof, and (b) cytotoxic agent.

28. The method of claim 27, wherein the respective amounts of the compound as described in any one of claims 1-21 or a pharmaceutically acceptable salt thereof and the cytotoxic agent are effective to increase the period of cancer sensitivity and/or delay the development of cell resistance to the cytotoxic agent.

29. A method of increasing efficacy of a cancer treatment comprising a cytotoxic agent in an individual comprising administering to the individual an effective amount of a compound as described in any one of claims 1-21 or a pharmaceutically acceptable salt thereof.

30. A method of treating cancer in an individual wherein cancer treatment comprises administering to the individual (a) an effective amount of a compound as described in any one of claims 1-21 or a pharmaceutically acceptable salt thereof and (b) a cytotoxic agent, wherein the cancer treatment has increased efficacy compared to a standard treatment comprising administering an effective amount of the cytotoxic agent without (in the absence of) the compound as described in any one of claims 1-21 or the pharmaceutically acceptable salt thereof.

31. A method of delaying and/or preventing development of cancer resistant to a cytotoxic agent in an individual, comprising administering to the individual an effective amount of a compound as described in any one of claims 1-21 or a pharmaceutically acceptable salt thereof.

32. A method of treating an individual with cancer who has increased likelihood of developing resistance to a cytotoxic agent comprising administering to the individual (a) an effective amount of a compound as described in any one of claims 1-21 or a

pharmaceutically acceptable salt thereof and (b) an effective amount of the cytotoxic agent.

33. A method of increasing sensitivity to a cytotoxic agent in an individual with cancer comprising administering to the individual an effective amount of a compound as described in any one of claims 1-21 or a pharmaceutically acceptable salt thereof.

34. A method of extending the period of a cancer therapy agent sensitivity in an individual with cancer comprising administering to the individual an effective amount of a compound as described in any one of claims 1-21 or a pharmaceutically acceptable salt thereof.

35. A method of extending the duration of response to a cancer therapy in an individual with cancer comprising administering to the individual an effective amount of a compound as described in any one of claims 1-21 or a pharmaceutically acceptable salt thereof.

36. The method of any one of claims 28, 29, 31 , and 33 wherein the method further comprises (b) administering to the individual an effective amount of the cytotoxic agent.

37. The method of any one of claims 25-36, wherein the cytotoxic agent is a chemotherapeutic agent.

38. The method of claim 37 wherein the chemotherapeutic agent is a taxane.

39. The method of claim 38, wherein the taxane is paclitaxel or docetaxel.

40. The method of claim 35 wherein the chemotherapeutic agent is a platinum agent.

41. The method of any one of claims 25-36, wherein the cytotoxic agent is selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, ; inhibitors of LDH-A; inhibitors of fatty acid biosynthesis; cell cycle signaling inhibitors; HDAC inhibitors, proteasome inhibitors; and inhibitors of cancer metabolism.

42. The method of claim 37 wherein the chemotherapeutic agentis an antagonist of EGFR.

43. The method of claim 42, wherein the antagonist of EGFR is N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine or a pharmaceutically acceptable salt thereof.

44. The method of claim 37, wherein the chemotherapeutic agentis a RAF inhibitor.

45. The method of claim 44, wherein the RAF inhibitor is a BRAF and/or CRAF inhibitor.

46. The method of claim 44, wherein the RAF inhibitor is vemurafenib.

47. The method of claim 37 wherein the chemotherapeutic agent is a PI3K inhibitor.

48. A method of treating a proliferative disorder in an individual comprising administering to the individual an effective amount of a compound as described in any one of claims 1-21 or a pharmaceutically acceptable salt thereof.

49. The method of claim 48 wherein the proliferative disorder is lung cancer, melanoma, colorectal cancer, pancreatic cancer, and/or breast cancer.

50. A compound as described in any one of claims 1-21, or a pharmaceutically acceptable salt thereof, for use in medical therapy.

51. A compound as described in any one of claims 1-20, or a pharmaceutically acceptable salt thereof, for the prophylactic or therapeutic treatment of a proliferative disorder.

52. The use of a compound as described in any one of claims 1-21, or a pharmaceutically acceptable salt thereof, to prepare a medicament useful for treating a proliferative disorder.

53. The compound or use of any one of claims 51-52 wherein the proliferative disorder is lung cancer, melanoma, colorectal cancer, pancreatic cancer, and/or breast cancer.