Pyrrolopyridines useful as inhibitors of protein kinase

This application claims the benefit of U.S. Provisional Application 60/683,554, filed May 20, 2005, which is herein incorporated by reference in its entirety.

The present invention relates to compounds useful as inhibitors of Janus kinases (JAK) and Rho-associated coiled-coil forming protein serine/threonine kinases (ROCK). The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

The Janus kinases (JAK) are a family of tyrosine kinases consisting of JAK1, JAK2, JAK3 and TYK2. The JAKs play a critical role in cytokine signaling. The down-stream substrates of the JAK family of kinases include the signal transducer and activator of transcription (STAT) proteins. JAK3 has been implicated in the mediation of many abnormal immune responses such as allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis as well as in solid and hematologic malignancies such as leukemias and lymphomas. JAK2 has been implicated in myeloproliferative disorders, which include polycythemia vera, essential thrombocythemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome and systematic mast cell disease.

The Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK) family are effectors of Ras-related small GTPase Rho. The ROCK family includes p160ROCK (ROCK-1), ROKα/Rho-kinase/ROCK-II, protein kinase PKN, and citron and citron kinase. ROCK has been implicated in various diseases and disorders including hypertension, cerebral vasospasm, coronary vasospasm, bronchial asthma, erectile dysfunction, glaucoma, vascular smooth muscle cell proliferation, myocardial hypertrophy, malignoma, ischemia/reperfusion-induced injury, endothelial dysfunction, Crohn's Disease and colitis, neurite outgrowth, Raynaud's Disease, angina, Alzheimer's disease, atherosclerosis, and cardiac hypertrophy and perivascular fibrosis.

Accordingly, there is a great need to develop compounds useful as inhibitors of protein kinases. In particular, it would be desirable to develop compounds that are useful as inhibitors of JAK family kinases and ROCK family kinases.

It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of protein kinases, particularly the JAK family kinases and ROCK family kinases. These compounds have the general formula I:

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , Z and Q are as defined below.

These compounds, and pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of a variety of disorders, including allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis, multiple sclerosis, solid and hematologic malignancies such as leukemias and lymphomas, myeloproliferative disorders, hypertension, cerebral vasospasm, coronary vasospasm, bronchial asthma, erectile dysfunction, glaucoma, vascular smooth muscle cell proliferation, myocardial hypertrophy, malignoma, ischemia/reperfusion-induced injury, endothelial dysfunction, Crohn's Disease and colitis, neurite outgrowth, Raynaud's Disease, angina, Alzheimer's disease, atherosclerosis, and cardiac hypertrophy and perivascular fibrosis.

The compounds provided by this invention are also useful for the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors.

Definitions and General Terminology

As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75 th Ed. 1994. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5 th Ed., Smith, M. B. and March, J., eds. John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general, the term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position.

As described herein, when the term “optionally substituted” precedes a list, said term refers to all of the subsequent substitutable groups in that list. If a substituent radical or structure is not identified or defined as “optionally substituted”, the substituent radical or structure is unsubstituted. For example, if X is halogen; optionally substituted C 1-3 alkyl or phenyl; X may be either optionally substituted alkyl or optionally substituted phenyl. Likewise, if the term “optionally substituted” follows a list, said term also refers to all of the substitutable groups in the prior list unless otherwise indicated. For example: if X is halogen, C 1-3 alkyl or phenyl wherein X is optionally substituted by J X , then both C 1-3 alkyl and phenyl may be optionally substituted by J X . As is apparent to one having ordinary skill in the art, groups such as H, halogen, NO 2 , CN, NH 2 , OH, or OCF 3 would not be included because they are not substitutable groups.

Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, preferably, their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and In yet other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Further examples of aliphatic groups include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, and sec-butyl.

The term “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C 3 -C 8 hydrocarbon or bicyclic C 9 -C 12 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule, and wherein any individual ring in said bicyclic ring system has 3-7 members. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Further examples of aliphatic groups include cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cycloheptenyl.

The term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” as used herein refers to a monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are an independently selected heteroatom and that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. In some embodiments, the “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members.

Examples of heterocyclic rings include, but are not limited to, the following monocycles: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl; and the following bicycles: 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and 1,3-dihydro-imidazol-2-one.

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), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl).

The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems having a total of six to fourteen ring members, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 3 to 7 ring members and that has a single point of attachment to the rest of the molecule. The term “aryl” may be used interchangeably with the term “aryl ring”. Examples of aryl rings would include phenyl, naphthyl, and anthracene.

The term “heteroaryl”, used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, wherein each ring in the system contains 3 to 7 ring members and that has a single point of attachment to the rest of the molecule. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.

Further examples of heteroaryl rings include the following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, and the following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

In some embodiments, an aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group are selected from those listed in the definition of J Q , J R , J V , J U and J X below. Other suitable substituents include: halogen; —R o ; —OR o ; —SR o ; 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl (Ph) optionally substituted with R o ; —O(Ph) optionally substituted with R o ; —(CH 2 ) 1-2 (Ph), optionally substituted with R o ; —CH═CH(Ph), optionally substituted with R o ; —NO 2 ; —CN; —N(R o ) 2 ; —NR o C(O)R o ; —NR o C(S)R o ; —NR o C(O)N(R o ) 2 ; —NR o C(S)N(R o ) 2 ; —NR o CO 2 R o ; —NR o NR o C(O)R o ; —NR o NR o C(O)N(R o ) 2 ; —NR o NR o CO 2 R o ; —C(O)C(O)R o ; —C(O)CH 2 C(O)R o ; —CO 2 R o ; —C(O)R o ; —C(S)R o ; —C(O)N(R o ) 2 ; —C(S)N(R o ) 2 ; —OC(O)N(R o ) 2 ; —OC(O)R o ; —C(O)N(OR o ) R o ; —C(NOR o ) R o ; —S(O) 2 R o ; —S(O) 3 R o ; —SO 2 N(R o ) 2 ; —S(O)R o ; —NR o SO 2 N(R o ) 2 ; —NR o SO 2 R o ; —N(OR o )R o ; —C(═NH)—N(R o ) 2 ; or —(CH 2 ) 0-2 NHC(O)R o ; wherein each independent occurrence of R o is selected from hydrogen, optionally substituted C 1-6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, —O(Ph), or —CH 2 (Ph), or, two independent occurrences of R o , on the same substituent or different substituents, taken together with the atom(s) to which each R o group is bound, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group of R o are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), O(haloC 1-4 aliphatic), or haloC 1-4 aliphatic, wherein each of the foregoing C 1-4 aliphatic groups of R o is unsubstituted.

In some embodiments, an aliphatic or heteroaliphatic group, or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic or heteroaliphatic group, or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the following: ═O, ═S, ═NNHR*, ═NN(R*) 2 , ═NNHC(O)R*, ═NNHCO 2 (alkyl), ═NNHSO 2 (alkyl), or ═NR*, where each R* is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic. Optional substituents on the aliphatic group of R* are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), O(halo C 1-4 aliphatic), or halo(C 1-4 aliphatic), wherein each of the foregoing C 1-4 aliphatic groups of R* is unsubstituted.

In some embodiments, optional substituents on the nitrogen of a non-aromatic heterocyclic ring include —R + , —N(R + ) 2 , —C(O)R + , —CO 2 R + , —C(O)C(O)R + , —C(O)CH 2 C(O)R + , —SO 2 R + , —SO 2 N(R + ) 2 , —C(═S)N(R + ) 2 , —C(═NH)—N(R + ) 2 , or —NR + SO 2 R + ; wherein R + is hydrogen, an optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted —O(Ph), optionally substituted —CH 2 (Ph), optionally substituted —(CH 2 ) 1-2 (Ph); optionally substituted —CH═CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, two independent occurrences of R + , on the same substituent or different substituents, taken together with the atom(s) to which each R + group is bound, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group or the phenyl ring of R + are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), O(halo C 1-4 aliphatic), or halo(C 1-4 aliphatic), wherein each of the foregoing C 4 aliphatic groups of R + is unsubstituted.

As detailed above, in some embodiments, two independent occurrences of R o (or R + , or any other variable similarly defined herein), may be taken together with the atom(s) to which each variable is bound to form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring. Exemplary rings that are formed when two independent occurrences of R o (or R + , or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of R o (or R + , or any other variable similarly defined herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R o ) 2 , where both occurrences of R o are taken together with the nitrogen atom to form a piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two independent occurrences of R o (or R + , or any other variable similarly defined herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for example where a phenyl group is substituted with two occurrences of

these two occurrences of R o are taken together with the oxygen atoms to which they are bound to form a fused 6-membered oxygen containing ring:

It will be appreciated that a variety of other rings can be formed when two independent occurrences of R o (or R + , or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound and that the examples detailed above are not intended to be limiting.

In some embodiments, an alkyl or aliphatic chain can be optionally interrupted with another atom or group. This means that a methylene unit of the alkyl or aliphatic chain is optionally replaced with said other atom or group. Examples of such atoms or groups would include, but are not limited to, —NR—, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NR—, —C(═N—CN), —NRCO—, —NRC(O)O—, —SO 2 NR—, —NRSO 2 —, —NRC(O)NR—, —OC(O)NR—, —NRSO 2 NR—, —SO—, or —SO 2 —, wherein R is defined herein. Unless otherwise specified, the optional replacements form a chemically stable compound. Optional interruptions can occur both within the chain and at either end of the chain; i.e. both at the point of attachment and/or also at the terminal end. Two optional replacements can also be adjacent to each other within a chain so long as it results in a chemically stable compound. Unless otherwise specified, if the replacement or interruption occurs at the terminal end, the replacement atom is bound to an H on the terminal end. For example, if —CH 2 CH 2 CH 3 were optionally interrupted with —O—, the resulting compound could be —OCH 2 CH 3 , —CH 2 OCH 3 , or —CH 2 CH 2 OH.

As described herein, a bond drawn from a substituent to the center of one ring within a multiple-ring system (as shown below), represents substitution of the substituent at any substitutable position in any of the rings within the multiple ring system. For example, Figure a represents possible substitution in any of the positions shown in Figure b.

This also applies to multiple ring systems fused to optional ring systems (which would be represented by dotted lines). For example, in Figure c, X is an optional substituent both for ring A and ring B.

If, however, two rings in a multiple ring system each have different substituents drawn from the center of each ring, then, unless otherwise specified, each substituent only represents substitution on the ring to which it is attached. For example, in Figure d, Y is an optionally substituent for ring A only, and X is an optional substituent for ring B only.

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 within the scope of the invention.

Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. 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 except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

Description of Compounds of the Invention

The present invention relates to a compound of formula I:

or a pharmaceutically acceptable salt thereof

wherein

Q is a 3-8 membered saturated, partially saturated, or unsaturated monocyclic ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur; or an 8-12 membered bicyclic ring having 0-6 heteroatoms selected from nitrogen, oxygen, or sulfur; wherein Q is optionally substituted with 1-10 occurrences of J Q ;

Z is a bond, NH, N(C 1-3 aliphatic) or C═CH 2 ;

R 1 is —(C 1-2 aliphatic) p -R 4 wherein each R 1 is optionally substituted with 1-3 occurrences of J;

R 2 is —(C 1-2 aliphatic) d -R 5 wherein each R 1 is optionally substituted with 1-3 occurrences of J;

R 3 is halogen, —CN, —NO 2 or —(U) m —X, wherein

U is a C 1-6 aliphatic, wherein up to two methylene units are optionally and independently replaced by G U and wherein U is optionally substituted with 1-4 J U ; X is H, halogen, CN, NO 2 , S(O)R, SO 2 R, C 1-4 haloaliphatic, or a group selected from C 1-6 aliphatic, a C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl; wherein said group is optionally substituted with 1-4 J X ; G U is —NH—, —NR—, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR—, —C(═N—CN)—, —NHCO—, —NRCO—, —NHC(O)O—, —NRC(O)O—, —SO 2 NH—, —SO 2 NR—, —NHSO 2 —, —NRSO 2 —, —NHC(O)NH—, —NRC(O)NH—, —NHC(O)NR—, —NRC(O)NR, —OC(O)NH—, —OC(O)NR—, —NHSO 2 NH—, —NRSO 2 NH—, —NHSO 2 NR—, —NRSO 2 NR—, —SO—, or —SO 2 —;

R 4 is H, halogen, CN, NH 2 , NO 2 , CF 3 , C 1-3 aliphatic, cyclopropyl, NCH 3 , OCH 3 , —C(═O)NH 2 , —C(═O)CH 3 , —NC(═O)CH 3 , or OH;

R 5 is H, halogen, CN, NH 2 , NO 2 , CF 3 , C 1-3 aliphatic, cyclopropyl, NCH 3 , OCH 3 , —C(═O)NH 2 , —C(═O)CH 3 , —NC(═O)CH 3 , or OH;

J Q is halogen, OCF 3 , —(V n )—R″, —(V n )—CN, —(V n )—NO 2 , or —(V n )—(C 1-4 haloaliphatic), wherein J Q is not H;

V is a C 1-10 aliphatic, wherein up to three methylene units are replaced by G V , wherein G V is selected from —NH—, —NR—, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR—, —C(═N—CN), —NHCO—, —NRCO—, —NHC(O)O—, —NRC(O)O—, —SO 2 NH—, —SO 2 NR—, —NHSO 2 —, —NRSO 2 —, —NHC(O)NH—, —NRC(O)NH—, —NHC(O)NR—, —NRC(O)NR, —OC(O)NH—, —OC(O)NR—, —NHSO 2 NH—, —NRSO 2 NH—, —NHSO 2 NR—, —NRSO 2 NR—, —SO—, or —SO 2 —; and wherein V is optionally substituted with 1-6 occurrences of J V ;

R″ is H, or is an optionally substituted group selected from C 1-6 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl; or two R″ groups, on the same substituent or different substituents, together with the atom(s) to which each R″ group is bound, form an optionally substituted 3-8 membered heterocyclyl; wherein each optionally substituted R″ group is independently and optionally substituted with 1-6 occurrences of J R ;

R is an optionally substituted group selected from C 1-6 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl; or two R groups, on the same substituent or different substituents, together with the atom(s) to which each R group is bound, form an optionally substituted 3-8 membered heterocyclyl; wherein each R group is independently and optionally substituted with 1-4 occurrences of J R ;

J V , J U , J X , and J R are each independently selected from halogen, L, -(L n )-R′, -(L n )-N(R′) 2 , -(L n )-SR′, -(L n )-OR′, -(L n )-(C 3-10 cycloaliphatic), -(L n )-(C 6-10 aryl), -(L n )-(5-10 membered heteroaryl), -(L n )-(5-10 membered heterocyclyl), oxo, C 1-4 haloalkoxy, C 1-4 haloalkyl, -(L n )-NO 2 , -(L n )-CN, -(L n )-OH, -(L n )-CF 3 , —CO 2 R′, —CO 2 H, —COR′, —COH, —OC(O)R′, or —NC(O)R′; or two J V , J U , J X , or J R groups, on the same substituent or different substituents, together with the atom(s) to which each J V , J U , J X , and J R group is bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring;

R′ is H or C 1-6 aliphatic; or two R′ groups, together with the atom to which they are attached, optionally form a 3-6 membered cycloaliphatic or heterocyclyl, wherein said aliphatic, cycloaliphatic or heterocyclyl is optionally substituted with R*, —OR*, —SR*, —NO 2 , —CF 3 , —CN, —CO 2 R*, —COR*, OCOR*, NHCOR*, wherein R* is H or C 1-6 aliphatic;

L is a C 1-6 aliphatic wherein up to three methylene units are replaced by —NH—, —NR 6 —, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR 6 —, —C(═N—CN), —NHCO—, —NR 6 CO—, —NHC(O)O—, —NR 6 C(O)O—, —SO 2 NH—, —SO 2 NR 6 , —NHSO 2 —, —NR 6 SO 2 —, —NHC(O)NH—, —NR 6 C(O)NH—, —NHC(O)NR 6 —, —NR 6 C(O)NR 6 , —OC(O)NH—, —OC(O)NR 6 —, —NHSO 2 NH—, —NR 6 SO 2 NH—, —NHSO 2 NR 6 , —NR 6 SO 2 NR 6 —, —SO—, or —SO 2 —;

R 6 is selected from C 1-6 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl; or two R 6 groups, on the same substituent or different substituents, together with the atom(s) to which each R 6 group is bound, form a 3-8 membered heterocyclyl;

J is halogen, OCH 3 , OH, NO 2 , NH 2 , SCH 3 , NCH 3 , CN, unsubstituted C 1-2 aliphatic; two J's, together with the carbon to which they are attached, form a cyclopropyl ring or C═O;

m, n, d, and p are each independently 0 or 1; provided that

when R 1 , R 2 , and R 3 are H and Z is a bond, then Q is not

is —NH-tBu, —NH-phenyl or phenyl;

when R 1 and R 2 are H, R 3 is H, COOEt or COOH, and Z is a bond, then Q is not

when R 1 is I, R 2 is H, R 3 is Br and Z is NH, then Q is not

when R 1 and R 3 are H, R 2 is H, Cl, F, Me or CF 3 , and Z is NH; then Q is not 2-fluoro-4-amino phenyl, 2-fluoro-4-nitro phenyl or

when R 1 and R 3 are H, R 2 is H or Me, and Z is NH, then Q is not 2,6-fluoro-4-amino phenyl,

when R 1 and R 3 are H, R 2 is Me, and Z is NH, then Q is not

when R 1 , R 2 and R 3 are H, and Z is NH; then Q is not 3,5-difluoro phenyl, 4-amino phenyl, 4-nitro phenyl, 2-chloro-4-amino phenyl, 2-chloro-4-nitro phenyl, 3,4-methoxyphenyl,

when R 1 and R 2 are H, R 3 is C(═O)NH 2 and Z is NH, then Q is not 2-ethylphenyl; and

when R 1 , R 2 , and R 3 are H and Z is NCH 3 ; then Q is not unsubstituted phenyl, 2-fluoro-4-amino phenyl, 2-fluoro-4-nitro phenyl or

In another embodiment, the invention provides a compound of formula I-a

or a pharmaceutically acceptable salt thereof,

wherein Q, R 1 , R 2 and R 3 are as defined for formula I above,

when R 1 , R 2 , and R 3 are H, then Q is not

is —NH-tBu, —NH-phenyl or phenyl;

when R 1 and R 2 are H, and R 3 is H, COOEt or COOH, then Q is not

In another embodiment, the invention provides a compound of formula I-b

or a pharmaceutically acceptable salt thereof,

wherein Q, R 1 , R 2 and R 3 are as defined above,

and Z′ is NH, N(C 1-3 aliphatic) or C═CH 2 ;

provided that

when R 1 is I, R 2 is H, R 3 is Br and Z′ is NH, then Q is not

when R 1 and R 3 are H, R 2 is H, Cl, F, Me or CF 3 , and Z′ is NH; then Q is not 2-fluoro-4-amino phenyl, 2-fluoro-4-nitro phenyl or

when R 1 and R 3 are H, R 2 is H or Me, and Z′ is NH, then Q is not 2,6-fluoro-4-amino phenyl,

when R 1 and R 3 are H, R 2 is Me, and Z′ is NH, then Q is not

when R 1 , R 2 and R 3 are H, and Z′ is NH; then Q is not 3,5-difluoro phenyl, 4-amino phenyl, 4-nitro phenyl, 2-chloro-4-amino phenyl, 2-chloro-4-nitro phenyl, 3,4-methoxyphenyl,

when R 1 and R 2 are H, R 3 is C(═O)NH 2 and Z′ is NH, then Q is not 2-ethylphenyl;

and

when R 1 , R 2 , and R 3 are H and Z′ is NCH 3 ; then Q is not unsubstituted phenyl, 2-fluoro-4-amino phenyl, 2-fluoro-4-nitro phenyl or

In one embodiment of the invention, p is 0. In a further embodiment, R 1 is H, halogen, CN, NH 2 , NO 2 , CF 3 , CH 3 , NCH 3 , OCH 3 , or OH. In yet another embodiment, R 1 is H, halogen, or CF 3 . In another embodiment, R 1 is H.

In one embodiment, d is 0. In a further embodiment, R 2 is H, halogen, CN, NH 2 , NO 2 , CF 3 , CH 3 , NCH 3 , OCH 3 , or OH. In another embodiment, R 2 is H, halogen, or CF 3 . In yet another embodiment, R 2 is H.

In another embodiment, both R 1 and R 2 are H.

In another embodiment, m is 0 and R 3 is H, halogen, —CN, —NO 2 or X. In yet another embodiment, R 3 is H, halogen or C 1-3 aliphatic. In another embodiment, R 3 is H or Cl.

In a different embodiment, m is 1 and U is an optionally substituted C 1-3 aliphatic, wherein up to two methylene units are optionally replaced with 0-2 G U groups. In another embodiment, G U is selected from —NH—, —NR—, —O—, —CO 2 —, —OC(O)— or —C(O)—. In a further embodiment, X is selected from H, C 1-6 aliphatic, halogen, CN, NO 2 , S(O) 0-2 R, or C 1-4 haloalkyl. In yet a further embodiment, X is H, C 1-6 alkyl or halogen. In another embodiment, X is H or Cl. In a further embodiment, R 1 and R 2 are H and R 3 is H or Cl.

In one embodiment, Z is a bond and R 3 is selected from H, Cl, Br, F, —CN, —COOH, —COOMe, —NH 2 , —N(R′) 2 , —NO 2 , —OR′, —CON(R′) 2 , —COOR′, —OH, —SR′, —C(R′) 2 OR′, —N(R′)COR′, —N(R′)C(O)OR′, —SO 2 NH 2 , —SO 2 N(R′) 2 , or an optionally substituted group selected from C 1 -C 4 aliphatic, C 1 -C 4 alkyloxy or —C≡C—C 1 -C 4 aliphatic. In a further embodiment, R 3 is selected from H, Cl, —Br, —CN, —COOH, —COOMe, —CONHR′, —CON(Me) 2 , —CH 2 OH, —NO 2 , —NH 2 or an optionally substituted C 1 -C 4 aliphatic. In yet a further embodiment, R 3 is selected from Cl, —Br, —CN or an optionally substituted C 1 -C 4 aliphatic. Yet further, R 3 is Cl.

In another embodiment, J U is selected from halogen, CN, NO 2 , C 1-2 haloalkyl, OH, C 1-3 alkyl, —O—(C 1-2 alkyl), NH 2 , —NH—(C 1-2 alkyl), —N(C 1-2 alkyl) 2 , —O—(C 1-2 haloalkyl), or oxo.

In another embodiment, J X is selected from halogen, CN, NO 2 , C 1-2 haloalkyl, OH, C 1-3 alkyl, —O—(C 1-2 alkyl), NH 2 , —NH—(C 1-2 alkyl), —N(C 1-2 alkyl) 2 , —O—(C 1-2 haloalkyl), or oxo.

In another embodiment, Q is a 5-10 membered aryl or heteroaryl ring optionally substituted with 1-5 J Q groups. In a further embodiment, Q is a 5-6 membered aryl or heteroaryl ring optionally substituted with 1-5 J Q groups.

In another embodiment, Q is a 5-6 membered ring selected from:

In a further embodiment, Q is a 6-membered ring selected from phenyl (a), pyridyl (b), pyrimidyl (c), pyrazinyl (d), triazinyl (e), or pyridazinyl (f). In a further embodiment, Q is phenyl (a), pyridyl (b), or pyrimidyl (c). In yet a further embodiment, Q is 2-pyridyl, 4-pyridyl, 2,6-pyrimidyl or phenyl. In a further embodiment, when Q is as described herein, R 1 and R 2 are H. In a further embodiment, when Q is as described herein, R 3 is H, halogen, or C 1-6 aliphatic. In yet a further embodiment, R 3 is H or Cl. In yet a further embodiment, when Q is as described herein, Z is a bond. In a different embodiment, when Q is as described herein, Z is NH.

In another embodiment, Q is a 5-membered ring selected from pyrazolyl (h), thiophenyl (v), furanyl (u) or pyrrolyl (w). In a further embodiment, pyrazolyl (h) or thiophenyl (v). In a further embodiment, when Q is as described herein, R 1 and R 2 are H. In a further embodiment, when Q is as described herein, R 3 is H, halogen, or C 1-6 aliphatic. In yet a further embodiment, R 3 is H or Cl. In yet a further embodiment, when Q is as described herein, Z is a bond. In a different embodiment, when Q is as described herein, Z is NH.

In another embodiment, Q is a 5-12 membered saturated or partially saturated monocyclic or bicyclic ring system optionally substituted with 1-5 J Q groups. In a further embodiment, Q is a 5-12 membered fully saturated or partially saturated monocyclic or bicyclic cycloaliphatic ring system.

In another embodiment, Q is a mono-unsaturated ring as represented by formula II:

In another embodiment, Q is a 5-6 membered fully saturated or partially saturated monocyclic cycloaliphatic ring system.

In another embodiment, Q is a 5-8 membered partially saturated heterocyclyl ring. In a further embodiment, Q is a 5-6 membered heterocyclyl containing 1-2 nitrogen atoms. In yet a further embodiment, Q contains 1 nitrogen atom. In yet a further embodiment, Q is the ring represented in formula III:

In another embodiment of the invention, Z is a bond or NH. In a further embodiment, R 1 and R 2 are H. In yet a further embodiment, R 3 is H, halogen, or C 1-6 aliphatic. In yet a further embodiment, R 3 is H or Cl. In another embodiment of the invention, the J Q substituent attached at the nitrogen atom of ring Q is —(V n )—R″, —(V n )—CN, —(V n )—NO 2 , or —(V n )—(C 1-4 haloaliphatic), wherein V is C(═O) or C(═O)O and n is 1.

In an embodiment of the invention, each occurrence of J Q is independently selected from R″, —CH 2 R″, halogen, CN, NO 2 , —COR″, —COR 8 R″, —N(R′)R″, —CH 2 N(R′)R″, —OR″, —CH 2 OR″, —SR″, —CH 2 SR″, —C(O)OR″, —NR′COR″, —NR′COR 8 R″, —NR′COOR″, —NR′COOR 8 R″, —CON(R′)R″, —CON(R′)R 8 R″, —SO 2 N(R′)R″, —SO 2 N(R′)R 8 R″, —CON(R′)R 8 N(R′)R″, —OR 8 OR″, —OR 8 N(R′)R″, —NR′CH(R 8 )R″, —NR′CH(R 8 )C(O)OR″, —N(R′)R 8 R″, —N(R′)R 8 R″, —N(R′)R 8 N(R′)R″, —N(R′) R 8 OR″, —NR′CH(R 8 )R″, —NR′CH 2 C(O)N(R′)R″, or —NR′CH(R 8 )C(O)N(R′)R″, wherein R 8 is H or an C 1-6 alkyl optionally substituted with 1-4 occurrences of J V .

In a further embodiment, each occurrence of J Q is independently selected from R″, —CH 2 R″, halogen, —CN, —NO 2 , —N(R′)R″, —CH 2 N(R′)R″, —OR″, —CH 2 OR″, —SR″, —CH 2 SR″, —COOR″, —NR′COR″, —NR′COCH 2 R″, —NR′CO(CH 2 ) 2 R″, —NR′COOR″, —CON(R′)R″, —SO 2 N(R′)R″, —CONR′(CH 2 ) 2 N(R′)R″, —CONR′(CH 2 ) 3 N(R′)R″, —CONR′(CH 2 ) 4 N(R′)R″, —O(CH 2 ) 2 OR″, O(CH 2 ) 3 OR″, O(CH 2 ) 4 OR″, —O(CH 2 ) 2 N(R′)R″, —O(CH 2 ) 3 N(R′)R″, —O(CH 2 ) 4 N(R′)R″, —NR′CH(CH 2 OR 8 )R″, —NR′CH(CH 2 CH 2 OR′)R″, —NR′CH(CH 3 )R″, NR′CH(CF 3 )R″, —NR′CH(CH 3 )C(O)OR″, —NR′CH(CF 3 )C(O)OR″, —NR′(CH 2 )R″, —NR′(CH 2 ) 2 R″, —NR′(CH 2 ) 3 R″, —NR′(CH 2 ) 4 R″, —NR′(CH 2 )N(R′)R″, —NR′(CH 2 ) 2 N(R′)R″, —NR′(CH 2 ) 3 N(R′)R″, —NR′(CH 2 ) 4 N(R′)R″, —NR′(CH 2 )OR″, —NR′(CH 2 ) 2 OR″, —NR′(CH 2 ) 3 OR″, —NR′(CH 2 ) 4 OR″, —NR′CH(CH 2 CH 3 )R″, —NR′CH 2 C(O)N(R′)R″, —NR′CH(CH 3 )C(O)N(R′)R″, NR′CH(CF 3 )C(O)N(R′)R″, —NR′CH(CH 2 CH 3 )C(O)N(R′)R″, —NR′CH(CH(CH 3 ) 2 )C(O)N(R′)R″, —NR′CH(C(CH 3 ) 3 )C(O)N(R′)R″, —NR′CH(CH 2 CH(CH 3 ) 2 )C(O)N(R′)R″, —NR′CH(CH 2 OR 8 )C(O)N(R′)R″ or —NR′CH(CH 2 CH 2 N(Me) 2 )C(O)N(R′)R″.

In another further embodiment, R″ is selected from hydrogen, a C 1 -C 6 aliphatic group optionally substituted with up to six occurrences of R 7 , or R″ is a ring selected from:

or two occurrences of R′ are taken together with the nitrogen atom to which they are bound to form an optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring selected from:

wherein y is 0, 1, 2, or 3, and each occurrence of R 7 is independently R′, —CH 2 R′, halogen, CH 2 CH, CN, NO 2 , —N(R′) 2 , —CH 2 N(R′) 2 , —OR′, —CH 2 OR′, —SR′, —CH 2 SR′, —COOR′, —COR′, —NR 9 COR′, —NR 9 COOR′, —CON(R′) 2 , —SO 2 N(R′) 2 , —NR 9 SO 2 R′, —CONR 9 (CH 2 ) 2 N(R 9 )R′, —CONR 9 (CH 2 ) 3 N(R 9 )R′, —CONR 9 (CH 2 ) 4 N(R 9 )R′, —O(CH 2 ) 2 OR′, O(CH 2 ) 3 OR′, O(CH 2 ) 4 OR′, —O(CH 2 ) 2 N(R 9 )R′, —O(CH 2 ) 3 N(R 9 )R′, —O(CH 2 ) 4 N(R 9 )R′, —NR 9 CH(CH 2 OH)R′, —NR 9 CH(CH 2 CH 2 OH)R′, —NR 9 (CH 2 )R′, —NR 9 (CH 2 ) 2 R′, —NR 9 (CH 2 ) 3 R′, —NR 9 (CH 2 ) 4 R′, —NR 9 (CH 2 )N(R 9 )R′, —NR 9 (CH 2 ) 2 N(R 9 )R′, —NR 9 (CH 2 ) 3 N(R 9 )R′, —NR 9 (CH 2 ) 4 N(R 9 )R′, —NR 9 (CH 2 )OR′, —NR 9 (CH 2 ) 2 OR′, —NR 9 (CH 2 ) 3 OR′, or —NR 9 (CH 2 ) 4 OR′; wherein R 9 is H or R 6 .

In another embodiment, J Q is H, halogen, OCF 3 , R″, CN, NO 2 , or C 1-4 haloaliphatic. In yet another embodiment, J Q is —V—R″, —V—CN, —V—NO 2 , or —V— (C 1-4 haloaliphatic). In a further embodiment, V is C 1-6 alkyl, wherein up to two methylene units are replaced by G V wherein G V is selected from —NH—, —NR—, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)—, —C(O)NH—, —C(O)NR—, —NHCO—, or —NRCO—. In yet a further embodiment, V is a C 1-6 alkyl wherein zero methylene units are replaced by G V . In yet a further embodiment, V is CH 2 . In still a further embodiment, V is substituted with 2 J V groups; wherein J V is C 1-3 alkyl or two J V groups, together with the methylene unit to which they are attached, form a 3-6 membered cycloalkyl ring.

In another embodiment, one methylene unit of V is replaced by G V . In a further embodiment, V is a C 1 alkyl, wherein one methylene unit is replaced by G V . In another embodiment, G V is bonded directly to R″.

In another embodiment, J V is selected from halogen, NH 2 , NO 2 , CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 haloalkoxy, —O—(C 1-3 alkyl), —NH—(C 1-3 alkyl), —N(C 1-3 alkyl) 2 , —C(═O)O(C 1-3 alkyl), —C(═O)OH, —C(═O)(C 1-3 alkyl), —C(═O)H, —OC(═O)(C 1-3 alkyl), —NC(═O)(C 1-3 alkyl), or oxo.

In an embodiment of the invention, when Z is O, R 1 and R 3 are H and R 2 is H or CH 3 , then Q is not an optionally substituted phenyl.

In another embodiment of the invention, Z is C═O.

In an embodiment of the invention, NH, C═O or O and Q is selected from an unsubstituted 5-7 membered cycloalkyl ring. In a further embodiment, Z is NH. In yet a further embodiment, Q is a cyclopentyl or cyclohexyl ring.

In another embodiment, Z is NH, C═O or O, and Q is a 5-8 membered saturated, partially saturated, or unsaturated monocycle optionally substituted with 0-4 occurrences of J Q . In a further embodiment, Z is NH.

In another embodiment, Q is 5-10 membered aryl or heteroaryl optionally substituted with 0-4 occurrences of J Q and J Q is halogen, OCF 3 , —(V n )—CN, —(V n )—NO 2 , or —(V n )—(C 1-4 haloaliphatic). In a further embodiment, J Q is —(V n )—R″ and V is a C 2-10 aliphatic, wherein up to three methylene units are replaced by G V , wherein G V is selected from —NH—, —NR—, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR—, —C(═N—CN), —NHCO—, —NRCO—, —NHC(O)O—, —NRC(O)O—, —SO 2 NH—, —SO 2 NR—, —NHSO 2 —, —NRSO 2 —, —NHC(O)NH—, —NRC(O)NH—, —NHC(O)NR—, —NRC(O)NR, —OC(O)NH—, —OC(O)NR—, —NHSO 2 NH—, —NRSO 2 NH—, —NHSO 2 NR—, —NRSO 2 NR—, —SO—, or —SO 2 —; and wherein V is optionally substituted with 1-4 occurrences of J V . In another embodiment, V is a Cl aliphatic, wherein up to one methylene unit is replaced by G V , wherein G V is selected from —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR—, —C(═N—CN), —NHCO—, —NRCO—, —NHC(O)O—, —NRC(O)O—, —SO 2 NH—, —SO 2 NR—, —NHSO 2 —, —NRSO 2 —, —NHC(O)NH—, —NRC(O)NH—, —NHC(O)NR—, —NRC(O)NR, —OC(O)NH—, —OC(O)NR—, —NHSO 2 NH—, —NRSO 2 NH—, —NHSO 2 NR—, —NRSO 2 NR—, —SO—, or —SO 2 —.

In a further embodiment, R″ is H, or is an optionally substituted group selected from C 1-6 aliphatic, C 3-10 cycloaliphatic, naphthyl, 5-membered heteroaryl, pyridinyl, pyridazinyl, pyrazinyl, 3,5-pyrimidinyl, triazinyl, 8-10 membered heteroaryl, or 5-10 membered heterocyclyl; or two R″ groups, on the same substituent or different substituents, together with the atom(s) to which each R″ group is bound, form an optionally substituted 3-8 membered heterocyclyl; wherein each optionally substituted R″ group is independently and optionally substituted with 1-4 occurrences of J R .

In another embodiment, Z is O, NH, N(C 1-3 aliphatic), S, CH 2 , C═CH 2 , or C═O; and Q is selected from a 3-8 membered saturated or partially saturated monocyclic ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur, wherein Q is optionally substituted with 1-5 J Q .

In another embodiment, a compound of the invention is selected from Tables 1 or 2.

Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

In another embodiment, the invention provides A pharmaceutical composition comprising a compound of formula I

or a pharmaceutically acceptable salt thereof

wherein

Q is a 3-8 membered saturated, partially saturated, or unsaturated monocyclic ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur; or an 8-12 membered bicyclic ring having 0-6 heteroatoms selected from nitrogen, oxygen, or sulfur; wherein Q is optionally substituted with 1-10 occurrences of J Q ;

Z is a bond, O, NH, N(C 1-3 aliphatic), S, CH 2 , C═CH 2 , C═O, SO or SO 2 ;

R 1 is —(C 1-2 aliphatic) p -R 4 wherein each R 1 is optionally substituted with 1-3 occurrences of J;

R 2 is —(C 1-2 aliphatic) d -R 5 wherein each R 1 is optionally substituted with 1-3 occurrences of J;

R 3 is halogen, —CN, —NO 2 or —(U) m —X, wherein

U is a C 1-6 aliphatic, wherein up to two methylene units are optionally and independently replaced by G U and wherein U is optionally substituted with 1-4 J U ; X is H, halogen, CN, NO 2 , S(O)R, SO 2 R, C 1-4 haloaliphatic, or a group selected from C 1-6 aliphatic, a C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl; wherein said group is optionally substituted with 1-4 J X ; G U is —NH—, —NR—, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR—, —C(═N—CN)—, —NHCO—, —NRCO—, —NHC(O)O—, —NRC(O)O—, —SO 2 NH—, —SO 2 NR—, —NHSO 2 —, —NRSO 2 —, —NHC(O)NH—, —NRC(O)NH—, —NHC(O)NR—, —NRC(O)NR, —OC(O)NH—, —OC(O)NR—, —NHSO 2 NH—, —NRSO 2 NH—, —NHSO 2 NR—, —NRSO 2 NR—, —SO—, or —SO 2 —;

R 4 is H, halogen, CN, NH 2 , NO 2 , CF 3 , C 1-3 aliphatic, cyclopropyl, NCH 3 , OCH 3 , —C(═O)NH 2 , —C(═O)CH 3 , —NC(═O)CH 3 , or OH;

R 5 is H, halogen, CN, NH 2 , NO 2 , CF 3 , C 1-3 aliphatic, cyclopropyl, NCH 3 , OCH 3 , —C(═O)NH 2 , —C(═O)CH 3 , —NC(═O)CH 3 , or OH;

J Q is halogen, OCF 3 , —(V n )—R″, —(V n )—CN, —(V n )—NO 2 , or —(V n )—(C 1-4 haloaliphatic), wherein J Q is not H;

V is a C 10 aliphatic, wherein up to three methylene units are replaced by G V , wherein G V is selected from —NH—, —NR—, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR—, —C(═N—CN), —NHCO—, —NRCO—, —NHC(O)O—, —NRC(O)O—, —SO 2 NH—, —SO 2 NR—, —NHSO 2 —, —NRSO 2 —, —NHC(O)NH—, —NRC(O)NH—, —NHC(O)NR—, —NRC(O)NR, —OC(O)NH—, —OC(O)NR—, —NHSO 2 NH—, —NRSO 2 NH—, —NHSO 2 NR—, —NRSO 2 NR—, —SO—, or —SO 2 —; and wherein V is optionally substituted with 1-6 occurrences of J V ;

R″ is H, or is an optionally substituted group selected from C 1-6 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl; or two R″ groups, on the same substituent or different substituents, together with the atom(s) to which each R″ group is bound, form an optionally substituted 3-8 membered heterocyclyl; wherein each optionally substituted R″ group is independently and optionally substituted with 1-6 occurrences of JR;

R is an optionally substituted group selected from C 1-6 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl; or two R groups, on the same substituent or different substituents, together with the atom(s) to which each R group is bound, form an optionally substituted 3-8 membered heterocyclyl; wherein each R group is independently and optionally substituted with 1-4 occurrences of JR;

J V , J U , J X , and J R are each independently selected from halogen, L, -(L n )-R, -(L n )-N(R′) 2 , -(L n )-SR′, -(L n )-OR′, -(L n )-(C 3-10 cycloaliphatic), -(L n )-(C 6-10 aryl), -(L n )-(5-10 membered heteroaryl), -(L n )-(5-10 membered heterocyclyl), oxo, C 1-4 haloalkoxy, C 1-4 haloalkyl, -(L n )-NO 2 , -(L n )-CN, -(L n )-OH, -(L n )-CF 3 , —CO 2 R′, —CO 2 H, —COR′, —COH, —OC(O)R′, or —NC(O)R′; or two J V , J U , J X , or J R groups, on the same substituent or different substituents, together with the atom(s) to which each J V , J U , J X , and J R group is bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring;

R′ is H or C 1-6 aliphatic; or two R′ groups, together with the atom to which they are attached, optionally form a 3-6 membered cycloaliphatic or heterocyclyl, wherein said aliphatic, cycloaliphatic or heterocyclyl is optionally substituted with R*, —OR*, —SR*, —NO 2 , —CF 3 , —CN, —CO 2 R*, —COR*, OCOR*, NHCOR*, wherein R* is H or C 1-6 aliphatic;

L is a C 1-6 aliphatic wherein up to three methylene units are replaced by —NH—, NR 6 , —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR 6 —, —C(═N—CN), —NHCO—, —NR 6 CO—, —NHC(O)O—, —NR 6 C(O)O—, —SO 2 NH—, —SO 2 NR 6 —, —NHSO 2 —, —NR 6 SO 2 —, —NHC(O)NH—, —NR 6 C(O)NH—, —NHC(O)NR 6 —, —NR 6 C(O)NR 6 , —OC(O)NH—, —OC(O)NR 6 —, —NHSO 2 NH—, —NR 6 SO 2 NH—, —NHSO 2 NR 6 —, —NR 6 SO 2 NR 6 —, —SO—, or —SO 2 —;

R 6 is selected from C 1-6 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl; or two R 6 groups, on the same substituent or different substituents, together with the atom(s) to which each R 6 group is bound, form a 3-8 membered heterocyclyl;

J is halogen, OCH 3 , OH, NO 2 , NH 2 , SCH 3 , NCH 3 , CN, unsubstituted C 1-2 aliphatic; two J's, together with the carbon to which they are attached, form a cyclopropyl ring or C═O;

m, n, d, and p are each independently 0 or 1;

wherein when R 1 and R 2 are H, R 3 is C(═O)NH 2 and Z is NH, then Q is not 2-ethylphenyl;

and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

In a further embodiment, the composition does not comprise a compound wherein when R 1 , R 2 , and R 3 are H and Z is a bond, then Q is not

In a further embodiment, the composition does not comprise a compound wherein when R 1 , R 2 , and R 3 are H and Z is O; then Q is not 3,4-diaminophenyl, 4-benzyloxyphenyl, 3-amino-4-hydroxyphenyl, 4-hydroxyphenyl, 2-fluoro-4-aminophenyl, 3-fluoro-4-aminophenyl, 2,6-difluoro-4-aminophenyl, 4-nitrophenyl, 4-aminophenyl; an optionally substituted group selected from

wherein Cy is an optionally substituted group selected from phenyl or piperidine; or a compound of formula X

wherein PY is an optionally substituted aminopyrimidine group and PH is phenyl mono- or disubstituted with fluoro.

In a further embodiment, the composition does not comprise a compound wherein when R 1 and R 3 are H, R 2 is methyl and Z is O, then Q is not 2-fluoro-4-aminophenyl.

In a further embodiment, the composition does not comprise a compound wherein when R 1 , R 2 , and R 3 are H and Z is NCH 3 ; then Q is not unsubstituted phenyl.

In a further embodiment, the composition additionally comprising a therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the compositions of this invention is such that is effective to measurably inhibit a protein kinase, particularly a JAK family or ROCK family kinase, in a biological sample or in a patient. Preferably the composition of this invention is formulated for administration to a patient in need of such composition. Most preferably, the composition of this invention is formulated for oral administration to a patient.

The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.

Accordingly, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitory active metabolite or residue thereof. As used herein, the term “inhibitory active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of a JAK family or ROCK family kinase.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.

Some examples of materials which can serve as pharmaceutically acceptable carriers 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, or 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, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

The term “measurably inhibit”, as used herein means a measurable change in kinase activity, particularly JAK family or ROCK family activity, between a sample comprising a compound of this invention and a JAK or ROCK kinase and an equivalent sample comprising JAK or ROCK kinase, respectively, in the absence of said compound.

The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic 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 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 may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

The pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable compositions may be formulated, e.g., as micronized suspensions in isotonic, pH adjusted sterile saline or other aqueous solution, or, preferably, as solutions in isotonic, pH adjusted sterile saline or other aqueous solution, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers 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 and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

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.

The 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 of the present invention, it is often 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.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type 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 polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain 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 that can be used include polymeric substances and waxes. Solid compositions of a similar type 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.

The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain 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 that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. 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.

The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism 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.

The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.

Depending upon the particular condition, or disease, to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated”.

For example, chemotherapeutic agents or other anti-proliferative agents may be combined with the compounds of this invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, but are not limited to, Gleevec™, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives.

Other examples of agents the inhibitors of this invention may also be combined with include, without limitation: treatments for Alzheimer's Disease such as Aricept® and Excelon®; 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®), Copaxone®, and mitoxantrone; treatments for asthma such as albuterol and Singulair®; 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 anti-Parkinsonian 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.

The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

Uses of the Compounds and Compositions

In another embodiment, the invention comprises a method of inhibiting ROCK kinase activity in a biological sample, comprising contacting said biological sample with a compound or a composition of the invention.

In another embodiment, the invention comprises a method of inhibiting ROCK kinase activity in a patient, comprising administering to said patient a compound or a composition of the invention.

In another embodiment, the invention comprises a method of treating or lessening the severity of a ROCK kinase-mediated condition or disease in a patient. The term “ROCK-mediated condition” or “disease”, as used herein, means any disease or other deleterious condition in which ROCK is known to play a role. The term “ROCK-mediated condition” or “disease” also means those diseases or conditions that are alleviated by treatment with a ROCK inhibitor. Such conditions include, without limitation, hypertension, angina pectoris, cerebrovascular contraction, asthma, peripheral circulation disorder, preterm labor, cancer, erectile dysfunction, atherosclerosis, spasm (cerebral vasospasm and coronary vasospasm), retinopathy (e.g., glaucoma), inflammatory disorders, autoimmune disorders, AIDS, osteoporosis, myocardial hypertrophy, ischemia/reperfusion-induced injury, and endothelial dysfunction. In another embodiment, the present invention relates to a method for treating or lessening the severity of benign prostatic hyperplasia or diabetes.

In another embodiment, the invention comprises a method of treating or lessening the severity of a disease, condition or disorder is selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, a psychotic disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, an immunologically mediated disorder, a viral disease, or a bone disorder, comprising the step of administering to said patient a compound or a composition of the invention.

In a further embodiment, the method comprises the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an anti-psychotic agent, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein said additional therapeutic agent is appropriate for the disease being treated and said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.

In a further embodiment, said disease, condition, or disorder is allergy, asthma, chronic obstructive pulmonary disease (COPD), diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-associated dementia, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy, vascular smooth muscle cell proliferation, reperfusion/ischemia, stroke, baldness, cancer, hepatomegaly, hypertension, cardiovascular disease, cardiomegaly, cystic fibrosis, viral disease, autoimmune diseases, restenosis, psoriasis, inflammation, hypertension, angina pectoris, cerebrovascular contraction, peripheral circulation disorder, premature birth, atherosclerosis, vasospasm, cerebral vasospasm, coronary vasospasm, retinopathy, glaucoma, erectile dysfunction (ED), AIDS, osteoporosis, Crohn's Disease, colitis, neurite outgrowth, or Raynaud's Disease.

In another embodiment, said disease, condition, or disorder is hypertension, cerebral vasospasm, coronary vasospasm, bronchial asthma, preterm labor, erectile dysfunction, glaucoma, vascular smooth muscle cell proliferation, myocardial hypertrophy, malignoma, ischemia/reperfusion-induced injury, endothelial dysfunction, Crohn's Disease, colitis, neurite outgrowth, Raynaud's Disease, angina pectoris, Alzheimer's disease, benign prostatic hyperplasia, cardiac hypertrophy, perivascular fibrosis or atherosclerosis. In a further embodiment, said disease, condition, or disorder is atherosclerosis, hypertension, erectile dysfunction (ED), reperfusion/ischemia, stroke, cerebral vasospasm, coronary vasospasm, cardiac hypertrophy or glaucoma.

In another embodiment, the present invention relates to a method of treating hypertension. In another embodiment, the present invention relates to a method of treating chronic obstructive pulmonary disease (COPD). In another embodiment, the present invention relates to a method of treating glaucoma. In another embodiment, the present invention relates to a method of treating cardiac hypertrophy and/or perivascular fibrosis.

In some embodiments, the present invention relates to a method for treating or lessening the severity of a cancer. In further embodiments, the present invention relates to a method for treating or lessening the severity of a cancer selected from brain (gliomas), breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, or thyroid. In yet further embodiments, the present invention relates to a method for treating or lessening the severity of pancreatic, prostate, or ovarian cancer.

In another embodiment, the invention provides a method of inhibiting JAK kinase activity in a biological sample, comprising contacting said biological sample with a compound or composition of the invention.

In another embodiment, the invention provides a method of inhibiting JAK kinase activity in a patient, comprising administering to said patient a compound or composition of the invention.

In another embodiment, the invention comprises a method of treating or lessening the severity of a JAK-mediated condition or disease in a patient. The term “JAK-mediated disease”, as used herein means any disease or other deleterious condition in which a JAK family kinase, in particular JAK2 or JAK3, is known to play a role. Such conditions include, without limitation, immune responses such as allergic or type I hypersensitivity reactions, asthma, autoimmune diseases such as transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis, neurodegenerative disorders such as familial amyotrophic lateral sclerosis (FALS), as well as in solid and hematologic malignancies such as leukemias and lymphomas.

In another embodiment, the invention provides a method of treating or lessening the severity of a disease of condition selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, an immune disorder or an immunologically mediated disorder, comprising administering to said patient a compound or composition of the invention.

In a further embodiment, the method comprises the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein said additional therapeutic agent is appropriate for the disease being treated and said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.

In one embodiment, the disease or disorder is allergic or type I hypersensitivity reactions, asthma, diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-associated dementia, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy, reperfusion/ischemia, stroke, baldness, transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis, and solid and hematologic malignancies such as leukemias and lymphomas. In a further embodiment, said disease or disorder is asthma. In another embodiment, said disease or disorder is transplant rejection.

In another embodiment, a compound or composition of this invention may be used to treat a myeloproliferative disorder. In one embodiment, the myeloproliferative disorder is polycythemia vera, essential thrombocythemia, or chronic idiopathic myelofibrosis. In another embodiment, the myeloproliferative disorder is myeloid metaplasia with myelofibrosis, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome, systematic mast cell disease, atypical CML or juvenile myelomonocytic leukemia.

The term “biological sample”, as used herein, means an ex vivo sample, and includes, without limitation, cell cultures or extracts thereof; tissue or organ samples 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.

Inhibition of kinase activity, particularly JAK or ROCK kinase activity, in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, biological assays and biological specimen preparation and storage.

In certain embodiments of the present invention an “effective amount” of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of the aforementioned disorders. The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorder or disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.

In an alternate embodiment, the methods of this invention comprise the additional step of separately administering to said patient an additional therapeutic agent. When these additional therapeutic agents are administered separately they may be administered to the patient prior to, sequentially with or following administration of the compositions of this invention.

The compounds of this invention or pharmaceutical compositions thereof may also be used for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a compound of this invention.

Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Implantable devices coated with a compound of this invention are another embodiment of the present invention. The compounds may also be coated on implantable medical devices, such as beads, or co-formulated with a polymer or other molecule, to provide a “drug depot”, thus permitting the drug to be released over a longer time period than administration of an aqueous solution of the drug.

Methodology for Synthesis and Characterization of Compounds

The compounds of this invention may be prepared in general by methods known to those skilled in the art for analogous compounds or by those methods depicted in the Examples below. See, e.g., the examples described in WO 2005/095400, which is herein incorporated by reference in its entirety.

All references provided in the Examples are herein incorporated by reference. As used herein, all abbreviations, symbols and conventions are consistent with those used in the contemporary scientific literature. See, e.g., Janet S. Dodd, ed., The ACS Style Guide: A Manual for Authors and Editors, 2nd Ed., Washington, D.C.: American Chemical Society, 1997, herein incorporated in its entirety by reference.

The following definitions describe certain of the terms and abbreviations used herein:

Ts-Cl p-toluenesulfonyl chloride (tosyl chloride) DMF dimethylformamide Tf triflate dppf 1,1′-bis(diphenylphosphino)-ferrocene Ac acetyl DME 1,2-Dimethoxyethane atm atmospheres EDC 1-Ethyl-3-(3-dimethylaminopropy)carbodiimide Hydrochloride DIPEA diisopropylethylamine KHMDS Potassium Hexamethyldisilazane THF tetrahydrofuran HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid Glu glutamate Tyr tyrosine ATP adenosine triphosphate Ph phenyl Me methyl BSA bovine serum albumin DTT dithiothreitol DMF dimethylformamide EtOAc ethyl acetate HPLC high performance liquid chromatography DMSO dimethyl sulfoxide TFA trifluoacetic acid NMP N-methylpyrrolidone HOBT hydroxybenzotriazole DCM dichloromethane LC-MS liquid chromatography-mass spectrometry