MX2008004335A - Deazapurines useful as inhibitors of janus kinases - Google Patents

Abstract

The present invention relates to compounds useful as inhibitors of protein kinases, particularly of JAK family kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

Description

USEFUL DEAZAPURINAS AS INHIBITORS OF JANUS QUINASAS TECHNICAL FIELD OF THE INVENTION The present invention relates to compounds useful as inhibitors of Janus kinases (JAK). The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods for using the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION Janus kinases (JAK) are a family of tyrosine kinases consisting of JAK1, JAK2, JAK3 and TYK2. JAKs play an essential role in cytokine signals. Substrates current under the JAK family of kinases include signal transducing and activating transcription proteins (STATs). JAK / STAT signals have 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 in addition to solid and haematological malignancies such as leukemias and linfornas. JAK2 has also been implicated in myeloproliferative disorders, These include polycythemia vera, essential thrombocythemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome and systemic mastocytic disease. Accordingly, it would be desirable to develop useful compounds as inhibitors of the kinases of the JAK family kinases.

SUMMARY OF THE INVENTION It was found that the compounds of this invention, and their pharmaceutically acceptable compositions, are effective as inhibitors of protein kinases, particularly the kinases of the JAK family. These compounds have the general formula I: or one of its pharmaceutically acceptable salts, wherein R1, R2, R3, Z and Q are as defined below. These compounds, and their pharmaceutically acceptable compositions, are useful for treating or reducing the severity of a variety of disorders, including proliferative disorders, cardiac disorders, neurodegenerative disorders, autoimmune disorders, pathological conditions associated with organ transplantation, inflammatory disorders or immunologically mediated disorders in a patient. The compounds and compositions provided by this invention are also useful for the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways measured by said kinases; and the comparative evaluation of new kinase inhibitors.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a schematic showing the synthesis of compound 1005 from 1001. Figure 2 is a schematic showing the synthesis of a compound of formula VIII from a compound of formula IV. Figure 3 is a schematic showing the synthesis of compound 18 from 1011. Figure 4 is a schematic showing the syntheses of compound 10 and compounds having formulas IX and X from 1015.

Figure 5 is a schematic showing the syntheses of compounds 33 and 20 from cyanuric chloride and 4-cyano-2,6-dichloropyridine, respectively. Figure 6 is a schematic showing the synthesis of a compound of formula XI from 1025. Figure 7 is a schematic showing the synthesis of compounds 29 and 30 from 2,6-dibromopyridine. Figure 8 is a schematic showing the synthesis of compound 108 from 5-nitro-2,4-dichloropyrimidine. Figure 9 is a scheme showing the synthesis of compound 110 from 5-bromo-2,4-dichloropyrimidine.

DETAILED DESCRIPTION OF THE INVENTION Definitions and general terminology As used herein, the following definitions apply unless otherwise indicated. For the purposes of the present invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Ed. In addition, the general principles of organic chemistry are described in " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito: 1999 and" March's Advanced Organic Chemistry ", 5th Ed., Ed .: Smith, MB and March, J., eds. , John Wiley & Sons, New York: 2001, whose complete contents are incorporated herein by reference. As described herein, the compounds of the invention can optionally be substituted with one or more substituents, as generally illustrated above or as exemplified by the 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" is preceded by the term "optionally" or not, refers to the replacement of one or more hydrogen radicals in a certain structure with the radical of a specific substituent. Unless otherwise indicated, an optionally substituted group may have a substituent in each substitutable position in the group. When more than one position in a certain structure can be substituted with more than one substituent selected from a specific group, the substituent can be the same or different in each position. As described herein, when the term "optionally substituted" precedes a list, said expression refers to all subsequent substitutable groups in that list. When a radical or substituent structure is not identified or defined as "optionally substituted", the radical or substituent structure is unsubstituted. For example, if X is halogen; optionally substituted C1-3 alkyl or phenyl; X may be optionally substituted alkyl or optionally substituted phenyl. In the same way, when the term "optionally substituted" follows a list, said expression also refers to all substitutable groups in the above list, unless otherwise indicated. For example: when X is halogen, C 1-3 alkyl or phenyl, wherein X is optionally substituted with J x, then both C 1-3 alkyl and phenyl may be optionally substituted with J x. As is obvious to the person skilled in the art, groups such as H, halogen, NO2, CN, NH2, OH or OCF3 will not be included because they are not substitutable groups. The combinations of substituents contemplated by this invention are preferably the result of the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to a compound that is not substantially altered when subjected to conditions to allow its production, detection, and, preferably, recovery, purification, and use for one or more of the objects described herein. In some embodiments, a stable compound or chemically feasible compound is one 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 linear (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, the aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, the aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, the aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, the aliphatic groups contain 1-6 aliphatic carbon atoms, and in still other embodiments, the 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. Other examples of aliphatic groups include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl and sec-butyl.

The term "cycloaliphatic" (or "carbocycle") refers to a monocyclic C3-C8 hydrocarbon or bicyclic Ce ~ Ci2 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, having 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. Cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Other examples of aliphatic groups include cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cycloheptenyl. The term "heterocycle", "heterocyclyl", "heterocycloaliphatic" or "heterocyclic" as used herein means non-aromatic, monocyclic, bicyclic or tricyclic ring systems wherein one or more ring members are a heteroatom selected from the group independent and that it is completely saturated or that it contains one or several units of instauration, but that it is not aromatic, that it has a single point of union with the rest of the molecule. In some embodiments, the group "heterocycle", "heterocyclyl", "heterocycloaliphatic" or "heterocyclic" has 3 to 14 ring members, wherein one to several members of the Ring is a heteroatom selected from oxygen, sulfur, nitrogen or phosphorus, and each ring in the system contains 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, l-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-lH-benzimidazol-2-one, 3- (l-alkyl) -benzimidazol-2-one, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzoditiano, and 1,3-dihydro-imidazol-2- ona 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 quaternary form of any basic nitrogen or a substitutable nitrogen of a heterocyclic ring, for example, N (as in 3, -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 defined above, attached to the main carbon chain through an oxygen atom ("alkoxy"). ) or sulfur ("thioalkyl"). The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" mean 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 such as "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to monocyclic, bicyclic and tricyclic ring systems having a total of 6 to 14 members of the ring, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 3 to 7 ring members and having a ring only point of union with the rest of the molecule. The term "aryl" can be used interchangeably with the term "aryl ring". Examples of aryl rings 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 5 to 14 ring members, in where 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 having a single point of attachment with the remainder of the ring. the molecule. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic". Examples of heteroaryl rings include, without limitation, 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 ( for example, 3-pyridazinyl), 2-thiazolyl, 4- thiazolyl, 5-thiazolyl, tetrazolyl (for example, 5-tetrazolyl), triazolyl (for example, 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (for example, 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-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, and the following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl, indolyl (for example, 2-indolyl), purinyl, quinolinyl (for example, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (for example, 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl). In some embodiments, an aryl group (including aralkyl, aralkoxy, aryloxyalkyl, and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group are selected from those recited in the definition of JQ, JR, Jv, Ju and Jx below. Other suitable substituents include: halogen; -R °; -OR °; -MR; 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl (Ph) optionally substituted with R °; -O (Ph) optionally substituted with R °; - ((¾) 1-2 (Ph), optionally substituted with R °; -CH = CH (Ph), optionally substituted with R °; -N02; CN; -N (R °) 2; -NR ° C (0) R °; -NR ° C (S) R °; -NR ° C (0) N (R °) 2; NR ° C (S) N (R0) 2; -NR ° C (0) 0R °; -NR ° NR ° C (0) R °; -NR ° NR ° C (0) N (R °) 2; ~ NR ° NRoC (0) 0R °; -C (0) C (0) R °; -C (0) CH2C (0) R °; -C (0) 0R °; -C (0) R °; -C (S) R °; -C (0) N (R °) 2; -C (S) N (R °) 2; -0C (0) N (R °) 2; -OC (0) R °; -C (0) N (OR °) R °; -C (= NOR °) R °; -S (0) 2R °; -S (0) 3R °; -S (0) 2N (R °) 2; -S (0) R °; -NR ° S (0) 2N (R °) 2; -NR ° S (0) 2R °; -N (OR °) R °; -C (= NH) -N (R °) 2; or - (CH2) 0-2NHC (O) R °; wherein each independent occurrence of R ° is selected from hydrogen, optionally substituted C 1-6 aliphatic, a 5-6 membered unsubstituted heteroaryl or heterocyclic ring, phenyl, -O (Ph) or -CH 2 (Ph) or two independent occurrences of R °, in the same substituent or in different substituents, taken together with the one or more atoms to which each R ° group is attached, form a 5-8 membered heterocyclyl, aryl or heteroaryl ring or a 3- cycloalkyl ring 8 members, wherein said heteroaryl or heterocyclyl ring has 1-3 heteroatoms selected, independently, from nitrogen, oxygen or sulfur. Optional substituents in the aliphatic group of R ° are selected from NH2, NH (aliphatic Ci-4), N (aliphatic Ci-4) 2, halogen, aliphatic C1-4, OH, O (aliphatic C1-4), N02 , CN, C (0) 0H, C (0) 0 (C1-4 aliphatic), 0 (C1-4 haloaliphatic) or C1-4 haloaliphatic, where each of the above C1-4 aliphatic groups of R ° 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 an unsaturated carbon of an aryl or heteroaryl group and additionally include the following: = 0, = S, = NNHR *, = NN (R *) 2, = NNHC (0) R *, = NNHC (0) 0 (alkyl), = NNHS (0) 2 (alkyl) or = NR *, where each R * is selected , independently, of hydrogen or an optionally substituted Ci-6 aliphatic. Optional substituents in the aliphatic group of R * are selected from NH2, NH (C1-4 aliphatic), N (aliphatic Ci-4) 2, halogen, aliphatic Ci-4, OH, O (C1-4 aliphatic), N02 , CN, C (0) 0H, C (0) 0 (C1-4 aliphatic), 0 (haloaliphatic Ci-4), or halo (C1-4 aliphatic), wherein each of the above Ci-4 aliphatic groups of R * is not substituted. In some embodiments, substituents on the nitrogen of a non-aromatic heterocyclic ring include -R +, -N (R +) 2, -C (0) R +, -C (0) 0R +, -C (0) C (0 ) R +, -C (0) CH2C (0) R +, -S (0) 2R \ -S (0) 2N (R +) 2, -C (= S) N (R +) 2, -C (= NH) - N (R +) 2, or -NR + S (0) 2R +; wherein R + is hydrogen, an optionally substituted Ci-6 aliphatic, optionally substituted phenyl, -O (Ph) optionally substituted, -CH2 (Ph) optionally substituted, - (CH2) 1-2 (Ph) optionally substituted; -CH = CH (Ph) optionally substituted; or an unsubstituted 5-6 membered heteroaryl ring or a heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen or sulfur or, despite the above definition, two independent occurrences of R +, in the same substituent or on different substituents, taken together with the one or more atoms to which each R + group is attached, form a 5-8 membered heterocyclyl, aryl or heteroaryl ring or a 3-8 membered cycloalkyl ring, wherein said ring heteroaryl or heterocyclyl has 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Optional substituents on the aliphatic group or the phenyl group of R + are selected from NH2, NH (C1-4 aliphatic), N (aliphatic Ci-4> 2, halogen, C1-4 aliphatic, OH, Ofaliphatic d-4) , N02, CN, C (0) OH, C (O) O (C1-4 aliphatic), O (C1-4 haloaliphatic), or halo (C1-4 aliphatic), wherein each of the C1- aliphatic groups 4 of R + is not substituted.

As detailed above, in some embodiments, two independent occurrences of R ° (or R + or any other variable similarly defined herein), it can be taken together with the atoms to which each variable is linked to form a 5-8 membered heterocyclyl, aryl or heteroaryl ring or a 3-8 membered cycloalkyl ring. Example rings that are formed when two independent occurrences of R ° (or R + or any other variable defined herein similarly) are taken together with the atom (s) to which each variable group is attached include, but are not limited to , the following: a) two independent occurrences of R ° (or R + or any other variable defined in the present in a similar way) that are linked to the same atom and are taken together with that atom to form a ring, for example, N ( R °) 2, where both occurrences of R ° 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 ° (or R + or any other variable defined herein in a similar manner) which are attached to different atoms and taken together with both atoms to form a ring, for example where a phenyl group is substituted with two apparitions of these two occurrences of R ° are taken together with the oxygen atoms to which they are attached to form a ring fused with 6-membered oxygen: It will be appreciated that a variety of other rings can be formed when two independent occurrences of R ° (or R + or any other variable defined herein similarly) are taken together with the atoms to which each variable is linked and that the examples detailed above are not intended to be limiting. In some embodiments, an alkyl or aliphatic chain may be optionally interrupted by another atom or group. This means that one methylene unit of the alkyl or aliphatic chain is optionally replaced with another atom or group. Examples of these atoms or groups will include, but are not limited to, but not limited to -NR-, -O-, -S-, -C (0) 0-, -OC (O) -, -C (0) C (0) -, -C (O) -, -C (0) NR-, -C (= N-CN), -NRC (O) -, -NRC (0) 0-, -S (0) 2NR -, -NRS (0) 2-, -NRC (0) NR-, -OC (0) NR-, -NRS (0) 2NR-, -S (O) -, or -S (0) 2-, where R is as defined herein. Unless otherwise specified, the optional replacements form a chemically stable compound. Optional interruptions can occur both within the chain and at the ends of the chain; both at the point of attachment as well as at the terminal end. Two optional replacements may also be adjacent to each other within a chain provided that a chemically stable compound results. Unless otherwise specified, when the replacement or interruption occurs at the terminal end, the replacement atom joins an H at the terminal end. For example, if -CH2CH2CH3 is optionally interrupted by -O-, the resulting compound can be -OCH2CH3, -CH2OCH3, or -CH2CH2OH. As described herein, a link drawn from a substituent to the center of a ring within a multi-ring system (as indicated below), represents the substitution of the substituent at any substitutable position on any of the rings within the ring. multi-ring system. For example, Figure a represents the possible substitution in any of the positions indicated in Figure b.

Figure a Figure b This also applies to multi-ring systems fused to optional ring systems (which will be represented by dotted lines). For example, in Figure c, X is an optional substituent of ring A and ring B.

Figure o However, if two rings in a multi-ring system each have different substituents taken from the center of each ring, then, unless otherwise specified, each substituent only represents the substitution in the ring to which it is attached . For example, in Figure d, Y is an optional substituent for ring A only, and X is an optional substituent for ring B only.

Figure d Unless otherwise stated, structures represented herein also include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) of the structure; for example, the R and S configurations for each asymmetric center, double bond isomers (Z) and (E) and conformational isomers (Z) and (E). Consequently, the Individual stereochemic isomers as well as the 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, the structures depicted herein also 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 13C- or 14C-enriched carbon are within the scope of the invention. Such compounds are useful, for example, as analysis tools or probes in biological assays.

Description of the compounds of the invention The present invention relates to a compound of the formula I: or one of its pharmaceutically acceptable salts wherein R1 is - (aliphatic Ci- ^ p-R4, wherein each R1 is optionally substituted with 1-3 occurrences of J; R2 is - (aliphatic Ci-2) d-R5, where each R1 is optionally substituted with 1-3 occurrences of J; R4 is H, halogen, CN, NH2, N02, CF3, aliphatic Ci-3, cyclopropyl, NCH3, OCH3, -C (= 0) NH2, -C ( = 0) CH3, -NHC (= 0) CH3, or OH; R5 is H, halogen, CN, NH2, N02, CF3, aliphatic Ci-3, cyclopropyl, NCH3, OCH3, -C (= 0) NH2, -C (= 0) CH3, -NHC (= 0) CH3, or OH; J is halogen, OCH3, OH, N02, NH2, SCH3, NCH3, CN or aliphatic Ci-2 unsubstituted, or two groups J, together with the carbon to which they are attached, form a cyclopropyl ring or C = 0; p and d are each, independently 0 6 1; Q is a saturated, partially saturated or unsaturated 5-8 membered monocyclic ring having 0-3 heteroatoms selected from nitrogen, oxygen or sulfur; or an 8-12 member bicyclic ring having 0-6 heteroatoms selected from nitrogen, oxygen or sulfur; wherein Q is optionally substituted with 1-10 occurrences of JQ; JQ is halogen, OCF3, - (V -R ", - (VJ-CN, - (VJ -N02 or - (VJ- (haloaliphatic Ci-4), or two JQ groups together with the carbon to which they are attached, form a saturated, partially saturated or unsaturated ring of 3-8 members having 0-3 heteroatoms selected from O, N, or S, wherein said ring is optionally substituted with 0-4 occurrences of Ju; V is an aliphatic Ci-i0 , wherein up to three methylene units are replaced by Gv, where Gv is selected from -NH-, -NR-, -O-, -S-, -C (0) 0-, -OC (O) -, -C (0) C (0) -, -C (O) -, -C (0) NH-, -C (0) NR-, -C (= N-CN), -NHC (O) -, -NRC (O) -, -NHC (0) 0-, -NRC (0) 0-, -S (0) 2NH-, -S (0) 2NR-, -NHS (0 ) 2-, -NRS (0) 2-, -NHC (0) NH-, -NRC (0) NH- -NHC (0) NR-, -NRC (0) NR, -OC (0) NH-, -OC (0) NR-, -NHS (0) 2NH-, -NRS (0) 2NH-, -NHS (0) 2NR-, -NRS (0) 2NR-, -S (O) -, or -S (0) 2-; and wherein V is optionally substituted with 1-6 occurrences of Jv; R "is H or is an optionally substituted group selected from Ci-6 aliphatic, C3-i0 cycloaliphatic, Ce-ar aryl, 5-10 membered heteroaryl or 5-10 heterocyclyl members; or two R "groups, in the same substituent or in different substituents, together with the one or more atoms to which each R" group is attached, 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 Ci-6 aliphatic, C3-10 cycloaliphatic, C6-io aryl, heteroaryl 5-10 members or 5-10 membered heterocyclyl, or two R groups, in the same substituent or in different substituents, together with the one or more atoms to which each R group is attached, form a 3-8 membered heterocyclyl optionally substituted, where each group R is substituted, independently and optionally, with 1-4 occurrences of Jx, each Jv, Ju, Jx, and JR are each independently selected from halogen, L, - (Ln ) -R ', - (Ln) -N (R') 2, - (Ln) -SR ', - (Ln) -OR', - (Ln) - (C3-10 cycloaliphatic), - (Ln) - (C6-io aryl), - (Ln) - (5-10 membered heteroaryl), - (Ln) - (5-10 membered heterocyclyl), oxo, C1-4 haloalkoxy, C1- haloalkyl 4, - (Ln) -NC > 2, - (Ln) ~ CN, - (LJ-OH, - (Ln) -CF3, -C (0) OR ', -C (0) OH, -C (0) R', -C (0) H, -OC (0) R ', or -NC (0) R'; or two groups Jv, Ju, Jx, or JR, either in the same substituent or in different substituents, together with the one or more atoms to which each group Jv, Ju, Jx and JR is attached, form a saturated, unsaturated or partially saturated of 5-7 members; R 'is H or aliphatic Ci-6; or two groups R ', or a group R' and a group R, together with the atom to which they are attached, optionally form a cycloaliphatic or heterocyclyl of 3-6 members, wherein said aliphatic, cycloaliphatic or heterocyclyl is optionally substituted with R *, -OR *, -SR *, -N02, -CF3, -CN, -C (0) OR *, -C (0) R *, OC (0) R *, or NHC (0) R *, wherein R * is H or an unsubstituted Ci-6 aliphatic; L is an aliphatic Ci-6, where up to three methylene units are replaced by -NH- -NR6-, -0-, -S-, -C (0) 0-, -0C (0) -, -C (0) C (0) -, -C (O) -, -C (0) NH-, -C (0) NR6-, -C (= N-CN), -NHC (O) -, -NR6C (0) -, -NHC (0) 0-, -NR6C (0) 0-, -S (0) 2NH-, -S (0) 2NR6-, -NHS (0) 2-, -NR6S (0) 2-, -NHC (0) NH-, -NR6C (0) NH-, -NHC (0) NR6-, -NR6C (0) NR6, -0C (0) NH-, -0C (0) NR6-, -NHS (0) 2NH-, -NR6S (O) 2NH-, -NHS (0) 2NR6-, -NR6S (0) 2NR6-, -S (0) -, O -S (0) 2 -R6 is selected from Ci-6 aliphatic, C3-i0 cycloaliphatic, C6-io aryl, 5-10 membered heteroaryl or -10 membered heterocyclyl; or two R6 groups, in the same substituent or in different substituents, together with the one or more atoms to which each R6 group is attached, form a 3-8 membered heterocyclyl; m and n are each, independently, 0 or 1; with the proviso that when R2 is Cl, NH2, or NCH3, then Q is not optionally substituted phenyl; and when R1 and R2 are H, then Q is not In one embodiment, when R1 is C (= 0) Et, then Q In another embodiment, Q is a 5-10 membered aryl or heteroaryl ring optionally substituted with 1-5 JQ groups. In another embodiment, Q is a 5-6 membered aryl or heteroaryl ring optionally substituted with 1-3 JQ groups. In still another embodiment, Q is a 6-membered heteroaryl ring selected from pyridyl, pyrimidyl, pyrazinyl, triazinyl or pyridazinyl optionally substituted with 1-3 JQ groups.

In another embodiment, the invention comprises a compound having the formula Il-a: Wherein each of R1, R2, and JQ is as defined for formula I; each of Z1 and Z2 is, independently, CH or N, wherein at least one of Z1 or Z2 is N; and Z3 is C-JQ or N. In one embodiment, each of Z1 and Z2 is N. In another embodiment, each of Z1 and Z2 is N and Z3 is C-JQ. In another embodiment, each of Z1, Z2, and Z3 is N. In another embodiment, Z1 is N, and each of Z2 and Z3 is CH. In yet another embodiment, each of Z1 and Z3 is N and Z2 is CH. The present invention also provides a compound of the formula I or the formula Il-a wherein JQ is halo, -NO2, -CN, - ", -V-R", -V-CN or -V-N02. In another embodiment, at least one JQ is -VR. "In another embodiment, V is C 1-6 alkyl, wherein two methylene units are replaced by Gv and each Gv is selected, individually, from -NH- , -NR-, -0-, -S-, -C (0) 0-, -0C (0) -, -C (O) -, -C (0) NH-, -C (0) NR- , -NHC (O) - or -NRC (O) - In another embodiment, a Gv is directly linked to R ".

In yet another embodiment, a Gv is directly linked to Q. In another embodiment of the invention, V is substituted with up to two group Jv, wherein each Jv is individually Ci-3 alkyl or two Jv groups, together with the carbon to which they are attached form a cycloalkyl ring of 3-6 members. Another embodiment, Jv is selected from halogen, NH2, N02, CN, OH, Ci-3 alkyl, C1-3 haloalkyl, C1-3 haloalkoxy, - (C1-3 alkyl) -0- (C1-3 alkyl) , - (Ci-6 alkyl) -0H, -0- (Ci-6 alkyl), -NH- (Ci-6 alkyl), -N (Ci-6 alkyl) 2, -C (= 0) 0 (alkyl) Ci-6), -C (= 0) OH, -C (= 0) (Ci-6 alkyl), -C (= 0) H, -0C (= 0) (Ci-6 alkyl), -NC ( = 0) (C 1-6 alkyl), C 1-6 alkyl-CN, or oxo. In still another embodiment, Jv is selected from Ci-6 alkyl, CF 3, - (Ci-3 alkyl) CF 3, -0- (Ci-6 alkyl), -CH 20- (C 1-3 alkyl), -C ( = 0) (Ci-6 alkyl), -C (= 0) 0H, or -C (= 0) 0 (Ci_6 alkyl). The present invention also provides a compound of formula I or formula Il-a wherein each occurrence of JQ is independently selected from R ", -CH2R", halogen, CN, N02, -C (0) R ", -C (0 ) R9R ", -N (R ') R", -CH2N (R') R ", -0R", -CH20R ", -SR", -CH2SR ", -C (0) 0R", -NR'C (0) R ", -NR 'C (0) R9R", -NR'C (0) 0R ", -NR'C (0) 0R9R", -C (0) (R') R ", -C (0) N (R ') R9R ", -C (0) NHR90R", -C (0) N (R') R90R ", -S (O) 2N (R ') R", -S (0) 2N (R ') R9R ", -C (0) N (R') R9N (R ') R", -OR9OR ", -0R9N (R') R", -NR 'C (R') (R) R -NR'C (R ') (R8) C (0) OR' -N (R ') R9R " -N (R ') R9R ", -N (R') R9N (R ') R", -N (R') R9OR ", -NR 'C (R') (R8) R", -NR'CH2C (0) N (R ') R ", or -NR' C (R ') (R8) C (O) N (R') R", wherein a) R8 is H, Ci-6 alkyl, CF3, CH2CF3, CH2CN, or CH2OR '; or R8 and R ', taken together with the atom (s) to which they are attached, form a 3-8 membered ring having 0-3 heteroatoms selected from O, N, or S optionally substituted with 0-4 occurrences of Jv, or b) R9 is aliphatic Ci-6; wherein each R8 and R9 is independently and optionally substituted with 1-4 occurrences of Jv; or two JQ groups, together with the atoms to which they are attached, form a saturated, unsaturated or partially saturated ring of 3-8 members with 0-3 heteroatoms selected from O, N, or S optionally substituted with 0-4 occurrences of Jv. In another embodiment of JQ, R "is selected from hydrogen, a C1-C6 aliphatic group optionally substituted with up to six occurrences of R7, or R" is a ring selected from: ?? or two occurrences of R ', or R' and R ", taken together with the nitrogen atom to which they are attached, form an optionally substituted 3-10 membered monocyclic or bicyclic heterocyclic ring selected from: where y is 0, 1, 2 6 3, and each occurrence of R7 is independently R ', -CH2R', halogen, -CH2CH, -CN, -N02, -N (R ') 2, -CH2N (R' ) 2, -OR ', -CH2OR', -SR ', -CH2SR', -C (0) OR ', -C (0) R', -NR9C (0) R ', -NR9C (0) OR' , -C (0) N (R ') 2, -S (O) 2N (R') 2, -NR 9 S (0) 2 R ', -C (0) NR 9 (CH 2) 2 N (R 9) R', - C (O) NR9 (CH2) 3N (R9) R ', -C (0) NR9 (CH2) 4N (R9) R ', -0 (CH2) 2OR', -0 (CH2) 3OR ', -0 (CH2) 4OR', -0 (CH2) 2N (R9) R ', -0 (CH2) 3N (R9) R', -0 (CH2) 4N (R9) R ', -NR9CH (CH2OH) R ', -NR9CH (CH2CH2OH) R', -NR9 (CH2) R ', NR 9 (CH 2) 2 R ', -NR 9 (CH 2) 3 R', -NR 9 (CH 2) R ', -NR 9 (CH 2) N (R 9) R', -NR 9 (CH 2) 2 N (R 9) R ', -NR 9 ( CH2) 3N (R9) R ', -NR9 (CH2) 4N (R9) R', NR9 (CH2) OR ', -NR9 (CH2) 2OR', -NR9 (CH2) 30R ', or -NR9 (CH2) 40R '; wherein R9 is H or R6. In another embodiment of the invention, J ° is selected from -N (R ') R ", -NR'C (0) R", -NR' C (0) R9R ", -NR'C (0) 0R ", -NR 'C (0) 0R9R", -NR' CH (R8) R ", -NR 'CH (R8) C (0) OR", -N (R') R9R ", -N (R ') R9R ", -N (R') R9N (R ') R", -N (R') R90R ", -NR'CH (R8) R", -NR'CH2C (0) N (R ') R ", or -NR 'CH (R8) C (0) N (R') R".

The present invention also relates to a compound having the formula Il-b: wherein each of Z1, Z2, and Z4 is, independently, CH or N, and wherein at least one of Z1 or Z2 is N. In one embodiment, each of Z1 and Z2 is N. In one form of realization, JQ is where R is optionally substituted with up to two occurrences of Jv. In one embodiment, r is 0 and R ', R8 and the intermediate carbons together are: It is still another embodiment, JQ is , wherein R is optionally substituted with up to two occurrences of Jv. The present invention also provides a compound of the formula I, of the formula ?? - a, or of the formula II-b, wherein p is 0. In one embodiment, R1 is H, halogen, CN, O2, CF3, CH3, OCH3 or OH. In another embodiment, R1 is H, halogen or CF3. It is still another embodiment, R1 is H. The present invention also provides a compound of the formula I, of the formula Il-a or of the formula II-b, in where d is 0. In one embodiment, R2 is H, halogen, CN, N02, CF3, CH3, OCH3 or OH. In another embodiment, R2 is H, halogen or CF3. It is still another embodiment, R2 is H. The present invention also provides a compound of the formula I, of the formula Il-a or the formula ??? b, wherein R1 and R2 are H. The present invention is also refers to a compound having the formula III: (III), wherein Z2 is CH or N; Z3 is C-JQ3 or N; JQ1 is -N (R ') R ", -CH2N (R') R", -NR'C (0) R ", -NR 'C (O) R9R", -NR'C (0) OR ", -NR'C (0) OR9R ", -NR 'C (R') (R8) R", NR'C (R ') (RB) C (0) OR ", -N (R') R9R", -N (R ') R9R ", -N (R ') R9N (R') R ", -N (R ') R9OR", -NR'C (R') (R8) R ", -NR'CH2C (0) N (R ') R ", or -NR' CR '(R8) C (O) N (R') R"; JQ2 is hydrogen, -C (0) OH, -C (0) OR ", -C (0) OR9R", -C (0) R ", - C (0) R9R", -C (0) NHR " , -C (0) N (R) R ", -C (O) HR9OR", -C (0) NHR9R ", -C (0) N (R) R9R", -OH, -OR ", -CN , or -R "; where a) R is H, Ci-6 alkyl, CF3, CH2CF3 CH2CN, or CH2OR '; or R8 and R ', taken together with the atom (s) to which they are attached, form a 3-8 membered ring having 0-3 heteroatoms selected from O, N , or S, wherein R6 or said ring is optionally substituted with 0-4 occurrences of Jv; b) R9 is aliphatic Ci-6; or R9 and R or R ', taken together with the atom (s) to which they are attached, form a 3-8 membered ring having 0-3 heteroatoms selected from O , or S, where R9 or said ring is optionally substituted with 0-4 occurrences of Jv; and JQ3 is hydrogen, halo or N02. In one embodiment of compounds having the formula III, Z2 is CH. In another embodiment, Z2 is N. In yet another embodiment, Z3 is C-JQ3 and JQ3 is hydrogen. In still another embodiment, Z3 is C-JQ3 and JQ3 is F. In another embodiment, Z3 is N. It is still another embodiment, both Z2 and Z3 are N. In another embodiment, JQ2 is hydrogen . In another embodiment, JQ2 is -C (0) OH, -C (0) OR ", -C (0) R", -C (0) NHR ", -C (0) N (R) R" , -C (O) (R) R9R ", -CN, O -R", wherein JQ2 is optionally substituted with up to two occurrences of Jv.

In another embodiment JQ is: , wherein R8 is optionally substituted with up to two occurrences of Jv. In still another embodiment, JQ1 is: R8 | _ | ? , wherein R8 is optionally substituted with up to two occurrences of Jv. In still another embodiment of compounds having the formula III, JQ1 is as defined directly above and JQ2 is hydrogen. In another embodiment of compounds having the formula III, JQ1 is , wherein ring A is optionally substituted with up to two occurrences of Jv. In yet another embodiment, ring A is selected from: where Jv 'is H or Jv. In still another embodiment of a compound of formula III, JQ1 is as defined directly above and JQ2 is hydrogen. In another embodiment of compounds having the formula III, JQ1 is In yet another embodiment of compounds having the formulas Il-a, β-b, or III, R8 is selected from In still another embodiment of compounds having the formulas Il-a, β-b or III, R ', Re, and the intermediate carbons are: In another embodiment of compounds having the formulas Il-a, β-b or III, R "is CH 3, CH 2 CH 3 or CH 2 CH 2 CH 3, CF 3, CH 2 CF 3 or CH 2 CH 2 CF 3.

In another aspect, the invention relates to a compound selected from the group of compounds listed in Table 1. 4 5 6 14 15 40 31 32 33 40 41 42 49 50 51 58 59 60 70 71 72 73 74 75 76 77 78 79 80 81 88 89 90 97 98 99 106 107 108 Formulation and administration of compounds of the invention In another embodiment, the invention provides a pharmaceutical composition comprising a compound of the formulas I, II-a, β-b or III. In still another embodiment, the composition further comprises a therapeutic agent selected from a chemotherapeutic agent or an antiproliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for the treatment of cardiovascular disease, an agent for the treatment of destructive bone disorders, an agent for the treatment of liver disease, an antiviral agent, an agent for the treatment of blood disorders, an agent for the treatment of diabetes or an agent for the treatment of 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 it is effective to measurably inhibit a protein kinase, in particular a kinase of the JAK family, 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 a composition. Most preferably, the composition of this invention is formulated to be administered orally to a patient. The term "patient", as used herein, means an animal, preferably a mammal, and more 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 also optionally comprise one or more additional therapeutic agents. It will also be appreciated that some of the compounds of the present invention may exist in free form for treatment or when appropriate, as its pharmaceutically acceptable derivative. According to the present invention, a pharmaceutically acceptable derivative includes, without limitation, prodrugs, salts, esters, salts of said pharmaceutically acceptable esters or any other adduct or derivative, which upon administration to a patient in need thereof is capable of providing , directly or indirectly, a compound as described elsewhere herein or as its metabolite or residue. As used herein, the term "pharmaceutically acceptable salt" refers to salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human and lower animals without undue toxicity, irritation , allergic response, and the like, and are associated with a reasonable risk / benefit ratio. A "salt "pharmaceutically acceptable" means any non-toxic salt or salt of an ester of a compound of this invention which upon administration to a recipient is capable of providing, directly or indirectly, a compound of this invention or its metabolite or active residue in an inhibitory manner. As used herein, the term "its metabolite or active residue in an inhibitory manner" means that one of its metabolites or residues is also an inhibitor of a kinase of the JAK family.Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al., Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences 1977, incorporated herein by reference, The pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic acids and bases. and organic are examples of pharmaceutically acceptable non-toxic acid addition salts of a 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 use other methods employed in the art such as ion exchange Other pharmaceutically acceptable salts include salts of adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorrate, camphorsulfonate, citrate, cyclopentanpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate , heptanoate, hexanoate, iodhydrate, 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, and the like. The salts derived from bases include alkali metal, alkaline earth metal, ammonium and N + (Ci-4 alkyl) 4 salts. The present invention also contemplates the quaternization of any basic nitrogen-containing group of the compounds described herein. Hydro-or liposoluble or dispersible products can be obtained by said quaternization. Representative salts of alkali or alkaline earth metals include those of sodium, lithium, potassium, calcium, magnesium, and the like. Other salts pharmaceutically acceptable include, when appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed with counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate. As described above, the pharmaceutically acceptable compositions of the present invention also comprise a pharmaceutically acceptable carrier, adjuvant or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid, auxiliary vehicle dispersion or suspension, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as is suitable for the particular dosage form desired. Re ington's Pharmaceutical Sciences, sixteenth edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980); Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia; and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, whose contents are incorporated herein by reference, describe various carriers used in the formulation of compositions pharmaceutically acceptable and known techniques for their preparation. Except when 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 of the pharmaceutically acceptable composition, its use is contemplated within the scope of the present invention. Some examples of materials that can serve as a pharmaceutically acceptable carrier include, without limitation, 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 mixtures of saturated vegetable fatty acid glycerides, 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, lanolin, 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; jelly; talcum powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cotton oil; sassafras oil; Sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laureate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic physiological solution; Ringer's solution; ethyl alcohol and phosphate buffer solutions, in addition to other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition, according to the formulator's criteria. The term "measurably inhibiting", as used herein means a measurable change in kinase activity, in particular of the JAK family, between a sample comprising a compound of this invention and a JAK kinase and a sample equivalent comprising JAK kinase in the absence of said compound.

The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or by an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. The sterile injectable forms of the compositions of this invention may be an aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art, using appropriate dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the vehicles and suitable solvents that may be employed are water, Ringer's solution, isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as solvent or suspension medium.

For this purpose, any soft fixed oil, including mono or synthetic diglycerides, can be used. In addition, fatty acids such as oleic acid and its glyceride derivatives are used in the preparation of injectables, as pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oily solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethylcellulose 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 moieties, which are commonly used in the manufacture of solid, liquid, or other pharmaceutically acceptable dosage forms can also be used for the purpose of formulation. . The pharmaceutically acceptable compositions of this invention can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, suspensions or aqueous solutions. In the case of tablets for oral use, commonly used carriers include lactose and starch of corn. Generally, lubricating agents are also added, such as magnesium stearate. For oral administration in capsule form, useful diluents include lactose and dried corn starch. 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 which is solid at room temperature but liquid at rectal temperature and consequently fuses in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutically acceptable compositions of this invention can also be administered topically, especially when the treatment target includes easily accessible areas or organs for topical application, including diseases of the eye, the skin or the lower intestinal tract. Suitable topical formulations are easily prepared for each of these organs or areas.

Topical application to the lower intestinal tract can be done in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical-transdermal patches can also be used. For topical applications, the pharmaceutically acceptable compositions can 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, emulsifying wax and water compounds. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components in suspension or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. For ophthalmic use, pharmaceutically acceptable compositions can be formulated, by example, as micronized suspensions in physiological solution or other isotonic aqueous solution, with adjusted pH, or, preferably, as solutions in physiological solution or other sterile isotonic aqueous solution, with adjusted pH, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum. The pharmaceutically acceptable compositions of this invention can also be administered by nasal spray or inhalation. Said compositions are prepared according to techniques well known in the pharmaceutical formulating art and can be prepared as solutions in physiological solution, employing benzyl alcohol or other suitable preservatives, absorption promoters to improve 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. Besides 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, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and its mixtures. In addition to inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, saaborizers and perfuming agents. Injectable preparations, for example sterile injectable aqueous and oily suspensions, can be formulated according to the known art by suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that Water, Ringer's solution, U.S.P. sodium chloride solution can be used. and isotonic. In addition, sterile fixed oils are conventionally used as solvent or suspension medium. For this purpose any soft fixed oil can be used, 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 bacteria retention 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 before their use. In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the subcutaneous or intramuscular injection compound. This can be achieved by the use of a liquid suspension of crystalline or amorphous material with low water solubility. The rate of absorption of the compound then depends on its rate of dissolution which, in turn, may depend on the size of the crystal and the crystalline form. Alternatively, delayed absorption of a compound administered parenterally is achieved by dissolving or suspending the compound in an oil vehicle.

Injectable depot forms are prepared by forming microencapsulated matrices of the compound into biodegradable polymers such as polylactide-polyglycolide. Depending on the proportion of the compound being polymerized and the nature of the particular polymer used, the rate of release of the compound 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 is solid at room temperature, but liquid at body temperature and consequently melts in the rectum or vaginal cavity and releases the active compound. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In said solid dosage forms, the active compound is mixed with the less an inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or) 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) agents solution delays 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 ) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulphate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form can also comprise buffering agents. Solid compositions of similar type can also be used as fillers in hard or soft filled gelatin capsules using excipients such as lactose or milk sugar in addition to polyethylene glycols of high molecular weight, 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 art of pharmaceutical formulations. Optionally they may contain opacifying agents and may also be a composition that releases the active ingredient (s) only or preferably in a certain part of the intestinal tract, optionally in a delayed manner. Examples of inclusive compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillings in soft or hard filled gelatin capsules by excipients such as lactose or milk sugar, in addition to high molecular weight polyethylene glycols, and the like. The active compounds may also be in microencapsulated 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 control coatings and other coatings well known in the art of pharmaceutical formulations. In said solid dosage forms, the active compound can be mixed with at least one diluent inert such as sucrose, lactose or starch. Said dosage forms may also comprise, as is normal practice, additional substances in addition to inert diluents, for example, compressed lubricants and other tablet auxiliaries such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Optionally they may contain opacifying agents and may also be a composition that releases the active ingredient (s) only or preferably in a certain part of the intestinal tract, optionally in a delayed manner. Examples of inclusive 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 mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservative or buffer that may be required. Ophthalmic formulations, ear drops and optical drops are also contemplated as being within the scope of this invention. In addition, the present invention contemplates the use of transdermal patches, which have the additional advantage of providing the controlled supply of a compound to the organism. Said dosage forms can be prepared by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer or gel matrix. The compounds of the invention are preferably formulated in a unit dosage form to facilitate administration and uniformity of dosage. The term "unit dosage form," as used herein, refers to a physically discrete unit of agent suitable for treating the patient. However, it will be understood that the total daily use 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 on a variety of factors including the disorder treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; age, body weight, general health, sex and patient's diet; the time of administration, the route of administration, and the rate of excretion of the specific compound employed; the duration of the treatment; the drugs used in combination or coincidentally with the specific compound employed and similar factors well known in the medical arts. The amounts of the compounds of the present invention that can be combined with the carrier materials to produce a composition in a single dosage form will vary according to the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a dose of between 0.01-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving said compositions. According to the particular pathological condition or disease to be treated or prevented, other therapeutic agents that are normally administered to treat or prevent said pathological condition in the compositions of this invention may also be present. As used herein, the therapeutic agents normally administered to treat or prevent a particular disease or pathological condition are termed "appropriate for the disease or condition treated".

For example, chemotherapeutic agents or other antiproliferative agents can 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 with which the inhibitors of this invention may also be combined include, without limitation: treatments for Alzheimer's disease such as Aricept® and Excelon®; treatments for Parkinson's disease such as L-DOPA / carbidopa, entacapone, ropinrol, pramipexole, bromocriptine, pergolide, trihexefendil and amantadine; agents for treating multiple sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; asthma treatments such as albuterol and Singulair®; agents for treating schizophrenia such as ziprexa, 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, interferons, corticosteroids, cyclophophamide, azathioprine and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole and antiparkinson agents; agents for the treatment of cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; agents for treating liver diseases such as corticosteroids, cholestyramine, interferons and antiviral agents; agents for treating blood disorders such as corticosteroids, antileukemic 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 not be greater than the amount that would normally be administered in a composition comprising said therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the compositions described herein will vary from about 50% to 100% of the amount normally present in a composition comprising said agent as the only therapeutically active agent.

Uses of the compounds and compositions of the invention In another embodiment, the invention comprises a method for inhibiting JAK activity in a biological sample, comprising contacting said biological sample with a compound or composition of the invention. In another embodiment, the invention comprises a method for inhibiting the activity of JAK kinase in a patient, comprising administering to said patient a compound or composition of the invention. In another embodiment, the invention comprises a method for treating or reducing the severity of a pathological condition or disease mediated by JAK in a patient. The term "JAK-mediated pathological condition" or "disease", as used herein, means any disease or other deleterious pathological condition in which it is known that the family of JAK kinases, in particular JAK2 or JAK3, play a role. big role. Such pathological 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, lateral sclerosis. amyotrophic, and multiple sclerosis, neurodegenerative disorders such as familial amyotrophic lateral sclerosis (FALS), in addition to solid and hematological malignancies such as leukemias and lympholas. In another embodiment, the invention provides a method for treating or reducing the severity of a disorder or pathological condition selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a pathological condition associated with an 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 another embodiment, the method comprises the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic agent or an antiproliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for the treatment of cardiovascular disease, an agent for the treatment of diabetes or an agent for the treatment of immunodeficiency disorders, wherein said additional therapeutic agent is appropriate for the disease in treatment and said additional therapeutic agent is administered together with said composition as a single or separate dosage form of said composition as part of a multiple dose form. In one embodiment, the disease or disorder is type I hypersensitivity or allergic reactions, asthma, diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-associated dementia, amyotrophic lateral sclerosis (ALS, Lou Gehrig), multiple sclerosis (MS), schizophrenia, cardiomyocytic hypertrophy, reperfusion / ischemia, stroke, baldness, transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis, and solid malignancies and hematologic such as leukemias and lympholas. In another 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 can 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, systemic mastocytic disease, atypical CML or juvenile myelomonocytic leukemia. The term "biological sample", as used herein, means a sample outside a living organism and includes, without limitation, cell cultures or their extracts; of a mammal or its extracts; and blood, saliva, urine, feces, semen, tears or other bodily fluids or their extracts. The inhibition of kinase activity, in particular the activity of JAK kinase, in a biological sample is useful for a variety of purposes as is known to one skilled in the art. Examples of such purposes include, but are not limited to, blood transfusions, organ transplants, storage of biological specimens and biological assays. In certain embodiments of the present invention, an "effective amount" of the pharmaceutically acceptable compound or composition is the amount effective to treat or reduce the severity of one or more of the aforementioned disorders. The compounds and compositions, according to the method of the present invention, can be administered using any amount and any route of effective administration to treat or reduce the severity of the disorder or disease. The exact amount required will vary from one subject to another, 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 alternative embodiment, the methods of this invention comprise the additional step of separately administering to said patient another therapeutic agent. When such additional therapeutic agents are administered separately, they can be administered to the patient before, in sequence or after administration of the compositions of this invention. The compounds of this invention or their pharmaceutical compositions can also be used to coat 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 vascular wall after an injury). However, patients who use stents or other implantable devices they run the risk of clot formation or platelet activation. These undesired effects can be prevented or mitigated by precoating the device with a pharmaceutically acceptable composition comprising a compound of this invention. Suitable covers and general preparation of coated implantable devices are described in U.S. Patents 6,099,562; 5,886,026 and 5,304,121. The covers are generally biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, ethylene vinyl polylactic acid acetate, and mixtures thereof. The covers can also optionally be coated with an upper cover of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics to the composition. Implantable devices coated with a compound of this invention are another embodiment of the present invention. The compounds can also be coated with an implantable medical device, such as beads or co-formulated with a polymer or other molecule, to provide a "pharmacological deposit", and thus allow drug release. for a longer period than the administration of an aqueous solution of the drug.

Preparation of compounds of the invention The compounds of this invention can be prepared in general by methods known to those skilled in the art for analogous compounds or by those methods shown in the following examples.

The following definitions describe some of the terms and abbreviations used herein: Ac acetyl atm atmosphere ATP adenosine triphosphate Boc tert-butoxycarbonyl BSA bovine serum albumin Bu butyl DCM dichloromethane DIEA diisopropylethylamine (also DIPEA) DME 1,2-dimethoxyethane DMF dimethylformamide DMSO dimethyl sulfoxide dppf 1,1'-bis (diphenylphosphine) -ferrocene DTT dithiothreitol EDC l-ethyl-3- (3-dimethylaminopropy) carbodiimide hydrochloride Et ethyl EtOAc ethyl acetate Glu glutamic acid or glutamyl HBTU O-benzotriazole-l-yl- N, N, N ', N' -tetramethyluronium hexafluorophosphate HEPES acid 4- (2-hydroxyethyl) -1-piperazineethanesulfonic HOBT hydroxybenzotriazole Me methyl MW MW NMP N-methyl pyrrolidone Ph phenyl rt room temperature R.T. retention time TFA trifluoroacetic acid THF tetrahydrofuran Ts toluenesulfonyl Tir tyrosine or tyrosyl Examples Example: Preparation of 5- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidine (compound 1005) As shown in Figure 1-step i, 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (compound 1001) (130 mg, 0.847 mmol) was dissolved in 3 mL of methanol and hydrogenated with 1 hydrogen atmosphere over Pd-C 10% for 16 hours. Concentration to dryness afforded 100 mg (98%) of ?? -pyrrolo [2,3-d] pyrimidine [compound 1002, 1 H-NMR (CD30D): d 9.4 (s, 1H); 9.1 (s, 1H); 7.9 (s, 1H); 7.1 (s, 1H)]. [0100] As shown in Figure 1-steps ii & iii, bromine (134 mg, 0.839 mmol) in DMF (2 mL) was added to a solution of compound 1002 (100 mg, 0.839 mmol) in 3 mL of DMF and the reaction mixture was stirred at room temperature for 2 hours. hours. The mixture was then poured into ice water and treated with aqueous sodium thiosulfate and potassium carbonate. The aqueous phase was extracted with EtOAc, washed with brine, dried with MgSO 4 and concentrated to give 120 mg of compound 1003 as a solid residue which was used directly for the next step. Sodium hydride (32 mg, 1.22 mmol) was added to a stirred solution of compound 1003 (120 mg, 0.61 mmol) in 3 mL of dry THF at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour. Toluenesulfonyl chloride (128 mg, 0.67 mmol) was added to the reaction mixture, which was then stirred at room temperature for an additional 1 hour. The volatiles were removed in vacuo and the residue was diluted with ice water, neutralized with saturated aqueous NH4C1 solution and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to a solid, which was purified by chromatography (silica gel, 30% EtOAc / hexanes) to provide 143 mg (67% yield) 2 steps) of 5-bromo-7-tosyl-7H-pyrrolo [2,3-d] pyrimidine [compound 1004, XH-NMR (DMSO-d6): d 9.1 (d, 2H); 8.3 (s, 1H); 8.0 (d, 2H); 7.5 (d, 2H); 2.4 (s, 3H)].

As shown in Figure 1-step iv, a mixture of compound 1004 (140 mg, 0.40 mmol), of 4,4,5,5,5-tetramethyl-1,3,2-dioxaborolane dimer (121 mg , 0.477 mmol), PdCl2 dppf2 (16 mg, 0.02 mmol) and potassium acetate (117 mg, 1.19 mmol) in 2 mL of DME were processed in the microwave at 150 ° C for 10 minutes. The reaction mixture was filtered through a short silica gel plate with 30% EtOAc-70% hexanes as eluent to give, after concentration to dryness, 158 mg (98%) of 5- (4,4%). , 5, 5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidine, compound 1005: ESMS M + l = 317, 07.

Example Ib: Preparation of (S) -2- (5-fluoro-2- (7H-pyrrolo [2,3-d] pyrimidin-5-yl) pyrimidin-4-ylamino) -N- (2.2.2 -trifluoroethyl) propanamide (compound 6) As shown in Figure 2-step i), to a stirred solution of the compound of formula IV, wherein R is a methyl group with the S configuration (Boc-L-alanine, compound 1006, 3.8 g, 0.02 mol), EDC (4.63 g, 0.024 mol), HOBt (4.0 g, 0.026 mol), DIEA (10.5 mL, 0.06 mol) in 100 mL of DCM was added trifluoroethylamine HC1 (2.92 g, 0.022 mol). The reaction mixture was stirred for 16 hours. The volatiles were extracted in vacuo and the obtained residue was dissolved in EtOAc, washed successively with 0.5N HC1, saturated aqueous solution of NaHCO3 and brine. The organics were dried (a 2SC> 4) and concentrated in vacuo to give a compound of the formula V, wherein R 1 is CH 3 ((S) -1- (2,2,2-trifluoroethylcarbamoyl) ethylcarbamate ternary). butyl, compound 1007) as a white solid (5.4 g, 98% yield), 1 H-NMR (CDC13): d 6.9 (bs, 1H); 4.9 (bs, 1H); 4.1 (bs, 1H); 3.8 (bs, 2H); 1.4 (s, 9H); 1.3 (d, 3H). As shown in Figure 2-step ii, compound 1007 (5.32 g, 0.0197 mol) was treated with a 1: 1 mixture of DCM / TFA at room temperature for 45 min. The Concentration to dryness afforded an intermediate amine, (S) -2-amino-N- (2,2,2-trifluoroethyl) propanamide, such as the TFA salt, which was used directly in the next reaction. Accordingly, a mixture of a compound of the formula VI, wherein R is fluorine (5-fluoro-2,4-dichloropyrimidine, compound 1008, 3.28 g, 0.0197 mol), the crude amine of the salt of TFA obtained directly before (5.25 g, 0.0197 mol) and DIEA (10.27 mL, 0.059 mol) was stirred in isopropanol at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, the residue was dissolved in EtOAc, and the organic compounds were washed successively with 0.5N of HC1, a saturated aqueous solution of NaHCO3 and brine. The organic compounds were dried (Na2SO4) and concentrated in vacuo to give a crude oil which was purified by chromatography on silica gel (50% EtOAc / hexanes) to give compound 1009 (a compound of formula VII, wherein R is fluorine, R1 is CH3, and X is N (4.21 g, 71% yield), 1 H-NMR (DMSO-d6): d 9.7 (d, 1H); 8.7 (t, 1H); 4.4 (q, 1H); 4.0-3.8 (m, 2H); 1.3 (d, 3H) As shown in Figure 2-step iii, a mixture of compound 1005 ( 30 mg, 0.075 mmol), compound 1009 (23 mg, 0.075 mmol), Pd (Ph3P) 4 (9 mg, 0.0078 mmol) and 2M sodium carbonate (115 uL, 0.23 mmol) in 1 mL of DME. HE processed in microwave at 150 ° C for 10 minutes. The reaction mixture was filtered through a short silica gel plate with 30% EtOAc-70% hexanes as eluent to provide, after concentration to dryness, a crude tosylate intermediate that was used directly for the next step. The crude intermediate was dissolved in 1 mL of dry methanol and 200 uL of 25% sodium methoxide in methanol was added. The reaction mixture was stirred at 60 ° C for 1 hour and was quenched with 6N HC1 (154 uL). After drying the reaction mixture with a flow of nitrogen, the product was purified by reverse phase HPLC (gradient: 10-60% MeCN / water with 0.5% TFA) to provide 19.6 mg (68%) of compound 6 (a compound of formula VIII, wherein R = F, R 1 = CH 3 with the S configuration, and X = N).

Example 2: Preparation of (S) -2- (2- (7H-pyrrolo [2, 3-d] pyrimidin-5-yl) pyrimidin-4-ylamino) -N- (2,2,2-trifluoroethyl) propanamide (compound 5) The title compound was prepared by the procedure of Example Ib, with the procedure change to replace 5-fluoro-2,4-dichloropyrimidine (compound 1008) with 2,4-dichloropyrimidine. Accordingly, compound 5 (a compound of the formula VIII, wherein R = H, R1 = Me, and X = N) (10.8 mg, 40% yield).

Example 3: Preparation of (S) -2- (6- (7H-pyrrolo [2, 3-d] pyrimidin-5-yl) pyridin-2-ylamino) -N- (2, 2, 2-trifluoroethyl) propanamide (compound 4) The title compound was prepared by the procedure of Example Ib, with the change in procedure of replacing 5-fluoro-2,4-dichloropyrimidine (compound 1008) with 1,6-dibromopyridine. Accordingly, compound 4 (a compound of formula VIII, wherein R = H, R 1 = Me, and X = CH) (12.4 mg, 45% yield) was isolated.

Example 4: Preparation of 1- ((2S, 6R) -4- (6- (7-pyrrolo [2, 3-d] pyrimidin-5-yl) pyridin-2-yl) -2,6-dimethylpiperazine-1 -yl) ethanone (compound 1) The title compound was prepared by the procedure of Example Ib, with the change in procedure of replacing (S) -2-amino-N- (2,2,2-trifluoroethyl) propanamide by 1 - (2,6-dimethylpiperazin-1-yl) ethanone and 5-fluoro-2,4-dichloropyrimidine (compound 1008) with 1,6-dibromoropyridine. Consequently, it was isolated compound 1 with the following structure (50 mg, 75% yield): Example 5: Preparation of ((S) -1- (5-fluoro-2- (7-Jipyrrolo [2,3-d] pyrimidin-5-yl) pyrimidin-4-yl) pyrrolidin-2-yl) methanol (compound 21) ) The title compound was prepared by the procedure of Example Ib, with the change in procedure of replacing (S) -2-amino-N- (2,2,2-trifluoroethyl) propanamide with (S) -pyrrolidinol.

Example 6: Preparation of ((R) -1- (5-fluoro-2- (7Jipyrrolo [2,3-d] pyrimidin-5-yl) pyrimidin-4-yl) pyrrolidin-2-yl) methanol (compound 22) ) The title compound was prepared by the procedure of Example Ib, with the change in procedure of replacing (S) -2-amino-W- (2,2,2-trifluoroethyl) propanamide with (R) -pyrrolidinol.

Example 7: Preparation of 5- (5-fluoro-4- ((S) -2- (methoxymethyl) pyrrolidin-1-yl) pyrimidin-2-yl) -7H-pyrrolo [2,3-d] pyrimidine (compound 23) The title compound was prepared by the procedure of Example Ib, with the change in procedure of replacing (S) -2-amino-W- (2,2,2-trifluoroethyl) propanamide with (S) -methoxymethylpyrrolidine.

Example 8: Preparation of 5- (5-fluoro-4- (pyrrolidin-1-yl) pyrimidin-2-yl) -7ff-pyrrolo [2,3-d] pyrimidine (compound 24) The title compound was prepared by the procedure of Example Ib, with the change in procedure of replacing (S) -2-amino-W- (2,2,2-trifluoroethyl) propanamide with pyrrolidine.

Example 9: Preparation of 5- (5-fluoro-4- ((R) -2- (methoxymethyl) pyrrolidin-1-yl) pyrimidin-2-yl) -7H-pyrrolo [2,3-d] pyrimidine (compound 25) The title compound was prepared by the procedure of Example Ib, with the change in procedure of replacing (S) -2-amino-N- (2,2,2-trifluoroethyl) propanamide with (R) -methoxymethylpyrrolidine.

Example 10: Preparation of (S) -1- (5-fluoro-2- (7H-pyrrolo [2,3-d] pyrimidin-5-yl) pyrimidin-4-yl) -N- (2,2,2 -trifluoroethyl) pyrrolidine-2-carboxamide) The title compound was prepared by the procedure of Example Ib, with the procedure change to replace (S) -1- (2,2,2-trifluoroethylcarbamoyl) ethylcarbamate tert -butyl by (S) -1- (tert-butoxycarbonyl) irrolidine-2-carboxylic acid. Accordingly, the following compound was isolated (9.5 mg, 45%): Example 11: Preparation of (R) -1- (5-fluoro-2- (7H-pyrrolo [2,3-d] pyrimidin-5-yl) pyrimidin-4-yl) -N- (2,2,2 -trifluoroethyl) pyrrolidine-2-carboxamide) The title compound was prepared by the procedure of Example Ib, with the procedure change to replace (S) -1- (2,2,2-trifluoroethylcarbamoyl) ethylcarbamate tert -butyl by ()) -1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid. Accordingly, the following compound was isolated (9.2 mg, 38%): Example 12: Preparation of. { R) -2- (2- (7H-pyrrolo [2,3-d] pyrimidin-5-yl) pyrimidin-4-ylamino) -N- (2,2,2-trifluoroethyl) propanamide (compound 39) The compound of the title was prepared by the procedure of Example 2, with the procedure change using (R) -1- (2,2,2-trifluoroethylcarbamoyl) tert-butylcarbamate as starting material to provide a compound of formula VIII , where R = H, R1 = Me, and X = N.

Example 13: Preparation of (R) -2- (5-fluoro-2- (7H-pyrrolo [2,3-d] pyrimidin-5-yl) pyrimidin-4-ylamino) -N- (2,2,2 -trifluoroethyl) propanamide (compound 40) The title compound was prepared by the procedure of Example Ib, with the change of procedure to be used. { R) -1- (2,2,2-trifluoroethylcarbamoyl) ethylcarbamate tert-butyl as starting material to provide a compound of formula VIII, wherein R = F, R 1 = Me, and X = N.

Example 14: Preparation of (S) -2- (5-fluoro-2- (7-pyrrolido [2,3-d] pyrimidin-5-yl) pyrimidin-4-ylamino) -N- (2,2,2-trifluoroethyl) ) butanamide (compound 41) The title compound was prepared by the procedure of Example Ib, with the procedure change using tert-butyl (S) -1- (2,2,2-trifluoroethylcarbamoyl) propylcarbamate as the starting material to provide a compound of formula VIII, wherein R = F, Ri = Et, and X = N.

Example 15: Preparation of (S) -2- (5-fluoro-2- (7H-pyrrolo [2,3-d] pyrimidin-5-yl) pyrimidin-4-ylamino) -N- (2,2,2 -trifluoroethyl) -3-methoxypropanamide (compound 42) The title compound was prepared by the procedure of Example Ib, with the procedure change using (S) -1- (2,2,2-trifluoroethylcarbamoyl) -2-methoxyethylcarbamate of tert-butyl as starting material to provide a compound of formula VIII, wherein = F, Ri = CH2OMe, and X =.

Example 16: Preparation of (S) -2- (2- (7H-pyrrolo [2, 3-d] pyrimidin-5-yl) pyrimidin-4-ylamino) -N- (2, 2, 2-trifluoroethyl) - 3-methoxypropanamide (compound 48) The title compound was prepared by the procedure of Example Ib, with the procedure change using (S) -1- (2,2,2-trifluoroethylcarbamoyl) -2-methoxyethylcarbamate tert -butyl as starting material to provide a compound of formula VIII, wherein R = H, Ri = CH2OMe, and X = N.

Example 17: Preparation of 2- (5-fluoro-2- (7H-pyrrolo [2,3-d] pyrimidin-5-yl) pyrimidin-4-ylamino) -4,4, -trifluoro-W-methylbutanamide (compound 43) The title compound was prepared by the procedure of Example Ib, with the process change of using tert-butyl 1- (methylcarbamoyl) -3,3,3-trifluoropropylcarbamate as starting material to provide a compound of the formula VIII, where R = F, Rx = CH2CF3, and X =.

Example 18: Preparation of 2- (5-fluoro-2- (7H-pyrrolo [2,3-d] pyrimidin-5-yl) pyrimidin-4-ylamino) -N-ethyl-4,4,4-trifluorobutanamide ( Compound 44) The title compound was prepared by the procedure of Example Ib, with the process change of using tert-butyl 1- (ethylcarbamoyl) -3,3,3-trifluoropropylcarbamate as starting material to provide a compound of the Formula VIII, where R = F, Ri = CH2CF3 and X = N.

Example 19: Preparation of 2- (5-fluoro-2- (7tf-pyrrolo [2, 3-d] pyrimidin-5-yl) pyrimidin-4-ylamino) -4,4, 4-trifluoro-N- (2 , 2, 2-trifluoroethyl) butanamide (compound 45) The title compound was prepared by the procedure of Example Ib, with the procedure change using 1- (2,2,2-trifluoroethylcarbamoyl) - 3, 3, 3- tert-butyl trifluoropropylcarbamate as starting material to provide a compound of formula VIII, wherein R = F, Ri = CH2CF3, and X = N.

Example 20: Preparation of 2- (5-fluoro-2- (7H-pyrrolo [2, 3-d] pyrimidin-5-yl) pyrimidin-4-ylamino) -N- (2,2,2-trifluoroethyl) - 2-methylpropanamide (compound 56) The title compound was prepared by the procedure of Example Ib, with the change in procedure of replacing tert-butyl (S) -1- (2,2,2-trifluoroethylcarbamoyl) ethylcarbamate with 2-tert-butyl). - (2, 2, 2-trifluoroethylcarbamoyl) propan-2-ylcarbamate tert -butyl. Accordingly, the following compound was isolated: Example 21: Preparation of (S) -2- (6-phenyl-2- (?? -pyrrolo [2, 3-d] pyrimidin-5-yl) pyrimidin-4-ylamino) -? G- (2, 2 , 2-trifluoroethyl) propanamide (compound 18) As shown in Figure 3-step i, a mixture of phenylboronic acid (1.22 g), 2,, 6-trichloropyrimidine (compound 1011), tetrakis (triphenylphosphine) palladium (O) and 2N sodium carbonate (15 mL) in DME (25 mL) was heated at 80 ° C overnight. After cooling to, addition of water (30 mL), extraction with dichloromethane (3 x 20 mL), drying and evaporation, purification by column chromatography (SIO2, 10-20% ethyl acetate in hexane) gave the desired product, 6-phenyl-2,4-dichloropyrimidine (compound 1012) (0.544 g). As shown in Figure 3-step ii, compound 1012 (0.34 g) was mixed with (S) -2-amino-N- (2,2,2-trifluoroethyl) propanamide (0.3 g) and diisopropylethylamine (0.63 mL) in isopropanol (5 mL) and the reaction mixture was heated at 80 ° C overnight. A residue was obtained by evaporation, which after aqueous work-up and purification (Si02, 20% ethyl acetate / hexane) yielded 2- (2-chloro-6-phenyl-pyrimidin-4-ylamino) -N- (2, 2,2-trifluoroethyl) propionamide (compound 1013) (0.165 g). As shown in Figure 3-step iii, compound 1013 (29 mg), 5- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -7- (toluene-4-sulfonyl) -7H-pyrrolo [2,3-d] pyrimidine (compound 1005), PdCl2dppf2 (7 mg) and potassium phosphate (32 mg) were heated in 1,4-dioxane (2 mL) to 80 ° C during the night. To the reaction was added aqueous solution of lithium hydroxide (2 mL). After heating at 60 ° C for 1 h, water (20 mL) was added. Extraction with dichloromethane (3X), drying, evaporation and purification (SiO2, 50-100% ethyl acetate / hexane) gave 3.7 mg of 2- [6-phenyl-2- (7H-pyrrolo [2, 3 -d] pyrimidin-5-yl) -pyrimidin-4-ylamino] -N- (2,2,2-trifluoro-ethyl) -propionamide (compound 18).

Example 22: Preparation of (S) -2- (, 6-dichloropyrimidin-2-ylamino) -N- (2, 2, 2-trifluoroethyl) propanamide (compound 1019) and (S) -2- (2, 6- dichloropyrimidin-4-ylamino) -N- (2,2,2-trifluoroethyl) propanamide (compound 1020) As shown in Figure 4-step i, to a solution of 3-hydroxytetrahydrofuran (446 mg, 5.00 mmol ) in tetrahydrofuran (50 mL) at room temperature was added sodium hydride (60% w / w in mineral oil, 144 mg, 6.00 mmol). After stirring for 1 hour, the mixture was cooled to 0 ° C and 2, 6-trichloropyrimidine (compound 1015) (917 mg, 5.00 mmol) was added. The mixture was warmed to room temperature and stirred overnight. Cold water was added and the mixture was extracted with ethyl acetate. ethyl. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate in hexanes) to give a mixture of isomers, 2-dichloro-6- (tetrahydrofuran-3-yloxy) -pyrimidine (compound 1016) and its 4,6-chloro-2- (tetrahydrofuran-3-yloxy) -pyrimidine regioisomer (62: 28, respectively, by 1 H-NMR, 1.17 g, 100%), as a colorless oil. As shown in Figure 4-step ii, (S) -2- (2-chloro-6- (tetrahydrofuran-3-yloxy) pyrimidin-4-ylamino) -N- (2, 2, 2-trifluoroethyl) Propanamide (compound 1017) was prepared according to the procedure of Example Ib. As shown in Figure 4-step iii, (S) -2- (6- (7H-pyrrolo [2, 3-d] pyrimidin-5-yl) -4- (tetrahydrofuran-3-yloxy) pyridine- 2-ylamino) -W- (2,2,2-trifluoroethyl) propanamide (compound 10) was prepared according to the procedure of Example Ib. As shown in Figure 4-step iv, to a solution of compound 1015 (1.83 g, 10.0 mmol) in ethanol (20 mL) at room temperature was added 2-amino-N- HC salt ( 2, 2, 2-trifluoro-ethyl) -propionamide (1.03 g, 5.00 mmol) and diisopropylethylamine (1.94 g, 2.61 mL, 15.0 mmol). The mixture was stirred overnight, diluted with ethyl acetate, washed with brine, dried over magnesium, and concentrated. The residue was purified by silica gel chromatography (25-35% ethyl acetate in hexanes) to give 2- (4,6-dichloro-pyrimidin-2-ylamino) -N- (2, 2, 2-trifluoro) ethyl) -propionamide (compound 1019, 670 mg, 42% yield) and 2- (2,6-dichloro-pyrimidin-4-ylamino) -N- (2,2,2-trifluoro-ethyl) -propionamide ( compound 1020, 760 mg, 48% yield), both as white solids.

Example 23: Preparation of (S) -2- (4- (pyrrolidin-1-yl) -6- (7H-pyrrolo [2, 3-d] pyrimidin-5-yl) pyrimidin-2-ylamino) -N- (2, 2, 2-trifluoroethyl) propanamide (compound 31) As shown in Figure 4-step v, to a solution of compound 1019 (31.7 mg, 0.100 mmol) in DME (0.50 mL) was added a nucleophilic amine (pyrrolidine, 10 μ? _, 0.11 mmol) and diisopropylethylamine (25.8 mg, 34.8 μL, 0.200 mmol). The mixture was heated at 160 ° C with microwaves for 5 min, followed by the addition of 5- (4,, 5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -7H-pyrrolo [2 , 3-d] pyrimidine (compound 1005, 39.9 mg, 0.100 mmol) and a solution of CsF (30 mg, 0.20 mmol) in water (0.25 mL). The mixture was heated at 160 ° C with microwaves for 5 min. The reaction mixture was filtered through a short silica gel plate using EtOAc / hexanes as eluent to provide, after concentration in vacuo, the crude intermediate tosylate. This intermediate was dissolved in 1 mL of dry methanol and 200 uL of 25% sodium methoxide in methanol was added. The reaction mixture was stirred at 60 ° C for 1 hour and was quenched with trifluoroacetic acid. Purification by reverse phase HPLC gave 35.0 mg of TFA salt of 2- [4-pyrrolidin-1-yl-6- (7H-pyrrolo [2,3-d] pyrimidin-5-yl) -pyrimidin- 2-ylamino] -N- (2,2,2-trifluoroethyl) -propionamide (a compound of the formula IX wherein R10 is 1-pyrrolidine).

Example 24: Preparation of (S) -2- (6- (pyrrolidin-1-yl) -2- (7H-pyrrolo [2,3-d] pyrimidin-5-yl) pyrimidin-4-ylamino) -N- (2, 2, 2-trifluoroethyl) propanamide (compound 32) As shown in Figure 4-step vi, the title compound was prepared according to the procedure of Example 23 using compound 1020 as starting material to provide the compound of the title (a compound of formula X, wherein R10 is 1-pyrrolidine).

Example 25: Preparation of (S) -2- (4- (pyrrolidin-1-yl) -6- (7H-pyrrolo [2,3-d] pyrimidin-5-yl) -1,3,5-triazine- 2-ylamino) -N- (2,2,2-trifluoroethyl) propanamide (compound 33) As shown in Figure 5-step i, a mixture of HC1 salt of 2-amino-N- (2, 2, 2-trifluoro-ethyl) -propionamide (103 mg, 1.00 mmol), acetone (1.0 mL) and aqueous sodium bicarbonate (1.0 mL) was cooled to 0 ° C and cyanuric chloride (compound 1015) was added. ) (184 mg, 1.00 mmol). The mixture was stirred for 0.5 hour and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (0-45% ethyl acetate in hexanes) to give 2- (4,6-dichloro- [1, 3, 5] triazin-2-ylamino) -N- (2 , 2,2-trifluoroethyl) -propionamide (compound 1024, 154 mg, 97% yield) as a white solid. By the procedure of Example 23, compound 1024 was reacted in sequence with pyrrolidine and compound 1005 to give compound 33.

Example 26: Preparation of (S) -2- (6-morpholino-2- (7H-pyrrolo [2,3-d] pyrimidin-5-yl) pyrimidin-4-ylamino) -N- (2,2,2 -trifluoroethyl) propanamide (compound 36) The title compound was prepared according to the procedure of Example 23 by reaction in sequence of compound 1024 with morpholino and compound 1005.

Example 27: Preparation of (S) -2- (4-morpholino-6- (7H-pyrrolo [2,3-d] pyrimidin-5-yl) -1,3,5-triazin-2-ylamino) -N - (2,2,2-trifluoroethyl) propanamide (compound 37) The title compound was prepared according to the procedure of Example 24 by reaction in sequence of compound 1020 with morpholino and compound 1005.

Example 28: Preparation of (S) -2- (4-cyano-6- (7H-pyrrolo [2,3-d] pyrimidin-5-yl) pyridin-2-ylamino) -N- (2.2.2 -trifluoroethyl) propanamide (compound 19) As shown in Figure 5-step iii, 4-cyano-2,6-dichloropyridine (compound 1021) (346 mg, 2.0 mmol), (S) -2-amino -N- (2, 2, 2-trifluoroethyl) propanamide (761 mg, 2.1 mmol), 2 mL of DIEA and 1 mL of NMP were placed in a sealed tube. The reaction mixture was stirred at 120 ° C for 2 hours and concentrated to dryness. The residue was dissolved in DCM and washed with saturated aqueous NaHCO 3 solution.

The organics were dried (Na2SO4) and concentrated in vacuo to give a residue which was purified by chromatography on silica gel (50% EtOAc / 50% hexanes) to provide 135 mg of compound 1022 (60% yield) . As shown in Figure 5-step iv, compound 1022 (31 mg, 0.1 mmol), compound 1005 (52 mg, 0.12 mmol), Pd (Ph3P) (6.4 mg) and Na 2 CO 3 2M (150 uL) in DME were heated at 160 ° C for 15 minutes by microwave irradiation. The reaction mixture was filtered through a short silica gel plate using EtOAc / hexanes as eluent to provide, after concentration in vacuo, the crude tosylate intermediate. This intermediate was dissolved in 1 mL of dry methanol and 200 uL of 25% sodium methoxide in methanol was added. The reaction mixture was stirred at 60 ° C for 1 hour and was quenched with 6N HC1 (154 uL). The volatiles were removed in vacuo and the product was purified by silica gel chromatography (20% EtOAc / hexane, 100% EtOAc and 5% MeOH / DCM) to provide 9 mg (19% yield) of compound 19 Example 29: Preparation of (S) -2- (6- (7H-pyrrolo [2, 3-d] pyrimidin-5-yl) -4- (1, 4-tetrazol-5-yl) pyridin-2-ylamino) - N- (2,2,2-trifluoroethyl) propanamide (compound 20) As shown in Figure 5-step v, to a solution of (S) -2- (4-cyano-6- (7H-pyrrolo [ 2, 3-d] pyrimidin-5-yl) pyridin-2-ylamino) -N- (2,2,2-trifluoroethyl) propanamide (compound 19, 4.5 mg, 0.012 mmol) in 1 mL of toluene was added azidotrimethylsilane (150 uL) and dibutyltin oxide (10 mg). The reaction bottle was sealed and the reaction mixture was heated for 3.5 hours at 130 ° C. The mixture was concentrated in vacuo followed by purification by reverse phase HPLC (gradient of 0-70% MeCN / water (0.1% TFA) for 20 minutes) to provide compound 20 (2.8 mg, 44% yield). ).

Example 30: Preparation of compounds of formula XI As shown in Figure 6-step i, compound 1026 was prepared by the procedure of Example 28, with 2,6-dichloropyrimidine-4-carboxylic acid ethyl ester (compound 1025) instead of 4-cyano-2,6-dichloropyridine as starting material. As shown in Figure 6, step ii, compound 1005 and compound 1026 were reacted by the procedure of Example 28, followed by saponification of the ethyl ester with sodium hydroxide for provide 6- ((S) -1- (2,2,2-trifluoroethylcarbamoyl) ethylamino) -2- (7tf-pyrrolo [2,3-d] pyrimidin-5-yl) pyrimidine-4-carboxylic acid (compound 1027) ). A representative example for the preparation of compounds of the formula XI is the following. As shown in Figure 6, step iii, to a solution of 6 - ((S) -l- (2,2,2-trifluoroethylcarbamoyl) ethylamino) -2- (7ff-pyrrolo [2, 3-d]) ] pyrimidin-5-yl) pyrimidine-4-carboxylic acid (5 mg) in 1.0 measured DMF was added (S) -pyrrolidin-2-yl) methanol (1.5 mg), 1 drop of Et3N, 4 mg of HBTU, 4 mg of HOBT. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with 2 mL of ethyl acetate and washed with water (2 mL x 3). The organic layer was concentrated and purified by reverse phase preparation HPLC to obtain a yield of 3 mg (60% yield) of the compound of formula XI wherein NR1R2 is (S) -2- (hydroxymethyl) pyrrolidin-1 -yl (compound 8).

Example 31: Preparation of 2- (7tf-pyrrolo [2, 3-d] pyrimidin-5-61) quinazolines Compounds such as, for example, compound 38, can be prepared by the procedure of Example Ib (see Figure 2) , with 2,4-dichloroquinazoline as starting material.

Example 32: Preparation of 3- (4- (6- (7H-pyrrolo [2, 3-d] pyrimidin-5-yl) pyridin-2-yl) -5,6-dihydropyridin-1 (2H) -yl) -3-oxopropanenitrile (compound 30) As shown in Figure 7-step i, to a solution of 2,6-dibromopyridine (4.738 g) in dichloromethane (80 mL) was added dropwise n-butyllithium (2)., 5 N, 8.9 mL) at -65 ° C or less, followed by stirring at this temperature for 20 min. 4-Oxo-piperidin-1-carboxylic acid tert-butyl ester (compound 1030) (4.38 g) was added. After 15 min, the temperature was raised to -30 ° C and a saturated aqueous solution of ammonium chloride (100 mL) was added. The organic and aqueous layers were separated, the aqueous layer was extracted with dichloromethane (2 x 80 mL). The combined organic layers were evaporated to obtain a residue which was triturated with hexane to give 6-bromo-4'-hydroxy-3 ',', 5 ', 6 * -tetrahydro-2'-H- [t-butyl acid ester] 2, 1] bipyridinyl-11-carboxylic acid (compound 1031) as a white solid (7.05 g). As shown in Figure 7-step ii, compound 1031 (2.0 g) was mixed with TFA (25 mL) in a sealed tube and heated at 128 ° C for 2 days. The extraction of TFA produced a residue, which was dissolved in methanol (30 mL) and treated with triethylamine (2 mL) and sodium bicarbonate. di-tert-butyl (1.4 mL). After 1 hour, the volatiles were removed in vacuo and water (100 mL) was added. Extraction with dichloromethane (3x), concentration and purification by chromatography (Si02, 20% ethyl acetate / hexane) gave a tert-butyl ester of 6-bromo-3 ', 6'-dihydro-2' H- [ 2, 4 '] bipyridinyl-1'-carboxylic acid (compound 1032) (0.96 g). As shown in Figure 7-step iii, a mixture of compound 1032 (0.18g), 5- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) - 7- (toluene-4-sulfonyl) -7H-pyrrolo [2,3-d] pyrimidine (compound 1005, 0.20 g), tetrakis (triphenylphosphine) palladium (50 mg) and 2N sodium carbonate (0.8mL) ) in DME (5 mL) was heated at 90 ° C overnight. Aqueous lithium hydroxide (2 mL) was added and the reaction mixture was heated at 60 ° C for 1 hour. The reaction mixture was diluted with EtOAc and washed with brine. The organic compounds were dried over sodium sulfate, concentrated and purified by chromatography (SiO2, 50% ethyl acetate / hexane) to give 6- (7H-Pyrrolo [2, 3-d] tert-butyl ester) pyrimidin-5-yl) -3 ', 6 · -dihydro-2? - [2, 4'] bipyridinyl-1'-carboxylic acid (compound 1033, 81.6 mg). As shown in Figure 7-step iv, a 2 N solution of HCl-ether (3 mL) was added to compound 1033 (78 mg) in methanol (5 mL). The obtained mixture was heated at 50 ° C for 40 min. Evaporation and trituration with ether gave 6- (7H-pyrrolo [2,3-d] pyrimidin-5-yl) -1 ', 2', 3 ', 6'-tetrahydro- [2,'] bipyridinyl hydrochloride. (compound 29, 51 mg). As shown in Figure 7-step v, compound 29 (30 mg) and 2-cyanoacetic acid, pyrrolidin-1-yl ester (47 mg) were mixed in ethanol (2 mL) and diisopropylethylamine (0.084 mL) was added. ). After stirring at room temperature for 12 hours, water (30 mL) was added. Extraction with dichloromethane (3x) and purification by chromatography (S1O2, ethyl acetate) yielded 5.3 mg of 3-oxo-3- [6- (7H-pyrrolo [2,3-d] pyrimidin-5-yl) ) -3 ', 6'-dihydro-21 H- [2, 4'] bipyridinyl-1 '-yl] -propionitrile (compound 30).

Example 33: Preparation of. { R) -2- (4- (7H-pyrrolo [2, 3-d] pyrimidin-5-yl) -1, 3, 5-triazin-2-ylamino) -N- (2,2,2-trifluoroethyl) propanamide (compound 78) To a solution of 2,4-dichloro-1,3,5-triazine (298 mg, 2.0 mmol) in 4 mL of THF and isopropanol (1: 1 v: v) at -20 ° C was added (R) -2-amino-N- (2,2, 2-trifluoroethyl) propanamide (412 mg , 2.0 mmol, 1.0 equiv.), Followed by the addition of N, N-isopropylethylamine (516 mg, 4.0 mmol, 2.0 equiv.). The The reaction was stirred at -20 ° C for 20 minutes, then allowed to warm to room temperature. After 30 minutes, the reaction mixture was poured into ethyl acetate and washed with water. The organic layer was concentrated. The oily residue was purified by chromatography (2: 1 hexane / ethyl acetate) to yield 186 mg of (i) -2- (-chloro-1,3,5-triazin-2-ylamino) -N- ( 2,2,2-trifluoroethyl) propanamide (compound 1034) (LC / MS: MS + 1 = 284.1, MS-1 = 282.3, RT = 1.5 min).

(R) -2- (4 - (7-pyrrolo [2,3-d] pyrimidin-5-yl) -1,3,5-triazin-2-ylamino) -A7- (2,2,2-trifluoroethyl) ) Propanamide was prepared by the procedure of Example Ib and compounds 1034 and 1005 as starting material.

Example 34: Preparation of (S) -2- (4- (7H-pyrrolo [2, 3-d] pyrimidin-5-yl) -1,3,5-triazin-2-ylamino) -N- (2, 2,2-trifluoroethyl) propanamide (compound 79) Using (S) -2-amino-N- (2, 2, 2-trifluoroethyl (propanamide as starting material, (S) -2- (4-chloro- l, 3, 5- triazin-2-ylamino) -N- (2,2, 2-trifluoroethyl) propanamide (compound 1035) by the same method as that used in preparation of compound 1034. (MS + 1 = 284.1, MS-1 = 282.3).

The title compound was prepared by the procedure of Example Ib with compounds 1035 and 1005 as starting material.

Example 35: Preparation of 2- (2- (7H-pyrrolo [2, 3-d] pyrimidin-5-yl) -9ff-purin-9-yl) -N- (2, 2, 2-trifluoroethyl) -2 -methylpropanamide (compound 108) As shown in Figure 8-stage i, 5-nitro-2,4-dichloropyrimidine (500 mg, 2.58 mmol), 2-amino-W- (2, 2, 2-trifluoroethyl) -2-methylpropanamide hydrochloride (568 mg, 2.58 mmol) and diisopropylethylamine (1.3 mL, 7.5 mmol) were mixed in isopropanol. After decreasing the exotherm obtained, the mixture was concentrated and purified by chromatography on silica gel (0-40% EtOAc / hexanes) to obtain 409 mg of compound 1036 as an orange solid, ESMS (M + 1) = 341, 9. As shown in Figure 8-step ii, compound 1036 (409 mg, 1.19 mmol) was dissolved in about 10 mL of methanol and ammonium chloride (320 mg, 6 mmol) was added followed by the addition of dust zinc (777 mg, 11.9 mmol). After decreasing the exotherm obtained, the reaction mixture was filtered through a Celite ™ plate, which was washed with methanol. Compound 1037 was recovered as a pale yellow solid after extracting the volatiles in vacuo, ESMS (M + 1) = 311, 9. As shown in Figure 8-step iii, compound 1037 (115 mg, 0, 49 mmol) was dissolved in 3 mL of methyl orthoformate and 1.5 mL of 4,4-diethoxybutan-2-one was added. The reaction mixture was microwaved for 20 minutes at 160 ° C followed by extraction of the volatiles in vacuo. The obtained crude product (compound 1038) was used in the next reaction. As shown in Figure 8-stages iv & v, compound 1038 (48 mg, 0.15 mmol), Pd (Ph3P) 4 (17 mg, 0.015 mmol) and 1 mL of 2M potassium acetate (ac) in 2 mL of DME were microwaved at 160 ° C for 10 minutes. The crude mixture was diluted with EtOAc, washed with water and dried over sodium sulfate. The volatiles were removed in vacuo and the crude product obtained was purified by reverse phase HPLC [gradient of CH3CN / H20 (0.1% TFA)] to give compound 1039 (15 mg, 0.026 mmol). Compound 1039 was then treated with 0.32 mL of 1M tetrabutylammonium fluoride (0.032 mmol) in 1 mL of THF at room temperature. After 1 hour, the volatiles were removed in vacuo and the product was purified by reverse phase HPLC (gradient of CH3CN / H20 (0.1% TFA)) to give compound 108.

Example 36: Preparation of. { R) -2- (2- (7H-pyrrolo [2,3-d] pyrimidin-5-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) -N- (2, 2, 2-trifluoroethyl) -3-methylbutanamide (compound 110) As shown in Figure 9-step i, 5-bromo-2,4-dichloropyrimidine (compound 1040, 460 mg, 2.0 mmol) in about 20 mL of isopropanol was treated with D-valine, t-butyl ester, hydrochloric acid (420 mg, 2.0 mmol) and DIEA (0.7 mL, 4 mmol). The reaction mixture was stirred at room temperature for 16 hours, concentrated in vacuo and purified by silica gel chromatography (10% EtOAc / hexanes) to give 720 mg of compound 1041, together with 15% of regioisomer 2- (5-bromo-4-chloropyrimidin-2-ylamino) -3-methylbutanoate de. { R) -ter-butyl ESMS (M + H) = 365.5. As shown in Figure 9-step ii, compound 1041 (720 mg, 1.97 mmol, as the 85:15 mixture of regioisomers), tributyl- (Z) -2-ethoxyvinyl) stannane (1.42 g, 3.9 mmol), Pd (Ph3P) 4 (225 mg, 0.195 mmol) and 10 mL of Toluene were placed in a sealed tube under a nitrogen atmosphere and heated at 125 ° C for 20 hours. The reaction mixture was cooled and the volatiles were removed in vacuo. Purification by silica gel chromatography (10-15% EtOAc / hexanes) yielded 376 mg of compound 1042 as oil, ESMS (M + H) = 357. As shown in Figure 9-step iii, the compound 1042 (376 mg, 1.06 mmol) was dissolved in pure formic acid and heated at 65 ° C for 1 hour. The reaction mixture was concentrated in vacuo to give compound 1043 (267 mg) as a brown powder. As shown in Figure 9-step iv, compound 1043 (143 mg, 0.56 mmol), 2,2,2-trifluoroethylamine hydrochloride (83 mg, 0.62 mmol), HOBT (83 mg, 0, 62 mmol), EDC (119 mg, 0.62 mmol) and DIEA (0.22 mL, 1.2 mmol) were dissolved in about 5 mL of DMF. After stirring at room temperature for 20 hours, the reaction mixture was diluted with EtOAc (ca. 25 mL) and washed with water (3x), 0.5 M HC1 (aq) (lx) and brine (lx). The organic compounds were dried over sodium sulfate and the volatiles were removed in vacuo to give the crude product, which was treated with ethyl ether / hexanes (approximately 1: 1), filtered and concentrated in vacuo to give compound 1044 (187 mg) as a viscous oil. As shown in Figure 9-step v, compound 1044 (45 mg, 0.13 mmol) was combined with 5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2) -yl) -7- (toluene-4-sulfonyl) -7H-pyrrolo [2, 3-d] pyrimidine (compound 1005, 47 mg, 0.12 mmol), Pd (PPh 3) 4 (25 mg, 0.02 mmol) and 1 mL of 2M Na 2 CO 3 in 2 mL of DME. The mixture was heated to 150 ° C by microwave irradiation for 10 minutes. At this time, 1 M of aqueous solution of lithium hydroxide (2 mL) was added to the reaction mixture and microwave irradiation was continued at 150 ° C for 10 min. The mixture was cooled and water (20 mL) was added. Purification by reverse phase HPLC yielded 27 mg of compound 110 as a yellow powder.

Example 37: NMR and mass spectrometry Analytical data were collected and recorded for certain compounds of the present invention: proton nuclear magnetic resonances (NMR) were obtained using a Bruker AMX 500 instrument and appropriate solvent. The method of mass spectrometry by liquid chromatography (LC / MS) used a column Hypersil BDS C18 5 microns 2.1 x 50 mm with a flow velocity of 1.0 ml / min with an appropriate gradient. Samples of the mass spectrometer were analyzed in a MicroMass ZQ or Quattro II mass spectrometer operated in single MS mode with electrospray ionization. The samples were introduced into the mass spectrometer using flow injection (FIA) or chromatography. The mobile phase for all mass spectrometer analyzes consisted of mixtures of acetonitrile-water or TFA in some cases. Table 2 below depicts mass spectral data (ESMS) and 1 H-NMR data (NMR) for certain compounds of the present invention, wherein the compound numbers in Table 2 correspond to the compounds represented in Table 1: Comment [Pl]: Retention Table 2 time data have been removed fro te table. In general, steep gradien retentíon time data are not veri characteristíc. ln tis case, tese dat are not characterizing, given the lack of gradient description in te specification (see Example 37).

While certain examples of embodiments are shown and described above and herein, it will be appreciated that the compounds of the invention can be prepared according to the methods generally described above by suitable starting material by the methods available in US Pat. general for those skilled in the art.

Example 38: JAK3 Inhibition Assay The compounds were analyzed for their ability to inhibit JAK by the assay shown below. The reactions were carried out in a kinase buffer containing 100 mM HEPES (pH 7.4), 1 mM DTT, 10 mM MgCl2, 25 mM NaCl and 0.01% BSA. The substrate concentrations in the assay were 5 μ? of ATP (200 uCi / pmol of ATP) and 1 μ? of poly (Glu) Tyr. The reactions were carried out at 25 ° C and 1 nM of JA 3. To each well of a 96-well polycarbonate plate was added 1.5 μ? of a JAK3 inhibitor candidate together with 50 μ? of a kinase buffer containing 2 μ? of poly (Glu) 4Tyr and 10 μ? of ATP. This was then mixed and 50 μ? of kinase buffer containing 2 nM of JAK3 enzyme to initiate the reaction.

After 20 minutes at room temperature (25 ° C), the reaction was stopped with 50 μ? of 20% trichloroacetic acid (TCA) that also contained 0.4 mM of ATP. The entire contents of each well were then transferred to a 96-well fiberglass filter plate with a TomTek cell harvester. After washing, 60 μ? of scintillation fluid and the incorporation of 33P into a Perkin Elmer TopCount was detected.

Example 39: JAK2 Inhibition Assay The assays were done as described above in Example 36 except that the JAK-2 enzyme was used, where the final concentration of poly (Glu) 4Tyr was 15 μ? and the final concentration of ATP was 12 μ ?. Table 3 shows enzyme inhibition data (Kj) for certain examples of compounds. The compound numbers in Table 3 correspond to the compounds shown in Table 1. In Table 3, "A" represents a Ki less than 0.5 μ ?, "B" represents a Ki of between 0.5 and 5 , 0μ ?, and "C" represents a Ki greater than 5.0 μ? for the indicated enzyme.

Table 3 151

Claims (3)

1. A compound that has the formula: or one of its pharmaceutically acceptable salts wherein R1 is - (aliphatic Ci-2) p-R4 wherein R1 is optionally substituted with 1-3 occurrences of J; R2 is - (aliphatic Ci-2) d-R5 wherein R2 is optionally substituted with 1-3 occurrences of J; R4 is H, halogen, CN, NH2, N02, CF3, aliphatic Ci-3, cyclopropyl, NCH3, OCH3, -C (= 0) NH2, -C (= 0) CH3, -NHC (= 0) CH3, or OH; R5 is H, halogen, CN, NH2, N02, CF3, aliphatic Ci-3, cyclopropyl, NCH3, 0CH3, -C (= 0) NH2, -C (= 0) CH3, -NHC (= 0) CH3, or OH; J is halogen, 0CH3, OH, N02, NH2, SCH3, NCH3, CN or unsubstituted Ci-2 aliphatic, or two J groups, together with the carbon to which they are attached, form a cyclopropyl ring or C = 0; p and d are each independently 0 or 1; Q is a 5-8 membered aromatic monocyclic ring having 0-3 heteroatoms selected from nitrogen, oxygen or sulfur, or an aromatic 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 °; JQ is halogen, OCF3, - (Vm) -R ", - < vm) -CN, - (VJ-N02 or - (VJ- (haloaliphatic Ci- <), two JQ groups, taken together with the atoms a those which are joined form a saturated, partially saturated or unsaturated ring with 0-3 heteroatoms selected from O, N, or S, wherein said ring is optionally substituted with 0-4 occurrences of Ju; V is aliphatic Ci-i0, wherein up to three methylene units are replaced by Gv, wherein Gv is selected from -NH-, -NR-, -O-, -S-, -C (0) 0-, -OC (O) -, - C (0) C (0) -, -C (O) -, -C (0) NH-, -C (0) NR-, -C (= N-CN), -NHC (O) -, - NRC (O) -, -NHC (0) 0-, -NRC (0) 0-, -S (0) 2NH-, -S (0) 2NR-, -NHS (0) 2-, -NRS (0 ) 2-, -NHC (0) NH-, -NRC (0) NH- -NHC (0) NR-, -NRC (0) NR, -OC (0) NH-, -OC (0) NR-, -NHS (0) 2NH-, -NRS (0) 2NH-, -NHS (0) 2NR-, -NRS (0) 2NR-, -S (O) -, or -S (0) 2-; where V is optionally substituted with 1-6 occurrences of Jv; R "is H or an optionally substituted group selected from Ci-6 aliphatic, C3-10 cycloaliphatic, C6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl, or two R" groups, or a group R "and a group R, in the same substituents or different substituents, together with the atom (s) to which they are (s) attached, form an optionally substituted heterocyclyl of 3-8 members; wherein each R "optionally substituted 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, in the same substituents or different substituents, together with the atom (s) to which they are attached, form an optionally substituted heterocyclyl of 3-8 members; wherein each R "optionally substituted group is independently and optionally substituted with 1-4 occurrences of Jx; each Jv, Ju, Jx, and JR are independently selected from halogen, L, - (LN) -R ', - (L ") -N (R ') 2, ~ (LN) -SR', - (LN) -OR ', - (Ln) - (C3-10 cycloaliphatic), - (Ln) - (C6- aryl) io) »- (Ln) - (5-10 membered heteroaryl), - (L -.) - (5-10 membered heterocyclyl), oxo, haloalkoxy Ci-4, haloalkyl Ci-4, - (Ln) - N02, - (Ln) -CN, - (Ln) -OH, - (Ln) - CF3, -C (0) OR ', -C (0) OH, -C (0) R', -C (0) ) H, -OC (0) R ', or -NC (0) R'; or two groups Jv, Ju, Jx, or JR any, in the same substituents or different substituents, together with the atom (s) to which each group is attached Jv, Ju, Jx, and JR, form a 5-7 membered saturated, unsaturated or partially saturated ring; R 'is H or aliphatic Ci-6; or two groups R ', or a group R' and a group R, together with the atom to which they are attached, optionally form a cycloaliphatic or heterocyclyl of 3-6 members, wherein said aliphatic, cycloaliphatic or heterocyclyl is optionally substituted with R *, -OR *, -SR *, -N02, -CF3, -CN, -C (0) OR *, -C (0) R *, OC (0) R *, or NHC (0) R *, wherein R * is H or an unsubstituted Ci-6 aliphatic; L is an aliphatic Ci-6 where up to three methylene units are replaced by -NH-, -NR6-, -O-, -S-, -C (0) 0-, -OC (O) -, -C (0) C (0) -, -C (O) -, -C (0) NH-, -C (O) NR6-, -C (= N-CN), -NHC (O) -, -NR6C (0) -, -NHC (0) 0-, -NR6C (0) 0-, -S (0) 2NH-, -S (0) 2NR6-, -NHS (0) 2-, -NR6S (0) 2-, -NHC (0) NH- -NR6C (0) NH-, -NHC (0) NR6-, -NR6C (0) NR6, -OC (0) NH-, -OC (0) NR6-, -NHS (0) 2NH-, -NR6S (O) 2NH-, -NHS (O) 2NR6-, -NR6S (0) 2NR6-, -S (O) -, O -S (0) 2-; R6 is selected from Ci-6 aliphatic, C3-i0 cycloaliphatic, C6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl; or two R6 groups, in the same substituent or different substituents, together with the atom (s) to which each R6 group is attached, form a 3-8 membered heterocyclyl; Each of m and n is, independently, 0 6 1; provided that when R2 is Cl, NH2, or NCH3, then Q is not optionally substituted phenyl; and when R1 and R2 are H, then Q is not

2. The compound according to claim 1, wherein Q is a 5-10 membered heteroaryl ring optionally substituted with 1-5 JQ groups.

3. The commentary according to claim 2 wherein each of Z1, Z2, and Z4 is, independently, CH or N, wherein at least one of Z1 or Z2 is N.

4. The compound according to claim 3, wherein JQ is , wherein each R is, independently, optionally substituted with up to two occurrences of Jv; and r is 0 or 1.

5. The compound according to claim 4, wherein JQ is I H vV - «- 0, where R8 is optionally substituted with up to two occurrences of

6. The compound according to claim 5, wherein R8 is selected from CH3 .CH3, CF3, CF3 ^ ?? ^ OH CH3 QH3 ^ '13 f ~' 3 f ^ OCH3 ^, OCH3 H3C ^ .CH3 H3C -CH3 H3Cv ^ CF3 H3C

7. The compound according to claim 3, wherein r is 0 and R ', R8, and the intermediate carbons together are c The compound according to claim 4, wherein each of Z1 and Z2 is N.

9. The compound according to claim 4, wherein R "is CF3, CH2CF3 or CH2CH2CF3.

10. The compound according to claim 2, wherein Q is a 5-6 membered heteroaryl ring optionally substituted with 1-3 JQ groups.

11. The compound according to claim 10, wherein Q is a 6-membered heteroaryl ring selected from pyridyl, pyrimidyl, pyrazinyl, triazinyl or pyridazinyl optionally substituted with 1-3 JQ groups.

12. The compound according to claim 11 having the formula: wherein Z2 is CH or N; Z3 is C-JQ3 or N; JQ1 is -N (R ') R ", -CH2N (R') R", -NR'C (0) R ", -NR 'C (0) R9R", -NR'C (0) OR ", -NR'C (0) OR9R ", -NR 'C (R') (R8) R", NR'C (R ') (R8) C (0) OR ", -N (R') R9R", -N (R ') R9R ", -N (R ') R9N (R') R ", -N (R ') 90R", -NR' C (R ') (R8) R ", -NR'CH2C (0) N (R ') R "O -NR'CR' (R8) C (0) N (R ') R"; JQ2 is hydrogen, -C (0) OH, -C (0) OR ", -C (0) OR9R", -C (0) R ", - C (0) R9R", -C (0) NHR " , -C (0) N (R) R ", -C (O) NHR9OR", -C (0) NHR9R ", -C (0) N (R) R9R", -OH, -OR ", -CN , or -R ", wherein a) R8 is H, alkyl Ci-6, CF3, CH2CF3, CH2CN, or CH2OR '; or R8 and R', taken together with the atom (s) at which are (s) joined, form a ring of 3-8 members having 0-3 heteroatoms selected from O, N or S, wherein R8 or said ring is optionally substituted with 0-4 occurrences of Jv; ) R9 is aliphatic Ci-6, or R9 and R or R ', taken together with the atom (s) to which they are bound, form a ring of 3-8 members which has 0-3 heteroatoms selected from O, N, or S, wherein R9 or said ring is optionally substituted with 0-4 occurrences of Jv; JQ3 is hydrogen, halo, or N02.

13. The compound according to claim 12, wherein Z2 is CH.

14. The compound according to claim 12, wherein Z2 is N.

15. The compound according to claim 12, wherein Z3 is C-JQ3.

16. The compound according to claim 15, wherein JQ3 is F.

17. The compound according to claim 15, wherein JQ3 is H.

18. The compound according to claim 12, wherein Z3 is N.

19. The compound according to claim 18, wherein Z2 is N.

20. The compound according to claim 12, wherein JQ2 is hydrogen.

21. The compound according to claim 12, wherein JQ2 is -C (0) OH, -C (0) OR ", -C (0) R", -C (0) NHR ", -C ( 0) N (R) R ", -C (0) (R) RR", -CN, or -R ", wherein JQ2 is optionally substituted with up to two occurrences of Jv.

22. The compound according to claim 12, wherein JQ1 is , wherein R8 is optionally substituted with up to two occurrences of Jv.

23. The compound according to claim 22, wherein JQ is , wherein R8 is optionally substituted with up to two occurrences of Jv.

24. The compound according to claim 23, wherein R8 is selected from CH3 gH3 fCH > ° "3 c0'3 CF3 f0H r °"

25. The compound according to claim 22, wherein JQ1 is , where ring A is optionally substituted with up to four occurrences of Jv.

26. The compound according to claim 25, wherein ring A is selected from where Jv 'is H or Jv.

27. The compound according to claim 22, wherein JQ1 is

29. The compound according to claim 22, wherein R "is CF3, CH2CF3, or CH2CH2CF3.

30. The compound according to claim 1, wherein said compound is selected from: i66 ??? 31 32 33 40 41 42 49 50 51 58 59 60 70 71 72 73 74 75 76 77 78 79 80 81 88 89 90 97 98 99 106 107 108 112 113

31. A pharmaceutical composition comprising a compound according to any of claims 1-30 and a pharmaceutically acceptable carrier, adjuvant or vehicle.

32. The composition according to claim 31, further comprising a therapeutic agent selected from a chemotherapeutic agent or an antiproliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for the treatment of cardiovascular disease, an agent for the treatment of destructive bone disorders, an agent for the treatment of liver disease, an antiviral agent, an agent for the treatment of blood disorders, an agent for the treatment of diabetes or an agent for the treatment of immunodeficiency disorders.

33. A method of inhibiting the activity of the JAK kinase in a biological sample, comprising contacting said biological sample with a compound according to any of claims 1-30 or a composition according to claim 31. 3 . A method to treat or reduce the severity of a disease, pathological condition or disorder selected from allergic reactions or type I hypersensitivity, asthma, diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-associated dementia, amyotrophic lateral sclerosis , multiple sclerosis, schizophrenia, cardiomyocytic hypertrophy, reperfusion / ischemia, stroke, baldness, transplant rejection, graft versus host disease, rheumatoid arthritis, solid malignancy, malignant hematological disease, leukemia, lymphoma and a disorder Myeloproliferative, wherein said method comprises the step of administering to said patient a compound according to any of claims 1-30 or a composition according to claim 31.

35. The method according to claim 34, wherein said disease or disorder is asthma.

36. The method according to claim 34, wherein said disease or disorder is transplant rejection.

37. The method according to claim 34, wherein said disease is a myeloproliferative disorder selected from the group consisting of polycythemia vera, essential thrombocythaemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia , hypereosinophilic syndrome and systematic mast cell disease.