KR20070043813A - Azaindoles useful as inhibitors of protein kinases - Google Patents

Abstract

The present invention relates to pyrrolo [2,3-b] pyridine compounds useful as inhibitors of protein kinases. The present invention also provides pharmaceutically acceptable compositions comprising the compounds and methods of using the compositions in the treatment of various diseases, conditions or disorders. The invention also provides a process for the preparation of the compounds of the invention.

Inhibitors of protein kinase, pyrrolo [2,3-b] pyridine

Description

Azaindoles useful as inhibitors of protein kinases

Technical background of the invention

The present invention relates to compounds useful as inhibitors of protein kinases. The present invention also relates to pharmaceutically acceptable compositions comprising the compounds of the present invention and provide methods of using the compositions in the treatment of various diseases. The invention also provides a process for the preparation of the compounds of the invention.

Background of the Invention

Recently, a better understanding of the structure of enzymes and other biomolecules associated with certain diseases has greatly encouraged the search for new therapeutic agents. One important class of enzymes under intensive study is protein kinases.

Protein kinases form a large family of structurally related enzymes involved in the regulation of various signaling processes in cells [Hardie, G. and Hanks, S., The Protein Kinases Facts Book, I and II , Academic] Press, San Diego, CA: 1995]. Protein kinases are thought to have evolved from a common ancestral gene because of their preservation of their structure and catalysis. All kinases contain between 250 and 300 similar amino acid catalytic domains. These kinases can be grouped by the substrates they phosphorylate (eg, protein-tyrosine, protein-serine / threonine, lipids, etc.). Sequence motifs corresponding generally to the kinase family have been identified (Hanks, SK, Hunter, T., FASEB J. , 1995, 9, 576-596; Knighton et al., Science , 1991, 253, 407-414; Hiles et al., Cell , 1992, 70, 419-429; Kunz et al., Cell , 1993, 73, 585-596; Garcia-Bustos et al., EMBO J., 1994, 13, 2352-2361.

In general, protein kinases regulate intracellular signaling by causing phosphoryl delivery from nucleoside triphosphates involved in the signaling pathway to protein receptors. These phosphorylation events act as molecular on / off switches that can mediate and regulate target protein biological function. These phosphorylation events ultimately give rise to responses to various extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (eg, osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxins and H ₂ O ₂ ), cytokines (eg, interleukin-1 (IL-1) and Tumor necrosis factor α (TNF-α), and growth factors (eg, granulocyte macrophage-colon-stimulating factor (GM-CSF), and fibroblast saint factor (FGF)). Extracellular stimulation results in one or more cellular responses involved in cell growth, migration, differentiation, hormone secretion, activity of transcription factors, muscle contraction, glucose metabolism, protein synthesis and cell cycle regulation.

Many diseases are associated with abnormal cellular responses triggered by phenomena mediated by protein kinases. These diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone related diseases. Thus, considerable efforts have been made in the medical chemistry field to find protein kinase inhibitors that are effective therapeutic agents.

The Tec family of nonreceptor tyrosine kinases plays a central role in signaling through antigen receptors such as TCR, BCR and Fcε receptors. Miller A, et al. Current Opinion in Immunology 14; 331-340 (2002). Tec family kinases are essential for T cell activation. Three members of the Tec family, Itk, Rlk and Tec, activate the downstream of entry of antigen receptors in T cells and signal to downstream effectors, including PLC-γ. Removal of Itk from mice results in a decrease in proliferation induced by the T cell receptor (TCR: T cell receptor) and a decrease in the secretion of cytokines IL-2, IL-4, IL-5, IL-10 and IFN-γ. See Schaeffer et al, Science 284; 638-641 (1999), Fowell et al, Immunity 11; 399-409 (1999), Schaeffer et al Nature Immunology 2, 12; 1183-1188 (2001). Immune symptoms of allergic asthma are weakened in Itk //-mice. In response to the attack of allergen OVA, lung inflammation, eosinophil infiltration and mucus production are drastically reduced in Itk-/-mice. Mueller et al, Journal of Immunology 170: 5056-5063 ( 2003)]. Itk is also associated with atopic dermatitis. The gene has been reported to be expressed more in peripheral blood T cells from patients with severe and / or severe atopic dermatitis compared to control patients with mild atopic dermatitis. Matsumoto et al, International archives of Allergy and Immunology 129; 327-340 (2002).

Splenocytes from Rlk − / − mice secrete half of IL-2 produced by various types of animals in response to TCR entry [Schaeffer et al, Science 284; 638-641 (1999)], by eliminating Itk and Rlk from mice, it sufficiently inhibits TCR-induced responses including the proliferation and production of cytokines IL-2, IL-4, IL-5 and IFN- [gamma]. See Schaeffer et al Nature Immunology 2, 12; 1183-1188 (2001)), Schaeffer et al, Science 284; 638-641 (1999). Intracellular signaling after TCR entry affects Itk / Rlk deficient T cells, resulting in reduced inositol triphosphate production, calcium mobilization, MAP kinase activation, and activation of the transcription factors NFAT and AP-1. Schaeffer et al, Science 284; 638-641 (1999), Schaeffer et al Nature Immunology 2, 12; 1183-1188 (2001).

In addition, Tec family kinases are essential for B cell development and activation. Patients with mutations in Btk severely block B cell development, resulting in almost complete absence of B lymphocytes and plasma cells, significantly reduced Ig levels, and significantly suppressed humoral responses to recall antigens [ See Vihinen et al Frontiers in Bioscience 5: d917-928. In addition, as a result of Btk deficiency in mice, the number of peripheral B cells decreases and the levels of IgM and IgG3 decrease significantly. Btk deficiency in mice has a significant effect on anti-IgM-induced B cell proliferation and inhibits immune responses to thyroid-independent type II antigens. Ellmeier et al, J Exp Med 192: 1611-1623 (2000)].

Tec kinases also play an important role in mast cell activation via high affinity IgE receptors (FcεRI). Itk and Btk are expressed in mast cells and are activated by FcεRI crosslinking (Kawakami et al, Journal of Immunology; 3556-3562 (1995). Btk-deficient murine mast cells have reduced degranulation and reduced production of pre-inflammatory mediator cytokines following FcεRI crosslinking. Kawakami et al. Journal of leukocyte biology 65: 286-290. In addition, Btk deficiency results in decreased macrophage effector function. See Mukhopadhyay et al, Journal of Immunology; 168, 2914-2921 (2002).

Janus kinase (JAK) is a family of tyrosine kinases consisting of JAK1, JAK2, JAK3 and TYK2. JAKs play a major role in cytokine signaling. Downstream substrates of the JAK family of kinases include signal transduction agents and transcriptional activator (STAT) proteins. JAK / STAT signaling is associated with a number of aberrant immune responses, such as allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, atrophy lateral sclerosis and multiple sclerosis, as well as solid and blood cancers, eg For example, it is involved in the control of leukemia and lymphoma. Pharmaceutical interventions in the JAK / STAT pathway have been evaluated in the literature. Frank Mol. Med. 5, 432-456 (1999) & Seidel, et al, Oncogene 19, 2645-2656 (2000).

JAK1, JAK2 and TYK2 are commonly expressed, but JAK3 is mainly expressed in hematopoietic cells. JAK3 is exclusively bound to the cytokine receptor gamma chain (γ _c ) and is activated by IL-2, IL-4, IL-7, IL-9 and IL-15. The proliferation and survival of murine mast cells induced by IL-4 and IL-9 is in fact dependent on JAK3- and γ _c -signaling (Suzuki et al, Blood 96, 2172-2180 (2000)).

Crosslinking of high-affinity immunoglobulin (Ig) E receptors in sensitive mast cells results in the release of proinflammatory mediators comprising a number of vascular active cytokines that cause acute allergic, or immediate (type I) hypersensitivity reactions. Gordon et al, Nature 346, 274-276 (1990) & Galli, N. Engl. J. Med., 328, 257-265 (1993)]. A major role of JAK3 in in vitro and in vivo IgE receptor-mediated mast cell responses has been established in Malaviya, et al, Biochem. Biophys. Res. Commun. 257, 807-813 (1999). In addition, the prevention of type I hypersensitivity reactions, including anaphylaxis mediated by mast cell-activity via inhibition of JAK3, has also been reported. Malaviya et al, J. Biol. Chem. 274,27028-27038 (1999). Target mast cells with JAK3 inhibitors regulate mast cell degranulation in vitro and prevent the IgE receptor / antigen-mediated anaphylactic response in vivo.

Current studies indicate a successful target of JAK3 for immune suppression and allograft acceptance. This study demonstrates dose-dependent survival of buffalo cardiac allografts in Wistar Furth beneficiaries, who show the possibility of modulating unwanted immune responses in graft-versus-host disease when inhibitors of JAK3 are administered. Kirken, Transpl. Proc. 33, 3268-3270 (2001).

IL-4-mediated STAT-phosphorylation is associated as a mechanism involved in the early and late stages of rheumatoid arthritis (RA). Pro-inflammatory cytokine up-regulation in RA synovial fluid and lubricating fluids is characteristic of the disease. IL-4-mediated activity of the IL-4 / STAT pathway has been mediated through Janus kinases (JAK 1 & 3), and it has been demonstrated that IL-4-related JAK kinases are expressed in RA synovial fluid. Muller-Ladner , et al, J. Immunol. 164, 3894-3901 (2000).

Familial amyotrophic lateral sclerosis (FALS) is a fatal neurodegenerative disease that affects about 10% of ALS patients. FALS mouse survival was increased when treated with JAK3 specific inhibitors. This suggests that JAK3 plays a major role in FALS. Trieu, et al, Biochem. Biophys. Res. Commun. 267, 22-25 (2000).

Signal transduction agents and transcriptional activator (STAT) proteins are activated by JAK family kinases, among others. Results from recent studies indicate the possibility of modulating JAK / STAT signaling pathways by targeting JAK family kinases with specific inhibitors in the treatment of leukemia. Sudbeck, et al, Clin. Cancer Res. 5, 1569-1582 (1999). JAK3-specific compounds have been shown to inhibit the clonal growth of JAK3-expressing cell lines DAUDI, RAMOS, LCl; 19, NALM-6, MOLT-3 and HL-60.

In animal models, the TEL / JAK2 fusion protein induces myeloproliferative disorders in hematopoietic cell lines, and the introduction of TEL / JAK2 leads to the activity of STAT1, STAT3, STAT5 and cytokine-dependent growth. See Schwaller, et al, EMBO. J. 17, 5321-5333 (1998).

Inhibition of JAK 3 and TYK 2 abolishes tyrosine phosphorylation of STAT3 and inhibits cell growth of mycosis sarcoma in the form of cutaneous T cell lymphoma. These results are related to JAK family kinases in the structurally activated JAK / STAT pathways present in fungal sarcoma [Nielsen, et al, Proc. Nat. Acad. Sci U.S.A. 94, 6764-6769 (1997). Similarly, STAT3, STAT5, JAK1 and JAK2 are initially characterized by LCK over-expression and thus further proved structurally activated in mouse T cell lymphoma involved in the JAK / STAT pathway in aberrant cell growth [ See Yu, et al, J. Immunol. 159, 5206-5210 (1997). In addition, IL-6-mediated STAT3 activity is inhibited by inhibitors of JAK that sensitize apoptosis of myeloid cells (Catlett-Falcone, et al, Immunity 10, 105-115 (1999)).

Thus, protein kinases. In particular, there is a need to develop compounds useful as inhibitors of the Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) and JAK family protein kinases, and in most disorders related to their activity. There is currently insufficient treatment available.

Summary of the Invention

At present, the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective against inhibitors of protein kinases. In certain embodiments, these compounds are effective as inhibitors of the Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) protein kinases and / or JAK kinases. These compounds are compounds of Formula 1 or pharmaceutically acceptable salts thereof.

The compounds of the present invention and pharmaceutically acceptable compositions thereof include, but are not limited to, various diseases, disorders or autoimmune diseases, inflammatory diseases, proliferative diseases or hyperproliferative diseases or immunologically-mediated diseases or Useful for treating or preventing a condition. In addition, the compounds provided by the present invention include the study of kinases for biological and pathological phenomena; Study of intracellular signal transduction pathways mediated by this kinase; And comparative evaluation of novel kinase inhibitors.

1. Description of Compounds of the Invention:

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In Formula I,

로부터 선택된 임의로 치환된 5원의 환이고; Ring A is

An optionally substituted 5 membered ring selected from;

x is 0, 1 or 2;

Each R ¹ is independently halogen, CN, NO ₂ or U _m R;

R ² is independently selected from T _n -R ';

X ₁ , X ₂ and X ₃ are independently of each other CR ¹ , N, S or O;

R ³ , R ⁴ and R ⁵ are independently of each other halogen, CN, NO ₂ or V _p -R ';

T, U or V are each independently an optionally substituted C _1-6 alkylidene chain, wherein up to two methylene units of the chain are optionally independently -NR-, -S-, -O-, -CS- _{, -CO 2 -, -OCO-, -CO-} , -COCO-, -CONR-, -NRCO-, -NRCO 2 -, -SO 2 NR-, -NRSO 2 -, -CONRNR-, -NRCONR-, -Is substituted by -OCONR-, -NRNR-, -NRSO ₂ NR-, -SO-, -SO _2- , -PO-, -PO ₂ -or -POR-;

m, n and p are each independently O or 1;

Each R is independently hydrogen or optionally substituted C _1-6 aliphatic;

Each R ′ is independently hydrogen or an optionally substituted C _1-6 aliphatic; 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic rings having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; Or an 8-12 membered saturated, partially unsaturated or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or

R and R ', two R or two R' together with the atoms to which they are attached are optionally substituted 3-12 membered saturated or partially unsaturated having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur or To form a fully unsaturated monocyclic or bicyclic ring;

Provided that at least one of R ³ , R ⁴ and R ⁵ is V _p -R 'wherein R' is not hydrogen.

Obviously, when present, (R ¹ ) _X is bonded except at the position occupied by R ² in the ring A position.

In one embodiment,

a) if n is 0, R 'is not H;

이고, R⁴가 2-페녹실페닐이면, R²는 COOH 또는 CONHR^X이고, 여기서, R^X는 n-프로필, 페닐, 사이클로헥실, 벤질, -CH₂CH₂OH, -CH₂-사이클로프로필, -CH₂CH₂OCH₃, 3-피리딜, 4-하이드록시-사이클로헥실 또는 -CH₂-C≡CH이다. b) ring A is

When R ⁴ is 2-phenoxylphenyl, then R ² is COOH or CONHR ^X , where R ^X is n-propyl, phenyl, cyclohexyl, benzyl, -CH ₂ CH ₂ OH, -CH ₂ -cyclopropyl , -CH ₂ CH ₂ OCH ₃ , 3-pyridyl, 4-hydroxy-cyclohexyl or -CH ₂ -C≡CH.

In another embodiment, the compounds of the present invention do not comprise the compounds described in claim 9 on pages 152 to 166 of WO 2004/078756 A2, which is incorporated by reference.

2. Compounds and Definitions:

Compounds of the present invention include compounds described generally above and are further exemplified by the classes, subclasses, and species described herein. As used herein, unless otherwise stated, the following definitions apply. In the present invention, the chemical element is according to the Periodic Table of Elements (CAS version, Handbook of Chemistry and Physics, 75 ^th Ed.). In addition, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999; and "March's Advanced Organic Chemistry", 5 ^th Ed., Ed .: Smith, MB and March, J., John Wiley & Sons, New York: 2001.

The compounds of the invention described herein may be optionally substituted with one or more substituents generally exemplified above or exemplified by the specific classes, subclasses and species of the invention. "Optionally substituted" is used interchangeably with "substituted or unsubstituted". In general, "optionally" preceded or not preceded, "substituted" means that the hydrogen radical in a given structure is replaced by a specific substituent radical. Unless stated otherwise, an optionally substituted group may have one substituent at each substitutable position of the group, and when one or more positions of a given structure may be substituted with one or more substituents selected from a particular group, substituents May be the same or different at all positions. Combinations of substituents included in the present invention are preferably those which form stable or chemically suitable compounds. As used herein, the term "stable" means that the compound does not substantially change under the conditions applied when used for the manufacture, detection, preferably recovery, purification and one or more purposes described herein. In some embodiments, a stable compound or chemically suitable compound is a compound that does not substantially change when maintained at temperatures below 40 ° C. for at least one week in the absence of moisture or other chemically reactive conditions.

As described herein, the specific number of atoms includes any integer. For example, a group having 1 to 4 atoms can have 1, 2, 3 or 4 atoms.

As used herein, the term "aliphatic" or "aliphatic group" is a straight (ie unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or refers to fully saturated or one or more unsaturated units. It is a monocyclic hydrocarbon or bicyclic hydrocarbon it contains but is not aromatic with a single point of attachment to the rest of the molecule (also called "carbocycle", "alicyclic" or "cycloalkyl"). Unless stated otherwise, aliphatic groups have 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups have 1-10 aliphatic carbon atoms. In another embodiment, aliphatic groups have 1-8 aliphatic carbon atoms. In another embodiment, aliphatic groups have 1-6 aliphatic carbon atoms, more preferably 1-4. In some embodiments, a "cycloaliphatic" (or "carbocycle" or "cycloalkyl") is a monocyclic C ₃ -which is fully aromatic or not aromatic which contains one or more unsaturated units but has a single point of attachment to the rest of the molecule. C ₈ hydrocarbon or acyclic C ₈ -C ₁₂ hydrocarbon, wherein the individual rings of the bicyclic ring system are 3- to 7-membered rings. Suitable aliphatic groups are linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl It includes, but is not limited to these.

As used herein, the term “heteroaliphatic” means an aliphatic group in which one or two carbon atoms are independently substituted with one or more of oxygen, sulfur, nitrogen, phosphorus and silicon. Heteroaliphatic groups may be substituted or unsubstituted branched or unbranched cyclic or acyclic groups and include "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" groups.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heteroalicyclic” or “heterocyclic” refer to non-aromatic, monocyclic, bicyclic or in which one or more reductions are independently selected heteroatoms; Tricyclic ring. In some embodiments, the "heterocycle", "heterocyclyl", "heterocycloaliphatic" or "heterocyclic" group is from 3 to 3 wherein at least one of the reducing members is a heteroatom independently selected from oxygen, sulfur, nitrogen and phosphorus. Having 14 ring members, each ring of the system contains 3 to 7 ring members. Suitable heterocycles include, but are not limited to, 3-1H-benzimidazol-2-one, 3- (1-alkyl) -benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydro Furanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4 -Thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1- Piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperididi Neyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imida Zolidinyl, 5-imidazolidinyl, indolinyl, tetrahi Droquinolinyl, tetrahydroisoquinolinyl, benzothiolan, benzodithiane and 1,3-dihydro-imidazol-2-one.

"Heteroatom" means one or more oxygen, sulfur, nitrogen, phosphorus or silicon (nitrogen, sulfur, phosphorus or silicon in oxidized form; nitrogen in quaternized form; or replaceable nitrogen in a heterocyclic ring, for example, 3, N of 4-dihydro-2H-pyrrolyl, NH of pyrrolidinyl or NR ⁺ of N-substituted pyrrolidinyl).

As used herein, the term “unsaturated” means that the residue has one or more unsaturated units.

As used herein, the term "alkoxy" or "thioalkyl" refers to an alkyl group attached to the main carbon chain via an oxygen ("alkoxy") or sulfur ("thioalkyl") atom, as already defined.

"Haloalkyl", "haloalkenyl" and "haloalkoxy" mean alkyl, alkenyl or alkoxy which may be optionally substituted with one or more halogen atoms. "Halogen" means F, Cl, Br or I.

"Aryl", used alone or as part of a large moiety, such as in "aralkyl", "aralkoxy" or "aryloxyalkyl", is a monocyclic, bicyclic and tricyclic having a total of 5 to 14 ring members; A cyclic ring system, wherein at least one ring of the system is aromatic and each ring of the system has 3 to 7 rings. "Aryl" can be used interchangeably with "aryl ring." In addition, "aryl" refers to a heteroaryl ring system as defined below.

“Heteroaryl”, used alone or as part of a large moiety, such as in “heteroaralkyl” or “heteroarylalkoxy”, is a monocyclic, bicyclic and tricyclic ring having a total of 5 to 14 ring members. System, wherein at least one ring in the system is aromatic, at least one ring in the system contains at least one heteroatom and each ring in the system has from 3 to 7 ring members. The term "heteroaryl" may be used interchangeably with "heteroaryl ring" or "heteroaromatic". Suitable heteroaryl rings include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g. 3-pyridazinyl), 2-thiazolyl , 4-thiazolyl, 5-thiazolyl, tetrazolyl (eg 5-tetrazolyl), triazolyl (eg 2-triazolyl and 5-triazolyl), 2-thienyl, 3-tier Neyl, benzofuryl, benzothiophenyl, indolyl (eg 2-indolyl), pyrazolyl (eg 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1 , 2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1, 2,5-thiadia Reel, furinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g. 2-quinolinyl, 3-quinolinyl, 4-quinolinyl) and isoquinolinyl ( For example 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl).

The aryl (including aralkyl, aralkoxy, aryloxyalkyl, etc.) or heteroaryl (including heteroaralkyl, heteroarylalkoxy, etc.) groups may contain one or more substituents and may be optionally substituted. Unless stated otherwise, suitable substituents on the unsaturated carbon atoms of an aryl or heteroaryl group are generally halogen; -R ^0- ; -OR ^0- ; -SR ^0- ; 1,2-methylenedioxy; 1,2-ethylenedioxy; Phenyl optionally substituted with R ⁰ (Ph); -O (Ph) optionally substituted with R ⁰ ; -(CH ₂ ) _1-2 (Ph), optionally substituted with R ⁰ ; -CH = CH (Ph) optionally substituted with R ⁰ ; -NO ₂ ; -CN; -N (R ⁰ ) ₂ ; -NR ⁰ C (O) R ⁰ ; -NR ⁰ C (S) R ⁰ ; -NR ⁰ C (O) N (R ⁰ ) ₂ ; -NR ⁰ C (S) N (R ⁰ ) ₂ ; -NR ⁰ CO ₂ R ⁰ ; -NR ⁰ NR ⁰ C (O) R ⁰ ; -NR ⁰ NR ⁰ C (O) N (R ⁰ ) ₂ ; -NR ⁰ NR ⁰ CO ₂ R ⁰ ; -C (O) C (O) R ⁰ ; -C (O) CH ₂ C (O) R ⁰ ; -CO ₂ R ⁰ ; -C (O) R ⁰ ; -C (S) R ⁰ ; -C (O) N (R ⁰ ) ₂ ; -C (S) N (R ⁰ ) ₂ ; -OC (O) N (R ⁰ ) ₂ ; -OC (O) R ⁰ ; -C (O) N (OR ⁰ ) R ⁰ ; -C (NOR ⁰ ) R ⁰ ; -S (O) ₂ R ⁰ ; -S (O) ₃ R ⁰ ; -SO ₂ N (R ⁰ ) ₂ ; -S (O) R ⁰ ; -NR ⁰ SO ₂ N (R ⁰ ) ₂ ; -NR ⁰ SO ₂ R ⁰ ; -N (OR ⁰ ) R ⁰ ; -C (= NH) -N (R ⁰ ) ₂ ; — (CH ₂ ) _0-2 NHC (O) R ⁰ wherein each R ⁰ is independently hydrogen, optionally substituted C _1-6 aliphatic, unsubstituted 5 to 6 membered heteroaryl or heterocyclic Ring, phenyl, -O (Ph) and -CH ₂ (Ph), or two R ⁰ on the same substituent or on different substituents, despite the definitions above, are nitrogen, together with the atoms to which each R ⁰ group is bonded, To form an optionally substituted saturated, partially unsaturated or fully unsaturated monocyclic or bicyclic 3 to 12 membered ring having 0 to 4 heteroatoms independently selected from oxygen and sulfur).

Optional substituents for aliphatic groups of R ⁰ are NH ₂ , NH (C _1-4 aliphatic), N (C _1-4 aliphatic) ₂ , halogen, C _1-4 aliphatic, OH, O (C _1-4 aliphatic) , NO ₂ , CN, CO ₂ H, CO ₂ (C _1-4 aliphatic), O (halo C _1-4 aliphatic) and halo C _1-4 aliphatic, wherein each C _1-4 of R ⁰ Aliphatic groups are not substituted.

Aliphatic or heteroaliphatic groups or non-aromatic heterocyclic rings may contain one or more substituents and may therefore be optionally substituted. Unless stated otherwise, suitable substituents on the saturated carbon of an aliphatic or heteroaliphatic group or non-aromatic heterocyclic ring are selected from the substituents listed above for the unsaturated carbon of an aryl or heteroaryl group, and further = O, = S, = NHNR ^* , = NN (R ^* ) ₂ , = NNHC (O) R ^* , = NNHCO ₂ (alkyl), = NNHSO ₂ (alkyl) or = NR ^* (where R ^* is independently hydrogen and optionally Selected from substituted C _1-6 aliphatic groups).

Optional substituents for the nitrogen of the non-aromatic heterocyclic ring are generally -R ⁺ , -N (R ⁺ ) ₂ , -C (O) R ⁺ , -CO ₂ R ⁺ , -C (O) C (O) R ⁺ , -C (O) CH ₂ C (O) R ⁺ , -SO ₂ R ⁺ , -SO ₂ N (R ⁺ ) ₂ , -C (= S) N (R ⁺ ) ₂ , -C (= NH ) -N (R ⁺ ) ₂ and -NR ⁺ SO ₂ R ⁺ (where R ⁺ is hydrogen, optionally substituted C _1-6 aliphatic, optionally substituted phenyl, optionally substituted -O (Ph), optionally substituted -CH ₂ (Ph), optionally substituted-(CH ₂ ) _1-2 (Ph), optionally substituted -CH = CH (Ph) or independently having 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur Unsubstituted heteroaryl or heterocyclic 5- to 6-membered ring) or two R ⁺ on the same or different substituents, despite the definitions above, with the atoms to which each R ⁺ group is attached 5-8 membered hetero with 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur To form a cycle reel, aryl or heteroaryl, or 3- to 8-membered cycloalkyl ring. Optional substituents on the phenyl ring of R ^+, or an aliphatic group of R ⁺ is -NH _2, -NH (C _1-4 aliphatic), -N (C _1-4 aliphatic) _2, halogen, C _1-4 aliphatic, OH , O (C _1-4 aliphatic), NO ₂ , -CN, -CO ₂ H, -CO ₂ (C _1-4 aliphatic), -O (halo C _1-4 aliphatic) and halo C _1-4 aliphatic Wherein each C _1-4 aliphatic group of R ⁺ is unsubstituted.

The term "alkylidene chain" is a straight or branched carbon chain which has one or more units that are fully saturated or unsaturated, and which may have two points attached to the rest of the molecule, wherein one or more methylene units are optionally independently, limited thereto But not necessarily include CO, CO ₂ , COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO ₂ , NRCONR, SO, SO ₂ , NRSO ₂ , SO ₂ NR, NRSO ₂ NR, O, S or NR Can be replaced by a group.

As used herein, the term “protecting group” is an agent used to temporarily block one or more desired reaction sites in a multifunctional compound. In certain embodiments, the protecting group has one or more or preferably all of the following features: a) selectively reacting in yield to provide a protective substrate that is stable to reactions that occur at one or more other reaction sites; b) Reagents that do not attack the functional groups to be regenerated and can be selectively removed in good yield. Exemplary protection groups are described in Greene, TW, Wuts, P. G in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999, incorporated herein by reference in its entirety. It is. As used herein, the term “nitrogen protecting group” refers to a reagent used to temporarily block one or more desired nitrogen reaction sites in a multifunctional compound. Preferred nitrogen protecting groups also have the properties exemplified above, and the nitrogen protecting groups specifically exemplified are also described in Chapter 7 in Greene, TW, Wuts, P. G in "Protective Groups". in Organic Synthesis ", Third Edition, John Wiley & Sons, New York: 1999.

로 치환되는 경우, 2개의 R⁰는 이들이 결합된 산소 원자와 함께 형성되는

의 융합된 산소 함유 6원의 환이 있지만 이들로 한정되지 않는다. 2개의 R⁰(또는 R⁺ 또는 기타 유사하게 정의된 라디칼)가 이들이 결합된 원자와 함께 기타의 각종 환을 형성할 수 있으며, 위에서 기술한 예는 본 발명을 한정하려는 것이 아니다. As noted above, in some embodiments, two independent R ⁰ (or R ⁺ or other similarly defined radicals) together with the atoms to which they are attached are 0 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur To form a 5-8 membered heterocyclyl, aryl or heteroaryl ring or a 3-8 membered cycloalkyl. Two R ⁰ (or R ^+, or any other similarly defined radical) with typical ring forming together with the they are attached atoms, (a) two R ⁰ (or R ^+, or any other similarly defined radical) is When bound to the same atom, a ring is formed together with the bound atom, for example N (R ⁰ ) ₂ , wherein two R ⁰ together with the nitrogen atom are piperidin-1-yl, piperazine-1 -Forms a yl or morpholin-4-yl group) and (b) a ring that forms together with the atoms to which it is bound when two R ⁰ (or R ⁺ or other similarly defined radicals) are bonded to different atoms , for example, a phenyl group, two OR ^O

When substituted with two R ⁰ are formed together with the oxygen atom to which they are attached

There are, but are not limited to, fused oxygen containing six-membered rings. Two R ⁰ (or R ⁺ or other similarly defined radicals) together with the atoms to which they are attached may form other various rings, the examples described above are not intended to limit the invention.

Unless stated otherwise, the structures shown herein also include all isomers (eg, enantiomers, diastereomers, and geometric (or structural) isomers), eg, R and S for each asymmetric center. Coordination, (Z) and (E) double bond isomers, and (Z) and (E) structural isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric and geometric (or structural) isomeric mixtures are within the scope of the present invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are also within the scope of the invention. Also, unless stated otherwise, the structures shown herein include compounds that differ only in the presence of one or more isotope-rich elements. For example, compounds having a structure except replacing hydrogen with deuterium or tritium or replacing carbon with ¹³ C or ¹⁴ C-rich carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical instruments or probes in biological assays.

3. Description of Exemplary Compounds

All descriptions of embodiments herein can be applied to compounds of Formulas (I), (II), (III), (IV), (V), and (VI).

In certain embodiments of the invention, R ⁴ and R ⁵ are independently of each other V _p -R '.

In another embodiment, one of R ³ , R ⁴ and R ⁵ is V _p -R 'wherein R' is optionally substituted 5 or 6 having 0 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur Full, unsubstituted (ie aromatic) monocyclic rings; Or an optionally substituted 9 or 10 membered completely unsubstituted bicyclic ring system having 0 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In other embodiments, one of R ³ , R ⁴ and R ⁵ is V _p -R 'wherein R' is independently optionally substituted C _1-6 aliphatic; Optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic rings having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; Or an optionally substituted 8-12 membered saturated, partially unsaturated or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In other embodiments, R ⁴ is V _p -R 'wherein R' is independently optionally substituted with 0 to 3 heteroatoms independently selected from optionally substituted C _1-6 aliphatic, nitrogen, oxygen or sulfur 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic rings; Or an optionally substituted 8-12 membered saturated, partially unsaturated or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur. In these embodiments specifically, R ³ and R ⁵ are V _p -R ', p is 0 and R' is hydrogen.

In another embodiment, R ⁴ is V _p -R 'wherein R' is independently optionally substituted C _1-6 aliphatic, or optionally substituted, having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring.

In other embodiments, R ⁴ is V _p -R 'wherein R' is an optionally substituted 3-8 membered saturated or partially unsaturated or fully having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Unsaturated monocyclic rings.

In another embodiment, R ⁴ is V _p -R 'wherein R' is an optionally substituted 5 or 6 membered completely unsubstituted having 0 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Monocyclic ring.

In another embodiment, R ⁴ is V _p -R 'wherein R' is an optionally substituted 6 membered, completely unsubstituted monocylic having 0 to 3 nitrogen heteroatoms or having 0 to 1 nitrogen heteroatoms. It is a click ring.

In another embodiment, R ⁴ is V _p -R 'wherein R' is an optionally substituted 3-8 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. to be.

In another embodiment, R ⁴ is V _p -R 'wherein R' is an optionally substituted 6 membered saturated monocyclic ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In another embodiment, R ⁴ is V _p -R 'wherein R' is optionally substituted C _1-6 aliphatic. In certain embodiments, R 'is C _1-6 alkynyl. In certain embodiments, R 'is -C≡CH.

In other embodiments, p is zero.

In another embodiment, p is 1.

In other embodiments, V is -NR-, -S- or -O-.

In other embodiments, R ³ is V _p -R 'wherein p is 0 and R' is hydrogen.

In other embodiments, R ⁵ is halogen or V _p -R 'wherein p is 0 and R' is hydrogen or C _1-6 aliphatic. In another embodiment, the C _1-6 aliphatic is C _1-3 alkyl.

이다. 이들 특정한 양태에서, X₂는 CR¹이다. In another embodiment, Ring A is

to be. In these particular embodiments, X ₂ is CR ¹ .

In another embodiment, Ring A is

이다.

to be.

In another embodiment, Ring A is

이다.

to be.

In certain embodiments, R ¹ is U _m R. In other embodiments, R ¹ is U _m R wherein m is 0 and R is H or CH ₃ .

In certain embodiments, R ² is T _n R 'wherein n is 1.

In other embodiments, R is T _n R 'wherein n is 0.

In certain embodiments, T is -NR-, -O-, -CO-, -CONR-, or -NRCO-.

In certain embodiments, T is -NR-. In certain embodiments, T is -O-. In these specific embodiments, R 'is C _1-6 aliphatic. In other embodiments, both R and R 'are H.

In certain embodiments, T is -NR- and R 'is C _1-6 aliphatic. In these specific embodiments, R 'is C _1-6 aliphatic. In some embodiments, both R and R 'are C _1-6 alkyl.

In certain embodiments, T is a C _1-6 alkylidene chain, wherein the alkylidene chain is attached to ring A via a methylene unit. In some of these embodiments, T is-(C _1-5 alkyl) NR-. In some embodiments, T is -CH ₂ NR-. In some of these embodiments, R ′ is C _1-6 aliphatic.

In other embodiments, T is a C _1-6 alkylidene chain, wherein zero methylene units are substituted with a group described herein.

In another embodiment, R ² is optionally substituted 5-7 membered N-attached heterocyclyl. In certain embodiments, the N-attached heterocyclyl is selected from morpholinyl, piperidinyl, pyrrolidinyl and piperazinyl. In certain embodiments, such N-attached heterocyclyls are optionally independently substituted with 0-4 amino, alkylamino, dialkylamino or C _1-6 alkyl.

As generally described above, another compound of the present invention is a compound of Formula II or a pharmaceutically acceptable salt thereof:

In another embodiment, the compound of the invention is a compound of Formula III or a pharmaceutically acceptable salt thereof:

In another embodiment, the compound of the invention is a compound of Formula IV or a pharmaceutically acceptable salt thereof:

In another embodiment, the compound of the invention is a compound of Formula V or a pharmaceutically acceptable salt thereof:

In another embodiment, the compound of the invention is a compound of Formula VI or a pharmaceutically acceptable salt thereof:

For the compounds of Formulas II-VI, modifications of the compounds of Formulas II-VI are evident as defined in the embodiments herein.

As described generally above, substituents and modifications (eg, R ′ groups) are carried out in the compounds listed in Table 1.

Thus, representative examples of compounds of Formula (I) are described in Tables 1 and 2 below.

4. Common Synthetic Methods:

Compounds of the invention can be prepared by methods known to those skilled in the art for similar compounds as shown in the following schemes and preparation examples.

The following abbreviations are used:

EtOH: Ethanol

RT: room temperature

Ts: Chubby

Ph: Phenyl

DME: Dimethyl Ether

Bu: Butyl

EDC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide

DMF: Dimethylformamide

O / N: overnight

Et ₂ O: ether

CDI: N, N'-carbonyldiimidazole

LCMS: Liquid Chromatography Mass Spectrometer

P-: suitable protection group

Reagents and Conditions: (a) AlCl ₃ , CH ₂ Cl ₂ , RT, 16 h; (b) EtOH, microwave radiation, 120 ° C., 10 min.

Scheme I described above represents a general synthetic route used to prepare compounds (5) of the present invention, wherein R ₁ to R ₅ are as described herein. Intermediate (3) was prepared using Friedel-Crafts acylation methods well known in the art. Reaction with various substituted chloroacetyl chlorides forms compounds of formula (3). Finally, the compound of formula 5 was obtained by cyclization of intermediate (3) according to step (b). Reaction was carried out with various substituted thioamides of formula (4).

Reagents and Conditions: (a) Br ₂ , CHCl ₃ , 0 ° C. to RT; (b) ⁿ BuLi, THF, TsCl;

(c) PdCl ₂ (dppf) ₂ , dioxane, KOAc, bis (pinacolato) diboron, 18 h;

(d) Pd (PPh ₃ ) ₄ , Na ₂ CO ₃ , DME, EtOH / H ₂ O, microwave radiation, 120 ° C., 2 hours;

(e) 3N NaOH, MeOH.

Scheme II shows the general synthetic route used to prepare compound 11 of the present invention, wherein A, R ₁ to R ₅ and x are as described herein. Intermediate (7) was prepared by brominating the compound of Structure 1 and subsequently protecting the intermediate (6) with tosyl groups. Boric acid ester (8) was formed according to Scheme II step (c). The formation of the biaryl bond derivative 10 is carried out by treating bromide 9 with a boric acid ester derivative 8 in the presence of palladium as a catalyst using the Suzuki coupling method well known in the art. It was reacted with various substituted aryl or heteroaryl bromide (9). Finally, the tosyl protecting group was removed in the basic state according to Scheme II step (e) to afford the compound of structure 11.

Reagents and Conditions: (a) Br ₂ , CHCl ₃ , O ° C. to RT; (b) ⁿ BuLi, THF, TsCl;

(c) Pd (PPh ₃ ) ₄ , Na ₂ CO ₃ , DME, EtOH / H ₂ O, microwave radiation, 120 ° C., 2 hours;

(d) 3N NaOH, MeOH.

Scheme III represents the general synthetic route used to prepare compounds 11 of the present invention, wherein A, R ₁ to R ₅ and x are as described herein. Intermediate 7 was prepared according to Scheme II. In this case, the formation of the biaryl bond derivative 10 is carried out by treating bromide 7 with a boric acid derivative 12 in the presence of palladium as a catalyst using the Suzuki coupling method well known in the art. It was reacted with various substituted aryl or heteroaryl boric acid (12). Once again, the tosyl protecting group was removed in the basic state according to Scheme III step (d) to afford the compound of structure 11.

Reagents and Conditions: (a) Rawensen reagent, toluene, 110 ° C., O / N; (b) EtOH, reflux, O / N;

(c) EtOH, 1N NaOH, 12 h; (d) EDC, HOBt, DMF, NHR'R, RT, O / N.

Scheme IV depicts a general synthetic route used to prepare compounds 18 of the present invention, wherein R, R ′ and R ₁ to R ₅ are as described herein. Starting materials (13) are substantially described in Schneller and Luo J. Org. Chem. 1980, 45, 4045]. Derivative 14 was formed by reacting compound 13 with Rawenson's reagent. Compound (14) was cyclized in the presence of β-ketoester (15) to afford intermediate (16). It reacted with various (beta) -ketoester (15). After deprotection under basic conditions with ester 16, derivative 18 was formed by a coupling reaction step known to those skilled in the art.

Reagents and Conditions: (a) ⁿ BuLi, THF, PCl;

(b) i) ^t BuLi, Et ₂ 0, −78 ° C., 1 hour, ii) R'SSR '; (c) Deprotection status.

Scheme V depicts the general synthetic route used to prepare compound 18 of the present invention, wherein R ′ is as described herein. Starting materials 19 can be prepared by the methods described in Mazeas, et al, Heterocycles 1999, 50, 1065. Intermediate 20 obtained by protecting compound (19) with suitable protecting group (P) was reacted according to Scheme V step (b) with suitable disulfide R'SSR '. After deprotection with indazole (21), a compound of formula (22) was formed.

Reagents and conditions: (a) R ₁ OH, NaOMe, CuBr, DMF, heated, 2.5 h.

Scheme VI depicts the general synthetic route used to prepare Compound 23 of the present invention, wherein R ′ is as described herein. Starting material 19 was treated with suitable alcohol R'OH according to Scheme VI step (a).

Reagents and Conditions: (a) ⁿ BuLi, THF, PCl;

_{(b) NHR'R, PdCl 2 (} dppf), NaO t Bu, THF, heating; Or HNR'R, Cu, K ₂ CO ₃ , nitrobenzene, heating; (c) Deprotection status.

Scheme VII above represents a general synthetic route used to prepare compounds 25 of the present invention, wherein R and R ′ are as described herein. Intermediate (20) obtained by protecting compound (19) with a suitable protecting group (P) with amine RR'NH in the presence of palladium as catalyst in the Buchwald-Hartwig cross, well known in the art Obtained using a coupling reaction. This cross coupling reaction can also be carried out by treating the intermediate 20 with the amine RR'NH in the presence of copper as a catalyst using the Ullmann reaction which is well known in the art. Both reactions were carried out with various substituted amines. After deprotecting the indazole 24, a compound of formula 25 was formed.

Reagents and Conditions: (a) R ₄ B (OH) ₂ , Pd (PPh ₃ ) ₄ , EtOH, H ₂ O, DME, 100 ° C., O / N;

(b) Br ₂ , CHCl ₃ , 0 ° C. to RT; (c) ⁿ BuLi, THF, TsCl;

(d) Pd (PPh ₃ ) ₄ , Na ₂ CO ₃ , DME, EtOH / H ₂ O, microwave radiation, 12O < 0 > C, 2 hours;

(e) 3N NaOH, MeOH.

Scheme VIII depicts a general synthetic route used to prepare compounds 30 of the present invention, wherein A, R ₁ to R ₄ and x are as described herein. The compound of structure 19 was treated with boric acid derivative R ₄ B (OH) ₂ in the presence of palladium as catalyst using Suzuki coupling method well known in the art. Reaction was performed with various substituted aryl or heteroaryl boric acids. Intermediate 27 was prepared by brominating the compound of structure 26 and subsequently protecting the intermediate 27 with tosyl groups. Another Suzuki cross coupling reaction was achieved according to Scheme VIII step (d). Finally, the tosyl protecting group was removed in the basic state according to Scheme VIII step (e) to give a compound of structure 30.

Reagents and Conditions: (a) ⁿ BuLi, THF, PCl;

(b) i) ^t BuLi, Et ₂ O, -78 ° C., 1 hour, ii) R'CHO; (c) Deprotection status.

Scheme IX represents a general synthetic route used to prepare compounds 32 of the present invention, wherein R ′ is as described herein. The intermediate (20) obtained by protecting compound (19) with a suitable protecting group (P) was treated according to Scheme IX step (b) with a suitable aldehyde R'CHO. After deprotection with indazole 31, a compound of formula 32 was formed.

Reagents and Conditions: (a) ⁿ BuLi, THF, PCl;

(b) i) ^t BuLi, Et ₂ 0, −78 ° C., 1 hour, ii) R′CH ₂ Br; (c) Deprotection status.

Scheme X represents a general synthetic route used to prepare compounds 32 of the present invention, wherein R ′ is as described herein. Intermediate 20 obtained by protecting compound (19) with a suitable protecting group (P) was treated according to Scheme X step (b) with suitable R′CH ₂ Br. After deprotection of indazole 33, a compound of formula 34 was formed.

Reagents and Conditions: (a) CDI, DMF; (b) P ₂ S ₅ , pyridine.

Scheme XI represents a general synthetic route used to prepare compounds 38 of the present invention, wherein R ₂ to R ₅ are as described herein. Starting materials 35 are described in Allegreti et al, Org. Proc. Res. Dev. 2003, 7, 209]. Intermediate 35 was reacted with amine 36 according to Scheme XI step (a). Reaction was carried out with various substituted amines 36. Compound (37) was cyclized in the presence of P ₂ S ₅ to afford the desired derivative (38).

Reagents and Conditions: (a) AlCl ₃ , CH ₂ Cl ₂ , RT, 16 h;

(b) NH ₂ OH-HCl, EtOH, heated, 1 h.

Scheme XII described above represents a general synthetic route used to prepare compounds 41 of the present invention, wherein R ₂ to R ₅ are as described herein. Intermediate 40 was prepared using Friedel-Craft acylation methods well known in the art. It was reacted with various substituted derivatives 39 to form a compound of formula 40. Compound of formula 41 was obtained by cyclization of intermediate 40 according to step (b).

While certain exemplary embodiments have been described and described above, it is apparent that the compounds of the present invention can be prepared in a manner generally available to one of ordinary skill in the art, using suitable starting materials, according to the methods generally described above.

Thus, in another aspect, the invention provides a method for preparing a compound of the invention substantially as described herein, in particular in schemes and examples.

5. Uses, Formulations, and Administration

Pharmaceutically Acceptable Compositions

As discussed above, the present invention provides inhibitor compounds of protein kinases, whereby the compounds are, but are not limited to, autoimmune diseases, inflammatory diseases, proliferative diseases or hyperproliferative diseases or immunologically-mediated. It is useful for the treatment of diseases, disorders and conditions, including predisposed diseases. Thus, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, which compositions comprise the compounds described herein and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally comprise one or more additional therapeutic agents.

In addition, some of the compounds of the present invention may exist in free form for treatment or, where appropriate, as pharmaceutically acceptable derivatives thereof. According to the present invention, pharmaceutically acceptable derivatives include salts of pharmaceutically acceptable prodrugs, salts, esters, esters; Or other adducts or derivatives which, when administered to a patient in need thereof, may directly or indirectly provide compounds other than those described herein; Or metabolites or residues thereof, including but not limited to.

As used herein, the term "pharmaceutically acceptable salt" is suitable for use in contact with tissues of humans and lower animals within normal medical judgment and without the use of excessive toxicity, irritation, allergic reactions, etc. It means salt that fits. "Pharmaceutically acceptable salt" means a salt of a nontoxic salt or ester of a compound of the invention that, when administered to a recipient, can provide directly or indirectly a compound of the invention or an inhibitory active metabolite or residue thereof. As used herein, the term “inhibitor active metabolite or residue thereof” refers to an inhibitor of a metabolite or residue thereof also in the Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) protein kinase kinase. Means to be.

Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al., J. Pharmaceutical Sciences , 1977, 66, 1-19, describe in detail the pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic acids, organic acids, inorganic bases and organic bases. Examples of non-toxic acid addition salts that are pharmaceutically employed are formed or ionized with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Salts of amino groups formed using other methods used in the art such as exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepro Cypionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- Hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, maleate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalic acid Salt, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalray , And the like propionic acid salt, stearic acid salt, succinic acid salt, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, to rate. Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternization of basic nitrogen containing groups of the compounds described herein. Water soluble or fat soluble or dispersible products may be obtained via quaternization. Representative alkali or alkaline earth metals include sodium, lithium, potassium, calcium, magnesium and the like. Additionally, pharmaceutically acceptable salts include counters such as non-toxic ammonium, quaternary ammonium, and halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates, where appropriate. Amine cations formed using ions are included.

As described above, the pharmaceutically acceptable salts of the present invention further comprise pharmaceutically acceptable carriers, adjuvants or vehicles, as used herein, which are solvents, diluents or other liquid vehicles, dispersions or Suspension aids, surface active agents, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like, which are suitable for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) describe various carriers used in the formulation of pharmaceutically acceptable compositions and techniques for their preparation. If the phosphorus carrier is incompatible with the compound of the present invention, for example, unless the conventional carrier produces undesirable biological effects or interacts in a deleterious manner with the other ingredients of the pharmaceutically acceptable composition, It is contemplated to use conventional carrier media within the scope of the present invention Some examples of materials that can be provided as pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins. (E.g. human serum albumin), buffer substances (e.g. phosphate, glycine, sorbic acid or potassium sorbate), Partial glyceride mixtures of saturated fatty acids, water, salts or electrolytes (e.g. protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride), zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, Polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, sheep fats, sugars (eg lactose, glucose and sucrose), starches (eg corn starch and potato starch), Cellulose and its derivatives (e.g. sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacand, malt, gelatin, talc, excipients (e.g. cocoa butter and suppository waxes), oils (e.g. For example, peanut oil, cottonseed oil, safflower seed oil, sesame oil, olive oil, corn oil and soybean oil), glycols (for example, propylene glycol or polyethylene glycol), esters Le (e.g. ethyl oleate and ethyl laurate), agar, buffers (e.g. magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol and phosphate Buffers are included and non-toxic compatible lubricants (e.g. sodium lauryl sulfate and magnesium stearate), colorants, release agents, coatings, sweeteners, flavors, fragrances, preservatives and antioxidants are also determined by the formulator. According to the present invention.

Use of Compounds and Pharmaceutically Acceptable Compositions

In another embodiment, a method of reducing or treating a Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) -mediated disease is a compound or a pharmaceutically acceptable composition comprising the compound. An effective amount of is provided to a patient in need thereof. In certain embodiments of the invention, an “effective amount” of a compound or pharmaceutically acceptable composition is an amount effective for a Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) -mediated disease to be. Compounds and compositions according to the methods of the invention employ doses and methods of administration that are effective in the treatment or alleviation of Tec family (e.g., Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) -mediated diseases. Can be administered. The exact requirements may vary depending on the species, age and general condition of the subject, the severity of the infection, the particular agent, the mode of administration of the agent, and the like. The compounds of the present invention are preferably formulated in unit dosage form in terms of ease of administration and dose uniformity. As used herein, the term “unit dosage form” means a physically discrete unit of preparation suitable for the patient to be treated. However, the total daily usage of the compounds and compositions of the present invention is determined by the attending physician within the scope of normal medical judgment. Specific effective dose levels for a particular patient or organ may include the disease to be treated and the severity of the disease; Activity of the specific compound employed; The specific composition employed; The age, body weight, general health, sex and diet of the patient; Time of administration, route of administration, and rate of secretion of the specific compound employed; It depends on various factors that are well known in the medical arts, such as the duration of treatment, the drug used with or concurrently with the particular compound used. The term "patient" as used herein means an animal, preferably a mammal, most preferably a human.

The pharmaceutically acceptable compositions of this invention, depending on the severity of the infection to be treated, are oral, rectal, parenteral, intracranial, vaginal, intraperitoneal, topical (via powder, ointment or drop) to humans or other animals. , Oral (oral or nasal spray) and the like. In certain embodiments, to achieve the desired therapeutic effect, the compounds of the present invention may be orally or parenterally administered at least once a day at a dosage of about 0.01 to about 50 mg, preferably about 1 to about 25 mg, per kg of body weight. have.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microfluids, solutions, suspensions, syrups and elixirs. Liquid dosage forms are inert diluents commonly used in the art, in addition to the active compound, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl Alcohols, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, embryo oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl Alcohols, polyethylene glycols, fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, compositions for oral administration may also include adjuvants such as wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents and fragrances.

Injectable preparations, for example, aqueous or oily suspensions for sterile infusion, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. Formulations for sterile infusion may also be sterile infusion solutions, suspensions or emulsions, such as solutions in 1,3-butanediol, parenterally acceptable non-toxic diluents or solvents. Acceptable vehicles and solvents include water, Ringer's solution, U.S.P. And isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, mild fixed oils can be employed including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable preparations.

Injectable formulations can be sterilized, for example, by filtration through a bacterial retention filter, or by incorporating a sterilant in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile infusion media prior to use. .

In order to sustain the effect of the compounds of the invention, it is desirable to delay the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound depends on the rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered compound form can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms can be prepared by forming microencapsule matrices of the compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the rate of release of the compound can be controlled. Examples of other biodegradable polymers are poly (orthoesters) and poly (anhydrides). Depot formulations for infusion may also be prepared by entrapping the compound in liposomes or microfluids suitable for living tissue.

Compositions for rectal or vaginal administration are preferably non-irritating excipients or carriers, such as cocoa butter, which solidify the compound of the present invention at ambient temperature but become liquid at body temperature to melt in the rectum or vagina to release the active compound Suppositories that can be prepared by mixing with polyethylene glycol or suppository waxes.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is one or more pharmaceutically acceptable inert excipients or carriers such as sodium citrate or dicalcium phosphate and / or fillers such as starch, lactose, sucrose, glucose, mannitol and silicic acid. Or extenders (a), carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, binders such as sucrose and acacia (b), humectants such as glycerol (c), agar-agar, carbonic acid Disintegrants such as calcium, potato or tapioca starch, alginic acid, silicates and sodium carbonate, solution retarders such as paraffin, e) absorption accelerators such as quaternary ammonium compounds, cetyl alcohol and glycerol monostearate and Wetting agents (g), sorbents such as kaolin and bentonite clay (h), and talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate Lubricant (i) and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise a buffer.

Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings or other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may release only the active compound in certain parts of the intestine or release the active compound preferentially in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycols and the like.

The active compound may also be microencapsulated with one or more excipients mentioned above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared using coatings and shells such as enteric coatings, controlled release coatings or other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with one or more inert diluents such as sucrose, lactose or starch. Such dosage forms may also include additional substances other than inert diluents, such as tablet lubricants such as magnesium stearate and microcrystalline cellulose and other tablet aids. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. They may optionally contain opacifying agents and may release only the active compound in certain parts of the intestine or release the active compound preferentially in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and the necessary preservative or buffer. Ophthalmic formulations, ear drops and eye drops are also within the scope of the present invention. The present invention also encompasses the use of transdermal patches having the advantage that the delivery of the compound to the body is controlled. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the influx of compounds through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer medium or gel.

As generally described above, the compounds of the present invention are useful as protein kinase inhibitors. In one embodiment, the compounds and compositions of the present invention are inhibitors of one or more Tec family (e.g., Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) kinases, and are therefore not limited in theory. In particular, the compounds and compositions of the present invention are particularly useful for treating or alleviating a disease, condition or disorder, wherein one or more Tec families (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) The activity of kinases is related to a disease, condition or disease. When the activity of a Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) is related to a particular disease, condition or disease, the disease, condition or disease may also be referred to as “Tec family (eg , Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) -mediated disease "or disease syndrome. Thus, in another aspect, the invention provides a method for treating a disease, condition or disorder in which one or more activities of the Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) are associated with a disease state or It provides a way to mitigate.

In the present invention, the activity of the compounds used as inhibitors of the Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) kinases is assayed in vitro, in vivo or in cell lines. In vitro assays include assays that measure the inhibition of phosphorylation activity or ATPase activity of an activated Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) kinase. Alternative in vitro assays quantify the ability of inhibitors to bind to the Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) kinases. Inhibitor binding is achieved by radiolabeling the inhibitor before binding, isolating inhibitor / Tec family (e.g., Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) complexes and measuring the amount of radiolabeled bound It can be measured. Alternatively, inhibitor binding involves competition experiments in which the novel inhibitor is incubated with a Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) kinase bound to known radioligands. Can be measured by performing.

As used herein, the term “measurable inhibition” refers to a sample comprising the composition and the Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) kinase, and Tec in the absence of the composition. Tec series (e.g., Tec, Btk, Itk / Emt / Tsk, Bmx, Txk) between equivalent samples containing the kinase (eg Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) / Rlk) means a measurable change in kinase activity.

As used herein, the term “Tec family tyrosine kinase mediated state” refers to a disease or other deleterious condition in which Tec family kinases are known to act. Such conditions include, but are not limited to, autoimmune, inflammation, proliferative and hyperproliferative diseases, and immune mediated diseases including rejection of transplanted organs or tissues and acquired immune deficiency syndrome (AIDS).

For example, Tec family tyrosine kinase mediated conditions include reversible obstructive airway diseases, including chronic asthma (eg, delayed asthma), including asthma (eg, bronchial, allergic, endogenous, exogenous, and dusty asthma). Airway hyperresponsiveness) and bronchitis, including but not limited to. In addition, Tec family tyrosine kinase diseases include diseases characterized by inflammation of the nasal mucosa, including acute rhinitis; Allergic, atrophic rhinitis and chronic rhinitis including rhinitis fetal fat; Thickening rhinitis, rhinitis farmers, dry rhinitis and rhinitis dermatitis; Membranous rhinitis including croupous rhinitis, fibrinitis and pseudomembranous rhinitis and scrofoulous rhinitis; Seasonal rhinitis including rhinitis hay fever and vasomotor rhinitis; Sarcoidosis, farmer's lung and related diseases, fibrous lung and idiopathic interstitial pneumonia are included, without limitation.

In addition, Tec family tyrosine kinase mediated conditions include rheumatoid arthritis (in which pannus forms), negative serum reactive spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter syndrome), Behcet's disease, Sjogren's syndrome and systemic sclerosis. Including but not limited to bone and joint diseases.

In addition, Tec series kinase mediated conditions include psoriasis, systemic sclerosis, atopic dermatitis, contact dermatitis and other eczema dermatitis, seborrheic dermatitis, Lichen planus, Pemphigus, bullous pemphigus, bullous epidermal detachment, urticaria, Skin diseases and disorders including but not limited to angiodermas, vasculitides, erythema, cutaneous eosinophilia, uveitis, alopecia areata and spring conjunctivitis.

In addition, Tec family tyrosine kinase-mediated conditions include food-related allergies that have an effect that is far away from intraperitoneal disease, proctitis, eosinophilic gastroenteritis, mastocytosis, pancreatitis, Knon disease, ulcerative colitis, and alimentary tract Gastrointestinal diseases and disorders including, but not limited to, migraine, rhinitis and eczema.

In addition, Tec family tyrosine kinase-mediated conditions include multiple sclerosis, atherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus, erythema, Hasitomo thyroiditis, myasthenia gravis, type I diabetes, nephrosis syndrome, eosinophilia ( eosinophilia fascitis, excessive IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenic purpura, restenosis after coronary angioplasty, tumors (eg leukemia, lymphoma), atherosclerosis, and Other tissues, including but not limited to systemic lupus erythematosus, and systemic diseases and disorders.

In addition, Tec family tyrosine kinase mediated conditions include acute and chronic allograft rejection following transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; And chronic graft versus host disease.

Compounds and pharmaceutically acceptable compositions of this invention may be used in combination therapy, i.e., compounds and pharmaceutically acceptable compositions may be administered concurrently with, or before or after, one or more other desirable therapeutic or medical procedures. . The combination of specific therapies (therapies or procedures) used in combination therapy takes into account the desired treatment and / or procedure and the suitability of the desired therapeutic effect. In addition, the therapy used may achieve the desired effect on the same disease (eg, a compound of the present invention may be administered simultaneously with another agent used to treat the same disease) or achieve different effects. (For example, suppressing side effects). As used herein, additional therapeutic agents commonly administered to treat or prevent certain diseases or conditions are known to be "suitable for the disease or condition being treated."

For example, chemotherapeutic or other antiproliferative agents may be mixed with the compounds of the present invention to treat proliferative diseases and cancers. Known chemotherapeutic agents can be used but are not limited to these. Other therapies or anticancer agents that may be used with the anticancer agents of the invention include surgery, radiation therapy (eg, γ-radiation, neutron beam radiation, proton therapy, brachytherapy, and systemic radioisotopes), endocrine therapy, biological responses Modulators (interferon, interleukin and tumor necrosis factor (TNF)), thermotherapy and cryotherapy, side effect alleviators (eg anti-emetic) and other approved chemotherapeutic agents such as alkylated drugs (mechloretamine , Chlorambucil, cyclophosphamide, melphalan, ifosfamide), metabolic antagonists (methotrexate), purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, citarabville, gemcitabine) , Spindle venom (vinplastin, vincristine, vinorelbine, paclitaxel), grape phytotoxin (etoposide, irinotecan, topotecan), antibiotics (doxorubicin, bleomycin, mitomycin), nitrosourea (camu Tin, romustine), inorganic ions (cisplatin, carboplatin), enzymes (asparaginase) and hormones (tamoxifen, leuprolide, flutamide and megestrol), gleevec ™, adriamycin, dexamethasone And cyclophosphamide is included without limitation. See http://www.nci.nih.gov/ for a more comprehensive discussion of the latest cancer therapies, and a list of FDA-approved tumor drugs at http://www.fda.gov/cder/cancer/druglistframe. .htm and in Merck Manual, Seventeenth Ed. 1999]. These contents are incorporated herein by reference in their entirety.

In addition, inhibitors of the present invention include: Alzheimer's disease therapeutics such as Aricept® and Excelon®; Parkinson's disease therapies such as L-DOPA / carbidopa, entacapone, ropinol, pramipexole, bromocriptine, pergolide, trihexefendil and amantadine; Beta interferon (e.g., multiple sclerosis (MS) treatments such as Avonex® and Rebif®, Copaxone® and mitoxantrone; asthma treatments such as albuterol and Singulair®; such as Ziprex, risperdal, serquoel and haloperidol) Agents for treating schizophrenia; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide and sulfasalazine; cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, Immunomodulatory and immunosuppressive agents such as cyclophosphamide, azathioprine, and sulfasalazine; anti-neuronal factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, rilusol and antiparkinsonants; Therapeutic agents for cardiovascular diseases such as blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; Steroids, cholestyramine, interferons, and liver disease therapeutics, such as anti-viral agents; corticosteroids, leukemia, and treatment of blood diseases such as growth factors; immune deficiency diseases, and therapeutic agents such as gamma globulin is included but not limited to.

The amount of additional therapeutic agent present in the composition of the present invention is about that amount normally administered in a composition comprising the therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent ranges from about 50 to 100% of the amount typically present in a composition comprising the therapeutic agent as the only therapeutically active agent.

Compositions or pharmaceutically acceptable compositions of the invention may also be incorporated into implantable medical device coating compositions such as implants, artificial valves, vascular implants, stents and catheters. Accordingly, the present invention includes, as another embodiment, a composition for coating an implantable device comprising a compound of the present invention and a carrier suitable for coating the implantable device. In another embodiment, the present invention includes an implantable device coated with a composition comprising a compound of the present invention and a carrier suitable for coating the implantable device.

Vascular stents have been used to overcome, for example, restenosis (restenosis of the vascular wall after injury). However, patients using stents or other implantable devices are at risk of clot formation or platelet activation. These unwanted effects are prevented or alleviated by precoating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Suitable cladding and general methods of making coated implantable devices are described in US Pat. Nos. 6,099,562, 5,886,026 and 5,304,121. The coating is typically a biocompatible polymeric material such as hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. The coating can further be applied with a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycols, phospholipids or mixtures thereof to impart controlled release properties to the composition.

Another aspect of the invention relates to inhibiting Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) activity in a biological sample or patient, the method comprising: Administering a compound or composition comprising the same, or contacting a biological sample with a compound of formula (I) or a composition comprising the same. As used herein, “biological sample” includes cell cultures or extracts thereof; Biopsied material obtained from a mammal or extracts thereof; And blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

Inhibition of Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) activity in biological samples is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, transfusion, organ transplantation, biological specimen storage, and biological assays.

Synthetic Example

As used herein, ¹ H NMR is nuclear magnetic resonance. HPLC is high performance liquid chromatography. The term "Rt (minutes)" is the HPLC retention time (minutes) associated with the compound. Unless stated otherwise, the HPLC method used to obtain the reported retention interdental is as follows:

Column: Ace 5 C8, 15cm x 4.6mm id

Gradient: 0-100% Acetonitrile + Methanol (50:50) (20 mM Tris Phosphate pH 7.0)

Flow rate: 1.5ml / min

Detection: 225 nm

Example 1

5-phenyl-1H-pyrrolo [2,3-b] pyridine

5-bromo-1H-pyrrolo [2,3-b] pyridine (2 g, 10.15 mmol), phenylboric acid (1.24 g, 10.15 mmol) and tetrakis- (triphenylphosphine) palladium (117 mg, 0.10 mmol) Was suspended in ethanol (5 ml), water (6 ml) and DME (22 ml) and heated to 100 ° C. overnight. The solvent is removed in vacuo and the reaction is purified by column chromatography eluting with 30% ethyl acetate in gasoline to afford the title compound as an off-white solid (1.51 g, 77%).

Example 2

2-Chloro-1- (5-phenyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -ethanone

5-phenyl-1H-pyrrolo [2,3-b] pyridine (200 mg, 1.03 mmol) and aluminum chloride (412 mg, 3.09 mmol) were suspended in anhydrous DCM, stirred at room temperature for 1 hour, and chloroacetyl chloride ( 98 μl, 1.24 mmol) was added dropwise and the resulting amber solution was stirred overnight at room temperature. The reaction was stopped with methanol (5 ml) and stirred at rt for 2 h. Then the solvent was evaporated to give an orange oil. It was partitioned between DCM and water. The organic layer was concentrated in vacuo and the product triturated with diethyl ether to afford the title compound as a beige solid (188 mg, 67%).

Example 3

Diethyl- [4- (5-phenyl-1 H-pyrrolo [2,3-6] pyridin-3-yl) -thiazol-2-yl] -amine

2-chloro-1- (5-phenyl-1H-pyrrolo [2,3-6] pyridin-3-yl) -ethanone (50 mg, 0.18 mmol) and 1,1-diethyl thiourea (24 mg, 0.18 mmol) was suspended / dissolved in ethanol (2 ml) and heated at 120 ° C. under microwave for 10 minutes. The crude reaction mixture was purified by HPLC eluting with acetonitrile / water to afford the title compound as a cream solid (9.5 mg, 15%).

Various other compounds of formula I were prepared in a manner substantially similar to that described in Example 3. Characteristic data for these compounds are summarized in Table 3 below and include HPLC, LC / MS (observation) and ¹ H NMR data.

Example 4

3-iodo-5-phenyl-1H-pyrrolo [2,3-b] pyridine

A solution of 5-phenyl-1H-pyrrolo [2,3-b] pyridine (2.96 g, 15.24 mmol, 1 eq) in anhydrous DMF (60 ml) stirred at ambient temperature was iodine (7.74 g, 30.50 mmol, 2 eq) Then treated with potassium hydroxide (3.20 g, 57.14 mmol, 3.75 eq). The reaction mixture was stirred at rt for 15 h and then diluted with a mixture of aqueous sodium thiosulfate and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The oil obtained was then dissolved in a DCM / MeOH mixture and adsorbed onto silica gel. Subsequently, the material was dried-loaded on a column and subjected to silica-gel chromatography using ethyl acetate (1): 40-60 petroleum ether (2) as eluent to 3-iodo-5-phenyl-1H. -Pyrrolo [2,3-b] pyridine (1) (3.16 g, 65%) was obtained as a white solid.

Example 5

3-iodo-5-phenyl-1-tosyl-1H-pyrrolo [2,3-b] pyridine

A suspension of 60% sodium hydride in mineral oil (79 mg, 1.98 mmol, 1.2 eq) in anhydrous DMF (30 ml) stirred at ambient temperature was transferred to 3-iodo-5-phenyl-1H-pyrrolo [2,2] in DMF (5 ml). 3-b] pyridine (1) (53Omg, 1.66mmol, 1.0eq). The reaction mixture was then stirred at rt for 1 h and then cooled to 0 ° C. A solution of p-toluenesulfonyl chloride (316 mg, 1.66 mmol, 1.0 eq) in anhydrous DMF (5 ml) was added and the reaction mixture was warmed at rt for 15 h. The reaction mixture was then diluted with a mixture of water and ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and then concentrated in vacuo. The oil thus obtained was subjected to silica-gel chromatography using a mixture of ethyl acetate (1): 40-60 petroleum ether (2) as eluent to 3-iodo-5-phenyl-1-tosyl-1H. -Pyrrolo [2,3-b] pyridine (2) was obtained as a white solid (743 mg, 95%).

Example 6

5-phenyl-3- (1H-pyrrole-2-yl) -1-H-pyrrolo [2,3-b] pyridine

3-iodo-5-phenyl-1-tosyl-1H-pyrrolo [2,3-b] pyridine (2) (150 mg, 0.32 mmol, 1eq), tetrakis (triphenylphosphine) palladium (0) ( 4 mg, 0.0035 mmol, 0.01 eq) and 1- (tert-butoxycarbonyl) -1H-pyrrol-2-yl-2-boric acid (67 mg, 0.32 mmol, 1 eq) were placed in a microwave tube. The mixture was then treated with DME (4 ml), EtOH (0.86 ml), water (1.14 ml) and 2N aqueous sodium carbonate solution (0.63 ml). The tube was placed in microwave and heated at 160 ° C. for 40 minutes. The tube was cooled to room temperature and dried over water / ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to afford a gum. Dissolve the gum in DMSO and perform reverse phase chromatography using ACN / water as the gradient eluent to 5-phenyl-3- (1H-pyrrole-2-yl) -1-H-pyrrolo [2,3-b] Pyridine (3) was obtained as a solid.

Various other compounds of formula I were prepared in a manner substantially similar to that described in Example 6. Property data for these compounds are summarized in Table 4 below and include HPLC, LC / MS (observation) and ¹ H NMR data.

Example 7: ITK Suppression Assay:

Compounds were screened for their ability to inhibit Itk using a radio-phosphate incorporation assay. The assay was performed in the presence of 30 nM Itk at 25 ° C. in a buffer consisting of 100 mM HEPES (pH 7.4), 10 mM MgCl ₂ , 25 mM NaCl, 0.01% BSA and 1 mM DTT. Final substrate concentrations were 15 μM [γ- ³³ P] ATP (400 μCi ³³ P ATP / μmol ATP, Amersham Pharmacia Biotech / Sigma Chemicals) and 2 μM peptide (SAM68 Δ332-443). Assay stock buffer solutions were prepared containing all of the reagents described above except ATP and the test compound of interest. 50 μl of stock solution is placed in 96 well plates, followed by two serial dilutions of test compounds containing 1.5 μl of DMSO stock (typically starting with a 2-fold serial dilution from a final concentration of 15 μM). Concentration 1.5%). The plate was incubated at 25 ° C. for 10 minutes in advance, and 50 μl [γ- ³³ P] ATP (final concentration 15 μM) was added to initiate the reaction.

The reaction was stopped after 10 minutes by adding 50 μl of TCA / ATP mixture (20% TCA, 0.4 mM ATP). Unifilter GF / C 96 well plates (Perkin Elmer Life Sciences, Cat no. 6005174) were pretreated with 50 μl Milli Q water before adding the entire reaction mixture (150 μl). Plates were washed with 200 μl Milli Q water and with 200 μl TCA / ATP mixture (5% TCA, 1 mM ATP). This wash cycle was repeated two more times. After drying, 30 μl Optiphase 'SuperMix' Liquid Scintillation Cocktail (Perkin Elmer) was added to the wells before scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).

IC50 data were calculated using a Prism software package (GraphPad Prism version 3.0a for Macintosh, GraphPad Software, San Diego California, USA) from nonlinear regression of initial ratio data.

The assay was performed in a mixture of 20 mM MOPS (pH 7.0), 100 mM MgCl ₂ , 0.1% BSA and 1 mM DTT. Final substrate concentrations in the assay were 7.5 μM [γ- ³³ P] ATP (40OmCi ³³ P ATP / mmol ATP, Amersham Pharmacia Biotech / Sigma Chemicals) and 3 μM peptide (SAM68 protein D332-443). The assay was performed at 25 ° C. in the presence of 50 nM Itk. Assay stock buffer solutions were prepared containing all of the reagents described above except ATP and the test compound of interest. 50 μl of stock solution is placed in 96 well plates, followed by two serial dilutions of test compound containing 2 μl of DMSO stock (typically starting with a 2-fold serial dilution at a final concentration of 50 μM). Concentration 2%). The plate was incubated for 10 minutes at 25 ° C. in advance and 50 μl [γ- ³³ P] ATP (final concentration 7.5 μM) was added to initiate the reaction.

The reaction was stopped after 10 minutes by adding 100 mL 0.2M phosphoric acid + 0.01% TWEEN 20. Multiscreen phosphocellulose filter 96-well plates (Millipore, Cat no. MAPHN0B50) were pretreated with 100 μL 0.2 M phosphoric acid + 0.01% TWEEN 20 before adding 17O mL of the stopped assay mixture. Plates were washed with 4 × 200 μl 0.2 M phosphoric acid + 0.01% TWEEN 20. After drying, 30 μl Optiphase 'SuperMix' Liquid Scintillation Cocktail (Perkin Elmer) was added to the wells before scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).

Ki (app) data were calculated using a Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA) from nonlinear regression of the initial rate data.

Example 8: ITK Inhibition Assay (AlphaScreen ™):

Compounds were screened for their ability to inhibit Itk using AlphaScreen ™ phosphotyrosine assay (Vertex Pharmaceuticals). The assay was performed in a mixture of 20 mM MOPS (pH 7.0), 100 mM MgCl ₂ , 0.1% BSA and 1 mM DTT. Final substrate concentrations in the assay were 100 μM ATP (Sigma Chemicals) and 2 μM peptide (Biotinylated SAM68 Δ332-443). The assay was performed at 25 ° C. in the presence of Itk (3OnM). Assay stock buffer solutions were prepared containing all of the reagents described above except ATP and the test compound of interest. 25 μl of stock solution was placed in each well of 96 well plates, and serial dilutions of test compound containing 1 μl of DMSO (typically starting from final concentration of 15 μM) were added twice (final DMSO concentration of 2%). It was. The plate was incubated at 25 ° C. for 10 minutes in advance and the reaction was initialized by adding 25 μl ATP (final concentration 100 μM). 5 μl 50 mM EDTA was added to control wells containing assay stock buffer and DMSO prior to initiating background counts with ATP.

The reaction was stopped after 30 min by diluting the reaction with 225-fold MOPS buffer containing 20 mM EDTA (20 mM MOPS, pH 7.0), 1 mM DTT, 10 mM MgCl ₂ , 0.1% BSA), and the final concentration of Biotin-SAM68 was 9 nM. It became.

AlphaScreen ™ reagents were prepared according to manufacturer's instructions (AlphaScreen ™ Phosphotyrosine (P-Tyr-100) Assay Kit, PerkinElmer catalog number 6760620C). Under low illumination, 20 μl of AlphaScreen ™ reagent was placed in each well of a white half area 96 well plate (Corning Inc.—COSTAR 3693) with 30 μl of the diluted diluted kinase reaction. Plates were incubated for 60 minutes in the dark before reading with a Fusion Alpha plate reader (PerkinElmer).

After removing the mean background value for all data points, Ki (app) data was calculated from nonlinear regression using Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).

In general, the compounds of the present invention, including the compounds of Tables 1 and 2, are effective at inhibiting ITK.

Example 9: ITK Inhibition Assay (UV):

Standard binding enzyme assays [Fox et al. (1998) Protein Sci. 7, 2249] for screening for the ability of compounds to inhibit Itk. The assay was performed with 20 mM MOPS (pH 7.0), 10 mM MgCl ₂ , 0.1% BSA, 1 mM DTT, 2.5 mM phosphoenolpyruvate, 300 μM NADH, pyruvate kinase 30 μg / ml and lactate dehydrogenase 10 μg / ml Run in ml of mixture. Final substrate concentrations in this assay were 100 μM ATP (Sigma Chemicals) and 3 μM peptide (Biotinylated SAM68 Δ332-443). The assay was performed at 20 ° C. in the presence of 100 mM Itk.

A measurement stock buffer containing all of the above reagents except ATP and the test compound of interest was prepared. 60 μl of Stock Solution Buffer was placed in 96 well plates and 2 μl of DMSO stock containing serial dilutions of test compounds of the invention (typically starting from a final concentration of 15 μM) was added. The plate was incubated at 25 ° C. for 10 minutes in advance and 25 μl of ATP was added to initiate the reaction. The reaction rate was measured over a 10 minute time period with a Molecular Devices SpectraMax Plus plate reader. IC50 and Ki data were calculated from nonlinear regression using Prism software package (GraphPad Prism version 3.0a for Macintosh, GraphPad Software, San Diego California, USA).

In general, the compounds of the present invention, including the compounds of Tables 1 and 2, are effective at inhibiting ITK.

Example 10 BTK Inhibition Assay:

Compounds were screened for their ability to inhibit Btk using a radio-phosphate incorporation assay (Vertex Pharmaceuticals). The assay was performed in a mixture of 100 mM HEPES pH 7.5, 10 mM MgCl ₂ , 25 mM NaCl, 0.01% BSA and 1 mM DTT. Final substrate concentrations in the assay were 100 μM ATP (Sigma Chemicals) and 5 μM peptide (SAM68 Δ332-443). The assay was performed at 25 ° C. in the presence of Btk (25 nM) and [γ- ³³ P] ATP (100 μCi ³³ P ATP / μmol ATP, Amersham Pharmacia Biotech, Amersham, UK). Assay stock buffer solutions were prepared containing all of the reagents described above except for SAM68 and the test compound of interest. 75 μl of stock solution was placed in 96 well plates, then serial dilutions of test compounds containing 1.5 μl of DMSO stock (usually starting at a final concentration of 15 μM) were added twice (final DMSO concentration 1.5%). The plate was incubated at 25 ° C. for 15 minutes in advance and the reaction was initiated by adding 25 μL SAM68 (final concentration 5 μM). 50 μL 20% TCA + 0.4 mM ATP was measured by adding to control wells containing assay stock buffer and DMSO prior to initializing the background count to SAM68.

The reaction was stopped after 60 minutes by adding 50 μl 20% TCA + 0.4 mM ATP. Unifilter GF / C 96 well plates (Perkin Elmer Life Sciences, Cat no. 6005174) were pretreated with 50 μl Milli Q water and the whole reaction mixture (150 μl) was added. Plates were washed with 200 μl Milli Q water and 200 μl 5% TCA + 1 mM ATP. The water / TCA wash cycle was repeated two more times. After drying, 30 μl Optiphase 'SuperMix' Liquid Scintillation Cocktail (Perkin Elmer) was added to the wells and the scintillation count (1450 Microbeta Liquid Scintillation Counter, Wallac) was performed.

After removing the mean background for all data points, Ki (app) data was calculated from nonlinear regression using Prism software package (GraphPad Prism version 3.0a for Macintosh, GraphPad Software, San Diego California, USA).

Compounds were screened for their ability to inhibit Btk using AlphaScreen ™ phosphotyrosine assay (Vertex Pharmaceuticals). The assay was performed in a mixture of 20 mM MOPS (pH 7.0), 100 mM MgCl ₂ , 0.1% BSA and 1 mM DTT. Final substrate concentrations in the assay were 50 μM ATP (Sigma Chemicals) and 2 μM peptide (Biotinylated SAM68 Δ332-443). The assay was performed at 25 ° C. in the presence of Btk (25 nM). Assay stock buffer solutions were prepared containing all of the reagents described above except Biotin-SAM68 and the test compound of interest. A 37.5 μl stock solution was placed in each well of 96 well plates, followed by two serial dilutions of DMSO containing the μl of test compound (typically starting from a final concentration of 15 μM) followed by a final DMSO concentration of 2%. It was. The plate was incubated for 15 min at 25 ° C. and the reaction was initialized by adding 12.5 μl Biotin-SAM68 (final concentration 2 μM). The background count was measured by adding 5 μl 50 mM EDTA to control wells containing assay stock buffer and DMSO before initializing with Biotin-SAM68.

After 30 minutes the reaction was stopped by diluting the reaction with 225-fold MOPS buffer containing 50 mM EDTA (20 mM MOPS (pH 7.0), 1 mM DTT, 10 mM MgCl ₂ , 0.1% BSA) and the final concentration of Biotin-SAM68 was 9 nM Became.

AlphaScreen ™ reagents were prepared according to manufacturer's instructions (AlphaScreen ™ Phosphotyrosine (P-Tyr-100) Assay Kit, PerkinElmer catalog number 6760620C). Under low illumination, 20 μl of AlphaScreen ™ reagent was placed with 30 μl of stopped and diluted kinase reaction in each well of a white half area 96 well plate (Corning Inc.—COSTAR 3693). Plates were incubated for 60 minutes in the dark before reading with Fusion Alpha plate reader (PerkinElmer).

After removing the mean background value for all data points, Ki (app) data was calculated from nonlinear regression using Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).

In general, the compounds of the present invention, including the compounds of Tables 1 and 2, are effective at inhibiting Btk.

Example 11: RLK Inhibition Assay:

Compounds were screened for their ability to inhibit Rlk using standard bound enzyme assays (Fox et ah, Protein ScL, (1998) 7, 2249). The assay was performed in a mixture of 20 mM MOPS (pH 7.0), 100 mM MgCl ₂ , 0.1% BSA and 1 mM DTT. Final substrate concentrations in the assay are 100 μM ATP (Sigma Chemicals) and 100 μM peptide (Poly Glu: Tyr 4: 1). The assay was performed at 30 ° C. in the presence of 4OnM Rlk. The concentrations of the final components of the bound enzyme system were 2.5 mM phosphoenolpyruvate, 300 μM NADH, 30 μg / ml pyruvate kinase and 10 μg / ml lactate dehydrogenase.

Assay stock buffer solutions were prepared containing all of the reagents described above except ATP and the test compound of interest. 60 μl of stock solution was placed in 96 well plates, and then serial dilutions of test compounds containing 2 μl of DMSO stock solution (typically starting at a final concentration of 7.5 μM) were added. The plate was incubated at 30 ° C. for 10 minutes and 5 μl of ATP was added to initiate the reaction. Initial reaction rates were measured over a 10 minute time period with a Molecular Devices SpectraMax Plus plate reader. IC50 and Ki data were calculated from a nonlinear regression using Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).

In general, the compounds of the present invention, including the compounds of Tables 1 and 2, are effective at inhibiting RLK.

Example 12 JAK3 Inhibition Assay:

Compounds were screened for their ability to inhibit JAK using the assay shown below. The reaction was carried out in kinase buffer containing 100 mM HEPES (pH 7.4), 1 mM DTT, 10 mM MgCl ₂ , 25 mM NaCl and 0.01% BSA.

Substrate concentrations in the assay were 5 μM ATP (200 uCi / μmole ATP) and 1 μM poly (Glu) 4Tyr. The reaction was carried out at 25 ° C. and 1 nM JAK3.

To each well of a 96 well polycarbonate plate was added 1.5 μl of candidate JAK3 inhibitor with 50 μl of kinase buffer containing 2 μM poly (Glu) 4Tyr and 10 μM ATP. This was then mixed and 50 μl of kinase buffer containing 2 nM JAK3 enzyme was added to initiate the reaction. After 20 minutes at room temperature (25 ° C.), the reaction was stopped with 50 μl of 20% trichloroacetic acid (TCA) which also contained 0.4 mM ATP. The entire contents of each well were then transferred to 96 well glass fiber filter plates using a TomTek Cell Harvester. After washing, 60 μl of scintillation fluid was added and ³³ P incorporation was detected in the Perkin Elmer TopCount.

In general, the compounds of the present invention, including the compounds of Tables 1 and 2, are effective at inhibiting JAK (eg, JAK-3).

Claims (60)

A compound of formula (I) or a pharmaceutically acceptable salt thereof. Formula I

In Formula I, Ring A is

An optionally substituted 5 membered ring selected from; x is 0, 1 or 2; R ¹ is halogen, CN, NO ₂ or U _m R; R ² is independently selected from T _n -R '; X ₁ , X ₂ and X ₃ are independently of each other CR ¹ , N, S or O; R ³ , R ⁴ and R ⁵ are independently of each other halogen, CN, NO ₂ or V _p -R '; T, U or V are independently of each other an optionally substituted C _1-6 alkylidene chain, wherein up to two methylene units of the chain are optionally independently -NR-, -S-, -O-, -CS- _{, -CO 2 -, -OCO-, -CO-} , -COCO-, -CONR-, -NRCO-, -NRCO 2 -, -SO 2 NR-, -NRSO 2 -, -CONRNR-, -NRCONR-, -Is substituted by -OCONR-, -NRNR-, -NRSO ₂ NR-, -SO-, -SO _2- , -PO-, -PO ₂ -or -POR-; m, n and p are each independently O or 1; R are independently of each other hydrogen or optionally substituted C _1-6 aliphatic; R 'is independently of each other hydrogen or an optionally substituted C _1-6 aliphatic; 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic rings having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; Or an 8-12 membered saturated, partially unsaturated or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or R and R ', two R or two R' together with the atoms to which they are attached are optionally substituted 3-12 membered saturated or partially unsaturated having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur or To form a fully unsaturated monocyclic or bicyclic ring; Provided that at least one of R ³ , R ⁴ and R ⁵ is V _p -R 'wherein R' is not hydrogen; if n is 0, R 'is not H; Ring A

If R ⁴ is 2-phenoxylphenyl, then R ² is not COOH or CONHR ^X , where R ^X is n-propyl, phenyl, cyclohexyl, benzyl, -CH ₂ CH ₂ OH, -CH ₂ -cyclo Propyl, -CH ₂ CH ₂ OCH ₃ , 3-pyridyl, 4-hydroxy-cyclohexyl or -CH ₂ -C≡CH. The compound of claim 1, wherein one of R ³ , R ⁴ and R ⁵ is V _p -R 'wherein R' is optionally substituted 5 having 0 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Or a 6 membered unsubstituted monocyclic ring; Or an optionally substituted 9 or 10 membered completely unsubstituted bicyclic ring system having 0 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur. The compound of claim 1, wherein one of R ³ , R ⁴ and R ⁵ is V _p -R ′, wherein R ′ is an optionally substituted C _1-6 aliphatic; Optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic rings having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; Or an optionally substituted 8-12 membered saturated, partially unsaturated or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur. 4. The compound of claim 1, wherein R ⁴ is V _p -R ′, wherein R ′ is optionally substituted C _1-6 aliphatic; Optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic rings having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; Or an optionally substituted 8-12 membered saturated, partially unsaturated or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur. The compound of claim 4, wherein R ⁴ is V _p -R ', wherein R' is optionally substituted C _1-6 aliphatic or optionally substituted with 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. To a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring. 6. The compound of claim 5, wherein R ⁴ is V _p -R ', wherein R' is C≡CH. The compound of claim 5, wherein R ⁴ is V _p -R 'wherein R' is an optionally substituted 3-8 membered saturated or partially unsaturated having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Or monounsaturated monocyclic ring. The method of claim 7, R ⁴ a ', wherein, R "-R _p V is not in the 5 or 6 membered optionally substituted with 0 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur completely substituted Compound which is a monocyclic ring. 10. The compound of claim 8, wherein R ⁴ is V _p -R 'wherein R' is an optionally substituted 6 membered, completely unsubstituted monocyclic ring having 0 to 3 nitrogen heteroatoms. 10. The compound of claim 9, wherein the 6-membered fully unsubstituted monocyclic ring comprises 0-1 nitrogen heteroatoms. 8. The compound of claim 7, wherein R ⁴ is V _p -R 'wherein R' is an optionally substituted 3-8 membered saturated monocylic having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Compound which is a click ring. 12. The compound of claim 11, wherein R ⁴ is V _p -R 'wherein R' is an optionally substituted 6 membered saturated monocylic having 0 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur. Compound which is a click ring. The compound of any one of claims 1-12, wherein p is zero. The compound of any one of claims 1-12 wherein p is 1. 15. The compound of claim 14, wherein V is -NR-, -S- or -O-. The compound of any one of claims 1-15, wherein R ³ is V _p -R 'wherein p is 0 and R' is hydrogen. 17. The compound of any one of claims 1-16, wherein R ⁵ is halogen or V _p -R 'wherein p is 0 and R' is hydrogen or C _1-6 aliphatic. 18. The compound of claim 17, wherein R ⁵ is halogen or V _p -R 'wherein p is 0 and R' is hydrogen or C _1-3 alkyl. The compound of any one of claims 1-18, wherein ring A is

Phosphorus compounds. The compound of claim 19, wherein X ₂ is CR ¹ . 20. The compound of claim 19, wherein ring A is

Phosphorus compounds. The compound of claim 21, wherein ring A is

Phosphorus compounds. The compound of any one of claims 1-22, wherein R ¹ is U _m R. The compound of any one of claims 1-23, wherein R ² is T _n R ′, wherein n is 1. 24. The compound of claim 24, wherein T is -NR-, -O-, -CO-, -CONR-, or -NRCO-. The compound of any one of claims 1-23, wherein R ² is T _n R ′, wherein n is 0. 24. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from Formulas II, III, IV, V and VI. Formula II

Formula III

Formula IV

Formula V

Formula VI

The compound of claim 27, or a pharmaceutically acceptable salt thereof, selected from Formulas II and III. Formula II

Formula III

The compound of claim 27 or 28, wherein R ¹ is U _m R wherein m is 0 and R is H or CH ₃ . 30. The compound of any one of claims 27-29, wherein R ² is T _n R ', wherein n is 1. The compound of claim 30, wherein T is -NR-, -O-, -CO-, -CONR-, or -NRCO-. 32. The compound of claim 31, wherein T is -NR-. 33. The compound of claim 32, wherein R and R 'are both C _1-6 aliphatic. 30. The compound of any one of claims 27-29, wherein R ² is T _n R ', wherein n is zero. 35. The compound of claim 34, wherein R 'is an optionally substituted N-attached heterocyclyl selected from morpholinyl, piperidinyl, pyrrolidinyl and piperazinyl. 36. The compound of any one of claims 27-35, wherein R ⁴ and R ⁵ are independently of each other V _p -R '. 37. The compound of claim 36, wherein R ⁴ is V _p -R ', wherein R' is CCH. 36. The compound of any one of claims 27-35, wherein one of R ³ , R ⁴ and R ⁵ is V _p -R 'wherein R' is 0-3 independently selected from nitrogen, oxygen or sulfur. Optionally substituted 5 or 6 membered completely unsubstituted (ie aromatic) monocyclic ring having heteroatoms; Or an optionally substituted 9 or 10 membered completely unsubstituted bicyclic ring system having 0 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur. 36. The compound of any one of claims 27-35, wherein one of R ³ , R ⁴ and R ⁵ is V _p -R 'wherein R' is independently optionally substituted C _1-6 aliphatic, nitrogen, Optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic rings having 0-3 heteroatoms independently selected from oxygen or sulfur; Or an optionally substituted 8-12 membered saturated, partially unsaturated or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur. 40. The compound of claim 39, wherein R ⁴ is V _p -R 'wherein R' is independently optionally substituted C _1-6 aliphatic; Optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic rings having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; Or an optionally substituted 8-12 membered saturated, partially unsaturated or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; R ³ and R ⁵ are V _p -R 'wherein p is 0 and R' is hydrogen. 41. The compound of claim 40, wherein R ⁴ is V _p -R 'wherein R' is independently optionally substituted C _1-6 aliphatic, or having 0 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Optionally a substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring. The compound of claim 41, wherein R ⁴ is V _p -R 'wherein R' is an optionally substituted 3-8 membered saturated or partially unsaturated having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Or monounsaturated monocyclic ring. 43. The optionally substituted 5 or 6 membered fully substituted 5 or 6 member of claim 42, wherein R ⁴ is V _p -R 'wherein R' is optionally substituted with 0 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Unsubstituted monocyclic ring. 44. The compound of claim 43, wherein R ⁴ is V _p -R 'wherein R' is an optionally substituted 6 membered fully unsubstituted monocyclic ring having 0 to 3 nitrogen heteroatoms. 45. The compound of claim 44, wherein the six-membered unsubstituted monocyclic ring has 0-1 nitrogen heteroatoms. 43. The compound of claim 42, wherein R ⁴ is V _p -R 'wherein R' is an optionally substituted 3-8 membered saturated monocylic having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Compound which is a click ring. 47. The optionally substituted 6 membered saturated monocyclic having 0 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein R ⁴ is V _p -R '. Cyclic compounds. 48. The compound of any one of claims 27-47, wherein p is 1. 49. The compound of claim 48, wherein V is -NR-, -S- or -O-. 48. The compound of any one of claims 27-47, wherein p is zero. 51. The compound of any one of claims 27 or 29-50, wherein R ³ is V _p -R 'wherein p is 0 and R' is hydrogen. 52. The compound of any one of claims 27-51, wherein R ⁵ is halogen or V _p -R 'wherein p is 0 and R' is hydrogen or C _1-6 aliphatic. The compound of claim 52, wherein R ⁵ is halogen or V _p -R 'wherein p is 0 and R' is hydrogen or C _1-3 alkyl. The method of claim 1,

Compound selected from. 55. A composition comprising a compound according to any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 56. The method of claim 55, wherein the agent is selected from a therapeutic agent for autoimmune disease, inflammatory disease, proliferative disease, hyperproliferative disease, or immunologically-mediated disease including rejection of transplanted organs or tissues and acquired immunodeficiency syndrome (AIDS). The composition further comprises an additional therapeutic agent. 55. A patient is administered a compound according to any one of claims 1 to 54 or by contacting a biological sample with a compound according to any one of claims 1 to 54 (a) the patient; Or (b) inhibits Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) kinase activity in a biological sample. 55. An autoimmune disease, inflammatory disease, proliferative disease, hyperproliferative disease or immunologically comprising administering to a patient in need thereof a composition comprising a compound according to any one of claims 1-54. A method of treating or alleviating the severity of a disease selected from a mediated disease. 59. The formulation of claim 58 for treating autoimmune disease, inflammatory disease, proliferative disease, hyperproliferative disease, or immunologically-mediated disease, including rejection of transplanted organs or tissues and acquired immunodeficiency syndrome (AIDS). Administering to the patient an additional therapeutic agent selected from wherein the additional therapeutic agent is suitable for the disease to be treated; Administered as a single dosage form with the composition, or separately from the composition as part of a multiple dosage form. 60. The disease or condition according to claim 58 or 59, wherein the disease or condition is asthma, acute rhinitis, allergic rhinitis, atopic rhinitis, chronic rhinitis, membranous rhinitis, seasonal rhinitis, sarcoidosis, farmer's lung, fibrous lung , Idiopathic interstitial pneumonia, rheumatoid arthritis, negative serum reactive spondyloarthropathy (including ankylosing spondylitis, psoriatic arthritis and lighter disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, psoriasis, systemic sclerosis, atopic dermatitis, contact dermatitis and Other eczema dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigus, bullous epidermis, urticaria, angiodermas, vasculitides, erythema, cutaneous eosinophilia, uveitis, alopecia areata, spring conjunctivitis, intraperitoneal Coeliac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, pancreatitis, Crohn's disease, ulcerative colitis, food allergies, multiple sclerosis, atherosclerosis , Acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus erythematosus, erythema, Hashitomo thyroiditis, myasthenia gravis, type I diabetes, nephrosis syndrome, eosinophilia, excessive IgE syndrome, lepromatous leprosy, sezary syndrome syndrome) and idiopathic thrombocytopenic purpura, restenosis after coronary angioplasty, tumors, atherosclerosis, systemic lupus erythematosus; Allograft rejection including but not limited to acute and chronic allograft rejection following kidney, heart, liver, lung, bone marrow, skin and corneal transplantation; And chronic graft versus host disease.