HK1194070A - Azaindoles useful as inhibitors of jak and other protein kinases - Google Patents

Description

Azaindoles as inhibitors of JAK and other protein kinases

The present application is a divisional application entitled "azaindoles useful as JAK and other protein kinase inhibitors" having application number 200910206575.8, filed 3/30/2005.

Technical Field

The present invention relates to protein kinase inhibitors. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

Background

In recent years, the search for new therapeutic agents has been greatly aided by a better understanding of the structure of enzymes and other biomolecules associated with disease. One important class of enzymes that has been the subject of extensive research is protein kinases.

Protein kinases are composed of a large family of structurally related enzymes that are responsible for the control of various signal transduction processes within the cell. (see Hardie, G. and Hanks, S.the Protein KinaseFacts Book, I and II, Academic Press, San Diego, CA: 1995). Protein kinases are thought to have evolved from a common ancestral gene due to conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The substrates phosphorylated by kinases differ and can be grouped into several families (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.). Sequence motifs that correspond generally to each of these kinase families have been identified (see, e.g., Hanks, s.k., Hunter, t., FASEB j.1995, 9, 576-.

Typically, protein kinases mediate intracellular signals by affecting the transfer of phosphoryl groups from nucleoside triphosphates to protein receptors involved in signaling pathways. These phosphorylation events may serve to modulate or regulate the target protein organismThe function of a molecular switch of a function. These phosphorylation events are ultimately triggered in response to various extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxins, and H₂O₂) Cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha), and growth factors such as granulocyte macrophage-colony stimulating factor (GM-CSF) and Fibroblast Growth Factor (FGF). Extracellular stimuli can affect one or more cellular responses associated with cell growth, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, glucose metabolism, protein synthesis control, and cell cycle regulation.

Many diseases are associated with abnormal cellular responses triggered by the aforementioned protein kinase-mediated events. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, alzheimer's disease, and hormone-related diseases. Thus, great efforts in medicinal chemistry have led to the discovery of protein kinase inhibitors that are effective as therapeutic agents.

Janus kinases (JAKs) belong to the tyrosine kinase family, consisting of JAK1, JAK2, JAK3 and TYK 2. JAKs play an important role in cytokine signaling. Downstream substrates of the kinase JAK family include protein-transcribing Signal Transducers and Activators (STATs). JAK/STAT signaling is implicated in the mediation of many aberrant immune responses, such as allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, and solid and hematologic malignancies such as leukemias and lymphomas. Pharmaceutical intervention of the JAK/STAT pathway has been reviewed [ Frank mol. Med.5, 432. sup. 456(1999) and Seidel et al, Oncogene, 19, 2645. sup. 2656(2000) ].

JAK1, JAK2, and TYK2 are ubiquitously expressed, whereas JAK3 is mainly expressed in hematopoietic cells. JAK3 binds only to the common cytokine receptor gamma chain (gamma)_c) Bound and bound by IL-2, IL-4, IL-7, IL-9 and IL-15 activation. Indeed, IL-4 and IL-9 induced proliferation and survival of murine mast cells has been shown to be dependent on JAK 3-and γ_cSignal transduction [ Suzuki et al, Blood, 96, 2172-]。

Crosslinking of high affinity immunoglobulin (Ig) E receptors in sensitized fertilizer large cells results in the release of pro-inflammatory mediators, including many vasoactive cytokines, leading to acute allergic responses, or mediating (type I) allergic responses [ Gordon et al, Nature, 346, 274-and 276(1990) and Galli, N.Engl. J.Med., 328, 257-and 265(1993) ]. An important role for JAK3 in IgE receptor-mediated mast cell responses has been established in vitro and in vivo [ Malaviya et al biochem. Furthermore, prevention of mast cell-activation mediated type I allergic reactions, including allergy, by inhibition of JAK3 has also been reported [ Malaviya et al, J.biol.chem.274, 27028-27038(1999) ]. Targeting mast cells with JAK3 inhibitors can modulate mast cell degranulation in vitro and prevent IgE receptor/antigen-mediated allergic reactions in vivo.

Recent studies describe the successful targeting of JAK3 for immunosuppression and allograft acceptance. Studies demonstrated dose-dependent survival of buffalo heart allografts in Wistar Furth recipients following administration of JAK3 inhibitor, suggesting the potential for modulation of adverse immune responses in graft-versus-host disease [ Kirken, Transpl. Proc., 33, 3268-3270(2001) ].

IL-4-mediated STAT-phosphorylation has been implicated in the early and late stages of Rheumatoid Arthritis (RA). Upregulation of pro-inflammatory cytokines in RA synovial and synovial fluid is a characteristic of the disease. IL-4 mediated activation of the IL-4/STAT pathway has been demonstrated to be mediated by Janus kinase (JAK 1&3), whereas the IL-4 associated JAK kinase is expressed in the RA synovium [ Muller-Ladner et al, J.Immunol., 164, 3894-3901(2000) ].

Familial Amyotrophic Lateral Sclerosis (FALS) is a fatal neurodegenerative disease that can affect about 10% of ALS patients. Survival of FALS mice increased after treatment with JAK3 specific inhibitors. This suggests that JAK3 plays a role in FALS [ Trieu et al, biochem. biophysis. res. commun., 267, 22-25(2000) ].

Signal transducers and activators of protein transcription (STATs) are activated, inter alia, by JAK family kinases. Recent findings suggest the possibility of treating leukemia by interfering with the JAK/STAT signaling pathway with specific inhibitors against JAK family kinases [ Sudbeck et al, Clin. cancer Res., 5, 1569-1582(1999)]. JAK 3-specific compounds have been shown to inhibit JAK 3-expressing cell lines DAUDI, RAMOS, LC₁-19, NALM-6, MOLT-3 and HL-60.

In animal models, the TEL/JAK2 fusion protein has induced myeloproliferative diseases, and in hematopoietic cell lines, the introduction of TEL/JAK2 resulted in the activation of STAT1, STAT3, STAT5, and cytokine-dependent growth [ Schwaller et al, EMBOJ.17, 5321-.

Inhibition of JAK3 and TYK2 abrogated tyrosine phosphorylation of STAT3 and inhibited growth of granuloma fungoides, a form of cutaneous T-cell lymphoma. These results suggest that constitutively activated JAK family kinases in the JAK/STAT pathway are present in granuloma fungoides [ Nielsen et al, Proc. Nat. Acad. Sci. U.S.A., 94, 6764-6769(1997) ]. Similarly, STAT3, STAT5, JAK1 and JAK2 were shown to be constitutively activated in mouse T-cell lymphomas originally characterized by overexpression of LCK, thereby further suggesting the JAK/STAT pathway in abnormal cell growth [ Yu et al, J.Immunol.159, 5206-5210(1997) ]. In addition, IL-6 mediated STAT3 activation can be blocked by JAK inhibitors, resulting in myeloma cells that are sensitive to apoptosis [ Catlet t-Falcone et al, Immunity10, 105-115(1999) ].

One kinase family of interest is the Rho-associated helix-helix forming protein serine/threonine kinase (ROCK), which is thought to be an effector of Ras-associated small gtpase Rho. The ROCK family includes p160ROCK (ROCK-1) (Ishizaki et al, EMBO J.1996, 15, 1885-1893) and ROK α/Rho-kinase/ROCK-I I (Leung et al, J.biol. chem.1995, 270, 29051-29054; Matsui et al, EMBO J.1996, 15, 2208-2216; Nakagawa et al, FEBSLett.1996, 392, 189-193), the protein kinase PKN (Amano et al, Science1996, 271, 648-650; Watanabe et al, Science1996, 271, 645-648) and lemon kinases (Madaule et al, Nature, 243, 394, 491-494; Madaule et al, FEBS Lett.1995, 377-248). ROCK family kinases have been shown to be involved in a number of functions, including Rho-induced agonist protein stress fiber and focal adhesion formation (Leung et al, mol. cell biol.1996, 16, 5313 5327; Amano et al, Science, 1997, 275, 1308-J1311; Ishizaki et al, FEBS Lett.1997, 404, 118-J124) and myosin phosphatase down-regulation (Kimura et al, Science, 1996, 273, 245-J248), platelet activation (Klages et al, J.biol., 1999, 144, 745-J754), aortic smooth muscle contraction induced by various stimuli (Fu et al, FEBS Lett., 1998, 440, 183-J187), thrombin-induced responses of aortic smooth muscle cells (Seastz et al, cir. Rez., 1999, 84, 6, 1193), cardiomyocytes (Shahara. yata, Kuwa et al, cell contraction, cell 118314, cell 118318, cell K318, Bio-K318), and various stimuli, 1999, 20, 1190-.

More specifically, ROCK and related diseases and disorders including Hypertension (Satoh et al, J.Clin. Inves. t.1994, 94, 1397-; Muka i et al, FASEBJ.2001, 15, 1062-, 11, 351-; chiba et al, Br.J.Pharmacol.1999, 127, 597-600; chiba et al, Br.J.Pharmacol.2001, 133, 886-; iizuka et al, Eur.J.Pharmacol.2000, 406, 273-; tahara et al, Endocrinology 2002, 143, 920-; kupittayanant et al, Pfleger research.2001, 443, 112-; mills et al, J.Appl.Physiol.2001, 91, 1269-; rao et al, invest, Ophtha lmol. Vis. Sci.2001, 42, 1029-; morisige et al, Arterioscler, Thromb, Vasc, Viol, 2001, 21, 548-doped 554; eto et al, am.j.physiol.heart circ.physiol.2000, 278, H1744-H1750; sawada et al circulation 2000, 101, 2030-2023; shibata et al, circulation 2001, 103, 284-289), myocardial hypertrophy (Hoshijima et al, J.biol.chem.1998, 273, 7725-77230; sah et al, J.biol.chem.1996, 271, 31185-; kuwahara et al, FEBS let.1999, 452, 314-; yanazume et al, j.biol.chem.2002, 277, 8618-; genda et al, Hepatology 1999, 30, 1027-; somlyo et al, biochem. Biophys. Res. Commun.2000, 269, 652-; miznuma et al, transplantation station 2003, 75, 579-; laufs et al, J.biol.chem.1998, 273, 24266-; eto et al, circle. Res.2001, 89, 583-; masumoto et al, Circulation 2002, 105, 1545-1547; shimokawa et al, j.cardiovasc.pharmacol, 2002, 40, 751-; satoh et al, jpn.j.pharmacol., 2001, 87, 34-40), alzheimer's disease (Zhou et al, Science 2003, 302, 1215-; ishibashi et al, Biochim. Biophys. acta2002, 1590, 123- "130). Thus, the development of inhibitors of ROCK kinase would be useful as therapeutic agents for the treatment of disorders in which the ROCK kinase pathway is involved.

Aurora proteins are a family of three very related serine/threonine kinases (called Aurora-a, -B and-C) that are important for the mitotic phase of the cell cycle. In particular, Aurora-a plays an important role in the maturation and detachment of centrosomes, the formation of mitotic spindles and the definitive detachment of chromosomes. Aurora-B is a chromosomal messenger protein that plays an important role in regulating the arrangement of chromosomes on metaphase plates, checkpoint spindle assembly and correct completion of cell movement.

Overexpression of Aurora-A, -B or-C has been observed in a number of human cancers, including colorectal, ovarian, gastric and invasive ductal adenocarcinomas. In addition to amplification of AURKA, the locus encoding Aurora-a is associated with a poor prognosis in node-negative breast cancer patients. Furthermore, overexpression of Aurora-a has been shown to transform mammalian fibroblasts, producing multipolar spindle-containing aneuploid cells.

Now, many studies have demonstrated the deletion or inhibition of Aurora-a or-B in human cancer cell lines by siRNA, dominant negative or neutralizing antibody disruption with progression of mitosis by accumulation of cells with 4NDNA, and in some cases, followed by endoreduplication and cell death.

Protein kinases are attractive and proven targets for new therapeutic agents for the treatment of human diseases, including Gleevec and Tarceva. Aurora kinases are particularly attractive because of their association with many human cancers and their role in promoting proliferation of these cancer cells (Harrington et al, Nature med., 2004, 10: 262-.

Therefore, there is a strong need to develop inhibitors of JAK, ROCK and Aurora, preferably JAK-3, ROCK and Aurora protein kinases, for the treatment of various diseases or disorders associated with the activation of JAK, ROCK and Aurora, and in particular for the vast majority of these diseases, currently less suitable treatments are being used.

Disclosure of Invention

It has now been found that the compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of JAK, ROCK and Aurora protein kinases. In particular embodiments, these compounds are effective as inhibitors of JAK-3, ROCK and Aurora protein kinases. These compounds, or pharmaceutically acceptable salts thereof, have the general formula I:

wherein R is¹、R²、R³、R⁴、X¹、X²、X³、R⁵And x is as defined below and in the sections herein.

These compounds and pharmaceutical compositions thereof are useful for treating or preventing a variety of conditions including, but not limited to, heart disease, diabetes, alzheimer's disease, immunodeficiency disorders, inflammatory diseases, hypertension, allergic diseases, autoimmune diseases, destructive bone disorders such as osteoporosis, proliferative disorders, infectious diseases, immune-mediated diseases, and viral diseases. The compositions are also useful in methods of preventing cell death and proliferation and are therefore useful in treating or preventing reperfusion/ischemia in stroke, heart attack, and organ hypoxia. The compositions are also useful in methods of preventing thrombin-induced platelet aggregation. The compositions are particularly useful in conditions such as Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML), Acute Promyelocytic Leukemia (APL), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer (including, but not limited to, ovarian, breast, and endometrial cancers), liver diseases including liver ischemia, heart diseases such as myocardial infarction and congestive heart failure, pathological immune conditions involving T cell activation, and neurodegenerative conditions.

Detailed Description

1. General description of the compounds of the invention:

the present invention relates to compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹is T-R 'or-Si (R')₃；

R²、R³And R⁴Each independently of the other being halogen, CN, NO₂Or V-R';

X¹、X²and X³Each independently is N, or CH, wherein the hydrogen atom of CH is optionally substituted by R⁵Substitution;

x is 1, 2, 3, or 4;

R⁵independently for each occurrence of (A) is halogen, CN, NO₂Or U-R';

t, V, and U are each independently a bond or optionally substituted C₁-C₆Alkylene chain, wherein the chain is optionally and independently represented by-NR' -, -S-, -O-, -CS-, -C0₂-、-OCO-、-CO-、-COCO-、-CONR′-、-NR′CO-、-NR′CO₂-、-SO₂NR′-、-NR′SO₂-、-CONR′NR′-、-NR′CONR′-、-OCONR′-、-NR′NR′-、-NR′SO₂NR′-、-SO-、-SO₂-、-PO-、-PO₂-, or-POR' -substitution; and is

Each occurrence of R' is independently hydrogen or an optionally substituted group selected from: c₁-C₆An aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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 both occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In particular embodiments, the two occurrences of R' forming the ring are on a single substituent (e.g., R)¹、R²、R³、R⁴Or in a single R⁵On a substituent) and form a monocyclic or bicyclic ring. In other embodiments, two occurrences of R' are on two substituents (e.g., on two R)⁵On a substituent) and may be reacted with R⁵The rings to which the substituents are attached form a bicyclic fused ring.

In particular embodiments, for the compounds described directly above:

a) if R is¹Is a substituted cyclopentyl group, X is 1, X¹And X³Is CH, then X²Is not C-R⁵Wherein R is⁵Is fluorine or OMe;

b) if R is²And R³Is simultaneously H and R¹And R⁴Independently selected from H or Me, X is 1, X¹And X³Is CH, then X²Is not C-R⁵Wherein R is⁵Is OMe, NO₂Or fluorine;

c) if R is¹、R²、R³And R⁴While being H, x is 1, R⁵is-SMe, NH₂Or an optionally substituted NH-piperidine, and X¹And X²Is N, then X³Is not CH;

d) if R is²、R³And R⁴At the same time being H, X¹、X²And X³Is CH, and two R⁵Form a fused optionally substituted bicyclic ring with the ring to which they are attached, then R¹Is not CH₂CH₂N(Me)₂；

e) If R is²And R³At the same time being H, R⁴Is NH₂And X¹、X²And X³Is CH, then R¹Is not a substituted phenyl group;

f) if R is²、R³And R⁴While being H, then R¹Is not Si (R')₃；

g) If R is¹、R²And R⁴Is simultaneously H and (i) X²And X³Is CH or CR⁵Or (i i) X¹、X²Or X³Is N, then R³Not being phenyl or substituted by O-phenyl or N (Me)₂A substituted phenyl group.

2. Compounds and definitions:

the compounds of the present invention include those generally described above, and they are further exemplified by the classes, subclasses, and species disclosed herein. The following definitions as used herein apply, unless otherwise indicated. For the purposes of the present invention, chemical elements are identified according to the periodic Table of the elements, CAS edition, Handbook of Chemistry and Physics, 75 th edition. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausal ito: 1999, and "March's advanced organic Chemistry", fifth edition, Smith, m.b. and March, edited by j, john wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, which are generally exemplified above, or exemplified by specific classes, subclasses, and species of the invention. It is to be understood that the phrase "optionally substituted" may be used interchangeably with the phrase "substituted or unsubstituted. Generally, the term "substituted", whether preceded by the term "optionally" or not, refers to the substitution of hydrogen groups in known structures with the indicated substituents. Unless otherwise specified, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any known structure may be substituted with more than one substituent selected from the specified groups, the substituents at each position may be the same or different. Combinations of substituents contemplated by the present invention are preferably those that can form stable or chemically useful compounds. The term "stable" as used herein refers to compounds that do not substantially change when subjected to the conditions for their production, detection, and preferably for their recovery, purification, and for one or more of the purposes disclosed herein. In certain embodiments, a stable compound or chemically useful compound is one that does not substantially change when held at a temperature of 40 ℃ or less for at least one week in the absence of moisture or other chemically reactive conditions.

The term "aliphatic" or "aliphatic group" as used herein refers to a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain which is fully saturated or which contains one or more units of unsaturation, or to a monocyclic or bicyclic hydrocarbon which is fully saturated or which contains one or more units of unsaturationContain one or more units of unsaturation, but which are not aromatic (also referred to herein as "carbocyclics," "cycloaliphatic," or "cycloalkyl"), which have a single point of attachment to the remainder of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In certain embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In certain embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C₃-C₈C of hydrocarbons or bicyclic rings₈-C₁₂A hydrocarbon, which is fully saturated or contains one or more units of unsaturation, but which is not aromatic, having a single point of attachment to the remainder of the molecule, wherein any individual ring in the bicyclic ring system has from 3 to 7 members. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl.

The term "heteroaliphatic" as used herein refers to an aliphatic group in which one or two carbon atoms are independently substituted with one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups can be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" groups.

The term "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" as used herein refers to a non-aromatic monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are independently selected heteroatoms. In certain embodiments, a "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" group has 3-14 ring members, wherein one or more ring members are heteroatoms independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3-7 ring members.

The term "heteroatom" means one or more oxygen, sulfur, nitrogen, phosphorus or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus or silicon; quaternized form of any basic nitrogen or; heterocyclic substitutable nitrogen such as N (3, 4-dihydro-2H-pyrrolyl), NH (pyrrolidinyl) or NR⁺(e.g., N-substituted pyrrolidinyl)).

The term "unsaturated" as used herein means that the moiety has one or more units of unsaturation.

The term "alkoxy", or "thioalkyl", as used herein, refers to an alkyl group as previously defined attached to a carbon backbone through an oxygen ("alkoxy") or sulfur ("thioalkyl") atom.

The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" refer to alkyl, alkenyl or alkoxy groups, as the case may be, substituted with one or more halogen atoms. The term "halogen" refers to F, Cl, Br or I.

The term "aryl", used herein alone or as part of a larger moiety, such as "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5-14 ring members, wherein at least one ring in the system is aromatic and each ring in the system contains 3-7 ring members. The term "aryl" is used interchangeably with the term "aromatic ring". The term "aryl" also refers to heteroaromatic ring systems as defined herein below.

The term "heteroaryl", used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5-14 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3-7 ring members. The term "heteroaryl" is used interchangeably with the term "heteroaromatic ring" or the term "heteroaromatic".

Aryl (including aralkyl, aralkoxy, aryloxyalkyl, and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxyEtc.) may comprise one or more substituents, and thus may be "optionally substituted. Unless defined otherwise above and herein, suitable substituents on the unsaturated carbon atom of an aryl OR heteroaryl group are selected from halogen, -R °, -OR °, -SR °, phenyl (Ph) optionally substituted with R °, O (Ph) optionally substituted with R °, and- (CH) optionally substituted with R °, (R-O-R₂)_1-2(Ph), -CH ═ CH (Ph) optionally substituted with R °, 5-6 membered heteroaryl or heterocycle optionally substituted with R °; -NO₂；-CN；-N(R°)₂；-NR°C(O)R°；-NR°C(S)R°；-NR°C(O)N(R°)₂；-NR°C(S)N(R°)₂；-NR°CO₂R°；-NR°NR°C(O)R°；-NR°NR°C(O)N(R°)₂；-NR°NR°CO₂R°；-C(O)C(O)R°；-C(O)CH₂C(O)R°；-CO₂R°；-C(O)R°；-C(S)R°；-C(O)N(R°)₂；-C(S)N(R°)₂；-OC(O)N(R°)₂；-OC(O)R°；-C(O)N(OR°)R°；-C(NOR°)R°；-S(O₂)R°；-S(O₃)R°；-SO₂N(R°)₂；-S(O)R°；-NR°SO₂N(R°)₂；-NR°SO₂R°；-N(OR°)R°；-C(＝NH)-N(R°)₂；-P(O)₂R°；-PO(R°)₂-OPO(R°)₂(ii) a Or- (CH)₂)_0-2NHC (O) R °, wherein each independently present R ° is selected from hydrogen, optionally substituted C_1-6Aliphatic, unsubstituted 5-6 membered heteroaryl or heterocycle, phenyl, - (O) Ph, or-CH₂(Ph), or, although defined above, two independently present R.cndot.on the same or different substituents, together with the atoms to which each R.cndot.group is bonded, form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated unit or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

The optional substituents on the aliphatic radical of R DEG are selected from NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), O (halogeno C_1-4Aliphatic group), or halogenGeneration C_1-4Aliphatic radical, in which R ° is each of the aforementioned C_1-4The aliphatic groups are all unsubstituted.

Aliphatic or heteroaliphatic groups, or non-aromatic heterocyclic rings may contain one or more substituents and thus may be "optionally substituted". Unless defined otherwise above and herein, suitable substituents on saturated carbons of aliphatic or heteroaliphatic groups, or non-aromatic heterocycles are selected from those listed above for unsaturated carbons of aryl or heteroaryl groups, and further include the following: o, S, NNHR^*、＝NN(R^*)₂、＝NNHC(O)R^*、＝NNHCO₂(alkyl) ═ NNHSO₂(alkyl), or ═ NR^*Wherein each R is^*Independently selected from hydrogen or optionally substituted C_1-4An aliphatic group.

Unless otherwise defined above and herein, optional substituents on the nitrogen of the non-aromatic heterocyclic ring are selected from the group consisting of-R⁺、-N(R⁺)₂、-C(O)R⁺、-CO₂R⁺、-C(O)C(O)R⁺、-C(O)CH₂C(O)R⁺、-SO₂R⁺、-SO₂N(R⁺)₂、-C(＝S)N(R⁺¹)₂、-C(＝NH)-N(R⁺)₂or-NR⁺SO₂R⁺(ii) a Wherein R is⁺Is hydrogen, optionally substituted C_1-6Aliphatic radical, optionally substituted phenyl, optionally substituted-O (Ph), optionally substituted-CH₂(Ph), optionally substituted- (CH)₂)_1-2(Ph), optionally substituted-CH ═ CH (Ph), or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, although as defined above, two independently present R on the same or different substituents⁺And each R⁺The atoms to which the groups are bonded together form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated unit or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

R⁺Is selected from the group consisting of-NH₂、-NH(C_1-4Aliphatic radical), -N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, -OH, -O (C)_1-4Aliphatic radical), -NO₂、-CN、-CO₂H、-CO₂(C_1-4Aliphatic group), -O (halo C)_1-4Aliphatic group), or halogen C_1-4Aliphatic radical, wherein R⁺Each of the foregoing C_1-4The aliphatic groups are all unsubstituted.

The term "alkylene chain" refers to a straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation and has two points of attachment to the rest of the molecule.

The term "protecting group" as used herein refers to an agent used to temporarily block one or more desired reactive sites in a polyfunctional compound. In particular embodiments, the protecting group has one or more, or preferably all, of the following properties: a) selective reaction in good yield, resulting in a protective substrate that is stable to reactions occurring at one or more other reaction sites; and b) can be selectively removed in good yield using reagents that do not attack the regenerating functional groups. Exemplary protecting groups are those described in Greene, t.w., Wuts, P.G, "protecting groups in organic synthesis", third edition, John Wiley & Sons, New York: 1999, which is incorporated herein by reference in its entirety. The term "nitrogen protecting group" as used herein refers to an agent used to temporarily block one or more desired nitrogen reactive sites in a polyfunctional compound. Preferred nitrogen protecting groups also have the properties exemplified above, and certain exemplary nitrogen protecting groups are also described in Chapter 7 in Greene, t.w., Wuts, P.G, "protecting groups in organic synthesis", third edition, John Wiley & Sons, New York: 1999, which is incorporated herein by reference in its entirety.

As noted above, in certain embodiments, two independently present R ° (or R [ - ])⁺R, R' or any other variable similarly defined herein) may be taken together with the atoms to which they are bound to form a cyclic or cyclic aliphatic hydrocarbon residue having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfurOptionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated unit or bicyclic ring.

Two independently present R (or R)⁺R, R', or any other variable similarly defined herein) and the atoms to which each variable is bound include, but are not limited to, the following: a) two independently present R (or R)⁺R, R' or any other variable similarly defined herein) is bound to the same atom and forms a ring with that atom, e.g., N (R °)₂Wherein two R DEG groups present form together with the nitrogen atom piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl; and b) two independently present R (or R)⁺R, R' OR any other variable similarly defined herein) are bonded to different atoms and together with those atoms form a ring, e.g., wherein phenyl is substituted by the presence of two OR degrees

And (b) substituted, the two R DEG groups present form together with the oxygen atom to which they are bound a fused 6-membered oxygen containing ring:

. It should be recognized that when two independently exist R (or R)⁺R, R' or any other variable similarly defined herein) may form various other rings when they are attached together with the atoms to which each variable is attached, and the examples detailed above are not to be considered as limiting.

Unless otherwise indicated, the structures described herein may also include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomeric) forms of the structure; for example, the R and S configuration of each asymmetric center, double bond isomers of (Z) and (E), and conformational isomers of (Z) and (E). Thus, the individual stereoisomers as well as enantiomers, diastereomers, and geometric isomers (or conformers) of the compounds of the invention are mixedCompounds also fall within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise indicated, the structures described herein also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, having the structure of the invention with only deuterium or tritium substituted for hydrogen, or having the structure with only deuterium or tritium substituted for hydrogen¹³C-or¹⁴C-enriched carbon-substituted carbon compounds of the present structures are also within the scope of the present invention. Such compounds are useful as analytical tools or probes in biological assays.

3. Description of exemplary Compounds:

as generally described above, R¹Is T-R ', or-Si (R')₃. In certain embodiments, when R1 is T-R', T is optionally substituted C₁-C₆Alkylene chain in which up to two methylene units are optionally and independently replaced by-O-, -S-, -NR' -, -OCO-, -COO-, -SO₂-or-CO-substituted, and R' is hydrogen, C₁-C₄Alkyl, or optionally substituted 5-or 6-membered aryl or heteroaryl. At R¹In other embodiments, R' may also be C₁-C₄An aliphatic group. In other embodiments, when R¹is-Si (R')₃R' is hydrogen, C₁-C₄An alkyl group, or an optionally substituted 5-or 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In other embodiments, R¹Is hydrogen, C₁-C₄Alkyl, -COR', -SO₂R ', or-Si (R')₃. In other embodiments, R¹Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, p-toluenesulfonyl (Ts), tert-butyldimethylsilyl (TBS), Triisopropylsilyl (TIPS) or Triethylsilyl (TES). Illustrative of R¹Groups are also described in tables 1 and 2 herein.

As generally described above, R²、R³And R⁴Each independently of the other being halogen, CN, NO₂Or V-R'. In certain embodiments, R²、R³And R⁴Each independently hydrogen, R', halogen, CN, NO₂、-N(R′)₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-COOR′、-NR′COR′、-CON(R′)₂、-SO₂N(R′)₂、-CONR′(CH₂)₂N(R′)₂、-CONR′(CH₂)₃N(R′)₂、-CONR′(CH₂)₄N(R′)₂、-O(CH₂)₂OR′、O(CH₂)₃OR′、O(CH₂)₄OR′、-O(CH₂)₂N(R′)₂、-O(CH₂)₃N(R′)₂or-O (CH)₂)₄N(R′)₂. In other embodiments, R²、R³And R⁴Each independently of the others is Cl, Br, F, -CN, -COOH, -COOMe, -NH₂、-N(CH₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COOCH₃、-OH、-CH₂OH、-NHCOCH₃、-SO₂NH₂、-SO₂N(Me)₂-, or an optionally substituted radical selected from C₁-C₄Alkyl radical, C₁-C₄Alkoxy, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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. In other embodiments, R²、R³And R⁴Each is hydrogen. In other embodiments, R²、R³Or R⁴Is hydrogen. In other embodiments, R²、R³Or R⁴Two of which are hydrogen. In other embodiments, R²And R⁴Are all hydrogen, and R³Is halogen, CN, NO₂Or V-R'. In thatIn other embodiments, R²And R⁴Are all hydrogen, and R³Is an optionally substituted group selected from a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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. In other embodiments, R²And R⁴Are all hydrogen, and R³Is an optionally substituted 5-or 6-membered saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In other embodiments, R²And R⁴Are all hydrogen, and R³Is an optionally substituted ring selected from phenyl, pyridyl, pyrimidinyl, thiazolyl,Oxazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl, orA diazolyl group. In other embodiments, when R¹、R²And R⁴Is H, then R³Is not an optionally substituted phenyl group. In other embodiments, when R¹、R²And R⁴Is H, then R³Is not an aryl, heteroaryl, carbocyclyl, or heteryl group. Exemplary R²、R³And R⁴Groups also include those given in tables 1 and 2 below.

As mentioned above, R²、R³And R⁴Each of which is optionally substituted, and in particular embodiments, R²、R³And R⁴Optionally and independently by R⁶Wherein z is 0 to 5 and R⁶Is ═ O, ═ NR ", ═ S, halogen, -CN, -NO₂Or Z-R' wherein Z is a bond or optionally substituted C₁-C₆An alkylene chain, wherein the chain is optionally and independently interrupted by-NR' -, -S-, (iii) a methylene unit of at most two,-O-、-CS-、-CO₂-、-OCO-、-CO-、-COCO-、-CONR″-、-NR″CO-、-NR″CO₂-、-SO₂NR″-、-NR″SO₂-、-CONR″NR″-、-NR″CONR″-、-OCONR″-、-NR″NR″-、-NR″SO₂NR″-、-SO-、-SO₂-、-PO-、-PO₂-, or-POR "-and each occurrence of R" is independently hydrogen or optionally substituted C₁-C₆An aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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 two occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In other embodiments, z is 0, 1, 2, or 3, and R⁶Independently for each occurrence of (a) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R″)₂、-CH₂N(R″)₂、-OR″、-CH₂OR″、-SR″、-CH₂SR″、-COOR″、-NR″COR″、-NR″COOR″、-CON(R″)₂、-SO₂N(R″)₂、-CONR″(CH₂)₂N(R″)₂、-CONR(CH₂)₃N(R″)₂、-CONR″(CH₂)₄N(R″)₂、-O(CH₂)₂OR″、O(CH₂)₃OR″、O(CH₂)₄OR″、-O(CH₂)₂N(R″)₂、-O(CH₂)₃N(R″)₂、-O(CH₂)₄N(R″)₂、-NR″CH(CH₂OH)R″、-NR″CH(CH₂CH₂OH)R″、-NR″(CH₂)R″、-NR″(CH₂)₂R″、-NR″(CH₂)₃R″、-NR″(CH₂)₄R″、-NR″(CH₂)N(R″)₂、-NR″(CH₂)₂N(R″)₂、-NR″(CH₂)₃N(R″)₂、-NR″(CH₂)₄N(R″)₂、-NR″(CH₂)OR″、NR″(CH₂)₂OR″、-NR″(CH₂)₃OR ', OR-NR' (CH)₂)₄OR ". In another embodiment, R⁶May also be-NR "CH (CH)₃) R' is adopted. In other embodiments, z is 1, 2, or 3 and R⁶Each occurrence of (A) is independently F, Cl, Br, CN, OH, NH₂、-CH₂OH、C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -CH₂O(C1-C₆Alkyl), -CO (C1-C)₆Alkyl), -COO (C)₁-C₆Alkyl), -NHSO₂(C₁-C₆Alkyl), -SO₂NH₂、-CONH₂、-CON(C₁-C₆Alkyl), -SO₂(C₁-C₆Alkyl), -SO₂Phenyl, benzyl, -N (C)₁-C₆Alkyl radical)₂or-S (C)₁-C₆Alkyl) wherein the foregoing phenyl, benzyl, and C₁-C₆Each alkyl is independently and optionally substituted, and wherein C is as previously described₁-C₆Each alkyl group is straight, branched, or cyclic. Other exemplary R⁶The groups are described in table 1.

As described above for the compounds of formula I in general, X¹、X²And X³Each independently is N or CH, wherein the hydrogen atom of CH is optionally substituted by R⁵And (4) substitution. In particular embodiments, X¹、X²Or X³Two of (a) are N, and X¹、X²Or X³The remaining one of (A) is CH, wherein the hydrogen atom of CH is optionally substituted by R⁵And (4) substitution. In other particular embodiments, X¹、X²Or X³Is N, and X¹、X²Or X³The remaining two of (A) are CH, wherein the hydrogen atom of CH is optionally substituted by R⁵And (4) substitution. In other embodiments, X¹、X²And X³Each is CH, wherein the hydrogen atom of CH is optionally substituted by R⁵And (4) substitution. In other specific exemplary embodiments, the compounds have the formula I-A,

In other embodiments, the compounds have the formula I-E:

as described above generally for compounds of formula I, x is 1, 2, 3, or 4; and R is⁵Independently for each occurrence of (A) is halogen, CN, NO₂Or U-R', wherein each occurrence of U is independently a bond or optionally substituted C₁-C₆Alkylene chain, wherein the chain is optionally and independently represented by-NR' -, -S-, -O-, -CS-, -CO₂-、-OCO-、-CO-、-COCO-、-CONR′-、-NR′CO-、-NR′CO₂-、-SO₂NR′-、-NR′SO₂-、-CONR′NR′-、-NR′CONR′-、-OCONR′-、-NR′NR′-、-NR′SO₂NR′-、-SO-、-SO₂-、-PO-、-PO₂-, or-POR' -substitution; and is

Each occurrence of R' is independently hydrogen or optionally substituted C₁-C₆An aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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 both occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, R⁵Independently for each occurrence of (A) is hydrogen, R', -CH₂R' halogen、CN、NO₂、-N(R′)₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-COOR′、-NR′COR′、-NR′COCH₂R′、-NR′CO(CH₂)₂R′、-NR′COOR′、-CON(R′)₂、-SO₂N(R′)₂、-CONR′(CH₂)₂N(R′)₂、-CONR(CH₂)₃N(R′)₂、-CONR′(CH₂)₄N(R′)₂、-O(CH₂)₂OR′、O(CH₂)₃OR′、O(CH₂)₄OR′、-O(CH₂)₂N(R′)₂、-O(CH₂)₃N(R′)₂、-O(CH₂)₄N(R′)₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、-NR′(CH₂)₃R′、-NR′(CH₂)₄R′、-NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-NR′(CH₂)₃N(R′)₂、-NR′(CH₂)₄N(R′)₂、-NR′(CH₂)OR′、-NR′(CH₂)₂OR′、-NR′(CH₂)₃OR ', OR-NR' (CH)₂)₄OR'. In certain embodiments, R⁵May also be-NR' CH (CH)₃)R′、NR′CH(CF₃)R′、-NR′CH(CH₃)C(O)OR′、-NR′CH(CF₃)C(O)OR′、-NR′CH(CH₂CH₃)R′、-NR′CH₂C(O)N(R′)₂、-NR′CH(CH₃)C(O)N(R′)₂、NR′CH(CF₃)C(O)N(R′)₂、-NR′CH(CH₂CH₃)C(O)N(R′)₂、-NR′CH(CH(CH₃)₂)C(O)N(R′)₂、NR′CH(C(CH₃)₃)C(O)N(R′)₂、-NR′CH(CH₂CH(CH₃)₂)C(O)N(R′)₂、-NR′CH(CH₂OR⁹)C(O)N(R′)₂or-NR' CH (CH)₂CH₂N(Me)₂)C(O)N(R′)₂. In certain exemplary embodiments, x is 1, 2, or 3, and R⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂or-NR' (CH)₂)₂N(R′)₂. In other embodiments, x is 1, 2, or 3, and R⁵is-OR' in at least one occurrence of (a). In other embodiments, x is 1, 2, or 3, and R⁵Is halogen. In other embodiments, x is 1, 2, or 3, and R⁵is-NR ' COR ', -NR ' COCH₂R′、-NR′CO(CH₂)₂R′-NR′CH(CH₂OH)R′、-NR′CH(CH₂OMe)R′、-NR′CH(CH₂OEt)R′、-NR′CH(CH₂OCF₃)R′、-NR′CH(CH₂CH₂OH)R′、-NR′CH(CH₂CH₂OMe)R′、-NR′CH(CH₂CH₂OEt)R′、-NR′CH(CH₂CH₂OCF₃)R′、-NR′CH(CH₃)C(O)OR′、-NR′CH(CF₃)C(O)OR′、-NR′CH(CH₃)C(O)N(R′)₂、-NR′CH(CF₃)C(O)N(R′)₂、-NR′CH(CH₂CH₃)C(O)N(R′)₂、-NR′CH(CH₂OH)C(O)N(R′)₂、-NR′CH(CH₂OMe)C(O)N(R′)₂、-NR′CH(CH₂OEt)C(O)N(R′)₂or-NR' CH (CH)₂OCF₃)C(O)N(R′)₂Wherein R' is optionally substituted C₁-C₄An aliphatic group; NHCH₂C(O)NHR′、-NHCH(CH₃)C(O)NHR′、-NHCH(CH₂CH₃)C(O)NHR′、-NHCH(CH(CH₃)₂)C(O)NHR′、-NHCH(C(CH₃)₃)C(O)NHR′、-NHCH(CH₂CH(CH₃)₂)C(O)NHR′、-NHCH(CH₂OH)C(O)NHR′、-NHCH(CH₂OMe) C (O) NHR', or-NHCH (CH)₂CH₂N(Me)₂) C (O) NHR ', wherein R' is optionally substituted C₁-C₄An aliphatic group; -NHR', -NH (CH)₂)R′、-NH(CH₂)₂R′、-NHCH(CH₃)R′、-NHCH₂C(O)NHR′、-NHCH(CH₃)C(O)NHR′、-NHCH(CH₂CH₃)C(O)NHR′、-NHCH(CH(CH₃)₂)C(O)NHR′、-NHCH(C(CH₃)₃)C(O)NHR′、-NHCH(CH₂CH(CH₃)₂)C(O)NHR′、-NHCH(CH₂OH)C(O)NHR′、-NHCH(CH₂OMe) C (O) NHR' or-NHCH (CH)₂CH₂N(Me)₂) C (O) NHR ', wherein R' is optionally substituted C₁-C₄An aliphatic group; -NHCH (CH)₃) R ', wherein R' is optionally substituted phenyl; H. halogen, CH₃、CF₃COOH, COOMe OR OR 'wherein R' is C₁-C₄An aliphatic group.

In other embodiments, x is 1, 2, or 3, and R⁵Is at least one occurrence of optionally substituted C₁-C₆An aliphatic group, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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.

In other embodiments, x is 1 or 2, and R⁵Each occurrence of (A) is independently halogen, R', CN, -CH₂CN、-(CH₂)₂CN、NO₂、-CH₂NO₂、-(CH₂)₂NO₂、CON(R′)₂、-CH₂CON(R′)₂、-(CH₂)₂CON(R′)₂、COOR′、-CH₂COOR′、-(CH₂)₂COOR′、-SO₂N(R′)₂、-CH₂SO₂N(R′)₂、-(CH₂)₂SO₂N(R′)₂、-NR′SO₂R′、-CH₂NR′SO₂R′、-(CH₂)₂NR′SO₂R′、NR′CON(R′)₂、-CH₂NR′CON(R′)₂、-(CH₂)₂NR′CON(R′)₂、-NR′SO₂N(R′)₂、-CH₂NR′SO₂N(R′)₂、-(CH₂)₂NR′SO₂N(R′)₂、-COCOR′、-CH₂COCOR′、-(CH₂)₂COCOR′、-N(R′)₂、-CH₂N(R′)₂、-(CH₂)₂N(R′)₂、-OR′、-CH₂OR′、-(CH₂)₂OR′、-NR′COR′、-NR′COCH₂R′、-NR′CO(CH₂)₂R′、-CH₂NR 'COR', or- (CH)₂)₂NR 'COR'. In other embodiments, R⁵Is CN, -CH₂CN、-(CH₂)₂CN、-NO₂、-CH₂NO₂、-(CH₂)₂NO₂、OR′、-CH₂OR′、-CON(R′)₂、-SO₂N(R′)₂、-N(R′)₂Or R'. In other embodiments, R⁵Independently for each occurrence of (a) is hydrogen, halogen, CN, -CH₂CN、-(CH₂)₂CN、NO₂、-CH₂NO₂、-(CH₂)₂NO₂、-CONH₂、-CON(C₁-C₄Alkyl), -SO₂NH₂、-SO₂N(C₁-C₄Alkyl), NH₂、-N(C₁-C₄Alkyl), -OH, -O (C)₁-C₄Alkyl), -CH₂OH、-CH₂O(C₁-C₄Alkyl), or an optionally substituted 5-or 6-membered unsaturated ring, wherein 0 to 3 ring carbon atoms are optionally substituted with oxygen, sulfur, or nitrogen.

As described above generally with respect to compounds of formula I, R⁵Optionally substituted with R⁷Y occurrences of (a) wherein y is 0-5 and R⁷Is ═ O, ═ NR ", ═ S, halogen, -CN、-NO₂Or W-R', wherein W is a bond or optionally substituted C₁-C₆An alkylene chain wherein at most two methylene units of the chain are optionally and independently replaced by-NR' -, -S-, -O-, -CS-, -CO-₂-、-OCO-、-CO-、-COCO-、-CONR″-、-NR″CO-、-NR″CO₂-、-SO₂NR″-、-NR″SO₂-、-CONR″NR″-、-NR″CONR″-、-OCONR″-、-NR″NR″-、-NR″SO₂NR″-、-SO-、-SO₂-、-PO-、-PO₂-, or-POR "-and each occurrence of R" is independently hydrogen or optionally substituted C₁-C₆An aliphatic group, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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 two occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In other embodiments, y is 0, 1, 2, or 3, and R⁷Independently for each occurrence of (a) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R″)₂、-CH₂N(R″)₂、-OR″、-CH₂OR″、-SR″、-CH₂SR″、-COOR″、-NR″COR″、-NR″COOR″、-CON(R″)₂、-SO₂N(R″)₂、-CONR″(CH₂)₂N(R″)₂、-CONR(CH₂)₃N(R″)₂、-CONR″(CH₂)₄N(R″)₂、-O(CH₂)₂OR″、O(CH₂)₃OR″、O(CH₂)₄OR″、-O(CH₂)₂N(R″)₂、-O(CH₂)₃N(R″)₂、-O(CH₂)₄N(R″)₂、-NR″CH(CH₂OH)R″、-NR″CH(CH₂CH₂OH)R″、-NR″(CH₂)R″、-NR″(CH₂)₂R″、-NR″(CH₂)₃R″、-NR″(CH₂)₄R″、-NR″(CH₂)N(R″)₂、-NR″(CH₂)₂N(R″)₂、-NR″(CH₂)₃N(R″)₂、-NR″(CH₂)₄N(R″)₂、-NR″(CH₂)OR″、-NR″(CH₂)₂OR″、-NR″(CH₂)₃OR ', OR-NR' (CH)₂)₄OR ". In certain embodiments, R⁷May also be-NR' CH (CH)₃) R' is provided. In other embodiments, y is 1, 2, or 3 and R⁷Each occurrence of (A) is independently F, Cl, Br, CN, OH, NH₂、-CH₂OH、C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -CH₂O(C₁-C₆Alkyl), -CO (C)₁-C₆Alkyl), -COO (C)₁-C₆Alkyl), -NHSO₂(C₁-C₆Alkyl), -SO₂NH₂、-CONH₂-、-CON(C₁-C₆Alkyl), -SO₂(C₁-C₆Alkyl), -SO₂Phenyl, benzyl, -N (C)₁-C₆Alkyl radical)₂、-S(C₁-C₆Alkyl) wherein the foregoing phenyl, benzyl and C₁-C₆Alkyl is independently and optionally substituted, and C is₁-C₆Each alkyl group is straight, branched, or cyclic. Other exemplary R⁷The groups are described in table 1.

In other embodiments, x is 1, 2, or 3; r⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、-NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R 'and R' is C₁-C₆Aliphatic radical or hetero having 0-3 hetero atoms independently selected from nitrogen, oxygen, or sulfurA 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring of atoms, 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 two occurrences of R 'taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each occurrence of R' is optionally substituted with R⁷Y occurrences of substitution. In a particular embodiment, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₆Alkyl, or a saturated, partially unsaturated, or fully unsaturated 5-to 10-membered monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is optionally substituted with R⁷1-3 occurrences of substitution. In other embodiments, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₄Alkyl, or is cyclic, selected from:

wherein y and R⁷Described above in general terms and subgroups.

In another embodiment, R' may be

Wherein y and R⁷Described above in general terms and subgroups.

In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionalA substituted 3-10 membered monocyclic or bicyclic heterocycle. In particular embodiments, the ring is selected from:

wherein y and R⁷Described above in general terms and subgroups.

Other specific subgroups of compounds of formula I include:

1. a compound of formula I-A:

wherein R is¹、R²、R³、R⁴、R⁵And x are each described in the general description above and in the subgroups described above and herein.

In certain embodiments, for compounds of formula I-a:

a.R¹the method comprises the following steps:

i.T-R', wherein T is a bond or optionally substituted C₁-C₆Alkylene chain in which up to two methylene units are optionally and independently replaced by-O-, -S-, -NR' -, -OCO-, -COO-, -SO₂-or-CO-substituted, and R' is hydrogen, C₁-C₄Alkyl, or optionally substituted 5-or 6-membered aryl or heteroaryl, or

ii.-Si(R′)₃Wherein R' is hydrogen, C₁-C₄An alkyl, or an optionally substituted 5-or 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

b.R²、R³and R⁴Each independently is hydrogen, R', halogen, CN、NO₂、-N(R′)₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-COOR′、-NR′COR′、-NR′COCH₂R′、-NR′CO(CH₂)₂R′、-CON(R′)₂、-SO₂N(R′)₂、-CONR′(CH₂)₂N(R′)₂、-CONR′(CH₂)₃N(R′)₂、-CONR′(CH₂)₄N(R′)₂、-O(CH₂)₂OR′、O(CH₂)₃OR′、O(CH₂)₄OR′、-O(CH₂)₂N(R′)₂、-O(CH₂)₃N(R′)₂or-O (CH)₂)₄N(R′)₂(ii) a Wherein R is²、R³And R⁴Each is optionally substituted by R⁶Wherein z is 0 to 5 and R⁶Is ═ O, ═ NR ", ═ S, halogen, -CN, -NO₂Or Z-R' wherein Z is a bond or optionally substituted C₁-C₆An alkylene chain wherein at most two methylene units of the chain are optionally and independently replaced by-NR' -, -S-, -O-, -CS-, -CO-₂-、-OCO-、-CO-、-COCO-、-CONR″-、-NR″CO-、-NR″CO₂-、-SO₂NR″-、-NR″SO₂-、-CONR″NR″-、-NR″CONR″-、-OCONR″-、-NR″NR″-、-NR″SO₂NR″-、-SO-、-SO₂-、-PO-、-PO₂-, or-POR "-and each occurrence of R" is independently hydrogen or optionally substituted C₁-C₆An aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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 two occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

c.R⁵Each of (1)Each occurrence independently is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R′)₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-COOR′、-NR′COR′、-NR′COCH₂R′、-NR′CO(CH₂)₂R′、-NR′COOR′、-CON(R′)₂、-SO₂N(R′)₂、-CONR′(CH₂)₂N(R′)₂、-CONR(CH₂)₃N(R′)₂、-CONR′(CH₂)₄N(R′)₂、-O(CH₂)₂OR′、O(CH₂)₃OR′、O(CH₂)₄OR′、-O(CH₂)₂N(R′)₂、-O(CH₂)₃N(R′)₂、-O(CH₂)₄N(R′)₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、-NR′(CH₂)₃R′、-NR′(CH₂)₄R′、-NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-NR′(CH₂)₃N(R′)₂、-NR′(CH₂)₄N(R′)₂、-NR′(CH₂)OR′、-NR′(CH₂)₂OR′、-NR′(CH₂)₃OR ', OR-NR' (CH)₂)₄OR', wherein R⁵Optionally substituted with R⁷Y occurrences of (a) wherein y is 0-5 and R⁷Is ═ O, ═ NR ", ═ S, halogen, -CN, -NO₂Or W-R', wherein W is a bond or optionally substituted C₁-C₆An alkylene chain wherein at most two methylene units of the chain are optionally and independently replaced by-NR' -, -S-, -O-, -CS-, -CO-₂-、-OCO-、-CO-、-COCO-、-CONR″-、-NR″CO-、-NR″CO₂-、-SO₂NR″-、-NR″SO₂-、-CONR″NR″-、-NR″CONR″-、-OCONR″-、-NR″NR″-、-NR″SO₂NR″-、-SO-、-SO₂-、-PO-、-PO₂-, or-POR "-takeAnd each occurrence of R' is independently hydrogen or optionally substituted C₁-C₆An aliphatic group, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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 two occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In other embodiments, for compounds of formula I-a:

a.R¹is hydrogen, C₁-C₄Alkyl, -COR', -SO₂R ', or-Si (R')₃；

b.R²、R³And R⁴Each independently of the others is Cl, Br, F, -CN, -COOH, -COOMe, -NH₂、-N(CH₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COOCH₃、-OH、-CH₂OH、-NHCOCH₃、-SO₂NH₂、-SO₂N(Me)₂-, or an optionally substituted radical selected from C₁-C₄Alkyl radical, C₁-C₄Alkoxy, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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; wherein R is²、R³And R⁴Each independently and optionally substituted with R⁶Wherein z is 0, 1, 2, or 3, and R⁶Independently for each occurrence of (a) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R″)₂、-CON(R″)₂、-OR″、-CH₂OR″、-SR″、-CH₂SR″、-COOR″、-NR″COR″、-NR″COOR″、-CH₂N(R″)₂、-SO₂N(R″)₂、-CONR″(CH₂)₂N(R″)₂、-CONR(CH₂)₃N(R″)₂、-CONR″(CH₂)₄N(R″)₂、-O(CH₂)₂OR″、O(CH₂)₃OR″、O(CH₂)₄OR″、-O(CH₂)₂N(R″)₂、-O(CH₂)₃N(R″)₂、-O(CH₂)₄N(R″)₂、-NR″CH(CH₂OH)R″、-NR″CH(CH₂CH₂OH)R″、-NR″(CH₂)R″、-NR″(CH₂)₂R″、-NR″(CH₂)₃R″、-NR″(CH₂)₄R″、-NR″(CH₂)N(R″)₂、-NR″(CH₂)₂N(R″)₂、-NR″(CH₂)₃N(R″)₂、-NR″(CH₂)₄N(R″)₂、-NR″(CH₂)OR″、NR″(CH₂)₂OR″、-NR″(CH₂)₃OR ', OR-NR' (CH)₂)₄OR″；

c.R⁵Independently for each occurrence of (A) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R′)₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-COOR′、-NR′COR′、-NR′COCH₂R′、-NR′CO(CH₂)₂R′、-NR′COOR′、-CON(R′)₂、-SO₂N(R′)₂、-CONR′(CH₂)₂N(R′)₂、-CONR(CH₂)₃N(R′)₂、-CONR′(CH₂)₄N(R′)₂、-O(CH₂)₂OR′、O(CH₂)₃OR′、O(CH₂)₄OR′、-O(CH₂)₂N(R′)₂、-O(CH₂)₃N(R′)₂、-O(CH₂)₄N(R′)₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、-NR′(CH₂)₃R′、-NR′(CH₂)₄R′、-NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-NR′(CH₂)₃N(R′)₂、-NR′(CH₂)₄N(R′)₂、-NR′(CH₂)OR′、-NR′(CH₂)₂OR′、-NR′(CH₂)₃OR ', OR-NR' (CH)₂)₄OR', wherein R⁵Optionally substituted with R⁷Wherein y is 0, 1, 2, or 3, and R⁷Independently for each occurrence of (a) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R″)₂、-CH₂N(R″)₂、-OR″、-CH₂OR″、-SR″、-CH₂SR″、-COOR″、-NR″COR″、-NR″COOR″、-CON(R″)₂、-SO₂N(R″)₂、-CONR″(CH₂)₂N(R″)₂、-CONR(CH₂)₃N(R″)₂、-CONR″(CH₂)₄N(R″)₂、-O(CH₂)₂OR″、O(CH₂)₃OR″、O(CH₂)₄OR″、-O(CH₂)₂N(R″)₂、-O(CH₂)₃N(R″)₂、-O(CH₂)₄N(R″)₂、-NR″CH(CH₂OH)R″、-NR″CH(CH₂CH₂OH)R″、-NR″(CH₂)R″、-NR″(CH₂)₂R″、-NR″(CH₂)₃R″、-NR″(CH₂)₄R″、-NR″(CH₂)N(R″)₂、-NR″(CH₂)₂N(R″)₂、-NR″(CH₂)₃N(R″)₂、-NR″(CH₂)₄N(R″)₂、-NR″(CH₂)OR″、-NR″(CH₂)₂OR″、-NR″(CH₂)₃OR ', OR-NR' (CH)₂)₄OR″。

In other embodiments, for compounds of formula I-A and the subgroups described directly above, R¹Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, p-toluenesulfonyl (Ts), tert-butyldimethylsilyl (TBS), Triisopropylsilyl (TIPS), or Triethylsilyl (TES).

In other embodiments, for compounds of formula I-A and the subgroups described directly above, R²、R³And R⁴Each is hydrogen. In other embodiments, R²、R³Or R⁴Is hydrogen. In other embodiments, R²、R³Or R⁴Two of which are hydrogen. In other embodiments, R²And R⁴Are all hydrogen, and R³Is halogen, CN, NO₂Or V-R'. In other embodiments, R²And R⁴Are all hydrogen, and R³Is an optionally substituted group selected from a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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. In other embodiments, R²And R⁴Are all hydrogen, and R³Is an optionally substituted 5-or 6-membered saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In other embodiments, R²And R⁴Are all hydrogen, and R³Is an optionally substituted ring selected from phenyl, pyridyl, pyrimidinyl, thiazolyl,Oxazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl, orA diazolyl group. In other embodiments, R³Is selected fromH、Cl、Br、F、-CN、-COOH、-COOMe、-NH₂、-N(R′)₂、-NO₂、-OR′、-CON(R′)₂、-COOR′、-OH、-SR′、-C(R′)₂OR′、-N(R′)COR′、-N(R′)C(O)OR′、-SO₂NH₂、-SO₂N(R′)₂Or an optionally substituted group selected from C₁-C₄Aliphatic radical, C₁-C₄Alkoxy or-C＝C-C₁-C₄An aliphatic group. In further embodiments, R²And R⁴Are both hydrogen and R³Directly selected from the preceding list.

In other embodiments, for compounds of formula I-A and the subgroups described directly above, R²、R³And R⁴Each independently and optionally substituted with R⁶Wherein z is 1, 2, or 3 and R⁶Each occurrence of (A) is independently F, Cl, Br, CN, OH, NH₂、-CH₂OH、C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -CH₂O(C1-C₆Alkyl), -CO (C1-C)₆Alkyl), -COO (C)₁-C₆Alkyl), -NHSO₂(C₁-C₆Alkyl), -SO₂NH₂、-CONH₂、-CON(C₁-C₆Alkyl), -SO₂(C₁-C₆Alkyl), -SO₂Phenyl, benzyl, -N (C)₁-C₆Alkyl radical)₂or-S (C)₁-C₆Alkyl) wherein the foregoing phenyl, benzyl, and C₁-C₆Each alkyl is independently and optionally substituted, and wherein C is as previously described₁-C₆Each alkyl group is straight, branched, or cyclic.

In certain exemplary embodiments, for compounds of formula I-A and the subgroups described directly above, x is 1, 2, or 3, and R is⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂or-NR' (CH)₂)₂N(R′)₂. In other embodiments, x is 1, 2, or 3, and R⁵is-OR' in at least one occurrence of (a). In other embodiments, x is 1, 2, or 3, and R⁵is-NR ' COR ', -NR ' COCH₂R ', or-NR' CO (CH)₂)₂R' is provided. In other embodiments, x is 1, 2, or 3, and R⁵Is at least one occurrence of optionally substituted C₁-C₆An aliphatic group, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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.

In other embodiments, for compounds of formula I-A and the subgroups described directly above, R⁵Optionally substituted with R⁷Wherein y is 1, 2, or 3 and R⁷Each occurrence of (A) is independently F, Cl, Br, CN, OH, NH₂、-CH₂OH、C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -CH₂O(C₁-C₆Alkyl), -CO (C)₁-C₆Alkyl), -COO (C)₁-C₆Alkyl), -NHSO₂(C₁-C₆Alkyl), -SO₂NH₂、-CONH₂-、-CON(C₁-C₆Alkyl), -SO₂(C₁-C₆Alkyl), -SO₂Phenyl, benzyl, -N (C)₁-C₆Alkyl radical)₂、-S(C₁-C₆Alkyl) wherein the foregoing phenyl, benzyl and C₁-C₆Alkyl is independently and optionally substituted, and C is₁-C₆Each alkyl group is straight, branched, or cyclic. In other embodiments, for compounds of formula I-a and the subgroups described directly above, x is 1, 2, or 3; r⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、-NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R 'and R' is C₁-C₆An aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 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 two occurrences of R 'taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each occurrence of R' is optionally substituted with R⁷Y occurrences of substitution. In a particular embodiment, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₆Alkyl, or a saturated, partially unsaturated, or fully unsaturated 5-to 10-membered monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is optionally substituted with R⁷1-3 occurrences of substitution. In other embodiments, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₄Alkyl, or is selected from (i) - (X) as described above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10-membered monocyclic or bicyclic heterocycle. In a particular embodiment, the ring is selected from (a) - (o) as described above.

In other embodiments, x is 1 and the compound has the general formula I-A-I:

wherein R is¹、R²、R³And R⁴In the general description above and in the subgroups above and described herein, and R⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is C₁-C₆An aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 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 two occurrences of R 'taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each occurrence of R' is optionally substituted with R⁷Y occurrences of substitution. In certain embodiments, R⁵Is N (R')₂. In a particular embodiment, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₆Alkyl, or a saturated, partially unsaturated, or fully unsaturated 5-to 10-membered monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is optionally substituted with R⁷1-3 occurrences of substitution. In other embodiments, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₄Alkyl, or is selected from (i) - (X) as described above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10-membered monocyclic or bicyclic heterocycle. In a particular embodiment, the ring is selected from (a) - (o) as described above.

In other embodiments, x is 1 and a compound having the general formula I-A-ii:

wherein R is¹、R²、R³And R⁴In the general description and subgroups above and described herein, and R⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is C₁-C₆An aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 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 two occurrences of R 'taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each occurrence of R' is optionally substituted with R⁷Y occurrences of substitution. In certain embodiments, R⁵Is N (R')₂. In particular embodiments, for each of the subgroups described above, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₆Alkyl, or a saturated, partially unsaturated, or fully unsaturated 5-to 10-membered monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is optionally substituted with R⁷1-3 occurrences of substitution. In other embodiments, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₄Alkyl, or is selected from (i) - (X) as described above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' with the nitrogen atom to which they are boundTogether form an optionally substituted 3-10-membered monocyclic or bicyclic heterocycle. In a particular embodiment, the ring is selected from (a) - (o) as described above.

In other embodiments, R¹、R²、R³And R⁴Each is hydrogen, and provides compounds of formula I-A-iii:

wherein x is 1, 2, or 3; and R is⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is optionally substituted by R⁷Y times of occurrence of substituted C₁-C₆Aliphatic radical, or is selected from (i) - (X) as defined above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10-membered monocyclic or bicyclic heterocycle. In a particular embodiment, the ring is selected from (a) - (o) as described above.

In other embodiments, R¹、R²、R³And R⁴Each is hydrogen and x is 1, and provides compounds of formula I-A-iv:

wherein R is⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is optionally substituted by R⁷Y times of occurrence of substituted C₁-C₆Aliphatic radical, or is selected from (i) - (X) as defined above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10-membered monocyclic or bicyclic heterocycle. In a particular embodiment, the ring is selected from (a) - (o) as described above.

In other embodiments, R¹、R²、R³And R⁴Each is hydrogen, x is 1, and provides compounds of formula I-A-v:

wherein R is⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is optionally substituted by R⁷Y times of occurrence of substituted C₁-C₆Aliphatic radical, or is selected from (i) - (X) as defined above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10-membered monocyclic or bicyclic heterocycle. In a particular embodiment, the ring is selected from (a) - (o) as described above.

In other embodiments, R¹、R²And R⁴Each is hydrogen, and provides compounds of formula I-A-vi:

wherein:

R³is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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; x is 1, 2, or 3; and R is⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is optionally substituted by R⁷Y times of occurrence of substituted C₁-C₆Aliphatic radical, or is selected from (i) - (X) as defined above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10-membered monocyclic or bicyclic heterocycle. In a particular embodiment, the ring is selected from (a) - (o) as described above.

In other embodiments, with respect to the compounds described directly above, R is³Is an optionally substituted 5-or 6-membered saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In other embodiments, R³Is an optionally substituted ring selected from phenyl, pyridyl, pyrimidinyl, thiazolyl,Oxazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl, orA diazolyl group. Such asAs generally described above, R³Optionally substituted with R⁶Z occurrences of substitution. In certain embodiments, wherein z is 0, 1, 2, or 3, and R⁶Independently for each occurrence of (a) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R″)₂、-CH₂N(R″)₂、-OR″、-CH₂OR″、-SR″、-CH₂SR″、-COOR″、-NR″COR″、-NR″COOR″、-CON(R″)₂、-SO₂N(R″)₂、-CONR″(CH₂)₂N(R″)₂、-CONR(CH₂)₃N(R″)₂、-CONR″(CH₂)₄N(R″)₂、-O(CH₂)₂OR″、O(CH₂)₃OR″、O(CH₂)₄OR″、-O(CH₂)₂N(R″)₂、-O(CH₂)₃N(R″)₂、-O(CH₂)₄N(R″)₂、-NR″CH(CH₂OH)R″、-NR″CH(CH₂CH₂OH)R″、-NR″(CH₂)R″、-NR″(CH₂)₂R″、-NR″(CH₂)₃R″、-NR″(CH₂)₄R″、-NR″(CH₂)N(R″)₂、-NR″(CH₂)₂N(R″)₂、-NR″(CH₂)₃N(R″)₂、-NR″(CH₂)₄N(R″)₂、-NR″(CH₂)OR″、NR″(CH₂)₂OR″、-NR″(CH₂)₃OR ', OR-NR' (CH)₂)₄OR″。

In other embodiments, R¹、R²、R³And R⁴Each is hydrogen, x is 1, and provides the formula

Compounds of formula I-a-vii:

wherein:

R³is optionalA substituted group selected from a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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; r⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is optionally substituted by R⁷Y times of occurrence of substituted C₁-C₆Aliphatic radical, or is selected from (i) - (X) as defined above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10-membered monocyclic or bicyclic heterocycle. In a particular embodiment, the ring is selected from (a) - (o) as described above.

In other embodiments, with respect to the compounds described directly above, R is³Is an optionally substituted 5-or 6-membered saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In other embodiments, R³Is an optionally substituted ring selected from phenyl, pyridyl, pyrimidinyl, thiazolyl,Oxazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl, orA diazolyl group. As generally described above, R³Optionally substituted with R⁶Z occurrences of substitution. In certain embodiments, wherein z is 0, 1, 2, or 3, and R⁶Independently for each occurrence of (a) is hydrogen, R', -CH₂R″、Halogen, CN, NO₂、-N(R″)₂、-CH₂N(R″)₂、-OR″、-CH₂OR″、-SR″、-CH₂SR″、-COOR″、-NR″COR″、-NR″COOR″、-CON(R″)₂、-SO₂N(R″)₂、-CONR″(CH₂)₂N(R″)₂、-CONR(CH₂)₃N(R″)₂、-CONR″(CH₂)₄N(R″)₂、-O(CH₂)₂OR″、O(CH₂)₃OR″、O(CH₂)₄OR″、-O(CH₂)₂N(R″)₂、-O(CH₂)₃N(R″)₂、-O(CH₂)₄N(R″)₂、-NR″CH(CH₂OH)R″、-NR″CH(CH₂CH₂OH)R″、-NR″(CH₂)R″、-NR″(CH₂)₂R″、-NR″(CH₂)₃R″、-NR″(CH₂)₄R″、-NR″(CH₂)N(R″)₂、-NR″(CH₂)₂N(R″)₂、-NR″(CH₂)₃N(R″)₂、-NR″(CH₂)₄N(R″)₂、-NR″(CH₂)OR″、-NR″(CH₂)₂OR″、-NR″(CH₂)₃OR ', OR-NR' (CH)₂)₄OR″。

In other embodiments, R¹、R²、R³And R⁴Each is hydrogen, x is 1, and provides a compound of formula I-A-viii:

wherein:

R³is an optionally substituted group selected from a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfurA system; r⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is optionally substituted by R⁷Y times of occurrence of substituted C₁-C₆Aliphatic radical, or is selected from (i) - (X) as defined above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10-membered monocyclic or bicyclic heterocycle. In a particular embodiment, the ring is selected from (a) - (o) as described above.

In other embodiments, with respect to the compounds described directly above, R is³Is an optionally substituted 5-or 6-membered saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In other embodiments, R³Is an optionally substituted ring selected from phenyl, pyridyl, pyrimidinyl, thiazolyl,Oxazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl, orA diazolyl group. As generally described above, R³Optionally substituted with R⁶Z occurrences of substitution. In certain embodiments, wherein z is 0, 1, 2, or 3, and R⁶Independently for each occurrence of (a) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R″)₂、-CH₂N(R″)₂、-OR″、-CH₂OR″、-SR″、-CH₂SR″、-COOR″、-NR″COR″、-NR″COOR″、-CON(R″)₂、-SO₂N(R″)₂、-CONR″(CH₂)₂N(R″)₂、-CONR(CH₂)₃N(R″)₂、-CONR″(CH₂)₄N(R″)₂、-O(CH₂)₂OR″、O(CH₂)₃OR″、O(CH₂)₄OR″、-O(CH₂)₂N(R″)₂、-O(CH₂)₃N(R″)₂、-O(CH₂)₄N(R″)₂、-NR″CH(CH₂OH)R″、-NR″CH(CH₂CH₂OH)R″、-NR″(CH₂)R″、-NR″(CH₂)₂R″、-NR″(CH₂)₃R″、-NR″(CH₂)₄R″、-NR″(CH₂)N(R″)₂、-NR″(CH₂)₂N(R″)₂、-NR″(CH₂)₃N(R″)₂、-NR″(CH₂)₄N(R″)₂、-NR″(CH₂)OR″、-NR″(CH₂)₂OR″、-NR″(CH₂)₃OR ', OR-NR' (CH)₂)₄OR″。

Other specific subgroups of compounds of formula I include:

II, Compounds of formula I-C

Wherein R is¹、R²、R³、R⁴、R⁵And x are each in the general descriptions and subgroups above and described herein.

In certain embodiments, for compounds of formula I-C:

a.R¹the method comprises the following steps:

i.T-R', wherein T is a bond or optionally substituted C₁-C₆Alkylene chain in which up to two methylene units are optionally and independently replaced by-O-, -S-, -NR' -, -OCO-, -COO-, -SO₂-or-CO-substituted, and R' is hydrogen, C₁-C₄Alkyl, or optionally substituted 5-or 6-membered aryl or heteroaryl, or

ii.-S i(R′)₃Wherein R' is hydrogen, C₁-C₄An alkyl, or an optionally substituted 5-or 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

b.R²、R³and R⁴Each independently hydrogen, R', halogen, CN, NO₂、-N(R′)₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-COOR′、-NR′COR′、-CON(R′)₂、-SO₂N(R′)₂、-CONR′(CH₂)₂N(R′)₂、-CONR′(CH₂)₃N(R′)₂、-CONR′(CH₂)₄N(R′)₂、-O(CH₂)₂OR′、O(CH₂)₃OR′、O(CH₂)₄OR′、-O(CH₂)₂N(R′)₂、-O(CH₂)₃N(R′)₂or-O (CH)₂)₄N(R′)₂(ii) a Wherein R is²、R³And R⁴Each is optionally substituted by R⁶Wherein z is 0 to 5 and R⁶Is ═ O, ═ NR ", ═ S, halogen, -CN, -NO₂Or Z-R' wherein Z is a bond or optionally substituted C₁-C₆An alkylene chain wherein at most two methylene units of the chain are optionally and independently replaced by-NR' -, -S-, -O-, -CS-, -CO-₂-、-OCO-、-CO-、-COCO-、-CONR″-、-NR″CO-、-NR″CO₂-、-SO₂NR″-、-NR″SO₂-、-CONR″NR″-、-NR″CONR″-、-OCONR″-、-NR″NR″-、-NR″SO₂NR″-、-SO-、-SO₂-、-PO-、-PO₂-, or-POR "-and each occurrence of R" is independently hydrogen or optionally substituted C₁-C₆Aliphatic radical, 3-8-membered saturated, partially unsaturated, or fully unsaturated having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfurA monocyclic ring, 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 two occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

c.R⁵Independently for each occurrence of (A) is hydrogen, halogen, R', CN, -CH₂CN、-(CH₂)₂CN、NO₂、-CH₂NO₂、-(CH₂)₂NO₂、CON(R′)₂、-CH₂CON(R′)₂、-(CH₂)₂CON(R′)₂、COOR′、-CH₂COOR′、-(CH₂)₂COOR′、-SO₂N(R′)₂、-CH₂SO₂N(R′)₂、-(CH₂)₂SO₂N(R′)₂、-NR′SO₂R′、-CH₂NR′SO₂R′、-(CH₂)₂NR′SO₂R′、NR′CON(R′)₂、-CH₂NR′CON(R′)₂、-(CH₂)₂NR′CON(R′)₂、-NR′SO₂N(R′)₂、-CH₂NR′SO₂N(R′)₂、-(CH₂)₂NR′SO₂N(R′)₂、-COCOR′、-CH₂COCOR′、-(CH₂)₂COCOR′、-N(R′)₂、-CH₂N(R′)₂、-(CH₂)₂N(R′)₂、-OR′、-CH₂OR′、-(CH₂)₂OR′、-NR′COR′、-NR′COCH₂R′、-NR′CO(CH₂)₂R′、-CH₂NR 'COR', or- (CH)₂)₂NR 'COR', wherein R⁵Optionally substituted with R⁷Y occurrences of (a) wherein y is 0-5 and R⁷Is ═ O, ═ NR ", ═ S, halogen, -CN, -NO₂Or W-R', wherein W is a bond or optionally substituted C₁-C₆An alkylene chain, whereinThe chain being optionally and independently represented by-NR' -, -S-, -O-, -CS-, -CO₂-、-OCO-、-CO-、-COCO-、-CONR″-、-NR″CO-、-NR″CO₂-、-SO₂NR″-、-NR″SO₂-、-CONR″NR″-、-NR″CONR″-、-OCONR″-、-NR″NR″-、-NR″SO₂NR″-、-SO-、-SO₂-、-PO-、-PO₂-, or-POR "-and each occurrence of R" is independently hydrogen or optionally substituted C₁-C₆An aliphatic group, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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 two occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In still other embodiments, for compounds of formula I-C:

a.R¹is hydrogen, C₁-C₄Alkyl, -COR', -SO₂R 'or-S i (R')₃；

b.R²、R³And R⁴Independently of one another Cl, Br, F, -CN, -COOH,

-COOMe，-NH₂，-N(CH₃)₂，-N(Et)₂，-N(iPr)₂，-O(CH₂)₂OCH₃，-

CONH₂，-COOCH₃，-OH，-CH₂OH，-NHCOCH₃，-SO₂NH₂，-

-SO₂N(Me)₂Or an optionally substituted group selected from: c₁-C₄Alkyl radical, C₁-C₄An alkyl fluoro group, a 3-8-membered saturated moiety having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfurA partially unsaturated, or fully unsaturated monocyclic ring, 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;

wherein R is²、R³And R⁴Each is optionally substituted by R⁶Wherein z is 0, 1, 2 or 3, and R⁶Independently for each occurrence of (a) is hydrogen. CN, NO₂，-N(R”)₂，-

CH₂N(R”)₂，-OR”，-CH₂OR”，-SR”，-CH₂SR”，-COOR”，-NR”COR”，-

NR”COOR”，-CON(R”)₂，-SO₂N(R”)₂，-CONR”(CH₂)₂N(R”)₂，-

CONR(CH₂)₃N(R”)₂，CONR”(CH₂)₄N(R”)₂，-O(CH₂)₂OR”，

O(CH₂)₃OR”，O(CH₂)₄OR”，-O(CH₂)₂N(R”)₂，-O(CH₂)₃N(R”)₂，-

O(CH₂)₄N(R”)₂，-NR”CH(CH₂OH)R”，-NR”CH(CH₂CH₂OH)R”，-

NR”(CH₂)R”，-NR”(CH₂)₂R”，-NR”(CH₂)₃R”，-NR”(CH₂)₄R”，-

NR”(CH₂)N(R”)₂，-NR”(CH₂)₂N(R”)₂，NR”(CH₂)₃N(R”)₂，-

NR”(CH₂)₄N(R”)₂，-NR”(CH₂)OR”，-NR”(CH₂)₂OR”，-

NR”(CH₂)₃OR”，or-NOR’(CH₂)₄OR”；

A 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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;

wherein R is⁵Optionally substituted with R⁷Wherein y is 0, 1, 2 or 3, and R⁷Independently for each occurrence of (A) is hydrogen, R', CH₂R', halogen,

CN，NO₂，-N(R”)₂，-CH₂N(R”)₂，-OR”，-CH₂OR”，-

SR”，-CH₂SR”，-COOR”，-NR”COR”，-NR”COOR”，-CON(R”)₂，-

SO₂N(R”)₂，-CONR”(CH₂)₂N(R”)₂，-CONR(CH₂)₃N(R”)₂，-

CONR”(CH₂)₄N(R”)₂，-O(CH₂)₂OR”，O(CH₂)₃OR”，O(CH₂)₄OR”，-

O(CH₂)₂N(R”)₂，-O(CH₂)₃N(R”)₂，-O(CH₂)₄N(R”)₂，-

NR”CH(CH₂OH)R”，-NR”CH(CH₂CH₂OH)R”，-NR”(CH₂)R”，-

NR”(CH₂)₂R”，-NR”(CH₂)₃R”，-NR”(CH₂)₄R”，-NR”(CH₂)N(R”)₂，-

NR”(CH₂)₂N(R”)₂，-NR”(CH₂)₃N(R”)₂，-NR”(CH₂)₄N(R”)₂，-

NR”(CH₂)OR”，-NR”(CH₂)₂OR”，-NR”(CH₂)₃OR”，or-

NR”(CH₂)₄OR”.

In other embodiments, for compounds of formulas I-C and the subgroups described directly above, R¹Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, p-toluenesulfonyl (Ts), tert-butyldimethylsilyl (TBS), Triisopropylsilyl (TIPS), or Triethylsilyl (TES).

In other embodiments, for compounds of formulas I-C and the subgroups described directly above, R²、R³And R⁴Each is hydrogen. In other embodiments, R²、R³Or R⁴Is hydrogen. In other embodiments, R²、R³Or R⁴Two of which are hydrogen. In other embodiments, R²And R⁴Are all hydrogen, and R³Is halogen, CN, NO₂Or V-R'. In other embodiments, R²And R⁴Are all hydrogen, and R³Is an optionally substituted group selected from a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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. In other embodiments, R²And R⁴Are all hydrogen, and R³Is an optionally substituted 5-or 6-membered saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In other embodiments, R²And R⁴Are all hydrogen, and R³Is an optionally substituted ring selected from phenyl, pyridyl, pyrimidinyl, thiazolyl,Oxazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl, orA diazolyl group.

In other embodiments, for compounds of formulas I-C and the subgroups described directly above, R²、R³And R⁴Each independently and optionally substituted with R⁶Wherein z is 1, 2, or 3 and R⁶Each occurrence of (A) is independently F, Cl, Br, CN, OH, NH₂、-CH₂OH、C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -CH₂O(Cl-C₆Alkyl), -CO (Cl-C)₆Alkyl), -COO (C)₁-C₆Alkyl), -NHSO₂(C₁-C₆Alkyl), -SO₂NH₂、-CONH₂、-CON(C₁-C₆Alkyl), -SO₂(C₁-C₆Alkyl), -SO₂Phenyl, benzyl, -N (C)₁-C₆Alkyl radical)₂or-S (C)₁-C₆Alkyl) wherein the foregoing phenyl, benzyl, and C₁-C₆Each alkyl is independently and optionally substituted, and wherein C is as previously described₁-C₆Each alkyl group is straight, branched, or cyclic.

In certain examples, for compounds of formulas I-C and the sub-groups of compounds described directly above, X is 1, 2 or 3, and at least one occurrence of R⁵Is halogen

CN，-CH₂CN，-(CH₂)₂CN，NO₂，-CH₂NO₂，-(CH₂)₂NO₂，-CONH₂，-CON(C₁-C₄Alkyl), -SO₂NH₂，-SO₂N(C₁-C₄Alkyl), NH₂，-N(C₁-C₄Alkyl), -OH, -O (C)₁-C₄Alkyl), -CH —₂OH，-CH₂O(C₁-C₄An alkyl group),

or having 0-3 heteroatom 5-or 6-membered unsaturated rings selected from oxygen, sulfur or nitrogen, in other embodiments X is 1, 2 or 3, and at least one occurrence of R⁵is-OR¹。

In other embodiments, for compounds of formulas I-C and the subgroups described directly above, R⁵Optionally substituted with R⁷Wherein y is 1, 2, or 3 and R⁷Each occurrence of (A) is independently F, Cl, Br, CN, OH, NH₂、-CH₂OH、C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -CH₂O(C₁-C₆Alkyl), -CO (C)₁-C₆Alkyl), -COO (C)₁-C₆Alkyl), -NHSO₂(C₁-C₆Alkyl), -SO₂NH₂、-CONH₂-、-CON(C₁-C₆Alkyl), -SO₂(C₁-C₆Alkyl), -SO₂Phenyl, benzyl, -N (C)₁-C₆Alkyl radical)₂or-S (C)₁-C₆Alkyl) wherein the foregoing phenyl, benzyl and C₁-C₆Alkyl is independently and optionally substituted, and C is₁-C₆Each alkyl group is straight, branched, or cyclic.

In other embodiments, x is 1 and the compound has the general formula I-C-I:

wherein R is¹、R²、R³And R⁴In general termsIn the description and subgroups above and described herein, and R⁵Is halogen, R', CN, -CH₂CN、-(CH₂)₂CN、NO₂、-CH₂NO₂、-(CH₂)₂NO₂、CON(R′)₂、-CH₂CON(R′)₂、-(CH₂)₂CON(R′)₂、COOR′、-CH₂COOR′、-(CH₂)₂COOR′、-SO₂N(R′)₂、-CH₂SO₂N(R′)₂、-(CH₂)₂SO₂N(R′)₂、-NR′SO₂R′、-CH₂NR′SO₂R′、-(CH₂)₂NR′SO₂R′、NR′CON(R′)₂、-CH₂NR′CON(R′)₂、-(CH₂)₂NR′CON(R′)₂、-NR′SO₂N(R′)₂、-CH₂NR′SO₂N(R′)₂、-(CH₂)₂NR′SO₂N(R′)₂、-COCOR′、-CH₂COCOR′、-(CH₂)₂COCOR′、-N(R′)₂、-CH₂N(R′)₂、-(CH₂)₂N(R′)₂、-OR′、-CH₂O R′、-(CH₂)₂OR′、-NR′COR′、-CH₂NR 'COR', or- (CH)₂)₂NR ' COR ' and R ' is C₁-C₆An aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 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 two occurrences of R 'taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each occurrence of R' is optionally substituted with R⁷Y occurrences of substitution. In certain embodiments, R⁵Is CN, -CH₂CN、-(CH₂)₂CN、-NO₂、-CH₂NO₂、-(CH₂)₂NO₂、O R′、-CH₂OR′、-CON(R′)₂、-SO₂N(R′)₂、-N(R′)₂Or R'. In a particular embodiment, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₆Alkyl, or a saturated, partially unsaturated, or fully unsaturated 5-to 10-membered monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is optionally substituted with R⁷1-3 occurrences of substitution. In other embodiments, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₄Alkyl, or is selected from (i) - (X) as described above¹vi) or (X)¹vii) ring.

In other embodiments, x is 1 and the compound has the general formula I-C-ii:

wherein R is¹、R²、R³And R⁴In the general description and subgroups above and described herein, and R⁵Is halogen, R', CN, -CH₂CN、-(CH₂)₂CN、NO₂、-CH₂NO₂、-(CH₂)₂NO₂、CON(R′)₂、-CH₂CON(R′)₂、-(CH₂)₂CON(R′)₂、COOR′、-CH₂COOR′、-(CH₂)₂COOR′、-SO₂N(R′)₂、-CH₂SO₂N(R′)₂、-(CH₂)₂SO₂N(R′)₂、-NR′SO₂R′、-CH₂NR′SO₂R′、-(CH₂)₂NR′SO₂R′、NR′CON(R′)₂、-CH₂NR′CON(R′)₂、-(CH₂)₂NR′CON(R′)₂、-NR′SO₂N(R′)₂、-CH₂NR′SO₂N(R′)₂、-(CH₂)₂NR′SO₂N(R′)₂、-COCOR′、-CH₂COCOR′、-(CH₂)₂COCOR′、-N(R′)₂、-CH₂N(R′)₂、-(CH₂)₂N(R′)₂、-OR′、-CH₂OR′、-(CH₂)₂OR′、-NR′COR′、-CH₂NR 'COR', or- (CH)₂)₂NR ' COR ' and R ' is C₁-C₆An aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 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 two occurrences of R 'taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having O-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each occurrence of R' is optionally substituted with R⁷Y occurrences of substitution. In certain embodiments, R⁵Is CN, -CH₂CN、-(CH₂)₂CN、-NO₂、-CH₂NO₂、-(CH₂)₂NO₂、OR′、-CH₂OR′、-CON(R′)₂、-SO₂N(R′)₂、-N(R′)₂Or R'. In a particular embodiment, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₆Alkyl, or a saturated, partially unsaturated, or fully unsaturated 5-to 10-membered monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is optionally substituted with R⁷1-3 occurrences of substitution. In other embodiments, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₄Alkyl, or is selected from (i) - (X) as described above¹vi) or (X)¹vii) ring.

In other embodiments, R⁵Independently for each occurrence of is CN, -CH₂CN、-(CH₂)₂CN、-NO₂、-CH₂NO₂、-(CH₂)₂NO₂、OR′、-CH₂OR′、-CON(R′)₂、-SO₂N(R′)₂、-N(R′)₂Or R'. In other embodiments, R⁵Independently for each occurrence of (a) is hydrogen, halogen, CN, -CH₂CN、-(CH₂)₂CN、NO₂、-CH₂NO₂、-(CH₂)₂NO₂、-CONH₂、-CON(C₁-C₄Alkyl), -SO₂NH₂、-SO₂N(C₁-C₄Alkyl), NH₂、-N(C₁-C₄Alkyl), -OH, -O (C)₁-C₄Alkyl), -CH₂OH、-CH₂O(C₁-C₄Alkyl), or an optionally substituted 5-or 6-membered unsaturated ring wherein 0 to 3 ring carbon atoms are optionally substituted with oxygen, sulfur, or nitrogen, wherein R⁵Optionally substituted with R⁷From 0 to 3 occurrences of substitution.

In other embodiments, x is 2 and the compound has the general formula I-C-iii:

wherein R is¹、R²、R³And R⁴In the general description and subgroups above and described herein, and R⁵Each occurrence of (A) is independently halogen, R', CN, -CH₂CN、-(CH₂)₂CN、NO₂、-CH₂NO₂、-(CH₂)₂NO₂、CON(R′)₂、-CH₂CON(R′)₂、-(CH₂)₂CON(R′)₂、COOR′、-CH₂COOR′、-(CH₂)₂COOR′、-SO₂N(R′)₂、-CH₂SO₂N(R′)₂、-(CH₂)₂SO₂N(R′)₂、-NR′SO₂R′、-CH₂NR′SO₂R′、-(CH₂)₂NR′SO₂R′、NR′CON(R′)₂、-CH₂NR′CON(R′)₂、-(CH₂)₂NR′CON(R′)₂、-NR′SO₂N(R′)₂、-CH₂NR′SO₂N(R′)₂、-(CH₂)₂NR′SO₂N(R′)₂、-COCOR′、-CH₂COCOR′、-(CH₂)₂COCOR′、-N(R′)₂、-CH₂N(R′)₂、-(CH₂)₂N(R′)₂、-OR′、-CH₂OR′、-(CH₂)₂OR′、-NR′COR′、-CH₂NR 'COR', or- (CH)₂)₂NR ' COR ' and R ' is C₁-C₆An aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 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 two occurrences of R 'taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each occurrence of R' is optionally substituted with R⁷Y occurrences of substitution. In certain embodiments, R⁵Is CN, -CH₂CN、-(CH₂)₂CN、-NO₂、-CH₂NO₂、-(CH₂)₂NO₂、OR′、-CH₂OR′、-CON(R′)₂、-SO₂N(R′)₂、-N(R′)₂Or R'. In a particular embodiment, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₆Alkyl, or a saturated, partially unsaturated, or fully unsaturated 5-to 10-membered monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is optionally substituted with R⁷1-3 occurrences of substitution. In other embodiments, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₄Alkyl, or is selected from (i) - (X) as described above¹vi) or (X)¹vii) ring.

In other embodiments, R⁵Independently for each occurrence of is CN, -CH₂CN、-(CH₂)₂CN、-NO₂、-CH₂NO₂、-(CH₂)₂NO₂、OR′、-CH₂OR′、-CON(R′)₂、-SO₂N(R′)₂、-N(R′)₂Or R'. In other embodiments, R⁵Independently for each occurrence of (a) is hydrogen, halogen, CN, -CH₂CN、-(CH₂)₂CN、NO₂、-CH₂NO₂、-(CH₂)₂NO₂、-CONH₂、-CON(C₁-C₄Alkyl), -SO₂NH₂、-SO₂N(C₁-C₄Alkyl), NH₂、-N(C₁-C₄Alkyl), -OH, -O (C)₁-C₄Alkyl), -CH₂OH、-CH₂O(C₁-C₄Alkyl), or an optionally substituted 5-or 6-membered unsaturated ring wherein 0 to 3 ring carbon atoms are optionally substituted with oxygen, sulfur, or nitrogen, wherein R⁵Optionally substituted with R⁷From 0 to 3 occurrences of substitution.

In other embodiments, R¹、R²、R³And R⁴Each is hydrogen, x is 2, and provides compounds of formula I-C-iv:

wherein R is⁵Is halogen, R', CN, -CH₂CN、-(CH₂)₂CN、NO₂、-CH₂NO₂、-(CH₂)₂NO₂、CON(R′)₂、-CH₂CON(R′)₂、-(CH₂)₂CON(R′)₂、COOR′、-CH₂COOR′、-(CH₂)₂COOR′、-SO₂N(R′)₂、-CH₂SO₂N(R′)₂、-(CH₂)₂SO₂N(R′)₂、-NR′SO₂R′、-CH₂NR′SO₂R′、-(CH₂)₂NR′SO₂R′、NR′CON(R′)₂、-CH₂NR′CON(R′)₂、-(CH₂)₂NR′CON(R′)₂、-NR′SO₂N(R′)₂、-CH₂NR′SO₂N(R′)₂、-(CH₂)₂NR′SO₂N(R′)₂、-COCOR′、-CH₂COCOR′、-(CH₂)₂COCOR′、-N(R′)₂、-CH₂N(R′)₂、-(CH₂)₂N(R′)₂、-OR′、-CH₂OR′、-(CH₂)₂OR′、-NR′COR′、-CH₂NR 'COR', or- (CH)₂)₂NR ' COR ' and R ' is C₁-C₆An aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 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 two occurrences of R 'taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each occurrence of R' is optionally substituted with R⁷Y occurrences of substitution. In certain embodiments, R⁵Is CN, -CH₂CN、-(CH₂)₂CN、-NO₂、-CH₂NO₂、-(CH₂)₂NO₂、OR′、-CH₂OR′、-CON(R′)₂、-SO₂N(R′)₂、-N(R′)₂Or R'. In a particular embodiment, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₆Alkyl or having a radical0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, saturated, partially unsaturated, or fully unsaturated 5-to 10-membered monocyclic or bicyclic ring, wherein said ring is optionally substituted with R⁷1-3 occurrences of substitution. In other embodiments, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₄Alkyl, or is selected from (i) - (X) as described above¹vi) or (X)¹v ii) ring.

In other embodiments, R⁵Independently for each occurrence of is CN, -CH₂CN、-(CH₂)₂CN、-NO₂、-CH₂NO₂、-(CH₂)₂NO₂、OR′、-CH₂OR′、-CON(R′)₂、-SO₂N(R′)₂、-N(R′)₂Or R'. In other embodiments, R⁵Independently for each occurrence of (a) is hydrogen, halogen, CN, -CH₂CN、-(CH₂)₂CN、NO₂、-CH₂NO₂、-(CH₂)₂NO₂、-CONH₂、-CON(C₁-C₄Alkyl), -SO₂NH₂、-SO₂N(C₁-C₄Alkyl), NH₂、-N(C₁-C₄Alkyl), -OH, -O (C)₁-C₄Alkyl), -CH₂OH、-CH₂O(C₁-C₄Alkyl), or an optionally substituted 5-or 6-membered unsaturated ring wherein 0 to 3 ring carbon atoms are optionally substituted with oxygen, sulfur, or nitrogen, wherein R⁵Optionally substituted with R⁷From 0 to 3 occurrences of substitution.

In other embodiments, R¹、R²、R³And R⁴Each is hydrogen, x is 1, and provides compounds of formula I-C-v:

wherein R is⁵Is halogen, R', CN, -CH₂CN、-(CH₂)₂CN、NO₂、-CH₂NO₂、-(CH₂)₂NO₂、CON(R′)₂、-CH₂CON(R′)₂、-(CH₂)₂CON(R′)₂、COOR′、-CH₂COOR′、-(CH₂)₂COOR′、-SO₂N(R′)₂、-CH₂SO₂N(R′)₂、-(CH₂)₂SO₂N(R′)₂、-NR′SO₂R′、-CH₂NR′SO₂R′、-(CH₂)₂NR′SO₂R′、NR′CON(R′)₂、-CH₂NR′CON(R′)₂、-(CH₂)₂NR′CON(R′)₂、-NR′SO₂N(R′)₂、-CH₂NR′SO₂N(R′)₂、-(CH₂)₂NR′SO₂N(R′)₂、-COCOR′、-CH₂COCOR′、-(CH₂)₂COCOR′、-N(R′)₂、-CH₂N(R′)₂、-(CH₂)₂N(R′)₂、-OR′、-CH₂OR′、-(CH₂)₂OR′、-NR′COR′、-CH₂NR 'COR', or- (CH)₂)₂NR ' COR ' and R ' is C₁-C₆An aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 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 two occurrences of R 'taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each occurrence of R' is optionally substituted with R⁷Y occurrences of substitution. In certain embodiments, R⁵Is CN, -CH₂CN、-(CH₂)₂CN、-NO₂、-CH₂NO₂、-(CH₂)₂NO₂、OR′、-CH₂OR′、-CON(R′)₂、-SO₂N(R′)₂、-N(R′)₂Or R'. In a particular embodiment, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₆Alkyl, or a saturated, partially unsaturated, or fully unsaturated 5-to 10-membered monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is optionally substituted with R⁷1-3 occurrences of substitution. In other embodiments, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₄Alkyl, or is selected from (i) - (X) as described above¹vi) or (X)¹vii) ring.

In other embodiments, R⁵Independently for each occurrence of is CN, -CH₂CN、-(CH₂)₂CN、-NO₂、-CH₂NO₂、-(CH₂)₂NO₂、OR′、-CH₂OR′、-CON(R′)₂、-SO₂N(R′)₂、-N(R′)₂Or R'. In other embodiments, R⁵Independently for each occurrence of (a) is hydrogen, halogen, CN, -CH₂CN、-(CH₂)₂CN、NO₂、-CH₂NO₂、-(CH₂)₂NO₂、-CONH₂、-CON(C₁-C₄Alkyl), -SO₂NH₂、-SO₂N(C₁-C₄Alkyl), NH₂、-N(C₁-C₄Alkyl), -OH, -O (C)₁-C₄Alkyl), -CH₂OH、-CH₂O(C₁-C₄Alkyl), or an optionally substituted 5-or 6-membered unsaturated ring wherein 0 to 3 ring carbon atoms are optionally substituted with oxygen, sulfur, or nitrogen, wherein R⁵Optionally substituted with R⁷From 0 to 3 occurrences of substitution.

In other embodiments, R¹、R²、R³And R⁴Each is hydrogen, x is 2, and provides compounds of formula I-C-vi:

wherein R is⁵Each occurrence of (A) is independently halogen, R', CN, -CH₂CN、-(CH₂)₂CN、NO₂、-CH₂NO₂、-(CH₂)₂NO₂、CON(R′)₂、-CH₂CON(R′)₂、-(CH₂)₂CON(R′)₂、COOR′、-CH₂COOR′、-(CH₂)₂COOR′、-SO₂N(R′)₂、-CH₂SO₂N(R′)₂、-(CH₂)₂SO₂N(R′)₂、-NR′SO₂R′、-CH₂NR′SO₂R′、-(CH₂)₂NR′SO₂R′、NR′CON(R′)₂、-CH₂NR′CON(R′)₂、-(CH₂)₂NR′CON(R′)₂、-NR′SO₂N(R′)₂、-CH₂NR′SO₂N(R′)₂、-(CH₂)₂NR′SO₂N(R′)₂、-COCOR′、-CH₂COCOR′、-(CH₂)₂COCOR′、-N(R′)₂、-CH₂N(R′)₂、-(CH₂)₂N(R′)₂、-OR′、-CH₂OR′、-(CH₂)₂OR′、-NR′COR′、-CH₂NR 'COR', or- (CH)₂)₂NR ' COR ' and R ' is C₁-C₆An aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 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 two occurrences of R 'taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each occurrence of R' is optionally substituted with R⁷Y occurrences of substitution. In certain embodiments, R⁵Is CN, -CH₂CN、-(CH₂)₂CN、-NO₂、-CH₂NO₂、-(CH₂)₂NO₂、OR′、-CH₂OR′、-CON(R′)₂、-SO₂N(R′)₂、-N(R′)₂Or R'. In a particular embodiment, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₆Alkyl, or is a saturated, partially unsaturated, or fully unsaturated 5-1O-membered monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is optionally substituted with R⁷1-3 occurrences of substitution. In other embodiments, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₄Alkyl, or is selected from (i) - (X) as described above¹vi) or (X)¹vii) ring.

In other embodiments, R⁵Independently for each occurrence of is CN, -CH₂CN、-(CH₂)₂CN、-NO₂、-CH₂NO₂、-(CH₂)₂NO₂、OR′、-CH₂OR′、-CON(R′)₂、-SO₂N(R′)₂、-N(R′)₂Or R'. In other embodiments, R⁵Independently for each occurrence of (a) is hydrogen, halogen, CN, -CH₂CN、-(CH₂)₂CN、NO₂、-CH₂NO₂、-(CH₂)₂NO₂、-CONH₂、-CON(C₁-C₄Alkyl), -SO₂NH₂、-SO₂N(C₁-C₄Alkyl), NH₂、-N(C₁-C₄Alkyl), -OH, -O (C)₁-C₄Alkyl), -CH₂OH、-CH₂O(C₁-C₄Alkyl), or an optionally substituted 5-or 6-membered unsaturated ring wherein 0 to 3 ring carbon atoms are optionally substituted with oxygen, sulfur, or nitrogen, wherein R⁵Optionally substituted with R⁷From 0 to 3 occurrences of substitution.

Representative ions of compounds of formula I are set forth in table 1 below:

TABLE 1 examples of Compounds of formula I

Other specific subgroups of compounds of formula I include:

compounds of formula I-B

Wherein R is¹、R²、R³、R⁴、R⁵And x are each in the general descriptions and subgroups above and described herein.

In certain embodiments, for compounds of formula I-B:

a.R¹the method comprises the following steps:

i.T-R', wherein T is a bond or optionally substituted C₁-C₆Alkylene chain in which up to two methylene units are optionally and independently replaced by-O-, -S-, -NR' -, -OCO-, -COO-, -SO₂-or-CO-substituted, and R' is hydrogen, C₁-C₄Alkyl, or optionally substituted 5-or 6-membered aryl or heteroaryl, or

ii.-Si(R′)₃Wherein R' is hydrogen, C₁-C₄An alkyl, or an optionally substituted 5-or 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

b.R²、R³and R⁴Each independently hydrogen, R', halogen, CN, NO₂、-N(R′)₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-COOR′、-NR′COR′、-NR′C(O)OR′、-NR′COCH₂R′、-NR′CO(CH₂)₂R′、-CON(R′)₂、-SO₂N(R′)₂、-CONR′(CH₂)₂N(R′)₂、-CONR′(CH₂)₃N(R′)₂、-CONR′(CH₂)₄N(R′)₂、-O(CH₂)₂OR′、O(CH₂)₃OR′、O(CH₂)₄OR′、-O(CH₂)₂N(R′)₂、-O(CH₂)₃N(R′)₂or-O (CH)₂)₄N(R′)₂(ii) a Wherein R is²、R³And R⁴Each is optionally substituted by R⁶Wherein z is 0 to 5 and R⁶Is ═ O, ═ NR ", ═ S, halogen, -CN, -NO₂Or Z-R' wherein Z is a bond or optionally substituted C₁-C₆An alkylene chain wherein at most two methylene units of the chain are optionally and independently replaced by-NR' -, -S-, -O-, -CS-, -CO-₂-、-OCO-、-CO-、-COCO-、-CONR″-、-NR″CO-、-NR″CO₂-、-SO₂NR″-、-NR″SO₂-、-CONR″NR″-、-NR″CONR″-、-OCONR″-、-NR″NR″-、-NR″SO₂NR″-、-SO-、-SO₂-、-PO-、-PO₂-, or-POR "-and each occurrence of R" is independently hydrogen or optionally substituted C₁-C₆An aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having O-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 two occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

c.R⁵Independently for each occurrence of (A) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R′)₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-COOR′、-NR′COR′、-NR′COCH₂R′、-NR′CO(CH₂)₂R′、-NR′COOR′、-CON(R′)₂、-SO₂N(R′)₂、-CONR′(CH₂)₂N(R′)₂、-CONR(CH₂)₃N(R′)₂、-CONR′(CH₂)₄N(R′)₂、-O(CH₂)₂OR′、O(CH₂)₃OR′、O(CH₂)₄OR′、-O(CH₂)₂N(R′)₂、-O(CH₂)₃N(R′)₂、-O(CH₂)₄N(R′)₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′CH₂(CH₃)R′、-NR′(CH₂)₂R′、-NR′(CH₂)₃R′、-NR′(CH₂)₄R′、-NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-NR′(CH₂)₃N(R′)₂、-NR′(CH₂)₄N(R′)₂、-NR′(CH₂)OR′、-NR′(CH₂)₂OR′、-NR′(CH₂)₃OR ', OR-NR' (CH)₂)₄OR', wherein R⁵Optionally substituted with R⁷Y occurrences of (a) wherein y is 0-5 and R⁷Is ═ O, ═ NR ", ═ S, halogen, -CN, -NO₂Or W-R', wherein W is a bond or optionally substituted C₁-C₆An alkylene chain wherein at most two methylene units of the chain are optionally and independently replaced by-NR' -, -S-, -O-, -CS-, -CO-₂-、-OCO-、-CO-、-COCO-、-CONR″-、-NR″CO-、-NR″CO₂-、-SO₂NR″-、-NR″SO₂-、-CONR″NR″-、-NR″CONR″-、-OCONR″-、-NR″NR″-、-NR″SO₂NR″-、-SO-、-SO₂-、-PO-、-PO₂-, or-POR "-and each occurrence of R" is independently hydrogen or optionally substituted C₁-C₆An aliphatic group, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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 two occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In other embodiments, for compounds of formula I-B:

a.R¹is hydrogen, C₁-C₄Alkyl, -COR', -SO₂R ', or-S i (R')₃；

b.R²And R⁴Each independently of the others is Cl, Br, F, -CN, -COOH, -COOMe, -NH₂、-N(CH₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COOCH₃、-OH、-CH₂OH、-NHCOCH₃、-SO₂NH₂、-SO₂N(Me)₂Or an optionally substituted group selected from C₁-C₄Alkyl radical, C₁-C₄Alkoxy, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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; wherein R is²And R⁴Each independently and optionally substituted with R⁶Wherein z is 0, 1, 2, or 3, and R⁶Independently for each occurrence of (a) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R″)₂、-CH₂N(R″)₂、-OR″、-CH₂OR″、-SR″、-CH₂SR″、-COOR″、-NR″COR″、-NR″COOR″、-CON(R″)₂、-SO₂N(R″)₂、-CONR″(CH₂)₂N(R″)₂、-CONR(CH₂)₃N(R″)₂、-CONR″(CH₂)₄N(R″)₂、-O(CH₂)₂OR″、O(CH₂)₃OR″、O(CH₂)₄OR″、-O(CH₂)₂N(R″)₂、-O(CH₂)₃N(R″)₂、-O(CH₂)₄N(R″)₂、-NR″CH(CH₂OH)R″、-NR″CH(CH₂CH₂OH)R″、-NR″(CH₂)R″、-NR″(CH₂)₂R″、-NR″(CH₂)₃R″、-NR″(CH₂)₄R″、-NR″(CH₂)N(R″)₂、-NR″(CH₂)₂N(R″)₂、-NR″(CH₂)₃N(R″)₂、-NR″(CH₂)₄N(R″)₂、-NR″(CH₂)OR″、-NR″(CH₂)₂OR″、-NR″(CH₂)₃OR ', OR-NR' (CH)₂)₄OR″；

c.R³Independently Cl, Br, F, -CN, -COOH, -COOMe, -NH₂、-N(CH₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-CO0CH₃、-OH、-CH₂OH、-NHCOCH₃、-SO₂NH₂、-SO₂N(Me)₂Or an optionally substituted group selected from C₁-C₄Alkyl radical, C₁-C₄An alkoxy group; wherein R is³Independently and optionally substituted with R⁶Wherein z is 0 or 1, and R⁶Independently for each occurrence of (a) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R″)₂、-CH₂N(R″)₂、-OR″、-CH₂OR″、-SR″、-CH₂SR″、-COOR″、-NR″COR″、-NR″COOR″、-CON(R″)₂、-SO₂N(R″)₂、-CONR″(CH₂)₂N(R″)₂、-CONR(CH₂)₃N(R″)₂、-CONR″(CH₂)₄N(R″)₂、-O(CH₂)₂OR″、O(CH₂)₃OR″、O(CH₂)₄OR″、-O(CH₂)₂N(R″)₂、-O(CH₂)₃N(R″)₂、-O(CH₂)₄N(R″)₂、-NR″CH(CH₂OH)R″、-NR″CH(CH₂CH₂OH)R″、-NR″(CH₂)R″、-NR″(CH₂)₂R″、-NR″(CH₂)₃R″、-NR″(CH₂)₄R″、-NR″(CH₂)N(R″)₂、-NR″(CH₂)₂N(R″)₂、-NR″(CH₂)₃N(R″)₂、-NR″(CH₂)₄N(R″)₂、-NR″(CH₂)OR″、-NR″(CH₂)₂OR″、-NR″(CH₂)₃OR ', OR-NR' (CH)₂)₄OR″；

d.R⁵Independently for each occurrence of (A) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R′)₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-COOR′、-NR′COR′、-NR′COCH₂R′、-NR′CO(CH₂)₂R′、-NR′COOR′、-CON(R′)₂、-SO₂N(R′)₂、-CONR′(CH₂)₂N(R′)₂、-CONR(CH₂)₃N(R′)₂、-CONR′(CH₂)₄N(R′)₂、-O(CH₂)₂OR′、O(CH₂)₃OR′、O(CH₂)₄OR′、-O(CH₂)₂N(R′)₂、-O(CH₂)₃N(R′)₂、-O(CH₂)₄N(R′)₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′CH₂(CH₃)R′、-NR′(CH₂)₂R′、-NR′(CH₂)₃R′、-NR′(CH₂)₄R′、-NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-NR′(CH₂)₃N(R′)₂、-NR′(CH₂)₄N(R′)₂、-NR′(CH₂)OR′、-NR′(CH₂)₂OR′、-NR′(CH₂)₃OR ', OR-NR' (CH)₂)₄OR', wherein R⁵Optionally substituted with R⁷Wherein y is 0, 1, 2, or 3, and R⁷Independently for each occurrence of (a) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R″)₂、-CH₂N(R″)₂、-OR″、-CH₂OR″、-SR″、-CH₂SR″、-COOR″、-NR″COR″、-NR″COOR″、-CON(R″)₂、-SO₂N(R″)₂、-CONR″(CH₂)₂N(R″)₂、-CONR(CH₂)₃N(R″)₂、-CONR″(CH₂)₄N(R″)₂、-O(CH₂)₂OR″、O(CH₂)₃OR″、O(CH₂)₄OR″、-O(CH₂)₂N(R″)₂、-O(CH₂)₃N(R″)₂、-O(CH₂)₄N(R″)₂、-NR″CH(CH₂OH)R″、-NR″CH(CH₂CH₂OH)R″、-NR″(CH₂)R″、-NR″(CH₂)₂R″、-NR″(CH₂)₃R″、-NR″(CH₂)₄R″、-NR″(CH₂)N(R″)₂、-NR″(CH₂)₂N(R″)₂、-NR″(CH₂)₃N(R″)₂、-NR″(CH₂)₄N(R″)₂、-NR″(CH₂)OR″、-NR″(CH₂)₂OR″、-NR″(CH₂)₃OR ', OR-NR' (CH)₂)₄OR″。

In other embodiments, for compounds of formula I-B and the subgroups described directly above, R¹Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, p-toluenesulfonyl (Ts), tert-butyldimethylsilyl (TBS), Triisopropylsilyl (TIPS), or Triethylsilyl (TES).

In other embodiments, for compounds of formula I-B and the subgroups described directly above, R²、R³And R⁴Each is hydrogen. In other embodiments, R²、R³Or R⁴Is hydrogen. In other embodiments, R²、R³Or R⁴Two of which are hydrogen. In other embodiments, R²And R⁴Are all hydrogen, and R³Is halogen, CN, NO₂Or V-R'. In other embodiments, R²And R⁴Are all hydrogen, and R³Is a halogen. In other embodiments, R²And R⁴Are all hydrogen, and R³Is Cl.

In other embodiments, of formula I-B and the subgroups described directly aboveIn the case of the compounds, R²、R³And R⁴Each independently and optionally substituted with R⁶Wherein z is 1, 2, or 3 and R⁶Each occurrence of (A) is independently F, Cl, Br, CN, OH, NH₂、-CH₂OH、C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -CH₂O(Cl-C₆Alkyl), -CO (C1-C)₆Alkyl), -COO (C)₁-C₆Alkyl), -NHSO₂(C₁-C₆Alkyl), -SO₂NH₂、-CONH₂、-CON(C₁-C₆Alkyl), -SO₂(C₁-C₆Alkyl), -SO₂Phenyl, benzyl, -N (C)₁-C₆Alkyl radical)₂or-S (C)₁-C₆Alkyl) wherein the foregoing phenyl, benzyl, and C₁-C₆Each alkyl is independently and optionally substituted, and wherein C is as previously described₁-C₆Each alkyl group is straight, branched, or cyclic, provided that R³Is not phenyl.

In certain exemplary embodiments, for compounds of formula I-B and the subgroups described directly above, x is 1, 2, or 3, and R is⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′CH₂(CH₃)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂or-NR' (CH)₂)₂N(R′)₂. In other embodiments, x is 1, 2, or 3, and R⁵is-OR' in at least one occurrence of (a). In other embodiments, x is 1, 2, or 3, and R⁵is-NR ' COR ', -NR ' COCH₂R ', or-NR' CO (CH)₂)₂R' is provided. In other embodiments, x is 1, 2, or 3, and R⁵Is at least one occurrence of optionally substituted C₁-C₆Aliphatic radical, 3-8 membered saturated, partially unsaturated, or fully unsaturated having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfurOr an 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, for compounds of formula I-B and the subgroups described directly above, R⁵Optionally substituted with R⁷Wherein y is 1, 2, or 3 and R⁷Each occurrence of (A) is independently F, Cl, Br, CN, OH, NH₂、-CH₂OH、C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -CH₂O(C₁-C₆Alkyl), -CO (C)₁-C₆Alkyl), -COO (C)₁-C₆Alkyl), -NHSO₂(C₁-C₆Alkyl), -SO₂NH₂、-CONH₂-、-CON(C₁-C₆Alkyl), -SO₂(C₁-C₆Alkyl), -SO₂Phenyl, benzyl, -N (C)₁-C₆Alkyl radical)₂、-S(C₁-C₆Alkyl) wherein the foregoing phenyl, benzyl and C₁-C₆Alkyl is independently and optionally substituted, and C is₁-C₆Each alkyl group is straight, branched, or cyclic.

In other embodiments, for compounds of formula I-B and the subgroups described directly above, x is 1, 2, or 3; r⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′CH₂(CH₃)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is C₁-C₆An aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-12 membered saturated monocyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfurAnd, partially unsaturated, or fully unsaturated bicyclic ring systems; or two occurrences of R 'taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each occurrence of R' is optionally substituted with R⁷Y occurrences of substitution. In a particular embodiment, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₆Alkyl, or a saturated, partially unsaturated, or fully unsaturated 5-to 10-membered monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is optionally substituted with R⁷1-3 occurrences of substitution. In other embodiments, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₄Alkyl, or is selected from (i) - (X) as described above¹vi) or (X)¹vi i) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10-membered monocyclic or bicyclic heterocycle. In certain embodiments, the ring is selected from (a) - (o) described above.

Wherein y and R⁷Described in the general description and subgroups above.

In other embodiments, x is 1 and the compound has the general formula I-B-I:

wherein R is¹、R²、R³And R⁴In the general description and subgroups above and described herein; r⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′CH₂(CH₃)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is C₁-C₆An aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 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 two occurrences of R 'taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each occurrence of R' is optionally substituted with R⁷Y occurrences of substitution. In certain embodiments, R⁵Is N (R')₂. In a particular embodiment, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₆Alkyl, or a saturated, partially unsaturated, or fully unsaturated 5-to 10-membered monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is optionally substituted with R⁷1-3 occurrences of substitution. In other embodiments, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₄Alkyl, or is selected from (i) - (X) as described above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10 membered monocyclic or bicyclic heterocycle. In certain embodiments, the ring is selected from (a) - (o) described above.

In other embodiments, x is 0-3 and the compound has the general formula I-B-ii:

wherein R is¹、R²、R³And R⁴In the general description and subgroups above and described herein; r⁵Each independently selected from halogen, optionally substituted C₁-C₆Alkyl, -SR', -CN, -COOH, -CO₂R′、-CON(R′)₂、-N(R′)₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′CH₂(CH₃)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is C₁-C₆An aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 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 two occurrences of R 'taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each occurrence of R' is optionally substituted with R⁷Y occurrences of substitution. In certain embodiments, R⁵Is N (R')₂. In a particular embodiment, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₆Alkyl, or a saturated, partially unsaturated, or fully unsaturated 5-to 10-membered monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is optionally substituted with R⁷1-3 occurrences of substitution. In other embodiments, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₄Alkyl, or is selected from (i) - (X) as described above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10 membered monocyclic or bicyclic heterocycle. In certain embodiments, the ring is selected from (a) - (o) described above.

In other embodiments, x is 1-4 and the compound has the general formula I-B-iii:

wherein:

R³is an optionally substituted radical selected from halogen, optionally substituted C_1-6Alkyl, CN, N (R')₂、CO₂R′、NR′COR′、CON(R′)₂、CH₂N(R′)₂、OR′、SR′、CH₂OR′；

x is 1, 2 or 3; and R is⁵At least one occurrence of (A) is selected from halogen, optionally substituted C₁-C₆Aliphatic radical, -SR', -CN, -COOH, -CO₂R′、-CON(R′)₂、-N(R′)₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′CH₂(CH₃)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is selected from hydrogen, optionally substituted by R⁷Y times of occurrence of substituted C₁-C₆Aliphatic radical, or is selected from (i) - (X) as defined above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10 membered monocyclic or bicyclic heterocycle. In certain embodiments, the ring is selected from (a) - (o) described above.

In other embodiments, R¹、R²And R⁴Each is hydrogen and x is 0 to 3, and provides compounds of formula I-B-iv:

wherein:

R³is an optionally substituted radical selected from halogen, optionally substituted C_1-6Aliphatic radical, CN, N (R')₂、CO₂R′、NR′COR′、CON(R′)₂、CH₂N(R′)₂、OR′、SR′、CH₂OR′；

R⁵Selected from halogen, optionally substituted C₁-C₆Aliphatic radical, -SR', -CN, -COOH, -CO₂R′、-CON(R′)₂、-N(R′)₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′CH₂(CH₃)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is selected from hydrogen, optionally substituted by R⁷Y times of occurrence of substituted C₁-C₆Aliphatic radical, or is selected from (i) - (X) as defined above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10 membered monocyclic or bicyclic heterocycle. In certain embodiments, the ring is selected from (a) - (o) described above.

In other embodiments, R¹、R²And R⁴Each is hydrogen and x is 2, and provides compounds of formula I-B-v:

wherein:

R³is an optionally substituted radical selected from halogen, optionally substituted C_1-6Aliphatic radical, CN, N (R')₂、CO₂R′、NR′COR′、CON(R′)₂、CH₂N(R′)₂、0R′、SR′、CH₂OR′；

R⁵Selected from halogen, optionally substituted C₁-C₆Aliphatic radical, -SR', -CN, -COOH, -CO₂R′、-CON(R′)₂、-N(R′)₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′CH(CH₃)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is selected from hydrogen, optionally substituted by R⁷Y times of occurrence of substituted C₁-C₆Aliphatic radical, or is selected from (i) - (X) as defined above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10 membered monocyclic or bicyclic heterocycle. In certain embodiments, the ring is selected from (a) - (o) described above.

In other embodiments, R¹、R²And R⁴Each is hydrogen and x is 2, and provides compounds of formula I-B-v I:

wherein:

R³is an optionally substituted radical selected from halogen, optionally substituted C_1-6Aliphatic radical, CN, N (R')₂、CO₂R′、NR′COR′、CON(R′)₂、CH₂N(R′)₂、OR′、SR′、CH₂OR′；

R⁵Selected from halogen, optionally substituted C₁-C₆Aliphatic radical, -SR', -CN, -COOH, -CO₂R′、-CON(R′)₂、-N(R′)₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′CH(CH₃)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is selected from hydrogen, optionally substituted by R⁷Y times of occurrence of substituted C₁-C₆Aliphatic radical, or is selected from (i) - (X) as defined above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10 membered monocyclic or bicyclic heterocycle. In certain embodiments, the ring is selected from (a) - (o) described above.

Other specific subgroups of compounds of formula I include:

a compound of formula I-E:

wherein R is¹、R²、R³、R⁴、R⁵And x are each in the general descriptions and subgroups above and described herein.

In certain embodiments, for compounds of formulae I-E:

a.R¹the method comprises the following steps:

i.T-R', wherein T is a bond or optionally substituted C₁-C₆Alkylene chain in which up to two methylene units are optionally and independently replaced by-O-, -S-, -NR' -, -OCO-, -COO-, -SO₂-or-CO-substituted, and R' is hydrogen, C₁-C₄Alkyl, or optionally substituted 5-or 6-membered aryl or heteroaryl, or

ii.-Si(R′)₃Wherein R' is hydrogen, C₁-C₄An alkyl, or an optionally substituted 5-or 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

b.R²、R³and R⁴Each independently hydrogen, R', halogen, CN, NO₂、-N(R′)₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-COOR′、-NR′COR′、-NR′C(O)OR′、-NR′COCH₂R′、-NR′CO(CH₂)₂R′、-CON(R′)₂、-SO₂N(R′)₂、-CONR′(CH₂)₂N(R′)₂、-CONR′(CH₂)₃N(R′)₂、-CONR′(CH₂)₄N(R′)₂、-O(CH₂)₂OR′、O(CH₂)₃OR′、O(CH₂)₄OR′、-O(CH₂)₂N(R′)₂、-O(CH₂)₃N(R′)₂or-O (CH)₂)₄N(R′)₂(ii) a Wherein R is²、R³And R⁴Each is optionally substituted by R⁶Wherein z is 0 to 5 and R⁶Is ═ O, ═ NR ", ═ S, halogen, -CN, -NO₂Or Z-R' wherein Z is a bond or optionally substituted C₁-C₆An alkylene chain wherein at most two methylene units of the chain are optionally and independently replaced by-NR' -, -S-, -O-, -CS-, -CO-₂-、-OCO-、-CO-、-COCO-、-CONR″-、-NR″CO-、-NR″CO₂-、-SO₂NR″-、-NR″SO₂-、-CONR″NR″-、-NR″CONR″-、-OCONR″-、-NR″NR″-、-NR″SO₂NR″-、-SO-、-SO₂-、-PO-、-PO₂-, or-POR "-and each occurrence of R" is independently hydrogen or optionally substituted C₁-C₆An aliphatic radical, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a monocyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfurAn 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system of a nitrogen, oxygen, or sulfur heteroatom; or two occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

c.R⁵Independently for each occurrence of (A) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R′)₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-COOR′、-NR′COR′、-NR′COCH₂R′、-NR′CO(CH₂)₂R′、-NR′COOR′、-CON(R′)₂、-SO₂N(R′)₂、-CONR′(CH₂)₂N(R′)₂、-CONR(CH₂)₃N(R′)₂、-CONR′(CH₂)₄N(R′)₂、-O(CH₂)₂OR′、O(CH₂)₃OR′、O(CH₂)₄OR′、-O(CH₂)₂N(R′)₂、-O(CH₂)₃N(R′)₂、-O(CH₂)₄N(R′)₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′CH₂(CH₃)R′、-NR′(CH₂)₂R′、-NR′(CH₂)₃R′、-NR′(CH₂)₄R′、-NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-NR′(CH₂)₃N(R′)₂、-NR′(CH₂)₄N(R′)₂、-NR′(CH₂)OR′、-NR′(CH₂)₂OR′、-NR′(CH₂)₃OR ', OR-NR' (CH)₂)₄OR', wherein R⁵Optionally substituted with R⁷Y occurrences of (a) wherein y is 0-5 and R⁷Is ═ O, ═ NR ", ═ S, halogen, -CN, -NO₂Or W-R', wherein W is a bond or optionallySubstituted C₁-C₆An alkylene chain, wherein the chain is optionally and independently represented by-NR ", -S-, -O-, -CS-, -CO₂-、-OCO-、-CO-、-COCO-、-CONR″-、-NR″CO-、-NR″CO₂-、-SO₂NR″-、-NR″SO₂-、-CONR″NR″-、-NR″CONR″-、-OCONR″-、-NR″NR″-、-NR″SO₂NR″-、-SO-、-SO₂-、-PO-、-PO₂-, or-POR "-and each occurrence of R" is independently hydrogen or optionally substituted C₁-C₆An aliphatic group, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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 two occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In other embodiments, for compounds of formulas I-E:

a.R¹is hydrogen, C₁-C₄Alkyl, -COR', -SO₂R ', or-Si (R')₃；

b.R²And R⁴Each independently of the others is Cl, Br, F, -CN, -COOH, -COOMe, -NH₂、-N(CH₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COOCH₃、-OH、-CH₂OH、-NHCOCH₃、-SO₂NH₂、-SO₂N(Me)₂Or an optionally substituted group selected from C₁-C₄Alkyl radical, C₁-C₄Alkoxy, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfurA saturated bicyclic ring system; wherein R is²、R³And R⁴Each independently and optionally substituted with R⁶Wherein z is 0, 1, 2, or 3, and R⁶Independently for each occurrence of (a) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R″)₂、-CH₂N(R″)₂、-OR″、-CH₂OR″、-SR″、-CH₂SR″、-COOR″、-NR″COR″、-NR″COOR″、-CON(R″)₂、-SO₂N(R″)₂、-CONR″(CH₂)₂N(R″)₂、-CONR(CH₂)₃N(R″)₂、-CONR″(CH₂)₄N(R″)₂、-O(CH₂)₂OR″、O(CH₂)₃OR″、O(CH₂)₄OR″、-O(CH₂)₂N(R″)₂、-O(CH₂)₃N(R″)₂、-O(CH₂)₄N(R″)₂、-NR″CH(CH₂OH)R″、-NR″CH(CH₂CH₂OH)R″、-NR″(CH₂)R″、-NR″(CH₂)₂R″、-NR″(CH₂)₃R″、-NR″(CH₂)₄R″、-NR″(CH₂)N(R″)₂、-NR″(CH₂)₂N(R″)₂、-NR″(CH₂)₃N(R″)₂、-NR″(CH₂)₄N(R″)₂、-NR″(CH₂)OR″、-NR″(CH₂)₂OR″、-NR″(CH₂)₃OR ', OR-NR' (CH)₂)₄OR″；

c.R³Independently Cl, Br, F, -CN, -COOH, -COOMe, -NH₂、-N(CH₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COOCH₃、-OH、-CH₂OH、-NHCOCH₃、-SO₂NH₂、-SO₂N(Me)₂Or an optionally substituted group selected from C₁-C₄Alkyl radical, C₁-C₄An alkoxy group; wherein R is³Independently and optionally substituted with R⁶Wherein z is 0, or 1, and R⁶Independently for each occurrence of (a) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R″)₂、-CH₂N(R″)₂、-OR″、-CH₂OR″、-SR″、-CH₂SR″、-COOR″、-NR″COR″、-NR″COOR″、-CON(R″)₂、-SO₂N(R″)₂、-CONR″(CH₂)₂N(R″)₂、-CONR(CH₂)₃N(R″)₂、-CONR″(CH₂)₄N(R″)₂、-O(CH₂)₂OR″、O(CH₂)₃OR″、O(CH₂)₄OR″、-O(CH₂)₂N(R″)₂、-O(CH₂)₃N(R″)₂、-O(CH₂)₄N(R″)₂、-NR″CH(CH₂OH)R″、-NR″CH(CH₂CH₂OH)R″、-NR″(CH₂)R″、-NR″(CH₂)₂R″、-NR″(CH₂)₃R″、-NR″(CH₂)₄R″、-NR″(CH₂)N(R″)₂、-NR″(CH₂)₂N(R″)₂、-NR″(CH₂)₃N(R″)₂、-NR″(CH₂)₄N(R″)₂、-NR″(CH₂)OR″、-NR″(CH₂)₂OR″、-NR″(CH₂)₃OR ', OR-NR' (CH)₂)₄OR″；

d.R⁵Independently for each occurrence of (A) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R′)₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-COOR′、-NR′COR′、-NR′COCH₂R′、-NR′CO(CH₂)₂R′、-NR′COOR′、-CON(R′)₂、-SO₂N(R′)₂、-CONR′(CH₂)₂N(R′)₂、-CONR(CH₂)₃N(R′)₂、-CONR′(CH₂)₄N(R′)₂、-O(CH₂)₂OR′、O(CH₂)₃OR′、O(CH₂)₄OR′、-O(CH₂)₂N(R′)₂、-O(CH₂)₃N(R′)₂、-O(CH₂)₄N(R′)₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′CH₂(CH₃)R′、-NR′(CH₂)₂R′、-NR′(CH₂)₃R′、-NR′(CH₂)₄R′、-NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-NR′(CH₂)₃N(R′)₂、-NR′(CH₂)₄N(R′)₂、-NR′(CH₂)OR′、-NR′(CH₂)₂OR′、-NR′(CH₂)₃OR ', OR-NR' (CH)₂)₄OR', wherein R⁵Optionally substituted with R⁷Wherein y is 0, 1, 2, or 3, and R⁷Independently for each occurrence of (a) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R″)₂、-CH₂N(R″)₂、-OR″、-CH₂OR″、-SR″、-CH₂SR″、-COOR″、-NR″COR″、-NR″COOR″、-CON(R″)₂、-SO₂N(R″)₂、-CONR″(CH₂)₂N(R″)₂、-CONR(CH₂)₃N(R″)₂、-CONR″(CH₂)₄N(R″)₂、-O(CH₂)₂OR″、-O(CH₂)₃OR″、-O(CH₂)₄OR″、-O(CH₂)₂N(R″)₂、-O(CH₂)₃N(R″)₂、-O(CH₂)₄N(R″)₂、-NR″CH(CH₂OH)R″、-NR″CH(CH₂CH₂OH)R″、-NR″(CH₂)R″、-NR″(CH₂)₂R″、-NR″(CH₂)₃R″、-NR″(CH₂)₄R″、-NR″(CH₂)N(R″)₂、-NR″(CH₂)₂N(R″)₂、-NR″(CH₂)₃N(R″)₂、-NR″(CH₂)₄N(R″)₂、-NR″(CH₂)OR″、-NR″(CH₂)₂OR″、-NR″(CH₂)₃OR ', OR-NR' (CH)₂)₄OR″。

In other embodiments, for compounds of formulas I-E and the subgroups described directly above, R¹Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, p-toluenesulfonyl (Ts), tert-butyldimethylsilyl (TBS), Triisopropylsilyl (TIPS), or Triethylsilyl (TES).

In other embodiments, for compounds of formulas I-E and the subgroups described directly above, R²、R³And R⁴Each is hydrogen. In other embodiments, R²、R³Or R⁴Is hydrogen. In other embodiments, R²、R³Or R⁴Two of which are hydrogen. In other embodiments, R²And R⁴Are all hydrogen, and R³Is halogen, CN, NO₂Or V-R'. In other embodiments, R²And R⁴Are all hydrogen, and R³Is a halogen. In other embodiments, R²And R⁴Are all hydrogen, and R³Is Cl.

In other embodiments, for compounds of formulas I-E and the subgroups described directly above, R²、R³And R⁴Each independently and optionally substituted with R⁶Wherein z is 1, 2, or 3 and R⁶Each occurrence of (A) is independently F, Cl, Br, CN, OH, NH₂、-CH₂OH、C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -CH₂O(C1-C₆Alkyl), -CO (C1-C)₆Alkyl), -COO (C)₁-C₆Alkyl), -NHSO₂(C₁-C₆Alkyl), -SO₂NH₂、-CONH₂、-CON(C₁-C₆Alkyl), -SO₂(C₁-C₆Alkyl), -SO₂Phenyl, benzyl, -N (C)₁-C₆Alkyl radical)₂or-S (C)₁-C₆Alkyl) wherein the foregoing phenyl, benzyl, and C₁-C₆Each alkyl is independently and optionally substituted, and wherein C is as previously described₁-C₆Each alkyl group is straight, branched, or cyclic.

In certain exemplary embodiments, for compounds of formulas I-E and the subgroups described directly above, x is 1, 2, or 3, and R is⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′CH(CH₃)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂or-NR' (CH)₂)₂N(R′)₂. In other embodiments, x is 1, 2, or 3, and R⁵is-OR' in at least one occurrence of (a). In other embodiments, x is 1, 2, or 3, and R⁵is-NR ' COR ', -NR ' COCH₂R ', or-NR' CO (CH)₂)₂R' is provided. In other embodiments, x is 1, 2, or 3, and R⁵Is at least one occurrence of optionally substituted C₁-C₆An aliphatic group, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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 O-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In other embodiments, for compounds of formulas I-E and the subgroups described directly above, R⁵Optionally substituted with R⁷Wherein y is 1, 2, or 3 and R⁷Each occurrence of (A) is independently F, Cl, Br, CN, OH, NH₂、-CH₂OH、C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -CH₂O(C₁-C₆Alkyl), -CO (C)₁-C₆Alkyl), -COO (C)₁-C₆Alkyl), -NHSO₂(C₁-C₆Alkyl), -SO₂NH₂、-CONH₂-、-CON(C₁-C₆Alkyl), -SO₂(C₁-C₆Alkyl), -SO₂Phenyl, benzyl, -N (C)₁-C₆Alkyl radical)₂or-S (C)₁-C₆Alkyl) wherein the foregoing phenyl, benzyl and C₁-C₆Alkyl is independently and optionally substituted, and C is₁-C₆Each alkyl group is straight, branched, or cyclic.

In other embodiments, for compounds of formulas I-E and the subgroups described directly above, x is 1, 2, or 3; r⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′CH(CH₃)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is C₁-C₆An aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 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 two occurrences of R 'taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each occurrence of R' is optionally substituted with R⁷Y occurrences of substitution. In a particular embodiment, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₆Alkyl, or a substituted or unsubstituted alkyl group having 0 to 4 substituents independently selected from nitrogen, oxygen, hydrogen, oxygen, or a substituted or unsubstituted alkoxy group,Or a 5-10 membered monocyclic or bicyclic ring saturated, partially unsaturated or fully unsaturated with a heteroatom of sulfur, wherein the ring is optionally substituted with R⁷1-3 occurrences of substitution. In other embodiments, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₄Alkyl, or is selected from (i) - (X) as described above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10 membered monocyclic or bicyclic heterocycle. In certain embodiments, the ring is selected from (a) - (o) described above.

Wherein y and R⁷Described in the general description and subgroups above.

In other embodiments, x is 1 and the compound has the general formula I-E-I:

wherein R is¹、R²、R³And R⁴In the general description and subgroups above and described herein; r⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′CH₂(CH₃)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is C₁-C₆An aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 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 two occurrences of R' taken together with the atoms to which they are bound form a ring having 0-4 of independentAn optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring of heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each occurrence of R' is optionally substituted with R⁷Y occurrences of substitution. In certain embodiments, R⁵Is N (R')₂. In a particular embodiment, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₆Alkyl, or a saturated, partially unsaturated, or fully unsaturated 5-to 10-membered monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is optionally substituted with R⁷1-3 occurrences of substitution. In other embodiments, R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₄Alkyl, or is selected from (i) - (X) as described above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10 membered monocyclic or bicyclic heterocycle. In certain embodiments, the ring is selected from (a) - (o) described above.

In other embodiments, R¹、R²And R⁴Each is hydrogen, and provides compounds of formula I-E-ii:

wherein:

R³is an optionally substituted radical selected from halogen, optionally substituted C_1-6Alkyl, CN, N (R')₂、CO₂R′、NR′COR′、CON(R′)₂、CH₂N(R′)₂、OR′、SR′、CH₂OR′；

x is 1, 2 or 3; and R is⁵At least one of the groups is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NRCH₂(CH₃)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is optionally substituted by R⁷Y times of occurrence of substituted C₁-C₆Aliphatic radical, or is selected from (i) - (X) as defined above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10 membered monocyclic or bicyclic heterocycle. In certain embodiments, the ring is selected from (a) - (o) described above.

In other embodiments, R¹、R²And R⁴Each is hydrogen, x is 0-3, and provides compounds of formula I-E-iii:

wherein:

R³is an optionally substituted radical selected from halogen, optionally substituted C_1-6Alkyl, CN, N (R')₂、CO₂R′、NR′COR′、CON(R′)₂、CH₂N(R′)₂、OR′、SR′、CH₂OR′；

R⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′CH₂(CH₃)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is optionally substituted by R⁷Y times of occurrence of substituted C₁-C₆Aliphatic radical, or is selected from (i) - (X) as defined above¹vi) or (X)¹vii) ring. In other embodimentsIn the embodiment, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10 membered monocyclic or bicyclic heterocycle. In certain embodiments, the ring is selected from (a) - (o) described above.

In other embodiments, R¹、R²And R⁴Each is hydrogen and x is 1, and provides compounds of formula I-E-iv:

wherein:

R³is an optionally substituted radical selected from halogen, optionally substituted C_1-6Alkyl, CN, N (R')₂、CO₂R′、NR′COR′、CON(R′)₂、CH₂N(R′)₂、OR′、SR′、CH₂OR′；

R⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′CH₂(CH₃)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R'; and R' is optionally substituted by R⁷Y times of occurrence of substituted C₁-C₆Aliphatic radical, or is selected from (i) - (X) as defined above¹vi) or (X)¹vii) ring. In other embodiments, R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10 membered monocyclic or bicyclic heterocycle. In certain embodiments, the ring is selected from (a) - (o) described above.

Representative examples of compounds of formula I are set forth below in table 2. The compounds of Table 2 can also be represented by II-x, where x is the compound number shown in Table 2.

Table 2 examples of compounds of formula I:

4. use, formulation and administration

Pharmaceutically acceptable compositions

As discussed above, the present invention provides protein kinase inhibitor compounds, and thus the compounds of the present invention are useful for treating diseases, disorders, and conditions, including, but not limited to, proliferative disorders, cardiac disorders, neurodegenerative disorders, psychiatric disorders, autoimmune disorders, conditions associated with organ transplantation, inflammatory disorders, immune-mediated disorders, viral diseases, or bone diseases. In particular embodiments, the compounds are used to treat an immune response, such as allergy or type I allergy or asthma; autoimmune diseases such as transplant rejection, graft-versus-host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis; neurodegenerative disorders such as familial amyotrophic lateral sclerosis (PALS); and solid and hematologic malignancies such as leukemia and lymphoma.

These compounds and pharmaceutical compositions thereof are also useful for treating or preventing a variety of conditions including, but not limited to, heart disease, diabetes, alzheimer's disease, immunodeficiency disorders, inflammatory diseases, hypertension, allergic diseases, autoimmune diseases, destructive bone disorders such as osteoporosis, proliferative disorders, infectious diseases, immune-mediated diseases, and viral diseases. The compositions are also useful in methods of preventing cell death and proliferation and thus can be used to treat or prevent reperfusion/ischemia in stroke, heart attack, and organ hypoxia. The composition can also be used for preventing thrombin-induced platelet aggregation. The compositions are particularly useful in conditions such as Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML), Acute Promyelocytic Leukemia (APL), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer (including, but not limited to, ovarian, breast, and endometrial cancers), liver diseases including liver ischemia, heart diseases such as myocardial infarction and congestive heart failure, pathological immune conditions involving T cell activation, and neurodegenerative conditions.

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

It will also be appreciated that certain compounds of the invention may be present in free form for processing, or, where appropriate, in the form of a pharmaceutically acceptable derivative thereof. In accordance with the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative that upon administration to a patient in need thereof is capable of providing, directly or indirectly, a compound described herein, or a metabolite or residue thereof.

The term "pharmaceutically acceptable salts" as used herein refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. "pharmaceutically acceptable salt" refers to any non-toxic salt or ester salt of a compound of the invention which, upon administration to a subject, is capable of providing, directly or indirectly, a compound of the invention or an inhibitory active metabolite or residue thereof. The term "an inhibitory active metabolite or residue thereof" as used herein means that the metabolite or residue thereof is also an inhibitor of JAK-3, ROCK and Aurora.

Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts are described in detail, for example, in j.pharmaceutical Sciences, 1977, 66, 1-19 to s.m.berge et al, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are amino salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, acid sulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, and mixtures thereofExamples of suitable salts include, but are not limited to, the salts of sugar, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, decaalkanoate, valerate, and the like. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄And (3) salt. The present invention also contemplates the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Water-or oil-soluble or dispersible products can be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

As noted above, the pharmaceutically acceptable compositions of the present invention may also comprise pharmaceutically acceptable carriers, adjuvants, or excipients, which, as used herein, include any and all solvents, diluents, or other liquid excipients, dispersing or suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, sixteenth edition, e.w. martin (Mack publishing co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for preparing them. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as one that produces any undesirable biological effect or interacts in a deleterious manner with any other component of a pharmaceutically acceptable composition, its use is contemplated to be within the scope of the present invention. Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered gum tragacanth; malt; gelatin; talc powder; excipients such as coconut oil and suppository waxes; oils such as peanut oil, cottonseed oil; safflower seed oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

Use of compounds and pharmaceutically acceptable compositions

In another aspect, there is provided a method for treating or lessening the severity of a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, a psychiatric disorder, an autoimmune disorder, a condition associated with organ transplantation, an inflammatory disorder, an immune-mediated disorder, a viral disease, or a bone disease, comprising administering to a subject in need thereof an effective amount of the compound, or a pharmaceutically acceptable composition comprising the compound. In certain embodiments of the invention, an "effective amount" of a compound or pharmaceutically acceptable composition refers to an amount effective to treat or reduce the severity of a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, a psychiatric disorder, an autoimmune disorder, a condition associated with organ transplantation, an inflammatory disorder, an immune-mediated disorder, a viral disease, or a bone disorder.

In other aspects, the invention includes methods for treating or lessening the severity of various disorders, including, but not limited to, heart disease, diabetes, alzheimer's disease, immunodeficiency disorders, inflammatory diseases, hypertension, allergic diseases, autoimmune diseases, destructive bone diseases such as osteoporosis, proliferative disorders, infectious diseases, immune-mediated diseases, and viral diseases. In other aspects, the invention includes methods for preventing cell death and proliferation and thus may be used to treat or prevent reperfusion/ischemia in stroke, heart attack, and organ hypoxia. In other embodiments, the invention includes methods for preventing thrombin-induced platelet aggregation. The invention also includes methods for treating, reducing the severity of, or preventing disorders such as Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML), Acute Promyelocytic Leukemia (APL), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer (including, but not limited to, ovarian, breast, and endometrial cancers), liver diseases including liver ischemia, heart diseases such as myocardial infarction and congestive heart failure, pathologic immune conditions involving T cell activation, and neurodegenerative disorders.

In accordance with the methods of the present invention, the compounds and compositions can be administered in any amount and by any route of administration effective to treat or ameliorate a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplantation, an inflammatory disorder, an immune-mediated disorder, a viral disease, or a bone disorder. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to the actual isolated unit of medicament suitable for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend upon a variety of factors including the condition being treated and the severity of the condition; the activity of the particular compound used; the specific composition used; the age, weight, general health, sex, and diet of the patient; the time of administration; the route of administration; and the rate of excretion of the particular compound employed; the duration of the treatment; drugs used in combination or concomitantly with the specific compounds employed; and factors well known in the medical arts. The term "patient" as used herein refers to an animal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of the present invention may be administered to a patient orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (e.g., powders, ointments, or drops), bucally, as a buccal or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention may be administered orally or parenterally at a dosage level of from about 0.01mg/kg of body weight of the subject to about 50mg/kg of body weight of the subject, preferably from about 1mg/kg of body weight of the subject to about 25mg/kg of body weight of the subject, one or more times per day to achieve the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated as known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Acceptable excipients and solvents used are water, ringer's solution, u.s.p. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending base. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

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

In order to prolong the effect of the compounds of the present invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous materials that have poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which in turn may depend on the size of the crystals and the crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are made 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 release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations can also be prepared by embedding the compounds in liposomes or microemulsions which are compatible with body tissues.

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

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

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition that releases the active ingredient(s) only, or preferably, in a particular portion of the intestinal tract, optionally, in a delayed manner. Examples of useful embedding components include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

The active compound may also be in the form of microcapsules with one or more of the excipients mentioned above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain, in accordance with standard practice, other substances in addition to the inert diluents, e.g., tablet lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may also optionally contain opacifying agents and may also be of a composition that releases the active ingredient(s) only, or preferably, in a specific part of the intestinal tract, optionally, in a delayed manner. Examples of useful embedding components include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed with a pharmaceutically acceptable carrier under sterile conditions and may require any preservatives or buffers required. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of the present invention. Furthermore, the present invention contemplates the use of transdermal patches, which have the added advantage of controlled release of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of a compound across the skin. The rate can be controlled by providing a rate controlling film or by dispersing the compound in a polymer matrix 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 of JAK-3, ROCK, and Aurora isoforms, and thus, without wishing to be bound by any particular theory, are particularly useful for treating or lessening the severity of a disease, disorder, or condition in which activation of one or more of JAK-3, ROCK, or Aurora is implicated. When the activation of JAK-3 is implicated in a particular disease, disorder or condition, the disease, disorder or condition may also be referred to as a "JAK-3-mediated disease," "ROCK-mediated disease," "Aurora-mediated disease," or disease symptom. Thus, in another aspect, the invention provides a method for treating or lessening the severity of a disease, disorder or condition in which activation of one or more of JAK-3, ROCK or Aurora is implicated.

The activity of the compounds used in the present invention as JAK-3, ROCK or Aurora inhibitors may be determined in vitro, in vivo, or in cell lines. In vitro assays include assays that measure the phosphorylation activity or ATPase activity inhibition of activated JAK-3, ROCK or Aurora. A selective in vitro assay may quantify the ability of an inhibitor to bind to JAK-3, ROCK or Aurora. Inhibitor binding can be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/JAK-3, inhibitor/ROCK or inhibitor/Aurora complexes, and determining the amount of radiolabel binding. Alternatively, inhibitor binding can be determined by performing a competition experiment in which the novel inhibitor is incubated with JAK-3, ROCK or Aurora which binds to a known radioligand.

The term "measurably inhibits" as used herein refers to a measurable change in JAK-3, ROCK or Aurora activity between a sample comprising the composition and JAK-3, ROCK or Aurora kinase and an equivalent sample comprising JAK-3, ROCK or Aurora kinase in the absence of the composition.

The term "JAK-mediated disease" as used herein refers to any disease or other deleterious condition for which JAK family kinases are known to function. Such disorders include, but are not limited to, immune responses such as allergic or type I allergies, asthma, autoimmune diseases such as transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis, neurodegenerative disorders such as Familial Amyotrophic Lateral Sclerosis (FALS), and solid and hematologic malignancies such as leukemias and lymphomas.

The term "ROCK-mediated disorder" or "disease" as used herein refers to any disease or other deleterious disorder for which ROCK family kinases are known to function. The term "ROCK-mediated disorder" or "disease" also refers to those diseases or conditions that are alleviated by treatment with a ROCK inhibitor. Such conditions include, but are not limited to, hypertension, angina, cerebrovascular atrophy, asthma, peripheral circulation disorders, premature labor, cancer, erectile dysfunction, arteriosclerosis, spasms (cerebral and coronary vasospasms), retinopathy (e.g., glaucoma), inflammatory disorders, autoimmune disorders, AIDS, osteoporosis, myocardial hypertrophy, ischemia/reperfusion-induced injury, or endothelial dysfunction.

The term "Aurora-mediated disorder" or "disease" as used herein refers to any disease or other deleterious disorder for which Aurora family kinases are known to play a role. The term "Aurora-mediated disorder" or "disease" also refers to those diseases or conditions that are alleviated by treatment with an Aurora inhibitor. Such conditions include, but are not limited to, immune responses such as allergic or type I allergies, asthma, autoimmune diseases such as transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, neurodegenerative disorders such as familial amyotrophic lateral sclerosis (PALS), and solid and hematologic malignancies such as leukemias and lymphomas.

It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the invention may be used in combination therapy, i.e., the compounds and pharmaceutically acceptable compositions may be administered simultaneously with, before, or after one or more other desired therapeutic or medical procedures. The particular combination of therapies (treatments or procedures) used in a combination regimen takes into account the compatibility of the treatments and/or procedures required and the therapeutic effect desired. It will also be appreciated that the therapies employed may achieve the desired effect with respect to the same condition (e.g., the compounds of the invention may be administered simultaneously with other agents used to treat the same condition), or they may achieve different effects (e.g., control of any side effects). Other therapeutic agents commonly administered for the treatment or prevention of a particular disease, or condition, as used herein, are referred to as "suitable for the disease, or condition, being treated.

Examples of agents that may be administered in combination with the inhibitors of the invention include, but are not limited to: treatment of Alzheimer's disease such as AriceptAnd ExcelonTreatment of Parkinson's disease such as L-DOPA/carbidopa, entacapone, ropinirole, perlesu, bromocriptine, pergolin, trihexyphenyl, and amantadine; agents such as interferon-beta (e.g., Avonex) for the treatment of Multiple Sclerosis (MS)And Rebif)、CopaxoneAnd mitoxantrone; treatment of asthma such as albuterol and SingulairAgents for treating schizophrenia such as olanzapine, vistone, quetiapine, and (halo) haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors,MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti-parkinson's disease agents; agents for treating cardiovascular diseases such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver diseases such as corticosteroids, cholestyramine, interferons and antiviral agents; agents for treating hematological disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.

The amount of the other therapeutic agent present in the compositions of the present invention will not exceed that which would normally be administered in a composition containing only that therapeutic agent as the active agent. Preferably, the amount of the other therapeutic agent in the presently disclosed compositions is from about 50% to 100% of the amount typically present in compositions containing only that agent as the therapeutically active agent.

The compounds of the present invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents and catheters. Thus, another aspect of the present invention includes a composition for coating an implantable device comprising a compound of the present invention as generally described above and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In another aspect, the invention includes an implantable device coated with a composition comprising a compound of the invention as generally described above and in classes and subclasses herein, and a carrier suitable for coating the implantable device.

Vascular stents, for example, have been used to overcome restenosis (restenosis of the vessel wall after injury). However, patients using stents or other implantable devices are at risk for clot formation or platelet activation. These deleterious effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. General preparation of suitable coatings and coated implantable devices are described in U.S. Pat. nos. 6,099,562, 5,886,026, and 5,304,121. The coating is typically a biocompatible polymeric material such as hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating may optionally be further covered by a suitable coating of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid or combinations thereof to impart controlled release characteristics to the composition.

Another aspect of the invention relates to a method of inhibiting JAK-3, ROCK or Aurora activity in a biological sample or a patient, comprising administering to the patient, or contacting said biological sample with a compound of formula I or a composition comprising said compound. The term "biological sample" as used herein includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or an extract thereof; and blood, saliva, urine, feces, tears, or other body fluids or extracts thereof.

Inhibition of JAK-3, ROCK or Aurora kinase activity in a biological sample can be used for various purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological sample storage, and biological assays.

Examples

While specific exemplary embodiments are described in detail below, it will be appreciated that other compounds of formula I may be prepared according to the methods generally described herein, by methods generally employed by those of ordinary skill in the art, using appropriate starting materials.

3-bromo-1H-pyrrolo [2, 3-b ] pyridine (2)

A solution of azaindole 1(4g, 0.025mol) in 100mL of chloroform was cooled to 0 ℃. A solution of bromine in 20mL of chloroform was added dropwise, and the resulting mixture was stirred at 0 ℃ for 1 hour. The resulting suspension was diluted with 0.5N HCl, the aqueous layer was basified with 0.5N NaOH, and the solid was filtered to give 4g (82%) of crude product 2, which was used directly in the next step.

3-bromo-1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b ] pyridine (3)

A solution of 3g (0.015mol) of 2 in 20mL of anhydrous THF was cooled to-78 deg.C and a solution of n-BuLi 2.5M in hexane (6.7mL, 0.167mol) was added dropwise. After stirring for 15 minutes, a solution of tosyl chloride in 5mL of THF was added dropwise. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 hour. Extraction with ether and washing of the organic phase with brine, drying over magnesium sulphate and concentration in vacuo gave a white solid which was then passed through a pad of silica (70% EtOAc; 30% hexane) to give 4.65g (84%) of 3.¹H NMR CDCl₃ 8.4(s，1H)，8.1(d，2H)，7.8(s，2H)，7.2(m，3H)，2.3(s，3H)。

3- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b ] pyridine (4)

3(850mg, 0.0024mol) was dissolved in 20mL DME, pinnacol borane (921mg, 0.0036mol), Pd were added₂Cl₂(dppf)₂(197mg, 0.24mmol) and KOAc (713mg, 0.00726mol), the mixture was stirred at 90 ℃ and refluxed for 18 hours. Dilute with ethyl acetate and wash the organic phase with water and brine, then dry (Na)₂SO₄) And concentrated in vacuo. The residue was subjected to flash chromatography (20% EtOAc/80% hexane) to afford 900mg (99%) of the desired product 4.

3- (2-methylsulfanyl-pyrimidin-4-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3b ] pyridine (5)

Boronate ester (borate ester)4(900mg, 0.0) was reacted under nitrogen023mol), 4-chloro-2-thiomethylpyrimidine (341mg, 0.0029mol), Pd (Ph)₃P)₄A mixture of (260mg, 0.23mmol) and 2M sodium carbonate (3.4mL, 0.0068mol) in 20mL DME was refluxed for 18 hours. Dilute with ethyl acetate and wash the organic phase with water and brine, then dry (Na)₂SO₄) And concentrated in vacuo. The residue was subjected to flash chromatography (40% EtOAc/60% hexane) to afford 460mg (51%) of the desired product 5.¹H NMR CDCl₃ 8.8(d，1H)，8.7(m，2H)，8.4(s，1H)，8.1(d，2H)，7.2(m，4H)，2.6(s，3H)，2.3(s，3H)。

3- (2-methanesulfonyl-pyrimidin-4-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b ] pyridine (6)

Pyrimidine 5(460mg, 0.0012mol) was dissolved in 20mL of methanol-water (1: 1), and oxone (2.14g, 0.0035mol) was added to the solution, followed by reflux reaction for 18 hours. The methanol was removed in vacuo and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with water and brine and then dried (Na)₂SO₄) And concentrated in vacuo. The residue was subjected to flash chromatography (40% EtOAc/60% hexane) to afford 160mg (32%) of the desired product 6. LCMS ES⁺＝428.9。

Benzyl- [4- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -pyrimidin-2-yl ] -amine (7)

A solution of 6(20mg, 0.047mmol) and benzylamine (0.007mL, 0.061mmol) in 1mL ethanol was heated in a sealed tube for 18 hours at 80 ℃. The solvent was evaporated and the crude product was purified by preparative TLC (50% EtOAc/50% hexane) to give 20mg of product, which was then deprotected using 2ml of 3N NaOH in methanol for 4 h. 2mL of 3N HCl was added and evaporated to dryness. Reverse phase HPLC (20-70% MeCN-water and 0.1% TFA (20 mL/min) gave 10mg (75%) of 7.¹H NMR DMSOD₆8.7(s，1H)，8.4(s，1H)，8.25(d，1H)，8.1(d，1H)，7.4(m，2H)，7.25(m，3H)，7.2(s，1H)，7.15(dd，1H)，7.1(s，1H)，4.8(s，2H)。LCMS ES⁺＝302.0。

3- (6-chloro-pyrimidin-4-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b ] pyridine (8)

Boronate 4(0.11g, 0.276mmol), 4, 6-dichloropyrimidine (0.049g, 0.331mmol), catalytic Pd (PPh) were heated with microwaves at 160 ℃₃)₄And excess potassium carbonate in DMF for 5 min, and converted to the product by TLC (20% EtOAc: hexanes). In EtOAc/H₂The reaction was partitioned between O, extracted, stripped in vacuo and purified by silica gel column (eluent: 5% EtOAc: hexanes) to give 8(0.035g) as a white solid in 33% yield.

1- {4- [6- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -pyrimidin-4-yl ] - [1, 4] diazepan-1-yl } -ethanone (9)

A solution of 8(0.035g, 0.091mmol), N-acetyl-homooxazine (homopiperazine) (0.025g, 0.181mmol), excess potassium carbonate in DMF was heated at 80 ℃ and the colour changed after 5 minutes. LC/MS and TLC showed conversion to tosyl protected product after 15 min. To the reaction was added 1ml of 6N NaOH and 1ml of methanol, and the tosyl group was immediately removed by LC/MS (M +1 ═ 337). In EtOAc/H₂The reaction was partitioned between O and extracted. The crude product was purified by preparative HPLC to give 9(0.022g) as a clear oil in 73% yield.

NMR：MeOD 2.0bs(2H)，2.1s(3H)，3.6m(2H)，3.8-4.3bm(6H)，7.1d(1H)，7.3m(1H)，8.2d(1H)，8.35m(2H)，8.65d(1H)。LC/MS(M+1)＝337

Benzyl- (2-chloro-pyrimidin-4-yl) -amine (10)

To a solution of 2, 4-dichloropyrimidine (0.15g, 1.0mmol), benzylamine (0.109ml, 1.0mmol) in THF was added DIPEA (0.526ml, 3.0mmol) and the reaction was heated at reflux for 2 hours to form a regioisomer (desired versus undesired) 4: 1 mixture by TLC (5% methanol: dichloromethane). The reaction was stripped in vacuo and purified by silica gel column (eluent: 2% methanol: dichloromethane) to give 0.12g (0.548mmol) of the desired product 10 in 54% yield. LC/MS (M +1) ═ 220

Benzyl- (6-chloro-pyrimidin-4-yl) -amine (12)

Benzylamine (0.697ml, 6.76mmol) was added to 4, 6-dichloropyrimidine (1.0g, 6.76mmol) causing a vigorous reaction and color change. The reaction was slowly diluted with dichloromethane to give a white precipitate. 1ml triethylamine was added and TLC indicated conversion to product (5% MeOH: dichloromethane). The reaction was loaded directly onto silica and purified (eluent: 2% MeOH: dichloromethane) to give 1.17g (5.32mmol) of 12 as a yellow wax in 79% yield.

Benzyl- [2- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -pyrimidin-4-yl ] -amine (11)

Microwave heating 4(0.36g, 0.09mmol), 10(0.028g, 0.108mmol) and 2.0M Na at 160 deg.C₂CO₃(0.108ml, 0.271mmol) and catalytic PdCl₂(PPh₃)₂Dissolved in 1ml DMSO for 5 min and converted to tosyl protected product, LC/MS (M +1) ═ 456. NaOtBu (0.026g, 0.271mmol) was added to the reaction and microwave heated at 160 ℃ for 5 minutes to complete the conversion to product 11. The reaction was filtered and purified by preparative HPLC to give 0.0032g11 as a white solid in 11% yield.

NMR：MeOD4.95bs(2H)，6.6d(1H)，7.2m(1H)，7.3-7.5mm(5H)，8.0d(1H)，8.3d(1H)，8.4s(1H)，8.55d(1H)。LC/MS(M+1)＝302

End product 13 was formed as described in 11 to give 0.012g (0.039mmol) of white solid 13. NMR: MeOD 4.8s (2H), 7.05s (1H), 7.2-7.6M (6H), 8.2s (1H), 8.4M (2H), 8.55s (1H) LC/MS (M +1) ═ 302

Scheme 2Synthesis of 5-H-azaindole pyrimidine and pyridine analogs

3- (2-chloro-pyridin-4-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b ] pyridine (14)

Heating aza under nitrogen and microwave at 160 deg.CIndole 3(80mg, 0.23mmol), 2-chloropyridine-4-boronic acid (41mg, 0.27mmol), Pd (Ph)₃P)₄(20mg, 0.11mmol) and 2M sodium carbonate (.34mL, 0.68mmol) were dissolved in a mixture of 2mL DME for 15 minutes. Dilute with ethyl acetate and wash the organic phase with water and brine, then dry (Na)₂SO₄) And concentrated in vacuo. The residue was subjected to flash chromatography (40% EtOAc/60% hexane) to afford 60mg (68%) of the desired product 14.¹H NMR CDCl₃8.6(d, 2H), 8.1(m, 4H), 7.25(m, 5H), 2.5(s, 3H). For example, benzylamine can be used instead of 2-chloropyridine for 30 minutes at 250 ℃ followed by deprotection to give compound 15.

1- (5-bromo-1H-pyrrolo [2, 3-b ] pyridin-3-yl) -ethanone (16)

7-azaindole 13(2.16g, 0.011mmol) was dissolved in 75mL anhydrous DCM. To the solution was added aluminum trichloride (4.36g, 0.0327mol) and the reaction mixture was stirred at room temperature for 1 hour. Acetyl chloride (1.16mL, 0.0164mol) was added dropwise to the mixture and stirred at room temperature for 18 hours. 20mL of methanol was added and the reaction was allowed to proceed for 1 hour. Concentrated in vacuo and suspended in water-EtOAc. The organic phase was extracted with EtOAc and dried, after concentration in vacuo, 2.37g (91%) of compound 14 were obtained.¹H NMRCDCl₃ 9.5(bs，1H)，8.8(s，1H)，8.5(s，1H)，7.9(s，1H)，2.4(s，3H)。

1- [ 5-bromo-1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -3-dimethylamino-propenone (properone) (17)

To a suspension of NaH (263mg, 0.0104mol) in dry THF at 0 deg.C was slowly added a solution of 16(2.37g, 0.01mol) in THF. After stirring at 0 ℃ for 15 minutes, a solution of p-toluenesulfonyl chloride (2.27g, 0.012mol) in THF was added and the reaction mixture was stirred at room temperature for 18 hours. Quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo to give 3.37g of a solid residue which was used directly in the next step. The above intermediate was mixed with DMF-DMA (5.7mL, 0.0428mol) and heated at 100 ℃ for 22 hours. Concentration in vacuo, and flash chromatography (60% EtOAc/40% hexanes) afforded 3.37g (76% from 17) of the desired product 15.¹H NMR CDCl₃8.8(s，1H)，8.3(s，1H)，8.1(s，1H)，8.05(d，2H)，7.8(d，1H)，7.2(s，2H)，5.7(d，1H)，3.0(bs，6H)，2.2(s，3H)。

6- (5-bromo-1H-pyrrolo [2, 3-b ] pyridin-3-yl) -1H-pyrimidine-2-thione (thione) (18)

To a freshly prepared solution of sodium (175mg, 0.0076mol) in ethanol (18mL) were added compound 17(1.0g, 0.0022mol) and thiourea (187mg, 0.0025mol) successively. The mixture was heated to reflux for 4 hours. The solvent was removed and the residue was dissolved in 8mL of water. The solution was neutralized with 1N HCl and extracted with ethyl acetate. The organic phase was dried and concentrated in vacuo to provide 570mg (75%) of technically pure 18.¹H NMR CDCl₃ 12.2(s，1H)，8.6(s，1H)，8.3(s，1H)，8.2(s，1H)，7.6(d，1H)，5.8(d，1H)。

5-bromo-3- (2-methylsulfanyl-pyrimidin-4-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b ] pyridine (19)

Reflux 18(565mg, 0.0018mol), sodium acetate (526mg, 0.0039mol), methyl iodide (0.126mL, 0.0020mol) was dissolved in a suspension of 15mL ethanol-THF (9: 1) for 2 hours. Cooled to room temperature and filtered. Chromatography (70% EtOAc-30% hexanes) afforded 48mg (9%) of the thiomethyl intermediate. Tosylation afforded 49mg (70%) of the desired compound 19.¹H NMR CDCl₃8.8(d，1H)，8.5(m，2H)，8.35(s，1H)，8.1(d，2H)，7.25(m，3H)，2.7(s，3H)，2.3(s，3H)。

Benzyl- [4- (5-bromo-1H-pyrrolo [2, 3-b ] pyridin-3-yl) -pyrimidin-2-yl ] -amine (20)

This compound can be prepared starting from 19, by oxone oxidation and benzylamine substitution according to scheme 1.

Scheme 3Synthesis of 5-substituted azaindole pyrimidine and pyridine analogs

5-bromo-1- (tert-butyl-dimethyl-silyl) -1H-pyrrolo [2, 3-b ] pyridine (19)

To a suspension of NaH (200mg, 0.0078mol) in 15mL of anhydrous DMF at 0 deg.C was added a solution of azaindole 13(1.36g, 0.007mol) in 5mL of DMF. Stirring is carried out at 0 ℃ for 10 minutes, a solution of TBDMSCl in 3mL of DMF is added, and the resulting mixture is stirred O.N. Put into EtOAc and washed with water, brine. The organic layer was dried and concentrated in vacuo to an oil, which was used in the next step without further purification.¹H NMR CDCl₃ 8.3(d，1H)，7.9(d，1H)，7.2(d，1H)，6.4(d，1H)，0.85(s，H)，0.5(s，6H)。

1- (tert-butyl-dimethyl-silyl) -5-pyridin-3-yl-1H-pyrrolo [2, 3-b ] pyridine (20)

To a solution of 19(1.77g, 0.0057mol) and 3-diethylpyridylborane (1.0g, 0.0068mol) in 80mL of DME under nitrogen was added PdCl₂(Ph₃P)₂(320mg, 0.455mmol) and 2M aqueous sodium carbonate (8.5mL, 0.017 mol). The reaction mixture was refluxed for 3 hours. Cooled to room temperature and diluted with ethyl acetate and washed with brine. The organic layer was dried and concentrated to an oil which was flash chromatographed (30% EtOAc-70% hexane) to give 1g (57%) of the desired material 20.¹H NMR CDCl₃8.9(s，1H)，8.5(d，1H)，8.4(d，1H)，8.0(d，1H)，7.9(d，1H)，7.5(d，1H)，7.2(d，1H)，6.5(d，1H)，0.85(s，9H)，0.55(s，6H)。

3-bromo-1- (tert-butyl-dimethyl-silyl) -5-pyridin-3-yl-1H-pyrrolo [2, 3-b ] pyridine (21)

Bromine (0.166mL, 0.0032mol) was dissolved in 1mL CCl at 0 deg.C₄Was added dropwise to 20(1.0g, 0.0032mol) and pyridine (0.314mL, 0.0039mol) dissolved in anhydrous CHCl₃(30ml) in a stirred solution. The reaction mixture was stirred at 0 ℃ for 1 hour and then neutralized with 10mL of a sodium bicarbonate-sodium thiosulfate mixture (1: 1). Separating the organic layer and usingDichloromethane (3X10mL) was further extracted and the combined organic layers were dried and dried in vacuo. The residue was subjected to flash chromatography (30% EtOAc-70% hexane) to afford 0.97g (78%) of the desired material 21.¹H NMRCDCl₃8.9(s，1H)，8.55(d，1H)，8.4(d，1H)，8.0(d，1H)，7.9(d，1H)，7.4(dd，1H)，7.2(s，1H)，0.9(s，9H)，0.5(s，6H)。

5-pyridin-3-yl-3- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b ] pyridine (22)

Compound 21 can be desilylated using, for example, 10% HCl and tosylated using, for example, NaH and p-toluenesulfonyl chloride. Compound 22 can be prepared using the same scheme as compound 4 in scheme 1.

3- (2-methanesulfonyl-pyrimidin-4-yl) -5-pyridin-3-yl-1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b ] pyridine (24)

Compound 24 can be prepared using the same scheme as compound 6 in scheme 1.

3- (6-chloro-pyrimidin-4-yl) -5-pyridin-3-yl-1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b ] pyridine (25)

Compound 25 can be prepared using the same scheme as compound 8 in scheme 1.

3- (2-chloro-pyridin-4-yl) -5-pyridin-3-yl-1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b ] pyridine (26)

Compound 26 can be prepared using the same protocol as compound 14 in scheme 2.

Scheme 4

2-methoxy-4- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -benzonitrile (29)

Boronic acid 28(35.4mg, 200 μmol) and tosyl protected azaindole 3(65.5mg, 194 μmol), sodium carbonate (61.8mg, 583 μmol) and tetrakis (triphenylphosphine) palladium (O) (8.3mg, 7.2 μmol) were placed in a test tube. Water (323mg) and ethylene glycol dimethyl ether (848mg) were added and the mixture was deoxygenated. The tube was sealed and heated at 160 ℃ for 10 minutes with magnetic stirring, using microwave irradiation. The crude product was extracted with ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product (83 mg). The crude product was purified via flash chromatography and eluted with a gradient of 1: 1 ethyl acetate/hexane-100% ethyl acetate-4/4/1 ethyl acetate/hexane/7N aqueous ammonia in methanol to give 29(42mg, 54%) and 30(7.7mg, 15%).

2-methoxy-4- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -benzonitrile (30)

By dissolving in a solution of di-sodium hydroxide containing 1N sodium hydroxide (200. mu.l, 2eq.)The tosyl protecting group in 29 was removed by refluxing in alkane (5ml) for 4.5 h. The reaction was concentrated and extracted with ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 30(30mg, 100%).¹H NMR CD₃CN10.00(s，1H)，8.32(m，2H)，7.83(s，1H)，7.65(d，1H)，7.40(m，2H)，7.20(dd，1H)，4.02(s，3H).LC/MS(M+1)＝250

2-methoxy-4- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -benzamide (31)

Nitrile 30(10mg, 40. mu. mo l) was dissolved in dimethyl sulfoxide (0.5 ml). To this was added potassium carbonate (20mg) and a solution of 30% hydrogen peroxide in water (100. mu.l). The reaction was warmed to about 60 ℃ for 15 minutes. The reaction was concentrated to dryness and triturated with water. The resulting precipitate was filtered and dried under vacuum overnight to give 31(10mg, 93%). 1H NMR DMSO-d 611.99 (s, 1H), 8.32(d, 1H), 8.24(m, 1H), 8.01(m, 1H), 7.88(d, 1H), 7.59(s, 1H), 7.40(s, 1H), 7.37(m, 2H), 7.15(dd, 1H), 4.00(s, 3H). LC/MS (M +1) ═ 268.

Scheme 5

Boronic acid 32B-32F (500 μmol) was placed in a test tube containing azaindole 3(87mg, 250 μmol). Into each vial were placed sodium carbonate (53mg, 500. mu. mol) and tetrakis (triphenylphosphine) palladium (0) (15mg, 13. mu. mol). Water (1ml) and ethylene glycol dimethyl ether (2ml) were added and the tube was deoxygenated and sealed. The tube was heated to 140 ℃ for 10 minutes via microwave. The reaction was cooled to 0 ℃ and quenched with 2N aqueous hydrochloric acid (1 ml). The reaction was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The product was purified on silica (50% ethyl acetate/hexane-100% ethyl acetate gradient) to afford 33B-33F.

Compounds 33B-33F were dissolved in methanol (20ml) and treated with 2N aqueous sodium hydroxide (1ml) overnight at room temperature. The reaction was neutralized with 2N hydrochloric acid (1ml) and concentrated to dryness. Purification via silica gel chromatography (50% ethyl acetate/hexane-100% ethyl acetate gradient) or mass directed reverse phase chromatography on C18 (15% acetonitrile/water with 0.09% trifluoroacetic acid-35% acetonitrile/water with 0.09% trifluoroacetic acid, 15 min) afforded the products 34B-34F.

3- (3-benzyloxy-phenyl) -1H-pyrrolo [2, 3-B ] pyridine (34B).

¹H NMR DMSO-d6 11.95(s，1H)，8.29(m，1H)，8.20(d，1H)，7.89(s，1H)，7.49(d，2H)，7.41(t，2H)，7.34(m，2H)，7.29(m，2H)，7.13(dd，1H)，6.90(m，1H)，5.20(s，2H).LC/MS(M+1)＝301.

3- (4-benzyloxy-phenyl) -1H-pyrrolo [2, 3-b ] pyridine (34C).

¹H NMR DMSO-d6 11.84(s，1H)，8.28(m，2H)，7.76(s，1H)，7.61(d，2H)，7.48(d，2H)，7.39(t，2H)，7.32(t，1H)，7.15(dd，1H)，7.09(d，2H)，5.13(s，2H).LC/MS(M+1)＝301.

3- (3, 4-dimethoxy-phenyl 1) -1H-pyrrolo [2, 3-b ] pyridine (34D).

¹H NMR DMSO-d6 11.90(s，1H)，8.31(d，1H)，8.28(d，1H)，7.80(s，1H)，7.21(m，2H)，7.19(dd，1H)，7.02(d，1H)，3.86(s，3H)，3.78(s，3H).LC/MS(M+1)＝255.

3- (3, 4, 5-dimethoxy-phenyl) -1H-pyrrolo [2, 3-b ] pyridine (34E).

¹H NMR DMSO-d6 11.85(s，1H)，8.29(d，1H)，8.27(d，1H)，7.83(s，1H)，7.15(d，1H)，6.92(s，2H)，3.86(s，6H)，3.69(s，3H).LC/MS(M+1)＝285.

2-methoxy-4- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -phenol (34F).

¹H NMR DMSO-d6/D₂O8.25-8.30(m，2H)，7.74(s，1H)，7-20(d，1H)，7.17(dd，1H)，7.10(dd，1H)，6.86(d，1H)，3.88(s，3H)，LC/MS(M+1)＝241.

Scheme 6

2-methoxy-5- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -benzaldehyde (36)

Borate 35(131mg, 500. mu. mol), and 3(175mg, 500. mu. mol), sodium carbonate (114mg, 1.08mmol), and tetrakis (triphenylphosphine) palladium (0) (22mg, 19. mu. mol) were placed in a test tube. Water (0.9g) and ethylene glycol dimethyl ether (2.1g) were added and the mixture was deoxygenated. The tube was sealed and heated to 110 ℃ overnight with magnetic stirring. The crude product was extracted with ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography eluting with a gradient of 1: 1 ethyl acetate/hexane-100% ethyl acetate-4/4/1 ethyl acetate/hexane/7N aqueous ammonia in methanol to give 36(98mg, 48%).

2-methoxy-5- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -benzonitrile (37)

Aldehyde 36(98mg, 241. mu. mol) was dissolved in tetrahydrofuran (5 ml). To this was added 30% aqueous ammonia (3ml) and iodine (79mg, 313. mu. mol). The reaction was stirred at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate. The organic phase was washed with a solution of sodium sulfite (50mg) in water (10 ml). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 37(95.8mg, 98%).

2-methoxy-5- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -benzonitrile (38)

Nitrile 37(95.8mg, 237. mu. mol) was dissolved in bisAlkane (5ml) and treated with a solution of 2N sodium hydroxide in water (250. mu.l, 500. mu. mol). The reaction was sealed and heated to reflux for 2 hours. The reaction was concentrated to dryness and extracted with ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product (72.3 mg). The crude product was purified by flash chromatography and gradient eluted with 1: 1 ethyl acetate/hexane-100% ethyl acetate-4/4/1 ethyl acetate/hexane/7N aqueous ammonia in methanol to give 38(26.7mg, 45%).

2-methoxy-5- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -benzamide (39)

The desmethylbenzenesulfonyl nitrile 38(26.7mg, 107. mu. mol) was dissolved in dimethyl sulfoxide (2.49 g). To this was added potassium carbonate (32.7mg, 237. mu. mol) and a solution of 30% hydrogen peroxide in water (85.5mg) and the reaction was stirred at room temperature overnight. The reaction was diluted with water and the resulting precipitate was washed with water, acetonitrile and ether to give the final product 39(25.3mg, 88%).¹H NMRDMSO-d6 11.86(s，1H)，8.28(m，1H)，8.19(d，1H)，8.11(m，1H)，7.81(m，2H)，7.70(s，1H)，7.55(s，1H)，7.21(d，1H)，7.16(m，1H)，3.91(s，3H).LC/MS(M+1)＝268

4-bromo-2-methoxybenzonitrile

In a 1L round-bottom flask, 53.94g (270mmol) of 4-bromo-2-fluorobenzonitrile were dissolved in 500mL of THF. Sodium methoxide (21.99g, 407mmol) was added and the mixture was heated at reflux until TLC (SiO)₂∶CH₂Cl₂) Indicating complete depletion of the starting material. The mixture was poured into 1N HCl and the THF was evaporated in vacuo. The remaining mixture was extracted with diethyl ether. Drying (MgSO)₄) The extract was filtered through a plug of silica gel. By CH₂Cl₂The stopper was eluted and the filtrate was evaporated in vacuo to yield 45.56g (80%) of the product as a white solid.¹H NMR(500MHz，CDCl₃)δ7.42(d，1H)，7.17(dd，1H)，7.14(d，1H)，3.95(s，3H)。

4-cyano-3-methoxyphenylboronic acid (28)

A3-neck 1-L round bottom flask was equipped with an overhead stirrer and nitrogen line. The flask was charged with 45.56g (215mmol) of 4-bromo-2-methoxybenzonitrile, 64mL (277mmol) of tri-isopropylborate and 500mL of THF. The solution was cooled in a dry ice/acetone bath to-78 ℃. N-butyllithium (2.5M, 110mL, 275mmol) was added dropwise via an addition funnel. The mixture was stirred for 30 minutes and 2N HCl was added. The mixture was stirred for 1 hour and poured into water. With Et₂And O, extracting the mixture. The organic solution was back-extracted with 1N NaOH. With Et₂The aqueous layer was washed with O and acidified with concentrated HCl. With Et₂And O, extracting the mixture. The organic extracts were dried (MgSO₄) And evaporated in vacuo to give 20.77g (55%) of the product as a white solid.¹H NMR(500MHz，d6-DMSO)87.68(d，1H)，7.59(s，1H)，7.47(d，1H)，3.95(s，3H).

Scheme 7:

5-chloro-3-iodo-pyridin-2-ylamine (40)

Iodine (16.28g, 64mmol) was added to a mixture of 1-amino-5-chloropyridine (8.25g, 64mmol) and silver sulfate (20g, 64mmol) dissolved in 400mL ethanol, and the mixture was stirred at room temperature for 20 hours. The mixture was filtered over celite and the solvent removed in vacuo. The residue was dissolved in DCM (600mL) and washed with 5% aqueous NaOH (500mL), water and brine. The organic layer was dried and concentrated in vacuo to give a solid residue which was flash chromatographed (20% EtOAc-80% hexanes) to give 9.8g (60%) of 40.¹H NMR(500MHz，CDCl₃)7.9(s，1H)，7.7(s，1H)，5.0(bs，2H)。

5-chloro-2- (triethyl-silyl) -1H-pyrrolo [2, 3-b ] pyridine (41)

40(9.5g, 37.3mmol) of Pd dissolved in 320mL of DMF and triethylsilylacetylene (20mL, 112mmol), Pd₂Cl₂(dppf)₂(1.52g, 1.9 mmol), lithium chloride (1.58g, 37.3mmol) and 2M Na₂CO₃(7.9mL, 74.7mL), the mixture was stirred under nitrogen and refluxed at 90 ℃ for 15 hours. Dilute with ethyl acetate-ether mixture (1: 1) and wash the organic phase with water and brine, then dry (Na)₂SO₄) And concentrated in vacuo. The residue was subjected to flash chromatography (2O% EtOAc/80% hexanes) to afford 4.37g (44%) of the desired product 41.¹HNMR(500MHz，CDCl₃)9.4(bs，1H)，8.2(s，1H)，7.9(s，1H)，6.6(s，1H)，0.9(t，9H)，0.75(q，6H)。

5-chloro-1H-pyrrolo [2, 3-b ] pyridine (42)

Compound 41(4.37g, 0.0164mol) was dissolved in THF. Molecular sieves (10g3A) were added followed by TBAF (32.75mL, 0.0328). The reaction mixture was stirred at room temperature for 5 hours. Diluted with ethyl acetate and washed several times with water, brine, the organic layer was dried and concentrated in vacuo to an oil which was flash chromatographed (30% EtOAc-70% hexanes) to give 0.23g (90%) of the desired material 42.¹H NMR DMSO d₆ 11.8(bs，1H)，8.2(s，1H)，8.1(s，1H)，7.5(s，1H)，6.5(s，1H)。

1- (tert-butyl-dimethyl-silyl) -5-chloro-1H-pyrrolo [2, 3-b ] pyridine (43)

In a sealed tube fitted with a septum, under nitrogen, 42(600mg, 0.00396mol) and 20mL of anhydrous THF were added and the solution was cooled to 0 ℃. NaH (110mg, 0.00435mol) was gradually added thereto, and after stirring at 0 ℃ for 15 minutes, TBSCl (656mg, 0.00435mol) was added thereto. The spacers were replaced with Teflon screw caps and the sealed tubes were heated at 80 ℃ for 3 hours. Cooled and neutralized with ammonium chloride solution and extracted with hexane. The organic phase was dried and concentrated in vacuo to an oil, which was filtered through a short plug (10% EtOAc-90% hexane) to give 871mg (82%) of compound 43.¹H NMR(500MHz，CDCl₃)8.2(s，1H)，7.8(s，1H)，7.25(s，1H)，6.4(s，1H)，0.9(s，9H)，0.6(s，6H)。

Compound 43 can be brominated at C-3 as previously described in scheme 3 with respect to compound 21.

Compound 19 can be lithiated with, for example, t-BuLi and quenched with DMF to provide 5-formylazaindole 44. Also on palladium catalysts, e.g. Pd (Ph)₃P)₄In the presence of carbon monoxide (carbon moxoxin) and methanolPhysico-chemical compound 19, thereby providing 5-methoxycarbonylazaindole 44. The functional groups are interconverted into acids, primary, secondary and tertiary amides, such as 45, by standard transformations. Compound 44 can be homologated to a compound such as 49 via, for example, a Witting reaction.

Compound 19 can be cyanated with, for example, KCN in the presence of a catalyst such as copper or palladium in hot DMF to provide 5-cyanoazaindole 46.

Amination of compound 19 with an amine in the presence of a palladium catalyst provides 5-aminated azaindoles such as 48.

Compound 19 can be arylated or heteroarylated using Suzuki or Stille coupling to provide a compound image 47.

In other aspects, other synthetic schemes and compound syntheses are provided:

scheme 9

5-chloro-3-iodo-pyridin-2-ylamine (1): a round-bottomed flask equipped with an air condenser was charged with 5-chloropyridin-2-ylamine (26g, 0.2ml), acetic acid (78ml) and water (18 ml). Concentrated sulfuric acid (2.6ml) was then added dropwise, and periodic acid (9.5g, 0.04mol) and iodine (20g, 0.08mol) were gradually added. The reaction mixture was stirred vigorously at 80 ℃ for 6 hours and then cooled to room temperature.

The reaction mixture was poured into ice (. about.700 g). The pH of the suspension was adjusted to 8-9 with 5M aqueous NaOH. The brown solid was filtered off and dissolved in EtOAc (1.21). With saturated Na₂S₂0₃The organic phase was washed with aqueous solution, 1M NaOH solution and brine. At MgS0₄The organic phase was dried and concentrated. The residue was recrystallized from cyclohexane to give an orange solid (42g, 80%).¹H NMR(CDCl₃)：4.8-5.1(2H，brs)，7.9(1H，s)，8.0(1H，s)。

5-chloro-3- (trimethyl-silanylethynyl) -pyridin-2-ylamine (2): a250 mL round bottom flask was charged with 5-chloro-3-iodo-pyridin-2-ylamine (1) (42g, 165mmol), THF (100mL), copper iodide (315mg, 1.65mmol), and PdCl under nitrogen₂(PPh₃)₂(1.15g, 1.65mmol), triethylamine (70ml, O.5mol), and trimethylsilylacetylene (30ml, 0.21 mol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then cooled to 0 ℃ and diethyl ether was added. The suspension was filtered through celite and washed thoroughly with diethyl ether. The filtrate was concentrated and pre-absorbed onto silica gel and purified by column chromatography using pentane/DCM 10% -100% as eluent to afford an off-white solid (36g, 100%).¹HNMR(CDCl₃)：0.3(9H，s)，5.0-5.1(2H，brs)，7.6(1H，s)，7.9(1H，s)。MS(ES+)：225，227。

5-chloro-1H-pyrrolo [2, 3-b]Pyridine (3): a solution of potassium tert-butoxide (36g, 320mmol) in N-methylpyrrolidone (70ml) was heated to 80 ℃ under nitrogen. A solution of 5-chloro-3- (trimethyl-silanylethynyl) -pyridin-2-ylamine (2) (36g, 160mmol) in NMP (200ml) was added dropwise via a dropping funnel. The reaction mixture was stirred for another 50 minutes at 80 ℃. The reaction mixture was allowed to cool to room temperature. Bromine (500ml) was added to the reaction mixture and extracted with diethyl ether (5 × 200 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography using pentane/EtOAc 0% -40% as eluent and recrystallized from cyclohexane to provide the title compound (10g, 41%).¹H NMR(CDCl₃)6.5(1H，s)，7.4(1H，s)，8.0(1H，s)，8.2(1H，s)，10.4-10.6(1H，brs)。MS(ES+)153。

3-bromo-5-chloro-1H-pyrrolo [2, 3-b ]]Pyridine (4): a solution of bromine (3.5ml) in chloroform (40ml) was added dropwise to 5-chloro-1H-pyrrolo [2, 3-b ]]Pyridine (3) (10g, 65mM) was dissolved in an ice-cold solution of chloroform (260 ml). The reaction mixture was stirred at 0 ℃ for 60 minutes. The reaction mixture was then hydrolyzed with water and the pH of the solution was adjusted to 10. The resulting solid was removed by filtration and the aqueous phase was extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo to provide the title compound (10.5g, 69%).¹H NMR(DMSO-d6)7.8(1H，s)，7.9(1H，s)，8.3(1H，s)。

3-bromo-5-chloro-1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b]Pyridine (5): sodium hydride (2.2g, 54mmol) was gradually added to 3-bromo-5-chloro-1H-pyrrolo [2, 3-b ] under nitrogen]Pyridine (4) (10.5g, 45mmol) was dissolved in an ice-cold solution of dimethylformamide (70 ml). After 30 min, tosyl chloride (8.7g, 46mmol) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was hydrolyzed with water (-150 ml) and filtered to give a brown solid, which was dried in vacuo to provide the title compound (14, 8g, 85%).¹HNMR(CDCl₃)2.4(3H，s)，7.3-7.4(2H，d)，7.8-7.9(2H.2s)，8.1-8.2(2H，d)，8.4(1H，s)；MS(ES+)387

5-chloro-3- (4, 4, 5, 5-tetramethyl- [1, 3, 2)]Dioxaborolan-2-yl) -1- (toluene-4-sulfonyl) -1H- [2, 3-b]Pyridine compound(6): a500 mL round bottom flask was charged with 3-bromo-5-chloro-1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b ] under nitrogen]Pyridine (5) (6.9g, 18mmol), bispinacolatodiboron (6.9g, 27mmol), PdCl₂(dppf)₂(1.5g, 1.8mmol), potassium acetate (5.3g, 54mmol) and dimethoxyethane (100 ml). The reaction mixture was stirred at 90 ℃ for 18 hours. The reaction mixture was diluted with ethyl acetate (200ml) and washed with brine. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography using pentane/EtOAc 0% -20% as eluent, then triturated with pentane to provide the title compound (4g, 50%).¹HNMR(CDCl₃)1.4(9H，s)，2.4(3H，s)，7.2(2H，d)，8.00-8.05(2H，d)，8.10(2H，s)，8.3(1H，s)。MS(ES+)433

(6-bromo-pyridin-2-yl) - (4-chloro-benzyl) -amine (7): a microwave vial was charged with 4-chlorobenzylamine (700 mg; 5 mmol; 5 equivalents) and 2, 6-dibromopyridine (238mg, 1 mmol). The reaction mixture was stirred with a microwave 3 times for 10 minutes (maximum 200W) at 150 ℃. The reaction mixture was diluted with diethyl ether (50ml), washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo to provide the title compound as an oil (300mg, 100% yield). LC/MS: 299[ M + H ]

(4-chloro-benzyl) - [6- (5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -pyridin-2-yl]-amine (8): a microwave vial was charged with (6-bromo-pyridin-2-yl) - (4-chloro-benzyl) -amine (300mg, 1mmol), 5-chloro-3- (4, 4, 5, 5-tetramethyl- [1, 3, 2]Dioxabolan-2-yl) -1- (toluene-4-sulfonyl-lH- [2, 3-b]Pyridine (7) (215mg, 0.5mmol), tetrakis (triphenylphosphine) palladium(60mg, 0.05mmol), 2M sodium hydroxide (0.75ml) and dimethoxyethane (5 ml). The suspension was degassed with nitrogen. The reaction mixture was stirred with a microwave at 130 ℃ for 10 minutes (maximum 200W). It was then diluted with ethyl acetate (60ml), washed twice with brine, dried over magnesium sulfate and, after filtration, concentrated in vacuo. This compound was purified by flash chromatography (eluent: petroleum ether/ethyl acetate 60/40) to afford 50mg of the tosyl protected title compound. The residue was dissolved in a mixture of methanol and tetrahydrofuran (1/3 ml). 1M sodium hydroxide solution (1ml) was added to the reaction mixture, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue triturated with methanol. The suspension was filtered to provide the title compound (35mg, 10%).¹H NMR(DMSO-d6)：4.60-4.70(2H，m)，6.35-6.40((1H，d)，7.05-7.10(1H，d)，7.20-7.25(1H，t)，7.35-7.45(4H，m)，8.15-8.20(2H，m)，8.55-8.60(1H，s)，12.5(1H，s)。LC/MS：369[M+H]，367[M-H]

Table 3 below describes data for specific exemplary compounds. Compound numbers correspond to those described in table 1. "-" indicates that no measurement was made.

TABLE 3

Table 4 below describes data for specific exemplary compounds, with compound numbers corresponding to those described in table 2. Blank indicates no measurement was performed.

Table4

B) Biological data

Example 1: JAK3 inhibition assay

Compounds were screened for their ability to inhibit JAK3 using standard radioactive enzyme assays. Stock DMSO containing serial dilutions of a compound of the invention (concentrations of 667. mu.M-46 nM) was plated onto 96-well polycarbonate plates at 1.5. mu.L/well. Add 50. mu.L/well to plate containing 2. mu.M poly (Glu)₄Kinase buffer of Tyr and 10. mu.M ATP (100mM HEPES (pH 7.4), 100mM MgCl₂25mM NaCl, 1mM DTT, and 0.01% Bovine Serum Albumin (BSA)). To start the reaction, 50 μ L of kinase buffer containing 2nM JAK3 enzyme was added. Final ATP concentration 5. mu.M [ gamma. -³³P]ATP(200μCi ³³P ATP/. mu.mol ATP (Perkin Elmer, Cambr idge, MA)). After 20 minutes at room temperature (25 ℃), the reaction was stopped by adding 50. mu.L of 20% trichloroacetic acid (TCA)/0.4mM ATP to each well. The entire contents of each well were then transferred to a 96-well glass fiber filter plate using a TomTek cellharvest. After washing, 60 μ L scintillation fluid was added and detected using a Perkin Elmer TopCount³³And (4) doping P. After removing the average background value for all data points, the data were fitted using Prism software to obtain K_i(app). Except for Final Poly (Glu)₄The inhibition of JAK2 was measured as described above, except for Tyr concentration of 15 μ M and final ATP concentration of 12 μ M.

Example 2: ROCK inhibition assay

Compounds were screened for their ability to inhibit ROCK I (AA 6-553) using a standard coupled enzyme system (Fox et al, (1998) Protein Sci.7, 2249). The reaction was carried out in the presence of 100mM HEPES (pH7.5), 10mM MgCl₂25mM NaCl, 2mM DTT and 1.5% DMSO. The final substrate concentration in the assay was 45. mu.M ATP (Sigma Chemicals, St Loui, Mo.) and 200. mu.M Peptide (American Peptide, Sunnyvale, Calif.). The reaction was carried out at 30 ℃ and 45 nROCK I. The final concentration of each component of the coupled enzyme system was 2.5mM phosphoenolpyruvate, 350. mu.M NADH, 30. mu.g/ml pyruvate kinase and 10. mu.g/ml lactate dehydrogenase.

Compounds were screened for their ability to inhibit ROCK using a standard radioactive enzyme system. The assay was carried out in the presence of 100mM HEPES (pH7.5), 10mM MgCl₂25mM NaCl, 2mM DTT and 1.5% DMSO. The final substrate concentration in the assay was 13. mu.M [ gamma-³³P]ATP(25mCi ³³P ATP/mmol ATP, Perkin Elmer, Cambr idge, MA/Sigma Chemicals, St Louis, MO) and 27. mu.M Myelin Basic Protein (MBP). The final enzyme concentration in the assay was 5nM ROCK. The measurement was carried out at room temperature. mu.L of stock DMSO containing serial dilutions of a compound of the invention (at a concentration of 10. mu.M-2.6 nM) was plated onto 96-well plates. To the plate, 50. mu.L of solution 1(100mM HEPES (pH7.5), 10mM MgCl₂、26mM[γ-³³P]ATP). By adding 50. mu.L of solution 2(100mM HEPES (pH7.5), 10mM MgCl₂4mM DTT, 54mM MBP and 10nM ROCK). After 2 hours, the reaction was quenched with 50 μ L of 30% trichloroacetic acid (TCA, Fisher) containing 9mM ATP. 140 μ L of the finished reaction was transferred to a glass fiber filter plate (Corning, Cat. No.3511) and washed 3 times with 5% TCA. Add 50 μ L Opt ima Gold scintillation liquid (Perkin Elmer) and Count plates on Top Count (Perkin Elmer). After removing the average background value for all data points, the data were fitted using Prism software to obtain K_i(app)。

Example 3: au coatingrora inhibition assay

Standard coupling enzyme systems were used (Fox et al,Protein Sci.7, 2249(1998)) screening compounds for their ability to inhibit Aurora-A (AA 1-403). The reaction was carried out in 100mM HEPES (pH7.5), 10mM MgCl₂25mM NaCl, 300. mu.M NADH, 1mM DTT and 3% DMSO. The final substrate concentrations in the assay were 200. mu.M ATP (SigmaChemicals, St Loui, MO) and 800. mu.M Peptide (LRRASLG, American Peptide, Sunnyvale, Calif.). The reaction was carried out at 30 ℃ and 35nM Aurora-A. The final concentrations of the components of the coupled enzyme system were 2.5mM phosphoenolpyruvate, 200. mu.M NADH, 60. mu.g/ml pyruvate kinase and 20. mu.g/ml lactate dehydrogenase.

Assay stock buffer solutions were prepared containing all the agents listed above except ATP and the test compound of interest. The assay stock buffer solution (60. mu.l) was incubated with 2. mu.l of the test compound of interest at a final concentration of 0.002. mu.M to 30. mu.M for 10 minutes at 30 ℃ in 96-well plates. Typically, a 12-point titration is performed by preparing serial dilutions (starting from a 1mM stock of compound) of the test compound in DMSO in a sub-plate. The reaction was started by adding 5. mu.l ATP (final concentration 200. mu.M). The reaction rate was obtained using a Molecular Devices Spectramax plate reader (Sunnyvale, Calif.) for 10 minutes at 30 ℃. Ki values were determined from rate data as a function of inhibitor concentration using computerized non-linear regression (Prism 3.0, Graphpad software, San Diego, CA). Aurora-C proteins were used to screen for Aurora-C activity in a similar manner. Aurora-B protein was used, and Aurora-B activity was screened using a radioactive assay, as described in examples 1 and 2.

The enzyme inhibition data (K) for specific exemplary compounds are described in Table 5 below_i). Compound numbers correspond to those described in table 1.

The enzyme inhibition data (K) for specific exemplary compounds are described in Table 6 below_i). Compound numbers correspond to those described in table 2.

In tables 5 and 6, enzymes are designatedIn other words, "A" represents a K of less than 0.5. mu.M_iAnd "B" represents a K between 0.5 and 5.0. mu.M_iAnd "C" represents a K of more than 5.0. mu.M_i. If more than one K is determined_iA value, then, represents the average K_i. If no value is given, K is not determined_i. In the case of ROCK, the term "enzyme" means that an enzyme-linked assay is used; term "³³P "indicates that a radioactive assay is used.

TABLE 5 enzyme inhibition data for the compounds of Table 1

Table 6 enzyme inhibition data for the compounds of table 2

Claims (66)

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹is T-R 'or-Si (R')₃；

R²、R³And R⁴Each independently of the other being halogen, CN, NO₂Or V-R';

X¹、X²and X³Each independently is N, or CH, wherein the hydrogen atom of CH is optionally substituted by R⁵Substitution;

x is 1, 2, 3, or 4;

R⁵independently for each occurrence of (A) is halogen, CN, NO₂Or U-R', wherein at least one R⁵Is not H;

t, V, and U are each independently a bond or optionally substituted C₁-C₆Alkylene chain, wherein the chain is optionally and independently represented by-NR' -, -S-, -O-, -CS-, -CO₂-、-OCO-、-CO-、-COCO-、-CONR′-、-NR′CO-、-NR′CO₂-、-SO₂NR′-、-NR′SO₂-、-CONR′NR′-、-NR′CONR′-、-OCONR′-、-NR′NR′-、-NR′SO₂NR′-、-SO-、-SO₂-、-PO-、-PO₂-, or-POR' -substitution; and is

Each occurrence of R' is independently hydrogen or an optionally substituted group selected from: c₁-C₆An aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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 two occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, with the proviso that:

a) if R is¹Is a substituted cyclopentyl group, X is 1, X¹And X³Is CH, then X²Is not C-R⁵Wherein R is⁵Is fluorine or OMe;

b) if R is²And R³Is simultaneously H and R¹And R⁴Independently selected from H or Me, X is 1, X¹And X³Is CH, then X²Is not C-R⁵Wherein R is⁵Is OMe, NO₂Or fluorine;

c) if R is¹、R²、R³And R⁴While being H, x is 1, R⁵is-SMe, NH₂Or an optionally substituted NH-piperidine, and X¹And X²Is N, then X³Is not CH;

d) if R is²、R³And R⁴At the same time being H, X¹、X²And X³Is CH, and two R⁵Form a fused optionally substituted bicyclic ring with the ring to which they are attached, then R¹Is not CH₂CH₂N(Me)₂；

e) If R is²And R³At the same time being H, R⁴Is NH₂And X¹、X²And X³Is CH, then R¹Is not a substituted phenyl group;

f) if R is²、R³And R⁴While being H, then R¹Is not Si (R')₃(ii) a And

g) if R is¹、R²And R⁴Is simultaneously H and (i) X²And X³Is CH or CR⁵Or (ii) X¹、X²Or X³Is N, then R³Not being phenyl or substituted by O-phenyl or N (Me)₂A substituted phenyl group.

2. The compound of claim 1, wherein:

a)R¹is T-R', wherein T is a bond or optionally substituted C₁-C₆Alkylene chain in which up to two methylene units are optionally and independently replaced by-O-, -S-, -NR' -, -OCO-, -COO-, -SO₂-or-CO-substituted, and R' is hydrogen, C₁-C₄-alkyl, or optionally substituted 5-or 6-membered aryl or heteroaryl; or

R¹is-Si (R')₃R' is hydrogen, C₁-C₄-alkyl, or an optionally substituted 5-or 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

3. According to the claimsThe compound of claim 1, wherein R¹Is hydrogen, C₁-C₄Alkyl, -COR', -SO₂R ', or-Si (R')₃。

4. The compound of claim 1, wherein R¹Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, p-toluenesulfonyl (Ts), tert-butyldimethylsilyl (TBS), Triisopropylsilyl (TIPS), or Triethylsilyl (TES).

5. The compound of claim 1, wherein R²、R³And R⁴Each independently hydrogen, R', halogen, CN, NO₂、-N(R′)₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-COOR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R′、-CON(R′)₂、-SO₂N(R′)₂、-CONR′(CH₂)₂N(R′)₂、-CONR′(CH₂)₃N(R′)₂、-CONR′(CH₂)₄N(R′)₂、-O(CH₂)₂OR′、O(CH₂)₃OR′、O(CH₂)₄OR′、-O(CH₂)₂N(R′)₂、-O(CH₂)₃N(R′)₂or-O (CH)₂)₄N(R′)₂。

6. The compound of claim 1, wherein R²、R³And R⁴Each independently of the others is Cl, Br, F, -CN, -COOH, -COOMe, -NH₂、-N(CH₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COOCH₃、-OH、-CH₂OH、-NHCOCH₃、-SO₂NH₂、-SO₂N(Me)₂Or optionallySubstituted radical selected from C₁-C₄Alkyl radical, C₁-C₄Alkoxy, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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.

7. The compound of claim 1, wherein:

a)R²、R³and R⁴Each is hydrogen;

b)R²、R³or R⁴One of which is hydrogen;

c)R²、R³or R⁴Two of which are hydrogen;

d)R²and R⁴Are all hydrogen, and R³Is halogen, CN, NO₂Or V-R';

e)R²and R⁴Are all hydrogen, and R³Is an optionally substituted group selected from a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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;

f)R²and R⁴Are all hydrogen, and R³Is an optionally substituted 5-or 6-membered saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or

g)R²And R⁴Are all hydrogen, and R³Is an optionally substituted ring selected from phenyl, pyridyl, pyrimidinyl, thiazolyl,Oxazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl, orA diazolyl group.

8. The compound of claim 1, wherein R²、R³And R⁴Each is optionally substituted by R⁶Wherein z is 0 to 5 and R⁶Is ═ O, ═ NR ", ═ S, halogen, -CN, -NO₂Or Z-R' wherein Z is a bond or optionally substituted C₁-C₆An alkylene chain wherein at most two methylene units of the chain are optionally and independently replaced by-NR' -, -S-, -O-, -CS-, -CO-₂-、-OCO-、-CO-、-COCO-、-CONR″-、-NR″CO-、-NR″CO₂-、-SO₂NR″-、-NR″SO₂-、-CONR″NR″-、-NR″CONR″-、-OCONR″-、-NR″NR″-、-NR″SO₂NR″-、-SO-、-SO₂-、-PO-、-PO₂-, or-POR "-and each occurrence of R" is independently hydrogen or optionally substituted C₁-C₆An aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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 two occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

9. The compound of claim 8, wherein z is 0, 1, 2, or 3, and R is⁶Independently for each occurrence of (a) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R″)₂、-CH₂N(R″)₂、-OR″、-CH₂OR″、-SR″、-CH₂SR″、-COOR″、-NR″COR″、-NR″COOR″、-CON(R″)₂、-SO₂N(R″)₂、-CONR″(CH₂)₂N(R″)₂、-CONR(CH₂)₃N(R″)₂、-CONR″(CH₂)₄N(R″)₂、-O(CH₂)₂OR″、O(CH₂)₃OR″、O(CH₂)₄OR″、-O(CH₂)₂N(R″)₂、-O(CH₂)₃N(R″)₂、-O(CH₂)₄N(R″)₂、-NR″CH(CH₂OH)R″、-NR″CH(CH₂CH₂OH)R″、-NR″(CH₂)R″、-NR″(CH₂)₂R″、-NR″(CH₂)₃R″、-NR″(CH₂)₄R″、-NR″(CH₂)N(R″)₂、-NR″(CH₂)₂N(R″)₂、-NR″(CH₂)₃N(R″)₂、-NR″(CH₂)₄N(R″)₂、-NR″(CH₂)OR″、-NR″(CH₂)₂OR″、-NR″(CH₂)₃OR ', OR-NR' (CH)₂)₄OR″。

10. The compound of claim 8, wherein z is 1, 2, or 3 and R⁶Each occurrence of (A) is independently F, Cl, Br, CN, OH, NH₂、-CH₂OH、C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -CH₂O(C1-C₆Alkyl), -CO (C1-C)₆Alkyl), -COO (C)₁-C₆Alkyl), -NHSO₂(C₁-C₆Alkyl), -SO₂NH₂、-CONH₂、-CON(C₁-C₆Alkyl), -SO₂(C₁-C₆Alkyl), -SO₂Phenyl, benzyl, -N (C)₁-C₆Alkyl radical)₂or-S (C)₁-C₆Alkyl) wherein the foregoing phenyl, benzyl, and C₁-C₆Each alkyl is independently and optionally substituted, and wherein C is as previously described₁-C₆Each alkyl group is straight, branched, or cyclic.

11. The method of claim 1A compound of formula (I) wherein X¹、X²Or X³Two of (a) are N, and X¹、X²Or X³The remaining one of (A) is CH, wherein the hydrogen atom of CH is optionally substituted by R⁵And (4) substitution.

12. The compound of claim 1, wherein X¹、X²Or X³Is N, and X¹、X²Or X³The remaining two of (A) are CH, wherein the hydrogen atom of CH is optionally substituted by R⁵And (4) substitution.

13. The compound of claim 1, wherein X¹、X²And X³Each is CH, wherein the hydrogen atom of CH is optionally substituted by R⁵And (4) substitution.

14. The compound of claim 1, wherein the compound has one of formulas I-A, I-B, I-C or I-D:

15. the compound of claim 1, wherein R⁵Independently for each occurrence of (A) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R′)₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-COOR′、-NR′COR′、-NR′COCH₂R′、-NR′CO(CH₂)₂R′、-NR′COOR′、-CON(R′)₂、-SO₂N(R′)₂、-CONR′(CH₂)₂N(R′)₂、-CONR(CH₂)₃N(R′)₂、-CONR′(CH₂)₄N(R′)₂、-O(CH₂)₂OR′、O(CH₂)₃OR′、O(CH₂)₄OR′、-O(CH₂)₂N(R′)₂、-O(CH₂)₃N(R′)₂、-O(CH₂)₄N(R′)₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、-NR′(CH₂)₃R′、-NR′(CH₂)₄R′、-NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-NR′(CH₂)₃N(R′)₂、-NR′(CH₂)₄N(R′)₂、-NR′(CH₂)OR′、-NR′(CH₂)₂OR′、-NR′(CH₂)₃OR ', OR-NR' (CH)₂)₄OR′。

16. The compound of claim 1, wherein x is 1, 2, or 3, and R⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、-NR′(CH₂)N(R′)₂or-NR' (CH)₂)₂N(R′)₂。

17. The compound of claim 1, wherein x is 1, 2, or 3, and R⁵is-OR' in at least one occurrence of (a).

18. The compound of claim 1, wherein x is 1, 2, or 3, and R⁵is-NR ' COR ', -NR ' COCH₂R ', or-NR' CO (CH)₂)₂R′。

19. The compound of claim 1, wherein x is 1, 2, or 3, and R⁵Is at least one occurrence of optionally substituted C₁-C₆An aliphatic group, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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.

20. The compound of claim 1, wherein x is 1 or 2, and R⁵Each occurrence of (A) is independently halogen, R', CN, -CH₂CN、-(CH₂)₂CN、NO₂、-CH₂NO₂、-(CH₂)₂NO₂、CON(R′)₂、-CH₂CON(R′)₂、-(CH₂)₂CON(R′)₂、COOR′、-CH₂COOR′、-(CH₂)₂COOR′、-SO₂N(R′)₂、-CH₂SO₂N(R′)₂、-(CH₂)₂SO₂N(R′)₂、-NR′SO₂R′、-CH₂NR′SO₂R′、-(CH₂)₂NR′SO₂R′、NR′CON(R′)₂、-CH₂NR′CON(R′)₂、-(CH₂)₂NR′CON(R′)₂、-NR′SO₂N(R′)₂、-CH₂NR′SO₂N(R′)₂、-(CH₂)₂NR′SO₂N(R′)₂、-COCOR′、-CH₂COCOR′、-(CH₂)₂COCOR′、-N(R′)₂、-CH₂N(R′)₂、-(CH₂)₂N(R′)₂、-OR′、-CH₂OR′、-(CH₂)₂OR′、-NR′COR′、-NR′COCH₂R′、-NR′CO(CH₂)₂R′、-CH₂NR 'COR', or- (CH)₂)₂NR′COR′。

21. The compound of claim 20, wherein R⁵Is CN, -CH₂CN、-(CH₂)₂CN、-NO₂、-CH₂NO₂、-(CH₂)₂NO₂、OR′、-CH₂OR′、-CON(R′)₂、-SO₂N(R′)₂、-N(R′)₂Or R'.

22. The compound of claim 20, wherein R⁵Independently for each occurrence of (a) is hydrogen, halogen, CN, -CH₂CN、-(CH₂)₂CN、NO₂、-CH₂NO₂、-(CH₂)₂NO₂、-CONH₂、-CON(C₁-C₄Alkyl), -SO₂NH₂、-SO₂N(C₁-C₄Alkyl), NH₂、-N(C₁-C₄Alkyl), -OH, -O (C)₁-C₄Alkyl), -CH₂OH、-CH₂O(C₁-C₄Alkyl), or an optionally substituted 5-or 6-membered unsaturated ring, wherein 0 to 3 ring carbon atoms are optionally substituted with oxygen, sulfur, or nitrogen.

23. The compound of claim 1, wherein R⁵Optionally substituted with R⁷Y occurrences of (a) wherein y is 0-5 and R⁷Is ═ O, ═ NR ", ═ S, halogen, -CN, -NO₂Or W-R', wherein W is a bond or optionally substituted C₁-C₆An alkylene chain wherein at most two methylene units of the chain are optionally and independently replaced by-NR' -, -S-, -O-, -CS-, -CO-₂-、-OCO-、-CO-、-COCO-、-CONR″-、-NR″CO-、-NR″CO₂-、-SO₂NR″-、-NR″SO₂-、-CONR″NR″-、-NR″CONR″-、-OCONR″-、-NR″NR″-、-NR″SO₂NR″-、-SO-、-SO₂-、-PO-、-PO₂-, or-POR "-and each occurrence of R" is independently hydrogen or optionally substituted C₁-C₆An aliphatic group, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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 two occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

24. The compound of claim 23, wherein y is 0, 1, 2, or 3, and R is⁷Independently for each occurrence of (a) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R″)₂、-CH₂N(R″)₂、-OR″、-CH₂OR″、-SR″、-CH₂SR″、-COOR″、-NR″COR″、-NR″COOR″、-CON(R″)₂、-SO₂N(R″)₂、-CONR″(CH₂)₂N(R″)₂、-CONR(CH₂)₃N(R″)₂、-CONR″(CH₂)₄N(R″)₂、-O(CH₂)₂OR″、O(CH₂)₃OR″、O(CH₂)₄OR″、-O(CH₂)₂N(R″)₂、-O(CH₂)₃N(R″)₂、-O(CH₂)₄N(R″)₂、-NR″CH(CH₂OH)R″、-NR″CH(CH₂CH₂OH)R″、-NR″(CH₂)R″、-NR″(CH₂)₂R″、-NR″(CH₂)₃R″、-NR″(CH₂)₄R″、-NR″(CH₂)N(R″)₂、-NR″(CH₂)₂N(R″)₂、-NR″(CH₂)₃N(R″)₂、-NR″(CH₂)₄N(R″)₂、-NR″(CH₂)OR″、-NR″(CH₂)₂OR″、-NR″(CH₂)₃OR ', OR-NR' (CH)₂)₄OR″。

25. The compound of claim 23, wherein y is 1, 2, or 3 and R⁷Each occurrence of (A) is independently F, Cl, Br, CN, OH, NH₂、-CH₂OH、C₁-C₆Alkyl, -O (C)₁-C₆Alkyl), -CH₂O(C₁-C₆Alkyl), -CO (C)₁-C₆Alkyl), -COO (C)₁-C₆Alkyl), -NHSO₂(C₁-C₆Alkyl), -SO₂NH₂、-CONH₂-、-CON(C₁-C₆Alkyl), -SO₂(C₁-C₆Alkyl), -SO₂Phenyl, benzyl, -N (C)₁-C₆Alkyl radical)₂、-S(C₁-C₆Alkyl) wherein the foregoing phenyl, benzyl and C₁-C₆Alkyl is independently and optionally substituted, and C is₁-C₆Each alkyl group is straight, branched, or cyclic.

26. The compound of claim 1, wherein x is 1, 2, or 3; r⁵is-N (R')₂、-NR′CH(CH₂OH)R′、-NR′CH(CH₂CH₂OH)R′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-OR′、-NR′COR′、-NR′COCH₂R ', or-NR' CO (CH)₂)₂R 'and R' is C₁-C₆An aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 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 two occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfurMonocyclic or bicyclic ring, wherein each occurrence of R' is optionally substituted by R⁷Y occurrences of substitution.

27. The compound of claim 26, wherein R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₆Alkyl, or a saturated, partially unsaturated, or fully unsaturated 5-to 10-membered monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is optionally substituted with R⁷1-3 occurrences of substitution.

28. The compound of claim 26, wherein R' is hydrogen, optionally substituted with R⁷1-3 occurrences of substituted C₁-C₄Alkyl, or is cyclic, selected from:

wherein y is 0-5 and R⁷Is ═ O, ═ NR ", ═ S, halogen, -CN, -NO₂Or W-R', wherein W is a bond or optionally substituted C₁-C₆Alkylene chain, wherein the chain is optionally and independently substituted by NR' -, -S-, -O-, -CS-, -CO₂-、-OCO-、-CO-、-COCO-、-CONR″-、-NR″CO-、-NR″CO₂-、-SO₂NR″-、-NR″SO₂-、-CONR″NR″-、-NR″CONR″-、-OCONR″-、-NR″NR″-、-NR″SO₂NR″-、-SO-、-SO₂-、-PO-、-PO₂-, or-POR "-substitution, and each occurrence of R" -, or-POR "-, withIndependently is hydrogen or optionally substituted C₁-C₆An aliphatic group, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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 two occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

29. The compound of claim 1, wherein R⁵is-N (R')₂And two occurrences of R' taken together with the nitrogen atom to which they are bound form an optionally substituted 3-10-membered monocyclic or bicyclic heterocycle. In particular embodiments, the ring is selected from:

wherein y is 0-5 and R⁷Is ═ O, ═ NR ", ═ S, halogen, -CN, -NO₂Or W-R', wherein W is a bond or optionally substituted C₁-C₆An alkylene chain wherein at most two methylene units of the chain are optionally and independently replaced by-NR' -, -S-, -O-, -CS-, -CO-₂-、-OCO-、-CO-、-COCO-、-CONR″-、-NR″CO-、-NR″CO₂-、-SO₂NR″-、-NR″SO₂-、-CONR″NR″-、-NR″CONR″-、-OCONR″-、-NR″NR″-、-NR″SO₂NR″-、-SO-、-SO₂-、-PO-、-PO₂-, or-POR "-and each occurrence of R" is independently hydrogen or optionally substituted C₁-C₆Aliphatic radical, 3-8 membered saturated having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfurAnd, a partially unsaturated, or fully unsaturated monocyclic ring, 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 two occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

30. A compound selected from table 1.

31. The compound according to claim 1, wherein the compound has one of formulas I-A, I-B or I-E:

32. the compound according to any one of claims 1, 14 or 31, wherein R²And R⁴Each independently selected from H, Cl, Br, F, -CN, -COOH, -COOR', -NH₂、-N(CH₃)₂、-N(Et)₂、-N(iPr)₂、-NHR′、-OR′、-SR′、-O(CH₂)₂OCH₃、-CONH₂、-CONHR′、CON(R′)₂、-OH、-CH₂OH、CH₂NH₂、-CH₂NHR′、-CH₂N(R′)₂、-C(R′)₂N(R′)₂、-NHCOCH₃、-N(R′)COR′、-SO₂NH₂、-SO₂N(Me)₂Or an optionally substituted group selected from C₁-C₆Aliphatic radical, C₁-C₆Alkoxy, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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。

33. The compound of claim 32, wherein R²And R⁴Each is hydrogen.

34. The compound of claim 31, wherein R¹Selected from hydrogen, C₁-C₄Alkyl, -COR', -SO₂R ', or-Si (R')₃。

35. The compound of claim 34, wherein R¹Is hydrogen.

36. The compound of claim 31, wherein R³Selected from H, Cl, Br, F, -CN, -COOH, -COOMe and-NH₂、-N(R′)₂、-NO₂、-OR′、-CON(R′)₂、-COOR′、-OH、-SR′、-C(R′)₂OR′、-N(R′)COR′、-N(R′)C(O)OR′、-SO₂NH₂、-SO₂N(R′)₂Or an optionally substituted group selected from C₁-C₄Aliphatic radical, C₁-C₄Alkoxy or-C ≡ C-C₁-C₄An aliphatic group.

37. The compound of claim 36, wherein R³Selected from H, Cl, -Br, -CN, -COOH, -COOMe, -CONHR', -CON (Me)₂、-CH₂OH、-NO₂、-NH₂Or optionally substituted C₁-C₄An aliphatic group.

38. The compound of claim 37, wherein R³Selected from Cl, -Br, -CN or optionally substituted C₁-C₄An aliphatic group.

39. The compound of claim 37, wherein R³Is Cl.

40. The compound according to any one of claims 1, 14 or 31, wherein R¹、R²And R⁴Is hydrogen and R³Selected from Cl, -Br, -CN or optionally substituted C₁-C₄An aliphatic group.

41. The compound of claim 37, wherein R³Is H, OR ', NR' C (O) R ', NR' C (O) OR ', CON (R')₂Or COOMe.

42. The compound of claim 37, wherein R³Is OR ', NR ' C (O) R ' OR NR ' C (O) OR '.

43. The compound according to any one of claims 1, 14 or 31, wherein R¹、R²And R⁴Is hydrogen and R³Selected from H, OR ', NR' C (O) R ', NR' C (O) OR ', CON (R')₂Or COOMe.

44. The compound of claim 31, wherein x is 1, 2, or 3; wherein R is⁵Each occurrence of (A) is independently selected from R', -CH₂R', halogen, CN, NO₂、-N(R′)₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-COOR′、-NR′COR′、-NR′COR⁸R′、-NR′COOR′、-CON(R′)₂、-SO₂N(R′)₂、-CONR′R⁸N(R′)₂、-OR⁸OR′、-OR⁸N(R′)₂、-NR′CH(R⁹)R′、-NR′CH(R⁹)C(O)OR′、-N(R′)R⁸R′、-N(R′)R⁸R′、-N(R′)R⁸N(R′)₂、-N(R′)R⁸OR′、-NR′CH(R⁹)R′、-NR′CH₂C(O)N(R′)₂or-NR' CH (R)⁹)C(O)N(R′)₂Wherein R is⁸Is optionally substituted C₁-C₄Alkyl and R⁹Is optionally substituted C₁-C₆An aliphatic group.

45. The compound of claim 44, wherein R⁵Each occurrence of (A) is independently selected from R', -CH₂R', halogen, -CN, -NO₂、-N(R′)₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-COOR′、-NR′COR′、-NR′COCH₂R′、-NR′CO(CH₂)₂R′、-NR′COOR′、-CON(R′)₂、-SO₂N(R′)₂、-CONR′(CH₂)₂N(R′)₂、-CONR(CH₂)₃N(R′)₂、-CONR′(CH₂)₄N(R′)₂、-O(CH₂)₂OR′、O(CH₂)₃OR′、O(CH₂)₄OR′、-O(CH₂)₂N(R′)₂、-O(CH₂)₃N(R′)₂、-O(CH₂)₄N(R′)₂、-NR′CH(CH₂OR⁹)R′、-NR′CH(CH₂CH₂OR⁹)R′、-NR′CH(CH₃)R′、NR′CH(CF₃)R′、-NR′CH(CH₃)C(O)OR′、-NR′CH(CF₃)C(O)OR′、-NR′(CH₂)R′、-NR′(CH₂)₂R′、-NR′(CH₂)₃R′、-NR′(CH₂)₄R′、-NR′(CH₂)N(R′)₂、-NR′(CH₂)₂N(R′)₂、-NR′(CH₂)₃N(R′)₂、-NR′(CH₂)₄N(R′)₂、-NR′(CH₂)OR′、-NR′(CH₂)₂OR′、-NR′(CH₂)₃OR′、-NR′(CH₂)₄OR′、-NR′CH(CH₂CH₃)R′、-NR′CH₂C(O)N(R′)₂、-NR′CH(CH₃)C(O)N(R′)₂、NR′CH(CF₃)C(O)N(R′)₂、-NR′CH(CH₂CH₃)C(O)N(R′)₂、-NR′CH(CH(CH₃)₂)C(O)N(R′)₂、-NR′CH(C(CH₃)₃)C(O)N(R′)₂、-NR′CH(CH₂CH(CH₃)₂)C(O)N(R′)₂、-NR′CH(CH₂OR⁹)C(O)N(R′)₂or-NR' CH (CH)₂CH₂N(Me)₂)C(O)N(R′)₂。

46. A compound according to claim 44, wherein R⁵Is independently selected from-NR' CH (CH)₂OH)R′、-NR′CH(CH₂OMe)R′、-NR′CH(CH₂OEt)R′、-NR′CH(CH₂OCF₃)R′、-NR′CH(CH₂CH₂OH)R′、-NR′CH(CH₂CH₂OMe)R′、-NR′CH(CH₂CH₂OEt)R′、-NR′CH(CH₂CH₂OCF₃)R′、-NR′CH(CH₃)C(O)OR′、-NR′CH(CF₃)C(O)OR′、-NR′CH(CH₃)C(O)N(R′)₂、-NR′CH(CF₃)C(O)N(R′)₂、-NR′CH(CH₂CH₃)C(O)N(R′)₂、-NR′CH(CH₂OH)C(O)N(R′)₂、-NR′CH(CH₂OMe)C(O)N(R′)₂、-NR′CH(CH₂OEt)C(O)N(R′)₂or-NR' CH (CH)₂OCF₃)C(O)N(R′)₂Wherein R' is optionally substituted C₁-C₄An aliphatic group.

47. A compound according to claim 44, wherein R is⁵Is selected from NHCH₂C(O)NHR′、-NHCH(CH₃)C(O)NHR′、-NHCH(CH₂CH₃)C(O)NHR′、-NHCH(CH(CH₃)₂)C(O)NHR′、-NHCH(C(CH₃)₃)C(O)NHR′、-NHCH(CH₂CH(CH₃)₂)C(O)NHR′、-NHCH(CH₂OH)C(O)NHR′、-NHCH(CH₂OMe) C (O) NHR', or-NHCH (CH)₂CH₂N(Me)₂) C (O) NHR ', wherein R' is optionally substituted C₁-C₄An aliphatic group.

48. The compound of claim 44, wherein R⁵Is independently selected from-NHR', -NH (CH)₂)R′、-NH(CH₂)₂R′、-NHCH(CH₃)R′、-NHCH₂C(O)NHR′、-NHCH(CH₃)C(O)NHR′、-NHCH(CH₂CH₃)C(O)NHR′、-NHCH(CH(CH₃)₂)C(O)NHR′、-NHCH(C(CH₃)₃)C(O)NHR′、NHCH(CH₂CH(CH₃)₂)C(O)NHR′、-NHCH(CH₂OH)C(O)NHR′、-NHCH(CH₂OMe) C (O) NHR' or-NHCH (CH)₂CH₂N(Me)₂) C (O) NHR ', wherein R' is optionally substituted phenyl.

49. A compound according to claim 44, wherein R is⁵is-NHCH (CH) at least one occurrence₃) R ', wherein R' is optionally substituted phenyl.

50. The compound of claim 44, wherein R⁵Is H, halogen, CH₃、CF₃COOH, COOMe OR OR 'wherein R' is C₁-C₄An aliphatic group.

51. The compound of claim 44, wherein x is 2 or 3 and R⁵Is F.

52. The compound of claim 44, wherein R¹、R²And R⁴Is hydrogen and R⁵Selected from-NHR', -NH (CH)₂)R′、-NH(CH₂)₂R′、-NHCH(CH₃)R′、-NHCH₂C(O)NHR′、-NHCH(CH₃)C(O)NHR′、-NHCH(CH₂CH₃)C(O)NHR′、-NHCH(CH(CH₃)₂)C(O)NHR′、-NHCH(C(CH₃)₃)C(O)NHR′、-NHCH(CH₂CH(CH₃)₂)C(O)NHR′、-NHCH(CH₂OH)C(O)NHR′、-NHCH(CH₂OMe) C (O) NHR' or-NHCH (CH)₂CH₂N(Me)₂) C (O) NHR ', wherein R' is optionally substituted phenyl.

53. The compound of claim 44, wherein R¹、R²And R⁴Is hydrogen and R⁵Selected from-NR' CH (CH)₂OH)R′、-NR′CH(CH₂OMe)R′、-NR′CH(CH₂OEt)R′、-NR′CH(CH₂OCF₃)R′、-NR′CH(CH₂CH₂OH)R′、-NR′CH(CH₂CH₂OMe)R′、-NR′CH(CH₂CH₂OEt)R′、-NR′CH(CH₂CH₂OCF₃)R′、-NR′CH(CH₃)C(O)OR′、-NR′CH(CF₃)C(O)OR′、-NR′CH(CH₃)C(O)N(R′)₂、-NR′CH(CF₃)C(O)N(R′)₂、-NR′CH(CH₂CH₃)C(O)N(R′)₂、-NR′CH(CH₂OH)C(O)N(R′)₂、-NR′CH(CH₂OMe)C(O)N(R′)₂、-NR′CH(CH₂OEt)C(O)N(R′)₂or-NR' CH (CH)₂OCF₃)C(O)N(R′)₂Wherein R' is optionally substituted C₁-C₄An aliphatic group.

54. The compound of claim 31, wherein R' is selected from hydrogen, optionally substituted with R⁷Y times of occurrence of substituted C₁-C₆Aliphatic radical, or R' is a ring selected from:

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

wherein y is 0, 1, 2, or 3, and R⁷Independently for each occurrence of (a) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R″)₂、-CH₂N(R″)₂、-OR″、-CH₂OR″、-SR″、-CH₂SR″、-COOR″、-NR″COR″、-NR″COOR″、-CON(R″)₂、-SO₂N(R″)₂、-CONR″(CH₂)₂N(R″)₂、-CONR(CH₂)₃N(R″)₂、-CONR″(CH₂)₄N(R″)₂、-O(CH₂)₂OR″、O(CH₂)₃OR″、O(CH₂)₄OR″、-O(CH₂)₂N(R″)₂、-O(CH₂)₃N(R″)₂、-O(CH₂)₄N(R″)₂、-NR″CH(CH₂OH)R″、-NR″CH(CH₂CH₂OH)R″、-NR″(CH₂)R″、-NR″(CH₂)₂R″、-NR″(CH₂)₃R″、-NR″(CH₂)₄R″、-NR″(CH₂)N(R″)₂、-NR″(CH₂)₂N(R″)₂、-NR″(CH₂)₃N(R″)₂、-NR″(CH₂)₄N(R″)₂、-NR″(CH₂)OR″、-NR″(CH₂)₂OR″、-NR″(CH₂)₃OR ', OR-NR' (CH)₂)₄OR 'and each occurrence of R' is independently hydrogen OR optionally substituted C₁-C₆An aliphatic group, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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 two occurrences of R' taken together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

55. The compound of claim 31, wherein x is 2, 3, or 4 and at least two R on adjacent ring members⁵Is R ', and wherein the two R' s⁵Together with the atoms to which they are bound form an optionally substituted 3-12 membered saturated, partially saturated or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

56. The compound of claim 55, wherein the compound is of formula I-B-vii or I-B-viii:

wherein y is 0, 1, 2, or 3, and R⁷Independently for each occurrence of (a) is hydrogen, R', -CH₂R', halogen, CN, NO₂、-N(R″)₂、-CH₂N(R″)₂、-OR″、-CH₂OR″、-SR″、-CH₂SR″、-COOR″、-NR″COR″、-NR″COOR″、-CON(R″)₂、-SO₂N(R″)₂、-CONR″(CH₂)₂N(R″)₂、-CONR(CH₂)₃N(R″)₂、-CONR″(CH₂)₄N(R″)₂、-O(CH₂)₂OR″、O(CH₂)₃OR″、O(CH₂)₄OR″、-O(CH₂)₂N(R″)₂、-O(CH₂)₃N(R″)₂、-O(CH₂)₄N(R″)₂、-NR″CH(CH₂OH)R″、-NR″CH(CH₂CH₂OH)R″、-NR″(CH₂)R″、-NR″(CH₂)₂R″、-NR″(CH₂)₃R″、-NR″(CH₂)₄R″、-NR″(CH₂)N(R″)₂、-NR″(CH₂)₂N(R″)₂、-NR″(CH₂)₃N(R″)₂、-NR″(CH₂)₄N(R″)₂、-NR″(CH₂)OR″、-NR″(CH₂)₂OR″、-NR″(CH₂)₃OR ', OR-NR' (CH)₂)₄OR 'and each occurrence of R' is independently hydrogen OR optionally substituted C₁-C₆An aliphatic group, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring 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 two occurrences of R' taken together with the atoms to which they are bound form a 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

57. A compound selected from table 2.

58. A pharmaceutical composition comprising a compound of any one of claims 1, 30, 31 or 57 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

59. The composition of claim 58, further comprising an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, a therapeutic agent for Alzheimer's disease, a therapeutic agent for Parkinson's disease, an agent for treating Multiple Sclerosis (MS), a therapeutic agent for asthma, an agent for treating schizophrenia, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disease, an agent for treating liver disease, an agent for treating hematologic disease, or an agent for treating immunodeficiency disease.

60. A method of inhibiting JAK-3, ROCK or Aurora kinase activity in a biological sample or a patient, comprising contacting said biological sample or said patient with:

a) the composition of claim 58; or

b) A step of contacting the compound of claim 1 or claim 31.

61. A method of treating or ameliorating a disease or condition selected from the group consisting of an immune response such as allergy or type I allergy or asthma; autoimmune diseases such as transplant rejection, graft-versus-host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, or multiple sclerosis; neurodegenerative disorders; or solid and hematological malignancies comprising the administration of the composition of claim 58 or the compound of claim 1 or claim 31 to a patient in need thereof.

62. The method of claim 61, including the step of administering to the patient an additional therapeutic agent.

63. The method of claim 61, wherein the disease is an autoimmune disease and transplant rejection, graft-versus-host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, or multiple sclerosis.

64. The method of claim 61, wherein the disease is hypertension, angina pectoris, cerebrovascular atrophy, asthma, a peripheral circulation disorder, premature labor, cancer, erectile dysfunction, arteriosclerosis, spasms (cerebral vasospasm and coronary vasospasm), retinopathy (e.g., glaucoma), an inflammatory disorder, an autoimmune disorder, AIDS, osteoporosis, myocardial hypertrophy, ischemia/reperfusion-induced injury, or endothelial dysfunction.

65. A method of treating, preventing or lessening the severity of a disease or condition selected from the group consisting of heart disease, diabetes, Alzheimer's disease, immunodeficiency disorders, inflammatory diseases, hypertension, allergic diseases, autoimmune diseases, destructive bone diseases, osteoporosis, proliferative disorders, infectious diseases, immune-mediated diseases, viral diseases, hyperplasia, reperfusion/ischemia in stroke, heart attack, organ hypoxia-thrombin-induced platelet aggregation, Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML), Acute Promyelocytic Leukemia (APL), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer, liver ischemia, myocardial infarction, congestive heart failure, pathologic immune disorders involving T-cell activation, and neurodegenerative disorders, which method comprises administering to a patient in need thereof, administering thereto a composition according to claim 58 or a compound according to claim 1 or claim 31.

66. The method of claim 65, wherein the cancer is selected from melanoma, lymphoma, neuroblastoma, leukemia, or a cancer selected from colon, breast, lung, kidney, ovary, endometrium, pancreas, kidney, central nervous system, cervix, prostate, or gastric cancer, CML, AML, APL, Acute Lymphocytic Leukemia (ALL), mastocytosis, or gastrointestinal stromal tumor (GIST).