JP2011504931A - 2-Fluoropyrazolo [1,5-a] pyrimidine as a protein kinase inhibitor - Google Patents

Abstract

Inhibitors of the pyrazolo [1,5-a] pyrimidine system of various kinases, compositions comprising the inhibitors, and methods of using the inhibitors and inhibitor compositions are described. The inhibitors and compositions containing such inhibitors are useful for treating diseases or symptoms. The invention also provides methods of making cyclin dependent kinase CDK-2 or CHK-1 inhibitor compounds, methods of inhibiting CDK-2 or CHK-1, and methods for treating diseases or symptoms.

Description

  The present invention relates to a novel pyrazolo [1,5-a] pyrimidine compound useful as a protein kinase inhibitor, a pharmaceutical composition containing the compound, and a cancer, inflammation, arthritis, viral disease, Alzheimer's disease, etc. It relates to methods of treatment using the compounds and compositions for treating diseases such as neurodegenerative diseases, cardiovascular diseases, and mycoses. The compounds disclosed herein are particularly useful as cyclin dependent kinase inhibitors such as CDK-1 and CDK-2 inhibitors, and checkpoint inhibitors such as CHK-1 inhibitors.

  Cell proliferation and differentiation are highly controlled processes that, if impaired, can result in abnormal cell functions that often result in pathology. Protein phosphorylation is one of the major post-translational mechanisms used to control cellular functions. Protein kinases catalyze the phosphorylation of serine, threonine, and tyrosine residues using either ATP or GTP. Analysis of the human genome has revealed that the presence of about 500 protein kinases is predicted (Manning G, White DB, Martinez R., Hunter T., Sudarsanam S., Science 298, 1912, 2002; Kostich M, England J, Madison V, Gheyas F, Wang L, Qiu P, Greene J, Laz TM., Genome Biol, 3 (9), 2002). If the phosphorylation regulation by these kinases is impaired, a number of diseases can occur including diabetes, Alzheimer's disease, inflammation, and cancer (Cohen P., Eur. J. Biochem. 268, 5001-5010, 2001; Cohen P., Nat. Rev. Drug Discovery 1, 309-315, 2002).

  Multiple cellular signals can stimulate proliferation, differentiation, and apoptosis, and the primary mechanism for regulating these processes involves the cell cycle, which is the G1 of DNA synthesis and mitosis. Controls cell division by regulating the passage of S, G2, and M phases. Protein kinase inhibitors, modulators, or modifiers include cyclin dependent kinases (CDK), mitogen activated protein kinases (MAPK / ERK), glycogen synthase kinase 3 (GSK3beta), checkpoints (Chk) (eg CHK-1, CHK-2, etc.) kinases such as kinase, AKT kinase, JNK, Aurora kinase (Aurora A, Aurora B, Aurora C, etc.) are altered. Examples of protein kinase inhibitors are described in WO 02/22610 A1, By Mettey et al. Med Chem. (2003) 46 222-236.

  Eukaryotic cell cycle progression is controlled by kinases of the cyclin dependent kinase (CDK) family. CDK is primarily a serine / threonine kinase and binds to several different regulatory subunits called cyclins. Different CDK / cyclin heterodimers regulate different processes in the cell cycle, ie CDK4 / cyclin D and CDK2 / cyclin E are thought to regulate the control of G1 to the onset of S phase. Down-regulation of cyclin D and cyclin E and up-regulation of cyclin A, which forms a heterodimer with CDK2 and CDK1, promotes passage from S phase to G2. Finally, activated complexes of CDK1 (Cdc2) / cyclin B and possibly CDK1 (Cdc2) / cyclin A are thought to promote the transition from G2 to M phase. (Reviewed by Murray A., Cell 116, 221-234, 2004). Some known substrates for CDK are tumor suppressor retinoblastoma protein (RB) and related family members p107 and p130 (Grana X., Garriga J., and Mayol X., Oncogene 17, 3365). ~ 3383, 1998). Phosphorylation of RB by CDK4 or CDK2 triggers the release of E2F transcription factor, which subsequently promotes expression of regulatory proteins and stimulates cell cycle progression and cell proliferation. In human tumors, control of RB function results in mutations in the RB gene, CDK4 amplification, overexpression of cyclin D and cyclin E, inactivation of the CDK4-specific protein inhibitor p16INK4A, and perturbed levels of the CDK inhibitor p27KIP1. (Sherr, C., Roberts J., Genes Dev. 13, 1501-1512, 1999; Hall M., Peters G., Adv. Cancer Res. 68, 67-108, 1996; Stewart T, Wesfall M., Pietenpol J., Trends Pharmacol. Sci. 24, 139-145, 2003). These functional disruptions are thought to contribute to the development of breast, large intestine, stomach, prostate, non-small cell lung, ovary, and other human cancers (Tsihiias J., Kapusta L, Slingerland J., Annu. Rev. Med. 50, 401-423, 1999; Lloyd R., Erickson L, Jin L., Kulig E., Qian X., Cheville J., Scheithauser B., Am. J. Pathol, 154 (4), 313-323, 1999).

  Due to the fact that uncontrolled regulation of the cell cycle pathway is believed to be responsible for human cancer, we believe that inhibition of non-regulated CDK activity by small molecule inhibitors would be beneficial in the treatment of cancer. Will be. Many chemo-synthetic efforts have focused on the development of CDK-specific ATP competitive inhibitors, but only a few molecules have been advanced into human clinical trials. This includes flavopiridol, roscovitine (CYC-202), and the 2-aminothiazole derivative BMS-387032 (Zhai, S., Senderowicz A, Sausville E., Figg W., Ann. Pharmacother. 36). McClue S., Blake D., Clarke R., Cummings L., Fischer P, MacKenzie M., Stewart K., Wang S., Zhelev N., Zheleva D., Lane D., 905-911, 2002; Int. J. Cancer 102 (5), 463-468, 2002; Misra R. et al., J. Med. Chem. 47, 1719-1728, 2004).

  Another series of protein kinases play an important role in checkpoints during cell cycle progression. Checkpoints prevent cell cycle progression at an inappropriate time, for example, in response to DNA damage, stop the cell while maintaining the metabolic balance of the cell, and if the checkpoint requirement is not met, In some cases, apoptosis (programmed cell death) can be induced. Checkpoint control can occur at G1 phase (before DNA synthesis) and at G2 before entering mitosis.

A series of checkpoints monitor the integrity of the genome, and these “DNA damage checkpoints”, when DNA damage is sensed, block cell cycle progression in the G ₁ and G ₂ phases and enter the S phase. Delay progress. This action allows the DNA repair process to complete its work prior to genome replication, followed by separation of this genetic material into new daughter cells. Inactivation of CHK1 has been shown to transduce signals from the DNA damage sensing complex and inhibit activation of cyclin B / Cdc2 kinase. Accordingly, it is promoted to enter mitosis, G ₂ arrest induced by DNA damage or endogenous DNA damage by anti-cancer drugs are discontinued, preferential killing of checkpoint deficient cells arising is provided. For example, Peng et al., Science, 277, 1501-1505 (1997); Sanchez et al., Science, 277, 1497-1501 (1997), Nurse, Cell, 91, 865-867 (1997); Weinert, Science, 277, 1450. ˜1451 (1997); Walworth et al., Nature, 363, 368-371 (1993); and Al-Khodairy et al., Molec. Biol. Cell. 5, 147-160 (1994).

  Selective manipulation of checkpoint control in cancer cells may provide broad use in cancer chemotherapy and radiation therapy regimens, and in addition, human cancer used as a selective criterion for cancer cell destruction Can provide common features of “genomic instability”. Several factors position CHK1 as a central target in DNA-damage checkpoint control. Elucidation of this inhibitor and functionally related kinases such as CDS1 / CHK2, ie kinases recently discovered to cooperate with CHK1 in regulating S-phase progression (Non-Patent Document 1; Non-Patent Document 2) See)), and may provide valuable new therapeutic entities for the treatment of cancer.

Zeng et al., Nature, 395, 507-510 (1998). Matsuoka, Science, 282, 1893-1897 (1998).

  There is a need to develop CDK and CHK1 inhibitors for the treatment of human diseases, and therefore it is an object of the present invention to describe compounds that would be useful in the prevention or alteration of these diseases. is there.

  The present invention relates to novel compounds, compositions containing the compounds, and methods of using the compounds. The compounds are heterocyclic molecules that are useful for therapeutic applications, including modulation of disease or symptom in a subject (eg, cat, dog, horse, or human). These diseases include Alzheimer's disease, cancer, diabetes, and inflammation. These compounds (including their stereoisomers) are synthesized alone or combinatorially to provide a structurally and stereochemically diverse library of compounds.

  In certain embodiments, the compound is a fluoro-substituted pyrazolopyrimidine compound. In one embodiment, provided herein is a compound of formula (I):

（式中：
Ｒ^３は、水素、アルキル、シクロアルキル、シクレニル、アルキニル、トリフルオロアルキル、ジフルオロアルキル、モノフルオロアルキル、ヘテロシクリル、ヘテロシクレニル、アリール、ヘテロアリール、ハロ、シアノ、−Ｏ−トリハロアルキル、ＮＲ^８Ｒ^９、ＣＯ_２Ｒ^８、ＣＯＮＲ^８Ｒ^９、−ＯＲ^８、−ＳＲ^８、−ＳＯ_２Ｒ^８、−ＳＯ_２ＮＲ^８Ｒ^９、−ＮＲ^８ＳＯ_２Ｒ^９、−ＮＲ^８ＣＯＲ^９、またはＮＲ^８ＣＯＮＲ^８Ｒ^９であり、ここでは、前記アルキル、シクロアルキル、シクレニル、アルキニル、トリフルオロアルキル、ジフルオロアルキル、モノフルオロアルキル、ヘテロシクリル、ヘテロシクレニル、アリール、ヘテロアリールはそれぞれ、非置換であっても、アルキル、シクロアルキル、アリール、ヘテロアリール、アルケニル、シクレニル、ヘテロシクレニル、ハロ、トリハロアルキル、アルコキシル、ヒドロキシアルキル、トリハロアルコキシル、およびＣＮからなる群から独立に選択される１つまたは複数の部分で置換されていてもよく；
Ｒ^５およびＲ^７は、水素、アルキル、アミノアルキル、アルケニル、アルキニル、アリール、ヘテロシクリル、ヘテロシクレニル、シクロアルキル、シクレニル、シクロアルキルアルキル、シクレニルアルキル、シクロアルキルアルケニル、シクレニルアルケニル、ヘテロアリール、ヘテロアリールアルキル、ヘテロアリールアルケニル、アリールアルキル、アリールアルケニル、ヘテロシクリルアルキル、ヘテロシクレニルアルキル、ヘテロシクリルアルケニル、ヘテロシクレニルアルケニル、−Ｓ−ヘテロシクリル、−Ｓ−アミノアルキル、−Ｓ−ヘテロシクレニル、ＮＲ^８Ｒ^９、ＮＲ^８ＣＯＲ^９、ＮＲ^８ＳＯ_２Ｒ^９、ＣＯＲ^８、ＣＯ_２Ｒ^８、ＣＯＮＲ^８Ｒ^９、ＣＨ_２ＯＲ^８、ＯＲ^８、ＳＲ^８、およびＳＯ_２Ｒ^８からなる群からそれぞれ選択され、ここでは、前記アルキル、アルケニル、アルキニル、アリール、ヘテロシクリル、ヘテロシクレニル、シクロアルキル、シクレニル、シクロアルキルアルキル、シクレニルアルキル、シクロアルキルアルケニル、シクレニルアルケニル、ヘテロアリール、ヘテロアリールアルキル、ヘテロアリールアルケニル、アリールアルキル、アリールアルケニル、ヘテロシクリルアルキル、ヘテロシクレニルアルキル、ヘテロシクリルアルケニル、ヘテロシクレニルアルケニル、−Ｓ−ヘテロシクリル、および−Ｓ−ヘテロシクレニルはそれぞれ、非置換であっても、ハロゲン、アルキル、トリハロアルキル、アルケニル、ジハロアルキル、モノハロアルキル、ヒドロキシアルキル、ＯＲ^８、−Ｏ、ＮＲ^８Ｒ^９、ＳＲ^８、ＳＯ_２Ｒ^９、ＣＮ、ＳＯ_２ＮＲ^８Ｒ^９、およびＮＯ_２からなる群から独立に選択される同じまたは異なり得る少なくとも１つの部分で置換されていてもよく；
Ｒ^６は、水素、ハロ、トリハロアルキル、アルキル、アルケニル、アリール、シクレニル、シクロアルキル、ヘテロアリール、ヘテロシクレニル、ヘテロシクリル、ヘテロアリールアルキル、ヘテロシクレニルアルキル、ヘテロシクリルアルキル、アリールアルキル、シクレニルアルキル、シクリルアルキル、ＮＲ^８Ｒ^９、ＮＲ^８ＣＯＲ^９、ＮＲ^８ＳＯ_２Ｒ^９、ＣＯＲ^８、ＣＯ_２Ｒ^８、ＣＯＮＲ^８Ｒ^９、ＣＨ_２ＯＲ^８、ＯＲ^８、ＳＲ^８、またはＳＯ_２Ｒ^８であり、ここでは、前記アルキル、アルケニル、アリール、シクレニル、シクロアルキル、ヘテロアリール、ヘテロシクレニル、ヘテロシクリル、ヘテロアリールアルキル、ヘテロシクレニルアルキル、ヘテロシクリルアルキル、アリールアルキル、シクレニルアルキル、およびシクリルアルキルはそれぞれ、非置換であっても、ハロゲン、アルキル、シクロアルキル、トリハロアルキル、ＯＲ^８、ＣＮ、ＮＲ^８Ｒ^９、ＣＯ_２Ｒ^８、ＣＯＮＲ^８Ｒ^９、−ＳＲ^８、ＳＯ_２Ｒ^８、ＳＯ_２ＮＲ^８Ｒ^９、ＮＯ_２、ＮＲ^８ＳＯ_２Ｒ^９、ＮＲ^８ＣＯＲ^９、およびＮＲ^８ＣＯＮＲ^８Ｒ^９からなる群から独立に選択される１つまたは複数の部分で置換されていてもよく；
Ｒ^８およびＲ^９は、水素、トリハロアルキル、ジハロアルキル、モノハロアルキル、アルキル、アルケニル、アリール、ヘテロアリール、アリールアルキル、シクロアルキル、シクレニル、シクロアルキルアルキル、シクレニルアルキル、シクレニルアルケニル、ヘテロシクレニル、ヘテロシクリル、ヘテロシクレニルアルキル、ヘテロシクレニルアルケニル、ヘテロシクリルアルキル、およびヘテロアリールアルキルからなる群からそれぞれ独立に選択され、ここでは、前記アルキル、アルケニル、アリール、ヘテロアリール、アリールアルキル、シクロアルキル、シクレニル、シクロアルキルアルキル、シクレニルアルキル、シクレニルアルケニル、ヘテロシクレニル、ヘテロシクリル、ヘテロシクレニルアルキル、ヘテロシクレニルアルケニル、ヘテロシクリルアルキル、およびヘテロアリールアルキルは、非置換であっても、ハロ、アルキル、シクロアルキル、シクレニル、アリール、ヘテロシクリル、ヘテロシクレニル、ヘテロアリール、トリハロアルキル、ＣＮ、ヒドロキシル、アルコキシル、およびＮＯ_２からなる群から独立に選択される同じまたは異なり得る少なくとも１つの部分で置換されていてもよい）、またはその医薬として許容され得る塩、溶媒和化合物、もしくはエステルである。

(Where:
R ³ is hydrogen, alkyl, cycloalkyl, cyclenyl, alkynyl, trifluoroalkyl, difluoroalkyl, monofluoroalkyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, halo, cyano, —O-trihaloalkyl, NR ⁸ R ⁹ , _{^{CO 2 R 8, CONR 8 R}} 9, -OR 8, -SR 8, -SO 2 R 8, -SO 2 NR 8 R 9, -NR 8 SO 2 R 9, -NR 8 COR 9 or ^NR 8 CONR, ⁸ R ⁹ wherein the alkyl, cycloalkyl, cyclenyl, alkynyl, trifluoroalkyl, difluoroalkyl, monofluoroalkyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl are each unsubstituted alkyl, Cycloalkyl, ants Le, heteroaryl, alkenyl, Shikureniru, heterocyclenyl, halo, trihaloalkyl, alkoxy, hydroxyalkyl, trihaloalkyl alkoxyl, and it may be substituted with one or more moieties selected from the group consisting of CN independently;
R ⁵ and R ⁷ are hydrogen, alkyl, aminoalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclenyl, cycloalkyl, cyclenyl, cycloalkylalkyl, cyclenylalkyl, cycloalkylalkenyl, cyclenylalkenyl, heteroaryl, heteroaryl alkyl, heteroaryl alkenyl, arylalkyl, arylalkenyl, heterocyclylalkyl, Heterocyclenylalkyl, heterocyclylalkenyl, Heterocyclenylalkyl alkenyl, -S- heterocyclyl, -S- aminoalkyl, -S- ^{heterocyclenyl,} NR ⁸ R 9, NR ⁸ COR ⁹ , NR ⁸ SO ₂ R ⁹ , COR ⁸ , CO ₂ R ⁸ , CONR ⁸ R ⁹ , CH ₂ OR ⁸ , OR ⁸ , SR ⁸ , and SO ₂ R Are each selected from the group consisting of ^8, wherein the said alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclenyl, cycloalkyl, Shikureniru, cycloalkylalkyl, Shikure alkenyl alkyl, cycloalkyl, cycloalkenyl, Shikure alkenyl, cycloalkenyl, heteroaryl, heteroaryl Arylalkyl, heteroarylalkenyl, arylalkyl, arylalkenyl, heterocyclylalkyl, heterocyclenylalkyl, heterocyclylalkenyl, heterocyclenylalkenyl, -S-heterocyclyl, and -S-heterocyclenyl, each independently of halogen, , alkyl, trihaloalkyl, alkenyl, dihaloalkyl, monohaloalkyl, ^{hydroxyalkyl, OR 8, -O, NR 8} R 9 _{^{SR 8, SO 2 R 9,}} CN, may be substituted with at least one portion the same or may differ chosen SO 2 ^NR 8 ^{R 9,} and from the group consisting of NO ₂ independently;
R ⁶ is hydrogen, halo, trihaloalkyl, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocyclylalkyl, arylalkyl, cyclenylalkyl, cyclyl Alkyl, NR ⁸ R ⁹ , NR ⁸ COR ⁹ , NR ⁸ SO ₂ R ⁹ , COR ⁸ , CO ₂ R ⁸ , CONR ⁸ R ⁹ , CH ₂ OR ⁸ , OR ⁸ , SR ⁸ , or SO ₂ R ⁸ Here, said alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocyclylalkyl, arylalkyl, cyclenyl Alkyl, and each heterocyclylalkyl can be unsubstituted or substituted, halogen, alkyl, cycloalkyl, _{^{trihaloalkyl, OR 8, CN, NR 8}} R 9, CO 2 R 8, CONR 8 R 9, -SR 8, One or more moieties independently selected from the group consisting of SO ₂ R ⁸ , SO ₂ NR ⁸ R ⁹ , NO ₂ , NR ⁸ SO ₂ R ⁹ , NR ⁸ COR ⁹ , and NR ⁸ CONR ⁸ R ⁹ ; May be substituted;
R ⁸ and R ⁹ are hydrogen, trihaloalkyl, dihaloalkyl, monohaloalkyl, alkyl, alkenyl, aryl, heteroaryl, arylalkyl, cycloalkyl, cyclenyl, cycloalkylalkyl, cyclenylalkyl, cyclenylalkenyl, heterocyclenyl, heterocyclyl , Heterocyclenylalkyl, heterocyclenylalkenyl, heterocyclylalkyl, and heteroarylalkyl, each independently selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl, arylalkyl, cycloalkyl, cyclenyl, cyclo Alkylalkyl, cyclenylalkyl, cyclenylalkenyl, heterocyclenyl, heterocyclyl, heterocyclenylalkyl, heterocyclenyl Alkenyl, heterocyclylalkyl, and heteroarylalkyl can be unsubstituted or substituted, comprising halo, alkyl, cycloalkyl, Shikureniru, aryl, heterocyclyl, heterocyclenyl, heteroaryl, trihaloalkyl, CN, hydroxyl, alkoxyl, and NO ₂ Which may be substituted with at least one moiety which may be the same or different, independently selected from the group), or a pharmaceutically acceptable salt, solvate or ester thereof.

  One or more provided herein that delivers an amount effective to treat, prevent, or ameliorate one or more symptoms of a disease or disorder modulated or affected by CDK-2 or CHK-1 Also provided are pharmaceutical compositions formulated for administration by an appropriate route and means containing a plurality of effective concentrations of the compound or a pharmaceutically acceptable derivative thereof. Effective amounts and concentrations are effective to ameliorate any symptom of any disease or disorder.

  Also provided are methods of treating, preventing, or ameliorating one or more symptoms of a disease or disorder that is modulated or affected by the involvement of CDK-2 or CHK-1. Such methods include one or more symptoms of inflammatory diseases, neurodegenerative diseases, cancer, and diabetes using one or more compounds provided herein, or pharmaceutically acceptable derivatives thereof. Treatment, prevention, and remission methods. Non-limiting examples of inflammatory diseases are acute pancreatitis, chronic pancreatitis, asthma, allergies, and adult respiratory distress syndrome. Non-limiting examples of neurodegenerative diseases are acute Alzheimer's disease, Parkinson's disease, cerebral ischemia, and other neurodegenerative diseases. Non-limiting examples of diabetes are diabetes mellitus and diabetes insipidus, such as type 1 diabetes and type 2 diabetes.

  In the implementation of the method, but not limited to, inflammatory disease, neurodegenerative disease, cancer, diabetes, acute pancreatitis, chronic pancreatitis, asthma, allergy, adult respiratory distress syndrome, Alzheimer's disease, Parkinson's disease, cerebral ischemia, Diabetes mellitus, diabetes insipidus, type 1 diabetes, type 2 diabetes, breast cancer, stomach cancer, ovarian cancer, colon cancer, lung cancer, brain cancer, laryngeal cancer, cancer of the lymphatic system, urogenital tract including bladder and prostate For systemic delivery, including parenteral, oral, or intravenous delivery, to treat CDK-2 or CHK-1 mediated diseases or disorders, including other cancers, bone cancer, and pancreatic cancer An effective amount of a compound formulated for topical or localized application, or a composition containing a therapeutically effective concentration of the compound, is administered to an individual who exhibits signs of these diseases or disorders. The

  These amounts are effective to ameliorate or eliminate one or more symptoms of the disease or disorder.

  A packaging material and a compound or composition provided herein, or a pharmaceutically acceptable agent provided within the packaging material and effective to modulate the activity of a CDK-2 or CHK-1-mediated disease or disorder Products and their compounds or compositions, or pharmaceutically acceptable derivatives thereof, that can be used to modulate the activity of CDK-2 or CHK-1 mediated diseases or disorders A label is provided.

  The compounds according to the invention can have pharmacological properties; in particular, the compounds of formula I are, for example, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, and CDK7, CDK8, mitogen activated protein kinase (MAPK / ERK). ), Glycogen synthase kinase 3 (GSK3beta), Pim-1 kinase, Chk kinase (such as Chk1 and Chk2), tyrosine kinases such as the HER subfamily (eg, including EGFR (HER1), HER2, HER3, and HER4) Insulin subfamily (including, for example, INS-R, IGF-IR, IR and IR-R), PDGF subfamily (including, for example, PDGF-alpha and beta receptors, CSFIR, c-kit, and FLK-II) ) The FLK family, including the kinase insert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4), and fms-like tyrosine kinase-1 (fit-1) ), Non-receptor protein tyrosine kinases (eg, LCK, Src, Frk, Btk, Csk, Abl, Zap70, Fes / Fps, Fak, Jak, Ack, and LIMK), growth factor receptor tyrosine kinases such as VEGF-R2, It can be an inhibitor of protein kinases such as FGF-R, TEK, Akt kinase, Aurora kinase (Aurora A, Aurora B, Aurora C).

  The novel compounds of formula I include cancer, autoimmune diseases, viral diseases, mycoses, neurological / neurodegenerative disorders, arthritis, inflammation, antiproliferative diseases (eg ocular retinopathy), neuronal diseases, alopecia, And is expected to be useful in the treatment of proliferative diseases such as cardiovascular diseases. Many of these diseases and disorders are listed in the previously cited US 6,413,974, the disclosure of which is incorporated herein.

More particularly, the compounds of formula I may be useful in the treatment of various cancers including but not limited to: bladder, breast, colon, kidney, liver, lung (including small cell lung cancer) Carcinomas, including carcinomas of the esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B Hematopoietic tumors of lymphoid lineages, including cellular lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma and Burquett lymphoma;
Hematopoietic tumors of the myeloid lineage, including acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia;
Mesenchymal tumors including fibrosarcoma and rhabdomyosarcoma;
Tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwannoma; and
Other tumors including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratophyte cell carcinoma, follicular thyroid carcinoma, and Kaposi sarcoma.

  In general, due to the major role of CDK in the regulation of cell proliferation, inhibitors may be used in any disease process characterized by abnormal cell proliferation (eg, benign prostatic hyperplasia, familial adenomatous polyposis, nerve fibers). Tumors, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, nephritis, restenosis after angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplant rejection, endotoxin shock, and fungal infection) May act as a reversible cytostatic agent that may also be useful in the treatment of

  Since recent findings suggest that CDK5 is involved in tau protein phosphorylation (J. Biochem, (1995) 117, 741-749), compounds of formula I are also useful in the treatment of Alzheimer's disease. Can also be useful.

  Compounds of formula I can induce or inhibit apoptosis. In various human diseases, the apoptotic response is abnormal. Compounds of formula I as modulators of apoptosis include cancer (including but not limited to the types listed above), viral infections (herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus, and Treatment of, including but not limited to, adenovirus, AIDS development in HIV-infected persons, autoimmune diseases (systemic lupus, lupus erythematosus, autoimmune mediated nephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and Including, but not limited to, autoimmune diabetes mellitus), neurodegenerative disorders (Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, and Associated with, but not limited to, cerebellar degeneration), myelodysplastic syndrome, aplastic anemia, myocardial infarction Blood injury, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol-related liver disease, hematological disorders (including but not limited to chronic anemia and aplastic anemia), musculoskeletal It may be useful in the treatment of systemic degenerative diseases (including but not limited to osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, and cancer pain.

  The compounds of formula I can regulate the level of cellular RNA and DNA synthesis as inhibitors of CDK. Thus, these agents are useful for the treatment of viral infections including but not limited to HIV, human papilloma virus, herpes virus, pox virus, Epstein-Barr virus, Sindbis virus, and adenovirus. Will.

  The compounds of formula I may also be useful for the chemoprevention of cancer. Chemoprevention suppresses the development of invasive cancer by preventing the initiation of mutagenic events, or by preventing the progression of pre-cancerous cells that have already been damaged, or by suppressing tumor recurrence Is defined as

  The compounds of formula I may also be useful in inhibiting tumor angiogenesis and metastasis.

  Compounds of formula I may also include other protein kinases such as protein kinase C, her2, raf 1, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, wee1 kinase, Src, Abl. It may also act as an inhibitor and is therefore effective in the treatment of diseases associated with other protein kinases.

  Accordingly, another aspect of the present invention is to provide CDK or CHK-1 by administering to a mammal a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound. A method of treating a mammal (eg, a human) having a disease or condition associated with.

  The pharmacological properties of the compounds of the invention can be confirmed by several pharmacological analyses. The exemplified pharmacological analyzes described below have been carried out using the compounds according to the invention and their salts.

  The present invention is also directed to a pharmaceutical composition comprising at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound, and at least one pharmaceutically acceptable carrier.

A. Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are a plurality of definitions for terms herein, the definitions in this section prevail unless stated otherwise.

As used above and throughout this disclosure, the following terms should be understood to have the following meanings unless otherwise indicated:
“Patient” includes humans and animals.

  “Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight or branched comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkyl chain. “Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. “Alkyl” can be unsubstituted or optionally substituted with one or more substituents, which can be the same or different, and each substituent is independently halo, alkyl, aryl, cycloalkyl, Selected from the group consisting of cyano, hydroxy, alkoxy, alkylthio, amino, —NH (alkyl), —NH (cycloalkyl), —N (alkyl) ₂ , carboxy, and —C (O) O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, and t-butyl.

  “Alkenyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. . Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain, more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkenyl chain. “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched. “Alkenyl” may be unsubstituted or optionally substituted with one or more substituents, which may be the same or different, each substituent independently being halo, alkyl, aryl, cycloalkyl, Selected from the group consisting of cyano, alkoxy, and -S (alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

  “Alkylene” means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene, and propylene.

  “Alkynyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain, more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkenyl chain. “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, and 3-methylbutynyl. “Alkynyl” may be unsubstituted or optionally substituted with one or more substituents which may be the same or different, each substituent independently consisting of alkyl, aryl, and cycloalkyl. Selected from the group.

  “Aryl” means an aromatic monocyclic or polycyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. Aryl groups can be optionally substituted with one or more “ring system substituents” as defined herein, which can be the same or different. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

  “Heteroaryl” contains about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, one or more of the ring atoms being an element other than carbon, such as nitrogen, oxygen, Or an aromatic monocyclic or polycyclic ring structure which is sulfur (alone or in combination). Preferred heteroaryls contain about 5 to about 6 ring atoms. “Heteroaryl” may be optionally substituted by one or more “ring system substituents” as defined herein, which may be the same or different. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The nitrogen atom of the heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridone), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo [1,2-a] pyridinyl, imidazo [2,1-b] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzo Thienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-to Azinyl, benzothiazolyl and the like. The term “heteroaryl” also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

  “Aralkyl” or “arylalkyl” means an aryl-alkyl-group in which the aryl and alkyl are as previously described. Preferred aralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl, and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.

  “Arylalkenyl” means an aryl group linked to the parent moiety through an alkenyl moiety as defined above.

  “Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are as previously described. Preferred alkylaryls contain a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.

  “Cycloalkyl” or cyclyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. Cycloalkyls can be optionally substituted with one or more “ring system substituents” as defined above, which can be the same or different. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.

  “Cycloalkylalkyl” or cyclylalkyl means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkylalkyl include cyclohexylmethyl, adamantylmethyl and the like.

  “Cycloalkenyl” or cyclenyl is a non-aromatic monocyclic ring containing at least one carbon-carbon double bond containing about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Or means a polycyclic ring structure. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more “ring structure substituents” as defined above, which can be the same or different. Non-limiting examples of suitable monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.

  “Cycloalkenylalkyl” or cyclenylalkyl means a cycloalkenyl moiety as defined above linked via an alkyl moiety (as defined above) to a parent core. Non-limiting examples of suitable cycloalkenylalkyl include cyclopentenylmethyl, cyclohexenylmethyl and the like.

  “Cycloalkenylalkenyl” or “cycloalkylalkenyl” means a cycloalkenyl or cycloalkyl moiety as defined above linked through an alkenyl moiety as defined above.

  “Halogen” or halo means fluorine, chlorine, bromine, or iodine. Preference is given to fluorine, chlorine and bromine.

“Ring structure substituent” means a substituent attached to an aromatic or non-aromatic ring structure, eg, replacing an available hydrogen on the ring structure. The ring structure substituents may be the same or different and are alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, respectively. , Alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, _{heterocyclyl, -C (= N-CN)} -NH 2, -C (= NH) -NH , -C (= NH) -NH _{(alkyl), Y 1 Y 2 N-,} Y 1 Y 2 N- alkyl _{-, Y 1 Y 2 NC (} O) -, Y 1 Y 2 NSO 2 -, and -SO Independently from a group consisting of ₂ NY ₁ Y ₂ , wherein Y ₁ and Y ₂ may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. Selected. “Ring system substituent” can also mean a single moiety that simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on the ring structure. . Examples of such moiety are methylene dioxy, ethylenedioxy, -C (CH ₃₎ 2 _- and the like, which, for example, form part of such following:

「ヘテロアリールアルキル」またはヘテロアリールアルケニルは、それぞれ、（先に定義した通りの）アルキルまたはアルケニル部分を介して親コアに連結された、先に定義した通りのヘテロアリール部分を意味する。適切なヘテロアリールの非限定的な例としては、２−ピリジニルメチル、キノリニルメチルなどが挙げられる。

“Heteroarylalkyl” or heteroarylalkenyl means a heteroaryl moiety as defined above linked to the parent core via an alkyl or alkenyl moiety (as defined above), respectively. Non-limiting examples of suitable heteroaryl include 2-pyridinylmethyl, quinolinylmethyl and the like.

  “Heterocyclyl” or heterocycloalkyl includes about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, wherein one or more of the atoms in the ring structure is other than carbon, such as A non-aromatic saturated monocyclic or polycyclic ring structure that is nitrogen, oxygen, or sulfur (alone or in combination). There are no adjacent oxygen and / or sulfur atoms present in the ring structure. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl radical name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any —NH in the heterocyclyl ring can be protected, eg, as a —N (Boc), —N (CBz), —N (Tos) group, etc .; such protection is also part of this invention. it is conceivable that. The heterocyclyl can be optionally substituted by one or more “ring system substituents” as defined herein, which can be the same or different. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide, or S, S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. “Heterocyclyl” can also mean a single moiety (eg, carbonyl) that simultaneously replaces two available hydrogens on the same carbon atom on a ring structure. Examples of these parts are pyrrolidone:

である。

It is.

  “Heterocyclylalkyl” or heterocycloalkylalkyl means a heterocyclyl moiety as defined above linked via an alkyl moiety (as defined above) to a parent core. Non-limiting examples of suitable heterocyclylalkyl include piperidinylmethyl, piperazinylmethyl and the like.

  “Heterocyclenyl” or heterocycloalkenyl includes about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, wherein one or more of the atoms in the ring structure is other than carbon, such as A non-aromatic monocyclic or polycyclic ring structure which is nitrogen, oxygen, or sulfur (alone or in combination) and contains at least one carbon-carbon double bond or carbon-nitrogen double bond; means. There are no adjacent oxygen and / or sulfur atoms present in the ring structure. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl radical name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. A heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein “ring system substituent” is as previously defined. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide, or S, S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1 , 4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazole, dihydrooxazole, dihydrooxadiazole, dihydrothiazole, 3,4-dihydro-2H-pyran, Examples include dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo [2.2.1] heptenyl, dihydrothiophenyl, dihydrothiopyranyl and the like. “Heterocyclenyl” can also mean a single moiety (eg, carbonyl) that simultaneously replaces two available hydrogens on the same carbon atom on a ring structure. Examples of these parts are pyrrolidinone:

である。

It is.

  “Heterocyclenylalkyl” or heterocycloalkenylalkyl means a heterocyclenyl moiety as defined above linked to a parent core via an alkyl moiety (as defined above).

  “Heteroalkyl” means a saturated or unsaturated chain containing carbon and at least one heteroatom. Here, one or more of the chain atoms is an element other than carbon, such as nitrogen, oxygen, or sulfur (alone or in combination) and the two heteroatoms are not adjacent. Heteroalkyl chains contain 2 to 15, preferably 2 to 10, more preferably 2 to 5 member atoms (carbon and heteroatoms) in the chain. For example, alkoxy (ie, —O-alkyl, or —O-heteroalkyl) radicals are included in heteroalkyl. A heteroalkyl chain can be straight or branched. Preferred branched heteroalkyls have one or two branches (preferably one branch). Preferred heteroalkyl are those that are saturated. An unsaturated heteroalkyl has one or more carbon-carbon double bonds and / or one or more carbon-carbon triple bonds. Preferred unsaturated heteroalkyls have 1 or 2 double bonds or 1 triple bond, more preferably 1 double bond. The heteroalkyl chain may be unsubstituted or substituted with 1 to 4 substituents. Preferred substituted heteroalkyl are mono-, di-, or tri-substituted. Heteroalkyl is lower alkyl, haloalkyl, halo, hydroxy, aryloxy, heteroaryloxy, acyloxy, carboxy, monocyclic aryl, heteroaryl, cycloalkyl, heterocyclyl, spirocycle, amino, acylamino, amide, keto, thioketo, It can be substituted with cyano, or any combination thereof.

  In the ring structure of the present invention containing a heteroatom, there is no hydroxyl group on the carbon atom adjacent to N, O, or S, and there is an N group on the carbon adjacent to another heteroatom. Note that neither the S nor the S group is present. Thus, for example, in the following ring:

２および５と印を付けた炭素に直接的に付着した−ＯＨは存在しない。

There is no -OH attached directly to the carbons marked 2 and 5.

  Tautomeric forms, for example:

が、本発明のある種の実施形態において、等価物と考慮されることにも留意されたい。

It should also be noted that in certain embodiments of the invention, it is considered equivalent.

  “Alkynylalkyl” means an alkynyl-alkyl-group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain lower alkynyl and lower alkyl groups. The bond to the parent moiety is through the alkyl. Non-limiting example of a suitable alkynylalkyl group is propargylmethyl.

  “Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.

  “Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as previously defined. Preferred hydroxyalkyl contains lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

  “Acyl” means an HC (O) —, alkyl-C (O) —, or cycloalkyl-C (O) — group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl, and propanoyl.

  “Aroyl” means an aryl-C (O) — group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1-naphthoyl.

  “Alkoxy” or “oxaalkyl” means an alkyl-O— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. The bond to the parent moiety is through the ether oxygen.

“Alkoxyoxo” is similar to alkoxycarbonyl (eg, —CO ₂ R), but the alkoxy group may further comprise a polyether functionality.

  “Oxaalkynyl” refers to an alkynyl ether (eg, a propargyloxy group) linked to the parent moiety through the oxygen of the oxaalkynyl.

  “Aryloxy” means an aryl-O— group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.

  “Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.

  “Alkylthio” means an alkyl-S— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through sulfur.

  “Arylthio” means an aryl-S— group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through sulfur.

  “Aralkylthio” means an aralkyl-S— group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through sulfur.

  “Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

  “Aryloxycarbonyl” means an aryl-O—C (O) — group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.

  “Aralkoxycarbonyl” means an aralkyl-O—C (O) — group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S (O ₂ ) — group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.

“Arylsulfonyl” means an aryl-S (O ₂ ) — group. The bond to the parent moiety is through the sulfonyl.

  The term “substituted” refers to the indication that one or more hydrogens on a given atom does not exceed the normal valence of the given atom in the current state, and the substitution results in a stable compound. It is meant to be replaced with one selected from the selected groups. Combinations of substituents and / or variables can only be tolerated if such combinations result in stable compounds. By “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation from a reaction mixture to a useful degree of purity and formulation into an effective therapeutic agent.

  The term “optionally substituted” means optional substitution with the specified groups, radicals or moieties.

  The terms “purified”, “purified form”, or “isolated and purified form” for a compound refer to the compound after being isolated from a synthetic process or natural source or combinations thereof. Refers to the physical state. Accordingly, the terms “purified”, “purified form”, or “isolated and purified form” for a compound are described herein or are well known to those of skill in the art. After being obtained from the purification process (s), the physical properties of the compound in sufficient purity to be characterized by standard analytical techniques as described herein or well known to those skilled in the art Refers to the state.

  Any unsatisfied carbon and heteroatoms in the text, schemes, examples, and tables herein have a sufficient number of hydrogen atom (s) to satisfy the valence. It should also be noted that it is considered to have

  When a functional group in a compound is referred to as “protected”, this is a modification to prevent undesired side reactions at the site where the group is protected when the compound is subjected to a reaction. Means in form. Suitable protecting groups are known to those skilled in the art and are described, for example, in T.W. W. It will be known by referring to standard texts such as Greene et al., Protective Groups in Organic Synthesis (1991) Wiley, New York.

When any variable (eg, aryl, heterocycle, R ^2, etc.) is present more than one time in any constituent in Formula I, that definition for each occurrence is that of any other occurrence being independent.

  As used herein, the term “composition” includes products that contain a particular amount of a particular component, as well as any product that results directly or indirectly from a combination of a particular amount of a particular component. Intended to do.

  Prodrugs and solvates of the compounds of the invention are also contemplated herein. For a discussion of prodrugs, see T.W. Higuchi and V. Stella, A.M. C. S. Symposium Series, Pro-drugs as Novel Delivery Systems (1987) 14, and Bioreversible Carriers in Drug Design, (1987) Edward B. Provided by Roche, American Pharmaceutical Association and Pergamon Press. The term “prodrug” refers to a compound (eg, a drug precursor) that is converted in vivo to yield a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate of the compound. means. Conversion can occur by various mechanisms (eg, by metabolic or chemical processes), such as through hydrolysis in the blood. A discussion of the use of prodrugs is given in T.W. Higuchi and W.H. Stella, A.M. C. S. Symposium Series “Pro-drugs as Novell Delivery Systems”, Volume 14, and Bioreversible Carriers in Drug Design, Edward B. Provided in Roche, American Pharmaceutical Association and Pergamon Press (1987).

For example, when the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, the prodrug may be a hydrogen atom of the acid group, for example Esters formed by substitution with groups such as: (C ₁ -C ₈ ) alkyl, (C ₂ -C ₁₂ ) alkanoyloxymethyl, with 4 to 9 carbon atoms Having 1- (alkanoyloxy) ethyl, 1-methyl-1- (alkanoyloxy) -ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 4 to 7 1- (alkoxycarbonyloxy) ethyl having carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) having 5 to 8 carbon atoms Ethyl, N- (alkoxycarbonyl) aminomethyl having 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotono Lactonyl, gamma-butyrolactone-4-yl, di-N, N- (C ₁ -C ₂ ) alkylamino (C ₂ -C ₃ ) alkyl (such as β-dimethylaminoethyl), carbamoyl- (C _1- C ₂ ) alkyl, N, N-di (C ₁ -C ₂ ) alkylcarbamoyl- (C ₁ -C ₂ ) alkyl, piperidino-, pyrrolidino- or morpholino (C ₂ -C ₃ ) alkyl, and the like.

Similarly, when the compound of formula (I) contains an alcohol functional group, a prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as, for example: C ₁ -C ₆ ) alkanoyloxymethyl, 1- (C ₁ -C ₆ ) alkanoyloxy) ethyl, 1-methyl-1-((C ₁ -C ₆ ) alkanoyloxy) ethyl, (C ₁ -C ₆ ) Alkoxycarbonyloxymethyl, N- (C ₁ -C ₆ ) alkoxycarbonylaminomethyl, succinoyl, (C ₁ -C ₆ ) alkanoyl, α-amino (C ₁ -C ₄ ) alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl. Here, each α-aminoacyl group is a naturally occurring L amino acid, P (O) (OH) ₂ , —P (O) (O (C ₁ -C ₆ ) alkyl) ₂ , or glycosyl (hemiacetal form) Radicals derived from the removal of the hydroxyl groups of carbohydrates).

When the compound of formula (I) incorporates an amine function, a prodrug can be formed by replacing a hydrogen atom in the amine group with a group such as, for example: R-carbonyl, RO-carbonyl, NRR′-carbonyl. Here, R and R ′ are each independently (C ₁ -C ₁₀ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, benzyl, or R-carbonyl is natural α-aminoacyl or natural Α-aminoacyl, —C (OH) C (O) OY ¹ (where Y ¹ is H, (C ₁ -C ₆ ) alkyl, or benzyl), —C (OY ² ) Y ³ (formula Wherein Y ² is (C ₁ -C ₄ ) alkyl and Y ³ is (C ₁ -C ₆ ) alkyl, carboxy (C ₁ -C ₆ ) alkyl, amino (C ₁ -C ₄ ) alkyl, or mono- -N- or di _{-N, N- (C 1 ~C 6} ) ^{alkylaminoalkyl), - C (Y 4)} Y 5 ( : in ^the formula, ^{Y 4} is H or methyl, ^{Y 5} is , mono- -N- or di _{-N,, N- (C 1 ~C} 6) Al Le amino morpholino, piperidin-1-yl or pyrrolidin-1-yl) and the like.

One or more compounds of the invention can exist in unsolvated forms or in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. Unsolvated forms are intended to be included. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, solvates can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanol solvates, methanol solvates and the like. “Hydrate” is a solvate wherein the solvent molecule is H ₂ O.

  One or more compounds of the invention can optionally be converted to a solvate. The preparation of solvates is generally known. For example, M.M. Caira et al. Pharmaceutical Sci. 93 (3), 601-611 (2004) describe the preparation of solvates of the antifungal agent fluconazole from ethyl acetate and water. Similar preparations of solvates, hemisolvates, hydrates, etc. are described in E.C. C. van Tonder et al., AAPS PharmSciTech. 5 (1), article 12 (2004); L. Bingham et al., Chem. Commun. 603-604 (2001). A typical non-limiting process involves dissolving the compound of the present invention in the desired amount of the desired solvent (organic solvent or water or mixtures thereof) above ambient temperature using standard methods. Cooling the solution at a rate sufficient to form crystals that are then isolated. Analytical techniques such as infrared spectroscopy indicate the presence of the solvent (or water) in the crystal as a solvate (or hydrate).

  An “effective amount” or “therapeutically effective amount” is a compound or composition of the invention effective to inhibit the above-described diseases, ie, to provide the desired therapeutic, ameliorative, inhibitory, or prophylactic effect. The amount of is described.

  The compounds of formula I can also form salts which are encompassed within the scope of the invention. It will be understood that reference herein to a compound of formula I includes reference to a salt thereof, unless otherwise indicated. As used herein, the term “salt (s)” refers to acid salts formed using inorganic and / or organic acids, and base salts formed using inorganic and / or organic bases. Show. Furthermore, when a compound of Formula I contains both a base moiety (such as, but not limited to, pyridine or imidazole) and an acid moiety (such as, but not limited to, a carboxylic acid), a zwitterion (“inner salt”) Which may be formed and are included in the term “salt (s)” as used herein. Although pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, other salts are useful. A salt of a compound of formula I can be obtained, for example, by reacting a compound of formula I with an amount of acid or base, such as 1 equivalent, in a medium such as a medium in which the salt is precipitated or in an aqueous medium, followed by freezing. It can be formed by drying.

  Typical acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate Acid salt, hydrochloride, hydrobromide, hydrogen iodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate Succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), and the like. Furthermore, acids that are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds include, for example, P.I. Stahl et al., Camille G. et al. (Eds) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; Berge et al., Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; Gould, International J. et al. of Pharmaceuticals (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Board. ). These disclosures are incorporated herein by reference.

  Typical base salts include ammonium salts, alkali metal salts (such as sodium, lithium, and potassium salts), alkaline earth metal salts (such as calcium and magnesium salts), and salts with organic bases (such as organic amines) (dicyclohexyl). Amines, t-butylamine, etc.), and salts with amino acids (arginine, lysine, etc.). Basic nitrogen-containing groups include lower alkyl halides (eg, chloride, bromide, and methyl iodide, ethyl, and butyl), dialkyl sulfates (eg, dimethyl sulfate, diethyl, and dibutyl), long chain halides (eg, Chloride, bromide, and decyl iodide, lauryl, and stearyl), and quaternization with reagents such as aralkyl halides (eg, benzyl bromide and phenethyl bromide).

  All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the present invention, and all acid and base salts are equivalent to the free compounds corresponding to the purposes of the present invention. It is thought that.

The pharmaceutically acceptable esters of the compounds of the present invention include the following groups: (1) Carboxylic acid esters obtained by esterification of hydroxy groups. Here, the non-carbonyl moiety of the carboxylic acid moiety of the ester group is a straight or branched chain alkyl (eg, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (eg, methoxymethyl), aralkyl. (Eg, benzyl), aryloxyalkyl (eg, phenoxymethyl), aryl (eg, phenyl optionally substituted with, for example, halogen, C _1-4 alkyl, or C _1-4 alkoxy or amino); 2) sulfonate esters such as alkyl- or aralkylsulfonyl (eg methanesulfonyl); (3) amino acid esters (eg L-valyl or L-isoleucil); (4) phosphonates; and (5) mono-, di- Or triphosphates. Phosphate esters can be further esterified, for example, with C _1-20 alcohols or reactive derivatives thereof, or with 2,3-di (C _6-24 ) acylglycerols.

  Compounds of formula I and their salts, solvates, esters, and prodrugs can exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

  Compounds of formula (I) may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of formula (I), as well as their mixtures, including racemic mixtures, are also part of this invention. Furthermore, the present invention encompasses all geometric and positional isomers. For example, where a compound of formula (I) incorporates a double bond or fused ring, both cis and trans forms, as well as mixtures, are also encompassed within the scope of the invention.

  Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physicochemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be converted to diastereomeric mixtures by reaction with a suitable optically active compound (eg, chiral auxiliary (eg, chiral alcohol or Mosher's acid chloride)). The individual diastereomers can be separated by converting (eg, hydrolyzing) the individual diastereomers into the corresponding pure enantiomers, and some compounds of formula (I) are: It can be an atropisomer (eg, substituted biaryl) and is considered part of this invention The enantiomers can also be separated by using a chiral HPLC column.

  The compounds of formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

  Due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotational isomers, atropisomers, and diastereomeric forms All of the compounds of the present invention, including those that may be present, including salts, solvates, esters, and prodrugs of the compound, and salts, solvates, and esters of the prodrug Stereoisomers (eg, geometric isomers, optical isomers, etc.) are intended within the scope of the invention, as are positional isomers (eg, 4-pyridyl, 3-pyridyl, etc.). (For example, where a compound of formula (I) incorporates a double bond or fused ring, both cis and trans forms, as well as mixtures, are also encompassed within the scope of the invention. All keto-enol and imine-enamine forms are also included in the present invention.) The individual stereoisomers of the compounds of the present invention can be, for example, substantially free of other isomers, For example, it may be mixed as a racemate or with all other stereoisomers or other selected stereoisomers. The chiral centers of the present invention can have the S or R structure as defined by the IUPAC 1974 recommendation. The terms “salt”, “solvate”, “ester”, “prodrug” and the like are used to refer to enantiomers, stereoisomers, rotational isomers, tautomers, positional isomers of the compounds of the invention, It shall apply equally to racemates, or prodrug salts, solvates, esters, and prodrugs.

The present invention is also identical to those listed herein except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. And isotope-labeled compounds of the present invention. Examples of isotopes that can be incorporated into compounds of the present invention, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine ^{(respectively, 2 H, 3 H, 13} C, 14 C, 15 N , ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl, and the like.

Certain isotopically-labelled compounds of formula (I) (eg, those labeled with ³ H and ¹⁴ C) are useful in compound and / or substrate tissue distribution assays. The tritiated (ie ³ H) and carbon-14 (ie ¹⁴ C) isotopes are particularly preferred because of their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium (ie ² H) can provide certain therapeutic advantages due to greater metabolic stability (eg, in vivo halved). Increased phase or reduced dosage requirements), which may be preferred in certain situations. Isotopically labeled compounds of formula (I) are generally similar to those disclosed in the following schemes and / or examples by replacing non-isotopically labeled reagents with appropriate isotopically labeled reagents. Can be prepared by following the procedure.

  Polymorphic forms of the compounds of formula I, and salts, solvates, esters, and prodrugs of the compounds of formula I are intended to be included in the present invention.

  As used herein, amelioration of symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any relief (permanent or temporary, permanent) resulting from or associated with administration of the composition. Pointed or transient).

As used herein, IC ₅₀ refers to the amount, concentration, or dosage of a particular test compound that achieves 50% inhibition of maximal response in an assay that measures such a response, such as modulation of CDK-2 kinase activity. Point to.

As used herein, EC ₅₀ is the dosage, concentration of a particular test compound that elicits a dose-dependent response of 50% of maximum expression of the particular response elicited, stimulated, or enhanced by the particular test compound. Or refers to the amount.

  In the case of amino acid residues, such residues can be in the L- or D-form. The configuration of naturally occurring amino acid residues is generally L. If not specified, the residue is in the L form. As used herein, the term “amino acid” means an α-amino acid in racemic or D- or L-configuration. The symbol “d” before the amino acid symbol (eg, dAla, dSer, dVal, etc.) refers to the D-isomer of the amino acid. The symbol “dl” (eg, dlPip) before the amino acid symbol refers to a mixture of L- and D-isomers of amino acids. It should be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. Accordingly, one of ordinary skill in the art will recognize that for a compound that has undergone epimerization in vivo, administration of the (R) form of the compound is equivalent to administration of the (S) form of the compound. .

  As used herein, “substantially pure” refers to thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), and mass used by those skilled in the art to assess such purity. Is sufficiently homogeneous to appear free of detectable impurities, as measured by standard analytical methods such as analysis (MS), or physical, such as the enzymatic and biological activity of a substance And that the chemical properties are sufficiently pure that further purification will not change to a detectable extent. Methods of purification of compounds to produce substantially chemically pure compounds are known to those skilled in the art. However, the substantially chemically pure compound may be a mixture of stereoisomers. In such instances, further purification can increase the specific activity of the compound.

  The terms “purified”, “purified form”, or “isolated and purified form” for a compound refer to the compound after being isolated from a synthetic process or natural source or combinations thereof. Refers to the physical state. Accordingly, the terms “purified”, “purified form”, or “isolated and purified form” for a compound are described herein or are well known to those of skill in the art. After being obtained from the purification process (s), the physical properties of the compound in sufficient purity to be characterized by standard analytical techniques as described herein or well known to those skilled in the art Refers to the state.

  As used herein, “haloalkoxy” refers to RO—, wherein R is a haloalkyl group.

  As used herein, “heterocyclyloxy” refers to RO— where R is a heterocyclyl group and heteroaryloxy refers to RO— where R is a heteroaryl group.

As used herein, “substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted cycloalkyl”, “substituted cycloalkenyl”, “substituted cycloalkynyl”, “Substituted aryl”, “substituted heteroaryl”, “substituted heterocyclyl”, “substituted alkylene”, “substituted alkenylene”, “substituted alkynylene”, “substituted cycloalkylene” , “Substituted cycloalkenylene”, “substituted cycloalkynylene”, “substituted arylene”, “substituted heteroarylene” and “substituted heterocyclylene” are each one Or a plurality of substituents, and in certain embodiments 1, 2, 3, or 4 substituents Substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, cycloalkynylene, arylene, heteroarylene, and heterocyclyl Refers to the ren group. Here, the substituent is as defined herein, for example, in one embodiment, selected from Q ¹ .

  As used herein, “amide” refers to the divalent group —C (O) NH—. “Thioamido” refers to the divalent group —C (S) NH—. “Oxyamido” refers to the divalent group —OC (O) NH—. “Thiamido” refers to the divalent group —SC (O) NH—. “Dithiaamido” refers to the divalent group —SC (S) NH—. “Ureido” refers to the divalent group —HNC (O) NH—. “Thioureido” refers to the divalent group —HNC (S) NH—.

If the number of any given substituent is not specified (eg, haloalkyl), one or more substituents can be present. For example, “haloalkyl” can include one or more of the same or different halogens. As another example, “C _1-3 alkoxyphenyl” can include one or more alkoxy groups that contain the same or different, containing 1, 2, or 3 carbons.

  As used herein, abbreviations for protecting groups, amino acids, and other compounds, unless otherwise indicated, are their general use, ie, the accepted abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature ((1972) Biochem. 11: 942-944). Certain abbreviations used herein are listed below.

B. Compounds In one embodiment, the compounds provided herein for use in the compositions and methods provided herein have formula I, wherein the variables are as described below. All combinations of such embodiments are within the scope of the disclosure.

  In one embodiment, provided herein is a compound of formula (I):

またはその医薬として許容され得る塩、溶媒和化合物、エステル、プロドラッグ、および立体異性体である。式中、Ｒ^３、Ｒ^５、Ｒ^６、およびＲ^７は、互いに独立に選択され、ここでは、
Ｒ^３は、水素、アルキル、シクロアルキル、シクレニル、アルキニル、トリフルオロアルキル、ジフルオロアルキル、モノフルオロアルキル、ヘテロシクリル、ヘテロシクレニル、アリール、ヘテロアリール、ハロ、シアノ、−Ｏ−トリハロアルキル、ＮＲ^８Ｒ^９、ＣＯ_２Ｒ^８、ＣＯＮＲ^８Ｒ^９、−ＯＲ^８、−ＳＲ^８、−ＳＯ_２Ｒ^８、−ＳＯ_２ＮＲ^８Ｒ^９、−ＮＲ^８ＳＯ_２Ｒ^９、−ＮＲ^８ＣＯＲ^９、またはＮＲ^８ＣＯＮＲ^８Ｒ^９であり、ここでは、前記アルキル、シクロアルキル、シクレニル、アルキニル、トリフルオロアルキル、ジフルオロアルキル、モノフルオロアルキル、ヘテロシクリル、ヘテロシクレニル、アリール、ヘテロアリールはそれぞれ、非置換であっても、アルキル、シクロアルキル、アリール、ヘテロアリール、アルケニル、シクレニル、ヘテロシクレニル、ハロ、トリハロアルキル、アルコキシル、ヒドロキシアルキル、トリハロアルコキシル、およびＣＮからなる群から独立に選択される１つまたは複数の部分で置換されていてもよく；
Ｒ^５およびＲ^７は、水素、アルキル、アミノアルキル、アルケニル、アルキニル、アリール、ヘテロシクリル、ヘテロシクレニル、シクロアルキル、シクレニル、シクロアルキルアルキル、シクレニルアルキル、シクロアルキルアルケニル、シクレニルアルケニル、ヘテロアリール、ヘテロアリールアルキル、ヘテロアリールアルケニル、アリールアルキル、アリールアルケニル、ヘテロシクリルアルキル、ヘテロシクレニルアルキル、ヘテロシクリルアルケニル、ヘテロシクレニルアルケニル、−Ｓ−ヘテロシクリル、−Ｓ−アミノアルキル、−Ｓ−ヘテロシクレニル、ＮＲ^８Ｒ^９、ＮＲ^８ＣＯＲ^９、ＮＲ^８ＳＯ_２Ｒ^９、ＣＯＲ^８、ＣＯ_２Ｒ^８、ＣＯＮＲ^８Ｒ^９、ＣＨ_２ＯＲ^８、ＯＲ^８、ＳＲ^８、およびＳＯ_２Ｒ^８からなる群からそれぞれ選択され、ここでは、前記アルキル、アルケニル、アルキニル、アリール、ヘテロシクリル、ヘテロシクレニル、シクロアルキル、シクレニル、シクロアルキルアルキル、シクレニルアルキル、シクロアルキルアルケニル、シクレニルアルケニル、ヘテロアリール、ヘテロアリールアルキル、ヘテロアリールアルケニル、アリールアルキル、アリールアルケニル、ヘテロシクリルアルキル、ヘテロシクレニルアルキル、ヘテロシクリルアルケニル、ヘテロシクレニルアルケニル、−Ｓ−ヘテロシクリル、および−Ｓ−ヘテロシクレニルはそれぞれ、非置換であっても、ハロゲン、アルキル、トリハロアルキル、アルケニル、ジハロアルキル、モノハロアルキル、ヒドロキシアルキル、ＯＲ^８、−Ｏ、ＮＲ^８Ｒ^９、ＳＲ^８、ＳＯ^２Ｒ^９、ＣＮ、ＳＯ_２ＮＲ^８Ｒ^９、およびＮＯ_２からなる群から独立に選択される同じまたは異なり得る少なくとも１つの部分で置換されていてもよく；
Ｒ^６は、水素、ハロ、トリハロアルキル、アルキル、アルケニル、アリール、シクレニル、シクロアルキル、ヘテロアリール、ヘテロシクレニル、ヘテロシクリル、ヘテロアリールアルキル、ヘテロシクレニルアルキル、ヘテロシクリルアルキル、アリールアルキル、シクレニルアルキル、シクリルアルキル、ＮＲ^８Ｒ^９、ＮＲ^８ＣＯＲ^９、ＮＲ^８ＳＯ_２Ｒ^９、ＣＯＲ^８、ＣＯ_２Ｒ^８、ＣＯＮＲ^８Ｒ^９、ＣＨ_２ＯＲ^８、ＯＲ^８、ＳＲ^８、またはＳＯ_２Ｒ^８であり、ここでは、前記アルキル、アルケニル、アリール、シクレニル、シクロアルキル、ヘテロアリール、ヘテロシクレニル、ヘテロシクリル、ヘテロアリールアルキル、ヘテロシクレニルアルキル、ヘテロシクリルアルキル、アリールアルキル、シクレニルアルキル、およびシクリルアルキルはそれぞれ、非置換であっても、ハロゲン、アルキル、シクロアルキル、トリハロアルキル、ＯＲ^８、ＣＮ、ＮＲ^８Ｒ^９、ＣＯ_２Ｒ^８、ＣＯＮＲ^８Ｒ^９、−ＳＲ^８、ＳＯ_２Ｒ^８、ＳＯ_２ＮＲ^８Ｒ^９、ＮＯ_２、ＮＲ^８ＳＯ_２Ｒ^９、ＮＲ^８ＣＯＲ^９、およびＮＲ^８ＣＯＮＲ^８Ｒ^９からなる群から独立に選択される１つまたは複数の部分で置換されていてもよく；
Ｒ^８およびＲ^９は、水素、トリハロアルキル、ジハロアルキル、モノハロアルキル、アルキル、アルケニル、アリール、ヘテロアリール、アリールアルキル、シクロアルキル、シクレニル、シクロアルキルアルキル、シクレニルアルキル、シクレニルアルケニル、ヘテロシクレニル、ヘテロシクリル、ヘテロシクレニルアルキル、ヘテロシクレニルアルケニル、ヘテロシクリルアルキル、およびヘテロアリールアルキルからなる群からそれぞれ独立に選択され、ここでは、前記アルキル、アルケニル、アリール、ヘテロアリール、アリールアルキル、シクロアルキル、シクレニル、シクロアルキルアルキル、シクレニルアルキル、シクレニルアルケニル、ヘテロシクレニル、ヘテロシクリル、ヘテロシクレニルアルキル、ヘテロシクレニルアルケニル、ヘテロシクリルアルキル、およびヘテロアリールアルキルはそれぞれ、非置換であっても、ハロ、アルキル、シクロアルキル、シクレニル、アリール、ヘテロシクリル、ヘテロシクレニル、ヘテロアリール、トリハロアルキル、ＣＮ、ヒドロキシル、アルコキシル、およびＮＯ_２からなる群から独立に選択される同じまたは異なり得る少なくとも１つの部分で置換されていてもよい。

Or a pharmaceutically acceptable salt, solvate, ester, prodrug, and stereoisomer thereof. In which R ³ , R ⁵ , R ⁶ and R ⁷ are selected independently of each other, where
R ³ is hydrogen, alkyl, cycloalkyl, cyclenyl, alkynyl, trifluoroalkyl, difluoroalkyl, monofluoroalkyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, halo, cyano, —O-trihaloalkyl, NR ⁸ R ⁹ , _{^{CO 2 R 8, CONR 8 R}} 9, -OR 8, -SR 8, -SO 2 R 8, -SO 2 NR 8 R 9, -NR 8 SO 2 R 9, -NR 8 COR 9 or ^NR 8 CONR, ⁸ R ⁹ wherein the alkyl, cycloalkyl, cyclenyl, alkynyl, trifluoroalkyl, difluoroalkyl, monofluoroalkyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl are each unsubstituted alkyl, Cycloalkyl, ants Le, heteroaryl, alkenyl, Shikureniru, heterocyclenyl, halo, trihaloalkyl, alkoxy, hydroxyalkyl, trihaloalkyl alkoxyl, and it may be substituted with one or more moieties selected from the group consisting of CN independently;
R ⁵ and R ⁷ are hydrogen, alkyl, aminoalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclenyl, cycloalkyl, cyclenyl, cycloalkylalkyl, cyclenylalkyl, cycloalkylalkenyl, cyclenylalkenyl, heteroaryl, heteroaryl alkyl, heteroaryl alkenyl, arylalkyl, arylalkenyl, heterocyclylalkyl, Heterocyclenylalkyl, heterocyclylalkenyl, Heterocyclenylalkyl alkenyl, -S- heterocyclyl, -S- aminoalkyl, -S- ^{heterocyclenyl,} NR ⁸ R 9, NR ⁸ COR ⁹ , NR ⁸ SO ₂ R ⁹ , COR ⁸ , CO ₂ R ⁸ , CONR ⁸ R ⁹ , CH ₂ OR ⁸ , OR ⁸ , SR ⁸ , and SO ₂ R Are each selected from the group consisting of ^8, wherein the said alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclenyl, cycloalkyl, Shikureniru, cycloalkylalkyl, Shikure alkenyl alkyl, cycloalkyl, cycloalkenyl, Shikure alkenyl, cycloalkenyl, heteroaryl, heteroaryl Arylalkyl, heteroarylalkenyl, arylalkyl, arylalkenyl, heterocyclylalkyl, heterocyclenylalkyl, heterocyclylalkenyl, heterocyclenylalkenyl, -S-heterocyclyl, and -S-heterocyclenyl, each independently of halogen, , alkyl, trihaloalkyl, alkenyl, dihaloalkyl, monohaloalkyl, ^{hydroxyalkyl, OR 8, -O, NR 8} R 9 ^{SR 8, SO 2 R 9,} CN, may be substituted with at least one portion the same or may differ chosen SO 2 ^NR 8 ^{R 9,} and from the group consisting of NO ₂ independently;
R ⁶ is hydrogen, halo, trihaloalkyl, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocyclylalkyl, arylalkyl, cyclenylalkyl, cyclyl Alkyl, NR ⁸ R ⁹ , NR ⁸ COR ⁹ , NR ⁸ SO ₂ R ⁹ , COR ⁸ , CO ₂ R ⁸ , CONR ⁸ R ⁹ , CH ₂ OR ⁸ , OR ⁸ , SR ⁸ , or SO ₂ R ⁸ Here, said alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocyclylalkyl, arylalkyl, cyclenyl Alkyl, and each heterocyclylalkyl can be unsubstituted or substituted, halogen, alkyl, cycloalkyl, _{^{trihaloalkyl, OR 8, CN, NR 8}} R 9, CO 2 R 8, CONR 8 R 9, -SR 8, One or more moieties independently selected from the group consisting of SO ₂ R ⁸ , SO ₂ NR ⁸ R ⁹ , NO ₂ , NR ⁸ SO ₂ R ⁹ , NR ⁸ COR ⁹ , and NR ⁸ CONR ⁸ R ⁹ ; May be substituted;
R ⁸ and R ⁹ are hydrogen, trihaloalkyl, dihaloalkyl, monohaloalkyl, alkyl, alkenyl, aryl, heteroaryl, arylalkyl, cycloalkyl, cyclenyl, cycloalkylalkyl, cyclenylalkyl, cyclenylalkenyl, heterocyclenyl, heterocyclyl , Heterocyclenylalkyl, heterocyclenylalkenyl, heterocyclylalkyl, and heteroarylalkyl, each independently selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl, arylalkyl, cycloalkyl, cyclenyl, cyclo Alkylalkyl, cyclenylalkyl, cyclenylalkenyl, heterocyclenyl, heterocyclyl, heterocyclenylalkyl, heterocyclenyl Alkenyl, each heterocyclylalkyl, and heteroarylalkyl can be unsubstituted or substituted, halo, alkyl, cycloalkyl, Shikureniru, aryl, heterocyclyl, heterocyclenyl, heteroaryl, trihaloalkyl, CN, hydroxyl, alkoxyl, and NO ₂ It may be substituted with at least one moiety that may be the same or different, independently selected from the group consisting of

In one embodiment, R ³ is selected from the group consisting of heteroaryl, alkyl, halogen, and cycloalkyl, wherein said heteroaryl can be unsubstituted or substituted with alkyl.

In another embodiment, R ³ is

である。

It is.

In yet another embodiment, R ³ is

である。

It is.

In another embodiment, R ³ is ethyl.

In yet another embodiment, R ³ is cyclopropyl.

In yet another embodiment, R ³ is bromine.

In another embodiment, R ⁵ is heterocyclyl, aryl,

からなる群から選択され、ここでは、前記ヘテロシクリルは、非置換であっても、ヒドロキシアルキルで置換されていてもよく、前記アリールは、非置換であっても、ハロゲンで置換されていてもよい。

Wherein the heterocyclyl may be unsubstituted or substituted with hydroxyalkyl, and the aryl may be unsubstituted or substituted with halogen. .

In another embodiment, R ⁵ is

である。

It is.

In yet another embodiment, R ⁵ is

である。

It is.

In another embodiment, R ⁶ is halogen or (C ₁ -C ₆ ) alkyl.

In yet another embodiment, R ⁶ is bromine, methyl, or ethyl.

In another embodiment, R ⁷ is —NHR ⁸ wherein R ⁸ is selected from the group consisting of hydrogen, heteroaryl, and heteroarylalkyl, wherein said heteroarylalkyl is unsubstituted Or optionally substituted with one or more moieties independently selected from the group consisting of hydroxyl, oxo, alkyl, and alkoxyl, wherein said heteroaryl is unsubstituted or substituted with alkyl May be.

In another embodiment, R ⁸ is

である。

It is.

In yet another embodiment, R ⁸ is

である。

It is.

In yet another embodiment, R ⁸ is

である。

It is.

In yet another embodiment, R ⁸ is

である。

It is.

  In another embodiment, the compound having the formula:

またはその医薬として許容され得る塩、溶媒和化合物、エステル、プロドラッグ、および立体異性体。式中、Ｒ^３、Ｒ^５、Ｒ^６、およびＲ^７は、互いに独立に選択され、
ここでは、
Ｒ^３は、ヘテロアリール、アルキル、ハロゲン、およびシクロアルキルからなる群から選択され、前記ヘテロアリールは、非置換であっても、アルキルで置換されていてもよく；
Ｒ^５は、ヘテロシクリル、アリール、

Or a pharmaceutically acceptable salt, solvate, ester, prodrug, and stereoisomer thereof. Wherein R ³ , R ⁵ , R ⁶ , and R ⁷ are independently selected from each other;
here,
R ³ is selected from the group consisting of heteroaryl, alkyl, halogen, and cycloalkyl, said heteroaryl may be unsubstituted or substituted with alkyl;
R ⁵ is heterocyclyl, aryl,

からなる群から選択され、前記ヘテロシクリルは、非置換であっても、ヒドロキシアルキルで置換されていてもよく、前記アリールは、非置換であっても、ハロゲンで置換されていてもよく；
Ｒ^６は、ハロゲンまたは（Ｃ_１〜Ｃ_６）アルキルであり；
Ｒ^８は、水素、ヘテロアリール、およびヘテロアリールアルキルからなる群から選択され、前記ヘテロアリールアルキルは、非置換であっても、ヒドロキシル、オキソ、アルキル、およびアルコキシルからなる群から独立に選択される１つまたは複数部分で置換されていてもよく、前記ヘテロアリールは、非置換であっても、アルキルで置換されていてもよい。

The heterocyclyl may be unsubstituted or substituted with hydroxyalkyl, and the aryl may be unsubstituted or substituted with halogen;
R ⁶ is halogen or (C ₁ -C ₆ ) alkyl;
R ⁸ is selected from the group consisting of hydrogen, heteroaryl, and heteroarylalkyl, said heteroarylalkyl being independently selected from the group consisting of hydroxyl, oxo, alkyl, and alkoxyl, even if unsubstituted. It may be substituted with one or more moieties, and the heteroaryl may be unsubstituted or substituted with alkyl.

In another embodiment,
Compound having the formula:

またはその医薬として許容され得る塩、溶媒和化合物、エステル、プロドラッグ、および立体異性体。式中、Ｒ^３、Ｒ^５、Ｒ^６、およびＲ^７は、互いに独立に選択され、
ここでは、
Ｒ^３は、

Or a pharmaceutically acceptable salt, solvate, ester, prodrug, and stereoisomer thereof. Wherein R ³ , R ⁵ , R ⁶ , and R ⁷ are independently selected from each other;
here,
R ³ is

、エチル、シクロプロピル、および臭素からなる群から選択され；
Ｒ^５は、フェニル、

Selected from the group consisting of, ethyl, cyclopropyl, and bromine;
R ⁵ is phenyl,

からなる群から選択され、ここでは、前記フェニルは、非置換であっても、フッ素で置換されていてもよく；
Ｒ^６は、臭素、メチル、またはエチルであり；
Ｒ^８は、水素、

Wherein the phenyl may be unsubstituted or substituted with fluorine;
R ⁶ is bromine, methyl, or ethyl;
R ⁸ is hydrogen,

である。

It is.

  Non-limiting examples of compounds of formula I include

あるいは、それらの医薬として許容され得る塩、溶媒和化合物、またはエステルが挙げられる。

Alternatively, pharmaceutically acceptable salts, solvates, or esters thereof can be mentioned.

  In another embodiment, a pharmaceutical composition comprising a compound of formula 1 and a pharmaceutically acceptable carrier.

  In another embodiment, a pharmaceutical composition comprising a compound of formula I formulated for single dosage administration.

  In another embodiment, the use of a compound of formula I in the preparation of a medicament for the treatment of a CDK-2 mediated disease.

  In another embodiment, a method of treating, preventing, or ameliorating one or more symptoms of a disease or disorder modulated or affected by CDK-2, the amount effective for a patient in need thereof Administering a compound of formula I or a pharmaceutically acceptable salt thereof.

  In another embodiment, the use of a compound of formula I in the preparation of a medicament for the treatment of a CHK-1 mediated disease.

  In another embodiment, a method of treating, preventing, or ameliorating one or more symptoms of a disease or disorder modulated or affected by CHK-1, wherein the effective amount is in a patient in need thereof Administering a compound of formula 1 or a pharmaceutically acceptable salt thereof.

  In another embodiment, the disease or disorder to be treated is selected from the group consisting of inflammatory diseases, neurodegenerative diseases, cancer, and diabetes.

  In another embodiment, the disease to be treated is an inflammatory disease selected from the group consisting of acute pancreatitis, chronic pancreatitis, asthma, allergy, and adult respiratory distress syndrome.

  In another embodiment, the disease to be treated is a neurodegenerative disease selected from the group consisting of acute Alzheimer's disease, Parkinson's disease, cerebral ischemia, and other neurodegenerative diseases.

  In another embodiment, the disease to be treated is diabetes selected from diabetes mellitus and diabetes insipidus.

  In another embodiment, the diabetes to be treated is selected from type 1 diabetes and type 2 diabetes.

In another embodiment, the disease to be treated is a cancer selected from the group consisting of:
Bladder, breast (including BRCA mutant breast cancer), colorectal, colon, kidney, liver, lung tumor, small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, bladder, gallbladder, ovary, pancreas, stomach, uterus Cervical, thyroid, prostate, and skin tumors (including squamous cell carcinoma);
Leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia ("CLL"), acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia;
B cell lymphoma, T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burquett lymphoma;
Fibrosarcoma, rhabdomyosarcoma;
Head and neck mantle cell lymphoma, myeloma;
Astrocytoma, neuroblastoma, glioma, glioblastoma, malignant glial tumor, astrocytoma, hepatocellular carcinoma, gastrointestinal stromal tumor ("GIST"), and schwannomas;
Melanoma, multiple myeloma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratophyte cell carcinoma, follicular thyroid carcinoma, and Kaposi sarcoma.

  In another embodiment, a method of treating one or more diseases associated with a cyclin-dependent kinase in a mammal, wherein the compound is a compound of formula I, an amount of the first compound, or a pharmaceutically acceptable. A method comprising administering to said mammal a salt, solvate, ester, or prodrug thereof obtained; and at least one amount of a second compound that is an anticancer agent. Here, an amount of the first compound and the second compound provides a therapeutic effect.

  In another embodiment, the method comprises administering to the mammal an amount of a first compound that is a compound of formula I and at least one amount of a second compound that is an anticancer agent, the method comprising: A method of treatment further comprising.

  In another embodiment, the anticancer agent is a cytostatic, cytostatic, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5- Fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH66336, R115777, L778, 123, BMS214662, Iressa, Tarceva, antibodies against EGFR, Gleevec, Gleetron Adriamycin, cytoxan, gemcitabine, uracil mustard , Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, o Lustin, L ), Dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucobilin, ELOXATIN ™, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin (Dactionomyc n), daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17α-ethynylestradiol, testosterone , Fluoxymesterone, drmostanolone propionate, test lactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine Med acetate Roxyprogesterone, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole (levamisole), naberbene, anastrazol, citraxol, letrazol (Reloxafine), droloxafine, or hexamethylmelamine, Avastin, Herceptin, Bexar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porphymer, Erbitux, Erbitux Liposomal, thio PA, Altretamine, Melphalan, Trastuzumab, Lerozole, Fluvestrant, Exemestane, Fulvestrant, Ifosfamide, Rituximab, C225, C ), Cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triadipide, triadine (Tri IDOX), Amidokkusu (amidox), is selected from the group consisting of 3-AP, and MDL-101,731.

  In another embodiment, a medicament comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, in combination with at least one pharmaceutically acceptable carrier. Composition.

  In another embodiment, the compound of formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, containing at least one of cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, Camptostar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH66336, R115777, L778,123, BMS214662, Iressa, Tarceva, antibodies against EGFR -C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipe Roman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucobilin, ELOXATIN (trademark) ), Pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17α-ethynylestradiol, diethylstilbest Roll, testosterone, prednisone, fluoxymesterone, drmostanono propionate Lon, test lactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianicene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, cisplatin , Carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, naberben, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, abastin, herceptin, bexal, velcade, zevalin, trisenox , Xeloda, vinorelbine, porfimer, erbitux, liposomal, chi Tepa, Altretamine, Melphalan, Trastuzumab, Rerosol, Fulvestrant, Exemestane, Fulvestrant, Ifosfamide, Rituximab, C225, Campus, Clofarabine, Cladribine, Afidicolon, Rituxan, Sunitinib, Dasatinib, Tezacitabine, Sml1, Fludarabine A pharmaceutical composition further comprising one or more anticancer agents selected from the group consisting of statins, triapine, zidox, trimidox, amidox, 3-AP, and MDL-101,731.

  In another embodiment, a method of inhibiting one or more cyclin dependent kinases in a patient, in combination with at least one pharmaceutically acceptable carrier, in a therapeutically effective amount of a compound of formula I, or thereof Administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising at least one of a pharmaceutically acceptable salt, solvate, ester, or prodrug.

  In another embodiment, a method of inhibiting one or more checkpoint kinases in a patient in combination with at least one pharmaceutically acceptable carrier in a therapeutically effective amount of a compound of formula I, or a medicament thereof Administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising at least one of a pharmaceutically acceptable salt, solvate, ester, or prodrug.

  A method of treating one or more diseases by inhibiting one or more kinases selected from the group consisting of cyclin dependent kinases, checkpoint kinases, tyrosine kinases and Pim-1 kinases, comprising the following: Administering an effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof to a patient in need of such treatment.

  In another embodiment, a purified form of a compound of formula I.

C. Compound Preparation The compounds described herein can be synthesized by conventional methods, as shown below, using starting materials and reagents obtained from commercial sources or available commercially. For example, the compounds can be made using the chemical scheme provided below:
Compounds of Formula I where R ⁵ is a C-linked substituent (eg, compound 1a) are 2-fluoro-5-aminopyrazoles (J. Heterocyclic Chem, 1978, 15, 1447. and Tetrahedron Letters, 1979, 34, 3179. .) And the corresponding beta-ketoester can be prepared as shown in Scheme 1:
Scheme 1

Ｒ^５がＮ連結型置換基である式Ｉの化合物（例えば化合物１ｂ）は、２−フルオロ−５−アミノピラゾールおよび適切に置換されたマロン酸ジメチルから、スキーム２に示す通りに調製することができる：
スキーム２

Compounds of formula I where R ⁵ is an N-linked substituent (eg compound 1b) can be prepared from 2-fluoro-5-aminopyrazole and an appropriately substituted dimethyl malonate as shown in Scheme 2. it can:
Scheme 2

本明細書に記載される化合物は、カラムクロマトグラフィー、高速液体クロマトグラフィー、または再結晶などの方法によって反応混合物から分離し、さらに精製することができる。当業者によって理解できる通り、本明細書の式の化合物を合成するさらなる方法は、当業者に明白であろう。さらに、様々な合成ステップを、所望の化合物を与えるための代替の順序または順番で実施することができる。本明細書に記載される化合物を合成するのに有用な合成化学的転換および保護基方法論（保護および脱保護）は、当技術分野で知られており、Ｒ．Ｌａｒｏｃｋ、Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ、ＶＣＨ Ｐｕｂｌｉｓｈｅｒｓ（１９８９）；Ｔ．Ｗ．ＧｒｅｅｎｅおよびＰ．Ｇ．Ｍ．Ｗｕｔｓ、Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ、第２版、Ｊｏｈｎ Ｗｉｌｅｙ ａｎｄ Ｓｏｎｓ（１９９１）；Ｌ．ＦｉｅｓｅｒおよびＭ．Ｆｉｅｓｅｒ、Ｆｉｅｓｅｒ ａｎｄ Ｆｉｅｓｅｒ’ｓ Ｒｅａｇｅｎｔｓ ｆｏｒ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ、Ｊｏｈｎ Ｗｉｌｅｙ ａｎｄ Ｓｏｎｓ（１９９４）；ならびにＬ Ｐａｑｕｅｔｔｅ編、Ｅｎｃｙｃｌｏｐｅｄｉａ ｏｆ Ｒｅａｇｅｎｔｓ ｆｏｒ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ、Ｊｏｈｎ Ｗｉｌｅｙ ａｎｄ Ｓｏｎｓ（１９９５）およびその以降の版に記載されているものなどが挙げられる。

The compounds described herein can be separated from the reaction mixture by methods such as column chromatography, high performance liquid chromatography, or recrystallization and further purified. As will be appreciated by those skilled in the art, further methods of synthesizing compounds of the formulas herein will be apparent to those skilled in the art. Furthermore, the various synthetic steps can be performed in an alternate order or sequence to provide the desired compound. Synthetic chemical transformations and protecting group methodologies (protection and deprotection) useful for synthesizing the compounds described herein are known in the art and Larock, Comprehensive Organic Transformations, VCH Publishers (1989); W. Greene and P.M. G. M.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons (1991); Fieser and M.M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L Packetet, Encyclopedia of Regens for Orgent. Etc.

  The compounds according to the invention can have pharmacological properties; in particular, the compounds of the formula I are, for example, cyclin dependent kinases, checkpoint kinases, mitogen activated protein kinases (MAPK / ERK), glycogen synthase kinase 3 ( It can be an inhibitor of a protein kinase, such as an inhibitor such as GSK3beta). Examples of cyclin-dependent kinase (CDK) include CDC2 (CDK1), CDK2, CDK4, CDK5, CDK6, CDK7, and CDK8. One such checkpoint kinase is CHK-1. The novel compounds of formula I include cancer, autoimmune diseases, viral diseases, mycoses, neurological / neurodegenerative disorders, arthritis, inflammation, antiproliferative diseases (eg ocular retinopathy), neuronal diseases, alopecia And are expected to be useful in the treatment of proliferative diseases such as cardiovascular diseases. Many of these diseases and disorders are listed in the previously cited US 6,413,974, the disclosure of which is incorporated herein.

More particularly, the compounds of formula I may be useful in the treatment of various cancers including but not limited to: bladder, breast, colon, kidney, liver, lung (including small cell lung cancer) Carcinomas, including carcinomas of the esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B Hematopoietic tumors of lymphoid lineages, including cellular lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma and Burquett lymphoma;
Hematopoietic tumors of the myeloid lineage, including acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia;
Mesenchymal tumors including fibrosarcoma and rhabdomyosarcoma;
Tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwannoma; and
Other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratophyte cell carcinoma, follicular thyroid carcinoma, and Kaposi's sarcoma.

  In general, due to the primary role of CDK in the regulation of cell proliferation, inhibitors may be used in any disease process characterized by abnormal cell proliferation (eg, benign prostatic hyperplasia, familial adenomatous polyposis, nerve fibers). Tumors, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, nephritis, restenosis after angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplant rejection, endotoxin shock, and fungal infection) May act as a reversible cytostatic agent that may also be useful in the treatment of

Checkpoint some series, the integrity of the genome is monitored, these "DNA damage checkpoints" detects DNA damage, and inhibit cell cycle progression in G ₁ and G ₂ phases, to S phase Delay progress. This action allows the DNA repair process to complete its work prior to genome replication, followed by separation of this genetic material into new daughter cells. Inactivation of CHK1 has been shown to transduce signals from the DNA damage sensing complex and inhibit activation of cyclin B / Cdc2 kinase. Accordingly, it is promoted to enter mitosis, G ₂ arrest induced by DNA damage or endogenous DNA damage by anti-cancer drugs are discontinued, preferential killing of checkpoint deficient cells arising is provided. For example, Peng et al., Science, 277, 1501-1505 (1997); Sanchez et al., Science, 277, 1497-1501 (1997), Nurse, Cell, 91, 865-887 (1997); Weinert, Science, 277, 1450. ˜1451 (1997); Walworth et al., Nature, 363, 368-371 (1993); and Al-Khodairy et al., Molec. Biol. Cell. 5, 147-160 (1994).

  Selective manipulation of checkpoint control in cancer cells may provide broad use in cancer chemotherapy and radiation therapy regimens, and in addition, human cancer used as a selective criterion for cancer cell destruction Can provide common features of “genomic instability”. Several factors position CHK1 as a central target in DNA-damage checkpoint control. This inhibitor and functionally related kinases such as CDS1 / CHK2, ie kinases recently discovered to cooperate with CHK1 in regulating S-phase progression (Zeng et al., Nature, 395, 507-510 (1998) Elucidation of Matsuoka, Science, 282, 1893-1879 (1998)) may provide valuable new therapeutic entities for the treatment of cancer.

  Since recent discoveries suggest that CDK5 is involved in tau protein phosphorylation, compounds of formula I may also be useful in the treatment of Alzheimer's disease (J. Biochem, (1995) 117. 741-749).

  Compounds of formula I can induce or inhibit apoptosis. In various human diseases, the apoptotic response is abnormal. Compounds of formula I as modulators of apoptosis are cancer (including but not limited to the types listed above), viral infections (herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus, and Treatment of, including but not limited to, adenovirus, AIDS development in HIV-infected persons, autoimmune diseases (systemic lupus erythematosus, autoimmune mediated nephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune trueness Including but not limited to diabetes, neurodegenerative disorders (Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, and cerebellar degeneration) Including, but not limited to), myelodysplastic syndromes, aplastic anemia, myocardial infarction Disorders, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol-related liver disease, hematological disorders (including but not limited to chronic anemia and aplastic anemia), musculoskeletal system May be useful in the treatment of various degenerative diseases (including but not limited to osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, and cancer pain.

  The compounds of formula I can regulate the level of cellular RNA and DNA synthesis as inhibitors of CDK. Thus, these agents are useful for the treatment of viral infections including but not limited to HIV, human papilloma virus, herpes virus, pox virus, Epstein-Barr virus, Sindbis virus, and adenovirus. Will.

  The compounds of formula I may also be useful for the chemoprevention of cancer. Chemoprevention suppresses the development of invasive cancer by preventing the initiation of mutagenic events, or by preventing the progression of pre-cancerous cells that have already been damaged, or by suppressing tumor recurrence Is defined as

  The compounds of formula I may also be useful in inhibiting tumor angiogenesis and metastasis.

  The compounds of formula I also inhibit other protein kinases such as protein kinase C, her2, raf1, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, wee1 kinase, Src, Abl It can also act as an agent and is therefore effective in the treatment of diseases associated with other protein kinases.

  Accordingly, another aspect of the present invention is to provide a disease associated with CDK by administering to a mammal a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound. Or a method of treating a mammal (eg, a human) having a condition.

  The compounds of the present invention may also be useful in combination with one or more anti-cancer treatments such as radiation therapy and / or one or more anti-cancer agents selected from the group consisting of: cytostatics, cells Toxic agents (eg, but not limited to DNA interacting agents (eg, cisplatin or doxorubicin)); taxanes (eg, taxotere, taxol); topoisomerase II inhibitors (eg, etoposide); topoisomerase I inhibitors (eg, irinotecan (or CPT-11), camptostar, or topotecan); tubulin interactors (eg, paclitaxel, docetaxel, or epothilone); hormone agents (such as tamoxifen); thymidylate synthase inhibitors (such as 5-fluorouracil); Metoto Alkylating agents (temozolomide (from TEMODAR ™, Schering-Plow Corporation, Kenilworth, New Jersey), cyclophosphamide, etc.); farnesyl protein transferase inhibitors (SARASAR ™) (4- [2- [4-[(11R) -3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-yl-]-1- Piperidinyl] -2-oxoethyl] -1-piperidinecarboxamide, or from SCH66336, Schering-Plow Corporation, Kenilworth, New Jersey), tipifarnib (Zarnestra (Registered trademark) or R115777, from Janssen Pharmaceuticals), L778, 123 (farnesyl protein transferase inhibitor, Merck & Company, Whitehouse Station, New Jersey, BMS21466, Farnesyl protein transferase, Brice-Pirc, BMS214662 (farnesyl protein transferase) Signaling inhibitors (Iressa (from Astra Zeneca Pharmaceuticals, England)), Tarceva (EGFR kinase inhibitor), antibodies against EGFR (eg C225), GLEEVEC ™ (C-abl kinase) Pesticides, Novartis Pharmaceuticals, East Hanover, New Jersey, etc.); interferon (eg, intron) (from Schering-Plow Corporation), Peg-intron (from Schering-Plough Corporation; allotherapy combination; hormone therapy combination; ara-C, adriamycin, cytoxan, and gemcitabine.

  Other anti-cancer agents (also known as anti-neoplastic agents) include, but are not limited to, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, piperobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, Carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucobilin, oxaliplatin (from ELOXATIN ™, Sanofi-SynthelaboPharmaceutical,) Pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxo Bicine, epirubicin, idarubicin, mitramycin, deoxycoformycin, mitomycin C, L-asparaginase, teniposide 17α-ethynylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, test lactone, methyl acetate Guest roll, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianicene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine , Procarbazine, mitotane, mitoxantrone, levamisole Naberbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, or hexamethylmelamine, avastin, herceptin, bexal, velcade, zevalin, trisenox, xeloda, vinorelbine, porfimer, erbitux, liposomal, thiotepa, altretamine, mel Faran, trastuzumab, relozole, fulvestrant, exemestane, fulvestrant, ifosfamide, rituximab, C225, campus, clofarabine, cladribine, afidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, tripinedi , Trimidox, amidox, 3-AP, and MDL-101,7 1, and the like.

  When a combination therapy is administered to a patient in need of such administration, the therapeutic agent in the combination agent or pharmaceutical composition (s) comprising the therapeutic agent may be combined in any order (eg, sequentially, simultaneously, together) In parallel, etc.). The amounts of the various active substances in such combination therapy may be different (different dosages) or the same (same dosage). Thus, for non-limiting illustrative purposes, the compound of formula I and the additional therapeutic agent can be present in a fixed amount (dosage) in a single dosage unit (eg, capsule, tablet, etc.). A commercial example of such a single dosage unit containing a certain amount of two different active compounds for oral administration is VYTORIN® (available from Merck Schering-Plough Pharmaceuticals, Kenilworth, New Jersey) .

  When formulated as a fixed dose, such combination products utilize the compounds of the invention within the dosage ranges described herein, and other pharmaceutically active agents or treatments within that dosage range. . For example, the CDC2 inhibitor oromsin has been shown to act synergistically with known cytotoxic agents in inducing apoptosis (J. Cell Sci., (1995) 108, 2897.). If the combination is inappropriate, the compound of formula I can also be administered sequentially with known anti-cancer or cytotoxic agents. The present invention is not limited in the order of administration; compounds of formula I can be administered before or after administration of a known anticancer or cytotoxic agent. For example, the cytotoxic activity of the cyclin-dependent kinase inhibitor flavopiridol is affected by the order of administration with anticancer agents. Cancer Research, (1997) 57, 3375. Such techniques are within the skills of those skilled in the art as well as attending physicians.

  Accordingly, in certain aspects, the present invention includes an amount of at least one compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and an amount of one or more anti-cancer treatments listed above. And a combination drug containing an anticancer drug. Here, an amount of compound / treatment provides the desired therapeutic effect.

  The pharmacological properties of the compounds of the invention can be confirmed by several pharmacological analyses.

  The present invention is also directed to a pharmaceutical composition comprising at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound, and at least one pharmaceutically acceptable carrier.

D. Formulation of a pharmaceutical composition The pharmaceutical composition provided herein is useful in the prevention, treatment, or amelioration of symptoms of one or more diseases or disorders associated with CDK-2 or CHK-1. One or more therapeutically effective amounts of the compounds provided herein are contained in a pharmaceutically acceptable carrier. Diseases or disorders associated with CDK-2 or CHK-1 include, but are not limited to, inflammatory diseases, neurodegenerative diseases, cancer, and diabetes. Pharmaceutical carriers suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.

  In addition, the compounds can be formulated as the only pharmaceutically active ingredient in the composition or can be combined with other active ingredients.

  The composition contains one or more compounds provided herein. The compound, in one embodiment, in a suitable pharmaceutical preparation such as a liquid, suspension, tablet, dispersible tablet, pill, capsule, powder, sustained release formulation, or elixir for oral administration, Alternatively, they are formulated in sterile solutions or suspensions for parenteral administration, as well as transdermal patch formulations and dry powder inhalers. In one embodiment, the above compounds are formulated into pharmaceutical compositions using techniques and procedures well known in the art (e.g., Ansel Induction to Pharmaceutical Dosage Forms 4th edition, 1985, 126). See

  In the composition, an effective concentration of one or more compounds or pharmaceutically acceptable derivatives thereof is mixed with a suitable pharmaceutical carrier. The compound may be the corresponding salt, ester, enol ether or ester, acetal, ketal, orthoester, hemiacetal, hemiketal, acid, base, solvate, hydrate, or, prior to formulation as described above It can be derivatized as a prodrug. The concentration of the compound in the composition at the time of administration treats one or more symptoms of a disease or disorder associated with, or associated with, CDK-2 or CHK-1 activity; It is effective in preventing or delivering a remission amount.

  In one embodiment, the composition is formulated for a single dosage implementation. To formulate the composition, a weight fraction of the compound was selected at an effective concentration such that the condition being treated is reduced, prevented, or one or more symptoms are ameliorated. It is dissolved, suspended, dispersed or mixed in the carrier.

  The active compound is included in a pharmaceutically acceptable carrier in an amount sufficient to produce a therapeutically useful effect without undesirable side effects on the patient being treated. The therapeutically effective concentration is determined empirically by testing the compound using the in vitro and in vivo systems described herein and then estimating from it for dosages for humans. can do.

  The concentration of the active compound in the pharmaceutical composition is determined by the absorption, inactivation, and excretion rates of the active compound, the physicochemical properties of the compound, the dosage regimen, and the amount to be administered, as well as other It depends on the factors. For example, the amount delivered is one or more of a disease or disorder associated with CDK-2 or CHK-1 activity, or associated with CDK-2 or CHK-1 activity, as described herein. Enough to ameliorate symptoms.

  In one embodiment, a therapeutically effective dosage should provide a serum concentration of the active ingredient from about 0.1 ng / ml to about 50-100 μg / ml. The pharmaceutical composition, in another embodiment, should provide a dosage of about 0.001 mg to 2000 mg of compound per kilogram body weight per day. A pharmaceutical dosage unit form is about 0.01 mg, 0.1 mg, or 1 mg to about 500 mg, 1000 mg, or 2000 mg, in one embodiment about 10 mg to about 500 mg of active ingredient, or active ingredient, per dosage unit form. Prepared to provide a concomitant drug.

  The active ingredient can be administered at once or can be divided into several smaller doses administered at intervals of time. The exact dosage and duration of treatment is a function of the disease being treated and can be empirically determined by estimation from in vivo or in vitro test data using known test protocols. Note that concentration and dosage values may also vary depending on the severity of the condition being alleviated. For any particular subject, the individual dosage regimen should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition, and It is further understood that the concentration ranges set forth in the document are exemplary only and are not intended to limit the scope or practice of the claimed composition.

  If the compound exhibits insufficient solubility, a method of solubilizing the compound can be used. Such methods are known to those skilled in the art and include, but are not limited to, using a co-solvent such as dimethyl sulfoxide (DMSO), using a surfactant such as TWEEN®, or bicarbonate. Includes dissolution in aqueous sodium. Derivatives of compounds such as prodrugs of the compounds can also be used in preparing effective pharmaceutical compositions.

  Upon mixing or addition of the compound (s), the resulting mixture can be a solution, suspension, emulsion, and the like. The form of the resulting mixture depends on several factors, including the intended mode of administration and the solubility of the compound in the selected carrier or excipient. The effective concentration is sufficient to ameliorate the symptoms of the disease, disorder, or condition being treated and can be determined empirically.

  Pharmaceutical compositions include tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions containing an appropriate amount of the compound or a pharmaceutically acceptable derivative thereof. Liquid and unit dosage forms such as oil-water emulsions are provided for human and animal administration. The pharmaceutically therapeutically active compounds and derivatives thereof are, in one embodiment, formulated and administered in unit dosage forms or multiple dose forms. Unit dosage forms as used herein refer to physically separate units that are suitable for human and animal subjects and are individually packaged as is known in the art. Each unit dose contains a predetermined amount of a therapeutically active compound sufficient to produce the desired therapeutic effect, in combination with the required pharmaceutical carrier, excipient or diluent. Examples of unit dosage forms include ampoules and syringes and individually packaged tablets or capsules. A unit dosage form can be administered in that quantity or in multiples. A multiple dose form is a plurality of identical unit dosage forms packaged in a single container to be administered in separate unit dosage forms. Examples of multiple dose forms include vials, tablet or capsule bottles, or pint or gallon bottles. Thus, a multi-dose form is a multiple of a unit dose that is not separated within the package.

  The pharmaceutically administrable liquid composition comprises an active compound as defined above and any pharmaceutical adjuvant, for example in a carrier such as water, saline, aqueous dextrose, glycerol, glycol, ethanol etc. Can be dissolved, dispersed, or mixed thereby forming a solution or suspension. Where necessary, the administered pharmaceutical composition may also contain minor amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, such as acetates, sodium citrate, cyclodextrin derivatives, monolauric acid Sorbitan, sodium triethanolamine acetate, triethanolamine oleate, and other such agents can also be included.

  Actual methods of preparing such dosage forms are known or apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. , 15th edition, 1975.

  Dosage forms or compositions containing active ingredient in the range of 0.005% to 100% with the balance made up from non-toxic carrier can be prepared. Methods for the preparation of these compositions are known to those skilled in the art. A contemplated composition may contain 0.001% to 100% active ingredient, in one embodiment 0.1 to 95%, and in another embodiment 75 to 85%.

1. Compositions for oral administration Oral pharmaceutical dosage forms are solid, gel or liquid. Solid dosage forms are tablets, capsules, granules and bulk powders. Oral tablet types include compressed chewable lozenges and tablets that are enteric, sugar-coated, or film-coated. Capsules can be hard or soft gelatin capsules, while granules and powders can be provided in a non-foamed or foamable form in combination with other ingredients known to those skilled in the art.

a. Solid Composition for Oral Administration In certain embodiments, the formulation is a solid dosage form, in one embodiment a capsule or tablet. Tablets, pills, capsules, troches and the like can contain one or more of the following ingredients or compounds of similar nature: binders; lubricants; diluents; lubricants; disintegrants; Sweeteners; flavoring agents; wetting agents; enteric coatings; and film coatings. Examples of binders include microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, molasses, porvinylpyrrolidine, povidone, crospovidone, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium, and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol, and dicalcium phosphate. Lubricants include, but are not limited to, colloidal silicon dioxide. Disintegrants include croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethylcellulose. Coloring agents include, for example, any approved water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include artificial sweeteners such as sucrose, lactose, mannitol, and saccharin, as well as many spray-dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds that provide a pleasant sensation such as, but not limited to, mint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene laural ether. Enteric coatings include fatty acids, fats, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Film coatings include hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate.

  The compound or pharmaceutically acceptable derivative thereof can be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition can also be formulated in combination with an antacid or other such ingredient.

  When the dosage unit form is a capsule, it can contain, in addition to the types of materials described above, a liquid carrier such as a fatty oil. In addition, the dosage unit form may contain a variety of other materials that modify the physical form of the dosage unit, such as coatings of sugar and other enteric solvents. The compound can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

  The active substance can also be mixed with other active substances that do not impair the desired action, such as antacids, H2 blockers, and diuretics, or with materials that supplement the desired action. The active ingredient is a compound as described herein or a pharmaceutically acceptable derivative thereof. High concentrations of active ingredient up to about 98% by weight may be included.

  In all embodiments, tablet and capsule formulations can be coated as known by one skilled in the art to modify or maintain dissolution of the active ingredient. Thus, for example, they can be coated with conventional enterally digestible coatings such as phenyl salicylate, wax, and cellulose acetate phthalate.

b. Liquid Compositions for Oral Administration Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-foamable granules, and foamed granules. Examples include foamable preparations. Examples of the aqueous liquid preparation include elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

  An elixir is a clear, hydrous alcoholic preparation of sweetened sugar. The pharmaceutically acceptable carrier used in the elixir includes a solvent. A syrup is a concentrated aqueous solution of sugar (eg, sucrose) and may contain a preservative. An emulsion is a two-phase system in which one liquid is dispersed in the form of globules throughout another liquid. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifiers, and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable materials used in non-foamable granules that will be reconstituted into a liquid oral dosage form include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable substances used in effervescent granules that will be reconstituted into a liquid oral dosage form include organic acids and carbon dioxide raw materials. Coloring and flavoring agents are used in all of the above dosage forms.

  Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Examples of emulsifiers include gelatin, acacia, gum tragacanth, bentonite, and surfactants (such as polyoxyethylene sorbitan monooleate). Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth gum, bee gum, and gum arabic. Sweetening agents include sucrose, syrup, glycerin, and artificial sweeteners (such as saccharin). Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Examples of the raw material for carbon dioxide include sodium hydrogen carbonate and sodium carbonate. Coloring agents include any approved water soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds that provide a pleasant taste.

  For solid dosage forms, for example, solutions or suspensions in propylene carbonate, vegetable oil, or triglycerides, in one embodiment, are encapsulated in gelatin capsules. For liquid dosage forms, for example, solutions in, for example, polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, which is easily measured for administration.

  Alternatively, liquid or semisolid oral formulations can be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (eg, propylene carbonate), and other such carriers, and in solutions or suspensions thereof. Liquids can be prepared by encapsulating in hard or soft gelatin capsule shells. In brief, such formulations include the compounds provided herein, including but not limited to 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol- Dialkylated mono- or polyalkylene glycols, including 550-dimethyl ether, polyethylene glycol-750-dimethyl ether (where 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol) and butylated Hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid Malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, as well as include those containing one or more antioxidants, such as dithiocarbamate, but are not limited thereto.

  Other formulations include, but are not limited to, aqueous alcohol solutions including pharmaceutically acceptable acetals. The alcohol used in these formulations is any pharmaceutically acceptable water-miscible solvent having one or more hydroxyl groups, including but not limited to propylene glycol and ethanol. Acetals include, but are not limited to, di (lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal.

2. Injectables, solutions, and emulsions Parenteral administration, in one embodiment, is characterized by infusion either subcutaneously, intramuscularly, or intravenously, and is contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as solid forms suitable for dissolution or suspension in liquid prior to injection, or as emulsions. Injectables, solutions, and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical composition to be administered can also include wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents (sodium acetate, sorbitan monolaurate, oleic acid). Non-toxic trace amounts of adjuvants such as triethanolamine and cyclodextrins) may also be included.

  Sustained release or sustained release implants are also contemplated herein such that a constant level of dosage is maintained. Briefly, the compounds provided herein are composed of outer polymeric membranes that are insoluble in body fluids (eg, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / acetic acid Vinyl copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymer with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl Solid inner matrix (eg, polymethylmethacrylate) surrounded by alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer) Polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, In silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers (such as hydrogels of esters of acrylic and methacrylic acid), collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate) Is distributed. Such compounds diffuse through the outer polymeric membrane during the release rate control step. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.

  Parenteral administration of the composition includes intravenous, subcutaneous, and intramuscular administration. Preparations for parenteral administration include sterile, soluble solutions for injection and sterilized, soluble, dry products (including lyophilized powders that can be combined with solvents just prior to use) Etc.), sterilized suspensions for injection, sterilized insoluble dry products adapted to be combined with excipients just prior to use, and sterilized emulsions. The solution may be aqueous or non-aqueous.

  When administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and thickeners and solubilizers (glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof) Etc.).

  Pharmaceutically acceptable carriers used in parenteral preparations include aqueous excipients, non-aqueous excipients, antibacterial agents, isotonic agents, buffers, antioxidants, local anesthetics, Suspending and dispersing agents, emulsifiers, sequestering or chelating agents, and other pharmaceutically acceptable substances.

  Examples of aqueous excipients include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose, and lactated Ringer's injection. Non-aqueous parenteral excipients include plant-derived non-volatile oils, cottonseed oil, corn oil, sesame oil, and peanut oil. Many antibacterial or bacteriostatic concentrations, including phenol or cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl p-oxybenzoate, thimerosal, benzalkonium chloride and benzethonium chloride Must be added to parenteral preparations packaged in single dose containers. Isotonic agents include sodium chloride and dextrose. Buffering agents include phosphate and citrate. Examples of the antioxidant include sodium bisulfate. An example of a local anesthetic is procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Examples of the emulsifier include polysorbate 80 (TWEEN (registered trademark) 80). Examples of the sequestering agent or chelating agent for metal ions include EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol, and propylene glycol for water miscible excipients; and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

  The concentration of the pharmaceutically active compound is adjusted so that the injection provides an amount effective to produce the desired pharmacological effect. The exact dose will depend on the age, weight and condition of the patient or animal as is known in the art.

  Unit dose parenteral preparations are packaged in ampoules, vials or syringes with needles. All preparations for parenteral administration must be sterilized as is known and practiced in the art.

  Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect.

  Injectables are designed for local and systemic administration. In one embodiment, the therapeutically effective dosage is at least about 0.1% w / w to about 90% w / w or more for certain tissues or tissues to be treated. In form, it is formulated to contain an active compound at a concentration of 1% w / w or greater.

  The compound can be suspended in micronized or other suitable form and derivatized to produce a more soluble active product or to produce a prodrug. You can also. The form of the resulting mixture depends on several factors, including the intended mode of administration and the solubility of the compound in the selected carrier or excipient. The effective concentration is sufficient to ameliorate the symptoms of the condition and can be determined empirically.

3. Lyophilized powders Of interest herein are also lyophilized powders that can be reconstituted for administration as solutions, emulsions, and other mixtures. It can also be reconstituted and formulated as a solid or gel.

  A sterile lyophilized powder is prepared by dissolving the compound provided herein or a pharmaceutically acceptable derivative thereof in a suitable solvent. The solvent may contain excipients that improve the stability or other pharmacological factors of the powder or of the reconstituted solution prepared from the powder. Excipients that can be used include, but are not limited to, dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, or other suitable agent. The solvent can also contain a buffer such as citrate, sodium or potassium phosphate, or in one embodiment, other such buffers known to those skilled in the art at about neutral pH. . Subsequent filter sterilization of the solution followed by lyophilization under standard conditions known to those skilled in the art provides the desired formulation. In one embodiment, the resulting solution is dispensed into vials for lyophilization. Each vial contains a single dosage or multiple dosages of the compound. The lyophilized powder can be stored under appropriate conditions, eg, from about 4 ° C. to room temperature.

  Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, lyophilized powder is added to sterile water or other suitable carrier. The exact amount depends on the compound selected. Such an amount can be determined empirically.

4). Topical administration Topical mixtures are prepared as described for local and systemic administration. The resulting mixture can be a solution, suspension, emulsion, etc., suitable for topical administration, cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol Formulated as an irrigant, spray, suppository, bandage, transdermal patch or any other formulation.

  The compound or pharmaceutically acceptable derivative thereof can be formulated as an aerosol for topical application, such as by inhalation. These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for nebulizers, or as a microfine powder for inhalation, alone or in combination with an inert carrier such as lactose. In such cases, the particles of the formulation have a diameter of less than 50 microns in one embodiment and less than 10 microns in one embodiment.

  The compounds are for topical or topical application, eg for topical application to the skin and mucous membranes (such as in the eye), in the form of gels, creams and lotions, and for application to the eye Or can be formulated for intracisternal or intraspinal application. Localized administration is intended for transdermal delivery and for administration to the eye or mucosa, or for inhalation therapy. Nasal solutions of the active compounds can also be administered alone or in combination with other pharmaceutically acceptable excipients.

  These solutions, particularly those intended for ophthalmic use, can be formulated as 0.01% -10% isotonic solutions (pH about 5-7) with appropriate salts.

5. Compositions for other routes of administration Other routes of administration, such as transdermal patches, including iontophoretic and electrophoretic devices, and rectal administration are also contemplated herein.

  Transdermal patches including iontophoresis and electrophoresis devices are well known to those skilled in the art.

  For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules, and tablets for systemic action. As used herein, a rectal suppository means a solid for insertion into the rectum that melts or softens at body temperature and releases one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances utilized for rectal suppositories are bases or excipients and agents that increase the melting point. Examples of bases include cocoa butter (cocoa butter), glycerin-gelatin, carbowax (polyoxyethylene glycol), and suitable mixtures of mono-, di- and triglycerides of fatty acids. Combination agents of various bases can also be used. Agents that increase the melting point of suppositories include whale wax and waxes. Rectal suppositories can be prepared either by the compression method or by molding. The weight of a rectal suppository is about 2 to 3 grams in one embodiment.

  Tablets and capsules for rectal administration are manufactured in the same way as preparations for oral administration, using the same pharmaceutically acceptable substances as preparations for oral administration.

6). Targeted Formulations Compounds provided herein or pharmaceutically acceptable derivatives thereof are also formulated to target specific tissues, receptors, or other regions of the subject's body to be treated. Can be Many such targeting methods are well known to those skilled in the art. All such targeting methods are contemplated herein for use in the subject compositions.

  In one embodiment, liposome suspensions comprising tissue targeted liposomes such as tumor targeted liposomes may also be suitable as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. Briefly, liposomes such as multilamellar vesicles (MLV) can be formed by drying down egg phosphatidylcholine and brain phosphatidylserine (7: 3 molar ratio) inside the flask. A solution of a compound provided herein in phosphate buffered saline (PBS) lacking divalent cations is added and the flask is shaken until the lipid coating is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

7). Articles of Manufacture The compound or pharmaceutically acceptable derivative is effective to modulate the activity of CDK-2 or CHK-1 in the packaging material and the packaging material, or is mediated by CDK-2 or CHK-1. A compound or medicament provided herein that is effective for the treatment, prevention, or amelioration of one or more symptoms of a sex disease or disorder, or a disease or disorder associated with CDK-2 or CHK-1 activity Or a pharmaceutically acceptable derivative thereof for modulating the activity of CDK-2 or CHK-1, or mediated by CDK-2 or CHK-1 Treatment, prevention of one or more symptoms of a sexually transmitted disease or disorder, or a disease or disorder involving CDK-2 or CHK-1. Or it can be packaged as an article of manufacture containing a label indicating that it will be used for remission.

  The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those skilled in the art. Examples of pharmaceutical packaging materials include, but are not limited to, blister packaging, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and selected formulations and intended modes of administration and treatment Any packaging material suitable for the above can be mentioned. The compounds and compositions provided herein, as well as various treatments for any disease or disorder involving CDK-2 or CHK-1 as a mediator or causative factor for the symptoms or causes, A wide variety of formulations are contemplated.

  Normal phase silica gel chromatography was performed on a Biotage instrument using a Quad UV System (P / N07052) utilizing a KP-SIL 32-63 μm column, 60A with flash cartridge 12 + M or 25 + M.

Commonly used abbreviations AcOH acetic acid (BoC) ₂ O di-tert-butyl-dicarbonate DMAP 4-dimethylaminopyridine Et ₂ O diethyl ether EtOAc ethyl acetate EtOH ethanol mCPBA meta-chloroperbenzoic acid MeOH methanol NBS N-bromo Succinimide NMP 1-methyl-2-pyrrolidinone Pd (OAc) ₂ palladium acetate POCl ₃ phosphorous oxychloride RT room temperature SEMCL 2- (trimethylsilyl) ethoxymethyl chloride SiO ₂ silica gel.

  Preparation Example 1

酸（５０．０ｇ、２１８ｍｍｏｌ）とピリジン（４４．０ｍＬ）とを無水ＣＨ_２Ｃｌ_２（３００ｍＬ）に入れた撹拌混合物に、ＳＯＣｌ_２（１８．５ｍＬ）をＮ_２下でゆっくりと加えた。混合物を、２０分間２５℃で撹拌し、次いで、メルドラム酸（３５．０ｇ、２４３ｍｍｏｌ）とＤＭＡＰ（６６．６ｇ、５４６ｍｍｏｌ）とを加え、混合物を、Ｎ_２下で１時間撹拌した。次いで、Ｅｔ_２Ｏ（２Ｌ）を加え、混合物を、１Ｍ ＨＣｌ（３×５００ｍＬ）、ブライン（５００ｍＬ）で洗浄し、有機層をＮａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させた。残渣を、ＭｅＯＨ（５８０ｍＬ）に溶解し、混合物を、４時間還流させた。溶媒を蒸発させ、残渣を、溶離液として１０：１ＣＨ_２Ｃｌ_２／ＥｔＯＡｃを用いるシリカゲル上のカラムクロマトグラフィーによって精製した。淡黄色のオイル（２６．５ｇ、４３％）が得られた。

To a stirred mixture of acid (50.0 g, 218 mmol) and pyridine (44.0 mL) in anhydrous CH ₂ Cl ₂ (300 mL) was added SOCl ₂ (18.5 mL) slowly under N ₂ . The mixture was stirred for 20 minutes at 25 ° C., then Meldrum's acid (35.0 g, 243 mmol) and DMAP (66.6 g, 546 mmol) were added and the mixture was stirred under N ₂ for 1 hour. Et ₂ O ( ₂ L) was then added and the mixture was washed with 1M HCl (3 × 500 mL), brine (500 mL), the organic layer was dried over Na ₂ SO ₄ , filtered and the solvent was evaporated. The residue was dissolved in MeOH (580 mL) and the mixture was refluxed for 4 hours. The solvent was evaporated and the residue was purified by column chromatography on silica gel using 10: 1 CH ₂ Cl ₂ / EtOAc as eluent. A pale yellow oil (26.5 g, 43%) was obtained.

  Preparation Example 2

無水トルエン中の、調製実施例１からのベータ−ケトエステル（１．１当量）と２−フルオロ−５−アミノピラゾール（Ｊ．Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍ．１９７８、１５、１４４７．およびＴｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔｅｒｓ、１９７９、３４、３１７９．）（１．０当量）との混合物を撹拌し、Ｎ_２下で還流させる。溶媒を蒸発させ、残渣を、溶離液としてＣＨ_２Ｃｌ_２／ＭｅＯＨを用いるシリカゲル上のカラムクロマトグラフィーによって精製する。

Beta-ketoester (1.1 eq) from Preparative Example 1 and 2-fluoro-5-aminopyrazole (J. Heterocyclic Chem. 1978, 15, 1447. and Tetrahedron Letters, 1979, 34, 3179 in anhydrous toluene. .) (1.0 eq) is stirred and refluxed under N ₂ . The solvent is evaporated and the residue is purified by column chromatography on silica gel using CH ₂ Cl ₂ / MeOH as eluent.

  Preparation Example 3

調製実施例２からの生成物と、Ｎ，Ｎ−ジメチルアニリンと、ＰＯＣｌ_３との混合物を、２５℃で撹拌する。過剰のＰＯＣｌ_３を蒸発させ、残渣を、飽和ＮａＨＣＯ_３水溶液に注ぐ。混合物を、ＣＨ_２Ｃｌ_２（３×２００ｍＬ）で抽出し、合わせた抽出物を、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させる。残渣を、溶離液としてＣＨ_２Ｃｌ_２／ＥｔＯＡｃを用いるシリカゲル上のカラムクロマトグラフィーによって精製する。

A mixture of the product from Preparative Example 2, N, N-dimethylaniline and POCl ₃ is stirred at 25 ° C. Excess POCl ₃ is evaporated and the residue is poured into saturated aqueous NaHCO ₃ solution. The mixture is extracted with CH ₂ Cl ₂ (3 × 200 mL), the combined extracts are dried over Na ₂ SO ₄ , filtered and the solvent is evaporated. The residue is purified by column chromatography on silica gel using CH ₂ Cl ₂ / EtOAc as eluent.

  Preparation Example 4

調製実施例３からの生成物と、２−プロパノール中２．０ＭのＮＨ_３と、濃ＮＨ_４ＯＨ水溶液との混合物を、密閉した圧力容器中で、７０℃で撹拌する。溶媒を蒸発させ、残渣を、溶離液としてＣＨ_２Ｃｌ_２／ＭｅＯＨを用いるシリカゲル上のカラムクロマトグラフィーによって精製する。

A mixture of the product from Preparative Example 3, 2.0M NH ₃ in 2-propanol, and concentrated aqueous NH ₄ OH is stirred at 70 ° C. in a sealed pressure vessel. The solvent is evaporated and the residue is purified by column chromatography on silica gel using CH ₂ Cl ₂ / MeOH as eluent.

  Preparation Example 5

乾燥１，２‐ジクロロエタン中の、調製実施例４からの生成物（１．０当量）と、ＳＥＭＣｌ（３．５当量）と、ジイソプロピルエチルアミン（７．０当量）との混合物を撹拌し、Ｎ_２下で還流させる。次いで、混合物を、飽和ＮａＨＣＯ_３水溶液に注ぎ、ＣＨ_２Ｃｌ_２で抽出し、Ｎａ_２ＳＯ_４で乾燥させ、濾過する。溶媒を蒸発させ、残渣を、溶離液としてＣＨ_２Ｃｌ_２／ＥｔＯＡｃを用いるシリカゲル上のカラムクロマトグラフィーによって精製する。

Stir a mixture of the product from Preparative Example 4 (1.0 eq), SEMCl (3.5 eq) and diisopropylethylamine (7.0 eq) in dry 1,2-dichloroethane and add N ₂ under reflux. The mixture is then poured into saturated aqueous NaHCO ₃ solution, extracted with CH ₂ Cl ₂ , dried over Na ₂ SO ₄ and filtered. The solvent is evaporated and the residue is purified by column chromatography on silica gel using CH ₂ Cl ₂ / EtOAc as eluent.

  Preparation Example 6

調製実施例５からの生成物（１．０当量）の無水ＣＨ_３ＣＮ撹拌溶液に、ＮＢＳ（０．９当量）の無水ＣＨ_３ＣＮ溶液をＮ_２下で加える。混合物を撹拌し、溶媒を蒸発させ、残渣を、溶離液としてヘキサン／ＥｔＯＡｃを用いるシリカゲル上のカラムクロマトグラフィーによって精製する。

To a stirred solution of the product from Preparative Example 5 (1.0 eq) in anhydrous CH ₃ CN is added NBS (0.9 eq) in anhydrous CH ₃ CN under N ₂ . The mixture is stirred, the solvent is evaporated and the residue is purified by column chromatography on silica gel using hexane / EtOAc as eluent.

  Preparation Example 7

１，２−ジメトキシエタンおよびＨ_２Ｏ中の、調製実施例６からの生成物（１．０当量）と、１−メチル−４−（４，４，５，５−テトラメチル１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピラゾール（１．４当量）と、Ｐｄ［ＰＰｈ_３］_４（０．１０当量）と、Ｎａ_２ＣＯ_３（３．０当量）との混合物を撹拌し、Ｎ_２下で還流させる。溶媒を蒸発させ、残渣を、溶離液としてヘキサン／ＥｔＯＡｃを用いるシリカゲル上のカラムクロマトグラフィーによって精製する。

The product from Preparative Example 6 (1.0 eq) in 1, ₂ -dimethoxyethane and H2O and 1-methyl-4- (4,4,5,5-tetramethyl 1,3, Stir a mixture of 2-dioxaborolan-2-yl) -1H-pyrazole (1.4 eq), Pd [PPh ₃ ] ₄ (0.10 eq) and Na ₂ CO ₃ (3.0 eq). It is refluxed under _{N 2.} The solvent is evaporated and the residue is purified by column chromatography on silica gel using hexane / EtOAc as eluent.

  Preparation Example 8

調製実施例７からの生成物と、３Ｎ ＨＣｌ水溶液プラスＥｔＯＨとの混合物を６０℃で撹拌する。溶媒を蒸発させ、Ｎａ_２ＣＯ_３と６：１ ＣＨ_２Ｃｌ_２／ＭｅＯＨの混合物とを残渣に加え、混合物を１５分間Ｎ_２下で撹拌する。次いでこれを、カラム上に装填し、溶離液としてＣＨ_２Ｃｌ_２／ＭｅＯＨ中７Ｎ ＮＨ_３を用いるシリカゲル上のカラムクロマトグラフィーによって精製する。

A mixture of the product from Preparative Example 7 and 3N aqueous HCl plus EtOH is stirred at 60 ° C. The solvent is evaporated, a mixture of Na ₂ CO ₃ and 6: 1 CH ₂ Cl ₂ / MeOH is added to the residue and the mixture is stirred for 15 minutes under N ₂ . It is then loaded onto a column and purified by column chromatography on silica gel using CH ₂ Cl ₂ / 7N NH ₃ in MeOH as eluent.

  Preparation Example 9

Ｂｒ_２（１．０当量）の乾燥ＣＨ_２Ｃｌ_２溶液を、調製実施例８からのアミン（１．０当量）のｔｅｒｔ−ＢｕＮＨ_２およびＣＨ_２Ｃｌ_２撹拌溶液に滴下する。混合物を、２５℃で撹拌し、溶媒を蒸発させ、残渣を溶離液としてＣＨ_２Ｃｌ_２／ＭｅＯＨを用いるシリカゲル上のカラムクロマトグラフィーによって精製する。

Br ₂ (1.0 eq) in dry CH ₂ Cl ₂ is added dropwise to a stirred solution of the amine from Preparative Example 8 (1.0 eq) in tert-BuNH ₂ and CH ₂ Cl ₂ . The mixture is stirred at 25 ° C., the solvent is evaporated and the residue is purified by column chromatography on silica gel using CH ₂ Cl ₂ / MeOH as eluent.

  Preparation Example 10

マロン酸ジエチル（２．０当量）と２−フルオロ−５−アミノピラゾール（Ｊ．Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍ．１９７８、１５、１４４７．およびＴｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔｅｒｓ、１９７９、３４、３１７９．）（１．０当量）との混合物を撹拌し、Ｎ_２下で還流させる。次いで、ＭｅＯＨ中のＭｅＯＮａを残渣に加え、混合物をＮ_２下で還流させる。次いで、混合物を酸性化し、沈殿物を濾過し、Ｈ_２Ｏ、次いでＣＨ_２Ｃｌ_２で洗浄し、真空中で乾燥させる。

Mixture of diethyl malonate (2.0 eq) and 2-fluoro-5-aminopyrazole (J. Heterocyclic Chem. 1978, 15, 1447. and Tetrahedron Letters, 1979, 34, 3179.) (1.0 eq) Is stirred and refluxed under N ₂ . Then added to the residue and MeONa in MeOH, to the mixture is refluxed under _{N 2.} The mixture is then acidified and the precipitate is filtered, washed with H ₂ O, then CH ₂ Cl ₂ and dried in vacuo.

  Preparation Example 11

調製実施例１０からの生成物と、Ｎ，Ｎ−ジメチルアニリンと、ＰＯＣ１_３との混合物を１００℃で撹拌する。過剰のＰＯＣｌ_３を蒸発させ、残渣を、飽和ＮａＨＣＯ_３水溶液に注ぐ。混合物を、ＣＨ_２Ｃｌ_２（３×２００ｍＬ）で抽出し、合わせた抽出物をＮａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させる。残渣を、溶離液としてＣＨ_２Ｃｌ_２／ＥｔＯＡｃを用いるシリカゲル上のカラムクロマトグラフィーによって精製する。

And the product from Preparative Example 10, N, and N- dimethylaniline, stirring in a mixture of 100 ° C. with POC1 _3. Excess POCl ₃ is evaporated and the residue is poured into saturated aqueous NaHCO ₃ solution. The mixture is extracted with CH ₂ Cl ₂ (3 × 200 mL), the combined extracts are dried over Na ₂ SO ₄ , filtered and the solvent is evaporated. The residue is purified by column chromatography on silica gel using CH ₂ Cl ₂ / EtOAc as eluent.

  Preparation Example 12

ジオキサン中の、調製実施例１１からの生成物と、３−アミノメチルピリジンと、トリエチルアミンとを、１００℃で撹拌する。残渣を、飽和ＮａＨＣＯ_３水溶液に注ぎ、混合物を、ＣＨ_２Ｃｌ_２（３×２００ｍＬ）で抽出する。合わせた抽出物を、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させる。残渣を、溶離液としてＣＨ_２Ｃｌ_２／ＥｔＯＡｃを用いるシリカゲル上のカラムクロマトグラフィーによって精製する。

The product from Preparative Example 11, 3-aminomethylpyridine and triethylamine in dioxane are stirred at 100 ° C. The residue is poured into saturated aqueous NaHCO ₃ and the mixture is extracted with CH ₂ Cl ₂ (3 × 200 mL). The combined extracts are dried over Na ₂ SO ₄ , filtered and the solvent is evaporated. The residue is purified by column chromatography on silica gel using CH ₂ Cl ₂ / EtOAc as eluent.

  Preparation Example 13

乾燥１，２‐ジクロロエタン中の、調製実施例１２からの生成物（１．０当量）と、ＳＥＭＣｌ（３．５当量）と、ジイソプロピルエチルアミン（７．０当量）との混合物を撹拌し、Ｎ_２下で還流させる。次いで、混合物を飽和ＮａＨＣＯ_３水溶液に注ぎ、ＣＨ_２Ｃｌ_２で抽出し、Ｎａ_２ＳＯ_４で乾燥させ、濾過する。溶媒を蒸発させ、残渣を、溶離液としてＣＨ_２Ｃｌ_２／ＥｔＯＡｃを用いるシリカゲル上のカラムクロマトグラフィーによって精製する。

Stir a mixture of the product from Preparative Example 12 (1.0 eq), SEMCl (3.5 eq) and diisopropylethylamine (7.0 eq) in dry 1,2-dichloroethane and add N ₂ under reflux. The mixture is then poured into saturated aqueous NaHCO ₃ solution, extracted with CH ₂ Cl ₂ , dried over Na ₂ SO ₄ and filtered. The solvent is evaporated and the residue is purified by column chromatography on silica gel using CH ₂ Cl ₂ / EtOAc as eluent.

  Preparation Example 14

ジオキサン中の、調製実施例１３からの生成物と、２−ヒドロキシエチルピペリジンと、トリエチルアミンとの混合物を、１００℃で撹拌する。残渣を飽和ＮａＨＣＯ_３水溶液に注ぎ、混合物を、ＣＨ_２Ｃｌ_２（３×２００ｍＬ）で抽出する。合わせた抽出物を、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させる。残渣を、溶離液としてＣＨ_２Ｃｌ_２／ＭｅＯＨを用いるシリカゲル上のカラムクロマトグラフィーによって精製する。

A mixture of the product from Preparative Example 13, 2-hydroxyethylpiperidine and triethylamine in dioxane is stirred at 100 ° C. The residue is poured into saturated aqueous NaHCO ₃ and the mixture is extracted with CH ₂ Cl ₂ (3 × 200 mL). The combined extracts are dried over Na ₂ SO ₄ , filtered and the solvent is evaporated. The residue is purified by column chromatography on silica gel using CH ₂ Cl ₂ / MeOH as eluent.

  Preparation Example 15

調製実施例１４からの生成物（１．０当量）の無水ＣＨ_３ＣＮ撹拌溶液に、ＮＢＳ（０．９当量）の無水ＣＨ_３ＣＮ溶液をＮ_２下で加える。混合物を撹拌し、溶媒を蒸発させ、残渣を、溶離液としてＣＨ_２Ｃｌ_２／ＥｔＯＡｃを用いるシリカゲル上のカラムクロマトグラフィーによって精製する。

To a stirred solution of the product from Preparative Example 14 (1.0 eq) in anhydrous CH ₃ CN is added NBS (0.9 eq) in anhydrous CH ₃ CN under N ₂ . The mixture is stirred, the solvent is evaporated and the residue is purified by column chromatography on silica gel using CH ₂ Cl ₂ / EtOAc as eluent.

  Preparation Example 16

ジオキサン中の、調製実施例１５からの生成物（１．０当量）と、トリブチルエチニルスズ（１．４当量）と、Ｐｄ［ＰＰｈ_３］_４（０．１０ｅｑ）との混合物を撹拌し、Ｎ_２下で還流させる。溶媒を蒸発させ、残渣を、溶離液としてＣＨ_２Ｃｌ_２／ＥｔＯＡｃを用いるシリカゲル上のカラムクロマトグラフィーによって精製する。

Stir a mixture of the product from Preparative Example 15 (1.0 eq), tributylethynyltin (1.4 eq) and Pd [PPh ₃ ] ₄ (0.10 eq) in dioxane and add N ₂ under reflux. The solvent is evaporated and the residue is purified by column chromatography on silica gel using CH ₂ Cl ₂ / EtOAc as eluent.

  Preparation Example 17

ＥｔＯＡｃ中の、調製実施例１６からの生成物とＰｄ／Ｃとの混合物を、Ｈ_２下で撹拌する。溶媒を蒸発させ、残渣を、溶離液としてＣＨ_２Ｃｌ_２／ＥｔＯＡｃを用いるシリカゲル上のカラムクロマトグラフィーによって精製する。

In EtOAc, and the mixture of product and Pd / C from Preparative Example 16, and stirred under _{H 2.} The solvent is evaporated and the residue is purified by column chromatography on silica gel using CH ₂ Cl ₂ / EtOAc as eluent.

  Preparation Example 18

ＣＨ_２Ｃｌ_２中の、調製実施例１７からの生成物とＭＣＰＢＡとの混合物を、Ｎ_２下で撹拌する。混合物を、飽和ＮａＨＣＯ_３水溶液に注ぎ、ＣＨ_２Ｃｌ_２（３×２００ｍＬ）で抽出する。合わせた抽出物を、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させる。残渣を、溶離液としてＣＨ_２Ｃｌ_２／ＭｅＯＨを用いるシリカゲル上のカラムクロマトグラフィーによって精製する。

A mixture of the product from Preparative Example 17 and MCPBA in CH ₂ Cl ₂ is stirred under N ₂ . The mixture is poured into saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ (3 × 200 mL). The combined extracts are dried over Na ₂ SO ₄ , filtered and the solvent is evaporated. The residue is purified by column chromatography on silica gel using CH ₂ Cl ₂ / MeOH as eluent.

  Preparation Example 19

調製実施例１８からの生成物と、３Ｎ ＨＣｌ水溶液プラスＥｔＯＨとの混合物を、６０℃で撹拌する。溶媒を蒸発させ、Ｎａ_２ＣＯ_３と、ＣＨ_２Ｃｌ_２／ＭｅＯＨの６：１混合物とを残渣に加え、混合物を１５分間Ｎ_２下で撹拌する。次いで、これをカラム上に装填し、溶離液としてＣＨ_２Ｃｌ_２／ＭｅＯＨを用いるシリカゲル上のカラムクロマトグラフィーによって精製する。

A mixture of the product from Preparative Example 18 and 3N aqueous HCl plus EtOH is stirred at 60 ° C. The solvent is evaporated, Na ₂ CO ₃ and a 6: 1 mixture of CH ₂ Cl ₂ / MeOH are added to the residue and the mixture is stirred for 15 minutes under N ₂ . This is then loaded onto the column and purified by column chromatography on silica gel using CH ₂ Cl ₂ / MeOH as the eluent.

  All references cited herein, including but not limited to printed materials, electronic devices, computer-readable storage media or other forms, are abstracts, articles, journals, publications. , Including text, papers, Internet websites, databases, software packages, patents and patent publications. While several embodiments of the invention have been described, it will be understood that various modifications can be made without departing from the spirit and scope of the invention. These modifications specifically include, but are not limited to, the addition of substituents to carbon or nitrogen atoms, or as envisioned herein and as described herein. As such, other suitable ones are included and the resulting molecules are within the spirit and scope of the present invention. Accordingly, other embodiments are within the scope of the following claims and summary of the invention (above).

Claims (38)

Compound of formula (I)

(Where:
R ³ is hydrogen, alkyl, cycloalkyl, cyclenyl, alkynyl, trifluoroalkyl, difluoroalkyl, monofluoroalkyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, halo, cyano, —O-trihaloalkyl, NR ⁸ R ⁹ , _{^{CO 2 R 8, CONR 8 R}} 9, -OR 8, -SR 8, -SO 2 R 8, -SO 2 NR 8 R 9, -NR 8 SO 2 R 9, -NR 8 COR 9 or ^NR 8 CONR, ⁸ R ⁹ wherein the alkyl, cycloalkyl, cyclenyl, alkynyl, trifluoroalkyl, difluoroalkyl, monofluoroalkyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl are each unsubstituted alkyl, Cycloalkyl, ants Le, heteroaryl, alkenyl, Shikureniru, heterocyclenyl, halo, trihaloalkyl, alkoxy, hydroxyalkyl, trihaloalkyl alkoxyl, and it may be substituted with one or more moieties selected from the group consisting of CN independently;
R ⁵ and R ⁷ are hydrogen, alkyl, aminoalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclenyl, cycloalkyl, cyclenyl, cycloalkylalkyl, cyclenylalkyl, cycloalkylalkenyl, cyclenylalkenyl, heteroaryl, heteroaryl alkyl, heteroaryl alkenyl, arylalkyl, arylalkenyl, heterocyclylalkyl, Heterocyclenylalkyl, heterocyclylalkenyl, Heterocyclenylalkyl alkenyl, -S- heterocyclyl, -S- aminoalkyl, -S- ^{heterocyclenyl,} NR ⁸ R 9, NR ⁸ COR ⁹ , NR ⁸ SO ₂ R ⁹ , COR ⁸ , CO ₂ R ⁸ , CONR ⁸ R ⁹ , CH ₂ OR ⁸ , OR ⁸ , SR ⁸ , and SO ₂ R Are each selected from the group consisting of ^8, wherein the said alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclenyl, cycloalkyl, Shikureniru, cycloalkylalkyl, Shikure alkenyl alkyl, cycloalkyl, cycloalkenyl, Shikure alkenyl, cycloalkenyl, heteroaryl, heteroaryl Arylalkyl, heteroarylalkenyl, arylalkyl, arylalkenyl, heterocyclylalkyl, heterocyclenylalkyl, heterocyclylalkenyl, heterocyclenylalkenyl, -S-heterocyclyl, and -S-heterocyclenyl, each independently of halogen, , alkyl, trihaloalkyl, alkenyl, dihaloalkyl, monohaloalkyl, ^{hydroxyalkyl, OR 8, -O, NR 8} R 9 ^{SR 8, SO 2 R 9,} CN, may be substituted with at least one portion the same or may differ chosen SO 2 ^NR 8 ^{R 9,} and from the group consisting of NO ₂ independently;
R ⁶ is hydrogen, halo, trihaloalkyl, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocyclylalkyl, arylalkyl, cyclenylalkyl, cyclyl Alkyl, NR ⁸ R ⁹ , NR ⁸ COR ⁹ , NR ⁸ SO ₂ R ⁹ , COR ⁸ , CO ₂ R ⁸ , CONR ⁸ R ⁹ , CH ₂ OR ⁸ , OR ⁸ , SR ⁸ , or SO ₂ R ⁸ Here, said alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocyclylalkyl, arylalkyl, cyclenyl Alkyl, and each heterocyclylalkyl can be unsubstituted or substituted, halogen, alkyl, cycloalkyl, _{^{trihaloalkyl, OR 8, CN, NR 8}} R 9, CO 2 R 8, CONR 8 R 9, -SR 8, One or more moieties independently selected from the group consisting of SO ₂ R ⁸ , SO ₂ NR ⁸ R ⁹ , NO ₂ , NR ⁸ SO ₂ R ⁹ , NR ⁸ COR ⁹ , and NR ⁸ CONR ⁸ R ⁹ ; May be substituted;
R ⁸ and R ⁹ are hydrogen, trihaloalkyl, dihaloalkyl, monohaloalkyl, alkyl, alkenyl, aryl, heteroaryl, arylalkyl, cycloalkyl, cyclenyl, cycloalkylalkyl, cyclenylalkyl, cyclenylalkenyl, heterocyclenyl, heterocyclyl Each independently selected from the group consisting of heterocyclenylalkyl, aminoalkyl, heterocyclenylalkenyl, heterocyclylalkyl, and heteroarylalkyl, wherein the alkyl, alkenyl, aryl, heteroaryl, arylalkyl, cycloalkyl, Cyclenyl, cycloalkylalkyl, cyclenylalkyl, cyclenylalkenyl, heterocyclenyl, heterocyclyl, heterocyclenylalkyl, Minoalkyl, heterocyclenylalkenyl, heterocyclylalkyl, and heteroarylalkyl are each unsubstituted, halo, alkyl, cycloalkyl, cyclenyl, aryl, heterocyclyl, heterocyclenyl, heteroaryl, trihaloalkyl, CN, hydroxyl, alkoxyl And may be substituted with at least one moiety that may be the same or different, independently selected from the group consisting of NO ₂ ),
Or a pharmaceutically acceptable salt, solvate, ester, prodrug, or stereoisomer thereof. The compound according to claim 1, wherein R ³ is selected from the group consisting of heteroaryl, alkyl, halogen, and cycloalkyl, wherein the heteroaryl may be unsubstituted or substituted with alkyl. The heteroaryl is

The compound according to claim 2, wherein The substituted heteroaryl is

The compound according to claim 3, wherein The compound of claim 2, wherein the alkyl is ethyl. The compound of claim 2, wherein the cycloalkyl is cyclopropyl. The compound of claim 2, wherein the halogen is bromine. R ⁵ is heterocyclyl, aryl,

2. The heterocyclyl selected from the group consisting of: wherein the heterocyclyl may be unsubstituted or substituted with hydroxyalkyl, and the aryl may be unsubstituted or substituted with halogen. Compound. The heterocyclyl is

The compound according to claim 8, wherein The substituted heterocyclyl is

The compound according to claim 8, wherein R ⁶ is halogen or _(C 1 -C ₆₎ A compound according to claim 1 is alkyl. 12. A compound according to claim 11 wherein the halogen is bromine and the alkyl is methyl or ethyl. R ⁷ is —NHR ⁸ wherein R ⁸ is selected from the group consisting of hydrogen, heteroaryl, and heteroarylalkyl, wherein said heteroarylalkyl is unsubstituted, hydroxyl, oxo, alkyl And optionally substituted with one or more moieties independently selected from the group consisting of alkoxyl, wherein said heteroaryl may be unsubstituted or substituted with alkyl. The described compound. The heteroaryl is

The compound according to claim 13. The substituted heteroaryl is

The compound according to claim 14, wherein The heteroarylalkyl is

The compound according to claim 13. The substituted heteroarylalkyl is

The compound according to claim 16. The compound of claim 1 having the formula:

(Where
R ³ is selected from the group consisting of heteroaryl, alkyl, halogen, and cycloalkyl, said heteroaryl may be unsubstituted or substituted with alkyl;
R ⁵ is heterocyclyl, aryl,

The heterocyclyl may be unsubstituted or substituted with hydroxyalkyl, and the aryl may be unsubstituted or substituted with halogen;
R ⁶ is halogen or (C ₁ -C ₆ ) alkyl;
R ⁸ is selected from the group consisting of hydrogen, heteroaryl, and heteroarylalkyl, said heteroarylalkyl being independently selected from the group consisting of hydroxyl, oxo, alkyl, and alkoxyl, even if unsubstituted. Which may be substituted with one or more moieties, the heteroaryl may be unsubstituted or substituted with alkyl). A compound having the following structure:

Or a pharmaceutically acceptable salt, solvate, ester, prodrug, or stereoisomer thereof. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. 21. A pharmaceutical composition according to claim 20 formulated for single administration. Use of a compound according to claim 1 in the preparation of a medicament for the treatment of CDK-2 or CHK-1 mediated diseases. A method for the treatment, prevention, or amelioration of one or more symptoms of a disease or disorder modulated or affected by CDK-2 or CHK-1, in an effective amount for a patient in need thereof A method comprising administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 24. The method of claim 23, wherein the disease or disorder is selected from the group consisting of inflammatory diseases, neurodegenerative diseases, cancer, and diabetes. 25. The method of claim 24, wherein the inflammatory disease is selected from the group consisting of acute pancreatitis, chronic pancreatitis, asthma, allergy and adult respiratory distress syndrome. 25. The method of claim 24, wherein the neurodegenerative disease is selected from the group consisting of acute Alzheimer's disease, Parkinson's disease, cerebral ischemia, and other neurodegenerative diseases. 25. The method of claim 24, wherein the diabetes is selected from the group consisting of diabetes mellitus and diabetes insipidus. 28. The method of claim 27, wherein the diabetes is selected from type 1 diabetes and type 2 diabetes. 25. The method of claim 24, wherein the cancer is selected from the group consisting of:
Bladder, breast (including BRCA mutant breast cancer), colorectal, colon, kidney, liver, lung tumor, small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, bladder, gallbladder, ovary, pancreas, stomach, Cervical, thyroid, prostate, and skin tumors (including squamous cell carcinoma);
Leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia ("CLL"), acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia;
B cell lymphoma, T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burquett lymphoma;
Fibrosarcoma, rhabdomyosarcoma;
Head and neck, mantle cell lymphoma, myeloma;
Astrocytoma, neuroblastoma, glioma, glioblastoma, malignant glial tumor, astrocytoma, hepatocellular carcinoma, gastrointestinal stromal tumor (“GIST”), and schwannoma;
Melanoma, multiple myeloma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratospyocytoma, follicular thyroid cancer, and Kaposi sarcoma. A method of treating one or more diseases associated with cyclin-dependent kinase or checkpoint kinase 1 in a mammal, wherein the compound is a compound according to claim 1 in an amount, or a pharmaceutical thereof. An acceptable salt, solvate, ester, or prodrug; and administering an amount of at least one second compound that is an anticancer agent to the mammal, wherein an amount of said A method wherein the first compound and the second compound provide a therapeutic effect. 32. The method of claim 30, further comprising radiation therapy. The anticancer agent is a cytostatic, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide 115, cyclophosphamide S , L778, 123, BMS 214662, Iressa, Tarceva, antibody against EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipbloman, triethylenemelamine, triethylene Thiophosphoramine, busulfan, carmustine, lomustine, strep Zocine, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucobilin, ELOXATIN ™, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, Doxorubicin, epirubicin, idarubicin, mitramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17α-ethynylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, drmostanolone propionate, test lactone, acetic acid Megestrol, methylprednisolone, methyltestosterone, prednisolone, triamushi Norone, chlorotrianicene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, 31. The method of claim 30, wherein the method is selected from the group consisting of naberbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, or hexamethylmelamine. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or at least one pharmaceutically acceptable salt, solvate, ester or prodrug thereof in combination with at least one pharmaceutically acceptable carrier. . Cytostatic, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH7336L7 , BMS214466, Iressa, Tarceva, antibodies against EGFR, Gleevec, Intron, ara-C, Adriamycin, Cytoxan, Gemcitabine, Uracil Mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Daka Vadine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitramycin, deoxycophore Mycin, mitomycin-C, L-asparaginase, teniposide 17α-ethynylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, drmostanolone propionate, test lactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, Triamcinolone, chlorotrianicene, hydroxyprogesterone, aminoglutethimide , Estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, naberben, anastrazole, letrazole, capecitabine, reloxafine, drolo 34. The pharmaceutical composition according to claim 33, further comprising one or more anticancer agents selected from the group consisting of xafin or hexamethylmelamine. 34. A method of inhibiting one or more cyclin dependent kinases in a patient, comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 33. A method of treating one or more diseases by inhibiting one or more kinases, comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester thereof. Or at least one of the prodrugs is administered to a patient in need of such treatment, wherein the kinase is selected from the group consisting of cyclin dependent kinases, checkpoint kinases, tyrosine kinases, and Pim-1 kinases How to be. A method of treating one or more diseases by inhibiting one or more kinases, comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester thereof. Or administering at least one of the prodrugs to a patient in need of such treatment, wherein said kinase is selected from the group consisting of cyclin dependent kinase 2 and checkpoint kinase 1. 2. A compound according to claim 1 in purified form.