JP2007507552A - Method for treating hyperglycemia induced by IGF1R inhibitors - Google Patents

Abstract

A method of treating cancer using an IGF1R inhibitor in combination with an insulin sensitizer provides treatment or prevention of hyperglycemia.

Description

Detailed Description of the Invention

(Related application)
This application claims priority based on US Provisional Application No. 60 / 508,890, title 35§119 (e), filed Oct. 6, 2003, the contents of which are incorporated herein by reference.

(Technical background)
The present invention relates to a method of treating cancer using a tyrosine kinase inhibitor. Cancer is a disease characterized by overexpression or upregulation of tyrosine kinase activity. Tyrosine kinases include cell proliferation, carcinogenesis, apoptosis, and cell differentiation (Plowman, GD; Ullrich, A .; Shawver, LK: Receptor Tyrosine Kinases As Targets For Drug Intervention. DN & P (1994) 7: 334-339), It plays an important role in signal transduction for several cellular functions.

  Epidemiological evidence suggests that overexpression or activation of receptor protein tyrosine kinases that induce constitutive cell division signals is an important factor in the number of human malignancies growing. One tyrosine kinase that has been implicated in these processes is the IGF1 receptor (IGF1R). Several clinical reports highlight the important role of the IGF-1 pathway in human tumor development. IGFIR overexpression is often found in various tumors such as breast, colon, lung, sarcoma and is well associated with an active phenotype. High circulating IGF1 levels are strongly correlated with prostate, lung and breast cancer risk.

  Inhibition of the IGF1 receptor has been found useful for the treatment of cancer. Several in vitro and in vivo methods have provided important evidence that inhibition of the IGF1R signal replaces the transformed phenotype and inhibits tumor cell growth. However, although IGF1R inhibitors are promising chemotherapeutic agents, the use of these agents is problematic because of the homology of the IGF1 receptor and the insulin receptor (IR). The insulin receptor kinase domain is 84% homologous to the IGF1R kinase domain and there are several reports of IGF1R tyrosine kinase inhibitors that are selective for the insulin receptor.

  Insulin receptors are proteins that are expressed on the cell surface, especially muscle, fat and liver cells. When insulin binds to the insulin receptor, it initiates the insulin signaling pathway within the cell that produces a variety of physiological responses, including the transfer of glucose into the cell. This disruption of cell signaling pathways can lead to a variety of symptoms including hyperglycemia.

  It has been found that administration of small molecule IGF1R inhibitors induces hyperglycemia, presumably by blocking the insulin receptor. Reference is made to WO 02/102804. Therefore, there is a need in the art to find methods for treating or preventing hyperglycemia induced by IGF1R inhibitors so that the full potential of these promising new agents can be realized.

  Insulin and insulin secretagogues are a viable option in the treatment of IGF1R-induced hyperglycemia because their primary mechanism of action involves increased levels of insulin and probably requires a prototypical insulin receptor. Absent.

  Insulin-sensitizers such as metformin are widely used as drugs used to treat type II diabetes or non-insulin dependent diabetes. The mechanism of action of metformin was not very clear. The scientific literature, however, suggests that clinical efficacy requires the presence of insulin. See Weinsperger and Bailey: Drugs 58: Supp. 1, 31-39 (1999) and Baylor: Diabetes Care, 15: 755 to 772 (1992). Metformin is known to inhibit glucose production from the liver, and one study suggests that this action involves activation of the insulin receptor (IR). See Gunton et al., J. of Clin. Endocrinology and Metabolism, 88 (3): 1323-1332. In support of this view, it has been found that individual treatments with known IR mutations are not very effective with insulin sensitizers such as metformin. See Vestegard et al., J. Internal Med. 250: 406-414 (2001). Gunton et al., When given in combination with an IR inhibitor, metformin blocked the ability of an insulin sensitizer to reduce or prevent IGF1R-induced hyperglycemia, where inhibition of the IR receptor caused by the IGF1R inhibitor It also reports that IR phosphorylation suggesting that it cannot be increased.

  Currently, there is a need in the art for cancer treatment with IGF1R inhibitors that do not produce hyperglycemia.

(Overview)
Surprisingly, insulin sensitizers have been found to be effective in treating, reducing or preventing hyperglycemia induced by IGF1R inhibitors. Accordingly, the present invention is characterized in that an effective amount of an IGF1R inhibitor is administered to a mammal in need thereof in combination with an effective amount of an insulin sensitizer to reduce, treat or prevent hyperglycemia. A method of treating cancer is provided.

(Detailed description of the invention)
According to the present invention, there is provided a method for treating or preventing hyperglycemia induced by an IGF1R inhibitor in a patient receiving treatment with an IGF1R inhibitor. The discovery that insulin sensitizers have the ability to treat or prevent hyperglycemia induced by IGF1R without altering cell proliferation effects or the anti-cancer efficacy of these inhibitors is a drug discovery effort in this area. To increase.

  As used herein, hyperglycemia is defined as a measurement where the fasting glucose level is 110 mg / dl or higher and the postprandial glucose level is 140 mg / dl or higher.

  An “acceptable glucose level” is a measured value of about 140 mg / dl or less after a meal and about 110 mg / dl or less in a fasted state.

  As used herein, the phrase “IGF1R-induced hyperglycemia” refers to a hyperglycemic state caused by administering an IGF1R inhibitor to a mammal in need of treatment for a disease susceptible to IGF1R inhibition, such as cancer. Means.

In this specification, the term “alkyl” used alone or as part of another group, unless otherwise defined, means a group derived from a monovalent alkane (hydrocarbon) containing 1 to 12 carbon atoms. To do. An alkyl group is an optionally substituted linear, branched or cyclic saturated hydrocarbon group. When substituted, at any point capable of attachment, R can be substituted with up to four substituents, as defined, for R. When an alkyl group is substituted with an alkyl group, this is used synonymously with “branched alkyl group”. Specifically, unsubstituted groups are methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4 -Including trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Specific substituents include, but are not limited to, one or more of the following groups: hydroxy, halo (F, Cl, Br, I, etc.), haloalkyl (CCl ₃ or CF ₃ etc.), alkoxy, alkylthio, Cyano, carboxy (—COOH), alkylcarbonyl (—C (O) R), alkoxycarbonyl (—OCOR), amino, carbamoyl (—NHCOOR or —OCONHR), urea (—NHCONHR), thiol (—SH), sulfoxy , Sulfonyl, aryl, heteroaryl, and heterocycloalkyl. An alkyl group as defined may also contain one or more carbon-carbon double bonds, or one or more carbon-carbon triple bonds. An alkyl group can also be represented by the formula: alkyl-R ²⁵ . In a preferred embodiment, the alkyl group is a methyl, ethyl, propyl or butyl group and includes a substituted methyl, ethyl, propyl or butyl group.

  As used herein, the term “alkenyl”, used alone or as part of another group, refers to a straight, branched, or cyclic chain containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. A hydrocarbon group is meant. Alkenyl groups can be optionally substituted in a manner similar to that described for alkyl groups.

  As used herein, the term “alkynyl”, alone or as part of another group, refers to a straight chain, branched chain, or cyclic, containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. A hydrocarbon group is meant. Alkynyl groups can be optionally substituted in a manner similar to that described for alkyl groups.

As used herein, the term “alkoxy” used alone or in combination means a straight or branched alkyl group that contains 1 to 10 carbon atoms and is covalently bonded to the parent molecule through a bond with an oxygen atom. The terms “C _1-6 alkoxy” and “lower alkoxy” refer to 1 to 6 carbon atoms such as, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and the like. Means a containing group. When used in combination with an alkoxy substituent, the term “optionally substituted” means no more than two hydrogens, preferably lower alkyl, phenyl, cyano, halo, trifluoromethyl, nitro, hydroxy, alkanoyl, amino, By substitution with different carbon atoms in a group selected from the group of monoalkylamino and dialkylamino is meant. Alkoxy groups can be substituted in a manner similar to that in which the alkyl group is substituted as described above.

  As used herein, the term “sulfoxy”, used alone or as part of another group, means —SO, which can be substituted, for example, with an alkyl or aryl group.

As used herein, the term “sulfonyl”, used alone or as part of another group, means —SO ₂ and can be substituted with an alkyl or aryl group.

As used herein, the term “amino”, used alone or as part of another group, means —NH ₂ . “Amino” is alkyl, aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. The same or different 1 or 2 substituents can be optionally substituted. Preferred substituents include alkylamino and dialkylamino such as methylamino, ethylamino, dimethylamino, and diethylamino. These substituents can be further substituted with any of the carboxylic acid or alkyl or aryl substituents described herein. In addition, amino substituents, together with nitrogen atoms, are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, which are optionally substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy. 4-thiamorpholinyl, 4-sulfoxymorpholine, 4-sulfonylmorpholine, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-homopiperazinyl, Joined to form 4-alkyl-1-homopiperazinyl, 4-arylalkyl-1-homopiperazinyl, 4-diarylalkyl-1-homopiperazinyl; 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl.

As used herein, the term “aryl”, used alone or as part of another group, refers to monocyclic or bicyclic aromatic rings such as, for example, phenyl, substituted phenyl, and the like, for example, naphthyl, It means a condensed group such as phenanthrenyl. Thus, an aryl group has alternating (resonant) double bonds between adjacent carbon atoms or suitable heteroatoms, containing no more than 22 atoms therein, no more than 5 rings shown and at least It contains at least one ring having 6 atoms. Aryl groups include, but are not limited to, halogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, alkylaminocarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano, alkyl S ( O) _m (m = 0, 1, 2), or may be optionally substituted with one or more groups including thiols. Aryl groups are heterocycloalkyl to form condensed rings such as dihydrobenzfuranyl, oxyindolyl, indolyl, indolinyl, oxyindolyl, benzoxazolidinonyl, benzoxazolinyl and benzoxazolidinone. And can also be substituted with heterocycloaryl groups.

As used herein, the term “cycloalkyl”, used alone or as part of another group, refers to a fully saturated and partially unsaturated of 3-9, preferably 3-7 carbon atoms. Meaning a hydrocarbon ring. In addition, cycloalkyl can be substituted. Substituted cycloalkyl means halo, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, oxo (═O), hydroxy, alkoxy, thioalkyl, —CO ₂ H, —OC (═O) H, CO ₂ -alkyl, —OC (═O) alkyl, ═N—OH, ═N—O-alkyl, aryl, heteroaryl, heterocyclo, 5- or 6-membered ring ketal (ie 1,3-dioxolane or 1,3 - dioxane), - NR'R ", - C (= O) NR'R", - OC (= O) NR'R '', - NR'CO 2 'R ", - NR'C (= O) R ″, —SO ₂ NR′R ″, and —NR′SO ₂ ′ R ″ (R ′ and R ″ are each independently selected from hydrogen, alkyl, substituted alkyl, and cycloalkyl Or R ′ and R ″ are one Means a ring having 1, 2, or 3, preferably 1, substituents selected from the group consisting of: (forms heterocyclo or heteroaryl rings together). Cycloalkyl groups can also be substituted with heteroatoms such as O, N, and S to form heterocycloalkyl groups. Preferred heterocycloalkyl groups include optionally substituted morpholine, homomorpholine (7-membered ring), thiomorpholine, piperazine, homopiperazine (7-membered ring), and piperidine, which substituents can be further substituted heterocycloalkyl. An alkyl group may also be included.

As used herein, the term “heteroaryl” used alone or as part of another group refers to substituted and unsubstituted having at least one heteroatom (O, S, or N) in at least one ring. An aromatic 5- or 6-membered monocyclic group, a 9- or 10-membered bicyclic group, and a 11- to 14-membered tricyclic group are meant. Each ring of the heteroaryl group containing heteroatoms can contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or Below that, each ring has at least one carbon atom. Fused rings forming bicyclic and tricyclic groups can contain only carbon atoms and can be saturated, partially saturated, or unsaturated. Nitrogen and sulfur atoms can be oxidized as appropriate, and nitrogen atoms can be quaternized as appropriate. A heteroaryl group that is bicyclic or tricyclic must contain at least one complete aromatic ring, while the other condensed ring or ring can be an aromatic or non-aromatic ring. The heteroaryl group can be attached at any available nitrogen or carbon atom of any ring. Heteroaryl ring systems are halo, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, hydroxy, alkoxy, thioalkyl, —CO ₂ H, —OC (═O) H, —CO ₂ -alkyl, —OC (═O) alkyl, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, cycloalkyl, substituted cycloalkyl, heterocyclo, heteroaryl, —NR′R ″, —C (═O) NR′R ″, — OC (= O) NR'R '' , - NR'CO 2 'R ", - NR'C (= O) R", - SO 2 NR'R ", and -NR'SO ₂ R"(R' And R ″ are each independently selected from hydrogen, alkyl, substituted alkyl, and cycloalkyl, or R ′ and R ″ together form a heterocyclo or heteroaryl ring. Is selected from the group consisting of to), it may include 0, 1, 2 or 3 substituents.

  Specific monocyclic heteroaryl groups include pyrrolyl, pyrrolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like .

  Specific bicyclic heteroaryl groups are indolyl, indolinyl, oxyindolyl, benzoxazolidinone, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl , Indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydroisoindolyl, tetrahydroquinolinyl and the like.

  Specific tricyclic heteroaryl groups include carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

  As used herein, the term “halogen” or “halo”, used alone or as part of another group, means chlorine, bromine, fluorine or iodine selected on an individual basis.

  As used herein, the term “hydroxy”, used alone or as part of another group, means —OH.

  As used herein, the term “thioalkoxy”, used alone or as part of another group, means an alkyl group, as defined herein, attached to the parent molecular group through a sulfur atom. Specific examples of thioalkoxy include, but are not limited to, thiomethoxy, thioethoxy, and the like.

  In one aspect of the invention, the method comprises administering an effective amount of an IGF1R inhibitor used in combination with an effective amount of an insulin sensitizer to a mammal in need of such treatment, a cancer that affects IGF1R inhibition Provide treatment. The insulin sensitizer may be administered to the mammal prior to, sequentially or simultaneously with the administration of the IGF1R inhibitor.

  The insulin sensitizers of the present invention include, inter alia, biguanides, metformin and phenformin, glitazones (rosiglitazone, piogliatisone) and other PPAR agonists such as those described in US Pat. No. 6,414,000 and WO02 / 26729, PPARα, PPARγ, And PPAR dual agonists, the disclosures of which are incorporated herein by reference.

  In one embodiment of the present invention, an insulin sensitizer is administered to a patient who is treated with an IGF1R inhibitor in combination with other known anticancer therapeutic agents. The treatment may include radiotherapy or, for example, but not limited to, a DNA interacting agent such as cisplatin or doxorubicin; a topoisomerase II inhibitor such as etoposide; a topoisomerase I inhibitor such as CPT-11 or topotecan; Or a synthetic tubulin interacting agent such as paclitaxel, docetaxel or epothilone; a hormonal agent such as tamoxifen; a thymidylate synthase inhibitor such as 5-fluorouracil and UFT; an antimetabolite such as methotrexate; Tyrosine kinase inhibitors such as Iressa and OSI-774; angiogenesis inhibitors; EGF inhibitors; VEGF inhibitors; CDK inhibitors; Her1 / 2 inhibitors and growth such as Erbitux (EGF) and Herceptin (Her2) Including the child receptor, monoclonal antibodies that act directly, SRC, treatment of cytostatic or cytotoxic agents, such as C-Kit.

  IGF1R inhibitors of the present invention include, but are not limited to, US patent application 10/105599; US patent application 10/263448; US patent application 10/751798; US patent application 10/674098; WO 03/048133; WO 01/25220; US Pat. No. 6,337,338 (WO 00/35455); WO 02/102804; WO 02/092599; WO 03/024967; WO 03/035619; WO 03/035616; WO US 2004/63705 and US 2003/125346. The entire contents of which are incorporated herein by reference.

［式中、
Ｘは、Ｎ、Ｃまたは直接結合であり；
Ｙは、ＯまたはＳであり；
Ｗは、Ｎ、Ｃ、Ｏ、またはＳであり；但し、ＷがＯまたはＳなら、Ｒ⁹は存在せず；
Ｒ¹は、Ｈ、アルキル、またはアルコキシであり；
Ｒ²およびＲ⁹は、独立して、Ｈまたはアルキルであり；
Ｒ³は、Ｈ、Ｃ_1-6アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、ハロ、アミノ、−ＯＲ⁶⁰、−ＮＯ₂、−ＯＨ、−ＳＲ⁶⁰、−ＮＲ⁶⁰Ｒ⁶¹、−ＣＮ、−Ｃ（Ｏ）Ｒ⁶⁰、−ＣＯ₂Ｒ⁶⁰、−ＣＯＮＲ⁶⁰Ｒ⁶¹、ＯＣＯＮＲ⁶⁰Ｒ⁶¹、−ＮＲ⁶²ＣＯＮＲ⁶⁰Ｒ⁶¹、−ＮＲ⁶⁰ＳＯ₂Ｒ⁶¹、−ＳＯ₂ＮＲ⁶⁰Ｒ⁶¹、−ＳＯ₂Ｒ⁶³、−Ｃ（ＮＲ⁶²）ＮＲ⁶⁰Ｒ⁶¹、−Ｃ（ＮＨ⁶²）−モルホリン、アリール、ヘテロアリール、−（ＣＨ₂）_nＣ（Ｏ）₂−Ｒ⁶⁰、−ＮＲ⁶⁰Ｒ⁶¹−（ＣＨ₂）_nＯＲ⁶⁰、−（ＣＨ₂）_nＮＲ⁶⁰Ｒ⁶¹、−（ＣＨ₂）_nＳＲ⁶⁰、−（ＣＨ₂）_nアリール、−（ＣＨ₂）_nヘテロアリール、または−（ＣＨ₂）_nヘテロシクロアルキルであって、ｎは、１〜３であり：
Ｒ⁴は、Ｈ、ハロ、アルキルまたはハロアルキルであり；
Ｒ⁵は、Ｈ、アルキル、ハロ、またはアリールであり；
Ｒ⁶、Ｒ⁷、およびＲ⁸は、各々独立して、−ＮＨ−Ｚ−アリールまたは−ＮＨ−Ｚ−ヘテロアリール（Ｚは、Ｃ₁−Ｃ₄アルキル、アルケニル、またはアルキニル）であり；Ｚは、適宜１またはそれ以上のヒドロキシ、チオール、アルコキシ、チオアルコキシ、アミノ、ハロ、ＮＲ⁶⁰ＳＯ₂Ｒ⁶¹基を有し；Ｚは、適宜ＣＯ、ＣＮＯＨ、ＣＮＯＲ⁶⁰、ＣＮＮＲ⁶⁰、ＣＮＮＣＯＲ⁶⁰およびＣＮＮＳＯ₂Ｒ⁶⁰からなる群から選択される１またはそれ以上の基を導入し；
Ｒ⁶⁰、Ｒ⁶¹、Ｒ⁶²、およびＲ⁶³は、独立して、Ｈ、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルキルアルキル、ヒドロキシ、アルコキシ、アリール、ヘテロアリール、ヘテロアリールアルキル、およびアルキル−Ｒ²⁵からなる群から選択され；
Ｒ²⁵は、水素、アルケニル、ヒドロキシ、チオール、アルコキシ、チオアルコキシ、アミノ、アルキルアミノ、ジアルキルアミノ、アリール、ヘテロアリール、シアノ、ハロ、スルホキシ、スルホニル、−ＮＲ³⁰ＣＯＯＲ³¹、−ＮＲ³⁰Ｃ（Ｏ）Ｒ³¹、−ＮＲ³⁰ＳＯ₂Ｒ³¹、−Ｃ（Ｏ）ＮＲ³⁰Ｒ³¹、ヘテロアリールまたはヘテロシクロアルキルであって；
Ｒ³⁰およびＲ³¹は、独立して、水素、アルキル、またはシクロアルキルである］
を有し、そのエナンチオマー、ジアステレオマー、医薬的に許容される塩、水和物およびその溶媒和物を含む。 In one embodiment of the invention, the IGF1R inhibitor has the formula I:

[Where:
X is N, C or a direct bond;
Y is O or S;
W is N, C, O, or S; provided that if W is O or S, then R ⁹ is not present;
R ¹ is H, alkyl, or alkoxy;
R ² and R ⁹ are independently H or alkyl;
R ³ is H, C _1-6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halo, amino, —OR ⁶⁰ , —NO ₂ , —OH, —SR ⁶⁰ , —NR ⁶⁰ R ⁶¹ , —CN ^{, -C (O) R 60,} -CO 2 R 60, -CONR 60 R 61, OCONR 60 R 61, -NR 62 CONR 60 R 61, -NR 60 SO 2 R 61, -SO 2 NR 60 R 61, ^{_{-SO 2 R 63, -C (NR}} 62) NR 60 R 61, -C (NH 62) - morpholine, aryl, _{heteroaryl, - (CH 2) n C} (O) 2 -R 60, -NR 60 R _{^{61 - (CH 2) n oR}} 60, - (CH 2) n NR 60 R 61, - (CH 2) n SR 60, - (CH 2) n aryl, - (CH _{2) n} heteroaryl or, - ( a CH _{2) n} heterocycloalkyl, n is located at 1-3:
R ⁴ is H, halo, alkyl or haloalkyl;
R ⁵ is H, alkyl, halo, or aryl;
R ⁶ , R ⁷ , and R ⁸ are each independently —NH—Z-aryl or —NH—Z-heteroaryl (Z is C ₁ -C ₄ alkyl, alkenyl, or alkynyl); Optionally has one or more hydroxy, thiol, alkoxy, thioalkoxy, amino, halo, NR ⁶⁰ SO ₂ R ⁶¹ groups; Z is optionally CO, CNOH, CNOR ⁶⁰ , CNNR ⁶⁰ , CNNCOR ⁶⁰ and CNNSO ₂ introducing one or more groups selected from the group consisting of R ⁶⁰ ;
R ⁶⁰ , R ⁶¹ , R ⁶² , and R ⁶³ are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, hydroxy, alkoxy, aryl, heteroaryl, heteroarylalkyl, and alkyl-R Selected from the group consisting of ²⁵ ;
R ²⁵ is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aryl, heteroaryl, cyano, halo, sulfoxy, sulfonyl, —NR ³⁰ COOR ³¹ , —NR ³⁰ C (O ) R ³¹ , —NR ³⁰ SO ₂ R ³¹ , —C (O) NR ³⁰ R ³¹ , heteroaryl or heterocycloalkyl;
R ³⁰ and R ³¹ are independently hydrogen, alkyl, or cycloalkyl]
And the enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates and solvates thereof.

As an aspect of the present invention,
R ¹ is H, alkyl or alkoxy;
R ² is H;
R ³ is H, alkyl, —CN, halo, —C (O) R ⁶⁰ , —C (O) NR ⁶⁰ R ⁶¹ , —S (O) ₂ R ⁶³ , piperazine, piperidine, morpholine, triazole, imidazole. Yes, piperazine, piperidine, morpholine, triazole, or imidazole is H, alkyl, —NHC (O) alkyl, —NHC (O) ₂ alkyl, —NHC (O) alkoxy, —O— (CH ₂ ) _n R ⁶⁴ R ⁶⁴ is hydroxy, alkoxy, morpholine, or tetrahydropyrimidine;
R ⁶ is —NH—Z-phenyl, —NH—Z-imidazole, or —NH—Z-pyrazole, and Z is C1-C2 alkyl.

In a preferred embodiment, R ³ is piperidine, morpholine or piperazine.

In one embodiment of the invention, the IGF1R inhibitor is:
(S) -4- (2-Hydroxy-1-phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one ;
(±) -4- [2-hydroxy-2- (3-iodophenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H- Pyridin-2-one;
(±) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine -2-one;
(±) -4- [2- (3-Bromophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H- Pyridin-2-one;
(S) -4- [2- (2-Chlorophenyl) -1-hydroxymethylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H- Pyridin-2-one;
(S) -4- [2- (3-Chlorophenyl) -1-hydroxymethylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H- Pyridin-2-one;
(S) -4- [2- (4-Chlorophenyl) -1-hydroxymethylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H- Pyridin-2-one;
(S) -4- [2- (2-Bromophenyl) -1-hydroxymethylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H -Pyridin-2-one;
(S) -4- [2- (3-Bromophenyl) -1-hydroxymethylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H -Pyridin-2-one;
(±) -4- (1-hydroxymethyl-2-pentafluorophenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-on;
(S) -4- (1-Hydroxymethyl-2-pyridin-4-yl-ethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H -Pyridin-2-one;
(S) -4- [1-hydroxymethyl-2- (2-naphthalenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H- Pyridin-2-one;
3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (pyridin-2-ylmethoxy) -1H-pyridin-2-one;
(±) -4- [2- (3-Bromophenyl) -2-fluoroethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H- Pyridin-2-one;
(S) -2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazole-5-carbonitrile ;
(±) -2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5 -Carbonitrile;
(S) -2- {4- [2- (3-Chlorophenyl) -1-hydroxymethylethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole- 5-carbonitrile;
(±) -2- {4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H -Benzimidazole-5-carbonitrile;
(±) -2- {4- [2- (3-Fluorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole- 5-carbonitrile;
(±) -2- {4- [2- (3-Bromophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole- 5-carbonitrile;
(S) -2- [4- (2-Hydroxy-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazole-5-carbonitrile;
(±) -3- (1H-benzimidazol-2-yl) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one;
(S) -3- (1H-benzimidazol-2-yl) -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridin-2-one;
(±) -3- (1H-benzimidazol-2-yl) -4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxyethylamino] -1H-pyridin-2-one;
(S) -4- {2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazole-5 -Yl} piperazine-1-carboxylic acid isopropylamide;
(S) -4- {2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazole-5 -Yl} piperazine-1-carboxylic acid ethylamide;
(S) -4- (1-hydroxymethyl-2-phenylethylamino) -3- {4-methyl-6- [4- (1-phenylmethanoyl) piperazin-1-yl] -1H-benzimidazole- 2-yl} -1H-pyridin-2-one;
(S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [6- (4-isopropylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -1H -Pyridin-2-one;
(S) -3- [6- (4-Benzylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -4- (1-hydroxymethyl-2-phenylethylamino) -1H -Pyridin-2-one;
(±) -3- [6- (4-Acetylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -4- [2- (3-chlorophenyl) -2-hydroxyethylamino ] -1H-pyridin-2-one;
(±) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl) -1H-pyridine -2-one;
(±) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- [6- (4-isopropylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl ] -1H-pyridin-2-one;
(S) -6- (1-Hydroxymethyl-2-phenylethylamino) -5- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -3H-pyrimidine-4- on;
(S) -2- [6-Chloro-5- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -pyrimidin-4-ylamino] -3-phenylpropane-1- All;
(S) -4- (2-Hydroxy-2-phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one ;
(R) -4- (2-hydroxy-2-phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one ;
(1S, 2R) -4- (1-Hydroxyindan-2-ylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2- on;
(±) -4- [2-hydroxy-2- (3-hydroxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H- Pyridin-2-one;
(S) -4- (2-Hydroxy-2-pyridin-2-yl-ethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H- Pyridin-2-one;
(±) -N- (3- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2- Dihydropyridin-4-ylamino] ethyl} phenyl) methanesulfonamide;
(±) -4- [2- (3-Fluorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H- Pyridin-2-one;
(±) -4- [2- (3-Chloro-4-fluorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl ) -1H-pyridin-2-one;
(S) -4- [2- (3-Fluorophenyl) -1-hydroxymethylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H -Pyridin-2-one;
(±) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-1H-benzimidazol-2-yl) -1H-pyridin-2-one ;
(±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl ) -1H-pyridin-2-one;
(S) -4- [2- (3-Bromophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H- Pyridin-2-one;
(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine -2-one;
(R) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine -2-one;
(±) -4- [2- (3-Chloro-4-methoxyphenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl ) -1H-pyridin-2-one;
(±)-(2-Chloro-4- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1, 2-dihydropyridin-4-ylamino] ethyl} phenyl) carbamic acid methyl ester;
(S) -4- (1-hydroxymethyl-2-phenylethylamino) -3- [4-methyl-6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H -Pyridin-2-one;
(S) -4- (1-hydroxymethyl-2-phenylethylamino) -3- [4-methyl-6- (4-n-butylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyridin-2-one;
(S) -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H-benzimidazol-2-yl} -4- (1-hydroxymethyl-2-phenyl) Ethylamino) -1H-pyridin-2-one;
(S) -4- {2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazole-5 -Yl} piperazine-1-carboxylic acid amide;
(±) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl) -1H-pyridine -2-one;
(±) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- [6- (4-ethylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl ] -1H-pyridin-2-one;
(±) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H-benz Imidazol-2-yl} -1H-pyridin-2-one;
(±) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl) -1H-pyridine -2-one;
(±) -4- [2- (3-Bromophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl) -1H- ;
(±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl ) -1H-pyridin-2-one;
(±) -4- [2- (3-Bromophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H- Benzimidazol-2-yl} -1H-pyridin-2-one;
(±) -4- [2- (3-Bromophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl} -1H- Pyridin-2-one;
(±) -4- [2- (3-Bromophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl} -1H- Pyridin-2-one;
(±) -3- [6- (4-Acetylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -4- [2- (3-bromophenyl) -2-hydroxyethyl Amino] -1H-pyridin-2-one;
(S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [4-methyl-6- (2-morpholin-4-yl-ethylamino) -1H-benzimidazol-2-yl] -1H-pyridin-2-one;
(±) -6- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -5- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -3H-pyrimidine -4-one;
(±) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- [6- (1-hydroxy-1-methylethyl) -4-methyl-1H-benzimidazol-2-yl ] -1H-pyridin-2-one;
(±) -3- (6-Aminomethyl-4-methyl-1H-benzimidazol-2-yl) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -1H-pyridin-2- on;
(±) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- (6-hydroxymethyl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2- on;
(S) -4- (1-Benzyl-2-hydroxyethylamino) -3- (4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl) -1H-pyridin-2-one ;and
(S) -4- (1-Benzyl-2-hydroxyethylamino) -3- (4-methyl-6-piperidin-1-yl-1H-benzimidazol-2-yl) -1H-pyridin-2-one ;
(S) -4- (1-Benzyl-2-hydroxyethylamino) -3- (4-methyl-6-piperidin-1-yl-1H-benzimidazol-2-yl) -1H-pyridin-2-one ;
4- [2- (3-Chloro-4-methylsulfanylphenyl) -2-hydroxyethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl) -1H -Pyridin-2-one;
4- [2- (3-Chloro-4-fluorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl) -1H- Pyridin-2-one;
3- [4- (2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole -5-yl) piperazin-1-yl] propionitrile;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-methanesulfonylethyl) piperazin-1-yl] -4-methyl-1H-benzimidazole-2 -Yl} -1H-pyridin-2-one;
3- [4- (2- {4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -3H-benzo Imidazol-5-yl) -7-methylpiperazin-1-yl] propionitrile;
4- (2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5 Yl) piperazine-1-carboxylic acid 2-fluoroethyl ester;
4- (2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5 Yl) piperazine-1-carboxylic acid 2-methoxyethyl ester;
4- (2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5 Yl) piperazine-1-carboxylic acid tert-butyl ester;
4- (2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5 Yl) piperazine-1-carboxylic acid 2-propynyl ester;
4- (2- {4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H- Benzimidazol-5-yl) piperazine-1-carboxylic acid tert-butyl ester;
(S) -4- (2- {4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7- Methyl-3H-benzimidazol-5-yl) piperazine-1-carboxylic acid ethyl ester;
4- [2- (3-Chloro-4-methoxyphenyl) -2-hydroxyethylamino] -3- {6- [4- (3-fluoropropyl) piperazin-1-yl] -4-methyl-1H- Benzimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-fluoroethyl) piperazin-1-yl] -4-methyl-1H-benzimidazol-2- IL} -1H-pyridin-2-one;
4- [2- (3-Chloro-4-fluorophenyl) -2-hydroxyethylamino] -3- {6- [4- (3-fluoropropyl) piperazin-1-yl] -4-methyl-1H- Benzimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- {6- [4- (3-fluoropropyl) piperazin-1-yl] -4-methyl-1H- Benzimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {4-methyl-6- [4- (3,3,3-trifluoropropyl) piperazin-1-yl] -1H- Benzimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (3-fluoropropyl) piperazin-1-yl] -4-methyl-1H-benzimidazol-2- IL} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {4-methyl-6- [4- (3,4,4-trifluoro-3-butenyl) piperazin-1-yl] -1H-benzoimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (3-fluoro-2-hydroxypropyl) piperazin-1-yl] -4-methyl-1H-benzo Imidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxy-2-methylpropyl) piperazin-1-yl] -4-methyl-1H-benzo Imidazol-2-yl} -1H-pyridin-2-one;
(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H-benz Imidazol-2-yl} -1H-pyridin-2-one;
(S) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4- Methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one;
[4- (2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5 -Yl) piperazin-1-yl] acetonitrile;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (4-fluorobutyryl) piperazin-1-yl] -4-methyl-1H-benzimidazole-2 -Yl} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2,2-difluoroacetyl) piperazin-1-yl] -4-methyl-1H-benzimidazole- 2-yl} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-methanesulfonylacetyl) piperazin-1-yl] -4-methyl-1H-benzimidazole-2 -Yl} -1H-pyridin-2-one;
3- [6- (4-Acetylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -1H- Pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6- {4- [2- (1-oxo-1,4-thiomorpholin-4-yl) acetyl ] Piperazin-1-yl} -1H-benzimidazol-2-yl) -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- (6- {4- [2- (1,1-dioxo-1,6-thiomorpholin-4-yl) acetyl] piperazine -1-yl} -4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {4-methyl-6- [4- (2-thiomorpholin-4-yl-acetyl) piperazin-1-yl] -1H -Benzimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-methanesulfinylacetyl) piperazin-1-yl] -4-methyl-1H-benzimidazole-2 -Yl} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-methoxyacetyl) piperazin-1-yl] -4-methyl-1H-benzimidazol-2- IL} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {4-methyl-6- [4- (2-methylsulfanylacetyl) piperazin-1-yl] -1H-benzimidazole-2 -Yl} -1H-pyridin-2-one;
3- {6- [4- (2-Chloroacetyl) piperazin-1-yl] -4-methyl-1H-benzimidazol-2-yl} -4- [2- (3-chlorophenyl) -2-hydroxyethyl Amino] -1H-pyridin-2-one;
(S) -4- (2- {4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7- Methyl-3H-benzimidazol-5-yl) piperazine-1-carbaldehyde;
(S) -4- (2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benz Imidazol-5-yl) piperazine-1-carbaldehyde;
(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl) -1H-pyridine -2-one;
4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl) -1H- Pyridin-2-one;
4- [2- (3-Chloro-4-fluorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl) -1H- Pyridin-2-one;
4- [2- (3-Chloro-4-methoxyphenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl) -1H- Pyridin-2-one;
4- [2- (7-Bromo-2,3-dihydrobenzofuran-5-yl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzimidazole-2 -Yl) -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2 (S) -hydroxyethylamino] -3- [4-methyl-6- [2 (S), 6 (R) -dimethylmorpholin-4-yl] -1H -Benzimidazol-2-yl] -1H-pyridin-2-one;
4- [2- (3-Bromo-4-methoxyphenyl) -2 (S) -hydroxyethylamino] -3- [4-methyl-6- [2 (S), 6 (R) -dimethylmorpholine-4 -Yl] -1H-benzimidazol-2-yl] -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl)-(S) -2-hydroxyethylamino] -3- {6-[(R) -2-fluoromethylmorpholin-4-yl] -4-methyl-1H-benz Imidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chlorophenyl)-(S) -2-hydroxyethylamino] -3- {6-[(S) -2-fluoro Methylmorpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Bromo-4-methoxyphenyl)-(S) -2-hydroxyethylamino] -3- {6-[(R) -2-fluoromethylmorpholin-4-yl] -4- Methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-bromo-4-methoxyphenyl)-(S) -2-hydroxyethylamino] -3- { 6-[(S) -2-fluoromethylmorpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Chloro-4-methoxyphenyl)-(S) -2-hydroxyethylamino] -3- {6-[(R) -2-fluoromethylmorpholin-4-yl] -4- Methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chloro-4-methoxyphenyl)-(S) -2-hydroxyethylamino] -3- { 6-[(S) -2-fluoromethylmorpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (7-Bromo-2,3-dihydrobenzofuran-4-yl)-(S) -2-hydroxyethylamino] -3- {6-[(R) -2-fluoromethylmorpholine-4 -Yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (7-bromo-2,3-dihydrobenzofuran-4-yl)-(S ) -2-Hydroxyethylamino] -3- {6-[(S) -2-fluoromethylmorpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2- on;
4- [2- (3-Chlorophenyl)-(S) -2-hydroxyethylamino] -3- {6-[(R) -2-hydroxymethylmorpholin-4-yl] -4-methyl-1H-benz Imidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chlorophenyl)-(S) -2-hydroxyethylamino] -3- {6-[(S) -2-hydroxy Methylmorpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Bromo-4-methoxyphenyl)-(S) -2-hydroxyethylamino] -3- {6-[(R) -2-hydroxymethylmorpholin-4-yl] -4- Methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-bromo-4-methoxyphenyl)-(S) -2-hydroxyethylamino] -3- { 6-[(S) -2-hydroxymethylmorpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Chloro-4-methoxyphenyl)-(S) -2-hydroxyethylamino] -3- {6-[(R) -2-hydroxymethylmorpholin-4-yl] -4- Methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chloro-4-methoxyphenyl)-(S) -2-hydroxyethylamino] -3- { 6-[(S) -2-hydroxymethylmorpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl)-(S) -2-hydroxyethylamino] -3- {6-[(R) -2-methylmorpholin-4-yl] -4-methyl-1H-benzimidazole -2-yl} -1H-pyridin-2-one and 4- [2- (3-chlorophenyl)-(S) -2-hydroxyethylamino] -3- {6-[(S) -2-methylmorpholine -4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Bromo-4-methoxyphenyl)-(S) -2-hydroxyethylamino] -3- {6-[(R) -2-methylmorpholin-4-yl] -4-methyl -1H-benzimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-bromo-4-methoxyphenyl)-(S) -2-hydroxyethylamino] -3- {6 -[(S) -2-methylmorpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Chloro-4-methoxyphenyl)-(S) -2-hydroxyethylamino] -3- {6-[(R) -2-methylmorpholin-4-yl] -4-methyl -1H-benzimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chloro-4-methoxyphenyl)-(S) -2-hydroxyethylamino] -3- {6 -[(S) -2-methylmorpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl)-(S) -2-hydroxyethylamino] -3- {6-[(R) -2-methoxymethylmorpholin-4-yl] -4-methyl-1H-benz Imidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chlorophenyl)-(S) -2-hydroxyethylamino] -3- {6-[(S) -2-methoxy Methylmorpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Bromo-4-methoxyphenyl)-(S) -2-hydroxyethylamino] -3- {6-[(R) -2-methoxymethylmorpholin-4-yl] -4- Methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-bromo-4-methoxyphenyl)-(S) -2-hydroxyethylamino] -3- { 6-[(S) -2-methoxymethylmorpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Chloro-4-methoxyphenyl)-(S) -2-hydroxyethylamino] -3- {6-[(R) -2-methoxymethylmorpholin-4-yl] -4- Methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chloro-4-methoxyphenyl)-(S) -2-hydroxyethylamino] -3- { 6-[(S) -2-methoxymethylmorpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2 (S) -hydroxyethylamino] -3- [4-methyl-6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyridin-2-one;
4- [2- (3-Bromo-4-methoxyphenyl) -2 (S) -hydroxyethylamino] -3- [4-methyl-6- (4-methylpiperazin-1-yl) -1H-benzimidazole -2-yl] -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (acetamido) piperidin-1-yl] -4-methyl-1H-benzimidazol-2-yl}- 1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyacetamido) piperidin-1-yl] -4-methyl-1H-benzimidazol-2- IL} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-fluoroacetamido) piperidin-1-yl] -4-methyl-1H-benzimidazol-2- IL} -1H-pyridin-2-one;
4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- {6- [4- (acetamido) piperidin-1-yl] -4-methyl-1H-benzimidazole- 2-yl} -1H-pyridin-2-one;
4- [2- (3-Bromophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyacetamido) piperidin-1-yl] -4-methyl-1H-benzimidazole-2 -Yl} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-fluoroacetamido) piperidin-1-yl] -4-methyl-1H-benzimidazol-2- IL} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-methoxyethoxycarbamoyl) piperidin-1-yl] -4-methyl-1H-benzimidazole-2 -Yl} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (methoxycarbamoyl) piperidin-1-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-fluoroethoxycarbamoyl) piperidin-1-yl] -4-methyl-1H-benzimidazole-2 -Yl} -1H-pyridin-2-one;
(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (2-morpholin-4-ylethoxy) -1H-benzimidazol-2-yl] -1H-pyridin-2-one;
(S) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (2-morpholin-4-ylethoxy) -1H-benzimidazole -2-yl] -1H-pyridin-2-one;
(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (2-methoxyethoxy) -1H-benzimidazol-2-yl] -1H- Pyridin-2-one;
(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (2-hydroxyethoxy) -1H-benzimidazol-2-yl] -1H- Pyridin-2-one;
(S) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (2-morpholin-4-ylpropoxy) -1H-benz Imidazol-2-yl] -1H-pyridin-2-one;
(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (2-morpholin-4-ylpropoxy) -1H-benzimidazol-2-yl ] -1H-pyridin-2-one;
(S) -3- (4-Bromo-6-morpholin-4-ylmethyl-1H-benzimidazol-2-yl) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -1H-pyridine -2-one;
(S) -3- [4-Bromo-6- (4-methylpiperazin-1-ylmethyl-1H-benzimidazol-2-yl) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one;
(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (4-methylpiperazin-1-ylmethyl) -1H-benzimidazol-2-yl ] -1H-pyridin-2-one;
4- [2- (3-Chlorophenyl) -2 (S) -hydroxyethylamino] -3- [4-methyl-6- (1,4,5,6-tetrahydropyrimidin-1-yl) -1H-benzo Imidazol-2-yl] -1H-pyridin-2-one; and
4- [2- (4-Methoxy-3-chlorophenyl) -2 (S) -hydroxyethylamino] -3- [4-methyl-6- (1,4,5,6-tetrahydropyrimidin-1-yl) -1H-benzoimidazol-2-yl] -1H-pyridin-2-one;
4- [2- (3-Chloro-4-methoxyphenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl) -1, 5-dihydropyrrol-2-one;
4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl) -1, 5-dihydropyrrol-2-one;
(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl) -1,5 -Dihydropyrrol-2-one;
(S, S and S, R) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -5-methyl-3- (4-methyl-6-morpholin-4-yl-1H-benzo Imidazol-2-yl) -1,5-dihydropyrrol-2-one;
[1- (2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5 -Yl) piperidin-4-yl] carbamic acid tetrahydrofuran-3-ylmethyl ester;
[1- (2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5 -Yl) piperidin-4-yl] carbamic acid 2-methoxypropyl ester;
(S) -2- [4- (2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl- 3H-Benzimidazol-5-yl) piperazin-1-yl] acetamide dihydrochloride;
(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6 [4- (2-methoxyethyl) piperazin-1-yl] -4-methyl-1H-benzimidazole -2-yl-1H-pyridin-2-one dihydrochloride;
(S) -4- [2- (3-Bromophenyl) -2-hydroxyethylamino] -3- {6 [4- (2-methoxyethyl) piperazin-1-yl] -4-methyl-1H-benzo Imidazol-2-yl-1H-pyridin-2-one dihydrochloride;
(S) -4- [2- (3-Cyanophenyl) -2-hydroxyethylamino] -3- {6 [4- (2-methoxyethyl) piperazin-1-yl] -4-methyl-1H-benzo Imidazol-2-yl-1H-pyridin-2-one dihydrochloride;
(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H-benz Imidazol-2-yl} -1H-pyridin-2-one dihydrochloride;
(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {4-methyl-6- [4- (2-methylsulfanylethyl) piperazin-1-yl] -1H- Benzimidazol-2-yl} -1H-pyridin-2-one dihydrochloride;
(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (3R-methylpiperazin-1-yl) -1H-benzimidazol-2-yl ] -1H-pyridin-2-one dihydrochloride; and
(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-methoxyethyl) -3 (R) -methylpiperazin-1-yl]- 4-Methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one dihydrochloride
Selected from the group consisting of

［式中、
ｎは、０〜４であり；
Ｒ_aは、アルキル、置換されたアルキル、−Ｃ（Ｏ）ｐＲ⁷⁰、アミノールアルキルアミノ、−ＳＯ₂Ｒ⁷¹、シクロアルキル、ヘテロシクロアルキル、ヘテロアリール、またはアルコキシアルコキシアルキルであり；ｐは、１または２であり；Ｒ⁷⁰およびＲ⁷¹は、アルキルまたは置換されたアルキルであり；Ｒ_bは、アルキルまたは置換されたアルキルであって；Ｒ³およびＲ⁶は、上と同義である］
を有する。好ましい態様として、Ｒ⁶は、−ＮＨ−Ｚ−ヘテロアリールまたは−ＮＨ−Ｚ−アリールである。 In one embodiment of the present invention, the IGF1R inhibitor has the following formula:

[Where:
n is 0-4;
R _a is alkyl, substituted alkyl, —C (O) pR ⁷⁰ , aminolalkylamino, —SO ₂ R ⁷¹ , cycloalkyl, heterocycloalkyl, heteroaryl, or alkoxyalkoxyalkyl; p is R ⁷⁰ and R ⁷¹ are alkyl or substituted alkyl; R _b is alkyl or substituted alkyl; R ³ and R ⁶ are as defined above]
Have In a preferred embodiment, R ⁶ is —NH—Z-heteroaryl or —NH—Z-aryl.

も含む。 The IGF1R inhibitor of the present invention comprises the following compound:

Including.

  The IGF1R inhibitors of the present invention are useful for various pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to a salt that has been revealed by medicinal chemists, ie substantially non-toxic, with the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion. Means a salt that provides Other factors that are more practical and practical and important in selection are raw material price, ease of crystallinity, yield, stability, hygroscopicity and fluidity of the resulting bulk drug. Conveniently, the pharmaceutical composition may be prepared from the active ingredients or their pharmaceutically acceptable salts used in combination with a pharmaceutically acceptable carrier.

  The IGF1R inhibitor of the present invention is formulated as a pharmaceutical composition. These pharmaceutical compositions can be in a form suitable for oral use such as, for example, a tablet, troche, troche, aqueous or oily suspension, dispersible powder or granules, emulsion, hard or soft capsule, or syrup or elixir. . Compositions intended for oral use can be prepared by any method known in the art for the manufacture of pharmaceutical compositions, such that the composition provides a pharmaceutically elegant and palatable formulation One or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginic acid. Granulating and disintegrating agents; binders such as starch, gelatin, polyvinylpyrrolidone or acacia, and lubricants such as magnesium stearate, stearic acid or talc. Tablets are uncoated or coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time. For example, a water soluble taste masking material such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate butyrate may be used.

  Formulations for oral use are hard gelatin capsules where the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient is water soluble such as polyethylene glycol Or a soft gelatin capsule mixed with an oily medium such as peanut oil, liquid paraffin, or olive oil.

  Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. The excipient is, for example, a suspending agent such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia; a dispersing or wetting agent is a natural such as lecithin Phosphatides derived from, or condensation products of alkylene oxides and fatty acids such as polyoxyethylene stearate, or condensation products of ethylene oxide and long chain fatty alcohols such as heptadecaethyleneoxycetanol, or Condensation products of ethylene oxide with fatty acid-derived partial esters and hexitol, such as polyoxyethylene monooleate sorbitol, or, for example, polyethylene sorbitan monooleate It may be condensation products of partial esters and hexitol anhydrides derived from ethylene oxide with fatty acids,. A water-soluble suspension may contain, for example, ethyl or one or more preservatives such as n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and sucrose. One or more sweetening agents such as saccharin or aspartame may also be included.

  Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil, for example liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or α-tocopherol.

  Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are embodied by those already mentioned above. In addition, excipients such as sweetening, flavoring and coloring agents can also be present. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.

  The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oily layer can be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents are, for example, naturally occurring phosphatides such as soy lecithin, and fatty acid derived esters or partial esters such as sorbitan monooleate and hexitol anhydrides, and for example polyoxyethylene sorbitan monooleate. Such a partial ester and ethylene oxide condensation product may be used. The emulsion may also contain sweetening agents, flavoring agents, preservatives and antioxidants.

  Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. The formulations may also contain a demulcent, a preservative, flavoring and antioxidants.

  The pharmaceutical composition may also take the form of a sterile injectable aqueous solutions. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.

  The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily layer. For example, the active ingredient can be first dissolved in a mixture of soybean oil and lecithin. The oil solution was then introduced into the water and glycerol mixture and carried out to form a microemulsion.

  Injection solutions or microemulsions can be introduced into the patient's bloodstream by topical bolus injection. It may also be advantageous to administer a solution or microemulsion so as to maintain a sustained blood concentration of the compound instantaneously. To maintain such a sustained concentration, a continuous intravenous delivery device can be utilized. A specific example of such a device is the Deltec CADD-PLUS. TM. Model 5400 intravenous pump.

  The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any sterile fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in injectable formulations.

When an IGF1R inhibitor is administered to a human patient, the dosage is generally a dose that varies depending on the age, height and weight of the individual patient, and the severity of the patient's symptoms, and is usually by the prescribing physician. It is determined. In determining the appropriate dose, renal and / or liver function was also assessed and adjusted accordingly. The IGF1R inhibitor can be administered at a fixed dose in the range of about 100 to about 1000 mg / m ² .

  Although the dosage of the insulin sensitizer can also be determined by the administering physician, specifically, the dosage is in the range of 500 to 3000 mg / day, once or twice daily, Given in. A preferred dosage of metformin is in the range of about 1000-2500 mg / day.

(Example)
Example 1
Figure 1: Insulin receptor inhibitory effect was measured using the oral glucose tolerance test (OGTT). IGF1R inhibitor A (4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl) -1H- Pyridin-2-one) was tested on rats in an acute OGTT study: fed rats were 50, 100, and 200 mpk by single administration for 4 hours prior to glucose challenge (1 g / kg). Inhibitor A was administered orally. Glucose was monitored using a saccharimeter at 30, 60, 90 and 120 minutes after the glucose challenge. As shown, there was a marked effect at higher concentrations of drug after basal and glucose challenge.

Example 2
Figure 2: An acute OGTT study to determine the effect of combination treatment with metformin and inhibitor A to lower glucose was performed in rats. To stabilize glucose levels, food was cut off for 1 hour prior to administration of either drug. A glucose challenge was administered 2 hours after administration of inhibitor A and plasma glucose was monitored. Plasma glucose levels increased with inhibitor (200 mpk) administration before 150 mg / dl glucose challenge and after 250 mg / dl glucose challenge. However, when the animals were pretreated with metformin (450 mpk) for 1 hour, the hyperglycemic effect observed was completely improved to show that metformin opposes the hyperglycemic effect induced by inhibitor A in rats. did.

  The above examples are for illustrative purposes only and do not limit the scope of the invention in any way.

FIG. 1 shows the effect of an IGF1R inhibitor on rat plasma glucose levels when treated with an IGF1R inhibitor. FIG. 2 shows that hyperglycemia-induced IGF1R is preventable in rats treated with IGF1R inhibitors.

Claims (19)

  A method of treating a tumor responsive to IGF1R inhibition comprising administering an effective amount of an IGF1R inhibitor in combination with an insulin sensitizer to a mammal in need thereof.   2. The method of claim 1, wherein the insulin sensitizer is administered to the mammal prior to administration of the IGF1R inhibitor.   2. The method of claim 1, wherein the tumor is a breast, lung, ovary, or colon tumor.   The method of claim 1, wherein the insulin sensitizer is a PPARα agonist, a PPARγ agonist, or a PPAR dual agonist.   The method of claim 1, wherein the insulin sensitizer is a biguanide or a glitazone.   The method of claim 1, wherein the insulin sensitizer is metformin. The IGF1R inhibitor has the formula I:

[Where:
X is N, C or a direct bond;
Y is O or S;
W is N, C, O, or S; provided that if W is O or S, then R ⁹ is not present;
R ¹ is H, alkyl, or alkoxy;
R ² and R ⁹ are independently H or alkyl;
R ³ is H, C _1-6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halo, amino, —OR ⁶⁰ , —NO ₂ , —OH, —SR ⁶⁰ , —NR ⁶⁰ R ⁶¹ , —CN ^{, -C (O) R 60,} -CO 2 R 60, -CONR 60 R 61, OCONR 60 R 61, -NR 62 CONR 60 R 61, -NR 60 SO 2 R 61, -SO 2 NR 60 R 61, ^{_{-SO 2 R 63, -C (NR}} 62) NR 60 R 61, -C (NH 62) - morpholine, aryl, _{heteroaryl, - (CH 2) n C} (O) 2 -R 60, -NR 60 R _{^{61 - (CH 2) n oR}} 60, - (CH 2) n NR 60 R 61, - (CH 2) n SR 60, - (CH 2) n aryl, - (CH _{2) n} heteroaryl or, - ( CH ₂₎ a _n heterocycloalkyl, n is a 1 to 3;
R ⁴ is H, halo, alkyl or haloalkyl;
R ⁵ is H, alkyl, halo, or aryl;
R ⁶ , R ⁷ , and R ⁸ are each independently —NH—Z-aryl or —NH—Z-heteroaryl, wherein Z is C ₁ -C ₄ alkyl, alkenyl, or alkynyl; Z has optionally one or more hydroxy, thiol, alkoxy, thioalkoxy, amino, halo, NR ⁶⁰ SO ₂ R ⁶¹ groups; Z is optionally CO, CNOH, CNOR ⁶⁰ , CNNR ⁶⁰ , CNNCOR ^60; And one or more groups selected from the group consisting of CNNSO ₂ R ⁶⁰ may be bonded;
R ⁶⁰ , R ⁶¹ , R ⁶² , and R ⁶³ are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, hydroxy, alkoxy, aryl, heteroaryl, heteroarylalkyl, and alkyl-R Selected from the group consisting of ²⁵ ;
R ²⁵ is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aryl, heteroaryl, cyano, halo, sulfoxy, sulfonyl, —NR ³⁰ COOR ³¹ , —NR ³⁰ C (O ) R ³¹ , —NR ³⁰ SO ₂ R ³¹ , —C (O) NR ³⁰ R ³¹ , heteroaryl or heterocycloalkyl;
R ³⁰ and R ³¹ are independently hydrogen, alkyl, or cycloalkyl]
The method of Claim 1 which is a compound shown by these, its enantiomer, diastereomer, its pharmaceutically acceptable salt, hydrate, prodrug, and solvate. W is N;
X is CH;
R ² , R ⁴ , R ⁷ and R ⁸ are H;
R ³ is substituted or unsubstituted heterocycloalkyl;
8. The method of claim 7, wherein R < ⁶ > is -NH-Z-aryl or -NH-Z-heteroaryl.   9. The method of claim 8, wherein the aryl is phenyl.   9. The method of claim 8, wherein the heteroaryl is pyridinyl, imidazolyl, pyrazolyl, pyrrolyl or triazolyl. R ³ is morpholinyl, piperazinyl, pyrrolidinyl or piperidinyl, The method of claim 8. The IGF1R inhibitor is
(±) -4- [2- (3-Chloro-4-fluorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl ) -1H-pyridin-2-one;
(S) -4- [2- (3-Fluorophenyl) -1-hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl)- 1H-pyridin-2-one;
(±) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-1H-benzimidazol-2-yl) -1H-pyridin-2-one ;
(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl) -1H-pyridine -2-one;
(S) -2- [4- (2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl- 3H-Benzimidazol-5-yl) -piperazin-1-yl] -acetamide dihydrochloride;
(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {4-methyl-6- [4- (2-methylsulfanylethyl) -piperazin-1-yl] -1H -Benzimidazol-2-yl} -1H-pyridin-2-one dihydrochloride;
(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (3R-methylpiperazin-1-yl) -1H-benzimidazol-2-yl ] -1H-pyridin-2-one dihydrochloride; and (S) -4- [2- (3-chlorophenyl) -2-methoxyethylamino] -3- {6- [4- (2-hydroxyethyl) The method of claim 1 selected from the group consisting of -piperazin-1-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one. The IGF1R inhibitor has the formula:

[Where:
n is 0-4;
R _a is alkyl, substituted alkyl, —C (O) pR ⁷⁰ , aminolalkylamino, —SO ₂ R ⁷¹ , cycloalkyl, heterocycloalkyl, heteroaryl, or alkoxyalkoxyalkyl; p is R ⁷⁰ and R ⁷¹ are alkyl or substituted alkyl; R _b is alkyl or substituted alkyl]
The method of claim 7 comprising: R _a is H, cyanoalkyl, hydroxyalkyl, fluoroalkyl, methoxyalkyl, acetyl, methoxyalkylcarboxyl, dimethylaminocarbonylalkyl, methylsulfonyl, cycloalkylcarbonyl, morpholinyl, imidazolyl, isoxazolyl, or tetrahydrofuranyl. 13 methods.   13. The method of claim 12, wherein the insulin sensitizer is metformin.   14. The method of claim 13, wherein the insulin sensitizer is metformin.   A method for preventing hyperglycemia induced by an IGF1R inhibitor in a mammal in need of treatment comprising administration of an insulin sensitizer to a mammal.   18. The method of claim 17, wherein the insulin sensitizer is metformin.   The insulin sensitizer is metformin, and the IGF1R inhibitor is (S) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholine) 8. The method of claim 7, which is -4-yl-1H-benzimidazol-2-yl) -1H-pyridin-2-one.

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