HK1157779A

HK1157779A - 5,6-bicyclic heteroaryl-containing urea compounds as kinase inhibitors

Info

Publication number: HK1157779A
Application number: HK11112347.2A
Authority: HK
Inventors: 江山; 邢兴龙; 王其杉; 孔韧
Original assignee: 苏州爱斯鹏药物研发有限责任公司
Priority date: 2009-08-24
Filing date: 2010-08-20
Publication date: 2012-07-06

Description

5, 6-membered heteroaryl bicyclic compounds containing a urea group as kinase inhibitors

Background

Protein kinases constitute the largest family of human enzymes, containing over 500 proteins. Kinases play a major role in many fundamental biological processes of a cell including, but not limited to, cell proliferation, survival, motility, morphogenesis, angiogenesis, and the like. In addition, most kinases are found in association with many pathological processes, such as cancer, autoimmune diseases, inflammatory diseases, ocular diseases, and cardiovascular diseases. Typically, kinases transmit cell-to-cell or intracellular signals by phosphorylating proteins downstream of signaling pathways. Downstream proteins are activated so that the signal can be passed down the signalling cascade one step at a time. Under normal physiological conditions, these signal transduction pathways are well regulated in cells. They are activated or deactivated appropriately in response to the intracellular or intercellular environment. In many pathological processes, one or more signal transduction pathways often appear to be overactive, leading to the onset and progression of disease. Therefore, the use of chemical or biological agents to inhibit the function of kinases in disease processes, to block signal pathways in pathological processes, and to block or slow down the progression of disease, can lead to clinical effects for the relevant patients. Among many disease-related kinases, the receptor tyrosine kinases c-Met (HGF/SF receptor), VEGFR2(KDR, Flk1), PDGFR β and c-Kit have been well studied and are considered as effective targets in the clinical treatment of diseases, such as cancer, autoimmune diseases, inflammatory diseases and ocular diseases. See Carmeliet, p., Nature, 2005, 438: 932-936; ferrara, n.et al, Nature, 2005, 438: 967-974; comeglio, p.m.et al, Nature Reviews: drug discovery, 2008, 7: 504-516.

Angiogenesis, the formation of new blood vessels on the basis of existing blood vessels, plays an important role in pathological processes including cancer, chronic inflammation, diabetic retinopathy, psoriasis, rheumatoid arthritis and macular degeneration. Anti-angiogenic therapy represents an important tool for the potential treatment of solid tumors and other diseases associated with disturbed blood vessel growth. The clinical efficacy of a series of approved anti-angiogenesis inhibitor drugs for cancer therapy, such as bevacizumab, sorafenib, and sunitinib, is continuously being confirmed. See Atkins, m.et al, Discovery, 2006, 5: 279-280; wilhelm, s.et al, Nature Reviews: drug Discovery, 2006, 5: 835-844.

The angiogenic process requires the co-participation of multiple angiogenic growth regulators and various types of cells. Many important angiogenesis regulators have been found, including VEGF, FGF and angioproteins 1and 2 (angiopoietins 1and 2, or Ang 1and Ang 2), which bind to the corresponding receptors expressed by endothelial cells (VEGFRs, FGFRs and Tie1, Tie2 in this order). Platelet Derived Growth Factor (PDGF) binds its receptors PDGFR α and PDGFR β, with PDGFR α being expressed on the surface of VEGF-secreting vascular stromal cells and PDGFR β being expressed on the surface of perivascular nuclear smooth muscle cells. The various molecules above, including VEGF, FGF, PDGF, VEGFRs, FGFRs, PDGFRs, Tie1, and Tie2, are important components of a number of different signaling channels that together regulate angiogenesis in physiological and pathological processes. Among these molecules, the signal transduction pathway mediated by VEGFR2 plays a particularly critical role in tumor angiogenesis.

A number of monoclonal antibodies directed against single angiogenic signalling channel component molecules such as VEGF and FGF have been developed to inhibit vascular growth and have been shown to delay tumor growth in both preclinical and clinical studies. However, for a linear signal channel, suppression of a single component of the channel is not as effective as simultaneous suppression of multiple components of the channel. Therefore, development of multi-target small molecule kinase inhibitors is expected to achieve more effective angiogenesis inhibition. Since VEGFR2 and PDGFR β are both targets of sorafenib and sunitinib, the clinical efficacy of these two drugs undoubtedly demonstrates that VEGFR2 and PDGFR β kinases are important targets for disease treatment, such as cancer. See Atkins, m.et al, supra; wilhelm, s.et al, supra.

The c-Kit proto-oncogene, also designated Kit, CD-117, stem cell factor receptor or mast cell growth factor receptor, is one of the tyrosine kinase receptors, members of the split kinase domain subfamily. Stem Cell Factor (SCF), the activation of c-Kit by its natural ligand, initiates receptor dimerization and autophosphorylation of the tyrosine residues Tyr567 and Tyr 719. See Chian R.et al, Blood, 2001, 98: 1365-1373. c-Kit mediated signaling plays an important role in cell migration and differentiation including proliferation, survival, attachment and chemotaxis. See Linnekin d., int.j.biochem.cell biol., 1999, 31: 1053-1074. The expression of c-Kit has been reported in a variety of human malignancies, such as Small Cell Lung Cancer (SCLC), gastrointestinal stromal tumor (GIST), colorectal cancer, etc. As targets that have been shown to be effective in cancer therapy, c-Kit inhibitors such asAre used to treat CML, GIST and other cancers.

The c-Met tyrosine kinase is a cell surface receptor, normally activated by its natural ligand, Hepatocyte Growth Factor (HGF)/Scatter factor (Scatter factor). Through binding to HGF, the c-Met protein is activated by autophosphorylation and mobilizes downstream effector binding to its cytoplasmic domain. The result is a multi-protein signaling complex that can further activate multiple downstream intracellular signaling events in endothelial cells, ultimately leading to a wide range of cellular responses including but not limited to proliferation, survival, angiogenesis, wound healing, tissue regeneration, dissemination, motility, and invasion. See, e.g., Comoglio, p.m.et al, supra; and Benvenuti, s.and Comoglio, p.m., j.cellular physics, 2007, 213: 316-325.

There is a large body of evidence that c-Met is one of the important targets in cancer therapy. See Knudsen, b.s.et., Current Opinion in Genetics & Development, 2008, 18: 87-96. c-Met is disclosed as a proto-oncogene, and in many tumors, gene amplification, overexpression, mutation or abnormal activation of the c-Met gene can often be found, suggesting a role in tumor growth, invasion and metastasis. Furthermore, during the course of treatment it was found that: in solid tumors that develop resistance to EGFR drugs, c-Met expression is greatly increased, suggesting that activation of c-Met expression is a compensation for EGFR signaling pathways. (see, e.g., Smolen, G.A.et al., Proc. Natl Acad.Sci.USA, 2006, 103: 2316-. Thus, it is believed that blocking the c-Met signaling pathway can treat solid tumors in which c-Met dominates growth in whole or in part (see, e.g., Smolen, G.A et al, supra). Therefore, it would be pharmaceutically promising to develop small molecule kinase inhibitors against c-Met for the treatment of cancer.

Anti-angiogenic therapies have been reported to cause local invasion and terminal metastasis of tumor cells, leading to malignant growth of tumors (see, e.g., Ebos, J.M.L.et al, Cancer Cell, 2009, 15: 232-. This unexpected but very important discovery has placed new demands on the development of a new generation of anti-angiogenic therapeutics. The new generation of treatment needs to be able to not only destroy the angiogenesis of the tumor and hinder the growth of the tumor, but also prevent the invasion and metastasis of the tumor. Due to the important role c-Met plays in tumor invasion and metastasis, it is conceivable that therapies that inhibit both VEGF/VEGFR2 and the c-Met signaling pathway will produce better clinical efficacy in the treatment of solid tumors than existing anti-angiogenic therapies (see, e.g., Loges, s.et al, Cancer Cell, 2009, 15: 167-.

The present invention provides a solution that combines two anti-tumor therapeutic mechanisms, namely targeting small molecule drugs (such as VEGFR and c-Met) against one or more protein kinases, to produce better clinical efficacy than existing anti-angiogenic therapies.

Brief description of the drawings

The present invention provides compounds of formula I or II and methods of using these compounds to treat tumors, rheumatoid arthritis, autoimmune diseases, acute inflammation, nephritis, diabetic retinopathy, psoriasis, macular degeneration by inhibiting one or more protein kinases (e.g., VEGFR2, c-Met, PDGFR, c-Kit, CSF1R, EphA2, or any combination thereof).

In one aspect, the invention provides compounds of formula I or II and crystalline forms, chelates, non-covalent complexes, prodrugs, stereoisomers, solvates, N-oxides, pharmaceutically acceptable salts, and mixtures thereof.

In formula I or II:

u, V, X, Y and Z are each independently selected from N or C-R¹：

L is O, S (O)_n，N-R²Or is orIs optionally substituted by one or more independent R³A group-substituted alkylene group;

R²is hydrogen, alkyl, aryl, heteroaryl, -C (═ O) -alkyl, -C (═ O) -aryl, or-C (═ O) -heteroaryl, any of which may optionally be substituted with one or more independent Q¹Substituted by groups;

l' is a covalent bond, -C (═ O) -alkylene, or alkylene, any of which may optionally be substituted with one or more independent R⁴Substituted by groups;

a isWherein B, D, E, G and J are independently selected from N or C-R⁵The five-membered ring in A is connected with L in a chemical formula I or II, and the six-membered ring in A is connected with carbamido in a chemical formula I or II;

ar is aryl or heteroaryl, optionally substituted with one or more independent R⁶Substituted by groups;

R¹，R³，R⁴，R⁵and R⁶Each independently selected from hydrogen, halogen, -CN, -CF₃，-NO₂，-NH₂，-OH，-OCF₃，-OCH₃，-CO₂H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl, any of which may be optionally substituted with one or more independent Q²Substituted by groups;

q1 and Q2 are each independently selected from the group consisting of hydrogen, halogen, -CN, -CF₃，-OCF₃，-NO₂Oxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocycloaryl, -OR⁷，-S(O)_nR⁸，-NR⁹R¹⁰，-SO₂NR⁹R¹⁰，-C(O)R¹¹，-C(O)NR⁹R¹⁰，-C(O)OR¹²，-OC(O)R¹³，-NR⁹C(O)R¹¹，-NR⁹S(O)₂R¹⁴，-NR¹⁵C(O)NR⁹R¹⁰，-NR¹⁵S(O)₂NR⁹R¹⁰or-NR¹⁵S(O)NR⁹R¹⁰Any of the foregoing groups may optionally be substituted with one or more independent hydrogen, halogen, -CN, -OH, -NH₂，-NO₂Oxy, -CF₃，-OCF₃，-CO₂H，-S(O)_nH, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroaryl or-O-alkyl, any of which may be partially or fully halogenated;

R⁷，R⁸，R¹¹，R¹²，R¹³，R¹⁴or R¹⁵Each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and heterocycloaryl;

R⁹and R¹⁰Each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heterocycloaryl; or when in-NR⁹R¹⁰In the middle, R⁹And R¹⁰Together with the nitrogen atom to which they are attached form a 3-12 membered saturated or unsaturated ring, where said ring may optionally include one or more independently of each other O, N, or S (O)_nAn atom of (a);

n is 0, 1, or 2.

In some embodiments, X, Y, Z, V and U are each independently C-R¹Thus giving a compound of formula Ia or IIa, wherein R¹The groups may be the same or different.

In some embodiments, each R is¹Is hydrogen and L' is a covalent bond.

In some embodiments, Y is N, and X, Z, V and U are each independently C-R¹Thus giving a compound of formula Ib or IIb, wherein R¹The groups may be the same or different.

In some embodiments, each R is¹Is hydrogen and L' is a covalent bond.

In some embodiments, Z is N, and X, Y, V and U are each independently C-R¹Thus giving a compound of formula Ic or IIc, wherein R¹The groups may be the same or different.

In some embodiments, each R is¹Is hydrogen and L' is a covalent bond.

In some embodiments, a compound of formula I, wherein X is N, and Y, Z and V are each independently C-R¹Thus giving a compound of formula Id, wherein R¹The groups may be the same or different.

In some embodiments, each R is¹Is hydrogen and L' is a covalent bond.

In some embodiments, a compound of formula I; wherein X and Z are N; y and V are each independently C-R¹Thus giving a compound of formula Ie wherein R¹The radicals canTo be the same or different.

In some embodiments, each R is¹Is hydrogen and L' is a covalent bond.

In some embodiments, L is alkylene, optionally substituted with one or more R³And (4) substituting the group.

In some embodiments, L is alkylene (e.g., methylene, ethylene, propylene, or isopropylene).

In some embodiments, L' is a covalent bond.

In some embodiments, Ar is phenyl or indolinyl, optionally substituted with one or more halo, alkoxy, alkyl, haloalkoxy, cyano, oxy, or optionally substituted heterocycloalkyl.

In some embodiments, A is A1-a, A1-b, A1-c, A1-d, A1-e, A1-f, A1-g, A1-h, A1-i, A2-a, A2-b, A3-a, A3-b, A3-c, A3-d, or A3-e (as shown in the figures below), and may optionally be substituted with one or more R⁵And (4) substituting the group.

In some embodiments, A is A1-a, A1-b, A1-d, A1-e, A1-g, A2-a, A2-b, A3-a, or A3-c, optionally substituted with one or more independent R⁵And (4) substituting the group.

In some embodiments, A is A1-a, A1-b, A1-d, A1-g, A2-a, or A2-b, optionally substituted with one or more independent R⁵And (4) substituting the group.

In some embodiments, A is A1-a or A2-a, optionally substituted with one or more independent R⁵And (4) substituting the group.

In some embodiments, A is A1-a or A2-a without any substitution.

In some embodiments, the compound is of the following structure:

in some embodiments, Ar is phenyl, naphthyl, pyridyl, pyridonyl, pyrimidinyl, pyridazinyl, triazinyl, imidazolyl, thienyl, furyl, thiazolyl, oxazolyl, triazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzotriazolyl, 2-oxoindolyl, or indolinyl, and is optionally substituted with one or more independent halo, alkoxy, alkyl, haloalkoxy, cyano, oxy, or optionally substituted heterocycloalkyl.

In some embodiments, the compound is as follows:

1-phenyl-3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (3-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (3-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (3-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (3-tolyl) -3- [1- (1H-pyrrolo [2, 3-pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (3-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-trifluoromethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (3-trifluoromethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-trifluoromethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (3-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-cyanophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (3-cyanophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-cyanophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methoxy-5-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methoxy-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methoxy-5-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methoxy-5-methylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2, 5-dimethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methoxy-5-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-fluoro-5-methylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-fluoro-5-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-fluoro-5-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-fluoro-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-fluoro-5-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-trifluoromethyl-5-methylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-oxo-2, 3-dihydro-1H-indol-5-yl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- [4- (5-oxotetrahydropyrrolyl-2-yl) phenyl ] -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1-phenyl-3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (3-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (3-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (3-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (3-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (3-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-trifluoromethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (3-trifluoromethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-trifluoromethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (3-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-cyanophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (3-cyanophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-cyanophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methoxy-5-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methoxy-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methoxy-5-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methoxy-5-methylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2, 5-dimethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methoxy-5-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-fluoro-5-methylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-fluoro-5-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-fluoro-5-trifluoromethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-fluoro-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-fluoro-5-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-trifluoromethyl-5-methylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-oxo-2, 3-dihydro-1H-indol-5-yl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- [4- (5-oxotetrahydropyrrolyl-2-yl) phenyl ] -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1-phenyl-3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (3-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (4-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (3-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (4-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (3-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (4-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (3-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (4-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (3-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (4-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-trifluoromethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (3-trifluoromethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (4-trifluoromethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (3-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (4-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-cyanophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (3-cyanophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (4-cyanophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-methoxy-5-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-methoxy-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-methoxy-5-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-methoxy-5-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2, 5-dimethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-methoxy-5-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-fluoro-5-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-fluoro-5-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-fluoro-5-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-fluoro-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-fluoro-5-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-trifluoromethyl-5-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-oxo-2, 3-dihydro-1H-indol-5-yl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- [4- (5-oxotetrahydropyrrolyl-2-yl) phenyl ] -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1-phenyl-3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (3-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (4-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (3-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (4-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (3-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (4-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (3-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (4-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (3-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (4-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-trifluoromethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (3-trifluoromethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (4-trifluoromethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (3-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (4-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-cyanophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (3-cyanophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (4-cyanophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-methoxy-5-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-methoxy-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-methoxy-5-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-methoxy-5-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2, 5-dimethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-methoxy-5-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-fluoro-5-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-fluoro-5-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-fluoro-5-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-fluoro-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-fluoro-5-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-trifluoromethyl-5-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-oxo-2, 3-dihydro-1H-indol-5-yl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea;

1- (2-chloro-5-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-bromo-5-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-fluoro-4-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-fluoro-6-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-morpholinomethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methyl-5-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methyl-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methyl-5-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-chloro-5-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-bromo-5-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-fluoro-6-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-morpholinomethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methyl-5-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methyl-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methyl-5-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methoxy-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea.

In some embodiments, the compound is as follows:

1- (3-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-trifluorotolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (3-trifluorotolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-trifluorotolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-trifluorotolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (3-trifluorotolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (4-trifluorotolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-fluoro-4-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

1- (2-methyl-3-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea;

In some embodiments, the compound is as follows:

1- (2-methoxy-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea; or

in some embodiments, the compound is as follows:

1- (2-fluoro-5-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea.

In some embodiments, the compound is as follows:

1- (2-fluoro-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea.

In some embodiments, the compound is as follows:

1- (2-methoxy-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea.

In some embodiments, the compound is as follows:

1- (3-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea; or

1- (4-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea.

In some embodiments, the compound is as follows:

1- (3-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea; or

1- (4-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea.

In some embodiments, the compound is as follows:

1- (2-fluoro-5-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea; or

1- (2-fluoro-4-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea.

In some embodiments, the compound is as follows:

Another aspect of the invention is to provide a pharmaceutical composition comprising a therapeutically effective dose of any of the compounds described above and a pharmaceutically acceptable carrier. The dosage form of the pharmaceutical composition may be any of the following: injections, aerosols, creams, gels, capsules, pills, tablets, syrups, eye drops or ointments.

The above compounds exhibit inhibitory effects on one or more kinases, such as c-Met, VEGFR2, PDGFR β, c-Kit, CSF1R, and EphA 2.

In accordance therewith, another aspect of the invention provides a method for treating a patient suffering from a disease caused by abnormal protein kinase activity (e.g., overexpression of a protein kinase). The method comprises administering to a patient in need thereof a therapeutically effective dose of any of the compounds or pharmaceutical compositions described above. The compound or pharmaceutical composition may be administered in a suitable form, such as intravenously, subcutaneously, orally, intraperitoneally, or topically. Examples of kinases include VEGFR2, C-Met, RON, PDGFR α, PDGFR β, C-Kit, CSF1R, EphA2, Alk, Tie-1, Tie-2, Flt3, FGFR1, FGFR2, FGFR3, FGFR4, EGFR, Her2, Abl, Aurora A, Aurora B, Aurora C, Src, Lck, IGF-1R, and IR. Examples of diseases include cancer, tumors, rheumatoid arthritis, autoimmune diseases, acute inflammation, nephritis, diabetic retinopathy, psoriasis and macular degeneration. The tumour or cancer may be, for example, bone cancer (e.g. Ewing's sarcoma, osteosarcoma, chondrosarcoma or orthopaedic tumors), brain or CNS tumour (e.g. auditory neuroma, chordoma, brain tumour blast of hope), chest cancer, colorectal cancer (e.g. rectal cancer), endocrine adenocarcinoma (e.g. adrenocortical cancer, pancreatic cancer (e.g. pancreatic cancer such as exocrine pancreatic cancer), pituitary cancer, thyroid cancer, parathyroid cancer, thymus cancer, multiple endocrine adenomas or other endocrine adenocarcinomas, gastrointestinal cancer (e.g. gastric cancer, oesophageal cancer, small intestine cancer, gall bladder cancer, liver cancer, extrahepatic bile duct cancer or gastrointestinal benign tumours), genitourinary cancer (e.g. testicular cancer, penile cancer or prostate cancer), gynaecological cancer (e.g. spinal cord cancer, ovarian cancer, vaginal cancer, uterine/endometrial cancer, vulval cancer, trophoblastic carcinoma, fallopian tube cancer or uterine neoplasia), Head and neck cancer (i.e., oral, lip, salivary gland, larynx, hypopharynx, oropharynx, nose, paranasal or nasopharyngeal cancer), non-leukemic leukemia (e.g., acute lymphoid leukemia, acute myeloid leukemia, chronic lymphoid leukemia, chronic myeloid leukemia, hairy cell leukemia, acute promyelocytic leukemia, plasma cell leukemia), lung cancer (e.g., adenocarcinoma, small cell lung cancer or non-small cell lung cancer), lymphoma (e.g., hodgkin's disease, non-hodgkin's lymphoma, AIDS-related lymphoma), eye cancer (e.g., retinoblastoma or intraocular melanoma), skin cancer (e.g., melanoma, non-melanoma skin cancer, Merkel cell carcinoma), soft tissue sarcoma (e.g., kaposi's sarcoma), urinary system cancer (e.g., renal cancer, Wilm's tumor, bladder cancer, urinary tract cancer or transnational cell cancer) and other types and related diseases (e.g., histiocytosis, polycythemia, leukemia, and other types and related diseases, Mesothelioma, metastatic cancer, benign tumor, neurofibroma multiplex, blastoblastoma, desmoplastic small ring cytoma, malignant rod cytoma, desmoma, dyskinetic telangiectasia, Nijmegen fragmentation syndrome, Ro-Tourette's syndrome, Leveroming syndrome, von Hipple-Lindau disease, Beckwith-Wiedemann syndrome, Down's syndrome, Denys-Drash syndrome, WAGR syndrome, or CIN cervical intraepithelial neoplasia).

The compound entities of the present invention include, but are not limited to, compounds of formula I or II and all forms of pharmaceutically acceptable formulations thereof. Pharmaceutically acceptable formulations of the compounds detailed herein include pharmaceutically acceptable salts, solvates, crystal forms (including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof. In certain embodiments, the compound is present as a pharmaceutically acceptable salt. Thus, the term "compound entity" and its plural forms also encompass pharmaceutically acceptable salts, solvates, crystal forms, chelates, non-covalent complexes, prodrugs, and mixtures.

As mentioned above, prodrugs also fall within the scope of compound entities, such as ester or amide derivatives of compounds of formula I or II. The term "prodrug" encompasses any compound that, upon administration to a patient, becomes a compound of formula I or II, for example, by metabolic processes. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate salts of compounds of formula I or II and derivatives of similar functional groups (e.g., alcohols or amines).

As used herein, the term "solvate" refers to an entity of a compound formed by the interaction of a solvent and the compound. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemihydrate.

As used herein, the term "chelate" refers to a compound entity formed by coordination of a compound with a metal ion at two or more points.

As used herein, the term "non-covalent complex" refers to a compound entity formed by the interaction of a compound and another molecule, wherein no covalent bond is formed between the compound and the molecule. For example, complexation may occur through van der waals interactions, hydrogen bonding, and electrostatic interactions (also referred to as ionic bonding).

The term "active agent" is used to designate a compound entity having biological activity. In certain embodiments, an "active agent" is a compound having a pharmaceutical utility. For example, the active agent may be an anti-cancer drug.

As used herein, the term "alkyl", used alone or as part of a bulky substituent (e.g., in "cycloalkenylalkyl" or "haloalkoxy"), refers to a saturated aliphatic hydrocarbon radical. The alkyl group can contain 1 to 8 (e.g., 1 to 6 or 1 to 4) carbon atoms. As a group, alkyl may be written as-C_nH_2n+1. The alkyl group may be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, and 2-ethylhexyl. An alkyl group may be substituted (i.e., optionally substituted) with one or more groups.

As used herein, the term "alkylene", alone or as part of a bulky substituent (e.g., in "arylalkyleneoxy" or "haloarylalkyleneoxy"), refers to saturated aliphatic hydrocarbon groups bearing two moieties which can form two with other moietiesThe point of attachment of a covalent bond. The alkylene group can contain 1 to 8 (e.g., 1 to 6 or 1 to 4) carbon atoms. As a group, alkylene can be written as-C_nH_2n-. Examples of alkylene groups include, but are not limited to, methylene (-CH)₂-, ethylene (-CH)₂CH₂-) and propylene (-CH)₂CH₂CH₂-)。

As used herein, the term "alkynyl", used alone or as part of a bulky substituent (e.g., in "alkynyl alkyl" or "haloalkynyl alkoxy"), refers to an aliphatic hydrocarbon group having at least one triple bond. Alkynyl groups contain 2 to 8 (i.e., 2 to 6 or 2 to 4) carbon atoms. An alkynyl group may be straight or branched. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl.

As used herein, the term "alkenyl", used alone or as part of a bulky substituent (e.g., in "alkenylalkyl" or "alkenylalkoxy"), refers to an aliphatic hydrocarbon group having at least one double bond. Alkenyl groups contain 2 to 8 (e.g., 2 to 6 or 2 to 4) carbon atoms. An alkenyl group having one double bond may be designated as-C_nH_2n-1Or having two double bonds and may be designated as-C_nH_2n-3. Like the alkyl groups, the alkenyl groups may be straight or branched. Examples of alkenyl groups include, but are not limited to, allyl, isophentyl, 2-butenyl, and 2-hexenyl.

As used herein, the term "cycloalkyl", used alone or as part of a bulky substituent (e.g., in "cycloalkylalkyl" or "halocycloalkylalkoxy"), refers to a saturated single, two, or three (fused or bridged or spiro) carbocyclic ring system. The cycloalkyl group can contain 3 to 12 (e.g., 3 to 10 or 5 to 10) carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubic alkyl, octahydroindenyl, decahydronaphthyl, bicyclo [3.2.1] octanyl, bicyclo [2.2.2] octanyl, bicyclo [3.3.1] nonanyl, bicyclo [3.3.2] decanyl, bicyclo [2.2.2] octanyl, adamantyl, azacycloalkyl, or ((aminocarbonyl) cycloalkyl.

As used herein, the term "cycloalkenyl," used alone or as part of a bulky substituent (e.g., in "cycloalkenylalkyl" or "cyanocycloalkenylalkoxy"), refers to a non-aromatic carbocyclic ring system having one or more double bonds. Cycloalkenyl groups can contain 3 to 12 (e.g., 3 to 10 or 5 to 10) carbon atoms. Examples of cycloalkenyl include cyclopentenyl, 1, 4-cyclohexadienyl, cycloheptenyl, cyclooctenyl, hexahydroindenyl, octahydronaphthyl, cyclohexenyl, cyclopentenyl, bicyclo [2.2.2] octenyl, or bicyclo [3.3.1] nonenyl.

As used herein, the term "heterocycloalkyl," used alone or as part of a larger group (e.g., in "heterocycloalkyl alkyl" or "heterocycloalkoxy"), refers to a saturated 3-to 16-membered monocyclic, bicyclic, or tricyclic (fused or bridged or spiro) structure in which one or more ring atoms are heteroatoms (e.g., N, O, S, and combinations thereof). In addition to heteroatoms, heterocycloalkyl groups can contain 3 to 15 carbon atoms (e.g., 3 to 12 or 5 to 10). Examples of heterocycloalkyl include, but are not limited to, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, 1, 4-dioxane, 1, 4-dithianyl, 1, 3-dioxane, oxazolyl, isoxazolyl, morpholinyl, thiomorpholinyl, octahydrobenzofuranyl, octahydropyranyl, octahydrothiopyranyl, octahydroindolyl, octahydropyridinyl, nonahydroquinolinyl, octahydrobenzo [ b ] thienyl, 2-oxobicyclo [2.2.2] octanyl, 1-azabicyclo [2.2.2] octanyl, 3-azabicyclo [3.2.1] octanyl, and 2, 6-dioxotricyclo [3.3.1.03, 7] nonane. A monocyclic heterocycloalkyl group may be fused to the benzene ring, such as tetrahydroisoquinoline.

As used herein, the term "aryl", used alone or as part of a larger group (e.g., as in "aralkyl", "aralkoxy", or "haloaryloxyalkyl"), refers to a monocyclic ring (e.g., a benzene ring); bicyclic (e.g., indenyl, naphthyl, or tetrahydronaphthyl); tricyclic (e.g., fluorenyl, tetrahydrofluorenyl, tetrahydroanthracenyl, or anthracenyl) ring systems in which a single ring is an aryl group (e.g., a phenyl ring), or in which at least one ring in the bicyclic or tricyclic ring system is an aryl group (e.g., a phenyl ring). Bicyclic and tricyclic groups include, but are not limited to, benzo 2 or 3 membered carbocycles. For example, a benzo group includes a phenyl ring fused to two or more C4-8 carbocyclic groups.

As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring system of 5 to 15 atoms in which at least one ring atom is a heteroatom (e.g., N, O, S or a combination thereof), and in which the monocyclic ring system is aromatic, or at least one ring of the bicyclic or tricyclic ring system is aromatic. Heteroaryl groups may contain, for example, 5 to 12 or 8 to 10 ring atoms. Heteroaryl groups include, but are not limited to, benzo ring systems having 2 to 3 rings. The benzo group includes the condensation of benzene with one or two 4-to 8-membered heterocycloalkyl groups (e.g., indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [ b ] furanyl, benzo [ b ] thiophenyl, quinolinyl, or isoquinolinyl). Some heteroaryl groups are exemplified by pyridyl 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolyl, benzothiazolyl, xanthyl, thioxanthyl, phenothiazinyl, indolinyl, benzo [1, 3] dioxacyclopentadienyl, benzo [ b ] furyl, benzo [ b ] thiophenyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl, quinolyl, quinazolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, isoquinolyl, 4H-quinolyl, benzo-1, 2, 5-thiadiazo, and 1, 8-naphthyl.

As used herein, the term "bridged bicyclic ring system" refers to a bicyclic heterocycloalkyl system or a bicyclic cycloalkyl system having at least two atoms in common in the ring. Examples of bridged bicyclic ring systems include, but are not limited to, adamantyl, norbornyl, bicyclo [3.2.1] octanyl, bicyclo [2.2.2] octanyl, bicyclo [3.3.1] nonanyl, bicyclo [3.2.3] nonanyl, 2-oxobicyclo [2.2.2] octanyl, 1-azabicyclo [2.2.2] octanyl, 3-azabicyclo [3.2.1] octanyl, 2, 6-dioxotricyclo [3.3.1.03, 7] nonanyl.

As used herein, the term "halo" refers to fluoro, chloro, bromo, or iodo.

As used herein, the term "independent", e.g., in "optionally substituted with one or more independent R3 groups", means that when the number of substituents is more than one (e.g., two or three), the plurality of substituents can be the same or different.

As used herein, the term "optionally" means (as in "optionally substituted") that the group in question may or may not be substituted, and that substitution is only at chemically possible positions. For example, an H atom cannot be substituted by a substituent, a covalent bond or a-C (═ O) -group cannot be substituted by a substituent.

As used herein, "oxo" refers to ═ O.

As used herein, "carbonyl" refers to-C (O) -or-C (═ O) -.

As used herein, "cyano" refers to — CN.

As used herein, when at the terminus of a compound, the "ureido" group refers to the structure-NR_X-CO-NR_YR_ZWhen in the middle of a compound, refers to the structure-NR_X-CO-NR_Y-。

As used herein, the term "substituted," whether preceded by the term "optionally," refers to the replacement of a hydrogen atom in a given structure with a particular substituent. Specific substituents are described in the above definitions as well as in the following description of the compounds and in the examples thereof. Unless otherwise specified, an optionally substituted group may have a substituent at each position where substitution is possible; when more than one position in any given structure may be substituted with more than one substituent selected from a particular group, the substituents at each substitution position may be the same or different. A cyclic substituent, such as heterocycloalkyl, may be attached to another ring, such as cycloalkyl, to form a helical bicyclic ring system, i.e., the two rings share the same atom. As one of ordinary skill in the art will recognize, the combination of substituents in the present invention results in stable or chemically feasible compounds.

For convenience and as a general understanding, the term "optionally substituted" is used only for entities of compounds that may in fact be substituted with suitable substituents, and not for those compounds that may not be chemically substituted. Thus, it is effective only when chemically feasible. For example, in "R²Is hydrogen, alkyl, aryl, heteroaryl, -C (═ O) -alkyl, -C (═ O) -aryl, or-C (═ O) -heteroaryl, any of which may optionally be substituted with one or more independent Q¹Substituted with groups, "wherein, although the phrase" any group may be optionally substituted with one or more independent Q¹Group substitution "is grammatically applicable to hydrogen, but since hydrogen (hydrogen atom) is chemically impossible to be substituted, this case does not apply to hydrogen. As another example, where "L' is a covalent bond, -C (═ O) -alkylene, or alkylene, any group may optionally be substituted with one or more independent R⁴In group substitution "substitution will not apply to a covalent bond or-C (═ O) -, since both are chemically impossible to substitute.

As used herein, the term "stable" or "chemically feasible" means that the compound does not change its nature under the conditions of manufacture, testing, and even recovery, purification, and the like, and does not change its nature for one or more of the purposes described above. In some embodiments, a stable or chemically feasible compound refers to a compound that can be stored at or below 40 degrees celsius for at least one week without humidity or other chemical reaction conditions.

As used herein, the term "or", e.g., in "one or more independent halo, alkoxy, alkyl, cyano, oxy, or optionally substituted heterocycloalkyl" may refer to "or" and ". In other words, in this context, for example, the substituents (when more than one) may be two halogens or one halogen and one alkyl. In another example, "VEGFR 2 or c-Met" may mean "VEGFR 2", "c-Met", or "VEGFR 2 and c-Met".

As used herein, the phrase "pharmaceutically acceptable salt" means salts of the compounds of the present invention that are safe and effective for internal (or topical) use in a subject (e.g., a mammal such as a human patient, dog, or cat) and that possess the desired biological activity. Pharmaceutically acceptable salts include salts formed from the acid or base groups of the compounds of the invention. Pharmaceutically acceptable acid salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, acetylglucose ester, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1, 1' -methyl-bis- (2-hydroxy-3-naphthoic acid) salts). Certain compounds of the invention may form pharmaceutically acceptable salts with different amino acids. Suitable basic salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. An overview of pharmaceutically acceptable salts can be found in Berge et al, j.pharm.sci., 1977, 66, 1-19, including the references.

As used herein, the term "subject" is sometimes used interchangeably with "patient" and generally refers to an animal (e.g., a mammal such as a human, cat, or dog) in treatment.

As used herein, an "effective amount" is defined as the amount required to produce a clinical effect in the patient being treated. Typically, the dosage will be determined by age, surface area, weight and condition of the patient. In Freireich et al, Cancer chemi. rep, 50: 219(1966) the intrinsic relationship between animal and human dosages (based on milligrams per square meter of body surface area) is described. The body surface area can be approximately determined by the height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970).

Unless otherwise indicated, when a cyclic substituent is referred to herein in combination with another moiety in any formula included herein, such combination may occur at any atom of the cyclic substituent.

Unless otherwise indicated, a structure described herein is intended to include all stereoisomeric forms (e.g., enantiomers, diastereomers, and geometric (or conformational) isomers) of the structure, e.g., the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, individual stereochemical isomers or mixtures of enantiomers, diastereomers, and geometric (or conformational) isomers of the instant compounds are intended to be within the scope of the present invention. Unless otherwise indicated, all tautomers of the compounds of the invention are included within the scope of the invention.

As used herein, the term "therapeutically effective amount" of a compound of the present invention refers to an effective amount administered to a human or non-human patient for the treatment of a disease. For example, a therapeutically effective dose can be an amount sufficient to treat a disease or condition susceptible to kinase inhibition. Therapeutically effective dosages may be determined experimentally, for example by measuring the blood concentration of the compound, or by theoretical calculations of bioavailability.

As used herein, the term "significant" refers to any detectable change of statistical significance, p < 0.05 in standard parametric hypothesis tests or non-parametric hypothesis tests, such as Student's test.

As used herein, the term "patient" or "subject" refers to an animal, such as a mammal, e.g., a human, dog, or cat, that has been or will become the subject of treatment, observation, and experiment. The methods of the invention can be used for both human and veterinary applications.

As used herein, the term "angiogenic kinase" refers to a kinase that plays a role in angiogenesis. Examples include VEGFR2, PDGFR β and c-Met.

As used herein, the term "inhibit" refers to a decrease in the activity of an enzyme exhibited as a direct or indirect reaction to the presence of a compound of formula I or II, as compared to the absence of the compound. This decrease may be caused by direct interaction of the compound with the enzyme or by interaction of the compound with one or more other factors that affect the activity of the enzyme. For example, the presence of a compound can reduce the activity of an enzyme by binding directly to the enzyme, by reducing the activity of the enzyme by other factors (directly or indirectly), or by reducing the amount of enzyme present in a cell or organ (directly or indirectly).

As used herein, the terms "treatment" or "treating" refer to any treatment of a disease in a patient, including: (a) arrest of disease progression, i.e., the clinical symptoms caused by the disease no longer progress; (b) inhibiting the disease; (c) slowing or inhibiting the development of clinical symptoms; or (d) relieving the disease, and restoring clinical symptoms.

As used herein, the term "disease or disorder susceptible to kinase inhibition" refers to a pathological condition that is at least partially dependent on the activity of one or more protein kinases, e.g., an angiogenic kinase. Kinases are involved, directly or indirectly, in signal transduction pathways for a number of cellular activities, including cell proliferation, differentiation and invasion. Diseases susceptible to kinase inhibition include, but are not limited to, tumor growth, angiogenesis supporting the growth of solid tumors, and diseases characterized by local vascular overgrowth such as diabetic retinopathy, macular degeneration, and inflammation.

As used herein, the term "change in angiogenesis" refers to a change in the vascular network or a qualitative change in the vascular system. Changes in angiogenesis can be measured using a variety of parameters, for example, to assess the delayed appearance of neovascular structures, the slowed development of neovascular structures, a decrease in the development of neovascular structures, a change in vascular permeability, a change in blood flow, a slowing or decrease in the severity of angiogenesis-dependent disease effects, inhibition of vascular growth, or the restoration of a previous vascular system.

Detailed Description

The present invention provides compounds of formula I or II, and pharmaceutically acceptable salts thereof.

In formula I or II:

u, V, X, Y and Z are each independently selected from N or C-R¹：

L is O, S (O)_n，N-R²Or optionally by one or more independent R³A group-substituted alkylene group;

R¹，R³，R⁴，R⁵and R⁶Each independently selected from hydrogen, halogenElement, -CN, -CF₃，-NO₂，-NH₂，-OH，-OCF₃，-OCH₃，-CO₂H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl, any of which may be optionally substituted with one or more independent Q²Substituted by groups;

R⁹and R¹⁰Each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heterocycloaryl; or when in-NR⁹R¹⁰In the middle, R⁹And R¹⁰Together with the nitrogen atom to which they are attached form a 3-12 membered saturated or unsaturated ring, in which caseThe ring may optionally include one or more independently of each other O, N, or S (O)_nAn atom of (a);

n is 0, 1 or 2.

General synthetic method

The compounds of the present invention are synthesized by known methods from industrial raw materials or known starting materials. Exemplary synthetic routes for preparing these compounds are set forth in the following schemes, wherein the substituents are well defined unless otherwise indicated. These general synthetic routes are illustrative only and not limiting and can be applied to the preparation of other compounds including different substitutions not explicitly listed below.

The following table lists abbreviations used:

NMR (nuclear magnetic resonance)

TMS-tetramethylsilane

DCM ═ dichloromethane

THF ═ tetrahydrofuran

EtOAc ═ ethyl acetate

MeCN ═ acetonitrile

DMSO ═ dimethyl sulfoxide

Boc ═ tert-butoxycarbonyl

DMF ═ N, N-dimethylformamide

DME ═ dimethoxyethane

TFA ═ trifluoroacetic acid

CDCl₃Deuterated chloroform

DMSO-d₆Deuterium-substituted dimethyl sulfoxide

TLC-thin plate chromatography

HPLC ═ high performance liquid chromatography

Min is minutes

h is hour

d is day

RT or RT ═ room temperature

t_RRetention time ═ retention time

L is liter

mL to mL

mmol or mM millimole

g is g ═ g

mg ═ mg

LG ═ leaving group

PG ═ protective group

Scheme 1:

as shown above, the intermediate 4 can be synthesized from the industrial raw material 7-azaindole (1) through several steps. The starting material 1 is oxidized with an oxidizing agent such as m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide or other peroxy acids, followed by POCl₃Or SOCl₂Chloro to obtain 4-chloro-7-azaindole (2). The compound 2 is jected to palladium catalytic cyanidation, alkaline hydrolysis, acidification, esterification and reduction to obtain the alcohol (3). The alcoholic hydroxyl group in the compound 3 may be reacted with SOCl₂、CBr₄+PPh₃、PBr₃、MeSO₂Cl、Tf₂O, TsCl into Leaving Groups (LG), e.g. Cl, Br, I, MeSO₃-, TfO-or TsO-. Protection of the amino group on the azaindole ring can be achieved by the commonly used nitrogen Protecting Groups (PG), such as Boc, Cbz, other carboxamides, PhSO₂-or other organic sulfonic acid groups, p-methoxybenzyl (PMB), methoxymethyl (MOM), [ beta- (trimethylsilyl) ethoxymethyl]Methyl (SEM), and the like.

Scheme 2:

the intermediate 7 can be conveniently synthesized from an industrial raw material 7-azaindole (1) through three steps of reactions. Condensing 1 with dimethylamine and formaldehyde to obtain amine 5, and protecting with amino group (PG), such as Boc, Cbz or other carbamide, PhSO₂-or other organic sulfonic acid groups, p-methoxybenzyl (PMB), methoxymethyl (MOM), [ beta- (trimethylsilyl) ethoxymethyl]Methyl (SEM) and the like to give compound 6. Reaction of compound 6 with a chloroformate (e.g., methyl, n-propyl, isopropyl, n-butyl, isobutyl) affords intermediate 7.

Scheme 3:

as shown in scheme 3, intermediate 11 can be synthesized from the industrial starting material 7-azaindole (1) via a four-step reaction. Treating the compound 1 with DMF/phosphorus oxychloride to obtain aldehyde 8, protecting the aldehyde 8 with Boc to obtain a compound 9, reducing the compound 9 with sodium borohydride to obtain alcohol 10, and treating the alcohol 10 with carbon tetrachloride/triphenylphosphine or carbon tetrabromide/triphenylphosphine to obtain corresponding chloride or bromide 11.

Reaction scheme 4

Scheme 4 above lists the synthetic routes for compounds of formula I or II. According to the reaction route 1-3, an intermediate A-1 or A-2 can be prepared, and then the intermediate A-1 or A-2 reacts with an industrial raw material monocyclic or bicyclic aryl or heteroaryl nitro compound under an alkaline condition to obtain C-1 or C-2. Catalytic hydrogenation reduction of nitro groups (typically using Pd-or Pt-supported catalysts), or by Fe/HCl, Zn/HOAc or SnCl₂Reducing to obtain amine D-1 or D-2, reacting amine with isonitrile acid ester E-1, or reacting with amine E-2, phosgene, triphosgene or carbonyl diimidazole, and removing Protecting Group (PG) under acidic or alkaline condition to obtain urea I or II. For example, 4-nitroindole (12) is reacted with 13 under NaH to give the alkylated product which is protected with Boc to give 14. The nitro group in the compound 14 is subjected to Pd/C catalytic hydrogenation reduction to obtain amine 15. Compound 15 reacts with the prepared isonitrile acid ester to obtain urea, and finally the protecting group is removed by HCl treatment to obtain the final product 16. Compound 20 can be synthesized starting from 4-nitroindole (12) and 17 according to the same reaction scheme.

Scheme 5:

scheme 5 illustrates an alternative route to compounds of formula I or II. Starting from industrial raw material 4-nitroindole F, reducing nitro to obtain 4-aminoindole G, and reacting with isocyanate E-1 or with amine E-2, phosgene, triphosgene or carbonyl diimidazole to obtain urea H. H with NaBH₃CN and acetic acid, carrying out alkylation reaction on the compound I and an intermediate A-1 or A-2 shown in a synthetic route 1-3 to obtain J-1 or J-2, and finally removing a Protecting Group (PG) under acidic or alkaline conditions to obtain a product I or II. For example, reduction of 4-nitroindoleIndole (12) gives amine 21 which is reacted with isocyanate 22 to give urea 23. Reduction of compound 23 gives indoline compound 24, which can be successfully alkylated with 17 to give 25. Compound 25 can be deprotected with HCl to give target 26 or oxidized with DDQ to 27 and then deprotected with Boc protecting group to give target 28.

General Experimental and analytical methods

Unless otherwise specified, all starting materials and reagents were purchased directly without further purification. NMR spectra were measured on a Bruker or Varian 300 or 400MHz instrument at room temperature using TMS or residual solvent peaks as internal standards. Chemical shifts are expressed in ppm (δ), and peak signals are expressed in s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). Chemical shifts and multiplicity are expressed in ppm (. delta.) and coupling constant (J) (Hz), respectively. The abbreviations of the peak signals in the nmr spectra are: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). Mass Spectra (MS) were determined by ESI. Thin Layer Chromatography (TLC) was used for detection of the reaction, and silica gel 60F-254(0.2mm) was used, and UV-irradiation was performed. The flash column chromatography is carried out by using a glass column filled with 230-400 mesh silica gel.

Preparation of I.2-methoxy-5-chlorobenzoyl isonitrile

Thionyl chloride (25mL, 130mmol) was added dropwise to a solution of 2-methoxy-5-chlorobenzoic acid (Int-1, 18.7g, 100mmol) in dry dichloromethane (120mL) under nitrogen. After the dropwise addition, the reaction solution becomes clear after refluxing for 2 hours, and a solid obtained after concentration is Int-2, and the reaction is directly carried out in the next step without purification.

Sodium azide (7.8g, 120mmol) and 50mL of water were added to a solution of acyl chloride Int-2 in acetone (100mL) under nitrogen. After stirring at room temperature for 2 hours, 50mL of water were added. Filtering, washing a filter cake with water, and drying to obtain white solid acyl azide Int-3 which is directly subjected to the next reaction without purification.

Dissolving the acyl azide Int-3 obtained in the last step in dry toluene (100mL), slowly heating to reflux, discharging nitrogen in the system, and continuing to heat for 1 hour. Cooled to room temperature and concentrated to give a yellow solid which was recrystallized from petroleum ether to give white crystals, the product Int-4(10.3g, 56% yield in three steps), which became yellow on standing. MS (ESI)⁺)：m/z 238.0(100)[M+MeOH+Na，³⁵Cl]⁺，240.0(33)[M+MeOH+Na，³⁷Cl]⁺.

Preparation II: 1- (tert-Butoxycarbonyl) -4-chloromethyl-7-azaindole (Int-11)

7-azaindole (Int-5, 23.6g, 200mmol) was dissolved in diethyl ether/n-heptane (1: 2, 300mL) and m-chloroperoxybenzoic acid (85 wt%, 44.7g, 220mmol) was added portionwise. The mixture was stirred at room temperature for 3 hours. Filtering, washing with n-heptane (100mL), and drying to obtain N-O-7-azaindole-3-chlorobenzoic acid (51.9g, 89%), mp 140-.

Phosphorus oxychloride (200mL) was slowly added to 7-azaindole-3-chlorobenzoic acid N-oxide (51.9g, 178mmol), dissolved and heated to 85-90 ℃ overnight. Phosphorus oxychloride was distilled off under reduced pressure, and water was added to the residue to neutralize to pH9 with an aqueous solution of sodium hydroxide. Cooling to room temperature, suction filtration, and resuspension of the resulting filter cake in water (200mL), stirring, and filtration afforded Int-6(21.7g, 80%).

¹H NMR(400MHz，CDCl₃)δ11.40(brs，1H)，8.24(d，J＝5.2Hz，1H)，7.43(d，J＝3.6Hz，1H)，7.15(d，J＝5.2Hz，1H)，6.63(d，J＝3.6Hz，1H)。

4-chloro-7-azaindole (Int-6, 18.2g, 119mmol) was dissolved in degassed nitrogen, N-dimethylacetamide (100mL), zinc powder (720mg, 11mmol), 1, 1' -bisdiphenylphosphinoferrocene (2.1g, 3.8mmol), zinc cyanide (8.2g, 69.8mmol), and palladium dibenzylideneacetone (1.74g, 1.9mmol) were added to the mixture under nitrogen protection, and the mixture was heated to 120 ℃ and held for 2 hours. Cooled to room temperature, added with water (300mL), extracted with ethyl acetate, combined organic phases, washed with saturated ammonium chloride, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated by column chromatography to give Int-7(12.3g, yield: 70%).

MS(ESI⁺)：m/z 144.1[M+H]⁺。

A mixture of Int-7(11.5g, 80mmol), sodium hydroxide (32g, 800mmol), water (100mL), and ethanol (100mL) was heated under reflux for 6 hours, cooled to room temperature, acidified with concentrated hydrochloric acid, and the solid was precipitated and filtered to give 7-azaindole-4-carboxylic acid (10.4g, 80%) which was directly subjected to the next reaction without purification.

A solution of 7-azaindole-4-carboxylic acid (10.4g, 64mmol) and thionyl chloride (17.8g, 150mmol) in ethyl acetate (150mL) was heated under reflux until the reaction was complete (TLC detection), concentrated, neutralized to pH9 with potassium carbonate, extracted with ethyl acetate, the organic phases combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was isolated by column chromatography to give Int-8(11.0g, 90%).

¹H NMR(400MHz，CDCl₃)δ10.51(brs，1H)，8.45(d，J＝4.4Hz，1H)，7.75(d，J＝4.4Hz，1H)，7.54(s，1H)，7.08(d，J＝2.0Hz，1H)，4.50(q，J＝7.2Hz，2H)，1.49(t，J＝7.2Hz，3H)。

To a solution of Int-8(9.5g, 50mmol) in tetrahydrofuran (150mL) were added sodium borohydride (3.8g, 100mmol) and calcium chloride (11.1g, 100mmol), and the mixture was heated under reflux for 6 h. After the reaction (TLC detection), adding methanol and water, extracting with ethyl acetate, combining organic phases, washing with water, washing with saturated salt solution, drying with anhydrous sodium sulfate, filtering and concentrating. The residue was isolated by column chromatography to give Int-9(5.0g, 67%).

¹H NMR(400MHz，DMSO-d₆)δ11.84(brs，1H)，8.22(d，J＝5.6Hz，1H)，7.51(t，J＝2.8Hz，1H)，7.31(d，J＝6.4Hz，1H)，6.74(q，J＝1.6Hz，1H)，5.65(t，J＝6.0Hz，1H)，4.92(d，J＝5.2Hz，2H)。

To a solution of Int-9(4.4g, 30mmol) in dichloromethane (100mL) was added thionyl chloride (11.9g, 100mmol) and stirred at room temperature overnight. The mixture was concentrated, neutralized with potassium carbonate to pH9, extracted with ethyl acetate, the organic phases combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was isolated by column chromatography to give Int-10(4.3g, 87%).

MS(ESI⁺)：m/z 167.0(100)[M+H，35Cl]⁺，169.0(33)[M+H，37Cl]⁺。

A round-bottomed flask was charged with Int-10(4.2g, 25mmol), di-tert-butyl dicarbonate (10.9g, 50mmol), 4-dimethylaminopyridine (catalyst), triethylamine (75mmol) and dichloromethane (80mL), stirred at room temperature for 6 hours and concentrated, and the residue was isolated by column chromatography to give Int-11(6.1g, 91%).

Preparation III.1- (tert-Butoxycarbonyl) -3-chloromethyl-7-azaindole (Int-14)

7-azaindole (Int-5, 8.3g, 70mmol) was dissolved in isopropanol (100mL), dimethylamine hydrochloride (5.7g, 70mmol), 38% aqueous formaldehyde (5.5g, 70mmol) was added. The mixture was stirred at room temperature overnight and then refluxed for 2 hours. Cooling, concentrating, adding water (50mL) and concentrated hydrochloric acid (5mL), extracting with ethyl acetate, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain Int-12, which can be directly used in the next reaction without purification.

¹H NMR(400MHz，DMSO-d₆)δ11.44(s，1H)，8.18，8.17(dd，J＝4.8，1.2Hz，1H)，7.98，7.96(dd，J＝7.6，1.6Hz，1H)，7.32(d，J＝2.8Hz，1H)，7.03，7.01(dd，J＝8.0，4.8Hz，1H)，3.51(s，2H)，2.12(s，6H).

The Int-12 from the previous step, di-tert-butyl dicarbonate (30g, 140mmol), DMAP (catalyst), triethylamine (210mmol) and dichloromethane (80mL) were added to a round-bottomed flask, and the mixture was stirred overnight, concentrated and isolated by column chromatography to give Int-13(12.7g, 66% over two steps).

Isobutyl chloroformate (6.8g, 50mmol) was added under nitrogen to a solution of Int-13(12.4g, 45mmol) in toluene (100mL) and stirred at room temperature overnight. Adding water, extracting with ethyl acetate, mixing organic phases, washing with water, washing with saturated salt solution, drying with anhydrous sodium sulfate, filtering, and concentrating. The residue was isolated by column chromatography to give Int-14(1.6g, 12% yield).

¹H NMR(400MHz，CDCl₃)δ8.55(d，J＝4.4Hz，1H)，8.01(d，J＝7.2Hz，1H)，7.69(s，1H)，7.27-7.24(m，1H)，4.76(s，2H)，1.67(s，9H)。

Preparation V: 1- (tert-Butoxycarbonyl) -3-chloromethyl-7-azaindole (Int-14)

DMF (33mL, 425mmol) is added into a three-neck flask, phosphorus oxychloride (35mL, 340mmol) is slowly added dropwise after cooling in a salt-freezing bath, stirring is carried out for 10 minutes after the addition is finished, and then 7-azaindole (Int-5, 10.8g, 91mmol) is added, and the temperature is controlled not to exceed 10 ℃. The mixture was heated to 80 ℃ for 48 hours until the reaction was complete. Cooling, addition of crushed ice, clarification of the mixture, neutralization with sodium hydroxide, extraction with ethyl acetate, combination of the organic phases, drying, concentration and column chromatography gave the product Int-15(6.6g, 50%).

A round-bottomed flask was charged with Int-15(6.6g, 45mmol), di-tert-butyl dicarbonate (10.7g, 50mmol), 4-dimethylaminopyridine (catalyst), triethylamine (130mmol) and dichloromethane (80mL), stirred at room temperature for 6 hours, concentrated and the residue was isolated by column chromatography to give Int-16(9.8g, 89%).

A mixture of 1- (tert-butoxycarbonyl) -3-formyl-7-azaindole (Int-16, 9.8g, 40mmol), sodium borohydride (1.7g, 44mmol) and methanol (50mL) was stirred at room temperature until the reaction was complete, detected by TLC, extracted with water and ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried, concentrated and subjected to column chromatography to give alcohol Int-17(8.4g, 85%).

A mixture of 1- (tert-butyloxycarbonyl) -3- (hydroxymethyl) -7-azaindole (Int-17, 8.4g, 34mmol), triphenylphosphine (9.9g, 37mmol), dry CCl4(50mL) and dry DMF (35mL) was stirred at room temperature for 48 h. The solvent was removed by rotation and the residue was isolated by column chromatography to give the chloride Int-14(3.45g, 38%).

¹H NMR(400MHz，CDCl₃)δ8.55(d，J＝4.4Hz，1H)，8.01(d，J＝7.2Hz，1H)，7.69(s，1H)，7.27-7.24(m，1H)，4.76(s，2H)，1.67(s，9H).

Example 1: 1- (2-methoxy-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea hydrochloride

A round-bottom flask was charged with 4-nitroindole (4.8g, 30mmol), palladium on carbon (10%, 480mg), and THF (50mL), and the mixture was stirred under an atmosphere of hydrogen overnight until the reaction was complete. Filtering, concentrating the filtrate to obtain 4-aminoindole, and directly carrying out the next reaction without purification.

5-chloro-2-methoxy isocyanate (Int-4, 5.5g, 30mmol) in dichloromethane (20mL) was added dropwise to the 4-aminoindole dichloromethane (30mL) obtained in the previous step, stirred overnight, filtered to give crude 1- (5-chloro-2-methoxyphenyl) -3- (1H-indol-4-yl) urea (6.6g, 70%) which was directly subjected to the next reaction without purification.

To a solution of 1- (5-chloro-2-methoxyphenyl) -3- (1H-indol-4-yl) urea (6.3g, 20mmol) in acetic acid (50mL) was added NaBH in portions₃CN (1.9g, 30mmol), the mixture was stirred at room temperature toThe reaction was complete. The reaction solution is NaHCO₃Neutralizing the solution, extracting with ethyl acetate, combining organic phases, washing with water, washing with salt water, drying, and concentrating to obtain 1- (5-chloro-2-methoxyphenyl) -3- (2, 3-dihydro-1H-indol-4-yl) urea (6.3g, 100%), and directly carrying out the next reaction without purification.

¹H NMR(300MHz，DMSO-d₆)δ8.72(s，1H)，8.65(s，1H)，8.22(d，J＝1.8Hz，1H)，7.14(d，J＝6.3Hz，1H)，7.03-6.94(m，2H)，6.83(t，J＝6.0Hz，1H)，6.20(d，J＝5.7Hz，1H)，5.47(s，1H)，3.88(s，3H)，3.44-3.40(m，2H)，2.86(t，J＝6.3Hz，2H).

1- (t-Butoxycarbonyl) -4-chloromethyl-7-azaindole (Int-11, 2.2g, 8.4mmol) was added portionwise to a mixture of 1- (5-chloro-2-methoxyphenyl) -3- (2, 3-dihydro-1H-indol-4-yl) urea (2.2g, 7mmol), potassium carbonate (1.16g, 8.4mmol), and DMF (30mL), and the mixture was heated to 80 ℃ to completion (TLC detection). Water and ethyl acetate were added for extraction, the organic phases were combined, washed with water, brine, dried, concentrated and the residue was chromatographed to give 1- (2-methoxy-5-chlorophenyl) -3- {1- [1- (tert-butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl ] -2, 3-dihydro-1H-indol-4-yl } urea (1.9g, 50%).

¹H NMR(400MHz，CDCl₃)δ8.49(d，J＝4.8Hz，1H)，8.29(d，J＝2.4Hz，1H)，7.65(d，J＝4.0Hz，1H)，7.43(s，1H)，7.22(d，J＝5.2Hz，1H)，7.12(t，J＝8.0Hz，2H)，6.91(dd，J＝8.8，2.4Hz，1H)，6.86(d，J＝8.4Hz，1H)，6.74(d，J＝8.8Hz，1H)，6.64(d，J＝4.0Hz，1H)，6.36(d，J＝8.0Hz，1H)，6.32(s，1H)，4.51(s，2H)，3.78(s，3H)，3.40(t，J＝8.4Hz，2H)，2.98(t，J＝8.0Hz，2H)，1.67(s，9H).

1- (2-methoxy-5-chlorophenyl) -3- {1- [1- (tert-butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl ] -2, 3-dihydro-1H-indol-4-yl } urea (500mg, 0.92mmol) was added to a 25% solution of hydrochloric acid in methanol, and the mixture was stirred overnight and concentrated to give the product 1- (2-methoxy-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -2, 3-dihydro-1H-indol-4-yl ] urea (412mg, 93%).

¹H NMR(400MHz，DMSO-d₆)：δ12.67(s，1H)，8.77(s，1H)，8.71(s，1H)，8.39(d，J＝6.0Hz，1H)，8.22(d，J＝2.4Hz，1H)，7.70(t，J＝2.4Hz，1H)，7.42(d，J＝6.0Hz，1H)，7.23(d，J＝8.0Hz，1H)，7.03-6.90(m，4H)，6.26(d，J＝8.0Hz，1H)，4.72(s，2H)，3.88(s，3H)，3.42(t，J＝8.4Hz，2H)，2.95(t，J＝8.4Hz，2H).MS(ESI⁺)：m/z 448.4(100)[M+H，³⁵Cl]⁺，450.3(33)[M+H，³⁷Cl]⁺.

Example 2 a: 1- (2-methoxy-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

DDQ (6mmol) was added portionwise to an acetone solution (20mL) of 1- (2-methoxy-5-chlorophenyl) -3- {1- [1- (tert-butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl ] -2, 3-dihydro-1H-indol-4-yl } urea (1.64g, 3mmol) (prepared from example 1), the mixture was stirred overnight at room temperature, the solvent was removed by spinning off, and the residue was chromatographed to give 1- (2-methoxy-5-chlorophenyl) -3- {1- [1- (tert-butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl ] -1H-indol-4-yl } urea (1.05g, 64%).

¹H NMR(400MHz，CDCl₃)：δ8.49(d，J＝5.2Hz，1H)，8.33(s，1H)，7.65(s，1H)，7.56(s，1H)，7.50(d，J＝8.0Hz，1H)，7.31(t，J＝6.8Hz，2H)，7.26-7.25(m，1H)，7.14(s，1H)，7.09(t，J＝6.0Hz，1H)，6.91(d，J＝8.8Hz，1H)，6.71-6.68(m，2H)，6.57(s，1H)，5.41(s，2H)，3.64(s，3H)，1.67(s，9H).

1- (2-methoxy-5-chlorophenyl) -3- {1- [1- (tert-butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl ] -1H-indol-4-yl } urea (500mg, 0.92mmol) was added to a 25% solution of hydrochloric acid in methanol, and the mixture was stirred overnight and concentrated to give the product 1- (2-methoxy-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea (400mg, 90%).

¹H NMR(400MHz，DMSO-d₆)：δ12.08(s，1H)，9.23(s，1H)，8.79(s，1H)，8.28(d，J＝2.8Hz，1H)，8.19(d，J＝5.2Hz，1H)，7.70(dd，J＝6.0，2.0Hz，1H)，7.54(s，1H)，7.50(d，J＝3.2Hz，1H)，7.05-6.96(m，4H)，6.79(d，J＝3.2Hz，1H)，6.73(d，J＝5.6Hz，1H)，6.47(t，J＝2.0Hz，1H)，5.80(s，2H)，3.91(s，3H).MS(ESI⁺)：m/z 446.2(100)[M+H，³⁵Cl]⁺，448.3(33)[M+H，³⁷Cl]⁺.

Example 2 b: 1- (2-methoxy-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

The title compound can also be synthesized by the route shown below.

Sodium hydride (144mg, 6mmol) was added to a solution of 4-nitroindole (973mg, 6mmol) in tetrahydrofuran (20mL), stirred at room temperature for 4 hours and then added with 1- (tert-butoxycarbonyl) -4-chloromethyl-7-azaindole (Int-11, 1.5g, 5.5 mmol). After the reaction (TLC detection), adding saturated ammonium chloride aqueous solution, extracting with ethyl acetate, combining organic phases, washing with water, washing with saturated salt solution, drying with anhydrous sodium sulfate, filtering and concentrating. The residue was separated by column chromatography to give 4- [ (4-nitro-1H-indol-1-yl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine (254mg, 16%).

¹H NMR(400MHz，CDCl₃)：δ10.00(brs，1H)，8.26(d，J＝4.8，1H)，8.20(d，J＝8.0，1H)，7.59(d，J＝8.0Hz，1H)，7.51(d，J＝1.2，1H)，7.41(d，J＝1.6，1H)，7.40(d，J＝1.6，1H)，7.29(t，J＝8.0，1H)，6.70(d，J＝4.0，1H)，6.33(d，J＝1.6，1H)，5.76(s，2H).

A round-bottom flask was charged with 4- [ (4-nitro-1H-indol-1-yl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine (526mg, 1.8mmol), di-tert-butyl dicarbonate (786mg, 3.6mmol), DMAP (catalyst), and dichloromethane (30 mL). The mixture was stirred at room temperature overnight, concentrated and separated by column chromatography to give 4- [ (4-nitro-1H-indol-1-yl) methyl ] -1- (tert-butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridine (516mg, 73%).

¹H NMR(400MHz，CDCl₃)δ8.38(d，J＝4.8，1H)，8.10(d，J＝8.4，1H)，7.59(d，J＝4.0，1H)，7.43(d，J＝8.0Hz，1H)，7.39(d，J＝3.2，1H)，7.31(d，J＝3.2，1H)，7.17(d，J＝8.0，1H)，6.70(d，J＝5.2，1H)，6.14(d，J＝4.0，1H)，5.62(s，2H)，1.61(s，9H).

A round-bottom flask was charged with 4- [ (4-nitro-1H-indol-1-yl) methyl ] -1- (tert-butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridine (510mg, 1.3mmol), palladium on carbon (50mg, 10%) and tetrahydrofuran (30 mL). The mixture was stirred at room temperature for 2 hours under hydrogen, filtered and concentrated to give 4- [ (4-amino-1H-indol-1-yl) methyl ] -1- (tert-butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridine (450 mg).

5-chloro-2-methoxyphenyl isonitrile acid ester (Int-14, 275mg, 1.5mmol) was added to a solution of 4- [ (4-amino-1H-indol-1-yl) methyl ] -1- (tert-butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridine (450mg) in dichloromethane (30mL) and stirred at room temperature overnight. Concentration and column chromatography gave 1- (2-methoxy-5-chlorophenyl) -3- {1- [1- (tert-butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl ] -1H-indol-4-yl } urea (540mg, 80% over two steps).

¹H NMR(400MHz，CDCl₃)：δ8.40(d，J＝1.6，1H)，8.34(s，J＝4.2，1H)，7.91(s，1H)，7.76(s，1H)，7.63(d，J＝4.0，1H)，7.46(d，J＝7.6，1H)，7.12(t，J＝8.0，1H)，7.03(d，J＝3.2，1H)，6.96(J＝8.4，1H)，6.90，6.87(dd，J＝8.8，2.8，1H)，6.68-6.64(m，3H)，6.27(d，J＝4.4，1H)，5.51(s，2H)，3.60(s，3H)，1.66(s，9H).

1- (2-methoxy-5-chlorophenyl) -3- {1- [1- (tert-butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl ] -1H-indol-4-yl } urea (500mg, 0.92mmol) was added to a 25% solution of hydrochloric acid in methanol, stirred overnight at room temperature, and concentrated to give the product 1- (2-methoxy-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride (400mg, 90%).

¹H NMR(400MHz，DMSO-d₆)：δ12.08(s，1H)，9.23(s，1H)，8.79(s，1H)，8.28(d，J＝2.8Hz，1H)，8.19(d，J＝5.2Hz，1H)，7.70(dd，J＝6.0，2.0Hz，1H)，7.54(s，1H)，7.50(d，J＝3.2Hz，1H)，7.05-6.96(m，4H)，6.79(d，J＝3.2Hz，1H)，6.73(d，J＝5.6Hz，1H)，6.47(t，J＝2.0Hz，1H)，5.80(s，2H)，3.91(s，3H).

Example 3: 1- (2-methoxy-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

Sodium hydride (144mg, 6mmol) was added to a solution of 4-nitroindole (973mg, 6mmol) in tetrahydrofuran (20mL), stirred at room temperature for 4 hours and then added with 1- (tert-butoxycarbonyl) -3-chloromethyl-7-azaindole (Int-14, 1.5g, 5.5 mmol). After the reaction (TLC detection), adding saturated ammonium chloride aqueous solution, extracting with ethyl acetate, combining organic phases, washing with water, washing with saturated salt solution, drying with anhydrous sodium sulfate, filtering and concentrating. The residue was separated by column chromatography to give 3- [ (4-nitro-1H-indol-1-yl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine (547mg, 34%).

¹H NMR(400MHz，CDCl₃)δ9.54(brs，1H)，8.34(brs，1H)，8.16(d，J＝7.6，1H)，7.76(d，J＝8.4Hz，1H)，7.65(d，J＝8.4，1H)，7.41(d，J＝3.6，1H)，7.29(d，J＝9.6，2H)，7.08(t，J＝6.4，1H)，5.57(s，2H)。

Adding 3- [ (4-nitro-1H-indol-1-yl) methyl into a round-bottom flask]-1H-pyrrolo [2, 3-b]Pyridine, Boc₂O (786mg, 3.6mmol), DMAP (catalyst), triethylamine (5.4mmol) and dichloromethane (30mL) were added, the mixture was stirred at room temperature overnight, concentrated and separated by column chromatography to give 3- [ (4-nitro-1H-indol-1-yl) methyl group]-1- (tert-butyloxycarbonyl) -1H-pyrrolo [2, 3-b]Pyridine (516mg, 73%).

¹H NMR(400MHz，CDCl₃)：δ8.51(d，J＝4.0，1H)，8.17(d，J＝8.0，1H)，7.74(d，J＝8.4Hz，1H)，7.63(s，1H)，7.45(d，J＝6.8，1H)，7.39(d，J＝2.8，1H)，7.32-7.29(m，2H)，7.10(dd，J＝6.8，2.8，1H)，5.49(s，2H)，1.67(s，9H).

A round-bottom flask was charged with 3- [ (4-nitro-1H-indol-1-yl) methyl ] -1- (tert-butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridine (510mg, 1.3mmol), palladium on carbon (50mg, 10%) and tetrahydrofuran (30 mL). The mixture was stirred at room temperature for 2 hours under hydrogen, filtered and concentrated to give 3- [ (4-amino-1H-indol-1-yl) methyl ] -1- (tert-butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridine (470 mg).

5-chloro-2-methoxyphenyl isonitrile acid ester (Int-14, 275mg, 1.5mmol) was added to a solution of 3- [ (4-amino-1H-indol-1-yl) methyl ] -1- (tert-butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridine obtained in the previous step in toluene (30mL), and the mixture was stirred at room temperature overnight. Concentration and column chromatography gave 1- (2-methoxy-5-chlorophenyl) -3- {1- [1- (tert-butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl ] -1H-indol-4-yl } urea (518mg, 73% over two steps).

¹H NMR(400MHz，CDCl₃)δ8.49(d，J＝5.2，1H)，8.33(s，1H)，7.65(s，1H)，7.56(s，1H)，7.50(d，J＝8.0，1H)，7.31(t，J＝6.8，2H)，7.26-7.25(m，1H)，7.14(s，1H)，7.09(t，J＝6.0，1H)，6.91(d，J＝8.8，1H)，6.71-6.68(m，2H)，6.57(s，1H)，5.41(s，2H)，3.64(s，3H)，1.67(s，9H)。

1- (2-methoxy-5-chlorophenyl) -3- {1- [1- (tert-butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl ] -1H-indol-4-yl } urea (500mg, 0.92mmol) was added to a solution of methanol hydrochloride (25%), the mixture was stirred overnight, and concentrated to give 1- (2-methoxy-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride (412mg, 93%).

MS(ESI⁺)：m/z 446.4(100)[M+H，³⁵Cl]⁺，448.3(33)[M+H，³⁷Cl]⁺.

General procedure 1:

in general procedure 1, phenyl chloroformate (1mmol) was added to a solution of aromatic amine (1mmol) in dichloromethane and NaHCO₃(1mmol) of the mixture, after the reaction is completed (TLC detection), the mixture is concentrated to be dry to obtain the aromatic carbamic acid phenyl ester, and the next reaction can be directly carried out without purification.

Phenyl aromatic carbamate, Et₃N (3mmol) and 3- [ (4-amino-1H-indol-1-yl) methyl]-1- (tert-butyloxycarbonyl) -1H-pyrrolo [2, 3-b]And heating and refluxing a mixture of pyridine (1mmol) in a MeCN (30mL) solution until the reaction is completed, concentrating, and performing column chromatography separation to obtain the product urea.

The following preparations and examples were carried out according to the general procedure 1 or the synthesis example 3:

example 4: 1-phenyl-3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 382.7[M+H]⁺

Example 4A: 1-phenyl-3- {1- [1- (tert-butyloxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl ] -1H-indol-4-yl } urea

¹H NMR(400MHz，CDCl₃)δ8.38(dd，J＝4.8，1.6Hz，1H)，8.22(s，1H)，7.78(s，1H)，7.65(s，1H)，7.56-7.53(m，2H)，7.42(dd，J＝8.0，1.2Hz，1H)，7.34(d，J＝2.0Hz，1H)，7.24(s，1H)，7.15-7.14(m，2H)，7.04(t，J＝8.0Hz，1H)，6.99(dd，J＝8.0，4.8Hz，1H)，6.89-6.87(m，1H)，6.79(d，J＝3.2Hz，1H)，6.09(d，J＝2.8Hz，1H)，5.27(s，2H)，1.63(s，9H).

Example 5: 1- (2-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 400.7[M+H]⁺

Example 6: 1- (3-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 400.7[M+H]⁺

Example 7: 1- (4-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 400.7[M+H]⁺

Example 8: 1- (2-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 416.7(100)[M+H，³⁵Cl]⁺，418.6(33)[M+H，³⁷Cl]⁺

Example 8A: 1- (2-chlorophenyl) -3- {1- [1- (tert-butyloxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl ] -1H-indol-4-yl } urea

¹H NMR(400MHz，CDCl₃)δ8.41(d，J＝5.2Hz，1H)，8.25(d，J＝8.4Hz，1H)，7.56(s，1H)，7.48(s，1H)，7.38(dd，J＝8.4，1.2Hz，1H)，7.30(d，J＝7.6Hz，1H)，7.25(d，J＝8.4Hz，1H)，7.20-7.14(m，3H)，7.06-6.98(m，3H)，6.86(t，J＝8.0Hz，1H)，6.50(d，J＝2.8Hz，1H)，5.34(s，2H)，1.59(s，9H).

Example 9: 1- (3-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride MS

(ESI⁺)：m/z 416.7(100)[M+H，³⁵Cl]⁺，418.6(33)[M+H，³⁷Cl]⁺

Example 10: 1- (4-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 416.7(100)[M+H，³⁵Cl]⁺，418.7(33)[M+H，³⁷Cl]⁺

Example 11: 1- (2-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 460.6(98)[M+H，⁷⁹Br]⁺，462.6(100)[M+H，⁸¹Br]⁺

Example 12: 1- (3-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 460.6(98)[M+H，⁷⁹Br]⁺，462.6(100)[M+H，⁸¹Br]⁺

Example 12A: 1- (3-bromophenyl) -3- {1- [1- (tert-butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl ] -1H-indol-4-yl } urea

¹H NMR(400MHz，CDCl₃)δ8.44(d，J＝4.8Hz，1H)，7.67(s，1H)，7.60(s，1H)，7.51(s，1H)，7.48(dd，J＝8.0，1.2Hz，1H)，7.40-7.34(m，2H)，7.29-7.21(m，2H)，7.14-7.04(m，4H)，6.99(d，J＝3.2Hz，1H)，6.34(d，J＝2.0Hz，1H)，5.38(s，2H)，1.67(s，9H).

Example 13: 1- (4-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 460.6(98)[M+H，⁷⁹Br]⁺，462.6(100)[M+H，⁸¹Br]⁺

Example 14: 1- (2-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

¹H NMR(400MHz，DMSO-d₆)δ11.51(s，1H)，8.71(s，1H)，8.11-8.10(m，2H)，7.79-7.76(m，2H)，7.59(d，J＝7.6Hz，1H)，7.55(d，J＝2.4Hz，1H)，7.43(d，J＝3.2Hz，1H)，7.24(d，J＝8.4Hz，1H)，7.11-7.07(m，2H)，6.99-6.86(m，3H)，6.53(d，J＝2.8Hz，1H)，5.43(s，2H)，2.20(s，3H).MS(ESI⁺)：m/z 396.5[M+H]⁺

Example 15: 1- (3-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 396.7[M+H]⁺

Example 16: 1- (4-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 396.7[M+H]⁺

Example 17: 1- (2-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 412.7[M+H]⁺

Example 18: 1- (3-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 412.7[M+H]⁺

Example 18A: 1- (3-methoxyphenyl) -3- {1- [1- (tert-butyloxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl ] -1H-indole-4-carboxylic acid

Radical urea

¹H NMR(400MHz，CDCl₃)δ8.43(d，J＝4.8Hz，1H)，8.34(s，1H)，8.08(s，1H)，7.77(d，J＝8.0Hz，1H)，7.59(s，1H)，7.44(dd，J＝7.6，1.6Hz，1H)，7.29(t，J＝1.6Hz，1H)，7.16(t，J＝8.0Hz，1H)，7.13-7.09(m，2H)，7.03(dd，J＝8.0，4.8Hz，1H)，6.99(d，J＝3.6Hz，1H)，6.85(dd，J＝8.0，0.8Hz，1H)，6.54(d，J＝3.2Hz，1H)，6.50(dd，J＝4.8Hz，1H)，5.33(s，2H)，3.75(s，3H)，1.62(s，9H).

Example 19: 1- (4-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 412.7[M+H]⁺

Example 20: 1- (2-trifluoromethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 466.3[M+H]⁺

Example 21: 1- (3-trifluoromethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 466.3[M+H]⁺

Example 22: 1- (4-trifluoromethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 466.3[M+H]⁺

Example 22A: 1- (4-trifluoromethoxyphenyl) -3- {1- [1- (tert-butyloxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl ] -1H-indol-4-yl } urea

¹H NMR(400MHz，CDCl₃)δ8.42(dd，J＝4.8，1.2Hz，1H)，8.05(s，1H)，7.89(s，1H)，7.65(s，1H)，7.49-7.44(m，2H)，7.36(s，1H)，7.34(s，1H)，7.22-7.16(m，2H)，7.04-7.01(m，3H)，6.89(d，J＝3.2Hz，1H)，6.21(d，J＝3.6Hz，1H)，5.31(s，2H)，1.64(s，9H).

Example 23: 1- (2-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 450.4[M+H]⁺

Example 24: 1- (3-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 450.4[M+H]⁺

Example 25: 1- (4-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 450.4[M+H]⁺

Example 26: 1- (3-cyanophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 407.7[M+H]⁺

Example 27: 1- (4-cyanophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 407.7[M+H]⁺

Example 28: 1- (2-fluoro-4-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 434.4(100)[M+H，³⁵Cl]⁺，436.4(33)[M+H，³⁷Cl]⁺

Example 29: 1- (2-fluoro-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 434.4(100)[M+H，³⁵Cl]⁺，436.4(33)[M+H，³⁷Cl]⁺

Example 30: 1- (2-fluoro-5-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 478.3(98)[M+H，⁷⁹Br]⁺，480.3(100)[M+H，⁸¹Br]⁺

Example 31: 1- (2-fluoro-5-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 430.5[M+H]⁺

Example 31A: 1- (2-fluoro-5-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea

¹H NMR(400MHz，DMSO-d₆)δ11.67(s，1H)，8.92-8.91(m，2H)，8.16(dd，J＝4.4，1.2Hz，1H)，7.89-7.85(m，2H)，7.69(d，J＝7.2Hz，1H)，7.64(d，J＝1.8Hz，1H)，7.52(d，J＝3.2Hz，1H)，7.34(d，J＝8.0Hz，1H)，7.15(dd，J＝11.2，9.2Hz，1H)，7.05(t，J＝8.0Hz，1H)，6.99(dd，J＝8.0，4.8Hz，1H)，6.56(d，J＝3.2Hz，1H)，6.51(td，J＝9.2，3.6Hz，1H)，5.50(s，2H)，3.78(s，3H)，3.71(s，3H).

Example 32: 1- (2, 5-Dimethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 442.5[M+H]⁺

Example 32A: 1- (2, 5-Dimethoxyphenyl) -3- {1- [1- (tert-Butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-ylmethyl ] -1H-indol-4-yl } urea

¹H NMR(400MHz，CDCl₃)δ8.48(dd，J＝8.4，1.2Hz，1H)，7.96(d，J＝3.2Hz，1H)，7.64(s，1H)，7.57(s，1H)，7.47(dd，J＝8.0，1.6Hz，1H)，7.37(d，J＝7.2Hz，1H)，7.30-7.24(m，2H)，7.12(d，J＝3.2Hz，1H)，7.08(dd，J＝8.0，4.4Hz，1H)，6.80(s，1H)，6.72(d，J＝8.8Hz，1H)，6.55(d，J＝3.6Hz，1H)，6.50(dd，J＝8.8，3.6Hz，1H)，5.40(s，2H)，3.78(s，3H)，3.61(s，3H)，1.67(s，9H).

General procedure 2:

in general procedure 2, phenyl chloroformate (1mmol) was added to a solution of aromatic amine (1mmol) in dichloromethaneLiquid and NaHCO₃(1mmol) of the mixture, after the reaction is completed (TLC detection), the mixture is concentrated to be dry to obtain the aromatic carbamic acid phenyl ester, and the next reaction can be directly carried out without purification.

Heating and refluxing a mixture of phenyl aromatic carbamate, Et3N (3mmol) and 4-aminoindole (1mmol) in a MeCN (30mL) solution until the reaction is completed, concentrating, performing column chromatography separation to obtain a product 1-aryl-3- (1H-indol-4-yl) urea, reducing the product into an indoline compound according to the methods of the embodiments 1and 2, alkylating the indoline compound with Int-11, oxidizing DDQ, and finally removing a Boc protecting group to obtain a final product

The following preparations and examples were carried out according to the general procedure 2 or the methods of synthesis examples 1and 2:

example 33: 1-phenyl-3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 382.7[M+H]⁺

Example 34: 1- (2-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 400.7[M+H]⁺

Example 35: 1- (3-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 400.7[M+H]⁺

Example 35A: 1- (3-fluorophenyl) -3- {1- [1- (tert-butyloxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl ] -2, 3-dihydro-1H-indol-4-yl } urea

¹H NMR(400MHz，CDCl₃)δ8.45(d，J＝4.8Hz，1H)，8.29(d，J＝4.8Hz，1H)，7.64(d，J＝4.4Hz，1H)，7.38(d，J＝3.6Hz，1H)，7.22-7.18(m，2H)，7.14(d，J＝4.8Hz，1H)，7.10(t，J＝8.0Hz，1H)，7.05(d，J＝8.4Hz，1H)，6.74(d，J＝9.6Hz，1H)，6.62-6.61(m，2H)，6.34(d，J＝8.4Hz，1H)，4.48(s，2H)，3.31(t，J＝8.0Hz，2H)，2.84(t，J＝8.0Hz，2H)，1.67(s，9H).

Example 36: 1- (4-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 400.7[M+H]⁺

Example 37: 1- (2-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 416.7(100)[M+H，³⁵Cl]⁺，418.6(33)[M+H，³⁷Cl]⁺

Example 38: 1- (3-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 416.7(100)[M+H，³⁵Cl]⁺，418.5(33)[M+H，³⁷Cl]⁺

Example 39: 1- (4-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 416.7(100)[M+H，³⁵Cl]⁺，418.6(33)[M+H，³⁷Cl]⁺

Example 40: 1- (2-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 460.6(98)[M+H，⁷⁹Br]⁺，462.7(100)[M+H，⁸¹Br]⁺

Example 41.1- (3-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 460.6(98)[M+H，⁷⁹Br]⁺，462.7(100)[M+H，⁸¹Br]⁺

Example 42: 1- (4-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 460.6(98)[M+H，⁷⁹Br]⁺，462.6(100)[M+H，⁸¹Br]⁺

Example 42A: 1- (4-bromophenyl) -3- {1- [1- (tert-butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl ] -1H-indol-4-yl } urea

¹H NMR(400MHz，CDCl₃)：δ8.61(s，1H)，8.19(s，1H)，8.05(d，J＝5.2Hz，1H)，7.49(d，J＝8.0Hz，1H)，7.34(d，J＝4.4Hz，1H)，7.16(s，1H)，7.07-7.05(m，3H)，6.88(d，J＝2.8Hz，1H)，6.76(t，J＝8.0Hz，1H)，6.54(d，J＝8.4Hz，1H)，6.51(d，J＝5.2Hz，1H)，6.47(d，J＝2.8Hz，1H)，6.04(d，J＝4.0Hz，1H)，5.36(s，2H)，1.35(s，9H).

Example 43: 1- (2-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 396.5[M+H]⁺

Example 44: 1- (3-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 396.7[M+H]⁺

Example 45: 1- (4-tolyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 396.7[M+H]⁺

Example 46: 1- (2-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 412.7[M+H]⁺

Example 47: 1- (3-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 412.7[M+H]⁺

Example 48: 1- (4-methoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 466.5[M+H]⁺

Example 49: 1- (4-trifluoromethoxyphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 466.5[M+H]⁺

Example 49A: 1- (4-trifluoromethoxyphenyl) -3- {1- [1- (tert-butyloxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl ] -2, 3-dihydro-1H-indol-4-yl } urea

¹H NMR(400MHz，CDCl₃)：δ8.39(d，J＝4.8Hz，1H)，8.00(s，1H)，7.62(d，J＝4.0Hz，1H)，7.44(s，1H)，7.42(s，1H)，7.16(d，J＝4.8Hz，1H)，7.10-7.06(m，4H)，6.99(s，1H)，6.60(d，J＝4.4Hz，1H)，6.30(t，J＝4.4Hz，1H)，4.41(s，2H)，3.12(t，J＝8.0Hz，2H)，2.53(t，J＝8.0Hz，2H)，1.65(s，9H).

Example 50: 1- (2-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 450.4[M+H]⁺

Example 51: 1- (3-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 450.4[M+H]⁺

Example 52: 1- (4-trifluoromethylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 450.4[M+H]⁺

Example 52A: 1- (4-trifluoromethylphenyl) -3- {1- [1- (tert-Butoxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl ] -1H-indol-4-yl } urea

¹H NMR(400MHz，CDCl₃)：δ8.37(d，J＝4.8Hz，1H)，7.62(d，J＝4.0Hz，1H)，7.55(s，1H)，7.50(s，4H)，7.35(d，J＝7.6Hz，1H)，7.18-7.14(m，2H)，7.08-7.04(m，2H)，6.74(d，J＝5.6Hz，1H)，6.48(d，J＝3.2Hz，1H)，6.24(d，J＝4.4Hz，1H)，5.56(s，2H)，1.65(s，9H).

Example 53: 1- (3-cyanophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 407.7[M+H]⁺

Example 53A: 1- (3-cyanophenyl) -3- {1- [1- (tert-butyloxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl ] -2, 3-dihydro-1H-indol-4-yl } urea

¹H NMR(400MHz，CDCl₃)：δ8.42(d，J＝5.2Hz，1H)，8.02(bs，1H)，7.83(s，1H)，7.78(d，J＝8.8Hz，1H)，7.65(d，J＝4.4Hz，1H)，7.38(t，J＝8.0Hz，1H)，7.31(d，J＝8.0Hz，1H)，7.19(d，J＝4.8Hz，1H)，7.16-7.09(m，2H)，6.63(s，1H)，6.62(d，J＝4.0Hz，1H)，6.39(d，J＝7.6Hz，1H)，4.46(s，2H)，3.09(t，J＝8.0Hz，2H)，2.37(t，J＝8.0Hz，2H)，1.66(s，9H).

Example 54: 1- (4-cyanophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 407.7[M+H]⁺

Example 55: 1- (2-fluoro-4-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 434.4(100)[M+H，³⁵Cl]⁺，436.4(33)[M+H，³⁷Cl]⁺

Example 56: 1- (2-fluoro-5-chlorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 434.4(100)[M+H，³⁵Cl]⁺，436.4(33)[M+H，³⁷Cl]⁺

Example 57: 1- (2-fluoro-5-bromophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 478.3(98)[M+H，⁷⁹Br]⁺，480.3(100)[M+H，⁸¹Br]⁺

Example 57A: 1- (2-fluoro-5-bromophenyl) -3- {1- [1- (tert-butyloxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl ] -2, 3-dihydro-1H-indol-4-yl } urea

¹H NMR(400MHz，CDCl₃)：δ8.48-8.45(m，2H)，7.65(d，J＝4.4Hz，1H)，7.24(d，J＝2.8Hz，1H)，7.20(d，J＝4.8Hz，1H)，7.12(t，J＝8.0Hz，1H)，7.08(td，J＝4.4，2.8Hz，1H)，6.92(d，J＝4.8Hz，1H)，6.89(d，J＝8.8Hz，1H)，6.63(d，J＝4.4Hz，1H)，6.57(s，1H)，6.37(d，J＝7.6Hz，1H)，4.50(s，2H)，3.35(t，J＝8.0Hz，2H)，2.89(t，J＝8.4Hz，2H)，1.67(s，9H).

Example 58: 1- (2-bromo-5-methylphenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 474.3(98)[M+H，⁷⁹Br]⁺，476.3(100)[M+H，⁸¹Br]⁺

Example 58A: 1- (2-bromo-5-methylphenyl) -3- {1- [1- (tert-butyloxycarbonyl) -1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl ] -2, 3-dihydro-1H-indol-4-yl } urea

¹H NMR(400MHz，CDCl₃)：δ8.47(d，J＝5.6Hz，1H)，8.08(s，1H)，7.64(d，J＝3.2Hz，1H)，7.34(d，J＝8.4Hz，1H)，7.20-7.18(m，2H)，7.13(t，J＝8.0Hz，1H)，6.81(d，J＝8.0Hz，1H)，6.73(d，J＝8.4Hz，1H)，6.62(d，J＝4.4Hz，1H)，6.39(d，J＝8.0Hz，1H)，6.26(s，1H)，4.50(s，2H)，3.41(t，J＝8.0Hz，2H)，3.00(t，J＝8.4Hz，2H)，2.32(s，3H)，1.67(s，9H).

Example 59: 1- (2-methyl-3-fluorophenyl) -3- [1- (1H-pyrrolo [2, 3-b ] pyridin-4-ylmethyl) -1H-indol-4-yl ] urea hydrochloride

MS(ESI⁺)：m/z 414.5[M+H]⁺

Example 60: biochemical assays for c-Kit, CSF-1R, and EPHA2

Standard competitive binding assays were used to test the ability of the compounds of the invention to competitively bind with various kinases under in vitro conditions.

To screen compounds for inhibition of different kinases, we performed competitive binding rate assays for the compounds of the invention using the active site binding technique of the KINOMEscan (Ambit Biosciences, san diego, ca, usa) service. The detection method comprises three parts, namely a kinase with a specific DNA sequence, an immobilized ligand and a compound to be detected. The competitive displacement capacity of the compounds of the invention for immobilized ligands can be estimated by quantitative PCR detection of specific DNA portions of the kinase.

A series of compounds of the invention were screened using this binding assay at a concentration of 100nM and the results are expressed as "% Ctrl", low values indicating very high binding rates in the reaction system and the results from example 44, example 56 are shown in the following table:

name of Compound	c-Kit	CSF-1R	EPHA2
				Example 56	3.8	3.4	12
Example 44	0.35	0.8	6

Example 61: detection of PDGFR beta at cellular level

The compounds of the invention can be tested for their effect on PDGFR β kinase activity using standard cell-level assays, and the methods can also be used to discover antagonists of PDGFR β.

Specifically, the compounds to be tested were first dissolved in 10mM DMSO and stored in a-20 ℃ freezer. Intracellular PDGFR β activity is then dependent on the level of phosphorylation of PDGFR β in the intracellular domain that is activated by the ligand. The complete DNA sequence of PDGFR beta is cloned into a PC-DNA3.1 vector, the plasmid is transfected into CHO cells, and after 48 hours, the PDGFR beta protein expressed in the cells can be detected by using conventional western blotting.

The compounds of the invention were detected and screened using an ELISA kit: before selection, the plasmid with the PDGFR β DNA sequence was transfected into CHO cells in its entirety. The day before screening, these CHO cells were changed to continue growing in serum-free medium, and on the day of testing, various CHO cells were not culturedThe same concentration of compound (0.5 nM to 500nM) was added to the medium separately, and after two hours 20% of calf serum was added to the medium and stimulated the phosphorylation expression of intracellular PDGFR β protein, approximately 5X10⁵The transfected CHO cells are finally degraded and are subjected to antigen-antibody reaction with phosphorylated PDGFR beta antibody or PDGFR beta antibody in a 96-well plate, and the protein expression level of phosphorylated PDGFR beta and PDGFR beta can pass through Streptavidin-HRP (R) in the presence of a detection antibody&D Systems) was detected by chemiluminescence detection method.

In this manner, it was generally determined that the compounds of the invention exert a significant phosphorylation-inhibiting effect on PDGFR β expression, which is activated by growth factors or is continuously phosphorylated. IC for inhibiting PDGFR beta phosphorylation of certain compounds₅₀Below 100nM (including 100nM), the inhibitory activity IC of some compounds₅₀Under 10nM (including 10 nM). Thus, the compounds of the present invention are useful in the treatment of various diseases involving angiogenesis.

The following table shows the inhibition of phosphorylation of PDGFR β kinase at 100nM of each of the inventive compounds, expressed as a percentage of remaining activity, with a indicating a percentage of less than 70% of the remaining PDGFR β protein kinase activity and B indicating greater than or equal to 70%.

Example 62: detection of VEGFR2 at the cellular level

The compounds of the invention can be tested for their effect on VEGFR2 kinase activity using standard cell-level assays, and can also be used to find antagonists of VEGFR 2.

Specifically, the compounds to be tested were first dissolved in 10mM DMSO and stored in a-20 ℃ freezer. Intracellular VEGFR2 activity was dependent on the level of intracellular phosphorylation of VEGFR2 activated by the ligand. The entire DNA sequence of VEGFR2 was cloned into the PC-DNA3.1 vector and the plasmid was transfected into CHO cells, and 48 hours later, the amount of VEGFR2 protein expressed intracellularly was examined by conventional western blotting.

ELISA kits were used to screen the compounds of the invention. Before screening, the plasmids carrying the VEGFR2DNA sequences were all transfected into CHO cells. The day before screening, these CHO cells were changed to grow in serum-free medium, and on the day of testing, various concentrations of compounds (from 0.5nM to 500nM) were added to the medium, two hours later, 20% of calf serum was added to the medium and the intracellular expression of the phosphorylation of VEGFR2 protein was stimulated, approximately 5X10⁵The transfected CHO cells were finally degraded and subjected to antigen-antibody reaction with the phosphorylated VEGFR2 antibody or VEGFR2 antibody in a 96-well plate, and the protein expression levels of phosphorylated VEGFR2 and VEGFR2 in the presence of the detection antibody were detected by a chemiluminescent detection method using Streptavidin-HRP.

In this manner, it was generally determined that the compounds of the invention were capable of significant inhibition of phosphorylation, either by growth factor activation or by sustained expression of phosphorylated VEGFR 2. IC for inhibiting phosphorylation of VEGFR2 with some compounds₅₀Below 100nM (including 100nM), the inhibitory activity IC of some compounds₅₀Under 10nM (including 10 nM). Thus, the compounds of the present invention are useful in the treatment of various diseases involving angiogenesis.

The following table shows the phosphorylation inhibition of VEGFR2 kinase at a concentration of 100nM for each of the inventive compounds, expressed as a percentage of remaining activity, a indicating a percentage of VEGFR2 protein kinase activity remaining of less than 70% and B indicating greater than or equal to 70%.

Example 63: detection of c-Met at cellular level

The compounds of the invention can be tested for their effect on c-Met kinase activity using standard cellular level assays, and can also be used to find antagonists of c-Met.

Specifically, the compounds to be tested were first dissolved in 10mM DMSO and stored in a-20 ℃ freezer. Intracellular c-Met activity is dependent on the level of phosphorylation of c-Met in the intracellular domain activated by the ligand (liver growth factor). To stimulate the production of phosphorylated c-Met by cells, non-small cell lung carcinoma A549 cells, which can be activated by hepatocyte growth factor, were grown in culture medium (DMSO) containing 10% fetal bovine serum.

The inhibition effect of the compound on the c-Met kinase activity can be detected and screened by an ELISA kit: the day before screening, A549 cells were changed to serum-free medium, and by the day of detection, various compounds (concentration from 0.5nM to 500nM) were added to the medium at different concentrations, and two hours later, 20% of calf serum was added to the medium and stimulated the intracellular phosphorylation expression of c-Met protein, approximately 5X10⁵The A549 cells of (a) are finally degraded and subjected to antigen-antibody reaction with a phosphorylated c-Met antibody or a c-Met antibody in a 96-well plate, and in the presence of these detection antibodies, the protein expression amounts of phosphorylated c-Met and c-Met can be measured by a chemiluminescent detection method using Streptavidin-HRP.

In this way it is generally possible to detect the effect of the compounds of the invention on the activation or sustained expression of phosphorylated c-Met by growth factors, which leads to a significant inhibition of phosphorylation. IC for inhibition of c-Met phosphorylation in certain compounds₅₀Below 100nM (including 100nM), the inhibitory activity IC of some compounds₅₀Under 10nM (including 10 nM). Thus, the compounds of the present invention are useful in the treatment of a variety of diseases involving angiogenesis, invasive growth, cell metastasis and Epithelial Mesenchymal Transition (EMT).

The following table shows the phosphorylation inhibition of c-Met kinase at a concentration of 100nM for each of the inventive compounds, expressed as a percentage of remaining activity, A indicating a percentage of remaining c-Met protein kinase activity of less than 70% and B indicating a percentage of greater than or equal to 70%.

Still other inventive compounds have the ability to inhibit the activity of both VEGFR2 and C-Met double kinases, or the ability to inhibit the activity of both VEGFR2, PDGFR β and C-Met triple kinases, or the ability to inhibit the activity of both VEGFR2, C-Met and C-Kit triple kinases, or the ability to inhibit the activity of both the following multiple kinases produced by different combinations (VEGFR2, C-Met, RON, PDGFR α, PDGFR β, C-Kit, CSF1R, EphA2, Alk, Tie-1, Tie-2, Flt3, FGFR1, FGFR2, FGFR3, FGFR4, EGFR, Her2, Abl, Aurora A, Aurora B, Aurora C, Src, Lck, IGF-1R, orIR, etc. tyrosine protein kinase receptors). The compound which can simultaneously inhibit several tyrosine protein kinase receptors has obvious clinical application value, and especially aims at various diseases related to angiogenesis, invasive growth, epithelial intercellular transformation and cell movement, such as tumors, rheumatoid arthritis, arterial restenosis, autoimmune diseases, acute inflammation, acute and chronic nephropathy, diabetic retinopathy, psoriasis, macular degeneration and the like.

Example 64 antitumor Effect in vivo

Human breast cancer tumor cell MDA-MB-231, human non-small cell lung cancer cell A549, human glioblastoma cell U87-MG, human prostate cancer cell PC-3, human colorectal cancer cell HT-29, human liver cancer cell BEL7404 andhuman gastric carcinoma cells MKN-45 (tumor cells 5X10 of various types purchased from ATCC⁵Suspended in 100ul DMEM culture solution) were injected into female nude mice (Balb/c additive mice) subcutaneously, respectively, and the tumors were grown to 200-400mm in average³Oral administration is started when the size is about, the nude mice are randomly divided into a plurality of groups, in a small sample pharmacodynamic test, each group comprises 3 nude mice, and the average value of the sizes of tumors of each group basically has little difference; in a large sample pharmacodynamic test, the nude mice are divided into a non-administration group (containing only solution without drug; the solution component is PEG400 and HCl of 0.01N in a volume ratio of 2: 1) and an administration group (the drug is dissolved in the solution, the solution component is the same as the non-administration group), each group contains 13 or 14 nude mice, and the administration dose comprises 12.5mg/kg, 25mg/kg, 50mg/kg, 100mg/kg and the like. The administration mode is oral administration, once a day. Tumor size can be measured with calipers, twice a week from the start of dosing; the measurement formula is 1/2 XLXW²(L: tumor major axis length, W: tumor minor axis length). The administration time is not less than two weeks or at least until the tumor size reaches 2500mm³And even larger. After completion of the experiment, the nude mice were sacrificed humanely.

The Tumor Growth Inhibition (TGI) is used to express the tumor growth inhibition effect of the compounds. The tumor growth inhibition rate (TGI) during treatment can be calculated from the average size measured for each group of tumors by the following formula:

TGI＝100×(V_{Vehicle_group}-V_{Treatment_group})÷V_{Vehicle_group}

here, V_{Vehicle_group}Indicating the mean size of the tumors in the non-drug group. V_{Treatmenf_group}Indicating the mean tumor size in the drug group.

In vivo pharmacodynamic assays, the Tumor Growth Inhibition (TGI) of each compound is presented below in tabular form, and B indicates that the tumor growth inhibition of the compounds is between 0% and 50%. A indicates that the tumor growth inhibition rate of the compound is 50% or more.

The following table summarizes the in vivo pharmacodynamic results for the different compounds:

other embodiments

It is to be understood and appreciated that while the present invention has been described in conjunction with the detailed description set forth above, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined in the following claims. Other aspects, benefits, and modifications are within the scope of the claims. The entire contents of all publications cited in this application are incorporated by reference into this application and are a part of this application.

Claims

1. A compound of formula I or II and pharmaceutically acceptable salts thereof,

wherein:

u, V, X, Y and Z are each independently selected from N or C-R¹；

L is O, S (O)_n，N-R²Or optionally one or moreIndependent R³A group-substituted alkylene group;

n is 0, 1, or 2.

2. A compound according to claim 1, wherein X, Y, Z, V and U are each independently C-R¹Thus giving a compound of formula Ia or IIa, wherein R¹The groups may be the same or different.

3. A compound as claimed in claim 2 wherein each R is¹Is hydrogen and L' is a covalent bond.

4. A compound according to claim 1, wherein Y is N, andx, Z, V and U are each independently C-R¹Thus giving a compound of formula Ib or IIb, wherein R¹The groups may be the same or different.

5. A compound of claim 4, wherein each R is¹Is hydrogen and L' is a covalent bond.

6. A compound according to claim 1, wherein Z is N, and X, Y, V and U are each independently C-R¹Thus giving a compound of formula Ic or IIc, wherein R¹The groups may be the same or different.

7. A compound of claim 6, wherein each R is¹Is hydrogen and L' is a covalent bond.

8. A compound according to claim 1, derived from formula I; x is N; while Y, Z and V are each independently of the other C-R¹Thus, a compound of formula Id is given, wherein the R1 groups may be the same or different.

9. A compound of claim 8, wherein each R is¹Is hydrogen and L' is a covalent bond.

10. A compound according to claim 1, derived from formula I; x and Z are N; while Y and V are each independently of the other C-R¹Thus giving a compound of formula Ie wherein R¹The groups may be the same or different.

11. A compound of claim 10, wherein each R is¹Is hydrogen and L' is a covalent bond.

12. A compound as claimed in claim 1, wherein L is alkylene, optionally substituted by one or more independent R³And (4) substituting the group.

13. A compound as claimed in claim 12, wherein L is alkylene.

14. A compound according to claim 13, wherein L is methylene, ethylene, propylene, or isopropylene.

15. A compound according to claim 14, wherein L' is a covalent bond.

16. A compound according to claim 1, wherein L' is a covalent bond.

17. A compound according to claim 1 wherein Ar is phenyl, naphthyl, pyridyl, pyridonyl, pyrimidinyl, pyridazinyl, triazinyl, imidazolyl, thienyl, furyl, thiazolyl, oxazolyl, triazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzotriazolyl, 2-oxoindolyl, or indolinyl, and is optionally substituted with one or more independent halo, alkoxy, alkyl, haloalkoxy, cyano, oxy, or optionally substituted heterocycloalkyl.

18. A compound according to claim 17, wherein L' is a covalent bond.

19. A compound as claimed in claim 18, wherein L is alkylene.

20. A compound according to claim 19, wherein L is methylene, ethylene, propylene, or isopropylene.

21. A compound as claimed in claim 19, wherein A is A1-a, A1-b, A1-c, A1-d, A1-e, A1-f, A1-g, A1-h, A1-i, A2-a, A2-b, A3-a, A3-b, A3-c, A3-d, or A3-e, each of which is optionally substituted with one or more R⁵And (4) substituting the group.

22. A compound according to claim 21, wherein A is A1-a, A1-b, A1-d, A1-e, A1-g, A2-a, A2-b, A3-a, or A3-c, each of which is optionally substituted with one or more independent R⁵And (4) substituting the group.

23. A compound as claimed in claim 22 wherein A is A1-a, A1-b, A1-d, A1-g, A2-a or A2-b, each of which is optionally substituted with one or more independent R⁵And (4) substituting the group.

24. A compound according to claim 23, wherein A is A1-a or A2-a, each of which is optionally substituted with one or more independent R⁵And (4) substituting the group.

25. A compound as claimed in claim 24, wherein a is a1-a or a 2-a.

26. A compound according to claim 1, wherein A is A1-a, A1-b, A1-c, A1-d, A1-e, A1-f, A1-g, A1-h, A1-i, A2-a, A2-b, A3-a, A3-b, A3-c, A3-d, or A3-e, each of which is optionally substituted with one or more R⁵And (4) substituting the group.

27. A compound according to claim 26 wherein a is a1-a, a1-b, a1-d, a1-e, a1-g, a2-a, a2-b, A3-a or A3-c, each of which is optionally substituted with one or more independent R⁵And (4) substituting the group.

28. A compound of claim 27, wherein A is A1-a, A1-b, A1-d, A1-g, A2-a, or A2-b, each of which is optionally substituted with one or more independent R⁵And (4) substituting the group.

29. A compound of claim 28, wherein A is A1-a or A2-a, each of which is optionally substituted with one or more independent R⁵And (4) substituting the group.

30. A compound as claimed in claim 29, wherein a is a1-a or a 2-a.

31. A compound according to claim 1, which compound is:

32. a compound according to claim 1 wherein Ar is phenyl, optionally substituted with one or two or three or four substituents, each substituent being independently selected from fluoro, bromo, chloro, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy, or oxopyrrolidinyl; or Ar is indoline, optionally substituted with one or two or three or four substituents each independently selected from fluoro, bromo, chloro, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy, or oxy.

33. A compound according to claim 1 which is:

34. A compound according to claim 1 which is:

35. A compound according to claim 1 which is:

36. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-35 and a pharmaceutically acceptable carrier.

37. A method of treating a protein kinase mediated disease, the method comprising: administering to a patient a therapeutically effective amount of a compound according to any one of claims 1 to 35 or a pharmaceutical composition according to claim 36.

38. A method according to claim 37 wherein the kinase comprises VEGFR2, C-Met, RON, pdgfra, pdgfrp, C-Kit, CSF1R, EphA2, Alk, Tie-1, Tie-2, Flt3, FGFR1, FGFR2, FGFR3, FGFR4, EGFR, Her2, Abl, Aurora a, Aurora B, Aurora C, Src, Lck, IGF-1R or IR.

39. A method as claimed in claim 37 wherein the disease treated comprises tumours, rheumatoid arthritis, autoimmune diseases, acute inflammation, nephritis, diabetic retinopathy, psoriasis and macular degeneration.