CN101137652A - Pyrimidine compounds with TIE2(TEK) inhibitory activity - Google Patents

Abstract

The invention relates to a compound of the Formula (I) or salt thereof wherein R<x>, R<y>, R<z>, R<5>, R<6>, A, B, L, n and m are as defined in the description. The invention also relates to pharmaceutical compositions of said compounds, the use of said compounds as medicaments and in the production of an anti-angiogenic effect in a warm blooded animal. The invention also relates to processes for the preparation of said compounds.

Description

Pyrimidine compounds with TIE2(TEK) inhibitory activity

The present invention relates to compounds, or pharmaceutically acceptable salts thereof, which have anti-angiogenic activity and are therefore useful in methods of treating disease states associated with angiogenesis in animals or humans. The present invention also relates to processes for the preparation of said compounds, pharmaceutical compositions containing said compounds as active ingredients, and methods of using said compounds in the manufacture of medicaments for producing anti-angiogenic effects in homeothermic animals such as humans .

Tie2 receptor tyrosine kinase (also known as TEK) is mainly expressed in endothelial cells and hematopoietic cells and is critical for blood vessel formation and maintenance (Jones, N. et al., Nature Reviews Molecular Cell Biology. 2001: 2, 257-67 ).

Angiogenesis is defined as the fundamental process of generating new blood vessels from existing vasculature. It is an important and complex biological process necessary for the formation and physiological function of virtually all organs. It is normally transient in nature and is governed by a multistep process involving e.g. endothelial cell (EC) activation, vascular instability, synthesis and release of degradative enzymes, Local equilibrium control of angiogenic factors and angiogenic inhibitors during EC migration, EC proliferation, EC organization and differentiation, and vascular maturation).

Normal angiogenesis plays an important role in several processes and is tightly controlled. In adults, physiological angiogenesis is largely restricted to wound healing and several components of female reproductive function and embryonic development. In unwanted or pathological angiogenesis, the local balance between angiogenic and angiogenic inhibitory factors is disturbed, resulting in inappropriate and/or structurally abnormal blood vessel formation. Pathological angiogenesis is associated with diseases including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma, and hemangioma (Fan et al., 1995, Trends Pharmacology. Science. 16:57-66 ; Folkman, 1995, Nature Medicine 1:27-31). In cancer, angiogenesis is required for the growth of primary and secondary tumors exceeding 1-2 mm3 (Folkman, J. New England Journal of Medicine 1995; 33, 1757-1763).

In diseases such as cancer, the development of which depends on abnormal angiogenesis, blocking this process can lead to prevention of disease progression (Folkman, J. 1995, Nature Medicine. 1:27-31). It is believed that many of the factors described in the scientific literature are of great importance in the regulation of angiogenesis. The two main classes of angiogenic factors are vascular endothelial growth factor (VEGF) and angiogenin. These polypeptide moieties interact with their respective receptors, membrane tyrosine kinase receptors, which are highly specific receptors for endothelial cells, to elicit cellular responses through ligand-mediated signaling. It is hypothesized that VEGF and angiogenin cooperate to regulate various aspects of the angiogenic process by sending signals to their respective receptors during normal and pathological angiogenesis.

Receptor tyrosine kinases (RTKs) are important in the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules are characterized as consisting of an extracellular ligand-binding domain linked by a plasma membrane segment to an intracellular tyrosine kinase domain. Ligand binding to the receptor produces stimulation of the receptor associated with tyrosine kinase activity, resulting in phosphorylation of tyrosine residues on the receptor and other intracellular molecules. These changes in tyrosine phosphorylation initiate signaling cascades that generate a variety of cellular responses. To date, at least 19 distinct RTK subfamilies defined by amino acid sequence homology have been identified. One of these subfamilies is currently composed of the fms-like tyrosine kinase receptor Flt or Flt1, the kinase insert domain-containing receptor, KDR (also known as Flk-1), and another fms-like tyrosine kinase receptor Flt4 composition. Two of these related RTKs, Flt and KDR, have been shown to bind VEGF with high affinity (De Vries et al., 1992, Science 255:989-991; Terman et al., 1992, Biochem. Biophys. Res. Comm. 1992, 187: 1579-1586). Binding of VEGF to these receptors expressed in xenogeneic cells is associated with changes in the tyrosine phosphorylation status of cellular proteins and calcium flux.

A second family of highly specific receptors for endothelial cells that regulate vascular instability and maturation has recently been identified. The Tie receptor and its ligands, angiogenin and VEGF, work closely together during normal and pathological angiogenesis. The transmembrane receptors Tie1 and Tie2 constitute a family of endothelial cell-specific tyrosine kinase receptors that are involved in maintaining the integrity of blood vessels, which is involved in angiogenesis and revascularization. Tie1 and Tie2 share many structural features (such as the intracellular domains of two of these receptors, each containing a tyrosine kinase domain blocked by a kinase insert region), and thus constitute distinct subfamilies of RTKs. The Tie1 and Tie2 receptors share an overall sequence identity of 44% at the amino acid level, while their intracellular domains share 76% identity. Targeted disruption of the Tie1 gene results in a lethal phenotype characterized by extensive hemorrhage and poor microvascular integrity (Puri, M. et al. 1995 EMBO Journal: 14:5884-5891). Transgenic mice deficient in Tie2 due to severe defects in embryonic vasculature exhibit defects in vascular growth and re-formation, as well as a lethal phenotype in the second trimester (E9.5-10.5) (Sato, T. et al. 1995 Nature 370:70-74) .

To date, no ligands for Tie1 have been identified and little is known about its signaling capabilities. However, it is believed that Tie1 affects Tie2 signaling ability through heterodimerization with Tie2 receptors, thus potentially regulating the ability of Tie2 autophosphorylation (Marron, M. et al. 2000 Journal of Biological Chemistry: 275, 39741-39746), while chimeric Tie1 Receptor studies have shown that Tie-1 can inhibit apoptosis through the PI3 kinase/Akt signaling pathway (Kontos, C.D. et al., 2002 Molecular and Cellular Biology: 22, 1704-1713). In contrast, multiple ligands for Tie2 have been identified, named angiopoietins, of which angiopoietin 1 (Ang1) is the best characterized. Binding to Ang1 causes Tie2 receptor tyrosine phosphorylation via autophosphorylation, and subsequent activation of its signaling pathway through signaling. Ang2 has been reported to antagonize these effects in endothelial cells (Maisonpierre, P. et al. 1997 Science: 277, 55-60). Isolation and transgenic manipulation of Tie2 and its ligand suggest that tight spatial and temporal control of Tie2 signaling is necessary for proper development of neovasculature. It has also been reported that there is the possibility of heterodimerization between at least two other ligands (Ang3 and Ang4) as well as between angiogenin ligands that modify their binding activity to the receptor (agonistic/ antagonistic potential. In vascular endothelial cells, the Tie2 receptor activated by Ang1 inhibits apoptosis (Papapetropoulos, A. et al., 2000Journal of Biological Chemistry: 2759102-9105), promotes growth (Witzenbicher, B. et al., 1998Jumal of Biological Chemistry: 273, 18514-18521), promoting vessel maturation and reducing mature microvascular permeability and subsequent leakage during angiogenesis in vivo (Thurston, G. et al., 2000 Nature Medicine: 6, 460-463). Thus, it has been reported that activation of Tie2 receptors would be involved in the branching, sprouting and formation of new blood vessels, as well as the recruitment and interaction of surrounding endothelial support cells important for maintaining vascular integrity, all apparently associated with improved microvascular stability. unanimous. Inactivation of Tie2 or inhibition of Tie2 autophosphorylation can lead to loss of vascular architecture and matrix/cell contacts (Thurston, G., CellTissue Res. (2003), 314:61-69), which can trigger endothelial cell death, especially in the absence of When survival or growth stimulation. Inhibition of Tie2 kinase may provide anti-angiogenic effects as reported above as a result of Tie2 kinase activity and thus have utility in the treatment of diseases associated with pathological angiogenesis. Tie2 expression has been shown to be upregulated in the neovasculature of various tumors (e.g. Peters, K.G. et al., (British Journal of Cancer 1998; 77, 51-56), suggesting that inhibition of Tie2 kinase activity would result in anti-angiogenic activity. In support of This assumption led to studies on soluble Tie2 receptors (extracellular domain) (Pengnian, L et al., 1997, Journal of Clinical Investigation 1997: 100, 2072-2078 and Pengnian, L et al., 1998, Proceedings of the National Academy of Sciences 1998: 95, 8829 -8834) showed antitumor activity in in vivo tumor models. Additionally, these experiments also showed that blocking Tie2 signaling in normal healthy individuals was well tolerated, as no deleterious toxicity was observed in these studies

Examination of human primary breast cancer samples and human and murine breast cancer cell lines (Stratmann, A. et al., 2001, International Journal of Cancer: 91, 273-282) indicated that the Tie2-dependent pathway of tumor angiogenesis could be linked to KDR-dependent Both pathways exist together, in fact they can operate independently (Siemeister G. et al., 1999 Cancer Research: 59, 3185-3191), and cooperate with each other (for example, VEGF A and Ang1 have been reported to cooperate to induce angiogenesis and produce non-leaky mature blood vessels Thurston, G, et al., 1999 Science: 286, 2511-2514). It is even quite possible that this mixture of angiogenic processes exists in a single tumor.

Tie2 has also been shown to play a role in the vascular abnormality known as venous deformation (VM) (Mulliken, J.B. & Young, A.E. 1998, Vascular Birthmarks: W.B. Saunders, Philadelphia). This defect can be inherited or occur by chance. VMs are usually found in the skin or mucous membranes but can affect any organ. Lesions are usually spongy blue to purple vascular plaques composed of vascular channels lined by swollen endothelial cells. Among the various genotypes of the disease, the most common defect is the Tie2 kinase mutation C2545T in the Tie2 coding sequence (Calvert, J.T. et al., 1999 Human Molecular genetics: 8, 1279-1289), which has an R849W amino acid substitution in the kinase domain . Analysis of this Tie2 mutant showed that it was still substantially activated even in the absence of ligand (Vikkula, M. et al., 1996 Cell: 87, 1181-1190).

Tie2 expression was also found to be upregulated in the vascular synovial pannus of arthritic human joints, consistent with inappropriate neovascularization.

This example provides further evidence that inhibition of Tie2 phosphorylation and subsequent signaling may be useful in the treatment of diseases and other events of inappropriate neovascularization. To date, only a few Tie2 inhibitors are known in the art. For example, International Application No: WO04/013141 describes groups of condensed pyridines and pyrimidines, and International Application No: WO04/058776 describes groups of pyridines and pyrimidines. There is therefore a need to find additional Tie2 inhibitors that can exploit all of the therapeutic potential of inhibiting/modulating the Tie2 signaling pathway.

We have discovered that certain compounds have activity that inhibits the Tie2 receptor tyrosine kinase and are therefore of value in the treatment of diseases associated with pathological angiogenesis such as cancer, rheumatoid arthritis, and other diseases.

According to the present invention, compound of formula I is provided:

Formula I

where R ^y is a group NR ¹ R ² , R ^x is a group R ^3a and R ^z is a group R ^4a ,

Or R ^x is a group NR ¹ R ² and R ^y is a group R ^4b and R ^z is a group R ^3b where

R ¹ and R ² are independently selected from hydrogen, (1-6C) alkylsulfonyl, phenyl (CH ₂ ) _u - (wherein u is 0, 1, 2, 3, 4, 5 or 6), (1 -6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxycarbonyl, (3-6C) cycloalkyl (CH ₂ ) _v - (where v is 0, 1, 2, 3, 4, 5 or 6) or a 5-membered or 6-membered heteroaryl ring, or R ¹ and R ² together with the nitrogen atom to which they are attached represent a saturated or partially saturated 3-7 membered heterocycle;

Where any (1-6C) alkyl, (1-6C) alkoxy, (1-6C) alkanoyl and (3-6C) cycloalkyl groups are optionally selected from one or more of the following independently Group substitution: fluorine, hydroxyl, (1-6C) alkyl, (1-6C) alkoxy, (1-6C) alkoxy (1-6C) alkoxy, (1-6C) alkoxy (1-6C) alkoxy (1-6C) alkoxy, amino, mono (1-6C) alkyl amino or di (1-6C) alkyl amino, carbamoyl, mono (1-6C) alkane Carbamoyl, di-[(1-6C)alkyl]carbamoyl, N(R ^d )C(O)(1-6C)alkyl, where R ^d is hydrogen or (1-6C)alkyl , a saturated or partially saturated 3-7 membered heterocyclic ring or a 5 or 6-membered heteroaryl ring;

Among them (1-6C) alkoxy, (1-6C) alkoxy (1-6C) alkoxy and (1-6C) alkoxy (1-6C) alkoxy (1-6C) alkoxy group, and mono(1-6C)alkylamino, di-[(1-6C)alkyl]amino, mono(1-6C)alkylcarbamoyl, di[(1-6C)alkyl]aminomethyl Acyl and/or (1-6C)alkyl of N(R ^d )C(O)(1-6C)alkyl are optionally substituted by one or more hydroxyl groups;

Wherein any phenyl in R ^and /or ^R is optionally substituted by one or more groups independently selected from the following groups: halogen, (1-6C) alkyl, (1-6C) alkoxy, amino , single (1-6C) alkylamino or bis (1-6C) alkylamino, wherein (1-6C) alkyl and (1-6C) alkoxy are optionally selected from one or more independently selected from hydroxyl , amino, single (1-6C) alkylamino or di-(1-6C) alkylamino group substitution;

and wherein any heterocyclic and heteroaryl rings within R ^and /or ^R are optionally substituted independently with one or more of the following groups: (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkoxy(1-4C)alkyl, hydroxy, amino, mono(1-6C)alkylamino, di-[(1-6C)alkyl]amino, saturated or partially saturated 3～ 7-membered heterocycle or -C(O)(CH ₂ ) _z Y, wherein z is 0, 1, 2 or 3, and Y is selected from hydrogen, hydroxyl, (1-4C)alkoxy, amino, mono(1 -6C) alkylamino, di-[(1-6C)alkyl]amino or saturated or partially saturated 3-7 membered heterocycle;

and with the proviso that when R ^and / ^or R are a (1C)alkanoyl group, then the (1C)alkanoyl group is not substituted by fluorine or hydroxyl;

R ^3a and R ^4a are independently selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxy,

Wherein (1-6C) alkyl and (1-6C) alkoxy are optionally substituted by one or more groups independently selected from the following groups: fluorine, hydroxyl, (1-6C) alkyl, (1-6C ) alkoxy, amino, single (1-6C) alkylamino or two (1-6C) alkylamino, carbamoyl, single (1-6C) alkylcarbamoyl or two [(1-6C) Alkyl]carbamoyl, saturated or partially saturated 3-7 membered heterocyclic rings or 5 or 6 membered heteroaryl rings, wherein the heterocyclic rings and heteroaryl rings are optionally independently replaced by one or more of the following groups Substitution: (1-4C) alkyl, (1-4C) alkoxy, hydroxyl, amino, mono(1-6C) alkylamino or di(1-6C) alkylamino or saturated or partially saturated 3～ 7-membered heterocycle;

or one of R ^3a and R ^4a is as defined above and the other represents a group -NR ¹ R ² as defined above,

R ^3b is selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxy, wherein (1-6C) alkyl and (1-6C) alkoxy are optionally selected by one or more independently Substitution from the following groups: fluorine, hydroxyl, (1-6C) alkyl, (1-6C) alkoxy, amino, mono (1-6C) alkyl amino, di (1-6C) alkyl amino, Carbamoyl, mono(1-6C)alkylcarbamoyl or di[(1-6C)alkyl]carbamoyl, saturated or partially saturated 3-7 membered heterocycle or 5 or 6-membered heteroaryl ring , wherein the heterocyclic and heteroaryl rings are optionally substituted independently by one or more of the following groups: (1-4C)alkyl, (1-4C)alkoxy, hydroxyl, amino, mono(1- 6C) alkylamino or di(1-6C) alkylamino or saturated or partially saturated 3-7 membered heterocycle;

Or R ^3b represents a group -NR ¹ R ² as defined above;

R ^4b is selected from hydrogen, (1-6C) alkyl, (1-6C) alkoxy or (3-7C) cycloalkyl;

A represents aryl or a 5- or 6-membered heteroaryl ring selected from the group consisting of furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, Oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl;

^R is selected from cyclopropyl, cyano, halogen, (1-6C) alkoxy or (1-6C) alkyl, wherein (1-6C) alkyl and (1-6C) alkoxy are optionally replaced by Cyano or substituted by one or more fluorines;

n is 0, 1, 2 or 3;

The connection point of L relative to the ethynyl group is connected at the meta or para position of ring A, and represents -N(R ⁸ )C(O)N(R ⁹ )-(CR ^a R ^b ) _x -Z- (CR ^a R ^b ) _y -,

Where Z is a direct bond, -O- or -N(R ⁸ )-,

where x and y are independently 0, 1, 2 or 3, provided that x+y>0 and <4,

Wherein R ⁸ and R ⁹ independently represent hydrogen or (1-6C) alkyl,

wherein R ^a and R ^b independently represent hydrogen or (1-6C) alkyl, or R ^a and R ^b together with the carbon atoms to which they are attached represent (3-6C) cycloalkyl; and

wherein the (1-6C) alkyl in R ^a and R ^b is optionally substituted by halogen, cyano, hydroxyl or a saturated or partially saturated 3-7 membered heterocycle;

B represents (3-7C) cycloalkyl ring, saturated or partially saturated 3-7 membered heterocyclic ring, aryl or 5 or 6 membered heteroaryl ring; or optionally contains 1, 2, 3 or 4 independently A heteroatom selected from N, O and S and is a saturated, partially saturated or aromatic 8, 9 or 10 membered bicyclic group;

R ⁶ is selected from halogen, hydroxyl, amino, mono(C1-6 alkyl)amino, di-(C1-6 alkyl)amino, cyano, oxo, (3-7C)cycloalkyl ring, saturated or partial Saturated 3-7 membered heterocycle and -N(R ^c )C(O)(1-6C)alkyl, wherein R ^c is hydrogen or (1-6C)alkyl;

Or R ^is selected from (1-6C) alkyl, S (O) _p (1-6C) alkyl (wherein p is 0, 1 or 2) or (1-6C) alkoxy,

Wherein (1-6C) alkyl, S (O) _p (1-6C) alkyl and (1-6C) alkoxy are optionally substituted by one or more groups independently selected from the following groups: cyano, Fluorine, hydroxy, (1-6C)alkoxy, amino, mono(1-6C)alkylamino, di(1-6C)alkylamino, (3-7C)cycloalkyl ring or saturated or partially saturated 3-7 membered heterocycles; and

Wherein the (3-7C) cycloalkyl ring and the saturated or partially saturated 3-7 membered heterocycle are optionally independently replaced by one or more selected from (1-6C) alkyl or hydroxy (1-6C) alkane radical substitution of radicals; and

m is 0, 1, 2 or 3;

And when B is a (3-7C) cycloalkyl ring, a saturated or partially saturated 3-7 membered heterocyclic ring, or a saturated or partially saturated 8, 9 or 10-membered bicyclic group, the ring and the bicyclic group The group optionally has 1 or 2 oxo or thio substituents;

and their salts or solvates.

Especially, in formula (I), when R ⁶ exists, it is selected from halogen, cyano, oxo, (3-7C) cycloalkyl ring, saturated or partially saturated 3-7 membered heterocyclic ring and- N(R ^c )C(O)(1-6C)alkyl, wherein R ^c is hydrogen or (1-6C)alkyl;

Or R ^is selected from (1-6C) alkyl, S (O) _p (1-6C) alkyl (wherein p is 0, 1 or 2) or (1-6C) alkoxy,

Wherein (1-6C) alkyl, S (O) _p (1-6C) alkyl and (1-6C) alkoxy are optionally substituted by one or more groups independently selected from the following groups: cyano, Fluorine, hydroxy, (1-6C)alkoxy, amino, mono(1-6C)alkylamino, di(1-6C)alkylamino, (3-7C)cycloalkyl ring or saturated or partially saturated 3-7 membered heterocycles; and

Wherein the (3-7C) cycloalkyl ring and the saturated or partially saturated 3-7 membered heterocycle are optionally independently replaced by one or more selected from (1-6C) alkyl or hydroxy (1-6C) alkane The group substitution of the group.

Additionally, R ⁶ is hydroxyl.

Alternatively, R ⁶ may be amino, mono(C1-6 alkyl)amino, di-(C1-6 alkyl)amino.

In particular embodiments wherein R ^y is a group NR ¹ R ² , R ^x is a group R ^3a and R ^z is a group R ^4a , R ⁶ is selected from the group consisting of halogen, cyano, oxo, (3-7C) Cycloalkyl ring, saturated or partially saturated 3-7 membered heterocycle and -N(R ^c )C(O)(1-6C)alkyl, wherein R ^c is hydrogen or (1-6C)alkyl;

Or R ^is selected from (1-6C) alkyl, S (O) _p (1-6C) alkyl (wherein p is 0, 1 or 2) or (1-6C) alkoxy,

Wherein (1-6C) alkyl, S (O) _p (1-6C) alkyl and (1-6C) alkoxy are optionally substituted by one or more groups independently selected from the following groups: cyano, Fluorine, hydroxy, (1-6C)alkoxy, amino, mono(1-6C)alkylamino, di(1-6C)alkylamino, (3-7C)cycloalkyl ring or saturated or partially saturated 3-7 membered heterocycles; and

Wherein the (3-7C)cycloalkyl ring and the saturated or partially saturated 3-7 membered heterocycle are optionally substituted independently by one or more groups selected from (1-6C)alkyl groups.

A specific example of a compound of formula (I) is a compound of formula (IA)

Formula IA

in:

R ¹ , R ² , R ^3a , R ^4a , A, R ⁵ , L, B, n and m are as defined above for formula (I), and

R ⁶ is selected from hydroxyl, halogen, cyano, oxo, (3-7C) cycloalkyl ring, saturated or partially saturated 3-7 membered heterocycle and -N(R ^c )C(O)(1-6C ) alkyl, wherein R ^c is hydrogen or (1-6C) alkyl;

Or R6 is selected from (1-6C) alkyl, S (O) _p (1-6C) alkyl (wherein p is 0, 1 or 2) or (1-6C) alkoxy,

Wherein (1-6C) alkyl, S (O) _p (1-6C) alkyl and (1-6C) alkoxy are optionally substituted by one or more groups independently selected from the following groups: cyano, Fluorine, hydroxy, (1-6C)alkoxy, amino, mono(1-6C)alkylamino, di(1-6C)alkylamino, (3-7C)cycloalkyl ring or saturated or partially saturated 3-7 membered heterocycles; and

wherein the (3-7C) cycloalkyl ring and the saturated or partially saturated 3-7 membered heterocycle are optionally substituted independently by one or more groups selected from (1-6C) alkyl; and

And when B is a (3-7C) cycloalkyl ring, a saturated or partially saturated 3-7 membered heterocyclic ring, or a saturated or partially saturated 8, 9 or 10-membered bicyclic group, the ring and the bicyclic group The group optionally has 1 or 2 oxo or thio substituents;

and their salts or solvates.

Examples of compounds of formula IA are compounds in which:

R ¹ , R ² , A, R ⁵ , L, n and m are as defined above for formula (I),

R ^3a and R ^4a are independently selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxy,

Wherein (1-6C) alkyl and (1-6C) alkoxy are optionally substituted by one or more groups independently selected from the following groups: fluorine, hydroxyl, (1-6C) alkyl, (1-6C ) alkoxy, amino, single (1-6C) alkylamino or two [(1-6C) alkyl] amino, carbamoyl, single (1-6C) alkylcarbamoyl or two-[(1 -6C) alkyl] carbamoyl, saturated or partially saturated 3-7 membered heterocyclic rings or 5 or 6 membered heteroaryl rings, wherein the heterocyclic rings and heteroaryl rings are optionally independently replaced by one or more The following groups are substituted: (1-4C) alkyl, (1-4C) alkoxy, hydroxyl, amino, mono(1-6C) alkylamino or di[(1-6C) alkyl] amino or saturated or Partially saturated 3-7 membered heterocycle;

B represents (3-7C) cycloalkyl ring, saturated or partially saturated 3-7 membered heterocyclic ring, aryl, selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, Pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-tri A 5- or 6-membered heteroaryl ring of azinyl, or 8, 9 or 8, 9 or 10-membered bicyclic group;

R ⁶ is selected from halogen, cyano, oxo, (3-7C) cycloalkyl ring, saturated or partially saturated 3-7 membered heterocycle or -N(R ^a )C(O)(1-6C)alkane A group, wherein R ^a is hydrogen or (1-6C) alkyl; or

R ⁶ is selected from (1-6C) alkyl, S (O) _p (1-6C) alkyl (wherein p is 0, 1 or 2) or (1-6C) alkoxyl, wherein (1-6C) Alkyl and (1-6C)alkoxy are optionally substituted by one or more groups independently selected from the group consisting of cyano, fluoro, hydroxyl, (1-6C)alkoxy, amino, mono(1- 6C) alkylamino, di(1-6C)alkylamino, (3-7C)cycloalkyl ring or saturated or partially saturated 3-7 membered heterocycle;

Wherein the (3-7C) cycloalkyl ring and the saturated or partially saturated 3-7 membered heterocycle are optionally independently replaced by one or more selected from (1-6C) alkyl or hydroxy (1-6C) alkane radical substitution of radicals; and

When B is a (3-7C) cycloalkyl ring, a saturated or partially saturated 3-7 membered heterocyclic ring, or a saturated or partially saturated 8, 9 or 10-membered bicyclic group, the ring and bicyclic group Optionally with 1 or 2 oxo or thio substituents;

and their salts or solvates.

According to another aspect of the present invention, compounds of formula IB are provided:

Formula IB

in:

R ¹ , R ² , R ^3b , R ^4b , A, R ⁵ , L, B, n and m are as defined above for formula (I),

R ⁶ is selected from halogen, cyano, oxo, (3-7C) cycloalkyl ring, saturated or partially saturated 3-7 membered heterocycle, -S(O) _p (1-6C) alkyl (wherein p is 0, 1 or 2) and -N(R ^c )C(O)(1-6C)alkyl, wherein R ^c is hydrogen or (1-6C)alkyl; or

R ⁶ is selected from (1-6C) alkyl or (1-6C) alkoxy, wherein (1-6C) alkyl, -S (O) p (1-6C) alkyl and (1-6C) alkane Oxygen is optionally substituted by one or more groups independently selected from the group consisting of cyano, fluorine, hydroxyl, (1-6C)alkoxy, amino, mono(1-6C)alkylamino, di[( 1-6C) alkyl] amino, (3-7C) cycloalkyl ring or saturated or partially saturated 3-7 membered heterocycle;

Wherein the (3-7C) cycloalkyl ring and the saturated or partially saturated 3-7 membered heterocycle are optionally independently replaced by one or more selected from (1-6C) alkyl or hydroxy (1-6C) alkane radical substitution of radicals; and

When B is a (3-7C) cycloalkyl ring, a saturated or partially saturated 3-7 membered heterocyclic ring, or a saturated or partially saturated 8, 9 or 10-membered bicyclic group, the ring and bicyclic group Optionally with 1 or 2 oxo or thio substituents;

and their salts or solvates.

Specific examples of compounds of formula IB are compounds wherein:

R ¹ , R ² , R ^4b , A, R ⁵ , L, n and m are as defined above for formula (I),

R ^3b is selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxy, wherein (1-6C) alkyl and (1-6C) alkoxy are optionally selected by one or more independently Substitution from the following groups: fluorine, hydroxyl, (1-6C) alkyl, (1-6C) alkoxy, amino, mono (1-6C) alkyl amino or di [ (1-6C) alkyl] Amino, carbamoyl, mono(1-6C)alkylcarbamoyl or di[(1-6C)alkyl]carbamoyl, saturated or partially saturated 3-7 membered heterocycle or 5 or 6 membered heteroaryl yl ring, wherein the heterocyclic and heteroaryl rings are optionally substituted independently by one or more of the following groups: (1-4C)alkyl, (1-4C)alkoxy, hydroxyl, amino, mono( 1-6C) alkylamino or di(1-6C) alkylamino or saturated or partially saturated 3-7 membered heterocycle;

B represents (3-7C) cycloalkyl ring, saturated or partially saturated 3-7 membered heterocyclic ring, aryl, selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, Pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-tri A 5- or 6-membered heteroaryl ring of azinyl, or 8, 9 or 8, 9 or 10-membered bicyclic group;

R ⁶ is selected from halogen, cyano, oxo, (3-7C) cycloalkyl ring, saturated or partially saturated 3-7 membered heterocycle, -S(O) _p (1-6C) alkyl (wherein p is 0, 1 or 2) and -N(R ^c )C(O)(1-6C)alkyl, wherein R ^c is hydrogen or (1-6C)alkyl; or

R ⁶ is selected from (1-6C) alkyl or (1-6C) alkoxy, wherein (1-6C) alkyl, -S (O) _p (1-6C) alkyl and (1-6C) alkane Oxygen is optionally substituted by one or more groups independently selected from the group consisting of cyano, fluorine, hydroxyl, (1-6C)alkoxy, amino, mono(1-6C)alkylamino, di[( 1-6C) alkyl] amino, (3-7C) cycloalkyl ring or saturated or partially saturated 3-7 membered heterocycle;

Wherein the (3-7C) cycloalkyl ring and the saturated or partially saturated 3-7 membered heterocycle are optionally independently replaced by one or more selected from (1-6C) alkyl or hydroxy (1-6C) alkane radical substitution of radicals; and

When B is a (3-7C) cycloalkyl ring or a saturated or partially saturated 3-7 membered heterocyclic ring or a saturated or partially saturated 8, 9 or 10-membered bicyclic group, the ring and bicyclic group Optionally with 1 or 2 oxo or thio substituents;

and their salts or solvates.

Additionally, examples of compounds of formula IB are compounds of formula IB':

Formula IB'

in:

R ¹ , R ² , R ^4b , A, R ⁵ , L, n and m are as defined above for formula (I),

B represents (3-7C) cycloalkyl ring, saturated or partially saturated 3-7 membered heterocyclic ring, aryl, selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, Pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-tri A 5- or 6-membered heteroaryl ring of azinyl, or 8, 9 or 8, 9 or 10-membered bicyclic group;

R ⁶ is selected from halogen, cyano, oxo, (3-7C) cycloalkyl ring, saturated or partially saturated 3-7 membered heterocycle, -S(O) _p (1-6C) alkyl (wherein p is 0, 1 or 2), -N(Rc)C(O)(1-6C)alkyl, wherein Rc is hydrogen or (1-6C)alkyl; or

R ⁶ is selected from (1-6C) alkyl or (1-6C) alkoxy, wherein (1-6C) alkyl, -S (O) p (1-6C) alkyl and (1-6C) alkane Oxygen is optionally substituted by one or more groups independently selected from the group consisting of cyano, fluorine, hydroxyl, (1-6C)alkoxy, amino, mono(1-6C)alkylamino, di[( 1-6C) alkyl] amino, (3-7C) cycloalkyl ring or saturated or partially saturated 3-7 membered heterocycle;

Wherein the (3-7C) cycloalkyl ring and the saturated or partially saturated 3-7 membered heterocycle are optionally independently replaced by one or more selected from (1-6C) alkyl or hydroxy (1-6C) alkane radical substitution of radicals; and

When B is a (3-7C) cycloalkyl ring or a saturated or partially saturated 3-7 membered heterocyclic ring or a saturated or partially saturated 8, 9 or 10-membered bicyclic group, the ring and bicyclic group optionally with 1 or 2 oxo or thio substituents; and

R ¹⁰ and R ¹¹ are independently selected from hydrogen or (1-6C) alkyl;

and their salts or solvates, especially their pharmaceutically acceptable salts.

For the avoidance of doubt, when L is shown to exist, it represents a formula with the left-hand side attached to ring A and the right-hand side attached to ring B. Thus, for example, when L is the group -N(R ⁸ )C(O)N(R ⁹ )-(CR ^a R ^b ) _x -Z-(CR ^a R ^b ) _y -, the moiety

is the following subgroup

where the variables are as defined above.

In this specification, the generic term "alkyl" includes both straight and branched chain alkyl groups, such as propyl, isopropyl and tert-butyl. However, references to individual alkyl groups such as "propyl" specifically refer to the straight chain form only, and references to branched chain alkyl groups such as "isopropyl" specifically refer to the branched chain form only. Similar provisions can be used for other general terms, for example (1-6C) alkoxy includes methoxy, ethoxy and isopropoxy, (1-6C) alkylamino includes methylamino, isopropylamino and ethylamino, and di-[(1-6C)alkyl]amino include dimethylamino, diethylamino and N-methyl-N-isopropylamino. The generic term aryl refers to phenyl or naphthyl, especially phenyl.

It should be understood that it is believed that certain compounds of formula I as defined above may exist in optically active or racemic forms due to one or more asymmetric carbon atoms, and that the present invention will have any such optically active or racemic forms of the above activities included in its definition. Synthesis of optically active forms can be carried out by standard techniques of organic chemistry well known in the art, for example from optically active starting materials or by resolution of racemic forms. Similarly, the above activities can be assessed using standard assay techniques mentioned hereinafter.

Suitable values for the above-mentioned general groups include those listed below.

Suitable 5- or 6-membered heteroaryl rings include, for example, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, Thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, 1,4,5-triazinyl or pyrazinyl. Specific 5 or 6 membered heteroaryl rings include imidazolyl, pyridyl, thiazolyl, thiadiazolyl, pyrimidinyl, isoxazolyl, isothiazolyl and pyrazolyl.

Suitable saturated or partially saturated 3-7 membered heterocycles include, for example, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2,3-dihydro-1,3-thiazolyl , 1,3-thiazolidinyl, 1,3-oxazolidinyl, oxepanyl, pyrrolinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, (perhydro-1,4-thiazinyl) , (8-oxa-3-azabicyclo[3.2.1]octyl), (7-oxa-3-azabicyclo[3.1.1]heptyl), perhydroazepinyl, perhydro Oxazepinyl, tetrahydro-1,4-thiazinyl, 1-oxotetrahydrothienyl, 1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiper Pyridyl, piperazinyl, homopiperazinyl, dihydropyridyl, tetrahydropyridyl, dihydropyrimidinyl or tetrahydropyrimidinyl, preferably tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, 1,1-dioxotetrahydro-4H-1,4-thiazinyl, piperidinyl or piperazinyl, more preferably tetrahydrofuran-3-yl, tetrahydropyran-4-yl, pyrrolidin-3- morpholinyl, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino, piperidin-4-yl or piperazin-1-yl. Suitable values for the group with 1 or 2 oxo or thio substituents are, for example, 2-oxopyrrolidinyl, 2-thiopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. The saturated or partially saturated 3-7 membered heterocycle is optionally substituted by one or more (C1-6) alkyl groups and/or by one or more hydroxyl groups. For the avoidance of doubt, it is understood that this definition includes tautomers of hydroxy-substituted ring systems in which hydroxy tautomerism constitutes an oxo group.

Suitable 8-, 9- or 10-membered bicyclic groups include thieno[2,3-b]furyl, imidazo[2,1-b]thiazolyl, dihydrocyclopentathiazolyl, tetrahydrocyclopenta Alkano[c]pyrazolyl, furo[3,2-b]furyl, pyrrolopyrrole, thienopyrazolyl, thieno[2,3-b]thienyl (thiophenyl), indolizine , indolyl, isoazaidenyl, 3H-indolyl, dihydroindolyl, benzo[b]furyl, benzo[b]thiophenephenyl, 1H-indazolyl, benzimidazolyl , benzothiazolyl, purinyl, 4H-quinolinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, Pteridinyl, chromanyl, isochromanyl, indenyl, naphthyl, 2,3-dihydro-1,4-benzodioxenyl, 1,3-benzene Dioxol-5-yl, decahydronaphthalene and norbornane. Specific 8-, 9-, or 10-membered bicyclic groups include thieno[2,3-b]furyl, indolizinyl, indolyl, isozaindenyl, 3H-indolyl, indoline, Base, benzo[b]furyl, benzo[b]thienyl, 1H-indazolyl, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinazinyl, quinolinyl, isoquinoline Base, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, chromanyl, isochromanyl, indene yl, naphthyl, 2,3-dihydro-1,4-benzodioxenyl and 1,3-benzodioxol-5-yl.

The bicyclic group is optionally substituted by one or more groups R ⁶ as defined above.

The radical A may in particular be attached to the ethynyl group via an aryl or a carbon atom in a 5- or 6-membered heteroaryl ring. The group B can in particular be bonded to the group L via a carbon atom.

Suitable values for any of the substituents herein, for example suitable values for the 'R' groups (R ¹ -R ⁶ ) or various groups within the A, B or L groups include

For halogens: Fluorine, chlorine, bromine and iodine;

For (1-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl;

For (1-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy;

For (1-6C) alkylsulfonyl: methylsulfonyl and ethylsulfonyl;

For (1-6C) alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino;

For di-[(1-6C)alkyl]amino: dimethylamino, diethylamino, N-ethyl-N-methylamino and diisopropylamino;

For (1-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl;

For (1-6C)alkanoyl: formyl, acetyl and propionyl;

For (1-6C)alkoxycarbonyl: methoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl;

For hydroxy(1-6C)alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl;

For (1-6C)alkoxy(1-6C)alkyl:

                                 Methoxymethyl, Ethoxymethyl, 1-Methoxyethyl, 2-Methoxy

Ethyl, 2-ethoxyethyl and 3-methoxypropyl;

For (3-7C)cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;

For (1-6C)alkoxy (1-6C)alkoxy:

                        Methoxymethoxy, Methoxyethoxy, Methoxypropoxy, Methoxy

                                                                           , 

Oxygen, Ethoxybutoxy, Propoxypropoxy, and Propoxybutoxy

base;

For (1-6C)alkoxy(1-6C)alkoxy(1-6C)alkoxy:

                                                                                   

                   Propoxymethoxy, Methoxybutoxyethoxy, Methoxyhexyloxy

                                                                        

                                                

Oxybutoxymethoxy;

For mono(1-6C)alkylcarbamoyl:

N-Methylcarbamoyl, N-Ethylcarbamoyl and N-Propylamine

formyl; and

For di[(1-6C)alkyl]carbamoyl:

                                                           

and N,N-diethylcarbamoyl.

When referring to (1-4C)alkyl in this specification, it is understood that said group refers to an alkyl group containing up to 4 carbon atoms. Those skilled in the art will recognize that representative examples of such groups are those listed above for (1-4C)alkyl groups containing up to 4 carbon atoms, such as methyl, ethyl, propyl, base, isopropyl, butyl and tert-butyl. Similarly, references to (1-3C)alkyl refer to alkyl groups containing up to 3 carbon atoms, such as methyl, ethyl, propyl and isopropyl. Similar provisions apply to other groups listed above, such as (1-4C)alkoxy, (2-4C)alkenyl, (2-4C)alkynyl and (1-4C)alkanoyl.

It will be appreciated that certain compounds of formula (I) may exist in solvated as well as unsolvated forms (such as, for example, in hydrated forms). It is to be understood that the present invention includes all solvated forms which exhibit an inhibitory effect on Tie2 receptor tyrosine kinase.

It should also be understood that certain compounds of formula I may exhibit polymorphism and that the invention includes all forms which exhibit inhibition of the Tie2 receptor tyrosine kinase.

It should also be understood that the present invention relates to all tautomeric forms of the compounds of formula I which exhibit an inhibitory effect on the Tie2 receptor tyrosine kinase.

Pharmaceutically acceptable salts of the compounds of the invention are preferred, although other non-pharmaceutically acceptable salts of the compounds of the invention are also useful, eg, in the preparation of pharmaceutically acceptable salts of the compounds of the invention.

Suitable pharmaceutically acceptable salts of compounds of formula I are, for example, acid addition salts of compounds of formula I, for example with inorganic or organic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, citric acid or Acid addition salts formed from maleic acid); or, for example, salts of compounds of formula I which are sufficiently acidic, such as alkali metal or alkaline earth metal salts (such as calcium or magnesium salts), or ammonium salts or with organic bases (such as methylamine, Dimethylamine, trimethylamine, piperidine, morpholine or tris(2-hydroxyethyl)amine).

As another aspect of the present invention, the present invention also provides prodrugs of the compounds of the present invention as defined hereinbefore or hereinafter. The compounds of the invention may be administered in the form of prodrugs which cleave in humans or animals to give compounds of formula (I). Examples of prodrugs include in vivo hydrolyzable esters of compounds of formula (I).

Various prodrug forms are known in the art. For example, such prodrug derivatives see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard, Chapter5 "Design and Application of Prodrugs", edited by H.Bundgaard p.113-191(1991);

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

d) H. Bundgaard, et al. Journal of Pharmaceutical Sciences, 77, 285 (1988); and

e) N. Kakeya, et al. Chem Pharm Bull, 32, 692 (1984).

In vivo hydrolyzable esters of compounds of formula (I) containing hydroxy groups are, for example, pharmaceutically acceptable esters which hydrolyze in the human or animal body to yield the parent acid or alcohol. Suitable pharmaceutically acceptable esters of carboxyl groups include C _1-6 alkoxymethyl esters (e.g. methoxymethyl esters), C _1-6 alkanoyloxymethyl esters (e.g. pivaloyloxymethyl esters), esters), 2-benzo[c]furanone esters,

C _3-8 cycloalkoxycarbonyloxy C _1-6 alkyl ester (eg 1-cyclohexylcarbonyloxyethyl ester); 1,3-dioxol-2-one methyl ester, For example, 5-methyl-1,3-dioxol-2-onyl methyl ester; and C _1-6 alkoxycarbonyloxyethyl ester.

In vivo hydrolyzable esters of compounds of formula (I) containing hydroxy groups include inorganic esters (e.g., phosphate esters (including phosphoramidate cyclic esters)) and α-acyloxyalkyl ethers and cleavage to give the parent hydroxy group due to in vivo hydrolysis of the ester related compounds. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy ethers. A selection of in vivo hydrolyzable ester-forming groups for hydroxyl groups include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, alkoxycarbonyl (to give alkyl carbonate), dialkyl Carbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamate), dialkylaminoacetyl and carboxyacetyl.

Specific novel compounds of the present invention include, for example, compounds of formula I or salts thereof, especially pharmaceutically acceptable salts thereof, wherein R ¹ , R ² , R ^3a , R ^4a , R ⁵ , R ⁶ , A, B, L, m and n each have any of the meanings defined above or any of the meanings defined in paragraphs (a) to (mmmmm) below:-

(a) relative to the attachment point of the ethynyl group, L is attached to the meta-position of the ring A;

(b) L is attached to the para-position of ring A with respect to the point of attachment of the ethynyl group;

(c) L is -N(R ⁸ )C(O)N(R ⁹ )-(CR ^a R ^b ) _x -Z-(CR ^a R ^b ) _y -, wherein x and y are as defined above, and Z is -O- or -N(H)-, and R ^a , R ^b , R ⁸ and R ⁹ are independently selected from hydrogen and (1-6C)alkyl (especially R ^a , R ^b , R ⁸ and R ⁹ are all hydrogen);

(d) L is -N(R ⁸ )C(O)N(R ⁹ )-(CR ^a R ^b ) _x -O-(CR ^a R ^b ) _y -, wherein x and y are as defined above, and R ^a , R ^b , R ⁸ and R ⁹ are independently selected from hydrogen and (1-6C)alkyl (in particular R ^a , R ^b , R ⁸ and R ⁹ are all hydrogen);

(e) L is -N(R ⁸ )C(O)N(R ⁹ )-(CR ^a R ^b ) _x -N(R ⁸ )-(CR ^a R ^b ) _y -, where R ^a , R ^b , R ⁸ and R ⁹ are independently selected from hydrogen and (1-6C) alkyl (especially R ^a , R ^b , R ⁸ and R ⁹ are all hydrogen);

(f) L is -N(R ⁸ )C(O)N(R ⁹ )-(CR ^a R ^b ) _x -O-, wherein x is as defined above, and R ^a , R ^b , R ⁸ and R ⁹ independently selected from hydrogen and (1-6C)alkyl (in particular R ^a , R ^b , R ⁸ and R ⁹ are all hydrogen);

(g) L is -N(R ⁸ )C(O)N(R ⁹ )-(CR ^a R ^b ) _x -N(H)-, wherein x is as defined above, and R ^a , R ^b , R ⁸ and R ⁹ are independently selected from hydrogen and (1-6C)alkyl (in particular R ^a , R ^b , R ⁸ and R ⁹ are all hydrogen);

(g') L is -N(R ⁸ )C(O)N(R ⁹ )-(CR ^a R ^b ) _x -, wherein x is as defined above (in particular x is 1 or 2), and wherein R ^a , R ^b , R ⁸ and R ⁹ are independently selected from hydrogen and (1-6C) alkyl (especially R ^a , R ^b , R ⁸ and R ⁹ are all hydrogen);

(g") L is -N(R ⁸ )C(O)N(R ⁹ )-CH ₂ -, wherein R ⁸ and R ⁹ are independently selected from hydrogen and (1-6C)alkyl (especially R ⁸ and ^R are all hydrogen);

(h) R ^a and R ^b represent hydrogen;

(h') R ^a and R ^b independently represent hydrogen or (1-6C) alkyl,

wherein the (1-6C) alkyl group in R ^a and R ^b is optionally substituted by a hydroxyl group or a saturated or partially saturated 3-7 membered heterocycle;

(h") R ^a and R ^b independently represent hydrogen or (1-6C) alkyl,

wherein the (1-6C) alkyl group in R ^a and R ^b is optionally substituted by a hydroxyl group or a saturated or partially saturated 5-6 membered heterocycle;

(h"') R ^a and R ^b independently represent hydrogen, methyl or ethyl,

Wherein the (1-6C) alkyl in R ^a and R ^b is optionally substituted by hydroxyl or pyrrolin-1-yl;

(i) A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl , triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl;

(i') A is selected from phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl;

(j) A is phenyl or pyridyl

(k) A is phenyl or pyridyl, wherein the nitrogen in the pyridyl ring is at the 3-position with respect to the alkyne bond.

(1) A is phenyl or thiazolyl;

(1') A is phenyl, pyridyl, thiazolyl or thiadiazolyl;

(1") A is phenyl;

(m) A is pyridyl;

(m') A is thiazolyl;

(m") A is thiadiazolyl;

(n) A is phenyl or pyridyl, and n is 0;

(n') A is phenyl or thiazolyl, and n is 0;

(o) A is phenyl, and n is 0 or n is 1, and R is ( ^1-4C ) alkyl;

(p) A is pyridyl, and n is 0 or n is 1, and ^R is (1-4C) alkyl;

(p') A is thiazolyl, and n is 0 or n is 1, and ^R is (1-4C)alkyl;

(q) A is selected from phenyl, oxazolyl, imidazolyl, pyrrolyl, pyrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl and pyrimidine base.

(r) when B is a (3-7C)cycloalkyl ring, then B is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

(s) When B is a saturated or partially saturated 3-7 membered heterocyclic ring, then B is selected from oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, morpholinyl, 1,3- Dioxolanyl, tetrahydrofuranyl, piperidinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, homopiperazinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyranyl , tetrahydropyridyl, 1,2,4-oxadiazolyl and dihydrothiopyranyl;

(t) When B is a 5 or 6 membered heteroaryl ring, then B is selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazole Base, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl;

(u) when B is a saturated, partially saturated or aromatic 8, 9 or 10 membered bicyclic group optionally containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, Then B is selected from 2,3-dihydro-1H-indenyl, benzodioxenyl, 1,2,3,4-tetrahydronaphthyl, 1,2,3,4-tetrahydropentalene, Benzofuryl, 2,3-dihydrobenzofuryl, benzimidazolyl, benzothienyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, Pyridoimidazolyl, pyrimidoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, indolyl and naphthyridinyl.

Or B is a group of the following formula:

Wherein W is a 5-7 membered ring (including bridging atoms), the W ring contains carbon atoms or optionally further contains heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein the bicyclic ring contains a total of no more than 4 heteroatoms. Examples of such rings include: pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-c]pyrimidinyl, pyrazolo[1,5-a][1,3,5] Triazinyl, 4,5-dihydropyrazolo[1,5-a]pyridyl, 4H-pyrazolo[5,1-c][1,4]thiazinyl, 4H-pyrazolo[ 5,1-c][1,4]oxazinyl, 1,2-benzisoxazolyl, isoxazolo[5,4-b]pyridyl, isoxazolo[5,4-d ]pyrimidinyl, 4H-thiopyrano[3,4-d]isoxazolyl, 4H-pyrano[3,4-d]isoxazolyl, 7aH-indolyl, 7aH-pyrrolo [2,3-b]pyridyl, 7aH-pyrrolo[2,3-d]pyrimidinyl, 4,7a-dihydrothiopyrano[4,3-b]pyrrolyl and 4,7a-di Hydropyrano[4,3-b]pyrrolyl.

(v) B is aryl, especially phenyl;

(w) B is a saturated or partially saturated 3-7 membered (especially 4-6 membered) heterocycle containing one or two heteroatoms (especially one heteroatom) selected from oxygen and nitrogen;

(x) B is a 5- or 6-membered heteroaryl ring;

(y) B is an 8, 9 or 10 membered bicyclic ring optionally containing 1, 2 or 3 (especially 1 or 2) heteroatoms independently selected from N and O and is saturated, partially saturated or aromatic group;

(z) B is selected from saturated or partially saturated 4-6 membered heterocycles, aryl, selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl , isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl 5-6 A membered heteroaryl ring, or an 8, 9 or 10 membered bicyclic group optionally containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and being saturated, partially saturated or aromatic ;

(aa) B is selected from saturated or partially saturated 4-6 membered heterocycles, aryl, or selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazole 5 or 6-membered heteroaryl ring;

(bb) B is selected from saturated or partially saturated 4-6 membered heterocycles, or selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, iso Thiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl 5 or 6-membered hetero Aryl ring;

(cc) B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, morpholinyl, Pyrrolidinyl, piperidinyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, Triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 2,3-dihydro-1,4-benzodioxinyl and 1,3-benzodioxol-5-yl;

(dd) B is selected from phenyl, tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, furyl, pyrrolidinyl, pyridyl and pyrimidinyl;

(dd')B is selected from phenyl, cyclobutyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxanyl, morpholinyl, furyl, pyrrolidinyl, piperidinyl, pyrazolyl , isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl;

(dd")B is selected from cyclohexyl, phenyl, tetrahydropyranyl, tetrahydrofuryl, morpholinyl, thiomorpholinyl, furyl, pyrrolidinyl, pyridyl and pyrimidinyl;

(dd"')B is selected from phenyl, imidazolyl, thienyl and isoxazolyl;

(ee) B is selected from phenyl, cyclobutyl, 2,3-dihydroindenyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl, 1,4-dioxanyl, morpholinyl, thio Morpholinyl, pyrrolidinyl, piperidinyl, furyl, imidazolyl, thienyl, pyrazolyl, isothiazolyl, thiadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridyl azinyl, benzodioxenyl, benzodioxolyl or tetrahydropyranyl.

(ee') B is selected from phenyl, cyclohexyl, cyclobutyl, 2,3-dihydroindenyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, 1,4-dioxanyl, morpholine base, thiomorpholinyl, pyrrolidinyl, piperidinyl, furyl, imidazolyl, thienyl, pyrazolyl, isothiazolyl, thiadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridyl azinyl, pyridazinyl, benzodioxinyl, benzodioxolyl or tetrahydropyranyl.

(ff) B is selected from piperidinyl, phenyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrazolyl and pyridyl;

(gg) B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl;

(hh) B is selected from isoxazolyl, thiadiazolyl and pyrazolyl;

(ii) B is selected from isoxazolyl and pyrazolyl;

(jj) B is phenyl;

(kk) B is isoxazolyl;

(11) B is pyrazolyl;

(mm) R ¹ and R ² are independently selected from hydrogen, phenyl (CH ₂ ) _u - (wherein u is 0, 1, 2, 3, 4, 5 or 6), (1-6C)alkanoyl, ( 1-6C) alkyl, (1-6C) alkoxycarbonyl, (3-6C) cycloalkyl (CH ₂ ) _v - (where v is 0, 1, 2, 3, 4, 5 or 6) or 5 or 6 membered heteroaryl ring;

Wherein (1-6C) alkyl group, (1-6C) alkanoyl group and (3-6C) cycloalkyl group are optionally replaced by one or more (such as 1 or 2), which may be the same or different, selected from The following groups are substituted: fluorine, hydroxyl, (1-6C) alkyl, (1-6C) alkoxy, (1-6C) alkoxy (1-6C) alkoxy, (1-6C) alkoxy Oxygen (1-6C) alkoxyl (1-6C) alkoxy, amino, single (1-6C) alkylamino, di-[(1-6C) alkyl] amino, carbamoyl, single ( 1-6C) alkylcarbamoyl, di[(1-6C)alkyl]carbamoyl or -N(R ^d )C(O)(1-6C)alkyl (wherein R ^d is hydrogen or (1 -6C) alkyl) or a saturated or partially saturated 3-7-membered heterocyclic ring, or a 5- or 6-membered heteroaryl ring, wherein the (1-6C) alkoxy, (1-6C) alkoxy ( 1-6C) alkoxy and (1-6C) alkoxy (1-6C) alkoxy (1-6C) alkoxy, and single (1-6C) alkylamino, di-[(1- 6C)alkyl]amino, mono(1-6C)alkylcarbamoyl, di[(1-6C)alkyl]carbamoyl and/or -N(R ^d )C(O)(1-6C) The (1-6C) alkyl group of the alkyl group is optionally substituted by one or more (for example, 1 or 2) hydroxyl groups;

Wherein the phenyl group is optionally substituted by one or more (for example 1 or 2), which may be the same or different, selected from the following groups: halogen, (1-6C) alkyl, (1-6C) alkoxy , amino, single (1-6C) alkylamino or di-[(1-6C) alkyl] amino, wherein said (1-6C) alkyl or (1-6C) alkoxy is optionally replaced by one or Multiple (for example, 1 or 2), which may be the same or different, are substituted by groups selected from hydroxyl, amino, mono(1-6C)alkylamino or di[(1-6C)alkyl]amino;

and wherein any heterocyclic and heteroaryl rings within R ^and /or ^R are optionally substituted independently by one or more (eg 1 or 2), which may be the same or different, groups selected from the group consisting of: (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkoxy (1-4C) alkyl, hydroxyl, amino, single (1-6C) alkylamino or two-[ (1-6C) alkyl] amino, or a saturated or partially saturated 3-7 membered heterocyclic ring or -C(O)(CH2)zY, wherein z is 0, 1, 2 or 3, and Y is selected from hydrogen, Hydroxy, (1-4C)alkoxy, amino, mono(1-6C)alkylamino, di[(1-6C)alkyl]amino or saturated or partially saturated 3-7 membered heterocyclic rings;

and with the proviso that when R ^and / ^or R are a (1C)alkanoyl group, then the (1C)alkanoyl group is not substituted by fluorine or hydroxyl;

(nn) R ¹ and R ² are independently selected from hydrogen, (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxycarbonyl or (3-6C) cycloalkyl (CH2 )v- (where v is 0, 1, 2, 3, 4, 5 or 6) or a 5 or 6 membered heteroaryl ring;

Wherein (1-6C) alkyl group, (1-6C) alkanoyl group and (3-6C) cycloalkyl group are optionally replaced by one or more (such as 1 or 2), which may be the same or different, as above ( mm) substitution of groups defined in;

and wherein any heterocyclic and heteroaryl rings within R1 and/or R2 are optionally independently replaced by one or more (eg 1 or 2), which may be the same or different, as defined above in (mm) group replacement;

(oo) R ^{and R} are independently selected from hydrogen, (1-6C)alkanoyl, (1-6C)alkyl, or a 5- or 6-membered heteroaryl ring;

wherein (1-6C) alkyl and (1-6C) alkanoyl groups are optionally replaced by one or more (for example 1 or 2), which may be the same or different, as defined in (mm) above replace;

and wherein any heterocyclic and heteroaryl rings within R ^and /or ^R are optionally independently replaced by one or more (eg 1 or 2), which may be the same or different, as defined above in (mm) group substitution;

(pp) R ¹ is hydrogen, and R ² is selected from hydrogen, (1-6C) alkylsulfonyl, phenyl (CH ₂ ) _u - (wherein u is 0, 1, 2, 3, 4, 5 or 6 ), (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxycarbonyl, (3-6C) cycloalkyl (CH ₂ ) _v - (where v is 0, 1, 2, 3, 4, 5 or 6) or a 5 or 6 membered heteroaryl ring;

Wherein (1-6C) alkyl group, (1-6C) alkanoyl group and (1-6C) cycloalkyl group are optionally replaced by one or more (such as 1 or 2), which can be the same or different, as above Substitution of groups as defined in (mm);

Wherein the phenyl group is optionally substituted by one or more (for example 1 or 2), which may be the same or different, as defined in (mm) above;

and wherein any heterocyclic and heteroaryl rings within R2 are optionally substituted independently by one or more (eg 1 or 2), which may be the same or different, as defined above in (mm);

(qq) R ¹ is hydrogen and R ² is selected from hydrogen, (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxycarbonyl or (3-6C) cycloalkyl (CH ₂ ) _v - (where v is 0, 1, 2, 3, 4, 5 or 6) or a 5 or 6 membered heteroaryl ring;

Wherein (1-6C) alkyl group, (1-6C) alkanoyl group and (3-6C) cycloalkyl group are optionally replaced by one or more (such as 1 or 2), which may be the same or different, as above ( mm) substitution of groups defined in;

and wherein any heterocyclic and heteroaryl rings ^within R are optionally substituted independently by one or more (eg 1 or 2), which may be the same or different, groups as defined above in (mm);

(rr) R ^is hydrogen and R ^is selected from hydrogen, (1-6C)alkanoyl, (1-6C)alkyl, or a 5- or 6-membered heteroaryl ring;

wherein (1-6C) alkyl and (1-6C) alkanoyl groups are optionally replaced by one or more (for example 1 or 2), which may be the same or different, as defined in (mm) above replace;

and wherein any heterocyclic and heteroaryl rings ^within R are optionally substituted independently by one or more (eg 1 or 2), which may be the same or different, groups as defined above in (mm);

(ss) R ¹ and R ² are independently selected from hydrogen, (1-6C) alkylsulfonyl, phenyl (CH ₂ ) _u - (wherein u is 0, 1, 2, 3, 4, 5 or 6) , (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxycarbonyl, (3-6C) cycloalkyl (CH2) v- (where v is 0, 1, 2, 3, 4, 5 or 6) or a 5 or 6 membered heteroaryl ring;

Wherein (1-6C) alkyl group, (1-6C) alkanoyl group and (3-6C) cycloalkyl group are optionally replaced by one or more (such as 1 or 2), which may be the same or different, selected from The following groups are substituted: hydroxyl, (1-6C) alkoxy, (1-6C) alkoxy (1-6C) alkoxy, amino, mono (1-6C) alkylamino, di-[( 1-6C)alkyl]amino, carbamoyl, mono(1-6C)alkylcarbamoyl, di[(1-6C)alkyl]carbamoyl or -N(R ^d )C(O)( 1-6C) alkyl (wherein Rd is hydrogen or (1-6C) alkyl), or a saturated or partially saturated 3-7 membered heterocyclic ring, or a 5 or 6-membered heteroaryl ring, wherein the (1- 6C) alkoxy and (1-6C) alkoxy (1-6C) alkoxy and said single (1-6C) alkylamino, di-[(1-6C) alkyl] amino, single ( The ⁽ 1-6C ) alkyl is optionally substituted by one or more (eg 1 or 2) hydroxyl groups;

Wherein the phenyl group is optionally substituted by one or more (for example 1 or 2), which may be the same or different, selected from the following groups: halogen, (1-6C) alkyl, (1-6C) alkoxy , amino, single (1-6C) alkylamino or di-[(1-6C) alkyl] amino, wherein said (1-6C) alkyl or (1-6C) alkoxy is optionally replaced by one or Multiple (for example, 1 or 2), which may be the same or different, are substituted with groups selected from hydroxyl, amino, mono(1-6C) alkylamino or di-[(1-6C) alkyl]amino;

and wherein any heterocyclic and heteroaryl rings within R1 and/or R2 are optionally substituted independently by one or more (eg, 1 or 2), which may be the same or different, groups selected from the group consisting of: (1 -4C) alkyl, (1-4C) alkoxy, (1-4C) alkoxy (1-4C) alkyl, hydroxyl, amino, single (1-6C) alkylamino or two-[(1 -6C) alkyl] amino, or a saturated or partially saturated 3-7 membered heterocyclic ring, or -C(O)(CH ₂ ) _z Y, wherein z is 0, 1, 2 or 3, and Y is selected from hydrogen , hydroxy, (1-4C) alkoxy, amino, mono(1-6C) alkylamino, di[(1-6C) alkyl] amino or a saturated or partially saturated 3-7 membered heterocycle;

and with the proviso that when R ^and / ^or R are a (1C)alkanoyl group, then the (1C)alkanoyl group is not substituted by fluorine or hydroxyl;

(tt) R ¹ and R ² are independently selected from hydrogen, (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxycarbonyl or (3-6C) cycloalkyl (CH ₂ ) _v - (where v is 0, 1, 2, 3, 4, 5 or 6) or a 5 or 6 membered heteroaryl ring;

Wherein (1-6C) alkyl group, (1-6C) alkanoyl group and (3-6C) cycloalkyl group are optionally replaced by one or more (such as 1 or 2), which may be the same or different, as above ( ss) as defined in the group substitution;

and wherein any heterocyclic and heteroaryl rings within R ^and /or ^R are optionally independently replaced by one or more (eg 1 or 2), which may be the same or different, as defined above in (ss) group substitution;

( ^uu ) R and ^R are independently selected from hydrogen, (1-6C)alkanoyl, (1-6C)alkyl, or a 5- or 6-membered heteroaryl ring;

wherein (1-6C) alkyl and (1-6C) alkanoyl groups are optionally replaced by one or more (eg 1 or 2), which may be the same or different, as defined in (ss) above replace;

and wherein any heterocyclic and heteroaryl rings within R ^and /or ^R are optionally independently replaced by one or more (eg 1 or 2), which may be the same or different, as defined above in (ss) group substitution;

(vv) R ¹ is hydrogen, and R ² is selected from hydrogen, (1-6C) alkylsulfonyl, phenyl (CH ₂ ) _u - (wherein u is 0, 1, 2, 3, 4, 5 or 6 ), (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxycarbonyl, (3-6C) cycloalkyl (CH2) v- (where v is 0, 1, 2 , 3, 4, 5 or 6) or a 5 or 6 membered heteroaryl ring;

Wherein (1-6C) alkyl group, (1-6C) alkanoyl group and (3-6C) cycloalkyl group are optionally replaced by one or more (such as 1 or 2), which may be the same or different, as above ( ss) as defined in the group substitution;

wherein the phenyl group is optionally substituted by one or more (eg 1 or 2), which may be the same or different, as defined in (ss) above;

and wherein any heterocyclic and heteroaryl rings within R2 are optionally substituted independently by one or more (eg 1 or 2), which may be the same or different, groups as defined above in (ss);

(ww) ^R1 is hydrogen and ^R2 is selected from hydrogen, (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxycarbonyl, (3-6C) cycloalkyl (CH ₂ ) _v - (wherein v is 0, 1, 2, 3, 4, 5 or 6) or 5 or 6 membered heteroaryl ring;

Wherein (1-6C) alkyl group, (1-6C) alkanoyl group and (3-6C) cycloalkyl group are optionally replaced by one or more (such as 1 or 2), which may be the same or different, as above ( ss) as defined in the group substitution;

and wherein any heterocyclic and heteroaryl rings ^within R are optionally substituted independently by one or more (eg 1 or 2), which may be the same or different, groups as defined above in (ss);

(xx) R is ^hydrogen and R ^is selected from hydrogen, (1-6C)alkanoyl, (1-6C)alkyl, or a 5- or 6-membered heteroaryl ring;

wherein (1-6C) alkyl and (1-6C) alkanoyl groups are optionally replaced by one or more (eg 1 or 2), which may be the same or different, as defined in (ss) above replace;

and wherein any heterocyclic and heteroaryl rings ^within R are optionally substituted independently by one or more (eg 1 or 2), which may be the same or different, groups as defined above in (ss);

(yy) R is ^hydrogen and ^R is selected from hydrogen, (1-6C)alkanoyl and (1-6C)alkyl;

wherein (1-6C) alkyl and (1-6C) alkanoyl groups are optionally replaced by one or more (eg 1 or 2), which may be the same or different, as defined in (ss) above replace;

and wherein any heterocyclic and heteroaryl rings ^within R are optionally substituted independently by one or more (eg 1 or 2), which may be the same or different, groups as defined above in (ss);

(zz) R is ^hydrogen and ^R is selected from hydrogen, (1-6C)alkanoyl and (1-6C)alkyl,

Wherein (1-6C) alkyl and (1-6C) alkanoyl groups are optionally substituted by one or more (for example 1 or 2), which may be the same or different, selected from the following groups: hydroxyl, ( 1-4C)alkoxy, (1-4C)alkoxy(1-4C)alkoxy, amino, mono(1-3C)alkylamino, di(1-3C)alkylamino, carbamoyl Or -N(R ^d )C(O)(1-3C)alkyl (wherein R ^d is hydrogen or (1-3C)alkyl), or a saturated 5 or 6-membered heterocycle, or a 5 or 6-membered heterocycle Aryl rings, where (1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkoxy and mono(1-3C)alkylamino, di-[(1-3C)alkane Base]amino and/or (1-3C)alkyl of N(R ^d )C(O)(1-6C)alkyl is optionally substituted by one or more (eg 1 or 2) hydroxyl groups;

and wherein any heterocyclic and heteroaryl rings ^within R are optionally substituted independently by one or more (eg, 1 or 2), which may be the same or different, selected from the group consisting of: (1-4C) Alkyl, (1-4C)alkoxy, (1-4C)alkoxy(1-4C)alkyl, hydroxyl, amino, mono(1-3C)alkylamino or di-[(1-3C) Alkyl] amino, or a saturated or partially saturated 3-7 membered heterocycle, or -C(O)(CH ₂ ) _z Y, wherein z is 0, 1, 2 or 3, and Y is selected from hydrogen, hydroxyl, (1-4C)alkoxy, amino, mono(1-6C)alkylamino, di[(1-6C)alkyl]amino or saturated or partially saturated 3-7 membered heterocycle;

and with the proviso that when R ^and / ^or R are a (1C)alkanoyl group, then the (1C)alkanoyl group is not substituted by fluorine or hydroxyl;

(aaa) R ^is hydrogen and R ^is selected from hydrogen, (1-3C)alkanoyl and (1-3C)alkyl;

wherein (1-3C) alkyl and (1-3C) alkanoyl groups are optionally replaced by one or more (eg 1 or 2), which may be the same or different, as defined in (zz) above replace;

and wherein any heterocyclic and heteroaryl rings ^within R are optionally substituted independently by one or more (eg 1 or 2), which may be the same or different, groups as defined in (zz) above;

(bbb) ^R is hydrogen, and R ^is selected from hydrogen and (1-6C)alkyl (especially (1-3C)alkyl);

Wherein the (1-6C) alkyl (especially (1-3C) alkyl) group is optionally replaced by one or more (eg 1 or 2), which may be the same or different, as defined in (zz) above group substitution;

and wherein any heterocyclic and heteroaryl rings within R2 are optionally substituted independently by one or more (eg 1 or 2), which may be the same or different, groups as defined in (zz) above;

(ccc) ^R is hydrogen, and ^R is (1-6C)alkyl (especially (1-3C)alkyl),

Wherein the (1-6C) alkyl (especially (1-3C) alkyl) group is optionally replaced by one or more (eg 1 or 2), which may be the same or different, as defined in (zz) above group substitution;

and wherein any heterocyclic and heteroaryl rings ^within R are optionally substituted independently by one or more (eg 1 or 2), which may be the same or different, groups as defined in (zz) above;

(ccc') ^R1 and ^R2 are both hydrogen, or ^R1 is hydrogen and ^R2 is (1-6C)alkyl,

Wherein (1-6C alkyl) is optionally substituted by amino, mono(1-6C) alkylamino or di(1-6C) alkylamino or saturated 3-7 membered heterocycle;

(ccc") ^R1 and ^R2 are both hydrogen, or ^R1 is hydrogen and ^R2 is (1-6C)alkyl,

Wherein (1-6C alkyl) is optionally substituted by di(1-6C) alkylamino or saturated 3-7 membered heterocycle;

(ccc""') R ^is hydrogen and ^R is selected from hydrogen, 3-(dimethylamino)propyl and 3-piperidin-1-ylpropyl;

(ccc""") ^R1 is hydrogen, and ^R2 is selected from hydrogen, 3-(dimethylamino)propyl, 2-piperidin-1-ylethyl and 3-piperidin-1-ylpropyl ;

(ddd) Both ^R1 and ^R2 are hydrogen, or ^R1 is hydrogen or (1-6C)alkyl and ^R2 is (1-6C)alkyl,

Wherein (1-6C alkyl) is optionally replaced by hydroxyl, amino, single (1-6C) alkylamino or two (1-6C) alkylamino, carbamoyl, (1-6C) alkoxy, (1 -6C)alkoxy(1-6C)alkoxy, -N(R ^d )C(O)(1-6C)alkyl (where R ^d is hydrogen or (1-6C)alkyl), aryl (especially phenyl), saturated or partially saturated 3-7 membered heterocycle or 5 or 6-membered heteroaryl ring substitution;

Wherein (1-6C) alkoxyl, mono(1-6C) alkylamino and -N(R ^d )C(O)(1-6C) alkyl are optionally substituted by hydroxyl;

Among them, the aromatic ring, saturated or partially saturated 3-7 membered heterocyclic ring or 5 or 6-membered heteroaryl ring is optionally replaced by (1-4C) alkyl, (1-4C) alkoxy or -C(O)CH2Y Substitution, wherein Y is selected from hydroxyl or di(1-6C)alkylamino.

( ^eee ) R and ^R are independently selected from hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl , 2-aminoethyl, 3-aminopropyl 2-(isopropylamino)ethyl, 3-(isopropylamino)propyl, 2-(dimethylamino)ethyl, 3-(dimethylamino ) propyl, carbamoyl methyl, 2-carbamoyl ethyl, 3-carbamoyl propyl, 2-(2-methoxyethoxy) acetyl, 2-morpholin-4-yl ethyl Base, 3-morpholin-4-ylpropyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 3-(4-methylpiperazin-1-yl)propyl Base, 3-piperidin-1-ylpropyl, 2-piperidin-1-ylethyl, 2-(1H-imidazol-4-yl)ethyl, 2-pyridin-2-ylethyl, 3- (1H-imidazol-1-yl)propyl, 2-pyridin-4-ylethyl, 2,4-dimethoxybenzyl and 5-tert-butylisoxazol-3-yl;

(fff) R ^is hydrogen, and ^R is selected from hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl base, 2-aminoethyl, 3-aminopropyl, 2-(isopropylamino)ethyl, 3-(isopropylamino)propyl, 2-(dimethylamino)ethyl, 3-(dimethyl (amino)propyl, carbamoylmethyl, 2-carbamoylethyl, 3-carbamoylpropyl, 2-(2-methoxyethoxy)acetyl, 2-morpholine-4- Ethyl, 3-morpholin-4-ylpropyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 3-(4-methylpiperazin-1-yl ) propyl, 3-piperidin-1-ylpropyl, 2-piperidin-1-ylethyl, 2-(1H-imidazol-4-yl)ethyl, 2-pyridin-2-ylethyl, 3-(1H-imidazol-1-yl)propyl, 2-pyridin-4-ylethyl, 2,4-dimethoxybenzyl and 5-tert-butylisoxazol-3-yl;

(ggg) R ^is hydrogen, and R ^is selected from hydrogen, methyl, ethyl, propyl, 3-(isopropylamino)propyl, 2-pyrrolidin-1-ylethyl, 5-tert-butylisoxanyl Azol-3-yl, 3-piperidin-1-ylpropyl, 2-morpholino-4-yl-ethyl, 2-pyrrolidin-1-ylethyl, 3-(dimethylamino)propyl Base, 2-hydroxyethyl and 2-piperidin-1-ylethyl;

(ggg')R ^is hydrogen, and R ^is selected from (1-6C)alkyl (especially (1-3C)alkyl),

Wherein (1-6C) alkyl (especially (1-3C) alkyl) group is substituted by saturated 5 or 6 membered heterocycle;

(ggg") R ^is hydrogen, and R is selected from ² -morpholin-4-yl-ethyl or 3-morpholinyl-4-ylpropyl;

(hhh) R ² is hydrogen or methyl, and R ^3a is selected from hydrogen, methyl, 2-hydroxyethyl, 2-methoxyethyl, 3-methoxypropyl, 2-(2-hydroxyethyl Oxy)ethyl, 2-methoxyethoxymethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 2-(isopropylamino)ethyl, 3-(isopropyl Amino)propyl, 2-(dimethylamino)ethyl, 3-(dimethylamino)propyl, 4-(dimethylamino)butyl, 2-(dimethylamino)-1-methyl Ethyl, carbamoylmethyl, 2-carbamoylethyl, 2-(2-methoxyethoxy)acetyl, 2-(2-hydroxyacetamido)ethyl, 3-[N -(2-Hydroxyethyl)amino]propyl, 2-morpholin-4-ylethyl, 3-morpholin-4-ylpropyl, 2-[(1-methyl-2-morpholin-4 -ylethyl), 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 1-glycoloylpyrrolidin-2-yl]methyl, 1-(N,N-di Methylglycyl)pyrrolidin-2-yl, 2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl, 3-(4-methylpiperazin-1-yl)propyl Base, 3-piperidin-1-ylpropyl, 2-(1H-imidazol-4-yl)ethyl, 2-pyridin-2-ylethyl, 3-(1H-imidazol-1-yl)propyl , 5-tert-butylisoxazol-3-yl, 2-pyridin-4-ylethyl and 2,4-dimethoxybenzyl;

(iii) R ^is hydrogen, and R is selected from ² -morpholin-4-ylethyl, 3-morpholin-4-ylpropyl, 3-piperidin-1-ylpropyl, 2-piperidine -1-ylethyl, 2-pyrrolidin-1-ylethyl, 4-methylpiperazin-1-ylpropyl and 3-pyrrolidin-1-ylpropyl;

(jjj) R ^is hydrogen, and R ^is selected from 2-morpholin-4-ylethyl, 3-morpholin-4-ylpropyl, 3-piperidin-1-ylpropyl, 2-piperidine -1-ylethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl and 4-methyl-piperazin-1-yl;

(kkk) R ¹ and R ² are both (1-6C)alkyl (especially (1-3C)alkyl);

(lll) ^R is hydrogen and ^R is methyl;

(mmm) R ¹ and R ² are both hydrogen;

(mmm) R ^3a or R ^3b are selected from hydrogen, (1-3C) alkyl or (1-3C) alkoxy,

Wherein (1-3C) alkyl and (1-3C) alkoxy are optionally substituted by one or more (for example 1 or 2), which may be the same or different, selected from the following groups: fluorine, hydroxyl, (1-6C) Alkyl, (1-6C) Alkoxy, Amino Mono(1-6C) Alkylamino, Di[(1-6C) Alkyl] Amino, Carbamoyl, Mono(1-6C) Alkylcarbamoyl or di-[(1-6C)alkyl]carbamoyl, saturated or partially saturated 3-7 membered heterocycle or 5 or 6 membered heteroaryl ring, wherein the heterocycle and heteroaryl The base ring is optionally independently replaced by one or more (such as 1 or 2), which may be the same or different, selected from (1-4C) alkyl, (1-4C) alkoxy, hydroxyl, amino, single ( 1-6C) alkylamino or di[(1-6C)alkyl]amino or a saturated or partially saturated 3-7 membered heterocyclic ring;

Or R ^3a or R ^3b represents the group -NR ¹ R ² as defined above;

(nnn) R ^3a or R ^3b are selected from hydrogen or (1-6C) alkyl,

Wherein (1-6C) alkyl is optionally substituted by one or more (for example 1 or 2), which may be the same or different, selected from the following groups: fluorine, hydroxyl, (1-6C) alkyl, ( 1-6C) alkoxy, amino, mono(1-6C) alkylamino, di-[(1-6C) alkyl] amino, carbamoyl, mono(1-6C) alkylcarbamoyl or di [(1-6C) alkyl] carbamoyl, saturated or partially saturated 3-7 membered heterocyclic ring or 5 or 6 membered heteroaryl ring, wherein the heterocyclic ring and heteroaryl ring are optionally independently replaced by one Or a plurality (such as 1 or 2), which can be the same or different, selected from (1-4C) alkyl, (1-4C) alkoxy, hydroxyl, amino, single (1-6C) alkylamino or Di-[(1-6C)alkyl]amino or a saturated or partially saturated 3-7 membered heterocyclic group is substituted;

Or R ^3a or R ^3b represents the group -NR ¹ R ² as defined above;

(ooo) R ^3a or R ^3b is selected from hydrogen and a group -NR ¹ R ² (especially -NH ₂ ) as defined above;

(ppp) R ^3a or R ^3b is hydrogen;

(qqq) R ^3a or R ^3b is the group -NR ¹ R ² (especially -NH ₂ ) as defined above;

(qqq') R ^3a or R ^3b is selected from hydrogen or a group -NR ¹ R ² (especially -NH ₂ ) as defined above;

(qqq") R ^3a or R ^3b is selected from hydrogen or -NH ₂ .

(rrr) R ^4a or R ^4b are independently selected from hydrogen and (1-6C) alkyl (especially (1-3C) alkyl);

(sss) R ^4a or R ^4b is hydrogen;

(ttt) R ^3a and R ^4a or R ^3b and R ^4b are both hydrogen;

(uuu) R ^3a or R ^3b is a group -NR ¹ R ² (in particular -NH ₂ ) as defined above, and R ^4a or R ^4b is hydrogen, respectively;

(uuu') R ⁵ is selected from (1-6C) alkyl and (1-6C) alkoxy;

(uuu")R ^is selected from (1-4C) alkyl and (1-4C) alkoxy;

(uuu"') R ^is selected from methyl and methoxy;

(vvv)n is 0, 1 or 2 (especially 0 or 1, more especially 0);

(vvv')n is 0 or 1;

(www) n is 1 or 2, and R is ^{independently} selected from halogen, (1-6C) alkoxy and (1-6C) alkyl, wherein (1-6C) alkyl and (1-6C) alk Oxygen is optionally substituted by cyano or one or more fluorines;

(xxx) n is 1 or 2, and R5 is independently selected from cyano, halogen, (1-6C) alkoxy and (1-6C) alkyl, wherein (1-6C) alkyl and (1-6C ) alkoxy is optionally substituted by cyano or one or more fluorines;

(yyy)n is 0 or 1, and when n is 1, R ⁵ is (1-4C)alkyl (especially methyl);

(zzz)n is 1 or 2, and R is ^{independently} selected from cyclopropyl and (1-6C) alkyl, wherein (1-6C) alkyl is optionally substituted by cyano or one or more fluorines;

(aaaa)n is 1, and R is (1-6C) ^alkyl , especially (1-3C)alkyl;

(bbbb)n is 0,

(cccc)n is 1;

(dddd)R ⁶ is independently selected from halogen, cyano, (3-4C)cycloalkyl ring, saturated or partially saturated 3-7 membered heterocycle or -N(R ^c )C(O)(1-6C ) alkyl, wherein R ^c is hydrogen or (1-6C) alkyl; or R ^is selected from (1-6C) alkyl or (1-6C) alkoxy, wherein (1-6C) alkyl and ( 1-6C) alkoxy is optionally substituted by one or more (for example 1 or 2), which may be the same or different, selected from the following groups: cyano, fluorine, hydroxyl, (1-6C) alkoxy radical, amino, mono(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (3-7C)cycloalkyl ring or saturated or partially saturated 3-7 membered heterocycle;

(eeee) R ⁶ is independently selected from halogen, cyano, saturated or partially saturated 3-7 membered heterocyclic rings or -N(R ^c )C(O)(1-6C)alkyl, wherein R ^c is hydrogen or (1-6C) alkyl; or R ⁶ is selected from (1-6C) alkyl or (1-6C) alkoxy, wherein said (1-6C) alkyl and (1-6C) alkoxy are any are optionally substituted by one or more (eg 1 or 2), which may be the same or different, selected from cyano, fluorine, hydroxyl and amino (especially fluorine) groups;

(ffff) R ⁶ is independently selected from halogen, cyano, saturated or partially saturated 3-7 membered heterocyclic rings or -N(R ^c )C(O)(1-6C)alkyl, wherein R ^c is hydrogen or (1-3C) alkyl; or R ⁶ is selected from (1-4C) alkyl or (1-4C) alkoxy, wherein said (1-4C) alkyl and (1-4C) alkoxy are any are optionally substituted by one or more (eg 1 or 2), which may be the same or different, selected from cyano, fluorine, hydroxyl and amino (especially fluorine) groups;

( ^ggg ) R is selected from fluorine, chlorine, cyano, acetamido, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl methoxy, ethoxy, propoxy, butoxy and morpholin-4-yl;

(hhhh) R is selected from fluorine, chlorine, acetamido, methyl, propyl, ^tert -butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy and morpholin-4-yl;

(iii) R ⁶ is independently selected from (1-6C) alkyl, (1-6C) alkoxy or saturated 3-7 membered heterocycle (especially morpholin-4-yl or piperidin-1-yl) ,

wherein (1-6C) alkyl and (1-6C) alkoxy are optionally substituted by 1 to 3 halogens, especially fluorine,

Wherein the saturated 3-7 membered heterocycle is optionally substituted by hydroxy (1-2C) alkyl;

(iii') R ⁶ is independently selected from hydroxyl, halogen (especially chlorine or fluorine), (1-6C) alkyl, (1-6C) alkoxy, two-(1-6C) alkylamino or saturated 3-7 membered heterocycles (especially morpholin-4-yl, piperidin-1-yl or piperazin-1-yl),

wherein (1-6C) alkyl and (1-6C) alkoxy are optionally substituted by 1 to 3 halogens, especially fluorine,

Wherein the saturated 3-7 membered heterocycle is optionally substituted by (1-2C) alkyl or hydroxy (1-2C) alkyl;

(iii") R ⁶ is independently selected from (1-6C) alkyl (optionally substituted by 1 to 3 groups independently selected from halogen, especially fluorine), halogen or (1-6C) alkoxy ;

(jjjj) R is ^{independently} selected from methyl, trifluoromethyl, morpholin-4-yl or piperidin-1-yl, 4-hydroxymethylpiperidin-1-yl;

(jjjj') R is ^{independently} selected from methyl, methoxy, di-methylamino, hydroxyl, oxo, chlorine, fluorine, trifluoromethyl, morpholin-4-yl or piperidin-1-yl , 4-hydroxymethylpiperidin-1-yl, 4-methylpiperazin-1-yl;

(jjjj") R is ^{independently} selected from chlorine, fluorine, trifluoromethyl, methyl or methoxy;

(kkkk) ^R6 is independently selected from halogen, trifluoromethyl, methyl, tert-butyl, methoxy, acetamido or morpholino.

(llll) R ⁶ is independently selected from halogen, cyano, oxo, (3-7C) cycloalkyl, saturated 3-7 membered heterocycle (optionally replaced by (1-4C) alkyl or hydroxyl (1-4C) ) alkyl substituted), -N(R ^c )C(O)(1-6C) alkyl (wherein R ^c is hydrogen or (1-6C) alkyl (especially (1-4C) alkyl)), (1-6C)alkyl (optionally substituted by up to three groups independently selected from halogen, especially fluorine) or (1-6C)alkoxy (optionally by up to three groups independently selected from Halogen radical substitution, especially fluorine).

(ll1l') R ⁶ is independently selected from hydroxyl, halogen, cyano, oxo, (3-7C) cycloalkyl, saturated 3-7 membered heterocycle (optionally replaced by (1-4C) alkyl or hydroxyl ( 1-4C) alkyl substituted), -N(R ^c )C(O)(1-6C) alkyl (wherein R ^c is hydrogen or (1-6C) alkyl (especially (1-4C) alkyl ), (1-6C)alkyl (optionally substituted by a saturated 3-7 membered heterocycle or up to three groups independently selected from halogen, especially fluorine), (1-6C)alkoxy (any optionally substituted with up to three groups independently selected from halogen, especially fluoro) or di-(1-6C)alkylamino;

(mmmm) R is ^{independently} selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, methyl, isopropyl, tert-butyl, methoxy, acetamido, oxo, cyclopropyl, Morpholin-4-yl, piperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl and 4-methylpiperazin-1-yl.

(mmmm') R ⁶ are independently selected from hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, methyl, isopropyl, tert-butyl, 1-cyanoethyl, methoxy, iso Propoxy, dimethylamino, acetylamino, oxo, cyclopropyl, morpholin-4-yl, piperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-methyl Basepiperazin-1-yl and 4-methylpiperazin-1-ylmethyl;

(mmmm") R ⁶ is independently selected from halogen (such as chlorine), trifluoromethyl, methoxy, dimethylamino, morpholin-4-yl or piperidin-1-yl.

(mmmm"') at least one ^R6 group is selected from amino, mono(C1-6 alkyl)amino, di-(C1-6 alkyl)amino, such as dimethylamino.

(nnnn)m is 1 or 2;

(oooo)m is 1;

(pPPP)m is 2;

(qqqq) ring BR ⁶ , wherein m is 1 or 2, selected from: 2-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, 2-oxopyrrolidin-1-yl , 2-morpholin-4-ylphenyl, 2-(piperidin-1-yl)phenyl, 2-[4-(hydroxymethyl)piperidin-1-yl)]phenyl, 5-methyl Furan-2-yl and 4-morpholin-4-ylpyrimidin-5-yl;

(qqqq') ring BR ⁶ , wherein m is 1 or 2, selected from: 2-hydroxycyclohexyl, 2-methylphenyl, 2-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl , 2-(dimethylamino)phenyl, 2-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, 2-oxopyrrolidin-1-yl, 2-morpholine- 4-ylphenyl, 3-morpholin-4-ylphenyl, morpholin-4-yl-5-fluorophenyl, 2-(piperidin-1-yl)phenyl, 2-[4-(hydroxy Methyl)piperidin-1-yl]phenyl, 5-methylfuran-2-yl, 2-(4-methylpiperazin-1-yl)phenyl and 4-morpholin-4-ylpyrimidine- 5-base;

(qqqq"') ring BR ⁶ , wherein m is 1 or 2, selected from 2-chloro-phenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 3,6-difluorophenyl, 2 -(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2-chloro-thiophen-5-yl, 1-methylimidazol-4-yl, 3-methoxyphenyl and 3 , 5-dimethylisoxazol-4-yl;

(qqqq"")ring BR ⁶ , wherein m is 1 or 2, selected from 2-chloro-phenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorobenzene Base, 3,6-difluorophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2-chloro-thiophen-5-yl, 1-methylimidazol-4 -yl, 3-methoxyphenyl and 3,5-dimethylisoxazol-4-yl;

(rrrr) ring BR ⁶ , wherein m is 1 or 2, selected from 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl , 2,3-dichlorophenyl, 3,4-dichlorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 4,5-difluorophenyl, 3,6- Difluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 2-(trifluoromethyl)phenyl, 2-( Trifluoromethoxy)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 3-acetamido Phenyl, 2-morpholin-4-ylphenyl, 3-fluoro-5-(4-methylpiperazin-1-yl)phenyl, 2-morpholin-4-ylphenyl, 2-(piperazine Pyridin-1-yl)phenyl, 2-(4-hydroxymethylpiperidin-1-yl)phenyl, 2-oxopyrrolidin-1-yl, 2-oxopiperidin-3-yl, 1 -Methylpiperidin-4-yl, 1-propylpiperidin-4-yl, 2,2-dimethyltetrahydropyran-4-yl, 5-methylfuran-2-yl, 5-methyl Base-1,3,4-thiadiazol-2-yl, 5-tert-butyl-1,3,4-thiadiazol-2-yl, 5-trifluoromethyl-1,3,4-thia Oxadiazol-2-yl, 5-cyclopropyl-1,3,4-thiadiazol-2-yl, 5-ethyl-1,3,4-thiadiazol-2-yl, 5-isopropyl Base-1,3,4-thiadiazol-2-yl, 5-ethylthio-1,3,4-thiadiazol-2-yl, 3-methylisoxazol-5-yl, 4 -Methylisoxazol-3-yl, 5-methylisoxazol-3-yl, 5-tert-butylisoxazol-3-yl, 3,5-dimethylisoxazol-4-yl, 4 -tert-butylthiazol-2-yl, 3-methylisothiazol-5-yl, 4-methylisothiazol-2-yl, 1-methyl-1H-imidazol-4-yl, 2-chloro-thiophene -5-yl, 1-methyl-3-tert-butyl-pyrazol-5-yl, 1-methyl-3-cyclopropyl-pyrazol-5-yl, 1-methyl-3-one iso Propyl-pyrazol-5-yl, 1-tert-butyl-pyrazol-4-yl, 1-tert-butyl-3-cyclopropyl-pyrazol-5-yl, 1-ethyl-pyrazole- 3-yl, 1-isopropyl-pyrazol-3-yl, 5-isopropyl-1,3,4-oxadiazol-2-yl, 4-trifluoro-pyridin-2-yl, 4- (Trifluoromethyl)pyridin-3-yl and 4-(trifluoromethyl)pyridin-2-yl; 5-methyl-pyrazin-2-yl and 4-morpholin-4-ylpyrimidin-5- base;

(rrrr') ring BR ⁶ , wherein m is 1 or 2, selected from

2-Hydroxycyclohexyl, phenyl, 2-methylphenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl , 2,3-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-difluoro-phenyl, 3,4-difluoro-phenyl, 4,5-difluorophenyl, 3,6-difluorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-isopropoxyphenyl, 3 -cyano-phenyl, 3-(1-cyanoethyl)phenyl, 2-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, 3-(trifluoromethyl) ) phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 2-(dimethylamino)phenyl, 3-acetamidophenyl, 2-morphine Lin-4-ylphenyl, 3-morpholin-4-ylphenyl, 2-morpholin-4-yl-5-fluorophenyl, 2-(4-methylpiperazin-1-yl)phenyl , 3-fluoro-5-(4-methylpiperazin-1-yl)phenyl, 2-(piperidin-1-yl)phenyl, 2-(4-hydroxymethylpiperidin-1-yl) Phenyl, 2-oxopyrrolidin-1-yl, 2-oxopiperidin-3-yl, 1-methylpiperidin-4-yl, 1-propylpiperidin-4-yl, 4-methyl Base-piperazin-1-ylmethylphenyl, 2,2-dimethyltetrahydropyran-4-yl, 5-methylfuran-2-yl, 5-methyl-1,3,4- Thiadiazol-2-yl, 5-tert-butyl-1,3,4-thiadiazol-2-yl, 5-trifluoromethyl-1,3,4-thiadiazol-2-yl, 5 -Cyclopropyl-1,3,4-thiadiazol-2-yl, 5-ethyl-1,3,4-thiadiazol-2-yl, 5-isopropyl-1,3,4- Thiadiazol-2-yl, 5-ethylthio-1,3,4-thiadiazol-2-yl, 3-methylisoxazol-5-yl, 4-methylisoxazol-3 -yl, 5-methylisoxazol-3-yl, 5-tert-butylisoxazol-3-yl, 3,5-dimethylisoxazol-4-yl, 4-tert-butyl-thiazole-2 -yl, 3-methyl-isothiazol-5-yl, 4-methyl-isothiazol-2-yl, 1-methyl-1H-imidazol-4-yl, 2-chloro-thiophen-5-yl, 1-methyl-3-tert-butyl-pyrazol-5-yl, 1-methyl-3-cyclopropyl-pyrazol-5-yl, 1-methyl-3-isopropyl-pyrazole- 5-yl, 1-tert-butyl-pyrazol-4-yl, 1-tert-butyl-3-cyclopropyl-pyrazol-5-yl, 1-ethyl-pyrazol-3-yl, 1- Isopropyl-pyrazol-3-yl, 5-isopropyl-1,3,4-oxadiazol-2-yl, 4-trifluoro-pyridin-2-yl, 4-(trifluoromethyl) Pyridin-3-yl and 4-(trifluoromethyl)pyridin-2-yl;

5-methylpyrazin-2-yl and 4-morpholin-4-ylpyrimidin-5-yl; benzodioxolyl;

(rrrr") ring BR ⁶ , wherein m is 1 or 2, selected from

2-Hydroxycyclohexyl, phenyl, 2-methylphenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl , 2,3-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-difluoro-phenyl, 3,4-difluoro-phenyl, 4,5-difluorophenyl, 3,6-difluorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-isopropoxyphenyl, 3 -cyano-phenyl, 3-(1-cyanoethyl)phenyl, 2-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, 3-(trifluoromethyl) ) phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 2-(dimethylamino)phenyl, 3-acetamidophenyl, 2-morphine Lin-4-ylphenyl, 3-morpholin-4-ylphenyl, 2-morpholin-4-yl-5-fluorophenyl, 2-(4-methylpiperazin-1-yl)phenyl , 3-fluoro-5-(4-methylpiperazin-1-yl)phenyl, 2-(piperidin-1-yl)phenyl, 2-(4-hydroxymethylpiperidin-1-yl) Phenyl, 2-oxopyrrolidin-1-yl, 2-oxopiperidin-3-yl, 1-methylpiperidin-4-yl, 1-propylpiperidin-4-yl, 4-methyl Base-piperazin-1-ylmethylphenyl, 2,2-dimethyltetrahydropyran-4-yl, 5-methylfuran-2-yl, 5-methyl-1,3,4- Thiadiazol-2-yl, 5-tert-butyl-1,3,4-thiadiazol-2-yl, 5-trifluoromethyl-1,3,4-thiadiazol-2-yl, 5 -Cyclopropyl-1,3,4-thiadiazol-2-yl, 5-ethyl-1,3,4-thiadiazol-2-yl, 5-isopropyl-1,3,4- Thiadiazol-2-yl, 5-ethylthio-1,3,4-thiadiazol-2-yl, 3-methylisoxazol-5-yl, 4-methylisoxazol-3 -yl, 5-methylisoxazol-3-yl, 5-tert-butylisoxazol-3-yl, 3,5-dimethylisoxazol-4-yl, 4-tert-butyl-thiazole-2 -yl, 3-methyl-isothiazol-5-yl, 4-methyl-isothiazol-2-yl, 1-methyl-1H-imidazol-4-yl, 2-chloro-thiophen-5-yl, 1-methyl-3-tert-butyl-pyrazol-5-yl, 1-methyl-3-cyclopropyl-pyrazol-5-yl, 1-methyl-3-isopropyl-pyrazole- 5-yl, 1-tert-butyl-pyrazol-4-yl, 1-tert-butyl-3-cyclopropyl-pyrazol-5-yl, 1-ethyl-pyrazol-3-yl, 1- Isopropyl-pyrazol-3-yl, 5-isopropyl-1,3,4-oxadiazol-2-yl, 4-trifluoro-pyridin-2-yl, 4-(trifluoromethyl) Pyridin-3-yl and 4-(trifluoromethyl)pyridin-2-yl; 5-methylpyrazin-2-yl, 4-morpholin-4-ylpyrimidin-5-yl; benzodioxine Cyclopentenyl and 2-(dimethylamino)phenyl;

(ssss)A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl , triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (especially phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidine base);

n is 0; and

L is attached at the meta position of ring A relative to the attachment point of the acetylene group, and represents -N(R ⁸ )C(O)N(R ⁹ )-(CR ^a R ^b ) _x -Z-(CR ^a R ^b ) _y -, where Z is -O- or -N(R ⁸ )-, or L represents -N(R ⁸ )C(O)N(R ⁹ )-CH ₂ -or -N(R ⁸ ) C(O)N(R ⁹ )-CH ₂ -CH ₂ -;

R ⁸ , R ⁹ , R ^a and R ^b independently represent hydrogen or (1-6C) alkyl (especially hydrogen or (1-3C) alkyl, more especially hydrogen);

x and y are independently 0, 1 or 2, provided that x+y>0 and x+y<3,

(tttt) A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl , triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (especially phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidine base);

n is 0; and

L is attached at the meta position of ring A relative to the attachment point of the acetylene group, and represents -N(R ⁸ )C(O)N(R ⁹ )-(CR ^a R ^b ) _x -Z-(CR ^a R ^b ) _y -, where Z is -O- or -N(R ⁸ )-, or L represents -N(R ⁸ )C(O)N(R ⁹ )-CH ₂ -or -N(R ⁸ ) C(O)N(R ⁹ )-CH ₂ -CH ₂ -;

R ⁸ , R ⁹ , R ^a and R ^b independently represent hydrogen or (1-6C) alkyl (especially hydrogen or (1-3C) alkyl, more especially hydrogen);

x and y are independently 0, 1 or 2, provided that x+y>0 and x+y<3,

(uuuu)A is phenyl;

n is 0; and

B is selected from saturated or partially saturated 4-6 membered heterocycles, aryl, selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazole 5-6-membered heteroaryl group, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl A base ring, or an 8, 9 or 10-membered bicyclic group optionally containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and being saturated, partially saturated or aromatic;

(vvvv)A is phenyl;

n is 0; and

B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl;

(wwww) A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl , triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (especially phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidine base);

n is 0;

L is attached meta to ring A with respect to the point of attachment of the ethynyl group and represents -N(R ⁸ )C(O)N(R ⁹ )-(CR ^a R ^b ) _x -Z-(CR ^a R ^b ) _y -, where Z is -O- or -N(R ⁸ )-, or L represents -N(R ⁸ )C(O)N(R ⁹ )-CH ₂ -or -N(R ⁸ )C(O)N( ^R9 ) _-CH2 - _CH2- ;

R ⁸ , R ⁹ , R ^a and R ^b independently represent hydrogen or (1-6C) alkyl (especially hydrogen or (1-3C) alkyl, more especially hydrogen);

where x and y are independently 0, 1 or 2, provided that x+y>0 and x+y<3,

B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl;

(xxxx) A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl , triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (especially phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidine base);

n is 0;

L is attached meta to ring A with respect to the point of attachment of the ethynyl group and represents -N(R ⁸ )C(O)N(R ⁹ )-(CR ^a R ^b ) _x -Z-(CR ^a R ^b ) _y -, where Z is -O- or -N(R ⁸ )-, or L represents -N(R ⁸ )C(O)N(R ⁹ )-CH ₂ -or -N(R ⁸ )C(O)N( ^R9 ) _-CH2 - _CH2- ;

R ⁸ , R ⁹ , R ^a and R ^b independently represent hydrogen or (1-6C) alkyl (especially hydrogen or (1-3C) alkyl, more especially hydrogen);

where x and y are independently 0, 1 or 2, provided that x+y>0 and x+y<3,

B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl;

(yyyy)m is 0, 1 or 2 (especially 1 or 2);

(zzzz)B is selected from cyclopentyl, cyclohexyl, piperidinyl, tetrahydropyranyl, phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl , thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 2,3-dihydro-1,4-benzodioxenyl and 1,3-benzodioxol-5-yl;

m is 1 or 2; and

^R is independently selected from fluorine, chlorine, cyano, acetamido, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl , methoxy, ethoxy, propoxy, butoxy and morpholin-4-yl;

(aaaaa)B is selected from phenyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrazolyl and pyridyl;

m is 1 or 2; and

R ⁶ is independently selected from halogen, cyano, (3-4C) cycloalkyl ring, saturated or partially saturated 3-7 membered heterocycle or -N(R ^c )C(O)(1-6C)alkyl , wherein R ^c is hydrogen or (1-6C) alkyl; or R ⁶ is selected from (1-6C) alkyl or (1-6C) alkoxy, wherein (1-6C) alkyl and (1-6C ) alkoxy is optionally substituted by one or more (for example 1 or 2), which may be the same or different, selected from cyano, fluorine, hydroxyl and amino (especially fluorine) groups;

(bbbbb)B is selected from phenyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrazolyl and pyridyl;

m is 1 or 2; and

^R is independently selected from fluorine, chlorine, cyano, acetamido, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl , methoxy, ethoxy, propoxy, butoxy and morpholin-4-yl;

(ccccc)B is phenyl;

m is 1 or 2; and

R ^is independently selected from fluorine, chlorine, cyano, acetamido, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, butoxy and morpholine- 4-base;

(ddddd)B is phenyl;

m is 1 or 2; and

R ^is independently selected from fluorine and trifluoromethyl;

(eeeee)B is isoxazolyl;

m is 1 or 2; and

^R is independently selected from fluorine, chlorine, cyano, acetamido, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl , methoxy, ethoxy, propoxy and butoxy;

(fffff)B is isoxazolyl;

m is 1 or 2; and

R ^is independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl (especially methyl and tert-butyl, more especially tert-butyl);

(ggggg)B is pyrazolyl;

m is 1 or 2; and

^R is independently selected from fluorine, chlorine, cyano, acetamido, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl , methoxy, ethoxy, propoxy and butoxy;

(hhhhh)B is pyrazolyl;

m is 1 or 2; and

R ^is independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl (especially methyl and tert-butyl, more especially tert-butyl);

(iiiiii) B is thiadiazolyl;

m is 1 or 2; and

^R is independently selected from fluorine, chlorine, cyano, acetamido, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, methoxy, ethyl Oxy, Propoxy and Butoxy;

(jjjjj) B is thiadiazolyl;

m is 1 or 2; and

R ^is independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl (especially methyl and tert-butyl, more especially tert-butyl);

(cccc) ring BR wherein m is 0, 1 or 2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, ^phenyl , 2-fluorophenyl, 3-fluorophenyl , 4-fluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoro Methyl)phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl , 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-acetamidophenyl, 3-acetamidophenyl, 4-acetamidophenyl, 5-tert-butyl-1 , 3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-cyclopropyl-1,3,4-thiadiazol-2- Base, 1-methyl-3-cyclopropyl-pyrazol-5-yl, 1-tert-butyl-3-cyclopropyl-pyrazol-5-yl, 3-methyl-isothiazol-5-yl , 3-methylisoxazol-5-yl, 5-methylisoxazol-3-yl, 5-tert-butyl-isoxazol-3-yl, 4-(trifluoromethyl)-pyridine- 2-yl, 2-oxopiperidin-3-yl, 2,2-dimethyltetrahydro-2H-pyran-4-yl, 2,3-dihydro-1,4-benzodioxene Base, 1,3-benzodioxol-5-yl, 2-morpholin-4-ylphenyl, 3-morpholin-4-ylphenyl, 4-morpholin-4-ylphenyl base, 1-methyl-piperidin-4-yl, 1-ethylpiperidin-4-yl and 1-propylpiperidin-4-yl; and

(kkkkk) ring BR wherein m is 1 or 2 is selected from 2-fluorophenyl, 3 ^- fluorophenyl, 4-fluorophenyl, 2,5-di-fluorophenyl, 3,4-difluorobenzene Base, 3,5-difluorophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-5- (Trifluoromethyl)phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5- Dichlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-acetylaminophenyl, 3-acetylaminophenyl, 4-acetylaminophenyl, 5-tert-butyl-1,3,4-thiadiazol-2-yl, 5-methyl-1,3, 4-thiadiazol-2-yl, 5-cyclopropyl-1,3,4-thiadiazol-2-yl, 3-cyclopropyl-pyrazol-5-yl, 1-tert-butyl-3 -Cyclopropyl-pyrazol-5-yl, 3-methylisothiazol-5-yl, 3-methylisoxazol-5-yl, 5-methylisoxazol-3-yl, 5-tert Butylisoxazol-3-yl, 4-(trifluoromethyl)-pyridin-2-yl, 2-oxopiperidin-3-yl, 2,2-dimethyltetrahydro-2H-pyran-4 -yl, 2-morpholin-4-ylphenyl, 3-morpholin-4-ylphenyl, 4-morpholin-4-ylphenyl, 1-methylpiperidin-4-yl, 1-ethyl Basepiperidin-4-yl and 1-propylpiperidin-4-yl.

(llllll) R ¹ and R ² are both hydrogen, R ^3a and R ^4a or R ^3b and R ^4b are both hydrogen, n is 0, L is -NHC(O)NH-CH ₂ -, and wherein m is 1 or Ring BR of ² is selected from 3-acetamidophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-methyl Oxyphenyl, 3-methoxyphenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 3,4-dichlorophenyl, 2-morpholin-4-ylphenyl, 5- tert-butyl-1,3,4-thiadiazol-2-yl, 3-methylisothiazol-5-yl, 3-methylisoxazol-5-yl, 5-tert-butylisoxazol-3- Base, 1-methyl-3-tert-butylpyrazol-5-yl, 1-methylpiperidin-4-yl, 1-propylpiperidin-4-yl, 4-(trifluoromethyl)pyridine -3-yl and 4-(trifluoromethyl)pyridin-2-yl;

(mmmmm) R ^y is the group -NR ¹ R ² , R ^x is the group R ^3a and R ^z is the group R ^4a , and R ^3a and R ^4a are hydrogen, ring A is phenyl or pyridyl, n is 0 or 1, and when n is 1, R ⁵ is methyl, L is -NHC(O)NH-CH ₂ -, ring BR ⁶ is selected from 2-chloro-phenyl, 2-(trifluoromethyl) Phenyl, 2-methoxyphenyl, 3-methoxy-phenyl, 2-methylaminophenyl, 2-morpholin-4-ylphenyl or 2-piperin-1-ylphenyl.

A specific embodiment of the compound of formula IA is the compound of formula IA(i):

Formula IA(i)

wherein R ¹ , R ² , R ^3a , R ^4a , R ⁵ , R ⁶ , L, B, n and m are as defined above,

and salts thereof, especially pharmaceutically acceptable salts thereof.

Another specific embodiment of the compound of formula I is the compound of formula IA(ii):

Formula IA(ii)

wherein R ¹ , R ² , R ^3a , R ^4a , R ⁵ , R ⁶ , L, B, n and m are as defined above,

and salts thereof, especially pharmaceutically acceptable salts thereof.

Another specific embodiment of the compound of formula I is the compound of formula IA(iii):

Formula IA(iii)

wherein R ¹ , R ² , R ^3a , R ^4a , R ⁵ , R ⁶ , L, B, n and m are as defined above,

and salts thereof, especially pharmaceutically acceptable salts thereof.

Another specific embodiment of the compound of formula I is the compound of formula IA(iv):

Formula IA(iv)

wherein R ¹ , R ² , R ^3a , R ^4a , R ⁵ , R ⁶ , L, B, n and m are as defined above,

and salts thereof, especially pharmaceutically acceptable salts thereof.

A specific embodiment of the compound of formula IB is the compound of formula IB(i):

Formula IB(i)

wherein R ¹ , R ² , R ^3b , R ^4b , R ⁵ , Ru, L, B, n and m are as defined above,

and salts thereof, especially pharmaceutically acceptable salts thereof.

Another specific embodiment of the compound of formula I is the compound of formula IB(ii):

Formula IB(ii)

wherein R ¹ , R ² , R ^3b , R ^4b , R ⁵ , R ⁶ , L, B, n and m are as defined above, and salts thereof, especially pharmaceutically acceptable salts thereof.

Another specific embodiment of the compound of formula I is the compound of formula IB(iii):

Formula IB(iii)

in:

wherein R ¹ , R ² , R ^3b , R ^4b , R ⁵ , R ⁶ , L, B, n and m are as defined above,

and salts thereof, especially pharmaceutically acceptable salts thereof.

Another specific embodiment of the compound of formula I is the compound of formula IB(iv):

Formula IB(iv)

wherein R ¹ , R ² , R ^3b , R ^4b , R ⁵ , R ⁶ , L, B, n and m are as defined above,

and salts thereof, especially pharmaceutically acceptable salts thereof.

Compounds of formula I, or pharmaceutically acceptable salts thereof, may be prepared by any known method suitable for the preparation of chemically related compounds. Said process, when used for the preparation of compounds of formula I, is provided as a further feature of the invention and is exemplified by the following representative process variants. Necessary starting materials can be obtained by standard methods of organic chemistry. The preparation of the starting materials is described in conjunction with the following representative process variants and described in the associated Examples. Alternatively, the necessary starting materials can be obtained by methods analogous to the schematic methods, which are within the purview of one of ordinary skill in the art of organic chemistry.

According to another aspect of the present invention, there is provided the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof (wherein unless otherwise specified, R ¹ , R ² , R ^3a , R ^4a , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , L, ring A and ring B, n and m are as defined in formula I), and the method is schematically described as follows.

Method (a) makes formula II compound:

wherein R ^x , R ^y , R ^z , R ⁵ , R ⁸ , n and A have any of the meanings defined above, but any functional groups are protected if necessary, to react with an isocyanate of formula IV:

wherein Z, R ⁶ , R ^a , R ^b , x, y, m and B have any of the meanings defined above, but any functional group is protected if necessary;

or

Process (b) reacts a compound of formula II as defined above with an aryl carbamate of formula III:

wherein Ar is a suitable aryl group, such as phenyl, and Z, R ⁶ , R ^a , R ^b , x, y, m and B have any of the meanings defined above, but any functional groups are protected if necessary;

or

Method (c) For the compound of formula I wherein Z is -O- or -N(R ^a )-, the compound of formula IX

wherein R ^x , R ^y , R ^z , R ⁵ , R ⁸ , R ⁹ , R ^a , R ^b , x, n and A have any of the meanings defined above, but any functional group is protected if necessary, and the compound of formula XI reaction,

wherein Lg ¹ is a suitable alternative group such as halogen (such as fluorine, chlorine, bromine), O-tosyl, O-methylsulfonyl or trifluorosulfonyloxy, and R ^a , R ^b , R ⁶ , y, m and B have any of the meanings defined above, but any functional groups are protected if necessary;

Method (d) For the compound of formula I wherein Z is -O- or -N(R ^a )-, the compound of formula XIV

wherein Lg ² is a suitable alternative group such as halogen (such as chlorine, bromine), O-tosyl, O-methylsulfonyl or trifluorosulfonyloxy, and R ^x , R ^y , R ^z , R ⁵ , R ⁸ , R ⁹ , R ^a , R ^b , n, x and A have any of the meanings defined above, but if necessary, any functional group is protected and reacted with the compound of formula XV,

wherein R ^a , R ^b , R ⁶ , y, m and B have any of the meanings defined above, but any functional group is protected if necessary;

or

Method (e) For a compound of formula I wherein L is -N(R ⁸ )C(O)N(H)-(CR ^a R ^b ) _x -Z-(CR ^a R ^b ) _y -, such that as defined above The compound of formula II is reacted with trichloroacetamide of formula XIII:

wherein Z, R ⁶ , R ^a , R ^b , x, y, m and B have any of the meanings defined above, but any functional group is protected if necessary;

or

Method (f) makes formula XVI or XVIA compound:

where ^Lg is a suitable replacement group such as halogen (such as fluorine, chlorine, bromine or iodine), methylsulfonyl, methylsulfinyl (ie methylsulfoxide), methylthio or aryloxy (such as phenoxy), and R ^3a , R ^4a , R ^3b , R ^4b , R ⁵ , R ⁶ , n, m, A, B and L have any of the meanings defined above, but any group is protected if necessary, Reaction with an amine of formula HNR ¹ R ² , wherein R ¹ and R ² have any of the meanings defined above, but any functional groups are protected if necessary;

or

Method (g) makes the compound of formula XVII:

wherein Lg ⁴ is a suitable alternative group such as halogen (such as chlorine, bromine or iodine) or sulfonyloxy (such as trifluoromethylsulfonyloxy), and R ⁵ , R ⁶ , n, m, A , B and L have any of the meanings defined above, but any functional group is protected if necessary, reacted with an alkyne of formula XVIII:

wherein R ^x , R ^y and R ^z have any of the meanings defined above, but any functional groups are protected if necessary;

or

Method (h) makes the compound of formula XVIIa:

wherein R ⁵ , R ⁶ , n, m, A, B and L have any of the meanings defined above, but any functional group is protected if necessary, to react with a pyrimidine of formula XVIIIa:

wherein Lg ⁵ is a suitable alternative group such as halogen (such as chlorine, bromine or iodine) or sulfonyloxy (such as trifluoromethylsulfonyloxy), and R ^x , R ^y and R ^z have the above definitions Any meaning of , but any functional group is protected if necessary;

or

Method (i) For the compound of formula I wherein L is -N(H)C(O)N(R ⁹ )-(CR ^a R ^b ) _x -Z-(CR ^a R ^b ) _y- , formula XIX The isocyanate:

wherein R ^x , R ^y , R ^z , R ⁵ , n and A have any of the meanings defined above, but any functional group is protected if necessary, to react with an amine of formula XV;

wherein R ⁹ , R ^a , R ^b , Z, B, R ⁶ , x, y and m are as defined above.

or

Process (j) For a compound of formula I wherein L is -N(H)C(O)N(R ⁹ )-, a compound of formula XX:

wherein Ar is a suitable aryl group such as phenyl, and R ^x , R ^y , R ^z , R ⁵ , n and A have any of the meanings defined above, but any functional groups are protected if necessary, with the formula as defined above Amine reactions of XV.

and thereafter if necessary:

i) converting a compound of formula (I) into another compound of formula (I);

ii) removing any protecting groups;

iii) Salt formation.

Reaction conditions for method (a)

The reaction of method (a) is desirably carried out in the presence of a suitable inert solvent or diluent, such as a halogenating agent (such as dichloromethane, chloroform or carbon tetrachloride), an ether (such as tetrahydrofuran or 1,4-dioxane ), amines (such as pyridine), or dipolar aprotic solvents (such as N,N-dimethylformamide or N,N-dimethylacetamide). The reaction is desirably carried out at a temperature in the range, for example, from ambient temperature to about 60°C, preferably at or near ambient temperature.

Reaction conditions for method (b)

The reaction of method (b) is desirably carried out in the presence of a suitable base. Suitable bases are, for example, organic amine bases, such as pyridine or trialkylamines (such as triethylamine or diisopropylethylamine).

The reaction of method (b) is desirably carried out in the presence of a suitable inert solvent or diluent, such as an ether (such as tetrahydrofuran or 1,4-dioxane) or a dipolar aprotic solvent (such as N,N-dimethyl formamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide). The reaction is desirably carried out at a temperature ranging from, for example, ambient temperature to about 120°C, preferably from about 80°C to about 100°C.

The reaction may also desirably be carried out by heating the reactants in a sealed vessel using a suitable heater, such as a microwave heater.

Reaction conditions for method (c)

The reaction of method (c) is desirably carried out in the presence of a suitable base. Suitable bases are, for example, organic amine bases, such as pyridine or trialkylamines (such as triethylamine or diisopropylethylamine), or, for example, alkali metal or alkaline earth metal carbonates (such as sodium carbonate or potassium carbonate) .

The reaction of method (c) is desirably carried out in the presence of a suitable solvent or diluent, such as tetrahydrofuran, 1,4-dioxane or a dipolar aprotic solvent such as dimethylformamide or dimethylacetamide . The reaction is desirably carried out at a temperature ranging from, for example, ambient temperature to about 100°C, and at atmospheric pressure.

Reaction conditions for method (d)

The reaction of method (d) is desirably carried out under the conditions as described above for method (c).

Reaction conditions for method (e)

The reaction of method (e) is desirably carried out in the presence of a suitable base. Suitable bases are, for example, organic amine bases, such as pyridine or trialkylamines (such as triethylamine or diisopropylethylamine).

The reaction of method (e) is desirably carried out in the presence of a suitable inert solvent or diluent, such as an ether (such as tetrahydrofuran or 1,4-dioxane) or a dipolar aprotic solvent (such as N,N-dimethyl formamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide). The reaction is desirably carried out at a temperature ranging from, for example, ambient temperature to about 120°C, preferably from about 100°C to about 120°C.

The reaction may also desirably be carried out by heating the reactants in a sealed vessel using a suitable heater, such as a microwave heater.

Reaction conditions for method (f)

The reaction of method (f) is desirably carried out in the presence of a catalytic amount of a suitable acid. A suitable acid is, for example, hydrogen chloride.

The reaction of method (f) may desirably be carried out in the absence or presence of a suitable inert solvent or diluent. When used, suitable inert solvents or diluents are, for example, alcohols (such as ethanol, isopropanol or butanol) or dipolar aprotic solvents (such as acetonitrile, N,N-dimethylformamide, N,N -dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide). The reaction is desirably carried out at a temperature ranging from, for example, ambient temperature to about 120°C, preferably from about 80°C to about 90°C.

Reaction conditions for method (g)

The reaction of method (g) is desirably carried out in the presence of a suitable palladium catalyst, optionally in combination with a suitable copper catalyst. Suitable palladium catalysts are, for example, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride or tetrakis(triphenylphosphine)palladium (0). A suitable copper catalyst is, for example, ketone iodide (I).

The reaction of method (g) is desirably carried out in the presence of a suitable base. Suitable bases are, for example, organic amine bases, such as trialkylamines (eg triethylamine) or tetramethylguanidine.

The reaction of method (g) may desirably be carried out in the absence or presence of a suitable inert solvent or diluent, such as an ester (such as ethyl acetate), an ether (such as tetrahydrofuran or 1,4-dioxane) or a dipolar Aprotic solvents (such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide). The reaction is desirably at a temperature in the range of, for example, about -20°C to about 100°C.

Reaction conditions for method (h)

The reaction of method (h) is desirably carried out under the conditions as described above for method (g).

Reaction conditions for method (i)

The reaction of method (i) is desirably carried out under the conditions as described above for method (a).

Reaction conditions for method (j)

The reaction of method (j) is desirably carried out under the conditions as described above for method (b).

Starting material for method (a)

Compounds of formula II can be obtained by conventional methods. For example, compounds of formula II can be obtained by reacting a pyrimidine of formula VI with an alkyne of formula VII, as illustrated in Reaction Scheme 1:

Reaction scheme 1

wherein ^Lg4 is a suitable substituent as described above, and ^Rx , ^Ry , ^Rz , ^R5 , ^R8 , n and A have any of the meanings defined above, but any functional groups are protected if necessary.

The reaction of Reaction Scheme 1 is desirably carried out under the conditions as described above for method (h).

Alternatively, compounds of formula II can be obtained by reacting a pyrimidine of formula VI with a protected alkyne of formula Via followed by an amine of formula VIb, as illustrated in Reaction Scheme 2:

Reaction scheme 2

wherein Lg in compounds of formula VI and VIb are ^each a suitable replacement group as described above, Pg is a suitable protecting group, such as a trialkylsilyl group (such as trimethylsilyl or tert-butyldimethylsilyl) or _Me2 (OH)C-, and ^Rx , ^Ry , ^Rz , ^R5R8 , n and A ^have any of the meanings defined above, but any functional groups are protected if necessary.

Step (i) of Reaction Scheme 2 is the coupling of a protected alkyne of formula Via to a pyrimidine of formula VI. Step (i) is carried out under the conditions described above for process (h). Step (ii) of Reaction Scheme 2 is to deprotect the resulting alkyne under basic or acidic conditions to provide the unprotected alkyne. A person skilled in the art can readily select appropriate conditions for deprotection in step (ii). Step (iii) of Reaction Scheme 2 is the coupling of an alkyne to an amine of formula VIb. Step (iii) of Reaction Scheme 2 is carried out under the conditions described above for process (h).

Alternatively, a compound of formula II may be obtained by reacting a compound of formula VIc or Vic', wherein Lg ³ is a suitable replacement group as described above, and R ³ , R ⁴ , R ⁵ , R ⁸ , n and A Has any meaning as defined above, but with protection of any functional groups if necessary, with an amine of formula HNR ¹ R ² using the reaction conditions as described above for method (g).

Starting materials of formula VI, VII, VIa and VIb and the amine HNR ¹ R ² are commercially available or they are known in the literature or they can be prepared by standard methods known in the art. Starting materials of formula VIc and VIc' can be prepared by standard methods known in the art.

Isocyanates of formula IV are commercially available or they are known in the literature, or they can be prepared by standard methods known in the art. For example, those skilled in the art will appreciate that the isocyanate can be desirably prepared by Curtis reaction of the corresponding acid or acid chloride with, for example, an azide or diphenylphosphoryl azide. Alternatively, the isocyanates may desirably be prepared by reaction of the corresponding amine with phosgene or a phosgene equivalent such as triphosgene, diphosgene or N,N'-carbonyldiimidazole (March J., Adv. Org. Chem., 4th edition, 1992, page 1290, Wiley Interscience).

Starting material for method (b)

Compounds of formula II can be obtained by conventional methods as described above.

Aryl carbamates of formula III are commercially available or they are known in the literature, or they can be prepared by standard methods known in the art. For example, the aryl carbamate can be prepared by reacting an amine of formula V with an aryl chloroformate, as illustrated in Reaction Scheme 3:

Reaction scheme 3

wherein R ⁶ , R ^a , R ^b , m, x, y, B, Z and Ar have any of the meanings defined above, but any functional groups are protected if necessary.

The reaction of Reaction Scheme 3 is desirably carried out in the presence of a suitable base. Suitable bases are, for example, organic amine bases such as pyridine or trialkylamines such as triethylamine.

The reaction is desirably carried out in the presence of a suitable inert solvent or diluent, for example an ether such as tetrahydrofuran or 1,4-dioxane. The reaction is desirably at a temperature in the range, for example, from about -20°C to about 100°C, preferably at or near 0°C.

Starting materials of formula V and aryl chloroformates are commercially available or they are known in the literature or they can be prepared by standard methods known in the art.

Starting material for method (c)

Compounds of formula IX can be obtained by conventional methods analogous to the methods used to prepare compounds of formula II under "Starting materials for process (a)" above.

Compounds of formula XI are commercially available or they are known in the literature, or they can be prepared by standard methods known in the art.

Starting material for method (d)

Compounds of formula XIV can be obtained by conventional methods analogous to the methods used for the preparation of compounds of formula II under "Starting materials for process (a)" above.

Starting material for process (e)

Compounds of formula II can be obtained by conventional methods as described above.

Trichloroacetamides of formula XIII are commercially available or they are known in the literature, or they can be prepared by standard methods known in the art.

Starting material for method (f)

Those skilled in the art will understand that the compound of formula XVI can be prepared using appropriate starting materials using methods similar to those described above, for example, wherein the starting material bears an optionally protected group Lg ³ O instead of the -NR ¹ R ² group group.

Amines of formula HNR ¹ R ² are commercially available or they are known in the literature, or they can be prepared by standard methods known in the art.

Starting material for method (g)

Compounds of formula XVII are commercially available or they are known in the literature, or they can be prepared using appropriate starting materials using methods analogous to those described above, as understood by those skilled in the art. For example, a compound of formula XVII wherein L is -N(R ⁸ )C(O)N(H)-(CR ^a R ^b ) _x -Z-(CR ^a R ^b ) _y - can be desirably obtained by making the compound of formula XVIIa Reaction of amines with aryl carbamates of formula XVIIb is obtained as illustrated in Reaction Scheme 4:

Reaction scheme 4

wherein Lg ⁴ is a suitable alternative group as described above, L is -N(R ⁸ )C(O)N(H)-(CR ^a R ^b ) _x -Z-(CR ^a R ^b ) _y -, and R ⁵ , R ⁶ , R ⁸ , n, m, A and B have any of the meanings defined above, but any functional groups are protected if necessary.

The reaction of Reaction Scheme 4 is desirably carried out under the conditions as described above for method (b).

Starting materials of formula XVIIa and XVIIb are commercially available or they are known in the literature, or they can be prepared by standard methods known in the art.

Alkynes of formula XVIII are commercially available or they can be prepared using appropriate starting materials using methods analogous to those described above, as understood by those skilled in the art. For example, a compound of formula XVIII may desirably be obtained by the following reaction to give a pyrimidine of formula XVIIIa:

wherein Lg ⁴ is a suitable substitution group as described above, and R ¹ , R ² , R ³ and R ⁴ have any of the meanings defined above, but any functional groups are protected if necessary, desirably with trimethylformazan The silylacetylene or 2-methyl-3-butyn-2-ol is reacted under the conditions described above for method (h), followed by removal of the protecting group using standard methods known in the art.

Starting material for method (h)

Compounds of formula XVIIa can be prepared using methods analogous to methods (a)-(e) and methods (i)-(j) described above.

Compounds of formula XVIIIa are commercially available or as understood by those skilled in the art, they can be prepared using appropriate starting materials using methods similar to those described above.

Starting material for method (i)

As will be appreciated by those skilled in the art, isocyanates of formula XIX may desirably be prepared by Curtis reaction of the corresponding acid or acid chloride with, for example, an azide or diphenylphosphoryl azide. Alternatively, the isocyanates may desirably be prepared by reaction of the corresponding amine with phosgene or a phosgene equivalent such as triphosgene, diphosgene or N,N'-carbonyldiimidazole (March J., Adv. Org. Chem., 4th edition, 1992, page 1290, Wiley Interscience).

Amines of formula XV are commercially available or they are known in the literature, or they can be prepared by standard methods known in the art.

Starting material for method (j)

Compounds of formula XX are commercially available or they are known in the literature, or they can be prepared using appropriate starting materials using methods analogous to those described above, as understood by those skilled in the art.

Amines of formula XV are commercially available or they are known in the literature, or they can be prepared by standard methods known in the art.

Compounds of formula I may be converted into other compounds of formula I using routine standard methods in the art.

Examples of the type of transformation reaction that can be used include introduction of a substituent by an aromatic substitution reaction or a nucleophilic substitution reaction, reduction of a substituent, alkylation of a substituent, and oxidation of a substituent. The reagents and reaction conditions used in the above methods are well known in the chemical arts.

Specific examples of the aromatic substitution reaction include, under Friedel Crafts conditions, introduction of an alkyl group using an alkyl halide and a Lewis acid such as aluminum trichloride; and introduction of a halogen group. Specific examples of nucleophilic substitution reactions include the introduction of alkoxy or monoalkylamino groups, dialkylamino groups or N-containing heterocycles using standard conditions. Specific examples of the reduction reaction include reduction of a carbonyl group to a hydroxyl group with sodium borohydride, or reduction of a nitro group to an amino group by catalytic hydrogenation with a nickel catalyst or by treatment with iron and heating in the presence of hydrochloric acid.

An example of a suitable conversion reaction is the conversion of ^Rx , ^Ry , ^Rz , ^R5 , ^R6 , n, m, A, B and L as defined in claim 1 and R1 and/or ^R2 are hydrogen Compounds of formula I are converted into compounds of formula I wherein R ¹ and/or R ² are, for example, optionally substituted (1-6C)alkoxycarbonyl groups. The conversion can be achieved using standard methods, for example by substituting one or both of the ^R1 and/or ^R2 hydrogen atoms with the desired, optionally substituted (1-6C)alkoxycarbonyl group.

Certain compounds of formula I can exist in stereoisomeric forms. It is to be understood that the present invention includes all geometric and optical isomers of the compounds of formula I and mixtures thereof (including racemates). Tautomers and mixtures thereof also form an aspect of the invention.

Isomers can be resolved or separated using conventional methods such as chromatography or fractional crystallization. Enantiomers may be separated by separation of racemic or other mixtures of compounds using conventional methods, eg chiral high performance liquid chromatography (HPLC). Alternatively, the desired optical isomer can be obtained by subjecting an appropriate optically active starting material under conditions that do not cause racemization or by derivatization, such as reaction with a homochiral acid, followed by conventional methods (such as HPLC, in Chromatography on silica) separates diastereomeric derivatives to obtain preparations, or they can be prepared using achiral starting materials and chiral reagents. All stereoisomers are included within the scope of this invention.

The compounds of the invention can be isolated from their reaction mixtures using conventional techniques.

It will be appreciated that in some of the reactions described herein it may be necessary/desirable to protect any sensitive groups in the compounds. Situations where protection is desired or desirable and suitable methods of doing so are well known to those skilled in the art. Conventional protecting groups can be used according to standard practice (see, eg, T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if the reactants contain groups such as amino, carboxy, or hydroxy, it may be desirable to protect such groups in some of the reactions described herein. Protecting groups can be removed by conventional methods as described in the literature or known to the skilled chemist, as the case may be, for removal of the protecting group, the above methods can be selected so as to generate Removal of protecting groups is accomplished in the least interfering manner.

For convenience, specific examples of protecting groups are given below, wherein, for example, "lower" in lower alkyl means that the applied group preferably has 1 to 4 carbon atoms. It should be understood that these examples are not exhaustive. In the specific examples of methods for removing protecting groups given below, these methods are likewise non-exhaustive. The use of protecting groups and methods of deprotection not explicitly described are of course included within the scope of the present invention.

It is also to be understood that various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions prior to or immediately after carrying out the methods described above, or may be formed by conventional functional group modifications, which are also included in the method aspects of the present invention middle. Such reactions and modifications include, for example, introduction of substituents by aromatic substitution reactions, reduction of substituents, alkylation of substituents, and oxidation of substituents. The reagents and reaction conditions used in the above methods are well known in the chemical arts. Specific examples of aromatic substitution reactions include introduction of nitro groups using concentrated nitric acid; introduction of acyl groups using, for example, acyl halides and Lewis acids such as aluminum trichloride under Friedel Crafts conditions; use of alkyl halides and Lewis acids such as trichloro Aluminum chloride) introduces an alkyl group under Friedel Crafts conditions; and introduces a halogen group. Specific examples of such modifications include reduction of nitro groups to amino groups by, for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid while heating; oxidation of alkylthio groups to alkylsulfinyl or alkyl Sulfonyl.

Certain intermediate compounds of formula II, XIV, XVI, XVIA, XIX, XX, VIc and VIc' are believed to be novel and are claimed herein as further aspects of the invention.

biological assay

The following assays can be used to measure the in vitro effects of compounds of the invention as Tie2 inhibitors and as Tie2 autophosphorylation inhibitors in whole cells.

a. In vitro receptor tyrosine kinase inhibition assay

To test the inhibition of Tie2 receptor tyrosine kinases, in non-cell-based protein kinase assays, by their inhibition of protein kinases in ELISA-based microtiter plate assays to phosphorylate tyrosine-containing polypeptide substrates ability to evaluate compounds. In this particular case, the assay was used to determine the _IC50 of three different recombinant human tyrosine kinases Tie2, KDR and Flt.

To facilitate production of tyrosine kinases, recombinant receptor genes are prepared using standard molecular biology cloning and mutagenesis techniques. These recombinant protein fragments encoded in these genes consist only of the intracellular C-terminal part of the corresponding receptor, in which the kinase domain is found. The recombinant gene encoding the fragment-containing kinase domain is cloned and expressed in a standard baculovirus/Sf21 system (or other equivalent system).

After protein expression, lysates were prepared from host insect cells by freezing lysis buffer (20 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) pH 7.5, 150 mM NaCl, 10% glycerol, 1% Triton X-100, 1.5 mM MgCl ₂ , 1 mM ethylene glycol-bis(β-aminoethyl ether) N',N',N',N'-tetraacetic acid (EGTA) Treated with protease inhibitors and clarified by centrifugation.

Tie2, KDR and Fltl lysates were stored in aliquots at -80°C.

The basal kinase activity of these recombinant proteins was determined by measuring their ability to phosphorylate a synthetic polypeptide consisting of a random interpolymer of glutamic acid, alanine and tyrosine in a 6:3:1 ratio. Specifically, Nunc Maxisorb™ 96-well immunoplates were coated with 100 μl of synthetic peptide SigmaP3899 (1 mg/ml stock solution in PBS, diluted to 1:500 with PBS before coating the plates), and then incubated overnight at 4°C. Plates were washed with 50 mM HEPES pH 7.4 at room temperature to remove any excess unbound synthetic peptide.

Tie2, KDR or Flt1 activity was assessed by incubating fresh appropriately diluted lysates (1:200, 1:400 and 1:1000, respectively) in peptide-coated plates by the following incubation assays: conditions were at room temperature Under 100mM HEPES pH7.4, 5μmol adenosine triphosphate (ATP) (or the Km concentration of the corresponding enzyme, 10mM MnCl ₂ , 0.1mM Na3VO4, 0.2mMDL-dithiothreitol (DTT), 0.1% Triton X-100 neutralization The test compounds were dissolved together in DMSO (2.5% final concentration) and the final compound concentration was 0.05 μmol-100 μmol, (Tie2) incubated for 60 minutes or incubated (KDR, Flt) for 20 minutes. Termination by removing the liquid components in the test The reaction was followed by washing the plate with PBS-T (phosphate buffered saline and 0.5% Tween-20) or equivalent wash buffer.

Immobilized phospho-peptide products of the reaction are detected immunologically. First, the plate was incubated with a mouse monoclonal anti-phosphotyrosine-HRP (horseradish peroxidase) conjugated antibody (4G10 from Upstate Biotechnology UBI16-105) for 4 hours at room temperature. After extensive washing with PBS-T, HR activity in each well of the plate was measured colorimetrically with 22'-azino-bis-[3-ethylbenzothiazolinesulfonate(6)]diammonium Salt crystal ABTS (Sigma P4922-prepared according to the preparation instructions) was used as a substrate, incubated for 30-45 minutes to develop the color, and then 100 μl of 1M H ₂ SO ₄ was added to terminate the reaction.

Chromogenic quantification and thus enzymatic activity was accomplished by measuring absorbance at 405 nm with a Molecular Devices ThermoMax microplate reader. Kinase inhibition by provided compounds is expressed as _IC50 values. This value was determined by calculating the concentration of compound required to produce 50% inhibition of phosphorylation in this assay. Phosphorylation ranges were calculated from positive (vehicle plus ATP) and negative (vehicle minus ATP) control values.

b. Cellular Tie2 autophosphorylation assay

The assay is based on measuring the ability of a compound to inhibit autophosphorylation of the Tie2 receptor, which normally results in an "activated" receptor, which in turn triggers specific signaling pathways related to receptor function.

Autophosphorylation can be achieved in a number of ways. Expression of recombinant kinase domains in the baculovirus system is known to result in phosphorylated and activated receptors. It has also been reported that overexpressing receptors in recombinant cell lines, in the absence of ligands, can itself lead to receptor autophosphorylation (Heldin C-H.1995 Cell: 80, 213-223; Blume-J.P, Hunter T. 2001 Nature: 411 , 355-65). In addition, there are numerous examples in the literature demonstrating that chimeric receptors have been constructed. In these instances, the native extracellular surface domain of the receptor has been known by adding an appropriate ligand (e.g. TrkA-Tie2/NGF ligand (Marron, M B. et al., 2000 Journal of Biological Chemistry: 275: 39741-39746) Or C-fms-Tie-1/CSF-1 ligand (Kontos, C.D. et al., 2002 Molecular and Cellular Biology: 22,1704-1713) easily dimerized domain replacement. Therefore when the chimeric receptor is expressed and added in the host cell line This results in autophosphorylation of the kinase domain of the chimeric receptor when the respective ligand is used. This approach generally allows the use of known (and often readily available) ligands without the need to identify and isolate each target receptor's native Ligand advantage.

Naturally, if a ligand is available, native cell lines or primary cells known to selectively express the receptor and stimulated with the ligand alone to obtain ligand-induced phosphorylation can be used. This assay can be used to measure the ability of a compound to inhibit autophosphorylation of the Tie2 receptor, e.g. , Chapel Hill, N.C.27599-41000, provided by USA) or native HUVEC (human umbilical vein endothelial cells - available from various commercial sources).

Native Ang1 ligands can be isolated from tumor cell supernatants using standard purification techniques, or the Ang1 gene can be cloned and recombinantly expressed using standard molecular biology techniques and expression systems. In this case, an attempt can be made to produce the ligand in its native state or as a recombinant protein which may have been genetically engineered to contain additional purified tails (e.g. polyhistidine peptides, antibody Fc domains) to facilitate the process .

Taking ligand stimulation of EA.hy926/B3 or HUVEC cell Tie2 receptor as an example, an Ang1 ligand stimulation cell receptor phosphorylation test can be established, which can be used to analyze and determine the potential of compounds to inhibit this process. For example, in 6-well plates, EA.hy926/B3 cells are grown for 2 days in appropriate tissue culture medium plus 10% fetal calf serum (FCS) starting at an initial seeding density of 5 x 105 cells/well. On the third day, cells were serum starved for a total of 2 hours by replacing the previous medium with medium containing only 1% FCS. After 1 hour and 40 minutes of serum starvation, the medium was removed and replaced with 1 ml of test compound dilutions (compound dilutions prepared in serum starved medium but kept below 0.8% DMSO concentration). After 1.5 hours of serum starvation, orthovanidate (orthovanidate) was added to a final concentration of 0.1 mM for the last 10 minutes of serum starvation.

After a total of 2 hours of serum starvation, add ligand and orthovanadate to stimulate cell Tie2 receptor autophosphorylation (purified ligand material diluted with serum starvation medium can be added, or mammalian cells containing ligand such as recombinant expression can be added unpurified cell supernatant).

After incubation with the ligand for 10 minutes at 37°C, the cells were cooled on ice, washed with about 5 ml of cold PBS containing 1 mM orthovanadate, and then 1 ml of ice-cold lysis buffer ((20 mM Tris pH 7.6 , 150mM NaCl, 50mM NaF, 0.1% SDS, 1% NP40, 0.5% DOC, 1mM orthovanadate, 1mM EDTA, 1mM PMSF, 30μl/ml aprotinin, 10μg/ml pepstatin, 10μg/ml leucin Aprotinin) was added to the cells and placed on ice for 10-20 minutes. The cell lysate was pipetted and transferred to a 1.5ml Eppendorf tube, and centrifuged at 13000rpm at 4°C for 3 minutes. Transfer 800μl of each cell lysate to a new Immunoprecipitation was performed in a 2ml Eppendorf tube. Add 3mg=15μl anti-phospho-tyrosine antibody (Santa Cruz PY99-sc-7020) to the cell lysate and incubate at 4°C for 2 hours. Wash 600μl MagnaBind Beads (goat anti-mouse IgG, Pierce 21354) were added to the lysate and tubes were rotated overnight at 4°C.

The samples were treated in the magnetic field for 1 min, and then the cell lysate supernatant was carefully removed. Then 1 ml of lysis buffer was added to the beads, and this step was further repeated 2 times. Beads were suspended in 25 μl of 94°C hot 2×Laemmli loading buffer plus β-mercaptoethanol and allowed to stand for 15 min at room temperature.

Beads were removed by exposing the tubes to a magnetic field for 1 min and all liquid isolated from each immunoprecipitated strain was loaded on a polyacrylamide/SDS protein gel (precast 4-12% BisTrisNuPAGE/MOPS 12 well gel from Novex). Protein gels were run at 200V and then blotted on NC membranes at 50V/250mA for 1h30min. All blots were treated with 5% Marvel in PBS-Tween for 1 hr at room temperature to reduce non-specific binding to the probing antibodies. Rabbit anti-Tie2 (Santa Cruz sc-324) was added to the solution diluted with 0.5% Marvel/PBS-Tween (1:500) and incubated overnight at 4°C. Blots were washed vigorously with PBS-Tween and then added to a solution of goat anti-rabbit-POD conjugate (Dako P0448) diluted in 0.5% Marvel/PBS-Tween (1 :5000). Antibodies were left at room temperature for 1 hr, and blots were subsequently washed with PBS-Tween. Western blots of various immunoprecipitated samples were developed with LumiGLO (NEB7003). Then move to the X-ray cassette and expose the film for 15 sec/30 sec and 60 sec. The relative intensities of protein bands associated with phosphorylated Tie2 receptors were evaluated with the FluorS BioRad image analyzer system. The percent phosphorylation for each test compound dilution series was determined by calculating _IC50 values by standard methods with reference to appropriate control samples.

Although the pharmacological properties of compounds of formula I vary as expected with structural changes, in general, the following concentrations or doses of compounds of formula I have activity that can be demonstrated in one or more of the above tests (a) and (b):

1(a): - IC ₅₀ in the range of eg <100 μM;

Assay (b): - _IC50 in the range of eg <50 μM;

For example, Table A illustrates the activity of representative compounds according to the invention. Column 2 of Table A shows the _IC50 data for the test (a) of inhibition of Tie2 receptor tyrosine kinase in vitro, and column 3 shows the IC50 data for test (b) of inhibition of Tie2 receptor tyrosine kinase autophosphorylation. _IC50 data.

Table A

Example number IC ₅₀ (μM) test (a): Inhibition of Tie2 receptor tyrosine kinase in vitro IC ₅₀ (μM) test (b): Inhibition of Tie2 receptor tyrosine kinase autophosphorylation 6 20 1.7 12 25 1.3 14 20 0.38 45 3.3 0.2 47 1.5 1.9 50 9.0 3.6

For example, Table A illustrates the activity of representative compounds according to the invention. Column 2 of Table A shows the _IC50 data for the test (a) of inhibition of Tie2 receptor tyrosine kinase in vitro, and column 3 shows the IC50 data for test (b) of inhibition of Tie2 receptor tyrosine kinase autophosphorylation. _IC50 data.

In the following paragraphs reference is made to compounds of the formula I and also to the subgroups of the invention as described above, for example, in other subgroups of the invention the compounds of the formulas Ia, Ib, Ic and Id will also apply.

According to another aspect of the present invention there is provided a pharmaceutical composition comprising the compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier.

The composition of the present invention may be in a form suitable for oral use (e.g. tablet, lozenge, hard or soft capsule, aqueous or oily suspension, emulsion, dispersible powder or granule, syrup or elixirs), for topical application (e.g. as a cream, ointment, gel, or aqueous or oily solution or suspension), for inhalation administration (e.g. as a finely divided powder or liquid aerosol), in a form for insufflation administration (e.g. as a finely divided powder) or in a form for parenteral administration (e.g. as a sterile aqueous or as an oily solution or as a suppository for rectal dosing).

The composition of the present invention can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavoring and/or preservative agents.

The amount of active ingredient which is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host being treated and the particular route of administration. For example, a formulation designed for oral administration to humans will generally contain, for example, 0.5 mg to 0.5 g (more suitably 0.5 to 100 mg, e.g. 1 to 30 mg) of the active agent in admixture with suitable and convenient amounts of excipients, The excipients may vary from about 5 to about 98% by weight of the total composition.

The size of the dose of the compounds of formula I used for therapeutic or prophylactic purposes may of course vary according to the nature and severity of the condition, the age and sex of the animal or patient and the route of administration, according to the well-known principles of pharmaceuticals.

When using a compound of formula I for therapeutic or prophylactic purposes, it is generally administered such that, for example, a daily dosage range of 0.1 mg/kg to 75 mg/kg body weight is accepted, in divided doses if necessary . When the parenteral route is used, generally lower dosages will be administered. Thus, eg, for intravenous administration, a dosage range of eg 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similarly, for administration by inhalation a dosage range of eg 0.05 mg/kg to 25 mg/kg body weight will be used. However, oral administration is preferred, especially in tablet form. Typically, unit dosage forms will contain from about 0.5 mg to 0.5 g of a compound of the invention.

The most beneficial aspect of the compounds according to the invention as defined herein is their anti-angiogenic effect. Compounds of the invention are expected to be useful in the treatment or prevention of a variety of disease states associated with undesirable or pathological angiogenesis, including cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangiomas, lymphedema, acute and chronic kidney disease , atheroma, restenosis after arterial surgery, autoimmune diseases, acute inflammation, excessive scarring and adhesions, endometriosis, functional menstrual disorders and ocular diseases with retinal vascular proliferation. Cancer can affect any tissue, and cancers include leukemia, multiple myeloma, and lymphoma. In particular, it is expected that the compounds of the present invention will advantageously reduce the growth of primary and recurrent solid tumors such as colon, breast, prostate, lung and skin.

We believe that the antiangiogenic properties of the compounds according to the invention derive from their Tie2 receptor tyrosine kinase inhibitory properties. Accordingly, it is expected that the compounds of the invention may be used to produce Tie2 inhibition in warm-blooded animals in need of such treatment. Thus, the compounds of the invention may exert an anti-angiogenic effect mediated solely or in part through inhibition of the Tie2 receptor tyrosine kinase.

More particularly, compounds of the invention are expected to inhibit any form of Tie2-associated cancer. For example, the growth of primary and recurrent solid tumors associated with Tie2, especially those whose growth and spread are significantly dependent on the Tie2 receptor tyrosine kinase.

According to another aspect of the present invention there is provided a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use as a medicament.

According to another aspect of the present invention, there is provided a compound of formula I as defined above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use as a Tie2 receptor tyrosine kinase inhibitor in a warm-blooded animal such as a human the use of.

According to another aspect of the present invention, there is provided a use of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for producing an anti-angiogenic effect in a warm-blooded animal such as a human.

According to another aspect of the present invention, there is provided the use of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a warm-blooded animal such as a human.

According to another aspect of the present invention, there is provided the use of the compound of formula I as defined above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer selected from the following in warm-blooded animals (such as humans): Blood cancer, breast cancer, lung cancer, colon cancer, rectal cancer, stomach cancer, prostate cancer, bladder cancer, pancreatic cancer, ovarian cancer, lymph gland cancer, testicular cancer, neuroblastoma, liver cancer, cholangiocarcinoma, renal cell carcinoma, uterine cancer , thyroid and skin cancers.

According to another aspect of the present invention, there is provided a method of inhibiting Tie2 receptor tyrosine kinase in a warm-blooded animal (such as a human being) in need of said treatment, comprising administering to said animal an effective amount of formula I as defined above compound or its pharmaceutically acceptable salt.

According to another aspect of the present invention, there is provided a method for producing an anti-angiogenic effect in a homeothermic animal (such as a human being) in need of said treatment, comprising administering to said animal an effective amount of a compound of formula I as defined above or a pharmaceutically effective amount thereof acceptable salt.

According to another aspect of the present invention, there is provided a method for treating cancer in a warm-blooded animal (such as a human) in need of said treatment, comprising administering to said animal an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable Accepted salt.

According to another aspect of the present invention, there is provided the treatment of cancers selected from the group consisting of blood cancer, breast cancer, lung cancer, colon cancer, rectal cancer, stomach cancer, prostate cancer, bladder cancer, pancreatic cancer in a warm-blooded animal (such as a human being) in need of said treatment. , ovarian cancer, lymph gland cancer, testicular cancer, neuroblastoma, liver cancer, cholangiocarcinoma, renal cell carcinoma, uterine cancer, thyroid cancer or skin cancer, comprising administering to said animal an effective amount of A compound of formula I or a pharmaceutically acceptable salt thereof.

According to another aspect of the present invention, there is provided a compound of formula I as defined above or a pharmaceutically acceptable salt thereof for use in inhibiting Tie2 receptor tyrosine kinase in a warm-blooded animal such as a human.

According to another aspect of the present invention, there is provided a compound of formula I as defined above or a pharmaceutically acceptable salt thereof for use in producing an anti-angiogenic effect in a warm-blooded animal such as a human.

According to another aspect of the present invention, there is provided a compound of formula I as defined above or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

According to another aspect of the present invention, there is provided a method for treating cancers selected from blood cancer, breast cancer, lung cancer, colon cancer, rectal cancer, stomach cancer, prostate cancer, bladder cancer, pancreatic cancer, ovarian cancer, lymph gland cancer, testicular cancer, adult A compound of formula I as defined above or a pharmaceutically acceptable salt thereof for neurocytoma, liver cancer, cholangiocarcinoma, renal cell carcinoma, uterine cancer, thyroid cancer or skin cancer.

As noted above, it is further expected that the compounds of the present invention will have activity against other diseases mediated by unwanted or pathological angiogenesis, including psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, lymphedema, acute and chronic kidney disease, atheroma, arterial postoperative restenosis, autoimmune disease, acute inflammation, excessive scarring and adhesions, endometriosis, functional menstrual disorders, and ocular diseases with retinal vascular proliferation.

The antiangiogenic activity as defined herein may be used as a sole therapy or may involve, in addition to the compounds of the invention, one or more other substances and/or treatments. Said combination therapy may be achieved by simultaneous, sequential or separate administration of the single therapeutic components. In the field of medical oncology, individual cancer patients can often be treated with a combination of different treatment modalities. In medical oncology, in addition to the cell cycle inhibitory therapy defined above, the other components of said combination therapy may be: surgery, radiotherapy or chemotherapy. The chemotherapy may include one or more of the following classes of antineoplastic agents:

(i) anti-invasive agents (such as metalloproteinase inhibitors (such as marimastat) and inhibitors of urokinase plasminogen activator receptor function);

(ii) Antiproliferative/antineoplastic agents and combinations thereof used in medical oncology, such as alkylating agents (e.g., cisplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, Nitrogen mustard, Maryland, and nitrosourea); antimetabolites (such as antifolates, such as fluoropyrimidines, such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, and hydroxy Urea, or, for example, one of the preferred antimetabolites disclosed in European Patent Application No. 562734, such as (2S)-2-{o-fluoro-p-[N-{2,7-dimethyl-4-oxo Substitute-3,4-dihydroquinazolin-6-ylmethyl}N-(prop-2-ynyl)amino]benzoamido}-4-(tetrazol-5-yl)butanoic acid); Antineoplastic antibiotics (eg, anthracyclines, such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, actin mithramycin and mithramycin); antimitotic agents (such as vinca alkaloids (such as vincristine, vinblastine, deacetylvinblastamide, and vinorelbine) and taxoids (such as paclitaxel and taxotere)); and topical Isomerase inhibitors (eg, epipodophyllotoxins (such as etoposide and epipodophyllotoxin), amyridine, topotecan, and camptothecin);

(iii) Cytostatic agents, such as antiestrogens (eg, tamoxifen, toremifene, raloxifene, droloxifene, and iodoxyfene), antiandrogens (eg, bicalutamide, flutamide Nilutamide, and Cypron acetate), LHRH antagonists or LHRH agonists (such as goserelin, leuprolide, and buserelin), progestins (such as megestrol), aromatase inhibitors agents (such as anastrozole, letrozole, vorazole, and exemestane) and 5α-reductase inhibitors (such as finasteride);

(iv) inhibitors of growth factor function, for example said inhibitors include growth factor antibodies, growth factor receptor antibodies, farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine-threonine kinase inhibitors, for example Epidermal growth factor family inhibitors (e.g. EGFR tyrosine kinase inhibitor N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazole Lin-4-amine (ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (CP358774) and 6-acrylamide -N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI1033)), such as platelet-derived growth factor family inhibitors and for example hepatocyte growth factor family inhibitors;

(v) Anti-angiogenic agents that work by different mechanisms as defined above, such as those that inhibit vascular endothelial growth factor, such as those disclosed in International Patent Applications WO97/22596, WO97/30035, WO97/32856 and WO98/13354 Compounds and those agents that work by other mechanisms (e.g., linominides, inhibitors of integrin αvβ3 function and angiogenesis);

(vi) Biotherapeutic therapeutics, such as those that use or array receptor ligands, block ligand binding to receptors, or reduce receptor signaling (e.g., due to enhanced receptor degradation or reduced expression levels) of peptides or proteins ( methods such as antibody or soluble external receptor domain structures);

(vii) antisense therapies, such as those directed at the above-mentioned targets, such as ISIS2503, anti-ras antisense;

(viii) Gene therapy approaches, including, for example, replacement of abnormal genes (such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (direct gene-targeted enzyme prodrug therapy) using, for example, cytosine deaminase, thymidine kinase or bacterial nitroreductase ) methods) and methods of enhancing patient resistance to chemotherapy or radiation therapy (e.g., multidrug resistance gene therapy); and

(ix) Immunotherapy approaches, including in vitro and in vivo approaches to enhance the immunogenicity of tumor cells in patients (eg, transduction with cytokines such as interleukin 2, interleukin 4, or granulocyte-macrophage colony-stimulating factor) transfection), methods of reducing T cell anergy, methods of using transfected immune cells (such as transfected cytokine dendritic cells), methods of using transfected cytokine tumor cell lines, and methods of using anti-atopic antibodies.

The combination therapy can be achieved by simultaneous, sequential or divided dosage administration of the single therapeutic components. Such combination products employ a compound of the present invention within the dosage range described above and the other pharmaceutically active agent within its approved dosage range.

According to this aspect of the invention there is provided a pharmaceutical product comprising a compound of formula I as defined above and a further antineoplastic substance as defined above for combination therapy of cancer.

In addition to their use in therapeutic drugs, the compounds of formula I and their pharmaceutically acceptable salts can also be used as effective pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of cellular The role of periodic active inhibitors in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice as part of the development of new therapeutic agents.

The invention will now be illustrated by the following non-limiting examples, where unless otherwise stated:

(i) Temperatures are given in degrees Celsius (°C); operations are carried out at room or ambient temperature, i.e., within the temperature range of 18°C to 25°C;

(ii) All organic solutions were dried with anhydrous sodium sulfate; solvent evaporation was carried out under reduced pressure (600-4000 Pascal; 4.5-30mmHg) using a rotary evaporator, and the bath temperature was as high as 60°C;

(iii) Chromatography refers to flash chromatography carried out on silica gel; thin layer chromatography (TLC) is carried out on silica gel plate;

(iv) Typically, TLC and/or analytical LC-MS are performed after the course of the reaction, and the reaction times are given as examples only;

(v) The final product has satisfactory proton nuclear magnetic resonance (NMR) spectral and/or mass spectral data;

(vi) Yields are for illustration only and are not necessarily those values that can be obtained through diligent process development; if more material is required, the preparation is repeated;

(vii) When given, NMR data are in the form of delta values for the primary determination of protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, unless otherwise stated, using Perdeuterated dimethyl sulfoxide (DMSO-d ₆ ) as solvent determined at 300 MHz; the following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad;

(viii) chemical symbols have their usual meanings, using SI units and symbols;

(ix) solvent ratios are given in volume:volume (v/v); and

(x) Mass spectrometry (MS) using a directly exposed probe, by chemical ionization (CI) run with an electron energy of 70 electron volts; where the indicated ionization is by electron impact (EI), fast atom bombardment (FAB ) or electrospray (ESP) implementation; if m/z values are given, usually only ions representing the parent mass are reported; and unless otherwise stated, the mass ions listed are MH ⁺ ;

(xi) Unless otherwise stated, compounds containing asymmetrically substituted carbon and/or sulfur atoms were not resolved;

(xii) wherein in the synthesis described similarly to the previous example, the amount used is a millimolar ratio corresponding to the amount used in the previous example.

(xvi) The following abbreviations are used:

AcOH Acetic acid

AIBN 2,2'-azobisisobutyronitrile

DCM dichloromethane

DIPEA Diisopropylethylamine

DMA N, N-Dimethylacetamide

DMF N,N-Dimethylformamide

DMSO Dimethyl Sulfoxide

DMTMM 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride

dppf 1,1'-bis(diphenylphosphino)ferrocene

EtOAc Ethyl acetate

HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate

iPrMgCl Isopropyl magnesium chloride

LDA Lithium diisopropylamide

LHMDS lithium bis(trimethylsilyl)amide

m-CPBA m-chloroperbenzoic acid

MeOH Methanol

MeCN Acetonitrile

MCX mixed cation exchange resin

MTBE Methyl tert-butyl ether

LCMS Liquid Chromatography-Mass Spectrometry

NMP 1-methyl-2-pyrrolidone

POCl ₃ phosphorus oxychloride

RPHPLC reversed phase high performance liquid chromatography

TFA Trifluoroacetic acid

THF Tetrahydrofuran

SM raw material

xvii) When the synthesis is described as resulting in an acid addition salt (eg the HCl salt), the stoichiometry of the salt is not stated. Unless otherwise stated, all NMR data are reported for the free base, and isolated salts were converted to the free base form prior to characterization.

Example 1

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-[(4-morpholin-4-ylpyrimidin-5-yl)methyl]urea

At 80°C, phenyl {3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}carbamate (Intermediate 2) (50 mg), 1-(4-morpholin-4-yl Pyrimidin-5-yl)methanamine (58 mg) and triethylamine (0.06 mL) were heated in THF (2 mL) for 24 hours. The reaction mixture was concentrated in vacuo, the resulting solid was triturated with diethyl ether and dried in vacuo at 60 °C to give the title compound (22 mg, 34%) as a solid;

¹ H NMR (DMSO-d ₆ ) 3.37-3.44 (m, 4H), 3.66-3.73 (m, 4H), 4.24-4.30 (d, 2H), 6.67-6.73 (t, 1H), 7.01-7.06 (m , 1H), 7.09(s, 2H), 7.21-7.31(m, 2H), 7.67(s, 1H), 8.30(s, 1H), 8.40(s, 1H), 8.57(s, 1H), 8.74( s, 1H);

MS m/e MH ⁺ 431.

Intermediate 1

5-[(3-Aminophenyl)ethynyl]pyrimidin-2-amine

2-Amino-5-iodopyrimidine (2.21 g), bis(triphenylphosphine)palladium dichloride (350 mg) and ketone(I) iodide (40 mg) were dissolved in DMF (100 mL)-triethylamine (20 mL). ) was stirred and degassed with nitrogen for 10 minutes. 3-Ethynylaniline (1.29 g) was added and the resulting mixture was heated to 95°C for 2 hours. The solvent was evaporated and the residue was purified by trituration with DCM (20 mL) to give the title compound (1.25 g, 60%) as a tan solid;

¹ H NMR (DMSO-d ₆ ) 5.21 (bs, 2H), 6.58-6.70 (m, 3H), 7.03-7.07 (m, 3H), 8.40 (s, 2H);

MS m/e MH ⁺ 211.

Intermediate 2

Phenyl {3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}carbamate

Phenyl chloroformate (1.79 mL) was added dropwise to 5-[(3-aminophenyl)ethynyl]pyrimidin-2-amine (Intermediate 1) (2.0 g) and pyridine (1.54 mL) at 0 °C ) in THF solution. After 2 hours, the reaction mixture was quenched with water (20 mL) and concentrated in vacuo. The solid formed was filtered off, washed with water and then with ether to give the title compound (2.95 g, 94%) as a beige solid;

¹ H NMR (DMSO-d ₆ ) 7.15 (s, 2H), 7.20-7.32 (m, 4H), 7.36-7.55 (m, 4H), 7.69 (s, 1H), 8.45 (s, 2H), 10.37 ( s, 1H);

MS m/e MH ⁺ 331

The following examples were prepared in a similar manner to Example 1 using Intermediate 2 and the appropriate amine:

Example 2

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-[3-(2-oxopyrrolidin-1-yl)propyl]urea

SM: intermediate 2,1-(3-aminopropyl)-2-pyrrolidone

¹ H NMR (DMSO-d ₆ ) 1.54-1.66(qn, 2H), 1.85-1.97(qn, 2H), 2.18-2.25(t, 2H), 2.99-3.08(q, 2H), 3.16-3.24(t , 2H), 3.26-3.37(m, 2H), 6.20(t, 1H), 6.98-7.04(m, 1H), 7.09(bs, 2H), 7.18-7.29(m, 2H), 7.67(s, 1H ), 8.40(s, 2H), 8.68(s, 1H);

MS m/e MH ⁺ 379.

Example 3

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-(tetrahydro-2H-pyran-4-ylmethyl)urea

SM: intermediate 2,4-aminomethyltetrahydropyran

¹ H NMR (DMSO-d ₆ ) 1.08-1.24 (m, 2H), 1.49-1.72 (m, 3H), 2.94-3.02 (t, 2H), 3.19-3.30 (m, 2H), 3.79-3.89 (m , 2H), 6.22-6.30(t, 1H), 6.98-7.03(m, 1H), 7.09(bs, 2H), 7.21-7.26(m, 2H), 7.66(s, 1H), 8.40(s, 2H ), 8.50(bs, 1H);

MS m/e MH ⁺ 352.

Example 4

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-(tetrahydrofuran-2-ylmethyl)urea

SM: Intermediate 2, Tetrahydrofurfurylamine

¹ H NMR (DMSO-d ₆ ) 1.45-1.58 (m, 1H), 1.76-1.94 (m, 3H), 3.03-3.13 (m, 1H), 3.18-3.28 (m, 1H), 3.58-3.67 (m , 1H), 3.72-3.90(m, 2H), 6.20-6.26(t, 1H), 6.98-7.03(m, 1H), 7.09(bs, 2H), 7.21-7.27(m, 2H), 7.64(s , 1H), 8.41(s, 2H), 8.63(bs, 1H);

MS m/e MH ⁺ 338.

Example 5

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-(2-pyridin-3-ylethyl)urea

SM: intermediate 2,3-(2-aminoethyl)pyridine

¹ H NMR (DMSO-d ₆ ) 2.74-2.79(t, 2H), 3.32-3.39(m, 2H), 6.17-6.24(t, 1H), 6.99-7.04(m, 1H), 7.09(bs, 2H ), 7.20-7.27(m, 2H), 7.29-7.35(m, 1H), 7.63-7.68(m, 2H), 8.37-8.47(m, 4H), 8.56(bs, 1H);

MS m/e MH ⁺ 359.

Example 6

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-[(5-methyl-2-furyl)methyl]urea

SM: intermediate 2,5-methylfurfurylamine

¹ H NMR (DMSO-d ₆ ) 2.22(s, 3H), 4.19-4.25(d, 2H), 5.96-5.99(m, 1H), 6.09-6.13(m, 1H), 6.51-6.59(t, 1H ), 6.99-7.06(m, 1H), 7.09(bs, 2H), 7.19-7.30(m, 2H), 7.65(s, 1H), 8.41(s, 2H), 8.59(bs, 1H);

MS m/e MH ⁺ 348.

Example 7

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-(2-morpholin-4-ylbenzyl)urea

SM: intermediate 2,1-(2-morpholin-4-ylphenyl)methanamine

¹ H NMR (DMSO-d ₆ ) 2.79-2.90 (m, 4H), 3.70-3.79 (m, 4H), 4.34-4.42 (m, 2H), 6.54-6.61 (m, 1H), 6.98-7.18 (m , 5H), 7.20-7.34(m, 4H), 7.69(s, 1H), 8.40(s, 2H), 8.69(bs, 1H);

MS m/e MH ⁺ 429.

Example 8

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-{2-[4-(hydroxymethyl)piperidin-1-yl]benzyl}urea

SM: Intermediate 2, [1-[2-(aminomethyl)phenyl]-4-piperidinyl]methanol

¹ H NMR (DMSO-d ₆ ) 1.24-1.54 (m, 4H), 1.69-1.80 (m, 2H), 2.55-2.68 (m, 2H), 2.96-3.06 (m, 2H), 3.29-3.32 (m , 1H), 4.31-4.37(d, 2H), 4.43-4.49(t, 1H), 6.48-6.55(t, 1H), 6.98-7.30(m, 9H), 7.69(s, 1H), 8.40(s , 2H), 8.67(bs, 1H);

MS m/e MH ⁺ 457.

Example 9

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-(2-piperidin-1-ylbenzyl)urea

SM; intermediate 2, (2-piperidinophenyl)methylamine

¹ H NMR (DMSO-d ₆ ) 1.48-1.58 (m, 2H), 1.62-1.72 (m, 4H), 2.76-2.82 (m, 4H), 4.30-4.38 (d, 2H), 649-6.55 (t , 1H), 6.98-7.31(m, 9H), 7.69(s, 1H), 8.40(s, 2H), 8.67(bs, 1H);

MS m/e MH ⁺ 427.

Example 10

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N’-[2-(trifluoromethyl)benzyl]urea

SM: intermediate 2,2-(trifluoromethyl)benzylamine

¹ H NMR (DMSO-d ₆ ) 4.46-4.52(d, 2H), 6.73-6.79(t, 1H), 7.01-7.05(m, 1H), 7.11(bs, 2H), 7.19-7.31(m, 2H ), 7.42-7.50(m, 1H), 7.56-7.61(m, 1H), 7.63-7.74(m, 3H), 8.40(s, 2H), 8.84(bs, 1H);

MS m/e MH ⁺ 412.

Example 11

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N’-[2-(trifluoromethoxy)benzyl]urea

SM: intermediate 2,2-(trifluoromethoxy)benzylamine

¹ H NMR (DMSO-d ₆ ) 4.34-4.40(d, 2H), 6.67-6.73(t, 1H), 7.00-7.06(m, 1H), 7.09(bs, 2H), 7.20-7.29(m, 2H ), 7.31-7.42(m, 3H), 7.43-7.49(m, 1H), 7.68(s, 1H), 8.40(s, 2H), 8.77(bs, 1H);

MS m/e MH ⁺ 428.

Example 12

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-(3-hydroxy-1-phenylpropyl)urea

SM: intermediate 2,3-amino-3-phenyl-1-propanol

¹ H NMR (DMSO-d ₆ ) 1.78-1.89 (m, 2H), 3.36-3.45 (m, 2H), 4.53-4.59 (t, 1H), 4.78-4.87 (m, 1H), 6.71-6.77 (d , 1H), 6.97-7.03(m, 1H), 7.08(bs, 2H), 7.17-7.25(m, 3H), 7.28-7.35(m, 4H), 7.64(s, 1H), 8.39(s, 2H ), 8.55(bs, 1H);

MS m/e MH ⁺ 388.

Example 13

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N’-(1-phenyl-2-pyrrolidin-1-ylethyl)urea

SM: intermediate 2,1-phenyl-2-pyrrolidinylethylamine

¹ H NMR (DMSO-d ₆ ) 1.62-1.70 (m, 4H), 2.41-2.81 (m, 6H), 4.69-4.79 (m, 1H), 6.62-6.67 (d, 1H), 6.96-7.02 (m , 1H), 7.08(bs, 2H), 7.16-7.26(m, 3H), 7.28-7.34(m, 4H), 7.66(s, 1H), 8.39(s, 2H), 8.77(bs, 1H);

MS m/e MH ⁺ 427.

Example 14

N-[(5-methyl-2-furyl)methyl]-N'-[3-({2-[(3-piperidin-1-ylpropyl)amino]pyrimidin-5-yl}acetylene base) phenyl] urea

Phenyl chloroformate (103 mg) was added dropwise to stirred 5-[(3-aminophenyl)ethynyl]-N-(3-piperidin-1-ylpropyl)pyrimidine at 0-5°C -2-Amine (Intermediate 4) (202 mg) and pyridine (95 mg) in THF (5 mL). The above reaction mixture was stirred and allowed to warm to ambient temperature. The solvent was evaporated and the resulting product was dissolved in THF (10 mL) and triethylamine (115 mg). 5-Methylfurfurylamine (0.5 mL) was added and the reaction was stirred and heated at 75 °C for 3 hours. The solvent was evaporated and the product was purified by flash chromatography on silica gel using 1-12% methanol/NH3 in DCM as eluent. Trituration of the final product with methanol afforded the title compound as an off-white solid. (196 mg);

¹ H NMR (DMSO-d ₆ ) 1.30-1.41 (m, 2H), 1.42-1.53 (m, 4H), 1.66 (quintet, 2H), 2.22 (s, 3H), 2.24-2.35 (m, 6H) ), 3.24-3.37(m, 2H), 4.21(d, 2H), 5.95-6.00(m, 1H), 6.11(d, 1H), 6.56(t, 1H), 6.99-7.05(m, 1H), 7.22-7.27(m, 2H), 7.66(s, 1H), 7.71(t, 1H), 8.44(s, 2H), 8.60(s, 1H);

MS m/e MH ⁺ 473

Intermediate 3

{3-[(2-chloropyrimidin-5-yl)ethynyl]phenyl}amine

Palladium (10 wt.%) on activated carbon (1.5 g) was added to a stirred solution of 5-bromo-2-chloropyrimidine (12.76 g) and 3-ethynylaniline (9.28 g) in DIPEA ( 120mL) solution. The above reaction mixture was stirred at 80°C for 4 hours. The resulting reaction mixture was filtered through celite and washed with DCM. The filtrate was purified by flash chromatography on silica using 0-30% EtOAc in DCM as eluent. The resulting solid was triturated with ether to give the title compound (4.28 g, 28%) as a cream solid;

¹ H NMR (DMSO-d ₆ ) 5.31 (s, 2H), 6.64 (dd, 1H), 6.69-6.76 (m, 2H), 7.08 (dd, 1H), 8.94 (s, 2H);

MS m/e(MH+MeCN) ⁺ 271.

Intermediate 4

5-[(3-Aminophenyl)ethynyl]-N-(3-piperidin-1-ylpropyl)pyrimidin-2-amine

p-{3-[(2-Chloropyrimidin-5-yl)ethynyl]phenyl}amine (Intermediate 3) (1.2 g) and 3-(1-piperidinyl)propylamine (3.7 g) in MeCN (15 mL) g) Stirring was carried out and HCl (1.0M in diethyl ether) (6.3 mL) was added dropwise. The above reaction mixture was stirred and heated at 80°C for 1 hour. The solvent was evaporated and the product was purified by flash chromatography on silica using 0-10% methanol/NH3 in DCM as eluent to give the title compound as an off-white solid (1.2 g, 69% );

¹ H NMR (DMSO-d ₆ ) 1.31-1.42 (m, 2H), 1.42-1.53 (m, 4H), 1.66 (quintet, 2H), 2.19-2.37 (m, 6H), 3.25-3.35 (m , 2H), 5.19(s, 2H), 6.53-6.63(m, 2H), 6.67(s, 1H), 7.01(t, 1H), 7.64(t, 1H), 8.40(s, 2H)

MS m/e MH ⁺ 336.

The following examples were prepared in a similar manner to Example 14 using intermediate 4 and the appropriate amine:

Example 15

N-(2-morpholin-4-ylbenzyl)-N'-[3-({2-[(3-piperidin-1-ylpropyl)amino]pyrimidin-5-yl}ethynyl)benzene base] urea

SM: intermediate 4, (2-morpholin-4-ylbenzyl)amine

¹ H NMR (DMSO-d ₆ ) 1.31-1.41 (m, 2H), 1.42-1.54 (m, 4H), 1.66 (quintet, 2H), 2.24-2.37 (m, 6H), 2.80-2.88 (m , 4H), 3.27-3.35(m, 2H), 3.71-3.78(m, 4H), 4.38(d, 2H), 6.58(t, 1H), 6.97-7.17(m, 3H), 7.18-7.34(m , 4H), 8.44(s, 2H), 8.44(s, 2H), 8.70(s, 1H)

MS m/e MH ⁺ 554.

Example 16

N-{5-[(2-aminopyrimidin-5-yl)ethynyl]-1,3-thiazol-2-yl}-N’-[(5-methyl-2-furyl)methyl]urea

In dry DMF (3 mL), p-2-amino-5-ethynylpyrimidine (Intermediate 6) (119 mg), N-(5-bromo-1,3-thiazol-2-yl)-N'-[ (5-methyl-2-furyl)methyl]urea (Intermediate 8) (316 mg), 1,1,3,3-tetramethylguanidine (138 mg) and ketone iodide (I) (10 mg) The mixture was stirred and degassed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (116 mg) was added thereto, and the resulting mixture was heated at 60°C for 3 hr. The resulting mixture was concentrated, cooled, stirred and diluted with water (20 mL). The solid formed was filtered off and dried. Purification by flash chromatography on silica using 0-40% methanol in DCM as eluent followed by trituration with DCM gave the title compound as a solid (33 mg, 9%);

¹ H NMR (DMSO-d ₆ ) 2.23(s, 3H), 4.29(d, 2H), 6.00(d, 1H), 6.17(d, 1H), 6.93(t, 1H), 7.12(s, 2H) , 7.59(s, 1H), 8.41(s, 2H) 10.70(s, 1H);

MS m/e MH ⁺ 355.

Intermediate 5

5-[(Trimethylsilyl)ethynyl]pyrimidin-2-amine

PdCl ₂ dppf (146 mg) was added to 2-amino-5-iodopyrimidine (221 mg), trimethylsilylacetylene (491 mg), CuI (57 mg) and DIPEA (259 mg) at 20 °C under an inert atmosphere ) in EtOAc (5 mL). The above reaction mixture was allowed to warm to ambient temperature and it was stirred for 6 hours. The above reaction mixture was diluted with water (10 mL). The organic layer was separated, dried ( _MgSO4 ), filtered and concentrated. The resulting crude product was used without further purification (191 mg, 100%);

¹ H NMR (CDCl ₃ ) 0.26(s, 9H), 5.19(bs, 2H), 8.39(s, 2H);

MS m/e MH ⁺ +MeCN233.

Intermediate 6

5-Ethynylpyrimidin-2-amine

Potassium carbonate (276 mg) was added to 5-[(trimethylsilyl)ethynyl]pyrimidin-2-amine (Intermediate 5) (191 mg) in MeOH (40 mL):water (20 mL). Under an inert atmosphere, the above reaction mixture was stirred at ambient temperature for 24 hours, then neutralized with 1M HCI. The reaction mixture was then concentrated and the residue was dissolved in DCM (30 mL). The resulting DCM phase was washed with water (15 mL), washed with brine (15 mL), dried ( _MgSO4 ), filtered and concentrated. The resulting crude product was used without further purification (119 mg, 100%);

¹ H NMR (CDCl ₃ ) 3.19(s, 1H), 5.26(bs, 2H), 8.41(s, 2H);

MS m/e MH ⁺ +MeCN161.

Intermediate 7

(5-Bromo-1,3-thiazol-2-yl)phenylcarbamate

A cooled (ice bath) solution of 2-amino-5-bromothiazole (6.27 g) and pyridine (3.22 mL) in anhydrous DCM (120 mL) was stirred under an inert atmosphere. A solution of phenylchloroformate (4.4 mL) in DCM (20 mL) was added dropwise, which was then stirred for 2 hours. The above mixture was concentrated and diluted with isohexane and water. The solid formed was filtered off, washed with water then isohexane:DCM and dried at ambient temperature. The resulting solid was taken up in THF (400 mL), dried ( _MgSO4 ) and the solvent was evaporated to give the product (9.5 g, 88%).

¹ H NMR (DMSO-d ₆ ) 7.27 (m, 3H), 7.44 (m, 2H), 7.52 (s, 1H);

MS m/e MH ⁺ 301, 299 (1x Br).

Intermediate 8

N-(5-bromo-1,3-thiazol-2-yl)-N’-[(5-methyl-2-furyl)methyl]urea

Phenyl (5-bromo-1,3-thiazol-2-yl)carbamate (Intermediate 7 ) (1.79 g) was stirred with [(5-methyl-2-furyl)methyl]amine (0.67 g) and triethylamine (1.0 mL) for 1 hour. It was concentrated and then purified by flash chromatography on silica using 0-100% EtOAc in DCM and then 0-10% MeOH in DCM as eluents to give Product (0.9g, 47%);

¹ H NMR (DMSO-d ₆ ) 2.22(s, 3H), 4.25(d, 2H), 5.98(d, 1H), 6.12(d, 1H), 6.87(t, 1H), 7.37(s, 1H) , 10.60(bs, 1H);

MS m/e MH ⁺ 318, 316 (1x Br).

Example 17

N-{5-[(2-aminopyrimidin-5-yl)ethynyl]-1,3-thiazol-2-yl}-N'-(2-morpholin-4-ylbenzyl)urea

Preparation was carried out in a similar manner to Example 16.

SM: 2-amino-5-ethynylpyrimidine (intermediate 6), N-(5-bromo-1,3-thiazol-2-yl)-N'-(2-morpholin-4-ylbenzyl) Urea (Intermediate 9)

¹ H NMR (DMSO-d ₆ ) 2.83(m, 4H), 3.75(m, 4H), 4.42(d, 2H), 6.91(m, 1H), 7.05-7.32(m, 6H), 7.57(s, 1H), 8.38(s, 2H), 10.83(bs, 1H);

MS m/e MH ⁺ 436.

Intermediate 9

N-(5-bromo-1,3-thiazol-2-yl)-N’-(2-morpholin-4-ylbenzyl)urea

Preparation was carried out in a similar manner to Intermediate 8.

SM: (5-bromo-1,3-thiazol-2-yl)phenylcarbamate (Intermediate 7), (2-morpholin-4-ylbenzyl)amine

¹ H NMR (DMSO-d ₆ ) 2.82(m, 4H), 3.74(m, 4H), 4.41(d, 2H), 6.88(t, 1H), 7.05-7.32(m, 4H), 7.37(s, 1H), 10.76(bs, 1H);

MS m/e MH ⁺ 399, 397 (1x Br).

The following examples were prepared in a manner similar to Example 1

Example 18

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-(2-morpholin-4-ylethyl)urea

SM: intermediate 2,4-(2-aminoethyl)morpholine

¹ H NMR (DMSO-d ₆ ) 2.36-2.42 (m, 6H), 3.23 (q, 2H), 3.60-3.63 (m, 4H), 6.13 (t, 1H), 7.02-7.05 (m, 1H), 7.12(s, 2H), 7.23-7.30(m, 2H), 7.69(s, 1H), 8.44(s, 2H), 8.74(s, 1H);

MS m/e MH ⁺ 367.

Example 20

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-(2-pyrrolidin-1-ylethyl)urea

SM: intermediate 2,1-(2-aminoethyl)pyrrolidine

¹ H NMR (DMSO-d ₆ ) 1.70-1.73 (m, 4H), 2.48-2.50 (m, 6H), 3.22 (q, 2H), 6.17 (t, 1H), 7.03 (dt, 1H), 7.12 ( s, 2H), 7.22-7.30 (m, 2H), 7.68 (s, 1H), 8.44 (s, 2H), 8.75 (s, 1H);

MS m/e MH ⁺ 351.

Example 21

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-[2-(pyridin-2-ylamino)ethyl]urea

SM: intermediate 2, N1-pyridin-2-yl-ethane-1,2-diamine

¹ H NMR (DMSO-d ₆ ) 3.28-3.35 (m, 4H), 6.33-6.35 (m, 1H), 6.51-6.56 (m, 3H), 7.03-7.05 (m, 1H), 7.12 (s, 2H) ), 7.23-7.32(m, 2H), 7.35-7.41(m, 1H), 7.69(s, 1H), 7.97-7.99(m, 1H), 8.44(s, 2H), 8.65(s, 1H);

MS m/e MH ⁺ 374.

Example 22

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-(3-pyrrolidin-1-ylpropyl)urea

SM: intermediate 2,1-(3-aminopropyl)pyrrolidine

¹ H NMR (DMSO-d ₆ ) 1.59-1.72 (m, 6H), 2.40-2.44 (m, 6H), 3.15 (q, 2H), 6.22 (t, 1H), 7.01-7.05 (m, 1H), 7.12(s, 2H), 7.22-7.30(m, 2H), 7.69(s, 1H), 8.44(s, 2H), 8.55(s, 1H);

MS m/e MH ⁺ 365.

The following examples required further purification by RPHPLC ( _H2O :MeCNO-70%) to provide the title compound as a TFA salt.

Example 24

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-(2-thiomorpholin-4-ylethyl)urea

SM: intermediate 2,4-(2-aminoethyl)thiomorpholine

¹ H NMR (DMSO-d ₆ ) 2.89-3.05(m, 4H), 3.14-3, 39(m, 4H), 3.50(q, 2H), 3.80-3.84(m, 2H), 6.61(s, 1H ), 7.06-7.15(m, 3H), 7.26-7.37(m, 2H), 7.70(s, 1H), 8.43(s, 2H), 9.09(s, 1H);

MS m/e MH ⁺ 383.

Example 25

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N’-[2-(benzylamino)ethyl]urea

SM: intermediate 2,2-benzylaminoethylamine

¹ H NMR (DMSO-d ₆ ) 3.01-3.12 (m, 2H), 3.41-3.44 (m, 2H), 4.20-4.22 (m, 2H), 6.48-6.56 (m, 1H), 7.06-7.14 (m , 3H), 7.26-7.36(m, 2H), 7.41-7.54(m, 5H), 7.69(s, 1H), 8.43(s, 2H), 8.81(s, 1H), 8.92(s, 1H);

MS m/e MH ⁺ 387.

Example 26

N-{3-[(2-{[3-(Dimethylamino)propyl]amino}pyrimidin-5-yl)ethynyl]phenyl}-N'-(2-morpholin-4-ylbenzyl base) urea

At 50°C, 2-(4-morpholino)benzylamine (0.167mg), triethylamine (0.12mL) and 3-[(2-{[3-(dimethylamino)propyl]amino }pyrimidin-5-yl)ethynyl]phenylcarbamate (Intermediate 11) (300 mg) was heated in THF (10 mL) for 16 hours. The reaction mixture was concentrated in vacuo and the residue was triturated with ether to give the title compound (332 mg, 89%) as a beige solid;

¹ H NMR (DMSO-d ₆ ) 1.66-1.79 (m, 2H), 2.27 (s, 6H), 2.31-2.35 (m, 2H), 2.86 (t, 4H), 3.30-3.40 (m, 2H), 3.76(t, 4H), 4.39(d, 2H), 6.58(s, 1H), 7.02-7.05(m, 1H), 7.10(t, 1H), 7.15(d, 1H), 7.23-7.35(m, 4H), 7.68(t, 1H), 7.72(s, 1H), 8.47(s, 2H), 8.70(s, 1H);

MS m/e MH ⁺ 514.

Intermediate 10

N'-{5-[(3-aminophenyl)ethynyl]pyrimidin-2-yl}-N,N-dimethylpropane-1,3-diamine

3-[(2-Chloropyrimidin-5-yl)ethynyl]aniline (Intermediate 3) (2.23g), N,N-dimethylpropane-1,3-diamine (6.11mL) and 1.0M HCl in ether (11.7 mL) was dissolved in MeCN (10 ml) and it was heated to reflux for 4 hours. Concentration in vacuo and purification by flash chromatography on silica using 1-10% (10% 7N NH in MeOH) in DCM as eluent afforded the title compound (2.70 g, 94%);

¹ H NMR (DMSO-d ₆ ) 1.59-1.69 (m, 2H), 2.11 (s, 6H), 2.24 (t, 2H), 3.30 (t, 2H), 5.19 (s, 2H), 6.56 (dd, 1H), 6.61(d, 1H), 6.67(s, 1H), 7.01(t, 1H), 7.62(t, 1H), 8.40(s, 2H

MS m/e MH ⁺ 296.

Intermediate 11

Phenyl 3-[(2-{[3-(dimethylamino)propyl]amino}pyrimidin-5-yl)ethynyl]phenylcarbamate

N'-{5-[(3-aminophenyl)ethynyl]pyrimidin-2-yl}-N,N-dimethylpropane-1,3-diamine (Intermediate 10) (1.5 g) and Pyridine (0.41 mL) was dissolved in THF (200 mL) and cooled to 0 °C. Phenyl chloroformate (0.89 mL) was added dropwise and the resulting solution was allowed to warm to ambient temperature over 1 hour. The above reaction mixture was concentrated in vacuo and the resulting residue was dissolved in ethyl acetate, washed with aqueous sodium carbonate, water and brine, concentrated in vacuo and triturated with ether to give a colorless solid The title compound (2.28g).

¹ H NMR (DMSO-d ₆ ) 1.60-1.79 (m, 2H), 2.12 (s, 6H), 2.26 (t, 2H), 3.30-3.40 (m, 2H), 7.15-7.51 (m, 8H), 7.66-7.70(m, 2H), 8.45(s, 2H), 10.33(s, 1H);

MS m/e MH ⁺ 416.

The following examples were prepared in a similar manner to Example 1 using Intermediate 2 and the appropriate amine:

Example 27

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-{[(1R,2R)-2-hydroxycyclohexyl]methyl}urea

SM: Intermediate 2, cis-2-aminomethyl-1-cyclohexanol

¹ H NMR (DMSO-d ₆ ) 1.20-1.73 (m, 9H), 2.99-3.15 (m.2H), 3.79 (s, 1H), 4.38 (d, 1H), 6.22 (t, 1H), 7.03 ( d, 1H), 7.11(s, 2H), 7.22-7.27(m, 2H), 7.68(s, 1H), 8.44(s, 2H), 8.63(s, 1H);

MS m/e MH ⁺ 366.

Example 28

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-{[(1S,2R)-2-hydroxycyclohexyl]methyl}urea

SM: Intermediate 2, trans-2-aminomethyl-1-cyclohexanol

¹ H NMR (DMSO-d ₆ ) 0.97-1.26 (m, 6H), 1.60-1.86 (m, 3H), 3.09-3.18 (m, 2H), 3.23-3.29 (m, 1H), 4.70 (d, 1H) ), 6.24(t, 1H), 7.02-7.05(m, 1H), 7.11(s, 2H), 7.22-7.28(m, 2H), 7.69(s, 1H), 8.44(s, 2H), 8.64( s, 1H);

MS m/e MH ⁺ 366.

Example 29

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-(5-fluoro-2-morpholin-4-ylbenzyl)urea

SM: intermediate 2,5-fluoro-2-morpholin-4-ylbenzonitrile (intermediate 13)

¹ H NMR (DMSO-d ₆ ) 2.80(t, 4H), 3.73(t, 4H), 4.38(d, 2H), 6.65(t, 1H), 7.01-7.69(m, 8H), 7.68(s, 1H), 8.40(s, 2H), 8.72(s, 1H);

MS m/e MH ⁺ 447.

Intermediate 12

5-fluoro-2-morpholin-4-ylbenzonitrile

A suspension of 2,5-difluorobenzonitrile (13.9 g), potassium carbonate (27.6 g) and morpholine (13.2 mL) in DMSO (150 mL) was heated at 100°C for 18 hours, cooled and poured into water (500mL). The resulting aqueous phase was extracted with ether, washed with water and brine and concentrated in vacuo. The resulting oily solid was purified by flash chromatography on silica using 10-50% EtOAc in iso-hexane as eluent to give the title compound as an off-white solid (10.9 g);

¹ H NMR (CDCl ₃ ) 3.14(t, 4H), 3.90(t, 4H), 7.02(dd, 1H), 7.20-7.36(m, 2H);

MS m/e MH ⁺ 207.

Intermediate 13

1-(5-fluoro-2-morpholin-4-ylphenyl)methanamine

10% Pd/C (1.0 g) and 5-fluoro-2-morpholin-4-ylbenzonitrile (Intermediate 12) (10.9 g) in ethanol (200 mL) and concentrated aqueous HCl (10 mL) were dissolved at room temperature The suspension was hydrogenated at 50 psi for 24 hours. The resulting mixture was filtered through celite, concentrated in vacuo and purified by flash chromatography on silica using 10-100% EtOAc in iso-hexane as eluent to give β-R as a yellow oil. The title compound (4.0 g).

¹ H NMR (CDCl ₃ ) 2.87(t, 4H), 3.84(t, 4H), 3.90(s, 2H), 6.92(dt, 1H), 7.05-7.12(m, 2H);

MS m/e MH ⁺ 211.

Example 30

N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N'-[2-(4-methylpiperazin-1-yl)benzyl]urea

SM: Intermediate 2, 1-[2-(4-methylpiperazin-1-yl)phenyl]methylamine (Intermediate 14)

¹ H NMR (DMSO-d ₆ ) 2.30 (s, 3H), 2.54 (4H, shadowed by DMSO), 2.84 (t, 4H), 4.34 (d, 2H), 6.53 (t, 1H), 6.99-7.14 ( m, 5H), 7.18-7.31(m, 4H), 7.69(s, 1H), 8.41(s, 2H), 8.69(s, 1H);

MS m/e MH ⁺ 442.

Intermediate 14

1-[2-(4-Methylpiperazin-1-yl)phenyl]methylamine

2-(4-Methylpiperazin-1-yl)benzonitrile (J.Med.Chem., 1983, 1116-1122) (18.0 g) and 10% Pd/C ( 1.0 g) in ethanol (200 mL) and liquid ammonia (20 mL) was hydrogenated for 24 hours. The resulting mixture was filtered through celite, concentrated in vacuo and purified by flash chromatography on silica using 1-12% MeOH/ _NH3 in DCM as eluent to give The title compound as an oil (2.7g).

¹ H NMR (CDCl ₃ ) 1.76 (s, br, 2H), 2.58 (s, br, 4H), 2.96 (t, 4H), 3.88 (s, 2H), 7.05-7.30 (m, 4H);

MS m/e MH ⁺ 205

The following examples were prepared using Intermediate 6 and Intermediate 16 in a similar manner to Example 16.

Example 31

N-{5-[(2-aminopyrimidin-5-yl)ethynyl]-1,3,4-thiadiazol-2-yl}-N'-(2-morpholin-4-ylbenzyl) Urea

SM: 2-amino-5-ethynylpyrimidine (intermediate 6), N-(5-bromo-1,3,4-thiadiazol-2-yl)-N'-(2-morpholine-4- benzyl)urea (Intermediate 16)

¹ H NMR (DMSO-d ₆ ) 2.83 (m, 4H), 3.75 (m, 4H), 4.46 (d, 2H), 7.00-7.40 (m, 7H), 8.51 (s, 2H), 11.28 (bs, 1H);

MS m/e MH ⁺ 437.

Intermediate 15

(5-Bromo-1,3,4-thiadiazol-2-yl)phenylcarbamate

A solution of phenylchloroformate (4.4 mL) in DCM (20 mL) was added dropwise to stirred 2-amino-5-bromo-1,3,4-thiadiazole {Eur J. Med. Chem. .Chim.Ther.(1975) 121} (6.3g) in pyridine (100mL) solution. After 3 hours, the resulting mixture was concentrated and diluted with water (400 mL). The solid formed was filtered off and dried in vacuo at ambient temperature. Purification by flash chromatography on silica using acetone as eluent followed by trituration with ether/isohexane gave the product as a solid (5.3 g, 51%);

¹ H NMR (DMSO-d ₆ ) 7.29 (m, 3H), 7.44 (m, 2H), 13.10 (bs, 1H);

MS m/e MH ⁺ 300, 302 (1x Br).

The following intermediates were prepared in a similar manner to Intermediate 9 by using Intermediate 15 instead of Intermediate 7.

Intermediate 16

N-(5-bromo-1,3,4-thiadiazol-2-yl)-N’-(2-morpholin-4-ylbenzyl)urea

¹ H NMR (DMSO-d ₆ ) 2.78-2.87 (m, 4H), 3.71-3.77 (m, 4H), 4.41-4.46 (m, 2H), 7.00-7.10 (m, 2H), 7.13-7.18 (m , 1H), 7.22-7.30(2H, m);

MS m/e MH ⁺ 397, 399 (1x Br)

Example 32

N-{5-[(2-aminopyrimidin-5-yl)ethynyl]pyridin-3-yl}-N'-(2-morpholin-4-ylbenzyl)urea

At 80°C, {5-[(2-aminopyrimidin-5-yl)ethynyl]-pyridinyl}carbamate (Intermediate 21) (331 mg), (2-morpholin-4-yl Benzyl)amine (230 mg) and triethylamine (303 mg) were heated in 1,4-dioxane (10 mL) for 3 hours. The reaction mixture was concentrated to low volume in vacuo and diluted with ether. The solid formed was filtered off and dried in vacuo at 60 °C to give the title compound as a solid (417 mg, 97%);

¹ H NMR (DMSO-d ₆ ) 2.87 (m, 4H), 3.77 (m, 4H), 4.41 (d, 2H), 6.78 (t, 1H), 7.05-7.35 (m, 6H), 8.12 (m, 1H), 8.25(m, 1H), 8.51(m, 3H), 8.91(s, 1H);

MS m/e(MH) ^- 428.

Intermediate 17

(5-Bromopyridin-3-yl)carbamate tert-butyl ester

Triethylamine (7 mL) followed by DPPA (10.9 mL) was added to a solution of 5-bromonicotinic acid (10.1 g) and t-BuOH (7.1 mL) in toluene (100 mL) and the reaction was heated under an inert atmosphere Reflux for 1.5 hours. The resulting reaction mixture was diluted with EtOAc (100 mL) and water (100 mL). The organic layer was separated, washed with NaHCO ₃ (3×50 mL), dried (Mg ₂ SO ₄ ), filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using 0-4% EtOAc in DCM as eluent to afford the title compound (9.82 g, 72%) as a beige solid;

¹ H NMR (DMSO-d ₆ ) 1.50(s, 9H), 8.19(t, 1H), 8.30(d, 1H), 8.57(d, 1H), 9.80(s, 1H);

MS m/e MH ⁺ 273/275.

Intermediate 18

(5-iodopyridin-3-yl)carbamate tert-butyl ester

Under an inert atmosphere, tert-butyl (5-bromopyridin-3-yl)carbamate (Intermediate 17) (14.9 g), CuI (520 mg), NaI (16.35 g) and N,N-dimethylethyl The diamine (481 mg) was heated in dioxane (300 mL) at 110°C for 24 hours. The reaction mixture was concentrated in vacuo to approximately 100 mL, then water (400 mL) was added. The resulting solid was filtered, dissolved in DCM, dried ( _MgSO4 ), filtered and concentrated to give the title compound (15.18 g, 87%) as a beige solid;

MS m/e MH ⁺ 321.

Intermediate 19

tert-Butyl {5-[(2-aminopyrimidin-5-yl)ethynyl]pyridin-3-yl}carbamate

PdCl ₂ dppf (907 mg) was added to degassed tert-butyl (5-iodopyridin-3-yl)carbamate (Int. 18) (7.94 g), 5-ethynylpyrimidin-2-amine (Int. 6 ) (3.7 g), CuI (94 mg) and Et ₃ N (63 mL) in DMF (250 mL). The reaction was stirred under an inert atmosphere for 24 hours at ambient temperature. Silica was added to the reaction mixture, and the solvent was evaporated in vacuo. The resulting pre-adsorbed product was purified by flash chromatography on silica using 0-10% MeOH in DCM as eluent, followed by water washing and subsequent drying in vacuo to give a beige solid The title compound of (5.3 g, 69%);

¹ H NMR (DMSO-d ₆ ) 1.51(s, 9H), 7.20(s, 2H), 8.05(s, 1H), 8.31(s, 1H), 8.48(s, 2H), 8.57(s, 1H) , 9.74(s, 1H);

MS m/e(M-H+)-310.

Intermediate 20

5-[(5-aminopyridin-3-yl)ethynyl]pyrimidin-2-amine

TFA (25 mL) was added to a solution of tert-butyl {5-[(2-aminopyrimidin-5-yl)ethynyl]pyridin-3-yl}carbamate (Intermediate 19) (2.92 g) under an inert atmosphere. DCM (150mL) solution. The above reaction was stirred for 3 hours at ambient temperature. It was then diluted with water (100 mL) and the DCM was removed in vacuo. The aqueous solution was neutralized with NaHCO ₃ , the resulting precipitate was filtered, washed with water and then dried in vacuo to give the title compound (2.00 g, 66%);

¹ H NMR (DMSO-d ₆ ) 5.49(s, 2H), 7.00(s, 1H), 7.88(s, 2H), 8.44(s, 2H);

MS m/e MH ⁺ 212.

The following intermediates were prepared in a similar manner to Intermediate 2 by using Intermediate 20 instead of Intermediate 1.

Intermediate 21

Phenyl {5-[(2-aminopyrimidin-5-yl)ethynyl]pyridin-3-yl}carbamate

¹ H NMR (DMSO-d ₆ ) 7.19 (br.s, 2H), 7.25-7.33 (m, 3H), 7.41-7.50 (m, 2H), 8.04 (s, 1H), 8.39 (s, 1H), 8.48(s, 2H), 8.65-8.68(m, 1H), 11.6(br.S, 1H);

MS m/e MH ⁺ 332.

The following examples were prepared in a similar manner to example 32 using intermediate 21 and the appropriate amine.

Example 33

N-{5-[(2-aminopyrimidin-5-yl)ethynyl]pyridin-3-yl}-N'-(2-methoxybenzyl)urea

SM: phenyl {5-[(2-aminopyrimidin-5-yl)ethynyl]pyridin-3-yl}carbamate (Intermediate 21) and 2-methoxybenzylamine.

¹ H NMR (DMSO-d ₆ ) 3.83(s, 3H), 4.25(d, 2H), 6.67(t, 1H), 6.91(t, 1H), 6.98(d, 1H), 7.15(s, 2H) 7.23(m, 2H), 8.08(t, 1H), 8.21(d, 1H), 8.41(d, 1H), 8.44(s, 2H), 8.90(s, 1H);

MS m/e MH ⁺ 375.

Example 34

N-{5-[(2-aminopyrimidin-5-yl)ethynyl]pyridin-3-yl}-N’-[2-(trifluoromethyl)benzyl]urea

SM: phenyl {5-[(2-aminopyrimidin-5-yl)ethynyl]pyridin-3-yl}carbamate (Intermediate 21) and 2-(trifluoromethyl)benzylamine. The product was purified by reverse phase chromatography.

¹ H NMR (DMSO-d ₆ ) 4.50(d, 2H), 6.93(t, 1H), 7.16(s, 2H) 7.40-7.77(m, 4H) 8.09(t, 1H), 8.23(d, 1H) , 8.43(m, 3H), 9.05(s, 1H);

MS m/e MH ⁺ 413.

Example 35

N-{5-[(2-aminopyrimidin-5-yl)ethynyl]pyridin-3-yl}-N'-(2-methylbenzyl)urea

SM: Phenyl {5-[(2-aminopyrimidin-5-yl)ethynyl]pyridin-3-yl}carbamate (Intermediate 21) and 2-methylbenzylamine. The product was purified by reverse phase chromatography.

¹ H NMR (DMSO-d ₆ ) 2.30(s, 3H), 4.28(d, 2H), 6.74(t, 1H), 7.10-7.30(m, 6H), 8.09(t, 1H), 8.22(d, 1H ), 8.43(m, 3H), 8.82(s, 1H);

MS m/e MH ⁺ 359.

Example 36

1-{4-methyl-3-[2-(2-morpholin-4-yl-ethylamino)-pyrimidin-5-ylethynyl]-phenyl}-3-(2-morpholine-4 -yl-benzyl)-urea

{4-Methyl-3-[2-(2-morpholin-4-yl-ethylamino)-pyrimidin-5-ylethynyl]-phenyl}-carbamate phenyl ester (Intermediate 26) ( 0.25 g), TEA (0.23 mL) and 2-morpholin-4-yl-benzylamine (113 mg) were added to dioxane (6 mL), and it was heated at 60° C. overnight. The solvent was removed in vacuo and the residue was purified by RPHPLC. The desired component was passed through an SCX column and the solvent was removed in vacuo to give an off-white solid (210 mg, 70%);

¹ H NMR (400.132MHz, DMSO) δ8.57(s, 1H), 8.47(s, 2H), 7.66(s, 1H), 7.48(t, 1H), 7.31(d, 1H), 7.25(t, 1H), 7.20(d, 1H), 7.16-7.14(m, 2H), 7.10(t, 1H), 6.53(t, 1H), 4.39(d, 2H), 3.76(t, 4H), 3.57(t , 4H), 3.44(q, 2H), 2.86-2.84(m, 4H), 2.48(t, 2H), 2.42-2.40(m, 4H), 2.35(s, 3H);

MS m/e MH ⁺ 557.

Intermediate 22

4-(5-Amino-2-methyl-phenyl)-2-methyl-but-3-yn-2-ol

3-iodo-4-methylaniline (100g), bis(triphenylphosphine)palladium(II) chloride (6.0g), triphenylphosphine (112g) and 2-methyl-but-3-yne -2-ol (83 mL) was added to piperidine (600 mL), and it was stirred at reflux for 4 hours under an inert atmosphere. The piperidine was removed in vacuo to give a sticky black sludge. The resulting slurry was stirred in diethyl ether (300 mL) before acidifying with aqueous citric acid (500 mL). The aqueous solution was washed with another portion of diethyl ether (150 mL), the resulting ether layers were combined and re-extracted with aqueous citric acid (500 mL), then the combined aqueous layers were basified with potassium carbonate and extracted with diethyl ether (3 x 500 mL) , dried ( _MgSO4 ) and solvent removed in vacuo to give a black viscous oil. The resulting oil was dissolved in 80% ether/isohexane and passed through a 4 inch plug of silica eluting with 80% ether/isohexane. Removal of the solvent gave an orange oil which solidified overnight (87g); MS m/eMH ⁺ 190.

Intermediate 23

3-ethynyl-4-methyl-aniline

4-(5-Amino-2-methyl-phenyl)-2-methyl-but-3-yn-2-ol (Intermediate 22) (81 g) was added to toluene followed by powdered NaOH (25.8 g) was added and the reaction was heated to reflux for 6 hours. Toluene was removed in vacuo, aqueous NaHCO ₃ (300 mL) was added, extracted with ether (3×400 mL), dried (MgSO ₄ ) and the solvent was removed in vacuo to give a black oil. The compound was purified by bulb-to-bulb distillation at 120°C and 0.30 mbar. A slightly yellow oil was obtained (47 g, 84% over two steps);

¹ H NMR (300.072MHz, cdcl ₃ ) δ6.97(d, 1H), 6.80(s, 1H), 6.60(d, 1H), 3.53(brs, 1H), 3.20(s, 1H), 2.33(s , 3H).

Intermediate 24

(5-Bromo-pyrimidin-2-yl)-(2-morpholin-4-yl-ethyl)-amine

2-Chloro-5-bromopyrimidine (100 g) was added to propan-2-ol (700 mL), DIPEA (184 mL) and aminoethylmorpholine (80.8 g), which was then heated at 80° C. for 7 hours. The reaction was allowed to cool and the solvent was removed in vacuo to give an orange gum which was quenched with water (200 mL), extracted with diethyl ether (3x600 mL), dried (MgSO ₄ ) and the solvent was removed in vacuo to give A yellow viscous oil was obtained. Trituration with diethyl ether (100 mL) gave a solid which was stirred in isohexane (200 mL) for 20 minutes, then filtered and dried. A white solid was obtained (118 g, 79%);

¹ H NMR (300.072MHz, cdcl ₃ ) δ8.28(s, 2H), 5.73(s, 1H), 3.72(t, 4H), 3.46(q, 2H), 2.59(t, 2H), 2.49(t ,4H);

MS m/e MH ⁺ 288.

Intermediate 25

[5-(5-Amino-2-methyl-phenylethynyl)-pyrimidin-2-yl]-(2-morpholin-4-yl-ethyl)-amine

(5-Bromo-pyrimidin-2-yl)-(2-morpholin-4-yl-ethyl)-amine (Intermediate 24) (15 g), PdCl ₂ (PPh3) 2 (0.37 g), triphenyl Phosphine (0.7 g) and 3-ethynyl-4-methyl-phenylamine (Intermediate 23) (8.2 mL) were added to piperidine (150 mL), and it was heated to reflux for 2 hours. The piperidine was then removed in vacuo to give a yellow solid. Water (200 mL) was added, this was extracted with DCM (2x250 mL), dried ( _MgSO4 ) and the solvent was removed in vacuo to give a yellow solid. The resulting solid was dissolved in a small amount of hot DCM, then diethyl ether was added to precipitate a solid which was cooled to give a yellow solid. The remaining liquid was purified by flash chromatography on silica using 2.5-10% MeOH in DCM as eluent to give the title compound (13.5 g, 77%) as a white solid;

¹ H NMR (300.132MHz, CDCl ₃ ) δ8.41(s, 2H), 7.00(d, 1H), 6.82(s, 1H), 6.60(d, 1H), 5.85(brs, 1H), 3.72(t , 4H), 3.60-3.50(m, 4H), 2.61(t, 2H), 2.50(t, 4H), 2.36(s, 3H);

MS m/e MH ⁺ 338.

Intermediate 26

{4-Methyl-3-[2-(2-morpholin-4-yl-ethylamino)-pyrimidin-5-ylethynyl]-phenyl}-carbamic acid phenyl ester

[5-(5-Amino-2-methyl-phenylethynyl)-pyrimidin-2-yl]-(2-morpholin-4-yl-ethyl)amine (Intermediate 25) (3.0 g) and NaHCO ₃ (1.1 g) were added to THF (40 mL), and it was cooled to 0 °C. Phenylchloroformate (1.1 mL) in THF (10 mL) was slowly added to the reaction over a period of 10 minutes. After the addition, the reaction was allowed to warm to ambient temperature and it was stirred for 1 hour. The reaction was quenched with water (100 mL), extracted with DCM (2x200 mL), dried ( _MgSO4 ) and the solvent was removed in vacuo to give a yellow solid. The resulting solid was dissolved in a small amount of DCM and diethyl ether was added followed by isohexane to precipitate a solid.

¹ H NMR (300.074MHz, dmso) δ8.46(s, 2H), 7.62(s, 1H), 7.49(t, 1H), 7.45-7.37(m, 3H), 7.27-7.20(m, 5H), 3.55(t, 4H), 3.42(q, 2H), 2.46(t, 2H), 2.41-2.37(m, 7H);

MS m/e MH ⁺ 458.

Example 37

N-[6-methyl-5-({2-[(2-morpholin-4-ylethyl)amino]pyrimidin-5-yl}ethynyl)pyridin-3-yl]-N'-(3 -morpholin-4-ylbenzyl)urea

{6-Methyl-5-[2-(2-morpholin-4-yl-ethylamino)-pyrimidin-5-ylethynyl]-pyridin-3-yl}-carbamate phenyl ester (intermediate 31) (0.17 g), TEA (0.2 mL) and 3-morpholin-4-yl-benzylamine (93 mg) were added to dioxane (6 mL), and it was heated at 60° C. overnight. The solvent was removed in vacuo and the residue was purified by RPHPLC. The combined fractions were passed through an SCX column and the solvent was removed in vacuo to give an off-white solid (111 mg, 54%);

¹ H NMR (400.132MHz, DMSO) δ8.73(s, 1H), 8.50(s, 2H), 8.32(s, 1H), 8.04(s, 1H), 7.54(t, 1H), 7.19(t, 1H), 6.89(s, 1H), 6.83(d, 1H), 6.78-6.73(m, 2H), 4.26(d, 2H), 3.74(t, 4H), 3.57(t, 4H), 3.44(q , 2H), 3.10(t, 4H), 2.54(s, 3H), 2.48(t, 2H), 2.43-2.39(m, 4H);

MS m/e MH ⁺ 557.

Intermediate 27

5-Bromo-2-methyl-3-nitro-pyridine

Sodium hydride (13.4 g) was added to DMF (500 mL), and to the mixture was slowly added diethylmalonate (45 mL) under an inert atmosphere. Once the addition was complete, the reaction was stirred for 10 minutes. 2-Chloro-3-iodo-5-nitropyridine (61 g) was then slowly added to the anion, forming a dark solution (exhibited exotherm). The above reaction was stirred for 1 h before it was quenched with 2.0N HCl (300 mL), extracted with diethyl ether (3x300 mL), dried ( _MgSO4 ) and the solvent was removed in vacuo to give a dark oil (2-( 3-iodo-5-nitro-pyridin-2-yl)-diethyl malonate) (87 g). This material was used without further purification, added to 7.0N HCl (300 mL) and refluxed for 4 hours, the reaction was cooled and extracted with diethyl ether (3x200 mL), the aqueous phase was basified with 10N NaOH to pH 10, then re-extracted with ether (3x200 mL), dried ( _MgSO4 ) and solvent removed in vacuo to give a black oil which solidified on standing. Purification by flash chromatography on silica using 30% diethyl ether in isohexane as eluent gave the title compound as a white solid. Recrystallization from 50% ether/isohexane gave a yellow solid. Repeat processing until no solid is produced (33g, two steps are 60%);

¹ H NMR (300.072MHz, cdcl ₃ ) δ9.26(s, 1), 8.82(s, 1), 2.87(s, 3H);

MS m/e MH ⁺ 264

Intermediate 28

5-iodo-6-methyl-pyridin-3-ylamine

5-Bromo-2-methyl-3-nitro-pyridine (Intermediate 27) (33 g) and iron (21 g) were added to acetic acid (200 mL) and the reaction was heated at 60 °C for 2 hours. The acetic acid was removed in vacuo and the remaining black viscous oil was basified with aqueous potassium carbonate (250 mL). The system was then extracted with diethyl ether (3x300 mL), dried ( _MgSO4 ) and the solvent removed in vacuo to give a solid. Purification by flash chromatography on silica using 80-100% diethyl ether in isohexane as eluent gave the title compound (25 g, 86%) as a white solid;

¹ H NMR (300.072MHz, cdcl ₃ ) δ7.96(s, 1H), 7.43(s, 1H), 3.59(brs, 2H), 2.62(s, 3H);

MS m/e MH ⁺ 236.

Intermediate 29

5-ethynyl-6-methyl-pyridin-3-ylamine

5-iodo-6-methyl-pyridin-3-ylamine (Intermediate 28) (22 g), PdCl ₂ (PPh3) ₂ (0.7 g), triphenylphosphine (24 g) and 2-methyl-butyl -3-yn-2-ol (17 mL) was added to piperidine (180 mL), and it was heated to reflux for 4 hours. The piperidine was removed in vacuo, the remaining residue was acidified with aqueous citric acid (300 mL) and extracted with diethyl ether (300 mL). The resulting ether layer was re-extracted with aqueous citric acid (100 mL), the aqueous layers were combined and basified to pH 12 with potassium carbonate, then extracted with diethyl ether (3x300 mL), dried ( _MgSO4 ) and the solvent removed in vacuo, whereby Obtained as a viscous black oil (4-(5-amino-2-methyl-pyridin-3-yl)-2-methyl-but-3-yn-2-ol). The above crude product was dissolved in toluene (300 mL), NaOH (5.6 g) was added thereto, and the reaction was refluxed for 5 hours. The reaction was cooled and the solvent was removed in vacuo. The remaining black viscous oil was added to aqueous NaHCO ₃ (300 mL), extracted with diethyl ether (3×300 mL), dried (MgSO ₄ ) and the solvent was removed in vacuo to give a brown solid. Purification by flash chromatography on silica using 70-100% diethyl ether in isohexane as eluent gave the title compound as an off-white solid (9.8 g, 80% for two steps);

¹ H NMR (300.072MHz, cdcl ₃ ) δ7.97(s, 1H), 7.05(s, 1H), 3.59(brs, 2H), 3.32(s, 1H), 2.56(s, 3H);

MS m/e MH ⁺ +MeCN174.

Intermediate 30

[5-(5-Amino-2-methyl-pyridin-3-ylethynyl)-pyrimidin-2-yl]-(2-morpholin-4-yl-ethyl)-amine

(5-Bromo-pyrimidin-2-yl)-(2-morpholin-4-yl-ethyl)-amine (Intermediate 24) (7.0 g), PdCl ₂ (PPh3) ₂ (0.17 g), Tris Phenylphosphine (0.2 g) and 3-ethynyl-4-methyl-aniline (Intermediate 29) (3.54 g) were added to piperidine (70 mL) and it was heated to reflux for 2 hours. The piperidine was then removed in vacuo to give a yellow gum. The above gum was dissolved in water (200 mL), extracted with DCM (2x250 mL), dried ( _MgSO4 ) and the solvent was removed in vacuo to give a yellow gum. The resulting gum was dissolved in hot DCM and triturated with ether to precipitate a yellow solid. The remaining liquid was purified by flash chromatography on silica using 2.5-10% MeOH in DCM as eluent to give the title compound (6.5 g, 78%) as a yellow solid;

¹ H NMR (300.132MHz, CDCl ₃ ) δ8.41(s, 2H), 7.00(d, 1H), 6.81(s, 1H), 6.59(d, 1H), 5.84(brs, 1H), 3.72(t , 4H), 3.56-3.50(m, 4H), 2.60(t, 2H), 2.49(t, 4H), 2.36(s, 3H);

MS m/e MH ⁺ 339

Intermediate 31

{6-Methyl-5-[2-(2-morpholin-4-yl-ethylamino)-pyrimidin-5-ylethynyl]-pyridin-3-yl}-phenylcarbamate

[5-(5-Amino-2-methyl-pyridin-3-ylethynyl)-pyrimidin-2-yl]-(2-morpholin-4-yl-ethyl)-amine (Intermediate 3) (3.0 g) and NaHCO ₃ (1.1 g) were added to THF (40 mL), and it was cooled to 0 °C. Phenylchloroformate (1.1 mL) in THF (10 mL) was slowly added to the reaction over a period of 10 minutes. After the addition, the reaction was allowed to warm to ambient temperature and it was stirred for 1 hour. The reaction was quenched with water (100 mL), extracted with DCM (2x200 mL), dried ( _MgSO4 ) and the solvent was removed in vacuo to give a yellow solid. The resulting solid was dissolved in a small amount of DCM and diethyl ether was added followed by isohexane until a solid precipitated out. The solid formed was filtered and dried. The remaining liquid was purified by flash chromatography on silica using 1.0-10% MeOH in DCM as eluent to give the title compound (1.1 g, 27%) as a white solid;

MS m/e MH ⁺ 459.

Example 38

N-(2-chlorobenzyl)-N'-[5-({2-[(2-morpholin-4-ylethyl)amino]pyrimidin-5-yl}ethynyl)pyridin-3-yl] Urea

p-[5-(5-Amino-pyridin-3-ylethynyl)-pyrimidin-2-yl]-(2-morpholin-4-yl-ethyl)-amine in dioxane (intermediate 34 ) (180 mg) and 1-chloro-2-isocyanatomethyl-benzene (120 mg) were premixed and heated at 80° C. for 24 hours. The solvent was removed in vacuo and the residue was purified by HPLC (60 peak method). The fractions obtained were combined, basified with potassium carbonate and the acetonitrile was removed in vacuo to give a solid which was filtered and dried (120 mg, 44%);

¹ H NMR (400.132MHz, DMSO) δ9.49(vbrs, 1H), 8.54-8.44(m, 3H), 8.22(s, 1H), 8.11(s, 1H), 7.53(brs, 1H), 7.45- 7.41(m, 2H), 7.35-7.27(m, 3H), 4.38(s, 2H), 3.56(t, 4H), 3.44(t, 2H), 2.48(t, 2H), 2.44-2.38(m, 4H);

MS m/e MH ⁺ 493.

Intermediate 32

4-(5-Amino-pyridin-3-yl)-2-methyl-but-3-yn-2-ol

5-Iodo-pyridin-3-ylamine (50 g), PdCl ₂ (PPh ₃ ) ₂ (1.6 g), triphenylphosphine (12 g) and 2-methyl-but-3-yn-2-ol ( 44 mL) was added to piperidine (300 mL), and it was heated to reflux for 2 hours. The piperidine was removed in vacuo to give a black gum, to which water (200 mL) and isohexane (200 mL) were added and the resulting gum was stirred at 50 °C for 20 minutes. A solid precipitated out, the isohexane was removed, another portion of isohexane (100 mL) was added and added at 50 °C, which was also removed. The above reaction was filtered and the solid obtained was dried;

MS m/e MH ⁺ 177.

Intermediate 33

5-ethynyl-pyridin-3-ylamine

4-(5-Amino-pyridin-3-yl)-2-methyl-but-3-yn-2-ol (Intermediate 32) (40 g) was added to toluene (350 mL) and heated at reflux , then crushed NaOH (13.8 g) was added slowly and the reaction was refluxed for 5 hours, after which the solvent was removed in vacuo to give a black viscous oil. The above viscous oil was treated with aqueous NaHCO ₃ (300 mL), extracted with diethyl ether (3×300 mL), dried (MgSO ₄ ) and the solvent was removed in vacuo to give a black gum. This was purified by kulgohlor bulb to bulb distillation at 140°C at 0.32 mmHg. A white solid was obtained (15.5 g, 58% for two steps);

¹ H NMR (300.072MHz, cdcl ₃ ) δ8.13(s, 1H), 8.03(s, 1H), 7.05(s, 1H), 3.76(brs, 2H), 3.14(s, 1H);

MS m/e MH ⁺ +MeCN160.

Intermediate 34

[5-(5-Amino-pyridin-3-ylethynyl)-pyrimidin-2-yl]-(2-morpholin-4-yl-ethyl)-amine

(5-Bromo-pyrimidin-2-yl)-(2-morpholin-4-yl-ethyl)-amine (Intermediate 24) (13 g), PdCl ₂ (PPh ₃ ) ₂ (0.32 g), Tris Phenylphosphine (0.3 g) and 5-ethynyl-pyridin-3-ylamine (Intermediate 33) (5.3 g) were added to piperidine (100 mL), and it was heated to reflux for 2 hours. The piperidine was then removed in vacuo to give a black gum. The above gum was dissolved in water (200 mL) and DCM (200 mL), extracted with DCM (2x250 mL), dried ( _MgSO4 ) and the solvent was removed in vacuo to give a black gum. The resulting gum was dissolved in a little hot DCM. Purification by flash chromatography on silica using 2.5-10% MeOH in DCM as eluent gave the title compound (10.3 g, 71%) as a yellow solid;

¹ H NMR (300.072MHz, cdcl ₃ ) δ8.44(s, 2H), 8.16(s, 1H), 8.04(s, 1H), 7.07(s, 1H), 5.92(brs, 1H), 3.75-3.72 (m, 6H), 3.55(q, 2H), 2.63(t, 2H), 2.53-2.50(m, 4H);

MS m/e MH ⁺ 325.

Example 39

N-[2-(Dimethylamino)benzyl]-N'-[5-({2-[(2-morpholin-4-ylethyl)amino]pyrimidin-5-yl}ethynyl)pyridine -3-yl]urea

{5-[2-(2-Morpholin-4-yl-ethylamino)-pyrimidin-5-ylethynyl]-pyridin-3-yl}-carbamic acid 4-chloro-phenyl ester (intermediate 35 ) (0.22g), TEA (0.19mL) and (2-amino-methyl-phenyl)-dimethyl-amine (77mg) were added to dioxane (6mL), and it was heated at 50°C Heat for 1 hour. The solvent was removed in vacuo and the residue was purified by RPHPLC. The fractions were combined, basified with potassium carbonate and the acetonitrile was removed in vacuo to give a white solid. The solid was filtered and dried (160 mg, 70%);

¹ H NMR (400.132MHz, DMSO) δ9.07(brs, 1H), 8.50(s, 2H), 8.45(s, 1H), 8.23(s, 1H), 8.13(s, 1H), 7.55(t, 1H), 7.28(d, 1H), 7.22(t, 1H), 7.13(d, 1H), 7.04(t, 1H), 6.92(brs, 1H), 4.39(s, 2H), 3.57(t, 4H ), 3.44(q, 2H), 2.66(s, 6H), 2.48(t, 2H), 2.42-2.40(m, 4H);

MS m/e MH ⁺ 501.

Intermediate 35

{5-[2-(2-Morpholin-4-yl-ethylamino)-pyrimidin-5-ylethynyl]-pyridin-3-yl}-carbamic acid 4-chloro-phenyl ester

Under inert atmosphere, [5-(5-Amino-pyridin-3-ylethynyl)-pyrimidin-2-yl]-(2-morpholin-4-yl-ethyl)-amine (Intermediate 34) (2.0 g) and TEA (1.0 mL) were added to anhydrous dioxane (60 mL). To the above solution was added p-chlorophenyl chloroformate (0.91 mL) slowly and the reaction was stirred for 10 minutes, then quenched with water (50 mL). The solvent was removed in vacuo to give a solid to which DCM (30 mL) was added, which was sonicated for 10 minutes, filtered and dried. An off-white solid was obtained (1.7 g, 57%);

¹ H NMR (400.132MHz, DMSO) δ10.66(s, 1H), 8.65(s, 1H), 8.52(s, 2H), 8.41(s, 1H), 8.04(s, 1H), 7.58(s, 1H), 7.51(d, 2H), 7.32(d, 2H), 3.61-3.54(m, 4H), 3.49-3.40(m, 2H), 2.51-2.35(m, 6H);

MS m/e MH ⁺ 479.

Example 40

N-(3-chlorobenzyl)-N'-[5-({2-[(2-morpholin-4-ylethyl)amino]pyrimidin-5-yl}ethynyl)pyridin-3-yl] Urea

{5-[2-(2-Morpholin-4-yl-ethylamino)-pyrimidin-5-ylethynyl]-pyridin-3-yl}-carbamic acid 4-chloro-phenyl ester (intermediate 35 ) (0.22 g), TEA (0.19 mL) and 3-chloro-benzylamine (72 mg) were added to dioxane (6 mL), and it was heated at 50° C. for 1 hour. The solvent was removed in vacuo and the residue was purified by RPHPLC. The fractions were combined, basified with potassium carbonate and the acetonitrile was removed in vacuo to give a white solid. The solid was filtered and dried (154 mg, 68%);

¹ H NMR (400.132MHz, DMSO) δ9.32(vbrs, 1H), 8.53-8.48(m, 3H), 8.22(s, 1H), 8.10(s, 1H), 7.54(s, 1H), 7.38- 7.34(m, 2H), 7.31-7.27(m, 3H), 4.31(s, 2H), 3.57(t, 4H), 3.44(q, 2H), 2.48(t, 2H), 2.42-2.40(m, 4H);

MS m/e MH ⁺ 493.

Example 41

N-(2-methoxybenzyl)-N'-[5-({2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}ethynyl)pyridine-3- base] urea

{5-[2-(2-Morpholin-4-yl-propylamino)-pyrimidin-5-ylethynyl]-pyridin-3-yl}-carbamic acid 4-chloro-phenyl ester (intermediate 38 ) (0.20 g), TEA (0.17 mL) and 2-methoxy-benzylamine (87 mg) were added to dioxane (6 mL) and heated at 50° C. for 1 hour. The solvent was removed in vacuo and the residue was purified by RPHPLC. The fractions were combined, basified with potassium carbonate and the acetonitrile was removed in vacuo to give a white solid. The solid formed was filtered and dried (138 mg, 67%);

¹ H NMR (400.132MHz, DMSO) δ8.94(s, 1H), 8.49(s, 2H), 8.42(s, 1H), 8.23(s, 1H), 8.11(s, 1H), 7.74(t, 1H), 7.28-7.23(m, 2H), 7.00(d, 1H), 6.93(t, 1H), 6.70(t, 1H), 4.28(d, 2H), 3.84(s, 3H), 3.57(t , 4H), 3.34 (q, 2H), 2.36-2.32 (m, 6H), 1.69 (quintet, 2H);

MS m/e MH ⁺ 502.

Intermediate 36

(5-Bromo-pyrimidin-2-yl)-(3-morpholin-4-yl-propyl)-amine

2-Chloro-5-bromopyrimidine (50 g) was added to propan-2-ol (300 mL), DIPEA (92 mL) and aminopropylmorpholine (46 mL), and the reaction was heated at 80° C. for 3 hours. The reaction was allowed to cool and the solvent was removed in vacuo to give an orange gum which was quenched with water (200 mL), extracted with diethyl ether (3x600 mL), dried (MgSO ₄ ) and the solvent was removed in vacuo to give A yellow viscous oil was obtained. Diethyl ether (100 mL) was quickly added to the gum while scratching until a solid precipitated, which was filtered. Repeat the treatment of the filtered mother liquor until no solid precipitates out. The obtained solids were combined and stirred in isohexane (200 mL) for 20 minutes before being filtered and dried. A white solid was obtained (67 g, 86%);

¹ H NMR (300.072MHz, cdcl ₃ ) δ8.25(s, 2H), 6.02(s, 1H), 3.73(t, 4H), 3.45(q, 2H), 2.49-2.44(m, 6H), 1.78 (Quintet, 2H);

MS m/e MH ⁺ 302.

Intermediate 37

[5-(5-Amino-pyridin-3-ylethynyl)-pyrimidin-2-yl]-(3-morpholin-4-yl-propyl)-amine

(5-Bromo-pyrimidin-2-yl)-(2-morpholin-4-yl-propyl)-amine (Intermediate 36) (7 g), PdCl ₂ (PPh ₃ ) ₂ (0.33 g), Tris Phenylphosphine (6.1 g) and 5-ethynyl-pyridin-3-ylamine (Intermediate 33) (2.7 g) were added to piperidine (100 mL), and it was heated to reflux for 4 hours. The piperidine was then removed in vacuo to give a black gum. This was treated with aqueous citric acid (200 mL), extracted with diethyl ether (100 mL), then the aqueous layer was basified with potassium carbonate (pH 12), extracted with DCM (2 x 250 mL), dried (MgSO ₄ ) and in The solvent was removed in vacuo to give a dark yellow solid. Purification by flash chromatography on silica using 3.5-10% MeOH in DCM as eluent gave the title compound as a tan solid. The resulting solid was added to hot acetonitrile and the resulting slurry was stirred for 10 min before it was filtered and dried. Obtained as an off-white solid (4.6 g, 59%);

¹ H NMR (300.132MHz, DMSO) δ8.46(s, 2H), 7.91(d, 1H), 7.84(d, 1H), 7.70(t, 1H), 6.99(t, 1H), 5.47(s, 2H), 3.57(t, 4H), 3.37-3.28(m, 2H), 2.35-2.31(m, 6H), 1.69(quint, 2H); MS m/e MH ⁺ 339.

Intermediate 38

{5-[2-(2-Morpholin-4-yl-propylamino)-pyrimidin-5-ylethynyl]-pyridin-3-yl}-carbamic acid 4-chloro-phenyl ester

Under inert atmosphere, [5-(5-Amino-pyridin-3-ylethynyl)-pyrimidin-2-yl]-(2-morpholin-4-yl-propyl)-amine (Intermediate 37) (0.9 g) and TEA (0.5 mL) were added to anhydrous dioxane (60 mL). To the above solution was added p-chlorophenyl chloroformate (0.45 mL) slowly and the reaction was stirred for 10 minutes, then quenched with water (50 mL). The solvent was removed in vacuo to give a solid to which DCM (30 mL) was added, which was sonicated for 10 minutes, filtered and dried. A yellow solid was obtained (0.7 g, 54%);

¹ H NMR (300.074MHz, dmso) δ10.64(s, 1H), 8.63(s, 1H), 8.49(s, 2H), 8.38(s, 1H), 8.01(s, 1H), 7.76(t, 1H), 7.49(d, 2H), 7.30(d, 2H), 3.59-3.54(m, 4H), 3.32(q, 2H), 2.39-2.26(m, 6H), 1.68(quintet, 2H) ;

MS m/e MH ⁺ 394

Example 42

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-(1,4-dioxan-2-ylmethyl)urea

At 80°C, {3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}carbamate (Intermediate 2) (50mg), C-[1,4]di Oxan-2-ylmethylamine (35 mg) and triethylamine (0.06 mL) were heated in THF (2 mL) for 24 hours. The reaction mixture was concentrated in vacuo and the resulting solid was triturated with diethyl ether and dried in vacuo at 60 °C to give the title compound (41 mg, 77%) as a solid;

¹ H NMR (DMSO-d ₆ ) 2.99-3.11(m, 1H), 3.13-3.27(m, 1H), 3.39-3.78(m, 7H), 6.25-6.31(t, 1H), 6.50(bs, 4H ), 7.16-7.26(m, 2H), 7.32-7.38(m, 1H), 7.60(s, 1H), 7.83(s, 1H), 8.52(bs, 1H);

MS m/e MH ⁺ 369.

Preparation of intermediate 38

5-[(3-Aminophenyl)ethynyl]pyrimidine-4,6-diamine

4,6-diamino-5-iodopyrimidine (J.Med.Chem., 2001, 44, 2133-2138) (2.36g), bis(triphenyl (phosphine) palladium dichloride (350 mg) and copper(I) iodide (40 mg) were stirred and degassed with nitrogen for 10 minutes. 3-Ethynylaniline (1.29 g) was added thereto, and the above mixture was heated at 95°C for 20 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica using 1-10% (7M ammonia in MeOH) in DCM as eluent. It was further purified by trituration with DCM (20 mL) to give the title compound (970 mg, 43%) as a tan solid;

¹ H NMR (DMSO-d ₆ ) 3.72 (bs, 2H), 5.17 (bs, 4H), 6.67-6.71 (m, 1H), 6.80-6.82 (m, 1H), 6.88-6.92 (m, 1H), 7.11-7.17(m, 1H), 8.08(s, 1H);

MS m/e MH ⁺ 226.

Preparation of intermediate 39

Phenyl {3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}carbamate

Phenylchloroformate (2.51 mL) was added dropwise to stirred 5-[(3-aminophenyl)ethynyl]pyrimidine-4,6-diamine (Intermediate 1) (3.0 g) at 0 °C and pyridine (2.15 mL) in THF (200 mL). After 2 hours, water (10 mL) was added and the reaction mixture was stirred for 10 minutes, then concentrated in vacuo. The solid obtained was purified by flash chromatography on silica using 0-10% MeOH in DCM as eluent by trituration with water and then with ether, followed by trituration with MeOH to give The title compound as a solid (2.51 g, 55%);

¹ H NMR (DMSO-d ₆ ) 6.53 (s, 4H), 7.17-7.46 (m, 8H), 7.77 (s, 1H), 7.83 (s, 1H), 10.24 (bs, 1H);

MS m/e MH ⁺ 346.

Example 43

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-[(5-methylpyrazin-2-yl)methyl]urea

SM: intermediate 2,2-(aminomethyl)-5-methylpyrazine

¹ H NMR (DMSO-d ₆ ) 4.38-4.44 (d, 2H), 6.48 (bs, 4H), 6.77-6.84 (t, 1H), 7.16-7.26 (m, 2H), 7.30-7.38 (m, 1H ), 7.63(s, 1H), 7.83(s, 1H), 8.48(s, 2H), 8.74(s, 1H);

MS m/e MH ⁺ 375.

Example 44

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-(tetrahydro-2H-pyran-4-ylmethyl)urea

SM: intermediate 2,4-aminomethyltetrahydropyran

¹ H NMR (DMSO-d ₆ ) 1.09-1.25 (m, 2H), 1.49-1.70 (m, 3H), 2.94-3.04 (t, 2H), 3.20-3.30 (m, 2H), 3.78-3.89 (m , 2H), 6.21-6.30(t, 1H), 6.50(bs, 4H), 7.16-7.24(m, 2H), 7.31-7.39(m, 1H), 7.61(s, 1H), 7.83(s, 1H ), 8.38(bs, 1H);

MS m/e MH ⁺ 367.

Example 45

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-(pyridin-3-ylmethyl)urea

SM: intermediate 2,3-(aminomethyl)pyridine

¹ H NMR (DMSO-d ₆ ) 4.29-4.34 (d, 2H), 6.50 (bs, 4H), 6.72-6.78 (t, 1H), 7.17-7.26 (m, 2H), 7.32-7.39 (m, 2H ), 7.62-7.66(m, 1H), 7.67-7.72(m, 1H), 7.82(s, 1H), 8.42-8.46(m, 1H), 8.50-8.53(m, 1H), 8.60(bs, 1H );

MS m/e MH ⁺ 360.

Example 46

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-[3-(1H-pyrazol-1-yl)propyl]urea

SM: Intermediate 2, [3-(1H-pyrazol-1-yl)propyl]amine hydrate

¹ H NMR (DMSO-d ₆ ) 1.85-1.98 (m, 2H), 3.00-3.09 (m, 2H), 4.10-4.18 (m, 2H), 6.20-6.23 (m, 1H), 6.24-6.33 (t , 1H), 6.50(bs, 4H), 7.18-7.26(m, 2H), 7.32-7.39(m, 1H), 7.41-7.45(m, 1H), 7.62(s, 1H), 7.70-7.73(m , 1H), 7.82(s, 1H), 8.46(bs, 1H);

MS m/e MH ⁺ 377.

Example 47

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-(tetrahydrofuran-2-ylmethyl)urea

SM: Intermediate 2, Tetrahydrofurfurylamine

¹ H NMR (DMSO-d ₆ ) 1.44-1.58 (m, 1H), 1.73-1.96 (m, 3H), 3.01-3.30 (m, 2H), 3.55-3.68 (m, 1H), 3.73-3.90 (m , 2H), 6.21-6.28(t, 1H), 6.50(bs, 4H), 7.16-7.25(m, 2H), 7.33-7.39(m, 1H), 7.59(s, 1H), 7.82(s, 1H ), 8.50(bs, 1H);

MS m/e MH ⁺ 353.

Example 48

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-(2-pyridin-3-ylethyl)urea

SM: intermediate 2,3-(2-aminoethyl)pyridine

¹ H NMR (DMSO-d ₆ ) 2.73-2.81(t, 2H), 3.31-3.40(q, 2H), 6.17-6.23(t, 1H), 6.50(bs, 4H), 7.17-7.26(m, 2H ), 7.29-7.37(m, 1H), 7.58-7.68(m, 2H), 7.82(s, 1H), 8.39-8.47(m, 3H);

MS m/e MH ⁺ 374.

Example 49

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-[(4-methyl-1,3-thiazol-2-yl)methyl]urea

SM: Intermediate 2, C-(4-methylthiazol-2-yl)methanamine

¹ H NMR (DMSO-d ₆ ) 2.32(s, 3H), 4.49-4.56(d, 2H), 6.51(bs, 4H), 6.91-6.98(t, 1H), 7.10-7.13(m, 1H), 7.19-7.28(m, 2H), 7.36-7.40(m, 1H), 7.65(s, 1H), 7.82(s, 1H), 8.76(bs, 1H);

MS m/e MH ⁺ 380.

Example 50

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-[(4-methylisoxazol-3-yl)methyl]urea

SM: Intermediate 2, (4-methyl-3-isoxazolyl)methanamine

¹ H NMR (DMSO-d ₆ ) 2.36(s, 3H), 4.27-4.32(d, 2H), 6.13(s, 1H), 6.71-6.79(t, 1H), 7.22-7.40(m, 3H), 7.76-7.79(m, 1H), 7.87(bs, 4H), 8.16(s, 1H), 8.74(bs, 1H);

MS m/e MH ⁺ 364.

Example 51

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-(3-methoxybenzyl)urea

SM: intermediate 2,3-methoxybenzylamine

¹ H NMR (DMSO-d ₆ ) 3.73 (s, 3H), 4.24-4.29 (d, 2H), 6.50 (bs, 4H), 6.61-6.68 (t, 1H), 6.76-6.89 (m, 3H), 7.17-7.27(m, 3H), 7.35-7.40(m, 1H), 7.62-7.65(m, 1H), 7.82(s, 1H), 8.54(bs, 1H);

MS m/e MH ⁺ 389.

Example 52

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-[(5-methyl-2-furyl)methyl]urea

SM: intermediate 2,5-methylfurfurylamine

¹ H NMR (DMSO-d ₆ ) 2.23(s, 3H), 4.19-4.24(d, 2H), 5.95-5.98(m, 1H), 6.18-6.23(m, 1H), 6.43-6.58(m, 5H ), 7.18-7.27(m, 2H), 7.33-7.39(m, 1H), 7.62(s, 1H), 7.82(s, 1H), 8.48(bs, 1H);

MS m/e MH ⁺ 363.

Example 53

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-(2-morpholin-4-ylbenzyl)urea

SM: intermediate 2,1-(2-morpholin-4-ylphenyl)methanamine

¹ H NMR (DMSO-d ₆ ) 2.81-2.87 (m, 4H), 3.72-3.77 (m, 4H), 4.35-4.41 (d, 2H), 6.46-6.60 (m, 5H), 7.04-7.16 (m , 2H), 7.20-7.32(m, 4H), 7.34-7.41(m, 1H), 7.64(s, 1H), 7.83(s, 1H), 8.57(bs, 1H);

MS m/e MH ⁺ 444.

The following compound examples were prepared in a similar manner to Example 42, but were purified by trituration with water, then ether.

Example 54

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-[2-(3,5-dimethyl-1H-pyrazol-1-yl) Ethyl]urea

SM: intermediate 2,1-aminomethyl-3,5-ethylpyrazole hydrochloride

¹ H NMR (DMSO-d ₆ ) 2.08(s, 3H), 2.17(s, 3H), 3.35-3.45(q, 2H), 3.95-4.01(t, 2H), 5.78(s, 1H), 6.19- 6.27(t, 1H), 6.50(bs, 4H), 7.16-7.27(m, 2H), 7.33-7.39(m, 1H), 7.61(s, 1H), 7.82(s, 1H), 8.58(bs, 1H);

MS m/e MH ⁺ 391.

Example 55

N-(3-cyanobenzyl)-N'-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}urea

SM: intermediate 2,3-cyanobenzylamine hydrochloride

¹ H NMR (DMSO-d ₆ ) 4.35-4.40 (d, 2H), 6.50 (bs, 4H), 6.78-6.84 (t, 1H), 7.17-7.27 (m, 2H), 7.33-7.39 (m, 1H ), 7.46(s, 1H), 7.49(s, 1H), 7.64(s, 1H), 7.77(s, 1H), 7.80(s, 1H), 7.83(s, 1H), 8.67(bs, 1H) ;

MS m/e MH ⁺ 384.

Example 56

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-[2-(pyridazin-3-yloxy)ethyl]urea

SM: intermediate 2,2-(pyridazin-3-yloxy)ethylamine

¹ H NMR (DMSO-d ₆ ) 3.50-3.58(q, 2H), 4.43-4.52(t, 2H), 6.42-6.50(t, 1H), 6.65(bs, 4H), 7.17-7.27(m, 3H ), 7.32-7.40(m, 1H), 7.57-7.66(m, 2H), 7.86(s, 1H), 8.57(bs, 1H), 8.87-8.90(m, 1H);

MS m/e MH ⁺ 391.

The following examples were prepared in a manner similar to Example 42, but purified by RPHPLC:

Example 57

N-(cyclopropylmethyl)-N'-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}urea

SM: Intermediate 2, (aminomethyl)cyclopropane

¹ H NMR (DMSO-d ₆ ) 0.00-0.06(m, 2H), 0.24-0.31(m, 2H), 0.70-0.85(s, 1H), 2.78-2.88(t, 2H), 6.10-6.19(t , 1H), 7.04-7.25(m, 3H), 7.60(s, 1H), 7.71(bs, 4H), 8.01(s, 1H), 8.36(bs, 1H);

MS m/e MH ⁺ 323.

Example 58

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-(2-pyrimidin-4-ylethyl)urea

SM: intermediate 2,2-pyrimidin-4-ylethylamine hydrochloride

¹ H NMR (DMSO-d ₆ ) 2.77-2.83(t, 2H), 3.31-3.39(m, 2H), 6.25-6.28(t, 1H), 7.21-7.32(m, 3H), 7.78(bs, 4H ), 8.15(s, 1H), 8.52(s, 1H), 8.68(s, 2H), 9.05(bs, 1H);

MS m/e MH ⁺ 375.

The following examples were prepared in a similar manner to Example 42, but purified by flash chromatography on silica using 1-10% MeOH in DCM as eluent.

Example 59

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-[3-(2-oxopyrrolidin-1-yl)propyl]urea

SM: intermediate 2,1-(3-aminopropyl)-2-pyrrolidone

¹ H NMR (DMSO-d ₆ ) 1.54-1.66(qn, 2H), 1.85-1.98(qn, 2H), 2.16-2.27(t, 2H), 2.99-3.09(q, 2H), 3.15-3.25(t , 2H), 3.26-3.38(m, 2H), 6.17-6.24(t, 1H), 6.49(bs, 4H), 7.18-7.25(m, 2H), 7.31-7.38(m, 1H), 7.62(s , 1H), 7.83(s, 1H), 8.55(s, 1H);

MS m/e MH ⁺ 394.

Example 60

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-[2-(3,5-dimethyl-1H-pyrazol-4-yl) Ethyl]urea

SM: intermediate 2,2-(3,5-dimethyl-1h-pyrazol-4-yl)ethylamine

¹ H NMR (DMSO-d ₆ ) 2.09 (s, 6H), 2.40-2.49 (t, 2H), 3.06-3.17 (q, 2H), 6.06-6.12 (t, 1H), 6.50 (bs, 4H), 7.18-7.24(m, 2H), 7.33-7.39(m, 1H), 7.61(s, 1H), 7.83(s, 1H), 8.45(bs, 1H), 11.89(bs, 1H);

MS m/e MH ⁺ 391.

Example 61

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-[(4-morpholin-4-ylpyrimidin-5-yl)methyl]urea

SM: intermediate 2, 1-(4-morpholin-4-ylpyrimidin-5-yl)methanamine

¹ H NMR (DMSO-d ₆ ) 3.38-3.45(m, 4H), 3.63-3.73(m, 4H), 4.25-4.30(d, 2H), 6.50(bs, 4H), 6.65-6.73(t, 1H ), 7.17-7.29(m, 2H), 7.34-7.40(m, 1H), 7.63(s, 1H), 7.82(s, 1H), 8.30(s, 1H), 8.56(s, 1H), 8.62( bs,1H);

MS m/e MH ⁺ 446.

The following examples were prepared in a similar manner to Example 42

Example 62

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-(2-morpholin-4-ylethyl)urea

SM: intermediate 2,4-(2-aminoethyl)morpholine

¹ H NMR (DMSO-d ₆ ) 2.39-2.45 (m, 6H), 3.23 (q, 2H), 3.61 (t, 4H), 6.15 (t, 1H), 6.52 (s, 4H), 7.23-7.25 ( m, 2H), 7.39-7.45(m, 1H), 7.64-7.65(m, 1H), 7.86(s, 1H), 8.64(s, 1H);

MS m/e MH ⁺ 382.

Example 63

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-(3-morpholin-4-ylpropyl)urea

SM: intermediate 2,4-(3-aminopropyl)morpholine

¹ H NMR (DMSO-d ₆ ) 1.61 (t, 2H), 2.27-2.37 (m, 6H), 3.13 (q, 2H), 3.55-3.61 (m, 4H), 6.21 (t, 1H), 6.52 ( s, 4H), 7.22-7.26(m, 2H), 7.36-7.40(m, 1H), 7.64(d, 1H), 7.86(s, 1H), 8.44(s, 1H);

MS m/e MH ⁺ 396.

Example 64

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-(2-pyrrolidin-1-ylethyl)urea

SM: intermediate 2,1-(2-aminoethyl)pyrrolidine

¹ H NMR (DMSO-d ₆ ) 1.70-1.74 (m, 4H), 2.40-2.50 (m, 6H), 3.22 (q, 2H), 6.18 (t, 1H), 6.52 (s, 4H), 7.22- 7.26(m, 2H), 7.35-7.39(m, 1H), 7.64(d, 1H), 7.86(s, 1H), 8.63(s, 1H);

MS m/e MH ⁺ 366.

Example 65

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-[2-(pyridin-2-ylamino)ethyl]urea

SM: intermediate 2, N1-pyridin-2-yl-ethane-1,2-diamine

¹ H NMR (DMSO-d ₆ ) 3.25-3.42 (m, 4H), 6.32-6.36 (m, 1H), 6.48-6.52 (m, 6H), 7.23-7.25 (m, 2H), 7.35-7.40 (m , 2H), 7.65(s, 1H), 7.86(s, 1H), 7.97(d, 1H), 8.54(s, 1H);

MS m/e MH ⁺ 389.

Example 66

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-(3-pyrrolidin-1-ylpropyl)urea

SM: intermediate 2,1-(3-aminopropyl)pyrrolidine

¹ H NMR (DMSO-d ₆ ) 1.59-1.71 (m, 6H), 2.40-2.45 (m, 6H), 3.14 (q, 2H), 6.22 (t, 1H), 6.53 (s, 4H), 7.22- 7.26(m, 2H), 7.36-7.40(m, 1H), 7.63-7.64(m, 1H), 7.86(s, 1H), 8.44(s, 1H);

MS m/e MH ⁺ 380.

Example 67

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-(2-piperidin-1-ylethyl)urea

SM: intermediate 2,1-(2-aminoethyl)piperidine

¹ H NMR (DMSO-d ₆ ) 1.35-1.48 (m, 2H), 1.50-1.57 (m, 4H), 2.34-2.38 (m, 6H), 3.21 (q, 2H), 6.11 (t, 1H), 6.52(s, 4H), 7.22-7.26(m, 2H), 7.36-7.40(m, 1H), 7.65(d, 1H), 7.86(s, 1H), 8.66(s, 1H);

MS m/e MH ⁺ 380.

The following compounds required further purification by RPHPLC ( _H2O :MeCNO-70%) to afford the title compound as a TFA salt.

Example 68

N-[2-(Benzylamino)ethyl]-N'-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}urea

SM: intermediate 2,2-benzylaminoethylamine

¹ H NMR (DMSO-d ₆ ) 3.07-3.12 (m, 2H), 3.44 (q, 2H), 4.18-4.26 (m, 2H), 6.76 (t, 1H), 7.26-7.35 (m, 2H), 7.42-7.55(m, 6H), 7.76(s, 1H), 7.80-8.00(m, 4H), 8.21(s, 1H), 8.87-9.01(m, 2H), 8.99(s, 1H);

MS m/e MH ⁺ 402

Example 69

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-[(1,5-dimethyl-1H-pyrazol-3-yl)methyl ] urea

SM: intermediate 2, (1,5-dimethyl-1h-pyrazol-3-yl)methanamine

¹ H NMR (DMSO-d ₆ ) 2.22(s, 3H), 3.65(s, 3H), 4.16(d, 2H), 5.94(d, 1H), 6.45(t, 1H), 6.52(s, 4H) , 7.21-7.27(m, 2H), 7.38-7.41(m, 1H), 7.64(s, 1H), 7.86(s, 1H), 8.53(s, 1H);

MS m/e MH ⁺ 377.

Example 70

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N'-benzylurea

5-[(3-Aminophenyl)ethynyl]pyrimidine-4,6-diamine (Intermediate 1) (45 mg) was stirred in THF and benzyl isocyanate (37 mg) was added dropwise . After 30 minutes, further benzyl isocyanate (37 mg) was added thereto. After 30 minutes, methylethylenediamine-polystyrene (400 mg) was added and stirring was continued for 30 minutes. The reaction mixture was filtered and concentrated to give a yellow solid which was triturated with DCM (7 mL) to give a beige solid (22 mg, 31%);

¹ H NMR (DMSO-d ₆ ) 4.35 (d, 2H), 6.44-6.57 (bs, 4H), 6.65-6.72 (m, 1H), 7.21-7.44 (m, 8H), 7.67 (s, 1H), 7.86(s, 1H), 8.57(s, 1H);

MSm/e MH ⁺ 359

Example 71

1-[5-[2-(2-aminopyrimidin-5-yl)ethynyl]pyridin-3-yl]-3-[[2-(1-piperidinyl)phenyl]methyl]urea

At 80°C, {5-[(2-aminopyrimidin-5-yl)ethynyl]-pyridin-3-yl}carbamate (Intermediate 21) (463 mg), (2-piperidine-1 -Ylbenzyl)amine (475 mg) and triethylamine (252 mg) were heated in DMF (4 mL) for 3 hours. Purification by RPHPLC gave the product as a solid (97mg, 16%).

¹ H NMR (DMSO-d ₆ ) 1.53 (m, 2H), 1.66 (m, 4H), 2.80 (m, 4H), 4.37 (d, 2H), 6.70 (t, 1H), 7.0-7.3 (m, 6H), 8.11(m, 1H), 8.23(m, 1H), 8.44(m, 3H), 8.92(s, 1H).

MS m/e MH ⁺ 428.

The following examples were prepared in a similar manner to example 37 using intermediate 31 and the appropriate amine.

Example 72

1-[(2-methoxyphenyl)methyl]-3-[6-methyl-5-[2-[2-(2-morpholin-4-ylethylamino)pyrimidin-5-yl ]ethynyl]pyridin-3-yl]-urea

SM: intermediate 31,2-methoxy-benzylamine

¹ H NMR (DMSO-d ₆ ) δ8.77(s, 1H), 8.50(s, 2H), 8.30(s, 1H), 8.04(s, 1H), 7.54(t, 1H), 7.28-7.22( m, 2H), 7.00(d, 1H), 6.92(t, 1H), 6.60(t, 1H), 4.27(d, 2H), 3.84(s, 3H), 3.57(t, 4H), 3.44(q , 2H), 2.54(s, 3H), 2.48(t, 2H), 2.42-2.40(m, 4H);

MS m/e MH ⁺ 502.

Example 73

1-[(2-Dimethylaminophenyl)methyl]-3-[6-methyl-5-[2-[2-(2-morpholin-4-ylethylamino)pyrimidine-5- [yl]ethynyl]pyridin-3-yl]-urea

SM: intermediate 31,2-dimethylamino-benzylamine

MS m/e MH ⁺ 515.

The following examples were prepared in a similar manner to example 38 using intermediate 31 and the appropriate isocyanate.

Example 74

3-[(2-chlorophenyl)methyl]-1-[6-methyl-5-[2-[2-(2-morpholin-4-ylethylamino)pyrimidin-5-yl]acetylene [yl]pyridin-3-yl]-urea

SM: intermediate 31, 2-chloro-benzyl isocyanate

¹ H NMR (DMSO-d ₆ ) δ8.49 (s, 2H), 8.38 (s, 1H), 8.03 (s, 1H), 7.62 (vbrs, 1H), 7.44-7.41 (m, 2H), 7.34- 7.26(m, 2H), 4.36(s, 2H), 3.57(t, 4H), 3.44(t, 2H), 2.53(s, 3H), 2.48(t, 2H), 2.42-2.40(m, 4H) .

MS m/e MH ⁺ 506.

Claims (28)

1. Formula I compound: where R ^y is a group NR ¹ R ² , R ^x is a group R ^3a and R ^z is a group R ^4a , Or R ^x is a group NR ¹ R ² and R ^y is a group R ^4b and R ^z is a group R ^3b where R ¹ and R ² are independently selected from hydrogen, (1-6C) alkylsulfonyl, phenyl (CH ₂ ) _u -, wherein u is 0, 1, 2, 3, 4, 5 or 6, (1- 6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxycarbonyl, (3-6C) cycloalkyl (CH ₂ ) _v -, wherein v is 0, 1, 2, 3, 4 , 5 or 6, or a 5-membered or 6-membered heteroaryl ring, or R ¹ and R ² together with the nitrogen atom to which they are attached represent a saturated or partially saturated 3 optionally containing another heteroatom selected from N or O ~ 7-membered heterocycle; Where any (1-6C) alkyl, (1-6C) alkoxy, (1-6C) alkanoyl and (3-6C) cycloalkyl groups are optionally selected from one or more of the following independently Group substitution: fluorine, hydroxyl, (1-6C) alkyl, (1-6C) alkoxy, (1-6C) alkoxy (1-6C) alkoxy, (1-6C) alkoxy (1-6C) alkoxy (1-6C) alkoxy, amino, mono (1-6C) alkyl amino or di (1-6C) alkyl amino, carbamoyl, mono (1-6C) alkane Carbamoyl, di-[(1-6C)alkyl]carbamoyl, -N(R ^d )C(O)(1-6C)alkyl, where R ^d is hydrogen or (1-6C)alk radical, saturated or partially saturated 3-7 membered heterocyclic ring or 5 or 6-membered heteroaryl ring; Among them (1-6C) alkoxy, (1-6C) alkoxy (1-6C) alkoxy and (1-6C) alkoxy (1-6C) alkoxy (1-6C) alkoxy group, and mono(1-6C)alkylamino, di-[(1-6C)alkyl]amino, mono(1-6C)alkylcarbamoyl, di[(1-6C)alkyl]aminomethyl Acyl and/or (1-6C)alkyl of -N(R ^d )C(O)(1-6C)alkyl are optionally substituted by one or more hydroxyl groups; Wherein any phenyl in R ^and /or ^R is optionally substituted by one or more groups independently selected from the following groups: halogen, (1-6C) alkyl, (1-6C) alkoxy, amino , single (1-6C) alkylamino or bis (1-6C) alkylamino, wherein (1-6C) alkyl and (1-6C) alkoxy are optionally selected from one or more independently selected from hydroxyl , amino, single (1-6C) alkylamino or di-(1-6C) alkylamino group substitution; and wherein any heterocyclic or heteroaryl ring within R ^and /or ^R is optionally substituted independently by one or more of the following groups: (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkoxy(1-4C)alkyl, hydroxy, amino, mono(1-6C)alkylamino, di-[(1-6C)alkyl]amino, saturated or partially saturated 3～ 7-membered heterocycle or -C(O)(CH ₂ ) _z Y, wherein z is 0, 1, 2 or 3, and Y is selected from hydrogen, hydroxyl, (1-4C)alkoxy, amino, mono(1 -6C) alkylamino, di-[(1-6C)alkyl]amino or saturated or partially saturated 3-7 membered heterocycle; and with the proviso that when R ^and / ^or R are a (1C)alkanoyl group, then the (1C)alkanoyl group is not substituted by fluorine or hydroxyl; R ^3a and R ^4a are independently selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxy, Wherein (1-6C) alkyl and (1-6C) alkoxy are optionally substituted by one or more groups independently selected from the following groups: fluorine, hydroxyl, (1-6C) alkyl, (1-6C ) alkoxy, amino, single (1-6C) alkylamino or two (1-6C) alkylamino, carbamoyl, single (1-6C) alkylcarbamoyl or two [(1-6C) Alkyl]carbamoyl, saturated or partially saturated 3-7 membered heterocyclic rings or 5 or 6 membered heteroaryl rings, wherein the heterocyclic rings and heteroaryl rings are optionally independently replaced by one or more of the following groups Substitution: (1-4C) alkyl, (1-4C) alkoxy, hydroxyl, amino, mono(1-6C) alkylamino or di(1-6C) alkylamino or saturated or partially saturated 3～ 7-membered heterocycle; or one of R ^3a and R ^4a is as defined above and the other represents a group -NR ¹ R ² as defined above, R ^3a is selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxy, wherein (1-6C) alkyl and (1-6C) alkoxy are optionally selected by one or more independently Substitution from the following groups: fluorine, hydroxyl, (1-6C) alkyl, (1-6C) alkoxy, amino, mono (1-6C) alkyl amino, di (1-6C) alkyl amino, Carbamoyl, mono(1-6C)alkylcarbamoyl or di[(1-6C)alkyl]carbamoyl, saturated or partially saturated 3-7 membered heterocycle or 5 or 6-membered heteroaryl ring , wherein the heterocyclic and heteroaryl rings are optionally substituted independently by one or more of the following groups: (1-4C)alkyl, (1-4C)alkoxy, hydroxyl, amino, mono(1- 6C) alkylamino or di(1-6C) alkylamino or saturated or partially saturated 3-7 membered heterocycle; Or R ^3b represents a group -NR ¹ R ² as defined above; R ^4b is selected from hydrogen, (1-6C) alkyl, (1-6C) alkoxy or (3-7C) cycloalkyl; A represents an aryl group or a 5- or 6-membered heteroaryl ring selected from the group consisting of furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, Oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or 1,3,5-triazinyl; ^R is selected from cyclopropyl, cyano, halogen, (1-6C) alkoxy or (1-6C) alkyl, wherein (1-6C) alkyl and (1-6C) alkoxy are optionally replaced by Cyano or substituted by one or more fluorines; n is 0, 1, 2 or 3; The connection point of L relative to the ethynyl group is connected at the meta or para position of ring A, and represents -N(R ⁸ )C(O)N(R ⁹ )-(CR ^a R ^b ) _x -Z- (CR ^a R ^b ) _y -, Where Z is a direct bond, -O- or -N(R ⁸ )-, where x and y are independently 0, 1, 2 or 3, provided that x+y>0 and <4, Wherein R ⁸ and R ⁹ independently represent hydrogen or (1-6C) alkyl, wherein R ^a and R ^b independently represent hydrogen or (1-6C) alkyl, or R ^a and R ^b together with the carbon atoms to which they are attached represent (3-6C) cycloalkyl; and wherein the (1-6C) alkyl in R ^a and R ^b is optionally substituted by halogen, cyano, hydroxyl or a saturated or partially saturated 3-7 membered heterocycle, B represents (3-7C) cycloalkyl ring, saturated or partially saturated 3-7 membered heterocyclic ring, aryl or 5 or 6 membered heteroaryl ring; or optionally contains 1, 2, 3 or 4 independently A heteroatom selected from N, O and S and is a saturated, partially saturated or aromatic 8, 9 or 10 membered bicyclic group; R ⁶ is selected from halogen, hydroxyl, amino, mono(C1-6 alkyl)amino, di-(C1-6 alkyl)amino, cyano, oxo, (3-7C)cycloalkyl ring, saturated or partial Saturated 3-7 membered heterocycle and -N(R ^c )C(O)(1-6C)alkyl, wherein R ^c is hydrogen or (1-6C)alkyl; Or R ^is selected from (1-6C) alkyl, S (O) _p (1-6C) alkyl (wherein p is 0, 1 or 2) or (1-6C) alkoxy, Wherein (1-6C) alkyl, S (O) _p (1-6C) alkyl and (1-6C) alkoxy are optionally substituted by one or more groups independently selected from the following groups: cyano, Fluorine, hydroxy, (1-6C)alkoxy, amino, mono(1-6C)alkylamino, di(1-6C)alkylamino, (3-7C)cycloalkyl ring or saturated or partially saturated 3-7 membered heterocycles; and Wherein the (3-7C) cycloalkyl ring and the saturated or partially saturated 3-7 membered heterocycle are optionally independently replaced by one or more selected from (1-6C) alkyl or hydroxy (1-6C) alkane radical substitution of radicals; and m is 0, 1, 2 or 3; And when B is a (3-7C) cycloalkyl ring, a saturated or partially saturated 3-7 membered heterocyclic ring, or a saturated or partially saturated 8, 9 or 10-membered bicyclic group, the ring and the bicyclic group The group optionally has 1 or 2 oxo or thio substituents; and their salts or solvates. 2. A compound according to claim 1 of formula (IA)

in: R ¹ , R ² , R ^3a , R ^4a , A, R ⁵ , L, B, n and m are as defined in claim 1, and R ⁶ is selected from hydroxyl, halogen, cyano, oxo, (3- 7C) Cycloalkyl ring, saturated or partially saturated 3-7 membered heterocycle and -N(R ^c )C(O)(1-6C)alkyl, wherein R ^c is hydrogen or (1-6C)alkyl ; Or R ⁶ is selected from (1-6C) alkyl, S (O) _p (1-6C) alkyl wherein p is 0, 1 or 2, or (1-6C) alkoxy, Wherein (1-6C) alkyl, S (O) _p (1-6C) alkyl and (1-6C) alkoxy are optionally substituted by one or more groups independently selected from the following groups: cyano, Fluorine, hydroxy, (1-6C)alkoxy, amino, mono(1-6C)alkylamino, di(1-6C)alkylamino, (3-7C)cycloalkyl ring or saturated or partially saturated 3-7 membered heterocycles; and Wherein the (3-7C) cycloalkyl ring and the saturated or partially saturated 3-7 membered heterocycle are optionally substituted independently by one or more groups selected from (1-6C) alkyl; and their salts or solvates. 3. The compound according to claim 2, wherein R ^3a and R ^4a are independently selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxy, Wherein (1-6C) alkyl and (1-6C) alkoxy are optionally substituted by one or more groups independently selected from the following groups: fluorine, hydroxyl, (1-6C) alkyl, (1-6C ) alkoxy, amino, single (1-6C) alkylamino, two (1-6C) alkylamino, carbamoyl, single (1-6C) alkylcarbamoyl or two-[(1-6C )alkyl]carbamoyl, saturated or partially saturated 3-7 membered heterocyclic rings or 5 or 6 membered heteroaryl rings, wherein the heterocyclic rings and heteroaryl rings are optionally independently replaced by one or more of the following groups Group substitution: (1-4C) alkyl, (1-4C) alkoxy, hydroxyl, amino, mono(1-6C) alkylamino or di[(1-6C) alkyl] amino or saturated or partially saturated 3-7 membered heterocyclic rings. 4. A compound according to claim 1 of formula IB:

in: R ¹ , R ² , R ^3b , R ^4b , A, R ⁵ , L, B, n and m are as defined in claim 1, R ⁶ is selected from halogen, cyano, oxo, (3-7C) cycloalkyl ring, saturated or partially saturated 3-7 membered heterocycle, -S(O) _p (1-6C) alkyl wherein p is 0, 1 or 2, -N(R ^c )C(O)(1-6C)alkyl, wherein R ^c is hydrogen or (1-6C)alkyl; or R ⁶ is selected from (1-6C) alkyl or (1-6C) alkoxy, wherein (1-6C) alkyl, -S (O) _p (1-6C) alkyl and (1-6C) alkane Oxygen is optionally substituted by one or more groups independently selected from the group consisting of cyano, fluorine, hydroxyl, (1-6C)alkoxy, amino, mono(1-6C)alkylamino, di[( 1-6C) alkyl] amino, (3-7C) cycloalkyl ring or saturated or partially saturated 3-7 membered heterocycle; Wherein the (3-7C) cycloalkyl ring and the saturated or partially saturated 3-7 membered heterocycle are optionally independently replaced by one or more selected from (1-6C) alkyl or hydroxy (1-6C) alkane radical substitution of radicals; and When B is a (3-7C) cycloalkyl ring, a saturated or partially saturated 3-7 membered heterocyclic ring, or a saturated or partially saturated 8, 9 or 10-membered bicyclic group, the ring and bicyclic group Optionally with 1 or 2 oxo or thio substituents; and their salts or solvates. 5. The compound according to claim 4, wherein R ^3b is selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxy, wherein (1-6C) alkyl and (1-6C) alkoxy Optionally substituted by one or more groups independently selected from: fluorine, hydroxyl, (1-6C) alkyl, (1-6C) alkoxy, amino, mono (1-6C) alkylamino or Di[(1-6C)alkyl]amino, carbamoyl, mono(1-6C)alkylcarbamoyl or di[(1-6C)alkyl]carbamoyl, saturated or partially saturated 3-7 A membered heterocycle or a 5- or 6-membered heteroaryl ring, wherein the heterocycle and heteroaryl ring are optionally substituted independently by one or more of the following groups: (1-4C)alkyl, (1-4C) Alkoxy, hydroxyl, amino, mono(1-6C)alkylamino or di[(1-6C)alkyl]amino or saturated or partially saturated 3-7 membered heterocyclic rings. 6. The compound according to claim 4, wherein the compound of formula IB is a compound of formula IB': in: R ¹ , R ² , R ^4b , R ⁵ , R ⁶ , L, n, m, A and B are as defined in claim 4, and R ¹⁰ and R ¹¹ are independently selected from hydrogen or (1-6C) alkyl; and their salts or solvates. 7. The compound according to any one of the preceding claims, wherein L is a group -N(R ⁸ )C(O)N(R ⁹ )-(CR ^a R ^b ) _x -, wherein x is 1 or 2, and wherein R ^a , R ^b , R ⁸ and R ⁹ are independently selected from hydrogen and (1-6C)alkyl. 8. The compound according to claim 7, wherein R ^a , R ^b , R ⁸ and R ⁹ are all hydrogen. 9. A compound according to any one of the preceding claims, wherein A is phenyl or pyridyl. 10. A compound according to any one of the preceding claims, wherein B is phenyl. 11. A compound according to any one of the preceding claims, wherein n is 0 or 1 . 12. A compound according to any one of the preceding claims, wherein n is other than 0, and ^R is selected from (1-6C)alkyl and (1-6C)alkoxy. 13. A compound according to any one of the preceding claims, wherein m is 1 or 2. 14. A method for preparing a compound according to claim 1 or a pharmaceutically acceptable salt thereof; the method comprising Method (a) makes formula II compound: wherein R ^x , R ^y , R ^z , R ⁵ , R ⁸ , n and A are as defined in claim 1, but any functional group is protected if necessary, and reacted with an isocyanate of formula IV:

Wherein Z, R ⁶ , R ^a , R ^b , x, y, m and B are as defined in claim 1, but any functional group is protected if necessary; or Process (b) reacts a compound of formula II as defined above with an aryl carbamate of formula III: wherein Ar is aryl, and Z, R ⁶ , R ^a , R ^b , x, y, m and B are as defined in claim 1, but any functional groups are protected if necessary; or Method (c) For the compound of formula I wherein Z is -O- or -N(R ^a )-, the compound of formula IX

wherein R ^x , R ^y , R ^z , R ⁵ , R ⁸ , R ⁹ , R ^a , R ^b , x, n and A are as defined in claim 1, but any functional group is protected if necessary, and formula XI compound reaction,

wherein Lg ¹ is a suitable replacement group, and R ^a , R ^b , R ⁶ , y, m and B are as defined in claim 1 , but any functional groups are protected if necessary; or Method (d) For the compound of formula I wherein Z is -O- or -N(R ^a )-, the compound of formula XIV wherein Lg ² is a suitable replacement group, and R ^x , R ^y , R ^z , R ⁵ , R ⁸ , R ⁹ , Ra, R ^b , n, x and A are as defined in claim ¹ , but Protection of any functional groups where necessary, react with a compound of formula XV,

Wherein R ^a , R ^b , R ⁶ , y, m and B are as defined in claim 1, but any functional group is protected if necessary; or Method (e) For a compound of formula I wherein L is -N(R ⁸ )C(O)N(H)-(CR ^a R ^b ) _x -Z-(CR ^a R ^b ) _y -, such that as defined above The compound of formula II is reacted with trichloroacetamide of formula XIII:

Wherein R ⁶ , R ^a , R ^b , x, y, m and B are as defined in claim 1, but any functional group is protected if necessary; or Method (f) makes formula XVI or XVIA compound:

wherein Lg ³ is a suitable replacement group, and R ^3a , R ^4a , R ^3b , R ^4b , R ⁵ , R ⁶ , n, m, A, B and L are as defined in claim 1, but where necessary Protecting any functional group, reacting with an amine of formula HNR ¹ R ² , wherein R ¹ and R ² are as defined in claim 1, but protecting any functional group if necessary; or Method (g) makes the compound of formula XVII:

wherein Lg ⁴ is a suitable substituent, and R ⁵ , R ⁶ , n, m, A, B and L are as defined in claim 1, but any functional groups are protected if necessary, reacted with an alkyne of formula XVIII :

wherein R ^x , R ^y and R ^z are as defined in claim 1, but any functional groups are protected if necessary; or Method (h) makes the compound of formula XVIIa:

wherein R ⁵ , R ⁶ , n, m, A, B and L are as defined in claim 1, but any functional group is protected if necessary, and reacted with a pyrimidine of formula XVIIIa:

wherein Lg ⁵ is a suitable replacement group, and R ^x , R ^y and R ^z are as defined in claim 1, but any functional groups are protected if necessary; or Method (i) For compounds of formula I wherein L is -N(H)C(O)N(R ⁹ )-(CR ^a R ^b ) _x -Z-(CR ^a R ^b ) _y- , the formula XIX Isocyanate:

wherein R ^x , R ^y , R ^z , R ⁵ , n and A are as defined in claim 1, but any functional group is protected if necessary, and reacted with an amine of formula XV;

wherein R ⁹ , R ^a , R ^b , Z, R ⁶ , B, x, y and m are as defined in claim 1; or Process (i) For a compound of formula I wherein L is -N(H)C(O)N(R ⁹ )-, a compound of formula XX:

wherein Ar is aryl, and ^Rx , ^Ry , ^Rz , ^R5 , n and A are as defined in claim 1, but any functional groups are protected if necessary, reacted with an amine of formula XV as defined above, and thereafter if necessary: i) converting a compound of formula (I) into another compound of formula (I); ii) removing any protecting groups; iii) Salt formation. 15. A pharmaceutical composition, comprising the compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier. 16. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use as a medicament. 17. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use as a Tie2 receptor tyrosine kinase inhibitor in a warm-blooded animal. 18. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for producing an anti-angiogenic effect in a warm-blooded animal. 19. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer in a warm-blooded animal. 20. A method of inhibiting Tie2 receptor tyrosine kinase in a warm-blooded animal in need of said treatment, such as a human, comprising administering to said animal an effective amount of a compound according to any one of claims 1 to 13 or its Pharmaceutically acceptable salts. 21. A method for producing an anti-angiogenic effect in a warm-blooded animal in need of said treatment, comprising administering to said animal an effective amount of the compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof, Wherein said warm-blooded animals such as humans. 22. A method of treating cancer in a warm-blooded animal in need of said treatment, comprising administering to said animal an effective amount of a compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof. 23. A compound of formula (II),

wherein ^Rx , ^Ry , ^Rz , ^R5 , ^R8 , n and A are as defined in claim 1, but any functional groups are optionally protected. 24. A compound of formula XIV,

wherein Lg ² is a suitable replacement group, and R ^x , R ^y , R ^z , R ⁵ , R ⁸ , R ⁹ , Ra, R ^{b ,} n, x and A are as defined in claim 1, but Any functional groups are optionally protected. 25. A compound of formula XVI or XVIA:

wherein Lg ³ is a suitable replacement group, and R ^3a , R ^4a , R ^3b , R ^4b , R ⁵ , R ⁶ , n, m, A, B and L are as defined in claim 1, but any functional group Optionally protected. 26. Compounds of formula XIX

wherein ^Rx , ^Ry , ^Rz , ^R5 , n and A are as defined in claim 1, but any functional groups are optionally protected. 27. Compounds of formula XX

wherein Ar is aryl, and ^Rx , ^Ry , ^Rz , ^R5 , n and A are as defined in claim 1, but any functional groups are optionally protected. 28. Formula VIc or VIc' compound:

wherein Lg ³ is a suitable replacement group, and R ⁵ , R ⁸ , n and A are as defined in claim 1, R ^3a and R ^4a are as defined in claim 2, and R ^3b and R ^4b are as defined in claim 2 As defined in claim 4, but any functional groups are optionally protected.