ES2372043T3 - SPYROCYCLIC AND GEM-DISPOSED AMINOPIRIDINS / PYRIMIDINS AS INHIBITORS OF THE CELL CYCLE. - Google Patents

Abstract

Composed of formulas I or II enantiomers, diastereomers, salts and solvates thereof in which A1 and A2 together with the ring carbon atoms to which they are attached combine to form benzene, cyclopentadiene, pyridine, pyridone, pyrimidine, pyrazine, pyridazine, 2H-pyran, pyrrole, imidazole, pyrazole, triazole, furan, oxazole, isoxazole, oxadiazole, thiophene, thiazole, isothiazole or thiadiazole any of which may be optionally partially saturated, and any of which may be independently substituted optionally with one or more Rx groups as allowed by valence; W and X are independently CH or N; Z is absent, -O-, -S (O) n-, or -NHR3-; R1 is -Y-Ra in which Y is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl any of which may be optionally independently substituted with one or more Rx groups as permitted by valence; and Ra is heterocycle, -NR3R4, -C (= O) NR3R4; -O-R5 or -S (O) n-R5; R2 and R2a are each independently alkyl or alkenyl any of which may be optionally substituted with one or more Rx as permitted by valence; or R2 and R2a together with the ring carbon atom to which they are attached combine to form a spirocondensed ring system of the following formula A in which M is -CRdRe-, -O-, -S (O) n- or -NHR3-; Rb, Rc, Rd and Re are each independently H or Rx, or alternatively Rb and Rd in adjacent carbon ring atoms may optionally combine to form a double bond as allowed by valence, and Rd and Re in Adjacent carbon ring atoms may optionally combine to form a double bond as allowed by valence; R3 and R4 at each occurrence are independently (i) hydrogen or (ii) alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylalkyl, arylalkyl or heteroarylalkyl any of which may be optionally independently substituted with one or more Rx groups as allow valence; or R3 and R4 together with the nitrogen atom to which they are attached can be combined to form an independently substituted heterocycle ring optionally with one or more Rx groups as allowed by valence; R3 * and R4 * at each occurrence are independently (i) hydrogen or (ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylalkyl, arylalkyl or heteroarylalkyl any of which may be optionally independently substituted with one or more Rx groups as allowed by valence; or R3 * and R4 * together with the nitrogen atom to which they are attached can be combined to form an independently substituted heterocycle ring optionally with one or more Rx groups as allowed by valence; R5 and R5 * at each occurrence is (i) hydrogen or (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylalkyl, arylalkyl or heteroarylalkyl any of which may be optionally independently substituted with one or more Rx groups as allowed by valence; R6, R7, R8 and R9 are each independently H or Rx, or alternatively (i) R6 and R7 together with the ring carbon atom to which they are attached can be combined to form = O, = S or = NR3, as valence permits; (ii) R8 and R9 together with the ring carbon atom to which they are attached can be combined to form = O, = S or = NR3, as allowed by valence; (iii) two R6 groups in adjacent ring carbon atoms can be combined to form a double bond as allowed by valence; (iv) R6 and R8 in adjacent ring carbon atoms can be combined to form a double bond as allowed by valence; Rx at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, - (alkylene) m-OR5, - (alkylene ) mS (O) nR5, - (alkylene) m-NR3R4, - (alkylene) mC (= O) R5, - (alkylene) mC (= S) R5, - (alkylene) mC (= O) OR5, - ( alkylene) m-OC (= O) R5, - (alkylene) mC (= S) OR5, - (alkylene) mC (= O) NR3R4, - (alkylene) mC (= S) NR3R4, - (alkylene) mN ( R3) C (= O) NR3R4, - (alkylene) mN (R3) C (= S) NR3R4, - (alkylene) m- N (R3) C (= O) R5, - (alkylene) mN (R3) C (= S) R5, - (alkylene) m-OC (= O) NR3R4, - (alkylene) m-OC (= S) NR3R4, - (alkylene) m-SO2NR3R4, - (alkylene) mN (R3) SO2R5, - (alkylene) mN (R3) SO2NR3R4, - (alkylene) m- N (R3) C (= O) OR5, - (alkylene) mN (R3) C (= S) OR5 or - (alkylene) mN (R3) SO2R5; wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, arylalkyl, heteroarylalkyl and cycloalkylalkyl groups may be independently substituted additionally with one or more - (alkylene) m-OR5 *, - (alkylene) mS (O) nR5 *, - (alkylene) m-NR3 * R4 *, - (alkylene) mC (= O) R5 *, - (alkylene) mC (= S) R5 *, - (alkylene) mC (= O) OR5 *, - (alkylene) m-OC (= O) R5 *, - (alkylene) mC (= S) OR5 *, - (alkylene) mC (= O) NR3 * R4 *, - (alkylene ) m- C (= S) NR3 * R4 *, - (alkylene) mN (R3 *) C (= O) NR3 * R4 *, - (alkylene) mN (R3 *) C (= S) NR3 * R4 * , - (alkylene) m- N (R3 *) C (= O) R5 *, - (alkylene) mN (R3 *) C (= S) R5 *, - (alkylene) m-OC (= O) NR3 * R4 *, - (alkylene) m- OC (= S) NR3 * R4 *, - (alkylene) m-SO2NR3 * R4 *, - (alkylene) mN (R3 *) SO2R5 *, - (alkylene) mN (R3 * ) SO2NR3 * R4 *, - (alkylene) mN (R3 *) C (= O) OR5 *, - (alkylene) mN (R3 *) C (= S) OR5 * or - (alkylene) mN (R3 *) SO2R5 *; n is 0, 1 or 2; m is 0 or 1; p and q are independently 0, 1 or 2; r is 1, 2 or 3 when Z is absent, or is 0, 1 or 2 when Z is present; wherein the alkyl, alkylenyl, alkenyl and alkynyl radicals may be optionally substituted with one or more functional groups selected from the group consisting of halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl and heterocycle; wherein alkoxy may be substituted with one or more halogen atoms; wherein aryl may have one or more substituents selected from the group consisting of C1-6 alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and C1-6 alkylamino, and in which phenyl substituted with -O-CH2- O- forms the arylbenzodioxolyl substituent; wherein heterocycle may have one to three substituents selected from the group consisting of hydroxyl, Boc, halo, haloalkyl, cyano, C1-6 alkyl, C1-6 aralkyl, oxo, C1-6 alkoxy, amino and C1-6 alkylamino ; wherein aryl in aralkyl may be further substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy; and in which cycloalkyl in cycloalkylalkyl may be further substituted with halo, alkyl, alkoxy and hydroxyl.

Description

Spirocyclic and gem-disubstituted aminopyridines / pyrimidines as cell cycle inhibitors

This invention is in the field of pharmaceutical agents and specifically relates to compounds, compositions, uses and compounds for use in the treatment of cancer.

Cyclin-dependent kinases (Cdk) are a family of serine protein / threonine kinases that perform important cellular functions. Cyclines are the regulatory subunits that activate catalytic Cdk. Cdk1 / Cyclin B1, Cdk2 / Cyclin A, Cdk2 / Cyclin E, Cdk4 / Cyclin D, Cdk6 / Cyclin D are critical regulators of cell cycle progression. Cdk also regulates transcription, DNA repair, differentiation, senescence and apoptosis (Morgan D.O., Annu. Rev. Cell. Dev. Biol. 1997: 13: 261-291).

Small molecule Cdk inhibitors were developed to treat cancer (from Career G et al., Curr Med Chem. 2007; 14: 969-85). A large amount of genetic evidence supports that Cdk play critical roles in the development of most human cancers (Malumbres M. et al, Nature Rev Cancer, 2001; 1: 222-231). Genetic alterations in Cdk, their substrates or regulators have been shown to be associated with human cancer. Endogenous Cdk protein inhibitors that include p16, p21 and p27 inhibit Cdk activity and its overexpression results in cell cycle arrest and tumor growth inhibition in preclinical models (Kamb A., Curr. Top. Microbiolus. Immunol, 1998; 227: 139-148).

Cdk small molecule inhibitors can also be used to treat a variety of other diseases that result from aberrant cell proliferation, including cardiovascular disorders, kidney diseases, certain infectious diseases and autoimmune diseases. Regulatory cell proliferation pathways that include genes involved at the control point of the S and G1 phase of the cell cycle (p53, pRb, p15, p16, and cyclin A, D, E, Cdk 2 and Cdk4) have been associated with the progression of plaques, stenosis and restenosis after angioplasty. It was shown that overexpression of the Cdk p21 inhibitor protein inhibits the proliferation of vascular smooth muscle and intimal layer hyperplasia after angioplasty (Chang MW et al., J. Clin. Invest., 1995; 96: 2260; Yang ZY. et al., Proc. Natl. Acad. Sci. (United States) 1996; 93: 9905). A small molecule Cdk2 inhibitor CVT-313 (Ki = 95 nM) was shown to cause a non-significant inhibition of neointimal layer formation in animal models (Brooks EE et al., J. Biol. Chem. 1997; 272: 29207-29211). Deregulation of the cell cycle has been associated with polycystic kidney diseases, which are characterized by the growth of fluid-filled cysts in the renal tubules. Treatment with small molecule inhibitors of the Cdk provided effective arrest of cystic disease in mouse models (Bukanov N. O., et al., Nature, 2006; 4444: 949-952). Infection by a variety of infectious agents, including fungi, protozoan parasites such as Plasmodium falciparum, and DNA and RNA viruses, can be treated with Cdk inhibitors. It has been shown that Cdk are required for herpes simplex virus (HSV) replication (Schang L.M. et al., J. Virol. 1998; 72: 5626). Cdk are essential proteins in yeasts. Synovial tissue hyperplasia plays important roles in the development of rheumatoid arthritis; inhibition of synovial tissue proliferation can suppress inflammation and prevent destruction of the joint. Overexpression of the Cdk p16 inhibitor protein has been shown to inhibit the growth of synovial fibroblasts (Taniguchi K. et al., Nat. Med. 1999; 5: 760-767) and joint swelling was substantially inhibited in models arthritis animals.

Selective inhibitors of some Cdk can also be used to protect normal non-transformed cells by inhibiting specific phases of cell cycle progression (Chen et al. J. Natl. Cancer Institute, 2000; 92: 19992008). Pretreatment with a selective Cdk inhibitor prior to the use of a cytotoxic agent that inhibits a different phase of the cell cycle may reduce the side effects associated with cytotoxic chemotherapy and possibly increase the therapeutic period. It has been shown that induction of Cdk cell protein inhibitors (p16, p27 and p21) conferred strong resistance to cytotoxicity mediated by paclitaxel or cisplatin in inhibitor-sensitive cells but not in non-inhibitor-sensitive cells (Schmidt, M, Oncogene, 2001 20: 616471).

WO-A-0138315 discloses specific 2-arylamino-quinazolines that are potent inhibitors of cyclin-dependent kinases (cdk). WO-A-02076396 discloses compounds that are useful as kinase inhibitors for the treatment of hyperproliferative diseases. Bathini Y et al. disclose cyclin-dependent 2-aminoquinazoline kinase inhibitors in BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 15, No. 17, September 1, 2005 (09/1/2005), pages 3881-3885. Vanderwel et al. disclose pyrido [2,3-d] pyrimidin-7-ones as specific inhibitors of cyclin-dependent kinase 4 in the JOURNAL OF MEDICINAL CHEMISTRY [online] vol. 48, February 3, 2005 (03/02/2005), pages 2371-2387.

A class of compounds useful in the treatment of cancer is defined by the following formulas I or II enantiomers, diastereomers, salts and solvates thereof in which

A1 and A2 together with the ring carbon atoms to which they are attached combine to form benzene, cyclopentadiene, pyridine, pyridone, pyrimidine, pyrazine, pyridazine, 2H-pyran, pyrrole, imidazole, pyrazole, triazole, furan,

5 oxazole, isoxazole, oxadiazole, thiophene, thiazole, isothiazole or thiadiazole any of which may be optionally partially saturated, and any of which may be optionally independently substituted with one or more Rx groups as permitted by valence;

W and X are independently CH or N;

Z is absent, -O-, -S (O) n- or -NHR3-;

10 R1 is -Y-Ra in which

Y is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl, any of which may be optionally independently substituted with one or more Rx groups as permitted by valence; Y

Ra is heterocycle, -NR3R4, -C (= O) NR3R4; -O-R5 or -S (O) n-R5;

R2 and R2a are each independently alkyl or alkenyl any of which may be optionally substituted with one or more Rx as permitted by valence;

or R2 and R2a together with the ring carbon atom to which they are attached combine to form a spirocondensed ring system of the following formula A

20 in which

M is –CRdRe-, -O-, -S (O) n- or –NR3-;

Rb, Rc, Rd and Re are each independently H or Rx, or alternatively Rb and Rd in adjacent carbon ring atoms may optionally combine to form a double bond as allowed by valence, and Rd and Re in adjacent carbon ring atoms can optionally combine to form

25 a double bond as allowed by valence;

R3 and R4 at each occurrence are independently

(i)

 hydrogen or

(ii)

 alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylalkyl, arylalkyl or heteroarylalkyl any of the

which may be optionally independently substituted with one or more Rx groups as allowed by valence;

or R3 and R4 together with the nitrogen atom to which they are attached can be combined to form an independently substituted heterocycle ring optionally with one or more Rx groups as allowed by valence;

R3 * and R4 * at each occurrence are independently

(i)

 hydrogen or

(ii)

alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylalkyl, arylalkyl or heteroarylalkyl any of which may be optionally independently substituted with one or more Rx groups as permitted by valence;

or R3 * and R4 * together with the nitrogen atom to which they are attached can be combined to form an independently substituted heterocycle ring optionally with one or more Rx groups as allowed by valence;

R5 and R5 * in each occurrence is

(i)

 hydrogen or

(ii)

 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylalkyl, arylalkyl or heteroarylalkyl any of which may be optionally independently substituted with one or more Rx groups as permitted by valence;

R6, R7, R8 and R9 are each independently H or Rx, or alternatively

(i)

 R6 and R7 together with the ring carbon atom to which they are attached can be combined to form = O, = S or = NR3, as allowed by valence;

(ii)

 R8 and R9 together with the ring carbon atom to which they are attached can be combined to form = O, = S

o = NR3, as allowed by valence;

(iii) two R6 groups in adjacent ring carbon atoms can be combined to form a double bond as allowed by valence;

(iv) R6 and R8 in adjacent ring carbon atoms can be combined to form a double bond as allowed by valence;

Rx at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, - (alkylene) m-OR5, - (alkylene ) mS (O) nR5, - (alkylene) m-NR3R4, - (alkylene) mC (= O) R5, - (alkylene) mC (= S) R5, - (alkylene) mC (= O) OR5, - ( alkylene) m-OC (= O) R5, - (alkylene) mC (= S) OR5, - (alkylene) mC (= O) NR3R4, - (alkylene) mC (= S) NR3R4, - (alkylene) mN ( R3) C (= O) NR3R4, - (alkylene) mN (R3) C (= S) NR3R4, - (alkylene) mN (R3) C (= O) R5, - (alkylene) mN (R3) C (= S) R5, - (alkylene) m-OC (= O) NR3R4, - (alkylene) m-OC (= S) NR3R4, - (alkylene) m-SO2NR3R4, - (alkylene) mN (R3) SO2R5, - ( alkylene) mN (R3) SO2NR3R4, - (alkylene) mN (R3) C (= O) OR5, - (alkylene) mN (R3) C (= S) OR5 or - (alkylene) mN (R3) SO2R5;

wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, arylalkyl, heteroarylalkyl and cycloalkylalkyl groups may be independently substituted additionally with one or more - (alkylene) m-OR5 *, - ( alkylene) mS (O) nR5 *, - (alkylene) m-NR3 * R4 *, - (alkylene) mC (= O) R5 *, - (alkylene) mC (= S) R5 *, - (alkylene) mC ( = O) OR5 *, - (alkylene) m-OC (= O) R5 *, - (alkylene) mC (= S) OR5 *, - (alkylene) mC (= O) NR3 * R4 *, - (alkylene) mC (= S) NR3 * R4 *, - (alkylene) mN (R3 *) C (= O) NR3 * R4 *, - (alkylene) mN (R3 *) C (= S) NR3 * R4 *, - ( alkylene) mN (R3 *) C (= O) R5 *, - (alkylene) mN (R3 *) C (= S) R5 *, - (alkylene) m-OC (= O) NR3 * R4 *, - ( alkylene) m-OC (= S) NR3 * R4 *, - (alkylene) m-SO2NR3 * R4 *, - (alkylene) mN (R3 *) SO2R5 *, - (alkylene) mN (R3 *) SO2NR3 * R4 * , - (alkylene) mN (R3 *) C (= O) OR5 *, - (alkylene) mN (R3 *) C (= S) OR5 * or - (alkylene) mN (R3 *) SO2R5 *;

n is 0, 1 or 2;

m is 0 or 1;

p and q are independently 0, 1 or 2;

r is 1, 2 or 3 when Z is absent, or is 0, 1 or 2 when Z is present;

wherein the alkyl, alkylenyl, alkenyl and alkynyl radicals may be optionally substituted with one

or more functional groups selected from the group consisting of halo, hydroxyl, nitro, amino, cyano, haloalkyl, aryl, heteroaryl and heterocycle;

wherein alkoxy may be substituted with one or more halogen atoms;

wherein aryl may have one or more substituents selected from the group consisting of C1-6 alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and C1-6 alkylamino, and in which phenyl substituted with -O-CH2- O- forms the arylbenzodioxolyl substituent;

5 wherein the heterocycle may have one to three substituents selected from the group consisting of hydroxyl, Boc, halo, haloalkyl, cyano, C1-6 alkyl, C1-6 arylalkyl, oxo, C1-6 alkoxy, amino and C1 alkylamino -6;

wherein the aryl in arylalkyl may be further substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy; Y

wherein the cycloalkylalkyl cycloalkyl may be further substituted with halo, alkyl, alkoxy and hydroxyl.

The compounds of this invention are selective inhibitors of the cyclin-dependent kinase Cdk4, which is like saying that they inhibit Cdk4 with greater potency than inhibit tyrosine kinases and other serine-threonine kinases including other cyclin-dependent kinases such as Cdk1. The Cdk6 is structurally and functionally similar to the Cdk4. The compounds of the present invention also inhibit Cdk6 at concentrations similar to those for

15 inhibit Cdk4. Preferred embodiments of the present invention are compounds of formula 1 that inhibit Cdk4 at least about 100 times more potently than what inhibits Cdk1.

The compounds of the present invention are useful for the treatment of cancer including leukemia and solid lung, breast, prostate and skin cancer such as melanoma, and other diseases with abnormal cell proliferation that include but are not limited to psoriasis, HSV, HIV, restenosis and atherosclerosis.

Preferred compounds within the scope of formula I include compounds in which A1 and A2 together with the ring atoms to which they are attached combine to form

Preferred compounds within the scope of formulas I and II include compounds in which Y is cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, phenyl, pyridinyl, pyrimidinyl, cyclopentadienyl, pyrrolyl, imidazolyl, oxazolyl or thiazolyl. Preferred compounds within the scope of formulas I and II include compounds in which Y is cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, phenyl, pyridinyl, pyrimidinyl, cyclopentadienyl, pyrrolyl, pyrazinyl, pyridazinyl, imidazolyl, oxazolyl or thiazolyl.

Preferred compounds within the scope of formulas I and II additionally include compounds in which R 1 is selected from

Preferred compounds within the scope of formulas I and II additionally include compounds in which R 1 is selected from

Preferred compounds within the scope of formulas I and II additionally include compounds in which R 1 is selected from

Preferred compounds within the scope of formulas I and II additionally include compounds in which Ra is selected from

(to)

 -OR5 or -S (O) nR5 in which R5 is alkyl optionally independently substituted with one or more -OR5 * or -NR3 * R4 *;

(b)

 -C (= O) NR3R4 or -NR3R4 in which R3 and R4 are independently alkyl optionally independently substituted with one or more -OR5 * or -NR3 * R4 *;

or R3 and R4 together with the nitrogen atom to which they are attached combine to form

The preferred compounds within the scope of formulas I and II additionally include compounds in which R2 and R2a together with the ring carbon atom to which they are attached combine to form a spirocondensed ring system selected from

Preferred compounds within the scope of formula I include compounds of the following formula 1A

in which t is 0 or 1; and v is 0, 1, 2, 3 or 4.

Preferred compounds within the scope of formula IA include compounds having any of the preferred substituents Y, R1, Ra and / or R2 / R2a listed above. Preferred compounds within the scope of formula I include compounds having the following formula IB in which t is 0 or 1; and v is 0, 1, 2, 3 or 4.

Preferred compounds within the scope of formula IB include compounds having any of the preferred substituents Y, R1, Ra and / or R2 / R2a listed above. Preferred compounds within the scope of formula IB include compounds in which v is 0, 1, 2 or 3.

Preferred compounds within the scope of formula I include compounds having the following formula IC

in which t is 0 or 1; and v is 0, 1, 2, 3 or 4.

Preferred compounds within the scope of formula IC include compounds having any of the preferred substituents Y, R1, Ra and / or R2 / R2a listed above. Preferred compounds within the scope of formula IC include compounds in which v is 0, 1, 2 or 3.

Preferred compounds within the scope of formula I include compounds having the following formula ID

in which t is 0 or 1; and v is 0, 1, 2, 3 or 4.

Preferred compounds within the scope of formula ID include compounds having any of the 15 preferred substituents Y, R1, Ra and / or R2 / R2a listed above previously. Preferred compounds within the scope of formula ID include compounds in which v is 0, 1, 2 or 3.

Certain compounds within the scope of the present invention exist as keto-enol tautomers. For example compounds such as the following:

The present invention further provides a compound for use in the treatment of disorders or conditions consisting of abnormal cell proliferation, such as cancer, atherosclerosis, post-surgical vascular stenosis, restenosis and endometriosis; infections, including viral infections such as DNA viruses such as herpes and RNA viruses such as HIV and fungal infections; autoimmune diseases such as psoriasis, inflammation such as rheumatoid arthritis, lupus, type 1 diabetes, diabetic nephropathy, multiple sclerosis and

Glomerulonephritis, rejection of organ transplantation, including graft versus host disease, in a mammal, which includes the human being, comprising administering to said mammal an amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof. , which is effective in treating such disorder or condition.

This invention further provides compounds of formulas I and II that are useful for the treatment of abnormal cell proliferation such as cancer. The invention provides a compound for use in the treatment of an abnormal cell proliferation disorder such as myeloid disorders, lymphoid disorders, tricoleukocytes in Hodgkin's disease, leukemia, cancers of the breast, lung, colon, ovary, cervix, prostate , testicles, esophagus, stomach, skin, bone, pancreas, thyroid, bile ducts, oral cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colorectal, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, squamous cell carcinoma, large cell carcinoma, adenocarcinoma, adenoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and kidney carcinoma, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a suj Eto with one or more of the above disorders.

An embodiment of this invention is also a compound for use in the treatment of subjects with diseases caused by cellular proliferation of vascular smooth muscle. Medical use comprises administering to a subject with such a disorder an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

This invention further provides a compound for use in the treatment of a subject suffering from gout which comprises administering to said subject in need of treatment an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, sufficient to treat the condition.

The present invention further provides a compound for use in the treatment of a subject with renal disease, such as polycystic kidney disease, which comprises administering to said subject in need of treatment an amount of a compound of formulas I and II, or a pharmaceutically acceptable salt. of it, enough to treat the state.

Definitions

The terms "cancer" and "cancerous" when used herein refer to or describe the physiological state in mammals that is typically characterized by unregulated cell growth. Examples of cancer include but are not limited to carcinoma, lymphoma, sarcoma, blastoma and leukemia. More particular examples of such types of cancer include spinocellular carcinoma, lung cancer, pancreatic cancer, cervical cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, and head and neck cancer. The terms "treat", "treatment" and "therapy" as used herein refer to curative therapy, prophylactic therapy and preventive therapy.

The term "mammal" as used herein refers to any mammal classified as a mammal, including humans, cows, horses, dogs and cats. In a preferred embodiment of the invention, the mammal is a human being.

The term "treatment" includes therapeutic treatment as well as prophylactic treatment (either preventing the onset of disorders altogether or delaying the onset of a preclinically evident stage of disorders in individuals).

The phrase "therapeutically effective" is intended to rate the amount of each agent, which will achieve the objective of improving the severity of the disorder and the frequency of incidence with respect to the treatment of each agent by itself, while avoiding associated adverse side effects. Normally with alternative therapies. For example, effective neoplastic therapeutic agents prolong patient survival, inhibit rapidly proliferating cell growth associated with the neoplasm or effect a regression of the neoplasm.

The term "H" indicates a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.

When the term "alkyl" is used, either alone or within other terms such as "haloalkyl" and "alkylamino", it encompasses linear or branched radicals having from one to about twelve carbon atoms. The most preferred alkyl radicals are "lower alkyl" radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like. Even more preferred are lower alkyl radicals having one or two carbon atoms. The term "alkylenyl" encompasses divalent alkyl radicals that form bridges such as methylene and ethylenyl. The term "lower alkyl substituted with R2" does not include an acetal moiety.

The term "alkenyl" encompasses linear or branched radicals having at least one carbon-carbon double bond of two to about twelve carbon atoms. More preferred alkenyl radicals are "lower alkenyl" radicals having two to about six carbon atoms. The most preferred lower alkenyl radicals are radicals having from two to about four carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl" encompass radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations.

The term "alkynyl" denotes linear or branched radicals that have at least one carbon-carbon triple bond and that have two to about twelve carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals having two to about six carbon atoms. Most preferred are lower alkynyl radicals having two to about four carbon atoms. Examples of such radicals include propargyl, butynyl and the like.

The alkyl, alkylenyl, alkenyl and alkynyl radicals may be optionally substituted with one or more functional groups such as halo, hydroxyl, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocycle and the like.

The term "halo" means halogens such as fluorine, chlorine, bromine or iodine atoms.

The term "haloalkyl" encompasses radicals in which any one or more of the alkyl carbon atoms is substituted with halo as defined above. Monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals including perhaloalkyl are specifically encompassed. A monohaloalkyl radical, for example, can have either an iodine, bromine, chlorine or fluorine atom within the radical. The dihalo and polyhaloalkyl radicals may have two or more of the same halogen atoms or a combination of different halo radicals. "Lower haloalkyl" encompasses radicals having 1-6 carbon atoms. Even more preferred are lower haloalkyl radicals having one to three carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichlorophenyl. "Perfluoroalkyl" means alkyl radicals having all hydrogen atoms replaced by fluorine atoms. Examples include trifluoromethyl and pentafluoroethyl.

The term "hydroxyalkyl" encompasses linear or branched alkyl radicals having one to about ten carbon atoms, any one of which may be substituted with one or more hydroxyl radicals. The most preferred hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals having one to three carbon atoms.

The term "alkoxy" encompasses linear or branched oxyl-containing radicals each having alkyl parts of one to about ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Even more preferred are lower alkoxy radicals having one to three carbon atoms. The alkoxy radicals may be further substituted with one or more halogen atoms, such as fluorine, chlorine or bromine, to provide "haloalkoxy" radicals. Even more preferred are lower haloalkoxy radicals having one to three carbon atoms. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one or two rings, such rings being able to be joined together in a fused manner. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl and indanyl. A more preferred aryl is phenyl. Said "aryl" group may have 1 or more substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like. Phenyl substituted with -O-CH2-O- forms the arylbenzodioxolyl substituent.

The term "heterocyclyl" (or "heterocycle") encompasses ring radicals containing heteroatoms, partially saturated and saturated, in which the heteroatoms can be selected from nitrogen, sulfur and oxygen. Does not include rings containing -O-O-, -O-S- or parts -S-S-. Said "heterocyclyl" group may have 1 to 3 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino, lower alkylamino and the like.

Examples of saturated heterocyclic radicals include heteromonocyclic groups of 3 to 6 saturated members containing 1 to 4 nitrogen atoms [eg pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; 3 to 6-membered saturated heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [eg morpholinyl]; 3 to 6-membered saturated heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [eg, thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrotienyl, dihydropyranyl, dihydrofuryl, dihydrotiazolyl and the like.

Particular examples of saturated and partially saturated heterocyclyl include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrotienyl, 2,3-dihydrobenzo [1,4] dioxanyl, indolinyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydrobenzyl dihydroxy benzyl dihydroxy benzyl dihydroxy benzyl dihydroxybenzyl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a, 9,9a-hexahydro-1H-3- azafluorenyl, 5,6,7-trihydro-1,2,4-triazolo [3,4-a] isoquinolyl, 3,4-dihydro-2H-benzo [1,4] oxazinyl, benzo [1,4] dioxanyl, 2,3-dihydro-1H-1A'-benzo [d] isothiazol-6-yl, dihydropyranyl, dihydrofuryl and dihydrotiazolyl, and the like.

The term heterocyclyl, (or heterocycle) also encompasses radicals in which heterocyclic radicals are fused / condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [eg, tetrazolo [1,5-b] pyridazinyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [eg benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [eg, benzothiazolyl, benzothiadiazolyl]; and unsaturated, partially unsaturated and saturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms [eg benzofuryl, benzothienyl, 2,3-dihydro-benzo [1,4] dioxinyl and dihydrobenzofuryl].

The term "heteroaryl" indicates aryl ring systems containing one or more heteroatoms selected from the group O, N and S, in which the nitrogen and sulfur atom (s) of the ring are optionally oxidized, and the / the nitrogen atom (s) are optionally quaternized. Examples include unsaturated 5- to 6-membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [ for example, 4H-1,2,4triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; 5 to 6 unsaturated heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc .; 5 to 6 unsaturated heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc .; 5 to 6 unsaturated heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [eg 1,2,4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,5-oxadiazolyl]; 5 to 6 unsaturated heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [eg 1,2,4-thiadiazolyl, 1,3,4- thiadiazolyl, 1,2,5-thiadiazolyl].

The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, respectively indicates divalent radicals -SO2-.

The terms "sulfanyl," "aminosulfonyl" and "sulfonamidyl" indicate a sulfonyl radical substituted with an amine radical, which forms a sulfonamide (-SO2NH2).

The term "alkylaminosulfonyl" includes "N-alkylaminosulfonyl" in which the sulfanyl radicals are independently substituted with one or two alkyl radicals. More preferred alkylaminosulfonyl radicals are "lower alkylaminosulfonyl" radicals having one to six carbon atoms. Even more preferred are lower alkylaminosulfonyl radicals having one to three carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl and N-ethylaminosulfonyl.

The terms "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", indicate -CO2H.

The term "carbonyl", whether used alone or with other terms, such as "aminocarbonyl", indicates - (C = O) -.

The term "aminocarbonyl" indicates an amide group of the formula -C (= O) NH2.

The terms "N-alkylaminocarbonyl" and "N, N-dialkylaminocarbonyl" indicate aminocarbonyl radicals independently substituted with one or two alkyl radicals, respectively. More preferred are "lower alkylaminocarbonyl" having lower alkyl radicals as described above attached to an aminocarbonyl radical.

The terms "N-arylaminocarbonyl" and "N-alkyl-N-arylaminocarbonyl" denote aminocarbonyl radicals substituted, respectively, with an aryl radical, or an alkyl radical and an aryl radical.

The terms "heterocyclylalkylenyl" and "heterocyclylalkyl" embrace alkyl radicals substituted with heterocyclic. Most preferred heterocyclylalkyl radicals are the "5 or 6 membered heteroarylalkyl radicals having alkyl parts of one to six carbon atoms and a 5 or 6 membered heteroaryl radical. Even more preferred are lower heteroarylalkylenyl radicals having alkyl parts of one to three carbon atoms. Examples include radicals such as pyridylmethyl and thienylmethyl.

The term "aralkyl" encompasses aryl substituted alkyl radicals. Preferable aralkyl radicals are "lower aralkyl" radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Even more preferred are "phenylalkylenyl" attached to alkyl parts having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may be further substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy.

The term "alkylthio" encompasses radicals containing a branched or linear alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower alkylthio radicals having one to three carbon atoms. An example of "alkylthio" is methylthio, (CH3S-).

The term "haloalkylthio" encompasses radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower haloalkylthio radicals having one to three carbon atoms. An example of "haloalkylthio" is trifluoromethylthio.

The term "alkylamino" encompasses "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are independently substituted with an alkyl radical and with two alkyl radicals, respectively. More preferred alkylamino radicals are "lower alkylamino" radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino and the like.

The term "arylamino" indicates amino groups, which have been substituted with one or two aryl radicals, such as N-phenylamino. The arylamino radicals may be further substituted in the aryl ring part of the radical.

The term "heteroarylamino" indicates amino groups, which have been substituted with one or two heteroaryl radicals, such as N-thienylamino. The "heteroarylamino" radicals may be further substituted in the heteroaryl ring part of the radical.

The term "aralkylamino" indicates amino groups, which have been substituted with one or two aralkyl radicals. More preferred radicals are phenyl-C1-C3 alkylamino, such as N-benzylamino. The aralkylamino radicals may be further substituted in the aryl ring part.

The terms "N-alkyl-N-arylamino" and "N-aralkyl-N-alkylamino" indicate amino groups, which have been independently substituted with an aralkyl radical and an alkyl radical, or an aryl radical and an alkyl radical, respectively, with respect to an amino group.

The term "aminoalkyl" encompasses linear or branched alkyl radicals having one to about ten carbon atoms, any one of which may be substituted with one or more amino radicals. Most preferred aminoalkyl radicals are the "lower aminoalkyl" radicals having one to six carbon atoms and one or more amino radicals. Examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl. Even more preferred are lower aminoalkyl radicals having one to three carbon atoms.

The term "alkylaminoalkyl" embraces alkyl radicals substituted with alkylamino radicals. Most preferred alkylaminoalkyl radicals are the "lower alkylaminoalkyl" radicals having alkyl radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkyl radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkyl radicals may be substituted with mono or dialkyl, such as N-methylaminomethyl, N, N-dimethyl-aminoethyl, N, N-diethylaminomethyl and the like.

The term "alkylaminoalkoxy" embraces alkoxy radicals substituted with alkylamino radicals. Most preferred alkylaminoalkoxy radicals are the "lower alkylaminoalkoxy" radicals having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxy radicals may be substituted with mono or dialkyl, such as N-methylaminoethoxy, N, N-dimethylaminoethoxy, N, N-diethylaminoethoxy and the like.

The term "alkylaminoalkoxyalkoxy" embraces alkoxy radicals substituted with alkylaminoalkoxy radicals. Most preferred alkylaminoalkoxyalkoxy radicals are the "lower alkylaminoalkoxyalkoxyl" radicals having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkoxyalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxyalkoxy radicals may be substituted with mono or dialkyl, such as N-methylaminomethoxyethoxy, N-methylaminoethoxyethoxy, N, N-dimethylaminoethoxyethoxy, N, N-diethylaminomethoxymethoxy and the like.

The term "carboxyalkyl" encompasses linear or branched alkyl radicals having one to about ten carbon atoms, any one of which may be substituted with one or more carboxyl radicals. More preferred carboxyalkyl radicals are "lower carboxyalkyl" radicals having one to six carbon atoms and a carboxyl radical. Examples of such radicals include carboxymethyl, carboxypropyl and the like. Even more preferred are the lower carboxyalkyl radicals having one to three CH2 groups.

The term "halosulfonyl" encompasses sulfonyl radicals substituted with a halogen radical. Examples of such halosulfonyl radicals include chlorosulfonyl and fluorosulfonyl.

The term "arylthio" encompasses aryl radicals of six to ten carbon atoms, attached to a divalent sulfur atom. An example of "arylthio" is phenylthio.

The term "aralkylthio" encompasses aralkyl radicals as described above, attached to a divalent sulfur atom. More preferred radicals are phenyl-C1-C3 alkylthio. An example of "aralkylthio" is benzylthio.

The term "aryloxy" encompasses optionally substituted aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy.

The term "aralkoxyl" encompasses oxyl-containing aralkyl radicals linked through an oxygen atom to other radicals. More preferred aralkoxyl radicals are "lower aralkoxyl" radicals having optionally substituted phenyl radicals attached to a lower alkoxy radical as described above.

The term "heteroaryloxy" encompasses optionally substituted heteroaryl radicals, as defined above, attached to an oxygen atom.

The term "heteroarylalkoxy" embraces oxyl-containing heteroarylalkyl radicals attached through an oxygen atom to other radicals. More preferred heteroarylalkoxy radicals are the "lower heteroarylalkoxy" radicals having optionally substituted heteroaryl radicals attached to a lower alkoxy radical as described above.

The term "cycloalkyl" includes saturated carbocyclic groups. Preferred cycloalkyl groups include C3-C6 rings. More preferred compounds include cyclopentyl, cyclopropyl and cyclohexyl.

The term "cycloalkylalkyl" embraces alkyl radicals substituted with cycloalkyl. The preferable cycloalkylalkyl radicals are "lower cycloalkylalkyl" radicals having cycloalkyl radicals bonded to alkyl radicals having one to six carbon atoms. Even more preferred are "5-6 membered cycloalkylalkyl" attached to alkyl parts having one to three carbon atoms. Examples of such radicals include cyclohexylmethyl. The cycloalkyl in said radicals may be further substituted with halo, alkyl, alkoxy and hydroxyl.

The term "cycloalkenyl" includes carbocyclic groups having one or more carbon-carbon double bonds that include "cycloalkyldienyl" compounds. Preferred cycloalkenyl groups include C3-C6 rings. More preferred compounds include, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cycloheptadienyl.

The term "comprising" is intended to be open, including the indicated component but not excluding other elements.

The present invention also comprises the use of a compound of the invention, or pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment either acutely or chronically of a pathological state mediated by angiogenesis, including those previously described. . The compounds of the present invention are useful in the preparation of an anticancer drug.

The present invention comprises a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in association with at least one pharmaceutically acceptable carrier, adjuvant or diluent.

The present invention also comprises a compound for use in the treatment of disorders related to angiogenesis in a subject that has or is susceptible to such a disorder, comprising treating the subject with a therapeutically effective amount of a compound of the present invention.

Combinations

Although the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents may be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents may be administered as the sole composition.

The phrase "co-therapy" (or "combination therapy"), in defining the use of a compound of the present invention and another pharmaceutical agent, is intended to encompass the administration of each agent in a sequential manner in a regimen that will provide beneficial effects. of the combination of drugs, and also intends to cover the co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple separate capsules for each agent.

Specifically, the administration of compounds of the present invention may be in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of neoplasia, such as with radiation therapy or with cytotoxic or cytostatic agents.

If formulated as a fixed dose, such combination products employ the compounds of this invention within the accepted dosage ranges. The compounds of the present invention can also be administered sequentially with known cytotoxic or anticancer agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration: the compounds of the invention can be administered either before, simultaneously with or after administration of the cytotoxic agents.

or known anticancer.

Currently, conventional treatment of primary tumors consists of surgical excision followed by either radiation or chemotherapy administered intravenously. The typical chemotherapy regimen consists of either DNA alkylating agents, DNA intercalating agents, Cdk inhibitors or microtubule toxins. The chemotherapy doses used are just below the maximum tolerated dose and therefore dose-limiting toxicities normally include nausea, vomiting, diarrhea, hair loss, neutrocytopenia and the like.

There are large amounts of antineoplastic agents available in commercial use, in clinical evaluation and in preclinical development, which would be selected for the treatment of neoplasms by chemotherapy with a combination of drugs. Such antineoplastic agents fall into several main categories, namely, antibiotic-like agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-like agents and a category of miscellaneous agents.

A first family of antineoplastic agents, which can be used in combination with compounds of the present invention, consists of thymidylate synthase / antimetabolite inhibitor antineoplastic agents. Suitable anti-metabolic antineoplastic agents may be selected from but are not limited to the group consisting of 5FU-fibrinogen, clifolic acid, aminothiadiazole, sodium brequinar, carmofur, Ciba-Geigy CGP-30694, cyclopentylcytosine, cytarabine phosphate conjugates, cytarabine conjugates, cytarabine conjugates of Lilly, DDFC of Merrel Dow, dezaguanine, dideoxycytidine, dideoxiguanosine, didox, DMDC of Yoshitomi, doxifluridine, EHNA of Wellcome, EX015 of Merck & Co., fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N- (2'-furanidyl) -5-fluorouracil, FO-152 from Daiichi Seiyaku, isopropyl pyrrolizine, LY-188011 from Lilly, LY-264618 from Lilly, metobenzaprim , methotrexate, Wellcome MZPES, norspermidine, NSC-127716 from NCI, NSC-264880 from NCI, NSC-39661 from NCI, NSC-612567 from NCI, PALA from Warner-Lambert, pentostatin, piritrexim, plicamycin, PL-AC from Asahi Chemical, TAC-788 from Takeda, thioguanine, thiazofurin, TIF from Erbamont, trimetrexate, tyrosine kinase inhibitors, UFT from Taiho and uricitin.

A second family of antineoplastic agents, which can be used in combination with compounds of the present invention, consists of antineoplastic alkylating agents. Suitable alkylating type antineoplastic agents may be selected from but not limited to the group consisting of 254-S of Shionogi, aldo-phosphamide analogs, altretamine, anaxirone, BBR-2207 from Boehringer Mannheim, bestrabucil, budotitan, CA-102 from Wakunaga , carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, CL-286558 of American Cyanamid, CY-233 of Sanofi, ciplatate, D-19-384 of Degussa, DACHP (Myr) 2 of Sumimoto, diphenylspiromustine, cytostatic diplatin, Erba distamycin derivatives, DWA-2114R from Chugai, E09 from ITI, elmustine, FCE-24517 from Erbamont, estramustine sodium phosphate, fotemustine, G-6-M from Unimed, GYKI172ul from Chinoin ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, NK-121 from Nippon Kayaku, NSC-264395 from NCI, NSC-342215 from NCI, oxaliplatin, UNCP from Upjohn, prednimustine, PTT-119 from Proter, ranimustina, semustina, semustina; -101772 by SmithKline, SN-22 by Yakult Honsha, spiromustine, TA-077 of Tanabe Seiyaku, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol.

A third family of antineoplastic agents that can be used in combination with compounds of the present invention consists of antibiotic-like antineoplastic agents. Suitable antibiotic-type antineoplastic agents may be selected from but not limited to the group consisting of 4181- A from Taiho, aclarubicin, actinomycin D, actinoplanone, ADR-456 from Erbamont, aeroplisinin derivatives, AN-201-II from Ajinomoto, AN -3 of Ajinomoto, Nippon Soda asynomycins, anthracycline, azinomycin-A, bisucaberine, BL-6859 from Bristol-Myers, BMY25067 from Bristol-Myers, BMY-25551 from Bristol- Myers, BMY-26605 from Bristol-Myers, BMY- 27557 from Bristol-Myers, BMY-28438 from Bristol-Myers, bleomycin sulfate, biostatin-1, Taiho C-1027, calichemycin, chromoximicin, dactinomycin, daunorubicin, DC-102 from Kyowa Hakko, DC-79 from Kyowa Hakko, DC-88A from Kyowa Hakko, DC89-Al from Kyowa Hakko, DC92-B from Kyowa Hakko, dithrisarubicin B, DOB-41 from Shionogi, doxorubicin, doxorubicin-fibrinogen, elsamycin-A, epirubicin, erbstatin, esorubicin, speramine-A1, speramine-spellinine, speramine-A1, speramin-A1 A1b, FCE21954 from Erbamont, FK-973 from Fujisawa, fostriecina, FR-900482 from Fujisawa, glidobact ina, gregatina-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, quesarirodines, KM-5539 from Kyowa Hakko, KRN-8602 from Kirin Brewery, KT-5432 from Kyowa Hakko, KT-5594 from Kyowa Hakko, KT-614 Kyowa Hakko, LL-D49194 of American Cyanamid, ME 2303 of Meiji Seika, menogaryl, mitomycin, mitoxantrone, M-TAG of SmithKline, neoenactin, NK313 of Nippon Kayaku, NKT-01 of Nippon Kayaku, NSC-357704 of SRI International, oxalisina , oxaunomycin, peplomycin, pilatin, pyrarubicin, porotramycin, pyrindamicin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin, sibanomycin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand, SN-07 sorangicin-A, sparsomycin, SS-21020 from SS Pharmaceutical, SS-7313B from SS Pharmaceutical, SS-9816B from SS Pharmaceutical, stefimycin B, 4181-2 from Tahio, talisomycin, TAN-868A from Takeda, terpentecin, trazine, tricrozarin A , U-73975 from Upjohn, UCN-10028A from Kyowa Hakko, WF-3405 from Fujisawa, Y-25024 from Yoshitomi and Zorubicin.

A fourth family of antineoplastic agents that can be used in combination with compounds of the present invention consists of a miscellaneous family of antineoplastic agents, including agents that interact with tubulin, topoisomerase II inhibitors, topoisomerase I inhibitors and hormonal agents, selected from but which are not limited to the group consisting of a-carotene, a-difluoromethyl-arginine, acitretin, AD-5 from Biotec, AH-C52 from Kyorin, alstonin, amonaphide, amphetin, amsacrine, Angiostat, anquinomycin, antineoplaston A10, antineoplaston A2 , antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, afidicolina glycinate, asparaginase, Avarol, bacarina, batracilina, benfluron, benzotript, BIM-23015 of Ipsen-Beaufour, bisantrene, BMY-40481 of Bristol boron-10 from Vestar, bromophosphamide, BW-502 from Wellcome, BW-773 from Wellcome, caracemide, carmetizol hydrochloride, CDAF from Ajinomoto, clorsulfaquinoxalone, CHX-2053 from Chemex, CHX-100 from Chemex, CI-921 from Warner-Lambert, CI-937 from Warner-Lambert, CI-941 from Warner-Lambert, CI-958 from Warner-Lambert, clanfenur, claviridenone, compound 1259 from ICN, compound 4711 from ICN, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, D-609 from Merz, DABIS maleate, dacarbazine, dateliptinium, didemnin-B, dihematoporphyrin ether, dihydrolenperone, dinalinamycin, dinalinemicone, dinalinemicone DM-341 by Toyo Farmar, DM-75 by Toyo Farmar, DN-9693 by Daiichi Seiyaku, docetaxel, eliprabine, elliptinium acetate, EPMTC from Tsumura, epothilones, ergotamine, etoposide, etretinate, pheretinide, FR-57704 from Fujisawa, Gallium nitrate, genkwadafnin, GLA-43 from Chugai, GR-63178 from Glaxo, grifolan NMF-5N, hexadecylphosphocholine, HO-221 from Green Cross, homoharingtonin, hydroxyurea, ICRF-187 from BTG, ilmophosin, isoglutamine, isotretinoin, J- 36 from Otsuka, K-477 from Ramot, K-76COONa from Otsuka, K-AM from Kureha Chemical, KI-8110 from MECT Corp, L623 from American Cyan amid, leucoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI MAP (US), maricine, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanine derivatives, methylanilinoacryrin, MGI-136 from Molecular Genetics, minactivin, mitonfide, mitochidone, mopidamol, motretinide, MST-16 from Zenyaku Kogyo, N- (retinoyl) amino acids, N-021 from Nisshin Flour Milling, N-acylated dehydroalanines, nafazatrom, NCU-190 of Taisho, nocodazole derivatives, Normosang, NSC-145813 of NCI, NSC-361456 of NCI, NSC-604782 of NCI, NSC-95580 of NCI, octreotide, ONO-112 of Ono, ochizanocin, Org-10172 of Akzo, paclitaxel , pancratistatin, pazeliptin, PD-111707 of Warner-Lambert, PD-115934 of Warner-Lambert, PD-131141 of Warner-Lambert, PE-1001 of Pierre Fabre, D-peptide of ICRT, pyroxantrone, polyhematoporphyrin, polyreic acid, porphyrin Efamol, probimano, procarbazine, proglumide, proteit nexin I from Invitron, RA-700 from Tobishi, razoxane, RBS from Sapporo Breweries, restrictin-P, reteliptin, retinoic acid, RP-49532 from Rhone-Poulenc, RP-56976 from Rhone-Poulenc, SK & F-104864 from SmithKline, SM-108 from Sumitomo, SMANCS from Kuraray, SP-10094 from SeaFarm, espatol, spirocyclopropane derivatives , spirogermanium, Unimed, SS-554 from SS Farmaceutical, stripoldinone, stippend, SUN 0237 from Suntory, SUN 2071 from Suntory, superoxide dismutase, T506 from Toyama, T-680 from Toyama, taxol, TEI-0303 from Teijin, teniposide, taliblastin , TJB-29 by Eastman Kodak, tocotrienol, topotecan, topostin, TT-82 from Teijin, UCN-01 from Kyowa Hakko, UCN-1028 from Kyowa Hakko, ucraina, USB-006 from Eastman Kodak, vinblastine sulfate, vincristine, vindesine , vinestramide, vinorelbine, vintriptol, vinzolidine, witanolides and YM-534 from Yamanouchi.

Alternatively, the present compounds can also be used in joint therapies with other antineoplastic agents, such as acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANC anthroxamide, ANC-anthroxamide, ANC-anthroxamide, ANC-anthroxamide, ANC-anthroxamide, ANC-anthroxamide, ANC-anthroxamide, ANC-anthroxamide, ANC-anthroxamide arsenic, BAM 002 (Novels), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocphosphate, DA 3030 (Dong-A), daclizumab, demleukin diftitox, doloxanzole, doloxanzole, doloxanzole, doloxanzole, doloxanzole, doloxethazole, doloxethazole, doloxanzole, doxylazole, dole , doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alfa, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, photemustine, ga nitrate lio, gemcitabine, gemtuzumab zogamycin, combination of gimeracil / oteracil / tegafur, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha fetoprotein, ibandronic acid, idarubicin, (imiquimod, alpha interferon, alpha interferon-alpha, natural alpha interferon , interferon alfa-2a, interferon alfa-2b, interferon alfa-Nl, interferon alfa-n3, interferon alfacon-1, interferon alfa, natural, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, interferon gamma- Natural 1a, interferon gamma-1b, interleukin-1 beta, iobenguan, irinotecan, irsogladin, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liaouzolecil lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, unpaired double stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafa relina, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis stimulating protein, NSC 631570, octreotide, oprelvekina, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegastergasium pentaterum, peginterose penta, peginteronetin, peginterose penta, peginteronetin, peginterone, peginterone, peginterone, peginterone, peginterone, peginterone, peginterone, peginterone, peginterone, peginterone, peginterone penta, peginterone, peginterone, peginterone peptide , picibanil, pyrarubicin, rabbit polyclonal antibody, rabbit antithymocyte, polyethylene glycol interferon alfa-2a, sodium porphimer, raloxifene, raltitrexed, rasburicase, rhenium etidronate Re 186, RII retinamide, rituximab, romurtida, samarium (153 Sm) sarimira, sidronx, ssimamiz, 153 smimam, sarimram , sobuzoxane, sonermin, strontium chloride-89, suramin, tasonermin, tazarotene, tegafur, temoporphine, temozolomide, teniposide, tetrachlocodeoxide, thalidomide, thymalfasine, thyrotropin alfa, topotecan, toremifene, tositumomabumato, thioethane, 131, thiophanedine, 131 , trimetrexate, triptorelin, tumor necrosis alpha factor, natural, ubenimex, c vaccine bladder cancer, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, VIRULIZIN, stimalamer zinostatin,

or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche),

eniluracil, ethanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), macrophage and granulocyte colony stimulating factor, histamine dihydrochloride, ibritumomab tiuxetane, imiutane, tiuxetane 862 (Cytran), interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, Acm anti-CA 125 (Biomira), Acm anticancer (Japan Pharmaceutical Development), Acm anti-Fc and HER-2 (Medarex), Idiotypic anti-105AD7 acm (CRC Technology), idiotypic anti-CEA acm (Trilex), Acm anti-LYM-1-iodine 131 (Techniclone), Polymorphic epithelial anti-mucin-yttrium 90 (Antisoma), marimastat, menogaryl, mitumomab , motexaphine gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, protein P 30, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparphic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetratiomolibdate, taliblas tub, thrombopoietin, tin ethylethiopurpurine, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma oncolysate vaccine (New York Medical College), viral melanoma cell lysate vaccine (Royal Newcastle Hospital)

or waltz.

Alternatively, the present compounds can also be used in joint therapies with VEGFR inhibitors. including N- (4-chlorophenyl) -4- (4-pyridinylmethyl) -1-phthalazinamine; 4- [4 - [[[[4-Chloro-3- (trifluoromethyl) phenyl] amino] carbonyl] amino] phenoxy] -N-methyl-2-pyridinecarboxamide; N- [2- (diethylamino) ethyl] -5 - [(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene) methyl] -2,4-dimethyl-1H-pyrrole- 3-carboxamide; 3 - [(4-Bromo-2,6-difluorophenyl) methoxy] -5 - [[[[4- (1-pyrrolidinyl) butyl] amino] carbonyl] amino] -4-isothiazolecarboxamide; N- (4-bromo-2-fluorophenyl) -6-methoxy-7 - [(1-methyl-4-piperidinyl) methoxy] -4-quinazolinamine; 3- [5,6,7,13-tetrahydro-9 - [(1-methylethoxy) methyl] -5-oxo-12H-indene [2,1-a] pyrrolo [3,4-c] carbazol-12 ester -yl] propyl of

N, N-dimethyl glycine; N- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] methyl] thio] -2-thiazolyl] -4-piperidinecarboxamide; N- [3-Chloro-4 - [(3-fluorophenyl) methoxy] phenyl] -6- [5 - [[[2- (methylsulfonyl) ethyl] amino] methyl] -2-furanyl] -4-quinazolinamine 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -phenyl] benzamide N- (3-Chloro-4-fluorophenyl) -7-methoxy-6- [3- (4-morpholinyl) propoxy] -4-quinazolinamine N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine N- (3 - ((((2R) -1-methyl-2-pyrrolidinyl) methyl) oxy) -5- (trifluoromethyl) phenyl) -2 - ((3- (1,3-oxazol-5-yl)) phenyl) amino) -3

pyridinecarboxamide; 2 - (((4-fluorophenyl) methyl) amino) -N- (3 - ((((2R) -1-methyl-2-pyrrolidinyl) methyl) oxy) -5- (trifluoromethyl) phenyl) -3-pyridinecarboxamide ; N- [3- (azetidin-3-ylmethoxy) -5-trifluoromethyl-phenyl] -2- (4-fluoro-benzylamino) -nicotinamide; 6-fluoro-N- (4- (1-methyl ethyl) phenyl) -2 - ((4-pyridinylmethyl) amino) -3-pyridinecarboxamide; 2 - ((4-pyridinylmethyl) amino) -N- (3 - (((2S) -2-pyrrolidinylmethyl) oxy) -5- (trifluoromethyl) phenyl) -3-pyridinecarboxamide; N- (3- (1,1-dimethylethI) -1H-pyrazol-5-yl) -2 - ((4-pyridinylmethyl) amino) -3-pyridinecarboxamide; N- (3,3-dimethyl-2,3-dihydro-1-benzofuran-6-yl) -2 - ((4-pyridinylmethyl) amino) -3-pyridinecarboxamide; N- (3 - ((((2S) -1-methyl-2-pyrrolidinyl) methyl) oxy) -5- (trifluoromethyl) phenyl) -2 - ((4-pyridinylmethyl) amino) -3-pyridinecarboxamide; 2 - ((4-Pyridinylmethyl) amino) -N- (3 - ((2- (1-pyrrolidinyl) ethyl) oxy) -4- (trifluoromethyl) phenyl) -3-pyridinecarboxamide; N- (3,3-dimethyl-2,3-dihydro-1H-indol-6-yl) -2 - ((4-pyridinylmethyl) amino) -3-pyridinecarboxamide; N- (4- (pentafluoroethyl) -3 - (((2S) -2-pyrrolidinylmethyl) oxy) phenyl) -2 - ((4-pyridinylmethyl) amino) -3-pyridinecarboxamide; N- (3 - ((3-azetidinylmethyl) oxy) -5- (trifluoromethyl) phenyl) -2 - ((4-pyridinylmethyl) amino) -3-pyridinecarboxamide; N- (3- (4-piperidinyloxy) -5- (trifluoromethyl) phenyl) -2 - ((2- (3-pyridinyl) ethyl) amino) -3-pyridinecarboxamide; N- (4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl) -2- (1H-indazol-6-ylamino) -nicotinamide; 2- (1H-indazol-6-ylamino) -N- [3- (1-methylpyrrolidin-2-ylmethoxy) -5-trifluoromethyl-phenyl] -nicotinamide; N- [1- (2-dimethylamino-acetyl) -3,3-dimethyl-2,3-dihydro-1 H -indol-6-yl] -2- (1 H -dazol-6-ylamino) -nicotinamide;

2- (1H-indazol-6-ylamino) -N- [3- (pyrrolidin-2-ylmethoxy) -5-trifluoromethyl-phenyl] -nicotinamide;

N- (1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl) -2- (1H-indazol-6-ylamino) -nicotinamide;

N- (4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl) -2- (1H-indazol-6-ylamino) -nicotinamide;

N- [4- (tert-Butyl) -3- (3-piperidylpropyl) phenyl] [2- (1H-indazol-6-ylamino) (3-pyridyl)] carboxamide;

N- [5- (tert-butyl) isoxazol-3-yl] [2- (1H-indazol-6-ylamino) (3-pyridyl)] carboxamide; Y

N- [4- (tert-butyl) phenyl] [2- (1H-indazol-6-ylamino) (3-pyridyl)] carboxamide.

Other compounds described in the following patents and patent applications can be used in combination therapy: US 6,258,812, US 2003/0105091, WO 01/37820, US 6,235,764, WO 01/32651, US 6,630,500, US 6,515 .004, US 6,713,485, US 5,521,184, US 5,770,599, US 5,747,498, WO 02/68406, WO 02/66470, WO 02/55501, WO 04/05279, WO 04/07481, WO 04 / 07458, WO 04/09784, WO 02/59110, WO 99/45009, WO 00/59509, WO 99/61422, US 5,990,141, WO 00/12089 and WO 00/02871.

In some embodiments, the combination comprises a composition of the present invention in combination with at least one antiangiogenic agent. Agents include, but are not limited to, synthetically prepared in vitro chemical compositions, antibodies, antigen binding regions, radionuclides, and combinations and conjugates thereof. An agent can be an agonist, antagonist, allosteric modulator, toxin or, more generally, can act to inhibit or stimulate its target (for example, activation or inhibition of receptor or enzyme), and thereby promote cell death or stop the cell growth

Exemplary antitumor agents include HERCEPTINTM (trastuzumab), which can be used to treat breast cancer and other forms of cancer, and RITUXANTM (rituximab), ZEVALINTM (ibritumomab tiuxethan), and LYMPHOCIDETM (epratuzumab), which can be used for treat non-Hodgkin lymphoma and other forms of cancer, GLEEV ACTM that can be used to treat chronic myeloid leukemia and gastrointestinal stromal tumors, and BEXXARTM (iodine 131 tositumomab) that can be used to treat non-Hodgkin lymphoma.

Exemplary antiangiogenic agents include KDR (kinase domain receptor) inhibitor agents (e.g., antibodies and antigen binding regions that specifically bind to the kinase domain receptor), anti-VEGF agents (e.g., antibodies or antigen binding regions that specifically bind to VEGF, or soluble VEGF receptors or a ligand binding region thereof, such as AVASTINTM or VEGF-TRAPTM, and anti-VEGF receptor agents (eg, antibodies or regions of binding to antigens that specifically bind to them), EGFR inhibitory agents (e.g., antibodies or antigen-binding regions that specifically bind to them) such as ERBITUXTM (IMC-C225), and VECTIBIXTM (panitumumab), IRESSATM (gefitinib), TARCEVATM (erlotinib), anti-Ang1 and anti-Ang2 agents (for example, antibodies or antigen binding regions that specifically bind to them or their receptors, for example, Ti e2 / Tek), and anti-Tie2 kinase inhibitors. The pharmaceutical compositions of the present invention may also include one or more agents (eg, antibodies, antigen-binding regions or soluble receptors) that bind to and specifically inhibit the activity of growth factors, such as the factor antagonists. hepatocyte growth (HGF, also known as dispersion factor), and antibodies or antigen binding regions that specifically bind to its "c-Met" receptor as well as small molecule inhibitors of c-Met kinase activity.

Other antiangiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (Ceretti et al., U.S. Publication No. 2003/0162712; U.S. Patent No. 6,413,932), anti-TWEAK agents (e.g., antibodies binding or specific antigen binding regions, or soluble TWEAK receptor antagonists; see, Wiley, US Patent No. 6,727,225), ADAM disintegration domain to antagonize integrin binding to its ligands (Fanslow et al. , U.S. Publication No. 2002/0042368), anti-eph binding receptor and / or anti-epinephrine antibodies or specific antigen binding regions (U.S. Patent Nos. 5,981,245; 5,728,813; 5,969,110; 6,596 .852; 6,232,447; 6,057,124 and members of their patent families) and anti-PDGF-BB antagonists (eg, binding antibodies or specific antigen binding regions) as well as antibodies or binding regions of antigens that specifically bind PDGF- ligands BB, and PDGFR kinase inhibitors (for example, antibodies or antigen binding regions that specifically bind to them).

Additional antitumor / antiangiogenic agents include: SD-7784 (Pfizer, United States); cilengitide (Merck KGaA, Germany, EPO 770622); Octadium pegaptanib (Gilead Sciences, United States); alfastatin (BioActa, RU); M-PGA (Celgene, United States, US 5712291); ilomastat (Arriva, United States, US 5892112); emaxanib (Pfizer, United States, US 5792783); vatalanib (Novartis, Switzerland); 2-methoxystradiol (EntreMed, United States); TLC ELL-12 (Elan, Ireland); anecortave acetate (Alcon, United States); Acm anti-alpha-D148, (Amgen, United States); CEP-7055 (Cephalon, United States); Acm anti-Vn (Crucell, The Netherlands), DAC: antiangiogenic (ConjuChem, Canada); angiocidine (InKine Pharmaceutical, United States); KM-2550 (Kyowa Hakko, Japan); SU-0879, (Pfizer, United States); CGP-79787, (Novartis, Switzerland, EP 970070); ARGENT technology (Ariad, United States); YIGSR-Stealth (Johnson & Johnson, United States); fibrinogen-E fragment, (BioActa, RU); angiogenesis inhibitor (Trigen, RU); TBC-1635 (Encysive Pharmaceuticals, United States); SC-236 (Pfizer, United States); ABT-567 (Abbott, United States); metastatin (EntreMed, United States); angiogenesis inhibitor (Tripep, Sweden); maspin (Sosei, Japan); 2-methoxystradiol (Oncology Sciences Corporation, United States); ER-68203-00 (IVAX, United States); Benefin (Lane Labs, United States); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR111142, (Fujisawa, Japan, JP 02233610); platelet factor 4 (RepliGen, United States, EP 407122); vascular endothelial growth factor antagonist (Borean, Denmark); cancer therapy (University of South Carolina, United States); bevacizumab (pINN) (Genentech, United States); angiogenesis inhibitor (SUGEN, United States); XL 784 (Exelixis, United States); XL 647 (Exelixis, United States); Acm, alpha5beta3 integrin, second generation (Applied Molecular Evolution, United States and Medlmmune, United States); gene therapy, retinopathy (Oxford BioMedica, RU); Enzastaurin hydrochloride (USAN) (Lilly, United States); CEP 7055 (Cephalon, United States and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); angiogenesis inhibitor (Alchemia, Australia); VEGF antagonist (Regeneron, United States); antiangiogenic derivatives of rBPI 21 and BPI (XOMA, United States); PI 88 (Progen, Australia); cilengitide (pINN) (Merck KGaA, German; Munich Technical University, Germany, Scripps Clinic and Research Foundation, United States); cetuximab (INN) (Aventis, France); AVE 8062 (Ajinomoto, Japan); AS 1404 (Cancer Research Laboratory, New Zealand); SG 292 (Telios, United States); endostatin (Boston Childrens Hospital, United States); ATN 161 (Attenuon, United States); ANGIOSTATINA (Boston Childrens Hospital, United States); 2-methoxystradiol (Boston Children's Hospital, United States); ZD 6474 (AstraZeneca, RU); ZD 6126 (Angiogene Pharmaceuticals, RU); PPI 2458 (Praecis, United States); AZD 9935 (AstraZeneca, RU); AZD 2171 (AstraZeneca, RU); vatalanib (pINN) (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitors (EntreMed, United States); pegaptanib (Pinn) (Gilead Sciences, United States); Xanthorrizol (Yonsei University, South Korea); VEGF-2 gene-based vaccine (Scripps Clinic and Research Foundation, United States); SPV5.2 (Supratek, Canada); SDX 103 (University of California in San Diego, United States); PX 478 (ProlX, United States); METASTATIN (EntreMed, United States); troponin I, (Harvard University, United States); SU 6668 (SUGEN, United States); OXI 4503 (OXiGENE, United States); o-guanidines (Dimensional Pharmaceuticals, United States); motuporamine C (British Columbia University, Canada); CDP 791 (Celltech Group, RU); atiprimod (pINN) (GlaxoSmithKline, RU); E 7820 (Eisai, Japan); CYC 381 (Harvard University, United States); AE 941 (Aeterna, Canada); angiogenesis vaccine (EntreMed, United States); urokinase type plasminogen activator inhibitor (Dendreon, United States); oglufanide (pINN) (Melmotte, United States); HIF-1alpha inhibitors (Xenova, RU); CEP 5214 (Cephalon, United States); BAY RES 2622 (Bayer, Germany); angiocidine (InKine, United States); A6 (Angstrom, United States); KR 31372, (Korea Research Institute of Chemical Technology, South Korea); GW 2286 (GlaxoSmithKline, RU); EHT 0101 (ExonHit, France); CP 868596 (Pfizer, United States); CP 564959 (OSI, United States); CP 547632 (Pfizer, United States); 786034 (GlaxoSmithKline, RU); KRN 633 (Kirin Brewery, Japan); drug delivery system, intraocular, 2-methoxystradiol (EntreMed, United States); anginex (Maastricht University, The Netherlands, and Minnesota University, United States); ABT 510 (Abbott, United States); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, United States); Tumor necrosis factor-alpha inhibitors (National Institute on Aging, United States); SU 11248 (Pfizer, United States and SUGEN United States); ABT 518 (Abbott, United States); YH16 (Yantai Rongchang, China); S-3APG (Boston Childrens Hospital, United States and EntreMed, United States); Acm, KDR (ImClone Systems, United States); Acm, alpha5 beta1 (Protein Design, United States); KDR kinase inhibitor (Celltech Group, RU, and Johnson & Johnson, United States); GFB 116 (South Florida University, United States and Yale University, United States); CS 706 (Sankyo, Japan); Combretastatin A4 prodrug, (Arizona State University, United States); AC chondroitinase (IBEX, Canada); BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, United States, Takeda, Japan, and TAP, United States); AG 13925 (Agouron, United States); tetratiomolibdate (University of Michigan, United States); GCS 100 (Wayne State University, United States) CV 247 (Ivy Medical, RU); CKD 732 (Chong Kun Dang, South Korea); Acm, vascular endothelial growth factor (Xenova, RU); Irsogladin (INN) (Nippon Shinyaku, Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); Squalamine (pINN) (Genaera, United States); RPI 4610 (Sirna, United States); cancer therapy (Marinova, Australia); heparanase inhibitors (InSight, Israel); KL 3106 (Kolon, South Korea); Honokiol (Emory University, United States); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland, and Schering AG, Germany); XMP 300 (XOMA, United States); VGA 1102 (Taisho, Japan); VEGF receptor modulators (Pharmacopoeia, United States); VE-Caderin-2 antagonists (ImClone Systems, United States); vasostatin (National Institutes of Health, United States); vaccine, FIk-1 (ImClone Systems, United States); TZ 93 (Tsumura, Japan); TumStatin (Beth Israel Hospital, United States); Truncated soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck & Co, United States); Tie-2 ligands (Regeneron, United States); and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, United States).

Alternatively, the present compounds can also be used in joint therapies with other antineoplastic agents, such as VEGF antagonists, other kinase inhibitors that include p38 inhibitors, KDR inhibitors, EGF inhibitors (such as panitumumab), CDK inhibitors, inhibitors of TNF, matrix metalloprotease inhibitors (MMPs), COX-2 inhibitors including celecoxib, NSAIDs, al3 inhibitors, phosphatidylinitis-3-kinase inhibitors, AKT / PCK inhibitors, proteasome inhibitors (such as

VelcadeTM), Trail receptor agonists (such as AMG 655), Trail (such as AMG 951), XIAP inhibitors, BCI2 inhibitors, Aurora kinase inhibitors, Raf kinase inhibitors, ubiquitin ligase inhibitors, HGF inhibitors (such as AMG 102) and c-Met inhibitors (such as the compounds described in WO 06/116713 and US with serial number 11 / 879.034).

Also included in the family of compounds herein are pharmaceutically acceptable salts and solvates thereof. The term "pharmaceutically acceptable salts" encompasses salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of compounds of the present invention can be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from the classes of aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic organic acids, examples of which are formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic acid , malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic, 2-diphenesulfonic, bhenodisulfonic, 2-diphenylsulfonic, 2-diphenylsulfonic, 2-phenodisulfonic, 2-dipheno-sulfonic, 2-phenodisulfonic, 2-dipheno-sulfonic acid hydroxyloethanesulfonic, toluenesulfonic, sulphanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic, glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic, nicotinic, palphatic, oxyprophenic, pemphinic, naphthinic, propionic, sulfonic picric , pivotal, propionic, succinic, tartaric, thiocyanic, mesyl, undecanoic, stearic, algeneic, l-hydroxybutyric, salicylic, galactic and galacturonic. Suitable pharmaceutically acceptable base addition salts of compounds of the present invention include metal salts, such as salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts prepared from organic bases including primary, secondary and tertiary amines, substituted amines that include cyclic amines, such as caffeine, arginine, diethylamine, N-ethylpiperidine, aistidine, glucamine, isopropylamine, lysine, morpholine, N-ethylmorpholine, piperazine, piperidine, triethylamine, trimethylamine. All these salts can be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of the present invention. When a basic group and an acid group are present in the same molecule, a compound of the present invention can also form internal salts.

The compounds of the present invention can be prepared by synthetic procedures reflected in the following examples, as well as other methods known to those skilled in the art. All LC-MS data were obtained using Agilent 1100 LC / MSD series, column: CAPCELL UG120 (3um, 4.6 mm ID x 50 mm), solvent system: H2O-MeCN with 0.1% formic acid. All separations by preparative reverse HPLC were carried out using a C-18 column, the solvent system: MeCN / H2O (each containing 0.1% TFA).

Example 1

Spiro [chromene-2,1'-cyclohexan] -4 (3H) -one (1) Pyrrolidine (6.3 ml, 75 mmol) was added dropwise to a stirred mixture of 1- (2-hydroxyphenyl) ethanone ( 6.8 g, 50 mmol) and cyclohexanone (6.7 ml, 65 mmol) in toluene (25 ml) at rt. Be

The resulting mixture was stirred at rt for 1.5 h and then refluxed for 12 h (equipped with a Dean-Stark condenser). After cooling, the reaction mixture was poured into ice cold 2N HCl solution, and extracted with EtOAc (2 X). The combined organic phases were washed with 2N NaOH aqueous solution (2 X) followed by brine (1 X), dried over Na2SO4 and concentrated in vacuo to give spiro [chromene-2,1'cyclohexan] -4 (3H ) -one (1) (10 g, 92% yield) as an almost colorless liquid. 1 H-NMR (400 MHz, CHLOROFORM-d) 8 ppm 7.84 (1 H, d, J = 7.8 Hz), 7.47 (1 H, t, J = 7.6 Hz), 6.90 - 7.00 (2 H, m), 2.71 (2 H, s), 1.93 2.06 (2 H, m), 1.59 - 1.78 (3 H, m), 1, 43-1.56 (4 H, m), 1.27-1.40 (1 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 217.1.

3,4-Dihydrospiro [chromene-2,1'-cyclohexan] -4-ol (2) A spiro solution [chromene-2,1'cyclohexan] -4 (3H) -one (1) was added dropwise (10.1 g, 47 mmol) in EtOH (50 ml) to a stirred suspension of sodium borohydride (0.88 g, 23.35 mmol) in EtOH (15 ml) at rt through an addition funnel. The resulting mixture was refluxed in a preheated oil bath for 1 h. The reaction mixture was concentrated in vacuo, poured onto ice and saturated aqueous NaHCO3 solution, and extracted with EtOAc (2 X). The combined organic phases were washed with brine (1 X), dried over anhydrous sodium sulfate and concentrated in vacuo to give 3,4-dihydrospiro [chromene-2,1'-cyclohexan] -4-ol (2) (10, 5 g, 98% yield) as a colorless oil. This crude material was taken to the next stage without purification.

Spiro [chromene-2,1'-cyclohexane] (3) A mixture of crude 3,4-dihydrospiro [chromene-2,1'cyclohexane] -4-ol (2) was heated to reflux (10.4 g, 47 mmol) and 2 N hydrochloric acid (55 ml, 220 mmol) for 12 h. The reaction mixture was then cooled to rt, poured into H2O and extracted with EtOAc (2 X). (Note: the reaction was not complete when the final treatment was performed). The combined organic phases were washed with brine (1 X), dried over Na2SO4 and concentrated in vacuo. Combi-flash column chromatography (EtOAc / hexanes) was subjected to the crude residue to give spiro [chromene-2,1'-cyclohexane] (3) (5.1 g, 55% yield) as a colorless crystalline solid. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 7.09 (1 H, td, J = 7.6, 1.6 Hz), 7.04 (1 H, dd, J = 7.4, 1 , 6 Hz), 6.83 (1 H, td, J = 7.4, 1.2 Hz), 6.76 (1 H, d, J = 8.2 Hz), 6.41 (1 H, d, J = 9.8 Hz), 5.76 (1 H, d, J = 9.8 Hz), 1.73 1.86 (2 H, m), 1.40 - 1.71 (7 H , m), 1.27-1.38 (1 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 201.1

1a ', 7b'-Dihydrospiro [cyclohexane-1,2'-oxirene [c] chromene] (4) Pyridine (0.21 ml, 2.6 mmol) was added to an ice cold spiro [chromene-2, 1'-cyclohexane] (3) crude (2.2 g, 11 mmol) and methyltrioxorrenium (vii) (0.055 g, 0.22 mmol) in DCM (30 ml) followed by dropwise addition of 31% hydrogen peroxide , 1% (2.7 ml, 27 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 0 ° C for 10 min. and at nighttime. 2.2 ml of NaClO (commercial Clorox) was added dropwise at rt. The resulting mixture was stirred at rt for 1 h. Then, the reaction mixture was poured into ice cold H2O and extracted with DCM (2 X). The combined organic phases were washed with brine (1 X), dried over Na2SO4. The concentration in vacuo gave 1a ’, 7b’ dihydroespiro [cyclohexane-1,2’-oxirene [c] chromene] (4) gross (2.3 g, 96% yield). This crude material was taken to the next stage without purification. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 7.44 (1 H, dd, J = 7.4, 1.6 Hz), 7.21 - 7.27 (1 H, m), 6, 92 (1 H, td, J = 7.4, 1.2 Hz), 6.79 (1 H, d, J = 7.8 Hz), 3.99 (1 H, d, J = 3.9 Hz), 3.66 (1 H, d, J = 4.3 Hz), 1.26 - 1.89 (10 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 217.1

Spiro [chromene-2,1'-cyclohexan] -3 (4H) -one (5) Boron trifluoride etherate (3.2 ml, 26 mmol) was added to a stirred solution of 1a ', 7b'-dihydrospiro [ cyclohexane-1,2'-oxirene [c] chromene] (4) (2.3 g, 11 mmol) in benzene (100 ml) under a nitrogen atmosphere and kept at rt for 2 h. After the final treatment, the mixture was poured into ice and saturated aqueous NaHCO3 solution and extracted with EtOAc (2 X). The combined organic phases were washed with brine (1 X), dried over Na2SO4 and concentrated in vacuo to give spiro [chromene-2,1'cyclohexan] -3 (4H) -one (5) (2.46 g, 98% yield), which was taken to the next stage without purification. CLEM-ESI (POS), M / Z, M + 1: Found 217.1

Spiro [chromene [3,4-d] -pyrimidin-5,1'-cyclohexan] -3-amine (6) A spiro mixture [chromene2,1'-cyclohexan] -3 (4H) was stirred under reflux one (5) (0.52 g, 2.41 mmol) and tert-butoxy-bis (dimethylamino) methane (0.75 ml, 3.61 mmol) for 80 min. The temperature was lowered to 80 ° C and n-propanol (6 ml), guanidine hydrochloride (1.2 g, 12.0 mmol) and sodium methoxide in MeOH (4.37 M solution, 1.5 ml, were added sequentially. 7.22 mmol). The resulting mixture was stirred at 80 ° C overnight, then poured into ice and saturated NaHCO3 aqueous solution and

15 was extracted with EtOAc (2 X). The combined organic phases were washed with brine (1 X), dried over Na2SO4 and concentrated in vacuo to give spiro [chromene [3,4-d] pyrimidin-5,1'-cyclohexan] -3-amine (6) crude (0.67 g, 98% yield) as an orange solid. Trituration with EtOAc / hexanes gave the spiro [chromene [3,4d] pyrimidin-5,1'-cyclohexan] -3-amine (6) pure. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 8.75 (1 H, s), 7.76 (1 H, dd, J = 7.8, 1.6 Hz), 7.17 (1 H , td, J = 7.6, 1.6 Hz), 6.94 - 7.04 (2 H, m), 6.86 (2 H, sa), 1.49 - 1.87 (9 H, m), 1.20 - 1.30 (1

20 h, m). CLEM-ESI (POS), M / Z, M + 1: Found 268.1

Example 2 N- (4 (1-piperazinyl) phenyl) spiro [chromene [3,4-d] pyrimidin-5,1’-cyclohexan] -3-amine 4- (4- (Spiro [chromene [3,4-d] pyrimidin-5,1’-cyclohexan] -3-ylamino) phenyl) -1-tert-butyl piperazinecarboxylate (8)

A 10 ml single-bottom round bottom flask was sequentially charged with spiro [chromene [3,4d] pyrimidin-5,1'-cyclohexan] -3-amine (6) (0.29 g, 1.1 mmol ), Tert-butyl 4- (4-bromophenyl) piperazin-1-carboxylate (7) (0.37 g, 1.1 mmol), tris (dibenzylideneacetone) dipaladium (o) (0.012 g, 0.011 mmol), 9 , 9-dimethyl-4.55 bis (diphenylphosphino) xanthene (0.016 g, 0.023 mmol) (Xantfos) and sodium tert-butoxide (0.15 g, 1.52 mmol). Then, the flask was subjected to 3 evacuation cycles and refilled with N2 before introducing 1,4-dioxane (4 ml) through a syringe under N2. The resulting mixture was then stirred at reflux overnight. The reaction was cooled and subjected to Combi-flash column chromatography (EtOAc / hexanes) to give 4- (4- (spiro [chromene [3,4-d] pyrimidin5,1'-cyclohexan] -3-ylamino) phenyl) Tert-butyl -1-piperazinecarboxylate (8) (40 mg, 7% yield) as a solid

10 whitish CLEM-ESI (POS), M / Z, M + 1: Found 528.3. Calculated 528.29.

N- (4- (1-Piperazinyl) phenyl) spiro [chromene [3,4-d] pyrimidin-5,1'-cyclohexan] -3-amine (9) TFA (1.0 ml, was added dropwise) 13 mmol) to a stirred solution of 4- (4- (spiro [chromene [3,4-d] pyrimidin-5,1'-cyclohexane] -3-ylamino) phenyl) -1piperazinecarboxylate tert-butyl (8) ( 0.040 g, 0.075 mmol) in DCM (7 ml) and stirred at rt for 1.5 h. Volatile compounds were removed and the residue was dissolved in EtOAc and subsequently washed with ice cold 2N NaOH solution (2 X). The organic phase was dried over Na2SO4 and after concentration in vacuo the residue was triturated with EtOAc / hexanes to give N- (4- (1-piperazinyl) phenyl) spiro [chromene [3,4-d] pyrimidin-5.1 '-cyclohexan] -3-amine

(9) pure (0.025 g, 80% yield) as a light yellow solid. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 9.56 (1 H, sa), 8.93 (1 H, s), 7.83 (1 H, dd, J = 7.8, 1, 2 Hz), 7.60 (2 H, d, J = 9.4 Hz), 7.22 (1 H, td, J = 7.6, 1.6 Hz), 6.98 - 7.08

20 (2 H, m), 6.89 (2 H, d, J = 9.4 Hz), 2.94 - 3.02 (4 H, m), 2.77 - 2.87 (4 H, m), 1.52 - 1.96 (9 H, m), 1.21 - 1.34 (1 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 428.2

Example 3

N- (4- (4-methyl-1-piperazinyl) phenyl) spiro [chromene [3,4-d] pyrimidin-5,1’-cyclohexan] -3-amine

The title compound (11) was prepared using chemistry similar to that described in example 1 except that

replaced guanidine hydrochloride with the corresponding arylguanidine [J. Med. Chem., 1993, Vol. 36, No. 19., pg 2716] as its carbonate. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 9.57 (1 H, sa), 8.93 (1 H, s), 7.83 (1 H, dd, J = 7.8, 1, 6 Hz), 7.60 (2 H, d, J = 9.0 Hz), 7.22 (1 H, td, J = 7.8, 1.6 Hz), 6.99 - 7.08 ( 2 H, m), 6.91 (2 H, d, J = 9.0 Hz), 3.00 - 3.14 (4 H, m), 2.42 - 2.48 (4 H, m) , 2.22 (3 H, s), 1.55 - 1.95 (9 H, m), 1.26 - 1.34 (1 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 442.1.

Example 4

N- (5- (1-piperazinyl) -2-pyridinyl) spiro [chromene [3,4-d] pyrimidin-5,1’-cyclohexan] -3-amine

The title compound 12 was prepared from compound 6 using chemistry similar to that described in example 2.

10 1 H-NMR (500 MHz, DMSO-d6) 8 ppm 10.60 (1 H, sa), 9.07 (1 H, s), 8.89 (2 H, sa), 8.07 (1 H , d, J = 2.4 Hz), 7.96 (1 H, d, J = 9.2 Hz), 7.93 (1 H, d, J = 7.9 Hz), 7.81 (1 H, dd, J = 9.5, 2.7 Hz), 7.30 (1 H, t, J = 7.9 Hz), 7.10 (1 H, t, J = 7.6 Hz), 7.07 (1 H, d, J = 7.9 Hz), 3.35 - 3.47 (4 H, m), 3.23 - 3.34 (4 H, m), 1.84 - 2 , 03 (4 H, m), 1.70 - 1.83 (3 H, m), 1.58 - 1.69 (2 H, m), 1.25 - 1.42 (1 H, m) ; CLEM-ESI (POS), M / Z, M + 1: Found 429.2

Example 5

1 ’- (phenylcarbonyl) spiro [chromene [3,4-d] pyrimidin-5,4’-piperidin] -3-amine

The title compound 13 was prepared using chemistry similar to that described in Example 1. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 8.81 (1 H, s), 7.79 (1 H, dd, J = 7.6, 1.4 Hz), 7.37 - 7.52 (5 H, m), 7.17 - 7.23 (1 H, m), 7.01 - 7.09 (2 H , m), 6.97 (2 H, sa), 4.27-4.45 (2 H, m), 3.50-3.59 (2 H, m), 1.98-2.08 ( 4 H, m). CLEM-ESI (POS), M / Z, M + 1:

20 Found 373.1

Example 6

N- (4- (4-methyl-1-piperazinyl) phenyl) -1 ’- (phenylcarbonyl) spiro [chromene [3,4-d] pyrimidin-5,4’-piperidin] -3-amine

The title compound (14) was prepared using chemistry similar to that described in example 3. Retention time in 25 reverse phase analytical HPLC: 7.462 min. CLEM-ESI (POS), M / Z, M + 1: Found 547.2

Example 7

N- (4- (4-methyl-1-piperazinyl) phenyl) spiro [chromene [3,4-d] pyrimidin-5,4’-piperidin] -3-amine

The title compound 15 was obtained together with the compound (14) (example 6) by in situ deprotection under the reaction conditions and then purified by chromatography. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 9.66 (1 H, sa), 8.98 (1 H, s), 8.25 (1 H, s), 7.86 (1 H, d, J = 7.8 Hz), 7.60 (2 H, d, J = 9.0 Hz), 7.21 - 7.29 (1 H, m), 7.03 - 7.12 (2 H, m), 6.91 (2 H, d, J = 9.0 Hz), 3.00 - 3.18 (8 H, m), 2.41 - 2.48 (4 H, m), 2.11 - 2.28 (5 H, m), 1.94 (2 H, d, J = 13.3 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 443.2

Example 8

2 ’, 3’, 5 ’, 6’-tetrahydrospiro [chromene [3,4-d] pyrimidin-5,4’-pyran] -3-amine

The title compound (16) was prepared using chemistry similar to that described in Example 1. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 8.79 (1 H, s), 7.78 (1 H, dd, J = 8.2, 1.6 Hz), 7.16 - 7.23 (1 H, m), 6.99 - 7.07 (2 H, m), 6.94 (2 H, sa ), 3.72-3.83 (4 H, m), 2.04-2.17 (2 H, m), 1.65-1.77 (2 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 270.1

15 Example 9 N- (4- (1-piperazinyl) phenyl) -2 ’, 3’, 5 ’, 6’-tetrahydrospiro [chromene [3,4-d] pyrimidin-5,4’-piran] -3-amine

The title compound (17) was prepared from the compound (16) using chemistry similar to that described in the example

2. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 9.63 (1 H, sa), 8.97 (1 H, s), 7.85 (1 H, dd, J = 7.6, 1.4 Hz), 7.59 (2 H, d,

20 J = 9.0 Hz), 7.19 - 7.27 (1 H, m), 7.01 - 7.12 (2 H, m), 6.90 (2 H, d, J = 9, 4 Hz), 3.74-3.90 (4 H, m), 2.93-3.05 (4 H, m), 2.77-2.87 (4 H, m), 2.10 - 2.24 (2 H, m), 1.80 (2 H, d, J = 12.9 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 430.1

Example 10

N- (6- (1-piperazinyl) -3-pyridinyl) -2 ', 3', 5 ', 6'-tetrahydrospiro [chromene [3,4-d] pyrimidin-5,4'-pyran] -3- amine

The title compound (18) was prepared from the compound (16) using chemistry similar to that described in the example

2. 1 H-NMR (500 MHz, DMSO-d6) 8 ppm 9.80 (1 H, s), 9.01 (1 H, s), 8.81 (2 H, sa), 8.59 (1 H, d, J = 2.4Hz), 8.01 (1 H, dd, J = 9.3, 2.7 Hz), 7.88 (1 H, dd, J = 7.7, 1.3 Hz), 7.23 - 7.30 (1 H, m), 7.07 - 7.13 (2 H, m), 7.05 (1 H, d, J = 9.3 Hz), 3, 80-3.86 (4 H, m), 3.65-3.72 (4 H, m), 3.17-3.31 (4 H, m), 2.10-2.23 (2 H , m), 1.82 (2 H, d, J = 12.7 Hz); CLEM-ESI (POS), M / Z, M + 1: Found 431.2

Example 11

N- (2- (1-piperazinyl) -5-pyrimidinyl) -2 ', 3', 5 ', 6'-tetrahydrospiro [chromene [3,4-d] pyrimidin-5,4'-pyran] -3- amine

The title compound (19) was prepared from the compound (16) using chemistry similar to that described in the example

2. 1 H-NMR (500 MHz, DMSO-d6) 8 ppm 9.74 (1 H, s), 9.00 (1 H, s), 8.81 (2 H, sa), 8.77 (2 H, s), 7.87 (1 H, dd,

J = 7.6, 1.2 Hz), 7.22 - 7.29 (1 H, m), 7.05 - 7.11 (2 H, m), 3.88 - 3.94 (4 H , m), 3.78-3.84 (4 H, m), 3.15-3.24 (4 H, 15 m), 2.07-2.19 (2 H, m), 1.76 - 1.84 (5 H, m); CLEM-ESI (POS), M / Z, M + 1: Found 432.2.

Example 12

N- (5- (1-piperazinyl) -2-pyridinyl) -2 ', 3', 5 ', 6'-tetrahydrospiro [chromene [3,4-d] pyrimidin-5,4'-pyran] -3- amine

The title compound (20) was prepared from the compound (16) using chemistry similar to that described in the example

20 2. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 9.77 (1 H, s), 9.03 (1 H, s), 8.04 (1 H, d, J = 9.0 Hz), 8.00 (1 H, d, J = 3.1 Hz), 7.89 (1 H, d, J = 7.8 Hz), 7.45 (1 H, dd, J = 9, 0, 3.1 Hz), 7.23 - 7.30 (1 H, m), 7.04 - 7.12 (2 H, m), 3.83 (4 H, d, J = 7.8 Hz), 2.96-3.11 (4 H, m), 2.76-2.89 (4 H, m), 2.10-2.25 (2 H, m), 1.81 (2 H, d, J = 12.9 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 431.2.

Example 13

spiro [chromene [3,4-d] pyrimidin-5,1’-cyclopentan] -3-amine

The title compound (21) was prepared using chemistry similar to that described in Example 1. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 8.75 (1 H, s), 7.76 (1 H, dd, J = 7.8, 1.6 Hz), 7.15 (1 H, td, J = 7.6, 1.6 Hz), 7.00 (1 H, td, J = 7A, 1, 2 Hz), 6.84 - 6.93 (3 H, m), 2.05 - 2.18 (2 H, m), 1.68 - 2.01 (6 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 254.1.

Example 14

N- (4- (1-piperazinyl) phenyl) spiro [chromene [3,4-d] pyrimidin-5,1’-cyclopentan] -3-amine

The title compound (22) was prepared from the compound (21) using chemistry similar to that described in the example

2. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 9.57 (1 H, s), 8.92 (1 H, s), 7.83 (1 H, dd, J = 7.8, 1.6 Hz), 7.59 (2 H, d, J = 9.0 Hz), 7.15 - 7.23 (1 H, m), 7.01 - 7.08 (1 H, m) , 6.93 (1 H, dd, J = 8.0, 1.0 Hz), 6.84 - 6.91 (2 H, m), 2.97 (4 H, dd, J = 6.1 , 3.7 Hz), 2.82 (4 H, dd, J = 5.9, 3.9 Hz), 2.14 - 2.25 (2 H, m), 1.99 - 2.09 ( 2 H, m), 1.86 - 1.96 (2 H, m, J = 7.6, 4.1 Hz), 1.77 - 1.86 (2 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 414.1.

15 Example 15 N- (5- (1-piperazinyl) -2-pyridinyl) spiro [chromene [3,4-d] pyrimidin-5,1’-cyclopentan] -3-amine

The title compound (23) was prepared from the compound (21) using chemistry similar to that described in the example

2. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 9.62 (1 H, s), 8.92 (1 H, s), 7.97 (1 H, d, J = 9.4 Hz ), 7.92 (1 H, d, J = 2.7 Hz),

20 7.80 (1 H, dd, J = 7.8, 1.2 Hz), 7.36 (1 H, dd, J = 9.0, 3.1 Hz), 7.12 - 7.19 (1 H, m), 6.96 - 7.03 (1 H, m), 6.88 (1 H, dd, J = 8.0, 1.0 Hz), 2.92 - 3.01 ( 4 H, m), 2.72 - 2.83 (4 H, m), 2.07 - 2.18 (2 H, m), 1.96 - 2.04 (2 H, m), 1, 81-1.92 (2 H, m), 1.69-1.80 (2 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 415.1.

Example 16

spiro [chromene [3,4-d] pyrimidin-5,1’-cyclobutan] -3-amine

The title compound (24) was prepared using chemistry similar to that described in Example 1. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 8.75 (1 H, s), 7.76 (1 H, dd, J = 7.8, 1.6 Hz), 7.17 (1 H, td, J = 7.8, 1.6 Hz), 6.97 - 7.05 (2 H, m), 6 , 94 (2 H, sa), 2.53 - 2.60 (2 H, m), 2.29 - 2.38 (2 H, m), 1.81 - 2.03 (2 H, m) . CLEM-ESI (POS), M / Z, M + 1: Found 240.1.

Example 17

N- (4- (1-piperazinyl) phenyl) spiro [chromene [3,4-d] pyrimidin-5,1’-cyclobutan] -3-amine

The title compound (25) was prepared from the compound (24) using chemistry similar to that described in the example

2. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 9.64 (1 H, s), 8.93 (1 H, s), 7.83 (1 H, dd, J = 7.8, 1.6 Hz), 7.66 (2 H, d, J = 9.0 Hz), 7.17 - 7.25 (1 H, m), 6.99 - 7.09 (2 H, m) , 6.89 (2 H, d, J = 9.4 Hz), 2.92 - 3.02 (4 H, m), 2.78 - 2.87 (4 H, m), 2.56

-

 2.66 (2 H, m), 2.36 - 2.47 (2 H, m), 1.87 - 2.07 (2 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 400.1.

Example 18

7-fluoro-2 ’, 3’, 5 ’, 6’-tetrahydrospiro [chromene [3,4-d] pyrimidin-5,4’-pyran] -3-amine

2-fluorophenyl acetate (27) Acetyl chloride (32 ml, 446 mmol) was added slowly through an addition funnel to a stirred solution of 2-fluorophenol (45 ml, 446 mmol) and pyridine (40 ml, 491 mmol) in DCM (300 ml)

20 to ta. After 2 h, 2 N HCl (300 ml) was added and the aqueous phase was separated and extracted with DCM (1 X). The organic phases were combined, washed with brine (2 X), dried over Na2SO4 and concentrated to give 2-fluorophenyl acetate (27) (69.0 g, 100% yield) as a colorless oil. 1 H-NMR (400 MHz, DMSOd 6) 8 ppm 7.18-7.40 (4 H, m), 2.32 (3 H, s).

1- (3-Fluoro-2-hydroxyphenyl) ethanone (28) A solution of 2-fluorophenyl acetate (27) (69.9 g, 453.49 mmol) in dichlorobenzene (40 ml) was added dropwise aluminum chloride solution (65 g) in dichlorobenzene (50 ml). After heating to 100 ° C for 24 h, the reaction mixture was allowed to cool to room temperature, diluted with dichloromethane and slowly poured into 2 N aqueous HCl solution cooled to 0 ° C. The mixture was meticulously stirred for 20 min. and the aqueous phase was separated and extracted with dichloromethane (2 X). The organic extracts were combined, washed with brine (2 X), dried over Na2SO4 and concentrated in vacuo. The residue was subjected to Combi-flash column chromatography (EtOAc / hexanes) to give 1- (3-fluoro-2-hydroxyphenyl) ethanone (28) (15.0 g, 21.5% yield) as a white solid. 1H-NMR (400 MHz,

10 CHLOROFORM-d) 8 ppm 7.68 - 7.79 (2 H, m), 7.07 (1 H, t, J = 8.4 Hz), 5.73 (1 H, d, J = 43 Hz), 2.57 (3 H, s).

8-fluoro-2 ’, 3’, 5 ’, 6’-tetrahydroespiro [chromene-2,4’-pyran] -4 (3H) -ona (29)

Pyrrolidine (4.8 ml, 58 mmol) was added to a stirred solution of 1- (3-fluoro-2-hydroxyphenyl) ethanone (28) (5.9 g, 39

mmol) and tetrahydro-4h-pyran-4-one (4.6 ml, 50 mmol) in toluene (40 ml) at rt. After decreasing the exothermic reaction, the reaction mixture was stirred at rt for 1 h, then underwent Dean-reflux conditions.

Stark for 6 h. The reaction mixture was cooled, poured into ice and 2N aqueous HCl solution and extracted with

EtOAc (2 X). The combined organic phases were washed with 2N HCl aqueous solution (1 X), aqueous solution.

2 N NaOH (2 X), brine (1 X) and dried over Na2SO4. The vacuum concentration gave 8-fluoro-2 ’, 3’, 5 ’, 6’

tetrahydrospiro [chromene-2,4’-pyran] -4 (3H) -one (29) (4.4 g, 48% yield) that was taken to the next stage without further purification. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 7.51 - 7.60 (2 H, m), 7.00 - 7.07 (1 H, m), 3.60 - 3.73 (4

H, m), 2.93 (2 H, s), 1.71-192 (4 H, m).

8-Fluoro-2 ’, 3.3’, 4.5 ’, 6’-hexahydroespiro [chromene-2,4’-pyran] -4-ol (30) A solution of 8- was added dropwise

fluoro-2 ', 3', 5 ', 6'-tetrahydrospiro [chromene-2,4'-pyran] -4 (3H) -one (29) (4.4 g, 19 mmol) in EtOH (90 ml) to a stirred suspension of sodium borohydride (0.33 ml, 9.3 mmol) in EtOH (30 ml) at rt. The resulting mixture was stirred.

at reflux for 2 h and then concentrated in vacuo. The residue was dissolved in EtOAc, washed with aqueous solution.

of saturated NaHCO3 (2 X), brine (1 X), dried over Na2SO4 and concentrated in vacuo to give 8-fluoro

2 ’, 3.3’, 4.5 ’, 6’-hexahydrospiro [chromene-2,4’-pyran] -4-ol (30) (4.4 g, 99% yield) as a yellow oil

of course it was used in the next stage without purification. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 7.22 (1 H, dd, J = 7.8, 0.8 30 Hz), 7.02-7.11 (1 H, m), 6 , 81-6.89 (1 H, m), 5.49 (1 H, d, J = 6.3 Hz), 4.67-4.78 (1 H, m), 3.56-3, 77 (4 H, m), 2.14 (1

H, dd, J = 13.7, 5.9 Hz), 1.75-1.86 (3 H, m), 1.60-1.75 (2 H, m).

8-Fluoro-2 ', 3', 5 ', 6'-tetrahydrospiro [chromene-2,4'-pyran] (31) A mixture of 8-fluoro2', 3,3 ', 4,5 was heated to reflux ', 6'-hexahydrospiro [chromene-2,4'-pyran] -4-ol (30) (4.4 g, 18 mmol) and 4 N hydrochloric acid (55 ml, 220 mmol) for 4 h. Then, the reaction mixture was cooled to rt, poured into H2O and extracted with EtOAc (2 X). The combined organic phases were washed with brine (1 X), dried over Na2SO4. Concentration in vacuo gave 8-fluoro-2 ', 3', 5 ', 6'-tetrahydrospiro [chromene-2,4'-pyran] (31) (4.0 g, 98% yield) as a crystalline solid colorless. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 7.04 - 7.12 (1 H, m), 6.93 (1 H, m), 6.82 - 6.89 (1 H, m) , 6.54 (1 H, dd, J = 9.8, 2.0 Hz), 5.89 (1 H, d, J = 9.8 Hz), 3.62 - 3.78 (4 H, m), 1.72-1.87 (4 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 221.1.

4-Fluoro-1a, 2 ’, 3’, 5 ’, 6’, 7b-hexahydro [oxireno [c] chromene-2,4’-pyran] (32) Peroxide peroxide was added dropwise

aqueous hydrogen (31%, 2.7 ml, 27 mmol) to a stirred frozen solution of 8-fluoro-2 ’, 3’, 5 ’, 6’

tetrahydrospiro [chromene-2,4’-pyran] (31) (4.0 g, 18 mmol) and methyltrioxorrenium (VII) (0.091 g, 0.36 mmol) in DCM (50

ml) and pyridine (0.36 ml, 4.4 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 0 ° C for 10 min. and 15 to ta overnight. 3.6 ml of NaClO (commercial Clorox) was added dropwise at rt. The mixture was stirred.

resulting at rt for 1 h. The reaction mixture was then poured into ice-H2O and extracted with DCM (2 X). Be

The combined organic phases were washed with brine (1 X), dried over Na2SO4. The concentration in vacuo gave

4-fluoro-1a, 2 ’, 3’, 5 ’, 6’, 7b-hexahydrospiro [oxireno [c] chromene-2,4’-pyran] (32) (4.0 g, 93% yield) that

It contained 31 (~ 9%) unreacted. This material was used in the next step without purification. 1 H-NMR (400 MHz, 20 DMSO-d6) 8 ppm 7.30 - 7.35 (1 H, m), 7.19 - 7.28 (1 H, m), 6.92 - 7.00 ( 1 H, m), 4.12 (1 H, dd, J = 4.7, 2.0 Hz), 3.65 -

3.87 (4 H, m), 3.52-3.61 (1 H, m), 2.00 - 2.09 (1 H, m), 1.73 - 1.85 (2 H, m ), 1.25-1.34 (1 H, m).

8-Fluoro-2 ', 3', 5 ', 6'-tetrahydrospiro [chromene-2,4'-pyran] -3 (4H) -one (33) Boron trifluoride etherate (0.5 ml, was added) 4 mmol) to a stirred solution of 4-fluoro-1a, 2 ', 3', 5 ', 6', 7b-hexahydrospiro [oxyrene [c] chromene-2,4'-pyran]

25 (32) crude (2.0 g, 8 mmol) in benzene (40 ml) under a nitrogen atmosphere and stirred at rt for 70 min. After the final treatment, the mixture was poured into ice and saturated aqueous NaHCO3 solution, and extracted with EtOAc (2 X). The combined organic phases were washed with brine (1 X), dried over Na2SO4 and concentrated in vacuo to give 8-fluoro-2 ', 3', 5 ', 6'-tetrahydrospiro [chromene-2,4'-pyran ] -3 (4H) -one (33) crude (1.97 g, 99% yield), which was used in the next step without purification.

7-Fluoro-2 ', 3', 5 ', 6'-tetrahydrospiro [chromene [3,4-d] pyrimidin-5,4'-pyran] -3-amine (26) A solution of 8 was stirred under reflux -fluoro-2 ', 3', 5 ', 6'-tetrahydrospiro [chromene-2,4'-pyran] -3 (4H) -one (33) crude (1,600 g, 6.77 mmol) and tert-butoxy -bis (dimethylamino) methane (2.10 ml, 10.2 mmol) for 1.5 h. The temperature was lowered to 85 ° C and n-propanol (5 ml), guanidine hydrochloride (3.2 g, 34 mmol) and sodium methoxide in MeOH (4.37 M solution) (4.6 ml, were added sequentially. 20 mmol). The resulting mixture was stirred at 85 ° C for 2.5 h, then poured into ice and saturated aqueous NaHCO3 solution, and extracted with EtOAc (2 X). The combined organic phases were washed with brine (1 X) and dried over Na2SO4. The residue was subjected to flash chromatography on Combi-flash column (EtOAc / hexanes) after concentration in vacuo to give 7-fluoro-2 ’, 3’, 5 ’, 6’

Tetrahydrospiro [chromene [3,4-d] pyrimidin-5,4’-pyran] -3-amine (26) (0.95 g, 49% 2-stage yield) as an off-white solid. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 8.81 (1 H, s), 7.59 - 7.64 (1 H, m), 7.09 - 7.16 (1 H, m) , 6.98 - 7.08 (3 H, m), 3.70 - 3.88 (4 H, m), 2.07 - 2.21 (2 H, m), 1.76 (2 H, d, J = 12.5 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 288.1.

Example 19

7-fluoro-N- (4- (1-piperazinyl) phenyl) -2 ', 3', 5 ', 6'-tetrahydrospiro [chromene [3,4-d] pyrimidin-5,4'-pyran] -3 -amine

The title compound (34) was prepared from the compound (36) using chemistry similar to that described in the example

2. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 9.73 (1 H, s), 8.99 (1 H, s), 7.68 (1 H, d, J = 7.8 Hz ), 7.59 (2 H, d, J = 9.0 Hz),

7.14 - 7.22 (1 H, m), 7.02 - 7.10 (1 H, m), 6.91 (2 H, d, J = 9.0 Hz), 3.72 - 3 , 93 (4 H, m), 2.94 - 3.05 (4 H, m), 2.79 - 20 2.88 (4 H, m), 2.13 - 2.25 (2 H, m ), 1.84 (2 H, d, J = 13.7 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 448.1.

4- (4 - ((7-Fluoro-2 ', 3', 5 ', 6'-tetrahydrospiro [chromene [3,4-d] pyrimidin-5,4'-pyran] -3-yl) amino) phenyl ) -1piperazinecarboxylate (36) A 10 ml single bottom round bottom flask was sequentially loaded with

(26) (0.105 g, 0.37 mmol), tert-butyl 4- (4-iodophenyl) piperazin-1-carboxylate (35) (0.14 g, 0.37 mmol),

25 tris (dibenzylideneacetone) dipaladium (o) (0.0033 g, 0.0037 mmol), 9.9-dimethyl-4,5-bis (diphenylphosphino) xanthene (0.0047 g, 0.0080 mmol) (Xantfos) and sodium tert-butoxide (0.049 g, 0.51 mmol). Then, the flask was subjected to 3 evacuation cycles and refilled with N2 before introducing 1,4-dioxane (1.8 ml) through a syringe under N2. The resulting mixture was then stirred at reflux in a preheated oil bath overnight. The reaction was cooled and subjected to Combi-flash column chromatography (EtOAc / hexanes) to give 4- (4 - ((7-fluoro-2 ', 3', 5 ', 6'tetrahydrospiro [chromene [3,4- d] pyrimidin-5,4'-pyran] -3-yl) amino) phenyl) -1-piperazinecarboxylate (36) (0.065 g, 32% yield) which was used directly in the next step. CLEM-ESI (POS), M / Z, M + 1: Found 548.2.

Example 20

7-fluorospiro [chromene [3,4-d] pyrimidin-5,1’-cyclohexan] -3-amine

The title compound (37) was prepared from the compound (40) using chemistry similar to that described in example 18 except the steps specified below.

4'-Fluoro-1a ', 7b'-dihydrospiro [cyclohexane-1,2'-oxirene [c] chromene] (39) NBS (1.7 g, 9.6 mmol) was added in 3 portions along a period of 30 min. to a stirred solution of 8-fluorospiro [chromene-2,1’-cyclohexane]

(38) (1.82 g, 8.3 mmol) in a mixed solvent containing t-BuOH (30 ml) and H2O (20 ml) at rt. Stirring was continued at rt for 5 h. A solution of sodium hydroxide (1.0 g, 25 mmol) in H2O (12 ml) was added at rt. Stirring was continued at rt for 1.5 h. Then, the mixture was poured into H2O and extracted with EtOAc (2 X). The combined organic phases were washed with brine (1 X), dried over Na2SO4 and concentrated in vacuo to give 4'-fluoro-1a ', 7b'-dihydrospiro [cyclohexane-1,2'-oxirene [c] chromene] (39) (2.0 g, 102% yield) as a slightly red oil, which was highly pure and was taken to the next stage without further purification. 1 H-NMR (400 MHz, CHLOROFORM-d) 8 ppm 7.09 - 7.14 (1 H, m), 7.02 - 7.09 (1 H, m), 6.82 - 6.89 (1 H, m), 3.89 (1

20 H, dd, J = 4.3, 2.0 Hz), 3.51 (1 H, d, J = 4.7 Hz), 2.10 - 2.20 (1 H, m), 1, 86 - 1.98 (1 H, m), 1.31 - 1.78 (8 H, m).

8-Fluorospiro [chromene-2,1'-cyclohexan] -3 (4H) -one (40) A mixture of 4'-fluoro-1a ', 7b'dihydrospiro [cyclohexane-1,2'-oxirene was refluxed [c] chromene] (39) (2.0 g, 8.5 mmol) and pyridinium tosylate (2.4 g, 9.4 mmol) in toluene (50 ml) for 2 h, then cooled and poured in ice and saturated aqueous NaHCO3 solution, and

25 extracted with EtOAc (2 X). The combined organic phases were thoroughly washed with saturated NaHCO3 aqueous solution (3 X) followed by brine (1 X), dried over Na2SO4 and concentrated in vacuo to give 8fluorospiro [chromene-2,1'-cyclohexane] -3 ( 4H) -one (40) (1.84 g, 92% yield) as a reddish oil that was taken to the next stage without purification. 1 H-NMR (400 MHz, CHLORFORM-d) 8 ppm 7.00 - 7.07 (1 H, m), 6.92 7.00 (1 H, m), 6.84 - 6.90 (1 H , m), 3.60 (2 H, s), 1.57 - 1.87 (9 H, m), 1.29 - 1.36 (1 H, m).

7-Fluorospiro [chromene [3,4-d] pyrimidin-5,1’-cyclohexan] -3-amine (37) A solution of 8 was heated to reflux

fluorospiro [chromene-2,1’-cyclohexan] -3 (4H) -one (40) (1.84 g, 7.85 mmol) in tert-butoxy-bis (dimethylamino) methane

(3.57 ml, 17.3 mmol) for 40 min. After brief cooling, n-propanol was added sequentially

5 (35 ml), guanidine hydrochloride (4.50 g, 47.1 mmol) and sodium methoxide in MeOH (4.37 M) (5.39 ml, 23.6 mmol).

The resulting mixture was stirred at 75 ° C overnight. After the final treatment, the mixture was poured on ice and

aqueous solution of saturated NaHCO3 and extracted with EtOAc (2 X). The combined organic phases were washed

with brine (2 X), dried over Na2SO4 and concentrated in vacuo to give 7-fluorospiro [chromene [3,4

d] pyrimidin-5,1’-cyclohexan] -3-amine (37) crude (2.15 g, 95.9% yield). 1 H-NMR (500 MHz, DMSO-d6) 8 ppm 10 8.78 (1 H, s), 7.59 (1 H, d, J = 7.8 Hz), 7.07 - 7.14 (1 H, m), 6.94 - 7.03 (3 H, m), 1.56 - 1.89 (9 H, m), 1.20 - 1.33 (1 H,

m). CLEM-ESI (POS), M / Z, M + 1: Found 286.1.

Example 21

7-fluoro-N- (4- (1-piperazinyl) phenyl) spiro [chromene [3,4-d] pyrimidin-5,1’-cyclohexan] -3-amine

The title compound (41) was prepared from the compound (37) using chemistry similar to that described in the example

19. 1H-NMR (500 MHz, DMSO-d6) 8 ppm 9.66 (1 H, s), 8.95 (1 H, s), 7.66 (1 H, d, J = 7.8 Hz ), 7.55 - 7.62 (2 H, m), 7.11 - 7.19 (1 H, m), 6.99 - 7.07 (1 H, m), 6.86 - 6, 92 (2 H, m), 2.94 - 3.02 (4 H, m), 2.78 - 2.87 (4 H, m), 1.85 - 1.97 (4 H, m), 1.59-1.81 (5 H, m), 1.27-1.37 (1 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 446.2.

Example 22

7-fluoro-N- (5- (1-piperazinyl) -2-pyridinyl) spiro [chromene [3,4-d] pyrimidin-5,1’-cyclohexan] -3-amine

The title compound (42) was prepared from the compound (37) using chemistry similar to that described in the example

19. 1H-NMR (400 MHz, DMSO-d6) 8 ppm 9.79 (1 H, s), 9.01 (1 H, s), 8.03 (1 H, d, J = 9.4 Hz ), 7.99 (1 H, d, J = 2.7 Hz),

7.69 (1 H, d, J = 7.8 Hz), 7.44 (1 H, dd, J = 9.0, 3.1 Hz), 7.13 - 7.22 (1 H, m ), 7.01 - 7.09 (1 H, m), 3.01 - 3.08 (4 H, m), 25 2.80 - 2.89 (4 H, m), 1.58 - 1 , 99 (9 H, m), 1.26-1.42 (1 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 447.3

Example 23

7- (methylsulfonyl) -N- (5- (1-piperazinyl) -2-pyridinyl) spiro [chromene [3,4-d] pyrimidin-5,1’-cyclohexan] -3-amine

The title compound (43) was prepared from the compound (45) using chemistry similar to that described in the example

2. 1H-NMR (500 MHz, MeOD-d3) 8 9.15 (1H, s), 8.23 (1H, m), 8.21 (1H, m), 7.97 (1H, d, J = 2.7 Hz), 7.95 (1H, dd, J1 = 7.8 Hz, J2 = 1.4 Hz), 7.57 (1H, d, J = 9.6 Hz), 7.33 ( 1H, t, J = 7.8 Hz), 3.54 (4H, m), 3.44 (4H, m), 3.30 (3H, s), 2.04-2.16 (6H, m ), 1.84 (1H, da, J = 13.5 Hz), 1.67 (2H, m), 1.41 (1H, m); CLEM-ESI (POS), M / Z, M + 1: Found 507.0.

10 7- (bromine) spiro [chromene [3,4-d] pyrimidin-5,1’-cyclohexan] -3-amine (44). Compound (44) was prepared using chemistry similar to that described in example 20. 1H-NMR (500 MHz, DMSO-d6) 8 8.79 (1H, s), 7.78 (1H, dd, J1 = 7 , 9 Hz, 1.3 Hz), 7.43 (1H, dd, J1 = 8.1 Hz, J2 = 1.5 Hz), 7.00 (2H, sa), 6.95 (1H, t, J = 7.8 Hz), 1.80-1.88 (6H, m), 1.75 (1H, da, J = 11.8 Hz), 1.58-1.62 (2H, m), 1.23-1.31 (1 H, m); CLEM-ESI (POS), M / Z, M + 1: Found 346.2.

7- (methylsulfonyl) spiro [chromene [3,4-d] pyrimidin-5,1'-cyclohexan] -3-amine (45). Copper (I) iodide was added (28

15 mg, 0.15 mmol, 0.4 eq.) To a degassed solution of 7-bromoespiro [chromene [3,4-d] pyrimidin-5,1'-cyclohexan] -3amine (44) (0.126 g, 0 , 36 mmol), (S) -pyrrolidin-2-carboxylic acid (0.034 g, 0.29 mmol), sodium methanesulphinate (0.074 g, 0.73 mmol) and sodium hydroxide (0.015 g, 0.36 mmol) in DMSO (1 ml) under argon. The mixture was heated at 100 ° C for 4 days. After the final treatment, silica gel chromatography provided 15 mg of 7 (methylsulfonyl) spiro [chromene [3,4-d] pyrimidin-5,1'-cyclohexan] -3-amine (45) as a brown solid. CLEM-ESI (POS),

20 M / Z, M + 1: Found 345.9.

Example 24

3 - ((5- (1-piperazinyl) -2-pyridinyl) amino) spiro [chromene [3,4-d] pyrimidin-5,1’-cyclohexane] -7-carbonitrile

The title compound (46) was prepared from the compound (47) using chemistry similar to that described in the example

25 2. 1 H-NMR (500 MHz, DMSO-d6) 8 10.40 (1H, sa), 9.12 (1H, s), 8.93 (2H, sa), 8.25 (1H, dd, J1 = 8.1 Hz, J2 = 1.5 Hz), 8.08 (1H, d, J = 2.9 Hz), 8.01 (1H, d, J = 9.0 Hz), 7.71 (1H, dd, J1 = 7.5 Hz, J2 = 1.4 Hz), 7.68 (1H, dd, J1 = 9.5 Hz, J2 = 3.4), 7.24 (1H, t, J = 7.9 Hz), 3.38 (4H, m), 3.26 (4H, m), 1.90-2.01 (4H, m), 1.77-1.85 (3H, m ), 1.65-1.71

(2H), 1.26-1.43 (1 H, m); CLEM-ESI (POS), M / Z, M + 1: Found 454.3.

3-Aminoespiro [chromene [3,4-d] pyrimidin-5,1’-cyclohexane] -7-carbonitrile (47). A solution of 7bromoespiro [chromene [3,4-d] pyrimidin-5,1'-cyclohexan] -3-amine (44) (0.233 g, 0.673 mmol), Zn (CN) 2 (0.0474 g, was degassed) 0.404 5 mmol) and TMEDA (0.0202 ml, 0.135 mmol), in DMF (2 ml) by bubbling nitrogen through the solution for min1 min. before adding Pd2 (dba) 3 (0.0462 g, 0.0505 mmol) and Xantfos (4,5-bis (diphenylphosphino) -9,9-dimethyl-9Hxanthene, 0.0584 g, 0.101 mmol). The mixture was heated to 160 ° C for 5 min. with microwave irradiation. The reaction mixture was diluted in water and extracted with 10% iPrOH / DCM (3X75 ml). The organic phase was dried with MgSO4 and concentrated in vacuo. Purification on a Combi-flash column of 40 g [(dry loaded), eluting

10 with 50% EtOAc: hexane to 100% EtOAc then with 4% MeOH / 36% DCM / EtOAc] provided 3-aminoespiro [chromene [3,4-d] pyrimidin-5,1'-cyclohexane] -7 -carbonitrile (47) as a white solid (0.133g, 68%). CLEM-ESI (POS), M / Z, M + 1: Found 293.0.

Example 25

15 N- (4- (1-piperazinyl) phenyl) -2,3,5,6-tetrahydrospiro [pyran-4,6'-pyrido [2 ', 3': 5.6] pyran [3,4-d ] pyrimidin] -8'-amine

2-Cyanopyridin-3-yl acetate (49) Acetic anhydride (4.1 ml, 43.71 mmol) was slowly added to a stirred solution of 3-hydroxypolycininitrile (5.0 g, 41.63 mmol) in pyridine ( 15 ml) to ta. The resulting mixture was stirred at rt overnight and then concentrated in vacuo. The residue was dissolved in EtOAc, washed with aqueous solution of

Saturated NaHCO3 (IX) and brine (IX), and dried over Na2SO4. Purification by Combi-flash chromatography (EtOAc / hexanes) gave 2-cyanopyridin-3-yl acetate (49) (6.5 g, 96.30% yield). 1H-NMR (400 MHz, DMSOd6) 8 ppm 8.67 (1 H, dd, J = 4.7, 1.2 Hz), 8.03 (1 H, dd, J = 8.6, 1.2 Hz), 7.87 (1 H, dd), 2.42 (3 H, s).

1- (3-Hydroxypyridin-2-yl) ethanone (50) A flask was charged with methylmagnesium iodide (67.0 ml, 200 mmol)

250 ml round bottom flame dried. This solution was stirred in an H2O ice bath as it

introduced by means of a cannula 2-cyanopyridin-3-yl acetate (49) (6.5 g, 40 mmol) in benzene (45 ml) along

5 a period of 40 min. The resulting mixture was refluxed for 5.5 h, then cooled in a bath of

ice-H2O and carefully quenched with saturated aqueous NH4Cl solution. It was neutralized carefully

the aqueous phase with 2N aqueous HCl solution and then extracted with EtOAc (2X). The organic phase was washed

combined with brine (IX) and dried over anhydrous Na2SO4. Purification by column chromatography

Combi-flash (EtOAc / hexanes) gave 1- (3-hydroxypyridin-2-yl) ethanone (50) (3.6 g, 65% yield) as a light yellow solid. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 11.58 (1 H, s), 8.27 (1 H, dd, J = 4.3, 1.6 Hz), 7.61 (1 H dd

J = 8.4, 4.3 Hz), 7.47 (1 H, dd, J = 8.4, 1.6 Hz), 2.69 (3 H, s).

2,3,5,6-Tetrahydrospiro [piran-4,2'-pyrano [3,2-b] pyridin] -4 '(3'H) -one (51) Pyrrolidine (5.5) was added dropwise ml, 66 mmol) to a stirred solution of 1- (3-hydroxypyridin-2-yl) ethanone (50) (6.0 g, 44 mmol) and tetrahydro-4h-pyran-415 one (5.3 ml, 57 mmol) in toluene (100 ml) and stirred at rt for 2 h. The mixture was then refluxed under Dean-Stark conditions for 5.5 h. Volatile compounds were removed and the residue was purified by Combi-flash column chromatography (EtOAc / hexanes) to give 2,3,5,6-tetrahydrospiro [pyran-4,2'-pyran [3,2b] pyridin] - 4 '(3'H) -one (51) (5.4 g, 57% yield) H-NMR LC-MS as a reddish oil that solidified on standing at rt. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 8.36 (1 H, dd, J = 3.3, 2.2 Hz), 7.55 - 7.62 (2 H, m), 3, 62 - 3.73

20 (4 H, m), 2.99 (2 H, s), 1.72 - 1.89 (4 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 220.0.

2,3,3 ’, 4’, 5,6-Hexahydroespiro [piran-4,2’-pyrano [3,2-b] pyridin] -4’-ol (52) A solution of

2,3,5,6-tetrahydrospiro [pyran-4,2'-pyrano [3,2-b] pyridin] -4 '(3'H) -one (51) (5.4 g, 24.63 mmol ) in EtOH (45 ml) by

an addition funnel to a stirred suspension of sodium borohydride (0.69 g, 18.47 mmol) in EtOH (15 ml) at rt. The resulting mixture was refluxed for 1.5 h. The reaction mixture was concentrated in vacuo, poured into

ice and saturated aqueous NaHCO3 solution, and extracted with EtOAc (2 X). The organic phases were washed

combined with brine (1 X), dried over anhydrous sodium sulfate and concentrated in vacuo to give

2,3,3 ', 4', 5,6-hexahydrospiro [pyran-4,2'-pyrano [3,2-b] pyridin] -4'-ol (52) (4.6 g, 84% of yield) as an oil

colorless. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 8.16 (1 H, dd, J = 3.9, 2.0 Hz), 7.17 - 7.27 (2 H, m), 5, 45 (1 H, d, J = 4.3 30 Hz), 4.63-4.71 (1 H, m), 3.60-3.73 (4 H, m), 2.17 (1 H , dd, J = 14.1, 6.3 Hz), 1.97 (1 H, dd, J = 14.1, 6.7 Hz), 1.59 -

1.86 (4 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 222.1.

2,3,5,6-Tetrahydrospiro [piran-4,2'-pyrano [3,2-b] pyridine] (53) Burgess reagent (1.6 g, 6.6 mmol) was added in one portion a a stirred solution of 2,3,3 ', 4', 5,6-hexahydrospiro [pyran-4,2'-pyrano [3,2-b] pyridin] -4'-ol (52) (1.2 g , 5.5 mmol) in benzene (30 ml) at rt. The resulting mixture was stirred at rt for 20 min. and then refluxed 5 for 1.5 h. The mixture was poured into ice and 2N aqueous NaOH solution, extracted with EtOAc (3 X), dried over Na2SO4 and concentrated in vacuo. The residue was purified by Combi-flash column chromatography (EtOAc / hexanes) to give 2,3,5,6-tetrahydrospiro [pyran-4,2'-pyran [3,2-b] pyridine] (53) (0 , 40 g, 36% yield) as a colorless liquid. 1 H-NMR (400 MHz, CHLOROFORM-d) 8 ppm 8.11 (1 H, dd, J = 4.7, 1.6 Hz), 7.10 - 7.15 (1 H, m), 7, 05 (1 H, dd, J = 8.4, 4.7 Hz), 6.59 (1 H, d, J = 10.6 Hz), 5.88 (1 H, d, J = 9.8 Hz), 3.86 - 3.96 (2 H, m), 3.75 -

10 3.82 (2 H, m), 1.94 - 2.03 (2 H, m), 1.77 - 1.88 (2 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 204.1.

1a, 2 ', 3', 5 ', 6', 7b-Hexahydrospiro [oxyrene [4,5] pyran [3,2-b] pyridine-2,4'-pyran] (54) NBS (0, 85 g, 4.8

mmol) in 4 portions over a period of 10 min. to a stirred solution of (53) (0.81 g, 4.0 mmol) in

mixed solvents of t-BuOH (10 ml) and water (14 ml) and stirred at rt for 3 h. Then, a solution of NaOH (0.236 g, 5.90 mmol) in water (12 ml) was added and stirred at rt for 100 min. The product was extracted in t-butylmethyl

ether (2 X), dried over Na2SO4 and concentrated in vacuo to give 1a, 2 ’, 3’, 5 ’, 6’, 7b

hexahydrospiro [oxireno [4,5] pyrano [3,2-b] pyridin-2,4’-pyrano] (54) (0.77 g, 88% yield) as a film

colorless that was used in the next step without further purification. 1H-NMR (400 MHz, CHLORFORM-d) 8 ppm

8.14 (1 H, dd, J = 4.5, 1.8 Hz), 7.11 - 7.20 (2 H, m), 4.07 (1 H, d, J = 4.3 Hz ), 3.85-3.97 (2 H, m), 3.63-3.77 (2 H, m), 20 3.54 (1 H, d, J = 4.3 Hz), 1, 96 - 2.03 (2 H, m), 1.71 - 1.82 (1 H, m), 1.42 (1 H, dd, J = 14.1, 2.3 Hz). CLEM-ESI (POS),

M / Z, M + 1: Found 220.0.

2,3,5,6-Tetrahydrospiro [piran-4,2'-pyrano [3,2-b] pyridin] -3 '(4'H) -one (55) A solution of 1a, 2 was refluxed ', 3', 5 ', 6', 7b-hexahydrospiro [oxireno [4,5] pyrano [3,2-b] pyridin-2,4'-pyrano] (54) (0.77 g, 3.5 mmol) and acid p

25 toluenesulfonic monohydrate (0.73 g, 3.9 mmol) in toluene (50 ml) for 1.5 h. After cooling, the reaction mixture was poured into ice and saturated aqueous NaHCO3 solution and then extracted with EtOAc (3 X). The organic phase was dried over Na2SO4 and concentrated in vacuo to give 2,3,5,6-tetrahydrospiro [pyran-4,2'-pyran [3,2-b] pyridin] 3 '(4'H) -one (55) (0.66 g, 86% yield) as a dark film that was used in the next step without further purification. CLEM-ESI (POS), M / Z, M + 1: Found 220.0.

2,3,5,6-Tetrahydrospiro [pyran-4,6'-pyrido [2 ', 3': 5,6] pyrano [3,4-d] pyrimidin] -8'-amine (56) A 2,3,5,6-tetrahydrospiro [pyran-4,2'-pyrano [3,2-b] pyridin] -3 '(4'H) -one (55) (0.61 g, 2, 78 mmol) in tert-butoxy-bis (dimethylamino) methane (1.15 ml, 5.6 mmol) at 105 ° C for 1.5 h then lowered to 80 ° C. N-propanol (15 ml), guanidine hydrochloride (1.33 g, 13.9 mmol) and sodium methanolate (1.9 ml, 8.3 mmol) were added sequentially. The mixture was stirred at 80 ° C overnight. After the final treatment, the reaction mixture was poured into ice and saturated aqueous NaHCO3 solution and extracted with EtOAc (3 X). The combined organic phases were dried over Na2SO4 and concentrated in vacuo and purified by Combi-flash chromatography (EtOAc / hexanes) to give 2,3,5,6-tetrahydrospiro [pyran-4,6'-pyrido [2 ', 3 ': 5.6] pyran [3,4-d] pyrimidin] -8'-amine (56) (150

10 mg) as an off-white solid. 1 H-NMR (400 MHz, CHLOROFORM-d) 8 ppm 9.10 (1 H, s), 8.25 (1 H, dd, J = 4.7, 1.2 Hz), 7.30 (1 H , dd, J = 8.0, 1.4 Hz), 7.15 (1 H, dd, J = 8.2, 4.7 Hz), 5.24 (2 H, s), 3.88 - 4.01 (4 H, m), 2.26 - 2.40 (2 H, m), 1.81 - 1.92 (2 H, m, J = 14.1, 2.0 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 271.0.

4- (4- (2,3,5,6-Tetrahydrospiro [pyran-4,6'-pyrido [2 ', 3': 5,6] pyrano [3,4-d] pyrimidin] -8'-ylamino ) phenyl) -1

15 piperazinecarboxylate (57) A 10 ml single-bottom round bottom flask was loaded with 2,3,5,6-tetrahydrospiro [pyran-4,6'-pyrido [2 ', 3': 5.6] pyran [3 , 4-d] pyrimidin] -8'-amine (56) (0.12 g, 0.44 mmol), tert-butyl 4- (4-iophenyl) piperazin-1-carboxylate (0.26 g, 0.67 mmol), tris (dibenzylideneacetone) dipaladium (o) (4.1 mg, 0.0044 mmol), 9.9-dimethyl-4,5-bis (diphenylphosphino) xanthene (7.7 mg, 0.013 mmol) and t- sodium butoxide (60 mg, 0.62 mmol). Then, the flask was subjected to 3 evacuation cycles and refilled with N2. Then, it was introduced

1,4-dioxane (3 ml) through a syringe under N2. The resulting crude mixture was then stirred at reflux for 17

h. The mixture was cooled to rt and subjected to Combi-flash column chromatography (EtOAc / hexanes) to give 4 (4- (2,3,5,6-tetrahydrospiro [pyran-4,6'-pyrido [2 ', 3 ': 5,6] pyran [3,4-d] pyrimidin] -8'-ylamino) phenyl) -1-piperazinecarboxylate

(57) pure (0.055 g, 23% yield) as a light yellow film, which was used in the next stage. CLEM-ESI (POS), M / Z, M + 1: Found 531.2.

N- (4- (1-Piperazinyl) phenyl) -2,3,5,6-tetrahydrospiro [pyran-4,6'-pyrido [2 ', 3': 5.6] pyran [3,4-d] pyrimidin] -8'-amine (48)

A mixture of 4- (4- (2,3,5,6-tetrahydrospiro [pyran-4,6'-pyrido [2 ', 3': 5.6] pyran [3,4-d] pyrimidin] was stirred -8'-ylamino) phenyl) 1-piperazinecarboxylate (57) (0.055 g, 0.10 mmol) and TFA (2.00 ml, 26 mmol) in DCM (15 ml) at rt for 2 h. After removing the volatile compounds in vacuo, the residue was dissolved in EtOAc, poured into ice and 2N NaOH aqueous solution, and extracted with EtOAc (2 X). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was triturated with EtOAc / hexanes to give N- (4- (1-piperazinyl) phenyl) -2,3,5,6 tetrahydrospiro [pyran-4,6'-pyrido [2 ', 3': 5.6] pyrano [3,4-d] pyrimidin] -8'-amine (48) (0.050 g) as a light yellow solid. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 9.89 (1 H, s) , 9.11 (1 H, s), 8.31 (1 H, dd, J = 4.7, 1.6 Hz), 7.66 (2 H, d, J = 9.0 Hz), 7 , 55 (1 H, dd, J = 8.0, 1.4 Hz), 7.33 (1 H, dd, J = 8.2, 4.7 Hz), 6.98 (2 H, d, J = 9.0 Hz), 3.81-3.97 (4 H, m), 3.02-3.11 (4 H, m), 2.85-2.95 (4 H, m), 2.20 - 2.33 (2 H, m), 1.91 (2 H, d, J = 13.7 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 432.1.

Example 26

4,4-dimethylspiro [cyclohexane-1,5’-pyrido [3 ’, 2’: 5,6] pyrano [3,4-d] pyrimidin] -3’-amine

1-Ethynyl-4,4-dimethylcyclohexanol (59) A 250 ml dry single-bottom round bottom flask was charged with ethynylmagnesium bromide, 0.5 M solution in THF (105 ml, 52 mmol). This solution was cooled in an ice-H2O bath while a solution of 4,4-dimethylcyclohexanone (6.0 g, 48 mmol) in THF (100 mL) was added dropwise through an addition funnel over of a period of 20 min. The resulting mixture was stirred at 0 ° C and then gradually heated to room temperature overnight. The mixture was poured onto ice and saturated aqueous NH4Cl solution and extracted with EtOAc (2 X). The combined organic phases were washed with brine (1 X), dried over Na2SO4 and concentrated in vacuo to give 1-ethynyl-4,4-dimethylcyclohexanol (59) (6.7 g, 93% yield) as a solid. off-white (the product tends to sublimate). 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 5.24 (1 H, s), 3.31 (1 H, s), 1.50 - 1.69 (4 H, m), 1.22 - 1.40 (4 H, m), 0.87 (6 H, d, J = 3.1 Hz).

1- (2- (2-Fluoropyridin-3-yl) ethynyl) -4,4-dimethylcyclohexanol (61) A 250 ml single-bottom round bottom flask was charged with 1-ethynyl-4,4-dimethylcyclohexanol ( 59) (6.7 g, 44 mmol), trans-dichlorobis (triphenyl phosphine) palladium (ii) (1.4 g, 2.0 mmol), and copper iodide (i) (0.76 g, 4 , 0 mmol) followed by triethylamine (100 ml, 716 mmol). The flask was then purged with N2 for 10 min. before introducing 3-bromo-2-fluoropyridine (60) (7.00 g, 40 mmol). The purge was continued with N2 for 15 min. and the resulting mixture was stirred at 105 ° C overnight. After cooling, the reaction mixture was filtered through a layer of Celite and the cake was washed with DCM (500 ml). The filtrate was concentrated in vacuo and the crude residue was subjected to Combi-flash column chromatography (EtOAc / hexanes) to give 1- (2- (2-fluoropyridin-3-yl) ethynyl) -4,4-dimethylcyclohexanol (61 ) (9.5 g, 97% yield) as an oil. 1 H-NMR (500 MHz, CHLORFORM-d) 8 ppm 8.12 - 8.19 (1 H, m), 7.79 - 7.86 (1 H, m), 7.14 - 7.19 (1 H, m), 2.05 (1 H,

s), 1.90 - 1.98 (2 H, m), 1.80 - 1.88 (2 H, m), 1.40 - 1.60 (4 H, m), 0.97 (6 H, d, J = 3.7 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 248.1

(Z) -1- (2- (2-Fluoropyridin-3-yl) vinyl) -4,4-dimethylcyclohexanol (62) A 1 l round-bottom round bottom flask was charged with 1- (2- ( 2-fluoropyridin-3-yl) ethynyl) -4,4-dimethylcyclohexanol (61) (3.5 g, 14 mmol) dissolved in EtOAc (70 ml) and quinoline (1.7 ml, 14 mmol). The flask was briefly purged with N2 before adding the Lindlar catalyst (5% Pd in CaCO3 contaminated with Pb) (1.5 g, 14 mmol). The resulting mixture was subjected to 3 evacuation cycles and refilled with H2 and then subjected to balloon hydrogenation for 5 h. Another 1 equivalent of Lindlar catalyst (5% Pd in CaCO3 contaminated with Pb) (1.5 g, 14 mmol) was added and balloon hydrogenation was continued over the weekend (2 days). The reaction was quenched with DCM (100 ml) followed by vacuum filtration through a layer of Celite. The cake was washed thoroughly with more DCM. After concentration in vacuo, the residue was subjected to Combi-flash column chromatography (EtOAc / hexanes) to give (Z) -1- (2- (2-fluoropyridin-3-yl) vinyl) -4,4-dimethylcyclohexanol ( 62) (~ 1.6 g) as an almost colorless liquid, (which contained some unreacted starting material (61).) This product was used in the next step. CLEM-ESI (POS), M / Z, M + 1: Found 250.1

4,4-Dimethylspiro [cyclohexane-1,2'-pyran [2,3-b] pyridine] (63) Sodium hydride (60% dispersion in mineral oil, 0.40 g, 11 mmol) was added in a portion to a stirred solution at rt of (Z) -1- (2- (2-fluoropyridin-3-yl) vinyl) 4,4-dimethylcyclohexanol (62) impure (2.2 g, 8.8 mmol) in DMF (90 ml). The resulting mixture was stirred at rt for 5 min. and then heated at 90 ° C for 1 h. After cooling, the mixture was poured into ice cold saturated NaHCO3 aqueous solution and extracted with EtOAc (2 X). The combined organic phases were washed with brine (1 X), dried over Na2SO4 and concentrated in vacuo. Purification by Combi-flash column chromatography (EtOAc / hexanes) gave 4,4-dimethylspiro [cyclohexane-1,2'-pyran [2,3-b] pyridine] (63) (0.7 g, ~ 85% yield) as a light yellow solid. 1 H-NMR (400 MHz, CHLOROFORM-d) 8 ppm 8.02 (1 H, dd, J = 5.1, 2.0 Hz), 7.25 (1 H, dd, J = 7.0, 2 , 0 Hz), 6.80 (1 H, dd, J = 7.0, 5.1 Hz), 6.31 (1 H, d, J = 9.8 Hz), 5.70 (1 H, d, J = 9.8 Hz), 1.92

-

 2.04 (2 H, m), 1.73 - 1.84 (2 H, m), 1.60 - 1.72 (2 H, m), 1.19 - 1.30 (2 H, m ), 1.01 (3 H, s), 0.95 (3 H, s). CLEM-ESI (POS), M / Z, M + 1: Found 230.2

4,4-Dimethyl-1a ', 7b'-dihydrospiro [cyclohexane-1,2'-oxyrene [4,5] pyran [2,3-b] pyridine] (64) NBS (0.62 g, 3 , 5 mmol) in 2 portions over a period of 10 min. to a stirred solution of 4,4-dimethylspiro [cyclohexane-1,2'-pyran [2,3-b] pyridine] (63) (0.70 g, 3.1 mmol) in a mixed solvent of t-BuOH (20 ml) and H2O (10 ml) at rt. Stirring at rt was continued until LC-MS showed completion of bromohydrin formation. An aqueous solution of sodium hydroxide (0.37 g, 9.2 mmol) (10 ml) was added to the reaction mixture. Stirring at rt continued for 3 h at which time LC-MS showed the completion of epoxy formation. After the final treatment, the mixture was poured into saturated aqueous NaHCO3 solution and extracted with EtOAc (3 X). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give 4,4dimethyl-1a ', 7b'-dihydrospiro [cyclohexane-1,2'-oxyrene [4,5] pyran [2,3-b] pyridine ] (64) crude (0.88 g,> 95% yield) as a colorless oil that was used in the next step without further purification. 1H-NMR (500 MHz, CHLORFORM-d) 8 ppm 8.22 (1 H, dd, J = 5.1, 2.0 Hz), 7.69 (1 H, dd, J = 7.3, 2 , 0 Hz), 6.92 (1 H, dd, J = 7.2, 5.0 Hz), 3.90 (1 H, d, J = 4.2 Hz), 3.55 (1 H, d, J = 4.2 Hz), 2.07 - 2.12 (1 H, m), 1.81 - 1.92 (2 H, m), 1.61 - 1.73 (2 H, m ), 1.49 - 1.56 (1 H, m), 1.36 - 1.41 (1 H, m), 1.20 - 1.26 (1 H, m), 1.02 (3 H , s), 0.98 (3 H, s). CLEM-ESI (POS), M / Z, M + 1: Found 246.1

4,4-Dimetilespiro [cyclohexane-1,2’-pyrano [2,3-b] pyridin] -3 ’(4’H) -one (65) A solution of reflux was heated to reflux

4,4-dimethyl-1a ', 7b'-dihydrospiro [cyclohexane-1,2'-oxyrene [4,5] pyran [2,3-b] pyridine] (64) (0.75 g, 3.1 mmol ) and tosylate

of pyridinium (0.88 g, 3.5 mmol) in toluene (20 ml) for 2 h. After cooling, the mixture was poured into ice 10 and saturated aqueous NaHCO3 solution and extracted with EtOAc (2 X). The combined organic phases were washed

with aqueous solution of saturated NaHCO3 (3 X) followed by brine (1 X), dried over Na2SO4 and dried

concentrated in vacuo to give 4,4-dimethylspiro [cyclohexane-1,2'-pyrano [2,3-b] pyridin] -3 '(4’H) -one (65) crude (0.53 g,

71% yield), which was used in the next stage without purification. 1H-NMR (400 MHz, CHLORFORM-d) 8

ppm 8.23 (1 H, dd, J = 4.9, 1.8 Hz), 7.46 (1 H, dd, J = 7.4, 2.0 Hz), 7.02 (1 H, dd, J = 7.4, 5.1 Hz), 3.61 (2 H, s), 1.75 15 1.97 (4 H, m), 1.61 - 1.69 (2 H, m ), 1.24 -1.32 (2 H, m), 1.02 (3 H, s), 0.97 (3 H, s). CLEM-ESI (POS), M / Z, M + 1:

Found 246.1, Calculated 246.14.

4,4-Dimethylspiro [cyclohexane-1,5'-pyrido [3 ', 2': 5.6] pyran [3,4-d] pyrimidin] -3'-amine (58) A solution of reflux was heated to reflux 4,4-dimethylspiro [cyclohexane-1,2'-pyran [2,3-b] pyridin] -3 '(4'H) -one (65) (0.88 g, 3.6 mmol) and tert- butoxy20 bis (dimethylamino) methane (1.6 ml, 7.9 mmol) in 2.5 ml of THF for 30 min. After a brief cooling, n-propanol (15 ml), guanidine hydrochloride (2.1 g, 22 mmol) and sodium methoxide in MeOH (4.37 M) (2.5 ml, 11 mmol) were added sequentially . The resulting mixture was stirred at 85 ° C for 40 min. After the final treatment, the mixture was poured into ice and saturated aqueous NaHCO3 solution and extracted with EtOAc (2 X). The combined organic phases were washed with aqueous saturated NaHCO3 solution (1 X) followed by brine (1 X), dried over Na2SO4 and concentrated in vacuo. Purification by Combi-flash column chromatography (EtOAc / hexanes) gave 4,4-dimethylspiro [cyclohexane-1,5'-pyrido [3 ', 2': 5.6] pyran [3,4-d] pyrimidin] -3'-amine (58) (0.23 g, 30% yield from compound (63)) as an off-white solid. 1 H-NMR (500 MHz, CHLOROFORM) 8 ppm 8.61 (1 H, s), 8.19 (1 H, dd, J = 4.9, 2.0 Hz), 7.89 (1 H, dd , J = 7.6, 2.0 Hz), 7.01 (1 H, dd, J = 7.6, 4.9 Hz), 5.26 (2 H, sa), 2.11-2, 20 (2 H, m), 1.82 - 1.97 (4 H, m), 1.27 - 1.34 (2 H, m), 1.05 (3 H, s), 1.02 ( 3 H, s). CLEM-ESI

30 (POS), M / Z, M + 1: Found 297.0.

Example 27

4,4-dimethyl-N- (5- (1-piperazinyl) -2-pyridinyl) spiro [cyclohexane-1,5'-pyrido [3 ', 2': 5.6] pyran [3,4-d] pyrimidin] -3'amine

4- (6 - ((4,4-Dimethylspiro [cyclohexane-1,5'-pyrido [3 ', 2': 5.6] pyran [3,4-d] pyrimidin] -3'-yl) amino) -3-pyridinyl) -1

5 tert-butyl piperazinecarboxylate (68) A 25 ml single-bottom round bottom flask was charged with 4,4-dimethylspiro [cyclohexane-1,5'-pyrido [3 ', 2': 5.6] pyran [3 , 4-d] pyrimidin] -3'-amine (58) (56 mg, 189 µmol), tert-butyl 4- (6-chloropyridin-3-yl) piperazin-1-carboxylate (67) (68 mg, 227 ! mol), tris (dibenzylideneacetone) -dipaladium (o) (8.7 mg, 9.4! mol), 9,9-dimethyl-4,5-bis (diphenylphosphino) -xanthene (14 mg, 24! mol) , 1,4-dioxane (2 ml) and sodium tert-butoxide (54 mg, 567 µmol). The vessel was subjected to 3 evacuation cycles and refilled with N2 before

10 add 1,4-dioxane under N2. The mixture was stirred at reflux under N2 for 2.5 h at which time the LC-MS showed completion. After removing volatile compounds, the residue was purified by Combiflash column chromatography (MeOH / DCM) to give 4- (6 - ((4,4-dimethylspiro [cyclohexane-1,5'-pyrido [3 ', 2': 5,6] pyran [3,4-d] pyrimidin] -3'yl) amino) -3-pyridinyl) -1-piperazinecarboxylate tert-butyl (68) (100 mg, 95% yield) as an off-white solid . CLEM-ESI (POS), M / Z, M + 1: Found 558.3.

Tert-Butyl 4- (6-Chloropyridin-3-yl) piperazin-1-carboxylate (67) A 250 ml single-bottom round bottom flask was charged with 5-bromo-2-chloropyridine (11.4 g , 59.2 mmol), tert-butyl 1-piperazinecarboxylate (11.0 g, 59.2 mmol), tris (dibenzylideneacetone) dipaladium (o) (0.542 g, 0.592 mmol), 9.9-dimethyl-4, 5-bis (diphenylphosphino) xanthene (1.03 g, 1.78 mmol) and sodium t-butoxide (8.54 g, 88.9 mmol). The flask was subjected to 3 evacuation cycles and again filled with N2 before introducing toluene (100 ml) under N2. The resulting mixture was stirred at 100 overnight. After cooling, the product was purified by Combi-flash column chromatography (EtOAc / hexanes) to give tert-butyl 4- (6-chloropyridin-3-yl) piperazin-1-carboxylate (66) (12.7 g , 72.0% yield) as an off-white solid. 1 H-NMR (500 MHz, DMSO-d6) 8 ppm 8.08 (1 H, d, J = 3.2 Hz), 7.43 (1 H, dd, J = 8.8, 3.2 Hz) , 7.31 (1 H, d, J = 8.8 Hz), 3.42 - 3.49 (4 H, m), 3.14 - 3.21 (4 H, m), 1.42 ( 9 H, s). CLEM-ESI (POS),

25 M / Z, M + 1: Found 298.1 4,4-Dimethyl-N- (5- (1-piperazinyl) -2-pyridinyl) spiro [cyclohexane-1,5'-pyrido [3 ', 2' : 5,6] pyrano [3,4-d] pyrimidin] -3'amine (66) Trifluoroacetic acid (2 ml, 26.9 mmol) was added to a stirred solution of 4- (6 - ((4,4-dimethylspiro) [cyclohexane-1,5'-pyrido [3 ', 2': 5,6] pyran [3,4-d] pyrimidin] -3'-yl) amino) -3-pyridinyl) -1-piperazinecarboxylate of

5-tert-butyl (68) (100 mg, 0.18 mmol) in DCM (8 ml) at rt and stirred overnight. After the final treatment, the mixture was poured into ice and 4 N aqueous HCl solution, extracted with 10% i-PrOH / chloroform (3 X) and dried over Na2SO4. After concentration in vacuo, the residue was triturated with EtOAc / hexanes to give 4,4-dimethyl-N (5- (1-piperazinyl) -2-pyridinyl) spiro [cyclohexane-1,5'-pyrido [3 ' , 2 ': 5,6] pyran [3,4-d] pyrimidin] -3'-amine (66) pure (80 mg, 98% yield) (93% r. In 2 steps) as an off-white solid. 1 H-NMR (500 MHz, DMSO-d6) 8 ppm 9.85 (1

10 H, s), 9.06 (1 H, s), 8.29 (1 H, dd, J = 7.6, 1.7 Hz), 8.11 (1 H, dd, J = 4, 9, 2.0 Hz), 8.03 (1 H, d, J = 9.3 Hz), 8.00 (1 H, d, J = 2.9 Hz), 7.40 (1 H, dd , J = 9.2, 3.1 Hz), 7.12 (1 H, dd, J = 7.6, 4.9 Hz), 3.00 - 3.09 (4 H, m), 2, 82 - 2.90 (4 H, m), 2.09

-

 2.19 (2 H, m), 1.81 (2 H, d, J = 13.4 Hz), 1.66 - 1.77 (2 H, m), 1.30 (2 H, d, J = 13.0 Hz), 1.01 (6 H, d, J = 2.0 Hz). EM-CLEM-ESI (POS), M / Z, M + 1: Found 458.0.

Example 28

4,4-dimethyl-N- (6- (1-piperazinyl) -3-pyridinyl) spiro [cyclohexane-1,5'-pyrido [3 ', 2': 5.6] pyran [3,4-d] pyrimidin] -3'amine (tri-TFA salt)

The title compound (69) was prepared from the compound (58) using chemistry similar to that described in the example

27. 1H-NMR (400 MHz, MeOH-d4) (taken as a TFA salt) 8 ppm 8.97 (1 H, s), 8.75 (1 H, d, J = 2.7 Hz), 8.35

20 (1 H, dd, J = 7.8, 1.6 Hz), 8.17 (1 H, dd, J = 9.4, 2.7 Hz), 8.13 (1 H, dd, J = 5.3, 1.8 Hz), 7.19 - 7.27 (2 H, m), 3.80 - 3.90 (4 H, m), 3.38 - 3.45 (4 H, m), 2.18 - 2.34 (2 H, m), 1.81 - 1.99 (4 H, m), 1.35 (2 H, d, J = 13.7 Hz), 1, 06 (6 H, d, J = 2.7 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 458.2.

Example 29

N- (4- (1-piperazinyl) phenyl) spiro [cyclohexane-1,5’-pyrido [3 ’, 2’: 5,6] pyrano [3,4-d] pyrimidin] -3’-amine

The title compound (70) was prepared using chemistry similar to that described in examples 26 and 27. 1 H-NMR (400

MHz, DMSO-d6) 8 ppm 9.67 (1 H, s), 9.00 (1 H, s), 8.26 (1 H, dd, J = 7.8, 2.0 Hz), 8 , 10 (1 H, dd, J = 4.9, 1.8 Hz), 7.59 (2 H, d, J = 9.0 Hz), 7.11 (1 H, dd, J = 7, 4, 5.1 Hz), 6.89 (2 H, d, J = 9.4 Hz), 2.95 - 3.03 (4 H, m), 2.79 - 2.87 (4 H, m), 1.20 - 1.97 (10 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 429.2.

Example 30

N- (6- (1-piperazinyl) -3-pyridinyl) spiro [cyclohexane-1,5'-pyrido [3 ', 2': 5,6] pyran [3,4-d] pyrimidin] -3'- amine

The title compound (71) was prepared using chemistry similar to that described in examples 26 and 27. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 9.67 (1 H, s), 8.99 (1 H, s), 8.45 (1 H, d, J = 2.7 Hz), 8.26 (1 H, dd, J = 7.6, 1.8 Hz), 8.10 (1 H, dd, J = 4.9, 1.8 Hz), 7.87 (1 H, dd, J = 9.4, 2.7 Hz), 7.11 (1 H, dd, J = 7.6, 4.9 Hz), 6.81 (1 H, d, J = 9.0 Hz), 3.31 - 3.35 (4

10 H, m), 2.74-2.83 (4 H, m), 1.26-1.96 (10 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 430.1.

Example 31

N- (5- (1-piperazinyl) -2-pyridinyl) spiro [cyclohexane-1,5'-pyrido [3 ', 2': 5,6] pyran [3,4-d] pyrimidin] -3'- amine

The title compound (72) was prepared using chemistry similar to that described in examples 26 and 27. 1 H-NMR (500

15 MHz, DMSO-d6) 8 ppm 10.61 (1 H, sa), 9.13 (1 H, s), 8.86 (2 H, sa), 8.37 (1 H, dd, J = 7.6, 1.7 Hz), 8.17 (1 H, dd, J = 4.9, 1.7 Hz), 8.07 (1 H, d, J = 2.9 Hz), 7, 96 (1 H, d, J = 9.0 Hz), 7.77 (1 H, dd, J = 9.4, 2.6 Hz), 7.16 (1 H, dd, J = 7.6 , 4.9 Hz), 3.35-3.42 (4 H, m), 3.23 - 3.32 (4 H, m), 1.89-2.00 (4 H, m), 1 , 72-1.86 (3 H, m), 1.64 (2 H, da, J = 9.3 Hz), 1.25-1.42 (1 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 430.1.

Example 32

2,3,5,6-tetrahydrospiro [piran-4,5’-pyrido [3 ’, 2’: 5,6] pyrano [3,4-d] pyrimidin] 3’-amine

The title compound (73) was prepared using chemistry similar to that described in example 26. 1H-NMR (400 MHz, DMSO-d6) 8 ppm 8.87 (1 H, s), 8.22 (1 H, dd, J = 7.4, 2.0 Hz), 8.08 (1 H, dd, J = 4.9, 1.8 Hz), 7.05 - 7.13 (3 H, m), 3 , 72

-

 3.85 (4 H, m), 2.09-2.23 (2 H, m), 1.75 (2 H, d, J = 12.1 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 271.1.

Example 33

N- (4- (1-piperazinyl) phenyl) -2,3,5,6-tetrahydrospiro [pyran-4,5'-pyrido [3 ', 2': 5,6] pyran [3,4-d] pyrimidin] -3'-amine

The title compound (74) was prepared from the compound (73) using chemistry similar to that described in the example

27. 1H-NMR (400 MHz, DMSO-d6) 8 ppm 9.74 (1 H, sa), 9.03 (1 H, s), 8.29 (1 H, dd, J = 7.6, 1.8 Hz), 8.12 (1 H, dd, J = 4.9, 1.8 Hz), 7.59 (2 H, d, J = 9.0 Hz), 7.14 (1 H , dd, J = 7.6, 4.9 Hz), 6.91 (2 H, d, J = 9.4 Hz), 3.78 - 3.89 (4 H, m), 2.95 - 3.04 (4 H, m), 2.76 - 2.86 (4 H, m), 2.16 - 2.28 (2 H, m), 1.76 - 1.88 (2 H, m ). CLEM-ESI (POS), M / Z, M + 1: Found 431.2

Example 34

N- (5- (1-piperazinyl) -2-pyridinyl) -2,3,5,6-tetrahydrospiro [pyran-4,5'-pyrido [3 ', 2': 5,6] pyran [3,4 -d] pyrimidin] -3'amine

The title compound (75) was prepared from the compound (73) using chemistry similar to that described in the example

27. 1H-NMR (400 MHz, DMSO-d6) 8 ppm 9.90 (1 H, s), 9.09 (1 H, s), 8.33 (1 H, dd, J = 7.8, 2.0 Hz), 8.14 (1 H, dd,

15 J = 4.9, 1.8 Hz), 7.97 - 8.06 (2 H, m), 7.46 (1 H, dd, J = 9.0, 3.1 Hz), 7, 16 (1 H, dd, J = 7.4, 5.1 Hz), 3.79-3.90 (4 H, m), 3.00 - 3.09 (4 H, m), 2.79 - 2.90 (4 H, m), 2.15 - 2.31 (2 H, m), 1.71 - 1.90 (2 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 432.2.

Example 35

2,2-Dimethyl-N- (4- (1-piperazinyl) phenyl) -2,3,5,6-tetrahydrospiro [pyran-4,5'-pyrido [3 ', 2': 5.6] pyran [3,4-d] pyrimidin] 3'-amine (racemic)

The title compound (76) was prepared using chemistry similar to that described in examples 26 and 27. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 9.73 (1 H, s), 9.03 (1 H, s), 8.29 (1 H, dd, J = 7.6, 1.8 Hz), 8.13 (1 H, dd, J = 4.9, 1.8 Hz), 7.58 (2 H, d, J = 9.0 Hz), 7.14 (1 H, dd, J = 7.4, 4.7 Hz), 6.90 (2 H, d, J = 9.4 Hz ), 4.00 - 4.13 (1 H, m), 3.73 (1 H, dd, J = 11.7,

25 3.9 Hz), 2.91 - 3.03 (4 H, m), 2.78 - 2.88 (4 H, m), 2.26 - 2.37 (1 H, m), 1 , 79-1.90 (3 H, m), 1.45 (3 H, s), 1.12 (3 H, s). CLEM-ESI (POS), M / Z, M + 1: Found 459.2.

Example 36

(4S) -2,2-dimethyl-N- (4- (1-piperazinyl) phenyl) -2,3,5,6-tetrahydrospiro [pyran-4,5'-pyrido [3 ', 2': 5, 6] pyrano [3,4d] pyrimidin] -3'-amine

5th

(4R) -2,2-dimethyl-N- (4- (1-piperazinyl) phenyl) -2,3,5,6-tetrahydrospiro [pyran-4,5'-pyrido [3 ', 2': 5, 6] pyrano [3,4d] pyrimidin] -3'-amine

The title compound (77) was prepared using chemistry similar to that described in examples 26 and 27. 1 H-NMR (500

10 MHz, DMSO-d6) 8 9.83 (1H, s), 9.06 (1H, s), 8.76 (2H, sa), 8.32 (1H, dd, J1 = 7.8 Hz, J2 = 2.0 Hz), 8.15 (1H, dd, J1 = 4.8 Hz, J2 = 1.9 Hz), 7.66 (2H, da, J = 9.1 Hz), 7.16 (1H, dd, J1 = 7.6, J2 = 4.9 Hz), 7.00 (2H, da, J = 9.1 Hz), 4.09 (1H, dt, J1 = 12.4 Hz, J2 = 1.7 Hz), 3.74 (1H, ddd, J1 = 11.7 Hz, J2 = 5.4 Hz, J3 = 1.5 Hz), 3.30 (4H, m), 3.26 (4H, m), 2.33 (1H, ddd, J1 = 13.5 Hz, J2 = 14.2 Hz, J3 = 5.4 Hz), 1.87 (3H, m), 1.46 (3H , s), 1.13 (3H, s). CLEM-ESI (POS), M / Z, M + 1: Found 459.2.

15 Example 37 (4R) -2,2-dimethyl-N- (4- (1-piperazinyl) phenyl) -2,3,5,6-tetrahydrospiro [pyran-4,5'-pyrido [3 ', 2': 5, 6] pyrano [3,4d] pyrimidin] -3'-amine

or

(4S) -2,2-dimethyl-N- (4- (1-piperazinyl) phenyl) -2,3,5,6-tetrahydrospiro [pyran-4,5'-pyrido [3 ', 2': 5, 6] pyrano [3,4d] pyrimidin] -3'-amine

The title compound (78) was prepared using chemistry similar to that described in examples 26 and 27. 1 H-NMR (500

5 MHz, DMSO-d6) 8 9.82 (1H, s), 9.05 (1H, s), 8.73 (2H, sa), 8.30 (1H, dd, J1 = 7.6 Hz, J2 = 1.7 Hz), 8.14 (1H, dd, J1 = 4.9 Hz, J2 = 1.9 Hz), 7.65 (2H, da, J = 9.1 Hz), 7.14 (1H, dd, J1 = 7.3 Hz, J2 = 4.7 Hz), 6.99 (2H, da, J = 9.0 Hz), 4.07 (1H, dt, J1 = 11.9, J2 = 1.7 Hz), 3.73 (1H, ddd, J1 = 11.3 Hz, J2 = 5.4 Hz, J3 = 1.2 Hz), 3.29 (4H, m), 3.25 (4H, m), 2.23 (1H, ddd, J1 = 13.4 Hz, J2 = 14.5 Hz, J3 = 5.7 Hz), 1.83 (3H, m), 1.45 (3H , s), 1.12 (3H, s); CLEM-ESI (POS), M / Z, M + 1: Found 459.2.

10 Example 38

diespiro [1,3-dioxolane-2,1’-cyclohexane-4 ’, 5” -pyrido [3 ’, 2’: 5,6] pyrano [3,4-d] pyrimidin] -3 ’- amina

The title compound (79) was prepared using chemistry similar to that described in examples 26 and 27. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 8.84 (1 H, s), 8.20 (1 H, dd, J = 7.8, 2.0 Hz), 8.06 (1 H, dd, J = 4.9, 1.8 Hz), 6.99 - 7.12 (3 H, m) , 15 3.91 (4 H, s), 2.11 - 2.23 (2 H, m), 1.80 - 1.99 (4 H, m), 1.57 - 1.70 (2 H , m). CLEM-ESI (POS), M / Z, M + 1: Found 327.1

Example 39

 3’-amino-4H-spiro [cyclohexane-1,5’-pyrido [3 ’, 2’: 5,6] pyrano [3,4-d] pyrimidin] -4-one

3'-Amino-4H-spiro [cyclohexane-1,5'-pyrido [3 ', 2': 5,6] pyran [3,4-d] pyrimidin] -4-one (80) A solution of di-spiro [1,3-dioxolane-2,1'-cyclohexane-4 ', 5' '- pyrido [3', 2 ': 5,6] pyrano [3,4-d] pyrimidin] -3' ' -amine (79) (0.50 g, 1.5 mmol) in THF (40 ml) and HCl (2 N aqueous, 20 ml, 20 mmol) at rt overnight. After the final treatment, the mixture was poured into ice and 2N aqueous NaOH solution and saturated NaHCO3 aqueous solution and extracted with EtOAc (3 X). The combined organic phases were washed with brine (2 X), dried over Na2SO4 and concentrated in vacuo. The residue was triturated with EtOAc / hexanes to give 3'-amino-4H-spiro [cyclohexane-1,5'pyrido [3 ', 2': 5.6] pyran [3,4-d] pyrimidin] -4- one (80) (0.41 g, 95% yield) as a yellow solid. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 8.90 (1 H, s), 8.26 (1 H, dd, J = 7.4, 2.0 Hz), 8.10 (1 H , dd, J = 4.9, 1.8 Hz), 7.14 (1 H, dd, J = 7.6,

10 4.9 Hz), 7.09 (2 H, s a), 2.63 - 2.78 (2 H, m), 2.12 - 2.42 (4 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 283.0.

Example 40

3 '- ((5- (1-piperazinyl) -2-pyridinyl) amino) spiro [cyclohexane-1,5'-pyrido [3', 2 ': 5,6] pyran [3,4-d] pyrimidin] -4-ol

The title compound (81) was prepared from (82) using chemistry similar to that described in example 27. 1H

15 NMR (500 MHz, DMSO-d6) 8 ppm 9.82 (1 H, s), 9.06 (1 H, s), 8.30 (1 H, dd, J = 7.6, 2.0 Hz), 8.13 (1 H, dd, J = 4.9, 1.7 Hz), 7.97 -8.05 (2 H, m), 7.44 (1 H, dd, J = 9 , 0, 3.2 Hz), 7.13 (1 H, dd, J = 7.6, 4.9 Hz), 4.72 (1 H, d, J = 4.4 Hz), 3.48 - 3.59 (1 H, m), 3.03 - 3.07 (4 H, m), 2.81 - 2.88 (4 H, m), 1.92 - 2.06 (4 H, m), 1.64-1.80 (4 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 446.2. (Note: The product is a 4.4: 1 mixture of 2 reverse phase HPLC-based stereoisomers. The 1 H-NMR data reported is for the main isomer).

3'-Aminoespiro [cyclohexane-1,5'-pyrido [3 ', 2': 5.6] pyrano [3,4-d] pyrimidin] -4-ol (82) Sodium borohydride (0.022 ml, was added 0.64 mmol) in one portion to a stirred suspension of 3'-amino-4H-spiro [cyclohexane-1,5'pyrido [3 ', 2': 5.6] pyran [3,4-d] pyrimidin] -4-one (80) (0.18 g, 0.64 mmol) in a mixed solvent of EtOH / THF (13 ml / 5 ml) at rt. The resulting mixture was stirred at rt for 0.5 h. After the final treatment, the mixture was poured into ice and saturated aqueous NaHCO3 solution and extracted with EtOAc (3 X). The combined organic phases were washed with brine (1 X), dried over Na2SO4 and concentrated in vacuo to give 3'-aminoespiro [cyclohexane-1,5'pyrido [3 ', 2': 5.6] pyran [3 , 4-d] pyrimidin] -4-ol (82) (0.15 g, 80% yield) as an orange solid. 1 H-NMR (500 MHz, DMSO-d6) 8 ppm 8.83 (1 H, s), 8.19 (1 H, dd, J = 7.5, 1.8 Hz), 8.06 (1 H , dd, J = 4.9, 1.7 Hz), 7.08 (1 H, dd, J = 7.5, 5.0 Hz), 7.02 (2 H, sa), 4.69 ( 1 H, d, J = 4.6 Hz), 3.43-3.56 (1 H, m), 1.82-1.98 (4 H, m), 1.64-1.77 (4 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 285.0.

Example 41

4,4-difluoro-N- (5- (1-piperazinyl) -2-pyridinyl) spiro [cyclohexane-1,5'-pyrido [3 ', 2': 5.6] pyran [3,4-d] pyrimidin] -3'10 amine

The title compound (83) was prepared from (87) using chemistry similar to that described in examples 26 and 27. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 11.68 (1 H, sa) , 9.60 (2 H, sa), 9.25 (1 H, s), 8.51 (1 H, dd, J = 7.8, 2.0 Hz), 8.25 (1 H, dd , J = 4.9, 1.8 Hz), 8.14 (1 H, dd, J = 9.4, 2.7 Hz), 8.05 (1 H, d, J = 2.7 Hz) , 7.82 (1 H, d, J = 9.4 Hz), 7.26 (1 H, dd, J = 7.6, 4.9 Hz), 3.39 - 3.57 (4 H, m), 3.25 (4 H, sa), 2.03-2.37 (8 H, m). CLEM-ESI (POS), M / Z, M + 1: Found

15 466.1

4H-spiro [cyclohexane-1,2'-pyrano [2,3-b] pyridin] -4-one (85) A solution of diespiro [1,3-dioxolane-2,1'-cyclohexane-4 'was refluxed , 2 '' - pyran [2,3-b] pyridine] (84) (1.0 g, 3.9 mmol) and p-toluenesulfonic acid monohydrate (3.7 g, 19 mmol) in acetone (50 ml) and H2O (2 ml) for 18 h. Concentrated HCl (4 ml) was added and refluxing was continued for another 24 h until the reaction showed completion by HPLC. After the final treatment, the reaction mixture was poured onto ice and a mixture of saturated NaHCO3 aqueous solution and 2N NaOH aqueous solution and extracted with EtOAc (2 X). The combined organic phases were washed with saturated aqueous NaHCO3 solution (1 X) followed by brine (1 X), dried over Na2SO4 and concentrated in vacuo. The residue was subjected to Combi-flash column chromatography (1st column, MeOH / DCM) 25 to give a secondary product, 3- (1-methyl ethylidene) -4H-spiro [cyclohexane-1,2'-pyran [2,3 -b] pyridin] -4-one (86) (0.20 g, 20% yield) as a bright yellow solid. The rapid elution fractions of the 1st column were combined, concentrated in vacuo and the residue was purified on another series of Combi-flash column chromatography (2nd column, EtOAc / hexanes) to give the 4H-spiro [cyclohexane-1, Desired 2'-pyran [2,3-b] pyridin] -4-one (85) (0.29 g, 35% yield) as an off-white crystalline solid. 1 H-NMR (500 MHz, CHLORFORM-d) 8 ppm 8.08 (1 H,

30 dd, J = 5.0, 1.8 Hz), 7.35 (1 H, dd, J = 7.2, 1.8 Hz), 6.90 (1 H, dd, J = 7.3 , 5.1 Hz), 6.44 (1 H, d, J = 9.8 Hz), 5.67 (1 H, d, J = 9.5 Hz), 2.94 - 3.09 (2 H, m), 2.43-2.53 (2 H, m), 2.27 -2.36 (2 H, m), 1.90-2.01 (2 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 216.1

4,4-Difluorospiro [cyclohexane-1,2'-pyran [2,3-b] pyridine] (87) DAST (0.36 ml, 2.7 mmol) was added to a stirred frozen solution of 4H-spiro [ cyclohexane-1,2'-pyran [2,3-b] pyridin] -4-one (85) (0.29 g, 1.3 mmol) in DCM (30 ml) under N2. The resulting mixture was allowed to warm to rt and stirred at room temperature for 21 h. Be

5 poured the mixture on ice and saturated NaHCO3 aqueous solution and extracted with DCM (2 X). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to give a 2: 1 mixture of 4,4-difluorospiro [cyclohexane-1,2'-pyran [2,3-b] pyridine] ( 87) and 4-fluorospiro [cyclohex-3-eno-1,2'-pyran [2,3b] pyridine] (88) (0.25 g, 80% yield). This material was taken to the next stage without separation. CLEM-ESI (POS), M / Z, M + 1: Found 238.1.

10 Example 42

4,4-dimethylspiro [cyclohex-2-eno-1,9’-pyrido [4 ’, 3’: 3,4] cyclopenta [1,2-d] pyrimidin] -2’-amine (racemic)

4- (4,4-Dimethylcyclohex-1-enyl) pyrimidin-2-amine (90) A single bottom round bottom flask of 25 was loaded

15 ml with 4-chloropyrimidin-2-amine (0.80 g, 6.2 mmol), 4,4-dimethylcyclohex-1-enylboronic acid (1.0 g, 6.5 mmol), transdichlorobis (triphenyl phosphine) palladium (ii) (0.14 g, 0.19 mmol) and tripotassium phosphate (1.4 g, 6.5 mmol). Then, the flask was subjected to 3 evacuation cycles and refilled with N2 before adding THF (10 ml) under N2. The resulting mixture was heated to reflux for 25 h. After the final treatment, the mixture was poured into ice and saturated aqueous NaHCO3 solution and extracted with EtOAc (3 X). The combined organic phases were washed with brine (1 X),

20 dried over Na2SO4 and concentrated in vacuo. The residue was purified by Combiflash column chromatography (EtOAc / hexanes) to give 4- (4,4-dimethylcyclohex-1-enyl) pyrimidin-2-amine (90) (1.0 g, 80% yield) as a off-white solid 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 8.14 (1 H, d, J = 5.1 Hz), 6.73 - 6.79 (1 H, m), 6.66 (1 H , d, J = 5.1 Hz), 6.38 (2 H, sa), 2.30 - 2.40 (2 H, m), 1.96 - 2.05 (2 H, m), 1 , 44 (2 H, t, J = 6.5 Hz), 0.92 (6 H, s). CLEM-ESI (POS), M / Z, M + 1: Found 204.1.

5-Bromo-4- (4,4-dimethylcyclohex-1-enyl) pyrimidin-2-amine (91) N-bromosuccinimide (482 mg, 2706 µmol) was added to a stirred solution of 4- (4,4- dimethylcyclohex-1-enyl) pyrimidin-2-amine (90) (0.55 g, 2706 µmol) in CHCI3 (5 ml) and stirred at rt for 1.5 h. The crude mixture was purified by Combi-flash column chromatography (EtOAc / hexanes) to give 5-bromo-4- (4,4-dimethylcyclohex-1-enyl) pyrimidin-2-amine (91) (790 mg) as a off-white solid 1 H-NMR (400 MHz, CHLOROFORM-d) 8 ppm 8.31 (1 H, s), 5.92 - 6.09 (1 H, m), 5.17 (2 H, sa), 2.28 2.46 (2 H, m), 1.92 - 2.06 (2 H, m), 1.51 (2 H, t, J = 6.5 Hz), 1.01 (6 H, s) . CLEM-ESI (POS), M / Z, M + 1: Found 282.0.

4,4-Dimethylspiro [cyclohex-2-eno-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'-amine (racemic) (89) and 5

10 (3-Chloropyridin-4-yl) -4- (4,4-dimethylcyclohex-1-enyl) pyrimidin-2-amine (92) A 75 ml pressure vessel was charged with 5-bromo-4- (4 , 4-dimethylcyclohex-1-enyl) pyrimidin-2-amine (91) (0.64 g, 2.3 mmol), 3-chloropyridin-4-borboronic acid (1.2 g, 7.9 mmol) and trans-dichlorobis (triphenyl phosphine) palladium (ii) (0.48 g, 0.68 mmol) and 1,4-dioxane (40 ml). The mixture was stirred and purged with N2 for 5 min. Then, sodium carbonate (2M aq. Solution, 7.9 ml, 16 mmol) was introduced and purging was continued for 5 min. additional. The vessel was sealed and heated at 140 ° C for

15 46 h. After cooling, the mixture was filtered through a layer of Celite. The filter cake was washed thoroughly with EtOAc and H2O. Aqueous saturated NaHCO3 solution was added to the filtrate and the phases were separated. The aqueous phase was extracted with EtOAc (1 X). The combined organic phase was washed with 2N aqueous HCl solution (2 X). The combined aqueous phase was extracted with EtOAc (1 X), then made basic with ice cold 4 N NaOH solution and extracted with EtOAc (2 X). The combined organic phases were dried over Na2SO4 and concentrated to

20 empty. The residue was purified after concentration in vacuo by Combi-flash column chromatography (EtOAc / hexanes) to give the main product 5- (3-chloropyridin-4-yl) -4- (4,4-dimethylcyclohex-1-enyl ) pyrimidin-2-amine

(92) (0.47 g, 66% yield) as an off-white solid. 1 H-NMR (400 MHz, CHLOROFORM-d) 8 ppm 8.67 (1 H, s), 8.54 (1 H, d, J = 4.7 Hz), 8.16 (1 H, s), 7.20 (1 H, d, J = 5.5 Hz), 5.71-5.81 (1 H, m), 2.26 - 2.39 (2 H, m), 1.70 1, 81 (2 H, m), 1.42 (2 H, t, J = 6.5 Hz), 0.86 (6 H, s). CLEM-ESI (POS), M / Z, M + 1: Found 315.1. It was obtained as

25 4,4-dimethylspiro [cyclohex-2-eno-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'-amine (racemic) product (89) (0.035 g, 5.5% yield) as a light yellow solid.

4,4-Dimethylspiro [cyclohex-2-eno-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'-amine (racemic) (89) A microwave reaction vessel was loaded with tris (dibenzylideneacetone) dipaladium (o) (99 mg, 0.11 mmol), 2 (diphenylphosphino) -1- (2- (diphenylphosphino) naphthalen-1-yl) naphthalene (134 mg , 0.22 mmol) and a solution of 5- (3-chloropyridin-45 yl) -4- (4,4-dimethylcyclohex-1-enyl) pyrimidin-2-amine (92) (85 mg, 0.27 mmol ) in DMA (3.6 ml). The vessel was purged with N2 for 3 min. before introducing 1,2,2,6,6-pentamethylpiperidine (244 µL, 1.35 mmol). After purging with N2 for 3 min., The vessel was covered and subjected to microwave condition (6 h at 250 ° C). The mixture was filtered through a layer of Celite and concentrated to dryness. The residue was purified by Combi-flash column chromatography (MeOH / DCM) to give 4,4-dimethylspiro [cyclohex-2-eno-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1 ,2

10 d] pyrimidin] -2'-amine (racemic) (89) (54 mg, 72% yield) as an off-white solid. 1 H-NMR (400 MHz, MeOH-d4) (taken as a TFA salt) 8 ppm 9.01 (1 H, s), 8.59 - 8.65 (2 H, m), 8.20 (1 H, dd, J = 6.1, 1.0 Hz), 6.03 (1 H, d, J = 9.8 Hz), 5.13 (1 H, d, J = 9.8 Hz), 2.13 - 2.27 (2 H, m), 1.72 - 1.96 (2 H, m), 1.24 (6 H, d, J = 7.0 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 279.1.

4- (4,4-Dimethylcyclohex-1-enyl) -5- (3-methoxypyridin-4-yl) pyrimidin-2-amine (93) A 75 ml pressure vessel was charged with 3-methoxypyridin-4 acid -ylboronic (2.93 g, 19.1 mmol) and trans-dichlorobis (triphenyl phosphine) palladium (ii) (0.448 g, 0.638 mmol) followed by a solution of 5-bromo-4- (4,4-dimethylcyclohex -1-enyl) pyrimidin-2-amine (91) (1.80 g, 6.38 mmol) in 1,4-dioxane (50 ml). The mixture was purged with N2 for 5 min. and sodium carbonate, solution ac. 2M (22.3 ml, 44.7 mmol). The purge was continued with N2 for 5 min. additional. The

20 container and heated at 135 ° C for 22 h. After the final treatment, the mixture was poured into saturated aqueous NaHCO3 solution and extracted with EtOAc (2 X). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by Combi-flash column chromatography (MeOH / DCM) to give 4- (4,4-dimethylcyclohex-1-enyl) -5- (3-methoxypyridin-4-yl) pyrimidin-2-amine (93 ) (1.56 g, 78.8% yield) as an off-white solid. 1 H-NMR (400 MHz, CHLOROFORM-d) 8 ppm 8.25 - 8.31 (2 H, m), 8.14 (1 H, s), 7.11 (1 H, d,

25 J = 4.7 Hz), 5.54-5.62 (1 H, m), 5.08 (2 H, sa), 3.85 (3 H, s), 2.24 - 2.34 (2 H, m), 1.69 - 1.74 (2 H, m), 1.39 (2 H, t, J = 6.3 Hz), 0.85 (6 H, s). CLEM-ESI (POS), M / Z, M + 1: Found 311.2.

4- (2-Amino-4- (4,4-dimethylcyclohex-1-enyl) pyrimidin-5-yl) pyridin-3-ol (94) A mixture was stirred in an oil bath

of 4- (4,4-dimethylcyclohex-1-enyl) -5- (3-methoxypyridin-4-yl) pyrimidin-2-amine (93) (0.24 g, 0.77 mmol) and hydrochloride

pyridine (0.72 g, 6.2 mmol) at 235 ° C for 3 h. After cooling, the crude solid was absorbed by

5 aqueous solution of saturated NH4Cl and EtOAc. After the phases were separated, the aqueous one was extracted with

EtOAc (1 X). The aqueous phase was basified with ice cold saturated NaHCO3 aqueous solution and extracted with i-PrOH.

10% / chloroform (3 X). The organic phases were combined, dried over Na2SO4 and concentrated in vacuo

to give 4- (2-amino-4- (4,4-dimethylcyclohex-1-enyl) pyrimidin-5-yl) pyridin-3-ol (94) (0.18 g, 79% yield) as a

off-white solid 1 H-NMR (500 MHz, MeOH-d4) 8 ppm 8.13 (1 H, s), 8.07 (1 H, s), 8.02 (1 H, d, J = 4.9 Hz), 7.19 (1 10 H, d, J = 4.9 Hz), 5.51 - 5.56 (1 H, m), 2.34 - 2.40 (2 H, m), 1.65 - 1.72 (2 H, m), 1.41 (2 H, t, J = 6.4 Hz), 0.87 (6 H, s).

CLEM-ESI (POS), M / Z, M + 1: Found 297.1.

4- (2-Amino-4- (4,4-dimethylcyclohex-1-enyl) pyrimidin-5-yl) pyridin-3-yl trifluoromethanesulfonate (95) was added

N-phenyltriflimide (0.36 g, 1.0 mmol) to a stirred ice-cold solution of 4- (2-amino-4- (4,4-dimethylcyclohex-115 enyl) pyrimidin-5-yl) pyridin-3 -ol (94) (0.10 g, 0.34 mmol), triethylamine (0.19 ml, 1.3 mmol) and 4- (dimethylamino) pyridine

(catalytic amount) in THF (12 ml) and at 0 ° C for 5 min. and then at rt for 1.5 h. The vacuum was concentrated in

mixture without heating and purified by Combi-flash column chromatography (EtOAc / hexanes) to give

4- (2-Amino-4- (4,4-dimethylcyclohex-1-enyl) pyrimidin-5-yl) pyridin-3-yl trifluoromethanesulfonate (95) (0.11 g, 76% of

yield) as an almost colorless crystalline solid. 1H-NMR (400 MHz, CHLORFORM-d) 8 ppm 8.64 (1 H, d, 20 J = 4.7 Hz), 8.57 (1 H, s), 8.17 (1 H, s) , 7.36 (1 H, d, J = 5.1 Hz), 5.47-5.53 (1 H, m), 5.43 (2 H, sa), 2.39 (2 H, sa ),

1.67 - 1.73 (2 H, m), 1.42 (2 H, t, J = 6.3 Hz), 0.87 (6 H, s). CLEM-ESI (POS), M / Z, M + 1: Found 429.1.

4,4-Dimethylspiro [cyclohex-2-eno-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'-amine (racemic) (89) A microwave reaction vessel was loaded with tris (dibenzylideneacetone) dipaladium (o) (0.062 g, 0.068 mmol), 2 (diphenylphosphino) -1- (2- (diphenylphosphino) naphthalen-1-yl) naphthalene (0.084 g, 0 , 14 mmol) and a solution of 4- (2-amino-4- (4,4-dimethylcyclohex-1-enyl) pyrimidin-5-yl) pyridin-3-yl trifluoromethanesulfonate (95) (0.29 g, 0.68 mmol) 5 in DMA (3.5 ml). The vessel was purged with N2 for 3 min. before introducing 1,2,2,6,6-pentamethylpiperidine (0.61 ml, 3.4 mmol) by syringe. After purging with N2 for 3 min. In addition, the vessel was covered and subjected to microwave condition (1 h at 150 ° C). The crude product mixture was filtered through a layer of Celite. The filtrate was concentrated in vacuo and purified by Combi-flash column chromatography (MeOH / DCM) to give 4,4-dimethylspiro [cyclohex-2-ene-1,9'-pyrido [4 ', 3': 3, 4] cyclopenta [1,2-d] pyrimidin] -2'-amine

10 (racemic) (89) (0.13 g, 69% yield) as an off-white solid.

Example 43

4,4-dimethyl-N- (5- (1-piperazinyl) -2-pyridinyl) spiro [cyclohex-2-eno-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1, 2-d] pyrimidin] 2'-amine (racemic)

The title compound (96) was prepared from the compound (89) using chemistry similar to that described in the example

27. 1 H-NMR (500 MHz, MeOH) (taken as a TFA salt) 8 ppm 9.37 (1 H, s), 8.84 (1 H, s), 8.79 (1 H, d, J = 6.1 Hz), 8.42 (1 H, d, J = 5.9 Hz), 7.97 - 8.07 (2 H, m), 7.86 (1 H, d, J = 9.3 Hz), 6.11 (1 H, d, J = 9.8 Hz), 5.20 (1 H, d, J = 9.8 Hz), 3.50 - 3.55 (4 H , m), 3.42 - 3.47 (4 H, m), 2.18 - 2.32 (2 H, m), 1.99 - 2.08 (1 H, m), 1.81 - 1.90 (1 H, m), 1.29 (6 H, d, J = 3.4 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 440.2.

20 Example 44 4,4-dimethyl-N- (4- (1-piperazinyl) phenyl) spiro [cyclohex-2-eno-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d ] pyrimidin] -2'amine (racemic)

The title compound (97) was prepared from the compound (89) using chemistry similar to that described in the example

25 27. 1 H-NMR (400 MHz, MeOH) (taken as a TFA salt) 8 ppm 9.12 (1 H, s), 8.61-8.71 (2 H, m), 8.24 ( 1 H, d, J = 6.3 Hz), 7.74 (2 H, d, J = 9.0 Hz), 7.04 (2 H, d, J = 9.0 Hz), 6.08 (1 H, d, J = 9.8 Hz), 5.17 (1 H, d, J = 9.8 Hz), 3.40 (8 H, s), 1.64 - 2.45 (4 H, m), 1.28 (6 H, d, J = 2.0 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 439.1.

Example 45

N- (6- (4- (dimethylamino) -1-piperidinyl) -3-pyridinyl) -4,4-dimethylspiro [cyclohex-2-eno-1,9'pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'-amine (racemic)

The title compound (98) was prepared from the compound (89) using chemistry similar to that described in the example

27. 1H-NMR (400 MHz, MeOH-d4) (taken as a TFA salt) 8 ppm 9.20 (1 H, s), 8.54-8.80 (3 H, m), 8.31 (1 H, d, J = 6.3 Hz), 8.20 (1 H, dd, J = 9.4, 2.7 Hz), 7.26 (1 H, sa), 6.07 (1 H, d, J = 9.8 Hz), 5.17 (1 H, d, J = 9.8 Hz), 4.41 (2 H, d, J = 13.7 Hz), 3.50 - 3.59 (1 H, m), 3.09 - 3.21 (2 H, m), 2.91 (6 H, s), 1.69 - 2.33 (8 H, m), 1, 26 (6 H, d, J = 6.7 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 482.2.

Example 46

4,4-dimethyl-N- (6- (4-methyl-1-piperazinyl) -3-pyridinyl) spiro [cyclohex-2-eno-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2d] pyrimidin] -2'-amine (racemic)

The title compound (99) was prepared from (89) using chemistry similar to that described in example 27. 1 H-NMR (400 MHz, MeOD-d3) (taken as a TFA salt) 8 ppm 9, 16 (1 H, s), 8.66 - 8.75 (2 H, m), 8.61 (1 H, d, J = 2.7 Hz), 8.29 (1 H, d, J = 5.5 Hz), 8.12 (1 H, dd, J = 9.0, 2.7 Hz), 7.03 (1 H, d, J = 9.4 Hz), 6.08 (1 H , d, J = 9.8 Hz), 5.17 (1 H, d, J = 9.8 Hz), 4.29 (4 H, sa), 3.61 (4 H, s), 2, 99 (3 H, s), 1.65 - 2.46 (4 H, m), 1.27 (6 H, d, J = 7.4 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 454.3.

15 Example 47 N- (6- (1-piperazinyl) -3-pyridinyl) spiro [cyclohexane-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'- amine

The title compound (100) was prepared from compound (104) using chemistry similar to that described in example 27. 1 H-NMR (500 MHz, DMSO-d6) 8 10.34 (1H, sa), 9, 28 (1H, s), 9.13 (1H, s), 8.83 (2H, sa), 8.82 (1H, d, J 20 = 5.9 Hz), 8.57 (1H, sa) , 8.33 (1H, d, J = 6.1Hz), 8.05 (1H, sa), 7.01 (1H, d, J = 8.8Hz), 3.68 (4H, m), 3.21 (4H, m), 2.15 (2H, m), 1.85 (2H, m), 1.75 (6H, m); CLEM-ESI (POS), M / Z, M + 1: Found 414.2.

2- (3-Bromopyridin-4-yl) -1-cyclohexeniletanone (101) Lithium bis (trimethylsilyl) amide (1 M solution in THF) (21 ml, 21 mmol) was added over a period of 5 min . to a stirred solution of 3-bromo-4-methylpyridine (3.0 g, 25 17 mmol) in THF (15 ml) cooled in a dry acetone-ice bath. The resulting mixture was stirred for 10 min. before replacing the dry acetone-ice bath with an ice-salt bath (-20ºC). Stirring was continued for 20 min. additional. A solution of 1- (carbomethoxy) cyclohexene (3.3 ml, 24 mmol) in THF (15 ml) was added to

through a syringe at this temperature. The resulting mixture was allowed to slowly warm to rt and stirred overnight. After the final treatment, the mixture was poured into ice and saturated aqueous NH4Cl solution and extracted with EtOAc (2 X). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by Combi-flash column chromatography (EtOAc / hexanes) to give 2- (3-bromopyridin4-yl) -1-cyclohexenyletanone (101) (2.0 g, 41% yield) as an off-white solid. 1 H-NMR (400 MHz, CHLORFORM-d) 8 ppm 8.71 (1 H, s), 8.46 (1 H, d, J = 5.1 Hz), 7.17 (1 H, d, J = 4.7 Hz), 7.02 - 7.11 (1 H, m), 4.13 (2 H, s), 2.22 - 2.40 (4 H, m), 1.55 -1 , 77 (4 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 280.0.

5- (3-Bromopyridin-4-yl) -4-cyclohexenylpyrimidin-2-amine (102) A solution of 2- (3-bromopyridin-4-yl) -1 was stirred

10 cyclohexenyletanone (101) (0.64 g, 2.3 mmol) and methoxy-N, N, N ', N'-tetramethylmethanediamine (1.7 ml, 11 mmol) in THF (2 ml) at 65 ° C (bath of oil) overnight. Guanidine hydrochloride (2.2 g, 23 mmol), n-propanol (9 ml) and sodium methoxide (4.37 M solution in MeOH) (3.7 ml, 16 mmol) were added sequentially. The resulting mixture was stirred at 75 ° C for 3 h. After cooling, the mixture was poured into ice and saturated NaHCO3 aqueous solution and extracted with EtOAc (2 X). The combined organic phases were dried over Na2SO4 and

15 concentrated in vacuo. The residue was purified by Combi-flash column chromatography (MeOH / DCM) to give 5- (3-bromopyridin-4-yl) -4-cyclohexenylpyrimidin-2-amine (102) (0.57 g, 75% yield ) as a light yellow solid. 1 H-NMR (400 MHz, MeOH-d4) 8 ppm 8.73 (1 H, s), 8.51 (1 H, d, J = 4.9 Hz), 8.07 (1 H, s), 7.41 (1 H, d, J = 4.9 Hz), 5.55 - 5.61 (1 H, m), 2.31 - 2.44 (2 H, m), 1.90 (2 H, sa), 1.62-1.72 (2 H, m), 1.48-1.61 (2 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 331.0.

Spiro [cyclohex-2-eno-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'-amine and spiro [cyclohex-3-eno-1 , 9 '

pyrido [4 ’, 3’: 3,4] cyclopenta [1,2-d] pyrimidin] -2’-amine (103) A microwave reaction vessel was charged with

tris (dibenzylideneacetone) dipaladium (0) (26 mg, 0.03 mmol), 2- (diphenylphosphino) -1- (2- (diphenylphosphino) naphthalen-1-yl) naphthalene

(36 mg, 0.06 mmol) and a solution of 5- (3-bromopyridin-4-yl) -4-cyclohexenylpyrimidin-2-amine (A) (95 mg, 0.29 mmol) in DMA (2, 5 ml) The vessel was purged with N2 for 3 min. before entering 1,2,2,6,6

Pentamethylpiperidine (0.26 ml, 1.4 mmol) by syringe. After a nitrogen purge for 3 min.,

the vessel was covered and subjected to microwave condition (1 h at 150 ° C). The crude product was filtered through

a layer of Celite and concentrated to dryness. The residue was purified by column chromatography.

Combi-flash (MeOH / DCM) to give (103) (54 mg, 75% yield) as a 5: 3 mixture of isomers, 30 spiro [cyclohex-2-eno-1,9'-pyrido [4 ', 3 ': 3,4] cyclopenta [1,2-d] pyrimidin] -2'-amine and spiro [cyclohex-3-eno-1,9'

pyrido [4 ’, 3’: 3,4] cyclopenta [1,2-d] pyrimidin] -2’-amine. CLEM-ESI (POS), M / Z, M + 1: Found 251.2.

Spiro [cyclohexane-1,9’-pyrido [4 ’, 3’: 3,4] cyclopenta [1,2-d] pyrimidin] -2’-amine (104)

The isomeric mixture (103) (90 mg) was hydrogenated in a mixed solvent of EtOH (10 ml) and EtOAc (6 ml) under an atmosphere of H2 in the presence of palladium (10% by weight (dry base) in activated carbon, ~ 1.9 mg, 18 µmol) over a period of 20 h. The mixture was filtered through a layer of Celite and concentrated in vacuo to give spiro [cyclohexane-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] - 2'-amine (104) (74 mg, 82% yield) as an off-white solid. 1 H-NMR (400 MHz, CHLOROFORM-d) 8 ppm 8.91 (1 H, s), 8.66 (1 H, s), 8.56 (1 H, d, J = 5.1 Hz), 7.50 (1 H, dd, J = 5.1, 0.8 Hz), 5.53 (2 H, sa), 1.55 - 2.15 (10 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 253.1.

Example 48

N- (4- (1-piperazinylcarbonyl) -1,3-thiazol-1-yl) spiro [cyclohexane-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'amine

The title compound (105) was prepared from the compound (104) using chemistry similar to that described in example 27. 1H-NMR (500 MHz, DMSO-d6) 8 9.10 (1H, s), 8, 97 (1H, s), 8.90 (1H, s), 8.38 (1H, d, J = 5.2 Hz), 8.05

15 (1H, s), 7.95 (1H, d, J = 5.2 Hz), 6.73 (1H, s), 5.20 (1H, sa), 3.39 (4H, m), 2.80 (4H, m), 2.18 (2H, sa), 2.14 (2H, s), 1.98 (2H, sa), 1.81 (2H, sa), 1.59 (2H , sa), see the rotamers present; CLEM-ESI (POS), M / Z, M + 1: Found 448.1.

Example 49

7,7-dimethyl-N- (4- (1-piperazinyl) phenyl) -6,7-dihydro-5H-cyclopenta [d] pyrimidin-2-amine

The title compound (106) was prepared from 2,2-dimethylcyclopentanone using chemistry similar to that described in examples 26 and 27. CLEM-ESI (POS), M / Z, M + 1: Found 324.2.

Example 50

N- (4- (1-piperazinyl) phenyl) spiro [indene [2,1-d] pyrimidin-9,4’-piperidin] -2-amine

The title compound (107) was prepared from commercially available N-BOC-1- [4-spiro-piperidin] -2-indanone using chemistry similar to that described in examples 26 and 27. 1 H-NMR (400 MHz , DMSO-d6) 8 ppm 9.52 (1 H, sa), 8.86 (1 H, s), 7.53 - 7.82 (4 H, m), 7.23 - 7.38 (2 H, m), 6.89 (2 H, d, J = 8.6 Hz), 3.43 - 3.53 (2 H, m), 2.91 - 3.07 (6 H, m), 2.77 - 2.87 (4 H, m), 1.75 - 1.86 (2 H, m), 1.56 - 1.67 (2 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 413.2.

Example 51

N- (4- (1-piperidinyl) phenyl) spiro [indene [2,1-d] pyrimidin-9,4’-piperidin] -2-amine

The title compound (108) was prepared from commercially available N-BOC-1- [4-spiro-piperidin] -2-indanone using chemistry similar to that described in Example 3. 1 H-NMR (500 MHz, CDCl 3 ) 8 8.69 (1H, s), 7.557.65 (4H, m), 7.30-7.37 (2H, m), 7.18 (1H, s), 6.99 (2H, t, J = 9.3 Hz), 3.77 (1H, ta, J = 10), 3.47 (1H, sa), \ 3.31 (1H,

15 ta, J = 9.6 Hz), 3.18-3.22 (1H, m), 3.14 (2H, t, J = 4.3), 3.10 (2H, t, J = 5 , 4 Hz), 3.07 (1H, m), 2.17 (1H, ta, J = 10.8 Hz), 2.07 (1H, ta, J = 10.0 Hz), 1.85 ( 1H, da, J = 13.0 Hz), 1.72-1.77 (2H, m), 1.66-1.71 (2H, m), 1.56-1.60 (1H, m) , 1.50-1.55 (1H, m); CLEM-ESI (POS), M / Z, M + 1: Found 412.1

Example 52

20 N- (4- (4-morpholinyl) phenyl) spiro [indene [2,1-d] pyrimidin-9,4’-piperidin] -2-amine

The title compound (109) was prepared from commercially available N-BOC-1- [4-spiro-piperidin] -2-indanone using chemistry similar to that described in Example 3. 1 H-NMR (500 MHz, DMSO -d6) 8 ppm 9.66 (1 H, s), 9.16 (1 H, d, J = 10.5 Hz), 8.95 (1 H, s), 8.69 (1 H, q , J = 10.0 Hz), 7.82 (1 H, d, J = 7.3 Hz), 7.62 (2 H, d, J = 8.8 Hz), 7.47 (1 H, d, J = 7.6 Hz), 7.39 - 7.44 (1 H, m), 7.34 - 7.39 (1 H, m), 7.01 (2 H, d, J = 9 , 0 Hz), 3.79 - 3.90 (2 H, m), 3.75

25 3.79 (4 H, m), 3.47 (2 H, d, J = 12.7 Hz), 3.03-3.15 (4 H, m), 2.25-2.36 ( 2 H, m), 1.78 (2 H, d, J = 13.9 Hz); CLEM-ESI (POS), M / Z, M + 1: Found 414.1

Example 53

1’-methyl-N- (4- (4-methyl-1-piperazinyl) phenyl) spiro [indene [2,1-d] pyrimidin-9,4’-piperidin] -2-amine

The title compound (110) was prepared from compound 107 in example 50 by bis-alkylation with methyl iodide. CLEM-ESI (POS), M / Z, M + 1: Found 441.2

Example 54

2 ’, 3’, 5 ’, 6’-tetrahydroespiro [indeno [2,1-d] pyrimidin-9,4’-piran] -2-amine

The title compound (111) was prepared from compound 112 using chemistry similar to that described in the

10 example 1. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 8.70 (1 H, s), 7.70 (1 H, d, J = 7.4 Hz), 7.62 (1 H , d, J = 7.4 Hz), 7.28 7.36 (1 H, m), 7.20 - 7.28 (1 H, m), 6.83 (2 H, sa), 4, 32 -4.45 (2 H, m), 3.80 - 3.94 (2 H, m), 1.88 - 2.03 (2 H, m), 1.50 - 1.66 (2 H , m). CLEM-ESI (POS), M / Z, M + 1: Found 254.1

2 ’, 3’, 5 ’, 6’-Tetrahidroespiro [indeno-1,4’-pyrano] (112) A single-bottom round bottom flask was loaded

15 200 ml oven-dried with NaHMDS (1 M solution in THF) (67 ml, 67.2 mmol). The solution was stirred and cooled in an ice-H2O bath while adding an indene solution (3.7 g, 31.9 mmol) in THF (6 mL) under N2 atmosphere. The resulting mixture was stirred at 0 ° C for 2 h and then introduced by cannula into a stirred and ice-cold solution of 1-bromo-2- (2-bromoethoxy) ethane (7.4 g, 31.9 mmol) in THF (15 ml). The resulting mixture was stirred at 0 ° C for 3 h and allowed to warm to rt overnight. After treatment

Finally, the reaction mixture was poured into ice and saturated aqueous NH4Cl solution and extracted with EtOAc (2 X). The combined organic phases were washed with brine (1 X), dried over Na2SO4 and concentrated in vacuo. The residue was purified by Combi-flash column chromatography (EtOAc / hexanes) to give 2 ', 3', 5 ', 6'tetrahydrospiro [indene-1,4'-pyran] (112) (0.7 g, 12 % yield) as an off-white solid. 1 H-NMR (400 MHz, CHLOROFORM-d) 8 ppm 7.35 - 7.44 (2 H, m), 7.22 - 7.32 (2 H, m), 6.99 (1 H, d, J = 5.9 Hz), 6.82 (1 H, d, J = 5.5

25 Hz), 4.09-4.15 (2 H, m), 3.82 (2 H, td, J = 11.9, 2.3 Hz), 2.24 (2 H, td), 1 , 30-1.37 (2 H, m).

Example 55

N- (4- (1-piperazinyl) phenyl) -2 ’, 3’, 5 ’, 6’-tetrahydrospiro [indene [2,1-d] pyrimidin-9,4’-piran] -2-amine

The title compound (113) was prepared from compound 111 using chemistry similar to that described in example 27. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 9.54 (1 H, s), 8, 88 (1 H, s), 7.77 (1 H, d, J = 7.0 Hz), 7.58-7.70 (3 H, m), 7.26-7.41 (2 H, m), 6.89 (2 H, d, J = 9.0 Hz), 4.36-4.47 (2 H, m), 3.85-3.96 (2 H, m), 2, 93 - 3.03 (4 H, m), 2.77 - 2.88 (4 H, m), 1.97 - 2.08 (2 H, m), 1.62 (2 H, d, J = 12.9 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 414.1.

Example 56

10 N- (4- (4-methyl-1-piperazinyl) phenyl) -2 ', 3', 5 ', 6'-tetrahydrospiro [indene [2,1-d] pyrimidin-9,4'-pyran] - 2-amine

The title compound (114) was prepared from compound 112 using chemistry similar to that described in examples 1 and 3. 1 H-NMR (500 MHz, DMSO-d6) 8 ppm 9.70 (1 H, sa), 9.63 (1 H, s), 8.91 (1 H, s), 7.79 (1 H, d, J = 7.1 Hz), 7.74 (2 H, d, J = 9, 0 Hz), 7.67 (1 H, d, J = 7.3 Hz), 7.38 (1 H, dt, J = 7.5, 1.0 Hz), 7.32 (1 H, dt , J = 7.5, 1.2 Hz), 7.01 (2 H, d, J = 9.3 Hz), 4.37 - 4.46 (2 H, m), 3.93 (2 H , dt, J = 11.3, 4.2 Hz), 3.78 (2 H, d, J = 13.2 Hz), 3.54 (2 H, d, J = 12.0

15 Hz), 3.12 - 3.28 (2 H, m), 2.93 (2 H, t, J = 12.1 Hz), 2.88 (3 H, d, J = 2.9 Hz ), 2.04 (2 H, ddd, J = 13.8, 9.8, 4.3 Hz), 1.64 (2 H, da, J = 13.4 Hz); CLEM-ESI (POS), M / Z, M + 1: Found 428.2.

Example 57

N- (3-fluoro-4- (4-methyl-1-piperazinyl) phenyl) -2 ', 3', 5 ', 6'-tetrahydrospiro [indene [2,1-d] pyrimidin-9,4'- pyran] -2-amine

The title compound (115) was prepared from compound 112 using chemistry similar to that described in examples 1 and 3. 1 H-NMR (500 MHz, DMSO-d6) 8 ppm 9.90 (1 H, s) , 9.73 (1 H, sa), 8.97 (1 H, s), 7.87 (1 H, dd, J = 15.3, 2.3 Hz), 7.81 (1 H, d , J = 6.8 Hz), 7.68 (1 H, d, J = 7.3 Hz), 7.52 (1 H, dd, J = 8.8, 2.0 Hz), 7.39 (1 H, ddd, J = 7.5, 1.1 Hz), 7.34 (1 H, ddd, J = 7.5, 1.2 Hz), 7.06 - 7.14 (1 H, m), 4.37-4.46 (2 H, m), 3.94 (2 H, dt, J = 11.4, 4.2, 4.2 Hz), 3.52 (2 H, d , J = 12.2 Hz), 3.45 (2 H, d, J = 13.2 Hz), 3.23 (2 H, q, J = 10.7 Hz), 3.00 (2 H, t, J = 11.9 Hz), 2.88 (3 H, d,

25 J = 3.4 Hz), 2.05 (2 H, ddd, J = 13.9, 10.0, 4.3 Hz), 1.64 (2 H, da, J = 13.9 Hz) ; CLEM-ESI (POS), M / Z, M + 1: Found 446.2

Example 58

spiro [cyclohexane-1,9’-indene [2,1-d] pyrimidin] -2’-amine

The title compound (116) was prepared from compound 117 using chemistry similar to that described in Example 1. 1 H-NMR (400 MHz, CHLORFORM-d) 8 ppm 8.59 (1 H, s), 7, 62 (2 H, d, J = 7.8 Hz), 7.34 (1 H, td, J = 7.4, 1.2 Hz), 7.28 (1 H, td, J = 7.5 , 1.0 Hz), 5.25 (2 H, sa), 2.06 - 2.19 (2 H, m), 1.62 - 1.90 (8 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 252.1

Spiro [cyclohexane-1,1’-inden] -2 ’(3’H) -ona (117) 1,5-dibromopentane was added to a stirred solution of 2

10 indanone (7.0 g, 53.0 mmol) and t-BuONa (12 g, 125 mmol) in benzene (60 ml) at rt. The resulting mixture was heated to reflux for 6 h. After cooling, the mixture was poured into ice and 2N aqueous HCl solution and extracted with EtOAc (2 X). The combined organic phase was washed with brine (2 X), dried over Na2SO4 and concentrated in vacuo. The residue was subjected to Combi-flash column chromatography (Et2O / hexanes) to give spiro [cyclohexane-1,1'-inden] -2 '(3'H) -one (117) impure (0.32 g), which was used in the next stage without purification

15 additional.

Example 59

tert-butyl 4- (4- (spiro [cyclohexane-1,9’-indene [2,1-d] pyrimidin] -2’-ylamino) phenyl) -1-piperazinecarboxylate

The title compound (118) was prepared from compound 116 using chemistry similar to that described in the

20 example 27. 1H-NMR (400 MHz, CHLOROFORM-d) 8 ppm 8.68 (1 H, s), 7.54-7.66 (4 H, m), 7.28-7.38 (2 H, m), 7.13 (1 H, sa), 6.98 (2 H, d, J = 8.8 Hz), 3.61 - 3.64 (4 H, m), 3.11 - 3.13 (4 H, m), 2.20 - 2.35 (2 H, m), 1.70 - 1.90 (8 H, m), 1.51 (9 H, s). CLEM-ESI (POS), M / Z, M + 1: Found 512.2

Example 60

N- (4- (1-piperazinyl) phenyl) spiro [cyclohexane-1,9’-indene [2,1-d] pyrimidin] -2’-amine

The title compound (119) was prepared from compound 118 using chemistry similar to that described in example 27. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 9.51 (1 H, s), 8, 6 (1 H, s), 7.76 (1 H, d, J = 7.3 Hz), 7.68 (2 H, d, J = 9.6 Hz), 7.62 (1 H, d , J = 7.3 Hz), 7.34 (1 H, td, J = 7.5, 1.0 Hz), 7.27 (1 H, td, J = 7.4, 1.2 Hz) , 6.89 (2 H, d, J = 9.6 Hz), 2.97 - 3.00 (4 H, m), 2.83 - 2.85 (4 H, m), 2.23 - 2.33 (2 H, m), 1.87 (1 H, s), 1.60 - 1.80 (8 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 412.1

Example 61

N- (5- (1-piperazinyl) -2-pyridinyl) spiro [cyclopentane-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'- amine

2- (3-Bromo-4-pyridinyl) -1-cyclopentyletanone (121) LiHMDS was added under nitrogen atmosphere (solution

1 M in tetrahydrofuran, 49.6 ml, 49.6 mmol) to a solution of methyl cyclopentanecarboxylate (3.630 g, 28.3 15 mmol) and 3-bromo-4-methylpyridine (2.62 ml, 23.6 mmol ) in 10 ml of anhydrous THF over a period of 5 min. to

-

78 ° C. After 10 min. The solution was allowed to warm to 20 ° C and stirred for 2 hours. So,

The solution was cooled in ice-water, before adjusting the pH to 4.5 with 25% citric acid. After extraction

with DCM, the organic phase was dried over Na2SO4 and then concentrated to provide 2- (3-bromo-4-pyridinyl)

1-cyclopentiletanone (121) (6.86 g, crude). 1H-NMR (500 MHz, DMSO-d6) 8 8.68 (1H, s), 8.48 (1H, d, J = 4.9Hz), 7.37 20 (H, d, J = 4.9 Hz), 4.07 (2H, s), 3.08 (1H, ddd, J1 = 16.1 Hz, J2 = 7.3 Hz, J3 = 1.2 Hz), 1.80-1.85 ( 2H, m), 1.72-1.77

(2H, m), 1.55-1.59 (4H, m); CLEM-ESI (POS), M / Z, M + 1: Found 268.0 (2E) -2- (3-Bromo-4-pyridinyl) -1-cyclopentyl-3- (dimethylamino) -2-propen-1 -one (122) A solution of 2 (3-bromo-4-pyridiniI) -1-cyclopentyletanone (121) (6.86 g, 25.9 mmol) and tert-butoxy-N, N, N ', was heated, N'-tetramethylmethanediamine (7.31 ml) at 105 ° C under a nitrogen atmosphere for 3 hours. The reaction was then cooled to 20 ° C and concentrated in vacuo. The residue was purified on a 120 g Combi-flash column (dry loaded), eluting with 100% EtOAc. Fractions containing the product were combined and concentrated in vacuo to give (2E) -2 (3-bromo-4-pyridinyl) -1-cyclopentyl-3- (dimethylamino) -2-propen-1-one (122) (5.79 g, 76%). 1H-NMR (500 MHz, DMSOd6) 8 8.68 (1H, s), 8.44 (1H, d, J = 4.9 Hz), 7.64 (1H, s), 7.25 (1H, d, J = 4.9Hz), 2.71 (6H, sa), 1.40-1.72 (8H, m); CLEM-ESI (POS), M / Z, M + 1: Found 323.0.

(3'Z) -3 '- ((Dimethylamino) methylidene) spiro [cyclopentane-1,1'-inden] -2' (3'H) -one (123) Pd2 (dba) 3 (0.806 g, 0.879 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo [3,3,3] undecano (0.603 g, 1,757 mmol) at a degassed solution of 2- (3- bromopyridin-4-yl) -1-cyclopentyl-3- (dimethylamino) prop-2-en-1-one (122) (4,738 g, 14.63 mmol) and sodium 2-methylpropan-2-olate (4, 23 g, 44 mmol) in 20 ml of anhydrous toluene under an atmosphere of

15 nitrogen The reaction was heated to 110 ° C for 1.5 h before cooling to 20 ° C and concentrated in vacuo to give mainly (3'Z) -3 '- ((dimethylamino) methylidene) spiro [cyclopentane-1,1'-inden] -2 '(3'H) -one (123). CLEM-ESI (POS), M / Z, M + 1: Found 243.1.

spiro [cyclopentane-1,9’-pyrido [4 ’, 3’: 3,4] cyclopenta [1,2-d] pyrimidin] -2’-amine (124)

A solution of (3'Z) -3 '- ((dimethylamino) methylidene) -spiro [cyclopentane-1,1'-inden] -2' (3'H) -one (123) (3.15) was heated g, 14.63 mmol) and guanidine hydrochloride (14.0 g, 146 mmol) in 50 ml of iPrOH at 215 ° C and the solvent was allowed to be removed by distillation. After 5 minutes of heating, the mixture was cooled to 20 ° C. 50 ml of H2O was added and the solution was sonicated to break the solids. After extraction with 10% iPrOH / DCM, the organic phases were concentrated in vacuo. The residue was purified on an 80 g Combi-flash column (dry loaded), eluting with a gradient of 6% DCM-MeOH / DCM. Fractions containing the product were combined and concentrated in vacuo. The residue obtained was triturated with Et2O and then with acetone to give spiro [cyclopentane-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'-amine ( 124) (0.824 g, 23%). 1H-NMR (500 MHz, DMSO-d6) 8 8.78 (1H, s), 8.63 (1H, d, J = 1 Hz), 8.46 (1H, d, J = 4.9 Hz) , 7.65 (1H, dd, J1 = 4.9 Hz, J2 = 1.2 Hz), 7.11 (2H, sa), 2.05-2.10 (6H, m), 1.89- 1.93 (2 H, m); CLEM-ESI (POS), M / Z, M + 1: Found 239.1.

N- (5- (1-Piperazinyl) -2-pyridinyl) spiro [cyclopentane-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'- amine

(125) Pd2 (dba) 3 (0.031 g, 0.034 mmol) and 4,5-bis (diphenylphosphino) -9,9-dimethyl-9H-xanthene (0.039 g, 0.068 mmol) was added to a degassed solution of 4- Tert-butyl (6-chloropyridin-3-yl) piperazin-1-carboxylate (0.12 g, 0.41 10 mmol), spiro [cyclopentane-1,9'-pyrido [4 ', 3': 3, 4] cyclopenta [1,2-d] pyrimidin] -2'-amine (124) (0.081 g, 0.34 mmol) and 2-methylpropan-2-olate (0.098 g, 1.0 mmol) in 4 ml of 1,4-dioxane under a nitrogen atmosphere. The solution was heated to 120 ° C with microwave irradiation for 1 h. Then, the solution was purified on a 40 g Combi-flash column (dry loaded), eluting with a gradient of 40% EtOAc / hexane to EtOAc then with 2% MeOH / DCM to 5% MeOH / DCM The fractions containing the product were combined and concentrated in vacuo. The residue obtained was dissolved in 5 ml of DCM and 1 ml of TFA and stirred at room temperature for 2 hours. The organic phases were removed in vacuo to provide N- (5- (1-piperazinyl) -2pyridinyl) spiro [cyclopentane-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d ] pyrimidin] -2'-amine (125) (253 mg, 100%) as the TFA salt. 1H-NMR (400 MHz, DMSO-d6) 8 10.69 (1H, s), 9.31 (1H, s), 9.01 (1H, s), 8.60 (2H, sa), 8, 83 (1H, d, J = 6.2 Hz), 8.36 (1H, d, J = 5.5 Hz), 8.12 (1H, d, J = 3.2 Hz), 8.10 ( 1H, d, J = 8.9 Hz), 7.63 (1H, dd, J1 = 9.4 Hz, J2 = 3.1

20 Hz), 3.39 (4H, m), 3.27 (4H, m), 2.12-2.20 (8H, m); CLEM-ESI (POS), M / Z, M + 1: Found 400.1.

Example 62

9,9-diethyl-N- (5- (1-piperazinyl) -2-pyridinyl) -9H-pyrido [4 ’, 3’: 3,4] cyclopenta [1,2-d] pyrimidin-2-amine

The title compound (126) was prepared using chemistry similar to that described in example 61. 1 H-NMR (400 MHz,

25 DMSO-d6) 8 10.82 (1H, s), 9.34 (1H, s), 9.03 (1H, s), 8.88 (1H, d, J = 5.9 Hz), 8 , 84 (2H, sa), 8.39 (1H, d, J = 5.9 Hz), 8.13 (1H, d, J = 3.2 Hz), 8.10 (1H, d, J = 8.9 Hz), 7.65 (1H, d, J1 = 9.3 Hz, J2 = 3.1 Hz), 3.94 (4H, m), 3.28 (4H, m), 2.21 (2H, dq, J1 = 13.7 Hz, J2 = 7.4 Hz), 2.12 (2H, dq, J1 = 13.7 Hz, J2 = 7.0 Hz), 0.38 (6H, t , J = 7.4 Hz); CLEM-ESI (POS), M / Z, M + 1: Found 402.2.

Example 63

N- (5- (1-piperazinyl) -2-pyridinyl) -2,3,5,6-tetrahydrospiro [pyran-4,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2 -d] pyrimidin] -2'amine

The title compound (127) was prepared using chemistry similar to that described in example 61. 1H-NMR (400 MHz, DMSO-d6) 8 10.74 (1H, s), 9.36 (1H, s), 9.24 (1H, s), 8.91 (2H, sa), 8.86 (1H, d, J = 6.3 Hz), 8.39 (1H, d, J = 5.9 Hz), 8.14 (1H, d, J = 3.2 Hz), 8.07 (1H, d, J = 9.0 Hz), 7.65 (1H, dd, J1 = 9.0 Hz, J2 = 3 , 1 Hz), 4.35 (2H, m), 3.93 (2H, m), 3.41 (4H, m), 3.28 (4H, m), 2.14 (2H, m), 1.80 (2H, m); CLEM-ESI (POS), M / Z, M + 1: Found 416.2.

Example 64

N- (5- (1-piperazinyl) -2-pyridinyl) spiro [cycloheptane-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'- amine

The title compound (128) was prepared using chemistry similar to that described in example 61. 1H-NMR (500 MHz, DMSO-d6) 8 9.89 (1H, s), 9.03 (1H, s), 8.54 (1H, d, J = 5.1 Hz), 8.16 (1H, d, J = 9.0 Hz), 8.03 (1H, d, J = 3.2 Hz), 7, 77 (1H, d, J = 4.9 Hz), 7.47 (1H, dd, J1 = 9.0 Hz, J2 = 3.0 Hz), 3.15 (4H, m), 2.99 ( 4H, m), 2.10 (2H, m), 1.90-1.96 (2H,

15 m), 1.81-1.86 (4H, m), 1.77 (4H, m); CLEM-ESI (POS), M / Z, M + 1: Found 428.2.

Example 65

N- (5- (1-piperazinyl) -2-pyridinyl) spiro [cyclohexane-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'- amine

The title compound (129) was prepared using chemistry similar to that described in example 61. 1 H-NMR (400 MHz,

20 DMSO-d6) 8 10.74 (1H, s), 9.36 (1H, s), 9.18 (1H, s), 8.89 (2H, sa), 8.85 (1H, d, J = 6.2 Hz), 8.40 (1H, d, J = 5.9 Hz), 8.13 (1H, d, J = 2.7 Hz), 8.10 (1H, sa), 7 , 66 (1H, dd, J1 = 9.0 Hz, J2 = 3.2 Hz), 3.40 (4H, m), 3.28 (4H, m), 2.18 (2H, m), 1 , 89 (2H, m), 1.72-1.82 (6H, m); CLEM-ESI (POS), M / Z, M + 1: Found 414.2.

Example 66

(3R) -1- (6- (spiro [cyclohexane-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'-ylamino) -3- pyridazinyl) -3-pyrrolidinol

The title compound (130) was prepared using chemistry similar to that described in example 61. 1H-NMR (500 MHz, DMSO-d6) 8 10.18 (1H, s), 9.03 (1H, s), 8.89 (1H, s), 8.55 (1H, d, J = 4.9 Hz), 8.07 (1H, d, J = 9.6 Hz), 7.80 (1H, dd, J1 = 4.9 Hz, J2 = 1 Hz), 6.99 (1H, d, J = 9.8 Hz), 4.99 (1H, d, J = 3.7 Hz), 4.43 (1H, m), 3.52-3.57 (3H, m), 3.38 (2H, da, J = 10.5), 2.01-2.14 (3H, m), 1.93 (1H, m), 1.72-1.77 (8H, m); CLEM-ESI (POS), M / Z, M + 1: Found 416.2.

Example 67

2 ’- ((4- (1-piperazinyl) phenyl) amino) spiro [cycloheptane-1,7’-pyrrolo [3,4-d] pyrimidin] -5’ (6’H) -one

1 - ((3-Methoxy-3-oxopropanoyl) amino) methyl cycloheptanecarboxylate (132) Methyl 3-chloro-3-oxopropanoate (4.50 ml, 42.0 mmol) was carefully added to a solution of hydrochloride-1-aminocycloheptanecarboxylate from

15 methyl (7.04 g, 33.9 mmol) and triethylamine (11.8 ml, 84.7 mmol) in 50 ml of THF and then heated at 50 ° C for 2 h. After cooling to rt, the solvent was removed in vacuo and the residue was extracted between ether and water. The organic phase was dried over Na2SO4 and concentrated to provide methyl 1- ((3-methoxy-3-oxopropanoyl) amino) cycloheptanecarboxylate (132) as a yellow oil (7.04, crude). CLEM-ESI (POS), M / Z, M + 1: Found 272.0.

Methyl 2,4-Dioxo-1-azaspiro [46] undecano-3-carboxylate (133) A solution of methyl 1 - ((3-methoxy-3-oxopropanoyl) amino) -cycloheptanecarboxylate (132) (7.29) g, 26.9 mmol) and sodium methoxide (25% by weight in methanol, 17.4 ml, 80.6 mmol) in 50 ml of MeOH under gentle reflux for two hours. After cooling to 20 ° C, the reaction was concentrated in vacuo to minimize the organic solvent. The residue was absorbed in ice water and adjusted to pH ~ 2-3 with 1 N HCl. After extraction with DCM, the organic phase was dried over Na2SO4 and concentrated to provide 2,4-dioxo-1-azaespiro [46 ] methyl undecano-3-carboxylate (133) (5.84 g, crude). CLEM-ESI (NEG), M / Z, M + 1: Found 238.0.

10 1-Azaspiro [46] undecano-2,4-dione (134). A solution of methyl 2,4-dioxo-1-azaspiro [46] undecano-3-carboxylate (133) (5.84 g, 24.4 mmol) in acetonitrile (100 ml) and water (1.32 ml, was heated. 73.2 mmol) at gentle reflux for 1 h. After cooling to 20 ° C, the solvent was removed in vacuo to provide 1azaspiro [46] undecano-2,4-dione (134) as a tan solid (4.08 g, crude). CLEM-ESI (NEG), M / Z, M + 1: Found 180.1.

3 - ((Dimethylamino) methylidene) -1-azaspiro [46] undecano-2,4-dione (135) Tert-butoxybis (dimethylamino) methane (2.04 ml, 9.88 mmol) was added to a solution of 1 -azaspiro [46] undecano-2,4-dione (134) (0,895 g, 4.94 mmol) in DCM (10 ml) and stirred at rt for 2 h. The product was collected as a white solid by filtration. The additional product was obtained by concentration of the filtrate and trituration with DCM. Performance

20 combined gave 3 - ((dimethylamino) methylidene) -1-azaspiro [46] undecano-2,4-dione (135) (803 mg, 68.8%) as a white solid. 1 H-NMR (500 MHz, DMSO-d6) 8 ppm 7.80 (1 H, s), 7.19 (1 H, s), 3.59 (3 H, s), 3.26 (3 H, s), 1.66-1.78 (2 H, m), 1.38-1.63 (10 H, m), (E and Z isomers present in a ratio of 2: 1); CLEM-ESI (POS), M / Z, M + 1: Found 237.1.

2 ’- ((4-Bromophenyl) amino) spiro [cycloheptane-1,7’-pyrrolo [3,4-d] pyrimidin] -5’ (6’H) -one (136). A solid mixture of 3 - ((dimethylamino) methylidene) -1-azaspiro [46] undecano-2,4-dione (135) (1.06 g, 4.49 mmol) and 1- (4- hydrochloride) was melted bromophenyl) guanidine (1.69 g, 6.73 mmol) in a heating bath set at 230 ° C under a nitrogen atmosphere. After 1.5 h the reaction was cooled to 20 ° C. The residue was triturated with 3X methanol to provide 2 '- ((4-bromophenyl) amino) spiro [cycloheptane-1,7'-pyrrolo [3,4-d] pyrimidin] -5' (6'H) -one ( 136) as a light brown solid (680 mg, crude). CLEM-ESI (POS), M / Z, M + 1: Found 387.0.

2 ’- ((4- (1-Piperazinyl) phenyl) amino) spiro [cycloheptane-1,7’-pyrrolo [3,4-d] pyrimidin] -5’ (6’H) -one (131). Was added

10 bis (trimethylsilyl) lithium amide (1.0 M solution in tetrahydrofuran, 1.68 ml, 1.68 mmol) under an atmosphere of N2 at a solution of 2 '- ((4-bromophenyl) amino) spiro [cycloheptane -1,7'-pyrrolo [3,4-d] pyrimidin] -5 '(6'H) -one (136) (0.217 g, 0.560 mmol) and piperazine (0.145 g, 1.68 mmol) in anhydrous toluene (3 ml). After degassing the solution with nitrogen, S-Phos (0.092 g, 0.224 mmol) and tris (dibenzylideneacetone) -dipaladium (0) (0.051 g, 0.056 mmol) were added and the reaction was heated at 100 ° C for 2 h. Lithium bis (trimethylsilyl) amide, 1.0 M solution in

Tetrahydrofuran (1.68 ml, 1.68 mmol), tris (dibenzylideneacetone) dipaladium (0) (0.051 g, 0.056 mmol) and S-Phos (0.092 g, 0.224 mmol) and the reaction was heated at 100 ° C for 1 h h before cooling to 20 ° C. The reaction was quenched with methanol and concentrated in vacuo. The residue was triturated with DCM and solids removed by filtration. The filtrate was concentrated in vacuo and purified by preparative HPLC eluting with a gradient of 20% MeCN-60% MeCN / H2O / 0.1% TFA. The fractions containing the product were combined

20 and concentrated in vacuo. Trituration with methanol gave 2 '- ((4- (1-piperazinyl) phenyl) amino) spiro [cycloheptane-1,7'pyrrolo [3,4-d] pyrimidin] -5' (6'H) -one ( 131) as a white solid (26 mg, crude). 1 H-NMR (500 MHz, DMSO-d6) 8 ppm 10.02 (1 H, s), 8.75 (1 H, s), 8.73 (2 H, sa), 8.62 (1 H, s), 7.68 (2 H, d, J = 8.5 Hz), 6.99 (2 H, d, J = 9.2 Hz), 3.28 - 3.32 (4 H, m) , 3.21 - 3.28 (4 H, m), 1.92 - 2.02 (2 H, m), 1.77 - 1.86 (2 H, m), 1.55 - 1.77 (8 H, m); CLEM-ESI (POS), M / Z, M + 1: Found 393.2.

Example 68 2 ’- ((4- (1-piperazinyl) phenyl) amino) spiro [cyclohexane-1,7’-pyrrolo [3,4-d] pyrimidin] -5’ (6’H) -ona

The title compound (137) was prepared using chemistry similar to that described in example 67. 1 H-NMR (500 MHz, DMSO-d6) 8 ppm 10.03 (1 H, s), 8.88 (1 H, s), 8.78 (2 H, sa), 8.64 (1 H, s), 7.66 (2 H, d, J = 7.9 Hz), 6.98 (2 H, d, J = 9.2 Hz), 3.27 - 3.31 (4 H, m), 3.22 - 3.27 (4 H, m), 1.74 - 1.89 (4 H, m), 1 , 61-1.72 (3 H, m), 1.45-1.53 (2 H, m), 1.31-1.40 (1 H, m); CLEM-ESI (POS), M / Z, M + 1: Found 379.1.

Example 69

2 ’- ((4- (1-piperazinyl) phenyl) amino) spiro [cyclopentane-1,7’-pyrrolo [3,4-d] pyrimidin] -5’ (6’H) -one

The title compound (138) was prepared using chemistry similar to that described in example 67. 1 H-NMR (500 MHz,

10 DMSO-d6) 8 ppm 10.02 (1 H, s), 8.74 (2 H, sa), 8.64 (1 H, s), 8.61 (1 H, s), 7.66 (2 H, d, J = 8.5 Hz), 6.97 (2 H, d, J = 9.2 Hz), 3.27 - 3.32 (4 H, m), 3.21 - 3 , 27 (4 H, m), 2.02 - 2.10 (2 H, m), 1.87 - 1.94 (4 H, m), 1.77 - 1.84 (2 H, m) ; CLEM-ESI (POS), M / Z, M + 1: Found 365.2.

Example 70

15 2 ′ - ((4- (4-methyl-1-piperazinyl) phenyl) amino) spiro [cyclohexane-1,7’-pyrrolo [3,4-d] pyrimidin] -5 ’(6’H) -ona

The title compound (139) was prepared using chemistry similar to that described in example 67. 1 H-NMR (500 MHz, DMSO-d6) 8 ppm 10.06 (1 H, s), 9.71 (1 H, sa), 8.91 (1 H, s), 8.65 (1 H, s), 7.67 (2 H, d, J = 8.1 Hz), 7.00 (2 H, d, J = 9.3 Hz), 3.79 (2 H, d, J = 13.0 Hz), 3.53 (2 H, d, J = 11.5 Hz), 3.12 - 3.27 (2 H, m), 2.93 (2 H, t, J = 12.0 Hz), 2.88 (3 H, d, J = 3.4 Hz), 1.75 - 1.89 (4 H, m), 1.62-1.73 (3 H, m), 1.50 (2 H, d, J = 12.2 Hz), 1.37 (1 H, m); CLEM-ESI (POS),

20 M / Z, M + 1: Found 393.2.

Example 71

(7'S) -5'-methyl-2 '- ((5- (1-piperazinyl) -2-pyridinyl) amino) -6', 7'-dihydro-5'H-spiro [cyclopent-3-eno-1 , 8'-quinazolin] 7'-ol

2,2-Diallyl-5-methylcyclohexane-1,3-dione (141) A 3-liter 2-liter flask was charged with mechanical agitation, hole

addition and reflux condenser with a solution of 5-methylcyclohexane-1,3-dione (50.53 g, 400.5 mmol) in

Acetone (500 ml) followed by powdered potassium carbonate (100 g) and heated to 50 ° C for 4 h. After

5 filtration, the solvent was removed in vacuo to provide 77.6 g of an oil containing a mixture of

O and C-alkylation products. This mixture was absorbed in 2N HCl (600 ml) and heated at reflux for 1 h.

After cooling, the acid solution was extracted with dichloromethane. The organic phase was washed with solution

10% NaOH, brine and dried over magnesium sulfate. Solvent removal in vacuo provided

2,2-diallyl-5-methylcyclohexane-1,3-dione (141) (37.48 g, 45% yield) as an oil. 1H-NMR (500 MHz, 10 DMSO-d6) 8 5.50 (2H, m), 5.05-4.97 (4H, m), 2,673 (dd, J = 19.5, 5 Hz, 2H) , 2,443 (dd, J = 19.5, 13 Hz, 2H) 2,428 (d,

J = 8.5 Hz, 4H), 2,039 (m, 1H), 0.947 (d, J = 8.5 Hz, 3H) ppm; FTIR 1695 cm -1.

2,2-Diallyl-3-hydroxy-5-methylcyclohexanone (142) A solution of LiHAl (OtBu) 3 (44 ml, 44) was added dropwise

mmol) 1 M in THF to a cold solution (0 ° C) of 2,2-diallyl-5-methylcyclohexane-1,3-dione (141) (6.00 g, 29 mmol) in 15 ml of THF. After stirring for 30 minutes, the reaction was carefully poured into an acid solution

5% cold citrus. The organic phase was separated and concentrated to remove THF. The aqueous phase was extracted with

dichloromethane The combined organic phase was washed with brine, dried over magnesium sulfate and then

concentrated to provide 5.86 g of a 6: 1 mixture of 2,2-diallyl-3-hydroxy-5-methylcyclohexanone (142) (cis / trans)

with ~ 2% excess reduction to diol, as indicated by capillary GC analysis. Mixture 20 was used directly in the next step. 1 H-NMR (500 MHz, DMSO-d6) (key signals of the main isomer) 8 3,681 (dd,

J = 11.5 Hz, 1H), 0.973 (d, J = 6 Hz, 3H) ppm; FTIR 3440, 1703 cm -1.

2,2-Diallyl-3- (tert-butyldimethylsilyloxy) -5-methylcyclohexanone (143) Tert-butyldimethylsilyl chloride (TBDMS) (5.14 g, 34.1 mmol) was added to a 2,2-diallyl solution -3-hydroxy-5-methylcyclohexanone (142) (5.68 g, 27.3 mmol) 25 and imidazole (4.64 g, 68.2 mmol) in 50 ml of DMF at 40 ° C. After several days, the reaction reached a conversion of 70% and an additional 1.6 g of TBDMS and 1.5 g of imidazole were added. At the end, the solvent was removed in vacuo and the residue was poured into ice-water and extracted into ether. The ether phase was washed with water, sodium bicarbonate solution and brine. The concentration gave 7.65 g of a mixture of isomers. A portion (5.3 g) was purified by silica chromatography, eluting with hexane, followed by dichloromethane to provide 2,2-diallyl-330 (tert-butyldimethylsilyloxy) -5-methylcyclohexanone (143) (3.82 g) as an 8: 1 mixture of cis: trans isomers. 1H-NMR (500 MHz, DMSO) (key signals of the cis isomer) 8 5.63 (, 1H), 5.53 (m, 1H), 5.02 (m, 2H), 4.97 (m, 2H ), 3,671 (dd,

J = 11.5 Hz, 1H), 2.56 (m, 1H), 2.53 (, 1H), 2.24 (, 1H), 2.19 (, 1H), 2.06 (, 1H) , 1.98 (, 1H), 1.82 (, 1H), 1.67 (, 1H), 1.60 (, 1H), 0.988 (d, J = 6.5 Hz, 3H), 0.887 (s , 9H), 0.083 (s, 3H), 0.042 (s, 3H) ppm; (key signals of the trans isomer) 8 4,028 (dd, J = 4, 2 Hz, 0.1H), 0.983 (d, J = 6.5 Hz, 0.3H); FTIR 1708 cm -1.

5 10 - ((Tert-Butyl (dimethyl) silyl) oxy) -8-methylpyrro [45] dec-2-en-6-one (144) Bis (tricyclohexylphosphine) benzylidinrutenium (IV) chloride (Grubbs catalyst) was added 1st generation) (0.193 g) to a degassed solution of 2,2-diallyl-3- (tert-butyldimethylsilyloxy) -5-methylcyclohexanone (143) (4.97 g, 15.4 mmol) in 500 ml of dichloromethane, under an atmosphere of argon and stirred for 60 h. Then, the mixture was washed with 2 N NaOH, 5% citric acid and brine. The organic phase was dried over magnesium sulfate and then concentrated in vacuo

10 to provide 4.37 g of a dark solid. Purification by silica chromatography eluting with 1: 1 hexane / dichloromethane gave 3.88 g of a 9: 1 cis / trans mixture of 10 - ((tert-butyl (dimethyl) silyl) oxy) -8-methyl-spiro [45] dec- 2-in-6-one (144) as a colorless solid. MP 56-59 ° C, 1H-NMR (500 MHz, DMSO-d6) (cis isomer signals) 8 5,550 (dt, J = 5.5, 2.5 Hz, 1H), 5.408 (dm, J = 6 Hz, 1H), 3,686 (dd, J = 11.4 Hz, 1H), 3,038 (dq, J = 16, 2.5 Hz, 1H), 2,833 (dp, J = 17, 2 Hz, 1H), 2,314 (dd , J = 14.5, 13, 1H), 2.11-2.16 (m, 2H), 2,066 (m, 1H), 1,833 (, 1H),

15 1,694 (m, 1H), 1,420 (ddd, J = 15, 12.5, 12 Hz, 1H), 0.975 (d, J = 6.5 Hz, 3H), 0.822 (s, 9H), 0.072 (s , 3H), 0.031 (s, 3H), 0.029 (s, 3H) ppm; FTIR 1710 cm 1; (key signals of the trans isomer) 8 4,028 (dd, J = 3.4, 2.1 Hz, 0.11H), 0.963 (d, J = 6.5 Hz, 0.3H) ppm; CLEM-ESI (POS), M / Z, M + 1: Found 295.1.

7'-Tert-butyl (dimethyl) silyl) oxy) -5'-methyl-6 ', 7'-dihydro-5'H-spiro [cyclopent-S-eno-1,8'-quinazolin] -2'- Amine (145)

The title compound (145) was prepared in 80% yield from the compound (144) using chemistry similar to that described in example 1. CLEM-ESI (POS), M / Z, M + 1: Found 346.1, Calculated 346.22.

(7'S) -5'-Methyl-2 '- ((5- (1-piperazinyl) -2-pyridinyl) amino) -6', 7'-dihydro-5'H-spiro [cyclopent-3-eno-1 , 8'-quinazolin] 7'-ol was prepared (140) from (145) using chemistry similar to that described in example 1 and silyl removal as described in example 72. 1 H-NMR (400 MHz, DMSO-d6) 8 ppm 11.45 (1 H, sa), 9.10 (2 H, sa), 8.63 (1 H,

25 s), 8.05 (1 H, dd, J = 9.4, 2.7 Hz), 7.80 (1 H, d, J = 2.7 Hz), 7.67 (1 H, d , J = 9.4 Hz), 5.95 - 6.09 (1 H, m), 5.71 - 5.83 (1 H, m), 3.78 (1 H, dd, J = 11, 2, 2.9 Hz), 3.36 - 3.48 (4 H, m), 3.29 (4 H, sa), 2.91 - 3.02 (2 H, m), 2.70 - 2.86 (2 H, m), 2.23 (1 H, d, J = 16.8 Hz), 1.97 - 2.09 (1 H, m), 1.41 (1 H, q) , 1.33 (3 H, d, J = 6.7 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 393.2.

Example 72

(7'S) -5'-methyl-2 '- ((5- (1-piperazinyl) -2-pyridinyl) amino) -6'7'-dihydro-5'H-spiro [cyclopentane-1,8'-quinazolin ] -7'-ol

The title compound 146 was prepared from 148 using chemistry similar to that described in example 1. 1 H-NMR (400 MHz, MeOH) 8 ppm 8.55 (1 H, s), 8.10 (1 H, dd, J = 9.6, 2.9 Hz), 7.89 (1 H, d, J = 2.3 Hz), 7.49 (1 H, d, J = 9.4 Hz), 3, 88 (1 H, dd, J = 10.6, 3.1 Hz), 3.46-3.53 (4 H, m), 3.40-3.46 (4 H, m), 2.99 - 3.10 (1 H, m), 2.12 - 2.28 (3 H, m), 1.56 - 2.08 (7 H, m), 1.43 (3 H, d, J = 6.7 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 395.2.

2’-Amino-5’-methyl-6 ’, 7’-dihydro-5’H-spiro [cyclopent-3-eno-1,8’-quinazolin] -7’-ol (147)

Tetrabutylammonium (1.0 M in THF, 13.0 ml, 13 mmol) at a solution of 145 (1.1 g, 3.2 mmol) in THF (20 ml) and stirred at rt for 90 h at a time which the LC-MS showed completion. After concentration in vacuo, the residue was purified by Combi-flash column chromatography (MeOH / DCM) to give alcohol 147 (0.75 g) as an 8: 1 mixture of cis and trans isomers based on 1 H-NMR and HPLC Reverse analytical phase. CLEM-ESI (POS), M / Z, M + 1: Found 232.1.

2'-Amino-5'-methyl-6 ', 7'-dihydro-5'H-spiro [cyclopentane-1,8'-quinazolin] -7'-ol (148) A 2' solution was subjected to hydrogenation -amino-5'-methyl-6 ', 7'-dihydro-5'H-spiro [cyclopent-3-eno-1,8'-quinazolin] -7'-ol (147) (0.65 g, 2 , 8 mmol) in EtOAc (30 ml) in the presence of palladium, 10% by weight (dry base) in activated carbon, wet, type E101 NE / W of Degussa (~ 0.3 g, 2.8 mmol) under 1 H2 atmosphere for 4 h. Then the mixture was filtered through

20 a layer of Celite and concentrated in vacuo to give 2'-amino-5'-methyl-6 ', 7'-dihydro-5'H-spiro [cyclopentane-1,8'quinazolin] -7'-ol ( 148) (0.46 g, 70% yield). CLEM-ESI (POS), M / Z, M + 1: Found 234.1.

Example 73

5’-methyl-2 ’- ((5- (1-piperazinyl) -2-pyridinyl) amino) -7’H-spiro [cyclopentane-1,8’-quinazolin] -7’-one

The title compound 149 was prepared from compound 152 using chemistry similar to that described in the example

2. 1 H-NMR (400 MHz, MeOH) 8 ppm 8.85 (1 H, s), 8.17 (1 H, dd, J = 9.6, 2.9 Hz), 7.96 (1 H , d, J = 2.7 Hz), 7.63 (1 H, d, J = 9.4 Hz), 6.18 (1 H, d, J = 1.2 Hz), 3.49 - 3 , 59 (4 H, m), 3.40 - 3.49 (4 H, m), 2.45 (3 H, d, J = 1.2 Hz), 2.13 - 2.30 (4 H , m), 1.92-2.12 (4 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 391.1. Calculated 391.22.

2’-Amino-5’-methyl-5 ’, 6’-dihydro-7’H-spiro [cyclopentane-1,8’-quinazolin] -7’-one (150) A solution of

10 2'-amino-5'-methyl-6 ', 7'-dihydro-5'H-spiro [cyclopentane-1,8'-quinazolin] -7'-ol (148) (0.42 g, 1, 8 mmol) in DCM (10 ml), 4-methylmorpholine 4-oxide (0.53 g, 4.5 mmol), and tetrapropylammonium perrutenate (0.095 g, 0.27 mmol) with 4A molecular sieves (<5 micrometers , activated (~ 1.8 g) at rt for 22 h After the final treatment, the mixture was filtered through a layer of Celite and the residue was purified after concentration in vacuo by Combi-flash column chromatography ( MeOH / DCM) to give 2'-amino-5'-methyl-5 ', 6'-dihydro-7'H-spiro [cyclopentane-1,8'-quinazolin]

15 7’-one (150) impure (0.28 g, 67% yield) as a colorless film. CLEM-ESI (POS), M / Z, M + 1: Found 232.1.

2'-Amino-6'-bromo-5'-methyl-7'H-spiro [cyclopentane-1,8'-quinazolin] -7'-one (151) and 2'-amino-5'-methyl-7 'Hespiro [cyclopentane-1,8'-quinazolin] -7'-one (152) A solution of 2'-amino-5'-methyl-5', 6'20 dihydro-7'H-spiro was heated to reflux [cyclopentane-1,8'-quinazolin] -7'-one (150) (0.27 g, 1.2 mmol) in mixed solvents of DCM (10 ml) and EtOAc (10 ml) with copper bromide (II ) (0.52 g, 2.3 mmol added in two equal portions over a period of 15 min.) For 9 h and then stirred at rt overnight. More copper (II) bromide (0.52 g, 2.3 mmol) was added to the reaction mixture and the mixture was heated to reflux again for 6 h. More copper (II) bromide (0.52 g, 2.3 mmol) was added to the reaction mixture and the mixture was refluxed once more overnight. After the final treatment, the mixture was cooled to rt and poured onto ice and saturated NH4Cl aqueous solution and extracted with EtOAc (2 X). The combined organic phase was washed with brine (1 X), dried over Na2SO4 and concentrated in vacuo. The crude residue was dissolved in THF (12 ml) and diisopropylethylamine (209 µL, 1.2 mmol) and heated at reflux for 20 h. After removing volatile compounds, the residue was purified by Combi-flash column chromatography (EtOAc / hexanes) to give 2’-amino-6’-bromo-5’-methyl-7’H

10 spiro [cyclopentane-1,8'-quinazolin] -7'-one (151) (57 mg) as a light yellow solid and 2'-amino-5'-methyl-7'Hespiro [cyclopentane-1,8 ' -quinazolin] -7'-one (152) (20 mg). For (151): CLEM-ESI (POS), M / Z, M + 1: Found 308.0 For (152): 1 H-NMR (400 MHz, CHLOROFORM-d) 8 ppm 8.38 (1 H, s ), 5.97 (1 H, s), 5.41 (2 H, sa), 2.30 (3 H, d, J = 1.2 Hz), 1.88 - 2.22 (8 H, m). CLEM-ESI (POS), M / Z, M + 1: Found 230.2.

Example 74

(5'R) -5'-methyl-2 '- ((5- (1-piperazinyl) -2-pyridinyl) amino) -5', 6'-dihydro-7'H-spiro [cyclopent-3-eno -1,8'-quinazolin] 7'-one

The title compound 153 was prepared from 154 using chemistry similar to that described in example 73. 1 H-NMR (500 MHz, MeOH-d4) 8 ppm 8.66 (1 H, s), 8.18 (1 H, dd, J = 9.7, 2.8 Hz), 7.80 (1 H, d, J = 2.4 Hz), 7.47 (1 H, d, J = 9.5

20 Hz), 5.88 (1 H, d, J = 2.0 Hz), 5.75 (1 H, d, J = 2.0 Hz), 3.48 - 3.56 (4 H, m ), 3.37 - 3.47 (5 H, m), 3.20 (1 H, d, J = 16.6 Hz), 2.83 - 3.03 (4 H, m), 2.56 (1 H, dd, J = 14.4, 6.6 Hz), 1.33 (3 H, d, J = 6.8 Hz). CLEM-ESI (POS), M / Z, M + 1: Found 391.1.

2’-Amino-5’-methyl-5 ’, 6’-dihydro-7’H-spiro [cyclopent-3-eno-1,8’-quinazolin] -7’-one. The title compound (154) was prepared from 147 using chemistry similar to that described for compound 150 in example 73. CLEM-ESI (POS), M / Z, M + 1: Found 230.2.

Example 75

4,4-Dimethyl-N- (6- (4- (dimethylamino) piperidin-1-yl) -3-pyridinyl) spiro [cyclohex-2-eno-1,9'pyrido [4 ', 3': 3, 4] cyclopenta [1,2-d] pyrimidin] -2'-amine (racemic) Prepared (155) from 89 using chemistry

5 similar to that described in example 27. 1H-NMR (400 MHz, MeOH-d4) (taken as a TFA salt) 8 ppm 9.46 (1 H, d, J = 2 Hz), 8.90 ( 1 H, s), 8.85 (1 H, d, J = 6.4 Hz), 8.53 (1 H, dd, J = 6, 2.8 Hz), 8.22 (1 H, dt , J = 9.2, 3.2 Hz), 7.98 (1 H, d, J = 3.2 Hz), 7.65 (1 H, d, J = 9.6 Hz), 6.13 (1 H, d, J = 9.6 Hz), 5.22 (1 H, d, J = 9.6 Hz), 4.91 (3 H, sa), 4.90 (3 H, s) , 3.99 (2 H, dm, J = 12.8 Hz), 3.46 (1H, tt, J = 12, 4 Hz), 2.99 (2H, td, J = 12.4, 1, 6 Hz), 2.94 (6H, m), 2.31-2.24 (4 H, m), 2.06 (1 H, m), 1.99 (3 H, m), 1,310 (3H , s), 1.30 (3H, s). CLEM-ESI (POS), M / Z, M + 1: Found 482.4.

10 Example 76

4,4-Dimethyl-N- (6- (4- (dimethylamino) piperidin-1-yl) -pyridazin-3-yl) spiro [cyclohex-2-eno-1,9'pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'-amine (racemic) Prepared (156) from 89 using chemistry similar to that described in example 27. 1 H-NMR (400 MHz, MeOH -d4) (taken as a TFA salt) 8 ppm 9.49 (1 H,

15 s), 8.92 (1 H, s), 8.86 (1 H, d, J = 6 Hz), 8.51 (1 H, dd, J = 6, 2 Hz), 8.11 ( 1 H, d, J = 10 Hz), 8.00 (1 H, d, J = 10 Hz), 6.14 (1 H, d, J = 10 Hz), 5.21 (1 H, d, J = 9.6 Hz), 4.91 (3 H, sa), 4.89 (3 H, s), 4.53 (2 H, dm, J = 14 Hz), 3.58 (1H, tt , J = 12, 3.6 Hz), 3.18 (2H, ta, J = 12 Hz), 2.91 (6H, s), 2.94 (6H, m), 2.27-2.21 (4 H, m), 2.09 (1 H, m), 1.85 (3 H, m), 1.30 (6H, sa). CLEM-ESI (POS), M / Z, M + 1: Found 483.3.

Example 77

4,4-Dimethyl-N- (6 - ((cis-3,5-dimethylpiperazin-1-yl) pyridin-3-yl) spiro [cyclohex-2-eno-1,9'pirido [4 ', 3' : 3,4] cyclopenta [1,2-d] pyrimidin] -2'-amine (racemic) Prepared (157) from 89 using chemistry similar to that described in example 27. 1 H-NMR (400 MHz, MeOH-d4) (taken as a TFA salt) 8 ppm 9.46 (1 H, s), 8.90 (1 H, s), 8.85 (1 H, d, J = 6 Hz), 8 , 53 (1 H, da, J = 5.6 Hz), 8.22 (1 H, d, J = 9.6 Hz), 8.06 (1 H, d, J = 2.8 Hz),

7.73 (1 H, d, J = 9.6 Hz), 6.13 (1 H, d, J = 9.6 Hz), 5.22 (1 H, d, J = 9.6 Hz) , 4.91 (12 H, sa), 3.98 (2 H, dd, J = 13.6, 2.4 Hz), 3.59 (2 H, m), 2.89 (2H, dd, J = 12.8, 11.6 Hz), 2.27 (2H, m), 2.06 (1H, m), 1.88 (1H, m), 1.45 (6 H, d, J = 6.8 Hz), 1.31 (3 H, s), 1.30 (3 H, s). CLEM-ESI (POS), M / Z, M + 1: Found 468.2.

Biological tests

The pharmacological properties of the compounds of this invention can be confirmed by in vitro assays such as those described below.

The inhibitory activity of Cdk4 and Cdk6 of the compounds is measured with a kinase inhibition assay using recombinant Cdk4 / Cyclin D1 or Cdk6 / Cyclin D3 protein complexes. The protein substrate used in the assay is retinoblastoma protein (Rb). The kinase reactions are carried out in a 96-well filter plate (MSDV N6B50, Millipore). The compounds are serially diluted in kinase buffer (20 mM Tris-HCl, pH 7.4, 50 mM NaCl, 1 mM DTT, 1 mg / ml BSA) and added to the reaction mixture containing Cdk4 / Cyclin D1 or Cdk6 / Cyclin D3 2.5 ng / ml, ATP 25 µM, [33P] -ATP 10! Ci / ml, Rb 0.1 µg / ml in the kinase buffer. The mixture is incubated at room temperature for 1 hour and the proteins are precipitated with an equal volume of 20% TCA. The plates are washed with 10% TCA according to the manufacturer's instructions and dried at room temperature. The amount of phosphorylated Rb is determined with a TopCount (PerkinElmer). The IC50 of a compound is determined by non-linear regression curve adjustment using a Prism 5 software program (GraphPad Software).

The cellular activity of the compounds is measured with a cell-based DNA synthesis inhibition assay. Cancer cells positive for Rb (for example Colo-205, MDA-MB-435) or negative for Rb (for example MDA-MB-436, H2009) are seeded in Cytostar 96-well plates (GE Healthcare, no. of cat. RPNQ0163) at a density of 3,000-5,000 cells / well. Dilutions of compounds are added to the cells. After a 24 hour incubation at 37 ° C, 14C-thymidine (0.1 µCi / well) is added. After an additional 48 hour incubation at 37 ° C, the incorporation of 14C-thymidine into the DNA of the cells was measured with a TopCount (PerkinElmer). The IC50 of a compound is determined by non-linear regression curve adjustment using a Prism 5 software program (GraphPad Software).

The inhibitory activity of the Cdk4 or Cdk6 of the compounds with kinase assays of a different format can also be measured, for example, a homogeneous temporal resolution fluorescent energy transfer (HTRF) assay (Jia Y. et al, Anal Biochem. 2006; 356: 273-281) or a fluorescence polarization (FP) assay (Sportsman JR, et al. Comb Chem High Throughput Screen. 2003; 6: 195-200).

The compounds shown by way of example are tested here and have IC50 of Cdk 4 in a range of from 3.5 µm to 0.8 nm, and have IC50 of Cdk 6, which were determined from 2 , 62 µm to 1.1 nm. Illustrative activity values are provided in the following table 5.

TABLE 5

Example compound

IC50 of Cdk 4 (IM) IC50 of Cdk 6 (IM)

3

0.0142 0.0142

fifteen

 0.084 0.0135

2. 3

 2.85 2.62

25

 0.33 0.54

27

 0.074 0.068

29

 0.0059 0.0011

35

 0.077 0.06

40

 0.084 0.033

44

 0.0008 0.027

48

 0.044 0.266

49

 0.668 ND

fifty

 0.0562 0.081

63

 0.41 ND

68

 1.14 ND

71

 0.71 0.51

73

 2.5 ND

74

 3.5 1.8

76

 0.0146 0.205

Formulations

Also encompassed within this invention is a class of pharmaceutical compositions comprising the active compounds of formulas I-II in association with one or more non-toxic pharmaceutically acceptable adjuvants and / or diluents and / or carriers (collectively referred to herein) "carrier" materials) and, if desired, other active ingredients. The active compounds of the present invention can be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted for such route, and in an effective dose for the intended treatment. The compounds and compositions of the present invention can be administered, for example, orally, mucosally, topically, rectally, pulmonaryly, such as by inhalation spray, or parentally including intravascularly. , intravenously, intraperitoneally, subcutaneously, intramuscularly, intraesternally and by infusion techniques, in unit dosage formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles.

The pharmaceutically active compounds of this invention can be processed according to conventional pharmacy methods to produce medicinal agents for administration to patients, including humans and other mammals.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably prepared in the form of a dosage unit containing a particular amount of the active substance. Examples of such dosage units are tablets or capsules. For example, they may contain an amount of active ingredient from about 1 to 2000 mg, preferably from about 1 to 500 mg. A suitable daily dose for a human or other mammal can vary widely depending on the condition of the patient and other factors, but, once again, can be determined using routine methods.

The amount of compounds that are administered and the dosage regimen for the treatment of a pathological condition with the compounds and / or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Therefore, the dosage regimen can vary widely, but can be determined routinely using conventional methods. A daily dose of about 0.01 to 500 mg / kg, preferably between about 0.01 and about 50 mg / kg, and more preferably about 0.01 and about 30 mg / kg with respect to body weight may be appropriate. The daily dose can be administered in one to four doses per day.

For therapeutic purposes, the active compounds of this invention are commonly combined with one or more adjuvants suitable for the indicated route of administration. If administered orally, the compounds can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, alkyl esters of cellulose, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol, and then compressed or encapsulated for convenient administration. Such capsules or tablets may contain a controlled release formulation since it can be provided in a dispersion of the active compound in hydroxypropyl methylcellulose.

In the case of psoriasis and other skin conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day.

Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin (for example, liniments, lotions, ointments, creams or pastes) and drops suitable for administration to the eye, ear or nose. A suitable topical dose of the active ingredient of a compound of the invention is 0.1 mg to 150 mg administered one to four, preferably once or twice daily. For topical administration, the active ingredient may comprise from 0.001% to 10% w / w, for example, from 1% to 2% by weight of the formulation, although it may comprise up to 10% w / w , but preferably not more than 5% w / w and more preferably from 0.1% to 1% of the formulation.

When formulated in an ointment, the active ingredients can be used with an ointment base either paraffinic or water miscible. Alternatively, the active ingredients can be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w / w of a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures. thereof. The topical formulation may desirably include a compound that enhances the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include DMSO and related analogs.

The compounds of this invention can also be administered by a transdermal device. Transdermal administration will preferably be carried out using a patch of either the deposit type and porous membrane or one of the solid matrix variety. In any case, the active agent is continuously supplied from the reservoir or microcapsules through a membrane to the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent can also act as a membrane.

The oil phase of the emulsions of this invention can be constituted from known components in a known manner. Although the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier (s) with or without stabilizer (s) constitute the so-called emulsifying wax, and the wax together with the oil and grease constitute the so-called emulsifying ointment base, which forms the dispersed oil phase of the cream formulations . Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, ketostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art.

The choice of suitable oils and fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound is very low in most oils likely to be used in pharmaceutical emulsion formulations. Therefore, the cream should preferably be a non-greasy product, which does not stain and washable with adequate consistency to prevent leakage of the tubes or other containers. Mono or dibasic, straight or branched chain alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, deisopropyl palmitate, butyl stearate, 2 palmitate can be used -ethylhexyl or a combination thereof branched chain. These can be used alone or in combination depending on the required properties. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

Formulations suitable for topical administration to the eye also include eye drops in which the active ingredients are dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredients. The active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously from 0.5 to 10% and in particular about 1.5% w / w.

Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injections or suspensions for injection. These solutions and suspensions may be prepared from sterile granules or powders using one or more of the carriers or diluents mentioned for use in formulations for oral administration or using other wetting or dispersing agents and suspending agents. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame seed oil, benzyl alcohol, sodium chloride, tragacanth gum and / or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active substance can also be administered by injection as a composition with suitable carriers including saline, dextrose or water, or with cyclodextrin (i.e. Captisol), solubilization of co-solvent (i.e. propylene glycol) or micellar solubilization (i.e. Tween 80) .

The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvent or suspension medium. For this purpose, any mild fixed oil, including synthetic mono or diglycerides, can be used. In addition, fatty acids such as oleic acid find their use in the preparation of injectables.

For pulmonary administration, the pharmaceutical composition may be administered in the form of an aerosol or with an inhaler that includes dry powder aerosol.

Suppositories can be prepared for rectal administration of the drug by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.

The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc. The tablets and pills can be further prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring and perfuming agents.

Claims (35)

1. Compound of formulas I or II enantiomers, diastereomers, salts and solvates thereof in which 5 A1 and A2 together with the ring carbon atoms to which they are attached combine to form benzene, cyclopentadiene, pyridine, pyridone, pyrimidine, pyrazine, pyridazine, 2H-pyran, pyrrole, imidazole, pyrazole, triazole, furan, oxazole , isoxazole, oxadiazole, thiophene, thiazole, isothiazole or thiadiazole any of which may be optionally partially saturated, and any of which may be optionally independently substituted with one or more Rx groups as permitted by valence; 10 W and X are independently CH or N; Z is absent, -O-, -S (O) n-, or -NHR3-; R1 is -Y-Ra in which Y is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl any of which may be optionally independently substituted with one or more Rx groups as 15 allow valence; Y Ra is heterocycle, -NR3R4, -C (= O) NR3R4; -O-R5 or -S (O) n-R5; R2 and R2a are each independently alkyl or alkenyl any of which may be optionally substituted with one or more Rx as permitted by valence; or R2 and R2a together with the ring carbon atom to which they are attached combine to form a spirocondensed ring system 20 of the following formula A in which M is -CRdRe-, -O-, -S (O) n- or -NHR3-; Rb, Rc, Rd and Re are each independently H or Rx, or alternatively Rb and Rd in adjacent carbon ring atoms may optionally combine to form a double bond as allowed by valence, and Rd and Re in Adjacent carbon ring atoms may optionally combine to form a double bond as allowed by valence; R3 and R4 at each occurrence are independently

(i)

 hydrogen or

(ii)

 alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylalkyl, arylalkyl or heteroarylalkyl any of which may be optionally independently substituted with one or more Rx groups as permitted by valence;

or R3 and R4 together with the nitrogen atom to which they are attached can be combined to form an independently substituted heterocycle ring optionally with one or more Rx groups as allowed by valence; R3 * and R4 * at each occurrence are independently

(i)

 hydrogen or

(ii)

 alkyl, alkenyl, alkynyl cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylalkyl, arylalkyl or heteroarylalkyl any of which may be optionally independently substituted with one or more Rx groups as permitted by valence;

or R3 * and R4 * together with the nitrogen atom to which they are attached can be combined to form an independently substituted heterocycle ring optionally with one or more Rx groups as allowed by valence; R5 and R5 * in each occurrence is

(i)

 hydrogen or

(ii)

 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylalkyl, arylalkyl or heteroarylalkyl any of which may be optionally independently substituted with one or more Rx groups as permitted by valence;

R6, R7, R8 and R9 are each independently H or Rx, or alternatively

(i)

 R6 and R7 together with the ring carbon atom to which they are attached can be combined to form = O, = S or = NR3, as allowed by valence;

(ii)

 R8 and R9 together with the ring carbon atom to which they are attached can be combined to form = O, = S or = NR3, as allowed by valence;

(iii) two R6 groups in adjacent ring carbon atoms can be combined to form a double bond as allowed by valence; (iv) R6 and R8 in adjacent ring carbon atoms can be combined to form a double bond as allowed by valence; Rx at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, - (alkylene) m-OR5, - (alkylene ) mS (O) nR5, - (alkylene) m-NR3R4, - (alkylene) mC (= O) R5, - (alkylene) mC (= S) R5, - (alkylene) mC (= O) OR5, - ( alkylene) m-OC (= O) R5, - (alkylene) mC (= S) OR5, - (alkylene) mC (= O) NR3R4, - (alkylene) mC (= S) NR3R4, - (alkylene) mN ( R3) C (= O) NR3R4, - (alkylene) mN (R3) C (= S) NR3R4, - (alkylene) mN (R3) C (= O) R5, - (alkylene) mN (R3) C (= S) R5, - (alkylene) m-OC (= O) NR3R4, - (alkylene) m-OC (= S) NR3R4, - (alkylene) m-SO2NR3R4, - (alkylene) mN (R3) SO2R5, - ( alkylene) mN (R3) SO2NR3R4, - (alkylene) mN (R3) C (= O) OR5, - (alkylene) mN (R3) C (= S) OR5 or - (alkylene) mN (R3) SO2R5; wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, arylalkyl, heteroarylalkyl and cycloalkylalkyl groups may be independently substituted additionally with one or more - (alkylene) m-OR5 *, - (alkylene) mS (O) nR5 *, - (alkylene) m-NR3 * R4 *, - (alkylene) mC (= O) R5 *, - (alkylene) mC (= S) R5 *, - (alkylene) mC (= O) OR5 *, - (alkylene) m-OC (= O) R5 *, - (alkylene) mC (= S) OR5 *, - (alkylene) mC (= O) NR3 * R4 *, - (alkylene ) mC (= S) NR3 * R4 *, - (alkylene) mN (R3 *) C (= O) NR3 * R4 *, - (alkylene) mN (R3 *) C (= S) NR3 * R4 *, - (alkylene) mN (R3 *) C (= O) R5 *, - (alkylene) mN (R3 *) C (= S) R5 *, - (alkylene) m-OC (= O) NR3 * R4 *, - (alkylene) m-OC (= S) NR3 * R4 *, - (alkylene) m-SO2NR3 * R4 *, - (alkylene) mN (R3 *) SO2R5 *, - (alkylene) mN (R3 *) SO2NR3 * R4 *, - (alkylene) mN (R3 *) C (= O) OR5 *, - (alkylene) mN (R3 *) C (= S) OR5 * or - (alkylene) mN (R3 *) SO2R5 *; n is 0, 1 or 2; m is 0 or 1; p and q are independently 0, 1 or 2;

r is 1, 2 or 3 when Z is absent, or is 0, 1 or 2 when Z is present;

wherein the alkyl, alkylenyl, alkenyl and alkynyl radicals may be optionally substituted

with one or more functional groups selected from the group consisting of halo, hydroxyl, nitro, amino,

cyano, haloalkyl, aryl, heteroaryl and heterocycle;

5

wherein alkoxy may be substituted with one or more halogen atoms;

wherein aryl may have one or more substituents selected from the group consisting of C1-6 alkyl,

hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and C1-6 alkylamino, and in which phenyl substituted with -O-CH2-

O- forms the arylbenzodioxolyl substituent;

10

wherein heterocycle may have one to three substituents selected from the group consisting of hydroxyl, Boc, halo, haloalkyl, cyano, C1-6 alkyl, C1-6 aralkyl, oxo, C1-6 alkoxy, amino and C1 alkylamino

6;

wherein aryl in aralkyl may be further substituted with halo, alkyl, alkoxy, haloalkyl and

haloalkoxy; Y

fifteen

wherein cycloalkyl in cycloalkylalkyl may be further substituted with halo, alkyl, alkoxy and hydroxyl.

2.

Compound according to claim 1, wherein A1 and A2 together with the ring atoms to which they are

united combine to form

3.

Compound according to claim 1, wherein Y is cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, phenyl, pyridinyl, pyrimidinyl, cyclopentadienyl, pyrrolyl, pyrazinyl, pyridazinyl, imidazolyl, oxazolyl or thiazolyl.

Four.

Compound according to claim 3, wherein R1 is selected from

5.

Compound according to claim 4, wherein Ra is selected from

(to)

 -OR5 or -S (O) nR5 in which R5 is alkyl optionally independently substituted with one or more -OR5 or -NR3R4;

(b)

-C (= O) NR3R4 or -NR3R4 in which R3 and R4 are independently alkyl optionally independently substituted with one or more -OR5 or -NR3R4;

or R3 and R4 together with the nitrogen atom to which they are attached combine to form

6. Compound according to claim 1, wherein R2 and R2a together with the ring carbon atom to which they are attached combine to form a spirocondensed ring system selected from 7. Compound according to claim 1, having the following formula IA in which t is 0 or 1; Y v is 0, 1, 2, 3 or 4.

8.

Compound according to claim 7, wherein Y is cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, phenyl, pyridinyl, pyrimidinyl, cyclopentadienyl, pyrrolyl, pyrazinyl, pyridazinyl, imidazolyl, oxazolyl or thiazolyl.

9.

Compound according to claim 8, wherein R1 is selected from

10.

Compound according to claim 9, wherein Ra is selected from

(to)

 -OR5 or -S (O) nR5 in which R5 is alkyl optionally independently substituted with one or more -OR5 or -NR3R4;

(b)

-C (= O) NR3R4 or -NR3R4 in which R3 and R4 are independently alkyl optionally independently substituted with one or more -OR5 or -NR3R4;

or R3 and R4 together with the nitrogen atom to which they are attached combine to form

11. Compound according to claim 9, wherein R1 is selected from

12.

Compound according to claim 7, wherein

13.

Compound according to claim 1, which has the following formula IB

in which t is 0 or 1; and v is 0, 1, 2 or 3.

14.

Compound according to claim 13, wherein Y is cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, phenyl, pyridinyl, pyrimidinyl, cyclopentadienyl, pyrrolyl, pyrazinyl, pyridazinyl, imidazolyl, oxazolyl or thiazolyl.

fifteen.

Compound according to claim 14, wherein R1 is selected from

16.

Compound according to claim 15, wherein Ra is selected from

(to)

 -OR5 or -S (O) nR5 in which R5 is alkyl optionally independently substituted with one or more -OR5 or -NR3R4;

(b)

-C (= O) NR3R4 or -NR3R4 in which R3 and R4 are independently alkyl optionally independently substituted with one or more -OR5 or -NR3R4;

or R3 and R4 together with the nitrogen atom to which they are attached combine to form

17. Compound according to claim 15, wherein R1 is selected from 18. Compound according to claim 13, wherein is selected from

19.

Compound according to claim 1, which has the following formula IC

in which t is 0 or 1; and v is 0, 1, 2 or 3.

twenty.

Compound according to claim 19, wherein Y is cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, phenyl, pyridinyl, pyrimidinyl, cyclopentadienyl, pyrrolyl, pyrazinyl, pyridazinyl, imidazolyl, oxazolyl or thiazolyl.

twenty-one.

Compound according to claim 20, wherein R1 is selected from

22

Compound according to claim 21, wherein Ra is selected from

(to)

 -OR5 or -S (O) nR5 in which R5 is alkyl optionally independently substituted with one or more -OR5 or -NR3R4;

(b)

-C (= O) NR3R4 or -NR3R4 in which R3 and R4 are independently alkyl optionally independently substituted with one or more -OR5 or -NR3R4;

or R3 and R4 together with the nitrogen atom to which they are attached combine to form

2. 3.

Compound according to claim 21, wherein R1 is selected from

24.

Compound according to claim 19, wherein

 is selected from 25. A compound according to claim 1, which has the following formula ID in which t is 0 or 1; and v is 0, 1, 2 or 3.

26.

Compound according to claim 25, wherein Y is cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, phenyl, pyridinyl, pyrimidinyl, cyclopentadienyl, pyrrolyl, pyrazinyl, pyridazinyl, imidazolyl, oxazolyl or thiazolyl.

27.

Compound according to claim 26, wherein R1 is selected from

28.

Compound according to claim 27, wherein Ra is selected from

(to)

 -OR5 or -S (O) nR5 in which R5 is alkyl optionally independently substituted with one or more -OR5 or -NR3R4;

(b)

-C (= O) NR3R4 or -NR3R4 in which R3 and R4 are independently alkyl optionally independently substituted with one or more -OR5 or -NR3R4;

or R3 and R4 together with the nitrogen atom to which they are attached combine to form

29. Compound according to claim 27, wherein R1 is selected from 10. A compound according to claim 25, wherein is selected from 31. Pharmaceutically acceptable compound and salts thereof selected from N- (4- (1-piperazinyl) phenyl) spiro [chromene [3,4-d] pyrimidin-5,1'-cyclohexan] -3-amine; N- (4- (4-methyl-1-piperazinyl) phenyl) spiro [chromene [3,4-d] pyrimidin-5,1'-cyclohexan] -3-amine; N- (5- (1-piperazinyl) -2-pyridinyl) spiro [chromene [3,4-d] pyrimidin-5,1'-cyclohexan] -3-amine; N- (4- (4-methyl-1-piperazinyl) phenyl) -1 ’- (phenylcarbonyl) spiro [chromene [3,4-d] pyrimidin-5,4’-piperidin] -3-amine; N- (4- (4-methyl-1-piperazinyl) phenyl) spiro [chromene [3,4-d] pyrimidin-5,4'-piperidin] -3-amine; N- (4- (1-piperazinyl) phenyl) -2 ’, 3’, 5 ’, 6’-tetrahydrospiro [chromene [3,4-d] pyrimidin-5,4’-pyran] -3-amine; N- (6- (1-piperazinyl) -3-pyridinyl) -2 ', 3', 5 ', 6'-tetrahydrospiro [chromene [3,4-d] pyrimidin-5,4'-pyran] -3- amine; N- (2- (1-piperazinyl) -5-pyrimidinyl) -2 ', 3', 5 ', 6'-tetrahydrospiro [chromene [3,4-d] pyrimidin-5,4'-pyran] -3- amine; N- (5- (1-piperazinyl) -2-pyridinyl) -2 ', 3', 5 ', 6'-tetrahydrospiro [chromene [3,4-d] pyrimidin-5,4'-pyran] -3- amine; N- (4- (1-piperazinyl) phenyl) spiro [chromene [3,4-d] pyrimidin-5,1'-cyclopentan] -3-amine; N- (5- (1-piperazinyl) -2-pyridinyl) spiro [chromene [3,4-d] pyrimidin-5,1'-cyclopentan] -3-amine; N- (4- (1-piperazinyl) phenyl) spiro [chromene [3,4-d] pyrimidin-5,1'-cyclobutan] -3-amine; 7-fluoro-N- (4- (1-piperazinyl) phenyl) -2 ', 3', 5 ', 6'-tetrahydrospiro [chromene [3,4-d] pyrimidin-5,4'-pyran] -3 -amine; 7-fluoro-N- (4- (1-piperazinyl) phenyl) spiro [chromene [3,4-d] pyrimidin-5,1'-cyclohexan] -3-amine; 7-fluoro-N- (5- (1-piperazinyl) -2-pyridinyl) spiro [chromene [3,4-d] pyrimidin-5,1'-cyclohexan] -3-amine; 7- (methylsulfonyl) -N- (5- (1-piperazinyl) -2-pyridinyl) spiro [chromene [3,4-d] pyrimidin-5,1'-cyclohexan] -3-amine; 3 - ((5- (1-Piperazinyl) -2-pyridinyl) amino) spiro [chromene [3,4-d] pyrimidin-5,1'-cyclohexane] -7-carbonitrile; N- (4- (1-piperazinyl) phenyl) -2,3,5,6-tetrahydrospiro [pyran-4,6'-pyrido [2 ', 3': 5.6] pyran [3,4-d] pyrimidin] -8'-amine; 4,4-dimethyl-N- (5- (1-piperazinyl) -2-pyridinyl) spiro [cyclohexane-1,5'-pyrido [3 ', 2': 5.6] pyran [3,4-d] pyrimidin] -3 ' amine; 4,4-dimethyl-N- (6- (1-piperazinyl) -3-pyridinyl) spiro [cyclohexane-1,5'-pyrido [3 ', 2': 5.6] pyran [3,4-d] pyrimidin] -3'amine; N- (4- (1-Piperazinyl) phenyl) spiro [cyclohexane-1,5’-pyrido [3 ’, 2’: 5,6] pyrano [3,4-d] pyrimidin] -3’-amine; N- (6- (1-piperazinyl) -3-pyridinyl) spiro [cyclohexane-1,5'-pyrido [3 ', 2': 5,6] pyran [3,4-d] pyrimidin] -3'- amine; N- (5- (1-piperazinyl) -2-pyridinyl) spiro [cyclohexane-1,5'-pyrido [3 ', 2': 5,6] pyran [3,4-d] pyrimidin] -3'- amine; N- (4- (1-piperazinyl) phenyl) -2,3,5,6-tetrahydrospiro [pyran-4,5'-pyrido [3 ', 2': 5,6] pyran [3,4-d] pyrimidin] -3'-amine; N- (5- (1-piperazinyl) -2-pyridinyl) -2,3,5,6-tetrahydrospiro [pyran-4,5'-pyrido [3 ', 2': 5,6] pyran [3,4 -d] pyrimidin] -3 ' amine; 2,2-dimethyl-N- (4- (1-piperazinyl) phenyl) -2,3,5,6-tetrahydrospiro [pyran-4,5'-pyrido [3 ', 2': 5.6] pyran [ 3,4-d] pyrimidin] 3'-amine; (4S) -2,2-dimethyl-N- (4- (1-piperazinyl) phenyl) -2,3,5,6-tetrahydrospiro [pyran-4,5'-pyrido [3 ', 2': 5, 6] pyrano [3,4 d] pyrimidin] -3’-amine; (4R) -2,2-dimethyl-N- (4- (1-piperazinyl) phenyl) -2,3,5,6-tetrahydrospiro [pyran-4,5'-pyrido [3 ', 2': 5, 6] pyrano [3,4d] pyrimidin] -3'-amine; diespiro [1,3-dioxolane-2,1’-cyclohexane-4 ’, 5” -pyrido [3 ’, 2’: 5,6] pyrano [3,4-d] pyrimidin] -3 ”-amine; 3 '- ((5- (1-piperazinyl) -2-pyridinyl) amino) spiro [cyclohexane-1,5'-pyrido [3', 2 ': 5,6] pyran [3,4-d] pyrimidin] -4-ol; 4,4-difluoro-N- (5- (1-piperazinyl) -2-pyridinyl) spiro [cyclohexane-1,5'-pyrido [3 ', 2': 5.6] pyran [3,4-d] pyrimidin] -3 ' amine; 4,4-dimethyl-N- (5- (1-piperazinyl) -2-pyridinyl) spiro [cyclohex-2-eno-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1, 2-d] pyrimidin] 2’-amine; 4,4-dimethyl-N- (4- (1-piperazinyl) phenyl) spiro [cyclohex-2-eno-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d ] pyrimidin] -2'amine; N- (6- (4- (dimethylamino) -1-piperidinyl) -3-pyridinyl) -4,4-dimethylspiro [cyclohex-2-eno-1,9 ’ pyrido [4 ’, 3’: 3,4] cyclopenta [1,2-d] pyrimidin] -2’-amine; 4,4-dimethyl-N- (6- (4-methyl-1-piperazinyl) -3-pyridinyl) spiro [cyclohex-2-eno-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2d] pyrimidin] -2'-amine; N- (6- (1-piperazinyl) -3-pyridinyl) spiro [cyclohexane-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'- amine; N- (4- (1-piperazinylcarbonyl) -1,3-thiazol-2-yl) spiro [cyclohexane-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] 2'-amine; 7,7-dimethyl-N- (4- (1-piperazinyl) phenyl) -6,7-dihydro-5H-cyclopenta [d] pyrimidin-2-amine; N- (4- (1-piperazinyl) phenyl) spiro [indene [2,1-d] pyrimidin-9,4’-piperidin] -2-amine; N- (4- (1-piperidinyl) phenyl) spiro [indene [2,1-d] pyrimidin-9,4'-piperidin] -2-amine; N- (4- (4-morpholinyl) phenyl) spiro [indene [2,1-d] pyrimidin-9,4’-piperidin] -2-amine; 1’-methyl-N- (4- (4-methyl-1-piperazinyl) phenyl) spiro [indene [2,1-d] pyrimidin-9,4’-piperidin] -2-amine; N- (4- (1-piperazinyl) phenyl) -2 ’, 3’, 5 ’, 6’-tetrahydrospiro [indene [2,1-d] pyrimidin-9,4’-piran] -2-amine; N- (4- (4-methyl-1-piperazinyl) phenyl) -2 ', 3', 5 ', 6'-tetrahydrospiro [indene [2,1-d] pyrimidin-9,4'-pyran] -2 -amine; N- (3-fluoro-4- (4-methyl-1-piperazinyl) phenyl) -2 ', 3', 5 ', 6'-tetrahydrospiro [indene [2,1-d] pyrimidin-9,4'- pyran] -2-amine; 4- (4- (spiro [cyclohexane-1,9’-indene [2,1-d] pyrimidin] -2’-ylamino) phenyl) -1-tert-butyl piperazinecarboxylate; N- (4- (1-piperazinyl) phenyl) spiro [cyclohexane-1,9’-indene [2,1-d] pyrimidin] -2’-amine; N- (5- (1-piperazinyl) -2-pyridinyl) spiro [cyclopentane-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'- amine; 9,9-diethyl-N- (5- (1-piperazinyl) -2-pyridinyl) -9H-pyrido [4 ’, 3’: 3,4] cyclopenta [1,2-d] pyrimidin-2-amine N- (5- (1-piperazinyl) -2-pyridinyl) -2,3,5,6-tetrahydrospiro [pyran-4,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2 -d] pyrimidin] -2 ' amine; N- (5- (1-piperazinyl) -2-pyridinyl) spiro [cycloheptane-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'- amine; N- (5- (1-piperazinyl) -2-pyridinyl) spiro [cyclohexane-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'- amine; (3R) -1- (6- (spiro [cyclohexane-1,9'-pyrido [4 ', 3': 3,4] cyclopenta [1,2-d] pyrimidin] -2'-ylamino) -3- pyridazinyl) -3 pyrrolidinol; 2 ’- ((4- (1-piperazinyl) phenyl) amino) spiro [cycloheptane-1,7’-pyrrolo [3,4-d] pyrimidin] -5’ (6’H) -one; 2 ’- ((4- (1-piperazinyl) phenyl) amino) spiro [cyclohexane-1,7’-pyrrolo [3,4-d] pyrimidin] -5’ (6’H) -one; 2 ’- ((4- (1-piperazinyl) phenyl) amino) spiro [cyclopentane-1,7’-pyrrolo [3,4-d] pyrimidin] -5’ (6’H) -one; 2 ’- ((4- (4-methyl-1-piperazinyl) phenyl) amino) spiro [cyclohexane-1,7’-pyrrolo [3,4-d] pyrimidin] -5’ (6’H) -one; 5'-methyl-2 '- ((5- (1-piperazinyl) -2-pyridinyl) amino) -6', 7'-dihydro-5'H-spiro [cyclopent-3-eno-1,8'- quinazolin] -7'-ol; 5'-methyl-2 '- ((5- (1-piperazinyl) -2-pyridinyl) amino) -6', 7'-dihydro-5'H-spiro [cyclopentane-1,8'-quinazolin] -7 '-ol; 5’-methyl-2 ’- ((5- (1-piperazinyl) -2-pyridinyl) amino) -7’H-spiro [cyclopentane-1,8’-quinazolin] -7’-one; 5'-methyl-2 '- ((5- (1-piperazinyl) -2-pyridinyl) amino) -5', 6'-dihydro-7'H-spiro [cyclopent-3-eno-1,8'- quinazolin] -7'-one; 4,4-dimethyl-N- (6- (4- (dimethylamino) piperidin-1-yl) -3-pyridinyl) spiro [cyclohex-2-eno-1,9 ’ pyrido [4 ’, 3’: 3,4] cyclopenta [1,2-d] pyrimidin] -2’-amine; 4,4-dimethyl-N- (6- (4- (dimethylamino) piperidin-1-yl) -pyridazin-3-yl) spiro [cyclohex-2-eno-1.9 ’ pyrido [4 ’, 3’: 3,4] cyclopenta [1,2-d] pyrimidin] -2’-amine; Y 4,4-dimethyl-N- (6 - ((cis-3,5-dimethylpiperazin-1-yl) pyridin-3-yl) spiro [cyclohex-2-eno-1,9'pirido [4 ', 3' : 3,4] cyclopenta [1,2-d] pyrimidin] -2'-amine. 32. Pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable carrier, adjuvant or diluent.

33.

Compound according to claim 1 for use in the treatment of cancer in a subject.

3. 4.

Compound for use according to claim 33, wherein said compound according to claim 1 is administered in combination with at least one compound selected from antibiotic type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, type agents

10 interferon and miscellaneous agents.

35

Compound according to claim 1 for use in reducing tumor size in a subject.

36.

Compound according to claim 1 for use in reducing metastasis in a tumor in a subject.

37.

Use of a compound according to claim 1 for the preparation of a medicament for the treatment of cancer.