HK1132734A - Tetrahydropyridothienopyrimidine compounds and methods of use thereof - Google Patents

Description

Tetrahydropyridothienopyrimidine compounds and methods of use thereof

RELATED APPLICATIONS

This application claims the benefit of U.S. provisional patent application No.60/784,146, filed 2006, 3, 20, the contents of which are incorporated herein by reference.

Technical Field

The present invention relates to novel compounds and methods for their preparation, methods for treating diseases, particularly cancer, comprising administering the compounds, and methods for preparing pharmaceutical compositions for treating or preventing disorders, particularly cancer.

Background

Cancer is a disease caused by abnormal growth of tissues. Some cancers may invade local tissues and may metastasize to distant organs. This disease can occur in a number of different organs, tissues and cell types. Thus, the term "cancer" refers to a collection of over a thousand different diseases.

In 2002, over 440 million people worldwide were diagnosed with breast, colon, ovarian, lung or prostate cancer, and over 250 million people died of these devastating diseases (Globocan 2002 reports). In the united states alone, over 125 million new cases and over 500,000 cases are expected to die of cancer in 2005. Most of these new cases will be colon (100,000), lung (170,000), breast (210,000) and prostate (230,000). It is predicted that the incidence and prevalence of Cancer will increase by about 15% in the next 10 years, reflecting an average growth rate of 1.4% (American Cancer Society for American Cancer, Cancer Facts and regulations Cancer accurate intelligence, 2005).

There are two main types of cancer treatments, radical or palliative. The primary curative treatments for cancer are surgery and radiation therapy. These approaches are often successful only when the cancer is found at an early local stage. Once the disease has progressed to locally advanced or metastatic cancer, these therapies are less effective and the aim of the treatment is to alleviate symptoms and maintain a good quality of life. The most common treatment options in any one treatment modality are combination surgery, radiation therapy and/or chemotherapy.

Cytotoxic drugs (also known as cytoreductive agents) are used to treat cancer, either as a curative therapy or for the purpose of prolonging life or alleviating symptoms. Cytotoxic agents may be used in combination with radiotherapy and/or surgery, as neo-adjuvant therapy (initial chemotherapy aimed at shrinking the tumour, thereby making local treatments such as surgery and radiation more effective) or as adjuvant chemotherapy (for combined or post-operative and/or local treatment). Combinations of different drugs are generally more effective than single drugs: they may advantageously enhance the response of certain tumors, reduce the incidence of drug resistance, and/or increase survival. For these reasons, the use of combination cytotoxic regimens in the treatment of many cancers is very common.

Cytotoxic agents in current use employ different mechanisms to block proliferation and promote cell death. Based on their mechanism of action, they can be generally classified into the following categories: microtubule modulators that interfere with the polymerization or depolymerization of microtubules (e.g., docetaxel, paclitaxel, vinblastine, vinorelbine); antimetabolites, including nucleoside analogs and other inhibitors of key cellular metabolic pathways (e.g., capecitabine, gemcitabine, methotrexate); drugs that interact directly with DNA (e.g., carboplatin, cyclophosphamide); anthracycline DNA interchelators (interchelators) that interfere with DNA polymerase and topoisomerase II (e.g., doxorubicin, epirubicin); and non-anthracycline inhibitors of topoisomerase II and I enzyme activity (e.g., topotecan, irinotecan, and etoposide). Although different cytotoxic drugs act through different mechanisms of action, tumors are usually caused to shrink at least transiently.

Cytotoxic agents would still be an important component in the arsenal of weapons for oncologists to fight cancer. Most drugs currently undergoing recent clinical trials phase I and II focus on the known mechanisms of action (tubulin binding agents, antimetabolites, DNA processing), and the ongoing improvement of known drug classes (e.g., taxanes or camptothecins). Recently, a few cytotoxic drugs based on new mechanisms have emerged. The modes of action of these cytotoxic agents include inhibition of enzymes involved in DNA modification (e.g., Histone Deacetylase (HDAC)), inhibition of proteins involved in microtubule movement and cell cycle progression (e.g., motor proteins, aurora kinases), and novel inducers of the apoptotic pathway (e.g., bcl-2 inhibitors).

Although cytotoxic agents are still at the forefront of approaches to treat patients with advanced solid tumors, their limited efficacy and narrow therapeutic index result in significant side effects. Furthermore, basic research on cancer has been directed towards the study of less toxic therapies based on specific mechanisms in the center of tumor progression. Such studies may lead to effective treatments that improve the quality of life of cancer patients. Thus, a new class of therapeutic agents, called cytostatics, has emerged. Cytostatics act directly on tumor stability, often with more limited and less aggravating side effect profiles. The development of these drugs has resulted from the identification of specific genetic alterations involved in cancer progression and the understanding of activated proteins (e.g., tyrosine kinases and serine/threonine kinases) in tumors.

In addition to direct inhibition of tumor target cells, cytostatic drugs are being developed to block the process of tumor angiogenesis. This process supplies the tumor with existing and new blood vessels to support continued nutrition, thereby helping to promote tumor growth. Key tyrosine kinase receptors including vascular endothelial growth factor receptor 2(VEGFR2), fibroblast growth factor 1(FGFR1), and Tie2 have been shown to modulate angiogenesis and have served as an extremely attractive drug target.

Over the last 5 years, several new drugs have been approved that act on different target molecules. Imatinib (Imatinib) is an inhibitor of Ab1 tyrosine kinase and is the first small molecule tyrosine kinase inhibitor approved for the treatment of Chronic Myelogenous Leukemia (CML). Imatinib was later approved for the treatment of advanced GISTs based on its additional activity against the receptor tyrosine kinase c-KIT activated in gastrointestinal stromal tumors (GISTs). Erlotinib, a small molecule EGFR inhibitor, was approved for the treatment of non-small cell lung cancer (NSCLC) by the end of 2004. Sorafenib, an inhibitor of multiple kinases including c-Raf and VEGFR2, was approved for the treatment of advanced Renal Cell Carcinoma (RCC) at 12 months 2005. Recently Sunitinib, a multi-kinase inhibitor, was approved for the treatment of refractory or drug-resistant GIST and advanced RCC at 1 month 2006. These small molecule inhibitors suggest that the targeted approach can be successfully used to treat different types of cancer.

Summary of The Invention

In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof

Wherein

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

q is 0 or 1;

R¹represents H, (C)₁-C₄) Alkyl, or halogen;

R²selected from H, -CN, halogen, (C)₁-C₄) Alkyl, -O (C)₁-C₄) Alkyl, (C)₂-C₄) Alkenyl, and (C)₂-C₄) An alkynyl group;

R³selected from H, halogen, -CN, (C)₁-C₄) Alkyl, ethynyl, propargyl, and^*-O(CH₂)_par, wherein p is 0, 1, or 2, Ar represents phenyl, pyridyl, thiazolyl, thiophenyl, or pyrazinyl, and wherein Ar optionally has 1 or 2 members selected from (C)₁-C₄) Alkyl and halogen substituents; or

R²And R³May combine, and together with the carbon atoms to which they are attached, form a fused five-or six-membered saturated or unsaturated carbocyclic ring, or form a fused heterocyclic ring in which the combined R is²And R³Radical formulaOrWherein Ar 'and Ar "each represent phenyl, pyridyl, thiazolyl, thienyl, or pyrazinyl, and wherein Ar' and Ar" each optionally have 1 or 2 substituents selected from (C)₁-C₄) Alkyl and halogen substituents;

R⁴selected from H, -CN, (C)₁-C₄) Alkyl, -O (C)₁-C₄) Alkyl, halogen, (C)₂-C₄) Alkenyl, and (C)₂-C₄) An alkynyl group;

R⁵represents H or halogen;

when n is 0, R⁷Is H;

when n is 1, 2, or 3, R⁷Represents:

H；

a hydroxyl group;

-NR¹²R¹³wherein

R¹²Represents H or (C)₁-C₆) Alkane (I) and its preparation methodOptionally having 1 or 2 hydroxyl groups or mono-or di- ((C)₁-C₄) Alkyl) amino groups; and is

R¹³Represents H, (C)₁-C₆) Alkyl, or (C)₃-C₆) Cycloalkyl, said alkyl and cycloalkyl optionally having 1 or 2 hydroxyl groups or mono-or di- ((C)₁-C₄) Alkyl) amino groups;

wherein R is¹⁴Is hydroxy, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, or mono-or di- ((C)₁-C₄) Alkyl) amino, and each alkyl substituent optionally has a hydroxyl substituent;

optionally having 1 or 2 hydroxyl groups, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, or mono-or di- ((C)₁-C₄) Alkyl) amino substituents, each alkyl substituent optionally bearing a hydroxyl substituent, and wherein r is 0, 1, or 2;

optionally having 1 or 2 (C)₁-C₄) Alkyl substituents, each of which optionally having a hydroxy substituent, and wherein

X represents O, S (O)_sOr NR¹⁵Wherein s is 0, 1, or 2; and is

R¹⁵Is represented by (C)₁-C₄) An alkyl group;

or

When n is 2, R⁷And R⁹Can be combined and form a structure with the carbon atoms to which they are attached and the intervening carbon atomsWherein R is¹⁶Is represented by (C)₁-C₄) An alkyl group;

R⁸represents halogen, hydroxy, or (C)₁-C₄) An alkyl group;

R⁹represents H or-CH₂-Y, wherein Y is mono-or di- ((C)₁-C₄) Alkyl) amino, or

R¹⁰Represents H;

or

R⁹And R¹⁰May be joined together to form a bond, forming an acetylenic linkage.

In certain embodiments, m is 0. In certain embodiments, n is 1. In certain embodiments, q is 0.

In certain embodiments, R¹Is hydrogen or fluorine; r²Selected from H, -CN, halogen, (C)₁-C₄) Alkyl, and (C)₂-C₄) An alkynyl group; r³Selected from H, halogen, and^*-O(CH₂)_par, wherein Ar is phenyl, pyridyl, or pyrazinyl, and wherein Ar may be optionally substituted with 1 or 2 halogens, and wherein p is 0 or 1; r⁴Selected from H, -CN and halogen; r⁵Is hydrogen; r⁷is-NR¹²R¹³Wherein R is¹²Represents H or (C)₁-C₆) An alkyl group; and R is¹³Represents H or (C)₁-C₆) An alkyl group.

In certain embodiments, R¹Is hydrogen; r²Selected from H, halogen, and ethynyl; r³Selected from H, halogen, -CN, methyl, and^*-O(CH₂)_par, wherein Ar is phenyl, pyridyl, or pyrazinyl, and wherein Ar may be optionally substituted with 0, 1, or 2 halogens, and wherein p is 0 or 1; r⁴Selected from H, halogen, and (C)₁-C₄) An alkyl group; r⁵Is hydrogen; and R is⁷Is mono-or di- ((C)₁-C₄) Alkyl) amino groups. In certain embodiments, R²Is an ethynyl group; r³Selected from H, halogen, and^*-O(CH₂)_par, wherein Ar is phenyl, pyridyl, or pyrazinyl, and wherein Ar may be optionally substituted with 0, 1, or 2 halogens, and wherein p is 0 or 1; and R is⁴Is hydrogen.

In certain embodiments, R²Is halogen; r³Selected from H, halogen, and^*-O(CH₂)_par, wherein Ar is phenyl, pyridyl, or pyrazinyl, and wherein Ar may be optionally substituted with 0, 1, or 2 halogens, and wherein p is 0 or 1. In certain embodiments, R³Is halogen.

In another aspect, the present invention provides a compound selected from the group consisting of: n- [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl ] -7- [ (2E) -4- (diethylamino) but-2-enoyl ] -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; n- [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl ] -7- [ (2E) -4- (dimethylamino) but-2-enoyl ] -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; n- (3-chloro-4-fluorophenyl) -7- [ (2E) -4- (dimethylamino) but-2-enoyl ] -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; n- (3-chloro-4-fluorophenyl) -7- [ (2E) -4- (diethylamino) but-2-enoyl ] -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; 7- [ (2E) -4- (diethylamino) but-2-enoyl ] -N- (3-ethynylphenyl) -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; 7- [ (2E) -4- (dimethylamino) but-2-enoyl ] -N- (3-ethynylphenyl) -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; n- (3-chloro-4-fluorophenyl) -7- { (2E) -4- [ isopropyl (methyl) amino ] but-2-enoyl } -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; n- (3-chloro-4-fluorophenyl) -7- { (2E) -4- [ ethyl (isopropyl) amino ] but-2-enoyl } -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; n- (3, 4-dichlorophenyl) -7- [ (2E) -4- (dimethylamino) but-2-enoyl ] -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; and N- (3, 4-dichlorophenyl) -7- { (2E) -4- [ isopropyl (methyl) amino ] but-2-enoyl } -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine;

in another aspect, the present invention provides a process for preparing a compound of formula (1), comprising contacting, under conditions to prepare a compound of formula (1),

(i) a compound of formula (7)

Wherein R is¹To R⁵、R⁸M and q have the meanings indicated above, with a compound of the formula (10)

Wherein R is⁷、R⁹And R¹⁰And n has the meaning indicated above, and X is hydroxy, chlorine or bromine, or

(ii) A compound of formula (9)

Wherein R is¹To R⁵、R⁸To R¹⁰M, n and q are as defined above and LG is a leaving group, with the formula R⁷Reaction of a compound of formula (I) -H, wherein R⁷The meaning of (A) is as described above; or

(iii) A compound of formula (14)

Wherein R is⁷To R¹⁰M and n have the meanings indicated above and LG is a leaving group, with a compound of formula (15)

Wherein R is¹To R⁵N and q are as defined above and LG is a leaving group.

In another aspect, the invention provides a pharmaceutical composition comprising a compound as described above and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition is provided in a form suitable for intravenous administration.

In another aspect, the invention provides a method of preparing a pharmaceutical composition. The method comprises the following steps: combining at least one compound as described above and at least one pharmaceutically acceptable carrier, and formulating the resulting composition into a suitable administration form.

In a further aspect, the present invention provides the use of a compound as described above for the manufacture of a pharmaceutical composition for the treatment or prevention of a cell proliferative disorder. In certain embodiments, the cell proliferative disorder is cancer.

In another aspect, the present invention provides a compound of formula (7),

wherein

m is 0, 1, or 2;

q is 0 or 1;

R¹represents H, (C)₁-C₄) Alkyl, or halogen;

R²selected from H, -CN, halogen, (C)₁-C₄) Alkyl, -O (C)₁-C₄) Alkyl, (C)₂-C₄) Alkenyl, and (C)₂-C₄) An alkynyl group;

R³selected from H, halogen, -CN, (C)₁-C₄) Alkyl, ethynyl, propargyl, and^*-O(CH₂)_par, wherein p is 0, 1, or 2, Ar represents phenyl, pyridyl, thiazolyl, thiophenyl, or pyrazinyl, and wherein Ar optionally has 1 or 2 substituents selected from (C)₁-C₄) Alkyl and halogen substituents; or

R²And R³May combine, and together with the carbon atoms to which they are attached, form a fused five-or six-membered saturated or unsaturated carbocyclic ring, or form a fused heterocyclic ring in which the combined R is²And R³Radical formulaOrWherein Ar 'and Ar "each represent phenyl, pyridyl, thiazolyl, thienyl, or pyrazinyl, and wherein Ar' and Ar" each optionally have 1 or 2 substituents selected from (C)₁-C₄) Alkyl and halogen substituents;

R⁴selected from H, -CN, (C)₁-C₄) Alkyl, -O (C)₁-C₄) Alkyl, halogen, (C)₂-C₄) Alkenyl, and (C)₂-C₄) An alkynyl group;

R⁵represents H or halogen; and

R⁸represents halogen, hydroxy, or (C)₁-C₄) An alkyl group.

In another aspect, the present invention provides a compound of formula (9),

wherein

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

q is 0 or 1;

R¹represents H, (C)₁-C₄) Alkyl, or halogen;

R²selected from H, -CN, halogen, (C)₁-C₄) Alkyl, -O (C)₁-C₄) Alkyl, (C)₂-C₄) Alkenyl, and (C)₂-C₄) An alkynyl group;

R³selected from H, halogen, -CN, (C)₁-C₄) Alkyl, ethynyl, propargyl, and^*-O(CH₂)_par, wherein p is 0, 1, or 2, Ar represents phenyl, pyridyl, thiazolyl, thiophenyl, or pyrazinyl, and wherein Ar optionally has 1 or 2 substituents selected from (C)₁-C₄) Alkyl and halogen substituents; or

R²And R³May combine and, together with the carbon atoms to which they are attached, form a fused five-or six-membered saturated or unsaturated carbocyclic ring, or form a fused heterocyclic ring in which the combinations are combinedR of (A) to (B)²And R³Radical formulaOrWherein Ar 'and Ar "each represent phenyl, pyridyl, thiazolyl, thienyl, or pyrazinyl, and wherein Ar' and Ar" each optionally have 1 or 2 substituents selected from (C)₁-C₄) Alkyl and halogen substituents;

R⁴selected from H, -CN, (C)₁-C₄) Alkyl, -O (C)₁-C₄) Alkyl, halogen, (C)₂-C₄) Alkenyl, and (C)₂-C₄) An alkynyl group;

R⁵represents H or halogen;

R⁸represents halogen, hydroxy, or (C)₁-C₄) An alkyl group;

R⁹represents H or-CH₂-Y, wherein Y is mono-or di- ((C)₁-C₄) Alkyl) amino, or

R¹⁰Represents H;

or

R⁹And R¹⁰May be joined together to form a bond, forming an acetylenic bond (acetylenic linkage);

and

LG is a leaving group.

In another aspect, the present invention provides a compound of formula (14),

wherein

m is 0, 1, or 2;

n is 0, 1, 2, or 3; q is 0 or 1;

when n is 0, R⁷Is H;

when n is 1, 2, or 3, R⁷Represents:

H；

a hydroxyl group;

-NR¹²R¹³wherein

R¹²Represents H or (C)₁-C₆) Alkyl, optionally having 1 or 2 hydroxyl groups or mono-or di- ((C)₁-C₄) Alkyl) amino groups; and

R¹³represents H, (C)₁-C₆) Alkyl, or (C)₃-C₆) Cycloalkyl, said alkyl and cycloalkyl optionally having 1 or 2 hydroxyl groups or mono-or di- ((C)₁-C₄) Alkyl) amino groups;

wherein R is¹⁴Is hydroxy, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, or mono-or di- ((C)₁-C₄) Alkyl) amino, and each alkyl substituent optionally has a hydroxyl substituent;

optionally having 1 or 2 hydroxyl groups, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, or mono-or di- ((C)₁-C₄) Alkyl) amino substituents, each alkyl substituent optionally bearing a hydroxyl substituent, and wherein r is 0, 1, or 2;

optionally having 1 or 2 (C)₁-C₄) Alkyl substituents, each of which optionally having a hydroxy substituent, and wherein

X represents O, S (O)_sOr NR¹⁵Wherein s is 0, 1, or 2; and

R¹⁵is represented by (C)₁-C₄) An alkyl group;

or

When n is 2, R⁷And R⁹Can be combined and form a structure with the carbon atoms to which they are attached and the intervening carbon atomsWherein R is¹⁶Is represented by (C)₁-C₄) An alkyl group;

R⁸represents halogen, hydroxy, or (C)₁-C₄) An alkyl group;

R⁹represents H or-CH₂-Y, wherein Y is mono-or di- ((C)₁-C₄) Alkyl) amino, or

R¹⁰Represents H;

or

R⁹And R¹⁰May be joined together to form a bond, forming an acetylenic bond (acetylenic linkage);

and

LG is a leaving group.

In another embodiment, the present invention provides a method of treating a cell proliferative disorder in a subject in need of such treatment, comprising administering to the subject an effective amount of a compound described above. In certain embodiments, the cell proliferative disorder is cancer.

Detailed Description

Unless otherwise indicated, the following definitions apply to technical expressions used throughout the specification and claims.

Adapted for the purposes of the inventionSalt (salt)Preferably, a pharmaceutically acceptable salt of a compound of the invention. See, for example, S.M.Berge et al, "Pharmaceutical salts", J.PharmSci.1977, 66, 1-19.

Pharmaceutically acceptable saltsIncluding mineral, carboxylic and sulfonic acid addition salts, for example, hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, ethanesulfonate, toluenesulfonate, benzenesulfonate, naphthalenedisulfonate, acetate, propionate, lactate, tartrate, malate, citrate, fumarate, maleate and benzoate.

Pharmaceutically acceptable saltsAlso included are salts of the usual bases, such as, and preferably, alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), and ammonium salts (from ammonia or organic amines having 1 to 16 carbon atoms, such as, and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, arginine, lysine, ethylenediamine, and methylpiperidine).

Alkyl radicalDenotes straight-chain or branched alkyl groups having usually 1 to 6, 1 to 4 or 1 to 3 carbon atoms, and illustratively methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Alkylamino radicalIs represented by having 1 or 2 (alone)Independently selected) alkyl substituents, illustratively methylamino, ethylamino, N-propylamino, isopropylamino, tert-butylamino, N-pentylamino, N-hexylamino, N-dimethylamino, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-N-propylamino, N-isopropyl-N-N-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-N-pentylamino, and N-N-hexyl-N-methylamino. The term "mono-or di- ((C)₁-C₄) Alkyl) amino "means having 1 or 2 (independently selected) C₁-C₄Alkylamino of an alkyl substituent.

Halogen elementRepresents fluorine, chlorine, bromine or iodine.

Beside the chemical bondStar signDenotes the point of attachment in the molecule.

The term "cell proliferation disorder" includes disorders involving unwanted or uncontrolled proliferation of cells. The compounds may be used to inhibit, block, reduce, etc., cell proliferation and/or cell division, and/or produce apoptosis. Such methods comprise administering to a patient (including mammals, including humans) in need of such treatment an amount of a compound of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, and the like, effective to treat the condition. Cell proliferative or hyperproliferative disorders include, but are not limited to, for example, psoriasis, keloids and other hyperplasia affecting the skin, Benign Prostatic Hyperplasia (BPH), solid tumors such as breast cancer, respiratory tract cancer, brain cancer, genital cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and their distant metastases. Those conditions also include lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of respiratory cancers include, but are not limited to, small cell and non-small cell lung cancers, as well as bronchial adenocarcinomas and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to, brainstem and hypothalamic (hypophtalmic) gliomas, cerebellum and cerebral astrocytomas, medulloblastomas, ependymomas, and neuroectodermal and pineal tumors.

Cancers of the male reproductive organs include, but are not limited to, prostate cancer and testicular cancer. Female reproductive organ cancers include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancers, as well as uterine sarcomas. Digestive tract cancers include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small bowel and salivary gland cancers.

Urethral cancers include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer, urethral cancer, and human papillary renal cancer.

Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variation), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

Head and neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal, lip and oral cavity cancers, and squamous cell carcinoma. Lymphomas include, but are not limited to, ADDS-associated lymphomas, non-Hodgkin's lymphomas, cutaneous T cell lymphomas, Burkitt's lymphoma, Hodgkin's disease and central nervous system lymphomas.

Sarcomas include, but are not limited to, soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, lymphosarcomas, and rhabdomyosarcomas.

Leukemias include, but are not limited to, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

These conditions are well characterized in humans, but other animals (including mammals) also have similar etiologies and can be treated by administering the pharmaceutical compositions of the present invention.

The term "treating" as used throughout this document is used conventionally, e.g., to treat or care for a subject, with the aim of counteracting, alleviating, reducing, alleviating, ameliorating a condition of a disease or disorder (e.g., cancer).

The term "subject" or "patient" includes organisms, such as humans and non-human animals, that are capable of suffering from a cell proliferative disorder or that benefit from administration of a compound of the invention. Preferably, a human includes a human patient suffering from or susceptible to a cell proliferative disorder or associated symptoms as described herein. The term "non-human animal" includes vertebrates, such as mammals (e.g., rodents, e.g., rats), and non-mammals, such as non-human primates, e.g., sheep, dogs, cows, chickens, amphibians, reptiles, and the like.

Throughout this document, it is preferred that, for brevity, the singular be used rather than the plural, but generally, the plural is intended to be included if not otherwise stated. For example, the expression "a method of treating a disease in a patient comprising administering to the patient an effective amount of a compound of claim 1" is meant to include treating more than one disease simultaneously with the administration of more than one compound of claim 1.

Depending on their structure, the compounds of the present invention may exist in the form of stereoisomers (enantiomers or diastereomers). The present invention therefore relates to enantiomers or diastereomers and to the respective mixtures thereof. These mixtures of enantiomers or diastereomers can be separated into stereoisomerically distinct components by known methods. In addition, certain compounds of the present invention have one or more double bonds, or one or more asymmetric centers. These compounds may be present as racemates, racemic mixtures, single enantiomers, single diastereomers, diastereomeric mixtures, and cis-or trans-or E-or Z-diastereomers. All such isomeric forms of these compounds are expressly included in the present invention.

In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof

Wherein

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

q is 0 or 1;

R¹represents H, (C)₁-C₄) Alkyl, or halogen;

R²selected from H, -CN, halogen, (C)₁-C₄) Alkyl, -O (C)₁-C₄) Alkyl, (C)₂-C₄) Alkenyl, and (C)₂-C₄) An alkynyl group;

R³selected from H, halogen, -CN, (C)₁-C₄) Alkyl, ethynyl, propargyl, and^*-O(CH₂)_par, wherein p is 0, 1, or 2, Ar represents phenyl, pyridyl, thiazolyl, thiophenyl, or pyrazinyl, and wherein Ar optionally has 1 or 2 substituents selected from (C)₁-C₄) Alkyl and halogen substituents; or

R²And R³May combine, and together with the carbon atoms to which they are attached, form a fused five-or six-membered saturated or unsaturated carbocyclic ring, or form a fused heterocyclic ring in which the combined R is²And R³Radical formulaOrWherein Ar 'and Ar "each represent phenyl, pyridyl, thiazolyl, thienyl, or pyrazinyl, and wherein Ar' and Ar" each optionally have 1 or 2 substituents selected from (C)₁-C₄) Alkyl and halogen substituents;

R⁴selected from H, -CN, (C)₁-C₄) Alkyl, -O (C)₁-C₄) Alkyl, halogen, (C)₂-C₄) Alkenyl, and (C)₂-C₄) An alkynyl group;

R⁵represents H or halogen;

when n is 0, R⁷Is H;

when n is 1, 2, or 3, R⁷Represents:

H；

a hydroxyl group;

-NR¹²R¹³wherein

R¹²Represents H or (C)₁-C₆) Alkyl, optionally having 1 or 2 hydroxyl groups or mono-or di- ((C)₁-C₄) Alkyl) amino groups; and is

R¹³Represents H, (C)₁-C₆) Alkyl, or (C)₃-C₆) Cycloalkyl, said alkyl and cycloalkyl optionally having 1 or 2 hydroxyl groups or mono-or di- ((C)₁-C₄) Alkyl) amino groups;

wherein R is¹⁴Is hydroxy, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, or mono-or di- ((C)₁-C₄) Alkyl) amino, and each alkyl substituent optionally has a hydroxyl substituent;

optionally having 1 or 2 hydroxyl groups, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, or mono-or di- ((C)₁-C₄) Alkyl) amino substituents, each alkyl substituent optionally bearing a hydroxyl substituent, and wherein r is 0, 1, or 2;

optionally having 1 or 2 (C)₁-C₄) Alkyl substituents, each of which optionally having a hydroxy substituent, and wherein

X represents O, S (O)_sOr NR¹⁵Wherein s is 0, 1, or 2; and is

R¹⁵Is represented by (C)₁-C₄) An alkyl group;

or

When n is 2, R⁷And R⁹Can be combined and form a structure with the carbon atoms to which they are attached and the intervening carbon atomsWherein R is¹⁶Is represented by (C)₁-C₄) An alkyl group;

R⁸represents halogen, hydroxy, or (C)₁-C₄) An alkyl group;

R⁹represents H or-CH₂-Y, wherein Y is mono-or di- ((C)₁-C₄) Alkyl) amino, or

R¹⁰Represents H;

or

R⁹And R¹⁰May be joined together to form a bond, forming an acetylenic linkage.

In certain embodiments of formula (I), m is 0. In certain embodiments, n is 1. In certain embodiments, q is 0.

In certain embodiments of formula (I), R¹Is hydrogen or fluorine; r²Selected from H, -CN, halogen, (C)₁-C₄) Alkyl, and (C)₂-C₄) An alkynyl group; r³Selected from H, halogen, and^*-O(CH₂)_par, wherein Ar is phenyl, pyridyl, or pyrazinyl, and wherein Ar may be optionally substituted with 1 or 2 halogens, and wherein p is 0 or 1; r⁴Selected from H, -CN and halogen; r⁵Is hydrogen; r⁷is-NR¹²R¹³Wherein R is¹²Represents H or (C)₁-C₆) An alkyl group; and R is¹³Represents H or (C)₁-C₆) An alkyl group.

In certain embodiments of formula (I), R¹Is hydrogen; r²Selected from H, halogen, and ethynyl; r³Selected from H, halogen, -CN, methyl, and^*-O(CH₂)_par, wherein Ar is phenyl, pyridyl, or pyrazinyl, and wherein Ar may be optionally substituted with 0, 1, or 2 halogens, and wherein p is 0 or 1; r⁴Selected from H, halogen, and (C)₁-C₄) An alkyl group; r⁵Is hydrogen; and R is⁷Is mono-or di- ((C)₁-C₄) Alkyl) amino groups. In certain embodiments, R²Is an ethynyl group; r³Selected from H, halogen, and^*-O(CH₂)_par, wherein Ar is phenyl, pyridyl, or pyrazinyl, and wherein Ar may be optionally substituted with 0, 1, or 2 halogens, and wherein p is 0 or 1; and R is⁴Is hydrogen.

In certain embodiments of formula (I), R²Is halogen; r³Selected from H, halogen, and^*-O(CH₂)_par, wherein Ar is phenyl, pyridyl, or pyrazinyl, and wherein Ar may be optionally substituted with 0, 1, or 2 halogens, and wherein p is 0 or 1. In certain embodiments, R³Is halogen.

In certain embodiments, R⁹And R¹⁰Not linked together to form an acetylenic linkage (acetyleniclinkage); in contrast, R⁹Represents H or-CH₂-Y, wherein Y is mono-or di- ((C)₁-C₄) Alkyl) amino, orAnd R is¹⁰Represents H.

In certain embodiments, R⁹And R¹⁰Taken together to form a bond, forming an acetylenic linkage. In these embodiments, the compounds of the present invention may be represented by formula (Ia):

wherein m, n, q and R¹To R⁵And R⁷To R⁸As described above for formula (I), except that R⁷Can not react with R⁹In combination with (in these embodiments, R of formula (I)⁹And R¹⁰Has been combined to form a carbon-carbon triple bond, as shown in formula (Ia).

In another aspect, the present invention provides a compound selected from the group consisting of: n- [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl ] -7- [ (2E) -4- (diethylamino) but-2-enoyl ] -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; n- [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl ] -7- [ (2E) -4- (dimethylamino) but-2-enoyl ] -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; n- (3-chloro-4-fluorophenyl) -7- [ (2E) -4- (dimethylamino) but-2-enoyl ] -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; n- (3-chloro-4-fluorophenyl) -7- [ (2E) -4- (diethylamino) but-2-enoyl ] -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; 7- [ (2E) -4- (diethylamino) but-2-enoyl ] -N- (3-ethynylphenyl) -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; 7- [ (2E) -4- (dimethylamino) but-2-enoyl ] -N- (3-ethynylphenyl) -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; n- (3-chloro-4-fluorophenyl) -7- { (2E) -4- [ isopropyl (methyl) amino ] but-2-enoyl } -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; n- (3-chloro-4-fluorophenyl) -7- { (2E) -4- [ ethyl (isopropyl) amino ] but-2-enoyl } -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; n- (3, 4-dichlorophenyl) -7- [ (2E) -4- (dimethylamino) but-2-enoyl ] -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; and N- (3, 4-dichlorophenyl) -7- { (2E) -4- [ isopropyl (methyl) amino ] but-2-enoyl } -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine.

In another aspect, the present invention provides a process for the preparation of a compound of formula (1) comprising contacting, under conditions to prepare a compound of formula (I),

(i) a compound of formula (7)

Wherein R is¹To R⁵、R⁸M and q have the meanings indicated above, with a compound of the formula (10)

Wherein R is⁷、R⁹And R¹⁰And n has the meaning indicated above, and X is hydroxy, chlorine or bromine, or

(ii) A compound of formula (9)

Wherein R is¹To R⁵、R⁸To R¹⁰M, n and q are as defined above and LG is a leaving group, with the formula R⁷Reaction of a compound of formula (I) -H, wherein R⁷The meaning of (A) is as described above; or

(iii) A compound of formula (14)

Wherein R is⁷To R¹⁰M and n have the meanings indicated above and LG is a leaving group, with a compound of formula (15)

Wherein R is¹To R⁵N and q are as defined above and LG is a leaving group.

The compounds (7), (9) and (14) as described above are useful intermediates for preparing the compounds of the formula (I). For this reason, they are also part of the invention.

It is also understood that the starting materials may be purchased commercially or readily prepared by standard methods well known in the art. These methods include, but are not limited to, the variations listed herein.

If not mentioned otherwise, the reaction is generally carried out in an inert organic solvent which does not change under the reaction conditions. These solvents include ethers such as diethyl ether, 1, 4-dioxane or tetrahydrofuran; halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane or tetrachloroethane; hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions; alcohols, such as methanol, ethanol or isopropanol, nitromethane, dimethylformamide or acetonitrile. It is also possible to use mixed solvents.

The temperature at which the reaction is carried out is usually 0 ℃ to 150 ℃, preferably 0 ℃ to 70 ℃. The reaction may be carried out under normal pressure, under increased pressure or under reduced pressure (e.g. 0.5 to 5 bar). Generally, the reaction is carried out under atmospheric pressure of air or an inert gas (typically nitrogen).

Known chemical reactions and methods may be used for the preparation of the compounds of the invention. However, the following general preparative procedures are set forth to aid the reader in synthesizing the compounds with more detailed specific examples set forth in the experimental section describing the examples below. The preparation of the compounds of the present invention can be illustrated by the following synthetic scheme (I):

schemes (I) and (II) describe the synthesis of certain compounds of formula (I).

Synthesis procedure (I)

As shown in scheme I, piperidone (1) is combined with the appropriate cyanoacetate (ii) in the presence of elemental sulfur and a base (e.g., morpholine), preferably at room temperature, to give the aminothiophene ester of formula (2), according to the procedure Gewald,J.Heterocyclic Chem.1999, 36, 333-345. The aminothiophene ester (2) is then converted to the compound of formula (3) by reaction with a formamide-containing reagent such as pure (neat) formamide or formamidine acetate in a polar solvent such as DMF with heating, preferably to 100 ℃ or above. Heating the compound (3) and a reagent such as phosphorus oxychloride to provide a compound (4) which can be reacted with a variety of substituted anilines(5) (these substituted anilines are readily available or can be synthesized by methods well known in the art), in the presence of a catalytic amount of a concentrated acid (e.g., HCl) and a protic solvent (e.g., ethanol, isopropanol) to afford compound (6). Removal of the protection of the protecting group under acidic conditions gives compounds of formula (7), which are reacted with reagent (10) under classical well-defined conditions to give compounds of formula (I), wherein R⁷As described above. Alternatively, the compound of formula (7) may be reacted with a reagent (8) containing a Leaving Group (LG) or a functional group convertible to LG to give a compound (9). Then using R⁷-H displacement of the leaving group in formula (9) to give the compound of formula (I).

Synthesis procedure (II)

As shown in scheme II, compound (4) is treated with acidic conditions to remove the protection of the Boc group, and the resulting intermediate (11) is combined with amino acid (12) (prepared according to WO 2004066919) to provide compound (13), which can be reacted with a variety of substituted anilines (5) (all of which are readily available or synthesized by methods well known in the art) in the presence of a catalytic amount of concentrated acid (e.g., HCl) and a protic solvent (e.g., ethanol, isopropanol) to provide the compound of formula (I).

Pharmaceutical compositions and methods of treatment

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described above and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition is provided in a form suitable for intravenous administration.

In another aspect, the invention provides a method of preparing a pharmaceutical composition. The method comprises the following steps: combining at least one compound of formula (I) as described above and at least one pharmaceutically acceptable carrier, and formulating the resulting composition into a suitable administration form.

In another embodiment, the present invention provides a method of treating a cell proliferative disorder in a subject in need of such treatment, comprising administering to the subject an effective amount of a compound of formula (I) as described above. In certain embodiments, the cell proliferative disorder is cancer.

In another embodiment, the present invention provides the use of a compound of formula (I) as described above for the manufacture of a pharmaceutical composition for the treatment or prevention of a cell proliferative disorder. In certain embodiments, the cell proliferative disorder is cancer.

When the compound of the present invention is administered as a pharmaceutical product to humans and animals, it can be administered as it is or as a pharmaceutical composition comprising, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of an active ingredient and a pharmaceutically acceptable carrier.

Regardless of the route of administration chosen, the compounds of the present invention may be used in the form of suitable hydrates and/or the pharmaceutical compositions of the present invention may be formulated into pharmaceutically acceptable dosage forms by conventional methods well known to those skilled in the art.

The actual dosage level and timing of administration of the active ingredient in the pharmaceutical compositions of this invention can be varied to obtain a quantity of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration without toxicity to the patient. Exemplary doses are 0.1 to 10mg/kg per day or 0.1 to 15mg/kg per day.

In certain embodiments, the compounds of the present invention may be used in combination therapy with conventional cancer chemotherapy. Conventional treatment regimens for leukemia and other tumors include radiation therapy, drug therapy, or a combination of both.

An antiproliferative therapeutically effective amount or an antiproliferative prophylactically effective amount of a compound of the invention can be readily determined by one of skill in the art, such as a physician or veterinarian ("attending clinician"), by using known techniques or by observing results obtained under similar circumstances. The dosage may vary according to the patient's needs, the severity of the condition being treated and the particular compound employed, at the discretion of the attendant clinician; in determining the antiproliferative therapeutically effective amount or dose, and the antiproliferative prophylactically effective amount or dose, the attending clinician will consider a number of factors including, but not limited to: the particular cell proliferation disorders involved; pharmacodynamic characteristics of a particular drug and its mode and route of administration; the required course of treatment time; the species of mammal; its size, age and general health; the specific conditions involved; severity or extent of involvement of the disorder; the response of the individual patient; the particular compound administered; the mode of administration; bioavailability characteristics of the administered formulation; the selected dosage regimen; the type of concurrent therapy (i.e., the interaction of the compounds of the present invention with other co-administered therapies); and other related circumstances.

Treatment may be initiated using smaller doses than the optimal dose of the compound. The dose can then be increased in small increments until the best effect in this case is achieved. For convenience, the total daily dose may be divided into several portions and administered in divided doses on the day, if desired. An antiproliferative therapeutically effective amount and an antiproliferative prophylactically effective amount of a compound of the invention is expected to vary from about 0.1 milligrams per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day.

The preferred dosage of the compounds of the invention is the maximum that can be tolerated by the patient without serious side effects. For example, the compounds of the present invention are administered at a concentration of about 0.001mg/kg to about 100mg/kg body weight, about 0.01 to about 10mg/kg or about 0.1mg/kg to about 10mg/kg body weight. Ranges intermediate to the above values are also intended to be part of the present invention.

A.Examples

Abbreviations and acronyms

When the following abbreviations are used herein, their meanings are as follows:

general analytical method

The structures of representative compounds of the invention were confirmed by the following methods.

High pressure liquid chromatography-electrospray mass spectrometry (LC-MS) was obtained using one of three analytical LC-MS systems (BRLCQ 1, 2 and 5) under the following conditions:

(A) BRLCQ1 & 2: Hewlett-Packard 1100 HPLC, equipped with quaternary pump, variable wavelength detector (set at 254nm), Waters Sunfire C18 column (2.1X 30mm, 3.5. mu.M), Gilson autosampler and Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra of 120 to 1200amu were scanned using variable ion times depending on the number of source ions. The eluent is A: 2% acetonitrile/water with 0.02% TFA and B: 2% water/acetonitrile with 0.018% TFA. Gradient elution was used from 10% B to 95% over 3.5 minutes at a flow rate of 1.0mL/min, held initially for 0.5 minutes and finally at 95% B for 0.5 minutes. The total run time was 6.5 minutes.

Or

(B) BRLCQ 5: HPLC-electrospray mass spectrometry (HPLC ES-MS) was obtained using an Agilent 1100 HPLC system. The Agilent 1100 HPLC system was equipped with an Agilent 1100 autosampler, a quaternary pump, and a variable wavelength detector (set at 254 nm). The HPLC column used was Waters Sunfire C18 (2.1X 30mm, 3.5. mu.M). HPLC eluates (no fragmentation) were directly ligated to Finnigan LCQ DECA ion trap mass spectrometer with electrospray ionization. Spectra of 140 to 1200amu were scanned using variable ion times depending on the number of source ions. The eluent is A: 2% acetonitrile/water with 0.02% TFA and B: 2% water/acetonitrile with 0.02% TFA. Gradient elution was used from 10% B to 90% B over 3.0 minutes at a flow rate of 1.0mL/min, starting at 1.0 minute and ending at 95% B for 1.0 minute. The total run time was 7.0 minutes.

Conventional one-dimensional NMR spectrum at 300MHzMercury-plus or 400 MHzOperate on a Mercury-plus spectrometer. The samples were dissolved in a solution purchased from Cambridge IsotropeIn a deuterated solvent of (2), and transferred to a 5mm internal diameterIn an NMR tube. Spectra were obtained at 293K. Chemical shifts are recorded on the ppm scale and are referenced to appropriate solvent signals, e.g. for¹H spectrum, DMSO-d₆2.49ppm, CD₃CN-d₃1.93ppm, CD₃OD-d₄3.30ppm, CD₂Cl₂-d₄5.32ppm, and CDCl₃D is 7.26 ppm. The NMR spectrum is consistent with the chemical structure shown.

The final product was sometimes purified using HLPC under the following conditions:

HPLC system equipped with two Gilson 333/334 pumps, Gilson 215 autosampler,UV 155 type diode array detector (dual wavelength), phenomenex gemini 75 x 30mm 5 micron column. The eluent is A: containing 0.1% NH₄Water of OH and B: and (3) acetonitrile. Gradient elution, from 10% B to 90% B over 14 min, flow rate of 100 mL/min. UV triggered acquisition (triggered collection) was performed at 220nm with a sensitivity of 0.5.

Preparation of starting Material

4-bromo-but-2-enoyl bromidePreparation of

To a solution of 4-bromo-crotonic acid (700 mg, 4.24 mmol) in DCM (10 ml)/DMF (1 drop) was added oxalyl bromide (2M/DCM, 2.33 ml, 4.67 mmol, 1.1 eq). The reaction mixture was heated at 40 ℃ for 6 hours. The reaction was allowed to cool to room temperature and then concentrated in vacuo. The crude product was used directly in the next reaction without further purification.

¹HNMR(CD₂Cl₂-d₂)δ 7.22(m，1H)，6.28(d，J＝14.6Hz，1H)，4.10(dd，J＝1.3，7.2Hz，2H).

Preparation of 3-chloro-4- (3-fluoro-benzyloxy) -aniline

To 90 ml of CH₃To CN was added 2-chloro-4-nitrophenol (15 g, 86.4 mmol), followed by potassium carbonate (17.9 g, 129.6 mmol). To the stirred suspension was added 10 ml of 3-fluoro-benzyl bromide (16.3 g, 86.4 mmol) in CH via a dropping funnel₃CN solution. The contents were stirred and heated at 70 ℃ for 18 hours, after which the bright yellow mixture was allowed to cool to room temperature. The yellow contents were poured into water (200 ml) and stirred, at which time solids formed. The solid was filtered and the filter cake was washed with water (50 ml). The collected solid was dried under vacuum to give 2-chloro-1- (3-fluoro-benzoyloxy) -4-nitro-benzene (23 g, 94%) as a white solid.

2-chloro-1- (3-fluoro-benzoyloxy) -4-nitro-benzene (10 g, 35.5 mmol) was suspended in a 500 ml flask containing 50ml of acetic acid and 150 ml of ethyl acetate. Iron (9.9 g, 177.5 mmol) was added to the suspension and the mixture was stirred at room temperatureThe mixture was allowed to stand overnight. The reaction mixture is passed throughFiltering with a thin pad. The filtrate was concentrated in vacuo and saturated Na₂CO₃The aqueous solution was neutralized and then extracted with ethyl acetate. The organic layer was washed with brine, over Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by flash chromatography, eluting with 15% ethyl acetate/hexanes to give 3-chloro-4- (3-fluoro-benzyloxy) -phenylamine [8.5g, 95%, TLC R as a brown solid_f0.4, 30% ethyl acetate/hexane (3:7)]。

¹H-NMR(DMSO-d₆)δ 4.94(s，2H)，5.00(s，2H)，6.40(dd，1H)，6.60(s，1H)，6.87(d，1H)，7.10-7.18(m，1H)，7.20-7.28(m，2H)，7.37-7.44(m，1H).

Preparation of 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamine

2-chloro-4-nitrophenol (10 g, 57.6 mmol, 1 eq), 2-methylpyridyl chloride hydrochloride (9.45 g, 57.6 mmol, 1 eq), cesium carbonate 41.3(126.8 mmol, 2.2 eq), and sodium iodide (8.64 g, 57.6 mmol, 1 eq) were suspended in 200 ml of acetonitrile. The reaction mixture was stirred at 60 ℃ for 5 hours. The resulting suspension was filtered and washed with water (400 ml) to give 2- (2-chloro-4-nitro-phenoxymethyl) -pyridine as a red solid (8 g, 52%).

2- (2-chloro-4-nitro-phenoxymethyl) -pyridine (8 g, 30.2 mmol, 1 eq) and iron (8.44 g, 151.1 mmol, 5 eq) were mixed in acetic acid (100 ml) and ethyl acetate (50ml) and stirred at room temperature overnight. The reaction mixture is passed throughFiltering with a thin pad. The filtrate was concentrated in vacuo and saturated Na₂CO₃Neutralizing the solution. The solution was extracted with ethyl acetate and the organic layer was washed with brine and concentrated in vacuo. The crude product was purified by flash chromatography eluting with ethyl acetate/hexane (3:7) to give 3-chloro-4- (pyridin-2-ylmethoxy) -aniline as a white solid (3.2 g, 52%).

¹H-NMR(CDCl₃-d)δ 5.18(s，2H)，6.50(dd，1H)，6.76(d，1H)，.6.80(d，1H)，7.22(m，1H)，7.64(d，1H)，7.73(td，1H)，8.55(m，1H)；

¹LCMS retention time 0.89 min, [ M + H]⁺＝235.1。

Preparation of 5-amino-1-N- (3-fluorobenzyl) indazole

5-nitroindazole (15 g, 92 mmol, 1 eq), 3-fluorobenzyl bromide (14.7 ml, 119.5 mmol, 1.3 eq) and potassium carbonate 25.4 g (184 mmol, 2 eq) were suspended in 150 ml acetonitrile. The reaction mixture was stirred at 70 ℃ for 12 hours and then allowed to cool to room temperature. The resulting solid was filtered and washed with CH₂Cl₂The filtrate was washed and concentrated in vacuo. The crude mixture of regioisomeric products was purified by column chromatography (5:1 to 4:1 hexanes/ethyl acetate) to give 5-nitro 1-N- (3-fluorophenylmethyl) indazole (7.9 g, 32%) and 5-nitro 2-N- (3-fluorophenylmethyl) indazole (9.2 g, 37%) as yellow solids.

5-Nitro-1-N- (3-fluorophenylmethyl) indazole (7.9 g, 29.1 mmol, 1 equiv.) and iron (8.13 g, 145.6 mmol, 5 equiv.) are mixed in 200 mL of acetic acid and 50mL of ethyl acetate and stirred at room temperature for 36 hours. The reaction mixture is passed throughFiltering with a thin pad. The filtrate was concentrated in vacuo to a volume of 10 ml. The contents were diluted with water (10 ml) and saturated Na₂CO₃Neutralizing the solution. The solution was extracted with ethyl acetate (3X 500 ml) and the combined organic layers were over MgSO₄Dried, filtered, and concentrated in vacuo. The resulting crude product was purified by column chromatography, eluting with hexane/ethyl acetate (4:1 to 3:1), to give 5-amino-1-N- (3-fluorobenzyl) indazole (5.32 g, 76%) as a light brown solid.

¹H-NMR(DMSO-d₆)δ 7.72(s，1H)，7.22-7.36(m，2H)，6.87-7.05(m，3H)，6.70-6.77(m，2H)，5.48(s，2H)，4.78(br s，2H)；

¹LCMS retention time 1.66 min; [ M + H ]]⁺＝242.2。

Using the same method and appropriate reagents described above, 1-pyridin-2-ylmethyl-1H-indazol-5-ylamine was prepared; LC/MS retention time 1.03 min; [ M + H ]]⁺＝225.2。

3-chloro-4- [ (6-methylpyridin-2-yl) methoxy]Preparation of anilines

To 35 ml of CH₃To CN was added (6-methyl-pyridin-2-yl) -methanol (3.5 g, 28.4 mmol), followed by potassium carbonate (17.9 g, 129.6 mmol) and 2-chloro-1-fluoro-4-nitrobenzene (6.48 g, 36.9 mmol). The suspension was stirred and heated at 70 ℃ for 30 hours, after which the bright yellow mixture was allowed to cool to room temperature. The contents were cooled to room temperature, filtered, and charged with CH₂Cl₂And (6) washing. The filtrate was concentrated in vacuo to give a pale yellow solid, triturated with hexane/ethyl acetate (5:1) (triterated) to give 2- [ (2-chloro-4-nitrophenoxy) methyl group as a white solid]6-methylpyridine (4.87 g, 61%).

2- [ (2-chloro-4-nitrophenoxy) methyl group]-6-methylpyridine (4.87 g, 17.5 mmol) and iron powder (4.87 g, 87.4 mmol) were mixed in 150 ml of acetic acid and stirred at room temperature overnight. The reaction mixture is passed throughThe pad was filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo and saturated Na₂CO₃Neutralizing the solution. The contents were extracted with ethyl acetate (5 × 300 ml). The combined organic layers were washed with brine, over MgSO₄Dried, filtered, and concentrated in vacuo. The crude product was triturated (tritulated) with hexane/ethyl acetate (2:1) to give 3-chloro-4- [ (6-methylpyridin-2-yl) methoxy ] as a white solid]Aniline (3.84 g, 88%).

¹H-NMR(DMSO)δ7.70(dd，1H)，7.31(d，1H)，7.17(d，1H)，6.88(d，1H)，6.65(d，1H)，6.44(dd，1H)，5.01(s，2H)，4.93(s，2H)，2.46(s，3H)；

LCMS retention time 0.25 min; [ M + H ] ═ 249.2.

Example 1

1- {4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino]-5, 8-dihydro-6H-9-thia Preparation of (E) -1, 3, 7-triaza-fluoren-7-yl } -4-morpholin-4-yl-but-2-en-1-one

Step 1.2-amino-4, 7-dihydro-5H-thieno [2, 3-c ]]Pyridine-3, 6-dicarboxylic acid 6-tert-butyl ester Preparation of 3-ethyl esters of the base esters

To a solution of 1-Boc-4-piperidone (25.0 g, 123 mmol) in ethanol (100 ml) was added ethyl cyanoacetate (14.2 g, 123 mmol, 1 eq), diethylamine (12.72 ml, 123 mmol, 1 eq) and sulfur (4.14 g, 129 mmol, 1.05 eq). The reaction was stirred at room temperature for 16 h, then filtered and washed with ethanol (25 ml) to give a white solid (33.11 g, 102 mmol, 83%).

¹H NMR(DMSO-d₆) δ 7.31 (width s, 2H), 4.22(s, 2H), 4.13(q, 2H), 3.49(t, 2H), 2.63(t, 2H), 1.39(s, 9H), 1.23(t, 3H);

LCMS retention time 3.49 min, [ M + H]⁺＝326.7。

Step 2.4-oxo-3, 5, 6, 8-tetrahydro-4H-9-thia-1, 3, 7-triaza-fluorene-7-carboxylic acid tert-butyl ester Preparation of butyl esters

To a solution of 6-tert-butyl 3-ethyl 2-amino-4, 7-dihydro-5H-thieno [2, 3-c ] pyridine-3, 6-dicarboxylic acid (5.0 g, 15 mmol) in DMF (50ml) was added formamidine acetate (2.39 g, 23 mmol, 1.5 equivalents). The mixture was heated in an oil bath at 100 ℃ overnight. The reaction mixture was cooled to room temperature and then concentrated in vacuo. Ethyl acetate (50ml) was added to the reaction solid mixture, and stirred at room temperature for 2 hours. The mixture was then filtered and washed with ethyl acetate (25 ml). The solid was placed in a vacuum oven to dry overnight to give a white solid (4.17 g, 90.6%).

¹H NMR(CD₃OD-d₄)δ 8.05(s，1H)，4.57(s，2H)，3.61(t，2H)，2.92(t，2H)，1.42(s，9H)；

LCMS retention time 2.78 min, [ M + H]⁺＝308.0。

Step 3.4-chloro-5, 8-dihydro-6H-9-thia-1, 3, 7-triaza-fluorene-7-carboxylic acid tert-butyl Preparation of esters

To a solution of phosphorus oxychloride (30 ml), triethylamine (30 ml) was added under argon at 0 ℃ for 15 minutes. The flask was then charged with 4-oxo-3, 5, 6, 8-tetrahydro-4H-9-thia-1, 3, 7-triaza-fluorene-7-carboxylic acid tert-butyl ester (4.20 g, 14 mmol). The reaction mixture was stirred at 0 ℃ for 30 minutes and then heated at 65 ℃ for 2 hours. The reaction mixture was allowed to cool to room temperature before concentration in vacuo. The residue was co-evaporated with toluene (2X 200 ml). To the solid residue was added DCM (50mL) and the residue was washed with ice/saturated NaHCO₃The aqueous solution quenches the reaction mixture. The resulting mixture was extracted with DCM (3 × 100 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 4.08 g (12.5 mmol, 89%) of a pale yellow solid.

1H-NMR(CD₂Cl₂-d₂)δ 8.74(s，1H)，4.74(s，2H)，3.78(t，2H)，3.19(t，2H)，1.49(s，9H)；

LCMS retention time 3.53 min, [ M + H]⁺＝326.0。

Step 4.4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino]-5, 8-dihydro-6H-9-thio Preparation of hetero-1, 3, 7-triaza-fluorene-7-carboxylic acid tert-butyl ester

To a solution of 4-chloro-5, 8-dihydro-6H-9-thia-1, 3, 7-triaza-fluorene-7-carboxylic acid tert-butyl ester (3.08 g, 9.40 mmol, 1.05 eq) in 40 ml of isopropanol at room temperature was added 3-chloro-4- (pyridin-2-ylmethoxy) phenylamine (2.10 g, 9.0 mmol, 1 eq). 4N HCl/dioxane (0.1 mL) was added to the reaction mixture to accelerate the reaction. The reaction mixture was heated at 80 ℃ for 16 hours. The mixture was allowed to cool to room temperature, then filtered and washed with IPA (50 ml). DCM (100 ml) and saturated sodium bicarbonate (100 ml) were added to the solid. The mixture was stirred at room temperature for 1 hour before separating the layers. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give 4.50 g of crude product. The crude product was purified by flash chromatography (50% THF/DCM) to give the product as a pale yellow solid (3.60 g, 6.87 mmol, 76%).

1H-NMR(DMSO-d₆) δ 9.32 (width s, 1H), 8.67(d, J ═ 4.0Hz, 1H), 8.40(s, 1H), 8.27(s, 1H), 8.05(t, 1H), 7.79(d, J ═ 2.7Hz, 1H), 7.70(d, J ═ 8.0Hz, 1H), 7.53(t, 1H), 7.24(d, J ═ 8.9Hz, 1H), 5.35(s, 2H), 4.66(s, 2H), 3.66(t, 2H), 3.19(t, 2H), 1.43(s, 9H);

LCMS retention time 3.39 min, [ M + H]⁺＝524.0。

Step 5.[ 3-chloro-4- (pyridin-2-ylmethoxy) -phenyl]- (5, 6, 7, 8-tetrahydro-9-thia) Preparation of (E) -1, 3, 7-triaza-fluoren-4-yl) -amines

To 4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino]To a solution of (e) -5, 8-dihydro-6H-9-thia-1, 3, 7-triaza-fluorene-7-carboxylic acid tert-butyl ester (3.6 g, 6.87 mmol) in DCM (45 ml) was added TFA (5.2 ml, 68.7 mmol)Mole, 10 equivalents). The reaction mixture was stirred at room temperature for 8 hours. The solution mixture was concentrated in vacuo. Saturated NaHCO was added to the residue₃The solution was stirred at room temperature for 1.5 hours. The mixture was then filtered and washed with water. The wet solid was placed in a vacuum oven to dry overnight to give a yellow solid (2.0 g, 67%).

¹H NMR(DMSO-d₆) δ 9.41 (width s, 2H), 8.71(d, J ═ 5.0Hz, 1H), 8.40(s, 1H), 8.11(t, 1H), 7.75(m, 2H), 7.57(m, 1H), 7.53(dd, J ═ 2.7, 9.0Hz, 1H), 7.25(d, J ═ 9.4Hz, 1H), 5.35(s, 2H), 4.48(m, 2H), 3.49(m, 2H), 3.41(m, 2H);

LCMS retention time 2.11 min, [ M + Na]⁺＝446.1。

Step 6.3-bromo-1- {4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino]-5, 8-dihydro Preparation of (E) -6H-9-thia-1, 3, 7-triaza-fluoren-7-yl } -propenone

To [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenyl]To a solution of (5, 6, 7, 8-tetrahydro-9-thia-1, 3, 7-triaza-fluoren-4-yl) -amine (266 mg, 0.63 mmol) in THF (4 ml)/NMP (0.8 ml) was added DIPEA (0.13 ml, 0.75 mmol, 1.2 eq) and the solution was cooled to 0 ℃. To the reaction mixture was added dropwise a solution of 4-bromo-but-2-enoyl bromide (217 mg, 0.75 mmol, 1.2 eq) in THF (2 ml). The mixture was stirred at 0 ℃ for 2 hours. The reaction mixture was washed with saturated NaHCO₃Partitioned between (25 ml) and ethyl acetate (50 ml). The organic layer was washed with water (25 ml) and brine (25 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used in the next reaction without further purification. LCMS retention time 2.89 min, [ M + H]⁺＝571.8。

Step 7.1- {4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino]-5, 8-dihydro Preparation of (E) -6H-9-thia-1, 3, 7-triaza-fluoren-7-yl } -4-morpholin-4-yl-but-2-en-1-one

To the 3-bromo-1- {4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino group]To a solution of-5, 8-dihydro-6H-9-thia-1, 3, 7-triaza-fluoren-7-yl } -propenone (50 mg, 0.09 mmol, 1 eq) in DMF (0.5 ml) was added sodium iodide (14 mg, 0.09 mmol, 1 eq), morpholine (76 mg, 0.9 mmol, 10 eq). The resulting mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo, then resuspended in DCM (10 ml) and saturated NaHCO₃(10 ml) to give a clear two phase. The aqueous layer was extracted with DCM (2 × 10 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude was purified by prep-TLC (10% methanol/DCM) to give a yellow solid (12.4 mg, 0.02 mmol, 24%).

1H-NMR(CD₂Cl₂-d₂) δ 8.50(d, J ═ 4.8Hz, 1H), 8.35(s, 1H), 7.74(m, 1H), 7.69(t, 1H), 7.54(d, J ═ 8.1Hz, 1H), 7.32 (width s, 1H), 7.18(m, 1H), 6.95(d, J ═ 9.0Hz, 1H), 6.78(m, 2H), 6.43(m, 1H), 5.18(s, 2H), 4.78(m, 2H), 3.90(m, 2H), 3.60(m, 4H), 3.08(m, 4H), 2.37(m, 4H);

LCMS retention time 2.18 min, [ M + H]⁺＝577.2。

Example 7

N- (3-chloro-4-fluorophenyl) -7- [ (2E) -4- (dimethylamino) but-2-enoyl]-5，6，7，8- Tetrahydropyrido [4 ', 3': 4, 5]]Thieno [2, 3-d ]]Preparation of pyrimidin-4-amines

Step 1. (3-chloro-4-fluoro-phenyl) - (5, 6, 7, 8-tetrahydro-9-thia-1, 3, 7-triaza-fluorene-4- Preparation of the amino-amines

To a mixture of 4-chloro-5, 8-dihydro-6H-9-thia-1, 3, 7-triaza-fluorene-7-carboxylic acid tert-butyl ester (6.86 g, 0.021 mol) and 3-chloro-4-fluoroaniline (3.2 g, 0.022 mol) in 2-propanol (96 ml) was added 4N HCl/dioxane (0.27 ml) and the mixture was heated to 80 to 85 ℃ overnight. LCMS and TLC (5% methanol/DCM) indicated the absence of the starting material (Boc-protected starting material). 4N HCl/dioxane (10.5 mL, 0.042 mol) was added and heating was continued until LCMS indicated the absence of Boc-protected product. Cooled to room temperature and concentrated to dryness. The mixture was then suspended in dichloromethane (200 ml) and stirred with 1N NaOH (200 ml) for 30 minutes. A clear two-phase layer was obtained. The layers were separated and the aqueous layer was washed with dichloromethane (100 ml). The combined organic layers were washed with water (2 × 100 ml) and then brine (100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to dryness. Drying under vacuum gave 6.61 g (94%) of product as indicated by LCMS and HNMR.

¹H NMR(DMSO-d₆) δ 8.41(s, 1H), 8.24(s, 1H), 7.92(m, 1H), 7.64(m, 1H), 7.39(t, J ═ 9.4Hz, 1H), 3.94 (width s, 1H), 3.32(m, 2H), 3.05(m, 2H), 3.01(m, 2H);

LCMS retention time 2.13 min, [ M + H]⁺＝335。

Step 2.4-bromo-1- [4- (3-chloro-4-fluoro-phenylamino) -5, 8-dihydro-6H-9-thia-1, 3, 7- Triaza-fluoren-7-yl]Preparation of (E) -but-2-en-1-one

To a solution of 4-bromocrotonic acid (2.07 g, 0.012 mol) in dichloromethane (48 ml) at 0 to 5 ℃ was added isobutyl chloroformate (1.70 ml, 0.013 mol) and further 4-methylmorpholine (1.40 ml, 0.013 mol) under nitrogen. The mixture was stirred at this temperature for 1 hour. The resulting suspension was added to a cooled solution of (3-chloro-4-fluoro-phenyl) - (5, 6, 7, 8-tetrahydro-9-thia-1, 3, 7-triaza-fluoren-4-yl) -amine (4.0 g, 0.012 mol) in dichloromethane (200 ml) over a period of 10 minutes. The mixture was stirred at room temperature for 1.5 hours. TLC (10% methanol/DCM) indicated the absence of starting material. The mixture was used directly for further reaction. LCMS retention time 3.55 min, [ M + H]⁺＝483.04。

Step 3N- (3-chloro-4-fluorophenyl) -7- [ (2E) -4- (dimethylamino) but-2-enoyl Base of]-5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]Pyrimidin-4-amines

To an ice-cooled solution of 4-bromo-1- [4- (3-chloro-4-fluoro-phenylamino) -5, 8-dihydro-6H-9-thia-1, 3, 7-triaza-fluoren-7-yl ] -but-2-en-1-one (0.125 g, 0.00026 mol) in dichloromethane (1.25 ml) was added dimethylamine (2.0M in THF) (0.65 ml, 0.001 mol) over 1 to 2 minutes. The resulting mixture was stirred at room temperature for 2 hours. TLC (10% methanol/dichloromethane) indicated the absence of starting material and the appearance of a new polar spot. The reaction mixture was concentrated to dryness under vacuum at 30 ℃. Purification by silica gel chromatography (ISCO system) using a gradient of dichloromethane to 30% methanol/dichloromethane. The fractions were combined, concentrated to dryness and the residue was dissolved in 10% methanol/DCM and filtered through filter paper. The filtrate was concentrated to dryness and dried under vacuum at room temperature O/N to give 0.03 g (23%) of the desired product.

¹H-NMR(CD₃OD-d₃)δ 8.46(m，1H)，8.39(s，1H)，7.88(m，1H)，7.62(m，1H)，7.42(t，1H)，6.67(m，1H)，3.94(m，2H)，3.87(m，4H)，2.75(m，2H)，2.56(s，6H)；

LCMS retention time 2.38 min, M + H]⁺＝446.0。

Example 36

N- (3-chloro-4-fluorophenyl) -7- { (2E) -4- [ isopropyl (methyl) amino group]But-2-enoyl Radical } -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5)]Thieno [2, 3-d ]]Preparation of pyrimidin-4-amines

4-bromo-1- [4- (3-chloro-4-fluoro-phenylamino) -5, 8-dihydro-6H-9-thia-1, 3, 7-triaza-fluoren-7-yl cooled in an ice bath]To a solution of (E) -but-2-en-1-one (0.14 g, 0.291 mmol) in dichloromethane (4.0 ml) was added isopropylmethylamine (0.121 ml, 1.16 mmol) and further DIEA (0.056 ml, 0.32 mmol). The resulting mixture was stirred at room temperature overnight. TLC (10% methanol/dichloromethane) indicated the absence of starting material. The crude product was rotary evaporated to dryness, dissolved in DMF and subjected to HPLC conditions [ H ]₂O (containing 0.1% NH)₄OH)-MeCN]To give the desired product (26 mg, 19%).

¹H-NMR(DMSO-d₆)δ 8.46(m，1H)，8.39(s，1H)，7.88(m，1H)，7.62(m, 1H), 7.42(t, 1H), 6.67(m, 1H), 3.94(m, 2H), 3.87(m, 4H), 2.75(m, 2H), 2.11(s, 3H), 0.96(d, 6H); LCMS retention time 2.53 min, [ M + H]⁺＝474.1。

Using the above-described methods and appropriate starting materials, examples 2 to 131, 186 and 188 to 210 were prepared similarly and are listed in table 1 along with their analytical data and IUPAC names.

Example 132

N- [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl]-7- (5-piperidin-1-ylpent-2-ynoyl) -substituted benzene 5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]Preparation of pyrimidin-4-amines

To a suspension of [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenyl ] - (5, 6, 7, 8-tetrahydro-9-thia-1, 3, 7-triaza-fluoren-4-yl) amine (0.051 g, 0.00028 mol), 5-piperidin-1-yl-pent-2-ynoic acid (0.100 g, 0.00023 mol), O- (benzotriazol-1-yl) -N, N' -tetramethyluronium tetrafluoroborate (0.091 g, 0.00028 mol) in a dichloromethane/tetrahydrofuran (1.2/1.2 ml) mixture was slowly added diisopropylethylamine (0.123 ml, 0.001 mol) over 15 minutes. The mixture was stirred at room temperature for 3 hours. The completion of the reaction was judged by TLC (eluent: 10% methanol/DCM). The reaction mixture was concentrated to dryness in vacuo, dissolved in methanol (1.5 ml), filtered, and purified by reverse phase HPLC to afford the desired product (0.087 g, 62.81%).

¹H-NMR(CD₂Cl₂)δ 8.60(d，1H)，8.45(s，1H)，7.80(m，2H)，7.63(d，1H)，7.41(m，1H)，7.28(m，1H)，7.04(m，2H)，5.25(s，2H)，4.98(d，2H)，4.05(dd，2H)，3.10(d，2H)，2.60(m，4H)，2.40(m，4H)，1.62(m，4H)，1.45(m，2H)；

LCMS retention time 2.37 minutes; [ M + H ]]⁺＝587.1。

HPLC separation conditions:

column-Phenomenex gemini 75X 30mm, 5 micron

The sample was dissolved in 1.5 ml of methanol

Eluent-water/acetonitrile/0.1% ammonium hydroxide @30 ml/min; gradient: from 10 to 90 in 20 minutes

Sensitivity 0.25

Using the above procedure and the appropriate starting materials, examples 133 to 142 were prepared similarly and are listed in table 1, along with their analytical data and IUPAC names.

Example 143

N- [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl]-7- {2- [ (diethylamino) methyl group]Propylene (PA) Acyl } -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5)]Thieno [2, 3-d ]]Preparation of pyrimidin-4-amines

To a suspension of [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenyl ] - (5, 6, 7, 8-tetrahydro-9-thia-1, 3, 7-triaza-fluoren-4-yl) amine (0.053 g, 0.00034 mol), 2-diethylaminomethyl-acrylic acid (0.12 g, 0.00028 mol), O- (benzotriazol-1-yl) -N, N' -tetramethyluronium tetrafluoroborate (0.109 g, 0.00033 mol) in a dichloromethane/tetrahydrofuran (1.2/1.2 ml) mixture was slowly added diisopropylethylamine (0.148 ml, 0.001 mol) over 15 minutes. The mixture was stirred at room temperature for 16 to 18 hours. The completion of the reaction was judged by TLC (eluent: 10% methanol/DCM). The reaction mixture was concentrated to dryness in vacuo, dissolved in methanol (1.5 ml), filtered, and purified by reverse phase HPLC to afford the desired product (0.0173 g, 11.0%).

¹H-NMR(CD₂Cl₂)δ 8.60(d，1H)，8.45(s，1H)，7.80(m，2H)，7.63(d，1H)，7.41(m，1H)，7.28(m，1H)，7.04(m，2H)，5.38(d，2H)，5.25(s，2H)，4.85(s，2H)，4.05(m，2H)，3.20(m，4H)，2.52(br，d，4H)，0.98(br，d，6H)；

LCMS retention time 2.32 min; [ M + H ]]⁺＝563.1。

HPLC separation conditions: column-Phenomenex gemini 75X 30mm, 5 microns. The sample was dissolved in 1.5 ml of methanol. Eluent-water/acetonitrile/0.1% ammonium hydroxide @30 ml/min; gradient: from 10 to 90 in 20 minutes. The sensitivity was 0.1.

Using the above procedure and the appropriate starting materials, examples 144 to 149 were prepared similarly and are listed in table 1, along with their analytical data and IUPAC names.

Example 150

1- {4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino]-5, 8-dihydro-6H-9-thia Preparation of (E) -1, 3, 7-triaza-fluoren-7-yl } -4-morpholin-4-yl-but-2-en-1-one

Step 1: synthesis of 2-but-3-enyloxy-tetrahydro-pyrane

In a 1000 ml round bottom flask, 350 ml of anhydrous dichloromethane containing 3-buten-1-ol (7.21 g, 100.00 mmol), 3, 4-dihydro-2H-pyran (12.62 g, 150.00 mmol) and pyridinium p-toluenesulfonate (2.51 g, 10.00 mmol) were placed. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then concentrated and the residue was purified by column chromatography with hexane/ethyl acetate 100/5 to yield 13.90 g of the desired product as an oil (89.0%).

¹H-NMR(DMSO-d₆)δ 5.851-5.742(m，1H)，5.103-5.011(d，1H)，4.997-4.985(d，1H)，4.555-4.537(t，1H)，3.745-3.611(m，2H)，3.433-3.347(m，2H)，2.290-2.236(m，2H)，1.698-1.675(m，2H)，1.611-1.566(m，4H).

Step 2.5- (tetrahydro-pyran-2-yloxy) -pent-2-enoic acid Synthesis

In a 500 ml round bottom flask, anhydrous dichloromethane (200 ml) containing acrylic acid (2.85 g, 39.6 mmol) and Grubbs' catalyst (1.68 g, 1.98 mmol) was placed. To this solution was added 2-but-3-enyloxy-tetrahydro-pyran (7.73 g, 49.50 mmol) and heated at reflux for 12 hours. The solvent was removed and the residue was purified by chromatography with hexane/ethyl acetate 100/5 to remove the unaltered 2-but-3-enyloxy-tetrahydro-pyran. The column was then eluted with ethyl acetate/methanol 100/1 to yield 6.66 g of a black oil (84%).

¹H-NMR(DMSO-d₆)δ 12.190(s，1H)，6.845-6.771(m，1H)，5.846-5.800(d，1H)，4.565-4.548(t，1H)，3.739-3.674(m，2H)，3.468-3.398(m，2H)，2.481-2.395(m，2H)，1.689-1.609(m，2H)，1.501-1.259(m，4H).

Step 3.1- {4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino]-5, 8-dihydro -6H-9-thia-1, 3, 7-triaza-fluoren-7-yl } -5- (tetrahydro-pyran-2-yloxy) -pent-2-en-1-one Synthesis of ketones

In a 100ml round bottom flask, anhydrous dichloromethane/THF (15 ml/15 ml) containing [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenyl ] - (5, 6, 7, 8-tetrahydro-9-thia-1, 3, 7-triaza-fluoren-4-yl) -amine (2.0 g, 4.71 mmol), 5- (tetrahydro-pyran-2-yloxy) -pent-2-enoic acid (0.94 g, 4.71 mmol) and O- (benzotriazol-1-yl) -N, N' -tetrafluoroborate (1.81 g, 5.66 mmol) was placed and cooled at 0 ℃. To the cooled suspension diisopropylethylamine (1.83 g, 14.15 mmol) (2.5 ml) was added slowly over 15 min. The reaction mixture was then warmed to room temperature and stirred at room temperature for 12 hours. The reaction mixture was concentrated at room temperature (without heating) to remove dichloromethane. Water was added to the residue and the precipitated off-white solid was filtered and washed with water. The off-white solid was further suspended in methanol, sonicated, filtered and dried to give 2.26 g of an off-white solid (80.0%). It was used for the next reaction without any purification.

¹H-NMR(DMSO-d₆)δ 8.593-8.575(m，1H)，8.391(s，1H)，8.191(s，1H)，7.872-7.868(m，1H)，7,769(s，1H)7.571-7.498(m，2H)，7.369-7.329(m，1H)，7.236-7.214(d，1H)，6.779-6.607(m，2H)，5.274(s，2H)，4.946-4.835(d，2H)，4.572(s，1H)，3.928-3.730(m，2H)，3.504-3.402(m，2H)，3.313-3.204(m，4H)，1.673-1.434(m，8H).

MSm/e605.9(M + H), retention time 3.02 min.

And 4, step 4: 1- {4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino]-5, 8-dihydro Synthesis of (E) -6H-9-thia-1, 3, 7-triaza-fluoren-7-yl } -5-hydroxy-pent-2-en-1-one

In a 250 ml round bottom flask, 1- {4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino ] -5, 8-dihydro-6H-9-thia-1, 3, 7-triaza-fluoren-7-yl } -5- (tetrahydro-pyran-2-yloxy) -pent-2-en-1-one (2.26 g, 3.73 mmol) and pyridinium p-toluenesulfonate (0.18 g, 0.74 mmol) in ethanol (100 ml) were placed. The reaction mixture was heated at 80 ℃ for 12 hours. Ethanol was removed by evaporation, methanol was added to the residue, sonicated, and the off-white solid was filtered and washed with methanol to give 1.72 g of an off-white solid (88.40%) after drying.

¹H-NMR(DMSO-d₆)δ 8.587-8.578(m，1H)，8.396(s，1H)，8.182(s，1H)，7.887-7.849(t，1H)，7.769(s，1H)，7.570-7.501(m，2H)，7.368-7.356(t，1H)，7.231-7.209(d，1H)，6.779-6.607(m，2H)，5.271(s，2H)，4.944(s，1H)，4.834(s，1H)，4.661(s，1H)，3.925-3.848(d，2H)，3.519(m，2H)，3.245-3.206(m，2H)，2.360(m，2H).

MS M/e 522.0(M + H), retention time 2.54 min.

Step 5. methanesulfonic acid 5- {4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino]-5，8- Synthesis of dihydro-6H-9-thia-1, 3, 7-triaza-fluoren-7-yl } -5-oxo-pent-3-enyl ester

In a 250 ml round bottom flask, 1- {4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino ] -5, 8-dihydro-6H-9-thia-1, 3, 7-triaza-fluoren-7-yl } -5-hydroxy-pent-2-en-1-one (1.00 g, 1.91 mmol) in THF (80 ml) was placed, to this solution was added triethylamine (0.58 g, 5.74 mmol) (0.80 ml) at 0 deg.C, followed by methanesulfonyl chloride (0.54 g, 4.79 mmol). The reaction mixture was stirred at room temperature overnight. The THF was removed by evaporation, and water and a small amount of methanol were added to the residue, followed by sonication. The precipitated off-white solid was filtered, washed with methanol and dried to yield 0.63 g of off-white solid (55%).

¹H-NMR(DMSO-d₆)δ 8.601-8.585(m，1H)，8.394(s，1H)，8.196(s，1H)，7.906-7.864(m，1H)，7.769(s，1H)，7.584-7.564(d，1H)，7.523-7.501(d，1H)，7.388-7.357(m，1H)，7.239-7.216(d，1H)，6.765-6.703(m，2H)，5.280(s，2H)，4.957(s，1H)，4.843(s，1H)，4.366-4.337(m，2H)，3.940-3.860(m，2H)，3.255-3.189(m，6H)，2.655-2.626(m，2H).

MS M/e 600.0(M + H), retention time 2.78 min.

Step 6.1- {4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino]-5, 8-dihydro -6H-9-thia-1, 3, 7-triaza-fluoren-7-yl]Synthesis of (E) -5-dimethylamino-pent-2-en-1-one

In a 25 ml round bottom flask, 5- {4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino ] -5, 8-dihydro-6H-9-thia-1, 3, 7-triaza-fluoren-7-yl } -5-oxo-pent-3-enyl ester of methanesulfonic acid (0.15 g, 0.25 mmol) in DMF (5.0 ml) was placed, to this solution was added cesium carbonate (0.16 g, 0.5 mmol), followed by dimethylamine (0.5 ml of a 2M/THF solution) and heating at 50 ℃ overnight. The yellow solution was purified twice by HPLC to give 27.5 mg of a light brown solid (20.0%).

¹H-NMR(DMSO-d₆)δ 8.592-8.574(m，1H)，8.378(s，1H)，8.181(s，1H)，7.890-7.847(m，1H)，7.781-7.752(m，1H)，7.572-7.552(d，1H)，7.514-7.492(m，1H)，7.372-7.341(m，1H)，7.237-7.207(m，1H)，5.271(s，2H)，4.942-4.761(m，2H)，3.922-3.781(m，2H)，3.282-3.169(m，4H)，2.343(m，2H)，2.127-1.977(m，8H).

MS M/e 549.1(M + H), retention time 2.26 min.

Using the above procedure and the appropriate starting materials, examples 151 to 159 were prepared similarly and are listed in table 1, along with their analytical data and IUPAC names.

Example 165

N- (3, 4-dichlorophenyl) -7- { (2E) -4- [ isopropyl (methyl) amino]But-2-enoyl Radical } -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5)]Thieno [2, 3-d ]]Preparation of pyrimidin-4-amines

Step 1: 4-chloro-5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]Preparation of pyrimidines Prepare for

To a solution containing 4-chloro-5, 8-dihydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]To a solution of pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (3500 mg, 10.7 mmol) in THF (100 ml) was added 4N cl/1, 4-dioxane (4N, 6 ml). Stirring at room temperatureThe reaction mixture was allowed to react for 24 hours. The white precipitate was collected and dried under reduced pressure to give 2000 mg (82%) of the desired product. LCMS retention time 0.21 min, [ M + 1%]⁺＝226。

Step 2.(2E) -4- (4-chloro-5, 8-dihydropyrido [4 ', 3': 4, 5)]Thieno [2, 3-d ]]Pyrimidines Preparation of (E) -7(6H) -yl) -N, N-dimethyl-4-oxobut-2-en-1-amine

To a solution containing 4-chloro-5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]To a solution of pyrimidine (1000 mg, 4.0 mmol, 90% pure) in THF (20 ml) was added (2E) -4- (dimethylamino) but-2-enoic acid hydrochloride (730 mg, 4.4 mmol), EDCI (840 mg, 4.4 mmol), DMAP (97 mg, 0.8 mmol), and diisopropylethylamine (120 mg, 8.0 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was then concentrated to dryness under reduced pressure. The residue was purified by ISCO using 20% ethyl acetate/methanol to give 1100 mg (82%) of the desired product. LCMS retention time ═ 1.51 min, [ M + 1-]⁺＝337。

And step 3: n- (3, 4-dichlorophenyl) -7- { (2E) -4- [ isopropyl (methyl) amino]But-2-enoyl Radical } -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5)]Thieno [2, 3-d ]]Preparation of pyrimidin-4-amines

To a solution of (2E) -4- (4-chloro-5, 8-dihydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-7 (6H) -yl) -N, N-dimethyl-4-oxobut-2-en-1-amine (50 mg, 0.15 mmol) in ethanol (2 ml) was added HCl/1, 4-dioxane (4N, 0.02 ml) and 3-bromoaniline (26 mg, 0.16 mmol). The reaction was heated (80 ℃) for 4 hours and then cooled to room temperature. The mixture was extracted with ethyl acetate (2 ml) and the extract was concentrated to dryness under reduced pressure. The residue was dissolved in a mixture of methanol and acetonitrile and purified by HPLC using 70% acetonitrile/water to give 9 mg (13%) of the desired product.

¹H-NMR(CD₃OD-d₃)δ 8.42(s，1H)，7.99(m，1H)，7.57(m，1H)，7.46(m，1H)，6.80(m，1H)，4.93(m，2H)，4.04(t，2H)，3.20(m，4H)，2.31(s，3H)，2.29(s，3H)；

LCMS retention time 2.60 min, [ M + 1%]⁺＝462.3。

Using the above-described methods and appropriate starting materials, examples 161 through 164 and 166 through 185 were prepared similarly and are listed in table 1 along with their analytical data and IUPAC names.

Example 187

N- (3, 4-dichlorophenyl) -7- { (2E) -4- [ isopropyl (methyl) amino]But-2-enoyl Radical } -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5)]Thieno [2, 3-d ]]Preparation of pyrimidin-4-amines

Step 1.(3, 4-dichloro-phenyl) - (5, 6, 7, 8-tetrahydro-9-thia-1, 3, 7-triaza-fluorene-4- Preparation of the amino-amines

Following the same procedure as described in example 7, step 1 used 4-chloro-5, 8-dihydro-6H-9-thia-1, 3, 7-triaza-fluorene-7-carboxylic acid tert-butyl ester (3.5 g, 0.011 mol), 3, 4-dichloroaniline (1.9 g, 0.012 mol), 4N HCl/dioxane (1.3 ml)/2-propanol (72 ml) to give the desired product (3.0 g, 72%). LCMS retention time 2.77 min, [ M + H]⁺＝351.8。

Step 2.N- (3, 4-dichlorophenyl) -7- { (2E) -4- [ isopropyl (methyl) amino group]But-2-enoyl Radical } -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5)]Thieno [2, 3-d ]]Preparation of pyrimidin-4-amines

To CH containing 4-bromo-but-2-enoic acid (638 mg, 3.87 mmol)₂Cl₂To this was added isopropylmethylamine (1.1 ml, 10.3 mmol), the mixture was stirred for 2 hours, then (3, 4-dichloro-phenyl) - (5, 6, 7, 8-tetrahydro-9-thia-1, 3, 7-triaza-fluoren-4-yl) -amine (1.0 g, 2.57 mmol), EDCI (493 mg, 2.58 mmol), DIPEA (1.8 ml, 10.3 mmol) were added. The resulting mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified by HPLC to give the desired compound (500 mg, 13%).

¹H-NMR(DMSO-d₆)δ 8.46(m，1H)，8.39(s，1H)，7.88(m，1H)，7.62(m，1H)，7.42(t，1H)，6.67(m，1H)，3.94(m，2H)，3.87(m，4H)，2.75(m，2H)，2.11(s，3H)，0.96(d，6H)；

LCMS retention time 2.72 min, [ M +1 ═ M]⁺＝490.3。

Analytical data for selected embodiments

The following is the analytical data for the examples:

example 2: n- [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl]-7- [ (2E) -4- (diethylamino) Radical) but-2-eneAcyl radical]-5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]Pyrimidin-4-amines

¹H-NMR(CD₂Cl₂-d₂) δ 8.50(d, J ═ 4.50Hz, 1H), 8.36(s, 1H), 7.74(s, 1H), 7.68(td, J ═ 7.63, 1.37Hz, 1H), 7.54(d, J ═ 7.83Hz, 1H), 7.33 (width s, 1H), 7.19(m, 1H), 6.95(d, J ═ 9.0Hz, 1H), 6.79(m, 2H), 6.42(m, 1H), 5.18(s, 2H), 4.81(m, 2H), 3.88(m, 2H), 3.19(m, 2H), 3.12(m, 2H), 2.49(m, 4H), 0.97(m, 6H);

LCMS retention time 2.37 min, [ M + H]⁺＝563.2。

Example 3: n- [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl]-7- [ (2E) -4- (dimethylamino) Radical) but-2-enoyl]-5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]Pyrimidin-4-amines

¹H-NMR(CD₂Cl₂-d₂)δ 8.50(d，J＝4.70Hz，1H)，8.36(s，1H)，7.75(s，1H)，7.69(td，J＝7.68，1.27Hz，1H)，7.54(d，J＝7.83Hz，1H)，7.32(s，1H)，7.18(m，1H)，6.96(d，J＝8.80Hz，1H)，6.79(m2H)，6.43(m，1H)，5.19(s，2H)，4.82(m，2H)，3.90(m，2H)，3.10(m，4H)，2.24(s，3H)，2.17(s，3H)；

LCMS retention time 2.31 min, [ M + H]⁺＝536.2。

Example 4: n- [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl]-7- [ (2E) -4-piperidine-1- Ylbut-2-enoyl]-5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]Pyrimidin-4-amines

¹H-NMR(CD₂Cl₂-d₂)δ 8.50(d，J＝4.70Hz，1H)，8.36(s，1H)，7.75(d，J＝1.76Hz，1H)，7.69(td，J＝7.68，1.66Hz，1H)，7.54(d，J＝7.83Hz，1H)，7.35(s，1H)，7.18(m，1H)，6.96(d，J＝8.80Hz，1H)，6.82(s，1H)，6.75(s，1H)，6.42(m，1H)，5.19(s，2H)，4.81(m，2H)，3.91(m，2H)，3.11(m，4H)，2.39(m，4H)，1.56(m，4H)，1.37(m，2H)；

LCMS retention time 2.39 min, [ M + H]⁺＝575.2。

Example 5: n- [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl]-7- [ (2E) -4- (4-methylpiperazine) Oxazin-1-yl) but-2-enoyl]-5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]Pyrimidines -4-amine

¹H-NMR(CD₃OD-d₃)δ 8.55(d，J＝4.50Hz，1H)，8.32(s，1H)，7.91(t，1H)，7.78(m，1H)，7.70(d，J＝7.83Hz，1H)，7.41(m，2H)，7.10(d，J＝9.00Hz，1H)，6.82(m，1H)，6.43(m，1H)，5.23(s，2H)，5.00(m，4H)，4.02(t，2H)，3.24(m，4H)，2.75(m，2H)，2.29(m，4H)，2.04(s，3H)；

LCMS retention time 2.32 min, [ M + H]⁺＝590.2。

Example 6: n- (3-chloro-4-fluorophenyl) -7- [ (2E) -4-morpholin-4-ylbut-2-enoyl Base of]-5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]Pyrimidin-4-amines

¹H-NMR(CD₂Cl₂-d₂)δ 8.49(s，1H)，7.93(m，1H)，7.46(m，1H)，7.18(t，1H)，6.84(m，1H)，6.65(m，2H)，4.89(m，2H)，4.00(m，2H)，3.68(m，4H)，3.17(m，4H)，2.46(m，4H)；

LCMS retention time 2.40 min, [ M + H]⁺＝488.1。

Example 8: n- (3-chloro-4-fluorophenyl) -7- [ (2E) -4- (4-methylpiperazin-1-yl) but-2-ene Acyl radical]-5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]Pyrimidin-4-amines

¹H-NMR(CD₃OD-d₃)δ 8.36(s，1H)，7.87(m，1H)，7.54(m，1H)，7.22(t，1H)，6.82(s，1H)，6.78(m，1H)，4.02(t，2H)，3.27(m，4H)，3.22(m，2H)，2.75(m，4H)，2.64(m，4H)，2.47(s，3H)；

LCMS retention time 2.32 min, [ M + H]⁺＝501.1。

Example 9: n- (3-chloro-4-fluorophenyl) -7- [ (2E) -4- (diethylamino) but-2-enoyl Base of]-5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]Pyrimidin-4-amines

¹H-NMR(CD₃OD-d₃)δ 8.39(s，1H)，7.87(m，1H)，7.54(m，1H)，7.24(t，1H)，7.13(dd，J＝15.0，37.0Hz，1H)，6.80(m，1H)，4.06(t，2H)，3.93(t，2H)，3.30(m，4H)，3.16(m，4H)，1.31(t，6H)；

LCMS retention time 2.52 min, [ M + H]⁺＝474.1。

Example 10: n- { 3-chloro-4- [ (3-fluorophenylmethyl) oxy]Phenyl } -7- [ (2E) -4-morpholine-4- Ylbut-2-enoyl]-5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]Pyrimidin-4-amines

¹H-NMR(CD₂Cl₂-d₂)δ 8.45(s，1H)，7.81(m，1H)，7.40(m，2H)，7.26(m，2H)，7.06(td，J＝8.48，2.34Hz，1H)，7.00(d，J＝8.77Hz，1H)，6.84(m，2H)，6.55(m，1H)，5.17(s，2H)，4.88(m，2H)，4.03(m，2H)，3.69(m，4H)，3.17(m，4H)，2.46(m，4H)；

LCMS retention time 2.86 min, [ M + H]⁺＝594.3。

Example 11: n- { 3-chloro-4- [ (3-fluorophenylmethyl) oxy]Phenyl } -7- [ (2E) -4- (dimethyl) benzene Alkylamino) but-2-enoyl]-5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]Pyrimidines -4-amine

¹H-NMR(DMSO-d₆)δ 8.38(s，1H)，8.19(m，1H)，7.76(d，J＝7.60Hz，1H)，7.51(d，J＝8.96Hz，1H)，7.45(m，1H)，7.32-7.15(m，5H)，6.77(m，1H)，5.23(s，2H)，3.90(m，2H)，3.57(m，2H)，3.32(m，4H)，2.51(s，6H)；

LCMS retention time 2.83 min, [ M + H]⁺＝552.2。

Example 12: n- (3-chloro-4-fluorophenyl) -7- [ (2E) -4-piperidin-1-ylbut-2-enoyl Base of]-5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]Pyrimidin-4-amines

¹H-NMR(DMSO-d₆)δ 8.42(s，1H)，8.34(m，1H)，7.86(m，1H)，7.60(m，1H)，7.39(t，1H)，6.69(m，2H)，4.94(s，1H)，4.83(s，1H)，3.87(m，2H)，3.23(m，2H)，3.06(m，2H)，2.31(m，4H)，1.47(m，4H)，1.36(m，2H)；

LCMS retention time 2.55 min, [ M + H]⁺＝486.2。

Example 13: n- { 3-chloro-4- [ (3-fluorophenylmethyl) oxy]Phenyl } -7- [ (2E) -4- (diethyl) acetate Alkylamino) but-2-enoyl]-5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]Pyrimidines -4-amine

¹H-NMR(DMSO-d₆)δ 8.40(s，1H)，8.20(m，1H)，7.74(m，1H)，7.46(d，J＝7.83Hz，1H)，7.43(m，1H)，7.30(m，2H)，7.21(d，J＝9.2Hz，1H)，7.16(t，1H)，6.72(m，2H)，5.24(s，2H)，4.96(s，1H)，4.86(s，1H)，3.88(m，2H)，3.28(m，8H)，0.97(m，6H)；

LCMS retention time 2.89 min, [ M + H]⁺＝580.2。

Example 14: n- { 3-chloro-4- [ (3-fluorophenylmethyl) oxy]Phenyl } -7- [ (2E) -4- (4-methyl) benzene Piperazin-1-yl) but-2-enoyl]-5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]Pyrimidine as one kind of food Pyridin-4-amines

¹H-NMR(DMSO-d₆)δ 8.40(s，1H)，8.22(s，1H)，7.78(m，1H)，7.54(d，J＝8.61Hz，IH)，7.49(m，1H)，7.34(m，2H)，7.24(d，J＝9.2Hz，1H)，7.20(t，1H)，6.73(m，2H)，5.27(s，2H)，4.97(s，1H)，4.87(s，1H)，3.94(m，2H)，3.38(s，3H)，3.26(m，2H)，3.14(m，2H)，2.37(m，8H)；

LCMS retention time 3.00 min, [ M + H]⁺＝607.3。

Example 15: n- (3-ethynylphenyl) -7- [ (2E) -4-morpholin-4-ylbut-2-enoyl Base of]-5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]Pyrimidin-4-amines

¹H-NMR(CD₂Cl₂-d₂)δ 8.50(s，1H)，7.87(m，1H)，7.69(m，1H)，7.36(t，1H)，7.27(d，J＝7.6Hz，1H)，7.05(d，J＝38.9Hz，1H)，6.86(m，1H)，6.55(m，1H)，4.89(m，2H)，4.00(m，2H)，3.70(m，4H)，3.21(s，1H)，3.18(m，4H)，2.47(m，4H)；

LCMS retention time 2.29 min, [ M + H]⁺＝460.2。

Example 16: 7- [ (2E) -4- (diethylamino) but-2-enoyl]-N- (3-ethynylbenzene Yl) -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]Pyrimidin-4-amines

¹H-NMR(CD₂Cl₂-d₂)δ 8.49(s，1H)，7.87(m，1H)，7.69(m，1H)，7.36(t，1H)，7.27(d，J＝7.6Hz，1H)，7.05(d，J＝38.9Hz，1H)，6.90(m，1H)，6.56(m，1H)，4.89(m，2H)，4.00(m，2H)，3.23(m，4H)，3.21(s，1H)，2.55(m，4H)，1.05(m，6H)；

LCMS retention time 2.32 min, [ M + H]⁺＝446.1。

Example 17: 7- [ (2E) -4- (dimethylamino) but-2-enoyl]-N- (3-ethynylbenzene

Yl) -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5]Thieno [2, 3-d ]]Pyrimidin-4-amines

¹H-NMR(CD₃OD-d₃)δ 8.37(s，1H)，7.81(m，1H)，7.62(m，1H)，7.32(t，1H)，7.22(d，J＝7.6Hz，1H)，6.89-6.70(m，2H)，4.02(t，2H)，3.52(s，1H)，3.27(m，2H)，3.20(m，4H)，2.29(s，6H)；

LCMS retention time 2.27 min, [ M + H]⁺＝418.1。

TABLE 1

B. Physiological activity of the compound

The utility of the compounds of the present invention can be demonstrated, for example, by their in vitro activity in the in vitro tumor cell proliferation assay described below. The art has clearly established a link between activity in vitro tumor cell proliferation assays and anti-tumor activity in clinical settings. For example, the therapeutic use of paclitaxel (Silvestrini et al, Stem Cells 1993, 11(6), 528-35), docetaxel (Bissery et al, Anti Cancer Drugs 1995, 6(3), 339), and topoisomerase inhibitors (Edelman et al, Cancer Chemother. Pharmacol. (Cancer chemotherapeutics) 1996, 37(5), 385-93) was demonstrated using in vitro tumor proliferation assays.

Many of the compounds and compositions described herein have antiproliferative activity, IC, in any of the cell lines specified₅₀Less than or equal to 50. mu.M, and are therefore useful in the prevention or treatment of conditions associated with hyperproliferation. The following assay is one of the methods used to determine the activity of compounds associated with the treatment of the conditions specified herein.

A tumor cell proliferation assay for detecting a compound of the invention, comprisingDeveloped under the name Cell Luminescent Cell visual Assay (cell luminescent drop)Luminescence cell viability assay) (Cunningham, BA "AGrowing Issue: cell Proliferation Assays, model kits for The quantification of Cell growth "The scientists 2001, 15(13), 26, and Crouch, SP et al," The use of ATP biologics as a means of Cell Proliferation and cytotoxicity (use of ATP bioluminescence to measure Cell Proliferation and cytotoxicity) "Journal of Immunological Methods (impurities in immunology) 1993, 160, 81-88," which was used to measure inhibition of Cell Proliferation. The production of a luminescent signal corresponds to the amount of ATP present, which is proportional to the number of metabolically active (proliferating) cells.

In vitro tumor cell proliferation assay in A431 and BT474 cell lines

At 2.5X 10³Cell/well Density A431 cells [ human epidermoid carcinoma, ATCC # HTB-20, overexpressing HER1(EGFR, ErbB1)]And N87[ human gastric carcinoma, ATCC # CRL-1555, overexpressing HER2(ErbB2) and HER1(EGFR, ErbB1)]The cells were placed in a 96-well black-clear bottom (black-clear bottom) tissue culture plate, and cultured in RPMI medium containing 10% fetal bovine serum at 37 ℃. After 24 hours, test compound was added to a final concentration of 100 μm up to 64pM low, depending on the activity of the test compound in serial dilutions at a final DMSO concentration of 0.1%. After addition of test compound, cells were cultured in whole growth medium at 37 ℃ for 72 hours. After 72 hours drug exposure, the plates were allowed to equilibrate to room temperature for approximately 30 minutes. Then, Promega Cell Titer Glo was usedAssay kit, a lysis buffer containing 100 microliters of a mixture of luciferase and its substrate luciferin is added to each well. The plates were mixed for 2 minutes on an orbital shaker to ensure cell lysis and incubated for 10 min at room temperatureThe clock stabilizes the light signal. The sample signals were read on VICTOR 2 using Luminescence recording (luminence protocol) and analyzed with Analyze5 software to yield IC₅₀Numerical values. Representative compounds of the invention in this assay showed inhibition of tumor cell proliferation.

Activity in a431 cell line: examples 1-7, 9-22, 26, 59, 92, 105, 108, 110, 114, 115, 118, 123, 124, 126, 150, 157, 158, 160, 194, 199, 205, and 206₅₀Less than 200 nM; examples 8, 24, 25, 36, 40, 41, 46, 47, 49, 51, 54, 56, 60-69, 85, 87, 93-95, 97-104, 109, 111, 113, 116, 117, 119, 122, 125 and 125, 129, 132, 135, 138, 143, 147, 149, 159, 161, 165, 170, 172, 176, 180, 182, 192, 200, 204, and 207, 209₅₀200 to 1000 nM; examples 23, 27-39, 42-45, 48, 50, 52, 53, 57, 58, 70, 72-84, 86, 88, 89, 90, 91, 96, 136, 137, 144, 146, 148, 151, 155, 166, 169, 171, 173, 175, 177, 179, 181 and 193 ICs₅₀Is 1. mu.M to 10. mu.M.

Activity in N87 cell line: examples 1-22, 24-28, 32, 33, 36, 37, 39-51, 53-70, 72-129, 131, 144, 146, 152, 165, and 167, 210₅0 is less than 200 nM; ICs of embodiments 23, 29, 30, 31, 35, 38, 52, 145, 151 and 166₅₀200 to 5000 nM.

In vitro tumor cell proliferation assay in H1975 cells

At 3X 10³Cell/well Density H1975 cells [ human non-Small cell Lung cancer, ATCC # CRL-5908, express mutant HER1[ (EGFR, ErbB1) (L858R, T790M)]The cells were placed in a 96-well black-clear bottom tissue culture plate, placed in RPMI medium containing 10% fetal bovine serum, and cultured at 37 ℃. After 24 hours, test compound was added to a final concentration of 10 μ M up to 64pM low, depending on the activity of the test compound in serial dilutions at a final DMSO concentration of 0.1%. After addition of test compound, cells were cultured in whole growth medium at 37 ℃ for 72 hours. Medicine and food additiveAfter 72 hours of exposure, the plates were allowed to equilibrate to room temperature for about 30 minutes. Then, Promega Cell Titer Glo was usedAssay kit, a lysis buffer containing 100 microliters of a mixture of luciferase and its substrate luciferin is added to each well. The plates were mixed for 2 minutes on an orbital shaker to ensure cell lysis and incubated for 10 minutes at room temperature to stabilize the luminescence signal. The sample signals were read on VICTOR 2 using luminescence recordings and analyzed using Analyze5 software to yield IC₅₀Numerical values. Representative compounds of the invention in this assay showed inhibition of tumor cell proliferation.

Activity in H1975 cell line: the ICs of examples 21, 24, 26, 28, 36, 59, 65, 70, 92, 93, 98, 107, 110, 1114, 115, 117, 118, 122, 124, 126, 129, 135, 150, 160, 165, 183, 187, 194, 195, 199, 205 and 206₅₀Less than 200 nM; examples 1, 3, 4, 7, 12, 16, 17, 20, 22, 25, 27, 40, 45-47, 49, 50, 54-57, 60-64, 66-69, 72, 75, 77, 79, 81-83, 85-91, 94-97, 99-101, 104-106, 108, 109, 111-113, 116, 119, 121, 125, 127, 128, 132-134, 139-143, 149, 157-159, 161, 163, 164, 172, 176, 186, 188-190, 192, 196-198, 200-202, 204, 207, 208 and 209₅₀200 to 1000 nM; examples 2, 5, 6, 8, 9, 10, 11, 13-15, 19, 23, 29, 30-35, 37-39, 41-44, 48, 51-53, 58, 73, 74, 76, 78, 80, 84, 102, 103, 136, 144, 148, 151, 156, 162, 166, 171, 173, 175, 177, 182, 184, 185, 191, 193 and 203₅₀Is 1. mu.M to 10. mu.M.

The disclosures of all patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety.

Although the present invention has been disclosed with reference to particular embodiments, it is evident that other embodiments and variations of the present invention may be devised by others skilled in the art without departing from the spirit and scope of the present invention. It is intended that the claims include all such embodiments and equivalent variations.

Claims (21)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof

Wherein

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

q is 0 or 1;

R¹represents H, (C)₁-C₄) Alkyl or halogen;

R²selected from H, -CN, halogen, (C)₁-C₄) Alkyl, -O (C)₁-C₄) Alkyl, (C)₂-C₄) Alkenyl, and (C)₂-C₄) An alkynyl group;

R³selected from H, halogen, -CN, (C)₁-C₄) Alkyl, ethynyl, propargyl, and^*-O(CH₂)_par, wherein p is 0, 1, or 2, Ar represents phenyl, pyridyl, thiazolyl, thiophenyl, or pyrazinyl, and wherein Ar optionally has 1 or 2 substituents selected from (C)₁-C₄) Alkyl and halogen substituents; or

R²And R³May combine, and together with the carbon atoms to which they are attached, form a fused five-or six-membered saturated or unsaturated carbocyclic ring, or form a fused heterocyclic ring in which the combined R is²And R³Radical formulaOrWherein Ar 'and Ar "each represent phenyl, pyridyl, thiazolyl, thienyl, or pyrazinyl, and wherein Ar' and Ar" each optionally have 1 or 2 substituents selected from (C)₁-C₄) Alkyl and halogen substituents;

R⁴selected from H, -CN, (C)₁-C₄) Alkyl, -O (C)₁-C₄) Alkyl, halogen, (C)₂-C₄) Alkenyl, and (C)₂-C₄) An alkynyl group;

R⁵represents H or halogen;

when n is 0, R⁷Is H;

when n is 1, 2, or 3, R⁷Represents:

H；

a hydroxyl group;

-NR¹²R¹³wherein

R¹²Represents H or (C)₁-C₆) Alkyl, optionally having 1 or 2 hydroxyl groups or mono-or di- ((C)₁-C₄) Alkyl) amino groupClustering; and is

R¹³Represents H, (C)₁-C₆) Alkyl, or (C)₃-C₆) Cycloalkyl, said alkyl and cycloalkyl optionally having 1 or 2 hydroxyl groups or mono-or di- ((C)₁-C₄) Alkyl) amino groups;

wherein R is¹⁴Is hydroxy, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, or mono-or di- ((C)₁-C₄) Alkyl) amino, and each alkyl substituent optionally has a hydroxyl substituent;

optionally having 1 or 2 hydroxyl groups, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, or mono-or di- ((C)₁-C₄) Alkyl) amino substituents, each alkyl substituent optionally bearing a hydroxyl substituent, and wherein r is 0, 1, or 2;

optionally having 1 or 2 (C)₁-C₄) Alkyl substituents, each of which optionally having a hydroxy substituent, and wherein

X represents O, S (O)_sOr NR¹⁵Wherein s is 0, 1, or 2; and is

R¹⁵Is represented by (C)₁-C₄) An alkyl group;

or

When n is 2, R⁷And R⁹Can be combined and form a structure with the carbon atoms to which they are attached and the intervening carbon atomsWherein R is¹⁶Is represented by (C)₁-C₄) An alkyl group;

R⁸represents halogen, hydroxy, or (C)₁-C₄) An alkyl group;

R⁹represents H or-CH₂-Y, wherein Y is mono-or di- ((C)₁-C₄) Alkyl) amino, or

R¹⁰Represents H;

or

R⁹And R¹⁰May be taken together to form a bond to form an acetylenic bond.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 0.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein n is 1.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein q is 0.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein

R¹Is hydrogen or fluorine;

R²selected from H, -CN, halogen, (C)₁-C₄) Alkyl, and (C)₂-C₄) An alkynyl group;

R³selected from H, halogen, and^*-O(CH₂)_par, wherein Ar is phenyl, pyridyl, or pyrazinyl, and wherein Ar may be optionally substituted with 1 or 2 halogens, and wherein p is 0 or 1;

R⁴selected from H, -CN and halogen;

R⁵is hydrogen;

R⁷is-NR¹²R¹³Wherein

R¹²Represents H or (C)₁-C₆) An alkyl group; and is

R¹³Represents H or (C)₁-C₆) An alkyl group.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein

R¹Is hydrogen;

R²selected from H, halogen, and ethynyl;

R³selected from H, halogen, -CN, methyl, and^*-O(CH₂)_par, wherein Ar is phenyl, pyridyl, or pyrazinyl, and wherein Ar may be optionally substituted with 0, 1, or 2 halogens, and wherein p is 0 or 1;

R⁴selected from H, halogen, and (C)₁-C₄) An alkyl group;

R⁵is hydrogen; and is

R⁷Is mono-or di- ((C)₁-C₄) Alkyl) amino groups.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein

R²Is an ethynyl group;

R³selected from H, halogen, and^*-O(CH₂)_par, wherein Ar is phenyl, pyridyl, or pyrazinyl, and wherein Ar may be optionally substituted with 0, 1, or 2 halogens, and wherein p is 0 or 1; and is

R⁴Is hydrogen.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein

R²Is halogen; and is

R³Selected from H, halogen, and^*-O(CH₂)_par, wherein Ar is phenyl, pyridyl, or pyrazinyl, and wherein Ar may be optionally substituted with 0, 1, or 2 halogens, and wherein p is 0 or 1.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R³Is halogen.

10. A compound selected from:

n- [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl ] -7- [ (2E) -4- (diethylamino) but-2-enoyl ] -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine;

n- [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl ] -7- [ (2E) -4- (dimethylamino) but-2-enoyl ] -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine;

n- (3-chloro-4-fluorophenyl) -7- [ (2E) -4- (dimethylamino) but-2-enoyl ] -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine;

n- (3-chloro-4-fluorophenyl) -7- [ (2E) -4- (diethylamino) but-2-enoyl ] -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine;

7- [ (2E) -4- (diethylamino) but-2-enoyl ] -N- (3-ethynylphenyl) -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine;

7- [ (2E) -4- (dimethylamino) but-2-enoyl ] -N- (3-ethynylphenyl) -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine;

n- (3-chloro-4-fluorophenyl) -7- { (2E) -4- [ isopropyl (methyl) amino ] but-2-enoyl } -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine;

n- (3-chloro-4-fluorophenyl) -7- { (2E) -4- [ ethyl (isopropyl) amino ] but-2-enoyl } -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine;

n- (3, 4-dichlorophenyl) -7- [ (2E) -4- (dimethylamino) but-2-enoyl ] -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine; and

n- (3, 4-dichlorophenyl) -7- { (2E) -4- [ isopropyl (methyl) amino ] but-2-enoyl } -5, 6, 7, 8-tetrahydropyrido [4 ', 3': 4, 5] thieno [2, 3-d ] pyrimidin-4-amine;

11. a process for the preparation of a compound as claimed in claim 1, which comprises, under the conditions of the preparation of a compound as claimed in claim 1,

(i) a compound of formula (7)

Wherein R is¹To R⁵、R⁸M and q have the meanings stated in claim 1,

with a compound of formula (10)

Wherein R is⁷、R⁹And R¹⁰And n has the meaning indicated in claim 1, and X is hydroxy, chlorine or bromine, or

(ii) A compound of formula (9)

Wherein R is¹To R⁵、R⁸To R¹⁰M, n and q have the meanings indicated in claim 1, and LG is a leaving group, with the formula R⁷Reaction of a compound of formula (I) -H, wherein R⁷Has the meaning as claimed in claim 1; or

(iii) A compound of formula (14)

Wherein R is⁷To R¹⁰M and n have the meanings stated in claim 1, and LG is a leaving group,

with a compound of formula (15)

Wherein R is¹To R⁵N and q have the meanings stated in claim 1, and LG is a leaving group.

12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12 in a form suitable for intravenous administration.

14. A process for preparing a pharmaceutical composition comprising combining at least one compound of claim 1 and at least one pharmaceutically acceptable carrier and formulating the resulting composition into a suitable administration form.

15. Use of a compound according to claim 1 for the manufacture of a pharmaceutical composition for the treatment or prevention of a cell proliferative disorder.

16. The use of claim 15, wherein the cell proliferative disorder is cancer.

17. A compound of formula (7)

Wherein

m is 0, 1, or 2;

q is 0 or 1;

R¹represents H, (C)₁-C₄) Alkyl, or halogen;

R²selected from H, -CN, halogen, (C)₁-C₄) Alkyl, -O (C)₁-C₄) Alkyl, (C)₂-C₄) Alkenyl, and (C)₂-C₄) An alkynyl group;

R³selected from H, halogen, -CN, (C)₁-C₄) Alkyl, ethynyl, propargyl, and^*-O(CH₂)_par, wherein p is 0, 1, or 2, Ar represents phenyl, pyridyl, thiazolyl, thiophenyl, or pyrazinyl, and wherein Ar optionally has 1 or 2 substituents selected from (C)₁-C₄) Alkyl and halogen substituents; or

R²And R³May combine, and together with the carbon atoms to which they are attached, form a fused five-or six-membered saturated or unsaturated carbocyclic ring, or form a fused heterocyclic ring in which the combined R is²And R³Radical formulaOrWherein Ar 'and Ar "each represent phenyl, pyridyl, thiazolyl, thienyl, or pyrazinyl, and wherein Ar' and Ar" each optionally have 1 or 2 substituents selected from (C)₁-C₄) Alkyl and halogen substituents;

R⁴selected from H, -CN, (C)₁-C₄) Alkyl, -O (C)₁-C₄) Alkyl, halogen, (C)₂-C₄) Alkenyl, and (C)₂-C₄) An alkynyl group;

R⁵represents H or halogen; and is

R⁸Represents halogen, hydroxy, or (C)₁-C₄) An alkyl group.

18. A compound of formula (9)

Wherein

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

q is 0 or 1;

R¹represents H, (C)₁-C₄) Alkyl, or halogen;

R²selected from H, -CN, halogen, (II) ((III))C₁-C₄) Alkyl, -O (C)₁-C₄) Alkyl, (C)₂-C₄) Alkenyl, and (C)₂-C₄) An alkynyl group;

R³selected from H, halogen, -CN, (C)₁-C₄) Alkyl, ethynyl, propargyl, and^*-O(CH₂)_par, wherein p is 0, 1, or 2, Ar represents phenyl, pyridyl, thiazolyl, thiophenyl, or pyrazinyl, and wherein Ar optionally has 1 or 2 substituents selected from (C)₁-C₄) Alkyl and halogen substituents; or

R²And R³May combine, and together with the carbon atoms to which they are attached, form a fused five-or six-membered saturated or unsaturated carbocyclic ring, or form a fused heterocyclic ring in which the combined R is²And R³Radical formulaOrWherein Ar 'and Ar "each represent phenyl, pyridyl, thiazolyl, thienyl, or pyrazinyl, and wherein Ar' and Ar" each optionally have 1 or 2 substituents selected from (C)₁-C₄) Alkyl and halogen substituents;

R⁴selected from H, -CN, (C)₁-C₄) Alkyl, -O (C)₁-C₄) Alkyl, halogen, (C)₂-C₄) Alkenyl, and (C)₂-C₄) An alkynyl group;

R⁵represents H or halogen;

R⁸represents halogen, hydroxy, or (C)₁-C₄) An alkyl group;

R⁹represents H or-CH₂-Y, wherein Y is mono-or di- ((C)₁-C₄) Alkyl) amino, or

R¹⁰Represents H;

or

R⁹And R¹⁰Can be connected withTogether form a bond, forming an acetylenic bond; and is

LG is a leaving group.

19. A compound of formula (14):

wherein

m is 0, 1, or 2;

n is 0, 1, 2, or 3; q is 0 or 1;

when n is 0, R⁷Is H;

when n is 1, 2, or 3, R⁷Represents:

H；

a hydroxyl group;

-NR¹²R¹³wherein

R¹²Represents H or (C)₁-C₆) Alkyl, optionally having 1 or 2 hydroxyl groups or mono-or di- ((C)₁-C₄) Alkyl) amino groups; and is

R¹³Represents H, (C)₁-C₆) Alkyl, or (C)₃-C₆) Cycloalkyl, said alkyl and cycloalkyl optionally having 1 or 2 hydroxyl groups or mono-or di- ((C)₁-C₄) Alkyl) amino groups;

wherein R is¹⁴Is hydroxy, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, or mono-or di- ((C)₁-C₄) Alkyl) amino, and each alkyl substituent optionally has a hydroxyl substituent;

optionally having 1 or 2 hydroxyl groups, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, or mono-or di- ((C)₁-C₄) Alkyl) amino substituents, each alkyl substituent being optionally substitutedHas a hydroxy substituent, and wherein r is 0, 1, or 2;

optionally having 1 or 2 (C)₁-C₄) Alkyl substituents, each of which optionally having a hydroxy substituent, and wherein

X represents O, S (O)_sOr NR¹⁵Wherein s is 0, 1, or 2; and is

R¹⁵Is represented by (C)₁-C₄) An alkyl group;

or

When n is 2, R⁷And R⁹Can be combined and form a structure with the carbon atoms to which they are attached and the intervening carbon atomsWherein R is¹⁶Is represented by (C)₁-C₄) An alkyl group;

R⁸represents halogen, hydroxy, or (C)₁-C₄) An alkyl group;

R⁹represents H or-CH₂-Y, wherein Y is mono-or di- ((C)₁-C₄) Alkyl) amino, or

R¹⁰Represents H;

or

R⁹And R¹⁰May be taken together to form a bond to form an acetylenic bond;

and is

LG is a leaving group.

20. A method of treating a cell proliferative disorder in a patient in need of such treatment comprising administering to the patient an effective amount of a compound of claim 1.

21. The method of claim 20, wherein the cell proliferative disorder is cancer.