RU2801302C2 - Cyclic iminopyrimidine derivatives as kinase inhibitors - Google Patents

Abstract

FIELD: heteroaromatic compounds.

SUBSTANCE: following is proposed: a compound of formula (I) or its stereoisomer, where: each X₁ and X₃ independently represents CR^a; X₂ is N or CR^a; each Y₁ and Y₃ is independently N or CR^b; Y₂ is CR^b; Z₁ is O or NR^c; Z₂ is a bond or NR^f; m is 0, 1 or 2; n is 1, 2 or 3; R₁ is C₁-C₆ alkyl or C₁-C₆ alkyl substituted with -NR^hRⁱ; R₂ is selected from the group consisting of hydrogen, halogen, CN, NO₂ and CF₃; R₃ is C₁-C₆ alkyl; C₁-C₆ alkyl substituted with halogen; C₁-C₆ alkyl substituted with OH; heterocyclyl containing from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen; heterocylyl substituted with halogen, wherein the heterocyclyl contains from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen; aryl substituted with halogen, where aryl contains from 6 to 14 ring carbon atoms; and heteroaryl containing from 1 to 10 ring carbon atoms and at least one ring heteroatom selected from the group consisting of nitrogen, sulfur and oxygen; R₄ is hydrogen or C₁-C₆ alkyl; R^a is H; R^b is H, halogen, -NH₂ or -NO₂; R^c represents H or C₁-C₆ alkyl; and each of R^f, R^h and Rⁱ independently represents C₁-C₆ alkyl. Also specific compounds and the use of a compound of formula (I) for the treatment of diseases susceptible to inhibition of B-Raf V600E kinase and inhibition of B-Raf V600E kinase activity in a cell are provided.

EFFECT: obtaining heterocyclic compounds with inhibitory activity against B-Raf V600E kinase.

48 cl, 7 tbl, 53 ex

Description

[0001] This application claims priority under U.S. Provisional Application No. 62/561,142, filed September 20, 2017, the contents of which are incorporated herein by reference in their entirety.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0002] Provided herein are cyclic iminopyrimidine derivatives containing such compounds, pharmaceutical compositions, and methods of using such compounds or compositions, such as methods for treating a proliferation disorder, cancer, or tumor, or, in some embodiments, a disease or disorder associated with kinase dysregulation. , such as but not limited to B-Raf V600E kinase.

BACKGROUND OF THE INVENTION

[0003] The present disclosure relates to the treatment of abnormal cell growth in mammals, especially humans, such as cancer, and more specifically brain cancer, with the novel cyclic iminopyrimidines and their bicyclic compounds described herein and their isotopic derivatives, as well as pharmaceutical compositions containing such compounds. In addition, the present disclosure relates to methods for preparing such compounds.

[0004] A kinase is an enzyme that catalyzes the transfer of phosphate groups from high energy phosphate donor molecules to specific substrates. This process is known as phosphorylation, in which the substrate receives a phosphate group and the high-energy ATP molecule donates a phosphate group. As a result of this intermolecular interesterification, a phosphorylated substrate and ADP are obtained.

[0005] Kinases are divided into large groups according to the substrate they act on: protein kinases, lipid kinases, carbohydrate kinases. Kinases can be found in a range of species ranging from bacteria to molds, worms and mammals. More than five thousand different kinases have been identified in humans.

[0006] MAP kinases (MAPKs) are a family of serine/threonine kinases that respond to a variety of extracellular growth signals. For example, growth hormone, epidermal growth factor, platelet growth factor, and insulin are thought to be mitogenic stimuli that may involve the MAPK cascade. Activation of this cascade at the receptor level initiates a signaling cascade through which Ras GTPase exchanges GDP for GTP. Ras then activates Raf kinase (also known as MAPKKK), which activates MEK (MAPKK). MEK activates MAPK (also known as ERK), which can further regulate transcription and translation. While RAF and MAPK are both serine/trenine kinases, MAPKK is a tyrosine/threonine kinase.

[0007] The carcinogenic potential of the MAPK metabolic pathway makes it clinically relevant. It is involved in cellular processes that can lead to uncontrolled growth and subsequent tumor formation. Mutations within this cascade of reactions alter its regulatory effects on cell differentiation, proliferation, survival, and apoptosis, all of which are involved in various forms of cancer.

[0008] It is known that such kinases are frequently aberrantly expressed in commonly occurring human cancers such as melanoma, colorectal cancer, thyroid cancer, glioma, breast cancer, and lung cancer. B-Raf, which has kinase activity, has also been shown to be mutated and/or overactive in many human cancers such as brain, lung, melanoma, colorectal, ovarian and papillary thyroid cancers.

[0009] Kinase inhibition is a useful method for inhibiting the growth of cancer cells in mammals, thereby being a method for treating certain forms of cancer. Various compounds such as pyrrolopyridine and thiazole derivatives have been shown to have kinase inhibiting properties. Numerous patent publications relate to certain bicyclic derivatives, in particular quinazolinone derivatives.

[0010] Several compounds with diverse chemical structures have been converted to inhibitors of the B-Raf V600E mutant, and two of them (Vemurafenib and Dabrafenib) are very effective in clinical practice. For example, Vemurafenib and Dabrafenib are marketed drugs for various cancers that target the B-Raf V600E mutation. Other compounds, such as Encorafenib, which also inhibit the B-Raf V600E mutant kinase, are in clinical development.

[0011] However, due to their structural characteristics, many kinase inhibitors are substrates of active transporters such as P-glycoproteins (P-gp) or breast cancer resistance protein (BCRP) and have very low cell membrane permeability as well as brain. Therefore, they are not suitable for use in the treatment of tumors or cancers of the brain, which is protected by the blood-brain barrier (BBB).

[0012] Thus, the compounds of the present disclosure, which are selective inhibitors of certain kinases, are useful in the treatment of abnormal cell growth, particularly cancer, in mammals. In addition, such compounds have good cell membrane permeability and are therefore useful in the treatment of tumors or cancers in humans, including brain tumors.

BRIEF DESCRIPTION OF THE INVENTION

[0013] In one aspect, a compound of formula (I) is provided:

(I)

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein:

each X ₁ , X ₂ and X ₃ is independently N or CR ^a ;

each Y ₁ , Y ₂ and Y ₃ is independently N or CR ^b ;

Z ₁ is O, S, NR ^c or CR ^d R ^e ;

Z ₂ is a bond or NR ^f ;

m is 0, 1, 2 or 3;

n is 1, 2 or 3;

each R ₁ , R ₂ , R ₃ , R ^a , R ^b , R ^d and R ^e is independently selected from the group consisting of hydrogen, halogen, CN, NO ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, OR ^g , SR ^g , S(O) ₂ R ^g , NR ^h R ⁱ , C(O)R ^g , OC(O)R ^g , C(O)OR ^g , C(O)NR ^h R ⁱ , OC(O)NR ^h R ⁱ , NR ^g C(O)R ^h , NR ^g C(O)OR ^h , substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl;

R ₄ is hydrogen or C ₁ -C ₆ alkyl; And

each R ^c , R ^f , R ^g , R ^h and R ⁱ is independently H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

[0014] In other aspects, compounds of formula (I-1) are provided,

(I-1)

Where

each X ₁ , X ₂ and X ₃ is independently N or CR ^a ;

each Y ₁ ,Y ₂ and Y ₃ independently represents N or CR ^b ;

Z ₁ is O, S, NR ^c or CR ^d R ^e ;

Z ₂ is a bond or NR ^f ;

m is 0, 1, 2 or 3;

n is 1, 2 or 3;

each R ₁ , R ₂ , R ₃ , R ^a , R ^b , R ^d and R ^e is independently selected from the group consisting of hydrogen, halogen, CN, NO ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, OR ^g , SR ^g , S(O) ₂ R ^g , NR ^h R ⁱ , C(O)R ^g , OC(O)R ^g , C(O)OR ^g , C(O)NR ^h R ⁱ , OC(O)NR ^h R ⁱ , NR ^g C(O)R ^h , NR ^g C(O)OR ^h , substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl; And

each R ^c , R ^f , R ^g , R ^h and R ⁱ independently represents H or C ₁ -C ₆ alkyl.

[0015] According to other aspects, compounds of formula (I-2a), (I-2b) and (I-2c) are provided:

(I-2a)

(I-2b)

(I-2c)

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein Y ₁ , Y ₂ , Y ₃ , Z ₁ , Z ₂ , R ₁ , R ₂ , R ₃ , m, n and R ^{a are} as defined for formula (I).

[0016] In other aspects, compounds of formula (I-2d), (I-2e) or (I-2f) are provided:

(I-2d)

(I-2e)

(I-2f)

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein X ₁ , X ₂ , X ₃ , Z ₁ , Z ₂ , R ₁ , R ₂ , R ₃ , m, n and R ^b are defined for formula (I).

[0017] In other aspects, compounds of formula (I-3a) or (I-3b) are provided:

(I-3a)

(I-3b)

or their pharmaceutically acceptable salt, solvate or isotopic derivative, where the values of Z ₁ , Z ₂ , R ₁ , R ₂ , R ₃ , m and R ^a are defined for formula (I).

[0018] In other aspects, compounds of formula (I-4a), (I-4b) or (I-4c) are provided:

(I-4a)

(I-4b)

(I-4c)

or their pharmaceutically acceptable salt, solvate or isotopic derivative, where the values of Z ₁ , Z ₂ , R ₁ , R ₂ , R ₃ , m, n and R ^a are defined for formula (I).

[0019] In other aspects, compounds of formula (I-5a) or (I-5b) are provided:

(I-5a)

(I-5b)

or their pharmaceutically acceptable salt, solvate or isotopic derivative, where the values of Z ₁ , R ₁ , R ₂ , R ₃ , m and R ^a are defined for formula (I).

[0020] According to some embodiments of any of the formulas provided herein, such as formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I- 2d), (I-2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a) or (I-5b), or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, Z ₁ is O. In some embodiments, any of the formulas provided herein, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, Z ₂ represents a connection.

[0021] According to some embodiments of any of the formulas provided herein, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, m is 0. In some embodiments, m is 1. In other embodiments, m is 2. According to in some embodiments of any of the formulas provided herein, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, n is 1. In some embodiments, n is 2.

[0022] According to some embodiments of any of the formulas provided herein, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, each R ₁ is independently hydrogen, -OH, -C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ dialkylamino, where C ₁ -C ₆ alkyl is optionally substituted with halogen. Examples of C ₁ -C ₆ dialkylamino (i.e. -NR ^x R ^y where R ^x and R ^y are each independently -C ₁ -C ₆ alkyl) include, but are not limited to -N(CH ₃ ) ₂ , - N(CH ₂ CH ₃ ) ₂ , -N(CH ₃ )CH ₂ CH ₃ and -N(CH(CH ₃ ) ₂ ) ₂ . In some embodiments, each R ₁ is independently C ₁ -C ₆ alkyl substituted with halo, -CN, NO ₂ , -OH, oxo, and -NR ^1a R ^1b , where each R ^1a and R ^1b are independently H or C ₁ -C ₆ alkyl. In some embodiments, R ₁ is hydrogen. According to some embodiments of any of the formulas provided herein, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, R ₂ is hydrogen, cyano, nitro, halogen, MeSO ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or NR ^h R ⁱ , where C ₁ -C ₆ alkyl is optionally substituted with one or more halogens, and each R ^h and R ⁱ is independently C ₁ -C ₆ alkyl. In some embodiments, R ₂ is CN. In some embodiments, R ₂ is Cl. According to some embodiments, R ₂ is CF ₃ .

[0023] According to some embodiments of any of the formulas provided herein, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, R ₃ is C ₁ -C ₆ alkyl or aryl or heteroaryl, where aryl or heteroaryl is optionally substituted with one or several groups selected from halogen and C ₁ -C ₆ alkyl. In some embodiments, R ₃ is 2-fluorophenyl. In some embodiments, R ₃ is pyrrolidinyl. In certain embodiments, R ₃ is 3-fluoropyrrolidinyl. In some embodiments, R ₃ is propyl. In some embodiments, R ₃ is thiophenyl. In some embodiments, R ₃ is C ₁ -C ₆ alkyl substituted with one or more groups selected from halo, -CN, NO ₂ , -OH, oxo, and -NR ^3a R ^3b where each R ^3a and R ^3b independently represents H or C ₁ -C ₆ alkyl. In particular embodiments, R ₃ is 3-fluoropropyl or 3-hydroxypropyl. In some embodiments, R ₃ is NR ^h R ⁱ and each R ^h and R ⁱ is independently H or C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. In certain embodiments, R ₃ is -N(CH ₃ )CH ₂ CH ₃ , -N(CH ₃ )CH ₂ CH ₂ F or -N(CH ₃ )CH ₃ .

[0024] In some embodiments, any of the formulas provided herein, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, R ^a is H. In some embodiments, R ^a is F. In some embodiments, any of of the formulas provided herein, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, R ^b is H. In some embodiments, R ^b is F.

[0025] In some embodiments, the compounds shown in Table 1 or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof are provided. Also provided are the compounds shown in Table 2, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

[0026] In some aspects, pharmaceutical compositions are provided comprising a compound of any of the formulas described herein, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, and a pharmaceutically acceptable diluent or carrier.

[0027] In some aspects, combinations are provided comprising at least one compound of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d) , (I-2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a), ( I-5b), or a compound from Tables 1 or 2, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, and a second prophylactic or therapeutic agent.

[0028] In some aspects, provided are compounds of formula (I), such as compounds of formula (I-1), (I-2a), (I-2b), (I-2c), (I-2d), (I -2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a), (I-5b ), or a compound of Tables 1 or 2, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, for use in the treatment and/or prevention of a proliferation disorder such as a cancer or tumor in a subject. In some embodiments, the proliferation disorder or cancer is selected from the group consisting of malignant or benign tumors of the liver, kidney, bladder, breast, stomach, ovary, colorectal, prostate, pancreas, lung, vulva, thyroid, liver carcinomas, sarcomas, glioblastomas, head and neck tumors, melanomas and other hyperplastic conditions such as benign skin hyperplasia and benign prostatic hyperplasia.

[0029] In some aspects, methods are provided for treating and/or preventing a proliferation disorder, such as a cancer or tumor, in a subject, wherein the method comprises administering to the subject an effective amount of a compound of any of the formulas provided herein, or a pharmaceutically acceptable salt, solvate, or an isotopic derivative, or a pharmaceutical composition containing a compound of any of the formulas disclosed herein, or a combination containing a compound of any of the formulas disclosed herein. In some embodiments, the proliferation disorder or cancer is selected from the group consisting of malignant or benign tumors of the liver, kidney, bladder, breast, stomach, ovary, colorectal, prostate, pancreas, lung, vulva, thyroid, liver carcinomas, sarcomas, glioblastomas, head and neck tumors, melanomas and other hyperplastic conditions such as benign skin hyperplasia and benign prostatic hyperplasia.

[0030] In some aspects, the present disclosure relates to the use of at least one compound of any of the formulas described herein, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, for the manufacture of a medicament.

[0031] According to some aspects, the present disclosure relates to a method of obtaining an antiproliferative effect in a subject with a proliferation disorder, a cancer, or a tumor that is susceptible to inhibition of B-Raf V600E kinase, comprising administering to the subject an effective amount of a compound of any of the formulas presented herein. document, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, or a pharmaceutical composition containing a compound of any of the formulas disclosed herein, or a combination containing a compound of any of the formulas disclosed herein.

[0032] In some aspects, provided are compounds of formula (I), such as compounds of formula I-1), (I-2a), (I-2b), (I-2c), (I-2d), (I- 2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a), (I-5b) , or a compound of Tables 1 or 2, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, for use in the treatment of a neurodegenerative disease. In some embodiments, the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease.

[0033] In some aspects, the present disclosure relates to a method of treating a neurodegenerative disease in a subject. In some embodiments, the method includes administering to a subject an effective amount of a compound of any of the formulas provided herein, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, or a pharmaceutical composition containing a compound of any of the formulas disclosed herein, or a combination containing a compound of any of the formulas disclosed herein. In some embodiments, the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease.

[0034] In yet another aspect, methods are provided for inhibiting B-Raf V600E kinase activity in a cell, comprising contacting the cell with an effective amount of a compound of any of the formulas provided herein, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof. , or a pharmaceutical composition containing a compound of any of the formulas disclosed herein, or a combination containing a compound of any of the formulas disclosed herein, where the contact is made in vitro , ex vivo or in vivo .

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0035] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. All patents, applications, published applications and other publications referenced herein are incorporated herein by reference in their entirety. If a definition in this section is contrary to or otherwise inconsistent with a definition in a patent, application, or other publication incorporated herein by reference, then the definition in this section will take precedence over the definition included in this document through a link.

[0036] As used herein, the singular forms mean "at least one" or "one or more."

[0037] As used herein, reference herein to an "approximate" value or parameter includes (and describes) embodiments that refer to such value or parameter per se . For example, a description referring to "about X" includes a description of "X".

[0038] Unless otherwise indicated, the term "individual" or "subject" as used herein means a mammal, including, without limitation, humans, cattle, primates, horses, dogs, cats, pigs, and sheep. Thus, the compositions and methods provided herein find their use in both human and veterinary medicine, including use in farm animals and pets. The subject may be a human who has been diagnosed or suspected of having a condition described herein, such as cancer. The subject may be a human who exhibits one or more symptoms associated with a condition described herein, such as cancer. The individual may be a human who has a mutated or abnormal gene associated with a condition described herein, such as cancer. The subject may be a human who is genetically or otherwise predisposed to developing a condition described herein, such as cancer, or at risk of developing it.

[0039] As used herein, the term "treatment" or "treatment" is an approach to obtain favorable or desired results, including clinical results. With respect to the compositions and methods provided herein, beneficial or desired clinical results include, without limitation, one or more of the following: relief of one or more symptoms resulting from the condition, reduction in the severity of the condition, stabilization of the condition (e.g., preventing or delaying the deterioration condition), preventing or delaying the spread (e.g., metastasis) of the condition, delaying or slowing the progression of the condition, reducing the severity of the disease state, achieving remission (both partial and total) of the disease, reducing the dose of one or more other drugs needed to treat the condition , enhancing the effect of another drug used to treat the condition, improving the quality of life of an individual with said condition, and/or prolonging survival. A method of treating cancer includes reducing the pathological effects of cancer. The methods described herein include any one or more of these aspects of treatment.

[0040] As used herein, the term "at risk" is an individual who is at risk of developing the disease or condition described herein, such as cancer. An "at risk" individual may or may not have a detectable disease, and may or may not have evidence of a detectable disease, prior to the use of the treatments described herein. The term "at risk" means that an individual has one or more so-called risk factors, which are measurable parameters that correlate with the development of the disease or condition described herein, such as cancer. An individual with one or more of these risk factors is more likely to develop a disease or condition than an individual without such risk factor(s).

[0041] As used herein, the term "combination therapy" means a therapy that includes two or more different compounds. Thus, in one aspect, a combination therapy is provided comprising a compound detailed herein and another compound. In some variations, the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, pharmaceutically inactive compounds, and/or inert substances. In various embodiments, treatment by combination therapy may result in an additive or even synergistic (eg, more than additive) result compared to administration of the compound provided herein alone. In some embodiments, compared to the amount typically used for individual therapy, a smaller amount of each compound is used as part of a combination therapy. Preferably, the combination therapy achieves the same or greater therapeutic benefit than any of the individual compounds alone. In some embodiments, in combination therapy, the same or greater therapeutic benefit is achieved using an amount (eg, lower dose or less frequent dosing schedule) of a compound less than the amount normally used for an individual compound or therapy. Preferably, the use of a small amount of the compound results in a reduction in the number, severity, frequency and/or duration of one or more side effects associated with the compound.

[0042] As used herein, the term "effective amount" means that amount of a compound provided herein which, in combination with its efficacy and toxicity parameters, would be effective in a given therapeutic form. It is believed in the art that an effective amount may be contained in one or more doses, i. a single dose or multiple doses may be necessary to achieve the desired therapeutic result. An effective amount may be considered in the context of the administration of one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if, in combination with one or more other agents, the desired or beneficial result can be achieved or has already been achieved. Suitable doses of any of the co-administered compounds may optionally be reduced due to the combined effects of the compounds (eg, additive or synergistic effects). According to various embodiments, an effective amount of the composition or therapy can (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, delay, slow down to some extent and preferably stop the penetration of cancer cells into peripheral organs; (iv) inhibit (eg, slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth, (vi) prevent or delay the onset and/or recurrence of a tumor; and/or (vii) alleviate to some extent one or more of the symptoms associated with the cancer. In various embodiments, the amount is sufficient to alleviate, alleviate, reduce and/or delay one or more symptoms of the disease or condition described herein, such as cancer.

[0043] As is to be understood in the art, an "effective amount" may be in the form of one or more doses, i. a single dose or multiple doses may be necessary to achieve the desired therapeutic result. An effective amount may be considered in the context of administering one or more therapeutic agents, and a compound, or a pharmaceutically acceptable salt thereof, may be considered for administration in an effective amount if, in combination with one or more other agents, the desired or beneficial result can be achieved or achieved.

[0044] The term "therapeutically effective amount" refers to an amount of a compound or salt thereof sufficient to produce the desired therapeutic result (e.g., reduction in severity or duration, stabilization of severity, or elimination of one or more symptoms of the disease or condition described herein, such as cancer). For therapeutic use, beneficial or desirable results include, for example, a reduction in one or more of the symptoms resulting from the disease (biochemical, histological and/or behavioral), including its complications and intermediate pathological phenotypes present during the development of the disease or condition, an increase in the quality life of patients suffering from the disease or condition, reducing the dose of other drugs needed to treat the disease or condition, enhancing the effect of another drug, delaying the progression of the disease or condition, and/or prolonging the survival of patients.

[0045] It should be understood that an effective amount of a compound or a pharmaceutically acceptable salt thereof, including a prophylactically effective amount, may be administered to an individual in combination with adjuvants, which refers to a clinical situation in which the individual has a history of cancer, and generally ( but not necessarily), a response to therapy has been observed, which includes, without limitation, surgery (eg, surgical resection), radiation therapy, and chemotherapy. However, because of the history of cancer in such individuals, they are considered to be at risk of developing cancer. Treatment or administration "in combination with adjuvants" refers to repeated treatments.

[0046] As used herein, the term “pharmaceutically acceptable” or “pharmacologically acceptable” means a substance that is not biologically or otherwise undesirable, for example, a substance can be included in a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or not interacting in a negative way with any of the other components contained in the composition. Pharmaceutically acceptable carriers or excipients preferably meet required toxicological and manufacturing testing standards and/or are included in the US Food and Drug Administration's Inactive Ingredient Guide.

[0047] "Pharmaceutical acceptable salts" are those salts that retain at least some of the biological activity of the compound in free base form (non-salt form), and which can be administered to an individual as drugs or pharmaceuticals. Such salts include, for example: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, and the like; (2) salts formed when an acid proton present in the parent compound is either replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or forms a coordination bond with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, and the like. Suitable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Pharmaceutically acceptable salts may be prepared in situ during manufacture, or by separately reacting the purified compound provided herein, in its free acid or base form, with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during the process. subsequent cleaning.

[0048] As used herein, the term "filler" means an inert or inactive substance that can be used to make a drug or pharmaceutical, such as a tablet, containing the compound as proposed herein as an active ingredient. Various substances may be encompassed by the term "filler" including, without limitation, any substance used as a binder, disintegrant, glazing agent, compression/encapsulation aid, cream or lotion, lubricant, parenteral solutions, chewable tablet substances, sweetener, or flavoring agent. , a suspending/gelling agent, or a wet granulating agent. Binders include, for example, carbomers, povidone, xanthan gum, and the like; glazing agents include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coating agents, and the like; compression/encapsulation additives include, for example, calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrate or monohydrate; optionally combined with aspartame, cellulose or microcrystalline cellulose), starch dc , sucrose, etc.; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, and the like; creams or lotions include, for example, maltodextrin, carrageenans, and the like; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, and the like; chewable tablets include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), and the like; suspending/gelatinizing agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, and the like; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, and the like; and wet granulation agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, and the like.

[0049] "Alkyl" means and includes saturated straight or branched monovalent hydrocarbon structures and combinations thereof. Particular alkyl groups are groups containing from 1 to 20 carbon atoms ("C ₁ -C ₂₀ alkyl"). More specific alkyl groups are groups containing 1 to 8 carbon atoms ("C ₁ -C ₈ alkyl") or 1 to 6 carbon atoms ("C ₁ -C ₆ alkyl"). When an alkyl residue containing a specific number of carbon atoms is named, it is understood that all geometric isomers containing the specified number of carbon atoms are to be included and described; for example, "butyl" is meant to include n-butyl, sec-butyl, isobutyl and t-butyl; "propyl" includes n-propyl and isopropyl. This term is illustrated by groups such as methyl, t-butyl, n-heptyl, octyl, and the like.

[0050] "Cycloalkyl" refers to and includes cyclic monovalent hydrocarbon structures. Cycloalkyl can be single ring like cyclohexyl or multiple rings like adamantyl. Cycloalkyl containing more than one ring may be fused, spiro- or bridged, or combinations thereof. Preferred cycloalkyl is a saturated cyclic hydrocarbon containing 3 to 13 carbon atoms in the ring. A more preferred cycloalkyl is a saturated cyclic hydrocarbon having 3 to 8 carbon atoms in the ring ("C ₃ -C ₈ cycloalkyl"). Examples of cycloalkyl groups include adamantyl, decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0051] "Alkenyl" refers to an unsaturated hydrocarbon group containing at least one unsaturated olefinic bond (i.e. containing at least one moiety of the formula C=C) and preferably containing from 2 to 10 carbon atoms and more preferably from 2 up to 8 carbon atoms. Examples of alkenyl include, without limitation, -CH ₂ -CH=CH-CH ₃ and -CH=CH-CH=CH ₂ .

[0052] "Cycloalkenyl" refers to an unsaturated hydrocarbon group in which the cycloalkyl contains at least one unsaturated olefinic bond (ie, contains at least one moiety of the formula C=C). Cycloalkenyl can be single ring like cyclohexyl or multiple rings like norbornenyl. A more preferred cycloalkenyl is a saturated cyclic hydrocarbon having 3 to 8 carbon atoms in the ring ("C ₃ -C ₈ cycloalkenyl"). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.

[0053] "Alkynyl" refers to an unsaturated hydrocarbon group containing at least one unsaturated acetylenic bond (i.e., containing at least one moiety of the formula C≡C) and preferably containing from 2 to 10 carbon atoms, and more preferably 2 to 8 carbon atoms, etc.

[0054] The term "alkoxy" refers to an -O-alkyl group, where O is the point of attachment to the remainder of the molecule, and the meaning of alkyl is defined above.

[0055] "Haloalkyl" refers to an alkyl group with one or more halogen substituents, such as one, two or three halogen substituents. Examples of haloalkyl groups include -CF ₃ , -(CH ₂ )F, -CHF ₂ , CH ₂ Br, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , and -CH ₂ CH ₂ F.

[0056] "Heterocycle", "heterocyclic" or "heterocyclyl" refers to a saturated or unsaturated non-aromatic group containing a single ring or multiple fused rings and containing 1 to 10 carbon atoms and 1 to 4 heteroatoms such as nitrogen , sulfur or oxygen, etc. A heterocycle containing more than one ring may be fused, spiro- or bridged, or any combination thereof. In fused ring systems, one or more rings may be aryl or heteroaryl. A heterocycle containing more than one ring, in which at least one ring is aromatic, can be connected to the primary structure at any position of the non-aromatic ring or at any position of the aromatic ring. According to one variation, a heterocycle containing more than one ring, in which at least one ring is aromatic, is connected to the primary structure at some position of the non-aromatic ring.

[0057] "Aryl" or "Ar" refers to an unsaturated aromatic carbocyclic group containing a single ring (eg, phenyl) or multiple fused rings (eg, naphthyl or anthryl), where the fused rings may or may not be aromatic. According to one variation, the aryl group contains from 6 to 14 carbon atoms in the ring. An aryl group containing more than one ring, in which at least one ring is non-aromatic, can be connected to the primary structure at some position of the aromatic ring or at some position of the non-aromatic ring. In one variation, an aryl group containing more than one ring, in which at least one ring is non-aromatic, is linked to the primary structure at some position on the aromatic ring.

[0058] "Heteroaryl" or "HetAr" refers to an unsaturated aromatic carbocyclic group containing from 1 to 10 carbon atoms in the ring and at least one heteroatom, including, without limitation, heteroatoms such as nitrogen, oxygen and sulfur. The heteroaryl group may contain a single ring (eg, pyridyl, furyl) or multiple fused rings (eg, indolizinyl, benzothienyl), where the fused rings may or may not be aromatic. A heteroaryl group containing more than one ring, in which at least one ring is non-aromatic, can be connected to the primary structure at some position of the aromatic ring or at some position of the non-aromatic ring. In one variation, a heteroaryl group containing more than one ring, in which at least one ring is non-aromatic, is connected to the primary structure at some position on the aromatic ring.

[0059] The term "halogen" is chlorine, fluorine, bromine, or iodine. The term "halogen-" represents chloro-, fluorine-, bromine- or iodine-.

[0060] The term "substituted" means that the specified group or fragment contains one or more substituents, including, without limitation, substituents such as alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl , heteroaryl, aryloxy, cyano, azido, halogen, hydroxy, nitro, carboxyl, thiol, thioalkyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl, heterocyclyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy, and the like. The term "unsubstituted" means that the specified group does not contain substituents. The term "optionally substituted" means that said group is unsubstituted or substituted with one or more substituents. When the term "substituted" is used to describe a structural system, it is understood that the substitution is present at any position of the system that has an allowed valency.

[0061] A composition containing a "substantially pure" compound means that the composition contains no more than 15%, or preferably no more than 10%, or more preferably no more than 5%, or even more preferably no more than 3%, and most preferably not more than 1% impurity, where the impurity may be a compound in a different stereochemical form. For example, a composition containing essentially pure ( S )-compound means that the composition contains no more than 15%, or no more than 10%, or no more than 5%, or no more than 3%, or no more than 1% ( R ) connection forms.

[0062] Any formula presented herein is intended to be compounds having structures with the structural formulas depicted as well as certain variations or forms. In particular, compounds according to any of the formulas provided herein, such as formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d) , (I-2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a) or ( I-5b) may contain asymmetric centers and therefore exist in different enantiomeric forms. Such mixtures of stereoisomers can be separated into individual stereoisomers based on their physicochemical or optical differences by methods known to those skilled in the art, such as chromatography or fractional crystallization methods. All such isomers, including diastereoisomers and enantiomers, are intended to be part of the present invention. It is intended that all optical isomers and stereoisomers of the compounds according to the general formula, and mixtures thereof in any ratio, fall within the scope of the formula according to the present invention. Thus, any formula presented herein is intended to be a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. In addition, certain structures may exist as geometric isomers (ie, cis and trans isomers), as tautomers, or as atropisomers. Furthermore, any formula presented herein is also intended to refer to any of the hydrates, solvates, and amorphous and polymorphic forms of such compounds and mixtures thereof, even if such forms are not explicitly stated. In some embodiments, the solvent is water and the solvates are hydrates.

[0063] Any formula presented herein is also intended to represent both the unlabeled forms and the isotopically labeled forms of the compounds. Isotopically labeled compounds are characterized by the structures of the formulas depicted herein, except that one or more atoms are replaced by an atom characterized by a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C , ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, and ¹²⁵ I, respectively. Substitution with heavier isotopes such as deuterium (ie, ² H) may confer certain therapeutic advantages resulting in greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. The isotopically labeled compounds and prodrugs thereof described herein can generally be prepared by following the procedures disclosed in the Schemes or Examples and the preparation methods described below by replacing the non-isotopically labeled reagent with a readily available isotopically labeled reagent.

[0064] When referring to any formula presented herein, it is assumed that the selection of a particular fragment from the list of possible options for a specified variable does not determine the same choice of options for a variable specified elsewhere herein. In other words, if a variable occurs more than once, then the choice of options from the specified list is independent of the choice of options for the same variable elsewhere in the formula, unless otherwise specified.

[0065] In accordance with the foregoing aspects of the interpretation of the definitions and nomenclature, it should be understood that in chemically significant cases, and unless otherwise indicated, the express reference in this document to a certain set implies an independent reference to embodiments of such a set and a reference to each separately of the possible embodiments of subsets of a given population, to which direct reference is made.

Illustrative Connections

Formula I

[0066] Compounds and their salts (such as pharmaceutically acceptable salts) are discussed in detail herein, including the description in the "Summary of the Invention" section and the appended claims. Also proposed is the use of all compounds described herein, including absolutely all stereoisomers, including geometric isomers ( cis / trans ), E / Z isomers, enantiomers, diastereoisomers and mixtures thereof in any ratio, including racemic mixtures, salts and solvates of the compounds described in herein, as well as methods for preparing such compounds. Each compound described herein may be referred to as a drug.

[0067] In one aspect, compounds of formula (I) are provided:

(I)

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein:

each X ₁ , X ₂ and X ₃ is independently N or CR ^a ;

each Y ₁ ,Y ₂ and Y ₃ independently represents N or CR ^b ;

Z ₁ is O, S, NR ^c or CR ^d R ^e ;

Z ₂ is a bond or NR ^f ;

m is 0, 1, 2 or 3;

n is 1, 2 or 3;

each R ₁ , R ₂ , R ₃ , R ^a , R ^b , R ^d and R ^e is independently selected from the group consisting of hydrogen, halogen, CN, NO ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, OR ^g , SR ^g , S(O) ₂ R ^g , NR ^h R ⁱ , C(O)R ^g , OC(O)R ^g , C(O)OR ^g , C(O)NR ^h R ⁱ , OC(O)NR ^h R ⁱ , NR ^g C(O)R ^h , NR ^g C(O)OR ^h , substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl;

R ₄ is hydrogen or C ₁ -C ₆ alkyl; And

each R ^c , R ^f , R ^g , R ^h and R ⁱ is independently H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

[0068] According to some embodiments, the compound of formula (I) is a compound of formula (I-1),

(I-1)

Where

each X ₁ , X ₂ and X ₃ is independently N or CR ^a ;

each Y ₁ ,Y ₂ and Y ₃ independently represents N or CR ^b ;

Z ₁ is O, S, NR ^c or CR ^d R ^e ;

Z ₂ is a bond or NR ^f ;

m is 0, 1, 2 or 3;

n is 1, 2 or 3;

each R ₁ , R ₂ , R ₃ , R ^a , R ^b , R ^d and R ^e is independently selected from the group consisting of hydrogen, halogen, CN, NO ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, OR ^g , SR ^g , S(O) ₂ R ^g , NR ^h R ⁱ , C(O)R ^g , OC(O)R ^g , C(O)OR ^g , C(O)NR ^h R ⁱ , OC(O)NR ^h R ⁱ , NR ^g C(O)R ^h , NR ^g C(O)OR ^h , substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl; And

each R ^c , R ^f , R ^g , R ^h and R ⁱ independently represents H or C ₁ -C ₆ alkyl.

[0069] According to other aspects, compounds of formula (I-2a), (I-2b) and (I-2c) are provided:

(I-2a)

(I-2b)

(I-2c)

where the values of Y ₁ , Y ₂ , Y ₃ , Z ₁ , Z ₂ , R ₁ , R ₂ , R ₃ , m, n and R ^a are defined for formula (I).

[0070] According to other aspects, compounds of formula (I-2d), (I-2e) and (I-2f) are provided:

(I-2d)

(I-2e)

(I-2f)

where the values of X ₁ , X ₂ , X ₃ , Z ₁ , Z ₂ , R ₁ , R ₂ , R ₃ , m, n and R ^b are defined for formula (I).

[0071] According to other aspects, compounds of formula (I-3a) and (I-3b) are provided:

(I-3a)

(I-3b)

where the values of Z ₁ , Z ₂ , R ₁ , R ₂ , R ₃ , m and R ^a are defined for formula (I).

[0072] According to other aspects, compounds of formula (I-4a), (I-4b) and (I-4c) are provided:

(I-4a)

(I-4b)

(I-4c)

where the values of Z ₁ , Z ₂ , R ₁ , R ₂ , R ₃ , m, n and R ^a are defined for formula (I).

[0073] According to other aspects, compounds of formula (I-5a) and (I-5b) are provided:

(I-5a)

(I-5b)

where the values of Z ₁ , R ₁ , R ₂ , R ₃ , m, n and R ^a are defined for formula (I).

[0074] According to some embodiments of formula (I) or any variation thereof, each X ₁ , X ₂ and X ₃ is independently N or CR ^a , where at least one of X ₁ , X ₂ and X ₃ is N In some embodiments, X ₁ , X ₂ and X ₃ are each CR ^a . In some embodiments, one of X ₁ , X ₂ and X ₃ is N. In some embodiments, X ₁ is N, X ₂ is CR ^a , and X ₃ is CR ^a . In some embodiments, X ₁ is CR ^a , X ₂ is N, and X ₃ is CR ^a . In some embodiments, X ₁ is CR ^a , X ₂ is CR ^a , and X ₃ is N. In some embodiments, two of X ₁ , X ₂ and X ₃ are N. In some embodiments, each of X ₁ and X ₂ is N, and X ₃ is CR ^a . In some embodiments, X ₁ and X ₃ are each N, and X ₂ is CR ^a . In some embodiments, X ₂ and X ₃ are each N, and X ₁ is CR ^a . In some embodiments, each of X ₁ , X ₂ and X ₃ is N. According to any of the preceding embodiments, each R ^a is selected from the group consisting of hydrogen, halogen, CN, NO ₂ , substituted or unsubstituted C ₁ - C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, OR ^g , SR ^g , S(O) ₂ R ^g , NR ^h R ⁱ , C(O)R ^g , OC(O)R ^g , C(O)OR ^g , C(O)NR ^h R ⁱ , OC(O)NR ^h R ⁱ , NR ^g C(O)R ^h , NR ^g C(O)OR ^h , substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl. In some embodiments, each R ^a is selected from the group consisting of hydrogen, halogen, CN, NO ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, OR ^g , SR ^g , S(O) ₂ R ^g , NR ^h R ⁱ , C(O)R ^g , OC(O)R ^g , C(O)OR ^g , C(O)NR ^h R ⁱ , OC(O)NR ^h R ⁱ , NR ^g C(O)R ^h and NR ^g C(O)OR ^h where each R ^g , R ^h and R ⁱ independently represents H or C ₁ -C ₆ alkyl . In some embodiments, each R ^a is selected from the group consisting of hydrogen, halogen, CN, NO ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and NR ^h R ⁱ , where each R ^h and R ⁱ is C ₁ -C ₆ alkyl. In some embodiments, each R ^a is selected from the group consisting of hydrogen, halogen, CN, and NO ₂ . In some embodiments, R ^a is H. In some embodiments, R ^a is halogen. In some embodiments, R ^a is fluoro. In some embodiments, X ₁ , X ₂ and X ₃ are each CH.

[0075] According to some embodiments of formula (I) or any variation thereof, each Y ₁ , Y ₂ and Y ₃ is independently N or CR ^b , where at least one of Y ₁ , Y ₂ and Y ₃ is N In some embodiments, each of Y ₁ , Y ₂ and Y ₃ is CR ^b . In some embodiments, one of Y ₁ , Y ₂ and Y ₃ is N. In some embodiments, Y ₁ is N, Y ₂ is CR ^b , and Y ₃ is CR ^b . In some embodiments, Y ₁ is CR ^b , Y ₂ is N, and Y ₃ is CR ^b . In some embodiments, Y ₁ is CR ^b , Y ₂ is CR ^b , and Y ₃ is N. In some embodiments, two of Y ₁ , Y ₂ and Y ₃ are N. In some embodiments, each of Y ₁ and Y ₂ is N, and Y ₃ is CR ^b . In some embodiments, Y ₁ and Y ₃ are each N, and Y ₂ is CR ^b . In some embodiments, Y ₂ and Y ₃ are each N, and Y ₁ is CR ^b . In some embodiments, each of Y ₁ , Y ₂ and Y ₃ is N. According to any of the preceding embodiments, each R ^b is selected from the group consisting of hydrogen, halogen, CN, NO ₂ , substituted or unsubstituted C ₁ - C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, OR ^g , SR ^g , S(O) ₂ R ^g , NR ^h R ⁱ , C(O)R ^g , OC(O)R ^g , C(O)OR ^g , C(O)NR ^h R ⁱ , OC(O)NR ^h R ⁱ , NR ^g C(O)R ^h , NR ^g C(O)OR ^h , substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl. In some embodiments, each R ^b is selected from the group consisting of hydrogen, halogen, CN, NO ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, OR ^g , SR ^g , S(O) ₂ R ^g , NR ^h R ⁱ , C(O)R ^g , OC(O)R ^g , C(O)OR ^g , C(O)NR ^h R ⁱ , OC(O)NR ^h R ⁱ , NR ^g C(O)R ^h and NR ^g C(O)OR ^h where each R ^g , R ^h and R ⁱ independently represents H or C ₁ -C ₆ alkyl . In some embodiments, each R ^b is selected from the group consisting of hydrogen, halogen, CN, NO ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and NR ^h R ⁱ , where each R ^h and R ⁱ is C ₁ -C ₆ alkyl. In some embodiments, each R ^b is selected from the group consisting of hydrogen, halogen, CN, and NO ₂ . In some embodiments, R ^b is H. In some embodiments, R ^b is halogen. In some embodiments, R ^b is fluoro. In some embodiments, R ^b is chlorine. In some embodiments, R ^b is C ₁ -C ₆ alkyl substituted with halo. In some embodiments, R ^b is C ₁ -C ₆ alkyl substituted with -CF ₃ . In some embodiments, R ^b is -CN. In some embodiments, R ^b is NO ₂ . In some embodiments, R ^b is NH ₂ . In some embodiments, Y ₁ , Y ₂ , and Y ₃ are each CH.

[0076] In some embodiments of Formula (I), or any variation thereof, X ₁ , X ₂ and X ₃ are each CR ^a and Y ₁ , Y ₂ and Y ₃ are each CR ^b . According to some embodiments of formula (I), or any variation thereof, each R ^a and R ^b is independently selected from the group consisting of hydrogen, halogen, CN, -NH ₂ and NO ₂ . In some embodiments, each R ^a is selected from the group consisting of hydrogen, halogen, CN, and NO ₂ . In some embodiments, each R ^a is H or halogen. In some embodiments, each R ^a is H. In some embodiments, one of X ₁ , X ₂ and X ₃ is CR ^a , where R ^a is selected from halogen, CN, -NH ₂ and NO ₂ ; and each of the other two of X ₁ , X ₂ and X ₃ is independently N or CH. In some embodiments, two of X ₁ , X ₂ and X ₃ are CR ^a , where each R ^a is independently selected from halogen, CN, -NH ₂ and NO ₂ ; and the remainder of X ₁ , X ₂ and X ₃ is N or CH. In other embodiments, three of X ₁ , X ₂ and X ₃ are CR ^a and each R ^a is independently selected from halogen, CN, -NH ₂ and NO ₂ . In some embodiments, one or more R ^a is halogen. In some embodiments, R ^a is F. In some embodiments, one of Y ₁ , Y ₂ and Y ₃ is CR ^b , where R ^b is selected from halogen, CN, -NH ₂ and NO ₂ ; and each of the other two of Y ₁ , Y ₂ and Y ₃ is independently N or CH. In some embodiments, two of Y ₁ ,Y ₂ and Y ₃ are CR ^b where each R ^b is independently selected from halo, CN, -NH ₂ and NO ₂ and the remainder of X ₁ , X ₂ and X ₃ is is N or CH. In other embodiments, three of Y ₁ , Y ₂ and Y ₃ are CR ^b , where each R ^b is independently selected from halogen, CN, -NH ₂ and NO ₂ . In some embodiments, each R ^b is selected from the group consisting of hydrogen, halogen, CN, -NH ₂ and NO ₂ . In some embodiments, each R ^b is H or halogen. In some embodiments, each R ^b is H. In some embodiments, one or more R ^b is halo. In some embodiments, R ^b is F. In some embodiments, R ^b is NH ₂ . In some embodiments, R ^a and R ^b are both H.

[0077] In some embodiments of Formula (I), or any variation thereof, Z ₁ is O. In some embodiments, Z ₁ is S. In some embodiments, Z ₁ is NR ^c or CR ^d R ^e . In some embodiments, Z ₂ is a bond. According to some embodiments, Z ₂ is NR ^f , where R ^f is H or C ₁ -C ₆ alkyl. According to some embodiments, Z ₁ is O and Z ₂ is NR ^f . In some embodiments, Z ₁ is O and Z ₂ is NH. According to some embodiments, Z ₁ is O and Z ₂ is N(CH ₃ ).

[0078] According to some embodiments of formula (I) or any variation thereof, each R ₁ is independently selected from the group consisting of hydrogen, halogen, CN, NO ₂ , substituted or unsubstituted C ₁ -C ₆ aalkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, OR ^g , SR ^g , S(O) ₂ R ^g , NR ^h R ⁱ , C(O)R ^g , OC(O)R ^g , C( O)OR ^g , C(O)NR ^h R ⁱ , OC(O)NR ^h R ⁱ , NR ^g C(O)R ^h and NR ^g C(O)OR ^h , where each R ^g , R ^h and R ⁱ is independently H or C ₁ -C ₆ alkyl. In some embodiments, each R ₁ is independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, OR ^g , and NR ^h R ⁱ , where C ₁ -C ₆ alkyl is optionally substituted with one or more halogens, and each R ^g , R ^h and R ⁱ independently represents H or C ₁ -C ₆ alkyl. In some embodiments of Formula (I), or any variation thereof, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. It should be understood that if m is equal to 0, then there are no substituents other than hydrogen on the ring bearing -(R ₁ ) _m . In some embodiments, R ₁ is hydrogen. According to some embodiments, R ₁ is unsubstituted C ₁ -C ₆ alkyl. In other embodiments, R ₁ is C ₁ -C ₆ alkyl substituted with halo, -CN, NO ₂ , -OH, oxo, and -NR ^1a R ^1b , where R ^1a and R ^1b are each independently H or C ₁ -C ₆ alkyl. In some embodiments, R ₁ is C ₁ -C ₆ alkyl substituted with -NR ^1a R ^1b , where R ^1a and R ^1b are each independently H or C ₁ -C ₆ alkyl. In some embodiments, m is 1 and each R ₁ is independently selected from the group consisting of halo, CN, NO ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, and substituted or unsubstituted C ₂ -C ₆ alkynyl. In some embodiments, m is 1 and R ₁ is methyl substituted with -N(CH ₃ ) ₂ . According to some embodiments, m is 1 or 2; and R ₁ is C ₁ -C ₆ alkyl, unsubstituted or substituted with -NR ^1a R ^1b , where R ^1a and R ^1b are each independently H or C ₁ -C ₆ alkyl. In some embodiments, m is 2 and each R ₁ is independently selected from the group consisting of halo, CN, NO ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, and substituted or unsubstituted C ₂ -C ₆ alkynyl. In some embodiments, m is 2 and each R ₁ is independently C ₁ -C ₆ alkyl. In certain embodiments, m is 2 and each R ₁ is methyl.

[0079] According to some embodiments of formula (I) or any variation thereof, R ₂ is selected from the group consisting of hydrogen, halogen, CN, NO ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, OR ^g , SR ^g , S(O) ₂ R ^g , NR ^h R ⁱ , C(O)R ^g , OC(O)R ^g , C(O) OR ^g , C(O)NR ^h R ⁱ , OC(O)NR ^h R ⁱ , NR ^g C(O)R ^h and NR ^g C(O)OR ^h , where each R ^g , R ^h and R ^{i are} independently is H or C ₁ -C ₆ alkyl. In some embodiments, R ₂ is selected from the group consisting of hydrogen, cyano, nitro, halogen, MeSO ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ dialkylamino, where C ₁ -C ₆ alkyl is optionally substituted with one or more halogens. Examples of C ₁ -C ₆ dialkylamino (i.e. -NR ^x R ^y where R ^x and R ^y are each independently -C ₁ -C ₆ alkyl) include, but are not limited to -N(CH ₃ ) ₂ , - N(CH ₂ CH ₃ ) ₂ , -N(CH ₃ )CH ₂ CH ₃ and -N(CH(CH ₃ ) ₂ ) ₂ . In some embodiments, R ₂ is hydrogen. In some embodiments, R ₂ is -CN. In some embodiments, R ₂ is -NO ₂ . In some embodiments, R ₂ is halogen. In some embodiments, R ₂ is Cl. In some embodiments, R ₂ is F. In some embodiments, R ₂ is C ₁ -C ₆ alkyl optionally substituted with one or more halogens. In some embodiments, R ₂ is -CF ₃ .

[0080] According to some embodiments of formula (I) or any variation thereof, R ₃ is selected from the group consisting of hydrogen, halogen, CN, NO ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, OR ^g , SR ^g , S(O) ₂ R ^g , NR ^h R ⁱ , C(O)R ^g , OC(O)R ^g , C(O) OR ^g , C(O)NR ^h R ⁱ , OC(O)NR ^h R ⁱ , NR ^g C(O)R ^h and NR ^g C(O)OR ^h , where each R ^g , R ^h and R ^{i are} independently is H or C ₁ -C ₆ alkyl. In some embodiments, R ₃ is C ₁ -C ₆ alkyl or aryl or heteroaryl, where aryl or heteroaryl is optionally substituted with one or more groups selected from halo and C ₁ -C ₆ alkyl. According to some embodiments, R ₃ is C ₁ -C ₆ alkyl. In some embodiments, R ₃ is C ₁ -C ₆ alkyl substituted with one or more groups selected from halo, -CN, NO ₂ , -OH, oxo, and -NR ^3a R ^3b where each R ^3a and R ^3b independently represents H or C ₁ -C ₆ alkyl. In some embodiments, R ₃ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl, or tert -butyl substituted with halo or —OH. In some embodiments, R ₃ is methyl. In some embodiments, R ₃ is ethyl. In some embodiments, R ₃ is propyl. In some embodiments, R ₃ is n -propyl or isopropyl. In some embodiments, R ₃ is n -propyl or isopropyl substituted with halogen or -OH. In some embodiments, R ₃ is 3-fluoropropyl or 3-hydroxypropyl. In some embodiments, R ₃ is NR ^h R ⁱ , where R ^h and R ⁱ are each independently H or C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. According to some embodiments, R ₃ is -N(CH ₃ )CH ₂ CH ₃ . In some embodiments, R ₃ is -N(CH ₃ )CH ₂ CH ₂ F. In other embodiments, R ₃ is -N(CH ₃ )CH ₃ . In some embodiments, R ₃ is aryl or heteroaryl, each optionally substituted with one or more groups selected from halo and C ₁ -C ₆ alkyl. In some embodiments, R ₃ is phenyl. In some embodiments, R ₃ is phenyl substituted with one or more groups selected from halo and C ₁ -C ₆ alkyl. In some embodiments, R ₃ is 2-fluorophenyl. In some embodiments, R ₃ is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydrothiophenyl, oxathiolanyl, sulfolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, thianyl, dithianyl, trithianyl, morpholinyl, or thiomorpholinyl, each optionally substituted one or more groups selected from halo and C ₁ -C ₆ alkyl. In some embodiments, R ₃ is an unsubstituted pyrrolidinyl. In other embodiments, R ₃ is pyrrolidinyl substituted with one or more groups selected from halo and C ₁ -C ₆ alkyl. In some embodiments, R ₃ is 3-fluoropyrrolidinyl. In certain embodiments, R ₃ is (R)-3-fluoropyrrolidinyl. In some embodiments, R ₃ is thiophenyl.

[0081] According to some embodiments of formula (I), or any variation thereof, R ₄ is hydrogen. In other embodiments, R ₄ is C ₁ -C ₆ alkyl, which includes, but is not limited to, methyl, ethyl, n -propyl, isopropyl, n -butyl, isobutyl, sec- butyl, or t- butyl. In certain embodiments, R ₄ is methyl.

[0082] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0083] Any of the embodiments detailed herein in relation to formula (I) are equally applicable to formula (I-1), (I-2a), (I-2b), (I-) as applicable. 2c), (I-2d), (I-2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c) , (I-5a) and (I-5b). It should also be understood that descriptions of any variable of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), (I-2e), ( I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a) or (I-5b) may be as applicable cases combined with one or more descriptions of any other variable, just as if each combination of variables were specifically and separately described. For example, each description R ₂ can be combined with each description R ₁ , R ₃ , Z ₁ , Z 2 , Y ₁ , Y ₂ , Y ₃ , X ₁ , X _{2 ,} X ₃ , m and n, just as if each combination of variables would be specifically and separately described. By analogy, each description R ₃ can be combined with each description R ₁ , R ₂ , Z ₁ , Z ₂ , Y ₁ , Y ₂ , Y ₃ , X ₁ , X ₂ , X ₃ , m and n, as well as if each combination of variables were specifically and separately described.

[0084] According to one variation, the compounds of the formulas presented herein contain one or more of the following structural features: (i) Z ₁ is selected from the group consisting of O, NH and N(CH ₃ ); (ii) Z ₂ is selected from the group consisting of a bond, N(CH ₃ ) and N(CH ₂ CH ₃ ); (iii) m is 0, m is 1 and R ₁ is -CH ₂ N(CH ₃ ) ₂ , or m is 2 and each R ₁ is -CH ₃ ; (iv) R ₂ is selected from the group consisting of hydrogen, -CN, NO ₂ , NH ₂ , -F, -Cl and CF ₃ ; (v) R ₃ is selected from the group consisting of n -propyl, isopropyl, 2-fluorophenyl, thiophenyl, 3-fluoropropyl, 3-hydroxypropyl, pyrrolidinyl, 3-fluoropyrrolidinyl, -N(CH ₃ )CH ₂ CH ₃ , -N (CH ₃ )CH ₂ CH ₂ F and -N(CH ₃ )CH ₃ ; (vi) n is 1 or 2; and (vii) R ₄ is hydrogen or -CH ₃ .

[0085] In some embodiments, provided herein are compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), (I -2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a) and (I-5b ) or their pharmaceutically acceptable salts.

[0086] In some embodiments, provided herein are the compounds and their salts described in Table 1 and their uses.

Table 1.

Compound
No. Structure chemical name 1 N-(2-Cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-1-sulfonamide 2 N-(2-Cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-N-methylpropane-1-sulfonamide 3 N-(2-Cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-4-fluorophenyl)propane-1-sulfonamide 4 N-(2-Cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-4,6-difluorophenyl)propane-1-sulfonamide 5 N-(2-Cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-6-fluorophenyl)propane-1-sulfonamide 6 N-(2-Chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-1-sulfonamide 7 N-(3-((2,3-Dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluoro-4-nitrophenyl)propane-1-sulfonamide 8 N-(4-Amino-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide 9 N-(3-((2,3-Dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide 10 N-(3-((2,3-Dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2,4-difluorophenyl)propane-1-sulfonamide eleven N-(3-((2,3-Dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-(trifluoromethyl)phenyl)propane-1-sulfonamide 12 N-(3-((2,3-Dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-nitrophenyl)propane-1-sulfonamide 13 N-(2-Amino-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-1-sulfonamide 14 N-(2-Cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-2-fluorobenzenesulfonamide 15 N-(2-Cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)thiophene-2-sulfonamide 16 N-(2-cyano-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)propane-1-sulfonamide 17 N-(2-cyano-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-4-fluorophenyl)propane-1-sulfonamide 18 N-(3-((3,4-Dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide 19 N-(3-((3,4-Dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2-fluoro-6-nitrophenyl)propane-1-sulfonamide 20 N-(6-Amino-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide 21 N-(2-Chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)propane-1-sulfonamide 22 N-(2-((3,4-Dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-3-nitropyridin-4-yl)propan-1-sulfonamide 23 N-(4-((3,4-Dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-3-nitropyridin-2-yl)propan-1-sulfonamide 24 N-(3-cyano-4-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)pyridin-2-yl)propan-1-sulfonamide 25 N-(3-Cyano-2-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)pyridin-4-yl)propan-1-sulfonamide 26 N-(3-Chloro-4-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)pyridin-2-yl)propan-1-sulfonamide 27 N-(2-cyano-3-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)oxy)phenyl)propane-1-sulfonamide 28 N-(2-Cyano-3-((2,3,4,5-tetrahydro-[1,3]diazepino[1,2-c]quinazolin-11-yl)oxy)phenyl)propane-1-sulfonamide 37 N-(2-Chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)ethanesulfonamide 38 N-(2-Chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-3-fluoropropane-1-sulfonamide 39 N-(2-Chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-3-hydroxypropane-1-sulfonamide 40 (R)-N-(2-Chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-3-fluoropyrrolidine-1-sulfonamide 41 N-(2-Chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-N-ethyl-N-methylamino-1-sulfonamide 42 N-(2-Cyano-3-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)(methyl)amino)phenyl)propane -1-sulfonamide 43 N-(2-Cyano-3-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)amino)phenyl)-propan-1- sulfonamide 44 N-(2-Chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-2-sulfonamide 45 N-(2-Chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-N-ethyl-N-methylamino-1-sulfonamide 46 (R)-N-(2-Chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-3-fluoropyrrolidine-1-sulfonamide 47 N-(2-Chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-(2-fluoroethyl)-(methyl)amino-1-sulfonamide 48 N-(2-Chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)pyrrolidine-1-sulfonamide 49 N-(5-((2,3-Dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)pyrrolidine-1-sulfonamide 50 N-(5-((2,3-Dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)-N, N-dimethylamino-1-sulfonamide 51 N-(5-((2,3-Dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide 52 N-(5-((2,3-Dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)propane-2-sulfonamide 53 (R)-N-(2-Chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-3-fluoropyrrolidine-1- sulfonamide 54 N-(2-Chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)pyrrolidine-1-sulfonamide 55 N-(2-Chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-1-sulfonamide 56 N-(2-Chloro-3-((3-((dimethylamino)methyl)-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propan-1-sulfonamide

and their pharmaceutically acceptable salts.

[0087] In some embodiments, provided herein are the compounds and their salts described in Table 2 and their uses.

Table 2.

Compound
No. Structure chemical name 1 N-(2-Cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-1-sulfonamide 16 N-(2-cyano-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)propane-1-sulfonamide 12 N-(3-((2,3-Dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-nitrophenyl)propane-1-sulfonamide 29 N-(3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2-nitrophenyl)propane-1-sulfonamide 9 N-(3-((2,3-Dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide 18 N-(3-((3,4-Dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide 6 N-(2-Chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-1-sulfonamide 21 N-(2-Chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)propane-1-sulfonamide eleven N-(3-((2,3-Dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-(trifluoromethyl)phenyl)propane-1-sulfonamide thirty N-(3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2-(trifluoromethyl)phenyl)-propane-1-sulfonamide 31 N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-6-fluorophenyl)propane-1-sulfonamide 32 N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-6-fluorophenyl)propane-1-sulfonamide 33 N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2,6-difluorophenyl)propane-1-sulfonamide 34 N-(3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2,6-difluorophenyl)propane-1-sulfonamide 10 N-(3-((2,3-Dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2,4-difluorophenyl)propane-1-sulfonamide 35 N-(3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2,4-difluorophenyl)propane-1-sulfonamide 36 N-(3-chloro-4-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)pyridin-2-yl)propane-1-sulfonamide 26 N-(3-Chloro-4-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)pyridin-2-yl)propan-1-sulfonamide 40 (R)-N-(2-Chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-3-fluoropyrrolidine-1-sulfonamide 46 (R)-N-(2-Chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-3-fluoropyrrolidine-1-sulfonamide 48 N-(2-Chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)pyrrolidine-1-sulfonamide

and their pharmaceutically acceptable salts.

[0088] Any formula or compound provided herein, such as formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I- 2d), (I-2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a) or (I-5b), or the compounds shown in Tables 1 or 2, are compounds characterized by the structures described by the structural formula, as well as various variations or forms. In particular, compounds according to the formula presented herein may contain asymmetric centers, and therefore exist in various enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of compounds according to the general formula, and mixtures thereof in any ratio, are considered to fall within the scope of said formula. Thus, any formula provided herein is intended to be a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. If a compound shown in Tables 1 or 2 is shown in a particular stereochemical configuration, then this document also provides for an alternative stereochemical configuration of the compound, as well as a mixture of stereoisomers of the compound in any ratio. For example, if a compound shown in Tables 1 or 2 contains a stereocenter that is in the "S" stereochemical configuration, then this document also contemplates the enantiomer of the compound in which the stereocenter is in the "R" stereochemical configuration. By analogy, if a compound shown in Tables 1 or 2 contains a stereocenter that is in the "R" configuration, then the enantiomer of the compound in the "S" stereochemical configuration is also provided herein. Mixtures of the compound in both "S" and "R" stereochemical configurations are also contemplated. In addition, if a compound shown in Tables 1 or 2 contains two or more stereocenters, then any enantiomer or diastereoisomer of the compound is also contemplated. In addition, certain structures may exist as geometric isomers (ie, cis and trans isomers), as tautomers, or as atropisomers. Furthermore, any compound shown in Tables 1 or 2 is intended to be a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. In addition, certain structures may exist as geometric isomers (ie, cis and trans isomers), as tautomers, or as atropisomers. In addition, any formula presented herein, such as formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d) , (I-2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a) or ( I-5b) refers to hydrates, solvates and amorphous forms of such compounds, and mixtures thereof, even if such forms are not explicitly listed. In some embodiments, the solvent is water and the solvates are hydrates.

[0089] Compounds depicted herein may be present as salts, even if salts are not shown, and it should be understood that the compositions and methods provided herein cover all salts and solvates of the compounds depicted herein, as well as non-salt and the non-solvate form of the compound, as is well understood by those skilled in the art. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0090] In one variation, the compounds provided herein are synthetic compounds prepared for administration to a subject. In another variation, compositions are provided that contain the compound in substantially pure form. According to another variation, proposed pharmaceutical compositions containing the compound described in detail in this document, and a pharmaceutically acceptable carrier. In another variation, methods for administering a compound are provided. Purified forms, pharmaceutical compositions, and routes of administration of the compounds are suitable for any compound or form thereof detailed herein.

[0091] Any variation or embodiment of X ₁ , X ₂ , X ₃ , Y 1 , Y ₂ , Y ₃ , Z ₁ , Z ₂ , R ₁ , R ₂ , R _{3 ,} R ₄ , m and n, presented in herein may be combined with every other variation or embodiment X ₁ , X ₂ , X ₃ , Y 1 , Y ₂ , Y ₃ , Z _{1 , Z 2 ,} R ₁ , R ₂ , _{R 3 ,} R ₄ , m and n, as if each combination were individually and specifically described.

Compositions

[0092] Also provided are compositions, such as pharmaceutical compositions, that include a compound disclosed and/or described herein and one or more additional medical agents, pharmaceuticals, adjuvants, carriers, excipients, and the like. Suitable medical and pharmaceutical agents include those described herein. In some embodiments, the pharmaceutical composition includes a pharmaceutically acceptable excipient or adjuvant and at least one chemical compound described herein. Examples of pharmaceutically acceptable excipients include, without limitation, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, sodium croscarmellose, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound as described above in admixture with at least one pharmaceutically acceptable carrier or excipient. In some embodiments, compositions are provided, such as pharmaceutical compositions, that contain one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof.

[0093] According to some embodiments, a pharmaceutically acceptable composition is provided comprising a compound of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), (I-2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a), (I -5b), or a compound from Tables 1 or 2, or a pharmaceutically acceptable salt thereof. In some aspects, the composition may contain a synthetic intermediate that can be used to prepare the compound described herein. The compositions described herein may contain any other suitable active or inactive agents.

[0094] Any of the compositions described herein may be sterile or contain components that are sterile. Sterilization can be achieved by methods known in the art. Any of the compositions described herein may contain one or more compounds that are essentially pure.

[0095] Also provided are packaged pharmaceutical compositions containing the pharmaceutical composition described herein and instructions for using the composition to treat a patient suffering from the disease or condition described herein.

Pharmaceutical dosage forms

[0096] The present disclosure also relates to a composition, for example, a pharmaceutical composition, containing one or more of the compounds described herein, included in the dosage form together with a pharmaceutically acceptable carrier. Pharmaceutical compositions according to the present invention can also be administered as a combination therapy, i. in combination with other agents. For example, combination therapy may include a compound described herein in combination with at least one other active agent.

[0097] Pharmaceutically acceptable carriers may include any and all carriers, excipients, stabilizers, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and agents that delay absorption, and the like, which are physiologically compatible. Preferably, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (eg, by injection or infusion). Depending on the route of administration, per active compound, ie. the compound described herein may be coated with some substance to protect the compound from acids and other natural conditions that may inactivate the compound.

[0098] Acceptable carriers, excipients, or stabilizers are non-toxic to the recipient at standard dosages and concentrations for administration, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and meta -cresol); low molecular weight polypeptides (less than about 10 residues); proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; a salt-forming counterion such as sodium; metal complexes (eg Zn-protein complexes); and/or nonionic surfactants such as TWEEN ^TM or polyethylene glycol (PEG).

[0099] Pharmaceutical compositions according to the present invention may include one or more pharmaceutically acceptable salts. A pharmaceutically acceptable salt retains the desired biological activity of the parent compound and does not introduce any undesirable toxicological effects. Examples of such salts include acid addition salts and base addition salts. Acid addition salts include salts derived from non-toxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous, and the like, as well as from non-toxic organic acids such as aliphatic mono- and dicarboxylic acids. acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Base addition salts include salts derived from alkaline earth metals such as sodium, potassium, magnesium, calcium, etc., as well as from non-toxic organic amines such as N,N'-dibenzylethylenediamine, N-methylglucamine , chlorprocaine, choline, diethanolamine, ethylenediamine, procaine, etc.

[0100] The pharmaceutical composition of the present invention may also include a pharmaceutically acceptable antioxidant. Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Suitable fluidity can be maintained, for example, by using coating agents such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0101] Any suitable dosage form of the compounds described herein may be formulated (in general, see Remington's Pharmaceutical Sciences, (2000) Hoover, JE editor, ^20th edition, Lippincott Williams and Wilkins Publishing Company, Easton, Pa. , pages 780-857). The dosage form is chosen to be suitable for the respective route of administration. In cases where the compounds are basic or acidic to a degree sufficient to form stable acidic or basic salts, it may be appropriate to introduce the compounds as salts. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiologically acceptable anion, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochlorides, sulfates, nitrates, bicarbonates and carbonates. Pharmaceutically acceptable salts are prepared using standard procedures well known in the art, for example for a sufficiently basic compound such as an amine with an appropriate acid to produce a physiologically acceptable anion. Alkali metal (eg sodium, potassium or lithium) or alkaline earth metal (eg calcium) salts of carboxylic acids are also prepared.

[0102] If the proposed compounds are administered in a pharmacological composition, it is contemplated that the compounds may be formulated in admixture with a pharmaceutically acceptable excipient and/or carrier. For example, the subject compounds can be administered orally as neutral compounds or as pharmaceutically acceptable salts, or intravenously in physiological saline. Conventional buffers such as phosphates, bicarbonates or citrates can be used for this purpose. Without a doubt, to obtain a variety of dosage forms for a particular route of administration, a person skilled in the art will be able to modify the dosage forms within the framework of the idea of the present description. In particular, the proposed compounds can be modified to make them more soluble in water or other base, which can be easily achieved with minimal modifications (salt formation, esterification, etc.) that are within the competence of a person skilled in the art. . It is also within the skill of one skilled in the art to modify the route of administration and dosing regimen for a particular compound in order to adjust the pharmacokinetics of the compounds of the present invention to maximize patient benefit.

[0103] Compounds of formula I-III described herein are generally soluble in organic solvents such as chloroform, dichloromethane, ethyl acetate, ethanol, methanol, isopropanol, acetonitrile, glycerol, N,N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, and the like. In one embodiment, the present invention relates to dosage forms prepared by mixing a compound of Formula I-III with a pharmaceutically acceptable carrier. In one aspect, the dosage form can be prepared using a method comprising: a) dissolving the described compound in a water-soluble organic solvent, a non-ionic solvent, a water-soluble lipid, a cyclodextrin, a vitamin such as tocopherol, a fatty acid, a fatty acid ester, a phospholipid, or their combination to obtain a solution; and b) adding saline or buffer containing 1-10% carbohydrate solution. According to one example, the carbohydrate includes dextrose. Pharmaceutical compositions obtained using the methods of the present invention are stable and applicable for use in animals and in the clinic.

[0104] Illustrative examples of water-soluble organic solvents for use in the methods of the present invention include, without limitation, polyethylene glycol (PEG), alcohols, acetonitrile, N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or their combinations. Examples of alcohols include, without limitation, methanol, ethanol, isopropanol, glycerol, or propylene glycol.

[0105] Illustrative examples of water-soluble nonionic surfactants for use in the methods of the present invention include, but are not limited to, ^CREMOPHOR® EL, polyethylene glycol modified ^CREMOPHOR® (polyoxyethylene glycerol triricinoleate 35), hydrogenated ^CREMOPHOR® RH40, hydrogenated ^CREMOPHOR® RH60, PEG-succinate, polysorbate 20, polysorbate 80, SOLUTOL ^® HS (polyethylene glycol 660 12-hydroxystearate), sorbitan monooleate, poloxamer, LABRAFIL ^® (ethoxylated peach oil), LABRASOL ^® (capryl-caproyl macrogol-8-glyceride), GELUCIRE ^® (glycerol ester) , SOFTIGEN ^® (PEG 6 caprylic glyceride), glycerin, polysorbate glycol, or combinations thereof.

[0106] Illustrative examples of water-soluble lipids for use in the methods of the present invention include, without limitation, vegetable oils, triglycerides, vegetable oils, or combinations thereof. Examples of lipid oils include, but are not limited to, castor oil, polyoxyl castor oil, corn oil, olive oil, cottonseed oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, coconut oil triglyceride. , palm oil and their hydrogenated forms, or combinations thereof.

[0107] Illustrative examples of fatty acids and fatty acid esters for use in the methods of the present invention include, without limitation, oleic acid, monoglycerides, diglycerides, PEG esters with one or two fatty acids, or combinations thereof.

[0108] Illustrative examples of cyclodextrins for use in the methods of the present invention include, without limitation, alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-cyclodextrin, or sulfobutyl ether-beta-cyclodextrin.

[0109] Illustrative examples of phospholipids for use in the methods of the present invention include, without limitation, soy phosphatidylcholine or distearoylphosphatidyl glycerol and their hydrogenated forms, or combinations thereof.

[0110] To obtain a variety of dosage forms for a particular route of administration, a person skilled in the art will be able to modify the dosage forms within the framework of the idea of the present description. In particular, the compounds may be modified to render them more soluble in water or other base. It is also within the skill of one skilled in the art to modify the route of administration and dosing regimen for a particular compound in order to adjust the pharmacokinetics of the compounds of the present invention to maximize patient benefit.

Drug Combinations

[0111] Methods according to embodiments include administering an effective amount of at least one exemplary compound according to the present disclosure; optionally, the compound may be administered in combination with one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is known to be useful for treating a proliferation disorder in a subject, such as a cancer or tumor. In some embodiments, the additional therapeutic agent is known to be useful in the treatment of a neurodegenerative disorder.

[0112] Additional active ingredients may be administered in a pharmaceutical composition separate from at least one exemplary compound of the present disclosure, or may be formulated together with at least one exemplary compound of the present disclosure in a single pharmaceutical composition. Additional active ingredients may be administered simultaneously, before or after the administration of at least one illustrative compound according to the present disclosure.

Dosages and dosage forms

[0113] For the prevention or treatment of a disease, the appropriate dosage of the compounds described herein will depend on the type of disease being treated, the severity and course of the disease, whether the compound is being administered for prophylactic or therapeutic purposes, the route of delivery, previous therapy, and the subject's clinical history. The compounds described herein are suitably administered to a subject in a single dose or as a course of treatment. Depending on the type and severity of the disease, the usual daily dosage may vary from about 0.0001 mg/kg to 100 mg/kg or more, depending on the factors mentioned above. For repeated administrations over several days or more, depending on the condition, the treatment is maintained until the desired suppression of disease symptoms occurs.

[0114] For example, dosages can be 0.3 mg/kg body weight, 1 mg/kg body weight, 3 mg/kg body weight, 5 mg/kg body weight, or 10 mg/kg body weight, or within 1- 10 mg/kg. Treatment regimens may include administration once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every three months, or once every 3 to 6 months. . In other embodiments, sustained release dosage forms are administered that will result in less frequent administration compared to non-sustained release dosage forms.

[0115] The amount of active ingredient that can be combined with a carrier substance to form a single dosage form will generally be the amount of the composition that provides a therapeutic effect without being toxic to the subject. Typically, such an amount will range from about 0.01 percent to about 99 percent of the active ingredient, preferably from about 0.1 percent to about 70 percent, most preferably from about 1 percent to about 30 percent of the active ingredient in combination with a pharmaceutically acceptable carrier. .

Introduction

[0116] The composition described herein can be administered via one or more routes of administration using one or more of a variety of methods known in the art. One skilled in the art will appreciate that the route and/or mode of administration will vary depending on the desired results. Routes of administration for the compounds and compositions described herein include oral, sublingual, buccal, intranasal, topical, rectal, intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal, or other parenteral routes of administration, for example, by injection or infusion. . As used herein, the expression "parenteral administration" means methods of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

Methods of treatment

[0117] The compounds and pharmaceutical compositions provided herein can be used for any suitable purpose. For example, the compounds of the present invention can be used for treatment and/or testing.

[0118] The compounds and pharmaceutical compositions provided herein can be used to treat and/or prevent a proliferation disorder such as a cancer or tumor in an individual. In some embodiments, methods are provided for treating or preventing a proliferation disorder, such as a cancer or tumor, in an individual, comprising administering to an individual in need thereof a compound of formula (I), (I-1), (I-2a), (I- 2b), (I-2c), (I-2d), (I-2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b) , (I-4c), (I-5a), (I-5b) or the compounds of Tables 1 or 2, or a pharmaceutically acceptable salt thereof. In some embodiments, methods are provided for treating or preventing a proliferation disorder, such as a cancer or tumor, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one chemical compound described herein.

[0119] According to some embodiments, compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), (I-2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a), (I-5b) or compounds from Tables 1 or 2, or a pharmaceutically acceptable salt thereof, are inhibitors of the MAPK family of oncogenic protein tyrosine kinases such as B-Raf, especially the B-Raf V600E mutant, and are therefore all adapted for therapeutic use as antiproliferative (e.g., anticancer) agents in mammals, especially humans. In particular, the compounds of the present invention are useful in the prevention and treatment of a wide range of human hyperproliferative disorders such as malignant and benign tumors of the liver, kidney, bladder, breast, stomach, ovary, colorectal, prostate, pancreas, lung, vulva, thyroid, liver carcinomas, sarcomas, glioblastomas, head and neck tumors, melanoma and other hyperplastic conditions such as benign skin hyperplasia (eg psoriasis) and benign prostatic hyperplasia (eg BPH). In addition, it is believed that the compound of the present invention may have activity against brain metastases resulting from these disorders.

[0120] According to some embodiments, compounds of formula I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), (I-2e), ( I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a), (I-5b) or compounds from Tables 1 or 2, or a pharmaceutically acceptable salt thereof, may also be useful in the treatment of additional disorders that involve aberrant ligand expression/receptor interaction or activation of signaling events associated with various protein tyrosine kinases. Such disorders may include disorders of neuronal, glial, astrocytic, hypothalamic, and other endocrine, macrophage, epithelial, stromal, and blastocele origins that involve aberrant functioning, expression, activation, or signaling of tyrosine kinases.

[0121] This document also provides the use of a compound of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), (I-2e) , (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a), (I-5b) or compounds of Tables 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a proliferation disorder such as a cancer or tumor in a subject.

[0122] In some embodiments, the proliferation disorder or cancer is selected from the group consisting of malignant or benign tumors of the liver, kidney, bladder, breast, stomach, ovary, colorectal, prostate, pancreas, lung, vulva, thyroid, liver carcinomas, sarcomas, glioblastomas, head and neck tumors, melanomas and other hyperplastic conditions such as benign skin hyperplasia (eg psoriasis) and benign prostatic hyperplasia (eg BPH). In some embodiments, a compound of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), (I-2e), (I- 2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a), (I-5b) or a compound from Table 1 or 2 may have activity against brain metastases resulting from these disorders.

[0123] Also provided are methods for inhibiting B-Raf V600E kinase activity, comprising administering to an individual in need thereof a therapeutically effective amount of at least one chemical compound described herein. In some embodiments, methods are provided for inhibiting B-Raf V600E kinase activity in a cell, comprising contacting the cell with at least one chemical compound described herein, such as a compound of formula (I), (I-1) , (I-2a), (I-2b), (I-2c), (I-2d), (I-2e), (I-2f), (I-3a), (I-3b), ( I-4a), (I-4b), (I-4c), (I-5a), (I-5b) or a compound from Tables 1 or 2, or a pharmaceutically acceptable salt thereof. This document further provides the use of at least one chemical compound described herein, such as a compound of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), (I-2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I -5a), (I-5b) or a compound of Tables 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting B-Raf V600E kinase activity in an individual.

[0124] Also provided are methods of treating and/or preventing a proliferation disorder, such as a cancer or tumor, in a subject, comprising administering to an individual in need thereof a therapeutically effective amount of at least one chemical compound described herein, such as a compound of formula (I) , (I-1), (I-2a), (I-2b), (I-2c), (I-2d), (I-2e), (I-2f), (I-3a), ( I-3b), (I-4a), (I-4b), (I-4c), (I-5a), (I-5b) or a compound from Tables 1 or 2, or a pharmaceutically acceptable salt thereof. This document further provides the use of at least one chemical compound described herein, such as a compound of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), (I-2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I -5a), (I-5b) or a compound of Tables 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of a proliferation disorder, cancer or tumor in a subject.

[0125] In one embodiment, the disease or condition being treated or prevented is an abnormal cell proliferation, such as a cancer. The term "cancer" refers to precancerous conditions, non-malignant, poorly differentiated, well-differentiated and malignant tumors. Treatment or prophylaxis with the compounds disclosed herein is contemplated for cancer of any type of tissue. Exemplary types of cancer include carcinoma, lymphoma, blastoma, sarcoma, leukemia, and lymphocytic leukemias. More specifically, in certain embodiments, the cancer is squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer, including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and squamous cell carcinoma of the lung, peritoneal cancer , hepatocellular carcinoma, gastric or gastric cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer colon, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, renal or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer.

[0126] Provided herein is a method of treating cancer in an individual in need thereof by administering to the individual a therapeutically effective amount of a compound or composition described herein. Also provided herein is the use of a compound or composition described herein for the manufacture of a medicament for the treatment of cancer in an individual in need thereof. Also provided herein is the use of a compound or composition described herein for the treatment of cancer in an individual in need thereof. Also provided herein is a compound or composition described herein for use in the treatment of cancer in an individual in need thereof.

[0127] In another embodiment, the disease or condition being treated or prevented is a neurodegenerative disease. Illustrative types of neurodegenerative disease include, without limitation, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease, which arise as a consequence of neurodegenerative processes.

[0128] According to some embodiments, methods for treating or preventing a neurodegenerative disease such as amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease are provided, comprising administering to an individual in need thereof a compound of formula (I), (I-1), ( I-2a), (I-2b), (I-2c), (I-2d), (I-2e), (I-2f), (I-3a), (I-3b), (I- 4a), (I-4b), (I-4c), (I-5a), (I-5b) or a compound from Tables 1 or 2, or a pharmaceutically acceptable salt thereof. In some embodiments, methods are provided for treating or preventing a neurodegenerative disease such as amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease, comprising administering to a subject a therapeutically effective amount of at least one chemical compound described herein.

[0129] Provided herein is a method of treating a neurodegenerative disease in an individual in need thereof by administering to the individual a therapeutically effective amount of a compound or composition described herein. Also provided herein is the use of a compound or composition described herein for the manufacture of a medicament for the treatment of a neurodegenerative disease in an individual in need thereof. Also provided herein is the use of a compound or composition described herein for the treatment of a neurodegenerative disease in an individual in need thereof. Also provided herein is a compound or composition described herein for use in the treatment of a neurodegenerative disease in an individual in need thereof.

[0130] In one aspect, provided herein are kits that include a compound or composition described herein and instructions for use. In some embodiments, the kits may include instructions for use in treating cancer in an individual in need thereof. In other embodiments, the kits may include instructions for use in the treatment of a neurodegenerative disease in an individual in need thereof. The kit may further include any substances or devices that can be used to administer the compound or composition, such as vials, syringes, or IV bags. The kit may also include sterile packaging.

General synthesis methods

[0131] The compounds of formula (I) will be further described by reference to the following illustrative synthetic schemes for their general preparation and the following specific examples. Those skilled in the art will recognize that, in order to prepare the various compounds described herein, the starting materials can be suitably selected so that the ultimately required substituents are carried through the reaction scheme, with or without the introduction of protecting groups as appropriate, to obtain target product. Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituent, a suitable group which can be carried through the reaction scheme and replaced as appropriate by the desired substituent. In addition, one skilled in the art will appreciate that protecting groups can be used to protect certain functional groups (amino, carboxy, or side chain groups) under reaction conditions, and that such groups can be removed under standard conditions where appropriate. . Unless otherwise indicated, the meanings of the variables are as defined above with respect to formula (I).

[0132] If it is desired to obtain a particular enantiomer of a compound, this can be done from an appropriate mixture of enantiomers using any suitable conventional technique for separating or cleaving enantiomers. Thus, for example, diastereomeric derivatives can be obtained by reacting a mixture of enantiomers, such as a racemate, and the corresponding chiral compound. Then, the diastereoisomers can be separated by any convenient means, for example, by crystallization to obtain the desired enantiomer. According to another separation process, the racemate can be separated using chiral high performance liquid chromatography. Alternatively, if desired, a particular enantiomer can be obtained by using the appropriate chiral intermediate in one of the described processes.

[0133] In the event that it is desirable to obtain a particular isomer of the compound or otherwise purify the reaction product, chromatography, recrystallization and other conventional separation techniques can also be used for intermediates or final products.

[0134] General methods for preparing the compounds described herein are reflected in the following illustrative methods. The values of variable groups in the schemes presented herein are defined for formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), (I -2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), (I-4c), (I-5a), (I-5b ) or any variation thereof. Other compounds described in this document can be obtained by similar methods.

[0135] General methods of synthesis that can be specified to obtain compounds according to the present invention, such as B1, are given in the document Claudi F. et al., J. Org. Chem. 1974, 39, p. 3508. Certain starting materials may be prepared according to methods familiar to those skilled in the art, and certain synthetic modifications may be made according to methods familiar to those skilled in the art. A standard procedure for the preparation of 2-alkyl-1-iminoquinazoline is provided in Bartra Sanmarti, M. et al., WO2011/076813.

[0136] In some embodiments, a compound of formula (I) is synthesized by reacting a phenol or aniline A1 with a quinazolineimine B1 as shown in Scheme A.

Scheme A

where the values of X ₁ , X ₂ , X ₃ , Y ₁ , Y ₂ , Y ₃ , Z ₁ , Z ₂ , R ₁ , R ₂ , R ₃ , R ₄ , m and n are defined for formula (I) or any of its variation detailed herein, and LG is the leaving group. Specific examples are provided in the Examples section below.

[0137] In some embodiments, a compound of formula (I) is synthesized by reacting a phenyl or heteroaryl compound A2 with a quinazoliminine B2 as shown in Scheme B.

Scheme B

where the values of X ₁ , X ₂ , X ₃ , Y ₁ , Y ₂ , Y ₃ , Z ₁ , Z ₂ , R ₁ , R ₂ , R ₃ , R ₄ , m and n are defined for formula (I) or any of its variation detailed herein, and LG is the leaving group. Specific examples are provided in the Examples section below.

[0138] Starting materials, the synthesis of which is not specifically described above, are either commercially available or can be obtained using methods well known to specialists in this field of technology.

[0139] In some embodiments, compounds of Formula A1 are prepared according to the synthesis depicted in Scheme C.

Scheme C

where the meanings of Y ₁ , Y ₂ , Y ₃ , Z ₁ , Z ₂ , R ₂ , R ₃ and R ₄ are defined for formula (I) or any variation thereof as detailed herein, and LG is a leaving group.

[0140] In some embodiments, compounds of formula B1 are prepared according to the synthesis depicted in Scheme D.

Scheme D

where the values of X ₁ , X ₂ , X ₃ , Z ₁ , R ₁ , m and n are defined for formula (I) or any variation thereof, described in detail herein, and LG is a leaving group.

[0141] In some embodiments, compounds of formula (I) are prepared according to the synthesis depicted in Scheme E.

Scheme E

where the values of X ₁ , X ₂ , X ₃ , Y ₁ , Y ₂ , Y ₃ , Z ₁ , Z ₂ , R ₁ , R ₂ , R ₃ , R ₄ , m and n are defined for formula (I) or any of its variation detailed herein, and LG is the leaving group. Specific examples are provided in the Examples section below.

EXAMPLES

[0142] The present examples are intended to illustrate, but not limit, the compositions, uses, and methods presented herein. A person skilled in the art will understand that subsequent reactions and synthesis schemes can be modified by choosing suitable starting materials and reagents in order to obtain compounds of formula (I), (I-1), (I-2a), (I-2b) , (I-2c), (I-2d), (I-2e), (I-2f), (I-3a), (I-3b), (I-4a), (I-4b), ( I-4c), (I-5a) or (I-5b) or salts thereof. Compounds are prepared using the general methods described above.

[0143] The following chemical abbreviations are used throughout the Examples section: ACN (acetonitrile), DCM (dichloromethane), DIEA (N, N-diisopropylethylamine), DMF (dimethylformamide), DMAP (4-dimethylaminopyridine), DMSO (dimethyl sulfoxide) , Et ₃ N (triethylamine), EtOAc (ethyl acetate), ¹ H-NMR (proton nuclear magnetic resonance), HPLC (high performance liquid chromatography), i-PrOH (isopropyl alcohol), LCMS (liquid chromatography/mass spectrometry), MeI (methyl iodide), MeOH (methanol), NMP (N-methyl-2-pyrrolidone), PE (petroleum ether), SEMCl (2-(trimethylsilyl)ethoxymethyl chloride), THF (tetrahydrofuran), and TFA (trifluoroacetic acid).

Example 1 Preparation of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-1-sulfonamide (compound 1)

Scheme 1

Stage 1: Synthesis of 6-methoxyquinazolin-4(3H)-one

[0144] A mixture of 2-amino-5-methoxybenzoic acid (10.0 g, 59.9 mmol), formamidine acetate (12.3 g, 119 mmol) in 80 ml of 2-methoxyethanol was heated at 125°C for 18 hours. After cooling to room temperature, the precipitate was collected by filtration, washed twice with 2-methoxyethanol and dried under vacuum to give 6-methoxyquinazolin-4(3H)-one (9.1 g, 87% yield).

Stage 2: Synthesis of 4-chloro-6-methoxyquinazoline

[0145] A solution of 6-methoxyquinazolin-4(3H)-one (3.0 g, 17.0 mmol) in POCl ₃ (30 ml) was stirred at 120° C. overnight. Then, the mixture was cooled to room temperature and evaporated. The residue was purified by silica gel column chromatography (PE/EtOAc 10:1 to 5:1, v/v) to give 4-chloro-6-methoxyquinazoline (3.0 g, 91% yield).

Stage 3: Synthesis of 2-((6-methoxyquinazolin-4-yl)amino)ethan-1-ol

[0146] To a solution of 4-chloro-6-methoxyquinazoline (2.5 g, 12.9 mmol) in i-PrOH (30 ml) was added 2-aminoethanol (5.0 ml) and Et ₃ N (5.0 ml ). The mixture was stirred at 80°C for 20 min, then cooled and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH 50:1 to 20:1, v/v) to give 2-((6-methoxyquinazolin-4-yl)amino)ethan-1-ol (2, 0 g, 71% yield.

Step 4: Synthesis of 9-methoxy-2,3-dihydroimidazo[1,2-c]quinazoline

[0147] _{SOCl 2 (} 10.0 ml ), degassed using N ₂ and stirred at 70°C overnight. The resulting mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in aq. NaHCO ₃ (50.0 ml) and extracted with DCM (200 ml x 3). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 9-methoxy-2,3-dihydroimidazo[1,2-c]quinazoline (1.5 g, 82% yield) as a tan solid .

Step 5: Synthesis of 2,3-dihydroimidazo[1,2-c]quinazolin-9-ol

[0148] NaSEt (200 mg, 2.0 mmol) was added to a solution of 9-methoxy-2,3-dihydroimidazo[1,2-c]quinazoline (200 mg, 1.0 mmol) in DMF (10.0 ml) . The reaction mixture was degassed using N ₂ and stirred at 130°C overnight and then cooled to room temperature. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 50:1 to 20:1, v/v) to give 2,3-dihydroimidazo[1,2-c]quinazolin-9-ol (150 mg, 80% yield).

Step 6: Synthesis of 2-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-6-fluorobenzonitrile

[0149] NaH (60% in mineral oil, 30 mg, 0.73 mmol). The reaction mixture was degassed with N ₂ and stirred at room temperature for 15 minutes. Then, 2,6-difluorobenzonitrile (78 mg, 0.56 mmol) was added and the mixture was stirred at 80°C for 1 hour. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH from 100:1 to 30:1, v/v) to give 2-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-6-fluorobenzonitrile (120 mg, 70% yield).

Step 7: Synthesis of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-1-sulfonamide

[0150] To a solution of propane-1-sulfonamide (48.0 mg, 0.39 mmol) in DMF (15.0 ml) at 0°C NaH (60% in mineral oil, 17.0 mg, 0. 43 mmol). The reaction mixture was degassed with N ₂ and stirred at room temperature for 30 minutes. Then, 2-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-6-fluorobenzonitrile (100 mg, 0.33 mmol) was added and the mixture was stirred at 100°C for nights in N ₂ atmosphere. The resulting mixture was evaporated and the residue was purified on a flash column (ACN/H ₂ O) to give N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy )phenyl)propane-1-sulfonamide (20 mg, 15% yield) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.73 (s, 1H), 8.06-7.96 (m, 3H), 7.75 (t, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 4.74-4.69 (m, 2H), 4, 19-4.15 (m, 2H), 3.25 (t, J=7.2 Hz, 2H), 1.85-1.79 (m, 2H), 1.02 (t, J=7, 2 Hz, 3H). LCMS (M+H ⁺ ) m/z: 410.7.

Example 2 Preparation of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-N-methylpropane-1-sulfonamide (compound 2)

Scheme 2

Synthesis of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-N-methylpropane-1-sulfonamide

[0151] To a solution of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propan-1-sulfonamide (80 mg, 0.20 mmol) in DMF (10.0 ml) NaH (60% in mineral oil, 16.0 mg, 0.39 mmol) was added slowly at 0°C. The reaction mixture was degassed with N ₂ and stirred at room temperature for 60 minutes. Then, iodomethane (43 mg, 0.30 mmol) was added and the mixture was stirred at room temperature overnight under N ₂ atmosphere. The resulting mixture was evaporated and the residue was purified on a flash column (ACN/H ₂ O) to give N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy )phenyl)-N-methylpropane-1-sulfonamide (30 mg, 35% yield) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.98 (s, 1H), 7.72 (t, J=8.4 Hz, 1H), 7.54-7.44 (m, 4H), 7.07 (d, J=8.4 Hz, 1H), 4.12 (t, J=9.6 Hz, 2H), 3.92 (t, J=9.6 Hz, 2H) , 3.34-3.30 (m, 2H), 3.29 (s, 3H), 1.81-1.75 (m, 2H), 1.02 (t, J=7.2 Hz, 3H ). LCMS (M+H ⁺ ) m/z: 424.2 [M+1].

Example 3 Preparation of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-4-fluorophenyl)propane-1-sulfonamide (compound 3)

Scheme 3

Step 1: Synthesis of 2-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-3,6-difluorobenzonitrile

[0152] NaH (60% in mineral oil , 111 mg, 2.78 mmol). The reaction mixture was degassed with N ₂ and stirred at rt. within 60 min. Then, 2,3,6-trifluorobenzonitrile (37.0 mg, 2.35 mmol) was added and the mixture was stirred at 80° C. for 1 hour. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 30:1, v/v) to give 2-((2,3-dihydroimidazo[1,2-c]quinazoline -9-yl)oxy)-3,6-difluorobenzonitrile (200 mg, 29% yield).

Step 2: Synthesis of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-4-fluorophenyl)propane-1-sulfonamide

[0153] NaH (60% in mineral oil, 32 mg, 0.81 mmol) was slowly added to a solution of propane-1-sulfonamide (84 mg, 0.68 mmol) in DMF (20 ml) at 0°C. The reaction mixture was degassed with N ₂ and stirred at rt. within 60 min. Then, 2-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)-oxy)-3,6-difluorobenzonitrile (200 mg, 0.62 mmol) was added and the mixture was stirred at 100° C during the night in an N ₂ atmosphere. The resulting mixture was evaporated and the residue was purified on a flash column (ACN/H ₂ O) to give N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy )-4-fluorophenyl)propane-1-sulfonamide (30 mg, 10% yield) as a white solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ 7.91 (s, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.43-7.34 (m, 3H ), 7.25 (t, J=9.6 Hz, 1H), 4.19 (t, J=9.6 Hz, 2H), 4.00 (t, J=9.6 Hz, 2H), 2.98-2.94 (m, 2H), 1.88-1.83 (m, 2H), 1.02 (t, J=7.2 Hz, 3H). LCMS (M+H ⁺ ) m/z: 428.7.

Example 4 Preparation of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-4,6-difluorophenyl)propane-1-sulfonamide (compound 4 )

Scheme 4

Step 1: Synthesis of 2-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-3,5,6-trifluorobenzonitrile

[0154] NaH (60% in mineral oil , 128 mg, 3.2 mmol). The reaction mixture was degassed with N ₂ and stirred at 0° C. for 30 minutes. Then, 2,3,5,6-tetrafluorobenzonitrile (308 mg, 1.8 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched by adding MeOH (5 ml) at 0°C. The resulting mixture was evaporated and the residue was purified by silica gel flash column chromatography (DCM/MeOH 60:1 to 10:1, v/v) to give 2-((2,3-dihydroimidazo[1,2-c ]quinazolin-9-yl)oxy)-3,5,6-trifluorobenzonitrile (200 mg, 36% yield) as a yellow solid.

Step 2: Synthesis of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-4,6-difluorophenyl)propane-1-sulfonamide

[0155] NaH (60% in mineral oil, 48 mg, 1.2 mmol) was slowly added to a solution of propane-1-sulfonamide (86 mg, 0.7 mmol) in NMP (10 mL) at 0°C. The reaction mixture was degassed with N ₂ and stirred at 0° C. for 30 minutes. Then, 2-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-3,5,6-trifluorobenzonitrile (200 mg, 0.6 mmol) was added and the mixture was stirred at 80 °C during the night in an N ₂ atmosphere. Then, cooled to room temperature. The resulting mixture was evaporated and the residue was purified by silica gel flash column chromatography (DCM/MeOH 60:1 to 10:1, v/v) to give a crude product which was purified by preparative TLC (DCM/MeOH=10: 1, v/v) to give N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-4,6-difluorophenyl)-propane -1-sulfonamide (16 mg, 6% yield) as a yellow solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ 8.11 (s, 1H), 7.71-7.66 (m, 2H), 7.56 (dd, J=8.8, 2, 8 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 4.37 (t, J=10.0 Hz, 2H), 4.08 (t, J=10.0 Hz , 2H), 3.19 (t, J=7.6 Hz, 2H), 1.97-1.91 (m, 2H), 1.07 (t, J=7.6 Hz, 3H). LCMS (M+H ⁺ ) m/z: 446.2.

Example 5 Preparation of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-6-fluorophenyl)propane-1-sulfonamide (compound 5)

Scheme 5

Step 1: Synthesis of N-(2-cyano-3,6-difluorophenyl)propane-1-sulfonamide

[0156] NaH (60% in mineral oil, 320 mg, 8.0 mmol) was slowly added to a solution of propane-1-sulfonamide (590 mg, 4.8 mmol) in DMF (10 mL) at 0°C. The reaction mixture was degassed with N ₂ and stirred at 0° C. for 30 minutes. Then, 2,3,6-trifluorobenzonitrile (628 mg, 4.0 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched by adding H ₂ O (5 ml) at 0°C. The resulting mixture was evaporated and the residue was purified by silica gel flash column chromatography (PE/EtOAc 10:1 to 4:1, v/v) to give N-(2-cyano-3,6-difluorophenyl)propane- 1-sulfonamide (920 mg, 88% yield) as a white solid.

Step 2: Synthesis of N-(2-cyano-3,6-difluorophenyl)-N-((2-(trimethylsilyl)ethoxy)methyl)propane-1-sulfonamide

[0157] NaH (60% in mineral oil, 212 mg, 5.3 mmol). The reaction mixture was degassed with N ₂ and stirred at 0° C. for 30 minutes. Then, (2-(chloromethoxy)ethyl)-trimethylsilane (709 mg, 4.3 mmol) was added and the mixture was stirred at room temperature overnight under N ₂ atmosphere. The reaction mixture was quenched by adding MeOH (5 ml) at 0°C. The resulting mixture was evaporated and the residue was purified by silica gel flash column chromatography (PE/EtOAc 10:1 to 4:1, v/v) to give N-(2-cyano-3,6-difluorophenyl)-N -((2-(trimethylsilyl)-ethoxy)methyl)propane-1-sulfonamide (800 mg, 58% yield) as a yellow oil.

Step 3: Synthesis of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-6-fluorophenyl)propane-1-sulfonamide

[0158] N-(2-cyano-3,6-difluorophenyl)-N-((2-(trimethylsilyl)ethoxy)methyl)propane-1-sulfonamide (580 mg, 1.5 mmol ), 2,3-dihydroimidazo[1,2-c]quinazolin-9-ol (277 mg, 1.5 mmol), Cs ₂ CO ₃ (724 mg, 2.2 mmol) and 20 ml NMP. The resulting solution was heated at 100°C for 18 hours. After cooling to room temperature, the resulting mixture was evaporated and the residue was purified by silica gel flash column chromatography (DCM/MeOH 40:1 to 10:1, v/v) to give N-(2-cyano-3- ((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-6-fluorophenyl)propane-1-sulfonamide (80 mg, 13% yield) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 10.48 (br, 1H), 8.13 (s, 1H), 7.63-7.52 (m, 3H), 7.45 (d, J=2.4 Hz, 1H), 6.99-6.96 (m, 1H), 4.24 (t, J=10.0 Hz, 2H), 3.96 (t, J= 10.0 Hz, 2H), 3.12 (t, J=7.6 Hz, 2H), 1.85-1.79 (m, 2H), 1.00 (t, J=7.2 Hz, 3H). LCMS (M+H ⁺ ) m/z: 428.2.

Example 6 Preparation of N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-1-sulfonamide (compound 6)

Scheme 6

Step 1: Synthesis of N-(3-bromo-2-chlorophenyl)propane-1-sulfonamide

[0159] To a solution of 3-bromo-2-chloroaniline (3.0 g, 12.7 mmol) in pyridine (30 ml) was added propane-1-sulfonyl chloride (5.4 g, 38.1 mmol), the reaction mixture was stirred at room temperature overnight under N ₂ atmosphere, and after completion of the reaction, the solvent was removed. The residue was purified by silica gel column chromatography (PE/EtOAc=10/1) to give N-(3-bromo-2-chlorophenyl)propane-1-sulfonamide (700 mg, 18% yield) as a yellow oil.

Step 2: Synthesis of N-(3-Bromo-2-chlorophenyl)-N-((2-(trimethylsilyl)ethoxy)methyl)propane-1-sulfonamide

[0160] NaH (60% in mineral oil, 176 mg, 4.4 mmol). The mixture was stirred for 1 hour at 0°C and then SEMCl (730 mg, 4.4 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was extinguished by adding water (5 ml) at 0°C. The solvent was removed. The residue was purified by silica gel column chromatography (PE/EtOAc=10/1) to give N-(3-bromo-2-chlorophenyl)-N-((2-(trimethylsilyl)ethoxy)-methyl)propane-1-sulfonamide ( 700 mg, 72% yield as a yellow oil.

Step 3: Synthesis of N-(2-Chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-1-sulfonamide

[0161] A mixture of N-(3-bromo-2-chlorophenyl)-N-((2-(trimethylsilyl)-ethoxy)methyl)propane-1-sulfonamide (700 mg, 1.58 mmol), 2,3-dihydroimidazo [1,2-c]quinazolin-9-ol (319 mg, 1.70 mmol), K ₂ CO ₃ (650 mg, 4.74 mmol), CuI (120 mg, 0.63 mmol) and L-Pro (60 mg, 0.63 mmol) in DMSO (20 ml) was stirred at 150°C for 16 hours under N ₂ atmosphere, after completion of the reaction, the mixture was filtered and concentrated. The residue was purified by preparative HPLC to give N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propan-1-sulfonamide (5 mg, yield 1%) as a white solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ 8.03 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.43-7.33 (m, 3H), 7.02 (d, J=7.2 Hz, 1H), 4.29 (t, J=10.0 Hz, 2H), 4.04 (t, J=10.0 Hz, 2H), 3.15 (t, J=7.6 Hz, 2H), 1.88-1.82 (m, 2H), 1.03 (t , J=7.6 Hz, 3H). LCMS (M+H ⁺ ) m/z: 419.1.

Example 7 Preparation of N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluoro-4-nitrophenyl)propane-1-sulfonamide (compound 7)

Scheme 7

Step 1: Synthesis of 9-(2,3-difluoro-6-nitrophenoxy)-2,3-dihydroimidazo[1,2-c]quinazoline

[0162] A mixture of 2,3-dihydroimidazo[1,2-c]quinazolin-9-ol (300 mg, 1.6 mmol), 1,2,3-trifluoro-4-nitrobenzene (852 mg, 4.8 mmol ) and Cs ₂ CO ₃ (783.6 mg, 2.4 mmol) in DMF (15 ml) was stirred at room temperature overnight. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH/NH ₃ H ₂ O 100:1:1 to 10:1:0.1, v/v/v) to give 9- (2,3-difluoro-6-nitrophenoxy)-2,3-dihydroimidazo[1,2-c]quinazoline (410 mg, 74% yield) as a yellow solid.

Step 2: Synthesis of N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluoro-4-nitrophenyl)propane-1-sulfonamide

[0163] NaH (60% in mineral oil, 119 mg, 2.98 mmol) was added to a solution of propane-1-sulfonamide (161 mg, 1.31 mmol) in DMF (10 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, and then a solution of 9-(2,3-difluoro-6-nitrophenoxy)-2,3-dihydroimidazo[1,2-c]quinazoline (410 mg, 1.19 mmol) in DMF (2 ml). The reaction mixture was stirred at room temperature overnight. Water (10 ml) was added to the mixture, the solvent was evaporated, and the residue was purified by preparative HPLC to give N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2- fluoro-4-nitrophenyl)propane-1-sulfonamide (221 mg, 38% yield) as a yellow solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.19 (broad s, 1H), 8.46 (s, 1H), 7.93 (d, J=9.6 Hz, 1H) , 7.85 (d, J=9.2 Hz, 1H), 7.78 (dd, J=9.2, 2.0 Hz, 1H), 7.50 (s, 1H), 7.38 ( t, J=8.8 Hz, 1H), 4.51 (t, J=10.0 Hz, 2H), 4.05 (t, J=10.0 Hz, 2H), 2.93 (t, J=7.6Hz, 2H), 1.73-1.68(m, 2H), 0.95(t, J=7.6Hz, 3H). LCMS (M+H ⁺ ) m/z: 448.1.

Example 8 Preparation of N-(4-Amino-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide (compound 8)

Scheme 8

Synthesis of N-(4-amino-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide

[0164] N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluoro-4-nitrophenyl) propane-1-sulfonamide mixture (160 mg, 0 .35 mmol), Fe (100 mg, 1.78 mmol) and NH ₄ Cl (144 mg, 2.68 mmol) in EtOH/H ₂ O (10 ml/1 ml) were stirred at 95°C for 2 hours . The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH/NH ₃ H ₂ O 100:1:1 to 10:1:0.1, v/v/v) to give N- (4-Amino-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide (100 mg, 68% yield) as white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.46 (br, 1H), 9.15 (s, 1H), 8.65 (s, 1H), 7.97 (d, J =9.2Hz, 1H), 7.79(dd, J=9.2, 2.4Hz, 1H), 7.64(s, 1H), 7.05(t, J=8.8Hz , 1H), 6.66 (d, J=8.4 Hz, 1H), 4.68 (t, J=10.0 Hz, 2H), 4.12 (t, J=10.0 Hz, 2H ), 2.97 (t, J=7.6 Hz, 2H), 1.73-1.67 (m, 2H), 0.92 (t, J=7.6 Hz, 3H). LCMS (M+H ⁺ ) m/z: 418.2.

Example 9 Preparation of N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide (compound 9)

Scheme 9

Synthesis of N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide

[0165] N-(4-Amino-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl) propane-1-sulfonamide mixture (70 mg, 0 .16 mmol) and isopentylnitrile (196 mg, 1.67 mmol) in THF (10 ml) were stirred at 75° C. for 2 hours. After completion of the reaction, the solvent was evaporated and the residue was purified by preparative HPLC to give N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)propan-1 -sulfonamide (trifluoroacetate, 20.1 mg, 23% yield) as a brown solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.62 (br, 1H), 9.92 (s, 1H), 8.67 (s, 1H), 7.98 (d, J =9.2 Hz, 1H), 7.86 (dd, J=9.2, 2.4 Hz, 1H), 7.78 (s, 1H), 7.40-7.38 (m, 1H) , 7.30 (t, J=8.8 Hz, 1H), 7.22-7.19 (m, 1H), 4.68 (t, J=10.0 Hz, 2H), 4.13 ( t, J=10.0 Hz, 2H), 3.15 (t, J=8.0 Hz, 2H), 1.76-1.71 (m, 2H), 0.96 (t, J=7 .6 Hz, 3H). LCMS (M+H ⁺ ) m/z: 403.2.

Example 10 Preparation of N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2,4-difluorophenyl)propane-1-sulfonamide (compound 10)

Scheme 10

Step 1: Synthesis of 9-(2,3,6-trifluorophenoxy)-2,3-dihydroimidazo[1,2-c]quinazoline

[0166] To a solution of 1,2,3,4-tetrafluorobenzene (300 mg, 2.0 mmol) and 2,3-dihydroimidazo[1,2-c]quinazolin-9-ol (374 mg, 2.0 mmol) in DMF (10 ml) was added K ₂ CO ₃ (552 mg, 4.0 mmol). The mixture was stirred at 120°C for 18 hours. After cooling to room temperature, the resulting mixture was evaporated and the residue was purified by silica gel flash column chromatography (DCM/MeOH 60:1 to 10:1, v/v) to give 9-(2,3,6- trifluorophenoxy)-2,3-dihydroimidazo[1,2-c]quinazoline (477 mg, 75% yield) as a brown solid.

Step 2: Synthesis of N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2,4-difluorophenyl)propane-1-sulfonamide

[0167] A 50 ml round bottom flask was charged with 9-(2,3,6-trifluorophenoxy)-2,3-dihydroimidazo[1,2-c]quinazoline (427 mg, 1.35 mmol), propane-1-sulfonamide (332 mg, 2.70 mmol), Cs ₂ CO ₃ (880 mg, 2.70 mmol) and 10 ml DMF. The resulting solution was heated at 120°C for 18 hours. After cooling to room temperature, the resulting mixture was evaporated and the residue was purified by silica gel flash column chromatography (DCM/MeOH 40:1 to 10:1, v/v) to give N-(3-((2, 3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2,4-difluorophenyl)-propane-1-sulfonamide (28.1 mg, 5% yield) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.61 (broad, 1H), 7.99 (s, 1H), 7.52-7.45 (m, 2H), 7.38 -7.35(m, 2H), 7.18(s, 1H), 4.14(t, J=9.6Hz, 2H), 3.91(t, J=9.6Hz, 2H) , 3.07 (t, J=7.6 Hz, 2H), 1.73-1.67 (m, 2H), 0.89 (t, J=7.6 Hz, 3H). LCMS m/z: 421.1 [M+1] ⁺

Example 11 Preparation of N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-(trifluoromethyl)phenyl)propane-1-sulfonamide (compound 11)

Scheme 11

Step 1: Synthesis of 9-(3-fluoro-2-(trifluoromethyl)phenoxy)-2,3-dihydroimidazo[1,2-c]quinazoline

[0168] NaH (60% in mineral oil, 48 mg, 1.2 mmol), the mixture was stirred at room temperature for 30 min, then 2,3-dihydroimidazo[1,2-c]quinazolin-9-ol (187 mg, 1.0 mmol) was added and the reaction mixture was stirred at room temperature in during the night. After completion of the reaction, water was added to quench the reaction mixture, the solvent was removed, and the residue was purified by silica gel column chromatography (DCM/MeOH=30/1+5‰ NH ₃ H ₂ O) to obtain 9-(3-fluoro-2 -(trifluoromethyl)phenoxy)-2,3-dihydroimidazo[1,2-c]quinazoline (130 mg, 37% yield) as a white solid.

Step 2: Synthesis of N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-(trifluoromethyl)phenyl)propane-1-sulfonamide

[0169] A mixture of 9-(3-fluoro-2-(trifluoromethyl)phenoxy)-2,3-dihydroimidazo[1,2-c]quinazoline (130 mg, 0.37 mmol), propane-1-sulfonamide (136 mg , 1.11 mmol) and Cs ₂ CO ₃ (241 mg, 0.74 mmol) in DMF (5 ml) were stirred at 120° C. for 16 hours under N ₂ and the solvent was removed after completion of the reaction. The residue was purified by preparative HPLC to give N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-(trifluoromethyl)phenyl)propane-1-sulfonamide (trifluoroacetate, 26 mg, 12% yield as a yellow solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.54 (br, 1H), 9.70 (s, 1H), 8.69 (s, 1H), 8.00 (d, J =8.8Hz, 1H), 7.87-7.84(m, 2H), 7.73(t, J=8.0Hz, 1H), 7.40(d, J=8.0Hz , 1H), 7.19 (d, J=8.0 Hz, 1H), 4.70 (t, J=10.0 Hz, 2H), 4.15 (t, J=10.0 Hz, 2H ), 3.18 (t, J=7.6 Hz, 2H), 1.82-1.76 (m, 2H), 1.02 (t, J=7.6 Hz, 3H). LCMS (M+H ⁺ ) m/z: 453.1.

Example 12 Preparation of N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-nitrophenyl)propane-1-sulfonamide (compound 12)

Scheme 12

Step 1: Synthesis of 9-(3-fluoro-2-nitrophenoxy)-2,3-dihydroimidazo[1,2-c]quinazoline

[0170] A solution of 2,3-dihydroimidazo[1,2-c]quinazolin-9-ol (500 mg, 2.67 mmol) in DMF (20 ml) was cooled to 0°C and then added to a mixture of NaH (60 % in mineral oil, 138 mg, 3.47 mmol). After the addition, the reaction mixture was stirred at 0°C for 30 min. 1,3-Difluoro-2-nitrobenzene (510 mg, 3.2 mmol) was added, followed by stirring at room temperature for 3 hours. The resulting mixture was evaporated and the residue was purified on a flash column (ACN/H ₂ O) to give 9-(3-fluoro-2-nitrophenoxy)-2,3-dihydroimidazo[1,2-c]quinazoline (600 mg, yield 69%) as a yellow solid.

Step 2: Synthesis of N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-nitrophenyl)propane-1-sulfonamide

[0171] NaH (60% in mineral oil, 80 mg, 1.99 mmol) was slowly added to a solution of propane-1-sulfonamide (226 mg, 1.84 mmol) in DMF (20.0 ml) at 0°C. The reaction mixture was degassed with N ₂ and stirred at room temperature for 60 minutes. Then, 9-(3-fluoro-2-nitrophenoxy)-2,3-dihydroimidazo[1,2-c]quinazoline (500 mg, 1.53 mmol) was added and the mixture was stirred at 80° C. overnight under a _N2 . The resulting mixture was evaporated and the residue was purified on a flash column (ACN/H ₂ O) to give N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2- nitrophenyl)propane-1-sulfonamide (240 mg, 37% yield) as a yellow solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.24 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.57-7.51 (m, 2H), 7.39-7.32 (m, 2H), 6.68 (d, J=7.2 Hz, 1H), 4.34 (t, J=10.0 Hz, 2H), 4, 00 (t, J=10.0 Hz, 2H), 2.96 (t, J=7.6 Hz, 2H), 1.72-1.66 (m, 2H), 0.96 (t, J =7.6 Hz, 3H). LCMS (M+H ⁺ ) m/z: 430.1.

Example 13 Preparation of N-(2-amino-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-1-sulfonamide (compound 13)

Scheme 13

Synthesis of N-(2-amino-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-1-sulfonamide

[0172] N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-nitrophenyl) propane-1-sulfonamide mixture (200 mg, 0.47 mmol) , Fe (130 mg, 2.33 mmol) and NH ₄ Cl (15 mg, 0.28 mmol) in EtOH/H ₂ O (20 ml/3 ml) were stirred at 60°C for 2 hours under N ₂ , and after completion of the reaction, the solvent was removed. The residue was purified by silica gel column chromatography (DCM/MeOH=25/1+5‰ NH ₃ H ₂ O) to give N-(2-amino-3-((2,3-dihydroimidazo[1,2-c] quinazolin-9-yl)oxy)phenyl)propane-1-sulfonamide (60 mg, 32% yield) as a yellow solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.94 (broad s, 1H), 7.89 (s, 1H), 7.43 (d, J=8.8 Hz, 1H) , 7.29 (dd, J=8.8, 2.8 Hz, 1H), 7.09 (d, J=2.8 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.62 (t, J=7.6 Hz, 1H), 5.00 (broad s, 2H), 4.07 ( t, J=10.0 Hz, 2H), 3.86 (t, J=10.0 Hz, 2H), 3.02 (t, J=7.6 Hz, 2H), 1.77-1, 68 (m, 2H), 0.95 (t, J=7.6 Hz, 3H). LCMS (M+H ⁺ ) m/z: 400.1.

Example 14 Preparation of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-2-fluorobenzenesulfonamide (compound 14)

Scheme 14

Synthesis of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-2-fluorobenzenesulfonamide

[0173] NaH (60% in mineral oil, 25 mg, 0.64 mmol) was slowly added to a solution of 2-fluorobenzenesulfonamide (103 mg, 0.58 mmol) in NMP (10.0 ml) at 0°C. The reaction mixture was degassed with N ₂ and stirred at room temperature for 60 minutes. Then, 2-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-6-fluorobenzonitrile (150 mg, 0.49 mmol) was added and the mixture was stirred at 80° C. for nights in N ₂ atmosphere. The resulting mixture was evaporated and the residue was purified on a flash column (ACN/H ₂ O) to give N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy )phenyl)-2-fluorobenzenesulfonamide (90 mg, 40% yield) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.92 (s, 1H), 7.82-7.76 (m, 1H), 7.69-7.64 (m, 1H), 7.45-7.30 (m, 3H), 7.25-7.17 (m, 3H), 7.07 (t, J=8.4 Hz, 1H), 6.95 (d, J= 8.8 Hz, 1H), 6.08 (d, J=7.6 Hz, 1H), 4.09 (t, J=9.6 Hz, 2H), 3.90 (t, J=9, 6 Hz, 2H). LCMS (M+H ⁺ ) m/z: 462.2.

Example 15 Preparation of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)thiophene-2-sulfonamide (compound 15)

Scheme 15

Synthesis of N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)thiophene-2-sulfonamide

[0174] NaH (60% in mineral oil, 33.0 mg, 0.85 mmol) was slowly added to a solution of thiophene-2-sulfonamide (130 mg, 0.78 mmol) in NMP (10.0 ml) at 0°C. ). The reaction mixture was degassed with N ₂ and stirred at room temperature for 60 minutes. Then, 2-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-6-fluorobenzonitrile (200 mg, 0.65 mmol) was added and the mixture was stirred at 80°C for nights in N ₂ atmosphere. The resulting mixture was evaporated and the residue was purified on a flash column (ACN/H ₂ O) to give N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy )phenyl)thiophene-2-sulfonamide (100 mg, 34% yield) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.92 (s, 1H), 7.54 (d, J=3.6 Hz, 1H), 7.44 (d, J=8, 8 Hz, 1H), 7.33-7.30 (m, 2H), 7.24 (d, J=2.8 Hz, 1H), 7.14-7.06 (m, 2H), 6, 96 (dd, J=4.8, 3.6Hz, 1H), 6.10 (d, J=7.6Hz, 1H), 4.09 (t, J=9.6Hz, 2H), 3.90 (t, J=9.6 Hz, 2H). LCMS (M+H ⁺ ) m/z: 450.1.

Example 16 Preparation of N-(2-cyano-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)propan-1-sulfonamide (compound 16)

Scheme 16

Step 1: Synthesis of 2-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-6-fluorobenzonitrile

[0175] To a solution of 3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-ol (500 mg, 2.48 mmol) in DMF (20.0 ml) at 0°C was slowly added NaH (60% in mineral oil, 150 mg, 3.72 mmol). The reaction mixture was degassed with N ₂ and stirred at room temperature for 60 minutes. Then, 2,6-difluorobenzonitrile (344.0 mg, 2.48 mmol) was added and the mixture was stirred at 80° C. for 1 hour. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 30:1, v/v) to give 2-((3,4-dihydro-2H-pyrimido[1,2 -c]quinazolin-10-yl)oxy)-6-fluorobenzonitrile (200 mg, 25% yield).

Step 2: Synthesis of N-(2-cyano-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)propane-1-sulfonamide

[0176] NaH (60% in mineral oil, 50 mg, 0.84 mmol) was slowly added to a solution of propane-1-sulfonamide (70 mg, 0.56 mmol) in DMF (20.0 ml) at 0°C. The reaction mixture was degassed with N ₂ and stirred at room temperature for 60 minutes. Then, 2-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-6-fluorobenzonitrile (180 mg, 0.56 mmol) was added and the mixture was stirred at 100 °C during the night in an N ₂ atmosphere. The resulting mixture was evaporated and the residue was purified on a flash column (ACN/H ₂ O) to give N-(2-cyano-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazoline-10 -yl)oxy)phenyl)propane-1-sulfonamide (50 mg, 21% yield) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.21 (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.78 (d, J=8, 8 Hz, 1H), 7.65 (dd, J=8.8, 2.4 Hz, 1H), 7.28 (t, J=8.4 Hz, 1H), 7.18 (d, J= 8.4 Hz, 1H), 6.26 (d, J=8.0 Hz, 1H), 4.17 (t, J=5.2 Hz, 2H), 3.56 (t, J=5, 2 Hz, 2H), 2.86 (t, J=7.6 Hz, 2H), 2.10-2.06 (m, 2H), 1.75-1.69 (m, 2H), 0, 96 (t, J=7.6 Hz, 3H). LCMS (M+H ⁺ ) m/z: 424.2.

Example 17 Preparation of N-(2-cyano-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-4-fluorophenyl)propane-1-sulfonamide ( connection 17)

Scheme 17

Step 1: Synthesis of 2-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-3,6-difluorobenzonitrile

[0177] NaH (60 % in mineral oil, 60 mg, 1.5 mmol). The mixture was stirred for 1 hour at 0°C and then 2,3,6-trifluorobenzonitrile (188 mg, 1.2 mmol) was added and the mixture was stirred at 0°C overnight. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 30:1, v/v) to give 2-((3,4-dihydro-2H-pyrimido[1,2 -c]quinazolin-10-yl)oxy)-3,6-difluorobenzonitrile (100 mg, 30% yield) as a yellow oil.

Step 2: Synthesis of N-(2-cyano-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-4-fluorophenyl)propane-1-sulfonamide

[0178] NaH (60% in mineral oil, 48 mg, 1.2 mmol) was slowly added to a solution of propane-1-sulfonamide (100 mg, 0.80 mmol) in NMP (20.0 ml) at 0°C. The reaction mixture was degassed with N ₂ and stirred at room temperature for 60 minutes. Then, 2-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-3,6-difluorobenzonitrile (188 mg, 0.56 mmol) was added and the mixture was stirred at 80°C overnight under N ₂ atmosphere. The resulting mixture was evaporated and the residue was purified on a flash column (ACN/H ₂ O) to give N-(2-cyano-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazoline-10 -yl)oxy)-4-fluorophenyl)propane-1-sulfonamide (40 mg, 16% yield) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 10.65 (broad s, 1H), 8.27 (s, 1H), 7.83-7.78 (m, 2H), 7, 71 (d, J=8.8 Hz, 1H), 7.38 (t, J=9.6 Hz, 1H), 7.28 (dd, J=9.6, 4.4 Hz, 1H), 4.18 (t, J=5.6 Hz, 2H), 3.56 (t, J=5.6 Hz, 2H), 2.82 (t, J=7.6 Hz, 2H), 2, 12-2.08 (m, 2H), 1.73-1.67 (m, 2H), 0.95 (t, J=7.6 Hz, 3H). LCMS (M+H ⁺ ) m/z: 442.4.

Example 18 Synthesis of N-(3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide (compound 18)

Scheme 18

Step 1: Synthesis of N-(3-Bromo-2-fluorophenyl)propane-1-sulfonamide

[0179] To a solution of 3-bromo-2-fluoroaniline (0.5 g, 2.63 mmol) in pyridine (20 ml) at rt. propane-1-sulfonyl chloride (3.75 g, 26.3 mmol) was added, the reaction mixture was stirred at 60°C for 3 h under N ₂ atmosphere, and after completion of the reaction, the solvent was removed. The residue was purified by silica gel column chromatography (PE/EtOAc=10/1) to give N-(3-bromo-2-fluorophenyl)propane-1-sulfonamide (364 mg, 47% yield) as a yellow solid (for product no MS data available).

Step 2: Synthesis of N-(3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide

[0180] A mixture of N-(3-bromo-2-fluorophenyl) propane-1-sulfonamide (95 mg, 0.32 mmol), 3,4-dihydro-2H-pyrimido[1,2-c]quinazoline-10- ol (129 mg, 0.64 mmol), K ₂ CO ₃ (132 mg, 0.96 mmol), CuI (61 mg, 0.32 mmol) and L-Pro (30 mg, 0.32 mmol) in DMSO (5 ml) was stirred at 150°C for 16 h in an atmosphere of N ₂ and after completion of the reaction, the mixture was filtered and concentrated. The residue was purified by preparative HPLC to give N-(3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide (trifluoroacetate , 17 mg, 10% yield) as a white solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ 8.30 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.79 (s, 1H), 7. 74 (d, J=8.8 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.09 ( t, J=7.6 Hz, 1H), 4.37 (m, 2H), 3.69 (t, J=4.8 Hz, 2H), 3.15 (t, J=7.2 Hz, 2H), 2.30 (m, 2H), 1.88-1.82 (m, 2H), 1.04 (t, J=7.2 Hz, 3H). LCMS (M+H ⁺ ) m/z: 417.3.

Example 19 Preparation of N-(3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2-fluoro-6-nitrophenyl)propane-1-sulfonamide ( connection 19)

Scheme 19

Step 1: Synthesis of N-(2,3-difluoro-6-nitrophenyl)-N-(propylsulfonyl)propane-1-sulfonamide

[0181] To a solution of 2,3-difluoro-6-nitroaniline (870 mg, 5.0 mmol) in THF (10 ml) at room temperature was added NaH (60% in mineral oil, 900 mg, 22.5 mmol), the mixture was stirred at room temperature for 30 minutes, then propane-1-sulfonyl chloride (3.56 g, 25 mmol) was added and the reaction mixture was stirred at room temperature overnight. After completion of the reaction, water was added to quench the reaction mixture, the mixture was extracted with EtOAc, the organic layer was dried over Na ₂ SO ₄ and concentrated, and the residue was purified by silica gel column chromatography (PE/EtOAc=4/1) to obtain N-(2, 3-difluoro-6-nitrophenyl)-N-(propylsulfonyl)-propane-1-sulfonamide (1.9 g, 98% yield) as a yellow solid.

Step 2: Synthesis of N-(3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2-fluoro-6-nitrophenyl)propane-1-sulfonamide

[0182] A mixture of N-(2,3-difluoro-6-nitrophenyl)-N-(propylsulfonyl)propane-1-sulfonamide (1.22 g, 3.16 mmol), 3,4-dihydro-2H-pyrimido[ 1,2-c]quinazolin-10-ol (635 mg, 3.16 mmol) and K ₂ CO ₃ (872 mg, 6.32 mmol) in DMF (20 ml) were stirred at 120°C for 16 hours in atmosphere of N ₂ and after completion of the reaction, the solvent was removed. The residue was purified by silica gel column chromatography (DCM/MeOH=30/1) to give N-(3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)- 2-fluoro-6-nitrophenyl)propane-1-sulfonamide (390 mg, 27% yield) as a yellow solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 10.36 (broad, 1H), 8.05 (s, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.71-7.61 (m, 3H), 6.88 (t, J=8.0 Hz, 1H), 4.08 (t, J=4.8 Hz, 2H), 3.53 (t , J=5.2 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.03-2.00 (m, 2H), 1.75-1.65 (m, 2H), 0.93 (t, J=7.6 Hz, 3H). LCMS (M+H ⁺ ) m/z: 462.1.

Example 20 Preparation of N-(6-amino-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide ( connection 20)

Scheme 20

Synthesis of N-(6-amino-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide

[0183] A mixture of N-(3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2-fluoro-6-nitrophenyl)propane-1-sulfonamide ( 330 mg, 0.72 mmol), Fe (200 mg, 3.58 mmol) and NH ₄ Cl (287 mg, 5.37 mmol) in EtOH/H ₂ O (30 ml/3 ml) were stirred at 90°C for 1 hour under N ₂ atmosphere, and after completion of the reaction, the solvent was removed. The residue was purified by silica gel column chromatography (DCM/MeOH=25/1+5‰ NH ₃ H ₂ O) to give N-(6-amino-3-((3,4-dihydro-2H-pyrimido[1, 2-c]quinazolin-10-yl)oxy)-2-fluorophenyl)-propane-1-sulfonamide (280 mg, 90% yield) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.00 (broad s, 1H), 7.56 (s, 1H), 7.35 (d, J=8.8 Hz, 1H) , 7.28 (d, J=2.4 Hz, 1H), 7.23 (dd, J=8.8, 2.8 Hz, 1H), 7.00 (t, J=8.8 Hz, 1H), 6.60 (d, J=8.8 Hz, 1H), 5.33 (broad s, 2H), 3.84 (t, J=5.2 Hz, 2H), 3.42 ( t, J=5.2 Hz, 2H), 3.06 (t, J=7.6 Hz, 2H), 1.84-1.79 (m, 2H), 1.77-1.69 (m , 2H), 0.93 (t, J=7.2 Hz, 3H). LCMS (M+H ⁺ ) m/z: 432.1.

Example 21 Preparation of N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)propan-1-sulfonamide (compound 21)

Scheme 21

Step 1: Synthesis of 10-(2-chloro-3-fluoro-6-nitrophenoxy)-3,4-dihydro-2H-pyrimido[1,2-c]quinazoline and 10-(2-chloro-3-fluoro-4 -nitrophenoxy)-3,4-dihydro-2H-pyrimido[1,2-c]quinazoline

[0184] To a solution of 3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-ol (30 g, 146 mmol) and 2-chloro-1,3-difluoro-4-nitrobenzene (56 g , 292 mmol) in DMF (300 ml) was added Cs ₂ CO ₃ (95 g, 292 mmol). The reaction mixture was degassed using N ₂ and stirred at room temperature for 2 hours. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH from 100:1 to 30:1, v/v) to obtain a mixture of 10-(2-chloro-3-fluoro-6-nitrophenoxy)- 3,4-dihydro-2H-pyrimido[1,2-c]quinazoline and 10-(2-chloro-3-fluoro-4-nitrophenoxy)-3,4-dihydro-2H-pyrimido[1,2-c] Quinazoline (43 g, 80% yield) as a yellow solid.

Step 2: Synthesis of N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-4-nitrophenyl)propane-1-sulfonamide

[0185] NaH (60% in mineral oil, 8.0 g, 200 mmol) was slowly added to a solution of propane-1-sulfonamide (19 g, 152 mmol) in DMF (200 ml) at 0°C. The reaction mixture was degassed with N ₂ and stirred at room temperature for 60 minutes. Then, a mixture of 10-(2-chloro-3-fluoro-6-nitrophenoxy)-3,4-dihydro-2H-pyrimido[1,2-c]quinazoline and 10-(2-chloro-3-fluoro-4 -nitrophenoxy)-3,4-dihydro-2H-pyrimido[1,2-c]quinazoline (38 g, 101 mmol) and the mixture was stirred at room temperature overnight under N ₂ atmosphere. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 50:1, v/v) to give N-(2-chloro-3-((3,4-dihydro- 2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-4-nitrophenyl)propane-1-sulfonamide (18 g, 37% yield) as a yellow solid.

Step 3: Synthesis of N-(4-amino-2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)propan-1-sulfonamide

[0186] A mixture of N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-4-nitrophenyl)propane-1-sulfonamide ( 18 g, 37.7 mmol), Fe (21 g, 377 mmol) and NH ₄ Cl (1.2 g, 22.6 mmol) in EtOH/H ₂ O (200 ml/40 ml) were stirred at 80°C for 2 hours under N ₂ atmosphere, and after completion of the reaction, the solvent was removed. The residue was purified by silica gel column chromatography (DCM/MeOH=25/1+5‰ NH ₃ H ₂ O) to give N-(4-amino-2-chloro-3-((3,4-dihydro-2H- pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-propane-1-sulfonamide (11 g, 65% yield) as a white solid.

Step 4: Synthesis of N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)propane-1-sulfonamide

[0187] To a solution of N-(4-amino-2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)propan-1- sulfonamide (11.0 g, 24.6 mmol) in THF (200 ml) was added amyl nitrate (32.8 g, 246 mmol). The reaction mixture was degassed with N ₂ and stirred at reflux overnight. The resulting mixture was evaporated and purified by silica gel column chromatography (DCM/MeOH 100:1 to 50:1, v/v) to give N-(2-chloro-3-((3,4-dihydro-2H- pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)propan-1-sulfonamide (4.0 g, 38% yield) as an off-white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.55 (broad, 1H), 7.63 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.36-7.28 (m, 4H), 6.96-6.94 (m, 1H), 3.86 (t, J=5.2 Hz, 2H), 3.43 (t, J= 5.2 Hz, 2H), 3.09 (t, J=7.6 Hz, 2H), 1.86-1.83 (m, 2H), 1.77-1.71 (m, 2H), 0.97 (t, J=7.6 Hz, 3H). LC-MS: 433.1 [M+1] ⁺ .

Example 22 Preparation of N-(2-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-3-nitropyridin-4-yl)propan-1-sulfonamide ( connection 22)

Scheme 22

Stage 1: Synthesis of N-(2-chloro-3-nitropyridin-4-yl) propane-1-sulfonamide

[0188] Cs ₂ CO ₃ (1.28 g, 3.92 mmol). The reaction mixture was degassed using N ₂ and stirred at 60°C for 3 hours. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 30:1, v/v) to give N-(2-chloro-3-nitropyridin-4-yl)propan- 1-sulfonamide (0.6 g, 82% yield) as a yellow solid.

Step 2: Synthesis of N-(2-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-3-nitropyridin-4-yl)propan-1-sulfonamide

[0189] To a solution of N-(2-chloro-3-nitropyridin-4-yl)propan-1-sulfonamide (138 mg, 0.50 mmol) and 3,4-dihydro-2H-pyrimido[1,2-c ]quinazolin-10-ol (100 mg, 0.50 mmol) in DMF (10 ml) was added Cs ₂ CO ₃ (326 mg, 1.02 mmol). The reaction mixture was degassed with N ₂ and stirred at 140° C. overnight. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 10:1, v/v) to give N-(2-((3,4-dihydro-2H-pyrimido[ 1,2-c]quinazolin-10-yl)oxy)-3-nitropyridin-4-yl)propan-1-sulfonamide (50 mg, 22% yield) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 10.94 (br, 1H), 8.41 (s, 1H), 8.24 (s, 1H), 7.84 (d, J =8.8 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.55 (d, J=6.0 Hz, 1H), 7.11 (d, J=6 .0 Hz, 1H), 4.30-4.25 (m, 2H), 3.60-3.58 (m, 2H), 2.77-2.73 (m, 2H), 2.20- 2.16 (m, 2H), 1.68-1.62 (m, 2H), 0.93 (t, J=7.2 Hz, 3H); LC-MS: 445.2 [M+1] ⁺ .

Example 23 Preparation of N-(4-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-3-nitropyridin-2-yl)propan-1-sulfonamide ( connection 23)

Scheme 23

Step 1: Synthesis of 10-((2-chloro-3-nitropyridin-4-yl)oxy)-3,4-dihydro-2H-pyrimido[1,2-c]quinazoline

[0190] To a solution of 2,4-dichloro-3-nitropyridine (710 mg, 3.72 mmol) and 3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-ol (500 mg, 2 .48 mmol) in DMF (10 ml) was added Cs ₂ CO ₃ (1.6 g, 4.96 mmol). The reaction mixture was degassed using N ₂ and stirred at 60°C for 2 hours. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 20:1, v/v) to give 10-((2-chloro-3-nitropyridin-4-yl)oxy )-3,4-dihydro-2H-pyrimido[1,2-c]quinazoline (600 mg, 68% yield) as a yellow solid.

Step 2: Synthesis of N-(4-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-3-nitropyridin-2-yl)propan-1-sulfonamide

[0191] NaH (60% in mineral oil, 42 mg, 1.06 mmol) was slowly added to a solution of propane-1-sulfonamide (100 mg, 0.81 mmol) in DMF (10.0 ml) at 0°C. The reaction mixture was degassed with N ₂ and stirred at room temperature for 60 minutes. Then, 10-((2-chloro-3-nitropyridin-4-yl)oxy)-3,4-dihydro-2H-pyrimido[1,2-c]quinazoline (180 mg, 0.50 mmol) was added, and the mixture was stirred at 100° C. overnight under N ₂ . The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 10:1, v/v) to give N-(4-((3,4-dihydro-2H-pyrimido[ 1,2-c]quinazolin-10-yl)oxy)-3-nitropyridin-2-yl)propan-1-sulfonamide (35 mg, 16% yield) as an off-white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 10.67 (broad, 1H), 8.46 (s, 1H), 8.17 (d, J=2.4 Hz, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.82 (dd, J=9.2, 2.4 Hz, 1H), 7.55 (d, J=6.0 Hz, 1H ), 7.12 (d, J=6.0 Hz, 1H), 4.28 (t, J=5.2 Hz, 2H), 3.60 (t, J=5.2 Hz, 2H), 2.78-2.73 (m, 2H), 2.20-2.16 (m, 2H), 1.68-1.63 (m, 2H), 0.93 (t, J=7.6 Hz, 3H); LC-MS: 445.2 [M+1] ⁺ .

Example 24 Preparation of N-(3-cyano-4-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)pyridin-2-yl)propan-1-sulfonamide (connection 24)

Scheme 24

Step 1: Synthesis of 2-chloro-4-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)nicotinonitrile

[0192] To a solution of 3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-ol (500 mg, 2.49 mmol) and 2,4-dichloronicotinonitrile (646 mg, 3.73 mmol) Cs ₂ CO ₃ (1.6 g, 4.96 mmol) was added to DMF (10.0 ml). The reaction mixture was degassed using N ₂ and stirred at 60°C for 2 hours. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 20:1, v/v) to give 2-chloro-4-((3,4-dihydro-2H-pyrimido [1,2-c]quinazolin-10-yl)oxy)nicotinonitrile (400 mg, 48% yield) as an off-white solid.

Step 2: Synthesis of N-(3-cyano-4-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)pyridin-2-yl)propan-1-sulfonamide

[0193] NaH (60% in mineral oil, 23 mg, 0.58 mmol) was slowly added to a solution of propane-1-sulfonamide (55 mg, 0.45 mmol) in DMF (6.0 ml) at 0°C. The reaction mixture was degassed with N ₂ and stirred at room temperature for 60 minutes. Then, 2-chloro-4-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)nicotinonitrile (100 mg, 0.30 mmol) was added and the mixture was stirred at 100°C overnight under N ₂ atmosphere. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 20:1, v/v) to give N-(3-cyano-4-((3,4-dihydro- 2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)pyridin-2-yl)propan-1-sulfonamide (40 mg, 31% yield) as an off-white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 10.67 (broad, 1H), 8.35 (s, 1H), 8.12 (s, 1H), 7.85-7.80 (m, 2H), 7.54 (d, J=6.4 Hz, 1H), 6.98 (d, J=6.4 Hz, 1H), 4.29-4.22 (m, 2H) , 3.61-3.58 (m, 2H), 2.81-2.77 (m, 2H), 2.20-2.16 (m, 2H), 1.73-1.68 (m, 2H), 0.96 (t, J=7.2 Hz, 3H); LC-MS: 425.3 [M+1] ⁺ .

Example 25 Synthesis of N-(3-cyano-2-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)pyridin-4-yl)propan-1-sulfonamide (compound 25)

Scheme 25

Stage 1: Synthesis of N-(2-chloro-3-cyanopyridin-4-yl) propane-1-sulfonamide

[0194] Cs ₂ CO ₃ (1.20 g , 3.66 mmol). The reaction mixture was degassed using N ₂ and stirred at 60°C for 3 hours. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 20:1, v/v) to give N-(2-chloro-3-cyanopyridin-4-yl)propan- 1-sulfonamide (200 mg, 31% yield) as a yellow solid.

Step 2: Synthesis of N-(3-cyano-2-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)pyridin-4-yl)propan-1-sulfonamide

[0195] To a solution of N-(2-chloro-3-cyanopyridin-4-yl)propan-1-sulfonamide (155 mg, 0.60 mmol) and 3,4-dihydro-2H-pyrimido[1,2-c ]quinazolin-10-ol (100 mg, 0.50 mmol) in DMF (10.0 ml) was added Cs ₂ CO ₃ (326 mg, 1.02 mmol). The reaction mixture was degassed with N ₂ and stirred at 130° C. overnight. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 10:1, v/v) to give N-(3-cyano-2-((3,4-dihydro- 2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)pyridin-4-yl)propan-1-sulfonamide (50 mg, 24% yield) as an off-white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 10.60 (broad, 1H), 8.47 (s, 1H), 8.19 (s, 1H), 7.92-7.86 (m, 2H), 7.54 (d, J=6.0 Hz, 1H), 6.99 (d, J=6.0 Hz, 1H), 4.29 (t, J=5.2 Hz , 2H), 3.61 (t, J=5.2 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 2.20-2.16 (m, 2H), 1 .74-1.68 (m, 2H), 0.96 (t, J=7.6 Hz, 3H); LC-MS: 425.3 [M+1] ⁺ .

Example 26 Preparation of N-(3-chloro-4-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)pyridin-2-yl)propan-1-sulfonamide (compound 26)

Scheme 26

Step 1: Synthesis of 10-((2,3-dichloropyridin-4-yl)oxy)-3,4-dihydro-2H-pyrimido[1,2-c]quinazoline

[0196] To a solution of 2,3-dichloro-4-iodopyridine (1.2 g, 4.4 mmol) and 3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-ol (0. 8 g, 4.0 mmol) in DMF (30 ml) was added Cs ₂ CO ₃ (14.7 g, 5.0 mmol). The reaction mixture was degassed using N ₂ and stirred at 60°C for 3 hours. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 30:1, v/v) to give 10-((2,3-dichloropyridin-4-yl)oxy)- 3,4-dihydro-2H-pyrimido[1,2-c]quinazoline (0.6 g, 44% yield) as a white solid.

Step 2: Synthesis of 3-chloro-4-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)pyridine-2-amine

[0197] A solution of 10-((2,3-dichloropyridin-4-yl)oxy)-3,4-dihydro-2H-pyrimido[1,2-c]quinazoline (1.0 g, 2.89 mmol) and tert-butyl carbamate (3.4 g, 28.9 mmol) in dioxane (30 ml) was added Pd ₂ (dba) ₃ (0.53 g, 0.58 mmol), Xantphos (0.67 g, 1.16 mmol ), Cs ₂ CO ₃ (2.0 g, 4.3 mmol). The reaction mixture was degassed using N ₂ and stirred at 100°C overnight. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 20:1, v/v) to give 3-chloro-4-((3,4-dihydro-2H-pyrimido [1,2-c]quinazolin-10-yl)oxy)pyridine-2-amine (0.5 g, 53% yield) as an off-white solid.

Step 3: Synthesis of N-(3-chloro-4-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)pyridin-2-yl)propan-1-sulfonamide

[0198] To a solution of 3-chloro-4-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)pyridine-2-amine (50 mg, 0.15 mmol ) in DMF (20 ml) at 0° C. NaH (60% in mineral oil, 8 mg, 0.20 mmol) was added slowly. The reaction mixture was degassed with N ₂ and stirred at room temperature for 30 minutes. Then, propane-1-sulfonyl chloride (26 mg, 0.20 mmol) was added and the mixture was stirred at 130° C. overnight under N ₂ atmosphere. The resulting mixture was evaporated and the residue was purified on a flash column (ACN/H ₂ O) to give N-(3-chloro-4-((3,4-dihydro-2H-pyrimido[1,2-c]quinazoline-10 -yl)oxy)pyridin-2-yl)propan-1-sulfonamide (20 mg, 31% yield) as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.03 (d, J=5.6 Hz, 1H), 7.94 (s, 1H), 7.55 (d, J=8.8 Hz , 1H), 7.48 (s, 1H), 7.30 (dd, J=8.8, 2.8 Hz, 1H), 6.43 (d, J=5.6 Hz, 1H), 3 .93 (t, J=5.6 Hz, 2H), 3.69-3.63 (m, 4H), 2.10-2.04 (m, 2H), 1.98-1.92 (m , 2H), 1.10 (t, J=7.2 Hz, 3H). LC-MS: 434.2 [M+1] ⁺ .

Example 27 Preparation of N-(2-cyano-3-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)oxy)phenyl)propane -1-sulfonamide (compound 27)

Scheme 27

Step 1: Synthesis of 10-methoxy-3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidine

[0199] To a solution of 10-chloro-3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidine (1.0 g, 4.54 mmol) in MeOH (5, 0 ml) was added CH ₃ ONa (aq.) (25 ml). The reaction mixture was degassed using N ₂ and stirred at 80°C overnight. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 20:1, v/v) to give 10-methoxy-3,4-dihydro-2H-pyrido[4,3 -e]pyrimido[1,2-c]pyrimidine (0.8 g, 82% yield) as a white solid.

Step 2: Synthesis of 3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-ol

[0200] To a solution of 10-methoxy-3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidine (0.8 g, 3.7 mmol) in DMF (15, 0 ml) NaSEt (940 mg, 11.2 mmol) was added. The reaction mixture was degassed with N ₂ and stirred at 130° C. overnight. After the reaction mixture was cooled to room temperature, the resulting mixture was evaporated, and the residue was purified by silica gel column chromatography (DCM/MeOH 50:1 to 20:1, v/v) to give 3,4-dihydro-2H-pyrido [4,3-e]pyrimido[1,2-c]pyrimidin-10-ol (400 mg, 54% yield) as a yellow solid.

Step 3: Synthesis of 2-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)oxy)-6-fluorobenzonitrile

[0201] To a solution of 3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-ol (100 mg, 0.50 mmol) in DMF (15 mL) at 0° C. NaH (60% in mineral oil, 40 mg, 1.0 mmol) was added slowly. The reaction mixture was degassed with N ₂ and stirred at room temperature for 15 minutes. Then, 2,6-difluorobenzonitrile (137 mg, 1.0 mmol) was added and the mixture was stirred at 60° C. overnight. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 30:1, v/v) to give 2-((3,4-dihydro-2H-pyrido[4,3 -e]pyrimido[1,2-c]pyrimidin-10-yl)oxy)-6-fluorobenzonitrile (60 mg, 38% yield).

Step 4: Synthesis of N-(2-cyano-3-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)oxy)phenyl)propane -1-sulfonamide

[0202] NaH (60% in mineral oil, 65 mg, 1.60 mmol) was slowly added to a solution of propane-1-sulfonamide (100 mg, 0.56 mmol) in DMF (10.0 ml) at 0°C. The reaction mixture was degassed with N ₂ and stirred at room temperature for 30 minutes. Then, 2-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)oxy)-6-fluorobenzonitrile (60 mg, 0.18 mmol) and the mixture was stirred at 120° C. overnight under N ₂ . The resulting mixture was evaporated and the residue was purified on a flash column (ACN/H ₂ O) to give N-(2-cyano-3-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1 ,2-c]pyrimidin-10-yl)oxy)phenyl)propane-1-sulfonamide (15 mg, 20% yield) as a white solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ 8.38 (s, 1H), 7.68 (s, 1H), 7.54 (s, 1H), 7.44-7.39 (m , 2H), 6.68 (dd, J=7.6, 1.2 Hz, 1H), 4.00 (t, J=5.6 Hz, 2H), 3.65 (t, J=5, 6 Hz, 2H), 2.07-2.04 (m, 2H), 1.92-1.81 (m, 2H), 1.38-1.29 (m, 2H), 1.08 (t , J=7.2 Hz, 3H). LC-MS: 425.3 [M+1] ⁺ .

Example 28 Preparation of N-(2-cyano-3-((2,3,4,5-tetrahydro-[1,3]diazepino[1,2-c]quinazolin-11-yl)oxy)phenyl)propan- 1-sulfonamide (compound 28)

Scheme 28

Step 1: Synthesis of 4-oxo-3,4-dihydroquinazolin-6-yl acetate

[0203] To a solution of 6-hydroxyquinazolin-4(3H)-one (5.0 g, 30.8 mmol) in DCM (50.0 ml) was added DMAP (0.75 g, 6.20 mmol) and Ac ₂ O (6.30 g, 6.20 mmol), Et ₃ N (6.20 g, 61.6 mmol). The reaction mixture was stirred at room temperature overnight. The resulting mixture was evaporated, added to the rest of H ₂ O (50 ml), and stirred at room temperature for 20 minutes. The solid was filtered and dried under vacuum to give 4-oxo-3,4-dihydroquinazolin-6-yl acetate (5.3 g, 85% yield) as a tan solid.

Stage 2: Synthesis of 4-chloroquinazolin-6-ol

[0204] DMF (1 ml) was added to a solution of 4-oxo-3,4-dihydroquinazolin-6-yl acetate (5.0 g, 24.4 mmol) in SOCl ₂ (50 ml). The reaction mixture was stirred at reflux overnight. The resulting mixture was evaporated, toluene (30 ml) was added to the residue, and stirred at room temperature for 20 minutes. The solid was filtered and dried under vacuum to give 4-chloroquinazolin-6-ol (3.0 g, 68% yield) as a tan solid.

Stage 3: Synthesis of 4-((4-hydroxybutyl)amino)quinazolin-6-ol

[0205] Et ₃ N (1.7 g, 16.8 mmol) under ice-cooling in water. The reaction mixture was stirred at reflux for 1 hour. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 20:1, v/v) to give 4-((4-hydroxybutyl)amino)quinazolin-6-ol (0 .8 g, 62% yield as a white solid.

Step 4: Synthesis of 2,3,4,5-tetrahydro-[1,3]diazepino[1,2-c]quinazolin-11-ol

[0206] A solution of 4-((4-hydroxybutyl)amino)quinazolin-6-ol (800 mg, 3.43 mmol) in SOCl ₂ (10 mL) was stirred at reflux for 2 hours. The mixture was concentrated and added to the residue with Et ₃ N (6 ml) and CHCl ₃ (30 ml). The reaction mixture was stirred at reflux for 3 days. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 30:1, v/v) to give 2,3,4,5-tetrahydro-[1,3]diazepino[ 1,2-c]quinazolin-11-ol (300 mg, 41% yield) as a white solid.

Step 5: Synthesis of 2-fluoro-6-((2,3,4,5-tetrahydro-[1,3]diazepino[1,2-c]quinazolin-11-yl)oxy)benzonitrile

[0207] To a solution of 2,3,4,5-tetrahydro-[1,3]diazepino[1,2-c]quinazolin-11-ol (200 mg, 0.93 mmol) in DMF (20 mL) at 0 °C 60% NaH (40% in mineral oil, 45 mg, 1.12 mmol) was added slowly. The reaction mixture was degassed with N ₂ and stirred at room temperature for 30 minutes. Then, 2,6-difluorobenzonitrile (130 mg, 0.93 mmol) was added and the mixture was stirred at room temperature for 2 hours under N ₂ atmosphere. The resulting mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 20:1, v/v) to give 2-fluoro-6-((2,3,4,5-tetrahydro -[1,3]diazepino[1,2-c]quinazolin-11-yl)oxy)benzonitrile (100 mg, 32% yield) as a white solid.

Step 6: Synthesis of N-(2-cyano-3-((2,3,4,5-tetrahydro-[1,3]diazepino[1,2-c]quinazolin-11-yl)oxy)phenyl)propan- 1-sulfonamide

[0208] To a solution of propane-1-sulfonamide (44 mg, 0.36 mmol) in DMF (10 ml) at 0°C was slowly added 60% NaH (40% in mineral oil, 16 mg, 0.40 mmol). The reaction mixture was degassed with N ₂ and stirred at room temperature for 30 minutes. Then, 2-fluoro-6-((2,3,4,5-tetrahydro-[1,3]diazepino[1,2-c]quinazolin-11-yl)oxy)benzonitrile (60 mg, 0.18 mmol) and the mixture was stirred at 100° C. overnight under N ₂ . The resulting mixture was evaporated and the residue was purified on a flash column (ACN/H ₂ O) to give N-(2-cyano-3-((2,3,4,5-tetrahydro-[1,3]diazepino[1, 2-c]quinazolin-11-yl)oxy)phenyl)propane-1-sulfonamide (18 mg, 23% yield) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 10.35 (br, 1H), 8.45 (s, 1H), 7.90 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.61 (dd, J=9.2, 2.0 Hz, 1H), 7.45-7.41 (m, 1H), 7.18 (d, J= 8.0 Hz, 1H), 6.55-6.52 (m, 1H), 3.81-3.79 (m, 4H), 3.07 (t, J=7.2 Hz, 2H), 1.94-1.92 (m, 4H), 1.80-1.74 (m, 2H), 0.99 (t, J=7.2 Hz, 3H). LC-MS: 438.2 [M+1] ⁺

Example 29 Preparation of N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)ethanesulfonamide (compound 37)

Scheme 29

Step 1: Synthesis of 2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)aniline

[0209] A solution of 10-iodo-3,4-dihydro-2H-pyrimido[1,2-c]quinazoline (2.0 g, 6.43 mmol), 3-amino-2-chlorophenol (1.85 g, 12.86 mmol), K ₃ PO ₄ (4.1 g, 19.3 mmol), CuI (366 mg, 1.93 mmol) and picolinic acid (79 mg, 0.64 mmol) in DMSO (20 ml) stirred at 90°C for 16 hours in an atmosphere of N ₂ . After completion of the reaction, EtOAc was added, the mixture was filtered, the filter cake was washed with EtOAc, the filtrate was added to water (50 ml) and extracted with EtOAc (100 ml × 3), the combined organic layers were washed with brine, dried and concentrated to give 2-chloro- 3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)aniline (800 mg, 38% yield) as a green solid.

Step 2: Synthesis of N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-N-(ethylsulfonyl)ethanesulfonamide

[0210] To a solution of 2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)aniline (1.0 g, 3.1 mmol) and Et ₃ N (3.7 g, 36.6 mmol) in DCM (50 ml) at 0°C was added ethanesulfonyl chloride (3.9 g, 30.4 mmol), then the reaction mixture was stirred at room temperature for 16 hours, 76% N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-N-(ethylsulfonyl)ethanesulfonamide and 8% 2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)aniline, the solvent was removed and the residue was used in the next step without purification.

Step 3: Synthesis of N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)ethanesulfonamide

[0211] To a solution of N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-N-(ethylsulfonyl)ethanesulfonamide ( 1.56 g, 3.07 mmol) in MeOH (20 ml) was added NaOH (245 mg, 6.13 mmol). The mixture was stirred at room temperature for 1 hour, the reaction was found to be incomplete by LCMS, NaOH (1.0 g, 25 mmol) was added, and after 2 hours the reaction was found to be complete by LCMS. Added conc. HCl to pH=6~7, the mixture was extracted with DCM (200 ml×3), the combined organic layers were dried and concentrated, and the residue was purified by silica gel column chromatography (DCM/MeOH=150/1+0.5% NH ₃ H ₂ O) to give N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)ethanesulfonamide (660 mg, 52% yield ) as a yellow solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.81 (broad s, 1H), 7.76 (s, 1H), 7.50 (d, J=8.8 Hz, 1H) , 7.45 (d, J=2.0 Hz, 1H), 7.38-7.35 (m, 3H), 7.03 (t, J=4.8 Hz, 1H), 3.93 ( t, J=5.6 Hz, 2H), 3.45 (t, J=5.6 Hz, 2H), 3.17 (kv, J=7.2 Hz, 2H), 1.92-1, 87 (m, 2H), 1.27 (t, J=7.2 Hz, 3H). LCMS (M+H ⁺ ) m/z: 419.2.

Example 30 Preparation of N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-3-fluoropropane-1-sulfonamide ( connection 38)

Scheme 30

Stage 1: Synthesis of 3-fluoropropane-1-sulfonamide

[0212] A solution of 3-fluoropropane-1-sulfonyl chloride (700 mg, 4.36 mmol) in THF (3 ml) at 0°C was slowly added to NH ₃ ·H ₂ O (20 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, the filtrate was concentrated to give 3-fluoropropane-1-sulfonamide (560 mg, 91% yield) as a white solid.

Stage 2: Synthesis of 10-(2-chloro-3-fluoro-6-nitrophenoxy)-3,4-dihydro-2H-pyrimido[1,2-c]quinazoline

[0213] A mixture of 2-chloro-1,3-difluoro-4-nitrobenzene (3.84 g, 20 mmol), 3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-ol (2 0 g, 10 mmol) and Cs ₂ CO ₃ (6.48 g, 20 mmol) in DMF (40 ml) were stirred at room temperature for 2 hours. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 30:1, v/v) to give 10-(2-chloro-3-fluoro-6-nitrophenoxy)-3 ,4-dihydro-2H-pyrimido[1,2-c]quinazoline (2.49 g, 66% yield) as a yellow solid.

Step 3: Synthesis of N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-4-nitrophenyl)-3-fluoropropan-1 -sulfonamide

[0214] NaH (94 mg, 2.34 mmol, 60% in mineral oil) was added to a solution of 3-fluoropropane-1-sulfonamide (300 mg, 2.12 mmol) in DMF (10 mL) at 0°C. The reaction mixture was stirred at room temperature for 30 minutes and then 10-(2-chloro-3-fluoro-6-nitrophenoxy)-3,4-dihydro-2H-pyrimido[1,2-c]quinazoline (717 mg , 1.91 mmol). The reaction mixture was stirred at room temperature overnight and quenched by adding MeOH (2 ml). The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (DCM/MeOH 50:1 to 10:1, v/v) to give N-(2-chloro-3-((3,4-dihydro- 2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-4-nitrophenyl)-3-fluoropropane-1-sulfonamide (570 mg, 54% yield) as a brown solid.

Step 4: Synthesis of N-(4-amino-2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-3-fluoropropane- 1-sulfonamide

[0215] N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-4-nitrophenyl)-3-fluoropropan-1 mixture -sulfonamide (570 mg, 1.15 mmol), Fe (330 mg, 5.75 mmol) and NH ₄ Cl (432 mg, 8.06 mmol) in EtOH (15 ml) and H ₂ O (5 ml) were stirred at 80°C overnight. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (DCM/MeOH 50:1 to 10:1, v/v) to give N-(4-amino-2-chloro-3-((3, 4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-3-fluoropropane-1-sulfonamide (480 mg, 89% yield) as a brown solid.

Step 5: Synthesis of N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-3-fluoropropane-1-sulfonamide

[0216] A mixture of N-(4-amino-2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-3-fluoropropane- 1-sulfonamide (480 mg, 1.03 mmol) and amyl nitrate (1.21 g, 10.3 mmol) in THF (15 mL) was stirred at 70° C. under N ₂ overnight. After removing most of the volatiles, the residue was purified by preparative HPLC to give N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl )-3-fluoropropane-1-sulfonamide (17 mg, 3.6% yield) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.72 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.40 (d, J=2, 8 Hz, 1H), 7.36-7.30 (m, 3H), 6.93 (dd, J=7.6, 2.4 Hz, 1H), 4.57 (dt, J=47.2 , 6.0 Hz, 2H), 3.91 (t, J=5.6 Hz, 2H), 3.44 (t, J=5.6 Hz, 2H), 3.22-3.17 (m , 2H), 2.17-2.07 (m, 2H), 1.89-1.87 (m, 2H). LCMS (M+H ⁺ ) m/z: 451.3.

Example 31 Preparation of N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-3-hydroxypropane-1-sulfonamide ( connection 39)

Scheme 31

Step 1: Synthesis of methyl 3-(N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)sulfamoyl)propanoate

[0217] 2-Chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)aniline mixture (100 mg, 0.31 mmol), methyl-3 -(chlorosulfonyl)propanoate (86 mg, 0.46 mmol) and DIEA (80 mg, 0.61 mmol) in DCM (10 ml) were stirred at room temperature for 4 hours. The mixture was concentrated and the residue was purified by silica gel column chromatography (DCM/MeOH 50:1 to 30:1, v/v) to give methyl-3-(N-(2-chloro-3-((3, 4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)sulfamoyl)propanoate (100 mg, 68% yield) as a brown oil.

Step 2: Synthesis of N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-3-hydroxypropane-1-sulfonamide

[0218] To a mixture of methyl 3-(N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)sulfamoyl)propanoate (100 mg, 0.21 mmol) in THF (10 ml) at 0°C was added LiAlH ₄ (40 mg, 1.1 mmol), the reaction mixture was stirred at room temperature for 2 hours. MeOH and EtOAc were added, the reaction mixture was stirred at room temperature for 30 minutes, the mixture was filtered, the filtrate was evaporated, and the residue was purified by preparative HPLC to give N-(2-chloro-3-((3,4-dihydro-2H-pyrimido [1,2-c]quinazolin-10-yl)oxy)phenyl)-3-hydroxypropane-1-sulfonamide (trifluoroacetate, 17 mg, 14% yield) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 10.73 (broad s, 1H), 9.69 (s, 1H), 8.47 (s, 1H), 7.95-7, 92 (m, 2H), 7.76-7.73 (m, 1H), 7.46-7.44 (m, 2H), 7.15-7.13 (m, 1H), 4.29 ( t, J=5.6 Hz, 2H), 3.64-3.56 (m, 4H), 3.24-3.20 (m, 2H), 2.19-2.16 (m, 2H) , 1.90-1.86 (m, 2H). LCMS (M+H ⁺ ) m/z: 449.3.

Example 32 Preparation of (R)-N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-3-fluoropyrrolidine- 1-sulfonamide (compound 40)

Scheme 32

[0219] To a solution of 2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)aniline (120 mg, 0.37 mmol) and DMAP ( 2.2 mg) and pyridine (2 ml) in DCM (5 ml) at 0°C was added (R)-3-fluoropyrrolidine-1-sulfonyl chloride (630 mg, 3.3 mmol). The reaction mixture was stirred at 0°C for 2 hours. The mixture was quenched by adding MeOH (2 ml) and concentrated. The residue was purified by preparative HPLC to give (R)-N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-3 -fluoropyrrolidine-1-sulfonamide (8.0 mg, 4.5% yield) as a yellow solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ 8.25 (s, 1H), 7.88 (d, J=9.2 Hz, 1H), 7.71 (d, J=2.4 Hz, 1H), 7.64 -7.61 (m, 2H), 7.38 (t, J=8.4 Hz, 1H), 7.04 (dd, J=8.4, 1.2 Hz , 1H), 5.24 (dt, J=52.8, 3.6 Hz, 1H), 4.33 (t, J=5.6 Hz, 2H), 3.67 (t, J=5, 6 Hz, 2H), 3.61-3.30 (m, 4H), 2.29-1.97 (m, 4H). LCMS (M+H ⁺ ) m/z: 478.1.

Example 33 Preparation of N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-N-ethyl-N-methylamino- 1-sulfonamide (compound 41)

Scheme 33

[0220] To a mixture of SO ₂ Cl ₂ (1.14 g, 8.47 mmol) in DCM (10 ml) at 0 ° C was slowly added N-methylethanamine (500 mg, 8.47 mmol), the mixture was stirred at 0 ° C in N ₂ atmosphere for 30 minutes. The mixture was added dropwise to a solution of 2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)aniline (100 mg, 0.31 mmol) and DMAP (2 mg, 0.01 mmol) in pyridine (5 ml), and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was evaporated and the residue was purified by preparative HPLC to give N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy) phenyl)-N-ethyl-N-methylamino-1-sulfonamide (trifluoroacetate, 2.7 mg, 1.5% yield) as a brown solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ 8.26 (s, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.72 (d, J=2.8 Hz, 1H), 7.65 (dd, J=9.2, 2.8 Hz, 1H), 7.56 (dd, J=8.4, 1.6 Hz, 1H), 7.38 (t , J=8.4 Hz, 1H), 7.03 (dd, J=8.4, 1.2 Hz, 1H), 4.34 (t, J=5.6 Hz, 2H), 3.68 (t, J=5.6 Hz, 2H), 3.25 (kv, J=7.2 Hz, 2H), 2.85 (s, 3H), 2.31-2.25 (m, 2H) , 1.11 (t, J=7.2 Hz, 3H). LCMS (M+H ⁺ ) m/z: 448.1.

Example 34 Preparation of N-(2-cyano-3-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)(methyl)amino) phenyl)propane-1-sulfonamide (compound 42)

Scheme 34

Step 1: Synthesis of 4-chloro-6-fluoropyrido[3,4-d]pyrimidine

[0221 _] DMF ( ₃ drops of ). The resulting mixture was stirred at 90°C for 48 hours. The mixture was evaporated to give 4-chloro-6-fluoropyrido[3,4-d]pyrimidine (1.1 g, 100% yield).

Step 2: Synthesis of 3-((6-fluoropyrido[3,4-d]pyrimidin-4-yl)amino)propan-1-ol

[0222] Et ₃ N (1. 8 g, 18.03 mmol). The resulting mixture was stirred at room temperature for 20 minutes. The mixture was evaporated and the residue was purified by silica gel flash column chromatography (PE/EtOAc 5:1 to DCM/MeOH 20:1, v/v) to give 3-((6-fluoropyrido[3,4-d ]pyrimidin-4-yl)amino)propan-1-ol (1.33 g, 100% yield).

Step 3: Synthesis of 10-fluoro-3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidine

[0223] To a solution of 3-((6-fluoropyrido[3,4-d]pyrimidin-4-yl)amino)propan-1-ol (1.33 g, 6.1 mmol) in CHCl ₃ (15 mL) SOCl ₂ (3 ml) was added under N ₂ atmosphere. The resulting mixture was stirred at 80° C. overnight. The mixture was evaporated to dryness under vacuum. The residue was added CHCl ₃ (15 ml), Et ₃ N (2.46 g, 24.4 mmol). The mixture was stirred at room temperature overnight. The mixture was evaporated and the residue was purified by silica gel flash column chromatography (PE/EtOAc 5:1 to DCM/MeOH 20:1, v/v) to give 10-fluoro-3,4-dihydro-2H-pyrido [4,3-e]pyrimido[1,2-c]pyrimidine (2.0 g, crude).

Step 4: Synthesis of 2-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)amino)-6-fluorobenzonitrile

[0224] To a solution of 10-fluoro-3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidine (400 mg, 2.0 mmol) in DMF (10 ml) in NaH (360 mg, 9.0 mmol, 60% in mineral oil) was added under N ₂ atmosphere. The mixture was stirred at room temperature for 15 minutes under N ₂ atmosphere. Then, 2-amino-6-fluorobenzonitrile (272 mg, 2.0 mmol) was added to the reaction mixture. The resulting mixture was stirred at 60°C for 48 hours under N ₂ atmosphere. The mixture was evaporated and the residue was purified by silica gel flash chromatography (2:1 PE/EtOAc to 20:1 DCM/MeOH, v/v) to give 2-((3,4-dihydro-2H-pyrido[ 4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)amino)-6-fluorobenzonitrile (140 mg, 22% yield).

Step 5: Synthesis of 2-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)(methyl)amino)-6-fluorobenzonitrile

[0225] To a solution of 2-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)amino)-6-fluorobenzonitrile (200 mg, 0 .64 mmol) in anhydrous THF (12 mL) was added under N ₂ NaH (33 mg, 0.83 mmol, 60% in mineral oil). The mixture was stirred at 0°C for 30 minutes under N ₂ atmosphere. Then, CH ₃ I (90 mg, 0.64 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 2 hours under N ₂ atmosphere. The mixture was evaporated and the residue was purified by silica gel column chromatography (2:1 PE/EtOAc to 20:1 DCM/MeOH, v/v) to give 2-((3,4-dihydro-2H-pyrido[4 ,3-e]pyrimido[1,2-c]pyrimidin-10-yl)(methyl)amino)-6-fluorobenzonitrile (100 mg, 48% yield).

Step 6: Synthesis of N-(2-cyano-3-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)(methyl)amino) phenyl) propane-1-sulfonamide

[0226] To a solution of 2-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)(methyl)amino)-6-fluorobenzonitrile (100 mg, 0.3 mmol) in NMP (6 ml) under N ₂ was added NaH (120 mg, 3.0 mmol, 60% in mineral oil). The mixture was stirred at 0° C. for 15 min under N ₂ atmosphere. Then, propane-1-sulfonamide (369 mg, 3.0 mmol) was added to the reaction mixture. The resulting mixture was stirred at 100° C. overnight under N ₂ atmosphere. The mixture was evaporated and the residue was purified by preparative HPLC to give N-(2-cyano-3-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidine-10- yl)(methyl)amino)phenyl)propane-1-sulfonamide (10.0 mg, 5% yield) as a white solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ 8.52 (s, 1H), 7.71 (s, 1H), 7.62 (t, J=8.4 Hz, 1H), 7, 52 (dd, J=8.4, 0.8Hz, 1H), 7.14 (dd, J=8.0, 0.8Hz, 1H), 7.09 (s, 1H), 4.06 (t, J=5.6 Hz, 2H), 3.60 (t, J=5.6 Hz, 2H), 3.52 (s, 3H), 3.17-3.13 (m, 2H) , 2.11-2.08 (m, 2H), 1.92-1.87 (m, 2H), 1.05 (t, J=7.2 Hz, 3H). LCMS (M+H ⁺ ) m/z: 438.1.

Example 35 Preparation of N-(2-cyano-3-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)amino)phenyl)propane -1-sulfonamide (compound 43)

Scheme 35

[0227] To a solution of 2-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)amino)-6-fluorobenzonitrile (120 mg, 0 .37 mmol) and propane-1-sulfonamide (54 mg, 0.44 mmol) in DMF (5.0 ml) was added NaH (22 mg, 0.55 mmol, 60% in mineral oil). The reaction mixture was stirred at 120°C overnight. The residue was purified by preparative HPLC to give N-(2-cyano-3-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)amino) phenyl)propane-1-sulfonamide (7.0 mg, 5% yield) as a yellow solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 10.19 (broad s, 1H), 9.38 (s, 1H), 8.41 (s, 1H), 7.69 (s, 1H), 7.54-7.53 (m, 2H), 7.49 (s, 1H), 7.12 (dd, J=6.8, 2.4 Hz, 1H), 3.94 (t , J=5.6Hz, 2H), 3.55(t, J=5.6Hz, 2H), 3.15-3.12(m, 2H), 1.96-1.93(m, 2H), 1.82-1.76 (m, 2H), 0.99 (t, J=7.6 Hz, 3H). LCMS (M+H ⁺ ) m/z: 424.2.

Example 36 Preparation of N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propan-2-sulfonamide (compound 44)

Scheme 36

Step 1: Synthesis of 2-Chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)aniline

[0228] To a solution of 9-iodo-2,3-dihydroimidazo[1,2-c]quinazoline (1.0 g, 3.36 mmol) and 3-amino-2-chlorophenol (0.96 g, 6.73 mmol) in DMSO (20.0 ml) were added CuI (64 mg, 0.34 mmol), K ₃ PO ₄ (1.40 g, 6.60 mmol), 2-pyridinecarboxylic acid (41 mg, 0.34 mmol ). The mixture was stirred at 80° C. under N ₂ overnight. The reaction mixture was cooled to room temperature and extracted with DCM (100 ml x 3) from water (30.0 ml), the organic layers were washed with brine (50 ml x 2), dried over Na ₂ SO _4, filtered, concentrated in vacuo. The resulting mixture was evaporated and purified by silica gel column chromatography (DCM/MeOH 100:1 to 50:1, v/v) to give 2-chloro-3-((2,3-dihydroimidazo[1,2-c ]quinazolin-9-yl)oxy)aniline (0.6 g, 60% yield) as a tan solid.

Step 2: Synthesis of N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-2-sulfonamide

[0229] To a solution of 2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)aniline (200 mg, 0.64 mmol) in DMF (5 mL) at 0°C under N ₂ was added NaH (256 mg, 6.4 mmol, 60% in mineral oil), the mixture was stirred at 0°C for 0.5 hours. Propane-2-sulfonyl chloride (454 mg, 3.2 mmol) was added to the mixture. The reaction mixture was stirred at 60°C overnight. The mixture was quenched by adding MeOH (1.0 ml) and concentrated to remove the solvent. The residue was purified by preparative HPLC to give N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propan-2-sulfonamide (trifluoroacetate, 4, 5 mg, 1.3% yield as a yellow solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.72 (broad, 1H), 8.09 (s, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.45-7.37(m, 3H), 7.27(s, 1H), 7.08(d, J=7.6Hz, 1H), 4.22(t, J=10.0Hz , 2H), 3.94 (t, J=10.0 Hz, 2H), 3.38-3.31 (m, 1H), 1.30 (d, J=6.8 Hz, 6H). LCMS (M+H ⁺ ) m/z: 419.2.

Example 37 Preparation of N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-N-ethyl-N-methylamino-1-sulfonamide ( connection 45)

Scheme 37

[0230] To a solution of 2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)aniline (150 mg, 0.48 mmol) in DCM (20 mL) at DMAP (3.0 mg, 0.05 mmol) ethyl(methyl)sulfamoyl chloride (136 mg, 1.44 mmol) and pyridine (75 mg, 0.96 mmol) were added at room temperature. The reaction mixture was stirred at 60°C for 4 days. The mixture was concentrated to remove the solvent. The residue was purified by preparative HPLC to give N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-N-ethyl-N-methylamino-1 -sulfonamide (trifluoroacetate, 18.0 mg, 7% yield) as a yellow solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.45 (br, 1H), 9.55 (s, 1H), 8.66 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.68 (s 1H), 7.48-7.46 (m, 2H), 7.15 ( e, J=6.4 Hz, 1H), 4.66 (t, J=10.0 Hz, 2H), 4.12 (t, J=10.0 Hz, 2H), 3.17-3, 12 (m, 2H), 2.76 (s, 3H), 1.03 (t, J=7.2 Hz, 3H). LCMS (M+H ⁺ ) m/z: 434.3.

Example 38 Preparation of (R)-N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-3-fluoropyrrolidine-1-sulfonamide ( connection 46)

Scheme 38

Step 1: Synthesis of N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-2-oxooxazolidin-3-sulfonamide

[0231] To a solution of chlorosulfonyl isocyanate (9.07 g, 64 mmol) in DCM (50 ml) at -5° C. under N ₂ was added 2-bromoethan-1-ol (7.93 g, 64 mmol). The mixture was stirred at -5-0°C for 2 hours. A solution of ₂ -chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)aniline (1.0 g, 3 .2 mmol) and Et ₃ N (8.74 ml, 64 mmol) in DCM (100 ml) _. The mixture was stirred at 10°C for 4 hours. The mixture was concentrated and the residue was purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to give N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c ]quinazolin-9-yl)oxy)phenyl)-2-oxooxazolidin-3-sulfonamide (800 mg, 54% yield) as a white solid.

Step 2: Synthesis of (R)-N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-3-fluoropyrrolidine-1-sulfonamide

[0232] To a solution of N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-2-oxooxazolidin-3-sulfonamide (120 mg, 0.26 mmol) and (R)-3-fluoropyrrolidine (231 mg, 2.6 mmol) in acetonitrile (5 ml) was added Et ₃ N (78 mg, 0.78 mmol). The mixture was stirred at 120° C. under microwave conditions for 40 minutes. The mixture was concentrated and the residue was purified by preparative HPLC to give (R)-N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-3 -fluoropyrrolidine-1-sulfonamide (trifluoroacetate, 43.5 mg, 29% yield) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.39 (s, 1H), 9.71 (s, 1H), 8.67 (s, 1H), 7.98 (d, J= 8.8 Hz, 1H), 7.81 (t, J=9.2, 2.8 Hz, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.54-7, 44 (m, 2H), 7.17 (d, J=8.4 Hz, 1H), 5.31 (d, J=54 Hz, 1H), 4.67 (t, J=10.0 Hz, 2H), 4.12 (t, J=10.0 Hz, 2H), 3.34-3.30 (m, 4H), 2.14-1.97 (m, 2H). LCMS (M+H ⁺ ) m/z: 464.2.

Example 39 Preparation of N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-(2-fluoroethyl)(methyl)amino-1- sulfonamide (compound 47)

Scheme 39

Stage 1: Synthesis of tert-butyl-(2-fluoroethyl)carbamate

[0233] To a solution of 2-fluoroethane-1-amine hydrochloride (5.0 g, 0.05 mol) in THF/H ₂ O (80 ml/80 ml) at 0° _C. 0.2 mol). After 5 minutes, Boc ₂ O (12.4 ml, 0.05 mol) was added. The reaction mixture was stirred at room temperature overnight. The solution was concentrated, diluted with H ₂ O (100 ml) and was extracted with DCM (100 ml × 3), the combined organic layers were washed with H ₂ O (100 ml) and dried over Na ₂ SO ₄ . Concentration gave tert-butyl-(2-fluoroethyl)carbamate (7.8 g, 96%) as a colorless oil.

Stage 2: Synthesis of tert-butyl-(2-fluoroethyl)(methyl)carbamate

[0234] NaH ( _2.25 g, 71 .7 mmol, 60% in mineral oil). The mixture was stirred at 0°C for 0.5 hour. MeI (10.1 g, 71.7 mmol) was added to the reaction mixture. The reaction mixture was stirred at rt. during the night. The mixture was quenched by adding H ₂ O (2 ml) and concentrated. The residue was partitioned between DCM and water. The organic layer was dried over Na ₂ SO ₄ and concentrated to give tert-butyl-(2-fluoroethyl)(methyl)carbamate (crude, 9.2 g, 100%) as an oil.

Stage 3: Synthesis of 2-fluoro-N-methylethane-1-amine hydrochloride

[0235] TFA (20 ml) was added to a solution of tert-butyl-(2-fluoroethyl)(methyl)carbamate (8.8 g, 49.7 mmol) in DCM (20 ml) at 0°C. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was dissolved in HCl/MeOH (2 M, 20 ml). The mixture was concentrated and the residue was washed with Et ₂ O (50 ml x 2). The solid was dried under vacuum to give 2-fluoro-N-methylethane-1-amine hydrochloride (5.0 g, 89%) as a white solid.

Step 4: Synthesis of N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-(2-fluoroethyl)(methyl)amino-1- sulfonamide

[0236] To a mixture of N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-2-oxooxazolidin-3-sulfonamide (100 mg, 0.22 mmol) and 2-fluoro-N-methylethane-1-amine hydrochloride (237 mg, 2.1 mmol) in CH ₃ CN (4 ml) at room temperature was added Et ₃ N (212 mg, 2.1 mmol ). The mixture was stirred at 120° C. under microwave conditions for 40 minutes. After removing the solvent, the residue was purified by preparative HPLC to give N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-(2-fluoroethyl) (methyl)amino-1-sulfonamide (trifluoroacetate, 6.7 mg, 5% yield) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.61 (broad s, 1H), 9.68 (s, 1H), 8.67 (s, 1H), 7.97 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.8, 2.8 Hz, 1H), 7.75 (d, J=2.8 Hz, 1H), 7.49- 7.43 (m, 2H), 7.17 (dd, J=7.2, 2.4 Hz, 1H), 4.70-4.65 (m, 2H), 4.51 (dt, J= 47.2, 4.8 Hz, 1H), 4.15-4.10 (m, 2H), 3.41 (dt, J=26.8, 4.8 Hz, 1H), 3.38 (t , J=4.8 Hz, 1H), 2.84 (s, 3H). LCMS (M+H ⁺ ) m/z: 452.2.

Example 40 Preparation of N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)pyrrolidin-1-sulfonamide (compound 48)

Scheme 40

[0237] N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-2-oxooxazolidin-3-sulfonamide mixture (50 mg, 0 .11 mmol), pyrrolidine (16 mg, 0.22 mmol) and Et ₃ N (34 mg, 0.33 mmol) in CH ₃ CN (5 ml) were heated at 120°C under microwave conditions for 1 hour . The mixture was evaporated and the residue was purified by preparative HPLC to give N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)pyrrolidine-1-sulfonamide ( 10 mg, 20% yield as a brown solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ 8.03 (s, 1H), 7.60-7.56 (m, 2H), 7.42-7.39 (m, 2H), 7 .33 (t, J=8.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 4.30 (t, J=10.0 Hz, 2H), 4.04 (t, J=10.0 Hz, 2H), 3.31-3.28 (m, 4H), 1.86-1.83 (m, 4H). LCMS (M+H ⁺ ) m/z: 446.1.

Example 41 Preparation of N-(5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)pyrrolidine-1-sulfonamide (compound 49)

Scheme 41

Step 1: Synthesis of 5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluoroaniline

[0238] To a solution of 9-iodo-2,3-dihydroimidazo[1,2-c]quinazoline (1.0 g, 3.37 mmol) and 3-amino-4-fluorophenol (0.85 g, 6.73 mmol) in DMSO was added CuI (64 mg, 0.34 mmol), K ₃ PO ₄ (2.14 g, 10.11 mmol), 2-pyridinecarboxylic acid (41 mg, 0.34 mmol). The mixture was stirred at 80° C. under N ₂ overnight. The reaction mixture was cooled to room temperature and partitioned between DCM and water. The organic layers were washed with saline (50 ml × 2), dried over Na ₂ SO ₄ . The resulting mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM/MeOH 100:1 to 50:1, v/v) to give 5-((2,3-dihydroimidazo[1,2-c]quinazoline -9-yl)oxy)-2-fluoroaniline (0.6 g, 60% yield) as a tan solid.

Step 2: Synthesis of N-(5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)-2-oxooxazolidin-3-sulfonamide

[0239] To a solution of chlorosulfonyl isocyanate (104 mg, 0.74 mmol) in DCM (20 ml) at -5°C was added 2-bromoethan-1-ol (92 mg, 0.74 mmol). The mixture was stirred at -5-0°C for 2 hours. A solution of 5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluoroaniline (200 mg, _0.67 mmol ) and Et ₃ N (135 mg, 1.34 mmol) in DCM (10 ml). The mixture was stirred at 10°C for 4 hours. The mixture was concentrated and the residue was purified by silica gel column chromatography (DCM/MeOH=30/1, v/v) to give N-(5-((2,3-dihydroimidazo[1,2-c]quinazoline-9 -yl)oxy)-2-fluorophenyl)-2-oxooxazolidin-3-sulfonamide (50 mg, 17% yield) as a white solid.

Step 3: Synthesis of N-(5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)pyrrolidine-1-sulfonamide

[0240] To a solution of N-(5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)-2-oxooxazolidin-3-sulfonamide (50 mg, 0 .11 mmol) and pyrrolidine (80 mg, 1.12 mmol) in acetonitrile (5 ml) were added Et ₃ N (33 mg, 0.33 mmol). The mixture was stirred at 150° C. under microwave conditions for 1 hour. The mixture was concentrated to remove the solvent. The residue was purified by preparative HPLC to give N-(5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)pyrrolidine-1-sulfonamide (trifluoroacetate, 10 mg, yield 16%) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.43 (broad, 1H), 9.93 (s, 1H), 8.67 (s, 1H), 7.98 (d, J =9.2 Hz, 1H), 7.82 (dd, J=8.8, 2.8 Hz, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.39 (t , J=9.2 Hz, 1H), 7.20 (dd, J=6.8, 2.8 Hz, 1H), 7.01-6.98 (m, 1H), 4.69 (t, J=10.0Hz, 2H), 4.14(t, J=10.0Hz, 2H), 3.17-3.13(m, 4H), 1.77-1.73(m, 4H ). LCMS (M+H ⁺ ) m/z: 430.3.

Example 42 Preparation of N-(5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)-N,N-dimethylamino-1-sulfonamide (compound 50)

Scheme 42

[0241] To a solution of N-(5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)-2-oxooxazolidin-3-sulfonamide (50 mg, 0 .11 mmol) and dimethylamine/THF (0.5 ml) in acetonitrile (5 ml) were added Et ₃ N (34 mg, 0.33 mmol). The mixture was stirred at 150° C. under microwave conditions for 60 minutes. The mixture was concentrated to remove the solvent. The residue was purified by preparative HPLC to give N-(5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)-N,N-dimethylamino-1-sulfonamide ( trifluoroacetate, 12 mg, 21% yield as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.41 (br, 1H), 9.97 (s, 1H), 8.67 (s, 1H), 7.98 (d, J =9.2 Hz, 1H), 7.82 (dd, J=9.2, 2.8 Hz, 1H), 7.76 (d, J=2.8 Hz, 1H), 7.39 (t , J=9.6 Hz, 1H), 7.21-7.18 (m, 1H), 7.02-6.98 (m, 1H), 4.68 (t, J=10.0 Hz, 2H), 4.14 (t, J=10.0 Hz, 2H), 2.70 (s, 6H). LCMS (M+H ⁺ ) m/z: 404.2.

Example 43 Preparation of N-(5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide (compound 51)

Scheme 43

[0242] A mixture of 5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluoroaniline (100 mg, 0.33 mmol), propane-1-sulfonyl chloride (433, 6 mg, 3.04 mmol) and Et ₃ N (411 mg, 4.05 mmol) in DCM (10 ml) was stirred at 30°C overnight. The mixture was concentrated, MeOH (10 ml) and aq. NaOH (10 ml, 2n). The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, conc. HCl to pH=6~7 mixture. After removal of volatiles, the residue was extracted with DCM/MeOH (10/1), dried over Na ₂ SO _4. Concentration gave the crude product, which was purified by preparative HPLC to give N-(5-((2,3-dihydroimidazo[1 ,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)-propane-1-sulfonamide (trifluoroacetate, 62.8 mg, 37% yield) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.49 (br, 1H), 9.96 (s, 1H), 8.68 (s, 1H), 7.98 (d, J =9.2 Hz, 1H), 7.84 (dd, J=9.2, 2.8 Hz, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.42 (t , J=9.2 Hz, 1H), 7.23-7.21 (m, 1H), 7.06-7.03 (m, 1H), 4.69 (t, J=10.0 Hz, 2H), 4.14 (t, J=10.0 Hz, 2H), 3.14 (t, J=7.2 Hz, 2H), 1.75-1.70 (m, 2H), 0, 96 (t, J=7.2 Hz, 3H). LCMS (M+H ⁺ ) m/z: 403.2.

Example 44 Preparation of N-(5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)propane-2-sulfonamide (compound 52)

Scheme 44

[0243] To a solution of 5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluoroaniline (100 mg, 0.33 mmol) in DMF (5 mL) at 0 °C under N ₂ NaH (60% in mineral oil, 270 mg, 6.7 mmol, 60% in mineral oil) was added. The mixture was stirred at 0°C for 0.5 hour. Propane-2-sulfonyl chloride (430 mg, 3.0 mmol) was added to the mixture. The reaction mixture was stirred at 80°C overnight. The mixture was quenched by adding MeOH (1.0 ml) and concentrated to remove the solvent. The residue was partitioned between DCM and water. The organic layer was concentrated and purified by preparative HPLC to give N-(5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)propane-2-sulfonamide (trifluoroacetate, 4.6 mg, 3% yield as a yellow solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.83 (broad, 1H), 7.95 (s, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.35-7.30(m, 2H), 7.25(d, J=2.4Hz, 1H), 7.16-7.14(m, 1H), 6.94-6.92( m, 1H), 4.11 (t, J=9.6 Hz, 2H), 3.90 (t, J=10.0 Hz, 2H), 3.32-3.30 (m, 1H), 1.25 (d, J=6.8 Hz, 6H). LCMS (M+H ⁺ ) m/z: 403.2.

Example 45 Preparation of (R)-N-(2-chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-3- fluoropyrrolidine-1-sulfonamide (compound 53)

Scheme 45

Stage 1: Synthesis of 2-((6-iodhinazolin-4-yl)amino)-2-methylpropan-1-ol

[0244] To a solution of 4-chloro-6-iodoquinazoline (3.0 g, 10.3 mmol) and 2-amino-2-methylpropan-1-ol (1.8 g, 20.6 mmol) in i-PrOH (30.0 ml) was added Et ₃ N (2.1 g, 20.6 mmol). The reaction mixture was stirred at 80°C for 16 hours. The resulting mixture was cooled to room temperature and the solid was filtered to give 2-((6-iodoquinazolin-4-yl)amino)-2-methylpropan-1-ol (3.5 g, 100% yield) as a white solid .

Step 2: Synthesis of 9-iodo-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazoline

[0245] To a solution of 2-((6-iodhinazolin-4-yl)amino)-2-methylpropan-1-ol (3.5 g, 10.2 mmol) in CHCl ₃ (10.0 ml) was added SOCl ₂ (20.0 ml). The reaction mixture was stirred at reflux overnight. The resulting mixture was concentrated, MeOH and DCM were added to the residue. The reaction mixture was stirred at room temperature for 10 minutes. The solid was filtered to give 9-iodo-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazoline (3.3 g, 100% yield) as an off-white solid.

Step 3: Synthesis of 2-chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)aniline

[0246] To a solution of 9-iodo-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazoline (1.0 g, 3.07 mmol) and 3-amino-2-chlorophenol (0. 88 g, 6.15 mmol) in DMSO (20.0 ml) was added CuI (176 mg, 0.92 mmol), K ₃ PO ₄ (2.94 g, 13.8 mmol), 2-pyridinecarboxylic acid (114 mg, 0.92 mmol). The mixture was stirred at 80° C. under N ₂ overnight. The reaction mixture was cooled to room temperature and was extracted with DCM (100 ml × 3) from water (40.0 ml), the organic layers were washed with brine (60 ml × 2), dried over Na ₂ SO _4, filtered, concentrated in vacuo. The resulting mixture was evaporated and purified by silica gel column chromatography (DCM/MeOH 100:1 to 20:1, v/v) to give 2-chloro-3-((2,2-dimethyl-2,3-dihydroimidazo [1,2-c]quinazolin-9-yl)oxy)aniline (0.43 g, 41% yield) as a tan solid.

Step 4: Synthesis of N-(2-chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-2-oxooxazolidin-3- sulfonamide

[0247] To a solution of chlorosulfonyl isocyanate (333 mg, 2.35 mmol) in DCM (20 ml) at 0°C was slowly added a solution of 2-bromoethan-1-ol (295 mg, 2.35 mmol) in DCM (5 ml) . The mixture was stirred at 0°C for 1 hour, then the mixture was added dropwise to a stirred solution of 2-chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl )oxy)aniline (200 mg, 0.59 mmol) and Et ₃ N (238 mg, 2.35 mmol) in DCM (15 ml), and the mixture was stirred at room temperature overnight. Concentration gave a crude product which was purified by silica gel column chromatography (DCM/MeOH 50:1 to 10:1, v/v) to give N-(2-chloro-3-((2,2-dimethyl -2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-2-oxooxazolidin-3-sulfonamide (100 mg, 35% yield) as a brown solid.

Step 5: Synthesis of (R)-N-(2-chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-3- fluoropyrrolidine-1-sulfonamide

[0248] A mixture of N-(2-chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-2-oxooxazolidin-3- sulfonamide (30 mg, 0.06 mmol), (R)-3-fluoropyrrolidine (7 mg, 0.07 mmol) and Et ₃ N (8 mg, 0.07 mmol) in CH ₃ CN (2 ml) was stirred at 120°C under microwave treatment conditions for 1 hour. The mixture was concentrated and the residue was purified by preparative HPLC to give (R)-N-(2-chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl) hydroxy)phenyl)-3-fluoropyrrolidine-1-sulfonamide (trifluoroacetate, 4 mg, 11% yield) as a white solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ 8.47 (s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.81 (dd, J=8.8 , 2.8 Hz, 1H), 7.66 (dd, J=8.4, 1.2 Hz, 1H), 7.45-7.39 (m, 2H), 7.13-7.09 ( m, 1H), 5.25 (dt, J=50.4, 3.6 Hz, 1H), 4.52 (s, 2H), 3.61-3.41 (m, 4H), 2.20 -2.00 (m, 2H), 1.58 (s, 6H). LCMS (M+H ⁺ ) m/z: 492.2.

Example 46: Preparation of N-(2-chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)pyrrolidine-1-sulfonamide (Compound 54)

Scheme 46

[0249] A mixture of N-(2-chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-2-oxooxazolidin-3- sulfonamide (70 mg, 0.14 mmol), pyrrolidine (13 mg, 0.17 mmol) and Et ₃ N (18 mg, 0.17 mmol) in CH ₃ CN (2 ml) was stirred at 120°C under working conditions microwave radiation for 1 hour. The mixture was concentrated and the residue was purified by preparative HPLC to give N-(2-chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl) pyrrolidine-1-sulfonamide (trifluoroacetate, 6 mg, 7% yield) as a white solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ 7.95 (s, 1H), 7.60-7.54 (m, 2H), 7.39-7.32 (m, 3H), 6 .99 (dd, J=8.0, 1.2 Hz, 1H), 3.98 (s, 2H), 3.34-3.28 (m, 4H), 1.86-1.83 (m , 4H), 1.36 (s, 6H). LCMS (M+H ⁺ ) m/z: 474.4.

Example 47 Preparation of N-(2-chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-1-sulfonamide (Compound 55)

Scheme 47

[0250] 2-Chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)aniline mixture (100 mg, 0.29 mmol), propane -1-sulfonyl chloride (378 mg, 2.64 mmol) and Et ₃ N (357 mg, 3.53 mmol) in DCM (10 ml) was stirred at 30°C overnight. The mixture was concentrated, MeOH (10 ml) and aq. NaOH (10 ml, 2N), and the reaction mixture was stirred at room temperature for 4 hours. Added concentrated HCl to pH=6~7. The mixture was evaporated, the residue was extracted with DCM/MeOH (10/1), dried over Na ₂ SO ₄ . Concentration gave the crude product which was purified by preparative HPLC to give N-(2-chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy) phenyl)propane-1-sulfonamide (trifluoroacetate, 37 mg, 22% yield) as a brown solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.57 (broad s, 1H), 9.70 (s, 1H), 8.64 (s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.86 (dd, J=9.2, 2.8 Hz, 1H), 7.59 (d, J=2.8 Hz, 1H), 7.50- 7.48 (m, 2H), 7.23 (t, J=4.8 Hz, 1H), 4.44 (s, 2H), 3.19-3.15 (m, 2H), 1.80 -1.72 (m, 2H), 1.52 (s, 6H), 0.97 (t, J=7.2 Hz, 3H). LCMS (M+H ⁺ ) m/z: 447.2.

Example 48 Preparation of N-(2-chloro-3-((3-((dimethylamino)methyl)-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propan-1- sulfonamide (compound 56)

Scheme 48

Step 1: Synthesis of 1-(9-iodo-2,3-dihydroimidazo[1,2-c]quinazolin-3-yl)-N,N-dimethylmethanamine

[0251] Solution (9-iodine-2,3-dihydroimidazo[1,2-c]quinazolin-3-yl)methanamine (100 mg, 0.31 mmol), formaldehyde (5 drops), NaBH ₃ CN (40 mg , 0.62 mmol) in MeOH (5 ml) was stirred at room temperature overnight. Water was added, the resulting mixture was extracted with EtOAc (20 ml × 3). The combined organic layers were washed with saline (20 ml × 2), dried over Na ₂ SO ₄ . Concentration gave the crude product, which was purified by silica gel column chromatography (DCM/MeOH 100:1 to 20:1, v/v) to give 1-(9-iodo-2,3-dihydroimidazo[1,2 -c]quinazolin-3-yl)-N,N-dimethylmethanamine (43 mg, 40% yield) as a white solid.

Step 2: Synthesis of 2-chloro-3-((3-((dimethylamino)methyl)-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)aniline

[0252] 1-(9-iodo-2,3-dihydroimidazo[1,2-c]quinazolin-3-yl)-N,N-dimethylmethanamine solution (43 mg, 0.12 mmol), 3-amino-2 -chlorophenol (34 mg, 0.24 mmol), CuI (3 mg, 0.012 mmol) in DMSO (5 ml) was stirred at 90° C. overnight. The residue was purified by preparative HPLC to give 2-chloro-3-((3-((dimethylamino)methyl)-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)aniline (15 mg, yield 33%) as a white solid.

Step 3: Synthesis of N-(2-chloro-3-((3-((dimethylamino)methyl)-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propan-1- sulfonamide

[0253] To a solution of 2-chloro-3-((3-((dimethylamino)methyl)-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)aniline (15 mg, 0.04 mmol) and Et ₃ N (10 mg, 0.08 mmol) in DCM (1 ml) was added propane-1-sulfonyl chloride (5 mg, 0.04 mmol). The mixture was stirred at room temperature for 2 hours. Added aq. NaOH (1 ml, 1 mmol/ml), the mixture was stirred at room temperature for an additional 2 hours. Concentration gave the crude product which was purified by preparative HPLC to give N-(2-chloro-3-((3-((dimethylamino)methyl)-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl )oxy)phenyl)propane-1-sulfonamide (10.0 mg, 50% yield) as a white solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ 7.97 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.42-7.36 (m, 2H), 7.33 (t, J=8.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 4.50-4.46(m, 1H), 4.37-4.33(m, 1H), 4.04-3.99(m, 1H), 3.15(t, J=7.6 Hz, 2H), 2.71-2.68 (m, 2H), 2.45 (s, 6H), 1.88-1.83 (m, 2H), 1.03 (t, J=7, 6 Hz, 3H). LCMS (M+H ⁺ ) m/z: 476.2.

[0254] While the foregoing description of the compounds, uses, and methods described herein enables one of ordinary skill in the art to make and use the compounds, uses, and methods described herein, the person of ordinary skill in the art should recognize and acknowledge the existence of variations, combinations, and equivalents of a particular embodiment, method. and examples described in this document. Therefore, the compounds, uses, and methods described herein should not be limited to the embodiments, methods, or examples described above, but rather encompass all embodiments and methods within the scope of the compounds, uses, and methods presented herein.

[0255] All references disclosed herein are incorporated herein in their entirety by reference.

[0256] The activity of the compounds of formula (I) in vitro and in vivo was determined using the following methods.

Biological example B1

Methods for the analysis of antiproliferative action

[0257] An in vitro study of the antiproliferative effect of test compounds on the A375 cell line by means of CellTiter Glo. Cells were routinely maintained as a monolayer culture in an appropriate culture medium at 37° C. under 5% CO ₂ .

[0258] Exponentially growing cells were collected by treatment with trypsin-EDTA. The cell pellet was resuspended in fresh culture medium and adjusted to the required concentration (cell density per well is given in the following form). Cell viability when stained with trypan blue was more than 98%. Cells were seeded in 96-well plates according to the plate scheme (90 μl per well). The plates were incubated at 37°C and 5% CO ₂ overnight. The next day, medium was prepared containing 10x compound according to the plate design. 10 μl of medium containing 10x compound was transferred to each well of the assay plates (final DMSO concentration was 0.5%). The medium was gently mixed and incubated at 37°C and 5% CO ₂ for another 72 hours or 144 hours.

[0259] The reagent was prepared in accordance with the manufacturer's instructions. 50 μl CellTiter-Glo reagent was added to each well. The contents were stirred for 2 minutes on an orbital shaker to induce cell lysis. The tablet was left to incubate at room temperature for 10 minutes to stabilize the luminescence signal. Transfer 100 μl of the reaction content of each well from the clear plates to 96-well white-walled/white opaque plates. Luminescence was recorded on Envision.

[0260] Using the luminescence measurements [time zero (T0), growth in control (C), and test growth in the presence of drug at six concentrations (Ti)], percent growth was calculated for each drug concentration level.

[0261] Percent growth inhibition (GI) was calculated as: GI(%)=[(Ti-T0)/(C-T0)]×100 for concentrations where Ti>=T0 and GI(%)=[(Ti -T0)/T0]×100 for concentrations where Ti<T0. To obtain concentration curves, the data were analyzed using the XLFit software (Excel) with extrapolation to a 4-parameter equation. The concentration of a compound that inhibits cell growth by 50% (GI50) in the control was interpolated backwards at y=50% net gain in DMSO-treated control wells using non-linear regression according to the equation: f(x) 205 [fit=(A+(( B-A)/(1+((C/x)^D))))], where A is the minimum response (Ymin), B is the maximum response (Ymax), C is the inflection point of the curve (Re GI50) , and D is the Hill coefficient. Growth inhibition by 50% (GI50) was determined from the 50% growth inhibition curve. The index values were the sum of the degree of inhibition (IR) for each test compound concentration. Table A shows the antiproliferative effect of the synthesized compounds on melanoma A375 cells and colon cancer HT-29 cells.

Table A

Comm. No. Compound MS (MH ⁺ ) ¹ H-NMR A375 Ht-29 1 N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-1-sulfonamide 410.70 ¹ H-NMR (400 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.06-7.96 (m, 3H), 7.75 (t, J=8.0 Hz, 1H ), 7.40 (d, J=8.0 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 4.74-4.69 (m, 2H), 4.19 -4.15(m, 2H), 3.25(t, J=7.2Hz, 2H), 1.85-1.79(m, 2H), 1.02(t, J=7.2 Hz, 3H) +++ +++ 2 N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-N-methylpropane-1-sulfonamide 424.2 ¹ H-NMR (400 MHz, DMSO-d6): δ 7.98 (s, 1H), 7.72 (t, J=8.4 Hz, 1H), 7.54-7.44 (m, 4H ), 7.07 (d, J=8.4 Hz, 1H), 4.12 (t, J=9.6 Hz, 2H), 3.92 (t, J=9.6 Hz, 2H), 3.34-3.30(m, 2H), 3.29(s, 3H), 1.81-1.75(m, 2H), 1.02(t, J=7.2Hz, 3H) + ND 3 N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-4-fluorophenyl)propane-1-sulfonamide 428.70 ¹ H-NMR (400 MHz, CD3OD): δ 7.91 (s, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.43-7.34 (m, 3H), 7.25 (t, J=9.6 Hz, 1H), 4.19 (t, J=9.6 Hz, 2H), 4.00 (t, J=9.6 Hz, 2H), 2, 98-2.94 (m, 2H), 1.88-1.83 (m, 2H), 1.02 (t, J=7.2 Hz, 3H) +++ ND 4 N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-4,6-difluorophenyl)propane-1-sulfonamide 446.2 ¹ H-NMR (400 MHz, CD3OD): δ 8.11 (s, 1H), 7.71-7.66 (m, 2H), 7.56 (dd, J=8.8, 2.8 Hz , 1H), 7.48 (d, J=2.4 Hz, 1H), 4.37 (t, J=10.0 Hz, 2H), 4.08 (t, J=10.0 Hz, 2H ), 3.19 (t, J=7.6 Hz, 2H), 1.97-1.91 (m, 2H), 1.07 (t, J=7.6 Hz, 3H) ++ ND 5 N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-6-fluorophenyl)propane-1-sulfonamide 428.2 ¹ H-NMR (400 MHz, DMSO-d6): δ 10.48 (br, 1H), 8.13 (s, 1H), 7.63-7.52 (m, 3H), 7.45 ( d, J=2.4 Hz, 1H), 6.99-6.96 (m, 1H), 4.24 (t, J=10.0 Hz, 2H), 3.96 (t, J=10 .0 Hz, 2H), 3.12 (t, J=7.6 Hz, 2H), 1.85-1.79 (m, 2H), 1.00 (t, J=7.2 Hz, 3H ) ++ ND 6 N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-1-sulfonamide 419.1 ¹ H-NMR (400 MHz, CD3OD): δ 8.03 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.43-7.33 (m, 3H), 7.02 (d, J=7.2 Hz, 1H), 4.29 (t, J=10.0 Hz, 2H), 4, 04 (t, J=10.0 Hz, 2H), 3.15 (t, J=7.6 Hz, 2H), 1.88-1.82 (m, 2H), 1.03 (t, J =7.6Hz, 3H) +++ ++ 7 N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluoro-4-nitrophenyl)propane-1-sulfonamide 448.1 ¹ H-NMR (400 MHz, DMSO-d6): δ 11.19 (broad s, 1H), 8.46 (s, 1H), 7.93 (d, J=9.6 Hz, 1H), 7.85 (d, J=9.2 Hz, 1H), 7.78 (dd, J=9.2, 2.0 Hz, 1H), 7.50 (s, 1H), 7.38 (t , J=8.8 Hz, 1H), 4.51 (t, J=10.0 Hz, 2H), 4.05 (t, J=10.0 Hz, 2H), 2.93 (t, J =7.6Hz, 2H), 1.73-1.68(m, 2H), 0.95(t, J=7.6Hz, 3H) + ND 8 N-(4-amino-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide 418.2 ¹ H-NMR (400 MHz, DMSO-d6): δ 11.46 (br, 1H), 9.15 (s, 1H), 8.65 (s, 1H), 7.97 (d, J= 9.2 Hz, 1H), 7.79 (dd, J=9.2, 2.4 Hz, 1H), 7.64 (s, 1H), 7.05 (t, J=8.8 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 4.68 (t, J=10.0 Hz, 2H), 4.12 (t, J=10.0 Hz, 2H) , 2.97 (t, J=7.6 Hz, 2H), 1.73-1.67 (m, 2H), 0.92 (t, J=7.6 Hz, 3H) + ND 9 N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide 403.2 ¹ H-NMR (400 MHz, DMSO-d6): δ 11.62 (broad, 1H), 9.92 (s, 1H), 8.67 (s, 1H), 7.98 (d, J= 9.2 Hz, 1H), 7.86 (dd, J=9.2, 2.4 Hz, 1H), 7.78 (s, 1H), 7.40-7.38 (m, 1H), 7.30 (t, J=8.8 Hz, 1H), 7.22-7.19 (m, 1H), 4.68 (t, J=10.0 Hz, 2H), 4.13 (t , J=10.0 Hz, 2H), 3.15 (t, J=8.0 Hz, 2H), 1.76-1.71 (m, 2H), 0.96 (t, J=7, 6Hz, 3H) ++ ND 10 N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2,4-difluorophenyl)propane-1-sulfonamide 421.1 ¹ H-NMR (400 MHz, DMSO-d6): δ 9.61 (broad, 1H), 7.99 (s, 1H), 7.52-7.45 (m, 2H), 7.38- 7.35 (m, 2H), 7.18 (s, 1H), 4.14 (t, J=9.6 Hz, 2H), 3.91 (t, J=9.6 Hz, 2H), 3.07 (t, J=7.6Hz, 2H), 1.73-1.67 (m, 2H), 0.89 (t, J=7.6Hz, 3H) + ND eleven N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-(trifluoromethyl)phenyl)propane-1-sulfonamide 453.1 ¹ H-NMR (400 MHz, DMSO-d6): δ 11.54 (broad, 1H), 9.70 (s, 1H), 8.69 (s, 1H), 8.00 (d, J= 8.8 Hz, 1H), 7.87-7.84 (m, 2H), 7.73 (t, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 4.70 (t, J=10.0 Hz, 2H), 4.15 (t, J=10.0 Hz, 2H) , 3.18 (t, J=7.6 Hz, 2H), 1.82-1.76 (m, 2H), 1.02 (t, J=7.6 Hz, 3H) ++ ND 12 N-(3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-nitrophenyl)propane-1-sulfonamide 430.1 ¹ H-NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.57-7.51 (m, 2H ), 7.39-7.32 (m, 2H), 6.68 (d, J=7.2 Hz, 1H), 4.34 (t, J=10.0 Hz, 2H), 4.00 (t, J=10.0 Hz, 2H), 2.96 (t, J=7.6 Hz, 2H), 1.72-1.66 (m, 2H), 0.96 (t, J= 7.6Hz, 3H) +++ ND 13 N-(2-amino-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-1-sulfonamide 400.1 ¹ H-NMR (400 MHz, DMSO-d6): δ 8.94 (broad s, 1H), 7.89 (s, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.29 (dd, J=8.8, 2.8 Hz, 1H), 7.09 (d, J=2.8 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H ), 6.83 (d, J=7.6 Hz, 1H), 6.62 (t, J=7.6 Hz, 1H), 5.00 (broad s, 2H), 4.07 (t , J=10.0 Hz, 2H), 3.86 (t, J=10.0 Hz, 2H), 3.02 (t, J=7.6 Hz, 2H), 1.77-1.68 (m, 2H), 0.95 (t, J=7.6Hz, 3H) + ND 14 N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-2-fluorobenzenesulfonamide 462.2 ¹ H-NMR (400 MHz, DMSO-d6): δ 7.92 (s, 1H), 7.82-7.76 (m, 1H), 7.69-7.64 (m, 1H), 7 .45-7.30 (m, 3H), 7.25-7.17 (m, 3H), 7.07 (t, J=8.4 Hz, 1H), 6.95 (d, J=8 .8 Hz, 1H), 6.08 (d, J=7.6 Hz, 1H), 4.09 (t, J=9.6 Hz, 2H), 3.90 (t, J=9.6 Hz, 2H) +++ ND 15 N-(2-cyano-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)thiophene-2-sulfonamide 450.1 ¹ H-NMR (400 MHz, DMSO-d6): δ 7.92 (s, 1H), 7.54 (d, J=3.6 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.33-7.30 (m, 2H), 7.24 (d, J=2.8 Hz, 1H), 7.14-7.06 (m, 2H), 6.96 (dd, J=4.8, 3.6Hz, 1H), 6.10 (d, J=7.6Hz, 1H), 4.09 (t, J=9.6Hz, 2H), 3 .90 (t, J=9.6 Hz, 2H) ++ ND 16 N-(2-cyano-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)propane-1-sulfonamide 424.2 ¹ H-NMR (400 MHz, DMSO-d6): δ 8.21 (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.65 (dd, J=8.8, 2.4 Hz, 1H), 7.28 (t, J=8.4 Hz, 1H), 7.18 (d, J=8 .4 Hz, 1H), 6.26 (d, J=8.0 Hz, 1H), 4.17 (t, J=5.2 Hz, 2H), 3.56 (t, J=5.2 Hz, 2H), 2.86 (t, J=7.6 Hz, 2H), 2.10-2.06 (m, 2H), 1.75-1.69 (m, 2H), 0.96 (t, J=7.6Hz, 3H) +++ +++ 17 N-(2-cyano-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-4-fluorophenyl)propane-1-sulfonamide 442.4 ¹ H-NMR (400 MHz, DMSO-d6): δ 10.65 (broad s, 1H), 8.27 (s, 1H), 7.83-7.78 (m, 2H), 7.71 (d, J=8.8 Hz, 1H), 7.38 (t, J=9.6 Hz, 1H), 7.28 (dd, J=9.6, 4.4 Hz, 1H), 4 .18 (t, J=5.6 Hz, 2H), 3.56 (t, J=5.6 Hz, 2H), 2.82 (t, J=7.6 Hz, 2H), 2.12 -2.08 (m, 2H), 1.73-1.67 (m, 2H), 0.95 (t, J=7.6Hz, 3H) +++ ND 18 N-(3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide 417.3 ¹ H-NMR (400 MHz, CD3OD): δ 8.30 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.79 (s, 1H), 7.74 ( d, J=8.8 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.09 (t, J=7.6Hz, 1H), 4.37(m, 2H), 3.69(t, J=4.8Hz, 2H), 3.15(t, J=7.2Hz, 2H) , 2.30 (m, 2H), 1.88-1.82 (m, 2H), 1.04 (t, J=7.2 Hz, 3H) +++ ++ 19 N-(3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2-fluoro-6-nitrophenyl)propane-1-sulfonamide 462.1 ¹ H-NMR (400 MHz, DMSO-d6): δ 10.36 (broad, 1H), 8.05 (s, 1H), 7.78 (d, J=2.0 Hz, 1H), 7 .71-7.61 (m, 3H), 6.88 (t, J=8.0 Hz, 1H), 4.08 (t, J=4.8 Hz, 2H), 3.53 (t, J=5.2Hz, 2H), 2.92(t, J=7.6Hz, 2H), 2.03-2.00(m, 2H), 1.75-1.65(m, 2H ), 0.93 (t, J=7.6 Hz, 3H) + ND 20 N-(6-amino-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide 432.1 ¹ H-NMR (400 MHz, DMSO-d6): δ 9.00 (broad s, 1H), 7.56 (s, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H), 7.23 (dd, J=8.8, 2.8 Hz, 1H), 7.00 (t, J=8.8 Hz, 1H ), 6.60 (d, J=8.8 Hz, 1H), 5.33 (broad s, 2H), 3.84 (t, J=5.2 Hz, 2H), 3.42 (t , J=5.2 Hz, 2H), 3.06 (t, J=7.6 Hz, 2H), 1.84-1.79 (m, 2H), 1.77-1.69 (m, 2H), 0.93 (t, J=7.2Hz, 3H) + ND 21 N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)propane-1-sulfonamide 433.1 ¹ H-NMR (400 MHz, DMSO-d6): δ 9.55 (broad, 1H), 7.63 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 7 .36-7.28 (m, 4H), 6.96-6.94 (m, 1H), 3.86 (t, J=5.2 Hz, 2H), 3.43 (t, J=5 .2 Hz, 2H), 3.09 (t, J=7.6 Hz, 2H), 1.86-1.83 (m, 2H), 1.77-1.71 (m, 2H), 0 .97 (t, J=7.6 Hz, 3H) +++ +++ 22 N-(2-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-3-nitropyridin-4-yl)propan-1-sulfonamide 445.2 ¹ H-NMR (400 MHz, DMSO-d6): δ 10.94 (broad, 1H), 8.41 (s, 1H), 8.24 (s, 1H), 7.84 (d, J= 8.8 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.55 (d, J=6.0 Hz, 1H), 7.11 (d, J=6, 0 Hz, 1H), 4.30-4.25 (m, 2H), 3.60-3.58 (m, 2H), 2.77-2.73 (m, 2H), 2.20-2 .16 (m, 2H), 1.68-1.62 (m, 2H), 0.93 (t, J=7.2 Hz, 3H) + ND 23 N-(4-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)-3-nitropyridin-2-yl)propan-1-sulfonamide 445.2 ¹ H-NMR (400 MHz, DMSO-d6): δ 10.67 (broad, 1H), 8.46 (s, 1H), 8.17 (d, J=2.4 Hz, 1H), 7 .90 (d, J=9.2 Hz, 1H), 7.82 (dd, J=9.2, 2.4 Hz, 1H), 7.55 (d, J=6.0 Hz, 1H) , 7.12 (d, J=6.0 Hz, 1H), 4.28 (t, J=5.2 Hz, 2H), 3.60 (t, J=5.2 Hz, 2H), 2 .78-2.73 (m, 2H), 2.20-2.16 (m, 2H), 1.68-1.63 (m, 2H), 0.93 (t, J=7.6 Hz , 3H) + + 24 N-(3-cyano-4-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)pyridin-2-yl)propan-1-sulfonamide 425.3 ¹ H-NMR (400 MHz, DMSO-d6): δ 10.67 (broad, 1H), 8.35 (s, 1H), 8.12 (s, 1H), 7.85-7.80 ( m, 2H), 7.54 (d, J=6.4 Hz, 1H), 6.98 (d, J=6.4 Hz, 1H), 4.29-4.22 (m, 2H), 3.61-3.58 (m, 2H), 2.81-2.77 (m, 2H), 2.20-2.16 (m, 2H), 1.73-1.68 (m, 2H ), 0.96 (t, J=7.2 Hz, 3H) + ND 25 N-(3-cyano-2-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)pyridin-4-yl)propan-1-sulfonamide 425.3 ¹ H-NMR (400 MHz, DMSO-d6): δ 10.60 (broad, 1H), 8.47 (s, 1H), 8.19 (s, 1H), 7.92-7.86 ( m, 2H), 7.54 (d, J=6.0 Hz, 1H), 6.99 (d, J=6.0 Hz, 1H), 4.29 (t, J=5.2 Hz, 2H), 3.61 (t, J=5.2 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 2.20-2.16 (m, 2H), 1, 74-1.68 (m, 2H), 0.96 (t, J=7.6 Hz, 3H) + ND 26 N-(3-chloro-4-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)pyridin-2-yl)propan-1-sulfonamide 434.2 ¹ H-NMR (400 MHz, CDCl3): δ 0.83 (d, J=5.6 Hz, 1H), 7.94 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.48 (s, 1H), 7.30 (dd, J=8.8, 2.8 Hz, 1H), 6.43 (d, J=5.6 Hz, 1H), 3, 93 (t, J=5.6 Hz, 2H), 3.69-3.63 (m, 4H), 2.10-2.04 (m, 2H), 1.98-1.92 (m, 2H), 1.10 (t, J=7.2Hz, 3H) +++ +++ 27 N-(2-cyano-3-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)oxy)phenyl)propane-1-sulfonamide 425.3 ¹ H-NMR (400 MHz, CD3OD): δ 8.38 (s, 1H), 7.68 (s, 1H), 7.54 (s, 1H), 7.44-7.39 (m, 2H ), 6.68 (dd, J=7.6, 1.2 Hz, 1H), 4.00 (t, J=5.6 Hz, 2H), 3.65 (t, J=5.6 Hz , 2H), 2.07-2.04 (m, 2H), 1.92-1.81 (m, 2H), 1.38-1.29 (m, 2H), 1.08 (t, J =7.2Hz, 3H) ++ ND 28 N-(2-cyano-3-((2,3,4,5-tetrahydro-[1,3]diazepino[1,2-c]quinazolin-11-yl)oxy)phenyl)propane-1-sulfonamide 438.2 ¹ H-NMR (400 MHz, DMSO-d6): δ 10.35 (br, 1H), 8.45 (s, 1H), 7.90 (s, 1H), 7.79 (d, J= 8.8 Hz, 1H), 7.61 (dd, J=9.2, 2.0 Hz, 1H), 7.45-7.41 (m, 1H), 7.18 (d, J=8 .0 Hz, 1H), 6.55-6.52 (m, 1H), 3.81-3.79 (m, 4H), 3.07 (t, J=7.2 Hz, 2H), 1 .94-1.92 (m, 4H), 1.80-1.74 (m, 2H), 0.99 (t, J=7.2 Hz, 3H) + ND 37 N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)ethanesulfonamide 419.2 ¹ H-NMR (400 MHz, DMSO-d6): δ 9.81 (broad s, 1H), 7.76 (s, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.38-7.35 (m, 3H), 7.03 (t, J=4.8 Hz, 1H), 3.93 (t , J=5.6Hz, 2H), 3.45(t, J=5.6Hz, 2H), 3.17(kv, J=7.2Hz, 2H), 1.92-1.87 (m, 2H), 1.27 (t, J=7.2Hz, 3H) ND ND 38 N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-3-fluoropropane-1-sulfonamide 451.3 ¹ H-NMR (400 MHz, DMSO-d6): δ 7.72 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.40 (d, J=2.8 Hz, 1H), 7.36-7.30 (m, 3H), 6.93 (dd, J=7.6, 2.4 Hz, 1H), 4.57 (dt, J=47.2, 6.0 Hz, 2H), 3.91 (t, J=5.6 Hz, 2H), 3.44 (t, J=5.6 Hz, 2H), 3.22-3.17 (m, 2H), 2.17-2.07 (m, 2H), 1.89-1.87 (m, 2H) +++ ND 39 N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-3-hydroxypropane-1-sulfonamide 449.3 ¹ H-NMR (400 MHz, DMSO-d6): δ 10.73 (broad s, 1H), 9.69 (s, 1H), 8.47 (s, 1H), 7.95-7.92 (m, 2H), 7.76-7.73 (m, 1H), 7.46-7.44 (m, 2H), 7.15-7.13 (m, 1H), 4.29 (t , J=5.6 Hz, 2H), 3.64-3.56 (m, 4H), 3.24-3.20 (m, 2H), 2.19-2.16 (m, 2H), 1.90-1.86 (m, 2H) ++ ND 40 (R)-N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-3-fluoropyrrolidine-1-sulfonamide 478.1 ¹ H-NMR (400 MHz, CD3OD): δ 8.25 (s, 1H), 7.88 (d, J=9.2 Hz, 1H), 7.71 (d, J=2.4 Hz, 1H), 7.64 -7.61 (m, 2H), 7.38 (t, J=8.4 Hz, 1H), 7.04 (dd, J=8.4, 1.2 Hz, 1H ), 5.24 (dt, J=52.8, 3.6 Hz, 1H), 4.33 (t, J=5.6 Hz, 2H), 3.67 (t, J=5.6 Hz , 2H), 3.61-3.30 (m, 4H), 2.29-1.97 (m, 4H) +++ ND 41 N-(2-chloro-3-((3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-10-yl)oxy)phenyl)-N-ethyl-N-methylamino-1-sulfonamide 448.1 ¹ H-NMR (400 MHz, CD3OD): δ 8.26 (s, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.72 (d, J=2.8 Hz, 1H), 7.65 (dd, J=9.2, 2.8 Hz, 1H), 7.56 (dd, J=8.4, 1.6 Hz, 1H), 7.38 (t, J =8.4Hz, 1H), 7.03(dd, J=8.4, 1.2Hz, 1H), 4.34(t, J=5.6Hz, 2H), 3.68(t , J=5.6Hz, 2H), 3.25(q, J=7.2Hz, 2H), 2.85(s, 3H), 2.31-2.25(m, 2H), 1 .11 (t, J=7.2 Hz, 3H) +++ ND 42 N-(2-cyano-3-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)(methyl)amino)phenyl)propan- 1-sulfonamide 438.1 ¹ H-NMR (400 MHz, CD3OD): δ 8.52 (s, 1H), 7.71 (s, 1H), 7.62 (t, J=8.4 Hz, 1H), 7.52 ( dd, J=8.4, 0.8 Hz, 1H), 7.14 (dd, J=8.0, 0.8 Hz, 1H), 7.09 (s, 1H), 4.06 (t , J=5.6 Hz, 2H), 3.60 (t, J=5.6 Hz, 2H), 3.52 (s, 3H), 3.17-3.13 (m, 2H), 2 .11-2.08 (m, 2H), 1.92-1.87 (m, 2H), 1.05 (t, J=7.2 Hz, 3H) + ND 43 N-(2-cyano-3-((3,4-dihydro-2H-pyrido[4,3-e]pyrimido[1,2-c]pyrimidin-10-yl)amino)phenyl)propane-1-sulfonamide 424.2 ¹ H-NMR (400 MHz, DMSO-d6): δ 10.19 (broad s, 1H), 9.38 (s, 1H), 8.41 (s, 1H), 7.69 (s, 1H ), 7.54-7.53 (m, 2H), 7.49 (s, 1H), 7.12 (dd, J=6.8, 2.4 Hz, 1H), 3.94 (t, J=5.6Hz, 2H), 3.55(t, J=5.6Hz, 2H), 3.15-3.12(m, 2H), 1.96-1.93(m, 2H ), 1.82-1.76 (m, 2H), 0.99 (t, J=7.6 Hz, 3H) ++ ND 44 N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-2-sulfonamide 419.2 ¹ H-NMR (400 MHz, DMSO-d6): δ 9.72 (broad, 1H), 8.09 (s, 1H), 7.58 (d, J=8.8 Hz, 1H), 7 .45-7.37 (m, 3H), 7.27 (s, 1H), 7.08 (d, J=7.6 Hz, 1H), 4.22 (t, J=10.0 Hz, 2H), 3.94 (t, J=10.0 Hz, 2H), 3.38-3.31 (m, 1H), 1.30 (d, J=6.8 Hz, 6H) +++ ND 45 N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-N-ethyl-N-methylamino-1-sulfonamide 434.3 ¹ H-NMR (400 MHz, DMSO-d6): δ 11.45 (br, 1H), 9.55 (s, 1H), 8.66 (s, 1H), 7.98 (d, J= 8.8 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.68 (s, 1H), 7.48-7.46 (m, 2H), 7.15 ( e, J=6.4 Hz, 1H), 4.66 (t, J=10.0 Hz, 2H), 4.12 (t, J=10.0 Hz, 2H), 3.17-3, 12 (m, 2H), 2.76 (s, 3H), 1.03 (t, J=7.2 Hz, 3H) + ND 46 (R)-N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-3-fluoropyrrolidine-1-sulfonamide 464.2 ¹ H-NMR (400 MHz, DMSO-d6): δ 11.39 (s, 1H), 9.71 (s, 1H), 8.67 (s, 1H), 7.98 (d, J=8 .8 Hz, 1H), 7.81 (t, J=9.2, 2.8 Hz, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.54-7.44 (m, 2H), 7.17 (d, J=8.4 Hz, 1H), 5.31 (d, J=54 Hz, 1H), 4.67 (t, J=10.0 Hz, 2H ), 4.12 (t, J=10.0 Hz, 2H), 3.34-3.30 (m, 4H), 2.14-1.97 (m, 2H) +++ ND 47 N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-(2-fluoroethyl)(methyl)amino-1-sulfonamide 452.2 ¹ H-NMR (400 MHz, DMSO-d6): δ 11.61 (broad s, 1H), 9.68 (s, 1H), 8.67 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.79 (dd, J=8.8, 2.8 Hz, 1H), 7.75 (d, J=2.8 Hz, 1H), 7.49-7 .43 (m, 2H), 7.17 (dd, J=7.2, 2.4 Hz, 1H), 4.70-4.65 (m, 2H), 4.51 (dt, J=47 .2, 4.8 Hz, 1H), 4.15-4.10 (m, 2H), 3.41 (dt, J=26.8, 4.8 Hz, 1H), 3.38 (t, J=4.8 Hz, 1H), 2.84 (s, 3H) +++ ND 48 N-(2-chloro-3-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)pyrrolidine-1-sulfonamide 446.1 ¹ H-NMR (400 MHz, CD3OD): δ 8.03 (s, 1H), 7.60-7.56 (m, 2H), 7.42-7.39 (m, 2H), 7.33 (t, J=8.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 4.30 (t, J=10.0 Hz, 2H), 4.04 (t , J=10.0 Hz, 2H), 3.31-3.28 (m, 4H), 1.86-1.83 (m, 4H) +++ ND 49 N-(5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)pyrrolidine-1-sulfonamide 430.3 ¹ H-NMR (400 MHz, DMSO-d6): δ 11.43 (broad, 1H), 9.93 (s, 1H), 8.67 (s, 1H), 7.98 (d, J= 9.2 Hz, 1H), 7.82 (dd, J=8.8, 2.8 Hz, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.39 (t, J=9.2Hz, 1H), 7.20(dd, J=6.8, 2.8Hz, 1H), 7.01-6.98(m, 1H), 4.69(t, J =10.0 Hz, 2H), 4.14 (t, J=10.0 Hz, 2H), 3.17-3.13 (m, 4H), 1.77-1.73 (m, 4H) + ND 50 N-(5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)-N, N-dimethylamino-1-sulfonamide 404.2 ¹ H-NMR (400 MHz, DMSO-d6): δ 11.41 (broad, 1H), 9.97 (s, 1H), 8.67 (s, 1H), 7.98 (d, J= 9.2 Hz, 1H), 7.82 (dd, J=9.2, 2.8 Hz, 1H), 7.76 (d, J=2.8 Hz, 1H), 7.39 (t, J=9.6Hz, 1H), 7.21-7.18(m, 1H), 7.02-6.98(m, 1H), 4.68(t, J=10.0Hz, 2H ), 4.14 (t, J=10.0 Hz, 2H), 2.70 (s, 6H) ND ND 51 N-(5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)propane-1-sulfonamide 403.2 ¹ H-NMR (400 MHz, DMSO-d6): δ 11.49 (br, 1H), 9.96 (s, 1H), 8.68 (s, 1H), 7.98 (d, J= 9.2 Hz, 1H), 7.84 (dd, J=9.2, 2.8 Hz, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.42 (t, J=9.2Hz, 1H), 7.23-7.21(m, 1H), 7.06-7.03(m, 1H), 4.69(t, J=10.0Hz, 2H ), 4.14 (t, J=10.0 Hz, 2H), 3.14 (t, J=7.2 Hz, 2H), 1.75-1.70 (m, 2H), 0.96 (t, J=7.2Hz, 3H) + ND 52 N-(5-((2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)-2-fluorophenyl)propane-2-sulfonamide 403.2 ¹ H-NMR (400 MHz, DMSO-d6): δ 9.83 (broad, 1H), 7.95 (s, 1H), 7.47 (d, J=8.8 Hz, 1H), 7 .35-7.30 (m, 2H), 7.25 (d, J=2.4 Hz, 1H), 7.16-7.14 (m, 1H), 6.94-6.92 (m , 1H), 4.11 (t, J=9.6 Hz, 2H), 3.90 (t, J=10.0 Hz, 2H), 3.32-3.30 (m, 1H), 1 .25 (d, J=6.8 Hz, 6H) ND ND 53 (R)-N-(2-chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)-3-fluoropyrrolidine-1- sulfonamide 492.2 ¹ H-NMR (400 MHz, CD3OD): δ 8.47 (s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.81 (dd, J=8.8, 2 .8 Hz, 1H), 7.66 (dd, J=8.4, 1.2 Hz, 1H), 7.45-7.39 (m, 2H), 7.13-7.09 (m, 1H), 5.25 (dt, J=50.4, 3.6 Hz, 1H), 4.52 (s, 2H), 3.61-3.41 (m, 4H), 2.20-2 .00 (m, 2H), 1.58 (s, 6H) +++ ND 54 N-(2-chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)pyrrolidine-1-sulfonamide 474.4 ¹ H-NMR (400 MHz, CD3OD): δ 7.95 (s, 1H), 7.60-7.54 (m, 2H), 7.39-7.32 (m, 3H), 6.99 (dd, J=8.0, 1.2 Hz, 1H), 3.98 (s, 2H), 3.34-3.28 (m, 4H), 1.86-1.83 (m, 4H ), 1.36 (s, 6H) +++ ND 55 N-(2-chloro-3-((2,2-dimethyl-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propane-1-sulfonamide 447.2 ¹ H-NMR (400 MHz, DMSO-d6): δ 11.57 (br s, 1H), 9.70 (s, 1H), 8.64 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.86 (dd, J=9.2, 2.8 Hz, 1H), 7.59 (d, J=2.8 Hz, 1H), 7.50-7 .48 (m, 2H), 7.23 (t, J=4.8 Hz, 1H), 4.44 (s, 2H), 3.19-3.15 (m, 2H), 1.80- 1.72 (m, 2H), 1.52 (s, 6H), 0.97 (t, J=7.2 Hz, 3H) +++ ND 56 N-(2-chloro-3-((3-((dimethylamino)methyl)-2,3-dihydroimidazo[1,2-c]quinazolin-9-yl)oxy)phenyl)propan-1-sulfonamide 476.2 ¹ H-NMR (400 MHz, CD3OD): δ 7.97 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.42-7.36 (m, 2H), 7.33 (t, J=8.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 4, 50-4.46 (m, 1H), 4.37-4.33 (m, 1H), 4.04-3.99 (m, 1H), 3.15 (t, J=7.6 Hz, 2H), 2.71-2.68 (m, 2H), 2.45 (s, 6H), 1.88-1.83 (m, 2H), 1.03 (t, J=7.6 Hz , 3H) ND ND

+++: <100 nM; ++: 100-1000 nM; +: >1000 nM; ND: not determined

Biological example B2

Permeability analysis method with MDCK-MDR1

[0262] MDCK-MDR1 cells are obtained by transfection of Madin-Darby dog kidney cells (MDCK) with the MDR1 gene encoding the efflux protein, P-glycoprotein. This cell line is ideal for detecting P-gp substrates in the presence or absence of an inhibitor. Cells were seeded into a Multiscreen™ plate until a confluent monolayer was obtained 4 days before the experiment. On the 4th day, the test compound (concentration 1-30 μM) was added to the apical side of the membrane and the transport of the compound across the monolayer was monitored for a period of 120 minutes. To study drug efflux, it is also necessary to study the transport of the compound from the basolateral compartment to the apical compartment and calculate the degree of elimination.

[0263] The permeability coefficient (P _app ) is calculated according to the following equation:

P _app =[(dQ/dt)/C ₀ ×A]

where dQ/dt is the cell penetration rate of the drug, C ₀ is the concentration in the donor compartment at time zero, and A is the area of the cell monolayer.

[0264] The degree of efflux is calculated from the mean P _app transport from the apical to the basolateral compartment (AB) and the P _app transport from the basolateral to the apical compartment (BA).

Degree of excretion=P _app (BA)/P _app (AB)

[0265] Table B summarizes the permeability of selected compounds in the MDCK-MDR1 assay.

Table B.

Connection No. P _app (AB) P _app (B.A.) Degree of excretion 1 3.65 23.83 6.53 2 19.01 50.01 2.63 3 2.15 21.18 9.85 5 1.21 2.19 1.82 6 26.30 37.25 1.42 9 17.59 43.36 2.47 eleven 34.64 42.34 1.22 12 6.60 28.37 4.30 14 3.03 8.29 2.73 15 3.10 5.36 1.73 16 1.01 8.89 8.79 17 0.70 9.28 13.21 21 24.10 40.54 1.68 26 3.95 19.63 4.98 46 20.79 57.91 2.79

Biological example B3

Permeability analysis method with Caco-2

[0266] Caco-2 cells are widely used as an in vitro assay method for measuring drug permeability. The Caco-2 cell line is derived from human colorectal carcinoma and upon cultivation the cells spontaneously differentiate into monolayers of polarized enterocytes. Caco-2 cells express P-glycoprotein and breast cancer resistance protein, two of the most important active cell membrane transporters that affect drug permeability into cells or across the blood-brain barrier.

[0267] Cells were seeded in Millipore Millicell plates to obtain a fused monolayer 20 days before the experiment. On the 20th day, the test compound (concentration 1-30 μM) was added to the apical side of the membrane and the transport of the compound across the monolayer was monitored for a period of 120 minutes. To study drug efflux, it is also necessary to study the transport of the compound from the basolateral compartment to the apical compartment.

[0268] The permeability coefficient (P _app ) is calculated according to the following equation:

P _app =[(dQ/dt)/C ₀ ×A]

where dQ/dt is the cell penetration rate of the drug, C ₀ is the concentration in the donor compartment at time zero, and A is the area of the cell monolayer. C ₀ is obtained by analyzing the dosing solution at the beginning of the experiment.

[0269] The permeability of selected compounds in the Caco-2 assay is summarized in Table C.

Table C.

Connection No. P _app (AB) P _app (B.A.) Degree of excretion 1 6.42 18.71 2.92 3 9.24 13.71 1.48 6 43.49 13.51 0.31 14 6.37 17.66 2.77 15 5.08 14.93 2.94 18 11.32 24.85 2.20 21 52.89 19.24 0.36

Biological example B4

Pharmacokinetic study in mice

[0270] The pharmacokinetic properties of selected compounds were studied in CD-1 mice when administered intravenously or orally using a standard protocol. The test samples were prepared in 20% hydroxypropyl-beta-cyclodextrin as a pure solution or as a fine suspension. Table D presents the pharmacokinetic characteristics of the selected compounds when injected intravenously in mice.

Table D

Comm. No. IV dose (mg/kg) t _1/2 (h) Cl _p (ml/min kg) _Vd (l/kg) 1 2.5 1.47±0.19 2.77±0.52 0.348±0.037 6 2.5 0.467±0.012 30.3±4.64 1.22±0.16 21 2.5 1.21±0.10 9.03±1.31 0.948±0.166

[0271] Table E shows the plasma levels of selected compounds when administered orally to mice.

Table E.

Comm.
No. po dose (mg/kg) _Cmax (ng/ml) T _max (h) AUC (ng/ml h) F(%) 1 thirty 37267±6243 1.00±0.00 206509±25861 112±14 6 25 4217±1351 0.250±0.00 8221±3003 58.9±21.5 21 25 11720±2378 0.500±0.000 53845±5207 113±11.1

Biological example B5

In vivo pharmacodynamic study

[0272] The in vivo activity of compounds of formula (I) can be determined by the degree of inhibition of tumor growth by a test compound compared to a control. The tumor growth inhibitory effects of various compounds were measured according to the method of Corbett TH, et al., "Tumor Induction Relationships in Development of Transplantable Cancers of the Colon in Mice for Chemotherapy Assays, with a Note on Carcinogen Structure", Cancer Res., 35, 2434-2439 (1975) and Corbett TH, et al., "A Mouse Colon-tumor Model for Experimental Therapy", Cancer Chemother. Rep. (Part 2)", 5, 169-186 (1975), with minor modifications. Tumors were induced in the left lateral surface by subcutaneous injection of 1-5 million cultured tumor cells in the logarithmic growth phase (human melanoma A375 cells or HT-29 cells human colorectal cancer) suspended in 0.1 ml of RPMI 1640 medium. After sufficient time for the tumors to become palpable (100-150 ^mm3 in size/5-6 mm in diameter), test animals (female BALB mice /c nude) were treated with the test compound (prepared in hydroxypropyl-beta-cyclodextrin at a concentration of 10 to 15 mg/ml) by oral administration once or twice a day.To determine the antitumor effect, the tumor was measured in millimeters using a caliper in the form of two transverse diameters, and the tumor size (mm ³ ) was calculated using the formula: Tumor size (mm ³ )=(length × width ² )/2, according to the methods of Geran, RI, et al. "Protocols for Screening Chemical Agents and Natural Products Against Animal Tumors and Other Biological Systems", Third Edition, Cancer Chemother. Rep., 3, 1-104 (1972). The results were expressed as percent inhibition according to the formula: Inhibition (%) = (TuW _control - TuW _test )/TuW _control × 100%. On the lateral surface with a tumor implant for a variety of chemotherapeutic agents, reproducible dose-dependent effects were obtained, and the method of measurement (tumor diameter) is a reliable method for assessing the degree of tumor growth.

[0273] Administration of the compounds of the present invention (hereinafter referred to as "active compound(s)") may be by any method that delivers the compounds to the site of action. Such methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular injection or infusion), topical and rectal administration.

[0274] The pharmaceutical composition may be in a form suitable for oral administration, for example, as a tablet, capsule, pill, powder, sustained release dosage forms, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream, or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage form suitable for single administration of a specific dosage. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound of the present invention as an active ingredient. In addition, it may include other medical or pharmaceutical agents, carriers, adjuvants, and the like.

[0275] The examples and preparations below further illustrate and exemplify the compounds of the present invention and methods for preparing such compounds. It should be understood that the scope of the present invention is in no way limited by the scope of the following examples and preparations. Unless otherwise indicated, in the following examples, molecules with a single chiral center exist as a racemic mixture. Unless otherwise indicated, molecules with two or more chiral centers exist as a racemic mixture of diastereoisomers. The individual enantiomers/diastereoisomers can be prepared by methods known to those skilled in the art.

Illustrative Embodiments

[0276] 1. A cyclic iminopyrimidine derivative of formula Ia

Ia

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein:

each X ₁ , X ₂ and X ₃ is independently N or CR ^a ;

each Y ₁ , Y ₂ and Y ₃ is independently N or CR ^b ;

Z ₁ is O, S, NR ^c or CR ^d R ^e ;

Z ₂ is a bond or NR ^f ;

m is 0, 1, 2 or 3;

n is 1, 2 or 3;

R ₁ is hydrogen, C ₁ -C ₆ alkyl which is optionally substituted with halogen, OH, C ₁ -C ₆ alkoxy or C ₁ -C ₆ dialkylamino;

R ₂ is hydrogen, cyano, nitro, halogen, CF ₃ , MeSO ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ dialkylamino;

R ₃ is C ₁ -C ₆ alkyl or aryl or heteroaryl, each optionally substituted with 1-3 halo or C ₁ -C ₆ alkyl;

R ^a and R ^b are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ dialkylamino;

R ^c is hydrogen or C ₁ -C ₆ alkyl;

each R ^d , R ^e and R ^f is independently selected from hydrogen and C ₁ -C ₆ alkyl.

[0277] 2. The cyclic iminopyrimidine derivative of formula Ia described in Embodiment 1 selected from the structures below

.

[0278] 3. The cyclic iminopyrimidine derivative of formula Ia described in Embodiment 1, selected from the structure below

.

[0279] 4. The cyclic iminopyrimidine derivative of formula Ia described in Embodiment 1 selected from the structure below

.

[0280] 5. The cyclic iminopyrimidine derivative of formula Ia described in Embodiment 1, selected from the structure below

.

[0281] 6. The cyclic iminopyrimidine derivative of formula Ia described in Embodiment 1, selected from the structure below

.

[0282] 7. Other specific embodiments of compounds of formula Ia include compounds where Z ₁ is O.

[0283] 8. Other specific embodiments of compounds of formula Ia include compounds where Z ₂ is a bond.

[0284] 9. Other specific embodiments of compounds of formula Ia include compounds where m=0.

[0285] 10. Other specific embodiments of compounds of formula Ia include compounds where n=1.

[0286] 11. Other specific embodiments of compounds of formula Ia include compounds where n=2.

[0287] 12. Other specific embodiments of compounds of formula Ia include compounds where R ₁ =H.

[0288] 13. Other specific embodiments of compounds of formula Ia include compounds where R ₂ is CN.

[0289] 14. Other specific embodiments of compounds of formula Ia include compounds where R ₂ is Cl.

[0290] 15. Other specific embodiments of compounds of formula Ia include compounds where R ₃ is 2-FPh.

[0291] 16. Other specific embodiments of compounds of formula Ia include compounds where R ₃ is propyl.

[0292] 17. Other specific embodiments of compounds of formula Ia include compounds wherein R ₃ is thiophenyl.

[0293] 18. Other specific embodiments of compounds of formula Ia include compounds where R ^a is H. Other specific embodiments of compounds of formula Ia include compounds where R ^b is H.

[0294] 19. Other specific embodiments of compounds of formula Ia include compounds where R ^a is F. Other specific embodiments of compounds of formula Ia include compounds where R ^b is F.

[0295] 20. A method of inducing an inhibitory effect on B-Raf V600E kinase enzymes in a mammal, which comprises administering to said animal an effective amount of a cyclic iminopyrimidine derivative of Formula Ia, or a pharmaceutically acceptable salt thereof, as described in any of Embodiments 1-19.

[0296] 21. A pharmaceutical composition that comprises a cyclic iminopyrimidine derivative of Formula Ia or a pharmaceutically acceptable salt thereof as described in any of Embodiments 1-19, together with a pharmaceutically acceptable diluent or carrier.

[0297] 22. A method of inducing an antitumor effect in a mammal in need of such treatment, which comprises administering to said animal an effective amount of a cyclic iminopyrimidine derivative of Formula Ia, or a pharmaceutically acceptable salt thereof, described in any of Embodiments 1-19.

[0298] 23. A method of inducing an anti-neurodegenerative effect in a mammal in need of such treatment, which comprises administering to said animal an effective amount of a cyclic iminopyrimidine derivative of Formula Ia or a pharmaceutically acceptable salt thereof, as described in any of Embodiments 1-19.

[0299] 24. A method of obtaining an antiproliferative effect in a mammal with a cancer that is susceptible to inhibition of B-Raf V600E kinase enzymes, which comprises administering to said animal an effective amount of a cyclic iminopyrimidine derivative of Formula Ia or a pharmaceutically acceptable salt thereof, as described in any of embodiments 1-19.

Claims (89)

1. Compound of formula (I): (I) or its stereoisomer, where: each X ₁ and X ₃ is independently CR ^a ; X ₂ is N or CR ^a ; each Y ₁ and Y ₃ is independently N or CR ^b ; Y ₂ is CR ^b ; Z ₁ is O or NR ^c ; Z ₂ is a bond or NR ^f ; m is 0, 1 or 2; n is 1, 2 or 3; R ₁ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl substituted with -NR ^h R ⁱ ; R ₂ is selected from the group consisting of hydrogen, halogen, CN, NO ₂ and CF ₃ ; R ₃ is C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyl substituted with halogen; C ₁ -C ₆ alkyl substituted with OH; heterocyclyl containing from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen; a heterocylyl substituted with halogen, wherein the heterocyclyl contains from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen; aryl substituted with halogen, where aryl contains from 6 to 14 ring carbon atoms; and heteroaryl containing from 1 to 10 ring carbon atoms and at least one ring heteroatom selected from the group consisting of nitrogen, sulfur and oxygen; R ₄ is hydrogen or C ₁ -C ₆ alkyl; R ^a is H; R ^b is H, halogen, -NH ₂ or -NO ₂ ; R ^c represents H or C ₁ -C ₆ alkyl; And each of R ^f , R ^h and R ⁱ independently represents C ₁ -C ₆ alkyl. 2. The compound according to claim 1, where the compound has the formula (I-2b): (I-2b) where the values of Y ₁ , Y ₂ , Y ₃ , Z ₁ , Z ₂ , R ₁ , R ₂ , R ₃ , m, n and R ^a are defined for formula (I). 3. The compound according to claim 1, where the compound has the formula (I-2d) or (I-2f): (I-2d) (I-2f) where the values of X ₁ , X ₂ , X ₃ , Z ₁ , Z ₂ , R ₁ , R ₂ , R ₃ , m, n and R ^b are defined for formula (I). 4. The compound according to claim 1, where the compound has the formula (I-3a) or (I-3b): (I-3a) (I-3b) where the values of Z ₁ , Z ₂ , R ₁ , R ₂ , R ₃ , m and R ^a are defined for formula (I). 5. The compound according to claim 1, where the compound has the formula (I-4a), (I-4b) or (I-4c): (I-4a) (I-4b) (I-4c), where the values of Z ₁ , Z ₂ , R ₁ , R ₂ , R ₃ , m, n and R ^a are defined for formula (I). 6. The compound according to claim 1, where the compound has the formula (I-5a) or (I-5b): (I-5a) (I-5b) where the values of Z ₁ , R ₁ , R ₂ , R ₃ , m and R ^a are defined for formula (I). 7. Connection according to any one of paragraphs. 1-6 where Z ₁ is O. 8. Connection according to any one of paragraphs. 1-5 and 7, where Z ₂ is a bond. 9. Connection according to any one of paragraphs. 1-3, 5 and 7-8 where n is 1. 10. Connection according to any one of paragraphs. 1-3, 5 and 7-8 where n is 2. 11. The connection according to any one of paragraphs. 1-10 where m is 1. 12. Connection according to any one of paragraphs. 1-10 where m is 2. 13. Connection according to any one of paragraphs. 1-10 where m is 0. 14. Connection according to any one of paragraphs. 1-12, where R ₁ represents -C ₁ -C ₆ alkyl. 15. Connection according to any one of paragraphs. 1-12, where R ₁ is C ₁ -C ₆ alkyl substituted with -NR ^h R ⁱ , where R ^h and R ⁱ are C ₁ -C ₆ alkyl. 16. Connection according to any one of paragraphs. 1-15, where R ₂ represents hydrogen. 17. Connection according to any one of paragraphs. 1-16 where R ₂ is nitro. 18. Connection according to any one of paragraphs. 1-15, where R ₂ represents -CN. 19. Connection according to any one of paragraphs. 1-15, where R ₂ represents Cl. 20. Connection according to any one of paragraphs. 1-15, where R ₂ represents -CF ₃ . 21. Connection according to any one of paragraphs. 1-20, where R ₃ is C ₁ -C ₆ alkyl, aryl substituted with halogen, where aryl contains from 6 to 14 ring carbon atoms, or heteroaryl containing from 1 to 10 ring carbon atoms and at least one ring heteroatom, selected from the group consisting of nitrogen, sulfur and oxygen. 22. Connection according to any one of paragraphs. 1-20, where R ₃ is 2-fluorophenyl. 23. Connection according to any one of paragraphs. 1-20, where R ₃ is pyrrolidinyl. 24. Connection according to any one of paragraphs. 1-20, where R ₃ is 3-fluoropyrrolidinyl. 25. Connection according to any one of paragraphs. 1-20, where R ₃ represents propyl. 26. Connection according to any one of paragraphs. 1-20, where R ₃ represents thiophenyl. 27. Connection according to any one of paragraphs. 1-20, where R ₃ is C ₁ -C ₆ alkyl substituted with halogen or -OH. 28. A compound according to claim 27 wherein R ₃ is 3-fluoropropyl or 3-hydroxypropyl. 29. Connection according to any one of paragraphs. 1-20, where R ₃ is a heterocyclyl containing from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, or a heterocyclyl substituted with halogen, where the heterocyclyl contains from 1 up to 10 ring carbon atoms; and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen. 30. Connection according to any one of paragraphs. 1-20, where R ₃ is aryl substituted with halogen, where aryl contains from 6 to 14 ring carbon atoms, or heteroaryl, comprising from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen. 31. Connection according to any one of paragraphs. 1-3 and 7-30 where R ^b is H. 32. Connection according to any one of paragraphs. 1-3 and 7-31, where R ^b represents -NH ₂ or -NO ₂ . 33. Connection according to any one of paragraphs. 1-3 and 7-32, where R ^b is halogen. 34. Connection according to any one of paragraphs. 1-3 and 7-32, where R ^b is F. 35. A compound selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And . 36. A compound selected from the group consisting of: , , , , , , , , , , , And . 37. The compound according to claim 1, which is . 38. The compound according to claim 1, which is . 39. The compound according to claim 1, which is . 40. The compound according to claim 1, which is . 41. The compound according to claim 1, which is . 42. The compound according to claim 1, which is . 43. The use of a compound according to any one of paragraphs. 1-42 for the treatment of a proliferation disorder, cancer, or tumor susceptible to B-Raf V600E kinase inhibition in a subject. 44. Use according to claim 43, where the proliferation disorder or cancer is selected from the group consisting of malignant or benign tumors of the liver, kidney, bladder, breast, stomach, ovary, colorectal tumors, tumors of the prostate, pancreas, lung, vulva , thyroid, liver carcinomas, sarcomas, glioblastomas, head and neck tumors, melanoma and other hyperplastic skin conditions, benign prostatic hyperplasia and brain metastases resulting from these diseases. 45. The use of a compound according to any one of claims 1 to 42 for obtaining an antiproliferative effect in a subject with a proliferation disorder, a malignant tumor, or a tumor that is susceptible to inhibition of B-Raf V600E kinase. 46. The use of a compound according to any one of claims 1-42 for the treatment of a neurodegenerative disease susceptible to inhibition of B-Raf V600E kinase in a subject. 47. Use according to claim 46 wherein the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease and Huntington's disease. 48. The use of a compound according to any one of claims 1 to 42 for inhibiting the activity of B-Raf V600E kinase in a cell, where the cell is brought into contact with a compound according to any one of claims. 1-42 in vitro , ex vivo , or in vivo .