HETEROCYCLIC COMPOUNDS AS AXL INHIBITORS

Abstract

Compounds of Formula I and their uses of effective AXL inhibitors and for the treatment of physical condition mediated by AXL.

##STR00001##

Claims

1. A compound of Formula I ##STR00025## or a pharmaceutically acceptable salt thereof, wherein: A is a 5- or 6-membered aryl or heteroaryl, and is optionally substituted with one or more R.sub.4 groups; p is 0, 1, or 2; k is 0 or 1; each of m and n independently is 0, 1, 2, or 3, and the sum of m and n is less than 4; X is CHR.sub.5 or NR.sub.6; R.sub.1 is hydrogen, aryl, heteroaryl, cycloalkyl, or heterocyclyl, and is optionally substituted with 1 to 4 R.sub.a groups; each of R.sub.2 and R.sub.3 independently is halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyl, hydroxylalkyl, alkoxy, alkenyloxy, alkynyloxy, carbonyl, carboxyl, cyano, amino, nitrile, sulfonyl, sulfinyl, sulfhydryl, aryl, cycloalkyl, heteroaryl, or heterocyclyl; each optional R.sub.4 group independently is halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyl, hydroxylalkyl, alkoxy, alkenyloxy, alkynyloxy, carbonyl, carboxyl, cyano, amino, nitrile, sulfonyl, sulfinyl, sulfhydryl, aryl, cycloalkyl, heteroaryl, or heterocyclyl; R.sub.5 is hydrogen, amine, alkylamine, cyclic amine, heterocyclyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, nitrile, sulfonyl, sulfinyl, sulfhydryl, halogen, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, alkenyloxy, alkynyloxy, carbonyl, or carboxyl; R.sub.6 is hydrogen, alkyl, alkenyl, cycloalkyl, alkynyl, aryl, CN, heteroaryl, or heterocyclyl; each optional R.sub.a group independently is halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyloxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylamino, amino carbonyl, acyl, carbonyl, carboxyl, amino, cyano, cyanato, nitrile, sulfonyl, sulfinyl, or sulfhydryl.

2. The compound of claim 1, wherein A is a 6- or 5-membered heteroaryl having 1 to 3 heteroatoms each of which independently is O, S, or N, and A is optionally substituted with 1 to 3 R.sub.4 groups.

3. The compound of claim 1, wherein A is ##STR00026##

4. The compound of claim 3, wherein A is ##STR00027##

5. The compound of claim 1, wherein R.sub.1 is aryl or heteroaryl and is optionally substituted with 1 to 4 R.sub.a groups.

6. The compound of claim 5, wherein R.sub.1 is ##STR00028##

7. The compound of claim 1, wherein each R.sub.a independently is halogen, alkyl, aryl, heteroaryl, cycloalkyl, alkoxy, cycloalkyloxy, aryloxy, amino carbonyl, cyano, cyanato, amino, or hydroxyl.

8. The compound of claim 7, wherein R.sub.a is isopropoxy, optionally substituted phenyl, or optionally substituted phenoxy.

9. The compound of claim 1, wherein R.sub.5 is ##STR00029## each of R.sub.7 and R.sub.8 independently is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, cyano, alkoxy, hydroxyl, carbonyl, carboxyl, or hydroxylalkyl; or R.sub.7 and R.sub.8, together with the nitrogen atom to which they are attached, form a 4- to 8-membered heterocyclyl or heteroaryl.

10. The compound of claim 9, wherein R.sub.5 is ##STR00030##

11. The compound of claim 1, wherein R.sub.6 is alkyl or cycloalkyl.

12. The compound of claim 1, wherein m is 1 and n is 1.

13. The compound of claim 1, wherein the compound is of Formula II: ##STR00031##

14. The compound of claim 13, wherein k is 0; P is 0; R.sub.1 is ##STR00032## W is CR.sub.b, CH, or N; each of R.sub.a and R.sub.b independently is halogen, alkyl, aryl, heteroaryl, cycloalkyl, alkoxy, cycloalkyloxy, aryloxy, amino carbonyl, cyano, cyanato, amino, or hydroxyl.

15. The compound of claim 14, wherein W is CR.sub.b, CH, or N; R.sub.b is halogen or lower alkyl; and each R.sub.a independently is halogen, aryl, heteroaryl, alkoxy, cycloalkyloxy, or aryloxy.

16. The compound of claim 15, wherein R.sub.a is isopropoxy, optionally substituted phenyl, or optionally substituted phenoxy.

17. The compound of any of claim 13, wherein X is CHR.sub.5 or NR.sub.6; R.sub.5 is ##STR00033## each of R.sub.7 and R.sub.8 independently is hydrogen or alkyl; or R.sub.7 and R.sub.8, together with the nitrogen atom to which they are attached, form a 4- to 8-membered heterocyclyl or heteroaryl; and R.sub.6 is alkyl or cycloalkyl.

18. The compound of claim 17, wherein R.sub.5 is ##STR00034##

19. The compound of claim 1, wherein the compound is 7-(2-isopropoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine; 7-(3-isopropoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine; 7-(4-isopropoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine; 7-(2-phenoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine; 7-(2-(cyclohexyloxy)phenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine; N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7-(2-(o-tolyloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine; N-isopropyl-2-(2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzamide; 7-(4-chloro-2-isopropoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine; 7-(2-isopropoxy-4-methoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine; 7-(3-isopropoxy-[1,1-biphenyl]-4-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine; 7-([1,1-biphenyl]-4-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine; 7-(2-methyl-[1,1-biphenyl]-4-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine; 7-(3-isopropoxypyridin-2-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine; or N-(7-(2-isopropoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine.

20. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. The composition of claim 20, further comprising an additional therapeutic agent selected from the group consisting of a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, an agent for treating a neurological disorder, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, and an agent for treating immunodeficiency disorders.

22. A method of treating a disease, disorder, or condition mediated by AXL, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

23. The method of claim 22, wherein the disease, disorder, or condition is cancer, asthma, chronic bronchitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, infant respiratory distress syndrome, cough, chronic obstructive pulmonary, adult respiratory distress syndrome, ulcerative colitis, Crohn's disease, hypersecretion of gastric acid, bacterial-, fungal-, or viral-induced sepsis or septic shock, endotoxic shock, spinal cord trauma, head injury, neurogenic inflammation, pain, reperfusion injury of the brain, psoriatic arthritis, rheumatoid arthritis, alkylosing spondylitis, osteoarthritis, inflammation, cytokine-mediated chronic tissue degeneration, thrombosis and the complications associated with thrombosis, macular degeneration, cataracts, diabetic retinopathy, glomerulonephritis, diabetic nephropathy, or renal plant rejection.

24. The method of claim 23, wherein the disease, disorder, or condition is a cancer.

25. The method of claim 24, wherein the cancer is lung cancer, myeloid leukemia, astrocytoma, uterine cancer, ovarian cancer, colorectal carcinoma, esophageal adenocarcinoma, glioblastoma, melanoma, prostate cancer, breast cancer, osteosarcoma, renal cell carcinoma, thyroid cancer, gastrointestinal stromal tumors, gastric cancer, hepatocellular carcinoma, kaposi sarcoma, pancreatic ductal adenocarcinoma, prostate cancer, or endometrial cancer.

26. (canceled)

27. (canceled)

28. (canceled)

29. (canceled)

Description

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0054] As use herein, unless clearly indicated otherwise, use of the terms a, an and the like refers to one or more.

[0055] Reference to about a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to about X includes description of X.

[0056] As used herein, the word or has the meaning of both or and and and is equivalent to and/orunless otherwise specifically limited to just or.

[0057] As used herein, the term halo or halogen, by itself or as part of another substituent (e.g, haloalkyl), refers to and includes fluoro, chloro, bromo, or iodo.

[0058] As used herein, the term alkyl, by itself or as part of another substituent (which usually takes the short form of alk, e.g., alkoxy), refers to and includes saturated linear (i.e. unbranched) or branched hydrocarbon radicals, having the number of carbon atoms designated (e.g., C.sub.1-10 means one to ten carbons). Particular alkyl groups include those having 1 to 10 carbon atoms (a C.sub.1-10 alkyl). More particular alkyl groups are those having 1 to 6 carbon atoms (a C.sub.1-6 alkyl), 1 to 4 carbon atoms (a C.sub.1-4 alkyl), 1 to 3 carbon atoms (a C.sub.1-3 alkyl) or 1 to 2 carbon atoms (a C.sub.1-2 alkyl). Examples of C.sub.1-10 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. An alkyl group can be optionally substituted with such substituents as halogen, cyano, amino, hydroxyl etc. As used herein, the term lower alkyl refers to alkyl of 1 to 6 carbon atoms which are optionally substituted with one or more appropriate substituents such as halogen, amino, cyano, or hydroxyl.

[0059] As used herein, the term alkenyl, by itself or as part of another substituent, refers to and includes unsaturated linear (i.e. unbranched) or branched hydrocarbon radicals containing at least one carbon-carbon double bond, having the number of carbon atoms designated (e.g., C.sub.2-10 means two to ten carbons). Particular alkenyl groups are those having 2 to 10 carbon atoms (i.e., a C.sub.2-10 alkenyl). More particular alkenyl groups are those having 2 to 8 carbon atoms (a C.sub.2-8 alkenyl) or 2 to 6 carbon atoms (a C.sub.2-6 alkenyl). Examples of C.sub.2-10 alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,2-dimethyl-1-propenyl, and 1,2-dimethyl-2-propenyl. As used herein, the term lower alkenyl refers to alkenyl of 1 to 6 carbon atoms which are optionally substituted with one or more appropriate substituents such as halogen, amino, cyano, or hydroxyl.

[0060] As used herein, the term aminocarbonyl refers to NRRC(O) wherein each of R and R independently can be hydrogen, lower (e.g., C.sub.1-6) alkyl or alkenyl which may be optionally substituted with halogen or cyano.

[0061] As used herein, the term heteroatom refers to S, O or N in a ring which can be saturated, unsaturated, or aromatic. The N heteroatom can be optionally subtitled with alkyl or alkenyl.

[0062] As used herein, the term cycloalkyl or cyclyl, by itself or as part of another substituent (e.g., cycloalkyloxy), refers to and includes saturated monocyclic hydrocarbon radicals, having the number of carbon atoms designated (e.g., C.sub.3-10 means three to ten carbons). Particular examples of cycloalkyl or cyclyl groups include those having 3 to 10 carbon atoms (a C.sub.3-10 cycloalkyl). More particular cycloalkyl groups include those having 3 to 8 carbon atoms (a C.sub.3-8 cycloalkyl), 3 to 6 carbon atoms (a C.sub.3-6 cycloalkyl) or 4 to 5 carbon atoms (a C.sub.4-5 cycloalkyl). Examples of C.sub.3-10 cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like.

[0063] As used herein, the term alkoxy refers to an alkyl group linked by an oxygen atom (i.e., O-alkyl), wherein alkyl is as defined above. Specific examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclohexyloxy, and cyclopentyloxy. An alkoxy group can be optionally substituted with one or more appropriate substituents such as halogen, amino, cyano, or hydroxyl.

[0064] As used herein, the term aryl or aryl group, by itself or as part of another substituent (e.g., aryloxy), refers to and includes monocyclic or polycyclic aromatic hydrocarbon radicals, having the number of annular carbon atoms designated (e.g., C.sub.6-14 means six to fourteen carbons). Particular aryl groups are those having 6 to 14 annular carbon atoms (a C.sub.6-14 aryl). Examples of C.sub.6-14 aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like. In some embodiments, an aryl may contain a single ring (e.g., phenyl). In some embodiments, an aryl may contain multiple (e.g., two or three) rings. In some embodiments, an aryl may contain multiple condensed rings where at least one of the condensed rings is aromatic (e.g., 1,2,3,4-tetrahydronaphthyl and naphthyl).

[0065] As used herein, a combined term such as arylalkyl denotes a group including aryl and alkyl wherein aryl is a substituent on alkyl.

[0066] As used herein, the term heterocyclyl or heterocycle, by itself or as part of another substituent (e.g., heterocyclyloxy), refers to monocyclic or bicyclic radicals which may be fully saturated, partially saturated, or fully unsaturated or aromatic, having the number of annular carbon atoms designated (e.g., C.sub.3-10 means three to ten annular carbon atoms) and containing at least one or more of the same or different heteroatoms selected from N, S or O, provided that at least one annular carbon atom is present and two annular oxygen atoms, if present, do not occupy directly neighboring positions. A heterocyclyl or heterocycle may be a 3 to 15-membered saturated or partially unsaturated ring containing 1 to 4 heteroatoms selected from O, S and N, where the ring may be monocyclic, bicyclic or tricyclic, contain at least one annular carbon atom and 1 to 3 nitrogen atoms, and/or 1 oxygen or sulfur atom or 1 or 2 oxygen and/or sulfur atoms; provided that when more than one annular oxygen atoms are present, they do not occupy directly neighboring positions. Examples of heterocyclyl or heterocycle include, but are not limited to, 2-oxiranyl, 2-aziridinyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolinyl, 4-isoxazolinyl, 5-isoxazolinyl, 3-isothiazolinyl, 4-isothiazolinyl, 5-isothiazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 2-oxazolinyl, 4-oxazolinyl, 5-oxazolinyl, 2-thiazolinyl, 4-thiazolinyl, 5-thiazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-triazol-2-yl, 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,4-dihydrofuran-2-yl, 2,4-dihydrofuran-3-yl, 2,3-dihydrothiophen-2-yl, 2,3-dihydrothiophen-3-yl, 2,4-dihydrothiophen-2-yl, 2,4-dihydrothiophen-3-yl, 2-pyrrolin-2-yl.

[0067] As used herein, the term heteroaryl, by itself or as part of another substituent (e.g., heteroaryloxy), refers to aromatic heterocyclyl or heterocycle as defined herein. Examples of heteroaryl include, but are not limited to, 2-furanyl, 3-furanyl, thiophen-2-yl, thiophen-3-yl, IH-pyrrol-2-yl, IH-pyrrol-3-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl.

[0068] As used herein, the term hydroxyalkyl refers to alkyl group with at least one hydroxyl substituents.

[0069] As used herein, the term amine or amino refers to any compound carrying at least one amino group, including primary amine (i.e., NH.sub.2), secondary amine (i.e., NHR), tertiary amine (i.e., NRR), as well as cyclic amines, wherein each of R and R independently is a non-hydrogen substituent such as optionally substituted aryl, heteroaryl, or lower (e.g., C.sub.1-6) alkyl defined above. Examples of cyclic amines include, but are not limited to, pyrrolidine, piperidine, 1-azacycloheptane, morpholine, and piperazine.

[0070] As used herein, the term substituted whether preceded by the term optionally or not, refers to replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any even structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different in every position. A ring substituent, such as heterocycloalkyl, can be bound to another ring, such as a cycloalkyl to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one or ordinary skill in the rat will recognize, combinations of substituents envisioned by this disclosure are those combinations that result in the formation of stable or chemically feasible compounds. For convenience and as commonly understood, the term optionally substituted is used interchangeably with the phrase substituted or unsubstituted and only applies to the chemical entities that can be substituted with. As describe herein, when the term optionally substituted precedes a list, this term refers to all of the subsequent substitutable group sin that list.

[0071] As used herein, the term therapeutically effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0072] As used herein, the term treatment or treating refers to the treatment of a mammal afflicted with a pathological condition and refers to an effect that alleviates the condition, e.g., by killing the cancerous cells, but also to an effect that results in the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition.

[0073] As used herein, the term pharmaceutically acceptable pertains to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, excipient, etc. must also be acceptable in the sense of being compatible with the other ingredients of the formulation.

[0074] As used herein, the term pharmaceutically acceptable saltunless otherwise specifiedrefers to salts which are suitable for use in contact with the tissues of a subject (e.g., human) without excessive adverse effect. In some embodiments, pharmaceutically acceptable salts include salts of a compound of the invention having an acidic group (e.g., potassium salts, sodium salts, magnesium salts, calcium salts) or a basic group (e.g., sulfate, hydrochloride, phosphate, nitrate, carbonate).

[0075] As used herein, the term patient refers to a mammal which include humans and non-human mammals such as cows.

[0076] Unless specifically otherwise defined, all the terms used herein have their common meanings as known to a skilled person in the art.

Synthesis of Compounds

[0077] Set forth below are some exemplary schemes of methods that have been used or can be used for synthesizing the compounds of this invention:

##STR00011##

[0078] In Scheme A, compound I and Compound II react under an acidic condition to give rise to coupled Compound III which is then treated with Compound IV in the presence of CuI to give Compound V of the invention.

##STR00012##

[0079] In Scheme B, compound I reacts with compound VI in the presence of an acid (e.g., hydrochloric acid) and alcohol to give rise to compound VII, which then reacts with compound VIII in the presence of a catalyst (e.g., CuI) to provide compound 6.

##STR00013## ##STR00014##

[0080] In Scheme C, compound IX reacts with a reducing agent (e.g., LiAlH.sub.4) in an organic solvent (e.g., tetrahydrofuran) to give rise to compound X, which then reacts with MsCl in an organic solvent (e.g., dichloromethane) in the presence of a base (e.g., triethylamine) to provide compound XI. Compound XI reacts with ammonia in the present of CH.sub.3CN to provide compound XII, which then reacts with HNO.sub.3 in the presence of an acid to give compound XIII. Compound XIII then reacts with HCHO in the presence of an acid to provide compound XIV, which in turn is converted to compound XV in the presence of a catalyst and H.sub.2. Compounds IV and I react in the presence of an acid (e.g., hydrochloric acid) and alcohol to give rise to compound XVI, which then reacts with compound XVIII in the presence of a catalyst (e.g., CuI) to provide compound 15.

[0081] The present invention is further exemplified by the following examples that illustrate the preparation of the compounds of the invention. These examples are for illustration only, and do not intend to limit to scope of the present invention in any way.

Example 1: Synthesis of N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7-(2-(o-tolyloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (compound 6)

[0082] The title compound was synthesized according to Scheme B with the following detailed.

Step 1. Preparation of N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo-[2,3-d]pyrimidin-2-amine (VII)

[0083] ##STR00015##

[0084] To a solution of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (280 mg, 1.82 mmol) and 7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-amine (461 mg, 2.0 mmol) in n-BuOH (6 mL) was added concentrated hydrochloric acid (0.46 mL, 5.46 mmol). The mixture was stirred in a capped vial at 140 C. overnight, cooled to room temperature, diluted with water (20 mL), basified with 5N NaOH to pH about 10, and extracted with EtOAc (20 mL3). The organic layer was washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated. The residue was purified by column chromatography (DCM:MeOH=30:1 to 8:1, with 1% ammonia) to give the title compound N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo-[2,3-d]pyrimidin-2-amine (485 mg, yield: 76%).

Step 2. Preparation of N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7-(2-(o-tolyloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (compound 6)

[0085] ##STR00016##

[0086] N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine from Step 1 (50 mg, 0.14 mmol), 1-bromo-2-(o-tolyloxy)benzene (37 mg, 0.14 mmol), (trans)-cyclohexane-1,2-diamine (5 mg, 0.042 mmol), CuI (8 mg, 0.042 mmol), and K.sub.3PO.sub.4 (104 mg, 0.49 mmol) in dioxane (2 mL) was stirred at 120 C. under nitrogen overnight. The mixture was diluted with water (5 mL), and extracted with EtOAc (20 mL). The organic layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated. The residue was purified by prep-HPLC to give the title compound N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7-(2-(o-tolyloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine as a TFA salt (12 mg, yield: 13%).

Example 2: Synthesis of N-(7-(2-isopropoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (compound 15)

[0087] The title compound was synthesized according to Scheme C with the following detailed.

Step 1. Preparation of 2,2-(1,2-phenylene)diethanol (X)

[0088] ##STR00017##

[0089] To a solution of 2,2-(1,2-phenylene)diacetic acid (4.0 g, 20.6 mmol) in THF (80 mL), cooled to 0 C., was added powered LiAlH.sub.4 (3.12 g, 82.4 mmol) slowly. After addition was complete, the mixture was stirred at room temperature overnight. The reaction mixture was quenched with water at 20 C., acidified to pH about 1 to 2 with concentrated hydrochloric acid, and diluted with Et.sub.2O (100 mL). The organic phase was collected, washed with brine (30 mL3), dried with Na.sub.2SO.sub.4, filtered, and concentrated to give the crude title compound 2,2-(1,2-phenylene)diethanol (3.0 g, yield: 71%).

Step 2. Preparation of 1,2-phenylenebis(ethane-2,1-diyl) dimethanesulfonate (XI)

[0090] ##STR00018##

[0091] 2,2-(1,2-phenylene)diethanol prepared in Step 1 was used without any further purification. To a solution of 2,2-(1,2-phenylene)diethanol X (3.0 g, 18 mmol) in DCM (30 mL), cooled to 0 C., was added triethylamine (5.46 g, 54 mmol), followed by the addition of methanesulfonyl chloride (6.18 g, 54 mmol). The mixture was stirred at this temperature for 0.5 hour, and diluted with 1N hydrochloric acid (50 mL). The organic phase was separated, washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give the crude title compound 1,2-phenylenebis(ethane-2,1-diyl) dimethanesulfonate (5.5 g, yield: 94%).

Step 3. Preparation of 2,3,4,5-tetrahydro-1H-benzo[d]azepine (XII)

[0092] ##STR00019##

[0093] A solution of 1,2-phenylenebis(ethane-2,1-diyl) dimethanesulfonate from Step 2 (5.5 g, 17 mmol) in CH.sub.3CN (75 mL) and ammonia (28%, 75 mL) was stirred at 100 C. for one hour in an autoclave (pressure raised to ca 40 psi). After cooled to room temperature, the mixture was poured into water (100 mL), and acidified to pH about 4 with concentrated hydrochloric acid. The resultant mixture was extracted with ether (100 mL). The aqueous phase was basified to PH about 14 with 30% NaOH, and extracted with 10% MeOH/DCM (100 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (MeOH:DCM=1:50 to 1:10) to give the title compound 2,3,4,5-tetrahydro-1H-benzo[d]azepine (500 mg, yield: 20%).

Step 4. Preparation of 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (XIII)

[0094] ##STR00020##

[0095] To a solution of 2,3,4,5-tetrahydro-1H-benzo[d]azepine from Step 3 (300 mg, 2.04 mmol) in TFA (1.86 g, 16.3 mmol) and concentrated H.sub.2SO.sub.4 (800 mg, 8.2 mmol), cooled to 0 C., was added 65% HNO.sub.3 (217 mg, 3.45 mmol) dropwise. The mixture was stirred at this temperature for 2 hours, poured into ice-water (10 mL), basified to pH about 10 with 5N NaOH, and extracted with EtOAc (50 mL). The organic layer was washed brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give the title compound 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (250 mg, yield: 63%).

Step 5. Preparation of 3-methyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (XIV)

[0096] ##STR00021##

[0097] 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine prepared in Step 4 was used without any further purification. A solution of 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine from Step 4 (250 mg, 1.3 mmol) in 37% formaldehyde (0.8 mL) and 88% formic acid (0.49 mL) was stirred at room temperature for 1 hour, warmed to 70 C., and stirred overnight. The reaction mixture was allowed to cool to room temperature, basified with saturated aqueous NaHCO.sub.3 to pH about 9, and extracted with MTBE (50 mL). The organic layer was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give the title compound 3-methyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (217 mg, yield: 81%).

Step 6. Preparation of 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (XV)

[0098] ##STR00022##

[0099] To a solution of 3-methyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine from Step 5 (150 mg, 0.73 mmol) in MeOH (5 mL) was added Pd/C (50 mg, 10% Pd, wet, with 50% water). The mixture was stirred at room temperature under hydrogen atmosphere (45 psi) overnight. The reaction mixture was filtered through celite to remove the catalyst. The filtrated was concentrated. The residue was purified by prep-TLC to give the title compound 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (48 mg, yield: 39%).

Step 7. Preparation of 3-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepin-7-amine (XVI)

[0100] ##STR00023##

[0101] To a solution of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine I (40 mg, 0.26 mmol) and 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine from Step 6 (48 mg, 0.28 mmol) in n-BuOH (1 mL) was added concentrated hydrochloric acid (0.065 mL, 0.78 mmol). The mixture was stirred in a capped vial at 140 C. overnight, cooled to room temperature, diluted with water (5 mL), basified with 5N NaOH to pH about 10, and extracted with EtOAc (20 mL). The organic layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give the title compound 3-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepin-7-amine (65 mg, crude).

Step 8. Preparation of N-(7-(2-isopropoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (compound 15)

[0102] ##STR00024##

[0103] 3-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepin-7-amine prepared in Step 7 was used without further purification. A solution of 3-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine from Step 7 (65 mg, crude, about 0.22 mmol), 1-bromo-2-isopropoxybenzene (57 mg, 0.27 mmol), (trans)-cyclohexane-1,2-diamine (7.5 mg, 0.066 mmol), CuI (12 mg, 0.066 mmol), and K.sub.3PO.sub.4 (164 mg, 0.77 mmol) in dioxane (2 mL) was stirred at 120 C. under nitrogen overnight. The mixture was diluted with water (5 mL), and extracted with EtOAc (20 mL). The organic layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated. The residue was purified by prep-TLC to give the title compound N-(7-(2-isopropoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (9 mg, yield: 9%).

[0104] Table 1 below lists exemplary compounds of this invention that were synthesized largely according to Scheme A, B, or C. For instance, Compound Nos. 1 and 3-14 were prepared according to Scheme A or B and compound 15 was prepared according to Scheme C.

TABLE-US-00001 TABLE 1 Compound No. Chemical Name LCMS (M + H) NMR 1 7-(2- 482.3 found .sup.1H NMR (400 MHz, CDCl.sub.3) 8.67 (s, isopropoxyphenyl)- 482.3 required 1H), 7.66 (s, 2H), 7.37 (d, J = 15.0 Hz, N-(7-(pyrrolidin-1- 2H), 7.24 (s, 1H), 7.10 (d, J = 7.7 Hz, yl)-6,7,8,9- 2H), 6.97 (d, J = 8.0 Hz, 1H), tetrahydro-5H- 6.50 (d, J = 3.6 Hz, 1H), 4.45 (m, benzo[7]annulen-2- 1H), 3.48 (m, 1H), 3.39 (m, 2H), yl)-7H-pyrrolo[2,3- 2.81 (m, 2H), 2.74 (m, 2H), 2.52 (m, d]pyrimidin-2-amine 2H), 2.06 (m, 6H), 1.55 (m, 2H), 1.20 (d, J = 6.1 Hz, 6H). 2 7-(2- 432.0 found .sup.1H NMR (400 MHz, CDCl.sub.3) 8.64 (s, isopropoxyphenyl)- 432.3 required 1H), 7.97 (s, 1H), 7.61 (d, J = 7.1 Hz, N-(1-(1- 1H), 7.41 (d, J = 21.3 Hz, 3H), methylpiperidin-4- 7.18 (d, J = 3.4 Hz, 1H), 7.11 (d, J = 8.0 Hz, yl)-1H-pyrazol-4-yl)- 2H), 6.49 (d, J = 3.5 Hz, 1H), 7H-pyrrolo[2,3- 4.52-4.37 (m, 1H), 4.17 (bs, 1H), d]pyrimidin-2-amine 3.15 (s, 2H), 2.70 (bs, 1H), 2.55 (bs, 3H), 2.40 (bs, 2H), 2.17 (bs, 2H), 1.19 (d, J = 5.9 Hz, 6H). 3 7-(3- 482.3 found .sup.1H NMR (400 MHz, CDCl.sub.3) isopropoxyphenyl)- 482.3 required 12.33 (s, 1H), 8.69 (s, 1H), 7.57 (s, 1H), N-(7-(pyrrolidin-1- 7.45 (d, J = 8.1 Hz, 1H), 7.39 (s, 1H), yl)-6,7,8,9- 7.29 (s, 1H), 7.25 (s, 1H), 7.18 (s, tetrahydro-5H- 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.90 (d, benzo[7]annulen-2- J = 7.0 Hz, 1H), 6.56 (d, J = 3.7 Hz, yl)-7H-pyrrolo[2,3- 1H), 4.68-4.50 (m, 1H), 3.63 (s, d]pyrimidin-2-amine 2H), 3.40 (s, 1H), 3.00-2.83 (m, 2H), 2.82-2.62 (m, 2H), 2.52 (s, 2H), 2.20 (s, 2H), 1.95 (s, 2H), 1.61 (m, 4H), 1.37 (d, J = 5.9 Hz, 6H). 4 7-(2- 522.4 found .sup.1H NMR (400 MHz, DMSO) (cyclohexyloxy)phenyl)- 522.3 required 10.51 (s, 1H), 9.27 (s, 1H), 8.74 (s, 1H), N-(7-(pyrrolidin- 7.74 (s, 1H), 7.58 (d, J = 7.4 Hz, 1H), 1-yl)-6,7,8,9- 7.43 (s, 1H), 7.39-7.26 (m, 3H), tetrahydro-5H- 7.12 (s, 1H), 6.95 (d, J = 7.9 Hz, 1H), benzo[7]annulen-2- 6.59 (s, 1H), 4.45-4.28 (m, 1H), yl)-7H-pyrrolo[2,3- 3.59-3.35 (m, 4H), 3.17-2.99 (m, d]pyrimidin-2-amine 2H), 2.80-2.57 (m, 4H), 2.40-2.22 (m, 2H), 1.89 (s, 4H), 1.72 (s, 2H), 1.53-1.26 (m, 8H). 5 7-(2- 516.3 found .sup.1H NMR (400 MHz, CDCl.sub.3) phenoxyphenyl)-N- 516.3 required 12.48 (s, 1H), 11.71 (s, 1H), 8.42 (s, 1H), (7-(pyrrolidin-1-yl)- 7.70 (d, J = 2.1 Hz, 1H), 7.65 (dd, J = 7.9, 6,7,8,9-tetrahydro- 1.5 Hz, 1H), 7.52 (d, J = 7.5 Hz, 5H- 1H), 7.48 (dd, J = 8.1, 2.2 Hz, 1H), benzo[7]annulen-2- 7.41 (d, J = 3.9 Hz, 1H), 7.35 (dd, J = 7.7, yl)-7H-pyrrolo[2,3- 1.1 Hz, 1H), 7.25-7.19 (m, d]pyrimidin-2-amine 2H), 7.14 (dd, J = 8.3, 1.0 Hz, 1H), 7.10-7.04 (m, 2H), 6.88-6.84 (m, 2H), 6.64 (d, J = 3.9 Hz, 1H), 3.71 (s, 2H), 3.46 (s, 1H), 2.90 (dd, J = 14.8, 6.6 Hz, 4H), 2.76-2.69 (m, 2H), 2.36 (s, 2H), 2.15 (m, 2H), 1.99 (s, 2H), 1.52 (m, 2H). 6 N-(7-(pyrrolidin-1- 530.3 found .sup.1H NMR (400 MHz, CDCl.sub.3) yl)-6,7,8,9- 530.3 required 12.20 (s, 1H), 11.70 (s, 1H), 8.46 (s, 1H), tetrahydro-5H- 7.77-7.63 (m, 2H), 7.58-7.43 (m, benzo[7]annulen-2- 3H), 7.31 (s, 1H), 7.20 (d, J = 3.4 Hz, yl)-7-(2-(o- 1H), 7.04 (dd, J = 4.7, 2.4 Hz, 3H), tolyloxy)phenyl)-7H- 6.94 (d, J = 8.3 Hz, 1H), pyrrolo[2,3- 6.84-6.75 (m, 1H), 6.68 (d, J = 3.9 Hz, 1H), d]pyrimidin-2-amine 3.72 (s, 2H), 3.47 (s, 1H), 2.92 (s, 4H), 2.75 (m, 2H), 2.37 (s, 2H), 2.17 (m, 2H), 2.09 (s, 3H), 2.00 (s, 2H), 1.52 (m, 2H). 7 7-(4- 482.4 found .sup.1H NMR (400 MHz, CDCl.sub.3) 8.70 (s, isopropoxyphenyl)- 482.3 required 1H), 7.65 (d, J = 8.9 Hz, 2H), 7.59 (d, N-(7-(pyrrolidin-1- J = 1.8 Hz, 1H), 7.44 (dd, J = 8.1, 2.0 Hz, yl)-6,7,8,9- 2H), 7.24 (d, J = 3.7 Hz, 1H), tetrahydro-5H- 7.05 (dd, J = 8.6, 3.3 Hz, 3H), benzo[7]annulen-2- 6.58 (d, J = 3.7 Hz, 1H), 4.70-4.59 (m, yl)-7H-pyrrolo[2,3- 1H), 3.68 (m, 2H), 3.42 (m, 1H), d]pyrimidin-2-amine 2.97-2.84 (m, 4H), 2.77 (m, 2H), 2.56 (m, 2H), 2.23 (m, 2H), 1.98 (m, 2H), 1.68-1.57 (m, 2H), 1.43 (d, J = 6.0 Hz, 6H). 8 7-([1,1-biphenyl]-4- 500.4 found .sup.1H NMR (400 MHz, CDCl.sub.3) 8.72 (s, yl)-N-(7-(pyrrolidin- 500.3 required 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.75 (d, 1-yl)-6,7,8,9- J = 8.7 Hz, 1H), 7.65 (s, 2H), 7.51 (s, tetrahydro-5H- 1H), 7.40 (s, 1H), 7.32 (s, 1H), benzo[7]annulen-2- 7.25-7.19 (m, 1H), 7.05 (d, J = 7.5 Hz, yl)-7H-pyrrolo[2,3- 1H), 6.61 (s, 1H), 3.72-3.44 (m, d]pyrimidin-2-amine 2H), 3.39-3.30 (m, 1H), 2.95-2.67 (m, 4H), 2.54 (s, 1H), 2.41 (s, 1H), 2.24-1.82 (m, 4H), 1.72-1.51 (m, 4H). 9 7-(2-isopropoxy-4- 512.4 found .sup.1H NMR (400 MHz, CDCl.sub.3) 8.64 (s, methoxyphenyl)-N- 512.3 required 1H), 7.62 (s, 1H), 7.49 (d, J = 8.2 Hz, (7-(pyrrolidin-1-yl)- 1H), 7.41 (s, 1H), 7.30 (s, 1H), 6,7,8,9-tetrahydro- 7.15 (s, 1H), 6.98 (d, J = 7.6 Hz, 1H), 5H- 6.64 (s, 2H), 6.49 (s, 1H), 4.41 (m, 1H), benzo[7]annulen-2- 4.12 (m, 1H), 3.89 (s, 3H), 3.39 (m, yl)-7H-pyrrolo[2,3- 2H), 2.78 (m, 4H), 2.50 (m, 2H), d]pyrimidin-2-amine 2.04 (s, 6H), 1.56 (m, 2H), 1.19 (d, J = 5.9 Hz, 6H). 10 7-(4-chloro-2- 516.3 found .sup.1H NMR (400 MHz, CDCl.sub.3) 8.66 (s, isopropoxyphenyl)- 516.3 required 1H), 7.60 (s, 2H), 7.40 (s, 1H), N-(7-(pyrrolidin-1- 7.27 (s, 1H), 7.18 (d, J = 3.6 Hz, 1H), yl)-6,7,8,9- 7.14-6.87 (m, 3H), 6.51 (d, J = 3.7 Hz, tetrahydro-5H- 1H), 4.47 (m, 1H), 3.70 (m, 2H), benzo[7]annulen-2- 3.44 (m, 1H), 2.83 (m, 2H), 2.76 (m, yl)-7H-pyrrolo[2,3- 2H), 2.57 (m, 2H), 2.19 (m, 2H), d]pyrimidin-2-amine 2.04 (m, 4H), 1.60 (m, 2H), 1.24 (d, J = 5.8 Hz, 6H). 11 N-isopropyl-2-(2-((7- 509.6 found .sup.1H NMR (400 MHz, CDCl.sub.3) 8.70 (s, (pyrrolidin-1-yl)- 509.3 required 1H), 7.79 (d, J = 6.7 Hz, 1H), 7.55 (d, 6,7,8,9-tetrahydro- J = 18.3 Hz, 3H), 7.46 (s, 1H), 5H- 7.34 (s, 1H), 7.21 (d, J = 7.7 Hz, 1H), benzo[7]annulen-2- 7.11 (s, 1H), 6.97 (d, J = 7.9 Hz, 1H), yl)amino)-7H- 6.59 (s, 1H), 3.90 (m, 1H), 3.35 (m, 2H), pyrrolo[2,3- 2.81 (m, 1H), 2.78-2.62 (m, 4H), d]pyrimidin-7- 2.48 (m, 2H), 2.06 (s, 6H), yl)benzamide 1.59-1.49 (m, 2H), 1.25 (d, 6H). 12 7-(2-methyl-[1,1- 514.4 found .sup.1H NMR (400 MHz, CDCl.sub.3) 8.73 (s, biphenyl]-4-yl)-N-(7- 514.3 required 1H), 7.86 (d, J = 8.4 Hz, 2H), (pyrrolidin-1-yl)- 7.68-7.59 (m, 1H), 7.48 (d, J = 8.4 Hz, 6,7,8,9-tetrahydro- 2H), 7.40 (d, J = 7.6 Hz, 1H), 5H- 7.36-7.27 (m, 4H), 7.18 (s, 1H), 7.03 benzo[7]annulen-2- (d, J = 7.9 Hz, 1H), 6.60 (d, J = 3.6 Hz, yl)-7H-pyrrolo[2,3- 1H), 3.40-2.99 (m, 3H), d]pyrimidin-2-amine 2.96-2.64 (m, 4H), 2.56-2.43 (m, 1H), 2.36 (b, 4H), 2.11-1.89 (m, 6H), 1.73-1.46 (m, 2H) 13 7-(3- 483.5 found .sup.1H NMR (400 MHz, CDCl.sub.3) 8.67 (s, isopropoxypyridin-2- 483.3 required 1H), 8.25 (s, 1H), 7.64 (s, 1H), yl)-N-(7-(pyrrolidin- 7.50-7.37 (m, 2H), 7.28 (d, J = 3.7 Hz, 1-yl)-6,7,8,9- 2H), 6.97 (d, J = 7.8 Hz, 1H), 6.55 (s, tetrahydro-5H- 1H), 4.49 (s, 1H), 3.64 (s, 1H), benzo[7]annulen-2- 3.46 (m, 2H), 2.91-2.66 (m, 4H), yl)-7H-pyrrolo[2,3- 2.59 (s, 1H), 2.46 (s, 1H), 2.09 (m, 6H), d]pyrimidin-2-amine 1.52 (m, 2H), 1.21 (d, J = 6.0 Hz, 6H). 14 7-(3-isopropoxy- 558.4 found .sup.1H NMR (400 MHz, CDCl.sub.3) 8.69 (s, [1,1-biphenyl]-4-yl)- 558.3 required 1H), 7.73 (s, 1H), 7.65 (d, J = 6.9 Hz, N-(7-(pyrrolidin-1- 3H), 7.51 (s, 2H), 7.40 (s, 1H), yl)-6,7,8,9- 7.26 (s, 5H), 6.99 (s, 1H), 6.54 (s, 1H), tetrahydro-5H- 4.54 (m, 1H), 3.22 (m, 2H), benzo[7]annulen-2- 3.10-3.04 (m, 1H), 2.74 (m, 4H), 2.44 (m, yl)-7H-pyrrolo[2,3- 2H), 2.23 (m, 2H), 1.97 (m, 4H), d]pyrimidin-2-amine 1.50 (m, 2H), 1.26 (d, J = 6.0 Hz, 6H) 15 N-(7-(2- 428.1 found .sup.1H NMR (400 MHz, CDCl.sub.3) 8.67 (s, isopropoxyphenyl)- 428.2 required 1H), 7.83 (s, 1H), 7.62 (s, 1H), 7H-pyrrolo[2,3- 7.40 (d, J = 18.6 Hz, 2H), 7.24 (s, 2H), d]pyrimidin-2-yl)-3- 7.10 (d, J = 7.6 Hz, 2H), 6.99 (d, J = 8.1 Hz, methyl-2,3,4,5- 1H), 6.52 (s, 1H), 4.46 (m, tetrahydro-1H- 1H), 3.17 (b, 8H), 2.79 (s, 3H), benzo[d]azepin-7- 1.20 (d, J = 5.5 Hz, 6H). amine

Example 3: AXL Enzymatic Assay

[0105] Compounds were tested in a LanthaScreen time-resolved fluorescence energy transfer (TR-FRET) enzymatic assay from Invitrogen. The assay used human AXL (Invitrogen, Cat. PV3971) recombinantly expressed his-tagged catalytic domain (amino acids 473-894) from insect cells. The substrate was fluorescein-labeled Poly GT (Invitrogen, Cat. PV3610). Test compounds were prepared and diluted in DMSO in 3-fold serial dilutions to 100 of the final testing concentrations. The compounds were then further diluted to 4 by the kinase reaction buffer (Invitrogen, Cat. PV3189). The enzymatic reaction for compound testing was performed in a white 384-well polypropylene plate (Packard, Cat. 6005214) with a total reaction volume of 10 l containing 200 ng/ml AXL, 200 nM substrate, and 18 M ATP that is around its K.sub.m. The assay started with loading 2.5 l of AXL diluted in kinase reaction buffer to wells, followed by addition of equal volume of 4 compounds for 15-min incubation at the room temperature for pre-treatment. The enzymatic reaction was initiated by addition of 5 l of mixture of the substrate and ATP prepared in kinase reaction buffer. After one hour reaction, 10 l mixture of EDTA (final 10 mM) and terbium-labeled anti-PY20 antibody (final 2 nM) (Invitrogen, Cat. PV3552) prepared in TR-FRET antibody dilution buffer (Invitrogen, Cat. PV3574) was added to stop the enzymatic reaction and produce TR-FRET signals. After 30 minutes of incubation at room temperature, the plate was read in Tecan Infinite F200 Pro with the following settings: Excitation 340 nm (30)/Emission1 495 nm (10)/Emission2 520 nm (25). The TR-FRET values were dimensionless numbers that were calculated as the ratio of the acceptor (Green Fluorescent Protein) signal to the donor (Terbium) signal. Percent of control was calculated as the percentage of compound-treated vs 1% DMSO vehicle-treated. The dose-response curves were generated and the IC.sub.50s were calculated by nonlinear sigmoid curve fitting using GraphPad Prism.

[0106] The growth inhibition activities of the disclosed compounds are shown in Table 2 below. In this table, the letter A represents an IC.sub.50 value within the range of 0 to 25 (including 25) nM; the letter B represents an IC.sub.50 value within the range of 25 to 50 (including 50) nM; the letter C represents an IC.sub.50 value within the range of 50 to 200 (including 200) nM; the letter D represents an IC.sub.50 value within the range of 200 to 400 (including 400) nM; the letter E represents an IC.sub.50 value within the range of 700 to 800 (including 800) nM; and the letter F represents an IC.sub.50 value within the range of over 1000 Nm.

TABLE-US-00002 TABLE 2 AXL IC.sub.50 Data Compound No. Compound Name AXL IC.sub.50 1 7-(2-isopropoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9- B tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine 2 7-(2-isopropoxyphenyl)-N-(1-(1-methylpiperidin-4-yl)-1H- E pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine 3 7-(3-isopropoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9- C tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine 4 7-(2-(cyclohexyloxy)phenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9- D tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine 5 7-(2-phenoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9- E tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine 6 N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H- A benzo[7]annulen-2-yl)-7-(2-(o-tolyloxy)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine 7 7-(4-isopropoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9- B tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine 8 7-([1,1-biphenyl]-4-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9- F tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine 9 7-(2-isopropoxy-4-methoxyphenyl)-N-(7-(pyrrolidin-1-yl)- C 6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine 10 7-(4-chloro-2-isopropoxyphenyl)-N-(7-(pyrrolidin-1-yl)- A 6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine 11 N-isopropyl-2-(2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H- F benzo[7]annulen-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)benzamide 12 7-(2-methyl-[1,1-biphenyl]-4-yl)-N-(7-(pyrrolidin-1-yl)- B 6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine 13 7-(3-isopropoxypyridin-2-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9- D tetrahydro-5H-benzo[7]annulen-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine 14 7-(3-isopropoxy-[1,1-biphenyl]-4-yl)-N-(7-(pyrrolidin-1-yl)- D 6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine 15 N-(7-(2-isopropoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)- D 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine