NZ749590A - Pyrimidine-based antiproliferative agents - Google Patents

Abstract

This invention is in the area of pyrimidine-based compounds for the treatment of disorders involving abnormal cellular proliferation, including but not limited to tumors and cancers.

Description

PYRIMIDINE-BASED ANTIPROLIFERATIVE AGENTS CROSS-REFERENCE TO RELATED ATIONS This application claims the benefit of US. Provisional Application 62/357,630 which was filed on July 1, 2016. The entirety of this application is hereby incorporated by reference herein for all purposes.

FIELD OF THE INVENTION This invention is in the area of pyrimidine-based compounds for the ent of disorders involving abnormal cellular proliferation, ing but not limited to tumors and cancers.

BACKGROUND In normal , cellular proliferation is generally restricted to cells that are required to replenish the tissue. Once cells have ally differentiated, they have a specialized function and no longer divide. Most tissues are made up of non-dividing cells. Thus normal cell proliferation is tightly controlled to ensure that only the necessary cells divide. There is also a l balance between cell division and mmed cell death (apoptosis).

Cell division, sometimes referred to as the cell cycle, has four phases: G1 phase (synthesis of various enzymes required for DNA replication), S phase (DNA replication producing two identical sets of chromosomes), G2 (significant protein synthesis, including production of microtubules) and M phase (nuclear division, cytoplasmic division and formation ofnew cell membrane). Cell division also includes a complex system of cell signaling networks that allow cells to ret information from us extracellular signals, including through receptor proteins, inflammatory factors and pro-apoptotic and anti-apoptotic signals.

Dysfunctional signals include those from genetic mutation, infection, exposure to environmental factors including toxins, system stress, autoimmune disorders, and ation.

A range of disorders can occur when the process of cell proliferation becomes dysfunctional, including benign growths, neoplasms, tumorigenesis, cancerogenesis, mune disorders, inflammatory disorders graft-versus-host rejection, and fibrotic disorders.

A number of spectrum anti-neoplastic agents have been developed. Cytoskeletal drugs like axel target tubulin to arrest mitotic cell division and are used to treat a variety of cancers including ovarian, breast, lung, pancreatic, and ular tumors (See e.g., Jordan, , Nature Reviews Cancer (2004) 4: 253-265). Organometallic—based drugs such as cisplatin have been used to treat lymphomas, sarcomas, germ cell tumors, and some carcinomas including bladder, small cell lung cancer, and ovarian cancer. Cisplatin has the ability to bind nitrogenous bases and cause extensive DNA cross-linking that ultimately leads to apoptosis (See e.g., Siddick, Oncogene (2003) 22: 7265—7279). Intercalating and ting agents have also been extensive use in the clinic for the ent ofvarious neoplasms, however, the global toxicity associated with these drugs presents a critical concern for patients requiring erm therapy.

Palbociclib (PD-033299, e) is sold by Pfizer for the ent of estrogen- positive, HER2—negative breast cancer in combination with letrozole. The compound inhibits CDK4 and CDK6. The structure of palbociclib is: K/NH Abemaciclib (LY2835219) is a CDK 4/6 inhibitor currently in human clinical trials for the treatment of various types of cancers. It is in a phase III trial for stage IV non-small cell lung carcinoma; in combination with Fulvestrant for women with breast cancer; and with either anastrozole or letrozole for first line treatment of breast cancer. The ure of abemaciclib \( N/LQ‘N *‘QNAY‘ ti.

Ribociclib (Lee011; Kisqali), is a CDK 4/6 inhibitor approved for use in combination with an aromatase inhibitor to treat some metastatic breast cancers, and is in clinical trials for the treatment of certain other tumors. The structure of ribociclib is: H 9 (“MAJ EJJ//N\ N\ N O N ______ HNJ " Various other pyrimidine-based agents have been developed for the treatment of hyperproliferative diseases. US. Patent Nos. 8,822,683; 197; 8,598,186; 8,691,830; 8,829,102; 8,822,683; 9,102,682; 9,499,564; 9,481,591; and 9,260,442, filed by s and Strum and assigned to G1 Therapeutics be a class of eroaryl)-pyrrolo[3,2- d]pyrimidinamine cyclin dependent kinase inhibitors including those of the formula (with variables as defined therein): R? i \ {ally I / b fig/N“ N\ N R Z.‘ \R R2 R8 Xi], {Rn \ y /~I)i( N \ / 0 XX ,1 iA /\ X 7‘5 R6 N N H \7/N\" R2 138:: x, Rlyi > Y 2X KM Pal; \ \ ’ NAN/ N\ Rb‘ H N \R WC 2013/148748 (U.S.S.N. 61/617,657) titled “Lactam Kinase tors”, WO 2013/163239 (U.S.S.N. 61/638,491) titled “Synthesis of Lactams” and filed by Tavares and also assigned to G1 eutics describes the synthesis of N—(heteroaryl)— pyrrolo[3,2-d]pyrimidinamines and their use as lactam kinase inhibitors.

Other publications include the following. WC 2014/144326 filed by Strum et al. and assigned to G1 Therapeutics describes compounds and methods for protection of normal cells during chemotherapy using pyrimidine-based CDK4/6 inhibitors. WC 2014/144596 filed by Strum et al. and ed to G1 Therapeutics bes compounds and methods for protection of hematopoietic stem and progenitor cells t ionizing radiation using pyrimidine-based CDK4/6 inhibitors. W0 2014/144847 filed by Strum et al. and assigned to G1 Therapeutics describes HSPC-sparing treatments of abnormal cellular proliferation using pyrimidine-based CDK4/6 inhibitors. W0 2014/144740 filed by Strum et al. and assigned to G1 Therapeutics bes highly active eoplastic and anti-proliferative pyrimidine-based CDK 4/6 inhibitors. W0 61285 filed by Strum et al. and assigned to G1 Therapeutics describes tricyclic pyrimidine-based CDK inhibitors for use in radioprotection. W0 2015/161287 filed by Strum et a1. and assigned to G1 Therapeutics describes analogous tricyclic pyrimidine-based CDK inhibitors for the protection of cells during chemotherapy. W0 2015/161283 filed by Strum et a1. and assigned to G1 Therapeutics bes analogous tricyclic pyrimidine-based CDK inhibitors for use in HSPC-sparing treatments of RB-positive abnormal ar proliferation. W0 2015/161288 filed by Strum et al. and assigned to G1 Therapeutics describes analogous tricyclic pyrimidine—based CDK inhibitors for use as anti-neoplastic and anti— proliferative agents. W0 2016/040858 filed by Strum et al. and assigned to G1 Therapeutics describes the use of ations of pyrimidine-based CDK4/6 inhibitors with other anti— neoplastic agents. W0 2016/040848 filed by Strum et al. and assigned to G1 Therapeutics describes compounds and methods for treating certain Rb-negative cancers with CDK4/6 inhibitors and topoisomerase inhibitors.

W0 03/062236 fies a series of 2-(pyridinylamino-pyrido[2,3]pyrimidin ones for the treatment of Rb ve cancers that show selectivity for CDK4/6, including 6- acetylcyclopentyl-5 -methyl(5 -piperazinyl-pyridinylammino)-8H-pyrido-[2,3-d]- pyrimidinone (PD0332991), which was given fast-track approval by the FDA and is tly sold as Ibrance (Palbociclib) by Pfizer for the treatment of metastatic breast cancer.

VanderWel et al. be an iodine-containing pyrido[2,3-d]pyrimidineone (CKIA) as a potent and selective CDK4 inhibitor (see VanderWel et al., J. Med. Chem. 48 (2005) 2371— 2387) W0 2010/020675 filed by Novartis AG describes pyrrolopyrimidine compounds as CDK inhibitors. W0 2011/101409 also filed by is describes pyrrolopyrimidines with CDK 4/6 inhibitory activity.

Johnson et al. ed that pharmacological inhibition of CDK4/6 using the CDK4/6 inhibitors 6-acetylcyclopentylmethyl(5-piperazin—1-yl-pyridinylammino)-8H- pyrido-[2,3-d]-pyrimidinone (PD0332991) and 2-bromo-12,13-dihydro-5H-indolo[2,3- a]pyrrolo[3,4]carbazole—5,6-dione ) exhibited IR protective characteristics in CDK4/6- dependent cell lines. (Johnson et al. Mitigation of hematological radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition. J Clin. Invest. 2010; 120(7): 2528-2536).

There remains a need for onal compounds to treat disorders associated with abnormal cellular proliferation, including a tumor or cancer.

SUMMARY Compounds are presented that have advantageous antiproliferative activity, including anticancer and antitumor activity. Based on this discovery, nds and methods are presented for the treatment of a patient with a proliferative disorder including a tumor or cancer that includes stering an ive amount of one or a combination of the compounds described herein to a patient in need thereof, optionally in a pharmaceutically acceptable carrier. In certain embodiments the antiproliferative disorder is selected from a benign , neoplasm, tumor, cancer, autoimmune disorder, inflammatory disorder, graft-versus-host rejection and a c disorder. In a typical embodiment the patient is a human.

The invention includes an active compound of Formula I, Formula II, Formula 111 Formula IV, Formula V, Formula VI, Formula VII, a VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, a XIX, Formula XX, Formula XXI, Formula XXII, or Formula XXIII or a pharmaceutically acceptable salt or composition thereof. In one embodiment, an active compound or its salt, composition, or prodrug thereof is used to treat a medical disorder involving abnormal cellular eration.

The invention includes an antiproliferative (including antineoplastic) compound of aI, Formula II, Formula III Formula IV, Formula V, Formula VI, Formula VII, a VIII, Formula IX, Formula X, Formula XI, a XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, or Formula XIX: WO 05860 (XVIII), or or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, prodrug, and/or a pharmaceutically acceptable composition thereof; X is NH, NR9, S, or O; yis 0,1,2, 3 or4, m is 0, 1, or 2; n is 0, 1, or 2, Z is independently CH, CR9, or N, Q is CH2 or CO; R is hydrogen, C1-C6alkyl, -(Co—C2alkyl)(C3-Cscarbocyclyl), -(Co-C2alkyl)(C3- Csheterocyclyl),-(Co-C2alkyl)(aryl), -(C0—C2alkyl)(heteroaryl), —COOalkyl, -COOarylalkyl, or —COOH; each R1 is independently alkyl, aryl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes heteroatoms O, N, or S in place of a carbon in the chain and two Rl’s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3membered cycle or two Rl’s on adjacent ring atoms together with the ring atom(s) to which they are attached ally form a 6-membered aryl ring; or R1 is hydrogen, R2 is —(alkylene)m—heterocyclo, —(alkylene)m—heteroaryl, —(alkylene)m—NR3R4, —(alkylene)m—C(O)—NR3R4, —(alkylene)m—C(O)—O-alkyl, —(alkylene)m—O—R5, 1ene)m—S(O)n—R5, or —(alky1ene)m—S(O)n—NR3R4 any of which may be optionally independently substituted with one or more RX groups as d by e, and wherein two Rx groups bound to the same or adjacent atom may optionally combine to form a ring; R3 and R4 at each occurrence are independently selected from: (i) hydrogen or (ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, lkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more Rx groups as allowed by valance, and n two RX groups bound to the same or adjacent atom may optionally combine to form a ring; or R3 and R4 together with the nitrogen atom to which they are ed may combine to form a heterocyclo ring optionally independently substituted with one or more RX groups as allowed by valance, and wherein two RX groups bound to the same or adjacent atom may optionally combine to form a ring; R5 is independently selected at each occurrence from: (i) hydrogen or (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently tuted with one or more RX groups as allowed by valance; Rx at each occurrence is independently selected from halo, cyano, nitro, oxo, alkyl, kyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, lkylalkyl, heterocycloalkyl, -(alkylene)m-OR5, -(alkylene)m-O-alkylene-OR5, - (alkylene)m-S(O)n—R5, —(alkylene)m-NR3R4, -(alkylene)m-CN, -(alkylene)m—C(O)—R5, - (alkylene)m-C(S)—R5, -(alkylene)m-C(O)—OR5, -(alkylene)m-O—C(O)—R5, -(a1ky1ene)m-C(S)—OR5, -(a1kylene)m-C(O)—(alky1ene)m-NR3R4, —(alkylene)m-C(S)—NR3R4, -(alkylene)m-N(R3)—C(O)—NR3R4, -(alkylene)m-N(R3)—C(S)—NR3R4, lene)m-N(R3)— C(O)—R5, -(alkylene)m-N(R3)—C(S)—R5, lene)m-O—C(O)—NR3R4, -(alkylene)m—O—C(S)— NR3R4, -(alkylene)m—SOz—NR3R4, -(alkylene)m—N(R3)—SOz—RS, -(alkylene)m-N(R3)—SOz— NR3R4, -(alkylene)m-N(R3)—C(O)—OR5) -(alkylene)m-N(R3)—C(S)—OR5, or -(alkylene)m- N(R3)—SOz—R5, wherein: said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted as described herein; R6 is ed independently at each ce from: hydrogen, halogen, alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, cycloalkyl, arylalkyl, or arylalkyl, R8 a3 R8 R8 R8 R8 \ V Y R \ l R8 / R3 / I / R7 is selected from: Y RS R8 R8 , , , , X2 X2 Y\ x2 x2 (:7 / \ 1/ x2 '-\ xix Y 47 N X:\ 1 Y\ X \ l X“ K I / M Y X1 Y WO 05860 / N 35/ X {it/1 Y 1,? Xv / Flirxd Y\’A>~<X\\J>ix‘/L~x Rik \ Aril / / x N N Y X g/Y\‘“‘><‘ /}\v Wfi RX" Y\X X\‘\:\ I X;\ / X:\ i Y\\ / i x3 yak/K Y x1 X3 de~ 4 x3 [\XZS X X 4" R x/ \\ or R7 is selected from cycloalkyl, heterocycle, and alkyl, each of which lkyl, cycle, and alkyl groups is optionally substituted with one or more substituents selected from amino, -NHR14, -NR14R15, hydroxyl, OR”, R6, and R2, R14 and R15 are independently selected from: hydrogen, alkyl, alkenyl, alkynyl, —C(O)H, -C(O)alkyl, -C(S)alkyl, aryl, —S02alkyl, heteroaryl, arylalkyl, and heteroarylalkyl.

Y is NH, O, S, or NR9, X1, X2, X3, and X4, are independently N or CR8, n at least one of X1, X2, X3, and X4, is CR8; R8 is selected independently at each instance from: R6 and R2, wherein one R8 is R2; R9 is selected from: —C(O)H, -C(O)alkyl, -C(S)alkyl, alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; R10 is ed from: hydrogen, —COOalkyl, -COOarylalkyl, —COOH, -OH, —C(O)H, - C(O)alkyl, -C(S)alkyl, alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; and wherein for compounds of Formula VII y is 0, 1, or 2.

In an additional aspect the invention includes an active compound of Formula XX, a XXI, Formula XXII, Formula XXIII, or Formula XXIV or a pharmaceutically acceptable salt or composition thereof. The compounds of Formula XX, Formula XXI, Formula XXII, a XXIII, and XXIV have the following structures: t: (R) ”N7 ’ My (XX), R (XXI), N.“ \ N \ N\ / N \IN N\ / N EWR )xN xv: [LN \Iro HNI (R )y mi (M), R (XXII), R (XXIII), and fl» \ JR N N‘”R I I” N H‘J ’ .7 k‘ 3n“: R" \(J (R‘).

Y (XXIV), wherein m, R, R1, R7, Q, and y are defined above.

In one embodiment the compound of Formula XX is: /\ \4 N N”R F? \ /\\LN/ N 7L{ N‘\ / “““N /N”R HN 0 )\N X? {Rl‘i R Hp‘l R" \ R1 ly 01‘ R7 In an additional aspect the invention includes an active compound of Formula XXV: N\ fitW’zx/O N”R /\"‘-N,f—mN\,\J “N {R1} R“ V (XXV), wherein R, R1, R2, R6, and y are defined above; R16 is selected from cycloalkyl, heterocycle, and alkyl, each of which lkyl, heterocycle, and alkyl groups is optionally substituted with one or more tuents selected from amino, , -NR14R15, hydroxyl, OR”, R6, and R2, R14 and R15 are independently selected from: hydrogen, alkyl, l, alkynyl, —C(O)H, -C(O)alkyl, -C(S)alkyl, aryl, —SOzalkyl, heteroaryl, arylalkyl, and heteroarylalkyl.

WO 05860 In an alternative embodiment the nd of the present invention is selected from N/ \ N / \ In another alternative embodiment the compound of the present invention is selected from Q Q C} C} 53 )m )W ,and f In another alternative embodiment the compound of the present invention is selected from NH NH NH , ,and In an alternative embodiment the compound of the present invention is: N/\N >"—“N HN ’J In another alternative embodiment the compound of the present invention is: These nds can be used to treat such condition in a host in need f, typically a human.

In one embodiment, the active compound acts as an inhibitor of a cyclin-dependent kinase (CDK), for example CDK4 and/or CDK6. In an aspect, the compound is a selective 2017/040093 inhibitor of CDK4 and/or CDK6. In another embodiment, the selectivity is for CDK4 and/or CDK6 over CDK2. Based on this, in one ment, the method for the ent of a disorder of abnormal cellular proliferation that is mediated by CDK4 and or CDK6 is provided that includes the administration of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt f, optionally in a pharmaceutically acceptable carrier, as described in more detail below.

In an alternative embodiment, a method for the treatment of a disorder of abnormal cellular proliferation that is not mediated by CDK4 and or CDK6 is provided that includes the administration of an ive amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, as described in more detail below.

In another embodiment, a method for the ent of a fibrotic disorder in a host is provided that includes the administration of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt f, optionally in a pharmaceutically acceptable carrier.

In another ment, a method for the treatment of rheumatoid arthritis or psoriasis in a host is provided that includes the administration of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

In yet another embodiment, a method for the treatment of an mune disorder in a host is provided that includes the administration of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

In a principal embodiment, a method for the treatment of a tumor or cancer in a host is provided that includes the administration of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable r. In an aspect of this embodiment, the cancer is an Rb-positive tumor or cancer. In another aspect of this embodiment, the cancer is an ative tumor or cancer. In certain aspects, the cancer is selected from breast cancer, prostate cancer (including androgen- resistant prostate cancer), another cancer of the uctive system such as endometrial, ovarian or testicular cancer, small cell lung carcinoma, glioblastoma and head and/or neck In yet r embodiment, a method for the treatment of a disorder of abnormal cellular proliferation in a host such as a human is provided that includes administering an effective amount of a ation of one or more of the active compounds described herein in combination or alternation with r active compound. In certain aspects of the invention, the second compound is a chemotherapeutic agent. In another aspect of this embodiment, the second active compound is an immune modulator, including but not limited to a checkpoint inhibitor such as an anti—PDl, TLA, anti-LAG—3, anti-Tim, etc antibody, small molecule, peptide, nucleotide or other inhibitor (including but not d to umab (Yervoy), Pembrolizumab (Keytruda) and nivolumab (Opdivo).

In yet another embodiment, one of the active compounds described herein is administered in an effective amount for the treatment of abnormal tissue of the female reproductive system such as breast, ovarian, endometrial, or uterine cancer, in combination or alternation with an effective amount of an estrogen tor including but not limited to a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader), a complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist.

In another embodiment, one of the active compounds described herein is administered in an effective amount for the treatment of abnormal tissue of the male reproductive system such as prostate or testicular cancer, in combination or alternation with an effective amount of an androgen (such as testosterone) inhibitor including but not limited to a selective androgen receptor tor, a selective androgen receptor degrader, a complete androgen or degrader, or another form of partial or complete androgen antagonist. In one embodiment, the te or testicular cancer is androgen-resistant.

In one embodiment, the nds described herein inhibit Cyclin Dependent .

For example, a compound described in the present invention provides a dose-dependent Gl— arresting effect on a subject’s CDK replication dependent healthy cells, for example HSPCs or renal epithelial cells. The s provided for herein are sufficient to afford chemoprotection to targeted CDK replication dependent healthy cells during chemotherapeutic agent exposure, for e, during the time period that a DNA—damaging chemotherapeutic agent is e of DNA-damaging effects on CDK replication dependent healthy cells in the subject.

In one embodiment, the use of the compounds or methods described herein is combined with the use of hematopoietic growth factors including, but not limited to, granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), thrombopoietin, interleukin (IL)-12, steel , and opoietin (EPO), or their derivatives.

In one embodiment, the compound is administered prior to administration of the hematopoietic WO 05860 growth factor. In one embodiment, the hematopoietic growth factor administration is timed so that the compound’s effect on HSPCs has dissipated.

The present invention thus includes at least the ing features: (a) a compound of the present invention as described herein, and pharmaceutically acceptable salts and prodrugs thereof; (b) a compound of the present invention as described herein, and pharmaceutically acceptable salts and prodrugs thereof that are useful in the treatment of a disorder of al ar eration, including a tumor or cancer, (c) use of a compound of the present invention, or pharmaceutically able salts and gs thereof in the manufacture of a ment for the treatment of a disorder of abnormal cellular proliferation, such as a tumor or cancer, ((1) a method for manufacturing a medicament intended for the eutic use of treating a er of abnormal cellular proliferation including a tumor or cancer, characterized in that a compound of the present invention as described herein is used in the manufacture, (e) a compound of the present ion as described herein, and pharmaceutically acceptable salts and prodrugs f that are useful in the treatment of cancer, including any of the cancers described herein; (f) use of a compound of the present invention, and pharmaceutically acceptable salts and prodrugs thereof in the manufacture of a medicament for the treatment of cancer, ing any of the cancers described herein, (g) a method for manufacturing a medicament intended for the therapeutic use of treating cancer, including any ofthe cancers described herein, characterized in that a compound of the present invention as described herein is used in the manufacture; (h) a compound of the present invention as described herein, and pharmaceutically acceptable salts and prodrugs thereof that are useful in the treatment of a tumor, including any of the tumors described herein; (i) use of a compound of the present invention, and pharmaceutically acceptable salts and gs thereof in the manufacture of a medicament for the treatment of a tumor, including any of the tumors described herein, (1') a method for cturing a medicament intended for the therapeutic use of treating a tumor, including any of the tumors described herein, characterized in that a compound of the present invention as described herein is used in the manufacture, WO 05860 (k) a compound of the present invention as described herein, and ceutically able salts and prodrugs thereof that are useful in the treatment of a flbrotic disorder; (1) use of a compound of the present ion, and pharmaceutically acceptable salts and prodrugs thereof in the manufacture of a medicament for the treatment of a fibrotic disorder; (m) a method for manufacturing a medicament intended for the therapeutic use of treating a fibrotic disorder, characterized in that a compound of the present invention as described herein is used in the manufacture, (n) a compound of the present invention as described herein, and pharmaceutically acceptable salts and prodrugs thereof that are useful in the treatment of an autoimmune or inflammatory disorder; (0) use of a compound of the present invention, and ceutically acceptable salts and prodrugs thereof in the manufacture of a medicament for the treatment of an autoimmune or inflammatory disorder, (p) a method for manufacturing a medicament intended for the therapeutic use of treating an autoimmune or atory disorder, characterized in that a compound of the present invention as described herein is used in the manufacture; (q) a pharmaceutical formulation comprising an effective host—treating amount of the compound of the present invention or a ceutically acceptable salt or prodrug thereof together with a pharmaceutically acceptable carrier or diluent; (r) a compound of the present invention as described herein as a mixture of enantiomers or diastereomers (as nt), including as a racemate; (s) a compound of the present invention as described herein in omerically or diastereomerically (as relevant) enriched form, including as an isolated enantiomer or disastereomer (i.e., greater than 85, 90, 95, 97 or 99% pure), and, (t) a process for the preparation oftherapeutic products that contain an effective amount of a nd of the present ion, as described herein. (u) a compound of the present invention as described herein, and pharmaceutically acceptable salts and prodrugs thereof that are useful in chemoprotection, (V) use of a compound of the present invention, and pharmaceutically acceptable salts and gs thereof in the manufacture of a medicament for chemoprotection; and (w) a method for cturing a medicament intended for the eutic use of chemoprotection, characterized in that a compound ofthe present invention as described herein is used in the manufacture.

BRIEF DESCRIPTION OF FIGURES is a bar graph showing the population of cells with a DNA content less than 2N, cells in the GO-Gl phase, cells in the S phase, and cells in the G2-M phase as a way to measure the relative amount of tic cells ing stration of control, Compound 30, Compound 36, Compound 37, Compound 38, Compound 39, nd 40, and Compound 41. The Compound number and dose, measured in uM and nM) are shown on the x—axis and the cell population, measured in percent, is shown on the y-axis. is a bar graph showing the population of cells with a DNA content less than 2N, cells in the GO-Gl phase, cells in the S phase, and cells in the G2-M phase as a way to measure the relative amount of apoptotic cells following administration of control, Compound 31, Compound 33, and Compound 34. The Compound number and dose, measured in uM and nM) are shown on the X-axis and the cell population, measured in percent, is shown on the . is Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, and Formula XXV. is a bar graph showing the population of cells with a DNA content less than 2N, cells in the GO-Gl phase, cells in the S phase, and cells in the G2-M phase as a way to e the relative amount of apoptotic cells following administration of control and Compound 28.

The population of apoptotic cells after exposure to Compound 28 was greater than 70% at * is <2000 . every dose administered. The assay was done in a population of H568 cells.

The Compound number and dose, measured in uM and nM, are shown on the x-axis and the cell population, measured in percent, is shown on the y-axis.

DETAILED DESCRIPTION I. COMPOUNDS In one embodiment, compounds of Formula 1, Formula II, Formula 111 Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, a X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, or Formula XIX are provided: NiHfifz NiNN” \ Wis? {Rlly HNx (I), R" _ N “’8‘“ ( R‘ )y W):N [JV/f: R" (XIII) WW , N /m\N’(N”R NVN“N )‘x‘N ”W “N. (R )3, HI): My R7 (XV), R7 (XVI), (XVIII), and r;2:; R' HN>- ‘ly (XIX) or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, or prodrug, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition thereof; wherein the variables are as defined above in the Summary section.

In an alternative embodiment, a compound of Formula XX, Formula XXI, Formula XXII, Formula XXIII or a XXIV is provided: / N HZ HN\/\QJ< 7 {RE}, HN‘ l: R1) \\I a“ \ N\«o i,I N lurk: 9%) N Q HN‘ IE1) y,(XXII) R7 y ) and RM? N MR \ /)_____ N i Y (XXIV) or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, or prodrug, optionally in a pharmaceutically acceptable r to form a ceutically able composition thereof; wherein the variables are as defined above in the Summary section.

In another embodiment, a compound of Formula 1-], Formula II-I, Formula III-I, Formula IV-l, Formula V-I, Formula VI-l, Formula VII-l, Formula , Formula IX-l, Formula X-l, a XI-l, Formula XII-l Formula XIII-l Formula XIV-1, Formula XV-I, , , Formula XVI-l, Formula XVII-l, Formula 1, Formula XIX-1, Formula XX-l Formula XXI-l, Formula XXII-1, Formula XXIII-l, Formula XXIV-l, or Formula XXV-l is provided: /\ \ Z: N‘ NI [MIR / /_______ ‘N ”N / R R R7 L ) R7’HN (R1)\ Y (VII-1), 3" (VIII-1), -1), \_ y R R7 (XIV-1), R' 1), (XVIII-1), 2:2 NRMN’R N NV ““KJ wQ >294 HN R7HN (R1) it? {R4} y(XIX-1), ' 3’ (XX-1), \ x \ \ Nx / N HZ Nx / N 1” Hit/LN “if; HN’LN XV? i i R!) i l: R R7 y (XXI-1), )3, R7 1), so \ if i / [\- “~-. \ ‘N N N”-R HN. ( } )\N\ f N I \I m WQ R \rj “Ni? (My (‘52?) R (XXIII-1), ‘1’ (XXIV-1), or /:\ \ >‘N \wv Hi‘l {R1} R15 V (XXV-1), or a pharmaceutically acceptable salt, N-oxide, isotopic denvative, or prodrug, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition thereof; wherein: 2017/040093 X is NH, NR9, S, or O; y is 0,1, 2, 3, or4; m is 0, 1, or 2, n is 0, 1, or 2; Z is independently CH, CR9, or N, Q is CH2 or CO; R is hydrogen, Ci-Cealkyl, -(Co-C2alkyl)(C3-Cscarbocyclyl), -(Co-C2alkyl)(C3— rocyclyl),-(Co-C2alkyl)(aryl), -(Co-C2alkyl)(heteroaryl), -COOalkyl, -COOarylalkyl, or —COOH; each R1 is independently alkyl, aryl, cycloalkyl or haloalkyl, n each of said alkyl, cycloalkyl and haloalkyl groups optionally includes heteroatoms O, N, or S in place of a carbon in the chain and two Rl’s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3—8—membered cycle or two Rl’s on adjacent ring atoms together with the ring atom(s) to which they are attached optionally form a 6-membered aryl ring; or R1 is hydrogen; R2 is —(alkylene)m—heterocyclo, —(alkylene)m—heteroaryl, —(alkylene)m—NR3R4, —(alkylene)m—C(O)—NR3R4; —(alkylene)m—C(O)—O-alkyl; —(alkylene)m—O—R5, —(alkylene)m—S(O)n—R5, or —(alkylene)m—S(O)n—NR3R4 any of which may be ally independently substituted with one or more RX groups as allowed by valance, and wherein two RX groups bound to the same or adjacent atom may optionally combine to form a ring; R3 and R4 at each occurrence are independently: (i) hydrogen or (ii) alkyl, lkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl, or R3 and R4 together with the nitrogen atom to which they are attached may e to form a heterocyclo ring; R5 is independently: (i) hydrogen or (ii) alkyl, alkenyl, alkynyl, cycloalkyl, cyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl; RX at each occurrence is independently selected from halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, lene)m-OR5, -(alkylene)m-O-a1kylene-OR5, — WO 05860 (alkylene)m-S(O)n—R5, -(alkylene)m-NR3R4, -(alkylene)m-CN, -(alkylene)m-C(O)—R5, - (alkylene)m-C(S)—R5, -(alkylene)m-C(O)—OR5, lene)m-O—C(O)—R5, -(alkylene)m-C(S)—OR5, -(alkylene)m-C(O)-(alkylene)m-NR3R4, -(alkylene)m-C(S)—NR3R4, -(a1kylene)m-N(R3)—C(O)—NR3R4, -(alkylene)m-N(R3)—C(S)—NR3R4, -(alky1ene)m-N(R3)— C(O)—R5, -(alkylene)m-N(R3)—C(S)—R5, -(alkylene)m-O—C(O)—NR3R4, -(alkylene)m—O—C(S)— NR3R4, -(alkylene)m—802—NR3R4, lene)m—N(R3)—802—R5, -(alkylene)m-N(R3)—SOz— NR3R4, -(alkylene)m-N(R3)—C(O)—OR5) -(alkylene)m-N(R3)—C(S)—OR5, or -(alkylene)m— N(R3)—SOz—R5; R6 is selected independently at each instance from: hydrogen, halogen, alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, lkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl; 8 n P‘3 R5 R R8 \ 8 :4] Y R \ l Xl l R3 / I / \ . Y R7 is selected from: Y R8 Ra , , , , X2 \A X2 xi”: x2 / \ / X2 \ 4:; Y 4:, N :1: N Y x1 l x1 x1 i v \ 1/ \\ r/ \ \ 4/ x Y X’ Y XF ._ Y \ X2 X X1 \ ""\ X‘ ’6! Y ’0 / ‘3‘. X2 / \X1 /}L‘“Y 4/}\x3 /\\-:x3 l /X1\Y xf’ \ x?- “ I ‘ \,/ X\ Y\ / <Y\\><1\ <4/ X“ x3 v x“ x3 x3 or R7 is selected from cycloalkyl, heterocycle, and alkyl, each of which cycloalkyl, heterocycle, and alkyl groups is optionally tuted with one or more substituents selected from amino, -NHR14, -NR14R15, hydroxyl, OR”, R6, and R2; WO 05860 R14 and R15 are independently selected from: hydrogen, alkyl, alkenyl, alkynyl, —C(O)H, —C(O)alkyl, -C(S)alkyl, aryl, —SOzalkyl, heteroaryl, kyl, and arylalkyl; R16 is ed from cycloalkyl, heterocycle, and alkyl, each of which cycloalkyl, heterocycle, and alkyl groups is optionally substituted with one or more substituents selected from amino, -NHR14, -NR14R15, yl, OR”, R6, and R2, Y is NH, O, S, or NR9; X1, X2, X3 and X4, are independently N or CR8, wherein at least one of X1, X2, X3, and X4, is CR3; R8 is selected independently at each instance from: R6 and R2, wherein one R8 is R2, R9 is selected from: —C(O)H, -C(O)alkyl, -C(S)alkyl, alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, R10 is selected from: hydrogen, -COOalkyl, -COOarylalkyl, —COOH, -OH, —C(O)H, - C(O)a1ky1, -C(S)alky1, alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; and wherein for compounds of Formula VII y is 0, 1, or 2.

WO 05860 N/QQQQQXQ QQQQQQ Raf? {Q :2;)9/-~N ”Q, , m M” Q Q“ “Q/N-~.N “ CQQQQ < ~Q2WNQ WO 05860 WO 05860 In another embodiment, a nd of Formula 1-2, Formula 11-2, Formula III-2, Formula IV-2, a V-Z, Formula VI-Z, Formula VII-2, Formula VIII-2, Formula IX-2, Formula X-2, Formula XI-2, Formula XII-2, Formula XIII-2, Formula XIV-2, Formula XV-Z, Formula XVI-2, Formula XVII-2, Formula XVIII-2, a XIX-2, Formula XX-2 Formula XXI-2, Formula XXII-2, Formula XXIII-2, or Formula XXIV—2 is provided: (IV-2), ”KW n N "’ )L-N/ hi HN fiR‘VQT/LéNAN :0 FL; Gym (V-2), (v1-2), FN \\ 27:2 N NH 29f )L WN ##H rx/ \\ ' N ‘ G HN >35“! k7 R7HN (VII-2), (VIII-2), WAN/NM/‘\1\N 1 .H R7 < HN h" : (X_2)> x 3a x N O (XI-2), (XII-2), NWN N x 1 Q‘N ”/11“ N9 )\ N» / N \N “N “N HN R7 \R7 (XIII-2), (XIV-2), x N N NH “N )<-= NW0?” 9.: N RT‘N N N H ”“5 (XV-2), R (XVI-2), (XVIII-2), WO 05860 )erz/ N i Q 32'! "”17 c R? (XXIII-2), 5’ (XXIV-2), or [9'3 f2: ‘\ N W’R \ / N J (XXV-2); or a pharmaceutically acceptable salt, N—oxide, isotopic derivative, or prodrug, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition thereof; wherein R“, R7, Q, Z, R1, y, and X are as defined in Formula X-l and Formula XIX- ] above.

In some aspects, R6 is hydrogen.

In some aspects, Rx is not further substituted.

In some s, R2 is —(alkylene)m—heterocyclo, —(alkylene)m—heteroaryl, —(alkylene)m—NR3R4, —(alkylene)m—C(O)—NR3R4; —(alkylene)m—O—R5, —(alkylene)m—S(O)n—R5, or lene)m—S(0)11—NR3R4 any of which may be optionally ndently substituted with one or more Rx groups as allowed by valance, and n two RK groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0 or 1 and n is 0, 1 or 2.

In some aspects, R2 is —(alkylene)m—heterocyclo, —(alkylene)m—NR3R4, —(alkylene)m—C(O)—NR3R4, —(alkylene)m—C(O)—O-alkyl or —(alkylene)m—OR5 any of which WO 05860 may be optionally independently substituted with one or more RX groups as allowed by valance, and wherein two RX groups bound to the same or nt atom may optionally combine to form a ring.

In some aspects, R2 is —(alkylene)m—heterocyclo, lene)m—NR3R4, —(alkylene)m—C(O)—NR3R4, —(alkylene)m—C(O)—O-alkyl or —(alkylene)m—ORS without further substitution.

In some aspects, m in R2 is 1. In a further aspect, the alkylene in R2 is methylene.

MR? (RX1 )1 In some aspects, R2 is wherein: R” is a bond, alkylene, -(alkylene)m-O-(alkylene)m-, -(alkylene)m-C(O)—(alkylene)m—, -(alkylene)m-S(O)2-(alkylene)m- and —(alkylene)m-NH-(alkylene)m- wherein each m is independently 0 or 1, P is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group; each RX1 is independently -(alkylene)m-(C(0))m-(alkylene)m-(N(RN))m-(alkyl)m wherein each m is independently 0 or 1 provided at least one m is 1, -(C(O))-O-alkyl, —(alkylene)m-cycloalkyl wherein m is 0 or 1, -N(RN)-cycloalkyl, -C(O)—cycloalkyl, lene)m-heterocyclyl wherein m is 0 or I, or -heterocyclyl, -C(O)—heterocyclyl,— S(O)2-(alkylene)m wherein m is 1 or 2, wherein: RN is H, C1 to C4 alkyl or C1 to C6 alkyl, and wherein two RX1 can, together with the atoms to which they attach on P, which may be the same atom, form a ring, and tis 0, l or 2.

In some aspects, each R"1 is only optionally substituted by unsubstituted alkyl, halogen or hydroxy.

In some aspects, RX1 is hydrogen or unsubstituted C1-C4 alkyl.

In some aspects, at least one RXI is -(alkylene)m-heterocyclyl wherein m is 0 or 1.

MRZ‘MN P* (in )t Ir...

In some aspects, R2 is n P* is a 4- t0 8- membered mono- or bicyclic saturated heterocyclyl group.

In some aspects, R2 is _R2*_ N_RX1 In some aspects, R2 is \—/ —R2* (RX2)s In some aspects, R2 is wherein: R” is a bond, alkylene, -(alkylene)m-O—(alkylene)m-, -(alkylene)m-C(O)—(alkylene)m-, -(alkylene)m-S(0)2-(alkylene)m- and -(alkylene)m-NH-(alkylene)m- wherein each m is independently 0 or 1; P is a 4- to ered mono- or bicyclic saturated heterocyclyl group; P1 is a 4- to 6-membered monocyclic saturated heterocyclyl group; each RX2 is independently hydrogen or alkyl, and sis 0,10r2. _R2*_N (RXZ)s In some aspects, R2 is In some s, P1 includes at least one nitrogen.

In some aspects, any alkylene in R2* in any previous aspect is not further substituted.

K,f5 K«K33 In some aspects, R2 is , , V 52Wfl‘\ S“\ (N N 5""me x"\N j k, ”a“ H; 4“ ,Mu—J K 33K AK <5” 3 w i «3“ $3! Ni «2 \\N/Ufr(‘h 33 \Nr’x KK,EL \E\'3.x”Q] K. LVKM 3 9 \ .w 33;. 5:» 3‘?\ V" H Nx‘l ,- NE‘ “W N 1 ,x \N’fi Kw” k '; Jib»;« V’O ‘VM OH H : é v v L “NAB\f ”NW “”1k“! ’ \?V x Ki“, \“M’ \J‘ b§ I N'JW i ‘K I Va 1 7 \j 087 55: m (S- \Nr “NNN’N 7 L ER S xv,“T/ N/fi , r’ W N“? x3 K, N" x/N”I 53R x L L am KW” NW” ”OB i MAN,” ‘ x‘ R \{ \rmwxfk N{JV 9% H 9 , N \\3”\~ cm SNx x kv' Km” “Now§ i 351“ , i“ 35: N, w 3 H I L \Vf \ \N/W xx" ‘xx’ is; K M" (N x $31» x“\ ,x QR s x /\ ,3“ M N’A‘ «*NH K L a f N .r"\ 4-" ’ f Nx’VVx ”Axfifi N" N H ¥ D 3 7 53:\ M 3 s‘KNm ‘N. xx ,J’V'x we» ‘3 “H (j N s { J k ,N- R3 :3: .N 33 [\v" 71/ x» Kx , N“ \{I H {3 Q S‘N V" "\\ » N ‘ NY w v\ F Nmex’ E 33““ x” 55:" , ,fi‘k a 3.; "(\Tflb |\ ‘ . . £¥ ,N \ 3334323 ’v" L\ \M 858?: \v’, : {d V»: fax. 551‘ .V. 5:.

N/W [J N(x Sax“[\Lfl .5 x N ”\T K!” g \w’ \(‘SN {\vffixw‘lcca kv", “Sit“: ; “"I‘N \vf" {:38 0 § g‘éfi a :4 3;“ 3‘ v N k 3 \NJ‘, ”N 3‘ \wx‘fl‘ ,«\NH 3‘\ 9% w” qu‘N fo5 H i“ j g“ i? i 5 w O w 7 7 wfixx‘ “a”: N ,OH I“ ”‘v ”‘6’”xv’ ‘OH (xx ‘3“ . 3 ”N\«x’m‘o’am; Kr’bj‘wf’“ : K/fi\x\x‘fi (‘3‘. "“ (v S§:""~ a S)\ ,m' N «I \ N“xx 3‘\\ \f \ a,” x “r“*3 3 33‘». \ rx ”-4” ¥\ N \ fl» x» 0‘5 W W NM W 0 :33»: NH:. F w H %“ N Y\:x:"’\ a In some aspects, the compound has l Formula la: Nm\ N’R Rzfl )QN NW1 x2: N ( R ) X1 H y la wherein R, R1, R2, X1, X2 and y are as previously defined.

In some aspects, the compound has general Formula lb: N H y 1b wherein R, R1, R2, and y are as previously defined.

In some aspects, the compound has general Formula Ic: Rzm NWCYLE‘J’RN\/” EN)?)‘EN Ic wherein R and R2 are as previously defined.

In some aspects, the compound has l Formula Id: R2f\ -------N \ )i"N \N 7/ X\ ‘X i H /’ wherein R, R2, X1 and X2 are as previously defined.

In some aspects, the compound has general Formula Ie: \/"J Ie wherein R, R2, X1 and X2 are as previously defined.

In some s, the compound has general a If: n R, R2, X1, X2, and X3 are as previously defined.

In some aspects, the compound has general Formula 11a: 2017/040093 wherein R, R1, R2, X1, X2, and y are as previously defined.

In some aspects, the compound has l Formula 11b: /N if N?~.. r»; \ N»? R2 \ ' / \ \\ /‘N N““1- \ Lt: /\~N < R I} N H 3’ 11b wherein R, R1, R2, and y are as previously defined.

In some aspects, the compound has general Formula 110: NWN m, R2 \? liq/R \< \ /\\*‘N “ \ \N N H IIc wherein R and R2, are as previously defined.

In some aspects, the compound has general Formula 11d: / N\ NWN N’R R2m / \ X mx'l2., N IId wherein R, R2, X1 and X2 are as previously defined.

In some aspects, the compound has general Formula He: NWN/ \ N”R Rzfl FM X2:X1 N wherein R, R2, X1 and X2 are as previously defined.

In some aspects, the compound has general Formula IIf: N/N\ NW NMR szx3 ,5/ >\ “N \N {g Hf wherein R, R2, X1, X2, and X3 are as previously defined, In some aspects, the compound has l Formula IIIa: Rfl )‘QN {Ifilly, Xzi‘x‘i E IIIa wherein R, R1, R2, X1, X2, and y are as usly defined.

In some aspects, the compound has general Formula IIIb: R2 //\\\\ ho N)\N 1’ R1) wherein R, R1, R2, X, and y are as usly defined.

In some aspects, the compound has general Formula IIIc: Mm“yet X R2/>:\km fl 1110 n R, X, and R2 are as previously defined.

In some aspects, the compound has general a 111d: / /R N \ / N R2 / N.

X \X12‘ N IIId wherein R, R2, X1, and X2 are as previously defined.

In some aspects, the compound has general Formula file: N/ \ / N’R 922%)\NX -:X1 IIIe wherein R, R2, X1, and X2 are as previously .

In some aspects, the compound has general Formula IIIf: wherein R, R2, X1, X2, and X3 are as previously defined.

In some aspects, the compound has general Formula IVa: x g f 0 N \ / R2 /fl)QNN X H (R1) ‘3/ wherein R, R1, R2, X1, X2 and y are as previously .

In some aspects, the compound has general Formula IVb: wherein R, R1, R2, X, and y are as previously defined.

In some aspects, the compound has general Formula IVc: R2 / NW0ow \N H IVc wherein R, X, and R2 are as usly defined.

In some aspects, the compound has general Formula IVd: x if: / 0 N \ / R flNFN2 X \Xl IVd wherein R, R2, X1, and X2 are as previously defined.

WO 05860 In some aspects, the compound has l Formula IVe: wherein R, R2, X1, and X2 are as previously defined.

In some aspects, the compound has general Formula 1sz IVf wherein R, R2, X1, X2, and X3 are as previously defined.

In some aspects, the compound has general Formula Va: xfitx’l H y Va wherein R, R1, R2, X1, X2 and y are as previously defined.

In some aspects, the compound has general Formula Vb: / O n R, R1, R2, and y are as previously defined.

In some aspects, the compound has general Formula Vc: ”WW 0 n R and R2 are as previously defined.

In some aspects, the compound has general a Vd: wherein R, R2, X1, and X2 are as usly defined.

In some aspects, the compound has general Formula Ve: wherein R, R2, X1, and X2 are as previously defined.

In some aspects, the compound has general Formula Vf: \ N / \ o x2~><3 N Xi >\ k“N wherein R, R2, X1, X2, and X3 are as previously defined.

In some aspects, the compound has general Formula VIa: thxi EAN/ N ( at) ’ VIa wherein R, R1, R2, X1, and X2 are as previously defined.

In some aspects, the compound has l Formula VIb: R QfiiN/i g: y v1b wherein R, R1, R2, and y are as previously defined.

In some aspects, the compound has general Formula VIc: RZ / \\ /l'\E / C) \N N N N H K/N\R wherein R and R2 are as previously defined. 2017/040093 In some aspects, the compound has general Formula VId: wherein R, R2, X1, and X2 are as previously defined.

In some aspects, the compound has general Formula VIe: a.X1 N VIe wherein R, R2, X1, and X2 are as previously .

In some aspects, the compound has general Formula VIf: wherein R, R2, X1, X2, and X3 are as previously defined.

In some aspects, the compound has general Formula VIIa: WX” N N 3 XL N \R \X1 H VIIa wherein R, R2, X1, and X2 are as previously .

In some aspects, the compound has general Formula VIIb: VIIb wherein R, R2, X1, X2, and X3 are as previously defined.

In some aspects, the compound has general Formula VIIIa: szzN N/ \ N%N X"-":X1 VIIIa wherein R2, X1, and X2 are as previously defined.

In some aspects, the compound has general a VIIIb: / Om N N Rifl>:'__"'“N XZ-lrxi NH VIIIb wherein R2, X1, and X2 are as previously defined.

In some aspects, the compound has general Formula VIIIc: N/\ “"‘N Rzfl:HmN VIIIc wherein R2, X1, and X2 are as previously .

In some aspects, the compound has general a VIIId: VIIId wherein R2, X1, and X2 are as previously defined.

In some aspects, the compound has general Formula VIIIe: / N flit>:N X2"? VIIIe wherein R2, X1, and X2 are as previously defined.

In some aspects, the compound has general Formula VIIIf: / \ N N N N ——_—-N o ngxl VIIIf wherein R2, X1, and X2 are as previously defined.

In some aspects, the compound has general Formula IXa: \ O A \ \ X":X1 fi wherein R, R2, X1, and X2 are as previously defined.

In some aspects, the compound has general a IXb: ~71”\\ : X/LNA>\xmlh, New/kw l <———-—“A?» IXb wherein R, R2, X1, X2, and X3 are as previously .

In some aspects, the compound has general Formula Xa: wherein R, R2, X1, and X2 are as previously defined.

In some aspects, the compound has general Formula Xb: wherein R, R2, X1, X2, and X3 are as previously defined.

In some aspects, the compound has general Formula XIa: wherein R, R2, X1, and X2 are as previously defined.

In some aspects, the nd has general Formula XIb: N x N" xzflflxg N // \ N X1 ~~~~ \ l I wherein R, R2, X1, X2, and X3 are as previously .

In some aspects, the compound has general Formula XIIa: N)\\ i . x3§x1 N XIIa wherein R, R2, X1, and X2 are as previously defined.

In some s, the compound has general Formula XIIb: XIIb wherein R, R2, X1, X2, and X3 are as previously defined.

In some aspects, the compound has general Formula XIIIa: WM \ N )(thl XIIIa wherein R2, X1, and X2 are as previously defined.

In some aspects, the compound has general Formula XIIIb: XIIIb n R2, X1, X2, and X3 are as previously defined.

In some aspects, the compound has general Formula XIVa: XIVa wherein X, R2, X1, and X2 are as previously defined.

In some aspects, the compound has general Formula XIVb: XIVb wherein X, R2, X1, X2, and X3 are as previously defined.

In some aspects, the compound has general Formula XVa: wherein R, R2, X1, and X2 are as previously defined.

In some aspects, the compound has general Formula XVb: wherein R, R2, X1, X2, and X3 are as usly defined.

In some aspects, the compound has general a XVIa: XVIa n R2, X1, and X2 are as previously defined, 2017/040093 In some aspects, the compound has general Formula XVIb: XVIb wherein R2, X1, X2, and X3 are as previously defined.

In some aspects, the compound has general Formula XVIIa: wherein R, R2, X1, and X2 are as previously defined.

In some aspects, the compound has general a XVIIb: XVIIb wherein R, R2, X1, X2, and X3 are as previously defined.

In some aspects, the compound has general Formula XVIIIa: 7 N X '—~..X12g E N N y XVIIIa n R1, R2, R10, X1, X2, X3, and y are as previously defined.

In some s, the compound has general Formula XVIIIb: R /\N\ W/NE \ (R1), XVIIIb wherein R, R1, R2, R10 and y are as previously defined.

In some aspects, the compound has l a XVIIIc: R2:N\ fixN/fi XVIIIc wherein R, R2 and R10 are as previously defined.

In some aspects, the compound has general Formula XVIIId: R2 / \ /’U\ / X2136 E N N XVIIId wherein R, R2, R10, X1, and X2 are as previously defined.

In some aspects, the compound has general Formula XVIIIe: R2 / \ l X 'zrxi2 E N XVIIIe wherein R, R2, R10 X1, and X2 are as previously defined. 2017/040093 In some aspects, the nd has general Formula XIVa: {jg/W).x2:\NH X. .

XIXa wherein R2, X1, and X2 are as previously defined.

In some aspects, the compound has general a XIXb: R2flXk{Cw \X I XIXb wherein R2, X1, and X2 are as previously defined.

In some aspects, the compound has general Formula XIXc: N/\N X xx] XIXC wherein R2, X1, and X2 are as previously defined.

In some s, the compound has general Formula XIXd: XIXd wherein R2, X1, and X2 are as previously defined.

In some aspects, the compound has general Formula XIXe: R‘------------NHx2=x1(KN/”“037 XIXe wherein R2, X1, and X2 are as previously defined.

In some aspects, the compound has general Formula XXa: Rzfl )\N/x:X1\WdNRxxaN wherein R, R2, X1, and X2 are as previously defined.

In some s, the compound has general Formula XXb: [N \ 4N” X2”"X3x)fip JN >\N ~~‘. \/ m wherein R, X1, X2, and X3 are as previously defined.

In some aspects, the compound has l Formula XXc: Rgfl N\N/X::X1H N XXc wherein R, R2, X1, and X2 are as previously defined.

In some aspects, the compound has l Formula XXd: wherein R, X1, X2, and X3 are as previously defined.

In some aspects, the compound has general Formula XXIa: RZfl”N2‘ X “X1 N XXIa wherein R2, X1, and X2 are as previously defined.

In some s, the compound has general Formula XXIb: --...._ \\ ”'/\ xzw—fl \ i I >\ )NI/ )xtj/N \3 g k I ””J/ XXIb wherein X1, X2, and X3 are as previously defined.

In some aspects, the compound has general a XXIIa: XXIIa wherein R2, X1, and X2 are as previously defined.

In some aspects, the compound has general Formula XXIIb: N N sz—mxs \ / N XXIIb n X1, X2, and X3 are as previously defined.

WO 05860 2017/040093 In some aspects, the compound has general Formula : R2flfi)‘N 640N/vw, X2a.X1 XXIIIa wherein R, R2, X1, and X2 are as previously defined, In some aspects, the compound has general Formula XXIIIb: X2WX) / ll] >\ N \N , NwN:R XXIIIb wherein R, X1, X2, and X3 are as previously defined.

In some embodiments, the compound is selected from a Formula presented above and X1 is N and X2 is CH. In other ments, the compound is selected from a Formula presented above and X1 is N and X2 is N. In other embodiments, the compound is selected from a Formula presented above and X1 is CH and X2 is CH. In other embodiments, the compound is selected from a Formula presented above and X1 is CH and X2 is N.

In some embodiments, the compound is selected from a Formula presented above and X1 is N, X2 is CH, X3 is CH, and X4 is CH. In other embodiments, the compound is selected from a Formula presented above and X1 is CH, X2 is N, X3 is CH, and X4 is CH. In other embodiments, the compound is selected from a Formula presented above and X1 is CH, X2 is N, X3 is N, and X4 is CH. In other embodiments, the compound is selected from a Formula ted above and X1 is CH, X2 is N, X3 is CH, and X4 is N. In other embodiments, the nd is selected from a Formula presented above and X1 is N, X2 is CH, X3 is N, and X4 is CH. In other embodiments, the compound is selected from a Formula presented above and X1 is N, X2 is CH, X3 is CH, and X4 is N.

In some embodiments, the compound is selected from a Formula ted above and _R2*_N P* (RX’I )t R2 is wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R”, R"1 and t are as previously defined.

In some embodiments, the compound is selected from a a presented above and —R2*—N P* (RX1)t R2 is wherein P* is a 4- to 8-membered mono— or bicyclic saturated heterocyclyl group, RX1 is hydrogen or unsubstituted C1-C4 alkyl and R2* is as previously defined.

In some embodiments, the compound is selected from a Formula presented above and I {\A $&&»’\ min “5‘“:g m R2 is selected from 0 A” ’ \ , x , ‘; A»! l 3““ xx} §\N/\\] 0 L\/i\l §\NA] \{’ s s ’8 \V \7/ L\/N\ and ‘ ‘C o N N— In some embodiments, the compound is selected from a Formula presented above and :», %, «x N/\l SK ‘3‘ i LVN W 1:wais selected from, \v” N\, and In some embodiments, the compound is selected from a a presented above and R is alkyl.

In some ments, the compound is selected from a Formula presented above and R is hydrogen.

In some embodiments Rx is further substituted with a substituent chosen from: -(alkylene)m-CN, —(alkylene)m-OR5*, lene)m-S(O)n—R5*, -(alkylene)m-NR3*R4*, -(alkylene)m-C(O)—R5*, -(alkylene)m-C(=S)R5*, -(alkylene)m-C(=O)O R5*, -(alky1ene)m-OC(=O)R5*, -(alkylene)m-C(S)—OR5*, -(alkylene)m-C(O)—NR3*R4*, -(alkylene)m-C(S)—NR3*R4*, —(alkylene)m-N(R3*)—C(O)—NR3*R4*, lene)m-N(R3*)—C(S)—NR3*R4*, -(alkylene)m-N(R3*)—C(O)—R5*, -(alkylene)m-N(R3*)—C(S)—R5*, —(alkylene)m-O—C(O)—NR3*R4*, lene)m-O—C(S)—NR3*R4*, -(alkylene)m-802—NR3*R4*, -(alkylene)m-N(R3*)—SOz—R5*, -(alkylene)m-N(R3*)—SOz—NR3*R4*, -(alkylene)m-N(R3*)—C(O)—OR5*, -(alkylene)m-N(R3*)—C(S)—OR5*, and -(alkylene)m-N(R3*)—SOz—R5*; R3* and R4* at each occurrence are independently selected from: (i) hydrogen or (ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, kyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more Rx groups as allowed by valance; or R3* and R4* together with the en atom to which they are attached may combine to form a cyclo ring optionally independently substituted with one or more RX groups as allowed by valance.

R5* is independently selected at each occurrence from: (i) hydrogen or (ii) alkyl, alkenyl, alkynyl, lkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more RX groups as allowed by valance; 2017/040093 In some embodiments the compound of the present invention is selected from: R2 (12), 1:12 (112), R2 3‘ O «.2 \ N /R N N O N\ J >60 \ / N HEN/LN 3;; N Ni \ , 1 C? HM (R) HN/L‘N/ N (1112), R2 (1V2), HN HN ‘ \R!,') N ~N ( R ) / I? y / / \ 1 3’ (V12), i2? (V112), R3 (V1112), R2 0 R1 X MIR i j / \ / N N N \ FM ( R‘) )‘N i W1 1 HM (I R HN )y f N / N 1 \ (IXz), R2 (Xz), R2 (XIz), (XVIz), R’2 (XVIIz) R2 (XVIIIz), and R2 (XIXz); n: N" N E ‘1 N R2 IS selected from,. \V" 7” LVN\ and 00-; In an ative embodiment, the compound of the present invention is selected from: N\\/ N IN/R N)\\/ z 7L0 N H~ 7* ( R1 N / [i] )y / 2 2 R (XX), R NfQTW NC] )\N , \BVQ )\N W0 HN (R1)y HN (R1) / N / N \ \ R2 (XXII),and R2 (XXIII), wherein: R2 is selected from, 0 NCN— \_/ § II. TERMINOLOGY Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

The nds in any of the as described herein include racemates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N— oxides, isomers; such as rotamers, as if each is specifically described.

The terms “a” and “an” do not denote a limitation of quantity, but rather denote the ce of at least one of the referenced item. The term “or” means “and/or”. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.

The endpoints of all ranges are included within the range and independently able. All methods described herein can be med in a le order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a tion on the scope of the invention unless otherwise claimed. Unless defined otherwise, technical and ific terms used herein have the same meaning as is commonly tood by one of skill in the art to which this invention belongs.

The present invention includes compounds of Formula 1, Formula II, Formula III Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, a XI, a XII, Formula XIII, Formula XIV, Formula XV, a XVI, Formula XVII, Formula XVIII, and Formula XIX with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.

Examples of isotopes that can be orated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine such as 2H, 3H, 11C, 13C, 14C, 15N, 18F 31P, 32P, 358, 36CI, and 125I respectively. In one non- limiting embodiment, isotopically labelled compounds can be used in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography ) including drug or substrate tissue bution assays, or in radioactive treatment of patients. In particular, an 18F labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this invention and prodrugs f can generally be ed by canying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a otopically labeled reagent.

By way of general e and without limitation, isotopes of hydrogen, for example, deuterium (2H) and tritium (3H) may be used anywhere in described structures that achieves the desired . Alternatively or in addition, isotopes of carbon, e.g., 13C and 14C, may be used.

Isotopic substitutions, for example ium substitutions, can be partial or te.

Partial deuterium substitution means that at least one hydrogen is substituted with deuterium.

In certain embodiments, the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In one non-limiting embodiment, deuterium is 90, 95 or 99% enriched at a desired location.

In one non-limiting embodiment, the substitution of a hydrogen atom for a ium atom can be provided in any of a I, Formula II, a III Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, a XVII, Formula XVIII, a XIX, Formula XX, Formula XXI, Formula XXII, or Formula XXIII. In one non- limiting embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within a group selected from any of R, R1, R2, R3, R4, R5, R6, R7, R8, R9, and RX. For example, when any of the groups are, or contain for example through substitution, methyl, ethyl, or methoxy, the alkyl residue may be ated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3 etc). In certain other embodiments, when two substituents are combined to form a cycle the unsubstituted carbons may be deuterated.

The compound of the present invention may form a solvate with solvents (including water). Therefore, in one non-limiting embodiment, the invention includes a solvated form of the compound. The term "solvate" refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a nd of the invention and water. Pharmaceutically acceptable es in accordance with the invention include those wherein the solvent may be isotopically substituted, e. g. D20, tone, d6- DMSO. A solvate can be in a liquid or solid form.

A dash ("-") that is not n two letters or s is used to te a point of attachment for a substituent. For example, -(C=O)NH2 is attached through carbon of the keto (C=O) group.

“Alkyl” is a branched or straight chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, the alkyl group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one non- limiting embodiment, the alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species. For example, the term C1-C6 alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species. For example, the term C1-C4 alkyl as used herein indicates a straight or ed alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is bed as an independent species. Examples of alkyl include, but are not limited to, methyl, ethyl, yl, pyl, n-butyl, isobutyl, sec-butyl, t-butyl, n— pentyl, isopentyl, tert—pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2- dimethylbutane, and 2,3—dimethylbutane. In an alternative embodiment, the alkyl group is optionally substituted. The term ” also encompasses cycloalkyl or carbocyclic groups.

For example, when a term is used that includes “alk” then “cycloalkyl” or cyclic” can be considered part of the definition, unless unambiguously excluded by the context. For example, and without limitation, the terms alkyl, alkoxy, haloalkyl, etc. can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context.

“Alkenyl” is a linear or branched aliphatic hydrocarbon groups having one or more carbon-carbon double bonds that may occur at a stable point along the chain. The specified ranges as used herein indicate an alkenyl group having each member of the range described as an ndent species, as described above for the alkyl moiety. Examples of alkenyl radicals include, but are not limited to ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.

The term “alkenyl” also embodies “cis” and “trans” alkenyl geometry, or altematively, “”E and “Z” alkenyl geometry. In an alternative embodiment, the alkenyl group is optionally substituted. The term “Alkenyl” also encompasses cycloalkyl or carbocyclic groups sing at least one point of unsaturation.

“Alkynyl” is a branched or straight chain tic arbon group having one or more -carbon triple bonds that may occur at any stable point along the chain. The specified ranges as used herein indicate an alkynyl group having each member of the range bed as an independent species, as described above for the alkyl . Examples of l include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, l-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. In an alternative embodiment, the alkynyl group is ally substituted. The term “Alkynyl” also encompasses cycloalkyl or carbocyclic groups possessing at least one point of unsaturation.

“Halo” and “Halogen” is fluorine, chlorine, bromine or iodine.

“Haloalkyl” is a branched or straight-chain alkyl groups substituted with 1 or more halo atoms described above, up to the maximum ble number of halogen atoms. es of haloalkyl groups include, but are not limited to, ethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, ochloromethyl, dichlorofluoromethyl, difluoroethyl, opropyl, dichloroethyl and dichloropropyl. “Perhaloalkyl” means an alkyl group having all hydrogen atoms replaced with halogen atoms, Examples include but are not limited to, trifluoromethyl and pentafluoroethyl.

“Haloalkoxy” indicates a haloalkyl group as defined herein attached through an oxygen bridge n of an l radical).

As used herein, “aryl” refers to a radical of a monocyclic or clic (e.g., bicyclic or lic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 7t electrons shared in a cyclic array) having 6—14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce—14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., ). In some embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”, e.g., yl such as 1—naphthyl and 2—naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. The one or more fused carbocyclyl or heterocyclyl groups can be 4 to 7 or 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl groups that optionally contain 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, to form, for example, a 3,4-methylenedioxyphenyl group. In one non-limiting embodiment, aryl groups are pendant. An example of a pendant ring is a phenyl group tuted with a phenyl group. In an alternative embodiment, the aryl group is optionally substituted as described above. In certain embodiments, the aryl group is an unsubstituted C67 14 aryl. In certain embodiments, the aryl group is a substituted C6714 aryl. An aryl group may be optionally tuted with one or more functional groups that include but are not limited to, halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocyclo.

The term “heterocyclyl” (or “heterocyclo”) includes saturated, and partially saturated heteroatom—containing ring radicals, where the heteroatoms may be ed from nitrogen, sulfur and oxygen. Heterocyclic rings comprise monocyclic 6-8 membered rings, as well as 5- 16 membered bicyclic ring systems (which can include bridged fused and Spiro-fused ic ring systems). It does not include rings containing -O-O-.—O-S- or -S-S— portions. Said 2017/040093 “heterocyclyl” group may be optionally substituted with 1 to 3 substituents that include but are not limited to, yl, Boc, halo, haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy, and amino.

Examples of saturated heterocyclo groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, irnidazolidinyl, inyl, pyrrolinyl, piperazinyl], saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6- membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. es of partially saturated and saturated heterocyclo groups include but are not limited to, pyrrolidinyl, irnidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, linyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2- dihydroquinolyl, 1,2,3,4- tetrahydro-isoquinolyl, 1 ,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a— hexahydro-lHaza—fluorenyl, 5,6,7- ro-l,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro- 2H-benzo[l,4]oxazinyl, benzo[l,4]dioxanyl, 2,3- dihydro—lH-lk’-benzo[d]isothiazolyl, dihydropyranyl, dihydrofuryl and othiazolyl.

Heterocyclo groups also include radicals Where heterocyclic radicals are fused/condensed with aryl radicals: such as unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for e, indoline, oline, unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, rated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms.

The term oaryl” s aryl ring systems that contain one or more heteroatoms ed from O, N and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized. Examples include but are not d to, unsaturated 5 to 6 membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, IH-l ,2,3-triazolyl, 2H-l,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic groups containing an oxygen atom, for e, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered monocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc; rated 5- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for e, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5- oxadiazolyl], rated 5 to 6—membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, thiadiazolyl, 1,2,5-thiadiazoly1].

The term “sulfonyl”, whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SOz-.

The terms “carboxy” or “carboxyl”, Whether used alone or with other terms, such as “carboxyalkyl”, denotes —C(O)—OH.

The term “carbonyl”, Whether used alone or with other terms, such as “aminocarbonyl”, denotes -C(O)-.

The term carbonyl” denotes an amide group of the formula -C(O)—NH2.

The terms “heterocycloalkyl” denotes heterocyclic-substituted alkyl ls. Examples include but are not d to, piperidylmethyl and morpholinylethyl.

“Arylalkyl” is an aryl group as defined herein attached through an alkyl group. Non— limiting examples of arylalkyl groups include: 3 “’ I . 315V.

“Heteroarylalkyl” is a heteroaryl group as defined herein attached h an alkyl “Aryloxy” is an aryl group as defined herein attached through a —O- linker. Non- QR); limiting examples of aryloxy groups include: 310 and ‘50 As used herein, “carbocyclyl”, c ‘carbocyclic”, cycle” or “cycloalkyl” is a saturated or partially unsaturated (i.e., not aromatic) group containing all carbon ring atoms WO 05860 and from 3 to 14 ring carbon atoms (“C3714 carbocyclyl”) and zero heteroatoms in the non— aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3710 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 9 ring carbon atoms (“C3_9 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C378 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C377 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C376 carbocyclyl”). In some ments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C476 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C576 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5710 yclyl”). Exemplary C376 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like.

Exemplary C3—3 carbocyclyl groups include, without limitation, the entioned C3_6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), and the like. Exemplary C3710 carbocyclyl groups include, without limitation, the aforementioned C378 carbocyclyl groups as well as cyclononyl (C9), onenyl (C9), ecyl (C10), cyclodecenyl (C10), and the like.

As the foregoing examples illustrate, in certain ments, the carbocyclyl group can be saturated or can contain one or more carbon—carbon double or triple bonds. In an alternative embodiment, “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more heterocyclyl, aryl or heteroaryl groups wherein the point of attachment is on the yclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. In an alternative embodiment, each instance of carbocycle is optionally substituted with one or more tuents. In n embodiments, the yclyl group is an unsubstituted C3714 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3714 carbocyclyl.

“Cycloalkylalkyl” is an cycloalkyl group as defined herein attached through an alkyl group. Non-limiting examples of cycloalkylalkyl groups include: 9 7 wax/O The term “oxo” as used herein contemplates an oxygen atom attached with a double bond.

III. METHODS OF TREATMENT In one aspect, a method of treating a proliferative disorder in a host, including , is provided comprising administering an effective amount of a compound of Formula I, Formula II, Formula III Formula IV, a V, a VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, a XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, a XXIV, or Formula XXV. or its pharmaceutically acceptable salt, N—oxide, deuterated derivative, g, and/or a pharmaceutically acceptable composition thereof as described herein optionally in a pharmaceutically acceptable carrier. Non-limiting examples of disorders e tumors, s, disorders related to abnormal cellular proliferation, inflammatory disorders, immune disorders, and autoimmune disorders.

A compound of Formula I, Formula II, Formula III a IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, a X, Formula XI, a XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or Formula XXV is useful as therapeutic agents when administered in an effective amount to a host, including a human, to treat , cancer , non-solid, diffuse, hematological, etc), abnormal cellular proliferation, immune disorder, inflammatory disorder, blood disorder, a myelo- or lymphoproliferative disorder such as B- or T-cell lymphomas, multiple myeloma, breast , prostate cancer, AML, ALL, ACL, lung cancer, pancreatic cancer, colon cancer, skin cancer, melanoma, Waldenstrom’s macroglobulinemia, Wiskott-Aldrich syndrome, or a post— transplant lymphoproliferative disorder; an autoimmune disorder, for example, Lupus, Crohn’s Disease, Addison disease, Celiac disease, dermatomyositis, Graves disease, ditis, multiple sclerosis, pernicious anemia, reactive arthritis, or type I diabetes, a disease of cardiologic malfunction, including hypercholesterolemia, an infectious disease, including a viral and/or bacterial infection; an inflammatory condition, ing asthma, chronic peptic ulcers, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, or hepatitis.

Exemplary proliferative disorders include, but are not limited to, benign growths, neoplasms, tumors, cancer (Rb positive or Rb ve), autoimmune disorders, atory disorders graft-versus-host rejection, and fibrotic disorders.

Non-limiting examples of cancers that can be treated according to the present ion include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, arcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, iosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, y cancer, medullary carcinoma of the breast), brain cancer (e.g., meningioma, glioma, e.g., astrocytoma, oligodendroglioma; oblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, eliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarinoma), Ewing’s sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g., stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell oma, oral cancer (e.g., oral squamous cell carcinoma (OSCC), throat cancer (e.g., laryngeal cancer, pharyngeal , nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic s (e. g, ia such as acute cytic leukemia (ALL) — also known as acute lymphoblastic leukemia or acute lymphoid leukemia (e.g., B—cell ALL, T—cell ALL), acute myelocytic leukemia (AML) (e.g., B—cell AML, T—cell AML), chronic myelocytic leukemia (CML) (e.g., B—cell CML, T—cell CML), and chronic lymphocytic ia (CLL) (e.g., B—cell CLL, T—cell CLL); lymphoma such as n lymphoma (HL) (e.g., B—cell HL, T—cell HL) and non—Hodgkin lymphoma (NHL) (e.g., B—cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B—cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B—cell mas (e.g., — associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B—cell lymphoma, c marginal zone B—cell lymphoma), primary mediastinal B—cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., “Waldenstrém's macroglobulinemia”), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B—lymphoblastic ma and primary central nervous system (CNS) lymphoma; and T—cell NHL such as precursor T—lymphoblastic lymphoma/leukemia, peripheral T—cell lymphoma (PTCL) (e.g., cutaneous T—cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome), mmunoblastic T—cell lymphoma, extranodal natural killer T—cell lymphoma, enteropathy type T—cell lymphoma, subcutaneous panniculitis—like T—cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above, and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory oblastic tumors, cytic amyloidosis, kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), all cell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e. g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., themia Vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) aka. brosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e. g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., enteropancreatic ndoctrine tumor (GEP—NET), carcinoid tumor), arcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e. g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm , Islet cell tumors), penile cancer (e.g., Paget’s disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., appendix cancer), soft tissue sarcoma (e. g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, rcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the d, papillary thyroid carcinoma (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget’s disease of the vulva).

In another embodiment, the er is myelodysplastic syndrome (MDS).

In certain embodiments, the cancer is ahematopoietic cancer. In n embodiments, the hematopoietic cancer is a ma. In certain embodiments, the hematopoietic cancer is a leukemia. In n embodiments, the leukemia is acute myelocytic leukemia (AML).

In certain embodiments, the proliferative er is a myeloproliferative neoplasm. In certain ments, the myeloproliferative neoplasm (MPN) is primary myelofibrosis (PMF).

In certain embodiments, the cancer is a solid tumor. A solid tumor, as used herein, refers to an al mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumors are named for the type of cells that form them. Examples of classes of solid tumors include, but are not limited to, sarcomas, carcinomas, and mas, as described above herein. Additional examples of solid tumors include, but are not limited to, squamous cell oma, colon cancer, breast cancer, prostate cancer, lung cancer, liver cancer, pancreatic cancer, and melanoma.

In certain ments, the condition treated with a compound of Formula I, Formula II, Formula III Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or Formula XXV is a disorder related to abnormal cellular proliferation.

Abnormal cellular proliferation, notably roliferation, can occur as a result of a wide variety of factors, including genetic mutation, infection, exposure to toxins, autoimmune disorders, and benign or malignant tumor ion.

There are a number of skin disorders associated with cellular hyperproliferation.

Psoriasis, for example, is a benign disease of human skin generally characterized by plaques covered by thickened scales. The disease is caused by increased proliferation of epidermal cells of unknown cause. c eczema is also associated with icant hyperproliferation of the epidermis. Other diseases caused by hyperproliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma and squamous cell carcinoma.

Other hyperproliferative cell disorders include blood vessel proliferation disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors and cancers.

Blood vessel proliferative ers include angiogenic and vasculogenic disorders. eration of smooth muscle cells in the course of development of plaques in vascular tissue cause, for example, restenosis, retinopathies and atherosclerosis. Both cell migration and cell proliferation play a role in the ion of atherosclerotic lesions. ic ers are often due to the abnormal ion of an extracellular matrix.

Examples of fibrotic disorders include hepatic cirrhosis and mesangial proliferative cell disorders, Hepatic cirrhosis is characterized by the increase in extracellular matrix constituents resulting in the ion of a hepatic scar. Hepatic cirrhosis can cause diseases such as cirrhosis of the liver. An increased extracellular matrix ing in a hepatic scar can also be caused by viral infection such as hepatitis. Lipocytes appear to play a major role in hepatic cirrhosis.

Mesangial disorders are brought about by abnormal proliferation of mesangial cells.

Mesangial hyperproliferative cell disorders include s human renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic micro- angiopathy syndromes, transplant rejection, and glomerulopathies.

Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid tis is generally considered an autoimmune disease that is thought to be associated with activity of autoreactive T cells, and to be caused by autoantibodies produced against collagen and IgE.

Other disorders that can include an abnormal cellular erative ent include Bechet’s syndrome, acute respiratory distress syndrome (ARDS), ic heart disease, post- dialysis syndrome, leukemia, acquired immune ncy syndrome, vasculitis, lipid histiocytosis, septic shock and inflammation in general.

In certain embodiments, a compound of the present invention and its pharmaceutically acceptable derivatives or pharmaceutically acceptable formulations containing these compounds are also useful in the prevention and treatment ofHBV infections and other related conditions such as anti-HBV antibody positive and HBV-positive conditions, chronic liver inflammation caused by HBV, cirrhosis, acute tis, fulrninant hepatitis, chronic persistent hepatitis, and e. These compounds or ations can also be used lactically to prevent or retard the progression of clinical illness in individuals who are anti-HBV antibody or tigen positive or who have been d to HBV.

In certain embodiments, the condition is associated with an immune response.

Cutaneous contact hypersensitivity and asthma are just two examples of immune responses that can be ated with significant morbidity. Others include atopic dermatitis, eczema, Sjogren's Syndrome, including keratoconjunctivitis sicca secondary to Sjogren's Syndrome, ia areata, allergic responses due to arthropod bite reactions, Crohn's disease, aphthous ulcer, intis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions may result in any one or more of the ing symptoms or signs: itching, swelling, s, blisters, crusting, ulceration, pain, scaling, cracking, hair loss, scarring, or oozing of fluid involving the skin, eye, or mucosal membranes.

In atopic dermatitis, and eczema in general, immunologically mediated leukocyte infiltration cularly infiltration of mononuclear cells, lymphocytes, neutrophils, and eosinophils) into the skin importantly contributes to the pathogenesis ofthese es. Chronic eczema also is ated with significant hyperproliferation of the epidermis.

Immunologically mediated leukocyte infiltration also occurs at sites other than the skin, such as in the airways in asthma and in the tear producing gland of the eye in keratoconjunctivitis sicca.

In one non-limiting embodiment compounds ofthe present invention are used as topical agents in treating contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's Syndrome, including keratoconjunctivitis sicca secondary to Sjogren‘s Syndrome, alopecia areata, allergic responses due to arthropod bite reactions, Crohn's disease, aphthous ulcer, iritis, ctivitis, keratoconjunctivitis, ulcerative colitis, , allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. The novel method may also be useful in reducing the infiltration of skin by malignant leukocytes in diseases such as mycosis fungoides. These compounds can also be used to treat an aqueous— deficient dry eye state (such as immune ed conjunctivitis) in a patient suffering therefrom, by administering the compound topically to the eye.

The term asia” or “cancer” is used throughout the specification to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue (solid) or cells (non-solid) that grow by cellular eration, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease. Malignant sms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, can metastasize to several sites, are likely to recur after attempted removal and may cause the death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states and embraces or asses the pathological process associated with malignant hematogenous, ascitic and solid tumors. Exemplary cancers which may be treated by the present disclosed compounds either alone or in ation with at least one additional anti-cancer agent include us-cell carcinoma, basal cell carcinoma, arcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, te, and h; leukemias; benign and malignant lymphomas, ularly Burkitt’s lymphoma and Non-Hodgkin's lymphoma, benign and malignant melanomas; myeloproliferative diseases; sarcomas, including s sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, stomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas, bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian , testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, atic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas.

Additional cancers which may be treated using the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, arcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast , triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are ve), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HERZ- negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast , luminal B breast cancer, Her2- negative breast cancer, HERZ—positive or ve breast cancer, progesterone or- ve breast cancer, progesterone receptor—positive breast cancer, ent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, c cytic leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal , ewing sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder , c cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin ma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC), inal Cancer, intrahepatic bile duct cancer, invasive/infiltrating breast cancer, Islet cell cancer, jaw , Kaposi sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal ases, leukemia, lip , liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary oma, medulloblastoma, melanoma, meningioma, Merkel cell oma, mesenchymal chondrosarcoma, mesenchymous, mesothelioma atic breast cancer, metastatic melanoma metastatic squamous neck , mixed gliomas, monodermal teratoma, mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma, Mycosis des, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, n epithelial cancer n germ cell tumor, ovarian primary neal carcinoma, n sex cord stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid , pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary gland cancer, primary l nervous system (CNS) lymphoma, prostate , rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine , spinal cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial a, T-cell lymphoma, testicular cancer, throat cancer, thymoma/thymic carcinoma, d cancer, tongue cancer, tonsil cancer, transitional cell cancer, tubal cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic ia (T-ALL), T-cell lineage lymphoblastic lymphoma (T- LL), peripheral T-cell lymphoma, Adult T-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia some positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, Adult T— cell chronic leukemia, diffuse large B cell lymphoma, follicular lymphoma, Mucosa— Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B cell lymphoma, nodal al zone B cell ma ; splenic marginal zone lymphoma (SMZL), intravascular large B-cell lymphoma; primary effusion lymphoma, or lymphomatoid granulomatosis,, B-cell prolymphocytic leukemia; splenic lymphoma/leukemia, unclassifiable, splenic diffuse red pulp small B—cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, for example, Alpha heavy chain e, Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, primary cutaneous follicle center lymphoma, T cell/histocyte rich large B-cell lymphoma, DLBCL associated with chronic inflammation, Epstein-Barr virus (EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell ma, plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated entric, Castleman disease, B-cell lymphoma, unclassifiable, with es intermediate between diffuse large B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B—cell lymphoma and classical Hodgkin lymphoma.

In another aspect, a method of increasing BIM expression (e. g., BCLC2L11 expression) is provided to induce apoptosis in a cell comprising contacting a compound of the t invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof with the cell. In certain ments, the method is an in vitro method. In certain embodiments, the method is an in viva method. BCL2L11 expression is tightly regulated in a cell. BCL2L11 s for BIM, a proapoptotic protein. 1 is downregulated in many cancers and BIM is inhibited in many cancers, including chronic myelocytic leukemia (CML) and non-small cell lung cancer (NSCLC) and that suppression of BCL2L11 expression can confer resistance to tyrosine kinase inhibitors. See, e.g., Ng et al., Nat. Med. (2012) 18:521— 528.

In yet another aspect, a method of treating a condition associated with angiogenesis is provided, such as, for example, a diabetic condition (e.g., diabetic pathy), an inflammatory condition (e.g., rheumatoid arthritis), macular degeneration, obesity, atherosclerosis, or a erative disorder, sing administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic , or prodrug thereof.

In certain embodiments, the condition associated with angiogenesis is macular degeneration. In certain embodiments, provided is a method of treating macular degeneration comprising administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof.

In certain embodiments, the condition associated with angiogenesis is y. As used herein, “obesity” and “obese” as used herein, refers to class I obesity, class II obesity, class III y and esity (e.g., being “over-weight”) as defined by the World Health Organization. In certain embodiments, a method of treating obesity is provided comprising administering to a subject in need thereof a compound of the present ion or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof In certain ments, the condition associated with angiogenesis is atherosclerosis.

In certain embodiments, provided is a method of ng atherosclerosis comprising administering to a t in need thereof a compound of the present invention or a ceutically able composition, salt, isotopic analog, or g thereof.

In certain embodiments, the condition associated with angiogenesis is a proliferative disorder. In certain embodiments, provided is a method of treating a proliferative disorder comprising administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof.

IV. METHODS TO REDUCE THE SIDE EFFECTS D TO CHEMOTHERAPY In certain embodiments, nds of the present ion decrease the effect of chemotherapeutic agent ty on CDK4/6 replication dependent healthy cells, such as hematopoietic stem cells and hematopoietic progenitor cells her referred to as HSPCs), and/or renal epithelial cells, in subjects, typically humans, that will be, are being, or have been exposed to the chemotherapeutic agent (typically a DNA-damaging agent).

In one embodiment, the subject has been exposed to a chemotherapeutic agent, and, using a compound described herein, the subj ect’s CDK4/6-replication dependent healthy cells are placed in G1 arrest following exposure in order to mitigate, for example, DNA damage. In one embodiment, the compound is administered at least 1/2 hour, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours or more post chemotherapeutic agent exposure.

In one embodiment, the compound can allow for dose intensification (e.g., more y can be given in a fixed period of time) in lly d chemotherapies, which will translate to better efficacy. Therefore, the presently disclosed methods can result in chemotherapy regimens that are less toxic and more effective.

In some embodiments, the use of a compound described herein may result in reduced or substantially free of off—target effects, for example, related to inhibition of kinases other than CDK4 and/or CDK6 such as CDK2. Furthermore, in certain embodiments, the use of the compounds described herein should not induce cell cycle arrest in CDK4/6 replication independent cells.

In some embodiments, the use of a nd described herein reduces the risk of undesirable off-target effects including, but not limited to, long term toxicity, anti—oxidant effects, and estrogenic effects. Anti-oxidant effects can be determined by standard assays known in the art. For example, a nd with no significant anti-oxidant s is a compound that does not significantly scavenge free-radicals, such as oxygen radicals. The anti-oxidant effects of a compound can be ed to a compound with known anti-oxidant activity, such as genistein. Thus, a compound with no significant anti-oxidant activity can be one that has less than about 2, 3, 5, 10, 30, or 100 fold anti-oxidant activity relative to genistein.

Estrogenic ties can also be determined via known assays. For instance, a non-estrogenic compound is one that does not significantly bind and activate the estrogen receptor. A nd that is substantially free of estrogenic effects can be one that has less than about 2, 3, 5, 10, 20, or 100 fold estrogenic activity relative to a compound with estrogenic activity, e. g., genistein.

V. METHODS TO TREAT ABNORMAL PROLIFERATION OF T-CELLS, B- CELLS AND/OR NK—CELLS In certain s, the invention includes the use of an effective amount of a compound described , or its pharmaceutically acceptable salt, prodrug or isotopic variant optionally in a pharmaceutical composition, to treat a host, typically a human, with a selected cancer, tumor, hyperproliferative condition or an inflammatory or immune disorder. Some of the disclosed compounds are highly active against T-cell proliferation. Given the paucity of drugs for T-cell cancers and abnormal proliferation, the identification of such uses represents a substantial improvement in the medical y for these diseases. al proliferation of T-cells, B-cells, and/or NK-cells can result in a wide range of es such as cancer, proliferative disorders and inflammatory/immune es. A host, for example a human, afflicted with any of these disorders can be treated with an effective amount of a compound as described herein to achieve a decrease in ms (a palliative agent) or a decrease in the underlying disease (a disease modifying agent).

Examples include T-cell or NK-cell lymphoma, for example, but not limited to: peripheral T-cell lymphoma; anaplastic large cell ma, for example anaplastic lymphoma kinase (ALK) positive, ALK negative anaplastic large cell lymphoma, or primary cutaneous anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, for example mycosis fungoides, Sézary syndrome, y ous anaplastic large cell lymphoma, y cutaneous CD30+ T-cell lymphoproliferative disorder, primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, primary cutaneous gamma-delta T-cell ma; primary cutaneous small/medium CD4+ T-cell lymphoma, and matoid papulosis; Adult T-cell Leukemia/Lymphoma (ATLL); Blastic NK-cell Lymphoma; Enteropathy-type T-cell lymphoma; Hematosplenic gamma—delta T-cell Lymphoma; Lymphoblastic Lymphoma; Nasal ell Lymphomas; Treatment-related T- cell lymphomas; for example lymphomas that appear after solid organ or bone marrow transplantation; T-cell prolymphocytic leukemia; T-cell large granular lymphocytic leukemia; Chronic lymphoproliferative disorder of NK—cells; Aggressive NK cell leukemia; Systemic EBV+ T-cell lymphoproliferative disease of childhood (associated with chronic active EBV infection); Hydroa vacciniforme-like ma; Adult T-cell ia/ lymphoma; pathy-associated T-cell lymphoma; Hepatosplenic T-cell lymphoma; or Subcutaneous panniculitis-like T-cell lymphoma.

In one embodiment, a compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for e a human, with a lymphoma or lymphocytic or myelocytic proliferation disorder or abnormality. For example, the compounds as described herein can be administered to a host suffering from a Hodgkin Lymphoma or a Non-Hodgkin Lymphoma. For example, the host can be suffering from a Non- Hodgkin Lymphoma such as, but not limited to: an AIDS-Related Lymphoma; Anaplastic Large-Cell Lymphoma; Angioimmunoblastic Lymphoma; Blastic NK-Cell Lymphoma; Burkitt’s Lymphoma; Burkitt—like Lymphoma (Small Non-Cleaved Cell ma); Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; ous T-Cell Lymphoma; Diffuse Large B-Cell Lymphoma; Enteropathy-Type T-Cell ma; Follicular Lymphoma; splenic Gamma-Delta T-Cell ma; Lymphoblastic Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Nasal T-Cell Lymphoma; Pediatric Lymphoma; Peripheral T-Cell Lymphomas; y Central s System Lymphoma; T— Cell Leukemias; Transformed Lymphomas; Treatment-Related T—Cell Lymphomas; or Waldenstrom's Macroglobulinernia.

Alternatively, a nd disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human, with a Hodgkin ma, such as, but not limited to: Nodular Sclerosis Classical Hodgkin’s ma (CHL); Mixed Cellularity CHL; Lymphocyte-depletion CHL; Lymphocyte-rich CHL; Lymphocyte Predominant Hodgkin Lymphoma; or Nodular Lymphocyte Predominant HL.

Alternatively, a nd disclosed herein, or its salt, prodrug, or isotopic variant can be used in an ive amount to treat a host, for example a human with a specific B-cell lymphoma or proliferative disorder such as, but not limited to: multiple myeloma; Diffuse large B cell lymphoma; Follicular lymphoma; Mucosa—Associated Lymphatic Tissue lymphoma (MALT); Small cell lymphocytic lymphoma;Mediastinal large B cell lymphoma; Nodal marginal zone B cell lymphoma (NMZL); Splenic marginal zone lymphoma (SMZL); Intravascular large B-cell ma; Primary effusion lymphoma; or Lymphomatoid granulomatosis;; B-cell prolymphocytic leukemia; Hairy cell leukemia; Splenic lymphoma/leukemia; unclassifiable; Splenic diffuse red pulp small B-cell lymphoma; Hairy cell leukemia—variant; Lymphoplasmacytic lymphoma; Heavy chain diseases; for example, Alpha heavy chain disease; Gamma heavy chain disease; Mu heavy chain disease; Plasma cell myeloma; Solitary plasmacytoma of bone; Extraosseous plasmacytoma; y cutaneous follicle center lymphoma; T istiocyte rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; Primary mediastinal (thymic) large B-cell lymphoma; Primary cutaneous DLBCL; leg type; ALK+ large B-cell lymphoma; Plasmablastic lymphoma; Large B-cell lymphoma g in HHV8- associated entric; Castleman disease; B-cell lymphoma; unclassifiable; with features intermediate between diffuse large B-cell lymphoma; or B-cell lymphoma; sifiable; with features intermediate between e large B-cell lymphoma and classical Hodgkin lymphoma.

In one embodiment; a compound disclosed herein; or its salt; prodrug; or isotopic t can be used in an ive amount to treat a host; for example a human with leukemia.

For e; the host may be suffering from an acute or chronic leukemia of a lymphocytic or enous origin, such as, but not limited to: Acute lymphoblastic leukemia (ALL); Acute myelogenous leukemia (AML); Chronic lymphocytic leukemia (CLL); Chronic myelogenous leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (a subtype of AML); large granular lymphocytic leukemia; or Adult T-cell chronic leukemia. In one embodiment; the patient suffers from an acute myelogenous leukemia; for example an erentiated AML (M0); myeloblastic ia (M1; with/without minimal cell maturation); myeloblastic leukemia (M2; with cell maturation); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic ia (M4 or M4 variant with eosinophilia [M4E]); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7).

VI. PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS An active compound described herein; or its salt; isotopic analog; or prodrug can be administered in an effective amount to a host to treat any of the disorders described herein using any suitable ch which achieves the desired therapeutic result. The amount and 2017/040093 timing of active compound administered will, of course, be ent on the host being treated, the instructions of the supervising medical specialist, on the time course of the exposure, on the manner of administration, on the pharmacokinetic properties of the ular active compound, and on the judgment of the prescribing physician. Thus, because of host to host variability, the dosages given below are a guideline and the physician can titrate doses of the compound to achieve the treatment that the physician ers appropriate for the host. In ering the degree of ent desired, the physician can balance a variety of factors such as age and weight of the host, presence of preexisting disease, as well as presence of other diseases.

The ceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, an injection or infusion on, a capsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, a dry powder, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral formulation, or an ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, eg., an effective amount to achieve the desired purpose.

The therapeutically ive dosage of any active compound described herein will be determined by the health care practitioner depending on the condition, size and age of the patient as well as the route of delivery. In one non-limited embodiment, a dosage from about 0.1 to about 200 mg/kg has therapeutic y, with all weights being calculated based upon the weight of the active compound, including the cases where a salt is employed. In one embodiment the dosage is at about or greater than 0.1, 0.5, 1, 5, 10, 25, 50, 75, 100, 125, 150, 175, or 200 mg/kg. In some embodiments, the dosage may be the amount of compound needed to e a serum concentration of the active compound of up to about 10 nM, 50 nM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, 1 ”M, 5 ”M, 10 nM, 20 nM, 30 nM, or 40 uM.

In certain embodiments, the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form. Examples of dosage forms with at least 5, 10, 15, 20, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt. The pharmaceutical composition may also include a molar ratio of the active compound and an additional active agent, in a ratio that achieves the d results.

Compounds disclosed herein or used as bed herein may be administered orally, topically, parenterally, by tion or spray, sublingually, via implant, including ocular implant, transdermally, via buccal administration, rectally, as an ophthalmic solution, injection, including ocular ion, intraveneous, intramuscular, inhalation, intra—aortal, intracranial, subdermal, intraperitioneal, subcutaneous, transnasal, gual, or rectal or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers. For ocular delivery, the compound can be administered, as desired, for example, via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial, conjunctival, junctival, eral, periocular, transscleral, retrobulbar, ior juxtascleral, circumcomeal, or tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion or via an ocular device.

In accordance with the presently disclosed s, an oral stration can be in any d form such as a solid, gel or liquid, including a solution, suspension, or emulsion.

In some embodiments, the nds or salts are administered by inhalation, intravenously, or intramuscularly as a liposomal suspension. When administered through inhalation the active compound or salt may be in the form of a plurality of solid particles or droplets having any desired particle size, and for example, from about 0.01, 0.1 or 0.5 to about 5, 10, 20 or more microns, and optionally from about 1 to about 2 microns. Compounds as disclosed in the present invention have demonstrated good cokinetic and pharmacodynamics properties, for instance when administered by the oral or intravenous routes.

The pharmaceutical formulations can comprise an active compound described herein or a pharmaceutically acceptable salt thereof, in any pharmaceutically acceptable carrier. If a solution is desired, water may sometimes be the carrier of choice for water-soluble compounds or salts. With respect to the water-soluble compounds or salts, an organic vehicle, such as ol, propylene glycol, polyethylene glycol, or mixtures thereof, can be suitable. In the latter instance, the organic vehicle can contain a substantial amount of water. The solution in either instance can then be sterilized in a suitable manner known to those in the art, and for illustration by filtration through a 0.22-micron filter. uent to sterilization, the solution can be dispensed into appropriate receptacles, such as depyrogenated glass vials. The dispensing is ally done by an c method. Sterilized closures can then be placed on the vials and, if d, the vial contents can be lyophilized.

Carriers include ents and diluents and must be of ently high purity and sufficiently low toxicity to render them suitable for administration to the t being treated.

The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employ ed in ction with the nd is sufficient to provide a practical quantity of material for administration per unit dose of the compound.

Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidents, lubricants, vatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one class, for example ble oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils. Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.

Additionally, auxiliary substances, such as wetting or emulsifying agents, biological buffering substances, surfactants, and the like, can be present in such vehicles. A biological buffer can be any solution which is cologically acceptable and which provides the formulation with the desired pH, i.e., a pH in the physiologically acceptable range. Examples of buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank’s buffered , and the like.

Depending on the intended mode of administration, the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, , ointments, lotions or the like, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, can include other ceutical agents, adjuvants, diluents, buffers, and the like.

Thus, the compositions of the disclosure can be stered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), , nasal, l, pulmonary, vaginal or parenteral (including intramuscular, arterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for stration by inhalation or insufflation. The preferred manner of administration is intravenous or oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.

For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, ium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, and the like, an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If d, the pharmaceutical composition to be stered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying , pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, anolamine oleate, and the like. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art, for example, see ton’s Pharmaceutical es, referenced above.

In yet another embodiment is the use of permeation er excipients including polymers such as: polycations (chitosan and its quaternary ammonium tives, poly-L- arginine, aminated n); polyanions boxymethyl chitosan, poly-acrylic acid); and, thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan— thiobutylamidine, chitosan-thioglycolic acid, chitosan—glutathione conjugates).

For oral administration, the ition will generally take the form of a , capsule, a softgel capsule or can be an aqueous or nonaqueous solution, suspension or syrup.

Tablets and capsules are preferred oral administration forms, Tablets and capsules for oral use can include one or more commonly used carriers such as lactose and corn . Lubricating agents, such as magnesium stearate, are also typically added. Typically, the compositions of the disclosure can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders e starch, n, l sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, anth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms e sodium , sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

When liquid suspensions are used, the active agent can be combined with any oral, non- toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like and with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents can be added as well. Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.

Parenteral formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions. Preferably, sterile inj ectable suspensions are formulated according to ques known in the art using suitable carriers, dispersing or g agents and suspending agents. The sterile inj ectable formulation can also be a sterile inj ectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media. In addition, parenteral administration can involve the use of a slow e or sustained release system such that a constant level of dosage is maintained.

Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and include aqueous and ueous, isotonic sterile injection ons, which can contain antioxidants, buffers, bacteriostats, and solutes that render the ation ic with the blood of the intended recipient, and aqueous and non—aqueous sterile suspensions that can e suspending , solubilizers, thickening agents, stabilizers, and preservatives. Administration via n eral routes can involve introducing the formulations of the disclosure into the body of a patient through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as an continuous infusion system. A formulation provided by the disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.

In addition to the active compounds or their salts, the pharmaceutical formulations can contain other additives, such as pH-adjusting additives. In particular, useful pH—adjusting agents include acids, such as hydrochloric acid, bases or buffers, such as sodium e, sodium acetate, sodium phosphate, sodium citrate, sodium , or sodium gluconate.

Further, the formulations can contain antimicrobial preservatives. Useful antimicrobial preservatives include paraben, propylparaben, and benzyl alcohol. An antimicrobial preservative is typically ed when the formulations is placed in a vial designed for multi- dose use. The pharmaceutical formulations described herein can be lyophilized using techniques well known in the art. 2017/040093 For oral administration a pharmaceutical composition can take the form of a solution suspension, tablet, pill, capsule, powder, and the like. Tablets ning various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch (e. g., potato or tapioca starch) and certain complex silicates, together with binding agents such as nylpyrrolidone, sucrose, gelatin and acacia.

Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate, and talc are often very useful for tableting purposes. Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules. als in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are d for oral administration, the compounds of the presently disclosed host matter can be combined with various sweetening agents, flavoring agents, coloring , emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

In yet another embodiment of the host matter bed herein, there are provided inj ectable, stable, sterile formulations sing an active compound as bed herein, or a salt thereof, in a unit dosage form in a sealed container. The compound or salt is provided in the form of a lyophilizate, which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form liquid formulation suitable for injection thereof into a host. When the compound or salt is ntially insoluble, a sufficient amount of emulsifying agent, which is physiologically acceptable, can be employed in sufficient quantity to emulsify the compound or salt in an aqueous carrier. Particularly useful emulsifying agents include phosphatidyl cholines and lecithin.

Additional embodiments provided herein include liposomal ations of the active compounds disclosed herein. The technology for forming liposomal suspensions is well known in the art. When the compound is an aqueous-soluble salt, using conventional liposome technology, the same can be orated into lipid vesicles. In such an instance, due to the water solubility of the active nd, the active compound can be substantially ned within the hydrophilic center or core of the liposomes. The lipid layer employed can be of any conventional composition and can either contain cholesterol or can be cholesterol-free. When the active compound of interest is water-insoluble, again employing conventional liposome ion technology, the salt can be substantially entrained within the hydrophobic lipid bilayer that forms the structure of the liposome. In either instance, the liposomes that are produced can be reduced in size, as h the use of standard sonication and nization techniques. The liposomal ations comprising the active compounds disclosed herein can be lyophilized to produce a lyophilizate, which can be reconstituted with a pharmaceutically able carrier, such as water, to rate a liposomal suspension.

Pharmaceutical formulations also are provided which are le for administration as an l by inhalation. These formulations comprise a solution or suspension of a desired compound described herein or a salt f, or a plurality of solid les of the nd or salt. The desired formulations can be placed in a small chamber and nebulized. Nebulization can be accomplished by compressed air or by ultrasonic energy to form a plurality of liquid droplets or solid particles comprising the compounds or salts. The liquid droplets or solid particles may for example have a particle size in the range of about 0.5 to about 10 microns, and ally from about 0.5 to about 5 microns. In one embodiment, the solid particles provide for controlled release through the use of a degradable polymer. The solid particles can be obtained by processing the solid compound or a salt thereof, in any appropriate manner known in the art, such as by rnicronization. Optionally, the size ofthe solid particles or droplets can be from about 1 to about 2 microns. In this respect, commercial nebulizers are available to achieve this e. The compounds can be administered via an l suspension of respirable particles in a manner set forth in US. Pat. No. 5,628,984, the disclosure of which is incorporated herein by reference in its entirety.

Pharmaceutical ations also are provided which provide a controlled release of a compound described herein, ing through the use of a degradable polymer, as known in the art.

When the pharmaceutical formulations suitable for administration as an aerosol is in the form of a liquid, the formulations can comprise a water-soluble active compound in a carrier that comprises water. A surfactant can be present, which lowers the surface tension of the formulations sufficiently to result in the formation of droplets within the desired size range when hosted to nebulization.

The term "pharmaceutically acceptable salts" as used herein refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with hosts (e.g., human hosts) without undue toxicity, tion, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the tly disclosed host matter.

Thus, the term "salts" refers to the relatively non-toxic, inorganic and organic acid on salts of the presently disclosed compounds. These salts can be prepared during the final ion and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Basic compounds are capable of forming a wide variety of ent salts with s inorganic and organic acids. Acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms may differ from their respective salt forms in certain al properties such as lity in polar solvents. Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as s, e, but are not limited to, sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include, but are not limited to, N,N‘- dibenzylethylenediamine, procaine, choline, nolamine, ethylenediamine, N- methylglucamine, and procaine. The base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms may differ from their respective salt forms somewhat in n physical properties such as solubility in polar solvents.

Salts can be prepared from inorganic acids sulfate, pyrosulfate, bisulfate, sulflte, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, te, e, ate, te, citrate, maleate, te, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, laurylsulphonate and isethionate salts, and the like. Salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted ic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and the like. Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, obenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts can include cations based on the alkali and ne earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, WO 05860 ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also plated are the salts of amino acids such as te, gluconate, galacturonate, and the like. See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference.

Preferably, sterile inj ectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and ding agents. The sterile injectable formulation can also be a e injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium de solution. In addition, sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or ding media. In addition, parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.

Preparations according to the disclosure for parenteral administration e sterile aqueous or ueous solutions, sions, or emulsions. Examples of ueous ts or vehicles are ene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and inj ectable organic esters such as ethyl oleate. Such dosage forms can also contain nts such as preserving, wetting, emulsifying, and dispersing agents. They can be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile inj ectable medium, immediately before use.

Sterile inj ectable ons are prepared by incorporating one or more ofthe compounds of the disclosure in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile inj e solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Thus, for example, a eral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

Formulations suitable for rectal administration are typically presented as unit dose suppositories. These may be prepared by admixing the active sed compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture. ations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.

Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. In one embodiment, microneedle patches or devices are provided for delivery of drugs across or into biological tissue, particularly the skin. The microneedle patches or devices permit drug delivery at clinically relevant rates across or into skin or other tissue barriers, with minimal or no damage, pain, or irritation to the tissue.

Formulations suitable for administration to the lungs can be delivered by a wide range of passive breath driven and active power driven single/-multiple dose dry powder inhalers (DPI). The devices most ly used for atory delivery e nebulizers, metered- dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Selection of a suitable lung delivery device s on parameters, such as nature of the drug and its formulation, the site of action, and pathophysiology of the lung.

Additional non-limiting examples of drug ry devices and methods include, for example, 0203709 titled “Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor” (Abbott Laboratories), US20050009910 titled “Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of a prodrug”, US 20130071349 titled “Biodegradable polymers for ng intn ocular re”, US 8,481,069 titled ine kinase pheres”, US 8,465,778 titled “Method of making tyrosine kinase pheres”, US 8,409,607 titled “Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods”, US 738 and US 2014/0031408 titled “Biodegradable intravitreal ne kinase ts”, US 2014/0294986 titled “Microsphere Drug ry System for Sustained Intraocular Release”, US 8,911,768 titled “Methods For Treating pathy With Extended Therapeutic Effect” (Allergan, Inc); US 6,495,164 titled “Preparation of injectable suspensions having improved injectability” mes Controlled eutics, Inc); WO 2014/047439 titled “Biodegradable Microcapsules Containing Filling Materia ” (Akina, Inc); WO 2010/132664 titled “Compositions And Methods For Drug Delivery” (Baxter International Inc. Baxter Healthcare SA); U820120052041 titled “Polymeric nanoparticles with enhanced drug loading and methods of use thereof” (The Brigham and Women’s Hospital, Inc); US20140178475, US20140248358, and US20140249158 titled peutic Nanoparticles Comprising a Therapeutic Agent and Methods of Making and Using Same” (BIND eutics, Inc); US 5,869,103 titled “Polymer microparticles for drug delivery” (Danbiosyst UK Ltd); US 8628801 titled “Pegylated Nanoparticles” (Universidad de Navarra); US2014/0107025 titled “Ocular drug delivery system” (Jade Therapeutics, LLC); US 6,287,588 titled “Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and s of use thereof”, US 6,589,549 titled “Bioactive agent ring system comprised of microparticles within a biodegradable to improve release profiles” (Macromed, Inc); US 6,007,845 and US 5,578,325 titled “Nanoparticles and microparticles of non-linear hydrophilic hydrophobic multiblock copolymers” (Massachusetts Institute of Technology); US20040234611, U820080305172, 0269894, and US20130122064 titled “Ophthalmic depot formulations for periocular or subconjunctival administration (Novartis Ag); US 539 titled “Block polymer” Med, Inc); US 20070071756 titled “Delivery of an agent to ameliorate inflammation” (Peyman); US 20080166411 titled “Injectable Depot Formulations And Methods For Providing ned Release Of Poorly Soluble Drugs sing Nanoparticles” (Pfizer, Inc.); US 6,706,289 titled “Methods and compositions for enhanced delivery of bioactive molecules” (PR ceuticals, Inc); and US 8,663,674 titled “Microparticle containing matrices for drug delivery” (Surmodics).

VII. COMBINATION THERAPY The sed compounds of Formula 1, Formula II, Formula III Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, a XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or a XXV can be used in an effective amount alone or in combination with another compound of the present invention or another bioactive agent to treat a host such as a human with a disorder as described herein.

The disclosed compounds described herein can be used in an effective amount alone or in combination with another compound of the present invention or another bioactive agent to treat a host such as a human with a disorder as described herein.

The term “bioactive agent” is used to describe an agent, other than the selected compound according to the present invention, which can be used in combination or alternation with a compound of the present invention to achieve a desired result of therapy. In one embodiment, the compound of the present invention and the bioactive agent are stered in a manner that they are active in vivo during overlapping time periods, for example, have time-period overlapping Cmax, Tmax, AUC or other pharmacokinetic parameter. In another embodiment, the compound of the t invention and the bioactive agent are administered to a host in need f that do not have overlapping pharrnacokinetic parameter, however, one has a therapeutic impact on the therapeutic efficacy of the other.

In one aspect of this embodiment, the bioactive agent is an immune modulator, including but not limited to a oint inhibitor, including as non-limiting examples, a PD- 1 inhibitor, PD-Ll inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, V-domain Ig suppressor of T-cell activation ) inhibitors, small molecule, peptide, nucleotide, or other inhibitor. In certain aspects, the immune modulator is an antibody, such as a monoclonal antibody.

PD-l inhibitors that blocks the interaction of PD-l and PD-Ll by g to the PD-l receptor, and in turn inhibit immune suppression include, for example, nivolumab (Opdivo), pembrolizumab uda), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF- 06801591 (Pfizer), MEDIO680 (AstraZeneca), PDROOl (Novartis), 10 (Regeneron), SHR—12-1 (Jiangsu i Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-Ll/VISTA inhibitor CA-170 (Curis Inc.) PD-Ll inhibitors that block the interaction of PD-l and PD-Ll by binding to the PD-Ll receptor, and in turn inhibits immune suppression, include for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 mab), and EMS-936559 ol-Myers Squibb). CTLA-4 checkpoint tors that bind to CTLA—4 and inhibits immune suppression include, but are not d to, ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884 and AGEN2041 (Agenus). LAG-3 checkpoint inhibitors, include, but are not limited to, EMS- 986016 (Bristol-Myers ), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-l and LAG-3 inhibitor MGD013 Genics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro).

W0 2018/005860 In yet r embodiment, one of the active compounds described herein can be administered in an effective amount for the ent of abnormal tissue of the female reproductive system such as breast, ovarian, endometrial, or uterine cancer, in ation or alternation with an effective amount of an estrogen tor including but not limited to a SERM tive estrogen receptor modulator), a SERD tive estrogen receptor degrader), a complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist or agonist. Partial anti-estrogens like raloxifene and tamoxifen retain some estrogen— like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases, an estrogen-like action during breast cancer progression which actually stimulates tumor growth. In contrast, fulvestrant, a complete strogen, is free of estrogen-like action on the uterus and is effective in tamoxifen-resistant tumors. Non-limiting examples of anti-estrogen compounds are provided in W0 2014/19176 assigned to Astra Zeneca, W02013/090921, W0 2014/203129, W0 2014/203132, and /0178445 assigned to Olema Pharmaceuticals, and US. Patent Nos. 871, 8,853,423, and 8,703, 810, as well as Us 005286, wo 2014/205136, and . Additional non-limiting examples of anti—estrogen compounds include: SERMS such as anordrin, xifene, estriol, chlorotrianisene, clomiphene e, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins such as leuprorelin, cetrorelix, allylestrenol, chloromadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone. Other estrogenic ligands that can be used according to the present invention are described in U. S. Patent Nos. 4,418,068; 5,478,847; ,393,763; and 5,457,117, WO2011/156518, US Patent Nos. 8,455,534 and 8,299,112, US.

Patent Nos. 871; 8,853,423; 8,703,810; US 2015/0005286; and , /0175289, /0258080, , WO 84711; ; ; WO 2002/003992; WO 2002/003991; W0 2002/003990; WO 2002/003989; ; ; ; ; ; ; US 6821989; US 2002/0128276; US 6777424; US 2002/0016340; US 6326392; US 6756401; US 2002/0013327; US 6512002; US 6632834; US 2001/0056099; US 6583170; US 6479535; W0 1999/024027; US 6005102; EP 0802184; US 5998402; US 5780497, US 5880137, and .

In r embodiment, an active compound described herein can be administered in an effective amount for the treatment of abnormal tissue of the male reproductive system such as prostate or testicular cancer, in combination or alternation with an effective amount of an androgen (such as testosterone) tor including but not limited to a selective androgen receptor modulator, a selective en receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist. In one embodiment, the prostate or testicular cancer is androgen-resistant. Non-limiting examples of anti-androgen compounds are provided in WO 56518 and US Patent Nos. 534 and 8,299,112.

Additional non-limiting examples of anti-androgen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.

In one embodiment, the bioactive agent is an ALK tor. Examples of ALK inhibitors include but are not limited to Crizotinib, Alectinib, ceritinib, TAE684 (NVP- TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-lOl), and AP26113.

In one embodiment, the bioactive agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), ib (Iressa), ib (Gilotrii), rociletinib (CO— 1686), osimertinib (Tagrisso), olmutinib (Olita), inib (ASP8273), nazartinib (EGF816), 47775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; PB272), avitinib (ACOOIO), EAIO45, tarloxotinib 00; ), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL- 7647, KD-019), inib, WZ-3146, WZ8040, CNX-2006, and dacomitinib 299804; Pfizer).

In one embodiment, the bioactive agent is an HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.

In one embodiment, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, mab, fatumumab, ibritumomab, tositumomab, and ocrelizumab.

In one embodiment, the ive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasocitinib.

In one embodiment, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-l99 (4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-l- en-l-yl]methyl]piperazin-l-yl]-N-[[3-nitro[[(tetrahydro-2H-pyran-4— hyl]amino]phenyl]sulfony1]-2—[(lH— pyrrolo[2,3-b]pyridinyl)oxy]benzarnide), ABT— 737 (4-[4- [ [2-(4-chlorophenyl)phenyl] methyl] piperazin- l -yl] -N- [4- -4— (dimethylamino)phenylsulfanylbutanyl] amino] nitrophenyl]sulfonylbenzamide) (navitoclax), ABT-263 ((R)(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[l, l'-biphenyl]— ethyl)piperazin-l -yl)-N-((4-((4-morpholino-l ylthio)butanyl)amino)— 3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (obatoclax mesylate, (ZZ)[(5Z)[(3,5- dimethyl-lH-pyrrolyl)methylidene]methoxypyrrol ylidene]indole; methanesulfonic acid))), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9- dihydronaphtho[2,3-d]thiazolylamino)-phenyl ester), pogosin, ethyl 2-aminobromo (1-cyanoethoxyoxoethyl)-4H—chromenecarboxylate, Nilotinib-d3, TW-37 (N-[4-[[2— (1,l-Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5 -[[2-(l - ethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2), HA14-1, ATIOI, sabutoclax, ic acid, or G3139 (Oblimersen).

In one aspect, a treatment regimen is provided comprising the administration of a compound ofFormula 1, Formula II, Formula III Formula IV, Formula V, Formula VI, Formula VII, a VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or Formula XXV in combination with at least one additional chemotherapeutic agent. The combinations disclosed herein can be administered for beneficial, additive, or synergistic effect in the ent of abnormal ar proliferative disorders.

In specific ments, the treatment regimen es the administration of a nd ula 1, Formula II, Formula III Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, a XVII, Formula XVIII, a XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or Formula XXV in combination with at least one kinase inhibitor. In one ment, the at least one kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton’s tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.

PI3k inhibitors that may be used in the present invention are well known. Examples of PI3 kinase inhibitors include but are not limited to Wortmannin, demethoxyviridin, perifosine, idelalisib, Pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-l36, duvelisib, GS-9820, BKMIZO, GDC-0032 (Taselisib), (2-[4-[2-(2-Isopropylmethyl-1,2,4— triazolyl)-5,6-dihydroimidazo[1,2-d][l,4]benzoxazepinyl]pyrazol-l-yl] methylpropanamide), MLN—l 1 17 ((2R)Phenoxy—2—butanyl hydrogen (S)- methylphosphonate, or (oxo) {[(2R)—l-phenoxybutanyl]oxy}phosphonium)), BYL- 7’ l 9 ((ZS)-N1-[4-Methyl[2-(2,2,2-trifluoro-l,1-dimethylethyl)pyridinyl]thiazolyl]- 1,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-Difluoro-N— {2-(methyloxy)—5-[4-(4— ziny1)quinoliny1]pyridiny1}benzenesulfonarnide) (omipalisib), l ((::) Methyl-2—(morpholiny1)(l-pheny1aminoethy1)-pyrido[1,2—a]-pyrimidinone), GSK2636771 (2-Methy1(2-methy1-3 -(trifluoromethy1)benzyl)—6-morpholino-1H- benzo[d]irnidazolecarboxy1ic acid dihydrochloride), 3 ((R)((1-(7-methy1 linooxo-4H-pyrido[1,2-a]pyrimidiny1)ethy1)amino)benzoic acid), TGR— 1202/RP5264, GS-9820 ((S)— (2-(2-aminopyrimidinyl)methy1 mohydroxypropan- 1 —one), GS-1101 (5-fluoropheny1-2—([S)][9H-purinylamino]— propyl)-3H-quinazolinone), AMG—319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5- dimethoxypheny1)arnino)quinoxaliny1)sulfamoy1)pheny1)-3—methoxy-4 methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy(3-morpholinopropoxy)—2,3-dihydroimidazo[1,2- c]quinaz), AS 252424 [5-(4-F1uorohydroxy-phenyl)—furan-2—y1]-meth—(Z)-ylidene]— lidine-2,4-dione), CZ 24832 (5-(2-aminofluoro-[1,2,4]triazolo[1,5-a]pyridiny1)-N- tert-butylpyridinesu1fonarnide), Buparlisib (5-[2,6-Di(4-morpholiny1) pyrimidinyl] (trifluoromethyl)—2-pyridinamine), GDC-0941 (2-(1H-Indazoly1)[[4-(methy1su1fony1)—1- piperazinyl]methyl](4-morpholiny1)thieno[3,2-d]pyrimidine), GDC-0980 ((S)(4-((2-(2- aminopyrimidin—5 -y1)methylmorpholinothieno[3,2-d]pyrimidin-6 y1)methy1)piperazin-l— yl)hydroxypropan-l-one (also known as RG7422)), SF1126 ((8S,14S,17S) (carboxymethyl)—8-(3-guanidinopropyl)—17-(hydroxymethy1)-3,6,9,12,15-pentaoxo(4-(4- oxopheny1-4H-chromenyl)morpholinoiurn)oxa—7,10,13,16-tetraazaoctadecan oate), PF-052123 84 [[4-(Dimethy1amino) piperidinyl]carbony1]pheny1]-N’-[4-(4,6- dimorpholiny1-1,3,5-triaziny1)pheny1]urea) (gedatolisib), LY3023414, BEZ235 (2- Methy1 {4-[3-methy1oxo(quinoliny1)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-l- y1]pheny1}propanenitri1e) (dactolisib), XL-765 (N-(3-(N—(3-(3,5- dimethoxyphenylamino)quinoxalinyl)su1famoy1)pheny1)—3-methoxymethylbenzamide), and GSK1059615 (5-[[4-(4-Pyridiny1)quinoliny1]methylene]-2,4-thiazolidenedione), PX886 ([(3aR,6E,9S,9aR,10R,1 1aS)—6-[[bis(propeny1)amino]methylidene]hydroxy (methoxymethyl)—9a,1 1a—dimethy1-1,4,7-trioxo—2,3,3a,9,10,11- hexahydroindeno[4,5h]isochromen- 10-y1] acetate (also known as sonolisib)) LY294002, AZD8186, PF-4989216, pilaralisib, ONE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, , PIK-93, AS—605240, BGT226 (NVP—BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TG1100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA hyladenine), AS—252424, 850, apitolisib (GDC-0980, RG7422), and the structure described in W02014/071109.

In one embodiment, the compound of Formula 1, Formula II, a 111 Formula IV, Formula V, a VI, Formula VII, a VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, a XXIV, or Formula XXV is ed in a single dosage form with the PIk3 inhibitor.

BTK inhibitors for use in the present invention are well known. Examples of BTK inhibitors include ibrutinib (also known as PCI-32765)(ImbruvicaTM)(1-[(3R)[4-amino (4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinyl]propenone), dianilinopyrimjdine-based tors such as AVL-lOl and AVL-29l/292 (N-(3-((5-fluoro-2— ((4-(2-methoxyethoxy)phenyl)amino)pyrimidinyl)amino)phenyl)acrylamide) (Avila Therapeutics) (see US Patent Publication No 2011/0117073, incorporated herein in its entirety), Dasatinib ([N-(2-chloromethylphenyl)(6-(4-(2-hydroxyethyl)piperazinyl)- 2-methylpyrimidinylamino)thiazole—5-carboxarnide], LFM-A13 (alpha-cyano-beta- hydroxy-beta-methyl-N-(2,5-ibromophenyl) propenamide), GDC-0834 ([R-N-(3-(6-(4-(1,4- dimethy1oxopiperazinyl)phenylamino)methy1oxo-4,5-dihydropyrazinyl) phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-Z—carboxamide], CGI-560 4-(tert-butyl)— N—(3-(8-(phenylamino)imidazo[1,2-a]pyrazinyl)phenyl)benzamide, CGI-1746 (4-(tert— butyl)—N-(2-methyl(4—methyl((4-(morpholinecarbonyl)phenyl)amino)—5-oxo-4,5- dihydropyrazinyl)phenyl)benzamide), CNX-774 (4-(4-((4-((3-acrylamidophenyl)amino) fluoropyrimidin-2—yl)amino)phenoxy)-N-methylpicolinamide), CTA056 zyl(3- (piperidinyl)propyl)(4-(pyridinyl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one), 34 ((R)-N-(3-(6-((4-(1,4-dimethy1oxopiperazin-Z-yl)phenyl)amino)methyl oxo-4,5-dihydropyrazinyl)methylphenyl)—4,5,6,7—tetrahydrobenzo[b]thiophene carboxamide), GDC-0837 ((R)-N-(3-(6-((4-(1,4-dimethyloxopiperazin yl)phenyl)amino)—4-methyloxo-4,5-dihydropyrazinyl)methylphenyl)—4,5,6,7- tetrahydrobenzo[b]thiophene-2—carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazolyl)phenyl)amino)(((lR,ZS) aminocyclohexyl)amino)pyrimidine—5-carboxamide hydrochloride), QL-47 (l -(1- acryloylindolinyl)—9-( 1 -methyl- 1 H-pyrazolyl)benzo [h] [l ,6]naphthyridin-2(lH)—one), and RN486 (6-cyclopropylfluoro(2-hydroxymethyl{1-methyl[5-(4-methyl- piperazin-l-y1)-py1idinylamino]-6—oxo-1,6-dihydro-py1idinyl}-pheny1)—2H—isoquinolin- 1-one), and other molecules capable of ting BTK activity, for example those BTK inhibitors sed in Akinleye et ah, Journal of Hematology & Oncology, 2013, 6:59, the entirety of which is incorporated herein by reference. In one embodiment, the compound of 2017/040093 Formula I, Formula II, Formula III Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or Formula XXV is combined in a single dosage form with the BTK tor.

Syk inhibitors for use in the present invention are well known, and include, for e, Cerdulatinib (4-(cyclopropylamino)((4-(4-(ethylsulfonyl)piperazin-1— yl)phenyl)amino)pyrimidinecarboxamide), entospletinib (6-(1H-indazolyl)-N—(4- morpholinophenyl)imjdazo[1,2—a]pyrazinarrnne), fostamatinib ([6-({5-Fluoro[(3,4,5- trimethoxyphenyl)amino]pyrimidinyl}amino)-2,2-dimethyloxo-2,3-dihydro-4H- pyrido[3,2-b] [1,4] yl]methyl dihydrogen ate), fostamatinib disodium salt (sodium (6-((5-fluoro((3,4,5 -trimethoxyphenyl)amino)pyrimidinyl)amino)-2,2- dimethyloxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate), BAY 61-3606 (2- (7-(3,4-Dimethoxyphenyl)-imidazo[1,2—c]pyrimidinylamino)-nicotinamide HCl), R0902] (6-[(1R,2S)Amino-cyclohexylamino](5,6-dimethyl-pyridinylamino)-pyridazine carboxylic acid amide), imatinib (Gleevac, 4-[(4-methylpiperazinyl)methyl]—N—(4—methy1- 3-{[4-(pyridinyl)pyrimidinyl]amino}phenyl)benzamide), staurosporine, GSK143 (2- (((3R,4R)aminotetrahydro-2H-pyran—4-yl)amino)(p-tolylarnino)pyrimidine—5- carboxamide), PP2 (1-(tert-butyl)—3-(4-chlorophenyl)-lH-pyrazolo[3,4-d]pyrimidinamine), PRT-060318 (2-(((1R,2S)aminocyclohexyl)amino)—4-(m-tolylamjno)pyrimidine carboxamide), PRT-062607 (4-((3-(2H-1,2,3-triazolyl)phenyl)amino)(((lR,2S) yclohexyl)amino)pyrimidine-S-carboxamide hydrochloride), R112 (3,3'—((5- fluoropyrimidine-2,4-diyl)bis(azanediy1))diphenol), R348 (3-Ethyl-4—methylpyridine), R406 (6-((5-fluoro((3,4,5-trimethoxyphenyl)amino)pyrimidinyl)amino)-2,2-dimethyl-2H— [3,2-b] [1,4]oxazin-3(4H)—one), piceatannol (3-Hydroxyresveratol), YM193306(see Singh et a1. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med.

Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER—27319 (see Singh et a1. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614- 3643 incorporated in its entirety herein), Compound D (see Singh et a1. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety ), PRT060318 (see Singh et a1. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J , Med. Chem. 2012, 55, 643 incorporated in its entirety herein), luteolin (see Singh et a1. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 643 incorporated in its entirety herein), apigenin (see Singh et al. ery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), quercetin (see Singh et al. Discovery and Development of Spleen ne Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), fisetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med.

Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), myricetin (see Singh et al.

Discovery and pment of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 643 incorporated in its entirety herein), morin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein). In one embodiment, the nd of Formula 1, Formula II, Formula III Formula IV, a V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, a XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or Formula XXV is combined in a single dosage form with the Syk inhibitor.

In one ment, the at least one additional chemotherapeutic agent is a protein cell 1 (PD-1) inhibitor. PD-l inhibitors are known in the art, and include, for example, nivolumab (BMS), pembrolizumab (Merck), pidilizumab (CureTech/Teva), AMP-244 mmune/GSK), EMS-936559 (EMS), and 36 (Roche/Genentech). In one embodiment, the compound of Formula 1, Formula II, Formula 111 Formula IV, Formula V, Formula VI, a VII, Formula VIII, Formula IX, Formula X, a XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or Formula XXV is combined in a single dosage form with the PD-l inhibitor.

In one embodiment, the at least one additional chemotherapeutic agent is a B-cell lymphoma 2 (Bcl-2) protein inhibitor. BCL-2 inhibitors are known in the art, and include, for example, ABT- l 99 (4-[4- [ [2-(4-Chlorophenyl)-4,4-dimethylcyclohexen-l - yl]methyl]piperazin-l-yl]-N-[[3-nitro[[(tetrahydro-2H-pyran yl)methyl]amino]phenyl]sulfonyl][(lH- pyrrolo[2,3-b]pyridinyl)oxy]benzamide), ABT- 737 (4-[4- [ [2-(4-chlorophenyl)phenyl] methyl] piperazinyl] -N- [4- [[(2R) (dimethylarnino)phenylsulfanylbutanyl] amino] nitrophenyl]sulfonylbenzarnide), ABT-263 ((R)(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[l, l'-biphenyl] yl)methyl)piperazinyl)-N-((4-((4-morpholino(phenylthio)butanyl)amino)— 3((trifluoromethy1)sulfony1)phenyl)sulfonyl)benzamide), GX15-070 (obatoclaX te, (ZZ)[(SZ)[(3,5- dimethyl-lH-pyrrolyl)methylidene]methoxypyrrol ylidene]indole; methanesulfonic acid))), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9- dihydronaphtho[2,3-d]thiazolylarnino)-phenyl , pogosin, ethyl 2-aminobromo (1-cyanoethoxyoxoethyl)—4H-chromenecarboxylate, Nilotinib-d3, TW-37 (N-[4-[[2— imethylethy1)pheny1]sulfonyl]phenyl]-2,3,4-trihydroxy -5 -[[2-(1- methylethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2), or G3139 (Oblimersen).

In one embodiment, the nd of Formula 1, a II, Formula III Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or Formula XXV is combined in a single dosage form with the at least one BCL-2 inhibitor.

In one embodiment, a combination described herein can be further combined with an additional therapeutic to treat the cancer. The second therapy can be an immunotherapy. As discussed in more detail below, the compound of Formula I, Formula II, a 111 Formula IV, a V, Formula VI, a VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or Formula XXV can be conjugated to an antibody, radioactive agent, or other targeting agent that directs the compound to the ed or abnormally proliferating cell. In r embodiment, the combination is used in combination with another pharmaceutical or a biologic agent (for example an antibody) to increase the efficacy of treatment with a combined or a synergistic approach. In an embodiment, combination can be used with T-cell vaccination, which lly involves immunization with inactivated autoreactive T cells to eliminate a cancer cell population as bed herein. In another embodiment, the combination is used in combination with a bispecific T-cell Engager (BiTE), which is an antibody designed to aneously bind to c antigens on endogenous T cells and cancer cells as described herein, linking the two types of cells.

In one embodiment, the bioactive agent is a MEK inhibitor. MEK inhibitors are well known, and e, for example, trametinib/GSK1120212 (N-(3-{3-Cyclopropyl[(2-fluoro- 4-iodophenyl)amino]—6,8-dimethyl-2,4,7-trioxo—3,4,6,7-tetrahydropyrido[4,3—d]pyrimidin- 1}pheny1)acetamide), selumetinib (6-(4-bromochloroanilino)fluoro-N-(2— hydroxyethoxy)methylbenzimidazolecarboxamide), pimasertib/AS703026/MSC 1935369 ((S)-N-(2,3-dihydroxypropyl)((2-fluoro-4— iodopheny1)amino)isonicotinamide), XL-518/GDC-0973 (l-({3,4-difluoro[(2-fluoro enyl)amino]phenyl}carbonyl)—3- [(2S)-piperidin-2—yl]azetidinol), refametinib/BAY869766/RDEAl 19 (N-(3,4-difluoro-2— (2-fluoroiodophenylamino)methoxyphenyl)(2,3-dihydroxypropyl)cyclopropane-1 - amide), PD-0325901 (N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro[(2-fluoro iodophenyl)amino]— benzamide), TAK733 ((R)(2,3-Dihydroxypropyl)—6-fluoro(2- fluoroiodophenylamino)—8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEKl62/ARRY438162 (5 - [(4—Bromofluorophenyl)amino] fluoro-N—(2— hydroxyethoxy)methyl-1H-benzimidazole—6-carboxamide), R05126766 (3-[[3-Fluoro (methylsulfamoylamino)pyridyl]methyl]methyl-7—pyrimidinyloxychromenone), WX-554, R04987655/CH4987655 (3,4-difluoro((2-fluoroiodophenyl)amino)-N—(2- hydroxyethoxy)—5-((3-oxo-l,2-oxazinan-2yl)methyl)benzami de), or AZD8330 (2-((2-fluoro iodophenyl)amino)—N—(2 hydroxyethoxy)-1 ,5-dimethyloxo-l,6-dihydropyridine carboxamide), EtOH, PD184352 40), GDC-0623, BI-847325, cobimetinib, PD98059, BIX 02189, BIX 02188, binimetinib, SL-327, TAK-733, PD318088.

In one embodiment, the bioactive agent is a Raf inhibitor. Raf inhibitors are known and include, for example, Vemurafinib [[5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin- 3-yl]carbonyl]-2,4-difluorophenyl]propanesulfonamide), sorafenib tosylate (4-[4-[[4- chloro(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine carboxamide,4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropanyl)-N-(4-methyl(3- methyloxo-3,4—dihydroquinazolinylamino)phenyl)benzamide), NVP-BHG712 (4- (1-methyl(pyridinyl)-lH-pyrazolo[3,4-d]pyrimidinylamino)—N—(3- (trifluoromethyl)phenyl)benzamide), RAF-265 (1-methyl[2-[5-(trifluoromethyl)-1H- imidazolyl]pyridin-4—yl]oxy-N—[4-(trifluoromethyl)phenyl]benzimidazolamine), 2- Bromoaldisine (2-Bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf Kinase Inhibitor IV oro(2-phenyl(pyridinyl)—1H-imidazolyl)phenol), Sorafenib N- OXide (4-[4-[[[[4-Chloro-3(trifluoroMethyl)phenyl]aMino]carbonyl]aMino]phenoxy]—N- Methyl-2pyridinecarboxaMide l-Oxide), PLX—4720, dabrafenib 18436), GDC-0879, RAF265, AZ 628, SB590885, ZM336372, GW5074, TAK-632, 496, LY3009120, and GX818 (Encorafenib).

In one embodiment, the additional therapy is a onal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to the antibodies produced naturally by B cells, these MAbs “coat” the cancer cell e, triggering its destruction by the immune system. For example, bevacizumab targets vascular endothelial growth factor(VEGF), a protein secreted by tumor cells and other cells in the tumor’s microenvironment that promotes the development of tumor blood vessels. When bound to zumab, VEGF cannot ct with its cellular receptor, preventing the signaling that leads to the growth of new blood vessels. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets the human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the ed receptors from sending their normal -promoting signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells, Another group of cancer therapeutic MAbs are the immunoconjugates. These MAbs, which are mes called immunotoxins or antibody-drug conjugates, t of an antibody attached to a cell-killing substance, such as a plant or bacterial toxin, a chemotherapy drug, or aradioactive molecule. The antibody s onto its ic antigen on the e of a cancer cell, and the cell-killing substance is taken up by the cell. FDA-approved conjugated MAbs that work this way include ado-trastuzumab emtansine, which targets the HER-2 molecule to deliver the drug DMI, which inhibits cell proliferation, to HER-2 expressing metastatic breast cancer cells.

Immunotherapies with T cells engineered to recognize cancer cells via bispecific antibodies (bsAbs) or chimeric antigen receptors (CARS) are approaches with potential to ablate both dividing and non/slow-dividing subpopulations of cancer cells.

Bispecific antibodies, by simultaneously recognizing target antigen and an activating receptor on the surface of an immune effector cell, offer an opportunity to redirect immune or cells to kill cancer cells. The other ch is the generation of chimeric antigen ors by fusing ellular antibodies to intracellular signaling domains. Chimeric antigen receptor-engineered T cells are able to cally kill tumor cells in a MHC- independent way In some embodiments, the combination can be administered to the subject in further combination with other herapeutic agents. If convenient, the combination described herein can be administered at the same time as another chemotherapeutic agent, in order to simplify the treatment regimen. In some embodiments, the combination and the other chemotherapeutic can be provided in a single formulation. In one embodiment, the use of the compounds described herein is combined in a therapeutic regime with other agents. Such agents may include, but are not limited to, tamoxifen, midazolam, letrozole, bortezomib, anastrozole, goserelin, an mTOR inhibitor, a PI3 kinase inhibitors, dual mTOR-PI3K inhibitors, MEK inhibitors, RAS inhibitors, ALK inhibitors, HSP inhibitors (for example, HSP70 and HSP 90 inhibitors, or a combination thereof), BCL-2 inhibitors, apopototic inducing compounds, AKT inhibitors, including but not limited to, MK-2206, GSK690693, sine, (KRX—0401), GDC—0068, Triciribine, AZD5363, Honokiol, PF-04691502, and Miltefosine, PD-l inhibitors ing but not limited to, Nivolumab, CT-Ol l, MK-3475, BMS936558, and 4 or FLT-3 inhibitors, ing but not limited to, P406, Dovitinib, Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib (MLN518), ENMD-2076, and KW- 2449, or combinations thereof.

In one embodiment, the bioactive agent is an mTOR inhibitor. es of mTOR tors include but are not limited to rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimus. Examples ofMEK inhibitors include but are not limited to tametinib/GSK1120212 {3-Cyclopropyl[(2-fluoro iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin—l(2H- yl}phenyl)acetamide), selumetinob (6-(4-bromochloroanilino)fluoro-N—(2- hydroxyethoxy)methy1benzimidazolecarboxamide), pimasertib/AS703026/MSC l 935369 ((S)-N-(2,3-dihydroxypropyl)-3 -((2-fluoro-4— iodophenyl)amino)isonicotinamide), XL-518/GDC-0973 (l-({3,4-difluoro[(2-fluoro-4— iodophenyl)amino]phenyl}carbonyl)[(ZS)-piperidinyl]azetidinol), refametinib/BAY869766/RDEA119 (N-(3,4-difluoro(2-fluoroiodophenylamino) methoxyphenyl)—l-(2,3-dihydroxypropyl)cyclopropane—l-sulfonamide), PD-0325901 (N- [(2R)—2,3-Dihydroxypropoxy]-3,4-difluoro[(2-fluoroiodophenyl)amino]-benzamide), TAK733 ((R)—3-(2,3-Dihydroxypropyl)fluoro(2—fluoroiodophenylamino) methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione), MEKl 62/ARRY438162 (5-[(4-Bromo fluoropheny1)amino]fluoro-N-(2-hydroxyethoxy)—1-methyl-lH-benzimidazole—6 carboxamide), R05126766 (3-[[3-Fluoro-2—(methylsulfamoylamino)pyridyl]methyl] methylpyrimidinyloxychromen-Z-one), WX-554, R04987655/CH4987655 (3,4- difluoro((2-fluoroiodophenyl)amino)-N-(2-hydroxyethoxy)((3-oxo-l,2-oxazinan-2 yl)methyl)benzamide), or AZD8330 (2-((2-fluoroiodophenyl)amino)-N-(2- hydroxyethoxy)—1,5-dimethyloxo-l,6-dihydropyridinecarboxamide).

In one ment, the ive agent is a RAS inhibitor. Examples ofRAS inhibitors include but are not limited to Reolysin and siGlZD LODER.

In one embodiment, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include but are not d to Ciizotinib, AP26113, and LDK37 8.

In one embodiment, the bioactive agent is a HSP inhibitor. HSP inhibitors include but are not limited to Geldanamycin or 17—N—Allylamino-l7-demethoxygeldanamycin (17AAG), and Radicicol. In a particular embodiment, a compound described herein is administered in combination with letrozole and/or tamoxifen. Other herapeutic agents that can be used in combination with the compounds bed herein include, but are not limited to, chemotherapeutic agents that do not require cell cycle activity for their anti-neoplastic effect.

Additional bioactive compounds e, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN—101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, anib, ARQ-197, 7, MLN8054, FHA—739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an aurora kinase inhibitor, a PIK-l modulator, an HDAC inhibitor, a c-MET tor, a PARP inhibitor, a Cdk inhibitor, an IGFR-TK inhibitor, an anti- HGF antibody, a focal adhesion kinase inhibitor, a Map kinase (mek) inhibitor, a VEGF trap antibody, pemetrexed, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, umab, zanolimumab, edotecarin, tetrandrine, can, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, B10 140, CC 8490, cilengitide, gimatecan, ILl3-PE38QQR, INC 1001, IPdRi KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744, de 102, anel, atrasentan, Xr 311, psin, ADS-1003 80, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5’-deoxyfluorouridine, vincristine, temozolomide, ZK—304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N-[4-[2-(2-amino-4,7- dihydrooxo-lH-pyrrolo[2,3-d]pyrimidinyl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, azole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, 11, CHIR-25 8); 3-[5-(methylsulfonylpiperadinemethyl)-indoly1-quinolone, vatalanib, AG—013736, 05, goserelin acetate, leuprolide acetate, triptorelin pamoate, yprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, 9, PKI-166, 016, Ionafamib, EMS-214662, tipifamib, amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L—asparaginase, Bacillus Calmette—Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, lstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, ib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, 2017/040093 mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, ycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, l3-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5- deooxyuridine, ne arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, Vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, EMS—275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin- 12, IM862, tatin, Vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin ox, gefitinib, bortezimib, paclitaxel, cremophor—free paclitaxel, docetaxel, epithilone B, 7550, EMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, trant, acolbifene, lasofoxifene, idoxifene, TSE— 424, HMR-3339, ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, cin, 2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, 23, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated eron alfa—2b, interferon alfa—2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic acid, nazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic de, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-l receptor antagonist, setron, aprepitant, hydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, n alfa, darbepoetin alfa and mixtures thereof.

In one embodiment, a compound of Formula 1, Formula II, Formula 111 Formula IV, Formula V, Formula VI, Formula VII, a VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, a XVIII, a XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or Formula XXV bed herein can be combined with a chemotherapeutic selected from, but are not limited to, Imatinib mesylate (Gleevac®), Dasatinib (Sprycel®), Nilotinib (Tasigna®), Bosutinib (Bosulif®), Trastuzumab (Herceptin®), Pertuzumab (PerjetaTM), Lapatinib (Tykerb®), ib (Iressa®), Erlotinib (Tarceva®), Cetuximab (Erbitux®), Panitumumab (Vectibix®), anib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat (Zolinza®), Romidepsin (Istodax®), Bexarotene (Tagretin®), Alitretinoin (Panretin®), Tretinoin (Vesanoid®), zomib (KyprolisTM), Pralatrexate yn®), Bevacizumab (Avastin®), Ziv-aflibercept (Zaltrap®), Sorafenib (Nexavar®), Sunitinib (Sutent®), Pazopanib (Votrient®), Regorafenib (Stivarga®), and Cabozantinib (CometriqTM).

In certain aspects, the additional therapeutic agent is an anti—inflammatory agent, a herapeutic agent, a radiotherapeutic, additional therapeutic agents, or immunosuppressive agents.

Suitable chemotherapeutic agents include, but are not limited to, radioactive molecules, toxins, also referred to as cytotoxins or cytotoxic agents, which includes any agent that is detrimental to the viability of cells, agents, and liposomes or other vesicles containing chemotherapeutic compounds. General anticancer ceutical agents include: Vincristine (Oncovin®) or liposomal Vincristine (Marqibo®), Daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®), Cytarabine (cytosine arabinoside, ara—C, or r®), L-asparaginase (Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide (VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Pun'nethol®), Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, thasone (Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), and ponatinib (IclusigTM). Examples of additional suitable chemotherapeutic agents include but are not limited to l-dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopunne, 6— thioguanine, actinomycin D, adriamycin, eukin, alkylating agents, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin , anti-mitotic agents, cis— dichlorodiamine um (II) (DDP) tin), o dichloro platinum, anthracycline, an antibiotic, an antimetabolite, asparaginase, BCG live (intravesical), thasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin e, busulfan, calcium leucouorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine , mbucil, Cisplatin, Cladribine, Colchicin, conjugated estrogens, Cyclophosphamide, hosphamide, Cytarabine, Cytarabine, cytochalasin B, Cytoxan, Dacarbazine, omycin, dactinomycin (formerly actinomycin), daunirubicin HCL, ucbicin citrate, denileukin diftitox, Dexrazoxane, Dibromomannitol, oxy anthracin dione, Docetaxel, dolasetron mesylate, doxorubicin HCL, dronabinol, E. coli L-asparaginase, WO 05860 emetine, epoetin-(x, Erwim'a L-asparaginase, esterified estrogens, estradiol, ustine phosphate sodium, ethidium bromide, ethinyl iol, etidronate, etoposide citrororum factor, etoposide ate, fllgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HCL, glucocorticoids, goserelin acetate, gramicidin D, etron HCL, hydroxyurea, idarubicin HCL, ifosfamide, interferon (x-2b, irinotecan HCL, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine, lomustine, maytansinoid, rethamine HCL, medroxyprogesterone acetate, megestrol acetate, melphalan HCL, mercaptipurine, mesna, methotrexate, methyltestosterone, mithramycin, rnitomycin C, mitotane, mitoxantrone, mide, octreotide acetate, ondansetron HCL, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCL, plimycin, polifeprosan 20 with carmustine implant, porfimer , ne, procarbazine HCL, nolol, rituXimab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCL, ifene citrate, trastuzumab, tretinoin, icin, stine sulfate, Vincristine sulfate, and Vinorelbine tartrate. onal therapeutic agents that can be administered in combination with a compound disclosed herein can include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, eukine, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLLl, huN901-DM1, atiprimod, natalizumab, omib, carfilzomib, marizornib, tanespimycin, saquinavir mesylate, vir, nelfinavir mesylate, indinavir e, belinostat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin, talmapimod, 0, enzastaurin, tipifamib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEEOl 1), amebaciclib (LY2835219), HDM201, trant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

In one aspect of the present invention, a compound described herein can be combined with at least one suppressive agent. The immunosuppressive agent is preferably selected from the group consisting of a eurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e. g. rapamycin or a derivative thereof, e. g. Sirolimus (RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e. g, ridaforolimus, azathioprine, h IH, a SIP receptor modulator, e.g. fmgolimod or an ue thereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof, e. g. sodium salt, or a prodrug thereof, e. g. Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE , Prednisone, ATGAM®, THYMOGLOBULIN®, Brequinar , OKT4, TIOB9.A-3A, 33B3.I, 15— deoxyspergualin, tresperimus, Leflunomide ARAVA®, Ig, anti-CD25, anti-ILZR, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtX-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA4lg (Abatacept), belatacept, LFA3lg,, etanercept (sold as ® by Immunex), adalimumab (Humira®), IO infliximab (Remicade®), an anti-LFA-I antibody, natalizumab (Antegren®), Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab, Alefacept efalizumab, pentasa, zine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and thacin, aspirin and ibuprofen.

In certain embodiments, a compound described herein is administered to the subject prior to treatment with another chemotherapeutic agent, during treatment with another chemotherapeutic agent, after stration of another chemotherapeutic agent, or a combination thereof.

In some embodiments, the compound of Formula 1, a II, Formula 111 Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, a XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or Formula XXV can be administered to the subject such that the other chemotherapeutic agent can be administered either at higher doses (increased chemotherapeutic dose intensity) or more frequently (increased chemotherapeutic dose density). ense chemotherapy is a chemotherapy treatment plan in which drugs are given with less time between treatments than in a standard chemotherapy treatment plan.

Chemotherapy dose intensity represents unit dose of chemotherapy stered per unit time.

Dose intensity can be increased or decreased through altering dose stered, time interval of administration, or both.

In one embodiment of the invention, the compounds described herein can be stered in a concerted regimen with another agent such as anon-DNA—damaging, targeted anti-neoplastic agent or a hematopoietic growth factor agent. It has been recently reported that the untimely administration of hematopoietic growth s can have serious side effects. For example, the use of the EPO family of growth factors has been associated with arterial hypertension, cerebral sions, hypertensive encephalopathy, thromboembolism, iron deficiency, influenza like syndromes and venous thrombosis. The G—CSF family of growth factors has been associated with spleen enlargement and rupture, respiratory ss syndrome, allergic reactions and sickle cell complications. As such, in one embodiment, the use of the compounds or methods described herein is combined with the use of hematopoietic growth factors including, but not limited to, granulocyte colony stimulating factor (G—CSF, for example, sold as en stin), Neulasta (peg-filgrastin), or lenograstin), granulocyte— macrophage colony stimulating factor (GM—CSF, for example sold as molgramostim and sargramostim (Leukine)), M-CSF (macrophage colony stimulating factor), opoietin (megakaryocyte growth development factor (MGDF), for example sold as Romiplostim and Eltrombopag) interleukin (IL)-12, interleukin-3, interleukin-ll (adipogenesis inhibiting factor or oprelvekin), SCF (stem cell factor, steel factor, kit-ligand, or KL) and erythropoietin (EPO), and their derivatives (sold as for example epoetin-0t as Darbopoetin, Epocept, Nanokine, Epofit, Epogin, Eprex and Procrit, epoetin-B sold as for example NeoRecormon, Recormon and Micera), epoetin-delta (sold as for example Dynepo), epoetin- omega (sold as for example ), epoetin zeta (sold as for example Silapo and Reacrit) as well as for example t, EPOTrust, Erypro Safe, Repoeitin, Vintor, Epofit, Erykine, Wepox, Espogen, Relipoeitin, Shanpoietin, Zyrop and EPIAO). In one embodiment, the compound of Formula I, Formula II, Formula III Formula IV, Formula V, a VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, a XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, a XVIII, Formula XIX, Formula XX, a XXI, Formula XXII, a XXIII, Formula XXIV, or Formula XXV is administered prior to administration of the hematopoietic growth factor. In one embodiment, the hematopoietic growth factor administration is timed so that the nd’s effect on HSPCs has dissipated. In one embodiment, the growth factor is administered at least 20 hours after the administration of a nd described herein.

If d, multiple doses of a compound described herein can be administered to the subject. Alternatively, the subject can be given a single dose of a compound described .

In one aspect of the invention, a compound disclosed herein can be beneficially administered in combination with any therapeutic regimen entailing radiotherapy, chemotherapy, or other therapeutic agents. In additional embodiments the compounds disclosed herein can be beneficially administered in combination with therapeutic agents ing auto—immune disorders.

VIII. SYNTHESIS The compounds described herein can be prepared by s known by those skilled in the art. In one non-limiting example the disclosed compounds can be made by the following schemes.

The disclosed compounds can be made by the following general schemes: my N .N N/ N/ N St 1 N>\ l ep Lag/k}; \> fl; N ‘GAN: LG, N g 0.961. 60% impel A4 A-Z N/ N NW” l ‘> \ ‘~ Stepsy. : E: \> Q . /J\ N A A view HN N ______.,_ L61 N N """MRTW 17 OPG; A—4 A5 «A N OLG ‘l l N/ N Step5 PGZNN/K‘NN/j: \N) \H Step6 PG2‘N/KN l “N C) 9&7 J: “oped, I7 ‘09:; R. :5 2 i N ............................... N N NHR l ”l“ E OH 7 “Min Rx R — N O N / I ———> HN N N NW 9%? C37 A-‘lfl Scheme 1A As demonstrated in Scheme 1A, compounds that adhere to Formula 1 can be prepared from readily ble purines. In Step 1, an appropriately substituted purine A-1 can be reacted with an appropriate substituted olefin at elevated temperature in the presence of an metallic catalyst in organic solvent to furnish A-2. LG1 and LG2 are leaving groups known by those skilled in the art. In one ment, LG1 and LG2 are chloro. PG1 is a protecting group known by those skilled in the art. In one embodiment, PG1 is TBDMS. In one embodiment, the solvent is toluene. In one embodiment, the catalyst is Au(I) salt bound to appropriate ligands. In one embodiment, the temperature is greater than 80°C. The olefin shown in Scheme 1 is a non-limiting example and other olefins may be used by those skilled in the art to generate derivatives of structure A-2. In Step 2, LG2 is replaced by another leaving group LG3 to yield A-3. In one embodiment, LG3 is amino, -NH2. In Step 3, LG3 is removed by methods known to those skilled in the art to generate structure A-4. In a limiting example, LG3 is ed by hydrogen. In Step 4, structure A—4 is coupled with an appropriately substituted amine at elevated temperature in the presence of base and an organometallic catalyst in organic solvent. In one embodiment, the amine is pyridin-Z-amine. In one embodiment, the base is potassium t-butoxide. In one ment, the catalyst is Pd(OAc)2 attached to a [1,1'- biphenyl]yldi-tert-butylphosphane . In one embodiment, the temperature is greater than 60°C. In one embodiment, the t is toluene. Structure A-5 is then protected with a ting group known to those in the art. In one embodiment, PG2 is trityl. Structure A-6 is then transformed to structure A-7 in Step 6 according to methods known in the art. In one embodiment, LG1 is phenyl. In Step 7, PG1 is d by methods known in the art to afford A-8. l A-8 is then converted to a leaving group, LG2 in Step 8 to afford compound A-9.

In one embodiment, LG2 is bromo. In Step 9, LG2 is displaced to form A-10 which is a compound of Formula I.

WO 05860 2017/040093 Step 3 Step 5 Step 7 Scheme 1B As demonstrated in Scheme 1B, compounds that adhere to Formula II can be prepared from readily available starting materials such as B-l. In Step 1, B-l is protected with protecting group PG1 known by those skilled in the art to furnish B-2. In one embodiment, PG1 is TBDMS.

In Step 2, B-2 is reacted with an appropriately substituted e in the presence of a Lewis acid to generate B-3. In one embodiment, the Lewis acid is boron trifluoride etherate. The epoxide shown in Scheme 2 is anon-limiting example and other epoxides may be used by those skilled in the art to access derivatives ofB-3. In Step 3, alcohol B-3 is protected with protecting group PG2 to furnish B-4. In one embodiment, PG2 is TBDMS. B-4 is then converted to structure B-S by methods known in the art. LG is a leaving group known by those in the art. In one embodiment, LG is phenyl. In Step 6, PG; is d according to s known in the art to yield B-7. In Step 7, B-7 is cyclized by methods known in the art to generate lactam B- 8. In Step 8, sulfide B-8 is ed to afford B-9. Sulfone B-9 is then displaced by an appropriately substituted amine to produce compound B-10 which is a compound of Formula H ,PG1 [P61 LG1AN/ / ifs/LNx / / / R7—-NH2 Hr? l\. 6-? 3-2 (3-3 PG: P81 ' N S- 3 N’ N \ l : ng x : R7 I , (3-4 (2-5 N OLG 2 Stepfi “if? MW Step6 PG7‘N/L\N/ / l OPG3 (1-? F31 E \l 0 \j \ O I'\. \ i P82\NAN/s / {ting AL «2 f? Step1 IN .,,, Step 8 IN-«g ' W .N/ Hi?! A? o -’ R7 < 33-8 {3-9 Scheme 1C As demonstrated in Scheme IC, compounds that adhere to Formula III can be prepared from readily available pyrimidines. In Step 1, an riately substituted pyrimidine C-l is protected with a protecting group, PGi, known to those skilled in the art to furnish C-2. In one embodiment, PGi is trityl. LG1 is a leaving group known by those skilled in the art. In one embodiment, LG1 is chloro. In Step 2, C-2 is coupled with an appropriately substituted amine at elevated temperature in the presence of base and an organometallic catalyst in organic solvent to yield structure C-3. In one embodiment, the amine is pyridin-Z-arnine. In one embodiment, the base is potassium t—butoxide. In one embodiment, the catalyst is Pd(OAc)2 attached to a [1,1'-biphenyl]—2-yldi-tert-butylphosphane ligand. In one embodiment, the temperature is greater than 60°C. In one ment, the solvent is toluene. In Step 3, structure C-3 is protected with protecting group PG2 known to those d in the art to generate structure C-4. In one ment, PG2 is trityl. In Step 4, C-4 can be reacted with an appropriate substituted epoxide in the presence of a Lewis acid to produce structure C-S. In one embodiment, the Lewis acid is trifluoroboron etherate. The epoxide shown in Scheme 3 is a miting example and other es may be used by those d in the art to generate derivatives of structure C-S. In Step 6, alcohol C-S is protected with protecting group PG3 known to those d in the art to generate C-6. In one embodiment, PG3 is TBDMS. In Step 6, C-6 is transformed to structure C-7 according to methods known in the art where LG2 is a leaving group. In one embodiment, LG2 is phenyl. In Step 7, C-7 is cyclized to afford lactam C-8 according to methods known in the art. In Step 8, PGi and PG2 are removed to furnish nd C-9 which is a compound of Formula III.

L‘Gg O N/KYO Step1 i\ Step2 : (j, HNJLN” m1} /I /i\>/ / LG; N _ l N R’---NH2 {3-1 [5-2 [3:3 “Mr ‘~ 0 we )L ,;> N “LimaSte 3 1‘» / ~~ 3: 4 If N “it“, p61, A x / N/\ o OLG3 Step 5 ‘G ”NAN/d / Step 6 O WWW—a» OPGZ RT I $997 Pel‘pg/LKN/ ‘ / NHR Step 8 A f - / _( Scheme 1D As demonstrated in Scheme 1D, nds that adhere to Formula III can be prepared from readily ble pyrimidines. LGi and LG2 are g groups known by those skilled in the art. In one embodiment, LGi and LG2 are chloro. In Step 1, LG2 is d according to methods known in the art to h structure D-2. In Step 2, D-2 is coupled with an appropriately substituted amine at ed temperature in the presence of base and an organometallic catalyst in organic solvent to yield structure D-3. In one embodiment, the amine is pyridin-Z-amine. In one embodiment, the base is potassium t—butoxide. In one embodiment, the catalyst is Pd(OAc)2 attached to a [l,1'-biphenyl]yldi-tert-butylphosphane ligand. In one embodiment, the temperature is greater than 60°C. In one embodiment, the solvent is toluene.

In Step 3, structure D-3 is protected with protecting group PGi known by those skilled in the art. In one embodiment, PGi is trityl. In Step 4, pyrimidine D-4 is reacted with an appropriately substituted epoxide in the presence of a Lewis acid to produce structure D-5. In one embodiment, the Lewis acid is trifluoroboron etherate. The epoxide shown in Scheme 3 is a non-limiting example and other epoxides may be used by those skilled in the art to generate derivatives of structure D-S. In Step 5, alcohol D-S is protected with protecting group PG2 known to those skilled in the art to generate D-6. In one embodiment, PG2 is TBDMS. In Step 6, D-6 is transformed to structure D-7 according to methods known in the art where LG3 is a leaving group. In one ment, LG3 is phenyl. In Step 7, ester D-7 is converted to amido species and the PG2 is subsequently removed to furnish the free alcohol which is then converted to leaving group LG4 by methods known in the art to produce ure D-8. In one ment, LG4 is bromo. In Step 9, D-8 is cyclized by methods known in the art to afford lactam D-9 which is a compound of Formula III. :3: \ Step? HNJLN/ f Step2 PG“ A ,j R? R7 £2 £43 N \ N ‘\ 5 48103 3‘9” ——+ PG1\:/li\ / / {3qu i , / o I? N CH “f N CFC-32 é R7 k”! RI L\/I E~4 E—5 Step5 Scheme 1E As demonstrated in Scheme 1E, compounds that adhere to Formula III can be prepared from readily available dines. In structure E-l, LGi is a leaving group known by those skilled in the art. In one embodiment, LGi is . In Step 1, E-l is coupled with an appropriately substituted amine at elevated temperature in the presence of base and an organometallic catalyst in organic solvent to yield structure E-2. In one embodiment, the amine is pyridin-Z-amine. In one embodiment, the base is potassium xide. In one embodiment, the catalyst is Pd(OAc)2 attached to a [l,1'-biphenyl]-2—yldi-tert-butylphosphane ligand. In one embodiment, the temperature is r than 60°C. In one embodiment, the solvent is toluene.

In Step 2, E-2 is protected with a ting group, PGi, known to those skilled in the art to furnish E-3. In one embodiment, PGi is trityl. In Step 3, E-3 can be reacted with an appropriately substituted epoxide in the presence of a Lewis acid to e structure E-4. In one embodiment, the Lewis acid is trifluoroboron te. The epoxide shown in Scheme 5 is a non-limiting example and other epoxides may be used by those skilled in the art to generate derivatives of structure E-4. In Step 4, alcohol E-4 is protected with protecting group PG2 known to those skilled in the art to generate E-S. In one embodiment, PG2 is TBDMS. In Step , E-S is transformed to structure E-6 according to methods known in the art where LGi is a leaving group. In one embodiment, LGi is phenyl. In step 6, ester E-6 is ormed to an amido species and PG2 is removed to yield E-7. In Step 7, the alcohol is converted to leaving group LG2 known by those skilled in the art. In one embodiment, LG2 is bromo. In Step 8, E- 8 is ed to afford lactam E-9 which is a compound of Formula III.

,NHz [PG N Step1 N \ N/(K‘YN Stecz l /E / J; , 5 4K? / -----------------------------I» Hit N LG N LG N R, F“! F~2 R3 Step3 N Whips N \ Step4 NE \E W pal, N,» / m,“ AL ,, J FE! N ‘ C) a OH R, R7 (R1), . g R i)?” , 3: F4 5’ F—5 PG. we Ni N; N \ l N \ MEL“,- PG1\N/JLN/ Pu1\N,il\N/’’j/ {I h ’1 ,, Step6 ~ LG”: W ' E ‘\ L81 7 1 ' 1“ (My R tR‘} -2.7 [PG H N N \ R Ste 7 i N=N~NHPh StepB HNAN/I {3 PG1\i\j/J\N/ ( / N l: ‘\ CN E I I7 7 I R R" A R R1) I R!) 3/ y Scheme 1F As demonstrated in Scheme 1F, compounds of Formula IV can be ed from y available starting materials such as F-l. In Step 1, F-l is protected by methods known by those skilled in the art to furnish F -2. In one embodiment, LG is ne. In one embodiment PG is trityl. In Step 2, F-2 undergoes SNAr nucleophilic addition, yielding F-3.

In Step 3, F-3 is protected to afford F-4. In Step 4, an appropriately substituted F-4 can be reacted with an appropriate substituted epoxide to furnish F-5. In Step 5, the hydroxyl of F-5 is converted to an appropriate leaving group to afford F-6. In Step 6, F-6 is converted to azide F-7. In Step 7, F-7 undergoes nucleophilic attack to install a cyano group and yield F-8. In Step 8, F-8 is cyclized by s known by those skilled in the art to afford F-9 which is a compound of Formula IV. (5-4 35 Step? PGW: N “\V):0 51698 HE}; K<szo Scheme 1G As demonstrated in Scheme 1G, compounds ofFormulaV can be prepared from readily available starting materials such as G-l. In Step 1, G—l is ted by methods known by those skilled in the art to furnish G -2. In one embodiment, LG is chlorine. In one embodiment PG is trityl. In Step 2, G-2 undergoes SNAr nucleophilic addition, yielding G-3. In Step 3, G—3 is protected to afford G-4. In Step 4, an appropriately substituted G—4 can be reacted With an appropriate substituted olefin at elevated temperature in the presence of an organometallic catalyst in organic solvent to furnish G-S. In one embodiment, the solvent is toluene. In one ment, the catalyst is Au(I) salt bound to appropriate ligands. In one embodiment, the temperature is greater than 80°C. The olefin shown in Scheme 1G is a non-limiting example and other olefins may be used by those skilled in the art to te derivatives of structure G- . In Step 5 G-S is converted to azide G-6. In Step 6, G-6 is undergoes nucleophilic attack to install a cyano group and yield G—7. In Step 7, G-7 is cyclized by methods known by those skilled in the art to afford G-8. In Step 8, G-8 is ected to afford G—9 which is a compound of Formula V.

Step3 CN 0 o .EAT\ WWw Step1 N \ NA“ H2N\/U\ , /K ,a/x. ~ I ---------------------------a» LG h. NHZ / ____________________9{1, ‘-G M NH? AL / LG N Halo (1 O Q N - DPG i La: / -u . ton N H Y i ill/m” U o “-4 H5 ._o o 0 0 Step6 ‘\ Sep'l' N N \ ’1!\ steps —_“* i """"""""""""" N' / ‘)wa [JL / (39¢ l ,. :i """"""""""""1* .I I LG1 LG N LG N ‘ fi LSANA’Q/ \IO 0 O " 0 H 7 H-8 H 9 0H ,3 \ k ly M? \ )n r , ---------------------------------------------------------->,, j: / if} N/Y F5 u H 11 Ste09 at: N Er LGAN/ "1 O VET)“' \Ei’ H41} " flLGz PG1 o y 0 Q step N \ R7,NH2 NM ———9 LrJ/L‘Nl I l i / O r” Q N “mm—"4” ’j‘m-“Y_ H13 Ste.) 12 N L N MF3 R, V, {RU l N“? {R‘- y \ ‘ H42 Formula VI Scheme 1H As demonstrated in Scheme 1H, compounds of Formula VI can be prepared from readily available ng materials such as H-1. In Step 1, H-1 is ted to a ketone by methods known by those skilled in the art to furnish H-2. In one embodiment, LG is chlorine.

In Step 2, H -2 is converted to an appropriate halide for uent displacement, yielding H -3. In Step 3, halide H-3 is displaced by glycine to afford H-4. H-4 is then protected to afford structure H -5 by methods known in the art. In one embodiment PG is ethyl, In Step 5 H-5 is converted to zwitterion H-6. In Step 6, H-6 is cyclized by methods known in the art to yield H-7. In one embodiment silyl is TMS. In Step 7, H-7 is dehydrated to afford H-8. In Step 8, H-8 is converted to an appropriate leaving group containing compound H-9. In one WO 05860 ment LGl is hydroxyl. In Step 9, the secondary amine is protected and then the LG] of H—9 is displaced by an appropriately substituted amine to produce compounds of Formula H010. In one embodiment PGl is a carbamate. In Step 10, the hydroxyl group of H-10 is converted to an appropriate leaving group to afford H-ll. In Step 11, H-ll is cyclized to afford H-12. In Step 12 SNAr nucleophilic addition of an amine displacing the leaving group of H- 12 affords a compound of Formula VI.

Ci NH2 WPAuOTf N/JEN -N N\> DMSCE/k(53m01%) NH4OH it. N\> kN”: ~o.BDMS HZO/MeOH or or N N OTBDMS 1 i To!uene 85°C 3 .,_ N \ NJ; m: l N 4 5 \ z 0 aux/”75%) N/ 1 ng“'P T..F 0:013:23 : 1.221339“ ; \.NAN Ph N 3 -----------------------------#- OCUD NEt3 fioraoMs 2 CECOQ'F’h N: (Shmom l 2% E NWN 1. NH?” MeOH Ph" \ N \N N NH; F’Pi'13.CBr4 SuxN NAN NHZ DC‘JI i ’\ 2.TBAF, A : Br OH N, N/ E 6} K I \ ------ N2 3 R2 g 1. NaH Nit:N4; 2 AcOH MeOH © On- Scheme 2 As exemplified in Scheme 2, An appropriately substituted purine (1) is dissolved in toluene and treated with tert-butyl(cycloheX-l-en-l-ylmethoxy)dimethylsilane in the presence of tic PhsPAuOTf at elevated temperature to produce 2. Compound 2 is subsequently aminiated with ammonium hydroxide to furnish amine 3. The amino moiety is then removed by conversion to the corresponding diazonium salt with nitrous acid followed by subsequent reduction with hydrophosphinic acid to yield 4. An riately substituted amine is then coupled with 4 at elevated temperature in the presence of base (NaOt—Bu) and a palladium WO 05860 source such as Pd(OAc)2 with an appropriate ligand to generate 5. This species is then protected with trityl chloride to produce compound 6. The trityl-protected species is then ted with an lithium reagent and quenched with an appropriately substituted electrophile to furnish compound 7. Amidation of 7 with ammonia, followed by subsequent deprotection of the silyl ether with TBAF yields an amido alcohol 8 that is converted to bromo species 9 with triphenylphosphine and carbon romide. Finally, cyclization of the alkyl bromide with the amide moiety, followed by acidic deprotection of trityl affords the title compound 10 which is a representative compound of Formula I.

WO 05860 2017/040093 Q OTBDMS A EBDMS N 1 ,N N/ M HN TBDMSCI N N' BFS'OEtZ \\ H3CSAN/‘NN:> l /L\x \ imidzole N H3CS \N 0 H308 “OH 11 12 EBDMS 1. n-BuLi, THF N” N, TBDMSCI, N\ 00C fl 9TBDMS imidazole H393 N OTBDMS 2. CICth 1.TBAF, DCM NJ’L‘N’N OPh Pd/C,H2 - \ 2. Pool3 H3cs’”‘NJk .\ o EtOH HO 1. BOCZO, K2C03, 1_ NH3, MeOH H cs 2- Pphfv CBr4 3 2. Oxone, ZO (\r 2 sz\ N HC' N-Boc e, 100°C Scheme 3 As exemplified in Scheme 3, Compound 11 is first protected with TBDMSCl to yield silyl ether 12 which reacts with an appropriately substituted epoxide in the presence of a suitable Lewis acid to produce alcohol 13. Silylation of 13 affords 14 and subsequent lithiation of the ic ring with an n—butyllithium followed by treatment with an appropriately substituted electrophile produces 15. Treatment of 15 with excess TBAF removes both silyl ethers and the free amide is then converted to chloride 16 with POC13. Chloride 16 is reduced to compound 17 in the presence of finely dispersed palladium on carbon with molecular hydrogen as the reductant. Treatment of 17 with ammonia in ol followed by a subsequent reaction with PPh3 CBr4 yields an intermediate bromide that undergoes cyclization in the presence of base such as NaH under elevated temperature to afford lactam 18. The amide is protected as a carbamate with BOC2O and the sulfide is uently oxidized to the sulfone by the action of oxone in aqueous media buffered to approximately pH 4.5. This ure furnishes compound 19 which readily undergoes aromatic substitution with an appropriately substituted amine at elevated temperature to generate 20. The Boc protecting group is then removed under acidic ions to yield title compound 21 which is a representative compound of Formula II.

MHZ <3}th H 13 (“Kg N \Ai N \ ClCDhs MAE/N sz / )L ,« A / ‘ “'“’ i 5;); / N ,. DCM N533 _ C! N CI‘ N Pd{OAc)g NaOi~Bu, 22 P(tBu)J 23 {‘5 Q"-"Q \ 24 Toluene, 110°C {1:53:13 . N .____E_E__Cf:E-_3_________.,.

W: pA “E \ 2 81,0512 x / Don/Hera3 ‘ N o \ 25 0.0m i ‘ ESPhg n...

N Ol-‘E‘: N \ \ N TBDMSCE Phgci )L /\/ :.n:::;l.::'l—IF PhaCNJ‘LN irnidazole l? “‘OTBDMS __-_,.. GTBDMS 2. CECOzF’h / / E 3N 28L CPhs 1.NE-{3.MeOH P313ch,1; /_<rH AcOH,MeOT—l —---------------a» 2.TBAF KAN 80°C 3.CBr,;,PPh3 4.NaH $2. R2 3o Scheme4 As exemplified in Scheme 4, Compound 22 is protected with trityl chloride in the presence of base to furnish 23. An appropriately substituted amine is then coupled with 23 at elevated temperature in the presence of base (NaOt—Bu) and a palladium source such as Pd(OAc)2 with an appropriate ligand to te 24. uent protection of 24 with trityl chloride yields 25 which is then reacted with an appropriately substituted epoxide in the ce of a suitable Lewis acid to produce alcohol 26. Silylation of 26 readily affords 27 which is transformed into nd 28 by n-butyllithium and an appropriately tuted electrophile. Amidation of 28 is effected by methanolic ammonia and the silyl ether is ected in the presence of TBAF. This procedure affords an intermediate alcohol that is converted to the corresponding bromide by CBr4 and PPh3 that undergoes cyclization in the presence of base such as NaH to yield compound 29. The trityl groups are then deprotected with acid under elevated temperatures to furnish 30 which is a representative compound of Formula 111.

(WT/MHZ N N \ £3in AL / / CiCPhg ca/E‘N/ ’/ N Pdcoamg u, :53! DCM, NEt3 P(t~8u) EN 31 \ 02,.BR“ E2. E TBDMSC! Phase“ / N¢~ PthNina" / O ' 13H OTBDMS imidazole . 1 N 3 O “--‘=TMF 1.NH3,MeOH PhaciNi; 2’? DOC—rt “Hz 2. TBAF 2. CECOZPh /' N </ 9H FE? 3? can, PPha mm mm _ 2. AcGH‘ MeOH R2 38 Schemes As exemplified in Scheme 5, Compound 31 is y coupled to an appropriately substituted amine at elevated temperature in the presence of base (NaOt—Bu) and a palladium source such as Pd(OAc)2 with an appropriate ligand to generate 32. The amino moiety is then protected with trityl chloride to furnish 33 which reacts with an appropriately substituted epoxide in the presence of a suitable Lewis acid to produce alcohol 34. Silylation of alcohol 34 produces 35 which is ormed to compound 36 by n-butyllithium and an appropriately substituted ophile. Ester 36 is then converted to an amide by methanolic ammonia and the silyl ether is cleaved in the presence of TBAF to yield 37. Bromination of alcohol 37 with CBr4 and PPh3 affords bromide 38 which readily undergoes ation in the presence of base to produce a cyclic lactam. This intermediate lactam is treated with acid at elevated temperature to remove the trityl protecting group which furnishes compound 39 which is a representative compound of Formula 111.

N fig o \ ' o R2 / N \ Poi/C H3. Etoei / HN N/ i / --------------------------------- NEAR/O C‘! N/ Pd(OAcb NaOt—Bu. A C! N ’ Paul-Bu)? l 40 41 V <1 42 Tcfiuerae, 11930 W33= Phsct ‘ /.J N 1 N c, WNA .3 .

, E/ N i V / R2 N7 o 0% .\ ‘l. n-BULL THE: TED:JISC! PhsC‘NAN/_ i PhacN11? ,i/ Q 000 “r? ' imidazoie UTBDMS W / ECKKTQWW / XOTBDMS E 1N V \ ' \’ 45 NWOH N.CN13; < “N [1NH EBAF / 2 ACOH MeOH C> 3. arm, PPhg R2 47 Scheme 6 As exemplified in Scheme 6, Compound 40 is reduced with finely dispersed palladium on carbon in the presence of molecular hydrogen to furnish loridate 41. An riately substituted amine is then d with 41 at elevated temperature in the presence of base Bu) and a palladium source such as )2 with an appropriate ligand to generate 42. Compound 42 is then protected with trityl de to yield 43 which is then reacted with an appropriately substituted epoxide in the presence of a suitable Lewis acid to produce alcohol 44. Silylation of alcohol 44 produces 45 which is transformed to compound WO 05860 46 by n—butyllithium and an appropriately substituted electrophile. Ester 46 is then converted to an amide by methanolic ammonia and the silyl ether is cleaved in the presence of TBAF.

Subsequent bromination of the ediate alcohol with CBr4 and PPh3 affords bromide 47 which readily undergoes cyclization in the presence of base to produce a cyclic lactam. This intermediate lactam is treated with acid at elevated temperature to remove the trityl ting group which hes compound 48 which is a representative compound of Formula 111. cw WNW ’CPhE '3 N I N N \ N )«\ ClCPhq I‘x' \. V R2 JL / / / A / / HN N N,» DOM N._-3n cg N Pd(OAc)2 NaOf-Bu, 1 59 1211231112 IN 51 dom- \ Toluene, 110°C J. Org. Chem, Vol. 65. No. 4, 2000 (312113?”h3 .3 N _____1: 33 3 3131:2113, 131-30512 33 3A“; “j DOM, MEN 3 ‘N N” 3’ a 52 i R2 R2 53131133309113 "2momma-~ / N—NNHPS‘. 1_ n-BuLJ,THF h 5233,: / 12.3333,133: 0°C“ imidazoie ‘ \‘OTBDMS ——* OTBDMS 2.113131: l R; 55 Cl’hg H N:N—1111111 133*Ni/E’NNl NH / / 1 TBAF DCM 333330WEE/f H0! ON, «J."-0 2 si 115136001: / N < N 6m 3 £15vaDMSO l \ V R2 56 R2 57 Scheme7 As exemplified in Scheme 7, Compound 49 is protected with trityl de in the presence of base to yield 50. An appropriately substituted amine is then coupled with 50 at elevated temperature in the presence of base (NaOt—Bu) and a palladium source such as Pd(OAc)2 with an appropriate ligand to generate 51. Subsequent trityl protection of 51 fumishes 52 which reacts with an appropriately substituted epoxide in the presence of a suitable Lewis acid to produce alcohol 53. Silylation of53 readily affords 54 which is transformed into compound 55 by n-butyllithium and phenylazide. The siyl ether is then cleaved with TBAF and the resulting alcohol is tosylated and displaced by NaCN to yield e 56. Heating compound 8 at elevated temperature in the ce of acid cleaves the trityl protecting groups and es hydrolysis of the nitrile and azo moieties to generate lactam 57 which is a entative compound of Formula IV.

. N . N \ \ ClCPhg “3% \ Riki‘v (I? Marm = /= HN N DcM,NEt3,3 _ BEAN/\j‘l Pd{OAc)2NaOf-Bu, 33pm H Ph3c ’/ N F-‘(t—Bu) 58 i I 59 \ 'Toluene, 110°C 1 BnCi, NEt3 Brx film' ' NANmN 2. ACGH 60°C f6:Ph3r‘Auoff(5 mo! Io) i c V (5OTBDWES Toluene 85°C 4 \\ :A.-B“03:1,L' THri" /\/>—N=NNHPt NA; N:N»NHl-hI) '; 1 8anIANAN “HEAR DOM ————»“’ OTBDMS 0N 2N3Ph 2.03r4J-N2h3 / N 3.NaCN,DMSO l \ \V.» R2 64 N \ \ 60°C Scheme 8 As exemplified in Scheme 8, Compound 58 is protected with trityl chloride in the ce of base to yield 59. An riately tuted amine is then coupled with 59 at elevated temperature in the presence of base (NaOt-Bu) and a palladium source such as Pd(OAc)2 with an appropriate ligand to generate 60. Subsequent tion of 3 with benzyl chloride and ediated hydrolysis of the pre-existing trityl protecting group yields 61.

Compound 61 is then reacted with tert-butyl(cycloheX-l-en-l-ylmethoxy)dimethylsilane in the presence of catalytic Ph3PAuOTf at elevated temperature to produce 62. Treatment of 62 with n-butyllithium followed by phenylazide furnishes 63. The silyl ether is deprotected with TBAF and the resulting alcohol is transformed into an alkyl halide with PPh3 and CB4 and is displaced by NaCN to produce nitrile 64. Hydrolysis of the nitrile and azo moieties in the presence of acid at elevated temperature es cyclization to lactam 65. Reductive cleavage of the benzyl protecting group by finely dispersed palladium with molecular en affords compound 66 which is a representative compound of Formula V.

CN 1. MeMr‘Br \ .3 _T_l:‘l_F_DOC"-“El NM\ 1‘ rlNOZ: H20 . ----> /M HgNV’lLOH Cl N NH-2.

HO! (aq)*10C (Si/1N 5L“H2 2 HBF4. reflux Ci/T‘NAF DMF K2C03 68 reflux o O o 3% 1-SOCE2 3e02, t~BuOOH A / OH ' 0E1 E ‘ i\ l/ / QB N ___ a _- CI N NHW )NL \ ttUH,F.l. r,w N EAT/i/ . 71 ‘ NEE (SN/1% “ED”... ”% K2003 OH CIAN/ fififlwl" a: : ...................... : I» A , TMSCE N/fif _ / OH HOH Erik: MeOHngo Cl N N TMSG 0 ‘30ch 1. TBDMSCI, NaH i}; HATU, DEPEA 2. BriCE, Kt (SI/1‘“ DMF NaH, DMF OTBDMS dioxane, H20 100%) H2.Pd/‘C i .. cDH GVN Scheme 9 As exemplified in Scheme 9, Compound 67 is chilled to reduced temperatures and treated with methyl magnesium bromide. Acidic workup of the on mixture yields 68.

Diazotination of 68 with nitrous acid ed by subsequent treatment with HBF4 at elevated temperatures produces fluoride 69. This intermediate is heated with glycine in the presence of base to furnish 70. Carboxylic acid 70 is converted to the acid chloride and esterified with EtOH to afford ethyl ester 71. Oxidation of the secondary nitrogen to nitrone 72 is accomplished with SeOz and t—BuOOH. Cyclization of 72 with TMSCl in the ce of base yields 73 which is reduced with Pd/C in the presence of molecular hydrogen to generate amine 74. Ethyl ester 74 is then hydrolyzed with aqueous base and simultaneously ted with Boo to afford carboxylic acid 75. Acid 75 is then coupled with an appropriately substituted amine to yield amide 76. The tertiary alcohol is silylated with TBDMSCl and the amide is benzylated with sodium hydride and benzyl bromide to furnish 77. Hydrolysis of B00 and the silane protecting group in aqueous acid produces a tertiary carbocation that undergoes cyclization at elevated temperature to produce 78. Chloride 78 is then coupled with an riately substituted amine to generate 79 which undergoes a Pd catalyzed reduction to cleave the benzyl protecting group which yields compound 80 which is a representative compound of Formula \ ,. s N N ix» 3 N a e ref H l“ NP 81 33 Ellisi , Q 0 ‘S/JxNZ/KN5 C0C3‘ e1 __............,,. “7W \s \N” N‘ . . _,\SAN E :M ,4 in p 34 85 o 0 o lo \ ”I ‘~ /=: \ N ixH: MAX‘ NH N NH_ \ / N , \ 42—»; \ / N ' NH w N --------------*> N ”NH )~~;\ "—m—“W Om; S I/\ (/1 W HN l \ ,1, 0 /~ l? \’j a? 88 89 N"3 Scheme 10 As shown in Scheme 10, bromide 81 is converted to aldehyde 82 followed by subsequent cyclization and oxidation to furnish carboxylic acid 83. Acid 83 is then transformed to an alkyl ester 84 and transamidated to yield amide 85. ection of the ting group P produces 86 which oes aminal formation in the presence of a ketone to generate aminal 87. Sulfonation of 87 affords 88 which subsequently undergoes nucleophilic aromatic substitution to furnish desired compound 89 which is a representative compound of Formula VII. iii-i2 M NH; N300 NW0 NBOC -~N H N / / “.1 + NW—NH tdepr‘otect W Mfg—N PM >2” ——p 2. giyoxcii F“ Ci R7HN 3. RNH2 9t) 91 92 Tetrahedron, 52(29), 6855-5861; 2006 1.Anti—Cancer Drug Design . 8(6), 439—631. 2. indian i of Chemistry, Section B: fjrganic try Including Medicinal Chemistry (1983), 228(12), 1233-5.

Scheme 11 As shown in Scheme 11, commercially available chloride 90 is coupled with an appropriate amine Via philic aromatic substitution to afford intermediate 91. Amine 91 is then deprotected, subjected to cyclization in the presence of glyoxal, and coupled with the desired amine to yield compound 92 which is a entative compound of a VIII.

NO: NO NH- N02 N800 if 2 iCi N300 N ./\ 1 deprotect - NH_ NQN MN>": :f: * -------I> .....

N >—N 2. cyciizeto aminoimidazoie. 05>— typioaiiy with 94 cyanogen bromide 95 i—BuOK, THF NzN NzN mum-ma» N82H2s n2V4 / \\ >§N -----------)u» l \\ >‘\“N 96 N N N N 97 R?__NH_ >=~ -*A A C! R'HN Jourwa'ofMe=dic'r~a'C'rie>rni,try 46(1) 1519-- 182; 2003 U3. Pai.Appi. Pubi.,20040192686 Journal of Organic Chemistry. 79(16) 7520-'7'31; 2014. sis (8) 855—857': E997 Science of Synthesis, ’17" 357-447; 26-04 Scheme 12 Alternatively compounds of Formula VIII can be formed as shown in Scheme 12.

Commercially available chloride 93 is coupled with an appropriate amine via nucleophilic ic substitution to afford intermediate 94. Amine 94 is then deprotected and subjected to cyclization in the presence of cyanogen bromide or an analogous reagent to afford compound 95. Compound 95 is further cyclized in the presence of a base to afford compound 96, which is reduced and subjected to an appropriately substituted amine to afford nd 97, which is a compound of Formula VIII.

NH; N800 treat with acid to remove Boo group m and convert acetai N to the aldehyde ‘1. air oxidation mmmnm-Db PM mum-nib >3—"N 7. RH“7- zwmm 191 102 Scheme 13 As shown in Scheme 13, bischloride 98 is coupled with an amine via nucleophilic ic substitution to furnish intermediate 99 which then undergoes amidation in the presence of a carboxylic acid to produce amide 100. Removal of B00 triggers intramolecular cyclization to yield intermediate 101 which is then oxidized upon re to air or other ts and coupled with a desired amine to afford target 102 which is a compound ofFormula WO 05860 OWN HumR “3‘33 NH N f0 N NH (Cl/k53M (,IL‘ / mm» ‘ )1“ HI, N 0 C! N l‘i Ll N 103 1055 /—’/ \ R7-NH2 \ N 0 Br QE/k/‘ii:H: WNWR R7 HH ‘N N N wo2012 082997 Scheme 14 As shown in Scheme 14, protected heterocycle 103 is reacted with an electrophile as known in the art to furnish intermediate 104 which then undergoes ection to produce amide 105. Nucleophilic attack of dibromoethane by 105 followed by intramolecular cyclization affords 106 which is coupled with a desired amine to afford compound 107 which is a compound of Formula I. ”far" i“):X /J\ / HszR7 ./l\ / Cessum acetate, NHG X. N NH H?- N NH Cu, MeOH, DMSO ‘ mum—nav- NHBGC R7 NHBQC us.‘ 1' at. ~ i Pub 4L100225a’9 ’ V52 103 109 N/le-lg N\ 0 HN/kN/ e H NH N/ N OH 1i Deproteot F E R7 NHBoc R7 NIHIBoe 2. Laotam formation 110 111 NWN O : X, X1 are halogens i an M HN N N Scheme 15 As shown in Scheme 15, protected heterocycle 108 is coupled with a desired amine to furnish intermediate 109. Intermediate 109 is then converted to an anilino compound 110 as known in the art. The anilino compound 110 is sed into an oxalate derivative 111 which is subsequently deprotected and cyclized to form compound 112, which is a compound of Formula I. 0 W0 NH ”Gk/MHZ HZNWR'7 N \ N ------------------------------------b» 5' PM TiCM, messi‘lylene JOC 59, 17, 1994, Pag355084—7 Scheme 16 As shown in Scheme 16, known compound 113 can be reacted with an amino ketal to form compound 114. Compound 114 is subsequently reacted with a desired amine to form compound 115, which is a representative compound of Formula XI. 116 117 118 Bioorg, Med Chem. Lett. 18, 2008, pp 5015-1? HZNwR7’ >”—“N 0H “mum, CI R”! ------------------------------1> 119 120 Scheme 17 General Procedure for the Synthesis of Diazepinones 118. A mixture of the suitable 2- arninobenzophenone derivative 116 (6.0 mmol) in pyridine (40 mL) containing 9.0 mrnol of e tive 117 is refluxed for 20 h under nitrogen. The on mixture is concentred under reduced pressure, poured into ice—water and ted with CH2C12. The organic layer is washed with 0.1 N HCl, dried over Na2S04, and evaporated in vacuo. The residue is purified by flash-chromatography eluting with the suitable solvent to afford the ed compounds, which after re-crystallization from the appropriate solvent gives 118.

Diazepinone 118 is then coupled with a dine to afford 119 which is subjected to an appropriate amine in a nucleophilic attack to afford 120, which is a compound of Formula XII.

In the following schemes methyl piperazines products and intermediates are synthesized. One skilled in the art, will appreciate that a variety of different heterocycles could be used in place of methylpiperazine (such as zine, isopropylpiperazine, morpholine, etc) by selection of the heteroaryl amine reactant in the following schemes. c ,0? o o O UQKO O\ H H NH2 0 \ O N \ “o N\.xvmc /’ ”/0 / A /l\ /E NazleN Wk” / c!5 M NH c; N Cl NH l?” ' BO“ Bow j 0’ m); ECI p l _0 CE! 121 122 123 124 125 \ Scheme 18 Scheme 18 provides a synthetic preparation of compound 126 of Formula I. First commercially available dichloride 121 undergoes nucleophilic addition to install a diamine moiety and afford 122. Intermediate 122 is then reduced to an anilino compound and uently reacted with either methyl chloromethoxyacetate, methyl 2,2,2- thoxyacetate, methyl 2,2,2-tn'chloroacetimidate, or a similar t to afford cyclization precursor 124. 124 is then deprotected and subsequently undergoes intramolecular cyclization to afford 125 which then undergoes nucleophilic attack to afford final compound 126.

Br N’Waf -0 /§{ 14005 N“ Br' i N o VA .4 o <_____/— 3" o/ki \ ‘1 #W a; OH_ 3’” 5 N sfiN \ 9 N T I OH 1 [/j a a Journai of i-Ieieroeyclic Chemistry, \v/ 127 2003, V0140, #2 [1219-2213 129 130 NfljBra: N/sjara; x O / , , CH CN ,1 Br \NHBOC I‘x/ K‘J 132 133 Br SH SAN/I =grams , $AN/,ixi'AI/ :omoms _______________,.,, "-9“ ! : : GNNHBQC @NHBCC 0 Cl \\ /\ S, O Q Sf’k}.../\ /~\M NR! 0 #82)” NA:( 0 \ f)‘# “rams ./=\ , ”x —b~ N }~‘NM\ ., /\ ”,BOC S)\N ,R x /b " I“; r.‘ «80c H / I $21 <\_,. 138 138 [fail/fl O REV/Syria? \ls I}: /3/ ‘N \ as N\ 45.1.!" NH NOW], "Jh —*" ’l x l‘d i’ aw w /~ <’ fiso I ,J / L \ Patent: W02015/180642 A1, 2015 ; on in patent: aph 00%; 00160 XN‘K 139 LN/ 140 141 '\ 142 Scheme 19 Scheme 19 provides a synthetic preparation of compound 142 of Formula III. First aldehyde 127 and carboxylic acid 128 are reacted as described in the Journal of Heterocyclic Chemistry to afford compound 129. Compound 129 is oxidized to 130 and then subsequently alpha brominated to bromide 131. Bromide 131 undergoes nucleophilic attack to afford cyano species 132 and then subsequent reduction and protection to afford the carbamate protected compound 133. Compound 133 is silyl ted to 134 and then dehalogenated to afford thiol 135. Thiol 135 is converted to ester 136 by reaction of an alpha brominated ester and then is subsequently ected (137) and ed to ketone intermediate 138. Ketone 138 undergoes intramolecular cyclization to afford 140 which then is oxidized as known in the art to sulfone 141. e 141 undergoes nucleophilic attack to afford compound 142.

Br B NW8? {:0 uf"\ 14C DC /l )LNJTT’‘- *'f1 NI; \5 ii O ‘N ’ / mm—w / + er mm—abL s \...../2 $ N l /s OH 5 = .

Journal of Heterocyclic Chemistry, J 127 2003, voE.40, #2 {1219—224 129 130 N \g I ,A,‘ x \ NHBoc 132 133 Ely OH N,A\ Ni.\ 3/1ka Voraoms _,, SAN”; VOTBDMS 1,, ------------------an» q ! @NHBOC @NHBOC ('Jl Q of?) O\ (3)0 £N:‘\/ O -0 o NEXT) 0 ”a‘TBDMS _/=~. n N OH x/Lpf‘f m...» fix a ~ 4 /-.S N / NH Bocr'Nl" &J Patent: WOZMSHBOS—Q A1, 2015 : N"‘\ Location in patent: Paragraph 0099; 00100 ; L )- 147 148 149 N\ 15f) Scheme 20 Scheme 20 es a synthetic preparation of compound 150 of Formula 111. First aldehyde 127 and ylic acid 128 are reacted as described in the Journal of cyclic Chemistry to afford compound 129. nd 129 is oxidized to 130 and then subsequently alpha brominated to e 131. Bromide 131 undergoes nucleophilic attack to afford cyano species 132 and then subsequent reduction and protection to afford the carbamate protected compound 133. Compound 133 is silyl protected to 134 and then dehalogenated to afford hydroxyl 143. Hydroxyl 144 is converted to ester 145 by reaction of an alpha brominated ester and then is subsequently deprotected (146) and oxidized to ketone intermediate 147. Ketone 147 oes intramolecular cyclization to afford 148 which then is oxidized as known in the art to sulfone 149. Sulfone 149 undergoes nucleophilic attack to afford compound 150.

N/.\‘~ NO; iperoxide NO Kr‘N i N/W 2 N33 N‘WNOZ u N’WNOZ LDA,THF \ A ('6‘ ,CN [41 \JL/l \/“\/i 8 N \ Br CN as S N \ “S N’AV 8 NA“. Bioorganic&Medicinal N Chemistry Letters 8 g (1998) 205-208 /’ 151 152 153 154 EtOt—i/HCI 55% j} x» \q/JLM/ / "'1W ,. c. .

COZEI A‘s/ii NF\‘\ [1’ [EMF/YER >650 )L r’ ’1, .....................p. ‘N \N L,I \:=( 158 159 Scheme 21 Scheme 21 provides a synthetic preparation of compound 160 of Formula IV.

Commercially available nd 151 is brominated in a radical reaction to afford 152 which then can be displaced by a philic source of cyano (such as potassium cyanide) to afford cyano 153. Cyano 153 is then deprotonated as described in BMCL to afford alkene 154. Alkene 154 is coupled with a metal such as zinc to afford ester 155, Ester 155 is then reduced with another metal (such as iron) to afford aniline 156. Aniline 156 then undergoes intramolecular ation to afford pyrazolopyrimindine 157 which then undergoes a base catalyzed intramolecular ation to afford the trifused cycle 158. nd 158 is then oxidized to the sulfone 159 which is subsequently displaced with an appropriate amine in the presence of an appropriate base to afford the final compound 160. 0 Benzoyl peroxide; Na-ZDZEHE.0H+. F’EE')’\-3 -. : . KLN/DMF3 Nx§ [\CN —+v kw/ M35; N’N AB? Cf, \nx—fl ELK: ’ ----------------------I» :I ——» I , ‘ ' healing \ ~3... \s N“ ‘cs N‘s/«N ‘0; \s ‘N‘ CI 161 EP1754708 7 “=2 153 164 165 oozzve H;N /’ >‘x NWA‘C‘N Nb“ \ \s’l‘V‘V‘WH it PM” /\ \ ’ N, 3"“ ”‘3'“ ”202 ~. ! CI5 ~ \QAN/- c‘’0245M .eaun ' mm ’ ‘, itmg \COZMe ”' [K’X<V \s N [M vI <,2? “M \ I Agricultural and Biological Chemistry, 1981 vol 45. 165 , 157 #9 p. 2031 -2035 "63 , ~ \g \N N u -------------x» 13w. ;—o \ I} (/‘N < / 169 u) we Scheme 22 Scheme 22 provides a synthetic preparation of compound 170 of Formula V.

Commercially available reagent 161 is ted to base and head as described in EP1754706 to afford 162. Compound 162 is then chlorinated as known in the art to afford 163. Compound 163 undergoes bromination in a radical reaction to afford bromide 164. Bromide 164 undergoes nucleophilic attack with a cyano source (such as ium cyanide) to afford cyano 165.

Cyano 165 is subjected to an amine to afford 166 and then intramolecular cyclization s 167 as known in the art. Compound 167 undergoes intramolecular cyclization again to afford 168 then subsequent oxidation to afford 169. The selectivity of the oxidation can be controlled by choice of reagents. Sulfone 169 is then displaced in a philic SNAr type reaction to afford 170. 172 17: PG PG H I N fq‘ \ \ \ i\l \: h "O \Ffo N =0 /\ N N2 J —: 1.: N \\ ~—» /~ N 3 C! I N HNH < V ‘37 R‘ 3- 174 175 176 Scheme 23 Scheme 23 provides an alternative synthetic preparation of compounds of Formula V.

NC COGEt. _ coca 0 COQH C H/N HM________“j ' BOG b 'I' \ BOG O 0—— --------»» é mun—a» “mun—«n» ---------------->— 17? 17g Helvetica Chimica Acta, 1998,voi.81,#12 0A 312218-2243 O O O I I ‘~. o W\ . 0 HN [TR HM NHZNHZH20 “‘ ’ / Nap; HN o EtOH Hw— Boo / x —-n- Boc -------------------.3» Soc. ----—--» rap-1475094; (2004); 131 182 133 N OH \ ‘3’ HMwkm- "W,”fir/go ,N\ HN "szN HN‘ — . P0013 ______________., 305' x ' ‘ ” NHz / a Hill->4 Him—u N a,» 0C a. 1”\2 Boo V \l wozo 1 0/43633; (2010) 184 135 186 N 11 JL NH HN N . / [‘1‘] :H‘: HN Ni‘r/QN PD; .—— A v «— A I/ HM dkA,“ ~ N 5/ ———> HQN N s” ——» :N \ > l l s \ l\v/l K/ \ 18'? 188 139 N )L "N er. A ,Nm NH ,9” , 193 191 Scheme 24 Scheme 24 provides a tic preparation of compound 191 of Formula XV.

Compound 177 undergoes reduction of the cyano group followed by protection of the resultant amine to afford protected compound 178. nd 178 is saponifled (typically by sodium hydroxide) to afford compound 179. Compound 179 is converted to the Weinreb amide 180 by reaction of the Weinreb salt and an excess of base, or alternatively by coupling the Weinreb salt in the presence of HATU or a similar reagent. The Weinreb amide is then reacted with a nucleophilic methyl source, such as methyl lithium or methyl magnesium bromide to afford a ketone 181. Ketone 181 is deprotonated and condensed to afford compound 182 which undergoes uent cyclization with hydrazine to form pyrazole 183 which undergoes uent lation of a nitro group to afford compound 184. Compound 184 is reduced to amine 185 as performed in W02010/43633 which is then cyclized to afford 186. Compound 186 is chlorinated with any suitable reagent (such as POCl3) to afford chloride 187. Chloride 187 is then dehalogenated with a proton source to afford 188. Compound 188 is coupled to an appropriate acid and then undergoes olecular cyclization to afford compound 189.

Compound 189 is oxidized to compound 190 and undergoes subsequent nucleophilic attack to afford compound 191.

IX. EXEMPLARY COMPOUNDS WO 05860 WO 05860 WO 05860 WO 05860 WO 05860 WO 05860 WO 05860 WO 05860 WO 05860 WO 05860 WO 05860 0 s N N N “N N f N N / N / Jim/4 N m NH )ELN/ )LN/ )&N HN HN “N N N N / \ / \ / \ x \7/ X. EXAMPLES General Methods: 1H NMR spectra were recorded on a 300 MHz Fourier transform Brt'rcker spectrometer.

Spectra were obtained from samples prepared in 5 mm diameter tubes in CDCl3, CD3OD or DMSO-de. The spin multiplicities are indicated by the symbols 5 et), d (doublet), t (triplet), m (multiplet) and, br (broad). Coupling constants (J) are reported in Hz. MS spectra were obtained using electrospray ionization (ESI) on an Agilent Technologies 6120 quadrupole MS apparatus. The reactions were generally d out under a dry nitrogen here using Sigma-Aldrich anhydrous ts. All common chemicals were purchased from commercial sources.

Compounds of the present invention with stereocenters are drawn ic for convenience. One skilled in the art will recognize that pure enantiomers can be prepared by methods known in the art. Examples of methods to obtain optically active materials include at least the following. i) physical separation of crystals—a technique whereby macroscopic ls of the individual enantiomers are manually separated. This technique can be used if ls of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are Visually distinct; ii) simultaneous crystallization—a technique whereby the dual enantiomers are separately llized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions—a technique whereby partial or complete tion of a te by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis—a synthetic technique y at least one step of the sis uses an enzymatic on to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis—a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e.; chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries; vi) diastereomer separations—a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The ing diastereomers are then separated by chromatography or crystallization by virtue oftheir now more distinct structural differences and the chiral auxiliary later removed to obtain the desired omer; vii) first- and second-order asymmetric transformations—a technique whereby diastereomers from the te equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereomer; viii) kinetic resolutions—this que refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue ofunequal reaction rates ofthe enantiomers with a chiral; non-racemic reagent or st under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors—a tic technique whereby the desired enantiomer is ed from non-chiral starting als and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography—a technique y the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including via chiral HPLC). The stationary phase can be made of chiral material or the mobile phase can n an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography—a technique whereby the racemate is volatilized and omers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents—a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiii) transport across chiral membranes—a technique whereby a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the ne barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through.

Chiral chromatography, including ted moving bed chromatography, is used in one embodiment. A wide y of chiral stationary phases are commercially available. e 1. Preparation of substituted 2-amin0pyridines. l-Methyl(6-nitr0pyridyl)piperazine MN/ \, / ’R To 5-bromonitropyridine (4.93 g, 24.3 mmole) in DMF (20 mL) was added N— piperazine (2.96 g, 1.1 eq) followed by the addition of DIPEA (4.65 mL, 26.7 mmole).

The contents were heated at 90 0C for 24 hrs. After the addition of ethyl e (200 mL), water (100 mL) was added and the layers were separated. Drying followed by concentration afforded the crude product which was purified on a silica gel column using (0-10%) thanol. 1H NMR (DMSO- d6) 5 8.26 (s, 1H), 8.15 (1H, d, J = 9.3 Hz), 7.49 (1H, d, J = 9.4 Hz), 3.50 (m, 4H), 2.49 (m, 4H), 2.22 (s, 3H). 5-(4-Methylpiperazinyl)pyridinamine "mm-"N/\/"“\M,N To 1-methyl(6-nitro—3-pyridyl)piperazine 3.4 g in ethyl acetate (100 mL) and ethanol (100 mL) was added 10% Pd/c (400 mg) and then contents stirred under hydrogen (10 psi) overnight. After filtration through Celite®, the solvents were evaporated and the crude product was purified over silica gel using DCM/ 7N Ammonia in MeOH (0- 5%) to afford 5- (4—methylpiperazinyl)pyridinamine (2.2 g). lHNMR (DMso- d6) 5 7.56 (1H, d, J = 3 Hz), 7.13 (1H, m), 6.36 (1H, d, J = 8.8 Hz), 5.33 (brs, 2H), 2.88 (m, 4H), 2.47 (m, 4H), 2.16 (s, 3H).

Iert-Butyl 4-(6-aminopyridyl)piperazine—l-carboxylate The compound was ed as described in A1.

To onitropyridine (1.2 g, 5.9 mmole) in DMSO (4 mL) was added 1-(4- piperidyl)piperidine (1.0 g, 5.9 mole) and triethylamine (0.99 mL, 7.1 mole), The contents were heated to 120 0C in a CEM Discovery microwave system for 3 hours. The crude reaction was then loaded over a silica gel column and eluted with DCM/methanol (0—20%) to afford 2- nitro[4-(1-piperidyl)—1-piperidyl]pyridine as an oil (457 mg). 1H NMR (600 MHz, DMSO-d6) 5 ppm 1.26 - 1.36 (m, 2 H) 1.43 (m, 6 H) 1.76 (m, 2 H) 2.37 (m, 5 H) 2.94 (t, J=12.74 Hz, 2 H) 4.06 (d, J=13.47 Hz, 2 H) 7.41 (dd, J=9.37, 2.64 Hz, 1 H) 8.08 (d, J=9.37 Hz, 1 H) 8.20 (d, J=2.64 Hz, 1 H). 5— [4-(1-Piperidyl)piperidyl]pyridin-Z-amine -[4-(1-Piperidyl)piperidyl]pyridinamine was prepared in a manner similar to that used in the synthesis of 5-(4-methylpiperazinyl)pyridinamine. 1H NMR (600 MHz, 6) 5 ppm 1.13 - 1.37 (m, 6 H) 1.40 - 1.63 (m, 6 H) 1.71 (m, 2 H), 2.24 (m, 1H) 2.43 (m, 2 H) 3.33 (d, J=12.30 Hz, 2 H) 5.31 (s, 2 H) 6.33 (d, J=8.78 Hz, 1 H) 7.10 (dd, J=8.78, 2.93 Hz, 1 H) 7.55 (d, J=2.64 Hz, 1 H). LCMS (E81) 261 (M + H). 4-[1-(6-Nitropyridyl)—4—piperidyl] morpholine WCQH 4-[(6-Nitr0-pyridyl)--piperidyl] morpholine was synthesizedin a manner similar to that used1n the synthesis of 2-nitro[4-(1-pipeIidyl)piperidy1]pyridine. 1H NMR (600 MHz, DMSO-d6) 5 ppm 1.41 (m, 2 H) 1.82 (m, 2 H) 2.42 (m, 5 H) 2.98 (t, J=12.44 Hz, 2 H) 3.52 (s, 4 H) 4.04 (d, J=12.88 Hz, 2 H) 7.42 (d, J=9.37 Hz, 1 H) 8.08 (d, J=9.08 Hz, 1 H) 8.21 (s, 1 H). 0rpholin0-l-piperidyl) pyridin-Z-amine -(4-Morpholinopiperidyl)pyridinamine was prepared in a manner similar to that used in the synthesis of5-(4-methylpiperaziny1)pyridinamine. 1H NMR (600 MHz, 6) 5 ppm 1.34 - 1.52 (m, 2 H) 1.78 (m, 2 H) 2.14 (m, 1 H) 2.43 (m, 4 H) 3.32 (d, J=12.30 Hz, 4 H) 3.47 - 3.59 (m, 4 H) 5.32 (s, 2 H) 6.34 (d, J=8.78 Hz, 1 H) 7.11 (dd, J=8.93, 2.78 Hz, 1 H) 7.47 - 7.62 (m, 1 H). LCMS (ESI) 263 (M + H). 4-[1-(6-Nitropyridyl)-4—piperidyl] thiomorpholine ,/ \ / 1 4-[(6-Nitro-3—pyridy1)-piperidy1] rpholine was synthesized in a manner similar to that usedin the synthesis of 2—nitro[4-(1-piperidyl)piperidyl]pyridine. 1H NMR (600 MHz, DMSO-d6) 5 ppm 1.40 - 1.52 (m, 2 H) 1.71 (m, 2 H) 2.49 - 2.55 (m, 4 H) 2.56 - 2.63 (m, 1 H) 2.68 - 2.75 (m, 4 H) 2.88 — 2.98 (m, 2 H) 4.09 (d, J=13.18 Hz, 2 H) 7.42 (dd, J=9.22, 3.07 Hz, 1 H) 8.08 (d, J=9.37 Hz, 1 H) 8.20 (d, J=3.22 Hz, 1 H). 5-(4-Thiom0rpholin0-l-piperidyl) pyridin-Z—amine -(4-Thiom0rpholin0piperidyl) pyridinamine was prepared in a manner similar to that used in the synthesis of 5—(4-methylpiperaziny1)pyridinamine. 1H NMR (600 MHz, DMSO-d6) 5 ppm 1.47 - 1.59 (m, 2 H) 1.65 (m, 2 H) 2.22 - 2.38 (m, 1 H) 2.50 - 2.59 (m, 6 H) 2.68 - 2.82 (m, 4 H) 3.33 (d, J=12.00 Hz, 2 H) 5.31 (s, 2 H) 6.33 (d, J=9.08 Hz, 1 H) 7.10 (dd, J=8.78, 2.93 Hz, 1 H) 7.55 (d, J=2.64 Hz, 1 H). LCMs (ESI) 279 (M + H). o(1-piperidyl)pyridine 2—Nitro(1-piperidyl) pyridine was synthesized in a manner similar to that used in the synthesis of 2-nitr0[4-(1-piperidyl)piperidyl]pyridine. 1H NMR (600 MHz, DMSO-d6) 5 ppm 1.56 (m, 6 H) 3.49 (d, J=4.39 Hz, 4 H) 7.30 - 7.47 (m, 1 H) 8.02 - 8.12 (m, 1 H) 8.15 - 8.26 (m, 1 H). -(1-Piperidyl)pyridin-2—amine -(1-Piperidyl) pyridin-2—amine was prepared in a manner similar to that used in the synthesis of 5-(4-methylpiperazinyl)pyridinamine. 1H NMR (600 MHz, DMSO-d6) 5 ppm 1.39 - 1.46 (m, 2 H) 1.51 - 1.62 (m, 4 H) 2.75 - 2.92 (m, 4 H) 5.30 (s, 2 H) 6.34 (d, J=8.78 Hz, 1 H) 7.09 (dd, J=8.78, 2.93 Hz, 1 H) 7.54 (d, J=2.93 Hz, 1 H). LCMS (E81) 178 (M + H). itropyridyl) thiomorpholine / \ / \ r402 4-(6-nitropyridyl) thiomorpholine was synthesized in a manner similar to that used in the synthesis of 2-nitro[4-(1-piperidyl)piperidyl]pyridine. 1H NMR (600 MHz, DMSO-d6) 5 ppm 2.56 - 2.69 (m, 4 H) 3.79 - 3.92 (m, 4 H) 7.43 (dd, J=9.22, 3.07 Hz, 1 H) 8.10 (d, J=9.37 Hz, 1 H) 8.20 (d, J=2.93 Hz, 1 H).

-Thiomorpholinopyridin-Z-amine 3/ \N / \ -Thiomorpholinopyridin-Z-amine was ed in a manner similar to that used in the synthesis of 5-(4-methylpiperaziny1)pyridinamjne. 1H NMR (600 MHZ, DMSO-d6) 5 ppm 2.59 - 2.73 (m, 4 H) 3.04 - 3.20 (m, 4 H) 5.41 (s, 2 H) 6.35 (d, J=8.78 Hz, 1 H) 7.10 (dd, J=8.78, 2.93 Hz, 1 H) 7.57 (d, J=2.64 Hz, 1 H). LCMS (E81) 196 (M + H). tert-Butyl (4R)(6-nitropyridyl)-2,5—diazabicyclo[2.2.1]heptane-2—carboxylate tert—Butyl (4R)(6-nitropyridy1)—2,5-diazabicyclo[2.2. 1]heptane—2-carboxy1ate was synthesized in a manner similar to that used in the synthesis of 2-nitro[4-(1-piperidy1)- 1-piperidyl]pyridine. 1H NMR (600 MHz, DMSO-d6) 5 ppm 1.33 (d, J=32.21 Hz, 11 H) 1.91 (m, 2 H) 3.15 (d, J=10.25 Hz, 1 H) 3.58 (m, 1 H) 4.46 (m, 1 H) 4.83 (s, 1 H) 7.16 (s, 1 H) 7.94 (s, 1 H) 8.05 - 8.16 (m, 1 H). tert-Butyl —(6-aminopyridyl)—2,S-diazabicyclo [2.2.1]heptane—2—carboxylate 131m WO 05860 tert—Butyl (4R)(6-aminopyridyl)-2,5-diazabicyclo[2.2.1]heptanecarb0xylate was prepared in a manner similar to that used in the synthesis of 5-(4-methylpiperazin yl)pyridinamine. 1H NMR (600 MHz, DMSO-d6) 5 ppm 1.31 (d, J=31.91 Hz, 11 H) 1.83 (m, 2 H) 2.71 - 2.82 (m, 1 H) 3.44 (ml H) 4.30 (d, 2H) 5.08 (s, 2 H) 6.35 (d, J=8.78 Hz, 1 H) 6.77 - 6.91 (m, 1 H) 7.33 (s, 1 H). LCMS (ESI) 291 (M + H).

N,N-dimethyl(6-nitropyridyl) piperidinamine N,N—dimethyl(6-nitr0pyridyl)piperidinamine was synthesized in a manner r to that used in the synthesis of 2—nitro[4-(1-piperidyl)piperidyl]pyridine. 1H NMR (600 MHz, DMSO-d6) 5 ppm 1.30 - 1.45 (m, 2 H) 1.79 (m, 2 H) 2.14 (s, 6 H) 2.33 (m, 1 H) 2.92 - 3.04 (m, 2 H) 4.03 (d, J=13.76 Hz, 2 H) 7.42 (dd, J=9.22, 3.07 Hz, 1 H) 8.04 - 8.11 (m, 1 H) 8.21 (d, J=2.93 Hz, 1 H). —[4-(Dimethylamino)piperidyl] pyridin-Z—amine >434} -[-4(dimethylamino)- 1-p—iperidyl]pyridin-amine was preparedin a manner r to that usedin the synthesis of 5-(4-methylpiperaziny1)pyridinamine. 1H NMR (600 MHz, DMSO-d6) 5 ppm 1.35 - 1.50 (m, 2 H) 1.69 - 1.81 (m, 2 H) 2,00 - 2.10 (m, 1 H) 2.11 - 2.22 (s, 6 H) 3.17 - 3.36 (m, 4 H) 5.19 - 5.38 (s, 2 H) 6.34 (d, J=8.78 Hz, 1H) 7.10 (dd, J=8.78, 2.93 Hz, 1 H) 7.55 (d, J=2.63 Hz, 1 H). LCMS (E81) 221 (M + H). 4-(6-Nitr0pyridyl) morpholine fl/WKMU 4-(6-Nitropyridyl) morpholine was synthesized in a manner similar to that used in the sis of 2-nitro[4-(l-piperidyl)piperidyl] pyridine.

S-Morpholinopyridin-Z-amine ,/"“\,/K \/____ -Morpholinopyridinamine was prepared in a manner similar to that used in the synthesis of 5-(4—methylpiperazinyl) pyridin—2—amine. 1H NMR (600 MHz, CHCl3-d) 5 ppm 2.91 - 3.00 (m, 4 H) 3.76 - 3.84 (m, 4 H) 4.19 (br. s., 2 H) 6.45 (d, J=8.78 Hz, 1 H) 7.12 (dd, J=8.78, 2.93 Hz, 1 H) 7.72 (d, J=2.93 Hz, 1 H). -(4-Isobutylpiperazin-l-yl) n-Z—amine {Q/___.\ 1-Isobutyl(6-nitropyridyl)piperazine was synthesized in a manner similar to that used in the synthesis of 2-nitro[4-(1-piperidyl)piperidyl]pyridine which was then converted 5-(4-isobutylpiperazinyl)pyridinamine in a manner similar to that used in the sis of 5-(4-methylpiperazinyl)pyridinamine. 1H NMR (600 MHz, CHCl3-d) 5 ppm 0.88 (d, J=6.73 Hz, 6 H) 1.71 - 1.84 (m, 1 H) 2.10 (d, J=7.32 Hz, 2 H) 2.46 - 2.58 (m, 4 H) 2.97 - 3.07 (m, 4 H) 4.12 (s, 2 H) 6.45 (d, J=8.78 Hz, 1 H) 7.14 (dd, J=8.78, 2.93 Hz, 1 H) 7.75 (d, J=2.93 Hz, 1 H). LCMs (E81) 235 (M + H). -(4-Isopropylpiperazin-l-yl) pyridin-Z-amine / t; N142 H\.._/ m— 1-Isopropyl(6—nitropyridyl)piperazine was sized in a manner similar to that used in the synthesis of 2-nitro[4-(1-piperidyl)piperidyl]pyridine which was then converted to s0pr0pylpiperazinyl)pyridinamine in a manner similar to that used in the synthesis of5-(4-methylpiperazinyl)pyridinamine. 1H NMR (600 MHz, CHCl3-a) 5 ppm 1.06 (d, J=6.44 Hz, 6 H) 2.59 - 2.75 (m, 5 H) 2.97 - 3.10 (m, 4 H) 4.13 (s, 2 H) 6.45 (d, J=8.78 Hz, 1 H) 7.15 (dd, J=9.08, 2.93 Hz, 1 H) 7.76 (d, J=2.93 Hz, 1 H). LCMS (E81) 221 (M + H). -[(2R,6S)-2,6-Dimethylmorpholinyl]pyridin-Z-amine Nit-12 (2S,6R)-2,6-Dimethyl(6-nitropyridyl)morpholine was synthesized in a manner similar to that used in the synthesis of 2-nitro—5-[4-(1-piperidyl)piperidyl]pyridine which WO 05860 was then converted to 5-[(2R,6S)-2,6-dimethylmorpholinyl]pyridinamine in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-l-yl)pyridinamine. 1H NMR (600 MHz, CHCl3-a) 5 ppm 1.20 (d, J=6.44 Hz, 6 H) 2.27 - 2.39 (m, 2 H) 3.11 - 3.21 (m, 2 H) 3.70 - 3.84 (m, 2 H) 4.15 (s, 2 H) 6.45 (d, J=8.78 Hz, 1 H) 7.12 (dd, J=8.78, 2.93 Hz, 1 H) 7.72 (d, J=2.63 Hz, 1 H). LCMS (E81) 208 (M + H). -[(3R,SS)-3,5-Dimethylpiperazin-l-yl]pyridin-Z-amine HN N'QNH; (3S,5R)-3,5-Dimethyl(6-nitropyn'dyl)piperazine was synthesized in a manner similar to that used in the synthesis of 2-nitro[4-(1-piperidyl)-l-piperidy1]pyridine which was then converted to 5-[(3R,5S)-3,5-dimethylpiperazinyl]pyridinamine in a manner similar to that used in the synthesis of 5-(4-methylpiperazinyl)pyridinamine. 1H NMR (600 MHz, CHCl3-d) 8 ppm 1.09 (d, J=6.44 Hz, 6 H) 2.20 (t, J=10.83 Hz, 2 H) 2.95 - 3.08 (m, 2 H) 3.23 (dd, J=l 1.71, 2.05 Hz, 2 H) 4.13 (s, 2 H) 6.45 (d, J=8.78 Hz, 1 H) 7.14 (dd, , 2.93 Hz, 1 H) 7.73 (d, J=2.63 Hz, 1 H). LCMS (E81) 207 (M + H). e 2: Compounds of the Present Invention: Final Structure Name 1Cmpd # lO,10-dimethyl((5 -(4- methylpiperazin- l -yl)pyridin no)-6,6a,9, l O-tetrahydro— 5H-pyrazino[l',2': rido[2,3- d]pyrimidine-5,7(8H)-dione , l 0-dimethyl((5 -(4- methylpiperazin- l -yl)pyridin yl)amino)-6,6a,9,10-tetrahydro— 5H-pyrazino[1',2': l,6]pyrido[2,3- d]pyrimidin-7(8H)-one 2'-((5-(4-methylpiperazin- l - yl)pyridinyl)amino)—6',6a',8',9'- tetrahydrospiro[cyclohexane-1,10'- pyrazino[l ',2': l,6]pyrido[2,3- d] pyrimidine] -5',7'-dione Final Structure Name Cmpd # 2'-((5-(4-methy1piperazin y1)pyridiny1)amino)—6',6a',8',9'- tetrahydrospiro[cyclohexane-1,10'- pyrazino[1',2':1,6]pyrid0[2,3- midin] -7'(5'H)-one 2'-((5-(4-methy1piperazin y1)pyridin-Z-yl)arnino)-6‘,6a’,8',9'- tetrahydrospir0[cyclopentane- 1,10'- pyrazin0[1',2':1,6]pyrido[2,3- d] pyrimidine] -5',7'-dione 6 2-((5-(4-methylpiperazin y1)pyridiny1)amino)-6,6a,9,10- ydro-SH- pyrazino[1',2’:1,6]pyrido[2,3- d]pyfimidine-5,7(8H)-dione 7 2-((5-(4-methylpiperazin y1)pyridiny1)amino)- 6,6a,7,8,9,10-hexahydro-5H- pyrimido[5,4-c]quinolizin-S-one ethyl 2-((5-(4-methy1piperazin y1)pyridinyl)amino)-5 -0XO- 6,6a,7,8,9,10-hexahydro-5H- pyrimido[5,4-c]quin01izine carboxylate N—(S ethylpiperazin yl)pyridinyl)—8',9'— dihydrospiro[cyc10hexane-1, 10'- pyrido[1,6-a:2,3-d']dipyrimidin]— 2'-amine WO 05860 Example 3: Biological Data for Compounds of the Present Invention: Biological Table 1 ical Table 2 F1nal Compound CDK7/CycH/ cmpd MATl # ICso (uM) Example 4. Preparation of Final Compounds Scheme 25: Synthesis of 2'-((5—(4-Methylpiperazin-l-yl)pyridin-2—yl)amino) -7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1,2-e]purin]-6'-one (Compound 10) NO~ NH NO2 4 aim: 2 Cir: NaHC<33 N \ A / :1ch093 C! N NH NHjCi St9;? 1 NH 8!ep?" HfilH StGD?‘ Bee Soc 193 194 \Njfiig/ /‘(“$ij ”(jfiH )3 NMP BINAF’ 100 0t: M“ Step 4 Step 5 195 196 R:N/ CQMPGUND 10 Step 1: Synthesis of tert-Butyl ((1-((2-chloro-5—nitropyrimidin-4— yl)amino)cyclohexyl)methyl)carbamate (193) To a solution of 2,4-dichloronitropyrimidine (192, 3 g, 15.5 mmol), utyl ((1- yclohexyl)methyl)carbamate (3.5 g, 15.5 mmol) in THF (20 mL) was added followed by NaHCO3 (4.0 g, 47.6 mmol). After stirring at room temperature for 3 hours, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL). The organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography to afford teIt-butyl ((1- ((2-chloronitropyrimidinyl)amino)cyclohexyl)methyl)carbamate (193, 3.5 g, 9.1 mmol).

MS : m/z 386 [M + H]+.

Step 2: Synthesis of tert—Butyl ((1-((5-aminochloropyrimidin yl)amin0)cyclohexyl)methyl)carbamate (194) To a solution of tert-butyl ((1-((2-chloronitropyrimidinyl)amino)cyclohexyl) methyl)carbamate (193, 3 g, 7.8 mmol) in EtOH (30 mL) was added Fe powder (6 g, 107 mmol) and sat. aq. NH4Cl (1 mL). The reaction mixture was refluxed overnight. After cooling to room temperature, the on mixture was filtered and the filtrate was concentrated to afford the crude product, which was purified by column chromatography to afford tert—butyl ((1-((5— aminochloropyrimidin yl)amino)cyclohexyl)methyl)carbamate (194, 2.2 g, 6.2 mmol).

MS (ESI+): m/Z 356 [M + H]+, Step 3: sis of Methyl 2—((4-((1-(((tert-but0xycarbonyl)amin0)methyl) exyl)amino)chloropyrimidin-S-yl)amino)—2—oxoacetate (195) To a solution of tert-butyl ((1-((5-aminochloropyrimidinyl)amino) cyclohexyl)methyl)carbamate (194, 2 g, 5.6 mmol) in THF (10 mL) was added methyl 2- chlorooxoacetate (0.7 g, 5.7 mmol) and NaHCO3 (3 g, 35.7 mmol). After stirring at room temperature for 4 h, the reaction mixture was quenched with H20 (20 mL) and extracted with EtOAc (20 mL). The organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography to afford methyl 2-((4-((1-(((tert- butoxycarbonyl)amino)methyl)cyclohexyl)amino) chloropyrimidin-S-yl)arnino)-2— tate (195, 2.5 g, 5.6 mmol). MS (ESI): m/z 442 [M + H]+.

Step 4: Synthesis of 2'-Chloro—7',8'-dihydr0-6'H-spiro[cyclohexane— 1,9'-pyrazino[l,2-e]purin]-6'-0ne (196) A solution of methyl 2-((4-((1-(((tert—butoxycarbonyl)amino)methyl)cyclohexyl) amino)chloropyrimidinyl)amino)oxoacetate (195, 1.5 g, 3.4 mmol) in NMP (50 mL) was stirred at 100 0C for 5h. The on mixture was cooled to room temperature and purified by column chromatography to afford 2'-chloro-7',8'- dihydro-6'H-spiro[cyclohexane-1,9'- pyrazino[l,2-e]purin]—6'—one (196, 300 mg, 1.0 mmol). MS (ESI +): m/z 292 [M + H]+.

Step 5: Synthesis of 2'-((5-(4-Methylpiperazinyl)pyridinyl)amino) -7',8'-dihydro- 6'H-spiro[cyclohexane—1,9'-pyrazino[1,2-e]purin]-6'-one (COMPOUND 10) Under N2 atmosphere, to a solution of 2'-chloro-7',8'-dihydro—6‘H- spiro[cyclohexane— 1,9'-pyrazino[l,2-e]purin]— 6'-one (196, 300 mg, 1.0 mmol), 5-(4-methylpiperazin-l- yl)pyridin- 2-amine (193 mg, 1.0 mmol), a)3 (92.23 mg, 0.1 mmol) and BINAP (125.4 mg, 0.2 mmol) in toluene (25 mL) was added LHMDS (1.5 mL, 1 M in THF). The reaction mixture was kept at 100 °C overnight. After g to room temperature, the reaction mixture was quenched with water (25 mL) and extracted with EtOAc (25 mL). The organic layer was separated and concentrated in vacuo. The resulting e was purified by prep TLC to provide 2'-((5—(4-methylpiperazin-1—yl)pyridiny1) amino)—7',8'-dihydro-6’H—spiro[cyclohexane-1,9'— pyrazino[l,2-e]purin]—6'—one (COMPOUND 10, 1.1 mg, 0.0025mmol). MS (ESI +): m/Z 448 [M + H]+, 1H NMR (300 MHz, MeOD ): 5 8.05 - 7.95 (m, 2H), 7.86 (d, J: 9.0 Hz, 1H), 7.49 (d, J: 8.4 Hz, 1H), 4.03 (s, 2H), 3.28 - 3.22 (m, 4H), 3.08 - 2.91 (m, 2H), 2.78 - 2.70 (m, 4H), 2.42 (s, 3H), 1.82 - 1.70 (m, 5H),1.47 - 1.39 (m, 3H).

Scheme 26: Synthesis of 2aR)((5-(4-Methylpiperazinyl)pyridin yl)amino)-1,3,4,4a,5,12a—hexahydropyrimido[5',4':4,5]pyrrolo[1,2—a]quinoxalin- 6(2H)—one (COMPOUND 22) o OEt C OB HQN \NH_ _>1 _/< _ <1“a hchoJ. H, HN N! HAUL , / N NH (Brecht) z N \chuA --------------------0» a» N\ ——---———;a» N\ r ~ N THF N DMF o) DMAF‘ DCM Mao ’ _ Mes step 1 _____ Step 2 Step 3 Step 4 137 198 199 200 O gm O «BEE-113:»- QM. g O _ ‘ le Tf o TEA2 ' ' “Al/V P" PM”H3151? “flail/w 4“!» NEoc .NBoc )1 #‘N NBoc Mes N ---------------------a» V153)L~N4’“N- WW ~ Mes N _____ GCN‘ DMF \ Step 5 Step ‘l 261 202 203 er” NH Tt'A 0 All/t:- . \ o A‘T \ \j/F \ \t 0cm Mc,./\N¢L‘I\J W TN q“ CpgA 0%)sz \N W LHMDS .....................in» /:;\x . —----------h» h'\£ DCN‘: '3 toluene ) / ”N“ Step., ..... A) _ _, I Step 8 Step 9 / __., 204 235 Tank.»[\mN commune 22 Step 1: sis of aR)-Octahydroquinoxalin-2(1H)-one (198) To a mixture of (1R,2R)—cyclohexane-l,2-diamine (197, 1 g, 8.75 mmol) and NaHCO3 (2.2 g, 26.2 mmol) in THF (40 mL) at 0 0C was added a solution of methyl oacetate (1.34 g, 8.75 mmol) in THF (20 mL) in se. After stirring at 0 °C for 2 h, the reaction mixture was warmed to room temperature and stirred for an additional 1 h. The reaction mixture was then quenched with water (40 mL) and extracted with EtOAc (50 mL X 2). The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by column tography to provide (4aR,8aR) -octahydroquinoxalin— 2(1H)-one (198, 700 mg, 4.54 mmol).

Step 2: Synthesis of Ethyl 2-(methylthio)((4aR,8aR)-3—oxooctahydroquinoxalin-1(2H)- yl)pyrimidinecarboxylate (199) To a solution of (4aR,8aR)-octahydroquinoxalin-2(1H)—one (198, 4.7 g’ 30.5 mmol) in DMF (140 mL) was added ethyl chloro(methylthio)pyrimidine carboxylate (7 g, 30.1 mmol) and K2CO3 (12.6 g, 91.2 mmol). After stirring at 80 0C for 2 h, the reaction mixture was cooled to room temperature, quenched with water (250 mL) and extracted with EtOAc (150 mL X 2). The combined organic phases were washed with water (100 mL x 2) and brine (100 mL). After concentration in vacuo, the resulting residue was purified by column chromatography to afford ethyl 2-(methylthio)((4aR,8aR) oxooctahydroquinoxalin- 1(2H)-yl)pyrimidine—5—carboxylate (199, 7.6 g, 21.6 mmol) as a white solid. MS (ESI+): m/z 351 [M + H]+.

Step 3: Synthesis of tert—Butyl(4aR,8aR)—4-(5-(ethoxycarbonyl) (methylthio)pyrimidinyl)oxooctahydroquinoxaline-1(2H)-carboxylate (200) To a solution of ethyl 2-(methylthio)-4—((4aR,8aR)oxooctahydroquinoxalin-1 (2H)-yl)pyrimidinecarboxylate (199, 7.6 g, 21.6 mmol) in DCM (200 mL) was added BoczO (7.1 g, 32.5 mmol) and DMAP (7.9 g, 64.7 mmol). After stirring at room temperature for 12 h, the reaction mixture was quenched with water (250 mL) and extracted with DCM (100 mL x 2). The combined c phases were washed with water (50 mL), brine (50 mL), dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography to provide utyl(4aR,8aR)—4-(5 -(ethoxycarbonyl) (methylthio)pyrimidinyl)oxooctahydroquinoxaline-l(2H)—carboxylate (200, 8,0 g, 17.7 mmol) as a colorless oil. MS (ESI+): m/z 451 [M + H]+.

Step 4: Synthesis of tert-Butyl 12aR)hydroxy(methylthio) 0x0- 1,2,3,4,4a,12a-hexahydropyrimido[5',4':4,5]pyrrolo[1,2—a]quinoxaline-5(6H)- carboxylate (201) To a solution of tert-butyl (4aR,8aR)(5-(ethoxycarbony1)(methylthio) pyrimidinyl)—2-oxooctahydroquinoxaline-l(2H)-carboxylate (200, 7.0 g, 15.5 mmol) in THF (100 mL) at 0 °C was added DBU (3.5 g, 23.0 mmol). The on was gradually warmed to room temperature. After stirring for 2 h, the reaction mixture was concentrated in vacuo.

The resulting e was purified by column chromatography to provide tert-butyl (4aR, 12aR)hydroxy-l0-(methylthio)—6-oxo-1,2,3 ,4,4a,12a— hexahydropyrimido[5',4':4,5]pyrrolo[l,2-a]quinoxaline-5(6H)-carboxylate (201, 4.8 g, 11.8 mmol) as a green solid. MS (ESI+): m/z 405 [M + H]+.

Step 5: Synthesis of tert-Butyl 2aR)-lO-(methylthi0)0xo((( trifluoromethyl)sulfonyl)oxy)-1,2,3,4,4a,12a-hexahydropyrimido[5',4':4,5]pyrrolo[1,2- a] quinoxaline-5(6H)-carboxylate (202) To a solution of tert-butyl (4aR,12aR)hydroxy(methylthio)oxo- 1,2,3,4,4a, 1 2a-hexahydropyrimido [5',4' : 4,5] py rrolo[ 1 ,2-a] quinoxaline-5 (6H)—carboxylate (201, 200 mg, 0.49 mmol) and Et3N (0.3 mL, 216 mmol) in DCM (5 mL) at 0 °C was added Tf20 (209 mg, 0.74 mmol). The reaction was gradually warmed to room temperature. After stirring for 2 h, the reaction mxiture was concentrated in vacuo. The resulting residue was purified by column chromatography to provide tert-butyl (4aR,12aR)—10-(methylthio)oxo— rifluoromethyl)sulfonyl)oxy)-1,2,3,4,4a,12a—hexahydropyrimido[5',4':4,5]pyrrolo[1,2- a] aline-5(6H)-carboxylate (202, 180 mg, 0.34 mmol). MS : m/Z 536 [M + H]+.

Step 6: sis of tert—Butyl (4aR,12aR)(methylthio)—6-oxo—1,2,3,4,4a,12a- hexahydropyrimido [5',4' :4,5] pyrrolo[1,2—a] quin0xaline-5(6H)—carboxylate (203) Under N2 atmosphere, to a solution of utyl (4aR,12aR)(methylthio)-6 -oxo(((trifluoromethyl)sulfonyl)oxy)-1,2,3 ,4,4a,12a- hexahydropyrimido[5’,4':4,5]pyrrolo[1,2-a]quinoxaline-S(6H)—carboxylate (202, 250 mg, 0.47 mrnol) and Pd(PPh3)4 (54 mg, 0.47 mmol) in DMF (5 mL) was added Et3SiH (81.4 mg, 0.70 mmol). After stirring at 50 0C for 12 h, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (10 mL X 3). The combined organic layers were washed with water (5 mL x 2) and brine (5 mL), dried over MgSO4, and concentrated in vacuo. The resulting e was purified by column chromatography to provide tert—butyl (4aR,12aR)—10- lthio) oxo-1,2,3,4,4a,12a-hexahydropyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxaline- 5(6H)-carboxylate (203, 70 mg, 0.18 mmol).

Step 7: Synthesis of (4aR,12aR)(Methylthio)-1,3,4,4a,5,12a- hexahydropyrimido [5',4' :4,5] pyrrolo[1,2—a] quinoxalin-6(2H)-0ne (204) To a solution of tert-butyl (4aR,12aR)(methylthio)oxo-1,2,3,4,4a,12a— hexahydropyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxaline-5(6H)—carboxylate (203, 70 mg, 0.18 mrnol) in DCM (1.5 mL) was added TFA (0.5 mL). After stirring at room temperature for 2 h, the reaction mixture was neutralized with saturated aqueous NaHCO3 (20 mL) and extracted with DCM (10 mL x 3). The combined organic phases were dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by column tography to provide (4aR,12aR)(methylthio)-1,3,4,4a,5,12a-hexahydropyrimido[5',4':4,5]pyrrolo[1,2- a] quinoxalin-6(2H)-one (204, 70 mg, 0.24 mmol).

Step 8: Synthesis of (4aR,12aR)(Methylsulfonyl)—1,3,4,4a,5,12a - hexahydropyrimido [5',4' :4,5] pyrrolo[1,2—a] quinoxalin-6(2H)—0ne (205) To a solution of (4aR,12aR)—10-(methylthio)-1,3,4,4a,5,12ahexahydropyrimido :4,5]pyrrolo[l,2-a]quinoxalin-6(2H)-one (204, 70 mg, 0.24 mmol) in DCM (5 mL) was added m—CPBA (126 mg, 0.73 mmol). After stirring at room temperature for 12 h, the on mixture was neutralized with saturated aqueous NaHCO3 (5 mL) and extracted with DCM (10 mL X 2). The combined organic phases were dried over MgSO4, and trated in vacuo. The resulting residue was purified by column chromatography to provide (4aR,12aR)-lO-(methylsulfonyl)—l,3,4,4a,5,12a— hexahydropyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxalin-6(2H)-one (205, 30 mg, 0.09 mmol).

MS: m/Z 321 (MH+).

Step 9: Synthesis of (4aR,12aR)((5-(4-Methylpiperazinyl)pyridin-2 -yl)amino)— 1,3,4,4a,5,12a-hexahydr0pyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxalin-6(2H)—0ne (COMPOUND 22) To a on of 5-(4-methylpiperazin-l-yl)pyridinamine (180 mg, 0.94 mmol) in toluene (10 mL) at 0 °C was added LHMDS (1.1 mL, 1.1 mol, 1 M in THF). After stirring at 0 0C for l h, a solution of (4aR,12aR)-lO-(methylsulfonyl)—l,3,4,4a,5,12a— hexahydropyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxalin-6(2H)-one (205, 300 mg, 0.94 mrnol) in toluene (5 mL) was added. The reaction was kept at 80 0C for 12 h. After g to room temperature, the reaction mixture was quenched with saturated aqueous NaHCO3 (5 mL) and extracted with DCM (10 mL x 3). The ed organic phases were dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography to provide ((4aR,12aR)—10—((5 -(4—methylpiperazinyl)pyridin-2—yl)arnino)—1,3,4,4a,5,12a- hexahydropyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxalin-6(2H)-one (COMPOUND 22, 3.0 mg, 0.007 mmol). MS (ESI+): m/Z 433 [M + H]+, 1H NMR (300 MHz, MeOD + CDCl3): 5 9.35 (s, 1H), 8.69 (d, J: 8.1 Hz, 1H), 8.52 (d, J: 3.0 Hz, 1H), 7.95 (dd, J: 9.0, 3.0 Hz, 1H), 7.80 (s, 1H), 4.62 - 4.44 (m, 2H), 4.23 - 4.13 (m, 1H), 3.78 (t, J: 4.8 Hz, 4H), 3.25 (t, J: 4.8 Hz, 4H), 2.97 (s, 3H), 2.75 - 2.60 (m, 1H), 2.52 — 2.40 (m, 2H), 2.26 - 2.04 (m, 4H).

Scheme 27: Synthesis of (4aS,12aS)((5-(4-Methylpiperazinyl)pyridin yl)amino)-1,3,4,4a,5,12a-hexahydropyrimid0[5',4':4,5]pyrrolo[l,2—a]quin0xalin- 6(2H)-one (COMPOUND 23) 197 Step 1 Step 2 Step 3 266 207 208 CH CT” 0 O . . . fi_ ”"Ky ”W E13$1H, Den, :HF —-—i9’- N\ }\ /N‘ )\\ 'TT’QQfF'EA N NBGC Pd(PPh)4 x. /L 1” N PM, NEE-SC Mes N , ——a» Mes (j WWW” Step4 Step5 299 210 R \ O )1 WNBQ"" ——"" Ti/YV \ N \ {/0 M 3 \s » ' w e O NF EECM Mes/\N R . DEAR/SK W / ‘b 0cm / Step6 Step 7 \ 211 212 213 N/l CAN-a\ N,“ LHMDS )5N toiuene , "fig Step8 Na R4.”'9 CGMPOUND 23 COMPOUND 23 was prepared according to the experimental procedure described in Scheme 26 for the synthesis of COMPOUND 22. MS (ESI+): m/z 433 [M + H]+; 1H NMR (300 MHz, MeOD + : 5 8.81 (s, 1H), 8.13 - 8.10 (m, 1H), 7.96 (d, J: 2.7 Hz, 1H),7.48 — 7.44 (m, 1H), 7.24 (s, 1H), 4.01 - 3.94 (m, 2H), 3.66 — 3.63 (m, 1H), 3.29 - 3.25 (m, 4H), 2.81 — 2.78 (m, 4H), 2.48 (s, 3H), 2.19 - 2.08 (m, 2H), 1.99 — 1.86 (m, 2H), 1.71 - 1.46 (m, 3H).

Scheme 28: Synthesis of (4aS,12aR)((5-(4-Methylpiperazinyl)pyridin yl)amin0)—1,3,4,4a,5,12a—hexahydropyrimido[5',4' :4,5] pyrrolo[1,2—a] quinoxalin-6(2H)— one (COMPOUND 24) O o 0 “GE? C‘ 4 K2432; ,2? M” -"- Nat-K303 N (Bog-20 /---- Oil-<0 HN NH NH N ----N New --------------------o -----------;>» ,fu-N >\__N :2 ——----——)a> / \ J THF 3 S DMF a) DMAF‘, DOM MesI . N 2””Rm 197 Steer Step? \_/ Step3 z” 214 215 216 OH on O ”V1 0 DBU,TE-IF \ V N \ men«we; ——-)> )L. f' vaO‘ TEA \ ‘ ‘ N/J‘N WPPM‘ \ N Nch N800 Step4 14128 N ,, --------------------------iv» M63 new: ' """ Step5 Step6 217 218 O O Pill/:TM /\ .0 N‘ \rw TFA 1 ‘?i .. .ANwN NH m-CPBA \NH .-\:JCM~ 3::j -——a>» m, DCM “C! Step 7 Step 8 {:3 219 229 221 \i 31H Ni \ NY ‘1 LHMDS K/ mm» HN toluene [TN ,. / ire-pg8.. K \\ \«NNV commune 24 COMPOUND 24 was ed according to the experimental described in Scheme 26 for the synthesis of COMPOUND 22. MS (ESI+): m/z 433 [M + H]+; 1H NMR (300 MHz, MeOH + CDC13): 5 8.83 (s, 1H), 8.34 (s, 1H), 7.96 (s, 1H), 7.52 - 7.47 (m, 1H), 7.20 (s, 1H), 4.19 — 4.13 (m, 2H), 3.64 (s, 1H), 3.29 - 3.26 (m, 4H), 2.80 - 2.78 (m, 4H), 2.48 (s, 3H), 2.15 - 1.99 (m, 4H),1.95 - 1.83 (m, 3H).

Scheme 29: Synthesis of N-(S-(4-Methylpiperazinyl)pyridinyl)-5'H -spir0[cyclohexane-1,6'-imidazo[2",1":3',4']pyrazino[1',2':1,5]pyrrolo[2,3—d]pyrimidin]- 9'-amine (COMPOUND 25) wx, 8, ' we rent/fl:\ HN 6; N2“-N \ ’ ’ AIDA JN Orig» NW N”) TFA, toluene N J" ‘11' /4::\1 j HCN (J HN 19 2 reflux \/ N reflux / (134‘ Step4 ‘“- 42Mpg Step 2 4 \ r, ,1 222 223 ND 25 Step 1: Synthesis of N6'-(2,2-Diethoxyethyl)—N2'-(5-(4-methylpiperazin-l-yl) pyridin yl)-8'H-spir0 [cyclohexane- 1,9'-pyrazin0 [1',2' : 1,5] pyrrolo [2,3-d]pyrimidine] -2',6'- diamine (223) To a solution of N-(5-(4-methylpiperazinyl)pyridinyl)-6'-(methylthio)—8'H- spiro[cyclohexane-1,9’-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-2’-arnine (222, 100 mg, 0.20 mmol) in toluene (5 mL) was added 2,2—diethoxyethanamine (100 mg, 0.37 mmol).

After stirring under reflux for 48 h, the reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by prep TLC to afford N6'—(2,2— diethoxyethyl)-N2'-(5-(4-methylpiperazinyl)pyridinyl)-8'H-spiro[cyclohexane-1,9'- pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]—2',6'—diamine (223, 70 mg, 0.12 mmol). MS (ESI+): m/z 562 [M + H]+.

Step 2: sis of N-(S-(4-Methylpiperazinyl)pyridinyl)-5'H-spiro[cyclohexane- l,6'-imidazo[2",1":3',4']pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-9'-amine (COMPOUND 25) To a solution of N6'-(2,2-diethoxyethy1)-N2'-(5-(4-methylpiperazinyl)pyridinyl)— 8'H-spiro[cyclohexane-l,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-2',6'-diamine (223, 65 mg, 0.11 mmol) in toluene (3 mL) was added TFA (3 drops). After ng under reflux for 1 h, the reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by prep TLC to afford N-(5-(4-methylpiperazinyl)pyridin yl)-5'H-spiro[cyclohexane-1,6'-imidazo[2",1":3',4']pyrazino[1’,2':1,5]pyrrolo[2,3- d]pyrimidin]—9'-amine UND 25, 6.9 mg, 0.015 mmol). MS (ESI+): m/Z 470 [M + H]+;1H NMR (300 MHz, MeOD): 6 8.74 (s, 1H), 8.06 (d, J= 12.0 Hz,1H), 7.98 (d, J= 3.3 Hz, 1H), 7.58 (dd, J: 9.9, 4.2 Hz, 1H), 7.24 (d, J: 1.2 Hz, 1H),7.18(d,J=1.2 Hz, 1H), 7.04 (s, 1H), 4.55 (s, 2H), 3.41 - 3.37 (m, 4H), 3.16 - 3.12 (m, 6H), 2.73 (s, 3H), 1.95 - 1.86 (m, 5H), 1.75 - 1.44 (m, 3H).

Scheme 30: Synthesis of N-(5—(4—Methylpiperazinyl)pyridinyl)-8'HSpiro hexane—1,9'-imidazo[2,1-h]pteridin]-2'-amine (COMPOUND 26) NH \ N“ TFA Ni/‘jNH 2 2 N N! \ glyoxa|,ElOH fl /‘;§ A / ” "MCI N N N Cl N NH DCM CI N NH 80 OC ......f '3” Step 1 ””2 Step 2 224 225 226 NAT)NNlN N Pd/C Pd2(dba)3 t0 Uene| ONE/j *1N/ /\\ BINAP / N N N n GNJN Step 3 Step 4 N21 COMPOUND 26 Step 1: Synthesis of N4-(1-(Aminomethyl)cyclohexyl)chloropyrimidine—4,5-diamine (225) To a solution of tert—butyl ((1-((5 -aminochloropyrimidin yl)amino)cyclohexyl)methyl)carbamate (224, 300 mg, 0.84 mmol) in DCM (10 mL) was added TFA (3 mL). After stirring at room temperature for 2 h, the reaction mixture was neutralized with saturated aqueous NaHCO3 and extracted with DCM (10 mL x 3). The combined organic phases were dried over MgSO4, filtered and trated in vacuo to provide N4—(1— (aminomethyl)cyclohexyl)—2-chloropyrimidine—4,5-diamine (225, 200 mg, 0.78 mmol), which was used for the next step without r purification.

Step 2: sis of 2'-Chloro-6',8'-dihydro-5'H—spiro[cyclohexane-1,9'-imidazo[2,1- h]pteridine] (226) To a solution of N4—(l-(aminomethyl)cyclohexyl)chloropyrimidine-4,5-diamine (225, 200 mg, 0.78 mmol) in EtOH (10 mL) was added glyoxal (113 mg, 0.?8 mmol). After stirred at 80 0C for 2 h, the reaction mixture was concentrated in vacuo. The resulting residue was purified by column chromatography to provide 2’-chloro-6',8'—dihydro-5’H- spiro[cyclohexane-l,9'-imidazo[2,l-h]pteridine] (226, 80 mg, 0.29 mmol). MS (ESI+): m/Z 278 [M + H]+.

Step 3: Synthesis of 2'-Chloro-8'H-spir0[cyclohexane-l,9'—imidazo[2,1-h]pteridine] (227) To a solution of 2'-chloro-6',8'-dihydro-5'H-spiro[cyclohexane-1,9'—imidazo[2,l- h]pteridine] (226, 60 mg, 0.22 mmol) in e (5 mL) was added Pd/C (10 mg). After stirred at 110 0C for 12 h, the reaction mixture was filtered. The filtrate was concentrated in vacuo.

The resulting residue was purified by column chromatography to provide 2'-chloro-8'H- spiro[cyclohexane-l,9'-imidazo[2,l-h]pteridine] (227, 20 mg, 0.07 mmol). MS (ESI+): m/Z 276 [M + H]+.

Step 4: Synthesis of N-(S-(4-Methylpiperazinyl)pyridinyl)-8'H-spiro [cyclohexane-1,9'-imidazo[2,1-h]pteridin]-2'-amine (COMPOUND 26) Under N2 atmosphere, to a solution of 2'-chloro-8'H-spiro[cyclohexane-1,9'- imidazo[2,1-h]pteridine] (227, 80 mg, 0.29 mmol), 5-(4-methylpiperazinyl)pyridinamine (55 mg, 0.29 mmol), Pd2(dba)3 (26.4 mg, 0.03 mmol) and BINAP (35.2 mg, 0.06 mmol) in e (20 mL) was added LHMDS (0.4 mL, 0.4 mmol). After stirred at 100 0C for 12 h, the reaction mixture was cooled to room ature, quenched with water (10 mL) and extracted with EtOAc (10 mL). The organic phase was separated and concentrated in vacuum. The resulting residue was d by column chromatography to provide N-(5 -(4-methylpiperazin— 1-yl)pyridinyl)—8'H-spiro[cyclohexane- l idazo[2, l -h] pteridin]—2'—amine (COMPOUND 26, 11.1 mg, 0.02 mmol). MS : m/z 432 [M + H]+, 1H NMR (300 MHz, MeOD): 5 8.47 (s, 1H), 8.03 - 8.09 (m, 2H), 7.90 (s, 1H), 7.39 - 7.43 (m, 1H), 4.00 (s, 2H), 3.28 — 3.36 (m, 4H), 2.88 (d, J: 12.6 Hz, 2H), 2.76 - 2.82 (m, 4H), 2.49 (s, 3H), 1.68 - 1.89 (m, 5H), 1.28 - 1.47 (m, 3H).

Scheme 31: Synthesis of 2'-((5-(4-Methylpiperazinyl)pyridinyl) amino)—5'H—spir0[cyclohexane-1,9'-imidazo[2,1—h]pteridin]-6'(8'H)—0ne (COMPOUND 42H- 229 {‘13 N \ NH2 7N /J\ / it \ \ HI?! N NH j NH : .———'p~ . / ri/NN NH C' N ”H ‘ i Pesgmbab ”EH Q 6301; BINAP, LHMDS toluene, 110 °C (N 228 :3pr 1 KM 23:: 231 O H m a: fig 0 N x V0 N f” / _ HN N HH 0 ~N NH )5“; ‘N NH, W )‘N‘N J HCVMeOH / N HN\ r DMSO H“; \a ------------------------ m g m ”'> Step3 . W)\ 100 c0 K2C03,E1C)H \g [N] 80°C SfepS l: l\j N 232 Step4 i N), 233 {K E \N [\l \ commune 27 \ Step 1: Synthesis of tert—Butyl ((1-((2-((5-(4-methylpiperazinyl)pyridinyl)amino)—5- nitropyrimidinyl)amin0)cyclohexyl)methyl)carbamate (230) Under N2 atmosphere, to a mixture of tert-butyl 2-chloronitropyrimidin Ul yl)amino)cyclohexyl)methyl)carbamate (228, 1.0 g, 2.6 mmol), 5-(4-methylpiperazin-l- yl)pyridinamine (229, 0.6 g, 3.1 mmol), Pd2(dba)3(120 mg, 0.13 mmol), and BINAP (160 mg, 0.25 mmol) in toluene (30 mL) was added LHMDS (0.52 mL, 1 M in THF). The reaction was kept at 100 0C overnight and was then quenched with water (50 mL) and extracted with EtOAc (50 mL). The organic layer was separated and concentrated in vacuo. The resulting residue was purified by column tography to afford tert—butyl ((1-((2-((5-(4— methylpiperazin-l -yl)pyridinyl)amino)—5 -nitropyrimidin yl)amino)cyclohexyl)methyl)carbamate (230, 400 mg, 0.74 mmol). MS : m/z 542 [M + H]+.

Step 2: Synthesis of tert-Butyl 5-amin0((5-(4-methylpiperazin-l-yl) pyridin-2— yl)amino)pyrimidinyl)amino)cyclohexyl)methyl)carbamate (231) To a solution of tert-butyl ((1-((2-((5-(4-methylpiperazinyl)pyridinyl)amino) nitropyrimidinyl)amino)cyclohexyl)methyl)carbamate (230, 180 mg, 0.33 mmol) in EtOH (10 mL) was added Fe powder (200 mg, 3.57 mmol) and aqueous NH4Cl solution (1 mL). After stirring under reflux overnight, the reaction mixture was cooled to room temperature, filtered and concentrated in vacuo to afford the crude product, which was purified by column chromatography to afford utyl 5—amino((5-(4-methylpiperazinyl)pyridin—2— yl)amino)pyrimidinyl)amino)cyclohexyl)methyl)carbamate (231, 40 mg, 0.08 mmol). MS (ESI+): m/Z 512 [M + H]+.

Step 3: Synthesis of N4-(1-(Aminomethyl)cyclohexyl)-N2-(5-(4-methylpiperazin yl)pyridinyl)pyrimidine-2,4,5-triamine (232) A on of tert-butyl ((1-((5-amino((5-(4-methylpiperazinyl)pyridin yl)amino)pyrimidinyl)amino)cyclohexyl)methyl)carbamate (231, 270 mg, 0.53 mmol) in sat. HCl/MeOH solution (5 mL) was stirred at room ature for 3 h. Then the mixture was trated in vacuo. To the ing residue was added MeOH (5 mL) and K2C03 (300 mg).

The mixture was heated to reflux for 1 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to afford N4-(1-(aminomethyl)cyclohexyl)—N2-(5 -(4- methylpiperazinyl)pyridin-2—yl)pyrimidine-2,4,5-triamine (232, 180 mg, 0.44 mmol), which was used for the next step without further purification. MS (ESI): m/z 412 [M + H]+.

Step 4: Synthesis of 2'-((5-(4-Methylpiperazinyl)pyridinyl)amino)— dihydro-5'H—spiro[cyclohexane—1,9'-imidazo[2,1-h]pteridin]-6'(6a'H)—one (233) To a mixture of N4-(1-(aminomethyl)cyclohexyl)-N2-(5-(4-methylpiperazin-l- yl)pyridinyl)pyrirnidine-2,4,5-t1iarnine (232, 170 mg, 0.41 mmol), K2CO3 (300 mg, 2.17 mmol) in EtOH (3 mL) was added a solution of ethyl 2-oxoacetate (85 mg, 0.83 mmol) in toluene (0.1 mL). After stirring at 80 °C for 2 h, the reaction mixture was filtered and the filtrate was concentrated to afford the residue, which was purified by prep TLC to afford 2'-((5-(4- methylpiperazinyl)pyridinyl)amino)-7', 8‘-dihydro-5'H-spiro[cyclohexane-1,9'- imidazo[2,1-h]pteridin]-6'(6a'H)—one (233, 80 mg, 0.18 mmol). MS (ESI +): m/Z 450 [M + H]+.

Step 5: Synthesis of 2'-((5-(4-Methylpiperazinyl)pyridinyl)amino)— 5'H- Spiro[cyclohexane—1,9'-imidazo[2,1-h]pteridin]-6'(8'H)—0ne (COMPOUND 27) A solution of 2'-((5-(4-methylpiperazin-1—yl)pyridinyl)amino)-7',8'-dihydro-5’H— spiro[cyclohexane-1,9'-imidazo[2,1-h]pteridin]-6'(6a'H)-one (233, 65 mg, 0.14 mmol) in DMSO (2 mL) was kept at 100 °C for 6 h. After cooled to room temperature, the reaction mixture was purified by prep TLC to afford 2'-((5-(4-methylpiperazinyl)pyridin-2— yl)amino)-5'H-spiro[cyclohexane-1,9'-imidazo[2,1-h]pteridin]-6'(8'H)-one (COMPOUND 27, 6.1 mg, 0.014 mmol). MS (ESI +): m/z 448 [M + H]+, 1H NMR (300 MHz, DMSO-d6 + D20): 5 8.04 (s, 1H), 7.97 (s, 1H), 7.93 (d, J: 9.6 Hz, 1H), 7.46 (d, J: 8.7 Hz, 1H), 3.91 (s, 2H), 3.10 - 3.05 (m, 2H), 3.05 - 3.03 (m, 2H), 3.00 - 2.96 (m, 2H), 2.84 - 2.76 (m, 5H), 2.02 - 1.96 (m, 2H),1.72 - 1.61 (m, 5H), 1.40 - 1.30 (m, 3H).

Scheme 32: Synthesis of 2'-((5-(4-Methylpiperazinyl)pyrimidinyl) amino)-7',8'-dihydro-6'H—spir0[cyclohexane—1,9'-pyrazino[1',2':1,5]pyrrolo[2,3- d]pyrimidin]-6'-one (COMPOUND 28) NH2 ”4 Pd2(dba)3, Pd(OAc)2, 11m~\ NH NH’) z- t--BL£ONa, N \N , )\N A if John—phos E H1“ / {332002 ——»- ——~»~ M K W 1009(34811 N Step1 ~ Br E 3 8119/32 234 235 {:4} COMPOUND 28“ Step 1: Synthesis of 5-(4-Methylpiperazin-l-yl)pyrimidinamine (235) Under N2 atmosphere, to a solution of 5-bromopyrimidin-2—amine (234, 2 g, 11.5 mmol) in toluene (200 mL) was added l-methylpiperazine (32 g, 3195 mmol), t-BuONa (1.8 g, 18.7 mmol), Pd2(dba)3 (520 mg, 0.57 mmol) and John-phos (680 mg, 2.28 mmol). After stirred at 100 °C for 48 h, the reaction mixture was concentrated in vacuo. The resulting residue was purified by column chromatography to provide 5-(4-methylpiperazin-1—yl)pyrimidin-2— amine (235, 200 mg, 1.0 mmol). MS (ESI+): m/Z 194 [M + H]+.

Step 2: sis of 2'-((5-(4-Methylpiperazinyl)pyrimidinyl)amin0)- 7',8'-dihydro- 6'H-spiro[cyclohexane- yrazino[1 ',2' : 1,5] pyrrolo [2,3-d] pyrimidin] -6'-one (COMPOUND 28) Under N2 atmosphere, to a solution of ethylpiperazinyl)pyrimidinamine (235, 13 mg, 0.07 mmol), 2'-chloro-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'— pyrazino[l',2':1,5]pyrrolo[2,3-d]pyrimidin]—6'-one (20 mg, 0.07 mmol) in dioxane (40 mL) was added Pd(OAc)2 (3 mg, 0.01 mmol), X-Phos (6 mg, 0.01 mmol) and CS2CO3 (45 mg, 0.14 mmol). After stirred at 100 0C for 4 h, the reaction mixture was cooled to room temperature, quenched with water (20 mL) and extracted with EtOAc (10 mL X 3). The combined c phases were dried over NazSO4, concentrated in vacuo. The resulting residue was purified by prep TLC to provide 2'-((5-(4-methy1piperaziny1)pyrimidiny1)arnino)-7',8'-dihydro-6'H- spiro[cyclohexane-1,9’-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6’-one (COMPOUND 28, 2.8 mg, 0.0063 mmol). MS : W2 448 [M + H]+, 1H NMR (300 MHz, MeOD): 5 8.89 (s, 1H), 8.40 (br s, 2H), 7.26 (s, 1H), 3.77 (s, 2H), 3.29 - 3.20 (m, 4H), 3.07 (t, J: 11.4 Hz, 2H), 2.80 - 2.72 (m 4H), 2.45 (s, 3 H), 2.00 - 1.90 (m, 2 H), 1.86 — 1.76 (m, 3 H), 1.60 - 1.47 (m, 3H).

Scheme 33: Synthesis of 2'-((5—(4-Methylpiperazinyl)pyridinyl)amino)— 6'H-spiro[cyclohexane—1,9'-pyrazino[ 1',2' : 1,5] pyrrolo [2,3-d] pyrimidine] (7'H)- dione (COMPOUND 30) NHZ I / . éé/J\0Et i O NH2 ------ \ /Z38 [:2 O N N 'NH m N NH NH J11 / / / 2 __;.. M $1 N fii‘ H NaHCCh, C. PdCb(PPh3h, >63, DMfiq ' Cm.DWEA,THF Step 1 Step 2 ALNM______< N \ \ [0 “fix g -----1” or N N 0E HOAc, H20 l/L, / NaCEOZ, TBAF Ci N g Q§_ ”c: NaHgPO4 ——-3P W THF HZN Step 4 Step 5 Step3 Z fi/Ndfflgr./ \ 4? PfiOAm2, NH 9 X-phos, WM ”{2} (if; (3329,03 HN Ir 0 / twic N NH )an N / #0 i6 \‘K‘ 829,06 f N~ fi compouwnso Step 1: Synthesis of Chloroiodopyrimidinyl)amino)cyclohexane carboxamide (237) 2017/040093 To a solution 2,4-dichloroiodopyrimidine (236, 26 g, 94.6 mmol) and 1- aminocyclohexane-l-carboxamide (15 g, 105.4 mmol) in DMAc (260 mL) was added NaHCO3 (33 g, 392.8 mmol). After stirring at 80 0C for 12 h, the reaction e was cooled to room ature, quenched with water (700 mL) and extracted with EtOAc (300 mL x 3). The combined organic phases were washed with water (200 mL X 2), brine (100 mL) and dried over anhydrous NazSO4. After concentration, the resulting residue was purified by column chromatography to provide 1-((2-chloroiodopyrimidinyl)amino)cyclohexane carboxamide (237, 12 g, 31.5 mmol). MS (ESI+): m/z 381 [M + H]+.

Step 2: Synthesis of 1-((2-Chloro-S-(3,3-diethoxypropynyl)pyrimidin yl)amin0)cyclohexane—l-carboxamide (239) Under N2 atmosphere, to a solution of 1-((2-chloroiodopyrimidin-4— yl)amino)cyclohexanecarboxarnide (237, 4 g, 10.5 mmol) and DIPEA (2.7 g, 20.9 mmol) in THF (170 mL) was added CuI (200 mg, 1.05 mmol) and Pd(PPh3)2Clz (294 mg, 0.42 mmol).

After stirring at room temperature for 10 min, a solution of 3,3-diethoxypropyne (238, 1.6 g, 12.5 mmol) in THF (5 mL) was added in dropwise and the reaction was stirred at room temperature for 12 h. After tration of the mixture in vacuo, the resulting e was purified by column chromatography to provide 1-((2-chloro(3,3-diethoxypropyn yl)pyrimidinyl)amino)cyclohexane-l-carboxamide (239, 2.4 g, 6.3 mmol). MS (ESI+): m/z 381 [M + H]+.

Step 3: Synthesis of 1-(2-Cloro—6-(diethoxymethyl)—7H-pyrrolo[2,3-d] pyrimidin yl)cyclohexane—1-carboxamide (240) To a on of 1-((2-chloro(3,3-diethoxypropynyl)pyrimidin yl)amino)cyclohexane-l-carboxamide (239, 2 g, 5.25 mmol) was added TBAF (20 mL, 20 mrnol, 1M in THF). After stirring at 60 0C for 2h, the reaction mixture was cooled to room temperature, quenched with water (70 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography to provide 1-(2-chloro-6— oxymethyl)-7H-pyrrolo[2,3-d]pyrimidinyl)cyclohexanecarboxamide (240, 400 mg, 1.05 mmol). MS (ESI+): m/z 381 [M + H]+.

Step 4: sis of 1-(2-Chlor0formyl-7H-pyrrolo[2,3-d]pyrimidinyl) cyclohexane— l-carboxamide (241) To a solution of l-(2-chloro(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin yl)cyclohexane—1-carboxamide (240, 800 mg, 2.1 mmol) in THF (4 mL) was added water (4 mL) and HOAc (4 mL). After stirring at 60 0C for 2h, the on mixture was ed with saturated aqueous NaHCOa and extracted with EtOAc (100 mL x 3). The combined organic phases were dried over , filtered and concentrated in vacuo. The resulting residue was d by column chromatography to provide 1-(2-chloroformyl-7H-pyrrolo[2,3- d]pyrimidinyl)cyclohexanecarboxamide (241, 527 mg, 1.72 mmol).

Step 5: Synthesis of 2'-Chloro-6'H-spiro[cyclohexane—1,9'-pyrazino[1',2':1,5] pyrrolo[2,3—d]pyrimidine]-6',8'(7'H)-dione (242) To a solution of hloroformyl-7H-pyrrolo[2,3-d]pyrimidinyl) exane- l-carboxamide (241, 100 mg, 0.33 mmol) in t-BuOH (5 mL) and acetonitrile (1 mL) was added NaH2P04 (405 mg, 3.38 mmol) and 2-methylbutene (183 mg, 2.6 mmol ). The reaction mixture was brought to 0 0C was a solution ofNaC102 (405 mg, 4.48 mmol) in water (10 mL) was added dropwise. After stirring at room temperature for 12 h, the reaction mixture was extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography to provide 2'-chloro-6'H-spiro[cyclohexane-1,9'- pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-6‘,8'(7'H)-dione (242, 95 mg, 0.31 mmol).

Step 6: Synthesis of 2'-((5-(4-Methylpiperazinyl)pyridinyl)amino)- 6'H- spiro[cyclohexane—1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-6',8'(7'H)-dione (COMPOUND 30) Under N2 atmosphere, to a solution of 2'-chloro-6'H-spiro[cyclohexane-1,9'- pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-6',8'(7'H)—dione (242, 100 mg, 0.33 mmol), 5-(4— methylpiperazinyl)pyridin-2—amine (76 mg, 0.4 mmol) in dioxane (5 mL) was added Pd(OAc)2 (7.4 mg, 0.03 mmol), CszCO3 (320 mg, 0.98 mmol) and X-Phos (62 mg, 0.13 mmol).

The reaction was stirred at 100 °C for 12 h. After cooled to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were concentrated in vacuo. The resulting residue was purified by prep TLC to prodive 2'-((5-(4-methy1piperazinyl)pyridin—2-yl) amino)-6'H-spiro[cyclohexane-l ,9'-pyrazino[l',2': 1,5]pyrrolo[2,3-d] pyrimidine] -6',8'(7'H)- dione (COMPOUND 30, 2.9 mg, 0.0063 mmol). MS : W2 461 [M + H]+, 1HNMR (300 MHz, MeOD + CDCl3): 5 8.93 (s, 1H), 8.34 (s, 1H), 8.02 (s, 1H), 7.48 - 7.42 (m, 2H), 3.32 — 3.21 (m, 6H), 2.93 - 2.84 (m, 4H), 2.55 (s, 3H), 2.30 - 2.15 (m, 2H), 2.13 - 2.02 (m, 2 H), 2.00 —1.91(m, 1H),1.91 -1.78(m,2H), 1.70 - 1.59 (m, 1 H).

Scheme 34: Synthesis of 4-Methylpiperazinyl)pyridin-2—yl)-6'H- Spiro[cyclohexane—1,9'-pyrazin0[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-2'-amine (COMPOUND 31) H3N (2001-1 LAH H205 Step 1 243 244 801330 [“1sz NHBOC / THF / 245 246 Step3 N/aé‘Ii 1 (mi/E: “LC:E’JE‘N/ DSSS Mamn- CHAN/ ' NH NH 0.1““1‘” Ci DMA DOM 80 °C Step 1 Step 2 248 249 NHBQC ///—NHBQC245 \ \ TBAF} THF N NHBOC TFA N “ma" x / N mm» \ / N0 PdCE2(PPh3}2 >~N N 00 Cn a C; DCM CULTEA C.

Step 3 Step 4 0 Step 5 253 251 / \\ / \ Pd(OAc)2 N l‘ HN iN fiszCO3 2» N N. may, h If M Q; 1,4—dioxane \ "“5. 3399 5 CQMPOUND 31 252 {:1} Step 1: Synthesis of (l-Aminocyclohexyl)methanol Intermediate (244) To a solution of 1-aminocyclohexane—1-carboxylic acid (243, 10 g, 69.9 mmol) in ous THF (300 mL) at 5 °C was added LiAlH4 (8 g, 210.5 mmol) in portions over 30 min. The reaction was then refluxed for 12 h. After cooling to 5 0C with an ice-bath, to the reaction mixture was added 8 mL of H20, 8 mL of 15% NaOH s, followed by addition of 16 mL of H20. After the completion of addition, the mixture was stirred for 30 min.

Anhydrous magnesium sulfate (20 g) was added. After stirring for 1h, the mixture was filtered and the filter cake was washed with EtOAc (50 mL). The filtrate was concentrated to provide (1 -aminocyclohexyl)methanol (244, 5.2 g, 40 mmol) as a yellow oil, which was used in the next step without further purification. MS (ESI+): m/z 130 [M + H]+.

Step 1: Synthesis of tert—Butyl prop-Z-yn-l-ylcarbamate Intermediate (246) To a solution of -yn-l-amine (245, 2.1 g, 38.2 mmol) in THF (30 mL) was added (Boc)20 (15 g, 68.8 mmol ). After stirring at room temperature for 1 h, the reaction mixture was concentrated in vacuo to afford the residue, which was purified by column chromatography with a gradient elution of hexane (100%) to hexane (80%) and EtOAc (20%) to provide tert- butyl propyn—l—ylcarbamate (246, 4.1 g, 26.4 mmol); 1H NMR (300 MHz, CDCl3): 5 4.70 (s, 1H), 3.85 (d, J: 3.0 Hz, 2H), 2.15 (t, J: 2.7 Hz, 1H), 1.38 (s, 9H).

Step 1: Synthesis of (1-((2-Chloro—5-iodopyrimidinyl)amino) cyclohexyl)methanol (248) To a on of 2,4-dichloroiodopyrimidine (247, 2.7 g, 9.8 mmol) in DMA (20 mL) was added (1-aminocyclohexyl)methanol (244, 1.4 g, 10.8 mmol) and NaHCO3 (5 g, 59.5 mol).

The reaction was stirred at 80 °C for 4 h. After cooling to room temperature, the reaction mixture was quenched with water (40 mL) and extracted with EtOAc (50 mL x 2). The ed organic phases were concentrated in vacuo to afford the residue, which was purified by column chromatography to afford (1 -((2-chloroiodopyrimidin-4— yl)amino)cyclohexyl)methanol (248, 1.5 g, 4.1 mmol). MS (ESI): m/Z 368 [M + H]+.

Step 2: Synthesis of 1-((2-Chloro—5-iodopyrimidinyl)amino)cyclohexane carbaldehyde (249) To a solution of (l-((2-chloroiodopyrimidinyl)amino)cyclohexyl)methanol (248, 1 g, 2.7 mmol) in DCM (50 mL) at room temperature was added PCC (1.1 g, 5.1 mmol). After stirring at room temperature overnight, the solid was removed. The filter cake was washed with DCM (100 mL) and the te was washed with ted sodium bicarbonate solution (50 mL). The organic layer was separated and concentrated in vacuo to afford the residue, which was purified by column chromatography with a gradient elution hexane (95%) and EtOAc (5%) to hexane (80%) and EtOAc (20%) to provide 1-((2-chloroiodopyrimidin yl)amino)cyclohexane-l-carbaldehyde (249, 0.3 g, 0.8 mmol), MS (E81 +): m/z 366 [M + H]*.

Step 3: Synthesis of tert—Butyl Chloro—4—((1-formylcyclohexyl)amino) pyrimidin-S— yl)propynyl)carbamate (250) Under N2 atmosphere, to a solution of 1—((2-chloroiodopyrimidin yl)amino)cyclohexane-l-carbaldehyde (249, 300 mg, 0.8 mmol) and TEA (165 mg, 1.6 mmol) in anhydrous THF (15 mL) at room temperature was added Cul (15.5 mg, 0.1 mmol) and PdC12(PPh3)2 (28.7 mg, 0.04 mmol), followed by the addition of tert-butyl propyn-l- ylcarbamate (246, 165 mg, 1.1 mmol) dropwise. After stirring at room temperature overnight, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL).

The c layer was separated and washed with brine, dried over MgSO4, filtered and trated in vacuo to afford the crude product, which was purified by column chromatography to provide tert-butyl (3-(2-chloro((1-formylcyclohexyl)amino)pyrimidin- -yl)propyn-l-yl)carbamate (250, 165 mg, 0.4 mmol). MS (ESI) m/Z 393 [M + H]+.

Step 4: Synthesis of tert—Butyl ((2—chloro—7—(l-formylcyclohexyl)-7H-pyrrolo [2,3- d]pyrimidinyl)methyl)carbamate (251) To a on of tert-butyl (3—(2-chloro-4—((1-formylcyclohexyl)amino)pyrimidin—S- yl)propynyl)carbamate (250, 800 mg, 2.0 mmol) in anhydrous THF (5 mL) was added TBAF (12 mL, 12 mmol, 1 M in THF). The reaction was stirred at 60 °C for 1 h. After cooling to room ature, the reaction mixture was quenched with H20 (10 mL) and extracted with EtOAc (10 mL). The organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the crude product, which was purified by column chromatography to afford tert-butyl((2-chloro(1-formylcyclohexyl)-7H-pyrrolo[2,3- d]pyrimidinyl)methyl)carbamate (251, 370 mg, 0.94 mmol). MS (ESI +): m/z 393 [M + H]+.

Step 5: sis of 2'-Chloro—6'H—spiro[cyclohexane-1,9'-pyrazino [1',2':1,5]pyrrolo[2,3—d]pyrimidine] (252) To a solution of utyl ((2-chloro(1-formylcyclohexyl)-7H-pyrrolo[2,3- d]pyrimidinyl)methyl)carbamate (251, 100 mg, 0.25 mmol) in DCM(1 mL) was added TFA (3 mL). After stirring at room temperature for 2 h, the reaction mixture was neutralized with ted sodium bicarbonate on (5 mL) and extracted with EtOAc (5 mL x 2). The combined organic phases were concentrated in vacuo and purified by prep TLC to afford 2'- chloro—6'H-spiro[cyclohexane—1,9'-pyrazino[1’,2':1,5]pyrrolo[2,3-d]pyrirnidine] (252, 55 mg, 0.20 mmol) as awhite solid. MS (ESI +): m/z 275 [M + H]+.

Step 6: Synthesis of N-(5-(4-Methylpiperazinyl)pyridinyl)—6'H-spiro [cyclohexane— 1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-2'-amine (COMPOUND 31) Under N2 atmosphere, to a solution of 2'-chloro-6'H-spiro[cyclohexane-1,9'- pyrazino[l',2':l,5]pyrrolo[2,3-d]pyrimidine (252, 100 mg, 0.36 mmol) and 5-(4- methylpiperazin—1—yl)pyridin-2—amine (80 mg, 0.41 mmol) in anhydrous 1,4—dioxane (5 mL) was added Pd(OAc)2 (40 mg, 0.18 mmol), X-phos (100 mg, 0.21 mmol) and CszCO3 (520 mg, 1.60 mmol). The reaction mixture was stirred at 110 °C overnight. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (20 mL). The organic phase was separated and concentrated in vacuo to afford the residue, which was purified by prep HPLC to e N-(5-(4-methylpiperazinyl)pyridinyl)—6'H- spiro[cyclohexane-l,9'-pyrazino[1',2':l,5]pyrrolo[2,3-d]pyrimidin]—2'-amine (COMPOUND 31, 15.2 mg, 0.03 mmol). MS (ESI +): m/z 431 [M + H]+, 1H NMR (300 MHz, CDC13 ): 5 8.68 (s, 1H), 8.30 (s, 1H), 8.22 (d, J: 9.3 Hz, 1H), 7.96 (d,J= 2.7 Hz, 1H), 7.93 (s, 1H), 7.25 (dd, J: 9.0, 3.0 Hz,1H), 6.55 (s, 1H), 4.00 (s, 2H), 3.17 - 3.14 (m, 4H), 2.83 (td, J: 13.5, 4.2 Hz, 2H), 2.62 - 2.59 (m, 4H), 2.34 (s, 3H), 1.82 - 1,72 (m, 6H), 1.59 - 1.46 (m, 2H).

Scheme 35: Synthesis of 2'-((5-(4-Methylpiperazinyl)pyridinyl)amino) -6',7'-dihydro-8'H—spiro [cyclohexane— 1,9'-pyrazino[1',2':1,5]pyrrolo[2,3—d]pyrimidin]- 8'-0ne (COMPOUND 33) NR l //¢/l\OF1_. ”/iLN/ ——aa~ C! Cl Peep-(Pm); \ 253 out, DIPEA THF >—N 254 Step 1 Ci:..

N> \ <0 N \ A /I \o . i JL %g N/n HOAQ, HZO m NhZOHHLE k >20E O N 0);. N—QH mum—w)» C: N N """""""""""" O Step 4 ; EEOH, 80 CC --—O ”’0 ”'W')flywlc Slat) 5 255 257 258 Baptism,, \ Zn NWQQ’KNH\ / N ‘\ \ , mm.» X-phos, “N “1= NH m 0 _ )‘rq\ i N- I .........,..

Step 6 , r 2W4 V Ci 0 Step 7 N \\ (\ commune 33 Step 1: Synthesis of 2,4-Dichloro(3,3-diethoxypropynyl)pyrimidine (254) Under N2 atmosphere, to a solution of 2,4-dichloro-S-iodopyrimidine (253, 1 g, 3.65 mmol) and DIEA (1.42 g, 10.99 mmol) in THF (20 mL) was added Cul (70 mg, 0.37 mmol) and 3)2Cl2 (100 mg, 0.14 mmol). After stirring at room temperature for 10 min, a solution of 3,3-diethoxyprop-1—yne (470 mg, 3.67 mmol) in THF (5 mL) was added. After ng at room temperature for 12 h, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were concentrated in vacuo. The resulting residue was purified by column chromatography to provide 2,4-dichloro- 5-(3,3-diethoxypropynyl)pyrimjdine (254, 1.1 g, 4.0 mmol).

Step 2: Synthesis of Methyl 1-((2-chloro(3,3-diethoxyprop-l-yn-l-yl) pyrimidin-4— n0)cyclohexanecarb0xylate (255) A solution of 2,4-dichloro(3,3-diethoxypropynyl)pyrimidine (254, 600 mg, 2.18 mmol) and methyl ocyclohexanecarboxylate (336 mg, 2.14 mmol) and DIEA (619 mg, 4.8 mmol) in DMAc (20 mL) was stirred at 60 °C for 12 h. After g to room temperature, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over NazSO4 and concentrated in vacuo. The ing e was d by column chromatography to afford methyl 1 -((2-chloro(3,3-diethoxypropyn-l-yl)pyrimidin-4— yl)amino)cyclohexanecarboxylate (255, 200 mg, 0.50 mmol).

Step 3: Synthesis ofMethyl 1-(2-chloro(diethoxymethyl)—7H-pyrrolo [2,3-d]pyrimidin- 7-yl)cyclohexane-l-carboxylate (256) To a solution of methyl 1-((2-chloro(3,3-diethoxyprop—l-ynyl)pyrimidin-4— yl)amino)cyclohexane-l-carboxylate (255, 50 mg, 0.13 mmol) in THF (1 mL) was added TBAF (0.4 mL, 0.4 mrnol, 1M in THF). After ng at 60 °C for 2 h, the reaction mixture was quenched with water (15 mL) and extracted with EtOAc (10 mL X 3). The combined organic phases were dried over NazSO4, filtered and trated in vacuo. The resulting residue was purified by column chromatography to provide methyl l-(2-chloro (diethoxymethyl)-7H—pyrrolo[2,3-d]pyrimidinyl)cyclohexane-1—carboxylate (256, 20 mg, 0.05 mmol). MS (ESI+): m/Z 396 [M + H]+.

Step 4: Synthesis of Methyl 1-(2-chloroformyl-7H-pyrrolo[2,3-d]pyrimidin-7 - yl)cyclohexane-l-carboxylate (257) To a solution of methyl l-(2-chloro(diethoxymethyl)—7H-pyrrolo[2,3-d]pyrimidin— 7-yl)cyclohexane-l-carboxylate (256, 300 mg, 0.75 mmol) in THF (4 mL) was added water (4 mL) and HOAc (4 mL). After stirring at 60 0C for 2 h, the reaction mixture was quenched with saturated aqueous NaHCO3 and ted with EtOAc (100 mL x 3). The combined organic phases were dried over NazSO4 and concentrated in vacuo. The resulting residue was purified by column chromatography to provide methyl 1-(2-chloroformyl- 7H-pyrrolo[2,3- d]pyrimidinyl)cyclohexanecarboxylate (257, 250 mg, 0.78 mmol).

Step 5: Synthesis of Methyl (E)(2-chloro((hydroxyimino)methyl) rrolo[2,3- d]pyrimidinyl)cyclohexane—l-carboxylate (258) To a solution of methyl 1-(2-chloroformyl-7H-pyrrolo[2,3-d]pyrimidin yl)cyclohexane-l-carboxylate (257 , 250 mg, 0.78 mmol) in EtOH (2 mL) at room temperature was added hydroxylamine hydrochloride (107 mg, 1.54 mmol). After stirring at 80 °C for 30 min, the reaction mixture was quenched with water (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were dried over NazSO4, filtered and trated in vacuo.

The resulting residue was purified by column chromatography to provide methyl (E)(2- 2017/040093 chloro((hydroxyimino)methyl)-7H-pyrrolo[2,3-d]pyrimidinyl)cyclohexane carboxylate (258, 220 mg, 0.65 mmol). MS (ESI+): m/z 337 [M + H]+.

Step 6: Synthesis of 2'-Chloro-6',7'-dihydro-8'H-spir0[cyclohexane- 1,9'- pyrazin0[1',2' : 1,5] pyrrolo [2,3—d] pyrimidin]-8'-one (259) Under N2 atmosphere, to a solution of methyl (E)—1-(2-chloro ((hydroxyimino)methyl)-7H-pyrrolo [2,3 -d]pyrimidinyl)cyclohexanecarboxylate (258, 200 mg, 0.59 mmol) in EtOH (4 mL) was added saturated aqueous NH4Cl (8 drops) and Zn power (193 mg, 2.95 mmol). After stirring at 80 0C for 2 h, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The ing residue was purified by column chromatography to provide 2'-chloro-6',7'-dihydro-8'H- spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]—8'—one (259, 150 mg, 0.52 mmol). MS (ESI-): m/z 289 [M - H]'.

Step 7: Synthesis of 2'-((5-(4-Methylpiperazinyl)pyridinyl)amino)-6',7'-dihydro- iro hexane—1,9'-pyrazino[1',2' : 1,5] pyrrolo [2,3—d] pyrimidin] -8'-one (COMPOUND 33) Under N2 atmosphere, to a solution of ethylpiperazin-l-yl)pyrimidinamine (40 mg, 0.21 mmol), 2'-chloro-6',7'-dihydro-8'H-spiro[cyclohexane-1,9'- pyrazino[1',2':l,5]pyrrolo[2,3-d]pyrimidin]—8'-one (259, 50 mg, 0.17 mmol) in dioxane (4 mL) at room temperature was added CszCO3 (160 mg, 0.49 mmol), Pd(OAc)2 (4 mg, 0.02 mmol) and X-Phos (16 mg, 0.03 mmol). After stirring at 100 °C for 12 h, the reaction mixture was cooled to room temperature and quenched with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were concentrated in vacuo. The ing residue was purified by prep TLC to provide 2'-((5-(4-methylpiperazinyl)pyridin-2—yl)amino)—6',7'- dihydro-8‘H-spiro[cyclohexane—1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-8'—one (COMPOUND 33, 4.6 mg, 0.01 mmol). MS : m/Z 447 [M + H]+; 1H NMR (300 MHz, MeOD): 5 8.64 (s, 1H), 8.12 (d, J: 9.4 Hz, 1H), 7.99 (s, 1H), 7.59 (d, J: 9.6 Hz, 1H), 6.38 (s, 1H), 4.64 (s, 2H), 3.42 - 3.33 (m, 4 H), 3.23 - 3.13 (m, 6 H), 2.75 (s, 3H), 2.25 — 2.02 (m, 4H), 1.91 - 1.72 (m, 3H), 1.67 - 1.45 (m, 1 H).

Scheme 36: Synthesis of 2'-((5-(4—Methylpiperazinyl)pyridin-2—yl)amino)—2,3,5,6,7',8'- hexahydr0-6'H-spiro[pyran-4,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one (COMPOUND 34) EEOH, Q TMECN N NH2 NH E ‘b H:N 2 Ti(O-iPr)4 NNz A; {Beqzo Bod-{N MM ——-IB>’ Q Step 1 Step 2 Step 3 Q 250 251 262 253 E N \ Sgfi‘h __ Pd(PPrt§)ZCEZ, cafl‘w” CU” ”WA NH NHBOC _________'____T_______,,.,, c: N\ / Step 4‘ Step 5 264 (JP—N ()Et HOAC, NE \ \ Ne-CIOZ, TBAF GEN/I\/\><O_____ H20 (ZN/[\N/ NaH2P04 N H , . . ,, SteP 6 , Ste 7 fr- p- SteP 8 BocHN o Boczi-EN \/0 267 263 270 CQMPQUND 34 Step 1: Synthesis of 4-Amin0tetrahydro-2H—pyrancarbonitrile (261) Under N2 atmosphere, to a solution of Ti(O-iPr)4 (68 g, 239 mmol) in NH3/EtOH (300 mL) at room temperature was added tetrahydro-4H-pyranone (260, 20 g, 200 mmol). After ng at 20 0C for 2 h, the reaction was cooled to -5 0C. TMSCN (20.6 g, 208 mmol) was added dropwise and the on was continued to stir at -5 °C for 3 h. The reaction was then warmed to room temperature and stirred for 12 h. The reaction mixture was quenched with water (20 mL), d, and the filter cake was washed with EtOH (20 mL x 2). The filtrate was concentrated in vacuo. The resulting residue was purified by column tography to provide 4-aminotetrahydro-2H-pyrancarbonitrile (261, 20.8 g, 165 mmol) as ayellow oil.

Step 2: Synthesis of 4-(Aminomethyl)tetrahydro-2H-pyran-4—amine (262) To a suspension of LiAlH4 (9.1 g, 240 mmol) in MTBE (120 mL) at room temperature was added 4-aminotetrahydro-2H-pyrancarbonitrile (261, 10 g, 80 mmol). After stirring at 40 0C for 2 h, the reaction mixture was quenched with water (9.1 mL) and 15 % aqueous NaOH (9.1 mL), followed by the addition of water (27.3 mL). After stirring for 1h, the mixture was filtered and the filter cake was washed with MTBE (20 mL x 2). The filtrate was concentrated in vacuo to provide 4-(aminomethyl)tetrahydro-2H-pyranamine (262, 6 g, 46.1 mmol), which was carried forward in the next step without further purification.

Step 3: sis of utyl inotetrahydr0-2H—pyranyl)methyl)carbamate (263) Under N2 atmosphere, to a solution of 4-(aminomethyl)tetrahydro-2H-pyranamine (262, 6 g, 46.1 mmol) in DCM (230 mL) at -78 °C was added BOC20 (8.5 g, 39 mmol) dropwise over 1 h. After stirring at -78 °C for an onal 2 h, the reaction was gradually warmed to room temperature. 1 M HCl was added to adjust pH = 5. The aqueous phase was extracted with EtOAc (200 mL). The aqueous phase was collected and ed to pH = 10 with 15% aqueous NaOH and extracted with DCM (200 mL x 3). The combined organic phases were dried over Na2SO4, filtered and concentrated to provide tert-butyl ((4—aminotetrahydro-2H-pyran yl)methyl)carbamate (263, 6.05 g, 26.3 mmol).

Step 4: Synthesis of tert-Butyl ((4-((2-chlor0iodopyrimidin-4—yl)amino) tetrahydro- 2H-pyranyl)methyl)carbamate (265) To a solution of 2,4-dichloroiodopyrimidine (264, 8.7 g, 31.6 mmol) and tert-butyl ((4-aminotetrahydro-2H-pyranyl)methyl)carbamate (263, 5 g, 21.7 mmol) in DMAc (200 mL) was added NaHCO3 (11.1 g, 132 mmol). After stirring at 80 °C for 12 h, the on mixture was ed with water (50 mL) and extracted with EtOAc (300 mL x 3). The combined organic phases were washed with water (200 mL x 2) and brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography to provide tert—butyl ((4-((2-chloro-5—iodopyrimidin—4—yl)amino)tetrahydro- 2H-pyranyl)methyl) carbamate (265, 5.02 g, 10.7 mmol).

Step 5: Synthesis of utyl ((4-((2—chloro—S—(3,3-diethoxyprop-l-yn- 1-yl) pyrimidin-4— yl)amino)tetrahydro-2H-pyran-4—yl)methyl)carbamate (266) WO 05860 Under N2 atmosphere, to a solution of tert—butyl((4-((2-chloroiodopyrimidin no) tetrahydro-ZH—pyran—4-yl) methyl)carbamate (265, 5.70 g, 12.2 mmol) and DIEA (3.11 g, 24.1 mmol) in THF (170 mL) was added Cul (228 mg, 1.2 mmol) and Pd(PPh3)2C12 (342 mg, 0.49 mmol). After ng at room temperature for 10 min, 3,3-diethoxypropyne (1.9 g, 14.8 mmol) in THF (5 mL) was added dropwise and the reaction was stirred at room temperature for 12 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were concentrated in vacuo. The resulting residue was d by column chromatography to provide tert-butyl ((4-((2-chloro(3,3- diethoxyprop-l -ynyl)pyrimidinyl)amino)tetrahydro-2H-pyranyl)methyl)carbamate (266, 5.03 g, 10.7 mmol). MS (ESI+): m/Z 469 [M + H]+.

Step 6: Synthesis of tert-Butyl ((4-(2-chloro(diethoxymethyl)—7H-pyrrolo [2,3- d] pyrimidinyl)tetrahydro—2H-pyran-4—yl)methyl)carbamate (267) To a solution of tert-butyl ((4-((2-chloro(3,3-diethoxypropyn yl)pyrimidin yl)amino)tetrahydro-2H-pyranyl)methyl)carbamate (266, 4.90 g, 10.4 mmol) in THF (50 mL) was added TBAF (50 mL, 50 mol, 1 M in THF). After stirring at 65 °C for 2 h, the on was cooled to room temperature and quenched with water (150 mL). The aqueous solution was extracted with EtOAc (100 mL x 3). The combined organic phases were dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was d by column chromatography to provide tert-butyl ((4-(2-chloro(diethoxymethyl)—7H-pyrrolo[2,3- d]pyrimidinyl)tetrahydro-2H-pyranyl)methyl)carbamate (267, 1.8 g, 3.84 mmol). MS (ESI+): m/Z 491 [M+Na]+.

Step 7: Synthesis of utyl ((4-(2-chloroformyl-7H-pyrrolo[2,3-d] pyrimidin yl)tetrahydro—2H—pyran-4—yl)methyl)carbamate (268) To a solution of tert-butyl -chloro(diethoxymethyl)-7H-pyrrolo[2,3- d]pyrimidinyl)tetrahydro-2H-pyranyl)methyl)carbamate (267, 800 mg, 1.71 mmol) in THF (4 mL) was added water (4 mL) and AcOH (4 mL). After stirring at 60 0C for 2 h, the reaction e was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc (100 mL x 3). The combined organic phases were dried over NazSO4 and concentrated in vacuo. The resulting residue was purified by column chromatography to provide tert-butyl ((4- (2-chloroformyl-7H-pyrrolo[2,3-d]pyrimidinyl)tetrahydro-2H-pyran yl)methyl)carbamate (268, 527 mg, 1.33 mmol).

Step 8: Synthesis of tert—Butyl 2'-chloro-6'-oxo-2,3,5,6-tetrahydro-6'H- spiro[pyran-4,9'- pyrazino[1',2':1,5]pyrrolo[2,3—d]pyrimidine]-7'(8'H)— carboxylate (269) To a solution of tert—butyl -chloroformyl-7H-pyrrolo[2,3-d]pyrimidin yl)tetrahydro—2H-pyranyl)methyl)carbamate (268, 200 mg, 0.51 mmol) in t-BuOH (5 mL) and acetonitrile (1 mL) at 0 0C was added NaH2P04 (610 mg, 5.08 mmol) and 2-methyl-2— butene (280 mg, 3.99 mmol). Then a solution of NaClOz (360 mg, 3.98 mmol) in H20 (3 mL) at 0 0C was added dropwise. After completion ofthe addition, the reaction was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were dried over NazSO4, d and concentrated in vacuo. The resulting residue was purified by column chromatography to provide tert—butyl 2'-chloro-6'—oxo-2,3,5,6-tetrahydro-6'H-spiro[pyran-4,9’- pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)-carboxylate (269, 130 mg, 0.33 mmol).

Step 9: Synthesis of tert—Butyl 2'-((5-(4-methylpiperazinyl)pyridinyl) amino)—6'- 0x0-2,3,5,6-tetrahydro-6'H-spiro[pyran-4,9'-pyrazino[1',2':1,5]pyrrolo[2,3- d]pyrimidine]-7'(8'H)—carboxylate (270) Under N2 atmosphere, to a mixture of tert-butyl 2'-chloro-6'-oxo-2,3,5,6-tetrahydro— 6'H-spiro[pyran-4,9'—pyrazino[l',2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)-carboxylate (269, mg, 0.05 mmol), 5-(4-methylpiperazin-l-yl)pyridinamine (11 mg, 0.06 mmol) and C52CO3 (33 mg, 0.10 mmol) in e (2 mL) was added Pd(OAc)2 (1.1 mg, 0.005 mmol) and X-Phos (9.6 mg, 0.02 mmol). The reaction was stirred at 100 0C for 12 h. After cooling to room temperature, the on was concentrated in vacuo. The resulting e was purified by prep TLC to provide tert-butyl 2'-((5-(4-methylpiperazin-1—yl)pyridinyl)amino)—6'-oxo—2,3,5,6- tetrahydro-6'H—spiro[pyran-4,9‘-pyrazino[1',2': 1,5]pyrrolo[2,3-d] pyrimidine] -7'(8'H)- carboxylate (270, 10 mg, 0.02 mmol). MS (ESI+): m/z 549 [M + H]+.

Step 10: Synthesis of 2'-((5—(4-Methylpiperazinyl)pyridinyl)amin0)-2,3,5,6,7',8'- hexahydro-6'H-spiro[pyran-4,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one (COMPOUND 34) To a solution of tert-butyl 2'-((5-(4-methylpiperazinyl)pyridinyl)amino)—6'-oxo- 2,3,5,6—tetrahy H-spiro[pyran-4,9'—pyrazino[1',2': 1,5]pyrrolo[2,3-d] pyrimidine] —7'(8'H)— carboxylate (270, 10 mg, 0.02 mmol) in DCM (3 mL) at 0 0C was added TFA (1 mL) dropwise over 5 min. After stirring for 2 h, the reaction e was neutralized with ted aqueous NaHCO3 and extracted with /DCM = 1/3 (20 mL x 2). The combined organic phases 2017/040093 were dried over NazSO4 and concentrated in vacuo. The resulting residue was purified by prep TLC to provide 2'-((5-(4-methy1piperaziny1)pyridiny1)arnino)—2,3,5,6,7',8'—hexahydro- 6'H-spir0[pyran-4,9'—pyrazin0[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-0ne (COMPOUND 34, .9 mg, 0.01 mmol). MS (ESI+): m/z 449 [M + H]+; 1H NMR (300 MHz, MeOD + CDC13): 5 8.83 (s, 1H), 8.26 (d, J: 9.1 Hz, 1H), 7.99 (d, J: 2.8 Hz, 1H), 7.63 (s, 1H), 7.53 (dd, J: 9.2, 2.8 Hz, 1H), 4.09 (dd, J: 120,48 Hz, 2H), 3.90 (s, 2H), 3.70 (t, J: 12.0 Hz, 2H), 3.47 (td, J = 13.4, 5.1 Hz, 2H), 3.33 - 3.29 (m, 4H), 2.92 - 2.82 (m, 4H), 2.54 (s, 3H), 1.94 (d, J: 13.2 Hz, 2H).

Scheme 37: Synthesis of 2'-(((1R,4R)(4-(Cyclopropylmethyl)piperazin- 1- yl)cyclohexyl)amino)—7',8'-dihydro-6'H-spir0[cyclohexane-1,9'- pyrazin0[1',2':1,5]pyrrolo[2,3—d]pyrimidin]-6'-one (COMPOUND 36) and 2'-(((IS,4S) (4-(Cyclopropy l)piperazinyl)cyclohexyl)amino)—7',8'-dihydro-6'H-spiro[cyclohexane-1,9'- pyrazino[1',2':1,5]pyrrolo[2,3—d]pyrimidin]-6'-0ne (COMPOUND 40) BrimN,‘ 1128:, an— N, Bn"'N,' "‘ Pd/C, HZ f K2503 "r‘ Dec < N”'\ ____,_,., x <\ -—-' < DCM a 1 —” 4‘ DMF ”4 Step 6 0H ‘0 2 OH we” 1 5‘9” Z4 , ~N> 271 272 273 (\J‘ NaHB(QAc)3 Bog Bog DOM NIB” {“3 8”” K2003 TFA ””3 Step5 > Pd/C, H; I ------------------§ ———bv~ ~NH {24>—- : ...................an». ' v4> DCM 1) new: “3 \fl "4“ Step 7 274 Step 3 4 Step 4 <{ N ~\,, ' ' < / m N 275 2'36 278 > \ 12 fl:— F—-» = N\ NH N N ,7 NB<< f' ‘3‘ Q ' , HM, \ ,J' /'r"“ 'Na\7 231 \fl compouuo 36 K. ’ N» TEA, 51cm W“3 X , "N 279 Step8 § 9 4 m‘ \ N NH \\ / N " o ~N TEA, EtOH y» 230 4:) Step 9 \_> commune 40 Step 1: Synthesis of (1R,4R)(Dibenzylamino)cyclohexan-l-ol (272) To a solution of (1R,4R)—4-aminocyclohexanol (270, 30 g, 261 mmol) and K2CO3 (80 g, 575 mmol) in DMF (250 mL) was added benzyl bromide (44 g, 257 mmol) dropwise over 30 min. After stirring at room temperature overnight, the reaction mixture was poured into 2 L of ice-water. The precipitated solid was collected, washed with water (2 x 100 mL) and dried to provide (1R,4R)(dibenzylamino)cyclohexanol (272, 69.3 g, 234 mrnol ). MS (ESI+): m/Z 296 [M + H]+.

Step 2: Synthesis of enzylamino)cyclohexan-l-one (273) To a solution of )(dibenzy1amino)cyclohexanol (272, 40 g, 136 mmol) in DCM (250 mL) was added PCC (75 g, 348 mmol) and silica gel (75 g). After stirring at room temperature overnight, the reaction mixture was filtered. The filter cake was washed with DCM (50 mL x 2) and the filtrate was washed with 100 mL of saturated sodium bicarbonate solution.

The c layer was ted and concentrated in vacuo. The resulting residue was purified by column chromatography with a gradient elution of hexane (90%) and EtOAc (10%) to hexane (75%) and EtOAc (25%) to provide 4-(dibenzylamino)cyclohexan-l-one (273, 25 g, 85 mmol). MS (ESI+): m/z 294 [M + H]+.

Step 3: Synthesis of tert—Butyl 4-(cycl0propylmethyl)piperazine-l-carboxylate To a solution of teIt-butyl piperazine—l-carboxylate (274, 32 g, 172 mmol) and (bromomethyl)cyclopropane (25 g, 185 mmol) in DCM (100 mL) at room temperature was added TEA (20 mL, 144 mmol). After stirring at room ature for 48 h, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography to afford utyl 4-(cyclopropylmethyl)piperazine carboxylate (275, 30 g, 124 mmol). MS (ESI): m/Z 241 [M + H]+.

Step 4: Synthesis of 1-(Cyclopropylmethyl)piperazine (276) To a solution of tert-butyl 4-(cyclopropylmethyl)piperazinecarboxylate (275, 30 g, 124 mmol) in DCM (100 mL) was added TFA (50 mL). After stirring at room temperature overnight, the reaction mixture was neutralized with saturated sodium bicarbonate solution (500 mL) and extracted with DCM (200 mL x 2). The combined organic phases were dried over MgSO4, filtered and trated in vacuo to e 1—(cyc1opropylmethyl)piperazine (276, 13 g, 92 mmol), which was used carried forward in the next step without further purification. MS (ESI +): m/z 141 [M + H]+.

Step 5: Synthesis of (1R,4R)-N,N-Dibenzyl(4-(cyclopropylmethyl) piperazin-lyl )cyclohexanamine (277) and (1S,4S)-N,N-Dibenzyl(4- (cyclopropylmethyl)piperazinyl)cyclohexanamine (278) To a solution of 4-(dibenzylamino)cyclohexanone (273, 5 g, 17.0 mmol) and 1- (cyclopropylmethyl)piperazine (276, 2.4 g, 17.1 mmol) in DCM (30 mL) was added HOAc (1 mL). NaHB(OAc)3 (20 g, 94.4 mmol) was then added in portions. After stirring at room temperature for 48 h, the reaction mixture was neutralized with saturated sodium bicarbonate on and extracted with DCM (50 mL x 3). The combined organic phases were dried over MgSO4 and concentrated in vacuo. The resulting residue was d by column chromatography to afford (1r,4r)—N,N-dibenzyl(4-(cyclopropy1methyl)piperazin yl)cyclohexanamine (277, 670 mg, 1.6 mmol) and (1s,4s)-N,N-dibenzyl(4— (cyc1opropylmethyl)piperaziny1)cyclohexanamine (278, 1.2 g, 2.9 mmol). (1R,4R)-N,N-Dibenzyl(4-(cyclopropylmethyl)piperazinyl)cyclohexan-1—amine (277): 1H NMR (300 MHz, CDC13 ): 5 7.29 - 7.26 (m, 4H), 7.24 - 7.18 (m, 4H), 7.15 - 7.10 (m, 2H), 3.53 (s, 4H), 2.81- 2.60 (m, 6H), 2.44 - 2.36 (m, 2H), 2.29 (d, J: 6.6 Hz, 2H), 1.96 - 1.88 (m, 4H), 1.58 - 1.29 (m, 4H), 1.21 - 1.10 (m, 2H), 0.88 - 0.77 (m, 1H), 0.50 - 0.42 (m, 2H), 0.10 - 0.02 (m, 2H). (1S,4S)-N,N-Dibenzyl(4-(cyclopr0pylmethyl)piperazinyl)cyclohexanamine (278): 1H NMR (300 MHz, CDC13 ): 5 7.29 - 7.27 (m, 4H), 7.23 - 7.18 (m, 4H), 7.14 - 7.09 (m, 2H), 3.57 (s, 4H), 2.96 - 2.49 (m, 8H), 2.40 (d, J: 6.6 Hz, 2H), 2.20 (s, 1H), 1.89 - 1.85 (m, 2H),1.77 - 1.66 (m, 2H),1.48 - 1.44 (m, 2H),1.26 - 1.17 (m, 3H),1.00 - 0.82 (m, 1H), 0.55 - 0.49 (m, 2H), 0.16 - 0.11 (m, 2H).

Step 6: Synthesis of (1R,4R)(4-(Cyclopropylmethyl)piperazinyl)cyclohexan amine (279) To a solution of (1R,4R)-N,N—dibenzyl(4-(cyclopropylmethyl)piperazin yl)cyclohexanamine (277, 500 mg, 1.2 mmol) in IPA (30 mL) was added Pd/C (10%, 200 mg). The reaction mixture was stirred at 40 °C under 1.8 MPa of hydrogen pressure for 24 h.

After completion of the reaction, the mixture was filtered and the filtrate was concentrated to e (1R,4R)(4-(cyclopropylmethyl)piperazinyl)cyclohexanamine (279, 160 mg, 0.67 mmol). MS (ESI +): m/Z 238 [M + H]+.

Step 7: sis of )(4-(Cyclopropylmethyl)piperazinyl)cyclohexanamine (280) (1S,4S)(4-(cyclopropylmethyl)piperazinyl)cyclohexan-l-amine (280) was prepared from (1S,4S)—N,N—dibenzyl(4-(cyclopropylmethyl)piperazinyl)cyclohexan amine (278) according to the experimental procedure as described in Step 6 for the synthesis of (1R,4R)(4—(cyclopropylmethyl)piperazinyl)cyclohexanamine (279). MS (ESI +): m/z 238 [M + H]+.

Step 8: Synthesis of 2'-(((1R,4R)(4-(Cyclopropylmethyl)piperazin yl)cyclohexyl)amino)-7',8'-dihydro-6'H-spir0[cyclohexane-1,9'- pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one (COMPOUND 36) To a solution of (1R,4R)(4-(cyclopropylmethyl)piperazin-l-yl)cyclohexan-l—amine (279, 40 mg, 0.17 mmol) and 2'-chloro-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'- pyrazino[1',2’:1,5]pyrrolo[2,3-d]pyrimidin]—6’-one (280, 40 mg, 0.14 mmol) in 95% EtOH (5 mL) was added TEA (0.3 mL). The reaction was stirred in a sealed tube at 140 0C overnight.

After cooling to room temperature, the reaction mixture was concentrated to the e, which was d by prep TLC to provide 2'-(((1R,4R)(4-(cyclopropylmethyl)piperazin 10hexy1)amin0)-7',8'-dihydr0-6'H-spir0[cyclohexane-1,9'- pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]—6'-one (COMPOUND 36, 4.3 mg, 0.008 mmol).

MS (ESI +): m/z 492 [M + H]+;1H NMR (300 MHz, MeOD ): 8 8.60 (s, 1H), 7.11 (s, 1H), 3.73 (s, 2H), 3.73 - 3.72 (m, 1 H), 3.04 (td, J=13.5, 3.9 Hz, 4H), 2.89 - 2.75 (m, 4H), 2.33 - 1.79 (m, 10H), 1.56 - 1.28 (m, 11H), 1.09 - 1.00 (m, 1H), 0.71 - 0.68 (m, 2H), 0.36 (s, 2H).

Step 9: Synthesis of 2'-(((1S,4S)(4-(Cyclopropylmethyl)piperazinyl) cyclohexyl)amin0)—7',8'-dihydr0-6'H-spiro [cyclohexane- 1,9'- pyrazin0[1',2':1,5]pyrrolo[2,3—d]pyrimidin]-6'-0ne (COMPOUND 40) 2'-(((1 S,4S)(4-(cyclopropylmethy1)piperaziny1)cyc10hexy1)arnin0)-7', 8'-dihydro- 6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one (COMPOUND 40) was prepared according to the procedure in Step 8 for the synthesis of COMPOUND 36. MS (ESI +): m/z 492 [M + H]+; 1H NMR (300 MHz, MeOD): 5 8.62 (s, 1H), 7.12 (s, 1H), 4.04 (s, 1H), 3.73 (s, 2H), 3.04 (td, J =13.5, 3.6 Hz,4H), 2.86 — 2,80 (m, 4H), 2.18 — 2.10 (m, 3H),1.95 —1.78(m,10H), 1.60 — 1.46 (m, 3H), 1.39 —1.29(m, 5H),1.13 — 1.02 (m, 1H), 0.71 — 0.68 (m, 2H), 0.36 (s, 2H).

Scheme 38: Synthesis of 2'-(((1R,4R)—4-(4-Methylpiperazinyl)cyclohexyl) amin0)-7',8'-dihydro-6'H—spiro hexane-1,9'-pyrazino[1',2' : 1,5] pyrrolo[2,3- d]pyrimidin]-6'-one (COMPOUND 37) and 1S,4S)(4-Methylpiperazin-l-yl) cyclohexyl)amin0)—7',8'-dihydr0-6'H-spiro hexane- 1,9'- pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-0ne (COMPOUND 41) Bar“, W» LAH <24» ,Bn Dd/C H2 BYVIN’ P THF ~ For fr.» " ’ Step2 Step4 286 \i [Bn Boo / x) EFFN, \,.N r \ kféo Nat-ia(oAc:}3 232 Step 1 .2,” an N {3 F3” Bn'"N “My ..AH Z 2 Pd/C, H2 .......................4., —-----------§9> 235 LN ‘HF Boc {N Step3 \WN\ , orepor £3 ""%EXI'E£6'§ "BK Step6 {W {rm/14H Q HAN Na />~t\l 1“” "- O ’94-!” <‘>2.! -~ NH 231 N I *8 ’ )‘t—N N'”\ «a ) TEA, EtOH H?» ”N\ Step 7 CQMPGUND 41 LNN”) Step 1: Synthesis of tert—Butyl ,4R)(dibenzylamino)cyclohexyl)piperazine ylate (284) and tert—Butyl 4-((1S,4S)—4—(dibenzylamino)cyclohexyl)piperazine carboxylate (285) To a solution of 4-(dibenzylamino)cyclohexan-l-one (282, 5 g, 17.0 mmol) and tert- butyl piperazine-l-carboxylate (283, 3.17 g, 22.6 mmol) in DCM (30 mL) was added HOAc (1 mL). NaHB(OAc)3 (20 g, 94.4 mmol) was then added in portions After stirring at room temperature for 48 h, the reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted with DCM (50 mL X 5). The combined organic phases were dried over anhydrous MgSO4 and concentrated in vacuo. The resulting e was purified by column chromatography to afford utyl 4-((1R,4R)—4-(dibenzylamino)cyclohexyl)piperazine carboxylate (284, 400 mg, 0.86 mmol) and tert-butyl 4-((1S,4S)—4— (dibenzylamino)cyclohexyl)piperazine-l-carboxylate (285, 1.4 g, 3.02 mmol). tert-Butyl 4-((1R,4R)—4-(Dibenzylamino)cyclohexyl)piperazine—l-carboxylate: 1H NMR (300 MHz, CDC13 ): 5 7.29 - 7.20 (m, 8H), 7.15 - 7.10 (m, 2H), 3.54 (s, 4H), 3.41 - 3.29 (m, 4H), 2.47 - 2.33 (m, 4H), 1.95 - 1.81 (m, 4H), 1.38 (s, 9H), 1.31 - 1.06 (m, 6H). tert-Butyl 4-((1S,4S)(dibenzylamino)cycl0hexyl)piperazine-l-carboxylate: 1H NMR (300 MHz, CDC13 ): 5 7.31 - 7.21 (m, 8H), 7.15 - 7.10 (m, 2H), 3.54 (s, 4H), 3.38 - 3.32 (m, 3H), 2.60 — 2.46 (m, 1H), 2.36 — 2.26 (m, 4H), 2.20 - 1.99 (m, 2H), 1.92 — 1.87 (m, 2H), 1.78 — 1.66 (m, 2H), 1.38 (s, 9H), 1.28 - 1.14 (m, 4H).

Step 2: Synthesis of (1R,4R)-N,N-Dibenzyl(4-methylpiperazinyl)cyclohexan amine (286) To a on of tert-butyl ,4R)(Dibenzylamino)cyclohexyl)piperazine carboxylate (284, 900 mg, 1.94 mmol) in anhydrous THF (20 mL) under ice-water bath was added LiAlH4 (300 mg, 7.90 mmol) in portions. After completion of the addition, the reaction mixture was refluxed for 3 h. After cooling to room temperature, the mixture was quenched with 0.3 mL of water, 0.3 mL of 15% sodium hydroxide aqueous solution, ed by the addition of 0.6 mL of water. The mixture was stirred for 30 min. and 1 g of anhydrous magnesium sulfate was added and the reaction was stirred for 1h. After filtration, the filter cake was washed with EtOAc (30 mL x 2). The filtrate was concentrated to afford the residue, which was d by a column chromatography with a gradient elution of EtOAc (100%) to EtOAc (83%) and MeOH (16%) and NH3.H20 (1%) to provide (1R,4R)-N,N-dibenzyl(4- methylpiperaziny1)cyclohexanamine (286, 500 mg, 1.32 mmol). MS (ESI +): m/z 378 [M + H]+.

Step 3: sis of (1S,4S)-N,N-Dibenzyl(4-methylpiperazinyl)cyclohexanamine (287) (lS,4S)-N,N-dibenzyl-4—(4-methylpiperazinyl)cyclohexanamine (287) was prepared from 4-((1S,4S)(dibenzylamino)cyclohexyl)piperazinecarboxylate (285) according to the experimental procedure of Step 2 for the synthesis of (1R,4R)-N,N-dibenzyl— ethylpiperazin-l-yl)cyclohexan-l-amine (286) MS (ESI +): m/z 378 [M + H]+, Step 4: Synthesis of (1R,4R)—4—(4-Methylpiperazinyl)cyclohexanamine (288) (1R,4R)—4-(4-methylpiperazinyl)cy an-l-amine (288) was prepared from (1R,4R)—N,N-dibenzyl(4-methylpiperazinyl)cyclohexanamine (286) according to the experimental procedure for the synthesis of (1R,4R)(4-(cyclopropylmethyl)piperazin yl)cyclohexan-l-amine (279, Scheme 37, Step 6). MS (ESI +): m/Z 198 [M + H]+.

Step 5: Synthesis of (1S,4S)(4-Methylpiperazin-1—yl)cyclohexan-1—amine (289) (1S,4S)(4-methylpiperazinyl)cyclohexanamine (289) was prepared from (1S,4S)-N,N—dibenzyl—4-(4-methylpiperazin—1-yl)cyclohexan—1-arnine (287) according to the experimental procedure for the synthesis of (1R,4R)(4-(cyclopropylmethyl)piperazin yl)cyclohexan—1-amine (279, Scheme 37, Step 6). MS (ESI +): m/z 198 [M + H]+. 2017/040093 Step 6: Synthesis of 2'-(((1R,4R)(4-Methylpiperazinyl)cyclohexyl)amino)—7',8'- dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one (COMPOUND 37) 2'-(((1R,4R)—4—(4-methylpiperazin-1—y1)cyclohexyl)amino)—7’,8'-dihy H— spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]py1imidin]-6'-one (COMPOUND 37) was ed from (1R,4R)(4-methylpiperaziny1)cyclohexanamine (288) according to the experimental procedure for the synthesis of COMPOUND 36 as shown in Step 8, Scheme 37. MS (ESI +): m/z 452 [M + H]+,1H NMR (300 MHz, MeOD ): 5 8.60 (s, 1H), 7.11 (s, 1H), 3.73 (s, 2H), 3.73 - 3,68 (m, 1 H), 3.03 (td, J=13.2, 3.3 Hz, 4H), 2.67 (br s, 3H), 2.33 - 2,28 (m, 2H), 2.19 - 2.13 (m, 2H),1.96 - 1.92 (m, 2H), 1.83 - 1.79 (m, 3H), 1.57 - 1.36 (m, 9H),1.31 - 1.25 (m, 5H).

Step 7: Synthesis of 2'-(((1S,4S)—4-(4—Methylpiperazinyl)cyclohexyl)amino)-7',8'- dihydro-6'H-spir0[cyclohexane-1,9'-pyrazin0[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one (COMPOUND 41) 2'-(((1S,4S)(4-methylpiperaziny1)cyclohexy1)amino)-7',8‘-dihydro-6'H- spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]py1imidin]-6'-one (COMPOUND 41) was prepared from (1 4-(4—methylpiperaziny1)cyclohexanamine (289) according to the experimental procedure for the synthesis of COMPOUND 36 as shown in Step 8, Scheme 37. MS (ESI +): m/z 452 [M + H]+;1H NMR (300 MHz, MeOD): 5 8.64 (s, 1H), 7.14 (s, 1H), 4.06 (s, 1H), 3.73 (s, 2H), 3.00 (td, J = 13.2, 3.9 Hz, 4H), 2.69 (br s, 3H), 2.21— 2.11 (m, 3H), 1.96 —1.74(m, 12H), 1.60 —1.47(m, 3H), 1.33 — 1.29 (m, 5H).

Scheme 39: Synthesis of (1S,4S)Methoxy-2'-((5-(4-methylpiperazin-l-yl) pyridin-2—yl)amino)-7',8'-dihydr0-6'H-spiro[cyclohexane—l,9'- pyrazin0[1',2':1,5]pyrrolo[2,3—d]pyrimidin]-6'-0ne (COMPOUND 38) and (1R,4R)—4- Methoxy—2'-((5-(4-methylpiperazin-1—yl)pyridinyl)amin0)-7',8'-dihydr0-6'HSpiro [cyclohexane— 1,9'-pyrazin0[1',2': 1,5] pyrrolo[2,3-d] pyrimidin]-6'-0ne (COMPOUND 39) TMSCN, M43, EtOH, Té(O-iPr)4 818,04 N\ NH \ NH? '3 . NH -- 2 LIAIH4. HzN‘ (800)20 BOCHN “mm-##— ————b- 8:45:35 326536 O\ \ O\ 294 295 296 2 OE: N\ /)-----NH§-----NHBoc >.....N - 3)ZCS2, m c: CUE BacHN N}Lr15] “NE-i;-----NHBQC TEA,TI-{F (:1 Step8 298 3&0 ./'“\ / C! N h L, EC) 29:7 OH . Pd<PPh3)2C52, N\ / Nag—wane Cu: _ >#N - *- N\ / ----- Ni—{s-"NHBOC CI TEAIHF >-N ‘ 299 i ,0 391 05: “1WD: N \ \ CIANJA‘N H A / Nauoz\. TBAF! c,= N N "Et HOA‘ H 0c; 2 l ......................a... WHW ___,., BocHN «0/ ——as» Stepg BQCHN K/{VO/ ”rep '0 Step 11 332 364 TBAr- N \ NI\E \ NaCIQ, \ ----- Hem H20 m/J‘ ’?‘*N H BocHN uh/ .0 o I [i :N \ _ _T‘ \ N MNBOC N 5...; N“ O x N x Faro/Ac); )LN/ N / \ x H/ .,/E\ / (352003: N W W C; N N \Boc x-phos \ I, TFA, DOM (~ : ——a-- / ----------»~ [,4 N \ N \ Step 12 L2- 0\ Step 13 \N O f- x O N 3 31:28 N~~. \ 396 < } commune 33 N ‘NN \ \ L1 o j: \ \ ..../< 1 paroxxmz, I /\ \«l [N \ N Cl NBoc N N 052003, N806 NH !Mr \____= N 2 JV“ __,.X‘ph°5 1111;” O\ ’7 k / '1'FA,DCM L. ”"5“ \/ (,> N ~——Ha> HN 4"“ ) :T Kr/)>‘ 0 Step 1: sis of 1,4-Di0xaspiro[4.5]decanol (291) To a solution of 1,4-dioxaspiro[4.5]decanone (290, 10 g, 64 mmol) in MeOH (100 mL) at 0 °C was added NaBH4 (4.8 g, 128 mmol) in portions. The reaction was gradually warmed to room temperature. After ng for 12 h, aqueous NaOH (26 mL, 2 N) was added.

The mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography to provide 1,4-dioxaspiro[4.5]decanol (291, 9.7 g, 61.3 mmol).

Step 2: Synthesis of 8-Methoxy-1,4-di0xaspiro[4.5]decane (292) To a solution of 1,4-dioxaspiro[4.5]decanol (291, 9.7 g, 61.3 mmol) in THF (150 mL) at 0 °C was added NaH (4.3 g, 184.0 mmol) in ns over 1 h. CH3I (43 g, 306.5 mmol) was added. After completion of the addition, the reaction mixture was d for 12 h. The reaction mixture was then cooled to room temperature, quenched with saturated aqueous NH4Cl and extracted with EtOAc (200 mL x 2), the combined organic phases were washed with water (50 mL), dried over NazSO4, d and concentrated in vacuo to afford 8-methoxy— 1,4-dioxaspiro[4.5]decane (292, 12 g, 69.7 mmol), which was used in the next step without further purification.

Step 3: Synthesis of 0xycyclohexan-l-one (293) A mixture of 8-methoxy—l,4-dioxaspiro[4.5]decane (292, 12.0 g, 69.7 mmol) and p- TsOH (1 g, 5.26 mmol) in H20 (300 mL) was stirred at 100 °C for l h. After cooling to room temperature, the on mixture was extracted with EtOAc (100 mL X 2). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to provide 4-methoxycyclohexan-l-one (293, 7.01 g, 54.7 mmol), which was used in the next step without further purification.

Step 4: Synthesis of 1-Amin0methoxycyclohexanecarbonitrile (294) 1-aminomethoxycyclohexanecarbonitrile (294) was prepared according to the synthesis of 4-methoxycyclohexanone (261) described in Step 1 of Scheme 36.

Step 5: Synthesis of 1-(Aminomethyl)methoxycyclohexanamine (295) 1-(aminomethyl)—4-methoxycyclohexanamine (295) was prepared from l-amino-4— methoxycyclohexanecarbonitrile (294) according to the experimental procedure for the synthesis of 4-(aminomethyl)tetrahydro—2H-pyranamine (262) bed in Step 2, Scheme Step 6: Synthesis of tert—Butyl ((1-amin0meth0xycyclohexyl)methyl)carbamate (296) Tert-butyl ((l-amino-4—methoxycyclohexyl)methyl)carbamate (296) was prepared from l-(aminomethyl)methoxycyclohexanamine (295) according to the experimental procedure for the synthesis of tert—butyl inotetrahydro—2H-pyranyl)methyl)carbamate (263) shown in Step 3, Scheme 36.

Step 7: Synthesis of utyl (((1S,4S)((2-chloroiodopyrimidinyl) amino)—4— methoxycyclohexyl)methyl)carbamate (298) and utyl 4R)—1-((2-chloro iodopyrimidinyl)amin0)methoxycyclohexyl)methyl)carbamate (299) To a solution 2,4-dichloroiodopyrimidine (297, 1013 g, 37.5 mmol) and utyl ((1—amin0—4-methoxycyclohexyl)methyl)carbamate (296, 9 g, 34.8 mmol) in DMAc (180 mL) was added NaHCO3 (10.8 g, 128 mmol). After stirring at 80 0C for 12 h, the reaction was quenched with water (500 ml) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with water (200 mL x 2) and brine (100 mL). The organic layer was dried over NazSO4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography to provide tert—butyl (((lS,4S)-l-((2-chloroiodopyrimidinyl)amino)—4— methoxycyclohexyl)methyl)carbamate (298, 3.2 g, 6.44 mmol) and tert-butyl (((1R,4R)((2- chloroiodopyrimidinyl)amino)methoxycyclohexyl)methyl)carbamate (299, 5.1 g, .3 mmol). MS (ESI+): m/Z 497 [M + H]+. tert-Butyl (((1S,4S)((2-chloro-S-iodopyrimidinyl)amino)—4- methoxycyclohexyl)methyl)carbamate (298): 1H NMR (300 MHz, CDCl3): 5 8.21 (s, 1H), 3.53 (d, J: 6.6 Hz, 2H), 3.49 (d, J: 6.3 Hz, 1H), 3.37 - 3.32 (m, 1H), 3.25 (s, 3H), 3.23 - 3.22 (m, 1H), 2.08 - 1.98 (m, 2H), 1.79 - 1.64 (m, 5H), 1.52 - 1.47 (m, 1H),1.36(s, 9H). tert-Butyl (((1R,4R)((2-chlor0i0d0pyrimidinyl)amin0) meth0xycyclohexyl)methyl)carbamate (299): 1H NMR (300 MHz, CD03): 6 8.22 (s, 1H), 3.56 (d, J: 6.6 Hz, 2H), 3.52 (s, 1H), 3.28 (s, 3H), 3.27 - 3.25 (m, 1H), 3.19 - 3.12 (m, 1H), 2.30 - 2.17 (m, 95 - 1.82 (m, 2H),1.79 - 1.65 (m, 2H), 1.45 - 1.39 (m, 2H),1.36(s, 9H).

Step 8: Synthesis of utyl (((IS,4S)((2-chloro(3,3-diethoxyprop-l-yn imidinyl)amino)—4-methoxycyclohexyl)methyl)carbamate (300) Under N2 atmosphere, to a solution of tert—butyl (((1s,4s)—1-((2-chloro iodopyrimidin-4—yl)amino)methoxycyclohexyl)methyl)carbamate (298, 3.2 g, 6.45 mmol) and Et3N (1.4 g, 13.8 mmol) in THF (70 mL) was added CuI (122 mg, 0.64 mmol) and Pd(PPh3)2C12 (181 mg, 0.26 mmol). After the reaction was stirred at 20 0C for 10 min, 3,3- diethoxyprop-l-yne (990 mg, 7.72 mmol) was added se and the reaction was stirred at 20 0C for 12 h. The reaction mixture was then quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography to provide tert—butyl (((1s,4s)—1-((2-chloro(3,3-diethoxyprop-l-yn- 1-yl)pyrimidinyl)amino)methoxycyclohexyl)methyl)carbamate (300, 2.60 g, 5.23 mmol), Step 9: Synthesis of tert—Butyl (((1S,4S)(2-chlor0—6-(diethoxymethyl)—7H- pyrrolo[2,3- d]pyrimidinyl)methoxycyclohexyl)methyl)carbamate (302) To a solution of teIt-butyl (((ls,4s)-l-((2-chloro(3,3-diethoxyprop—1-yn-l- imidinyl)amino)methoxycyclohexyl)methyl)carbamate (300, 2.60 g, 5.23 mmol) in THF (50 mL) was added TBAF (25 mL, 25 mmol, 1 M in THF). After stirring at 65 0C for 2 h, the reaction mixture was cooled room ature, quenched with water (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography to e tert-butyl (((1s,4s)(2-chloro(diethoxymethy1)-7H- pyrrolo[2,3-d]pyrimidinyl)-4—methoxycyclohexyl)methyl)carbamate (302, 1.2 g, 2.41 mmol).

Step 10: Synthesis of tert—Butyl (((1S,4S)—1-(2-chloroformyl-7H—pyrrolo [2,3- d]pyrimidinyl)methoxycyclohexyl)methyl)carbamate (304) To a solution of tert-butyl (((ls,4s)-1—(2-chloro(diethoxymethy1)-7H-pyrrolo[2,3- d]pyrimidinyl)methoxycyclohexy1)methy1)carbamate (302, 1.2 g, 2.41 mmol) in THF (4 mL) was added H20 (4 mL) and HOAc (4 mL). After stirring at 60 0C for 2 h, the on was quenched with saturated aqueous NaHCO3 and extracted with EtOAc (100 mL x 3). The combined organic phases were dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was d by column chromatography to provide tert-butyl (((ls,4s)(2- chloro—6-formyl-7H—pyrrolo[2,3-d]pyrimidin—7-yl)—4-methoxycyclohexy1)methy1)carbamate (304, 700 mg, 1.66 mmol).

Step 11: Synthesis of tert—Butyl )-2'-chloro—4-methoxy-6'-oxo-6'H-spir0 [cyclohexane— 1,9'-pyrazin0 [1',2' : 1,5] pyrrolo[2,3-d]pyrimidine]-7'(8'H)—carboxylate (306) To a on oftert—butyl (((1S,4S)(2-chloroformy1-7H-pyrrolo[2,3-d]pyrimidin- 4-methoxycyclohexy1)methy1)carbamate (304, 240 mg, 0.57 mmol) in t—BuOH (15 mL) and acetonitrile (3 mL) was added NaH2P04 (709 mg, 4.55 mmol) and 2-methy1butene (318 mg, 4.53 mmol ). After stirring at 0 °C for 5 min, a solution of NaClOz (318 mg, 3.52 mmol) in H20 (3 mL) was added dropwise over 1 h. After warming to room temperature and stirring for another 2 h, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were dried over , filtered and concentrated in vacuo. The resulting residue was purified by column chromatography to provide tert—butyl (1 S,4S)-2'—ch1oro—4-methoxy-6'-oxo-6'H-spiro[cyclohexane-1,9'— pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)-carboxylate (306, 200 mg, 0.47 mmol).

Step 12: Synthesis of tert—Butyl (1S,4S)methoxy-2'-((5-(4-methylpiperazin yl)pyridinyl)amino)-6'-oxo—6'H-spiro [cyclohexane— 1,9'-pyrazin0[1',2' : 1,5] pyrrolo [2,3- d]pyrimidine]-7'(8'H)—carb0xylate (308) Under N2 atmosphere, to a solution of tert-butyl (1S,4S)-2'-chloromethoxy-6'- oxo-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)- carboxylate (306, 100 mg, 0.24 mmol), 5-(4-methylpiperazin-l-yl)pyridinamine (55.4 mg, 0.28 mmol) in dioxane (5 mL) was added CS2CO3 (232 mg, 0.71 mmol), Pd(OAc)2 (5.3 mg, 0.02 mmol) and X-Phos (59 mg, 0.12 mmol). After stirring at 100 °C for 12 h, the reaction was quenched with water (10 mL) and extracted with EtOAc (10 mL X 2). The organic phases were concentrated in vacuo and the resulting residue was purified by column chromatography to provide tert-butyl (1 s,4s)methoxy-2'—((5 -(4-methylpiperazinyl)pyridinyl)amino)-6'- oxo-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)- carboxylate (308, 50 mg, 0.09 mmol). MS (ESI+): m/Z 577 [M + H]+.

Step 13: Synthesis of (1S,4S)Methoxy—2'-((5-(4-methylpiperazin-l-yl) pyridin-Z- yl)amin0)-7',8'-dihydro-6'H—spir0[cyclohexane—1,9'-pyrazino[1',2':1,5]pyrrolo[2,3- d]pyrimidin]-6'-0ne (COMPOUND 38) To a solution of tert-butyl (1S,4S)methoxy-2'—((5-(4-methylpiperazinyl)pyridin- mino)-6'-oxo-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]- 7'(8'H)-carboxylate (308, 50 mg, 0.09 mmol) in DCM (3 mL) at 0 0C was added TFA (1 mL) in dropwise. After stirring for 2 h, the reaction mixture was neutralized with saturated s NaHCO3 and extracted with i-PrOH/DCM = 1/3 (20 mL x 2). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by prep TLC to provide )—4-methoxy-2’-((5-(4-methylpiperazinyl)pyridinyl) amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'—pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]- 6'-one (COMPOUND 38, 6.7 mg, 0.01 mmol). MS : m/z 477 [M + H]+; 1H NMR (300 MHz, MeOD + CDCl3): 5 8.84 (s, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.51 - 7.41 (m, 1H), 7.27 (s, 1H), 3.78 (s, 2H), 3.46 (s, 3 H), 3.45 - 3.36 (m, 6 H), 3.23 - 3.06 (m, 5 H), 2.73 (s, 3H), 2.27 - 2.17 (m, 2H), 2.15 - 2.04 (m, 2H), 1.54 — 1.40 (m, 2H).

Synthesis of (1R,4R)Meth0xy-2'-((5-(4-methylpiperazinyl)pyridinyl)amino)— 7',8'-dihydro-6'H—spiro [cyclohexane-l,9'-pyrazin0 [1',2' : 1,5] o [2,3-d]pyrimidin] -6'- one (COMPOUND 39) COMPOUND 39 was prepared according to the experimental procedures in the synthesis of ND 38. MS : m/z 477 [M + H]+; 1H NMR (300 MHz, MeOD + CDCl3): 5 8.82 (s, 1H), 8.39 (br s, 1H), 7.98 (d, J: 2.5 Hz, 1H), 7.55 (d, J: 9.7 Hz, 1H), 7.26 (s, 1H), 3.77 (s, 2H), 3.63 (s, 1H), 3.41 (s, 3H), 3.40 - 3.34 (m, 6H), 3.16 - 2.94 (m, 4H), 2.67 (s, 3H), 2.19 - 2.09 (m, 2H), 1.87 - 1.76 (m, 2H), 1.72 - 1.59 (m, 2H).

Example 5. miting Examples of Compounds Table 3. Non-limiting Examples of Final Compounds Compound Structure WO 05860 WO 05860 WO 05860 WO 05860 WO 05860 WO 05860 WO 05860 WO 05860 WO 05860 Example 6: CDK4/6 tion In Vitro Assay Selected compounds disclosed herein were tested in CDK4/cyclinDl, CDK2/CycA and CDK2/cyclinE kinase assays by Nanosyn (Santa Clara, CA) to determine their inhibitory effect on these CDKs. The assays were performed using microfluidic kinase detection technology (Caliper Assay Platform). The compounds were tested in 12-point dose-response format in singlicate at Km for ATP. Phosphoacceptor substrate peptide concentration used was 1 uM 2017/040093 for all assays and Staurosporine was used as the reference compound for all assays. Specifics of each assay are as described below: CDK2/CyclinA: Enzyme concentration: 0.2 nM; ATP tration: 50 uM; Incubation time: 3 hr.

CDK2/CyclinE: Enzyme concentration: 0.28 nM; ATP concentration: 100 uM; Incubation time: 1 hr.

CDK4/CyclinD1: Enzyme concentration: 1 nM; ATP concentration: 200 uM; Incubation time: 10 hr.

Biolo_ical Table 3 Compd CDK4/ # Compound Structure Cyclin D1 (LLM) D3 (HM) E(uM) A(HM) T(MM) N~ 0.03 Nifl '{Nj/\- l 27 g 0 9.4 >100 >100 >100 WO 05860 WO 05860 WO 05860 39 0.06 40 O 0.09 \ NH N / \w-N/ R1?“'3 41 Q 0.14 \ NH N / LN””3 WO 05860

Claims (3)

1. A compound of Formula: R’HNQN/ 62:”\lély; or a pharmaceutically acceptable salt, e, isotopic derivative, prodrug, and/or a pharmaceutically acceptable composition thereof; wherein: X is NH, NR9, S, or O; yis 0,1,2, 3 or4, Z is CH, CR9, or N, Q is CH2 or CO; R is hydrogen, C1-C6alkyl, -(Co-C2alkyl)(C3-Cscarbocyclyl), -(Co-C2alkyl)(C3- Csheterocyclyl),-(Co-C2alkyl)(aryl), -(C0-C2alkyl)(heteroaryl), -COOalky1, -COOarylalkyl, or —COOH; each R1 is independently alkyl, aryl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups ally includes heteroatoms O, N, or S in place of a carbon in the chain and two Rl’s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3membered cycle or two Rl’s on adjacent ring atoms together with the ring ) to which they are attached optionally form a 6-membered aryl ring; R2 is —(alkylene)m—heterocyclo, —(alkylene)m—heteroaryl, —(alkylene)m—NR3R4, —(alkylene)m—C(O)—NR3R4; —(alkylene)m—C(O)—O-alkyl, —(alkylene)m—O—R5, —(alkylene)m—S(O)n—R5, or —(alkylene)m—S(O)n—NR3R4 any of which may be optionally independently tuted with one or more Rx groups as d by valance, and wherein two RX groups bound to the same or adjacent atom may optionally combine to form a ring; m is 0, 1, or 2, n is 0, l, or 2, R3 and R4 at each occurrence are independently selected from: (i) hydrogen or (ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl; or R3 and R4 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring, R5 is selected from: (i) hydrogen or (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl; Rx at each occurrence is independently selected from halo, cyano, nitro, oxo, alkyl, haloalkyl, l, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene)m-OR5, -(alkylene)m-O-alkylene-OR5, -(alkylene)m-S(O)n—R5, -(alkylene)m-NR3R4, -(alkylene)m-CN, -(alkylene)m-C(O)—R5, —(alkylene)m-C(S)—R5, -(alkylene)m-C(O)—OR5, -(alkylene)m-O—C(O)—R5, -(alkylene)m-C(S)—OR5, -(alkylene)m-C(O)-(alkylene)m-NR3R4, -(alkylene)m-C(S)—NR3R4, -(alkylene)m-N(R3)—C(O)—NR3R4, -(alkylene)m-N(R3)—C(S)—NR3R4, -(alkylene)m-N(R3)— C(O)—R5> lene)m-N(R3)—C(S)—R5, lene)m-O—C(O)—NR3R4, —(alkylene)m—O—C(S)— NR3R4, -(alkylene)m—SOz—NR3R4, -(alkylene)m—N(R3)—SOz—RS, lene)m-N(R3)—SOz— NR3R4, -(a1kylene)m-N(R3)—C(O)—OR5) -(alky1ene)m-N(R3)—C(S)—OR5, or -(alky1ene)m- SOz—R5; R6 is selected independently at each instance from: hydrogen, halogen, alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, kyl, or heteroarylalkyl; R8 :28 R8 R8 R8 R8 N V Y R8 / l R3 / \ R8 / I / R7 is selected from: Y R8 R8 Ra , , , , X: X2 YR 7 X2 X2 / N» X- N \ 4/ 1/ 47 Y 4/ N x 1 Y X l X‘ X1 I Y x1 v x? Y\ x X2 X" / / [X 4’ Y 2:2 W3 :3” WO 05860 or R7 is selected from cycloalkyl, heterocycle, and alkyl, each of which cycloalkyl, cycle, and alkyl groups is optionally substituted with one or more substituents selected from amino, -NHR14, 15, hydroxyl, OR”, R6, and R2, R14 and R15 are independently selected from: hydrogen, alkyl, alkenyl, alkynyl, —C(O)H, -C(O)alkyl, -C(S)alkyl, aryl, —SOzalkyl, heteroaryl, arylalkyl, and heteroarylalkyl. Y is NH, O, S, or NR9, X1, X2, X3 and X4 are independently N or CR8, wherein at least one of X1, X2, X3, X4, and X5 are CR8; R8 is selected independently at each instance from: R6 and R2, n one R8 is R2; R9 is selected from: , -C(O)alkyl, -C(S)alkyl, alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; and 10 is selected from: hydrogen, —COOalkyl, -COOarylalkyl, —COOH, -OH, —C(O)H, C(O)alkyl, -C(S)alkyl, alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl.

2. The compound of claim 1 of Formula grin:”R\ or a pharmaceutically acceptable salt, e, isotopic derivative, prodrug, and/or a pharmaceutically acceptable composition thereof.

3. The compound of claim 1 of Formula WN’N“”I N m N”R HN ( R1) 7 y