NZ718614B2 - Conformationally restricted pi3k and mtor inhibitors - Google Patents

Abstract

The invention relates to novel phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor compounds of formula (I), which are conformationally restricted, and for which the meaning of the substituents are listed in the description. Preferred compounds are those wherein X is oxygen, R1 is morpholino and R2 is substituted heteroaryl. These compounds are useful, either alone or in combination with further therapeutic agents, for treating disorders mediated by lipid kinases. oxygen, R1 is morpholino and R2 is substituted heteroaryl. These compounds are useful, either alone or in combination with further therapeutic agents, for treating disorders mediated by lipid kinases.

Description

Conformationally restricted PI3K and mTOR inhibitors Field of the Invention The ion relates to new morpholino-dihydropyrrolo-pyrimidines and related compounds as eutic agents and diagnostic probes useful for ting cellular activities such as signal transduction, eration, differentiation, programmed cell death, migration and cytokine secretion. The compounds of the invention modulate kinase activity, in particular phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), DNA-PK and ATM kinase activity.

Background of the Invention Protein kinases participate in the signaling events which control the activation, growth, differentiation, survival and migration of cells in response to extracellular mediators or stimuli including growth factors, cytokines or chemokines. In general, these kinases are classified in two groups, those that preferentially phosphorylate tyrosine residues and those that preferentially phosphorylate serine and/or threonine residues. The tyrosine kinases include membrane-spanning growth factor receptors, for example the epidermal growth factor receptor (EGFR) and lic non-receptor kinases including Src family kinases, the Syk family kinases and the Tec family kinases.

Inappropriately high protein kinase activity is involved in many diseases including cancer, metabolic diseases, logical diseases and inflammatory disorders. This can be caused either directly or ctly by the failure of control mechanisms due to mutation, overexpression or inappropriate activation of the enzyme.

Protein tyrosine kinases - both receptor tyrosine kinases and non-receptor kinases - are essential for the activation and proliferation of cells of the immune system. Among the st able events upon immunoreceptor activation in mast cells, T cells and B cells, is the ation of non-receptor tyrosine kinases.

Phosphoinositide 3-kinases (PI3Ks) were early on identified as lipid kinases associated with viral oncogens [Whitman et al., Nature 315:239-242 (1985)], and for the last 20 years, the connection between cancer and PI3K has been r substantiated [Wymann et al., Curr. Opin. Cell Biol. 17:141-149 (2005)]. PI3Ks have since been 33_1 (GHMatters) P41635NZ00 recognized to te a wide range of cellular activities, and to be central to the growth and metabolic control. Genetically modified mice ing the P|3K pathway, and the elucidation of human hereditary disease like Cowden's syndrome, us sclerosis, ataxia telangiectasia, X-linked myotubular myopathy and Charcot-Marie-Tooth neuropathy, have provided further insight in the cellular and systemic role of phosphoinositide signaling. Deregulation of phosphoinositide levels, and in particular the product of class I Pl3Ks, Ptdlns (3,4,5)P3, is involved in the pathogenesis of , chronic inflammation, allergy, metabolic disease, diabetes and cardiovascular problems.

P|3Ks are a family of enzymes, which phosphorylate the 3'-OH position of the inositol ring of phosphoinositides. They have been divided into three classes on the basis of structural features and in vitro lipid substrate specificity [Marone et al., Biochimica et sica Acta 1784:159—185 (2008)]. Class | P|3Ks form heterodimers, which consist of one of the four closely d approx. 110 kDa catalytic subunits, and an associated regulatory subunit belonging to two distinct families. In vitro they are capable to convert Ptdlns to PtdlnsP, PtdlnsP to Ptdlns(3,4)P2, and {4,5)P2 to Ptdlns(3,4,5)P3, but the in vivo substrate is Ptdlns(4,5)P2 [Cantley et at., Science 296:1655-1657 (2002)].

Class | P|3Ks are ted by a large variety of cell-surface ors, comprising growth factor receptors as well as G protein-coupled receptors.

Class II P|3Ks are capable to phosphorylate Ptdlns and P in vitro, but their nt in vivo substrates are still under investigation. This class of large (170- 200 kDa) enzymes has three s, all characterized by a C-terminal C2 homology domain.

No adaptor molecules for class II P|3Ks have been identified so far. Class III P|3Ks are solely able to phosphorylate Ptdlns, and thus generate only PtdlnsP. The single member of this class is Vps34, of which the S. cerevisiae Vps34p (vacuolar protein g mutant 34 protein) is the prototype, and has been shown to play an essential role in trafficking of newly synthesized proteins from the Golgi to the yeast vacuole, an organelle equivalent to lysosomes in mammals [Schu et al., Science 260:88—91 (1993)].

Phosphoinositide 4-kinases (Pl4Ks) phosphorylate the 4'-OH position of the inositol ring of Ptdlns, and thereby generate PtdlnsP. This lipid can then be further phosphorylated by PtdlnsP 5-kinases to generate Ptdlns (4,5)P2, which is the main source for phospholipase C and PI3K ing at the plasma membrane. Four P|4Ks isoforms are known: P|4Kllcx and B and P|4Klllcx and B. The P|4Kllls are most closely related to PI3Ks.

The class of PI3K-related proteins, referred to as class IV PI3Ks, consists of high molecular weight enzymes with a catalytic core similar to Pl3Ks and P|4Ks and include the target of rapamycin (mTOR, also known as FRAP), DNA-dependent protein kinase (DNA-PKcs), the ataxia telangiectasia mutated gene product (ATM), ataxia telangiectasia related (ATR), SMG-1 and transformation/transcription domain- associated protein (TRRAP). The first five members are active protein serine- threonine s that are ed in cell growth control and genome/transcriptome surveillance [Marone et al., Biochimica et Biophysica Acta 1784:159—185 ]. DNA-PKcs, ATM, ATR and SMG-1 are involved in DNA-damage responses. The only active kinase not involved in DNA-damage is mTOR, which is regulated by growth factors and nutrient availability, and coordinates protein sis, cell growth and proliferation. Target of rapamycin (mTOR) complexes 1 and integrate growth factor signaling (via KB and the Ras/MAPK cascade), energy status (LKB1 and AMPK) and nt detection.

TOR is positively regulated by PKB/Akt, which phosphorylates the negative regulator TSC2 in the tuberous sclerosis complex (TSC), resulting in activation of the GTPase Rheb and mTOR. In parallel, mTOR stimulates translation of ribosomal proteins and therefore ribosome biogenesis via the activation [Wullschleger et al., Cell 124:471 (2006)]. Rapamycin, and its derivatives RAD001 and CCI-779, bind to FKBP12, and the complex blocks mTOR x 1 (mTORC1) activity very selectively. Various clinical trials were initiated using rapamycin and derivatives, mostly in ts with tumors displaying elevated P|3K signaling and hyperactive mTOR.

The P|3K pathway is a key signaling transduction cascade controlling the regulation of cell growth, proliferation, al as well as cell migration. Pl3Ks are activated by a wide variety of different stimuli including growth factors, inflammatory mediators, hormones, neurotransmitters, and immunoglobulins and antigens [Wymann et al., Trends Pharmacol. Sci. 24:366-376 (2003)]. The class IA P|3K isoforms Pl3Ko, B and 6, are all bound to one of the p85/p55/p50 regulatory subunits, which all harbor two 8H2 s that bind with high ty to orylated Tyr- X-X-Met motifs. These motifs are present in activated growth factor receptors, their substrates and numerous adaptor ns. As described above, activation of the PI3K/PKB signaling cascade has a positive effect on cell , survival and eration. Constitutive up-regulation of PI3K ing can have a deleterious effect on cells leading to uncontrolled proliferation, enhanced migration and adhesion-independent growth. These events favor not only the ion of malignant tumors, but also the development of matory and autoimmune disease.

It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in New Zealand or any other country.

Summary of the Invention The invention relates to mationally restricted compounds of a (I) or (II) R3p R1 R3p R3x N R3x N X N N R2 X N N R1 R3y R3z R3y R3z (I) (II) pharmaceutical compositions comprising these, and their use as therapeutic agents and diagnostic probes.

The invention further relates to the use of these compounds as kinase inhibitors and kinase diagnostic probes, in particular as phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor compounds with anti-cancer activity.

The compounds of the invention are potentially useful in the treatment of diseases, conditions and/or disorders modulated by PI3K and mTOR kinases. The nds inhibit tumor growth in mammals, show anti-cancer activity, anti-inflammatory activity, immunoregulatory ties, and beneficial properties in associated pathological conditions. 17770837_1 (GHMatters) P41635NZ00 The invention also relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells and organisms, in particular human cancer ts.

In accordance with one aspect, provided are compounds of formula (I), and stereoisomers, ric isomers, tautomers and pharmaceutically acceptable salts thereof, wherein R1 is O O O O O O O N N N N N N N O O O O O O O N N N N N N N and the the wavy line indicates the point of attachment of R1; X is selected from the group consisting of O and NR7; R3x, R3y, R3z and R3p are independently selected from the group consisting of hydrogen, D, and C1-C12 alkyl; R5, R6 and R7 are independently selected from H, D, and C1-C12 alkyl; 18171233_1 ters) P41635NZ00 R2 is independently selected from the groups consisting of a monocyclic 5- or 6- membered heteroaryl with 1-3 heteroatoms selected from O, N, S, with 1-4 substituents ed from C1-C4 alkyl, CF3, CHF2, CFH2 and NR5R6. 17770837_1 (GHMatters) P41635NZ00 More specifically, the invention provides enantio-enriched pyrimidine compounds of formula (la), (lb), (Ila) and (Ilb) R R 2 2 R3p R3p R3x |\N R3X ’ |\J\l\/ XHN NAN?1 XHN N R1 R3y R32 R3y R32 (la) (lb) R3p R1 R3p R1 / 3 N)\R2/ XHN N R2 R32 XHN R3y R3y R32 (Ila) (Ilb) and stereoisomers, ric isomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

The substituents R1, R2 and R3 are described hereinbelow.

In another aspect, the invention provides a pharmaceutical composition comprising compounds of formula (I) or (II), in particular of formula (la), (lb), (Ila) or (Ilb), and a pharmaceutically able carrier. The pharmaceutical ition may further comprise one or more additional therapeutic agents selected from anti-proliferative agents, anti-inflammatory agents, immunomodulatory agents, neurotropic factors, agents for treating blood disorders, agents for treating diabetes, and agents for ng immunodeficiency disorders.

In another , the invention provides a method of inhibiting PI3 kinase activity, comprising contacting a PI3 kinase with an effective tory amount of a compound of formula (I) or (II), in particular of a (Ia), (lb), (Ila) or (Ilb), or a stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a method of preventing or treating a disease or disorder modulated by PI3 , comprising administering to a mammal in need of such ent an effective amount of a compound of formula (I) or (II), in particular of a (la), (lb), (lla) and (llb), or a stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof. es of such es, conditions and disorders include, but are not limited to, hyperproliferative disorders (e.g., cancer, including melanoma and other cancers of the skin), neurodegeneration, c rophy, pain, migraine, neurotraumatic diseases, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, neurological disorders, hormone-related diseases, conditions ated with organ transplantation, immunodeficiency disorders, destructive bone disorders, hyperproliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukaemia (CML), liver disease, pathologic immune conditions involving T cell activation, and CNS disorders.

In another aspect, the invention provides a method of preventing or treating a hyperproliferative disorder, comprising administering to a mammal in need of such treatment an effective amount of a compound of formula (I) or (II), in ular of formula (la), (lb), (lla) or (llb), or a isomer, ric isomer, tautomer, solvate, or pharmaceutically acceptable salt or thereof, alone or in combination with one or more additional compounds having yperproliferative properties. In a further aspect the present invention provides a method of using a compound of this invention to treat a disease or condition modulated by Pl3 kinase and/or mTOR in a mammal.

An additional aspect of the invention is the use of a compound of this invention in the ation of a medicament for the treatment or prevention of a disease or condition modulated by Pl3 kinase in a mammal.

Another aspect of the invention includes kits comprising a compound of formula (I) or (II), in particular of formula (la), (lb), (lla) or (llb), or a stereoisomer, geometric isomer, er, solvate, or pharmaceutically able salt thereof, a container, and optionally a package insert or label indicating a treatment.

Another aspect of the invention includes s of preparing, methods of separating, and methods of purifying compounds of formula (I) or (II), in ular of formula (la), (Ib), (IIa) or (IIb), and novel ediates useful for preparing compounds formula (I) or (II), in particular of formula (Ia), (Ib), (IIa) or (IIb).

Yet another aspect provides a compound selected from the group consisting of - (R)cyclopropyl(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo [2,1-c][1,4]oxazinyl)pyridinamine, - (R)cyclopropyl(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo [2,1-c][1,4]oxazinyl)pyrimidinamine, - (S)cyclopropyl(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo [2,1-c][1,4]oxazinyl)pyridinamine, and - cyclopropyl(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo [2,1-c][1,4]oxazinyl)pyrimidinamine.

Detailed Description of the Invention Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present invention as d by the claims. One d in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the ce of the present ion. The present invention is in no way limited to the methods and als herein described.

Definitions The term "alkyl" as used herein refers to a saturated linear or branched-chain monovalent hydrocarbon group of one to twelve carbon atoms (C1-C12), wherein the alkyl group may be optionally substituted independently with one or more substituents described below. In another embodiment, an alkyl group is one to eight carbon atoms (C1-C8), or one to six carbon atoms (C1-C6). Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2-propyl (i-propyl), 1- butyl (n-butyl), 2- methylpropyl (i-butyl), 2-butyl ( s-butyl), 2-methylpropyl (t-butyl), 1-pentyl tyl), 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 3-methylbutyl, 2-methylbutyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 3-methylpentyl, ylpentyl, 3- 33_1 (GHMatters) P41635NZ00 methylpentyl, 2-methylpentyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-heptyl, 1-octyl, and the like.

The term "alkenyl" refers to linear or branched-chain monovalent hydrocarbon radical of two to eight carbon atoms (C2-C8) with at least one site of unsaturation, i.e., a carboncarbon , sp2 double bond, wherein the alkenyl radical may be ally substituted independently with one or more substituents described herein, and includes radicals having "cis" and " orientations, or alternatively, "E" and "Z" ations. Examples 18171233_1 (GHMatters) P41635NZ00 1111 include, but are not limited to, ethylenyl or vinyl (-CH=CH2), allyl H=CH2), and the like.

The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical of two to eight carbon atoms (Oz-Cg) with at least one site of unsaturation, Le, a carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein. Examples include, but are not d to, ethynyl (-CECH), propynyl rgyl, -CHZCECH), and the like.

The term "halogen" (or halo) preferably represents chloro or fluoro, but may also be bromo or iodo.

The terms "carbocycle", "carbocyclyl", "carbocyclic ring" and alkyl" refer to a monovalent non-aromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms (Cs-C12) as a monocyclic ring or 7 to 12 carbon atoms as a ic ring. Bicyclic carbocycles having 7 to 12 atoms can be arranged, for example, as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, and bicyclic carbocycles having 9 or 10 ring atoms can be arranged as a bicyclo [5,6] or [6,6] system, or as bridged systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Examples of clic carbocycles e, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentenyl, 1-cyclopentenyl, 1-cyclopentenyl, cyclohexyl, 1-cyclohexenyl, 1-cyclohexenyl, ohexenyl, cyclohexadienyl, cycloheptyl, ctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

"Aryl" means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms (Cs-020) derived by the removal of one en atom from a single carbon atom of a parent ic ring system. Some aryl groups are represented in the exemplary structures as "Ar". Aryl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring. Typical aryl groups include, but are not limited to, radicals derived from benzene(phenyl), substituted benzenes, naphthalene, anthracene, biphenyl, indenyl, indanyl, 1,2-dihydronapthalene, 1,2,3,4- tetrahydronaphthyl, and the like. Aryl groups are optionally substituted independently with one or more substituents bed herein. 1212 The terms "heterocycle", "heterocyclyl" and "heterocyclic ring" are used interchangeably herein and refer to a saturated or a partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) carbocyclic radical of 3 to 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, , phosphorus and sulphur, the remaining ring atoms being carbon atoms, wherein one or more ring atoms are optionally substituted independently with one or more substituents described below.

A heterocycle may be a cle having 3 to 7 ring members (1 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S) or a e having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), for example a o [4,5], [5,5], [5,6], or [6,6] system. Heterocycles are described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968), ularly chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566.

"Heterocyclyl" also includes radicals where heterocycle radicals are fused with a saturated, partially unsaturated ring, or aromatic yclic or heterocyclic ring.

Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydro- furanyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydro- thiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homo- piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, nyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, oxolanyl, pyrazolinyl, nyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]octanyl, 3H-indolyl, and quinolizinyl. Spiro moieties are also included within the scope of this definition. Examples of a heterocyclic group wherein ring carbon atoms are substituted with oxo (=O) es are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The cyclic groups herein are optionally substituted independently with one or more tuents described herein.

The term "heteroaryl" refers to a monovalent aromatic radical of 5-, 6-, or 7-membered rings, and includes fused ring systems (at least one of which is aromatic) of 5-20 atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulphur. Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxy- pyridinyl), imidazolyl, imidazopyridinyl, dinyl (including, for example, 4-hydroxy- pyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, l, olyl, thiazolyl, 1313 oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl , indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, olyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, urazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups are ally substituted independently with one or more substituents described herein.

The heterocyclic or heteroaryl groups may be bound through carbon n-linked), or nitrogen (nitrogen-linked) where such is le. By way of example and not limitation, carbon-linked heterocycles or heteroaryls are bound at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, on 2, 4, 5, or 6 of a pyrimidine, on 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, ene, e or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.

By way of example and not limitation, nitrogen-linked heterocycles or heteroaryls are bound at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a ole or 13- carboline.

The term "monocyclic heteroaryl" refers to a five- or six-membered, unsubstituted or substituted, monocyclic heteroaryl radical which contains 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. Monocyclic heteroaryl radicals include, but are not limited to: 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-isoxazolyl, 4-isoxazolyl, azolyl, 2-midazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyrrolyl, 3-pyrrolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyridazinyl, dazinyl, 5-pyridazinyl, 2-pyrimidinyl, -pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 3-triazolyl, 1-triazolyl, 5-tetrazolyl, 1-tetrazolyl, and azolyl. Monocyclic heteroaryl are optionally substituted independently with one or more substituents described herein. 1414 The terms "treat" and "treatment" refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired pathological change or disorder, such as the development or spread of cancer. For purpose of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of ms, shment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether able or undetectable. "Treatment" can also mean prolonging al as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

The phrase "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or ts the particular disease, condition, or disorder, (ii) ates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) ts or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. In the case of cancer, the therapeutically effective amount of the drug may be reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and ably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the . To the extent the drug may prevent growth and/or kill existing cancer cells, it may be atic and/or cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TIP) and/or determining the response rate (RR).

The terms "cancer" and "cancerous" refer to or be the logical condition in mammals that is typically characterized by lated cell growth. A "tumor" comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukaemia or lymphoid malignancies.

More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, al cancer, ovarian 1515 cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon , rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, c carcinoma, anal carcinoma, penile carcinoma, bile duct cancer, mantle cell lymphoma, CNS lymphoma, chronic lymphocytic leukemia, non-Hodkin’s lymphoma, as well as head and neck cancer.

A therapeutic agent" is a chemical compound useful in the treatment of cancer. es of known chemotherapeutic agents include trastuzumab, umab, erlotinib (TARCEVA®, Genentech/Roche/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, is), imatinib mesylate (GLEEVEC®, Novartis), nate (VATALAN|B®, Novartis), latin (ELOXAT|N®, Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirolimus, NE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), rnib (SCH 66336), sorafenib (NEXAVAR, Bayer Labs), and gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, ulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins; a thecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins; dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); erobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chloro- phosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, lan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammal 1 and calicheamicin omegal 1; dynemicin, including dynemicin A; phonates, such as clodronate; an esperamicin; as well as zinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomysins, actinomycin, authramycin, ine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophillin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazoloxo-L-norleucine, ADRIAMYC|N® (doxorubicin), 1616 morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, enolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil ; folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, ur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as erone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, tane; folic acid isher such as ic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid; gallium e; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex; razoxane; rhizoxin; ran; ermanium; tenuazonic acid; triaziquone; trichothecenes; urethane; indesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb), ABRAXANET'V' (Cremophor—free), albumin-engineered rticle formulations of paclitaxel, and TAXOTERE® (docetaxel, doxetaxel; Sanofi- Aventis); nmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and latin; vinblastine; ide; ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; terin; capecitabine (XELODA®); ibandronate; CP-11; topoisomerase inhibitor RFS 2000; difluoromethyl- ornithine ; retinoids such as retinoic acid; and pharmaceutically acceptable salts; acids and tives of any of the above.

Also included in the definition of "chemotherapeutic agent" are: (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective receptor modulators (SERMs), including, for example, fen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, and ON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates 1717 estrogen production in the adrenal glands, such as, for example, 4(5)—imidazoles, MEGASE® (megestrol acetate); AROMAS|N® (exemestane; Pfizer), formestanie, fadrazole, RIVISOR® ole), FEMARA® zole; Novartis), and ARIMIDEX® (anastrozole; eneca); (iii) anti-androgens such as flutamide, nilutamide; (iv) protein kinase inhibitors; (v) lipid kinase tors; (vi) antisense oligonucleotides, ularly those which t expression of genes in signaling ys implicated in aberrant cell eration, such as, for example, PKC-alpha, Rafl and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECT|N®, LEUVECT|N®, and VAX|D®; PROLEUK|N® rll-2; a topoisomerase 1 tor such as LURTOTECANE®; ABAREL|X® rmRH; (ix) anti-angiogenic agents such as bevacizumab (AVAST|N®, Genentech/Roche); and (x) pharmaceutically acceptable salts, acids and derivatives of any of the above.

The term "prodrug" as used in this application refers to a precursor or derivative form of a compound of the invention that may be less cytotoxic to cells compared to the parent nd or drug and is capable of being enzymatically or hydrolytically activated or ted into the more active parent form. The prodrugs of this invention include, but are not limited to, ate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, O-amino acid-modified prodrugs, glycosylated prodrugs, B-lactam- containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs, optionally substituted phenylacetamide- containing prodrugs, 5-fluorocytosine and other 5-fluorouridine prodrugs which can be ted into the more active xic free drug. Examples of cytotoxic drugs that can be derivatized into a prodrug form for use in this invention include, but are not limited to, compounds of the invention and chemotherapeutic agents such as bed above.

A "metabolite" is a product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds of the invention, including nds produced by a 1818 process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.

A "liposome" is a small vesicle composed of various types of lipids, phospholipids and/or surfactant, which is useful for delivery of a drug (such as the P|3K and mTOR kinase inhibitors disclosed herein and, optionally, a chemotherapeutic agent) to a mammal. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.

The term "package insert" is used to refer to instructions arily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.

The term l" refers to molecules, which have the property of non-superimposability of the mirror image partner, while the term "achiral" refers to les, which are superimposable on their mirror image partner.

The term oisomers" refers to compounds, which have identical chemical constitution, but differ with regard to the ement of the atoms or groups in space. ereomer" refers to a stereoisomer with two or more centers of ity in which the compounds are not mirror images of one another. Diastereomers have ent physical properties, e.g. melting points, boiling points, spectral properties, and chemical and biological reactivities. Mixtures of diastereomers may be separated under high resolution analytical procedures such as electrophoresis and chromatography.

"Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

Stereochemical tions and conventions used herein generally follow S.P. Parker, Ed., McRaw—Hiff Dictionary of Chemical Terms (1984), McGraw—Hill Book Company, New York; and Eliel, E. and Wilen, 8., ochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in ent stereoisomeric forms. It is 1919 intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and somers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in lly active forms, i.e., they have the ability to rotate the plane of plane- polarized light. In describing an optically active nd, the prefixes D and L, or R and S, are used to denote the absolute uration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of on of plane-polarized light by the compound, with (-) orl meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one r. A specific stereoisomer may also be referred to as an enantiomer, and a e of such isomers is often called an enantiomeric mixture. A 50:50 e of enantiomers is referred to as a racemic mixture or a racemate. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies, which are interconvertible via a low energy barrier. For example, proton tautomers include interconversions via migration of a proton, such as nol and imine-enamine isomerizations.

The phrase "pharmaceutically acceptable salt" as used , refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention.

Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, de, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, te, glutamate, methanesulfonate (mesylate), ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The r ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. rmore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. lnstances where multiple charged atoms are part of the ceutically acceptable salt can have multiple counter ions.

Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion. 2020 If the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, ic acid, nitric acid, esulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the compound of the invention is an acid, the desired pharmaceutically able salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine, an alkali metal hydroxide or ne earth metal hydroxide, or the like. Illustrative examples of suitable salts e, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, ium and lithium.

The phrase aceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.

A "solvate" refers to an ation or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl ide (DMSO), ethyl acetate, acetic acid, and ethanolamine. The term te" refers to the complex where the solvent molecule is water.

The term "protecting group" refers to a substituent that is commonly employed to block or protect a ular functionality during the reaction of other onal groups on the compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or ts the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), 2121 benzyloxycarbonyl and 9-fluorenylmethylenoxycarbonyl (Fmoc). For a general description of protecting groups and their use, see T. W. Greene, tive Groups | Organic Synthesis, John Wiley & Sons, New York, 1991.

The terms "compound of this invention" and "compounds of the present invention" and "compounds of formula (I) or (ll)" or "compounds of formula (la), (lb), (Ila) and (llb)" include stereoisomers, geometric isomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.

The term "mammal" includes, but is not limited to, humans, mice, rats, guinea, pigs, monkeys, dogs, cats, , cows, pigs, and sheep.

The present invention provides new morpholino-dihydropyrrolo-pyrimidines and related compounds, and pharmaceutical formulations thereof, which are useful as therapeutic agents and novel stic probes. Moreover, these compounds are potentially useful in the treatment of diseases, conditions and/or disorders ted by protein kinases and lipid s.

More specifically, the present invention provides compounds of formula (I) and (II), Rsp R1 R2 \ N R3p R3X \ N | A | A X N N R2 X N N R1 HR H R3y 32 R3y R32 (I) (II) and isomers, geometric isomers, tautomers, solvates, and pharmaceutically acceptable salts thereof, wherein R1 iS R4XIYIR4y R4 N\ NH2 R4 N NH2 | \ R4P / N R4z LN "1"" or Wlw Or I 2222 X and Y are ndently selected from the group consisting of C(Rg)2, O, 8, 80, 802, and NR7; Rsx, Rsy, R32, Rsp and R4 are independently selected from the group consisting of hydrogen, D (i.e. deuterium), F, Cl, Br, |, 01-012 alkyl, Cz-Cg alkenyl, Cz-Cg alkynyl, -(C1-C12 alkylene)—(Cg-C12 carbocyclyl), -(C1-C12 ne)—(heterocyclyl having 3-20 ring atoms), -(C1-C12 alkylene)—C(=O)-(heterocyclyl having 3-20 ring atoms), -(C1-C12 ne)—(Cs-Czo aryl) and —(C1-C12 alkylene)—(heteroaryl having 5-20 ring atoms), -C(C1-Cs alkyl)2NR5R5, -(CR8R9)tNR5R6, —(CR8R9)nNR7C(=Z)Rg, (CR8R9)nNR7S(O)2R5, -CH(OR5)R5, -(CR8R9),,OR5, -(CR8R9),,S(O)2R5, -(CR8R9),,S(O)2NR5R5, -C(=Z)R5, -C(=Z)OR5, R5R5, NR7OR5, -C(=O)NR7S(O)2R5, -C(=O)NR7(CR8R9)m- NR5R6, -N02, -NHR7, -NR7C(=Z)R5, =Z)OR5, -NR7C(=Z)NR5R6, -NR7S(O)2R5, -NR7802NR5R5, -S(O)2R5, -S(O)2NR5R5, -SC(=Z)R5, -SC(=Z)OR5, 03-012 carbocyclyl, 02-020 heterocyclyl, Cs—Czo aryl, and C1-C=NR7, 0R5, -OC(=Z)R5, -OC(=Z)OR5, -OC(=Z)NR5R5, and -OS(O)2(OR5); R4X, R4y, R42 and R4pare independently selected from the group consisting of hydrogen, D, F, Cl, Br, |, 01-012 alkyl, Cz-Cg alkenyl, Cz-Cg alkynyl, or one or two of R4X, R4y, R42 and R4p are two geminal substituents methyl and the other ones are hydrogen, or R4X and R4p, or R4y and R42 form together an annullated five- or six-membered carbocyclyl, heterocyclyl, aryl or heteroaryl ring, or R4X and R4yform together bridging ethylene or ene, R4p and R4zform together bridging ethylene or methylene, or R4y and R4p form together bridging ethylene or ene; wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally tuted with one or more groups independently ed from F, Cl, Br, |, CN, CF3, N02, oxo, R5, -C(=Z)OR5, -C(=Z)NR5R6, -(CR8R9),,NR5R6, -(CR8R9),,C(=Z)NR5R5, -(CR8R9),,C(=Z)OR5, -(CR8R9),,NR7SOZR5, -(CR8R9),,OR5, -(CR8R9),,R5, -(CR8R9),,SOZR5, -NR5R6, -NR7C(=Z)R5, -NR7C(=Z)OR5, -NR7C(=Z)NR5R6, zR5,), -OP(OR5)(OR6), SR5, -S(O)Rs, -S(O)2R5. -S(O)2NR5R6, -S(O)(OR5), -S(O)2(OR5), -SC(=Z)R5, -SC(=Z)OR5, -SC(=Z)NR5R5, optionally substituted C1-C12 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted Cz-Cg alkynyl, optionally substituted 03-012 carbocyclyl, optionally substituted 02-020 heterocyclyl, optionally substituted Cs—Czo aryl, and optionally substituted 01-020 heteroaryl; 2323 R5, R5 and R7 are independently selected from H, D, C1-C12 alkyl, C2-C8 alkenyl, Cs-Cg alkynyl, 03-012 carbocyclyl, 02-020 heterocyclyl, Cs—Czo aryl, and 01-020 heteroaryl, or R5 and R6 together with the nitrogen to which they are attached form a 03-020 heterocyclic ring optionally containing one or more additional ring atoms selected from N, O or 8, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from oxo, CF3, F, Cl, Br, |, 01-012 alkyl, Cz-Cg alkenyl, Cz-Cg alkynyl, 03-012 carbocyclyl, 02-020 heterocyclyl, Cs—Czo aryl and 01-020 heteroaryl; R8 and R9 are independently selected from H, D, C1-C12 alkyl, and -(CH2),,-aryl, or R8 and R9 together with the atoms to which they are ed form a saturated or partially unsaturated 03-012 carbocyclic ring; misO, 1,2, 3,4,50r6; n is 1,2, 3, 4, 5,or 6; tis 2, 3,4,50r6; and R2 is independently selected from the groups ting of a monocyclic or bicyclic aryl or heteroaryl with 1-6 heteroatoms selected from O, N, S, with 1-4 substituents selected from C1-C4 alkyl, D, F, Cl, Br, I, -OR5, -COOH, COOR5, -CONR5R6, -SOZNR5R6, CN, CF3, CHF2, CFH2, OCF3, OCOR5, NR7COR5, R5, NR5R6, SOZR5, SOR5, and SR5.

R2 with the meaning monocyclic aryl is ably phenyl, meta- or para-substituted phenyl or 2,4-, 3,4- or 3,5-disubstituted phenyl, wherein the substituents are selected from halogen, C1-Cs-alkyl, halo-C1-Cs-alkyl, y, C1-Ce-alkoxy, or ally C1-Cs- alkylated or -acylated amino.

R2 with the meaning heteroaryl is preferably selected from optionally substituted pyridinyl, imidazolyl, pyrimidinyl, furyl, indolyl, benzimidazolyl, indazolyl, oxadiazolyl, and thiadiazolyl, n the substituents are ed from C1-Cs-alkyl, halo-C1-Cs-alkyl, pyridyl, aminopyridyl, amino or C1-Cg-acylamino, wherein C1-Cg-acyl is a C1-C7-alkyl, halo-C1-C7-alkyl, Cz-Cy-alkenyl, pyridyl or aminopyridyl group connected to yl, oxycarbonyl such as methoxycarbonyl, or aminocarbonyl such as aminocarbonyl or optionally substituted arylaminocarbonyl, for example [4-(4-dimethylaminopiperidino)— carbonylphenyl]aminocarbonyl; and combinations thereof. 2424 More preferably, R2 with the meaning heteroaryl is pyridinyl or pyrimidinyl, n the substituents are selected from C1-Cs-alkyl, halo-C1-Cs-alkyl, l, aminopyridyl, amino or C1-Cg-acylamino, wherein C1-Cg-acyl is a C1-C7-alkyl, halo-C1-C7-alkyl, Cz-Cy-alkenyl, pyridyl or aminopyridyl group connected to carbonyl, oxycarbonyl such as methoxy- yl, or aminocarbonyl such as methylaminocarbonyl or optionally substituted arylaminocarbonyl; and combinations thereof.

Preferred examples of R2 are selected from the group consisting of CI CN CF3 ONHZ QNHZ PEP 3 NH2 QNHZ NH2 QNHZ i NH2 NH "0H "E1HH E1H E1 E1 E1 Eu "E1HH E1" E122: or 11"" £161} E1? 2525 wherein the dotted line indicates the point of attachment of R2. In such preferred groups R2, the amino function may be further substituted with C1-Cg-acyl, oxycarbonyl or aminocarbonyl as defined above.

Most preferred examples of R2 are listed below: " " \ \ ‘~ | | | / / / CFs N NH2 N NH2 N NH2 \f ‘~ \N \N \N \N NAM I f"xNH (A Preferably Y is O (the ring containing Y being morpholine). In such red morpholines, the substituents R4X, R4y, R42 and R4pare preferably chosen such that morpholines correspond to substituents R1 of the following structures: 2626 @’§j;gvt§rfi©‘§rry tgy,§tgg,§o $0 @3gfiktgf\@J,§n gm" (ELM, [Em [if 13%" [Era §Lw§fvtfiwi flfflD fiflw Eflwfik, E Tfi-fi $ Q $ $ fijqfi @, optionally r substituted with one or more groups independently selected from D, F, Cl, Br, I, -CH3, -CHZCH3, -CHZCHZCH3, -CH(CH3)2, -C(CH3)3, -CHZOCH3, -CHF2, -CN, -CF3,-CH20H, -CHZOCH3, -CHZCH20H, -CHZC(CH3)20H, -CH(CH3)OH, -CH(CHZCH3)OH -CHZCH(OH)CH3, -C(CH3)ZOH, -C(CH3)ZOCH3, -CH(CH3)F, -C(CH3)F2, -CH(CH20H3)F, -C(CHZCH3)2F, -COZH, -CONH2, -CON(CHZCH3)2, -COCH3, -CON(CH3)2, -N02, -NH2, -NHCH3, -N(CH3)2, -NHCHZCH3, -NHCH(CH3)2, -NHCHZCH20H, -NHCHZCHZOCH3, H3, -NHCOCHZCH3, -NHCOCHZOH, )ZCH3, -N(CH3)S(O)ZCH3, :0, -OH, -OCH3, -OCHZCH3, -OCH(CH3)2, -SH, -NHC(=O)NHCH3, -NHC(=O)NHCHZCH3, 2727 -S(O)CH3,-S(O)CH2CH3, -S(O)2CH3, -S(O)2NH2, -S(O)2NHCH3, -S(O)2N(CH3)2, and -CH28(O)2CH3; wherein the wavy line indicates the attachment of R1 to the pyrimidine ring.

Preferred examples of R1 are listed below: [:1 [Zr 1:)" [EL £31., Tjr T31" "l. .Jw .JW .Jw "L. Ni. .Jw m1:]... 239 o 6:4 o 6% Most preferred example of R1 is morpholino.

Preferably X is O or S (the ring containing X being an annullated line or thiomorpholine, respectively). Most preferably X is 0.

Most preferred Rsx is H. Most preferred ng is H. Most preferred R32 is H. Most preferred Rgp is H. Most preferred R4is H. Most preferred R4X is H. Most preferred R4y is H. Most preferred R42 is H. Most preferred R4p is H. Most preferred R5 is H. Most preferred R5 is H. Most preferred R7 is H. Most red RgiS H. Most red R9 is H. Most preferred m is 1. Most preferred n is 1. Most preferred t is 1. ably, the present invention provides compounds of formula (la) and (lb): R2 R2 R3p R3p R3x \ N R3x \ N I I X N N/)\R1 X N/J\R1 2828 and isomers, geometric isomers, tautomers, solvates, and pharmaceutically acceptable salts thereof, wherein R1, R2, Rsx, Rsy, R32, and R3,, are as defined above for formula (I).

The preferences, particular aspects and embodiments set forth above for R1, R2, Rsx, ng, R32, and Rgp in formula (I) apply likewise to these structures in formula (la) and (lb).

In another , the ion provides compounds of a (lla) and (llb) mRap R1 Rap / "I / XHN N R2 XHN N R2 Ray R32 R3y R32 (Ila) (lib) and stereoisomers, geometric isomers, tautomers, solvates, and pharmaceutically acceptable salts thereof, wherein R1, R2, Rsx, Rsy, R32, R3,, are as defined above for formula (II).

The preferences, particular aspects and ments set forth above for R1, R2, Rsx, ng, R32, and Rgp in formula (II) apply likewise to these structures in formula (lla) and (llb).

Most preferred examples are described in Tables 1 to 4.

Table 1 gives the structures and the corresponding IUPAC names (using ChemDraw Ultra, Version 13.0.1 as well as lower and upper software versions thereof, CambridgeSoft Corp., Cambridge MA) of exemplary compounds (de) Nos. 1-16 of formula (la). 2929 de No. Structure Name 1 EN1 (4-morpho|ino—5a,6,8,9—tetrahydro—5H- WN pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin GUN (RE) yI)pyridin-Z-amine N NH2 2 EN1 (R)—4-methy|—5-(4-morpholino—5a,6,8,9— WN tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] GUN NI |: [1,4]oxaziny|)pyridinamine N NH2 3 EN1 chIoro(4-morpholino-5a,6,8,9— A?N 0' tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] O\,/N (RE: [1,4]oxaziny|)pyridinamine N NH2 4 EN1 (R)—2—amino—5-(4-morpholino—5a,6,8,9— Aim CN tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] OWN N/ |: [1,4]oxaziny|)isonicotinonitrile N NH2 EN1 (R)—4-(difluoromethyl)—5-(4-morpho|ino- AfNF F 5a,6,8,9—tetrahydro—5H-pyrimido[5',4':4,5] GUN N/ |: pyrrolo[2,1-c][1,4]oxazinyl)pyridinamine N NH2 6 EN1 (R)—5-(4-morpho|ino—5a,6,8,9—tetrahydro—5H- om" (i3 pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin \,/ IN/ y|)(trif|uoromethyl)pyridinamine 7 EN1 (R)—4-cyc|opropyI(4-morpholino—5a,6,8,9— tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] [1 ,4]oxaziny|)pyridinamine 3030 8 N ethy|—5-(4-morpholino—5a,6,8,9— AIR" tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] O\_JN N/ / [1,4]oxaziny|)pyridinamine N NH2 9 EN1 (R)—5-(4-morpho|ino—5a,6,8,9—tetrahydro—5H- | pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin O\_JN N/ | :1 y|)pyrimidinamine N NH2 EN1 (R)—4-methy|—5-(4-morpholino—5a,6,8,9— A?" tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] 0\,/N N/ | 1 [1,4]oxaziny|)pyrimidinamine N NH2 11 EN1 (R)—4-chIoro(4-morpholino-5a,6,8,9— \N 0' | tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] O\_JN N/ | :1 [1,4]oxaziny|)pyrimidinamine N NH2 12 EN1 (R)—2—amino—5-(4-morpholino—5a,6,8,9— A?N CN tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] OWN N/ | 1 [1,4]oxaziny|)pyrimidinecarbonitrile N NH2 13 EN1 (R)—4-(difluoromethyl)—5-(4-morpho|ino- WNF F 5a,6,8,9—tetrahydro—5H-pyrimido[5',4':4,5] OWN N/ | 1 pyrro|o[2,1-c][1,4]oxaziny|)pyrimidin N NH2 amine 14 EN1 (R)—5-(4-morpho|ino—5a,6,8,9—tetrahydro—5H- | CFs do[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin 0\,/N N/ | 1 y|)(trif|uoromethy|)pyrimidin-Z-amine 3131 N (R)—4-cyclopropyl(4-morpholino-5a,6,8,9— A?" tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] O\_JN N/ I1 [1,4]oxazinyl)pyrimidinamine N NH2 16 EN1 (R)—4-ethyl(4-morpholino-5a,6,8,9— tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1 ,4]oxazinyl)pyrimidinamine Table 2 gives the structures and the corresponding IUPAC names (using ChemDraw Ultra, Version 13.0.1 as well as lower and upper re versions thereof, CambridgeSoft Corp., Cambridge MA) of exemplary compounds (de) Nos. 17-32 of formula (lb). de No. ure Name 17 N (S)(4-morpholino-5a,6,8,9—tetrahydro-5H- 74f" pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin O\,/N N/Kfj yl)pyridinamine N NH2 18 N (S)methyl(4-morpholino-5a,6,8,9— W" tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] O\.JN N I: [1,4]oxazinyl)pyridinamine N NH2 19 EN1 (S)chloro(4-morpholino-5a,6,8,9— WN Cl tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1 ,4]oxazinyl)pyridinamine 3232 N (S)amino—5-(4-morpho|ino—5a,6,8,9— #fN CN tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] O\_JN N/Kfi [1,4]oxaziny|)isonicotinonitrile N/ NH2 21 N (S)(difluoromethyl)(4-morpho|ino—5a,6, AIR"F F 8,9—tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o 0\,/N N / [2,1-c][1,4]oxaziny|)pyridinamine N NH2 22 EN1 (S)(4-morpho|ino—5a,6,8,9—tetrahydro—5H- r/fN CF3 pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin GUN N |\ y|)(trif|uoromethyl)pyridinamine N/ NH2 23 EN1 (S)cyc|opropyI(4-morpholino—5a,6,8,9— r/fN tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] GUN N |\ [1,4]oxaziny|)pyridinamine N/ NH2 24 EN1 ethy|—5-(4-morpho|ino—5a,6,8,9— WM tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] GUN N/ I [1,4]oxaziny|)pyridinamine N/ NH2 EN1 (S)(4-morpho|ino—5a,6,8,9—tetrahydro—5H- \N pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin OWN N’ I j: imidinamine N/ NH2 26 EN1 (S)methy|—5-(4-morpho|ino—5a,6,8,9— \N tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] GUN N/ I j: [1,4]oxaziny|)pyrimidinamine 3333 27 [N] (S)chloro(4-morpholino-5a,6,8,9— \N Cl tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] OWN N/ I j: [1,4]oxazinyl)pyrimidinamine N NH2 28 [N] amino(4-morpholino-5a,6,8,9— \N CN tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] OWN N/ I j: [1,4]oxazinyl)pyrimidinecarbonitrile N NH2 29 [N] (difluoromethyl)(4-morpholino-5a,6, mNF F 8,9—tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo OWN "(REED)": [2,1-c][1,4]oxazinyl)pyrimidinamine N NH2 [N] (S)(4-morpholino-5a,6,8,9—tetrahydro-5H- mN CF3 pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin GUN N/ I j: yl)—4-(trifluoromethyl)pyrimidinamine N NH2 31 [N] (S)cyclopropyl(4-morpholino-5a,6,8,9— mN tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] OWN N/ I j: [1,4]oxazinyl)pyrimidinamine N NH2 32 [N] (S)ethyl(4-morpholino-5a,6,8,9— AfN"1%: tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] GUN [1,4]oxazinyl)pyrimidinamine N NH2 Table 3 gives the structures and the corresponding IUPAC names (using aw Ultra, Version 13.0.1 as well as lower and upper software versions thereof, CambridgeSoft Corp., Cambridge MA) of exemplary compounds (de) Nos. 33-48 of formula (Ila). 3434 de No. Structure Name 33 (R)—5-(2-morpho|ino—5a,6,8,9—tetrahydro—5H- do[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin y|)pyridinamine 34 \N | (R)—4-methy|—5-(2-morpholino—5a,6,8,9— tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] | :j: [1,4]oxaziny|)pyridinamine OWN N N/fi \N | (R)—4-chIoro(2-morpholino-5a,6,8,9— 0' tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] | :N [1,4]oxaziny|)pyridinamine GUN NAN/fl 36 \N | (R)—2-amino—5-(2-morpholino—5a,6,8,9— NC tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] l :N [1,4]oxaziny|)isonicotinonitrile GUN NAN/fl 37 (R)—4-(difluoromethyl)—5-(2-morpho|ino—5a,6, 8,9—tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o [2,1-c][1,4]oxazinyl)pyridinamine 38 (R)—5-(2-morpho|ino—5a,6,8,9—tetrahydro—5H- pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin y|)(trif|uoromethyl)pyridinamine 3535 39 Nl : (R)—4-cyc|opropyI(2-morpholino—5a,6,8,9— tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] | 1 [1,4]oxaziny|)pyridinamine DUN N N/fi 40 NI : (R)—4-ethy|—5-(2-morpholino—5a,6,8,9— tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] | 1 [1,4]oxaziny|)pyridinamine OWN N N/fi 41 NIJ:N (R)—5-(2-morpho|ino—5a,6,8,9—tetrahydro—5H- pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin y|)pyrimidinamine O N |N\/N N/fi \J K/O 42 NI):N (R)—4-methy|—5-(2-morpholino—5a,6,8,9— tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] [1,4]oxaziny|)pyrimidinamine o N |N:N N/fi u K/O 43 NIJ:N chIoro(2-morpholino-5a,6,8,9— 0' tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] [1 ,4]oxaziny|)pyrimidinamine 44 (R)—2—amino—5-(2-morpholino—5a,6,8,9— tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] [1 ,4]oxaziny|)isonicotinonitrile 3636 45 (R)—4-(difluoromethyl)—5-(2-morpholino-5a,6, 8,9—tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo [2,1-c][1,4]oxazinyl)pyrimidinamine 46 (R)—5-(2-morpholino-5a,6,8,9—tetrahydro-5H- pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin yl)—4-(trifluoromethyl)pyrimidinamine 47 Nl \N (R)—4-cyclopropyl(2-morpholino-5a,6,8,9— tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] I j: [1,4]oxazinyl)pyrimidinamine o N N/ N \,J @ 48 Nl N (R)—4-ethyl(2—morpho|Ino-5a,6,8,9—. tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] ' A [1 ,4]oxazinyl)pyrimidinamine O\_.JN N N/fi Table 4 gives the structures and the corresponding IUPAC names (using aw Ultra, Version 13.0.1 as well as lower and upper software versions thereof, CambridgeSoft Corp., Cambridge MA) of exemplary nds (de) Nos. 49-64 of formula (llb). 3737 de No. Structure Name 49 (S)(2-morpho|ino—5a,6,8,9—tetrahyd ro—5H- pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin y|)pyridinamine 50 (S)methy|—5-(2—morpho|ino—5a,6,8,9— tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] [1 ziny|)pyridinamine 51 (S)chIoro(2-morpholino—5a,6,8,9— tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] [1 ,4]oxaziny|)pyridinamine 52 (S)amino—5-(2—morpholino—5a,6,8,9— tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] [1 ,4]oxaziny|)isonicotinonitrile 53 (S)(difluoromethyl)(2-morph0|inO-5a,6, 8,9—tetrahyd ro—5H-pyrimido[5',4':4,5]pyrro|o [2,1-c][1,4]oxazinyl)pyridinamine 3838 54 (2-morpho|ino—5a,6,8,9—tetrahyd ro—5H- pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin y|)(trif|uoromethyl)pyridinamine 55 (S)cyc|opropyI(2-morpholino—5a,6,8,9— tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] [1 ,4]oxaziny|)pyridinamine 56 (S)ethy|—5-(2-morpholino—5a,6,8,9— tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] [1 ,4]oxaziny|)pyridinamine 57 (S)(2-morpho|ino—5a,6,8,9—tetrahyd ro—5H- pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin y|)pyrimidinamine 58 (S)methy|—5-(2—morpho|ino—5a,6,8,9— tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] [1 ,4]oxaziny|)pyrimidinamine 59 (S)chIoro(2-morpholino—5a,6,8,9— tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] [1 ,4]oxaziny|)pyrimidinamine 3939 60 (S)amino(2-morpholino-5a,6,8,9— tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1 ,4]oxazinyl)isonicotinonitrile 61 (S)(difluoromethyl)(2-morpholino-5a,6, trahyd ro-5H-pyrimido[5',4':4,5]pyrrolo [2,1 -c][1 ,4]oxazinyl)pyrimidinamine 62 (S)(2-morpholino-5a,6,8,9—tetrahyd ro-5H- pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin (trifluoromethyl)pyrimidinamine 63 (S)cyclopropyl(2-morpholino-5a,6,8,9— tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1 ,4]oxazinyl)pyrimidinamine 64 (S)ethyl(2-morpholino-5a,6,8,9— tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1 ,4]oxazinyl)pyrimidinamine Table 5 gives the structures and the corresponding IUPAC names (using ChemDraw Ultra, Version 13.0.1 as well as lower and upper software versions thereof, CambridgeSoft Corp., Cambridge MA) of exemplary compounds (de) Nos. 65-77 of formula (la). 4040 de Structure Name 65 [N] (R)—1-methyl(4-(4-morpholino—5a,6,8,9— m," tetrahydro—5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] OWN N’)\©\ J0L [1,4]oxaziny|)pheny|)urea H H 66 EN1 (R)—1-methyl(5-(4-morpholino—5a,6,8,9— AfN tetrahydro—5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] OWN N/ I: )OL / [1,4]oxaziny|)pyridiny|)urea 67 [N] (R)—1-methy|(5-(4-morpho|ino—5a,6,8,9— mp] tetrahydro—5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] o N N//K(§N o [1,4]oxazinyl)pyrimidinyl)urea U N/ H H 68 EN1 methyl (R)—(4-(4-morpholino—5a,6,8,9— AfN tetrahydro—5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] GUN N/ JOL / [1,4]oxazin-2—y|)pheny|)carbamate N o 69 EN1 methyl (R)—(5-(4-morpholino—5a,6,8,9— AIKN tetrahydro—5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] GUN N/ |\ JOL [1,4]oxazinyl)pyridinyl)carbamate N N o/ 70 EN1 methyl (R)—(5-(4-morpholino—5a,6,8,9— ydro—5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1 ,4]oxazinyl)pyrimidinyl)carbamate 4141 71 O (R)1- ' -(4 (4- -(d'Imethyl ammo)p'pIerl'd'Ine- 1 [j - N carbonyl)phenyl)—3-(4-(4-morpho|ino—5a,6,8,9— ml" 0 tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] U ~53 0 d0 HJLH - kHz [1 ,4]ovaIny|)pheny|)urea 72 0 ' [j (R)1 (4 Imethyl - - - ammo)p'pIerl'd'Ine N carbonyl)phenyl)—3-(5-(4-morpho|ino—5a,6,8,9— Odfiifj O tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] N’ NJLN DN/ [1,4]oxaziny|)pyridinyl)urea H H | 73 0 ' [j (R)1- -(4 (4- -(d'Imethyl ammo)p'pIerl'd'Ine N carbonyl)phenyl)—3-(5-(4-morpho|ino—5a,6,8,9— 061:1?" O ydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] NANJLN DN/ [1 ,4]oxaziny|)pyrimidinyl)urea H H | 74 [N] (R)—5-(4-morpho|ino—5a,6,8,9—tetrahydro—5H- AIR," CFs pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]thiazin SuN N’ \/ yl)(trifluoromethyl)pyridinamine N NH2 75 [N] (5aR)—2-(6-amino—4-(trifluoromethyl)pyridin A?!" CF yl)morpholino—5a,6,8,9—tetrahydro-5H- IN/ 3 0:8 N \ pyrimido[5',4':4,5]pyrro|o[2,1-c][1,4]thiazine 7- u | . d / OXI e N NH2 76 [N] (R) 2 (6 ' - - -amlno-4(-trI uoromet'fl hy|)pyn'd'In-3 yl)- - A?!" 4-morpholino—5a,6,8,9—tetrahydro—5H- ‘\s N IN/ \ pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]thiazine " \_J | 7,7-dioxide 4242 77 5-((5aR)—4-(8—oxaazabicyclo[3.2.1]octan WN ,6,8,9—tetrahydro-5H-pyrimido[5',4':4,5] pyrrolo[2,1-c][1,4]oxazinyl)—4-(trifluoro- o N N/ \ .. .

U | methyl)pyrIdInamlne N/ NH2 Table 6 gives the structures and the corresponding IUPAC names (using ChemDraw Ultra, Version 13.0.1 as well as lower and upper software versions thereof, dgeSoft Corp., Cambridge MA) of exemplary compounds (de) Nos. 78-90 of formula (lb) . de Structure Name 78 EN1 (S)—1-methyl(4-(4-morpholino-5a,6,8,9— Hf!" tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] OQN N/J\©\ JOL [1,4]oxazinyl)phenyl)urea N N’ H H 79 EN1 (S)methyl(5-(4-morpholino-5a,6,8,9— Hf!" tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] 09" N/ |\ [1,4]oxazinyl)pyridinyl)urea N/ JOL N N’ H H 80 EN1 (S)methyl(5-(4-morpholino-5a,6,8,9— HIE!" tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] o "N NéKCN o \4 | [14]oxazinyl)pyrimidinyl)urea NANJLN/ ’ H H 81 EN1 methyl -(4-morpholino-5a,6,8,9— Hf"! tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] OQN "(KO JOL [1,4]oxazinyl)phenyl)carbamate H 0’ 4343 methyl (S)-(5-(4-morpho|ino—5a,6,8,9— 82 EN1 tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1- | c][1,4]oxaziny|)pyridiny|)carbamate o N N/ \ o \,/ | N/ NAO/ 83 EN1 methyl -(4-morpho|ino—5a,6,8,9— HfN tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] oqN "/ka JOL xaziny|)pyrimidinyl)carbamate / / N N o (S)(4-(4-(dimethylamino)piperidine 84 Hf: carbonyl)phenyl)—3-(4-(4-morpho|ino—5a,6,8,9— - I I. a |\N tetrahydro 5H pyrlmldo[5 ,4 .4,5]pyrro|o[2,1- _ _ _c] oqN N/ [:LHJLHOO U NI/ [1,4]oxaziny|)pheny|)urea (S)(4-(4-(dimethylamino)piperidine 85 N carbonyl)phenyl)—3-(5-(4-morpho|ino—5a,6,8,9— Off/Gk O /©)OLN tetrahydro—5H-pyrimido[5',4':4,5]pyrro|o[2,1-c] u I N "A" Ofir [1 ,4]oxaziny|)pyridinyl)urea (S)(4-(4-(dimethylamino)piperidine 86 Hf: carbonyl)phenyl)—3-(5-(4-morpho|ino—5a,6,8,9— |\N O "1fo tetrahydro 5H pyrlmldo[5 ,4 .4,5]pyrro|o[2,1- - I I. a _ _ _c] oqN 0 d0 NANA" "IV [1 ,4]oxaziny|)pyrimidinyl)urea 87 [N] (S)(4-morpho|ino—5a,6,8,9—tetrahydro—5H- pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]thiazin \N CF I 3 N y|)(trif|uoromethyl)pyridinamine S N \ 4444 88 [N] (5aS)—2-(6-amino(trifluoromethyl)pyridin Hf"! morpholino-5a,6,8,9—tetrahydro-5H- CF?) 0:8 N N/ do[5',4':4,5]pyrrolo[2,1-c][1,4]thiazine 7- U I / oxide N NH2 89 [N] (S)(6-amino(trifluoromethyl)pyridinyl)— 4-morpholino-5a,6,8,9—tetrahyd ro-5H- \ N CF3 0‘ I , pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]thiazine :s N N \ O’ \J l 7,7-dioxide N NH2 90 5-((5aS)(8-oxaazabicyclo[3.2.1]octan HIS" yl)-5a,6,8,9—tetrahydro-5H-pyrimido[5',4':4,5] | 3 pyrrolo[2,1 . (trifluoro. _c][1,4]oxazm 2 yl) 4_ _ _ _ _ DUN N/ \ I thly)pyr|'d' ' / me In amine N NH2 Preparation of compounds of the invention The nds of the invention may be synthesized by synthetic routes that include processes ous to those well known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Aldrich Chemicals or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, N.Y. 1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4. Aufl. ed. Springer- Verlag, Berlin, ing supplements (also available via the Beilstein online database).

In certain embodiments, the compounds of the invention may be readily prepared using procedures well-known to prepare pyrimidines and other heterocycles, which are described in: hensive Heterocyclic Chemistry, Editors Katritzky and Rees, on Press, 1984.

Compounds of the invention may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, or 10 to 100 compounds. 4545 Libraries of nds of the invention may be prepared by a combinatorial 'split and mix' approach or by multiple parallel syntheses using either solution phase or solid phase chemistry, by procedures well known to those skilled in the art. Thus according to a further aspect of the invention there is provided a compound y comprising at least 2 compounds, or pharmaceutically acceptable salts thereof.

For illustrative purposes, Schemes 1-6 show general methods for preparing the compounds of the t invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples herein below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds of the invention. Although specific starting materials and reagents are ed in the Schemes and discussed below, other starting materials and ts can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the nds prepared by the methods described below can be r modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

In preparing nds of the invention, protection of remote functionality (e.g., y or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote onality and the conditions of the preparation methods. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t- butoxycarbonyl (BOC), benzyloxycarbonyl (082) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

Scheme 1 4646 Scheme 1 shows a general method for preparation of the pyrimidine intermediates 2 and 3 from 2,4,6-trihalo-1,3,5-pyrimidine reagent (1), wherein Hal is Cl, Br, or I; and Y, R4p, R4X, R4y and R42 are as d above.

Scheme 2 Scheme 2 shows a general method for preparation of sulfamidate intermediate 5 from (R) or (S) functionalized 3-hydroxymethyl morpholine (4).

Scheme 3 Hal Hal R R3,; R3 3x \N R R3X * * \N R4p I A 4D X I A R —> 4* Hal N/ N)\(R4X + O\ ,N X N N N Y o R3y H R42 R32 R3y R32 R42*(Y R R 4y 4y 2 5 s Scheme 3 shows a general method for preparation of fused morpholino pyrimidine 6 from intermediate 2.

Scheme 4 R4X Y1my R3,, R3" WX R4p N R42 R34) R4p N R42 | 0 x Hal NAHaI HR 3 5 7 4747 Scheme 4 shows a general method for preparation of fused morpholino pyrimidine 7 from intermediate 3.

Scheme 5 R3p Hal R3p R2 R \ I j: R4p R3X RX)2 I \j: R4p H R42/KKY Y R3y R32 H R3y R32 R4z/Kr R4y R4y 6 9 Scheme 5 shows a general method for Suzuki-type coupling of a 4-halo pyrimidine intermediate 6 with a cyclic aryl boronate acid (Rx = H) or ester (Rx: alkyl) reagent 8 to prepare the cyclic aryl (R1) compounds (9) of formula la-lb, wherein Hal is Cl, Br, or I; and R2 es are as defined for formula la-lb compounds, or precursors o. For reviews of the Suzuki reaction, see: Miyaura et al. (1995) Chem.

Rev. 95:2457-2483; Suzuki, A. (1999) J. Organomet. Chem. 576:147-168; The palladium catalyst may be any that is typically used for Suzuki-type cross-couplings, such as PdC|2(PPh3)2, Pd(PPh3)4, Pd(OAc)2, PdC|2(dppf)-DCM, Pd2(dba)3/Pt-Bu)3 (Owens et al.

, Bioorganic & Med. Chem. Letters 13:4143-4145; Molander et al. (2002), Organic Letters 4(11):1867-1870; US 6,448,433).

Scheme 6 R4XIY R4y R4XIY R4y R4p N R Rz-B(ORX)2 R4 42 p N R42 R3p 8 R3p R3X \ N R3X \ N l l / / XHN NkHal XHN N)\R2 R3y R32 R3y R32 7 1 0 Scheme 6 shows a general method for Suzuki-type coupling of a 2-halo morpholino pyrimidine intermediate 7 with a cyclic heteroaryl boronate acid (Rx = H) or ester (RX = 4848 alkyl) reagent 8 to prepare the cyclic heteroaryl (R1) compounds (10) of formula lla-llb, wherein Hal is Cl, Br, or I; and R1 residues are as defined for formula II compounds, or precursors thereto.

Methods of separation In the methods of preparing the compounds of this invention, it may be advantageous to separate reaction products from one another and/or from starting materials. The desired ts of each step or series of steps are separated and/or purified (hereinafter separated) to the desired degree of neity by the techniques common in the art.

Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can e any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and ative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.

Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render othenNise separable a desired product, unreacted starting material, reaction by t, or the like. Such ts include adsorbents or absorbents such as ted carbon, molecular sieves, ion exchange media, or the like.

Alternatively, the reagents can be acids in the case of a basic material, bases in the case of an acidic al, binding reagents such as antibodies, binding proteins, selective chelators such as crown , liquid/liquid ion extraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature of the materials involved, for example, boiling point and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like. One d in the art will apply techniques most likely to achieve the desired separation. reomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical ences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be 4949 separated by converting the enantiomeric e into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Also, some of the nds of the present invention may be somers (e.g., tuted biaryls) and are ered as part of this invention.

Enantiomers can also be ted by use of a chiral HPLC column.

A single stereoisomer, e.g., an enantiomer, substantially free of its isomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, 8. "Stereo- chemistry of Organic Compounds," John Wiley & Sons, Inc, New York, 1994; Lochmuller, C. H., (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) ion of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: "Drug Stereochemistry, Analytical Methods and Pharmacology," Irving W. Wainer, Ed., Marcel Dekker, Inc, New York (1993).

Under method (1), diastereomeric salts can be formed by on of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, or-methyl phenylethylamine (amphetamine), and the like with asymmetric nds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to te by onal crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a reomeric pair (E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, 1994, p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically 5050 pure chiral derivatizing reagents, such as menthyl tives, followed by separation of the diastereomers and ysis to yield the pure or enriched enantiomer. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl formate in the presence of base, or Mosher ester, d-methoxy-cx-trifluoro- methyl)pheny| acetate (Jacob lll, J. Org. Chem. (1982) 47:4165), of the racemic mixture, and analyzing the 1H NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers.

Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96/15111). By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase ("Chiral Liquid Chromatography" (1989) W. J. Lough, Ed., Chapman and Hall, New York; Okamoto, J. togr., (1990), 5-378). Enriched or purified enantiomers can be guished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and ar dichroism.

Examples The chemical ons described in the Examples may be readily adapted to prepare a number of other lipid kinase inhibitors of the invention, and alternative methods for ing the compounds of this invention are deemed to be within the scope of this invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by ing other suitable reagents known in the art other than those bed, and/or by making routine modifications of reaction conditions. atively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.

In the Examples described below, unless otherwise indicated, all temperatures are set forth in s Celsius (°C). Reagents were purchased from commercial suppliers such as Aldrich al Company, Fluorochem, Acros, Lancaster, TCI or Maybridge, and were used without further purification unless othenNise indicated. The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a 5151 drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. Column chromatography was conducted by using Merck silica gel. 1H NMR spectra were recorded on a Bruker instrument operating at 400 MHz, 500 MHz and 600 MHz. 1H NMR spectra were obtained in ated CDCI3, Ds-DMSO, 0133013 or Ds-acetone solutions (reported in ppm), using chloroform as the reference rd (7.25 ppm) or TMS (0 ppm). When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz). iations: h (hours), min (minutes), s (seconds), FC (flash chromatography), rt (room temperature), DCM (dichloromethane), ACN (acetonitrile), DMF (dimethylformamide), EtOAc (ethyl acetate), EtOH (ethanol), Cycl (cyclohexane), MeOH (methanol), THF (tetrahydrofuran), DIPEA (N, opropylethylamine).

Exam le 1: 4- 4 6-Dichloro rimidin l mor holine and 4- 2 6-dichloro rimidin yl)morpholine Cl Cl Cl Morpholine, EtOH \N \N + | NACI 0°Cto rt, ov | A f" Cl Cl N Nfi fN NACI O O A solution of morpholine (22.4 mL, 512.4 mmol, 4.2 eq) in EtOH (100 mL) is added dropwise to a cooled (0°C) solution of 2,4,6-trichloropyrimidine (14 mL, 122 mmol, 1 eq) in EtOH (200 mL). The mixture is stirred at rt overnight. The crude mixture is poured onto a saturated solution of NaHSO4 (1 L), and the resulting precipitate is collected by filtration. The solid is redissolved in a minimal amount of DCM and adsorbed on silica gel. FC (AcOEt/Cycl 1:3 —> 1:1) gives the d compounds 4-(4,6-Dichloropyrimidin yl)morpholine (20% yield) and 4-(2,6-dichloropyrimidinyl)morpholine (65% yield).

-Dichloropyrimidinyl)morpholine:1H NMR (400 MHz, CDCI3): 6 6.53 (s, 1H), 3.77 (m, 4H), 3.71 (m, 4H). 13C NMR (100.6 MHz, CDCI3): 6 161.6, 160.4, 108.2, 66.5, 44.3. 5252 4-(2,6-dichloropyrimidinyl)morpholine:1H NMR (400 MHz, CDCI3): 6 6.34 (s, 1H), 3.70 (m, 4H), 3.58 (m, 4H). 13C NMR (100.6 MHz, CDCI3): 6 162.9, 160.3, 159.5, 99.6, 66.9, 44.3.

Example 2: (R)—Tetrahydro-3H-|1,2,3|oxathiazolo|4,3-c||1,4|oxazine 1,1-dioxide (S) (R) 1. lmidazole, soc12, CH2C|2 2. RuOZ—HZO, Nalo4 ’ O\O’/\ A solution of SOCIZ (0.82 mL, 11.3 mmol) in DCM (0.8 mL) is added dropwise to a cooled (-5°C) solution of imidazole (2.38 g, 34.9 mmol) in DCM (15 mL), and the temperature kept at -5°C. The cooling bath is removed and the reaction mixture is stirred over 45 min while allowing it to warm up to rt. The mixture is cooled down to -10°C. A solution of (S)-morpho|iny|methanol (0.68 g, 5.8 mmol) in DCM (5.8 mL) is added dropwise while keeping the temperature around -10°C. The e is stirred at -5°C for 2 h, and then at +5°C for 1 h. Water (15 mL) is added and the layers are separated. The organic layer is washed with half concentrated brine (15 mL), and cooled to 0°C. A solution of NalO4 (3.73 g, 17.4 mmol) in water (40 mL) is added, followed by Ru20-H20 (8 mg). The bath is removed after 15 min and the dark on mixture stirred overnight.

The layers are ted and the organic layer is filtered through a silica gel column eluting with excess DCM until no more t is observed by TLC.

The corresponding (8) enantiomer is synthesized in the same manner. 1H NMR (400 MHz, CDCI3) 6 4.71 — 4.51 (m, 1H), 4.30 (m, 1H), 4.02 (dd, J = 11.6, 3.4 Hz, 1H), 3.94 — 3.68 (m, 3H), 3.61 (dd, J = 11.6, 7.8 Hz, 1H), 3.37 (dt, J = 12.1, 3.6 Hz, 1H), 3.24 — 3.07 (m, 1H).

R enantiomer: [010] = - 42.8 , c=0.65) S enantiomer: [do] = + 53.8 (CHCI3, c=0.75) 5353 1. nBuLi, Cul, THF ‘ /N O 3. NaOH A 1.6 M n-BuLi solution (1.4 mL) is cooled down to -78°C, and a on of 4-(2,6- dichloropyrimidinyl)morpholine (435 mg, 1.86 mmol) in THF (5 mL) is added dropwise.

The mixture is stirred at -78°C for 35 min. Cul (14 mg, 0.07 mmol) and a solution of (R)- ydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1,1-dioxide (333 mg, 1.86 mmol) in THF (3 mL) is added. The mixture is stirred at -78°C and then d to warm to rt, then stirred for 16 h. The reaction is quenched by addition of water (1 mL). 15% HCI (10 mL) and methanol (5 mL) are added, and the mixture heated to 60°C for 5 h. The organic solvents are removed by rotary evaporation and the remaining aqueous layer diluted with 2 M NaOH (5 mL). NaOH pellets are used to adjust the pH to 11. AcOEt (10 mL) is added and the mixture stirred for 30 minutes. The layers are separated and the aqueous layer extracted with AcOEt (2 x 10 mL). The combined organic layers are dried over sodium sulfate, ed and concentrated. The product is precipitated as a brown solid (530 mg, 96%), and is used without any further purification.

The corresponding (R) enantiomer is synthesized in the same manner. 1H NMR (400 MHz, CDCI3) 5 4.01 (dd, J = 13.6, 2.8 Hz, 1H), 3.97 — 3.85 (m, 1H), 3.75 (m, 2H), 3.66 (m, 4H), 3.61 — 3.47 (m, 4H), 3.38 (td, J = 11.7, 2.9 Hz, 1H), 3.23 (t, J = 11.0 Hz, 1H), 3.19 — 3.04 (m, 2H), 2.50 (dd, J = 15.0, 5.1 Hz, 1H).

R enantiomer: [010] = -3.3 (CHCI3, c=1.5) S omer: [01D] = +4.0 (CHCI3, c=1.2) 5454 Exam le 4: R 4-Mor holino-5a 6 8 9—tetrah dro-5H- rimido 5' 4':4 5 rrolo 2 1-c 1 4 l orometh l ridinamine (R) uuuuu N 1%?O’B (R) um I 1. Pd(OAc)2, SPHOS, K3PO4, DMF / > N CF3 o A01 N NH2 N m 11 O O / N NH2 The pyrimidine (147 mg, 0.495 mmol), boronate (255 mg, 0.74 mmol), K3PO4 (250 mg, 1.18 mmol), SPHOS (25 mg, 0.06 mmol) and Pd(OAc)2 (7 mg, 0.03 mmol) are placed into a round bottom flask under nitrogen. DMF (3 mL) is added, and nitrogen bubbled through the mixture for 15 min. The reaction mixture is heated to 100°C for 18 h, cooled to rt, diluted with AcOEt (10 mL) and poured into saturated NH4CI (10 mL). The layers are separated and the aqueous layer extracted with AcOEt (2 x 10 mL). The combined c layers are dried over sodium sulfate, filtered and concentrated. The crude mixture is purified by column chromatography (1:1—>1:3—> 0:1 Cycl: AcOEt). The product is obtained as a solid (77 mg, 37%).

The corresponding (8) enantiomer is synthesized in the same . 1H NMR (400 MHz, CDCI3) 6 8.63 (s, 1H), 6.77 (s, 1H), 4.76 (s, 2H), 4.17 — 4.05 (m, 1H), 4.03 — 3.89 (m, 1H), 3.87 — 3.72 (m, 6H), 3.72 — 3.56 (m, 6H), 3.47 (td, J = 11.7, 2.9 Hz, 1H), 3.35 (t, J = 11.0 Hz, 1H), 3.31 — 3.11 (m, 2H), 2.62 (dd, J = 15.0, 4.9 Hz, 1H).

R enantiomer: [010] = +13.5 (CHCI3,c=1.6) S enantiomer: [01D] = -13.2 (CHCI3, c=2.0) Exam le 5: S chloromor holino-5a 6 8 9—tetrah dro-5H- rimido 5' 4':4 5 pyrrolo|2,1-c||1,4|oxazine fiN O/\|AO i,Cul,THF CI NAB £83k) 2.HCI,ROH O O 3. NaOH n-BuLi (1.6 M, 1 mL) and THF (1 mL) are placed into a dry round bottom flask under nitrogen and cooled to -78°C. A solution of the pyrimidine (298 mg, 1.27 mmol) in THF 5555 (3.5 mL) is slowly added, and the reaction mixture stirred at -78°C for 30 min. Cul (12 mg, 0.06 mmol) and a solution of sulfamidate (228 mg, 1.27 mmol) in THF (2 mL) are added. The mixture is stirred at -78°C for 15 min and then allowed to warm up to rt and stirred over 16 h. The reaction mixture is quenched by addition of water (0.5 mL). A solution of 12 M HCI (5 le) and EtOH (5 mL) is added, and the mixture heated to 70°C for 1.5 h. The organic solvents are removed, the residue diluted with 2 M NaOH, and solid NaOH added to adjust the pH to 11. The mixtures is diluted with ethyl acetate and stirred at rt over 1.5 h. The solvent is removed, and the residue solved in EtOH (7 mL) and acidified with 12 M HCI until pH 1, then stirred at rt over 18 h. The e is cooled down, and NaOH is slowly added until pH 11, then d over 2 h and diluted with AcOEt. The layers are separated, and the aqueous layer extracted with AcOEt (2 x15 mL). The combined organic layers are dried over sodium sulfate, and purified by FC (2:1 —> 1:1 cycl: AcOEt). The desired product is obtained as a white solid (286 mg, 76%).

The corresponding (R) enantiomer is synthesized in the same manner. 1H NMR (400 MHZ, CDCI3) 6 4.04 — 3.90 (m, 2H), 3.87 (dt, J = 11.3, 4.4 Hz, 2H), 3.79 — 3.65 (m, 8H), 3.44 (td, J: 11.7, 2.9 Hz, 1H), 3.32 — 3.14 (m, 2H), 2.99 (dd, J: 16.1, 9.4 Hz, 1H), 2.42 (dd, J = 16.1, 5.0 Hz,1H).

R enantiomer: [do] = +56.2 (CHCI3,c=1.4) S omer: [up] = -61.0 (CHCI3, c=1.1) Exam le 6: R 2-Mor holino-5a 6 8 9-tetrah dro-5H- rimido 5' 4':4 5 rrolo 2 1-c 1 4 oxazin l trifluorometh l ridinamine Ogfimz 1. Pd(OAc)2 SPHOS K3PO4 DMF "Co O The pyrimidine (94 mg, 0.32 mmol), boronate (141 mg, 0.41 mmol), K3PO4 (134 mg, 0.64 mmol), SPHOS(14 mg, 0.035 mmol) and Pd(OAc)2 (4 mg, 0.016 mmol) are placed into a round bottom flask. DMF (2 mL) is added, and the on d with nitrogen for 10 min, then heated to 100°C under nitrogen for 3 h. The mixtures is cooled to rt and 5656 diluted with AcOEt. Saturated NH4CI (10 mL) is added and the layers are separated. The aqueous layer is extracted with AcOEt (2 x 10 mL), dried over sodium e, filtered, concentrated and purified by FC (1 :1 —> 1:3 Cycl: AcOEt —>100 % AcOEt —> 2% MeOH/ AcOEt). The d product is ed as a solid (70 mg, 52% yield).

The corresponding (8) enantiomer is synthesized in the same manner. 1H NMR (400 MHz, CDCI3) 5 8.11 (s, 1H), 6.79 (s, 1H), 4.77 (s, 2H), 4.04 (dd, J = 13.3, 2.9 Hz, 1H), 4.00 — 3.78 (m, 2H), 3.78 — 3.63 (m, 9H), 3.50 (td, J = 11.6, 3.0 Hz, 1H), 3.36 — 3.12 (m, 2H), 2.91 (dd, J = 15.8, 9.1 Hz, 1H), 2.32 (dd, J = 15.8, 5.2 Hz, 1H).

R enantiomer: [010] = +20.5 (CHCI3, c=1.5) S enantiomer: [01D] = -18.9 (CHCI3, c=1.1) Exam le 7: R 2-Mor holino-5a 6 8 9—tetrah dro-5H- rimido 5' 4':4 5 rrolo 2 1-c 1 4 oxazin l rimidinamine XPhos-Pd-GZ, K3PO4, 95°C dioxane/water 2:1 (R)—4-Chloromorpholino-5a,6,8,9—tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1,4]oxazine (40 mg, 0.135 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)— pyrimidinamine (45 mg, 0.2 mmol), K3PO4 (57 mg, 0.27 mmol), XPhos-Pd-G2 o(2-dicyclohexy|phosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’- bipheny|)]palladium(ll)) (5.3 mg, 0.007 mmol) are placed into a round bottom flask under nitrogen. e (3 mL) is added, followed by water (1.5 mL), and nitrogen bubbled through the mixture for 15 min. The reaction mixture is heated to 95°C for 2 h, cooled to room temperature, diluted with AcOEt (10 mL) and poured into saturated NH4CI (10 mL).

The layers are separated and the aqueous layer is extracted with AcOEt (2 x 10 mL).

The combined organic layers are dried over sodium e, filtered and concentrated.

The crude mixture is purified by column chromatography (CH2C|2/MeOH 20:1). The title compound is obtained as a solid (44 mg, 92%). 5757 1H NMR (400 MHz, De-DMSO) 5 8.73 (s, 2H), 7.01 (s, 2H), 3.97-3.90 (m, 2H), 3.81-3.75 (m, 2H), 3.66 — 3.63 (m, 8H), 3.31 — 3.11 (m, 4H), 2.67-2.62 (dd, J = 16.0, 4.5 Hz, 1H). 13c NMR (100 MHz, De-DMSO)6166.8, 163.3, 161.2, 157.3, 150.7, 120.3, 102.9, 70.2, 66.1, 65.6, 57.0, 44.3, 41.3, 27.3. MS (MALDI): 356 (M+H).

Exam le 8: S 2-Mor holino-5a 6 8 9-tetrah dro-5H- rimido 5' 4':4 5 rrolo 2 1-c 1 4 oxazin l rimidinamine \N K/ZONHBVNo Pd--c52 K3PO4 95°C N/ / dioxane/water 2:1 N HZNJLN/ K/O (S)Chloromorpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1,4]oxazine (40 mg, 0.135 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)- pyrimidinamine (45 mg, 0.2 mmol), K3PO4 (57 mg, 0.27 mmol), XPhos-Pd-G2 (chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’- biphenyl)]palladium(ll)) (5.3 mg, 0.007 mmol) are placed into a round bottom flask under nitrogen. Dioxane (3 mL) is added, followed by water (1.5 mL) and nitrogen bubbled h the e for 15 min. The reaction mixture is heated to 95°C for 2 h, cooled to room temperature, diluted with AcOEt (10 mL) and poured into saturated NH4CI (10 mL).

The layers are separated and the aqueous layer is extracted with AcOEt (2 x 10 mL).

The combined organic layers are dried over sodium sulfate, filtered and concentrated.

The crude mixture is purified by column chromatography (CH2C|2/MeOH 20:1). The title compound is obtained as a solid (42 mg, 88%). 1H NMR (400 MHz, De-DMSO) 5 8.73 (s, 2H), 7.01 (s, 2H), .90 (m, 2H), 3.81-3.75 (m, 2H), 3.66 — 3.63 (m, 8H), 3.31 — 3.11 (m, 4H), 2.67-2.62 (dd, J = 16.0, 4.5 Hz, 1H). 13c NMR (100 MHz, O)6166.8, 163.3, 161.2, 157.3, 150.7, 120.3, 102.9, 70.2, 66.1, 65.6, 57.0, 44.3, 41.3, 27.3. MS (MALDI): 356 (M+H). 5858 1 4 oxazin l rimidinamine IIIN 7%? N O’BfN XPhos-Pd-GZ, K3PO4, 95°C A A fN N N CI NH2 dioxane/water 2:1 fN N/ o l A (R)—2-Chloromorpholino-5a,6,8,9—tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] xazine (40 mg, 0.135 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)- pyrimidinamine (45 mg, 0.2 mmol), K3PO4 (57 mg, 0.27 mmol), XPhos-Pd-G2 (Chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’- biphenyl)]palladium(ll)) (5.3 mg, 0.007 mmol) are placed into a round bottom flask under nitrogen. Dioxane (3 mL) is added, followed by water (1.5 mL) and nitrogen bubbled through the mixture for 15 min. The reaction mixture is heated to 95°C for 2 h, cooled to room temperature, diluted with AcOEt (10 mL) and poured into saturated NH4CI (10 mL).

The layers are separated and the aqueous layer is extracted with AcOEt (2 x 10 mL).

The combined organic layers are dried over sodium sulfate, filtered and concentrated.

The crude mixture is purified by column chromatography (CH2C|2/MeOH 20:1). The title compound is obtained as a solid (46 mg, 96%). 1H NMR (400 MHz, De-DMSO) 5 9.0 (s, 2H), 7.01 (s, 2H), 4.06-4.02 (dd, J = 13.4, 2.6Hz, 1H), .84 (m, 1H), 3.78 — 3.70 (m, 2H),3.67 — 3.55 (m, 8H), 3.31 — 3.09 (m, 4H), 2.66-2.61 (dd, J: 15.4, 4.6 Hz, 1H).13C NMR (100 MHz, O)6167.1, 164.0, 158.8, 158.0, 157.7, 120.2, 93.5, 70.2, 69.6, 66.2, 65.7, 56.4, 45.4, 41.6, 28.7. MS (MALDI): 356 (M+H).

Exam le 10: S 4-mor holino-5a 6 8 9—tetrah - rimido 5' 4':4 5 rrolo 2 1-c 1 4 oxazin l namine (S) N 7%? (S) N 0’ N XPhos-Pd-GZ, K3PO4, 95°C (\N N N CI NH2 dioxane/water2:1 (\N N/ \N 5959 Chloromorpholino-5a,6,8,9—tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1,4]oxazine (40 mg, 0.135 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)— pyrimidinamine (45 mg, 0.2 mmol), K3PO4 (57 mg, 0.27 mmol), XPhos-Pd-G2 (chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’- biphenyl)]palladium(|l)) (5.3 mg, 0.007 mmol) are placed into a round bottom flask under en. Dioxane (3 mL) is added, followed by water (1.5 mL) and nitrogen bubbled h the mixture for 15 min. The reaction mixture is heated to 95°C for 2 h, cooled to rt, diluted with AcOEt (10 mL) and poured into saturated NH4C| (10 mL). The layers are separated and the aqueous layer extracted with AcOEt (2 x 10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated. The crude mixture is purified by column tography 2/MeOH 20:1). The title compound is obtained as a solid (32 mg, 67%). 1H NMR (400 MHz, De-DMSO) 6 9.0 (s, 2H), 7.01 (s, 2H), 4.06-4.02 (dd, J = 13.4, 2.6Hz, 1H), 3.91-3.84 (m, 1H), 3.78 — 3.70 (m, 2H),3.67 — 3.55 (m, 8H), 3.31 — 3.09 (m, 4H), 2.66-2.61 (dd, J: 15.4, 4.6 Hz, 1H).13C NMR (100 MHz,D5-DMSO)6167.1, 164.0, 158.8, 158.0, 157.7, 120.2, 93.5, 70.2, 69.6, 66.2, 65.7, 56.4, 45.4, 41.6, 28.7. MS (MALDI): 356 (M+H).

In-cel/ n blot A2058 cells were plated at 20,000 cells/well in a 96-well plate (Perkin Elmer, Cat. No. 6005558) and 24 h later treated with different compounds for 1 h. For each compound 7 different concentrations were applied on cells (5 uM, 1.25 uM, 0.625 uM, 0.3125 uM, 0.155 uM, 0.08 uM and 0.04 uM). Cells were fixed with 4% paraformaldehyde for 30 min at RT, washed 2 times with 1% BSA in PBS, permeabilized with 0.1% Triton X-100 in PBS/1% BSA for 30 min at rt and blocked with 5% goat serum in PBS/1% BSA/0.1% Triton X-100 for 30 min at rt. Cells were stained with primary antibody either with rabbit anti-pPKB S473 (1:500; Cell Signalling Technology, Cat. No. 4058) combined with mouse anti-d-Tubulin (1 :2000; used for normalization; Sigma, Cat. No. T9026) or with rabbit anti-pS6 236 (1 :500; Cell Signalling logy, Cat. 6) combined with mouse anti-o-Tubulin (1 :2000; used for normalization) over night at 4°C. After 3 times 5 min wash with PBS/1% BSA/0.1% Triton cells were treated with the secondary antibodies goat-anti-mouse lRDye680 (LICOR, Cat. No. 926-68070) and goat-anti-rabbit lRDye800 (LICOR, 926-32211) (each diluted 1:500 in PBS/1% BSA/0.1% Triton) for 1 h 6060 while shaking in the dark. Cells were washed 3 times 5 min with PB8/1% BSA/0.1% Triton and plate scanned with the Odyssey Infrared Scanning system using both 700 and 800 nm channels. As control for 0% inhibition e (0.2% DMSO) was added to cells.

To t for background staining in the data analysis wells were treated only with secondary antibodies.

For data analysis the mean background signal from channel 700 nm and 800 nm were subtracted from each signal in channel 700 nm and 800 nm, respectively. The signals in each channel were normalized to the 0% inhibition and then signal ratio 800 nm over 700 nm was performed to obtain the values for either pPBK 8473 or p86 8235/8236 normalized to o-Tubulin. |050 values of each compound were determined by plotting the normalized pPBK 8473 and p86 8235/8236 signals, respectively, versus the compound concentrations (in logarithmic scale) and then by fitting a sigmoidal dose-response curve with variable slope to the data using GraphPadTM Prism.

In vitro PI3K alpha binding assay inally His-tagged P|3K alpha (Cat. No. PV4789; 0.49 mg/ml), Alexa Fluor® 647 labeled kinase Tracer 314 (Cat. No. PV6087), Biotin anti-His Tag antibody (Cat. No PV6089) and 8creen® Eu-8treptavidin (Cat. No. PV5899) were purchased from Life Technologies. The 1x Kinase BufferA consists of 50mM HEPE8 pH 7.5, 10 mM MgClz, 1 mM EGTA, and 0.01% (v/v) Brij-35 (8igma Cat. No. B4184-100ML).

A 4-fold serial on of each compound to be tested was prepared in DMSO (master on) in a 96-well polystyrene plate (Falcon Cat. No. 353072, flat bottom) with the highest concentration at 1000 uM and the lowest at 0.004 uM. The master on series were diluted further 33.3-fold into Kinase BufferA by transferring 5 ul of each concentration of diluted nd to 162 pl Kinase BufferA in a new l plate resulting to a 3-fold serially compound dilution. Based on a Tracer 314 titration experiment a working concentration of 20 nM was chosen. ore a 60 nM Tracer 314 solution in Kinase Buffer A was prepared resulting in a 3-fold concentrated solution.

A 3-fold concentrated kinase/antibody solution at 15 nM kinase, 6 nM antibody and 6 nM 6161 Eu-Streptavidin was prepared in Kinase Buffer A. Five ul of each 3x serially diluted compound were dispensed in a || plate in duplicate. Then to each well 5 pl of 3x kinase/antibody mixture was added followed by the addition of 5 ul 3x Tracer 314 solution. After 1 h incubation at rt, esolved FRET was measured with a Synergy 4 multi-mode microplate reader (Biotek Instruments) using the following gs: 100 us delay before data collection, 200 us time for data collection, 10 measurements per data point. Emission filter: 665 nm/8 nm with ivity set to 163 and 620 nm/10 nm with sensitivity set to 135; Excitation filter: 340 nm/30 nm; Dichroic mirror 400 nm.

For data analysis, emission ratio was calculated by dividing the signal emitted at 665 nm from the or (Alexa Fluor® 647 labeled Tracer 314) by the signal emitted at 620 nm from the donor (Eu-labeled antibody). IC50 values of each compound were determined by plotting the emission ratio versus the compound concentrations (in thmic scale) and then by fitting a sigmoidal dose-response curve with variable slope to the data using GraphPadTM Prism.

Results Compound |n-ce|| Western blot in vitro PI3K alpha binding pPKB 8473 p86 8235/236 p110a p1100c IC50 [nM] IC50 [nM] IC50 [nM] Ki [nM] 6 425.4 695.9 390.4 n.d. 9 145 65 411 42 22 428.5 1088 98.1 n.d. 154 98 76 8 38 5909 9080 2623 n.d. 41 575 574 231 23 54 833 2111 383.1 n.d. 57 1261 594 1637 166 n.d. = not determined

Claims (12)

Claims

1. Compounds of formula (I), R3p R2 R3x N X N N R1 R3y R3z 5 (I) and stereoisomers, geometric isomers, ers and pharmaceutically acceptable salts thereof, wherein 10 R1 is O O O O O O O N N N N N N N O O O O O O O N N N N N N N and the the wavy line indicates the point of attachment of R1; 15 X is selected from the group consisting of O and NR7; R3x, R3y, R3z and R3p are independently selected from the group consisting of hydrogen, D, and C1-C12 alkyl; 20 R5, R6 and R7 are independently selected from H, D, and C1-C12 alkyl; R2 is independently selected from the groups ting of a monocyclic 5- or 6- membered heteroaryl with 1-3 heteroatoms selected from O, N, S, with 1-4 substituents selected from C1-C4 alkyl, CF3, CHF2, CFH2 and NR5R6. 18171233_1 ters) P41635NZ00

2. The compound of claim 1 wherein R2 is wherein the dotted line indicates the point of attachment of R2.

3. The nd of claim 1 wherein R2 is wherein the dotted line indicates the point of attachment of R2.

4. The compound of any of claims 1 to 3 wherein R1 is morpholino.

5. The compound of any of claims 1 to 3 wherein X is O. 15

6. The compound of any of claims 1 to 3 wherein R3x, R3y, R3z, and R3p are H.

7. The compound of claim 1 ed from the group consisting of 18171233_1 (GHMatters) P41635NZ00 - (R)(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin- 4-yl)pyridinamine, - (R)methyl(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] xazinyl)pyridinamine, 5 - (R)chloro(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1,4]oxazinyl)pyridinamine, - (R)amino(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1,4]oxazinyl)isonicotinonitrile, - (R)(difluoromethyl)(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo 10 [2,1-c][1,4]oxazinyl)pyridinamine, - (R)(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin- 4-yl)(trifluoromethyl)pyridinamine, - (R)ethyl(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1,4]oxazinyl)pyridinamine, 15 - (R)(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin- yrimidinamine, - (R)methyl(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1,4]oxazinyl)pyrimidinamine, - (R)chloro(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] 20 [1,4]oxazinyl)pyrimidinamine, - (R)amino(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1,4]oxazinyl)isonicotinonitrile, - (R)(difluoromethyl)(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo [2,1-c][1,4]oxazinyl)pyrimidinamine, 25 - (R)(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin- 4-yl)(trifluoromethyl)pyrimidinamine, - (R)ethyl(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1,4]oxazinyl)pyrimidinamine, - (S)(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin- 30 4-yl)pyridinamine, - (S)methyl(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1,4]oxazinyl)pyridinamine, - (S)chloro(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1,4]oxazinyl)pyridinamine, 18171233_1 (GHMatters) P41635NZ00 - (S)amino(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1,4]oxazinyl)isonicotinonitrile, - (S)(difluoromethyl)(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo [2,1-c][1,4]oxazinyl)pyridinamine, 5 - (S)(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin- 4-yl)(trifluoromethyl)pyridinamine, - (S)ethyl(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1,4]oxazinyl)pyridinamine, - (S)(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin- 10 4-yl)pyrimidinamine, - (S)methyl(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1,4]oxazinyl)pyrimidinamine, - chloro(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1,4]oxazinyl)pyrimidinamine, 15 - (S)amino(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1,4]oxazinyl)isonicotinonitrile, - (S)(difluoromethyl)(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo [2,1-c][1,4]oxazinyl)pyrimidinamine, - (2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin- 20 4-yl)(trifluoromethyl)pyrimidinamine, and - (S)ethyl(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c] [1,4]oxazinyl)pyrimidinamine.

8. A compound selected from the group consisting of 25 - cyclopropyl(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo [2,1-c][1,4]oxazinyl)pyridinamine, - (R)cyclopropyl(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo [2,1-c][1,4]oxazinyl)pyrimidinamine, - (S)cyclopropyl(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo 30 [2,1-c][1,4]oxazinyl)pyridinamine, and - (S)cyclopropyl(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo [2,1-c][1,4]oxazinyl)pyrimidinamine.

9. The compound of claim 1 selected from the group consisting of 18171233_1 (GHMatters) P41635NZ00 - (R)(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin- 4-yl)(trifluoromethyl)pyridinamine, and - (S)(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin- 4-yl)(trifluoromethyl)pyridinamine.

10. The compound of claim 1 selected from the group consisting of - (R)(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin- 4-yl)pyrimidinamine, and - (S)(2-morpholino-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin- 10 yrimidinamine.

11. A pharmaceutical composition comprising a compound of any of claims 1 to 10 and a pharmaceutically acceptable carrier. 15

12. Use of the compound of any one of claims 1 to 10 in the manufacture of a medicament for the treatment of cancer. 18171233_1 ters) P41635NZ00