WO2008109104A1 - Bivalent inhibitors of akt protein kinase - Google Patents

Abstract

The present disclosure describes compounds which are Akt kinase inhibitors useful for the treatment of cancer. The compounds disclosed herein are bivalent ligands capable of binding with both the kinase enzyme ATP binding domain and the kinase enzyme substrate binding domain.

Description

BIVALENT INHIBITORS OF Akt PROTEIN KINASE

STATEMENT REGARDING FEDERALLY FUNDED RESEARCH This invention was made with government support under Grant No. CAl 15521 awarded by the National Institutes of Health. The U.S. government has certain rights in the invention.

PRIORITY

This application claims the benefit of Provisional Application serial number 60/905,772 filed on March 7, 2007, and the entire disclosure of Provisional Application serial number 60/905,772 is incorporated herein by reference in its entirety.

BACKGROUND In living organisms kinase enzymes are ubiquitous and have therefore been the subject of intensive study. The subject of the present invention relates to a specific subgenus of kinase enzymes; Akt kinases and their inhibition as a means for abating cancer.

Kinases have generated considerable interest in the drug discovery community due to their involvement in key cellular processes, such as signal transduction and cell cycle control.^1"4 Being essential elements in pathways that mediate cell growth, cell division and programmed cell death, malfunctioning protein kinases are often responsible for the deregulation of signaling cascades and the oncogenic transformation of cells. The specific inhibition of such disease-related kinases promises to increase cure rates and to reduce toxic side-effects of chemotherapy. However, a central issue that must be addressed in the development of protein kinase-based drugs is target-specificity,⁵'⁶ because of the presence of over 500 protein kinases in the human genome.⁷'⁸ Most drug discovery approaches target the co-factor binding sites, which are usually quite conserved among kinases within a given family, making it difficult to obtain target-specific inhibitors. Compounds that are directed to the ATP-binding sites of these enzymes must contend with the presence with the presence of a large number of other kinases and ATP-utilizing proteins and, in addition, must compete with the high intracellular concentrations of ATP. While drug-discovery approaches that target the substrate-binding site promise greater selectivity, its large size and shallow nature have thwarted all attempts of developing small molecule inhibitors.⁹ Hence there is a great need for developing small molecule kinase inhibitors that are target- specific.

Serine/threonine (Ser/Thr) protein kinase Akt, also known as Protein Kinase B (PKB) is involved in the regulation of multiple cellular processes such as glucose metabolism, transcription, apoptosis, cell proliferation, angiogenesis, and cell motility.^10"13 Available data strongly suggests Akt/PKB to be oncogenic, if over-expressed ¹⁴'¹⁵ or constitutively activated. ^16"18 The gain of function in AfVPKB affects two distinct areas of cellular regulation important to cancer, the regulation of apoptosis ⁿ'^16>19"23 and the regulation of cell growth.²¹'^24"26 Akt/PKB inhibits apoptosis principally by down-regulating pro-apoptotic proteins like BAD (Bcl-2/Bcl-XL-antagonist, causing cell death), caspase-9 and forkhead transcription factor (FKHR).²⁷ In addition, Akt enhances cell growth by stimulating translation through mTOR (mammalian Target of Rapamycin), promoting transcription via NF B(nuclear factor B), interfering with the cyclin-dependent kinase inhibitor p27 and inhibiting the TLC tumor suppressor complex. ^27"33 Recent studies reveal a close link between Akt/PKB and the pathogenesis or progression of numerous and diverse human cancers, including non small cell lung cancer and small cell lung cancer, ^16>18'³⁴ breast cancer, ^28>35>36 cancers of the prostrate, ^23>37>38 pancreas, ³⁹'⁴⁰ colon, ⁴¹ thyroid, ¹⁴ brain ⁴²'⁴³ and the ovary.¹⁵ Several mechanisms have been identified that upregulate the phosphatidylinositol 3-kinase (Pl-3K)Akt signaling pathway in cancer. Increased upstream signaling is an important factor and is frequently seen in beast cancer where human epidermal growth factor receptor 2 (HER-2) activity feeds into the P1-3K pathway.³⁵'⁴⁴ Loss of function of the tumor suppressor PTEN (Phosphatase and Tensin homo log deleted on chromosome Ten), common in many tumors, takes away a critical negative regulator of Pl- 3K and results in elevated activity of Akt.⁴⁵ Increased transcription of Akt is detected in several human cancers and is often the result of gene amplification.³⁹'^46"50 Such amplification is particularly prevalent in cancers of the ovary and of the pancreas. Increased Akt/PKB activity in cancer cells results in resistance to drug-induced apoptosis and to increased cell replication.²¹'²³'^51"55 Cancer cells showing a gain in function of Akt are usually high sensitive to inhibitors of the Pl-3k/Akt signaling pathway, making Akt a promising target for drug development.²⁴'³⁴'⁵⁶'⁵⁷ In addition, the oncogenic signal from the upstream kinase phosphatidylinositol 3-kinase (P1-3K)²⁵'⁵⁸'⁶⁹ travels through Akt, further increasing the importance of Akt as a cancer target.²⁴"²⁶ Thus, the present disclosure relates to a treatment for P1-3K and Akt related cancers by selectively blocking the signal transduction cascade at Akt.

SUMMARY

The present disclosure through the following embodiments, iterations, and examples relates to compounds which can provide for selective Akt kinase inhibition. The compounds described herein can interact with the two binding domains of Akt kinases; the ATP binding domain and the substrate binding domain. The Akt kinase inhibitors disclosed herein have the formula:

wherein

W and Y can be each independently chosen from: i) hydrogen; or ii) Ci-C₆ linear, branched, or cyclic alkyl; Z has the formula:

the index b is 0 or 1 ; R can be chosen from: i) substituted or unsubstituted C₃-C₇ carbocyclic rings; ii) substituted or unsubstituted C₁-Cg heteroaryl rings; iii) substituted or unsubstituted C₁-Cg heterocyclic rings; or v) substituted or unsubstituted phenyl; L can have the formula:

-[C(R^IaR^lb)]_x[R³]_z[C(R^2aR^2b)]_y- R^la, R^lb, R^2a, and R^2b are each independently chosen from: i) hydrogen; or ii) Ci -C₄ linear or branched alkyl; R³ can be chosen from: i) -NR⁴-; ii) -NR⁴C(O)-; iii) -C(O)NR⁴-; iv) -C(O)-; vi) -OC(O)-; vii) -C(O)O-; viii) -NHC(O)NH-; ix) -NH(=NR⁴)NH-; x) -0-; or xi) -CR⁴=CR⁴-;

R⁴ is hydrogen, methyl, ethyl, or propargyl; the indices x and y can each be independently from O to 6; the index z is O or 1 ; L¹ has the formula: -[C(R^5aR^5b)]_m[R⁸]_q[C(R^6aR^6b)]_n[R⁹]_r[C(R^7aR^7b)]_p-

R^5a, R^5b, R^6a, R^6b, R^7a, and R^7b are each independently chosen from: i) hydrogen; ii) substituted or unsubstituted C]-C₆ linear or branched alkyl; iii) substituted or unsubstituted C₆ aryl; iv) substituted or unsubstituted C₆-Cg arylalkylene; v) -C(O)OR¹⁰; or vi) -C(O)NR¹¹³R^{1 lb};

R¹⁰, R^{l la}, and R^{l lb} can each be independently chosen from hydrogen or Ci-C₄ linear or branched alkyl; R⁸ and R⁹ are each independently chosen from: i) -NR¹²-; ii) - NR¹²NR¹²-; iii) -NR¹²C(O)-; iv) -C(O)NR¹²-; v) -C(O)-; vi) -OC(O)-; vii) -C(O)O-; or viii) -S-; and R¹² is independently hydrogen or C1-C4 linear or branched alkyl; the indices m, n, and p can each be independently from 0 to 6; the indices q and r can be each independently 0 or 1.

The present disclosure further relates to compositions which comprise: a) an effective amount of one or more Akt kinase inhibitors or salts thereof as disclosed herein; and b) one or more excipients.

Disclosed herein are methods for treating cancer comprising administering to a patient in need of treatment an effective amount of one or more compounds as described herein.

Disclosed herein are methods for selecting a unit that can bind to the Akt kinase ATP binding domains.

Disclosed herein are methods for selecting a unit that can bind to the Akt kinase substrate binding domains. Disclosed herein are methods for linking together a unit that can bind to the Akt kinase ATP binding domain with a unit that can bind to the Akt kinase substrate binding domain.

Also disclosed is the use of one or more compounds as described herein for making a medicament for the treatment of cancer. These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (° C) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.

DETAILED DESCRIPTION

Disclosed herein are novel Akt kinase inhibitors, compositions comprising Akt kinase inhibitors, and methods for treating cancer.

Akt is a serine-threonine kinase and functions as the central component of the PDK activity thus serves to recruit important cellular signaling pathway that starts with PI 3- kinase (PDK) at the plasma membrane. Akt has two major functional domains, an N- terminal pleckstrin homology domain that mediates lipid membrane interactions and a C- terminal kinase domain. The molecular structure of Akt has been determined. The human genome contains three Akt genes, coding for three closely related proteins, Aktl, Akt2, and Akt3. The three Akt proteins have overlapping functions and activities but also appear to have specific tasks.

The pleckstrin homology domain of Akt binds to PIP3, the product of PBK. PBK activity thus serves to recruit Akt to the plasma membrane. At this site enzymatic activity of Akt becomes activated by phosphorylation on threonine 308 in the activation loop and serine 47e in the hydrophobic tail. The two kinases mediating this activation are PDK-I and DNA-dependent protein kinase. Phosphorylation of Akt induces a conformational change that distinguishes the active from the inactive kinase.

Activation of Akt is one of the earliest changes seen in epithelial tissues after exposure to carcinogenic compounds of tobacco smoke. An important role of Akt in lung caner is suggested by the fact that about 50 percent of all non-small cell lung caners show enhanced expression of phosphorylated Akt and hence a gain in Akt functions. Included in these 50 percent Akt-positive tumors are those with a mutation in the EGF receptor. That mutation has been reported to be responsible for the constitutive activation of the Akt pathway in these tumors and accounts for the 10 percent of lung cancers that respond to treatment with the EGFR inhibitor Gefitinib.

Most currently available kinase inhibitors function by blocking the ATP binding domain of the enzyme. Because the ATP binding domains of different kinases can be structurally similar, these inhibitors often suffer from a lack of specificity and have unacceptable side effects. The present disclosure relates to the development of Akt inhibitors with high selectivity or high specificity. The compounds disclosed herein can provide a solution to the problem of inhibitor specificity through the design and preparation of bivalent ligand inhibitors. One end of the compounds disclosed herein binds to the ATP binding domain while the other end extends into the substrate binding domain. Although the ATP binding domains of different kinases are very similar in structure, the substrate binding domain of each kinase is more specific to that particular kinase and the substrate binding domain of each different kinase is located at different distances away from the respective ATP binding domain. As described here the disclosed compounds comprise two separate units; one that can bind to the ATP binding domain and one that can bind to the substrate binding domain. These two units are connected to one another by a linking unit or tether. As discussed herein above, because the distance between these two domains varies from kinase to kinase, the length of the linking unit or tether which connects these two units can be optimized for a particular kinase. This fact provides for compounds disclosed herein that can interact with a particular kinase with a high degree of selectivity, as well as specificity. The methods disclosed herein provide a means for selecting a unit that can effectively interact with a kinase enzyme ATP binding domain, for selecting a unit that can effectively interact with a kinase enzyme substrate binding domain and for a means of forming a link or tether between the two units thereby forming a compound that can be an effective Akt kinase inhibitor.

The following chemical hierarchy is used throughout the specification to describe and enable the scope of the present invention and to particularly point out and distinctly claim the units which comprise the compounds of the present invention, however, unless otherwise specifically defined, the terms used herein are the same as those of the artisan of ordinary skill. The term "hydrocarbyl" stands for any carbon atom-based unit (organic molecule), said units optionally containing one or more organic functional group, including inorganic atom comprising salts, inter alia, carboxylate salts, quaternary ammonium salts. Within the broad meaning of the term "hydrocarbyl" are the classes "acyclic hydrocarbyl" and "cyclic hydrocarbyl" which terms are used to divide hydrocarbyl units into cyclic and non-cyclic classes.

As it relates to the following definitions, "cyclic hydrocarbyl" units may comprise only carbon atoms in the ring (carbocyclic and aryl rings) or may comprise one or more heteroatoms in the ring (heterocyclic and heteroaryl). For "carbocyclic" rings the lowest number of carbon atoms in a ring are 3 carbon atoms; cyclopropyl. For "aryl" rings the lowest number of carbon atoms in a ring are 6 carbon atoms; phenyl. For "heterocyclic" rings the lowest number of carbon atoms in a ring is 1 carbon atom; diazirinyl. Ethylene oxide comprises 2 carbon atoms and is a C₂ heterocycle. For "heteroaryl" rings the lowest number of carbon atoms in a ring is 1 carbon atom; 1,2,3,4-tetrazolyl. The following is a non-limiting description of the terms "acyclic hydrocarbyl" and "cyclic hydrocarbyl" as used herein. A. Substituted and unsubstituted acyclic hydrocarbyl: For the purposes of the present invention the term "substituted and unsubstituted acyclic hydrocarbyl" encompasses 3 categories of units:

1) linear or branched alkyl, non-limiting examples of which include, methyl (Ci), ethyl (C₂), n-propyl (C₃), wo-propyl (C₃), n-butyl (C₄), sec-butyl (C₄), /so-butyl (C₄), tert- butyl (C₄), and the like; substituted linear or branched alkyl, non-limiting examples of which includes, hydroxymethyl (Ci), chloromethyl (Ci), trifluoromethyl (Ci), aminomethyl (C ι), 1-chloroethyl (C₂), 2-hydroxyethyl (C₂), 1 ,2-difluoroethyl (C₂), 3-carboxypropyl (C₃), and the like.

2) linear or branched alkenyl, non-limiting examples of which include, ethenyl (C₂), 3- propenyl (C₃), 1-propenyl {also 2-methylethenyl) (C₃), isopropenyl {also 2- methylethen-2-yl) (C₃), buten-4-yl (C₄), and the like; substituted linear or branched alkenyl, non-limiting examples of which include, 2-chloroethenyl {also 2- chlorovinyl) (C₂), 4-hydroxybuten-l-yl (C₄), 7-hydroxy-7-methyloct-4-en-2-yl (C₉), 7-hydroxy-7-methyloct-3,5-dien-2-yl (C₉), and the like. 3) linear or branched alkynyl, non-limiting examples of which include, ethynyl (C₂), prop-2-ynyl {also propargyl) (C₃), propyn-1-yl (C₃), and 2-methyl-hex-4-yn-l-yl (C₇); substituted linear or branched alkynyl, non-limiting examples of which include, 5-hydroxy-5-methylhex-3-ynyl (C₇), 6-hydroxy-6-methylhept-3-yn-2-yl (C₈), 5-hydroxy-5-ethylhept-3-ynyl (C₉), and the like. B. Substituted and unsubstituted cyclic hydrocarbyl:

For the purposes of the present invention the term "substituted and unsubstituted cyclic hydrocarbyl" encompasses 5 categories of units:

1) The term "carbocyclic" is defined herein as "encompassing rings comprising from 3 to 20 carbon atoms, wherein the atoms which comprise said rings are limited to carbon atoms, and further each ring can be independently substituted with one or more moieties capable of replacing one or more hydrogen atoms." The following are non-limiting examples of "substituted and unsubstituted carbocyclic rings" which encompass the following categories of units: i) carbocyclic rings having a single substituted or unsubstituted hydrocarbon ring, non-limiting examples of which include, cyclopropyl (C₃), 2-methyl- cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), 2,3-dihydroxycyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclopentadienyl

(C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cycloheptyl (C₇), cyclooctanyl (C₈), decalinyl (C₁O), 2,5-dimethylcyclopentyl (C₅), S^-dichlorocyclohexyl (C₆), 4- hydroxycyclohexyl (C₆), and 3,3,5-trimethylcyclohex-l-yl (C₆). ii) carbocyclic rings having two or more substituted or unsubstituted fused hydrocarbon rings, non-limiting examples of which include, octahydropentalenyl (C₈), octahydro-lH-indenyl (C₉), 3a,4,5,6,7,7a-hexahydro-3i/-inden-4-yl (C₉), decahydroazulenyl (C io). iii) carbocyclic rings which are substituted or unsubstituted bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, l,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

2) The term "aryl" is defined herein as "units encompassing at least one phenyl or naphthyl ring and wherein there are no heteroaryl or heterocyclic rings fused to the phenyl or naphthyl ring and further each ring can be independently substituted with one or more moieties capable of replacing one or more hydrogen atoms." The following are non-limiting examples of "substituted and unsubstituted aryl rings" which encompass the following categories of units: i) C₆ or C_1O substituted or unsubstituted aryl rings; phenyl and naphthyl rings whether substituted or unsubstituted, non- limiting examples of which include, phenyl (C₆), naphthylen-1-yl (Ci₀), naphthylen-2-yl (C io), 4-fluorophenyl (C₆), 2- hydroxyphenyl (C₆), 3-methylphenyl (C₆), 2-amino-4-fluorophenyl (C₆), 2-(NJV- diethylamino)phenyl (C₆), 2-cyanophenyl (C₆), 2,6-di-tert-butylphenyl (C₆), 3- methoxyphenyl (C₆), 8-hydroxynaphthylen-2-yl (Qo), 4,5-dimethoxynaphthylen-l- yl (Cio), and 6-cyano-naphthylen-l-yl (Cio). ii) C₆ or Cio aryl rings fused with 1 or 2 saturated rings non- limiting examples of which include, bicyclo[4.2.0]octa-l,3,5-trienyl (C₈), and indanyl (C₉).

3) The terms "heterocyclic" and/or "heterocycle" are defined herein as "units comprising one or more rings having from 3 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O), or sulfur (S), or mixtures of N, O, and S, and wherein further the ring which comprises the heteroatom is also not an aromatic ring." The following are non-limiting examples of "substituted and unsubstituted heterocyclic rings" which encompass the following categories of units: i) heterocyclic units having a single ring containing one or more heteroatoms, non- limiting examples of which include, diazirinyl (Ci), aziridinyl (C₂), urazolyl (C₂), azetidinyl (C₃), pyrazolidinyl (C₃), imidazolidinyl (C₃), oxazolidinyl (C₃), isoxazolinyl (C₃), isoxazolyl (C₃), thiazolidinyl (C₃), isothiazolyl (C₃), isothiazolinyl (C₃), oxathiazolidinonyl (C₃), oxazolidinonyl (C₃), hydantoinyl (C₃), tetrahydrofuranyl (C₄), pyrrolidinyl (C₄), moφholinyl (C₄), piperazinyl (C₄), piperidinyl (C₄), dihydropyranyl (C₅), tetrahydropyranyl (C₅), piperidin-2-onyl (valerolactam) (C₅), 2,3,4,5-tetrahydro-lH-azepinyl (C₆), 2,3-dihydro-lH-indole (C₈), and 1,2,3,4-tetrahydro-quinoline (C₉). ii) heterocyclic units having 2 or more rings one of which is a heterocyclic ring, non-limiting examples of which include hexahydro-l//-pyrrolizinyl (C₇), 3a,4,5,6,7,7a-hexahydro-lH-benzo[d]imidazolyl (C₇), 3a,4,5,6,7,7a-hexahydro-lH- indolyl (C₈), 1,2,3,4-tetrahydroquinolinyl (C₉), and decahydro-lH- cycloocta[b]pyrrolyl (Cio). The term "heteroaryl" is defined herein as "encompassing one or more rings comprising from 5 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O), or sulfur (S), or mixtures of N, O, and S, and wherein further at least one of the rings which comprises a heteroatom is an aromatic ring." The following are non- limiting examples of "substituted and unsubstituted heterocyclic rings" which encompass the following categories of units: i) heteroaryl rings containing a single ring, non-limiting examples of which include, 1,2,3,4-tetrazolyl (C₁), [l,2,3]triazolyl (C₂), [l,2,4]triazolyl (C₂), triazinyl (C₃), thiazolyl (C₃), lH-imidazolyl (C₃), oxazolyl (C₃), furanyl (C₄), thiopheneyl (C₄), pyrimidinyl (C₄), 2-phenylpyrimidinyl (C₄), pyridinyl (C₅), 3-methylpyridinyl (C₅), and 4-dimethylaminopyridinyl (C₅) ii) heteroaryl rings containing 2 or more fused rings one of which is a heteroaryl ring, non-limiting examples of which include: 7H-purinyl (C₅), 9H-purinyl (C₅), 6- amino-9H-purinyl (C₅), 5H-pyrrolo[3,2-cT|pyrimidinyl (C₆), 7H-pyrrolo[2,3- cTJpyrimidinyl (C₆), pyrido[2,3-cf)pyrimidinyl (C₇), 2-phenylbenzo[d]thiazolyl (C₇), lH-indolyl (C₈), 4,5,6,7-tetrahydro- 1 -H-indolyl (C₈), quinoxalinyl (C₈), 5- methylquinoxalinyl (C₈), quinazolinyl (C₈), quinolinyl (C₉), 8-hydroxy-quinolinyl (C₉), and isoquinolinyl (C₉). 5) Ci-C₆ tethered cyclic hydrocarbyl units (whether carbocyclic units, C₆ or C₁₀ aryl units, heterocyclic units, or heteroaryl units) which connected to another moiety, unit, or core of the molecule by way of a Cj-C₆ alkylene unit. Non- limiting examples of tethered cyclic hydrocarbyl units include benzyl Ci-(C₆) having the formula:

wherein R^a is optionally one or more independently chosen substitutions for hydrogen. Further examples include other aryl units, inter alia, (2- hydroxyphenyl)hexyl C₆-(C₆); naphthalen-2-ylmethyl Ci-(Cio), 4-fiuorobenzyl Ci- (C₆), 2-(3-hydroxy-phenyl)ethyl C₂-(C₆), as well as substituted and unsubstituted C₃-

Cio alkylenecarbocyclic units, for example, cyclopropylmethyl Cj-(C₃), cyclopentylethyl C₂-(C₅), cyclohexyhnethyl C]-(C₆);. Included within this category are substituted and unsubstituted C₁-Ci₀ alkylene-heteroaryl units, for example a 2- picolyl Ci-(C₆) unit having the formula:

wherein R^a is the same as defined above. In addition, Ci-C)₂ tethered cyclic hydrocarbyl units include Ci-C_1O alkyleneheterocyclic units and alkylene-heteroaryl units, non-limiting examples of which include, aziridinylmethyl Cr(C₂) and oxazol-

2-ylmethyl Ci-(C₃). For the purposes of the present invention carbocyclic rings are from C₃ to C₂o; aryl rings are C₆ or do; heterocyclic rings are from Ci to C₉; and heteroaryl rings are from Ci to C₉.

For the purposes of the present invention, and to provide consistency in defining the present invention, fused ring units, as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be characterized and referred to herein as being encompassed by the cyclic family corresponding to the heteroatom containing ring, although the artisan may have alternative characterizations. For example, 1,2,3,4- tetrahydroquinoline having the formula:

is, for the purposes of the present invention, considered a heterocyclic unit. 6,7-Dihydro- 5i/-cyclopentapyrimidine having the formula:

is, for the purposes of the present invent considered a heteroaryl unit. When a fused ring unit contains heteroatoms in both a saturated ring (heterocyclic ring) and an aryl ring (heteroaryl ring), the aryl ring will predominate and determine the type of category to which the ring is assigned herein for the purposes of describing the invention. For example, l,2,3,4-tetrahydro-[l,8]naphthyridine having the formula:

is, for the purposes of the present invention, considered a heteroaryl unit.

The term "substituted" is used throughout the specification. The term "substituted" is applied to the units described herein as "substituted unit or moiety is a hydrocarbyl unit or moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several substituents as defined herein below." The units, when substituting for hydrogen atoms are capable of replacing one hydrogen atom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbyl moiety at a time. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety, or unit. For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like. A two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. Three hydrogen replacement includes cyano, and the like. The term substituted is used throughout the present specification to indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkyl chain; can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as "substituted" any number of the hydrogen atoms may be replaced. For example, 4-hydroxyphenyl is a "substituted aromatic carbocyclic ring (aryl ring)", (N,N-dimethyl-5-amino)octanyl is a " substituted C₈ linear alkyl unit, 3-guanidinopropyl is a "substituted C₃ linear alkyl unit," and

2-carboxypyridinyl is a "substituted heteroaryl unit." The following are non-limiting examples of units which can substitute for hydrogen atoms on a carbocyclic, aryl, heterocyclic, or heteroaryl unit: i) Ci-C₄ linear or branched alkyl; for example, methyl (C₁), ethyl (C₂), n-propyl

(C₃), wo-propyl (C₃), n-butyl (C₄), iso-butyl (C₄), sec-butyl (C₄), and tert- butyl (C₄); ii) -OR³⁰; for example, -OH, -OCH₃, -OCH₂CH₃, -OCH₂CH₂CH₃; iii) -C(O)R³⁰; for example, -COCH₃, -COCH₂CH₃, -COCH₂CH₂CH₃; iv) -C(O)OR³⁰; for example, -CO₂CH₃, -CO₂CH₂CH₃, -CO₂CH₂CH₂CH₃; v) -C(O)N(R³⁰)₂; for example, -CONH₂, -CONHCH₃, -CON(CH₃)₂; vi) -N(R^3O)₂; for example, -NH₂, -NHCH₃, -N(CH₃)₂, -NH(CH₂CH₃); vii) halogen: -F, -Cl, -Br, and -I; viii) -CH_mX_n; wherein X is halogen, m is from O to 2, m + n =3; for example,

-CH₂F, -CHF₂, -CF₃, -CCl₃, or -CBr₃; and ix) -SO₂R³⁰; for example, -SO₂H; -SO₂CH₃; -SO₂C₆H₅ wherein each R³⁰ is independently hydrogen, substituted or unsubstituted C₁-C₄ linear, branched, or cyclic alkyl; or two R³⁰ units can be taken together to form a ring comprising 3-7 atoms. Substituents suitable for replacement of a hydrogen atom are further defined herein below.

The compounds disclosed herein include all salt forms, for example, salts of both basic groups, inter alia, amines, as well as salts of acidic groups, inter alia, carboxylic acids. The following are non-limiting examples of anions that can form salts with basic groups: chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, citrate, and the like. The following are non-limiting examples of cations that can form salts of acidic groups: sodium, lithium, potassium, calcium, magnesium, bismuth, and the like.

Akt Kinase Inhibitors The Akt kinase inhibitors disclosed herein have the formula:

wherein the following depicts one non-limiting example of the various units of the Akt kinase inhibitors as described herein.

ATP binding domain unit tether/linking unit Substrate binding domain unit

The tether/linking unit depicted in the example herein above, comprises a triazolyl unit that can be formed by reaction of an azide and an acetylene unit, and a linking unit L, which length can be adjusted by the formulator so that the distance between the ATP binding domain unit and the substrate binding domain unit is optimized for a particular Akt kinase. As is further disclosed herein, the Z unit comprises a second linking unit L¹ which length can also be adjusted by the formulator to optimize the distance between binding domains of a particular Akt kinase. The ATP Binding Domain Unit

The ATP Binding Domain Unit of the compounds disclosed herein can be any analog of Adenosine Triphosphate (ATP)which can effectively bind to the domain of Akt kinase that normally binds ATP.

In the compounds disclosed herein, the ATP Binding Domain Unit can typically employ a 7,8-disubstituted-3-phenyl-[l,2,4]triazolo[4,3-b]pyridazine derivative as shown above, bonded to the tether/linking unit at the 6 position, and having optional W and Y substituents at the 7 and 8 positions. One to three additional substituents may also optionally be bonded to the phenyl ring, at any position thereon, such as for example independently selected substituents such as hydroxy, fluoro, chloro, NH₂, NHCH₃, N(CH₃)₂, CN, OC(O)CH₃, SCH₃, S(O)CH₃, S(O)₂CH₃, S(O)₂NHCH₃, SC₂H₅, methyl, ethyl, propyl, isopropyl, vinyl, allyl, CN, CH₂OH, CH₂OCH₃, CH₂OCH₂CH₃, C(O)H, C(O)CH₃, methoxy, ethoxy, or isopropoxy groups.

In such 7,8-disubstituted-3-phenyl-[l,2,4]triazolo[4,3-b]pyridazine derivative embodiments, W can be chosen from: i) hydrogen; or ii) C₁-C₆ linear, branched, or cyclic alkyl.

In various related embodiments W can be hydrogen, W can be methyl,

W can be independently chosen from ethyl (C₂), n-propyl (C₃), /so-propyl (C₃), n- butyl (C₄), iso-buty\ (C₄), sec-butyl (C₄), and tert-butyl (C₄), W can be independently chosen from cyclopropyl (C₃), cyclobutyl (C₄), cyclopentyl (C₅), and cyclohexyl (C₆), or can be

W can be independently chosen from n-pentyl (Cs), 1-methylbutyl (C₅), 2-methylbutyl (C₅), 3-methylbutyl (C₅), 1 ,2-dimethyl-propyl (C₆), 1-methylpentyl (C₆), 2-methylpentyl (C₆), 3- methylpentyl (C₆), 4-methyl-pentyl (C₆), 1 ,2-dimethylbutyl (C₆),l-ethylbutyl (C₆), and 1- isopropylpropyl (C₆).

Y can be chosen from: i) hydrogen; or ii) Cj-C₆ linear, branched, or cyclic alkyl.

In related embodiments Y can be cyclobutyl (C₄), Y can be hydrogen, Y can be independently chosen from hydrogen, wo-propyl (C₃), and cyclobutyl (C₄),

Y can be methyl (C₁),

Y can be independently chosen from ethyl (C₂), n-propyl (C₃), iso-propyl (C₃), n- butyl (C₄), /sobutyl (C₄), sec-butyl (C₄), and tert-butyl (C₄), or

Y can be independently chosen from cyclopropyl (C₃), cyclopentyl (C₅), and cyclohexyl (C₆), n-pentyl (C₅), 1-methylbutyl (C₅), 2-methylbutyl (C₅), 3-methylbutyl (C₅), 1,2-dimethyl-propyl (C₆), 1-methylpentyl (C₆), 2-methylpentyl (C₆), 3-methylpentyl (C₆), 4- methyl-pentyl (C₆), 1,2-dimethylbutyl (C₆),l-ethylbutyl (C₆), and l-wo-propylpropyl (C₆).

The Tether/Linking Unit

L is a linking group which is part of the tether/linking unit that connects the substrate binding domain unit to the 3-phenyl-6-amino-[ 1 ,2,4]triazolo[4,3-&]pyridazinyl ATP binding domain unit.

L has the general formula:

-[C(R^laR^lb)]_x[R³]_z[C(R^2aR^2b)]_y- Wherein R^la, R^lb, R^2a, and R^2b can be each independently chosen from: i) hydrogen; or ii) Ci -C4 linear or branched alkyl; R³ can be chosen from: i) -NR⁴-; ii) -NR⁴C(O)-; iii) -C(O)NR⁴-; iv) -C(O)-; vi) -OC(O)-; vii) -C(O)O-; viii) -NHC(O)NH-; ix) -NH(=NR⁴)NH-; x) -0-; or xi) -CR⁴=CR⁴-; R⁴ can be hydrogen, methyl, ethyl, or propargyl (-CH₂CCH);

The indices x and y are each independently from O to 6; the index z is O or 1

Some related embodiment of L units relates to linking units having the formula:

-(CH₂)C(R^laR^lb)(CH₂)NH[CH₂]_y- wherein R^Ia and R^lb can be each independently chosen from hydrogen, methyl, or ethyl, and the index y is from 1 to 3. Non-limiting examples of such L units include units chosen from: i) -CH₂C(CH₃)₂CH₂NHCH₂-; ii) -CH₂C(CH₃)₂CH₂NHCH₂CH₂-; iii) -CH₂C(CHa)₂CH₂NHCH₂CH₂CH₂-; iv) -CH₂CH(CH₃)CH₂NHCH₂-; v) -CH₂CH(CH₃)CH₂NHCH₂CH₂-; vi) -CH₂CH(CH₃)CH₂NHCH₂CH₂CH₂-; vii) -CH₂CH₂CH₂NHCH₂-; ii) -CH₂CH₂CH₂NHCH₂CH₂-; and iii) -CH₂CH₂CH₂NHCH₂CH₂CH₂-.

Other related embodiment of L units relates to linking units having the formula: -(CH₂)C(R¹V)(CH₂)NHC(O)[CH₂J_y- wherein R^Ia and R^lb can be each independently chosen from hydrogen, methyl, or ethyl, and the index y is from 1 to 3. Non-limiting examples of this embodiment of L units include units chosen from: i) -CH₂C(CH₃)₂CH₂NHC(O)CH₂-; ii) -CH₂C(CH₃)ZCH₂NHC(O)CH₂CH₂-; iii) -CH₂C(CHa)₂CH₂NHC(O)CH₂CH₂CH₂-; iv) -CH₂CH(CH₃)CH₂NHC(O)CH₂-; v) -CH₂CH(CH₃)CH₂NHC(O)CH₂CH₂-; vi) -CH₂CH(CH₃)CH₂NHC(O)CH₂CH₂CH₂-; vii) -CH₂CH₂CH₂NHC(O)CH₂-; ii) -CH₂CH₂CH₂NHC(O)CH₂CH₂-; and iii) -CH₂CH₂CH₂NHC(O)CH₂CH₂CH₂-.

However, other embodiments of L units not specifically exemplified can be chosen by the formulator for use in preparing the compounds disclosed herein. The Substrate Binding Domain Unit

The Substrate Binding Domain Unit which can be termed the "2" unit, is moiety whose structure is optimized to provide highly specific binding to the Substrate Binding Domain of Akt.

Z has the general formula:

-^-σΛ-^R wherein the index b is O or 1. When the index b is O, L¹ is absent and the unit -Z composes an -R unit.

R can be chosen from: i) substituted or unsubstituted C₃-C₇ carbocyclic rings; ii) substituted or unsubstituted C₁-C₉ heteroaryl rings; iii) substituted or unsubstituted C₁-C₉ heterocyclic rings; or v) substituted or unsubstituted phenyl.

In some embodiments R can be a substituted or unsubstituted Ci, C₂, C₃, or C₄ heteroaryl or heterocyclic 5-member ring/, Non-limiting examples of R units which can be independently chosen from: i) a pyrrolidinyl ring having the formula;

ϋ) a pyrrolyl ring having the formula:

iii) a 4,5-dihydroimidazolyl ring having the formula:

iv) a pyrazolyl ring having the formula:

v) an imidazolyl ring having the formula:

vi) a [l,2,3]triazolyl ring having the formula:

vii) a [1,2,4] triazolyl ring having the formula:

viii) tetrazolyl ring having the formula:

ix) a [1,3,4] or [l,2,4]oxadiazolyl ring having the formula:

x) a pyrrolidinonyl ring having the formula:

xi) an imidazolidinonyl ring having the formula:

xii) an imidazol-2-only ring having the formula:

xiii) an oxazolyl ring having the formula:

xiv) an isoxazo IyI ring having the formula:

xv) a dihydrothiazolyl ring having the formula:

xvi) a furanly ring having the formula:

xvii) a thiophenyl having the formula:

Non-limiting examples of units which can substitute for one or more hydrogen ring atoms of the C₂, C₃, or C₄ heteroaryl or heterocyclic 5-member ring can be independently chosen from: a) Ci-C₄ linear or branched alkyl; b) Ci-C₄ linear or branched alkoxy; c) -C(O)OR¹³; or d) -SO₂NR^14aR^I4b; wherein R¹^R¹⁴⁸, and R^14b are each independently hydrogen, methyl or ethyl.

Non-limiting examples of substituted Ci, C₂, C₃, or C₄ heteroaryl or heterocyclic 5- member rings can include: i) 3-methylisoxazol-5-yl and 5-methylisoxazol-3-yl having the formulae:

ii) 3-methyl-5-phenylisoxazol-4-yl and 3-phenyl-5-methylisoxazol-4-yl having the formulae:

iii) 3,5-dimethylpyrazol-l-yl having the formulae:

iv) 1 -(methylcarboxyH 1 ,2,3]triazol-4-yl and 1 -(ethylcarboxy)-[ 1 ,2,3]triazol-4- yl having the formulae:

v) 4-(methylcarboxy)[l,2,3]triazol-l-yl and 4-(ethylcarboxy)[l,2,3]triazol-l-yl having the formulae:

vi) l-(methylcarboxy)methyl-[l,2,3]triazol-4-yl and l-(methylcarboxy)- methyl[l,2,3]triazol-l-yl having the formulae:

vii) 4-(methylcarboxy)methyl-[l,2,3]triazol-l-yl and 4-(ethylcarboxy)methyl- [l,2,3]triazol-l-yl having the formulae:

viii) 2-methlpyrrol- 1 -yl and 3 -methylpyrrol- 1 -yl having the formulae;

A further embodiment of R units relates to substituted or unsubstituted C₃, C₄ or C₅ heterocyclic or heteroaryl 6-member rings, non-limiting examples of which can be independently chosen from: i) a morpholinyl ring having the formula:

ϋ) a piperidinyl ring having the formula:

iii) a pyridinyl ring having the formula:

iv) a pyrimidinyl ring having the formula:

v) a piperazinyl ring having the formula:

vi) a triazinyl ring having the formula:

Non-limiting examples of units which can substituted for one or more hydrogen ring atoms of the C₂, C₃, or C₄ heteroaryl or heterocyclic 6-member ring are independently chosen from: a) C₁-C₄ linear or branched alkyl; b) C₁-C₄ linear or branched alkoxy; c) -C(O)OR¹³; or d) -SO₂NR^14aR^14b; wherein R¹³,R^14a, and R^14b are each independently hydrogen, methyl or ethyl. Non-limiting examples of substituted C₃, C₄, or C₅ heteroaryl or heterocyclic 6- member rings include: i) 4,6-dimethylpyrimidin-2-yl and 4-hydroxy-6-methylpyrimidin-2-yl having the formulae;

ii) 4-(methylcarboxy)pyridin-2-yl and 4-(ethylcarboxy)pyridin-2-yl having the formulae:

Another related embodiment of R units relates to substituted or unsubstituted C₇, C₈ or C₉ heterocyclic or heteroaryl fused rings, non-limiting examples of which can be independently chosen from: i) benzoimidazolyl rings having the formula:

ii) benzothiazolyl rings having the formula:

iii) benzoxazolyl rings having the formula:

iv) quinazolinyl rings having the formula:

v) 2,3-dihydrobenzo[l,4]dioxinyl rings having the formula:

vi) tetrahydroquinolinyl rings having the formula:

Non-limiting examples of units which can substitute for one or more hydrogen ring atoms of the C₇, C₈, or C₉ heteroaryl or heterocyclic fused rings can be independently chosen from: a) Ci -C₄ linear or branched alkyl; b) Ci -C₄ linear or branched alkoxy; c) -C(O)OR¹³; or d) -SO₂NR^14aR^14b; wherein R¹³,R^14a, and R^14b can be each independently hydrogen, methyl or ethyl.

Non-limiting examples of substituted C₇, C₈, or C₉ heteroaryl or heterocyclic fused rings include: i) 2-methylquinazolin-4-yl and 2-methylquinazolinon-3-yl having the formulae:

ii) 5-(methylcarboxy)benzothiazol-2-yl and 6-(methylcarboxy)benzothiazol-2- yl having the formulae:

Another related embodiment of R units relates to substituted or unsubstituted C₃-C₇ carbocyclic rings independently chosen from cyclopropyl (C₃), cyclobutyl (C₄), cyclobutyl (C₄), cyclobutyl (C₄), cyclopentyl (C₅), cyclohexyl (C₆), and cycloheptyl (C₇). The following embodiment of R units relates to substituted or unsubstituted phenyl, non-limiting examples of units which can substitute for hydrogen include one or more units independently chosen from: a) Ci-C₄ linear or branched alkyl; for example, methyl (Ci), ethyl (C₂), n-propyl (C₃), wo-propyl (C₃), n-butyl (C₄), sec-butyl (C₄), wo-butyl (C₄), and tert- butyl (C₄); b) Ci-C₄ linear or branched alkoxy; for example, methoxy (Ci), ethoxy (C₂), n- propoxy (C₃), /sopropoxy (C₃), n-butoxy (C₄), sec-butoxy (C₄), /so-butoxy

(C₄), and /ert-butoxy (C₄); c) -CCH₂)AO)OR¹³; for example, -CO₂CH₃, -CH₂CO₂CH₃, -CO₂CH₂CH₃, and -CO₂CH₂CH₂CH₃; d) -(CH₂XOC(O)R¹³; for example, -OCOCH₃, -OCOCH₂CH₃, and -OCOCH₂CH₂CH₃; e) -(CH₂),C(O)NR^14aR^14b; for example, -CONH₂, -CONH₂, -CONHCH₃,

-(CH₂)CONHCH₃, and -CON(CH₃)₂; f) -(CH₂)_tSO₂NR^14aR^14b; for example, -SO₂NH₂; and -SO₂ NHCH₃; g) -(CHjX_k)_u; for example, -CH₂F, -CHF₂, and -CF₃; h) -(CH₂)(OH; for example, -OH, and -CH₂OH; or i) halogen; wherein R¹³, R^14a, and R^14b can be each independently hydrogen, methyl, or ethyl; X is one or more halogen chosen from fluoro, chloro, or iodo; the index j is from O to 2; the index k is from 1 to 3; j + k = 3; the index t is from O to 3; the index u is from O to 3.

Non-limiting examples of substituted phenyl units that can be used in preparing the compounds disclosed herein include:

L¹ is a linking unit that when present (the index b = 1) serves to connect the R unit to the tether/linking unit. L¹ is present when the index b is equal to 1 and L¹ is absent when the index b is equal to O. L¹ has the formula: i) -[C(R^5aR^5b)]_m-; ii) -[C(R^5aR^5b)]_mC(O)NH[C(R^6aR^6b)]_n-; or iii) -[C(R^5aR^5b)]_mC(O)NH[C(R^6aR^6b)]_n[R⁹][C(R^7aR^7b)]p-

R^5a, R^5b, R^6a, R^6b, R^7a, and R™ are each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, wo-propyl, /so-butyl, 5ec-butyl, benzyl, -C(O)OR¹⁰ _; R¹⁰ is chosen from hydrogen or Ci-C₄ linear or branched alkyl; R⁹ is chosen from: i) -NHC(O)-; ii) -C(O)NH-; or iϋ) -S-; the indices m, n, and p each independently have the value from 0 to 4.

A first embodiment of L¹ units relates to units having the formula:

-[C(R^5aR^5b)]_m- wherein each R^5a and R^5b is independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, jsø-propyl, iso-butyl, and sec-butyl; and m is from 1 to 4.

Another related embodiment of L¹ relates to compounds which can be connected to the core scaffold by a methylene unit: -CH₂-. When these L¹ units is taken together with R units, this combination provides for methylene tethered Z units having the formula:

-CH₂-R; non-limiting examples of these Z units include units having the formulae:

Another embodiment of L¹ relates to compounds that can be connected to the core scaffold by alkylene units that are longer than a methylene unit, wherein R^5a and R^5b are each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, zso-propyl, iso- butyl, and sec-butyl; for example, unit chosen from: i) -CH₂CH₂-; ii) -CH₂CH₂CH₂-; iii) -CH₂CH₂CH₂CH₂-; iv) -CH₂CH(CH₃)CH₂-; v) -CH₂CH(CH₃)CH₂CH₂-; vi) -CH₂CH₂CH(CH₃)CH₂-; and vii) -CH₂CH[CH₂CH(CH₃)₂]CH₂-. These L¹ units when taken together with R units, provides for Z units having the formulae:

Another embodiment of L¹ units relates to units having the formula:

-[C(R^5aR^5b)]_mC(O)NH[C(R^6aR^6b)]_n- wherein each R^5a, R^5b, R^6a, and R^6b is independently chosen from hydrogen, methyl, hydroxy-methyl, ethyl, zsø-propyl, sec-butyl, /sø-butyl, and benzyl; and the indices m and n are each independently from 1 to 4. Another embodiment of L¹ relates to compounds wherein the indices m and n can each be equal to 1 thereby providing L¹ units having the formula:

-CHR^5aC(O)NHCHR^6a- non-limiting examples of which can be chosen from: i) -CH₂C(O)NHCH₂-; ii) -CH(CH₃)C(O)NHCH₂-; iii) -CH₂C(O)NHCH(CH₃)-; iv) -CH(CH₃)C(O)NHCH(CH₃)-; v) -CH[CH(CH₃)₂]C(O)NHCH₂-; vi) -CH₂C(O)NHCH[CH(CH₃)₂]-; vii) -CH[CH(CH₃)₂]C(O)NHCH[CH(CH₃)₂]-; v) -CH[CH(CH₃)₂C(O)NHCH(CH₃)-; vi) -CH(CH₃)C(O)NHCH[CH(CH₃)₂]-; vii) -CH[CH₂CH(CH₃)_Z]C(O)NHCH₂-; ix) -CH₂C(O)NHCH[CH₂CH(CH₃)₂]-; x) -CH[CH₂CH(CH-_S)₂]C(O)NHCH(CH₃)-; xi) -CH^H^C^NHCH^HzCH^H^]-; xii) -CH[CH₂CH(CH₃)₂]C(O)NHCH[CH(CH₃)₂]-; xiii) -CH[CH(CH₃)₂]C(O)NHCH[CH₂CH(CH₃)₂]-; xiv) -CH[CH₂CH(CH₃)₂]C(O)NHCH[CH₂CH(CH₃)₂]-; xv) -CH(CH₂C₆H₅)C(O)NHCH₂-; xvi) -CH₂C(O)NHCH(CH₂C₆H₅)-; xvii) -CH(CH₂C₆H₅)C(O)NHCH(CH₃)-; xviii) -CH(CH₃)C(O)NHCH(C₆H₅)-; xix) -CH(CH₂C₆H₅)C(O)NHCH[CH(CH₃)₂]-; xx) -CH(CH₂C₆H₅)C(O)N^CH[CH(CH₃)CH(CH₃)2]-; xi) -CH[CH(CH₃)CH(CH₃)₂]C(O)NHCH(CH₂C₆H₅>-; and xii) -CH[CH(CH₃)₂]C(O)NHCH[CH(CH₃)CH(CH₃)₂]-.

Another related embodiment of L¹ units taken together with R units, provides for Z units having the formulae:

The L¹ units of this aspect can have any stereochemical formula which the formulator chooses, for example, the L¹ unit having the formula:

can have any of the following diastereomeric forms:

Schemes V and VI herein describe the preparation of Z units and the formulator can determine, in many instances, the absolute stereochemistry that the resulting L¹ unit will have by the proper section of materials and intermediates. This applies equally well for all L¹ units disclosed herein.

Another related embodiment of L¹ relates to compounds wherein R^5b and R^6b can both be hydrogen and at least one of the indices m or n is equal to 2 thereby providing L¹ units having the formula: i) -(CHR^5a)C(O)NH(CHR^6a)₂-; ii) -(CHR^5a)₂C(O)NH(CHR^6a)-; or iii) -(CHR^5a)₂C(O)NH(CHR^6a)₂-.

Non-limiting examples of this aspect of this embodiment of L¹ include: i) -CH₂C(O)NHCH₂CH₂-; ii) -CH(CH₃)C(O)NHCH[CH(CH₃)CH(CH₃)₂]CH₂-; iii) -CH(CH₂C6H₅)C(O)NHCH[CH(CH₃)CH(CH3)₂]CH2-; iv) -CH(CH₂C₆H₅)C(O)NHCH[CH(CH₃)₂]CH₂-; v) -CH(CH₂OH)C(O)NHCH[CH₂CH(CH₃)₂]CH₂-; vi) -CH(CH₃)C(O)NHCH[CH₂CH(CH₃)₂]CH₂-; vii) -CH[CH(CH₃)₂]C(O)NHCH[CH₂CH(CH₃)₂]CH₂-; viii) -CH[CH(CH₃)CH(CH₃)₂]C(O)NHCH[CH(CH₃)CH(CH₃)₂]CH₂-; ix) -CH(CH₂C₆H₅)C(O)NHCHCH₃CH₂-; x) -CH[CH(CH₃)_Z]C(O)NHCH(CH₃)CH₂-; xi) -CH[CH(CH₃)₂]C(O)NHCH₂CH₂-. xii) -CH(CH₃)C(O)NHCH₂CH(CH₃)-; xiii) -CH₂C(O)NHCH₂CH(CH₃)-; xiv) -CH₂CH₂C(O)NHCH₂-;

XV) -CH₂CH(CH₃)C(O)NHCH₂-; xvi) -CH₂CH₂C(O)NHCH(CH₃)-; xvii) -CH₂CH(CH₃)C(O)NHCH(CH₃)-; xviii) -CH₂CH₂C(O)NHCH₂CH₂-; xix) -CH₂CH(CH₃)C(O)NHCH₂CH₂-;

XX) -CH₂CH₂C(O)NHCH₂CH(CH₃)-; xxi) -CH₂CH(CH₃)C(O)NHCH(CH₃)CH₂-; and xxii) -CH₂CH₂C(O)NHCH(CH₃)CH₂-.

Another related embodiment of L¹ units taken together with R units, provides for the following non-limiting examples of Z units having the formulae:

Another related embodiment of L¹ units relates to units having the formula: -[C(R^5aR^5b)]_mC(O)NH[C(R^6aR^6b)]_n- wherein each R^5a, R⁵¹¹, R^6a, and R^6b can be independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, /so-propyl, wø-butyl, sec-butyl, and benzyl; and at least one R^5a or R^6a can be a unit having the formula: -C(O)OR¹⁰ _; R¹⁰ can be chosen from hydrogen, methyl, or ethyl; and the indices m and n are each independently from 1 to 4. Non-limiting examples of this embodiment of L¹ include: i) -CH₂C(O)NHCH(CO₂CH₃)-; ii) -CH(CO₂CH₃)C(O)NHCH₂-; iii) -CH(CH₃)C(O)NHCH(CO₂CH₃)-; iv) -CH(CO₂CH₃)C(O)NHCH(CH₃)-; v) -CH(CH₃)C(O)NHCH(CO₂CH₃)CH₂-; and vi) -CH(CO₂CH₃)CH₂C(O)NHCH₂CH₂-. Another related embodiment of L¹ units relate to units having the formula:

-[C(R^5aR^5b)]_mC(O)NH[C(R^6aR^6b)]_n[R⁹][C(R^7aR^7b)]p-

R^5a, R⁵¹³, R^6a, R^6b, R^7a, and R⁷¹⁵ can be each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, zso-propyl, wø-butyl, sec-butyl, benzyl, -C(O)OR¹⁰; R¹⁰ can be chosen from hydrogen or Ci-C₄ linear or branched alkyl; R⁹ can be chosen from: i) -NHC(O)-; ii) -C(O)NH-; or iii) -S-; the indices m, n, and p independently have the value from O to 4.

Another related embodiment of L¹ units relates to compounds having the formula:

-C(R^5aH)C(O)NH[C(R^6aR^6b)] , _-2SC(R^7aH)- wherein R^5a, R^6a, R^6b, and R^7a can be each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, wo-propyl, iso-butyl, sec-butyl, benzyl, and -C(O)OR¹⁰; the indices m and p are equal to 1 and the index n is equal to 1 or 2.

Non-limiting examples of this embodiment of L¹ units include: i) -CH₂C(O)NHCH(CO₂CH₃)CH₂SCH₂-; ii) -CH₂C(O)NHCH₂CH(CO₂CH₃)SCH₂-; iii) -CH₂C(O)NHCH(CO₂CH₃)CH₂SCH(CH₃)-; iv) -CH₂C(O)NHCH₂CH(CO₂CH₃)SCH(CH₃)-; v) -CH(CH₃)C(O)NHCH(CO₂CH₃)CH₂SCH₂-; and vi) -CH(CH₃)C(O)NHCH₂CH(CO₂CH₃)SCH₂-.

Another related embodiment of L¹ units relates to compounds having the formula: -C(R^5aH)C(O)NH[C(R^6aR^6b)] , _-2NHC(R^7aH)- wherein R^5a, R^6a, R^6b, and R^7a can be each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, /so-propyl, iso-butyl, sec-butyl, benzyl, and -C(O)OR¹⁰ _; the indices m and p are equal to 1 and the index n is equal to 1 or 2.

Non-limiting examples of this aspect of this embodiment of L^units include: i) -CH₂C(O)NHCH(CO₂CH₃)CH₂NHCH₂-; ii) -CH₂C(O)NHCH₂CH(CO₂CH₃)NHCH₂-; iii) -CH₂C(O)NHCH(CO₂CH₃)CH₂NHCH(CH₃)-; iv) -CH₂C(O)NHCH₂CH(CO₂CH₃)NHCH(CH₃)-; v) -CH(CH₃)C(O)NHCH(CO₂CH₃)CH₂NHCH₂-; and vi) -CH(CH₃)C(O)NHCH₂CH(CO₂CH₃)NHCH₂-.

A further aspect of this embodiment of L¹ units relates to compounds having the formula:

-C(R^5aH)C(O)NH[C(R^6aR^6b)] , _-2C(O)C(R^7aH>- wherein R^5a, R^6a, R^6b, and R^7a can be each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, /sσ-propyl, iso-butyl, sec-butyl, benzyl, and -C(O)OR¹⁰; the indices m and p are equal to 1 and the index n is equal to 1 or 2.

Non-limiting examples of this embodiment of L¹ units include: i) -CH₂C(O)NHCH(CO₂CH₃)CH₂C(O)CH₂-; ii) -CH₂C(O)NHCH₂CH(CO₂CH₃)C(O)CH₂-; iii) -CH₂C(O)NHCH(CO₂CH₃)CH₂C(O)CH(CH₃)-; iv) -CH₂C(O)NHCH₂CH(CO₂CH₃)C(O)CH(CH₃)-; v) -CH(CH₃)C(O)NHCH(CO₂CH₃)CH₂C(O)CH₂-; and vi) -CH(CH₃)C(O)NHCH₂CH(CO₂CH₃)C(O)CH₂-.

Additional embodiments of L¹ units that relates to compounds having the formula:

-[C(R^6aR^6b)]_1-2S[C(R^7aH)]_0-i- wherein R^6a, R^6b, and R^7a are each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, wo-propyl, wo-butyl, .fee-butyl, benzyl; the index n is equal to 1 or 2 and the index p is equal to O or 1.

Non-limiting examples of this aspect of this embodiment of L¹ units include: i) -CH₂SCH₂-; ii) -CH₂CH₂SCH₂-; iii) - CH₂CH₂SCH(CH₃)-; iv) - CH₂CH[CH(CH₃)ISCH₂CH₂-; v) -CH₂S-; and vi) -CH₂CH₂S-. All L units disclosed herein can be present either in their racemic form, for example, a unit having the formula:

as a single diastereomer, for example:

or the formulator can choose to have only one chiral center with a specific stereochemistry, for example, L¹ units having the formula:

Preparation of the Compounds

The compounds disclosed herein can be assembled using a process wherein the unit that comprises the ATP binding domain unit and the unit that comprises the substrate binding domain unit are linked together through the tether/linking unit. One manner in which this connecting of binding domain units can be affected is by a process known as "click" chemistry. This chemical reaction is between a compound comprising an acetylene unit and a compound comprising an azide unit. The click chemistry forms a [l,2,3]triazolyl unit which can have two different substitution patterns depending upon which compound comprises the azide unit and which comprises the acetylene unit. This method serves as a convenient and facile means for joining the two separate units.

In Sequence I herein below, 3-phenyl-6-amino-[l,2,4]triazole[4,3-6]pyridazinyl is an example of an Akt enzyme ATP binding domain unit and this unit comprises an azide unit. The Akt enzyme substrate binding domain unit comprises an acetylene unit. This non-limiting example depicts the manner in which the two binding domain units are combined to form the final Akt kinase inhibitor. The reaction is typically conducted in the presence of sodium ascorbate and CuSO₄ at room temperature for approximately 12 hours. However, the conditions can be modified by the formulator to fit the specific molecules undergoing reaction. Sequence I

In Sequence II 3-phenyl-6-amino-[l,2,4]triazole[4,3-&]pyridazinyl Akt enzyme ATP binding domain unit comprises an acetylene unit and the Akt enzyme substrate binding domain unit comprises an azide moiety. Sequence II

A detailed description of the reaction is described herein below in Example 1. Selection of ATP and substrate binding domain units

As described herein above, ATP binding domains are found in most of the known kinases. Although ATP is a specific molecule, the structure of the ATP binding domain is not conserved among kinase species, therefore, one aspect of the present invention which provides increased specificity and selectivity to the final bivalent ligand compounds relates to identifying a unit which binds more tightly and selectively to the ATP binding domain of ATP binding domain-containing kinases. Precursors of these ATP binding domain units prior to connection to the substrate binding domain units, can have the formulae:

wherein, as described herein above, an azide moiety or an acetylene moiety provides one half of the two units which are reacted together to form a [l,2,3]triazole thereby linking the two portions of the final molecule together.

The first embodiment of ATP binding domain units according to the present disclosure can be azide comprising compounds having the formula:

wherein W, Y, and L are the same as defined herein above. Non-limiting examples of ATP binding domain units that can be suitable for combining with a variety of substrate binding domain units include:

Table A below provides examples of Akt-1 inhibition for various units within the first embodiment of ATP binding domain units disclosed herein.

TABLE A

Another embodiment of ATP binding domain units which can be tested for specificity toward binding at the ATP binding domain of a kinase enzyme are acetylenyl (terminal acetylene unit) comprising compounds having the formula:

wherein W, Y, and L are the same as defined herein above. Non-limiting examples of ATP binding domain units of this embodiment that are suitable for testing as ATP binding domain units in bivalent kinase inhibitors include:

Table B below provides examples of Akt-1 inhibition for various units within this further embodiment of ATP binding domain units disclosed herein.

TABLE B

PROCESS FOR PREPARING ATP BINDING DOMAIN UNITS The ATP binding domain units disclosed herein either comprise an azide unit or an acetylene unit for use in forming the [l,2,3]triazole linkage. The core scaffold of the ATP binding domain units can be prepared by the following general procedure outlined herein below in Scheme I.

Scheme I

A B

Reagents and conditions: (a) H₂SO₄, (NHj)₂S₂O₈, AgNO₃, H₂O.

B

Reagents and conditions: (b) TEA HCl, p-xylene, 130 ⁰C. Starting materials of type A can be made by the same procedure utilizing 3,6- dichloro-pyridazine and the acid WCO₂H, or the starting materials can be purchased.

Once the core 3-phenyl-[l,2,4]triazolo[4,3-b]pyridazinyl system is formed, the formulator can then attach a selected linker comprising either an acetylene or an azide moiety. Scheme II herein below depicts one of many general schemes useful for preparing and attaching a linking unit comprising an acetylene moiety to the core 3-phenyl- [l,2,4]triazolo[4,3-b]pyridazinyl ATP binding domain unit.

Scheme II

HO— [C(R^2aR^2b)]- — ≡≡ Br- [C(R^2aR^2b)]~

D E

Reagents and conditions: (a) PBr₃, Et₂O, 0⁰C.

H₂N- [C(R^laR^lb)— NH₂ + Br- [QR^2aR^2b)]_y ≡≡

E

H₂N- [C(R^laR^lb)— NH [C(R^2aR^2b)J

Reagents and conditions: (b) DBU, rt.

G

Reagents and conditions: (c) dioxane, 80 °C, 12 h

Scheme III herein below is a further non-limiting example of forming and attaching a linking unit which comprises an acetylene moiety to the core 3-phenyl-[l,2,4]triazolo[4,3- bjpyridazinyl ATP binding domain unit.

Scheme III

H₂N- [C(R^laR^lb)fc-NH₂ + HO₂C- [QR^2aR^2b)]-

H₂N- [C(R^laR^lb)]7-N-C — [C(R^2aR^2b)]_y = Il O

H Reagents and conditions (a): DCC, HOBt, Et₃N, dioxane, rt.

*^►

J

Reagents and conditions (b): dioxane; 80⁰C, 12 hr.

Scheme IV herein below depicts one of many general schemes useful for preparing and attaching a linking unit comprising an azide moiety to the core 3-phenyl- [l,2,4]triazolo[4,3-b]pyridazinyl ATP binding domain unit.

Scheme FV

H₂N- [C(R^laR^lb)k-NH₂ + HO₂C- [C(R^2aR^2b)]_y— N₃

H₂N- [C(R^laR^lb)]7-N-C — [C(R^2aR^2b)^-N₃

O K

Reagents and conditions: (a) DCC, HOBt, Et₃N, dioxane, rt

— [C(R^2aR^2b)b-N₃

Reagents and conditions: (b) dioxane; 80 ⁰C, 12 hr.

PROCESS FOR PREPARING SUBSTRATE BINDING DOMAIN UNITS

The substrate binding domain units disclosed herein either comprise an azide unit or an acetylene unit for use in forming the [l,2,3]triazole linkage. A non-limiting example of the preparation of a substrate binding domain unit is depicted herein below in Scheme V.

Scheme V

M

Reagents and conditions: (a) CuSO₄, sodium ascorbate, MeOH; rt.

M N

Reagents and conditions: (b) PBr₃, Et₂O; 0⁰C.

N O

Reagents and conditions: (c) NaN₃, DMF; rt. This procedure depicts a substituted (R³⁰ unit containing) [l,2,3]triazole R unit, wherein the L¹ unit is methylene (-CH₂-).

The following non-limiting example provides a substrate binding domain unit wherein L¹ is a unit having the formula:

wherein R^5a, R^5b, R^6a, and R^6b are defined herein above. Units of this type can be prepared according to the general procedure outlined herein below in Scheme VI. R³⁰ is hydrogen or a substitution for hydrogen as described herein above.

Scheme VI

P

Reagents and conditions: (a) Dess-Martin periodinane, CH₂Cl₂, rt.

P Q

Reagents and conditions: (b) dimethyl-2-oxopropyl phosphonate, TsN₃

K₂CO₃, MeOH; rt.

Q R

Reagents and conditions: (c) CuSO₄, sodium ascorbate, MeOH; rt;

BocH_N

R S Reagents and conditions: (d) 4 M HCl/dioxane, rt.

S T

Reagents and conditions: (e) EDCI, HOBt, NaHCO₃, THF; rt The compounds (compounds) of the present invention are arranged into several Categories to assist the formulator in applying a rational synthetic strategy for the preparation of compounds which are not expressly exampled herein. The arrangement into Categories does not imply increased or decreased efficacy for any of the compositions of matter described herein.

Category I of the compounds disclosed herein relates to Akt kinase inhibitors having the formula:

wherein R units which are C₂, C₃, or C₄ substituted or unsubstituted 5-member heterocyclic or heteroaryl units and Y units are further described herein below in Table I.

TABLE I

The compounds which comprise Category I of the present invention can be prepared rocedure outlined herein below in Scheme I and described in Example 1.

SCHEME I

Reagents and conditions: (a) H₂SO₄, (NH₄^S₂O₈, AgNO₃, H₂O; 70 ⁰C.

1 2

Reagents and conditions: (b) triethylamine HCl, p-xylene; 130 ⁰C, 24 hr.

Reagents and conditions: (c) PBr₃, Et₂O; 0 ⁰C.

3 4

Reagents and conditions: (d) DBU; 25 ⁰C, 18 hr.

2 5

Reagents and conditions: (e) 2,2-dimethyl-N¹-(pent-4-ynyl)propane-l,3-diamine, neat; 80 ⁰C.

7

Reagents and conditions: (f) Na ascorbate, CuSO⁴, MeOH/H₂O; 25 ⁰C, 18 hr.

EXAMPLE l

N¹ -(7-Cyclobutyl-3-phenyl-[ 1 ,2,4]triazole[4,3-b]pyridazin-6-yl)-2,2-dimethyl-N³-(3- { 1 -[(3- methyl-5-phenylisoxazol-4-yl)methyl]-lH-l,2,3-triazol-4-yl}propyl)propane-l,3-diamine

(7) Preparation of 3,6-dichloro-4-cyclobutylpyridazine (1): To a stirred suspension of 3,6-dichloropyridazine (10.0 g, 67.1 mmol) in water (250 mL) was added 11.0 mL of concentrated sulfuric acid (19.7 mmol) dropwise. The mixture was heated to 70 ⁰C before the addition of 7.0 mL of cyclobutane carboxylic acid (73.2 mmol) followed by a solution of silver nitrate (2.28 g, 13.4 mmol) in water (5.0 mL) over 1 min. At this point the mixture became milky in appearance, and a solution of ammonium persulfate (46.0 g, 226.4 mmol) in water (130 mL) was added slowly over 20-30 min, which caused the product to form as a sticky precipitate. After complete addition, the reaction mixture was stirred for an additional 5 min and allowed to cool to room temperature. The mixture was then poured into ice and basified with concentrated aqueous ammonia with the addition of more ice as required to keep the temperature below 5 ⁰C. The aqueous phase was extracted with dichloromethane (3 x 400 mL), and the combined extracts were dried over MgSO₄, filtered and concentrated under reduced pressure to give 12.5 g of the desired compound (92%) as an oil. This material was used without further purification. ¹H NMR (CDCl₃, 300 MHz): δ 7.38 (s, IH), 3.83 (pent, J = 8.4 Hz, IH), 2.36-2.56 (m, 2H), 1.99-2.21 (m, 3H), 1.86-1.94 (m, IH). ESI-MS: m/z 203 [M+H], 205 [M+2+H], 207 [M+4+H].

Preparation of 6-chloro-7-cyclobutyl-3-phenyl-[ 1 ,2,4]triazole[4,3-6]pyridazine (2): 3,6-Dichloro-4-cyclobutylpyridazine, 1, (24.9 g, 123 mmol), benzoic hydrazide (18.5 g, 136 mmol), and triethylamine hydrochloride (18.7 g, 136 mmol) in p-xylene (300 mL) were stirred and refluxed under argon for 24 hours. Upon cooling the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (300 mL) and water (300 mL) and the organic layer discarded. The aqueous layer was basified by the addition of solid K₂CO₃. Some dark insoluble solid was removed by filtration at this stage and the aqueous layer was then extracted with dichloromethane (300 mL). The combined extracts were dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient of hexane/ethyl acetate 5% - 40%) to yield the desired compound (12.46 g, 36%) as a white solid. ¹H NMR (CDCl₃, 300 MHz): δ 8.45 (m, 2H), 8.01 (s, IH), 7.56 (m, 3H), 3.74 (pent, J = 8.4 Hz, IH), 2.49 - 2.58 (m, 2H), 2.18 -2.24 (m, 3 H), 1.86 -197 (m, 2 H). ESI-MS: m/z 285 [M+H], 287 [M+2+H]. Preparation of 5-bromopent-l-yne (3): To a solution of 4-pentyn-l-ol (6.22 g, 73.9 mmol) in anhydrous ether (100 mL) at -10 ⁰C was added 10.0 g of PBr₃ (36.9 mmol) dropwise. The reaction was quenched by the addition of a saturated solution of aqueous ammonium chloride (30 mL) with further stirring for 1 hour. The mixture was then poured into ice and basified with a 5% aqueous solution OfNaHCO₃ with the addition of more ice to keep the temperature below 0 ⁰C. The aqueous phase was extracted with ether (3 x 200 mL) and the combined extracts were dried over Na₂SO₄, filtered and concentrated at 0 ⁰C to give the desired compound as an ethereal solution. This material was used without further purification. ¹H NMR (CDCl₃, 300 MHz): δ 3.56 (t, J = 7.0 Hz, 2H), 2.42 (dt, J = 7.0, 2.4 Hz, 2H), 2.00 (t, J = 2.4 Hz, IH), 1.89 (pent, J = 7.0 Hz, 2H).

Preparation of 2,2-dimethyl-N^I-(pent-4-ynyl)propane-l,3-diamine (4): To a solution of 2, 2-dimethyl-propane- 1,3 -diamine (10.0 g, 97.8 mmol) and DBU (4.0 g, 26.3 mmol) was added 30 mL of 4-pentyn-l -bromide, 3, solution (ca. 10 % w/w) dropwise in anhydrous 1 ,4-dioxane (150 mL), and the mixture was stirred overnight. After the removal of solvent under reduced pressure, the residue was repeatedly purified by flash chromatography on silica gel (dichloromethane/methanol 1% - 10 %) to yield the desired compound (5.1 g, 31%) as an oil. ¹H NMR (CDCl₃, 300 MHz): δ 2.80 (s, 2H), 2.79 (t, J = 7.0 Hz, 2H), 2.64 (s, 2H). 2.29 (dt, J = 7.0, 2.4 Hz, 2H), 2.04 (t, J = 2.4 Hz, IH), 1.78 (pent, J = 7.0 Hz, 2H), 1.00 (s, 3H). ¹³C NMR (CDCl₃, 75 MHz): δ 83.86, 68.97, 59.42, 51.48, 49.29, 34.29, 29.01, 24.00, 16.27. ESI-MS: m/z 169 [M+H].

Preparation of N¹ -(7-cyclobutyl-3-phenyl-[l,2,4]triazole[4,3-b]pyridine-6-yl)-2,2- dimethyl-N³-(pent-4-ynyl)propane-l ,3-diamine (5): 6-Chloro-7-cyclobutyl-3-phenyl- [l,2,4]triazolo[4,3-b]pyridazine, 2, (630 mg, 2.21 mmol), N-(4-pentynyl)-2,2-dimethyl- propane- 1,3 -diamine, 4, (2.5 g, 14.88 mmol) in 6.0 mL of 1 ,4-dioxane were heated together in a sealed tube at 80 ⁰C for 24 h and then cooled to room temperature. After removal of the volatiles under reduced pressure, the residue was purified by flash chromatography on silica gel (dichloromethane/methanol l%-5%) to provide the desired compound (642 mg, 70%) as a white powder. ¹H NMR (CDCl₃, 300 MHz): δ 8.55 (d, J = 6.9 Hz, 2H), 7.61 (s, IH), 7.41- 7.54 (m, 3 H), 7.38 (d, J = 4.5 Hz, IH), 3.35 (m, IH), 3.33 (d, J = 4.5 Hz, 2H), 2.79 (t, J = 7.0 Hz, 2H), 2.66 (s, 2H), 2.46 (m, 2H), 2.32 (dt, J = 7.0, 2.4 Hz, 2H), 2.17 (m, 3 H), 2.01 (t, J = 2.4 Hz, IH), 1.95 (m, 1 H), 1.81 (pent, J = 7.0 Hz, 2H), 1.05 (s, 6H). ¹³C NMR (CDCl₃, 75MHz): δ 153.09, 146.58, 144.65, 131.48, 129.12, 128.39, 127.54, 127.16, 118.32, 83.56, 69.10, 60.92, 53.99, 50.03, 35.54, 33.52, 28.29, 27.24, 24.87, 18.24, 16.56. ESI-MS: m/z 417 [M+H].

Preparation of 4-(azidomethyl)-3-methyl-5-phenylisoxazole (6): To a stirred solution of 258 mg OfNaN₃ (3.97 mmol) in dimethylformamide (DMF) (5.0 mL) and water (1.0 mL) was added 4-(bromomethyl)-3-methyl-5-phenylisoxazole (500 mg, 1.98 mmol). The reaction mixture was stirred overnight and then diluted with 25 ml of water and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over NaSO₄, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 5%-30%) to give 0.41 g of the desired compound (96%).¹H NMR (CDCl₃, 300 MHz): δ 7.69-7.24 (m, 2H), 7.49-7.51 (m, 3H), 4.33 (s, 2H), 2.40 (s, 3H). ESI-MS: m/z 215 [M+H].

Preparation ofN¹-(7-cyclobutyl-3-phenyl-[l,2,4]triazole[4,3-b]pyridazin-6-yl)-2,2- dimethyl-N³-(3-{l-[(3-methyl-5-phenylisoxazol-4-yl)methyl]-lH-l,2,3-triazol-4- yl}propyl)propane-l,3-diamine (7): Aqueous solutions OfCuSO₄ (100 mM, 50 μL) and sodium ascorbate (200 mM, 50 μL) were added to a solution of N'-(7-cyclobutyl-3-phenyl- [l,2,4]triazole[4,3-b]pyridine-6-yl)-2,2-dimethyl-N³-(pent-4-ynyl)propane-l,3-diamine, 5, (15 mg, 36 μmol) and 4-(azidomethy)-3-methyl-5-phenylisoxazole, 6, (15 mg, 70 μmol) in methanol (500 μL). The reaction mixture was stirred at room temperature for 24 hour. The product was purified by flash chromatography on silica gel (dichloromethane/ methanol 1- 10%) to yield the desired compound (16 mg, 69%). ¹H ΝMR (CDCl₃, 300 MHz): δ 8.52 (d, J = 7.3 Hz, 2H), 7.67 (m, 2H), 7.58 (s, IH), 7.40-7.53 (m, 7H), 7.21 (s, IH), 5.50 (s, 2H), 3.3 l(d, J = 3.9 Hz, 2H), 3.30 (m, IH), 2.78 (d, J = 7.4 Hz, 2H), 2.71 (d, J = 7.0 Hz, 2H), 2.62 (d, J = 3.6 Hz, 2H), 2.40 (m, 2H), 2.27 (s, 3H), 2.16 (m, 2H), 1.97 (m, 2H), 1.86 (m, IH), 1.04 (s, 3H). ¹³C ΝMR (CDCl₃, 75 MHz): δ 168.14, 160.30, 153.12, 147.91, 131.54, 130.89, 129.34, 129.14, 128.40, 127.52, 127.23, 127.12, 126.79, 120.01, 118.27, 107.73, 60.80, 53.62, 50.30, 43.11, 35.50, 33.63, 29.24, 27.16, 24.85, 23.46, 18.19, 10.17. ESI-MS: m/z 631 [M+H]. The disclosed compounds which comprise Category I can be prepared by the procedure outlined herein above in Scheme I and described in Example 1. The Artisan of ordinary skill will be able to adjust the reaction conditions to suit the various substitutions which allow for the compounds encompassed within the scope of this category to be prepared without undue experimentation. For example, in step (a) cyclobutane carboxylic acid, can be substituted by acetic acid (C₂), propanoic acid (C₃), isobutyric acid (C₄), and the like. In step (c) 5-bromopent-l-yne can be substituted by 4-bromobut-l-yne, 3- bromoprop-1-yne (propargyl bromide), and the like, hi step (f) the heteroaryl or heterocyclic azides describe herein above in the section describing substrate and further exampled herein can be substituted for 4-(azidomethy)-3-methyl-5-phenylisoxazole.

Category II relates to compounds having the formula:

wherein L¹ can be a unit having the formula: -[C(R^5aR^5b)]_mC(O)NH[C(R^6aR^6b)]_n- wherein R^5a, R^5b, R^6a, R^6b, and the indices m and n are further described herein below in Table II and R units are C₂, C₃, or C₄ substituted or unsubstituted 5-member heterocyclic or heteroaryl units.

TABLE II

The compounds which comprise Category I of the present invention can be prepared procedure outlined herein in Scheme II and described in Example 2.

Scheme II

H₇N. BocHN^^_\

OH OH

8

Reagents and conditions: (a) (Boc)₂θ, NaHCO₃, Dioxane-H₂θ/1 : 1 , rt.

BocHN^^^ BocHN^^^

OH OMs

8 9

Reagents and conditions: (b) MsCl, Et₃N, CH₂Cl₂, O ⁰C.

9 10

Reagents and conditions: (c) NaN₃, DMF, 70 ⁰C.

10 11

Reagents and conditions: (d) CuSO₄, Na-ascorbate, MeOH.

11 12

Reagents and conditions: (e) 4 M HCl, dioxane, rt.

12 13

Reagents and conditions (f): EDCI, HOBt, DMF, NaHCO₃, rt.

13

14 Reagents and conditions: (f) CuSO₄, Na-ascorbate, MeOH.

EXAMPLE 2

Methyl 4-{(15,2i?)-l-[(5)-2-(4-{3-[3-(7-cyclobutyl-3-phenyl-[l,2,4]-triazolo[4,3- ό]pyridazin-6-ylamino)-2,2-dimethylpropylamino]propyl} -IH- 1 ,2,3-triazol- 1 - yl)propanamido]-2-methylbutyl}-lH-[l,2,3]triazole-4-carboxylate (14)

Preparation of tert-butyl (25,3Λ)-l-hydroxy-3-methylpentan-2-ylcarbamate (8): To a stirred mixture of L-isoleucinol (20.Og, 0.171 mol) and NaHCO₃ (35.9 g, 0.427 mol) in dioxane/water (1 :1, 200 mL) at room temperature was added di-tert-butyl dicarbonate ((BoC)₂O) (44.7 g, 0.205 mol) in dioxane (150 mL) dropwise over 1 hour. The reaction mixture was stirred overnight and the solvents were then removed under reduced pressure. The residue was partitioned between ethyl acetate (300 mL) and water (300 mL). After separating the organic phase, the aqueous phase was extracted with ethyl acetate (2 x 300 mL). The combined organic extracts were washed with brine (300 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ethyl acetate/hexane 10%-50%) to afford 33.6 g of the desired compound (90%). ¹H NMR (CDCl₃, 300 MHz): δ 4.75 (d, J = 7.5 Hz, IH), 3.69 (m, IH), 3.62 (m, IH), 3.49 (m, IH), 1.57 (m, 2H), 1.45 (s, 9H), 1.15 (m, IH), 0.92 (d, J = 6.9 Hz, 3H), 0.91 (d, J = 7.2 Hz, 3H). ESI-MS: m/z 218 [M+H].

Preparation of (25',3i?)-2-(fert-butoxycarbonylamino)-3-methylpenyl methanesulfonate (9): To a stirred solution of tert-butyl (25,3i?)-l-hydroxy-3-methyl- pentan-2-ylcarbamate, 8, (10.0 g, 0.460 mol) and triethylamine (19.2 mL, 0.138 mol) in anhydrous dichloromethane (200 mL) at 0 ⁰C was added methanesulfonyl chloride (10.7 mL, 138 mmol) in anhydrous dichloromethane (50 mL) dropwise over 1 hour. The reaction mixture was allowed to warm to room temperature and stirred for an additional 2 hours before being poured into ice. After separating the organic phase, the aqueous phase was extracted with dichloromethane (2 x 200 mL). The combined organic extracts were washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ethyl acetate/hexane 10%- 30%) to afford 9.72 g of the desired compound (71%) as an oil. ¹H NMR (CDCl₃, 300 MHz): δ 4.64 (d, J = 9.6 Hz, IH), 4.27 (m, 2H), 3.69 (m, IH), 3.03 (s, 3H), 1.63 (m, 2H), 1.45 (s, 9H), 1.18 (m, IH), 0.96 (d, J - 7.0 Hz, 3H), 0.91 (d, J = 7.3 Hz, 3H). ESI-MS: m/z 296 [M+H].

Preparation of ter/-butyl (2₁S,3Λ)-l-azido-3-methylpentan-2-ylcarbamate (10): To a stirred solution OfNaN₃ (4.15 g, 63.84 mmol) in dimethyl- formamide (DMF) (100 mL) was added (2.S',3i?)-2-(ter/-butoxycarbonylamino)-3-methylpenyl methanesulfonate, 9, (9.43 g, 31.92 mmol) and the mixture heated to 70 ⁰C for 12 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford 6.36 g of the desired compound (69%) as white powder. ¹H NMR (CDCl₃, 300 MHz): δ 4.57 (d, J = 8.4 Hz, IH), 3.57 (m, IH), 3.42 (m, 2H), 1.56 (m, 2H), 1.45 (s, 9H), 1.12 (m, IH), 0.92 (d, J = 7.0 Hz, 3H), 0.90 (d, J = 7.2 Hz, 3H). ESI-MS: m/z 243 [M+H].

Preparation of methyl 4-[( \S,2R)- 1 -(tert-butoxycarbonylamino)-2-methylbutyl]- IH- 1,2,3-triazole-l-carboxylate (11): Aqueous solutions of CuSO₄ (0.26 g, 1.03 mmol in 3.0 mL of water) and sodium ascorbate (0.41 g, 2.07 mmol in 2.0 mL of water) were added to a solution of tert-butyl (25,3i?)-l-azido-3-methylpentan-2-ylcarbamate, 10, (2.59 g, 10.32 mmol) and methyl propiolate (1.72 mL, 20.04 mmol) in methanol (20 mL). The reaction was stirred at room temperature for 2 days. After removal of solvents under reduced pressure, the residue was purified by flash chromatography on silica gel (ethyl acetate/heaxane 10%-50%) to afford 2.81 g of the desired compound as white solid (83%). ¹H NMR (CDCl₃, 300 MHz): δ 8.14 (s, IH), 4.56 (m, 3H), 3.95 (s, 3H), 3.82 (m, IH), 1.58 (m, 2H), 1.38 (s, 9H), 1.19 (m, IH), 1.01 (d, J = 7.2 Hz, 3H), 0.92 (d, J = 7.2 Hz, 3H). ESI- MS: m/z 327 [M+H]. Preparation of methyl 4-(( 1 S,2R)- 1 -amino-2-methylbutyl)- IH- 1 ,2,3-triazole- 1 - carboxylate (12): To a stirred solution of 4-[(lS,2i?)-l-(tert-butoxycarbonylamino)-2- methylbutyl]-lH-l,2,3-triazole-l-carboxylate, 11, (1.75 g, 53.6 mmol) in dioxane (10.0 mL) at 0⁰C was added 110 mL of a 4 M solution of HCl in dioxane, and the reaction mixture was allowed to warm to room temperature and stir for 12 hours. After removal of volatiles under reduced pressure, the residue was dried under high vacuum to afford the desired compound (1.26 g, 90%) as white crystals. ¹H NMR (CD₃OD, 300 MHz): δ 8.67 (s, IH), 3.95 (s, 3H), 3.80 (m, IH), 1.81 (m, IH), 1.62 (m, IH), 1.36 (m, IH), 1.15 (d, J = (7.2 Hz, 3H), 1.04 (d, J = 7.2 Hz, 3H). ESI-MS: m/z 227 [M+H].

Preparation of methyl 4-[(15',2i?)-l-((5)-2-azidopropanamido)-2-methylbutyl]- IH- 1 ,2,3-triazole- 1 -carboxylate (13): (5)-Azidopropanoic acid (176 mg, 1.53 mmol) and NaHCO₃ (0.32 g, 3.83 mmol) were added to a stirring solution of methyl 4-((15,2,R)-I- amino-2-methylbutyl)-lH-l,2,3-triazole-l-carboxylate, 12, (201 mg, 0.766 mmol), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.53 g, 7.96 mmol), and 1-hydroxybenzotriazole hydrate (ΗOBt) (311 mg, 2.30 mmol) in dry TΗF (30 mL) under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure. The residue was partitioned between CH₂Cl₂ (50 mL) and water (50 mL). The aqueous layer was extracted with CH₂Cl₂ (2 x 50 mL), and the organic layers were combined, washed with brine (100 mL), dried over NaSO₄, and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (ethyl acetate/ hexane 10%-50%) to afford the desired compound (231 mg, 93(). ¹H NMR (CDCl₃, 300 MHz): δ 8.12 (s, IH), 6.50 (d, J = 9.0 Hz, IH), 4.57 (dd, J = 14.4. 8.4 Hz, 2H), 4.18 (m, IH), 4.01 (dd, J = 14.1, 6.0 Hz, 3H), 3.95 (s, 3H), 1.58 (m, 2H), 1.48 (d, J = 6.9 Hz, 3H), 1.19 (m, IH), 1.02 (d, J = 7.2 Hz, 3H), 0.92 (d, J = 7.2 Hz, 3H). ESI-MS: m/z 325 [M+H].

Preparation of methyl 4- {( 1 S,2R> 1 -[(5)-2-(4- {3-[3-(7-cyclobutyl-3-phenyl-[ 1 ,2,4]- triazolo[4,3-b]pyridazin-6-ylamino)-2,2-dimethylpropylamino]propyl} -iH-1 ,2,3-triazol- 1 - yl)propanamido]-2-methylbutyl}-lH-[l,2,3]triazole-4-carboxylate (14): Aqueous CuSO₄ (100 mM, 25 uL) and sodium ascorbate (200 mM, 25 μL) solutions were added to a solution ofmethyl 4-[(15;2φ-l-((;S>2-azidopropanamido)-2-methylbutyl]- lH-l,2,3-triazole-l- carboxylate, 13, (50 μmol) and N'-^-cyclobutyW-phenyl-fl^^Jtriazolel^S-bJpyridine-ό- yO^^-dimethyl-Λ^-φenM-ynyOpropane-l.S-diamine, 5, (50 μmol) in methanol (300 μL). The reaction was stirred at room temperature for 2-4 days. The product was purified by flash chromatography on silica gel (methanol/dichloromethane 1-10%) to afford the compound (11 mg, 31%). ¹H NMR (CDCl₃, 300 MHz): δ 8.52 (d, J = 7.3 Hz, 2H), 8.18 (s, IH), 7.73 (s, IH), 7.41-7.62 (m, 4H), 6.85 (brs, IH), 5.08 (m, IH), 4.51 (m, 2H), 4.20 (m, IH), 3.93 (s, 3H), 3.67 (s, 2H), 3.45 (m, IH), 2.88 (t, J - 7.0 Hz, 2H), 2.85 (t, J = 7.0 Hz, 2H), 2.74 (s, 2H), 2.48 (m, 2H), 2.11 (m, 2H), 2.04 (m, 3H), 1.89 (m, IH), 1.73 (d, J = 7.2 Hz, 3H), 1.50 (m, 2H), 1.25 (m, IH), 1.08 (s, 6H), 0.93 (d, J = 7.0 Hz, 3H), 0.83 (t, J = 7.0 Hz, 3H). ESI-MS: m/z 740 [M+H].

The following are non-limiting examples of other Akt kinase inhibitors:

N¹-(7-Cyclobutyl-3-phenyl-[l,2,4]triazolo[4,3-6]pyridazin-6-yl)-2,2-dimethyl-N³-(3- {l-[(5-methylisoxazol-3-yl)methyl]-lH-l,2,3-triazol-4-yl}propyl)propane-l,3-diamine: ¹H ΝMR (CDCl₃, 300 MHz): δ 8.54 (d, J = 7.5 Hz, 2H), 7.62 (s, IH), 7.37-7.53 (m, 4H), 5.97 (s, IH), 5.54 (s, 2H), 3.38(d, J = 3.9 Hz, 2H), 3.37 (m, IH), 2.80 (d, J = 6.9 Hz, 4H), 2.62 (s, 2H), 2.43 (m, 2H), 2.41 (s, 3H), 2.02- 2.17(m, 5H), 1.89 (m, IH), 1.07 (s, 3H). ESI-MS: m/z 555 [M+H].

Methyl 3-(benzylthio)-2-[2-(-4- {3-[3-(7-cyclobutyl-3-phenyl-[ 1, 2,4]-triazolo[4,3- ό]pyridazin-6-ylamino)-2,2-dimethylpropylamino]propyl} l-H-[l,2,3]triazole-l- yl)acetamido]propanoate: ¹H NMR (CDCl₃, 300 MHz): δ 8.53 (d, J = 6.9 Hz, 2H), 7.61 (s, IH), 7.41-7.53 (m, 4H), 7.21-7.33 (m, 5H), 7.10 (brs, IH), 7.08 (d, J - 7.5 Hz, IH), 5.06 (s, 2H), 4.75 (dd, J = 12.9, 6.0 Hz, IH), 3.72 (s, 3H), 3.67 (s, 2H), 3.38 (d, J = 4.5 Hz, 2H), 3.37 (m, IH), 2.80-2.93 (m, 6H), 2.68 (s, 2H), 2.44 (m, 2H), 1.99-2.20 (m, 5H), 1.88 (m, IH), 1.07 (s, 6H). ESI-MS: m/z 725 [M+H].

N'-(benzooxazol-2-yl)-2-(4-{3-[3-(7-cyclobutyl-3-phenyl-[l,2,4]triazolo[4,3- ό]pyridazin-6-ylamino)-2,2-dimethylpropylamino]-propyl} - 1 H-[ 1 ,2,3]triazole- 1 -yl)-_V- methylacetohydrazide: ¹H NMR (CDCl₃, 300 MHz): δ 8.46 (d, J = 6.9 Hz, 2H), 7.66 (s, IH), 7.40-7.52 (m, 4H), 7.33 (d, J = 7.8 Hz, IH), 7.22 (d, J = 7.8 Hz, IH), 7.12 (t, J = 7.8 Hz, IH), 6.97 (t, J - 7.8 Hz, IH), 6.89 (brs, IH), 5.27 (s, 2H), 3.45 (m, IH), 3.44 (s, 3H), 3.40 (d, J = 4.5 Hz, 2H), 2.90 (t, J = 7.0 Hz, 2H), 2.83 (t, J = 7.0 Hz, 2H), 2.69 (s, 2H), 2.40 (m, 2H), 2.06 (m, 3H), 1.82 (m, IH), 1.08 (s, 6H). ESI-MS: m/z 663 [M+H].

N¹-(7-Cyclobutyl-3-phenyl-[l,2,4]triazolo[4,3-6]ρyridazin-6-yl)-2,2-dimethyl-N³-(3-

{l-[(2,3-dihydrobenzo[6][l,4]dioxin-2-yl)methyl]-lH-l,2,3-triazol-4-yl}propyl)propane- 1,3-diamine: ESI-MS: m/z 608 [M+Η].

N¹ -(7-Cyclobutyl-3-phenyl-[ 1 ,2,4]triazolo[4,3-&]pyridazin-6-yl)-2,2-dimethyl-N³-(3- {l-[(benzothiazol-2-yl)methyl]-lH-l,2,3-triazol-4-yl}propyl)propane-l,3-diamine: ESI- MS: m/z 607 [M+H].

2-(4- {3-[3-(7-Cyclobutyl-3-phenyl-[ 1 ,2,4]triazolo[4,3-6]pyridazin-6-ylamino)-2,2- dimethylpropylaminojpropyl} - lH-[ 1 ,2,3]triazol- 1 -yl)-N-cyclopentyl-3-methylbutanamide: ESI-MS: m/z 627 [M+H].

Methyl 4-{2-[2-(4-{3-[3-(7-cyclobutyl-3-phenyl-[l,2,4]triazolo[4,3-6]pyridazin-6- ylamino)-2,2-dimethylpropylamino]propyl} - \H-[ 1 ,2,3]triazole- 1 -yl)-3- phenylpropanamido]-3,4-dimethylpentyl}-l//-[l,2,3]triazole-l-carboxylate: ESI-MS: m/z 740 [M+H].

Methyl 4- {2-[2-(4- {3-[3-(7-cyclobutyl-3-phenyl-[ 1 ,2,4]triazolo[4,3-ό]pyridazin-6- ylamino)-2,2-dimethylpropylamino]propyl}-lH-[l,2,3]triazole-l-yl)-3- phenylpropanamido]-3-methylpentyl}-li/-[l,2,3]triazole-l-carboxylate: ESI-MS: m/z 830 [M+H].

Methyl l-{2-[2-(4-{3-[3-(7-cyclobutyl-3-phenyl-[l,2,4]triazolo[4,3-6]pyridazin-6- ylamino)-2,2-dimethylpropylamino]propyl}-lH-[l,2,3]triazol-l-yl)-3- hydroxypropanamido]-4-methylpentyl}-lH-[l,2,3]triazole-4-carboxylate: ESI-MS: m/z 756 [M+Η].

Methyl 1 - {2-[2-(4- {3-[3-(7-cyclobutyl-3-phenyl-[ 1 ,2,4]triazolo[4,3-6]pyridazin-6- ylamino)-2,2-dimethylpropylamino]propyl } - 1 H- [ 1 ,2,3]triazol- 1 -yl)propanamido]-4- methylpentyl}-lH-[l,2,3]triazole-4-carboxylate: ESI-MS: m/z 740 [M+Η].

Methyl 1 - {2-[2-(4- {3-[3-(7-cyclobutyl-3-phenyl-[ 1 ,2,4]triazolo[4,3-ό]pyridazin-6- ylamino)-2,2-dimethylpropylamino]propyl}-lH-[l,2,3]triazol-l-yl)-3-methylbutanamido]- 4-methylpentyl}-lH-[l,2,3]triazole-4-carboxylate: ESI-MS: m/z 768 [M+Η].

Methyl l-{2-[2-(4-{3-[3-(7-cyclobutyl-3-phenyl-[l,2,4]triazolo[4,3-b]pyridazin-6- ylamino)-2,2-dimethylpropylamino]propyl } - 1 H-[ 1 ,2,3]triazol- 1 -yl)-4-methylpentanamido] - 4-methylpentyl}-lH-[l,2,3]triazole-4-carboxylate: ESI-MS: m/z 782 [M+H].

Ethyl 4- { 1 -[2-(4- {3-[3-(7-cyclobutyl-3-phenyl-[ 1 ,2,4]triazolo[4,3-b]pyridazin-6- ylamino)-2,2-dimethylpropylamino]propyl}-lH-[l,2,3]triazole-l-yl)propanamido]-2- phenylethyl}-l/7-[l,2,3]triazole-l-carboxylate: ESI-MS: m/z 788 [M+Η].

Ethyl 4-{l-[2-(4-{3-[3-(7-cyclobutyl-3-phenyl-[l,2,4]triazolo[4,3-ό]pyridazin-6- ylamino)-2,2-dimethylpropylamino]propyl}-lH-[l,2,3]triazole-l-yl)-3- phenylpropanamido]-2-phenylethyl}-lH-[l,2,3]triazole-l-carboxylate: ESI-MS: m/z 864 [M+Η].

Methyl l-{2-[2-(4-{3-[3-(7-cyclobutyl-3-phenyl-[l,2,4]triazolo[4,3-b]pyridazin-6- ylamino)-2,2-dimethylpropylamino]propyl} -IH-[1 ,2,3]triazol- 1 -yl)-3-phenylpropanamido]- propyl}-lH-[l,2,3]triazole-4-carboxylate: ESI-MS: m/z 774 [M+Η]

Methyl 1 - {2-[2-(4- {3-[3-(7-cyclobutyl-3-phenyl-[ 1 ,2,4]triazolo[4,3-δ]pyridazin-6- ylamino)-2,2-dimethylpropylamino]propyl} - lH-[ 1 ,2,3]triazol- 1 -yl)-3-methylbutanamido]- propyl}-lH-[l,2,3]triazole-4-carboxylate: ESI-MS: m/z 726 [M+Η].

2-(4- {3-[3-(7-Cyclobutyl-3-phenyl-[ 1 ,2,4]triazolo[4,3-b]pyridazin-6-ylamino)-2,2- dimethylpropylamino]propyl}-lH-[l,2,3]triazol-l-yl)-N-(2,5-dimethoxy-4- sulfamoylphenyl)acetamide: ESI-MS: m/z 732 [M+H].

2-(4-{3-[3-(7-Cyclobutyl-3-phenyl-[l,2,4]triazolo[4,3-b]pyridazin-6-ylamino)-2,2- dimethylpropylamino]propyl}- IH-[1, 2,3]triazol-l -yl)-3-methyl-N-[2-(thiophen-3- yl)ethyl]butanamide: ESI-MS: m/z 669 [M+Η].

N¹ (7-Cyclobutyl-3-phenyl-[ 1 ,2,4]triazolo[4,3-6]pyridazin-6-yl)-2,2-dimethyl-N³-(3- {l-[(3,5-dimethyl-lH-pyrazol-l-yl)methyl]-lH-l,2,3-triazol-4-yl}propyl)propane-l,3- diamine: ESI-MS: m/z 568 [M+Η].

3-[(4- {3-[3-(7-Cyclobutyl-3-phenyl-[ 1 ,2,4]triazolo[4,3-6]pyridazin-6-ylamino)-2,2- dimethylpropylamino]propyl}-lH-[l,2,3]triazol-l-yl)methyl]quinazolin-4(3H)-one: ESI- MS: m/z 618 [M+Η].

N'-(7-Cyclobutyl-3-phenyl-[l,2,4]triazolo[4,3-ό]ρyridazin-6-yl)-2,2-dimethyl-N³-(3- { 1 -[(quinazolin-4-yloxy)methyl]-lH- 1 ,2,3-triazol-4-yl}propyl)propane- 1 ,3-diamine: ESI- S: m/z 618[M+Η].

N¹-(7-Cyclobutyl-3-phenyl-[l,2,4]triazolo[4,3-b]pyridazin-6-yl)-2,2-dimethyl-N³-(3- {4-[(quinolin-4-yloxy)methyl]-lH-l ,2,3-triazol-4-yl}propyl)propane-l ,3-diamine: ESI-MS: m/z 618[M+Η].

2-(4-{3-[3-(7-Cyclobutyl-3-phenyl-[l,2,4]triazolo[4,3-6]pyridazin-6-ylamino)-2,2- dimethylpropylamino]propyl}-lH-l,2,3-triazol-l-yl)-N-(furan-2-ylmethyl)-3- methylbuatnamide: ESI-MS: m/z 639 [M+H].

2-[(l-{3-[3-(7-Cyclobutyl-3-phenyl-[l,2,4]triazolo[4,3-b]pyridazin-6-ylamino)-2,2- dimethylpropylamino]propyl}-l//-l,2,3-triazol-4-yl)methylthio]-6-methylpyrimidin-4-ol: ESI-MS: m/z 614[M+H].

Compounds listed and described herein above have been found in many instances to exhibit activities (IC₅₀ in the assays described herein below or ones which are referenced herein) at a concentration below 1 micromolar (μM).

Activated Akt has numerous and diverse functions that affect a broad spectrum of cellular activities related to growth, survival and differentiation. Because it was first isolated as the oncoprotein transduced by a leukemogenic murine retrovirus, its inhibition can be seen to inhibition can be seen as a potential for halting oncogenic transformation in cells. The compounds of the present invention are effective in the following disease states or conditions: i) as binary targeted Akt kinase inhibitors providing kinase specific inhibition of EGF receptor (EGFR) tyrosine kinase and thereby induces regression in lung cancers that carry a specific EGFR mutation; ii) Akt has been found to inhibit cell apoptosis by the following mechanisms: a) down-regulating pro-apoptotic proteins; b) stimulating translation through Target of Rapamycin (TOR); c) by promoting transcription via nuclear factor KB (NFKB); d) interfering with cyclin-dependent kinase inhibitor p27; and e) interfering with the tumor suppressor FoxOl .^60"73

Therefore, increased Akt activity in cancer cells can result in resistance to drug-induce apoptosis and enhances cell replication. Inhibition of Akt activity can provide a means of treating cancers, inter alia, breast, lung, colorectal, and prostate. Each of the disease states or conditions which the formulator desires to treat can require differing levels or amounts of the compounds described herein to obtain a therapeutic level. The formulator can determine this amount by any of the testing procedures known to the artisan.

The present disclosure further relates to forms of the present compounds, which under normal human or higher mammalian physiological conditions, can release the compounds described herein. One iteration of this aspect includes the pharmaceutically acceptable salts of the compoundcompounds described herein. The formulator, for the purposes of compatibility with delivery mode, excipients, and the like, can select one salt form of the present compoundcompounds over another since the compounds themselves are the active species which mitigate the disease processes described herein.

FORMULATIONS

The present disclosure also encompasses and relates to compositions or formulations which comprise the Akt kinase inhibitors according to the present invention. In general, the compositions of the present invention comprise: a) an effective amount of one or more Akt kinase inhibitors or salts thereof as described herein; and b) one or more excipients. The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.

Non-limiting examples of compositions according to this disclosure include: a) from about 0.001 mg to about 1000 mg of one or more Akt kinase inhibitors according to the present invention; and b) one or more excipients.

Another embodiment according to this disclosure relates to the following compositions: a) from about 0.01 mg to about 100 mg of one or more Akt kinase inhibitors according to the present invention; and b) one or more excipients.

A further embodiment according to this disclosure relates to the following compositions: a) from about 0.1 mg to about 10 mg of one or more Akt kinase inhibitors according to the present invention; and b) one or more excipients.

The term "effective amount" as used herein means "an amount of one or more 1-N- amino-2-imidazolidinones, effective at dosages and for periods of time necessary to achieve the desired or therapeutic result." An effective amount may vary according to factors known in the art, such as the disease state, age, sex, and weight of the human or animal being treated. Although particular dosage regimes may be described in examples herein, a person skilled in the art would appreciated that the dosage regime may be altered to provide optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. In addition, the compositions of this disclosure can be administered as frequently as necessary to achieve a therapeutic amount. METHOD OF USE

This disclosure also relates to a method for controlling cancer, inter alia, breast cancer, lung cancer, colorectal cancer, prostate cancer, and the like. The disclosed method comprises the step of administering to a human or higher mammal an effective amount of a composition comprising one or more of the Akt kinase inhibitors according to this disclosure.

This disclosure relates to:

A method for treating cancer comprising administering to a patient in need of treatment an effective amount of one or more compounds as described herein.

The present invention also relates to the use of the Akt kinases according to this disclosure in the manufacture of a medicament for the treatment of cancer and related disorders.

The present invention relates to a method for treating cancer in a mammal, said method comprising administering to said mammal an effective amount of one or more Akt kinases according to this disclosure.

The present invention relates to a method for treating cancer in a human, said method comprising administering to said human an effective amount of one or more Akt kinases according to this disclosure. The present invention relates to a method for inhibiting Akt kinase activity in humans comprising administering to said human an effective amount of one or more Akt kinases according to this disclosure.

The compounds of the present invention can be used in the manufacture of one or more medicaments, non-limiting examples of these medicaments are:

A compound for use in the manufacture of a medicament for the treatment of breast cancer. A compound for use in the manufacture of a medicament for the treatment of lung cancer.

A compound for use in the manufacture of a medicament for the treatment of colorectal cancer.

A compound for use in the manufacture of a medicament for the treatment of prostate cancer. PROCEDURES

The assay for Akt inhibitors was performed using the K-LISA Akt activity kit from Calbiochem (Cat. No. CBAOl 9), which is a rapid, sensitive, ELISA-based (Enzyme- Linked-Immunosorbent- Assay) activity assay. It utilizes a biotinylated peptide substrate (Crosstide, i.e., GRPRTSSFAEG) that is phosphorylated on the second serine by Aktl, Akt2, Akt3. The biotinylated Akt substrate and sample containing Akt are incubated in the presence of ATP in wells of a streptavidin-coated 96-well plate, which allows for phosphorylation and substrate capture, through biotine-streptavidine binding, in a single step. The extent of phosphorylation is detected colorimetrically with an anti-phosphoserine antibody. Screening hits were subjected to IC₅₀ determination based on the same assay, using N¹ -(7-cyclobutyl-3-phenyl[ 1 ,2,4]triazol-[4,3-b]pvridazin-6-yl)-N³,N³,2,2- tetramethylpropane-l,3-diamine as a control which was found to have an IC₅₀ = 1.2 μM.

The following are non-limiting examples of the Akt IC₅₀ values for compounds disclosed herein.

TABLE III

While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

References

The following are references which are cited herein and which are incorporated by reference herein in their entirety.

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(2002).

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Claims

WHAT IS CLAIMED IS:

1. A compound having the formula:

wherein

W and Y are each independently chosen from: i) hydrogen; or ii) Ci-C₆ linear, branched, or cyclic alkyl;

Z has the formula:

the index b is 0 or 1 ;

R is chosen from: i) substituted or unsubstituted C₃-C₇ carbocyclic rings; ii) substituted or unsubstituted C₁-C₉ heteroaryl rings; iii) substituted or unsubstituted C₁-C₉ heterocyclic rings; or v) substituted or unsubstituted phenyl;

L has the formula:

-[C(R^laR^lb)]_x[R³]_z[C(R^2aR^2b)]_y-

R^la, R^Ib, R^2a, and R^2b are each independently chosen from: i) hydrogen; or ii) Ci-C₄ linear or branched alkyl; R³ is chosen from: i) -NR'-; ϋ) -NR⁴C(O)-; iii) -C(O)NR⁴-; iv) -C(O)-;

Vi) -OC(O)-; vii) -C(O)O-; viii) -NHC(O)NH-; ix) -NH(=NR⁴)NH-; x) -O-; or xi) -CR⁴=CR⁴-;

R⁴ is hydrogen, methyl, ethyl, or propargyl; the indices x and y are each independently from 0 to 6; the index z is 0 or 1;

L¹ has the formula:

-[C(R^5aR^5b)]_m[R⁸]_q[C(R^6aR^6b)]_n[R⁹]_r[C(R^7aR^7b)]p- R^5a, R⁵¹⁵, R^6a, R^6b, R^7a, and R⁷" are each independently chosen from: i) hydrogen; ii) substituted or unsubstituted C₁-C₆ linear or branched alkyl; iii) substituted or unsubstituted C₆ aryl; iv) substituted or unsubstituted C₆-C₈ arylalkylene; v) -C(O)OR¹⁰; or vi) -C(O)NR¹¹²R^{1 lb};

R¹⁰, R^{l la}, and R^{l lb} are each independently chosen from hydrogen or Ci-C₄ linear or branched alkyl; R⁸ and R⁹ are each independently chosen from: i) -NR¹²-; ϋ) - NR¹²NR¹²-; iii) -NR¹²C(O)-; iv) -C(O)NR¹²-; v) -C(O)-;

Vi) -OC(O)-; vii) -C(O)O-; or viii) -S-; and

R¹² is independently hydrogen or Ci-C₄ linear or branched alkyl; the indices m, n, and p are each independently from O to 6; the indices q and r are each independently O or 1.

2. A compound having the formula:

wherein Y is chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, wo-butyl, sec-butyl, tert-butyl, or cyclobutyl;

R is chosen from: i) substituted or unsubstituted C₃-C₇ carbocyclic rings; ii) substituted or unsubstituted C₁-Cg heteroaryl rings; iii) substituted or unsubstituted C₁-Cg heterocyclic rings; or v) substituted or unsubstituted phenyl; said substitutions are each independently chosen from: a) Ci -C₄ linear or branched alkyl; b) Ci-C₄ linear or branched alkoxy; c) substituted or unsubstituted phenyl; each of said substitutions chosen from Ci-C₄ linear or branched alkyl; Ci-C₄ linear or branched alkoxy; -C(O)OR¹³; -OC(O)R¹³; d) -(CH₂XC(O)OR¹³; e) -(CH₂)_tOC(O)R¹³; f) -(CH₂)_tC(O)NR^14aR^14b; g) -(CH₂)_tSO₂NR^14aR^14b; h) -(CHjX_k)_u; or i) -(CH₂)_tOH;

R¹³, R^14a, and R^14b are each independently hydrogen, methyl, or ethyl; X is one or more halogen chosen from fluoro, chloro, or iodo; the index j is from O to 2; the index k is from 1 to 3; j + k = 3; the index t is from O to 3; the index u is from O to 3;

L¹ is a unit having the formula: i) -[C(R^5aR^5b)]_m-; ii) -[C(R^5aR^5b)]_mC(O)NH[C(R^6aR^6b)]_n-; or iii)

R^5a, R^5b, R^6a, R^6b, R^7a, and R⁷* are each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, wo-propyl, /so-butyl, benzyl, -C(O)OR¹ °_;

R¹⁰ is chosen from hydrogen or C₁-C₄ linear or branched alkyl;

R⁹ is chosen from: i) -NHC(O)-; ii) -C(O)NH-; or iii) -S-; the indices m, n, and p are from O to 4; and

L has the formula:

-[C(R^laR^Ib)]_xR³[C(R^2aR^2b)]y-

R^la, R^lb, R^2a, and R^2b are each independently chosen from hydrogen or methyl; R³ is chosen from: i) -NR⁴-; ii) -NR⁴C(O)-; iii) -C(O)NR⁴-;

R⁴ is hydrogen, methyl, ethyl, or propargyl; the indices x and y are each independently from O to 6.

3. A compound according to Claim 2 wherein L is chosen from: i) -CH₂C(CH₃)₂CH₂NHCH₂-; ii) -CH₂C(CH₃)₂CH₂NHCH₂CH₂-; iii) -CH₂C(CH₃)₂CH₂NHCH₂CH₂CH₂-; iv) -CH₂NHCH₂C(CH₃)₂CH₂-; v) -CH₂CH₂NHCH₂C(CH₃)₂CH₂-; vi) -CH₂CH₂CH₂NHCH₂C(CH₃)₂CH₂-; vii) -CH₂CH(CH₃)CH₂NHCH₂-; viii) -CH₂CH(CH₃)CH₂NHCH₂CH₂-; ix) -CH₂CH(CH₃)CH₂NHCH₂CH₂CH₂-; x) -CH₂NHCH₂CH(CH₃)CH₂-; xi) -CH₂CH₂NHCH₂CH(CH₃)CH₂-; xii) -CH₂CH₂CH₂NHCH₂CH(CH₃)CH₂-; xiii) -CH₂CH₂NHCH₂CH₂-; xiv) -CH₂CH₂NHCH₂CH₂CH₂-; xv) -CH₂CH₂NHCH₂CH₂CH₂CH₂-; xvi) -CH₂CH₂CH₂NHCH₂CH₂-; xvii) -CH₂CH₂CH₂CH₂NHCH₂CH₂-; xviii) -CH₂CH₂CH₂CH₂NHCH₂CH₂CH₂-; or xix) -CH₂CH₂CH₂NHCH₂CH₂CH₂CH₂-.

4. A compound according to Claim 3 wherein L is chosen from: i) -CH₂C(CHa)₂CH₂NHCH₂-; ii) -CH₂C(CHJ)₂CH₂NHCH₂CH₂-; or iii) -CH₂C(CH₃)₂CH₂NHCH₂CH₂CH₂-.

5. A compound according to Claim 2 wherein L is chosen from: i) -CH₂C(CHj)₂CH₂NHC(O)-; ii) -CH₂C(CH₃)₂CH₂NHC(O)CH₂-; iii) -CH₂C(CH₃)_ZCH₂NHC(O)CH₂CH₂-; iv) -CH₂NHC(O)CH₂C(CH₃)_ZCH₂-; v) -CH₂CH₂NHC(O)CH₂C(CH₃)₂CH₂-; vi) -CH₂CH₂CH₂NHC(O)CH₂C(CH₃)₂CH₂-; vii) -CH₂CH(CH₃)CH₂NHC(O)-; viii) -CH₂CH(CH₃)CH₂NHC(O)CH₂-; ix) -CH₂CH(CH₃)CH₂NHC(O)CH₂CH₂-; x) -CH₂NHC(O)CH₂CH(CH₃)CH₂-; xi) -CH₂CH₂NHC(O)CH₂CH(CH₃)CH₂-; xii) -CH₂CH₂CH₂NHC(O)CH₂CH(CH₃)CH₂-; xiii) -CH₂CH₂NHC(O)CH₂-; xiv) -CH₂CH₂NHC(O)CH₂CH₂-; xv) -CH₂CH₂NHC(O)CH₂CH₂CH₂-; xvi) -CH₂CH₂CH₂NHC(O)CH₂-; xvii) -CH₂CH₂CH₂CH₂NHC(O)CH₂CH₂-; or xviii) -CH₂CH₂CH₂CH₂NHC(O)CH₂CH₂CH₂-.

6. A compound according to Claim 5 wherein L is chosen from: i) -CH₂C(CH₃)₂CH₂NHC(O)-; ii) -CH₂C(CHa)₂CH₂NHC(O)CH₂-; or iii) -CH₂C(CHa)₂CH₂NHC(O)CH₂CH₂-.

7. A compound according to Claim 2 wherein R is a substituted or unsubstituted C₁, C₂, C₃, or C₄ heteroaryl or heterocyclic 5-member ring chosen from: i) a pyrrolidinyl ring having the formula;

ii) a pyrrolyl ring having the formula:

iii) a 4,5-dihydroimidazolyl ring having the formula:

iv) a pyrazolyl ring having the formula:

v) an imidazolyl ring having the f ΌorΓmΠHu; tllaa::

vi) a [ 1 ,2,3]triazolyl ring having the formula:

vii) a [1,2,4] triazolyl ring having the formula:

viii) tetrazolyl ring having the formula:

ix) a [ 1 ,3,4] or [ 1 ,2,4]oxadiazolyl ring having the formula:

x) a pyrrolidinonyl ring having the formula:

xi) an imidazolidinonyl ring having the formula:

xii) an imidazol-2-only ring having the formula:

xiii) an oxazolyl ring having the formula:

xiv) an isoxazolyl ring having the formula:

xv) a dihydrothiazolyl ring having the formula:

xvi) a furanly ring having the formula:

xvii) a thiophenyl having the formula:

wherein any of the ring hydrogen atoms can be substituted by a hydrocarbyl unit.

8. A compound according to Claim 7 wherein each of said substitution is independently chosen from: a) C₁-C₄ linear or branched alkyl; b) C₁-C₄ linear or branched alkoxy; c) -C(O)OR¹³; or d) -SO₂NR^14aR^14b; wherein R¹³,R^14a, and R^14b are each independently hydrogen, methyl or ethyl.

9. A compound according to Claim 8 wherein R is chosen from l-(methylcarboxy)- [l,2,3]triazol-4-yl, 4-(methylcarboxy)[l,2,3]triazol-l-yl, l-(ethylcarboxy)- [l,2,3]triazol-4-yl, 4-(ethylcarboxy)[l,2,3]triazol-l-yl, l-(methylcarboxy)methyl- [l,2,3]triazol-4-yl, 4-(methylcarboxy)methyl[l,2,3]triazol-l-yl, l-(ethylcarboxy)- methyl[l,2,3]triazol-4-yl, or 4-(ethylcarboxy)methyl-[l,2,3]triazol-l-yl.

10 A compound according to Claim 2 wherein R is a substituted or unsubstituted C₃, C₄, or C₅ heteroaryl or heterocyclic 5-member ring chosen from: i) a morpholinyl ring having the formula:

ii) a piperidinyl ring having the formula:

iii) a pyridinyl ring having the formula:

iv) a pyrimidinyl ring having the formula:

v) a piperazinyl ring having the formula:

vi) a ketopiperazinyl ring having the formula:

vii) a dihydropyrazin2-onyl ring having the formula:

viii) a pyrazin2-onyl ring having the formula:

ix) dihydropyrimidin-4-onyl having the formula:

x) a uracil ring having the formula:

xi) a triazinyl ring having the formula:

wherein any of the ring hydrogen atoms can be substituted by a hydrocarbyl unit.

11. A compound according to Claim 2 wherein R is a substituted or unsubstituted C₇ or C₈ heteroaryl or heterocyclic fused ring chosen from: i) a quinazolinonyl ring having the formula:

ii) a 2,3-dihydobenzo[b][l ,4]dioxinyl ring having the formula:

iii) a benzoxazolyl ring having the formula:

iv) a benzothiazolyl ring having the formula:

wherein any of the ring hydrogen atoms can be substituted by a hydrocarbyl unit.

12. A compound according to Claim 2 wherein L¹ has the formula:

-[C(R^5aR^5b)]_m- each R^5a and R^5b unit is independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, wo-propyl, iso-butyl, or benzyl; the index m is from 0 to 4.

13. A compound according to Claim 12 wherein L¹ is chosen from: i) -CH₂-; ii) -CH₂CH₂-; iii) -CH₂CH₂CH₂-; iv) -CH₂CH₂CH₂CH₂-; v) -CH₂CH(CH₃)CH₂-; vi) -CH₂CH(CH₃)CH₂CH₂-; or vii) -CH₂CH[CH₂CH(CH₃)2]CH₂-.

14. A compound according to Claim 13 wherein L¹ is -CH₂-.

15. A compound according to Claim 2 wherein L¹ has the formula:

-[C(R^5aR^5b)]_mC(O)NH[C(R^6aR^6b)]_n-

R^5a, R⁵¹³, R^6a, and R^6b are each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, iso-propyl, iso-butyl, or benzyl.

16. A compound according to Claim 15 wherein L¹ is chosen from: i) -CH₂C(O)NHCH₂-; ii) -CH(CH₃)C(O)NHCH₂-; iii) -CH₂C(O)NHCH(CH₃)-; iv) -CH(CH₃)C(O)NHCH(CH₃)-; v) -CH[CH(CH₃)₂]C(O)NHCH₂-; vi) -CH₂C(O)NHCH[CH(CH₃)₂]-; vii) -CH[CH(CH₃)₂]C(O)NHCH[CH(CH₃)₂]-; v) -CH[CH(CHS)₂C(O)NHCH(CH₃)-; vi) -CH(CH₃)C(O)NHCH[CH(CHS)₂]-; vii) -CH[CH₂CH(CH₃)₂]C(O)NHCH₂-; ix) -CH₂C(O)NHCH[CH₂CH(CH₃)₂]-; x) -CH[CH₂CH(CH₃)₂]C(O)NHCH(CH₃)-; xi) -CH(CH₃)C(O)NHCH[CH₂CH(CH₃);_!]-; xii) -CH[CH₂CH(CH₃)₂]C(O)NHCH[CH(CH₃)₂]-; xiii) -CH[CH(CH₃)₂]C(O)NHCH[CH₂CH(CH₃)₂]-; xiv) -CH[CH₂CH(CH₃)₂]C(O)NHCH[CH₂CH(CH₃)₂]-; xv) -CH(CH₂C₆H₅)C(O)NHCH₂-; xvi) -CH₂C(O)NHCH(CH₂C₆H₅)-; xvii) -CH(CH₂C₆H₅)C(O)NHCH(CH₃)-; xviii) -CH(CH₃)C(O)NHCH(C₆H₅)-; xix) -CH(CH₂C₆H₅)C(O)NHCH[CH(CH₃);!]-; xx) -CH(CH₂C₆H₅)C(O)NHCH[CH(CH₃)CH(CH3)₂]-; xi) -CH[CH(CH₃)CH(CH₃)₂]C(O)NHCH(CH₂C₆H₅)-; and xii) -CH[CH(CH₃)₂]C(O)NHCH[CH(CH₃)CH(CH₃)₂]-.

17. A compound according to Claim 2 wherein L¹ is chosen from: i) -CH₂C(O)NHCH₂CH₂SCH₂-; ii) -CH₂C(O)NHCH(CO₂CH₃)CH₂SCH₂-; iii) -CH₂C(O)NH-; iv) -CH₂C(O)NHNCH₃-; v) -C(O)NHCH₂-; or vi) -CH[CH(CH₃)₂]C(O)NHCH₂CH₂-.

18. A compound having the formula:

wherein Y is chosen from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, wø-butyl, sec-butyl, tert-buty\, or cyclobutyl; Z has the formula:

-^-(L¹V-R the index b is O or 1 ;

R is chosen from: i) substituted or unsubstituted C₃-C₇ carbocyclic rings; ii) substituted or unsubstituted C₁-C₉ heteroaryl rings; iii) substituted or unsubstituted Ci -Cg heterocyclic rings; or v) substituted or unsubstituted phenyl; said substitutions are each independently chosen from: a) C₁-C₄ linear or branched alkyl; b) C₁-C₄ linear or branched alkoxy; c) substituted or unsubstituted phenyl; each of said substitutions chosen from C₁-C₄ linear or branched alkyl; C₁-C₄ linear or branched alkoxy; -C(O)OR¹³; -OC(O)R¹³; d) -(CH₂)AO)OR¹³; e) -(CH₂)_tOC(O)R¹³; f) -(CH₂),C(O)NR^14aR^14b; g) -(CH₂)_tSO₂NR^14aR^14b; h) -(CHjX_k)₁₁; or i) -(CH₂)_tOH;

R¹³, R^14a, and R^14b are each independently hydrogen, methyl, or ethyl; X is one or more halogen chosen from fluoro, chloro, or iodo; the index j is from O to 2; the index k is from 1 to 3; j + k = 3; the index t is from O to 3; the index u is from O to 3;

L¹ is a unit having the formula: i) -[C(R^5aR^5b)]_m-; ii) -[C(R^5aR^5b)]_mC(O)NH[C(R^6aR^6b)]_n-; or iii) -[C(R^5aR^5b)]_mC(O)NH[C(R^6aR^6b)]_n[R⁹] [C(R⁷³R^)J_p-

R^5a, R^5b, R^6a, R^6b, R^7a, and R⁷¹⁵ are each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, /so-propyl, /sø-butyl, benzyl, -C(O)OR¹⁰ _;

R¹⁰ is chosen from hydrogen or Ci-C₄ linear or branched alkyl;

R⁹ is chosen from: i) -NHC(O)-; ii) -C(O)NH-; or iii) -S-; the indices m, n, and p are from O to 4; and

L has the formula:

-[C(R^laR^lb)]_xR³[C(R^2aR^2b)]_y-

R^la, R^lb, R^2a, and R^2b are each independently chosen from hydrogen or methyl; R³ is chosen from: i) -NR⁴-; ii) -NR⁴C(O)-; iii) -C(O)NR⁴-;

R⁴ is hydrogen, methyl, ethyl, or propargyl; the indices x and y are each independently from 0 to 6.

19. A compound according to Claim 18 wherein L is chosen from: i) -CH₂C(CH₃)₂CH₂NHCH₂-; ii) -CH₂C(CH₃)₂CH₂NHCH₂CH₂-; iii) -CH₂C(CH₃)₂CH₂NHCH₂CH₂CH2-; iv) -CH₂NHCH₂C(CH₃)₂CH₂-; v) -CH₂CH₂NHCH₂C(CH₃)₂CH₂-; vi) -CH₂CH₂CH₂NHCH₂C(CH₃)₂CH₂-; vii) -CH₂CH(CH₃)CH₂NHCH₂-; viii) -CH₂CH(CH₃)CH₂NHCH₂CH₂-; ix) -CH₂CH(CH₃)CH₂NHCH₂CH₂CH₂-; x) -CH₂NHCH₂CH(CH₃)CH₂-; xi) -CH₂CH₂NHCH₂CH(CH₃)CH₂-; xii) -CH₂CH₂CH₂NHCH₂CH(CH₃)CH₂-; xiii) -CH₂CH₂NHCH₂CH₂-; xiv) -CH₂CH₂NHCH₂CH₂CH₂-; xv) -CH₂CH₂NHCH₂CH₂CH₂CH₂-; xvi) -CH₂CH₂CH₂NHCH₂CH₂-; xvii) -CH₂CH₂CH₂CH₂NHCH₂CH₂-; xviii) -CH₂CH₂CH₂CH₂NHCH₂CH₂CH₂-; or xix) -CH₂CH₂CH₂NHCH₂CH₂CH₂CH₂-.

20. A compound according to Claim 19 wherein L is chosen from: i) -CH₂C(CH_S)₂CH₂NHCH₂-; ii) -CH₂C(CH₃)₂CH₂NHCH₂CH₂-; or iii) -CH₂C(CH₃)₂CH₂NHCH₂CH₂CH₂-.

21. A compound according to Claim 18 wherein L is chosen from: i) -CH₂C(CH₃)₂CH₂NHC(O)-; ii) -CH₂C(CH₃)₂CH₂NHC(O)CH₂-; iii) -CH₂C(CH₃)₂CH₂NHC(O)CH₂CH₂-; iv) -CH₂NHC(O)CH₂C(CH₃)₂CH₂-; v) -CH₂CH₂NHC(O)CH₂C(CH₃)₂CH₂-; vi) -CH₂CH₂CH₂NHC(O)CH₂C(CH₃)₂CH₂-; vii) -CH₂CH(CH₃)CH₂NHC(O)-; viii) -CH₂CH(CH₃)CH₂NHC(O)CH₂-; ix) -CH₂CH(CH₃)CH₂NHC(O)CH₂CH₂-; x) -CH₂NHC(O)CH₂CH(CH₃)CH₂-; xi) -CH₂CH₂NHC(O)CH₂CH(CH₃)CH₂-; xii) -CH₂CH₂CH₂NHC(O)CH₂CH(CH₃)CH₂-; xiii) -CH₂CH₂NHC(O)CH₂-; xiv) -CH₂CH₂NHC(O)CH₂CH₂-; xv) -CH₂CH₂NHC(O)CH₂CH₂CH₂-; xvi) -CH₂CH₂CH₂NHC(O)CH₂-; xvii) -CH₂CH₂CH₂CH₂NHC(O)CH₂CH₂-; or xviii) -CH₂CH₂CH₂CH₂NHC(O)CH₂CH₂CH₂-.

22. A compound according to Claim 21 wherein L is chosen from: i) -CH₂C(CH₃)₂CH₂NHC(O)-; ii) -CH₂C(CH₃)₂CH₂NHC(O)CH₂-; or iii) -CH₂C(CH₃)₂CH₂NHC(O)CH₂CH₂-.

23. A compound according to Claim 18 wherein R is a substituted or unsubstituted Ci, C₂, C₃, or C₄ heteroaryl or heterocyclic 5-member ring chosen from: i) a pyrrolidinyl ring having the formula;

ii) a pyrrolyl ring having the formula:

iii) a 4,5-dihydroimidazolyl ring having the formula:

iv) a pyrazolyl ring having the formula:

v) an imidazolyl ring having the formula:

Vi) a [l,2,3]triazolyl ring having the formula:

vii) a [1,2,4] triazolyl ring having the formula:

viii) tetrazolyl ring having the formula:

ix) a [1,3,4] or [l,2,4]oxadiazolyl ring having the formula:

x) a pyrrolidinonyl ring having the formula:

xi) an imidazolidinonyl ring having the formula:

xii) an imidazol-2-only ring having the formula:

xiii) an oxazolyl ring having the formula:

xiv) an isoxazolyl ring having the formula:

xv) a dihydrothiazolyl ring having the formula:

xvi) a furanly ring having the formula:

xvii) a thiophenyl having the formula:

wherein any of the ring hydrogen atoms can be substituted by a hydrocarbyl unit.

24. A compound according to Claim 23 wherein each of said substitution is independently chosen from: a) Ci -C₄ linear or branched alkyl; b) C_J-C₄ linear or branched alkoxy; c) -C(O)OR¹³; or d) -SO₂NR^14aR^14b; wherein R¹³ _;R^14a, and R^14b are each independently hydrogen, methyl or ethyl.

25. A compound according to Claim 24 wherein R is chosen from methyl, ethyl, phenyl, l-(methylcarboxy)-[l,2,3]triazol-4-yl, 4-(methylcarboxy)[l,2,3]triazol-l-yl, 1- (ethylcarboxy)-[l,2,3]triazol-4-yl, 4-(ethylcarboxy)[l,2,3]triazol-l-yl, 1- (methylcarboxy)methyl-[ 1 ,2,3]triazol-4-yl, 4-methylcarboxy)methyl[ 1 ,2,3]triazol- 1 - yl, l-(ethylcarboxy)-methyl[l,2,3]triazol-4-yl, or 4-(ethylcarboxy)methyl- [l,2,3]triazol-l-yl.

26 A compound according to Claim 18 wherein R is a substituted or unsubstituted C₃, C₄, or C₅ heteroaryl or heterocyclic 5 -member ring chosen from: i) a morpholinyl ring having the formula:

ii) a piperidinyl ring having the formula:

iii) a pyridinyl ring having the formula:

iv) a pyrimidinyl ring having 1 the i ormula:

v) a piperazinyl ring having the formula:

vi) a ketopiperazinyl ring having the formula:

vii) a dihydropyrazin2-onyl ring having the formula:

viii) a pyrazin2-onyl ring having the formula:

ix) dihydropyrimidin-4-onyl having the formula:

x) a uracil ring having the formula:

xi) a triazinyl ring having the formula:

wherein any of the ring hydrogen atoms can be substituted by a hydrocarbyl unit.

27. A compound according to Claim 18 wherein R is a substituted or unsubstituted C₇ or C₈ heteroaryl or heterocyclic fused ring chosen from: i) a quinazolinonyl ring having the formula:

iii) a 2,3-dihydobenzo[b][ 1 ,4]dioxinyl ring having the formula:

iii) a benzoxazolyl ring having the formula:

iv) a benzothiazolyl ring having the formula:

wherein any of the ring hydrogen atoms can be substituted by a hydrocarbyl unit.

28. A compound according to Claim 18 wherein L¹ has the formula:

__[c(R5a_R5b_)]m_ each R^5a and R^5b unit is independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, wo-propyl, wo-butyl, or benzyl; the index m is from 0 to 4.

29. A compound according to Claim 28 wherein L¹ is chosen from: i) -CH₂-; ii) -CH₂CH₂-; iii) -CH₂CH₂CH₂-; iv) -CH₂CH₂CH₂CH₂-; v) -CH₂CH(CH₃)CH₂-; vi) -CH₂CH(CH₃)CH₂CH₂-; or vii) -CH₂CH[CH₂CH(CH₃)₂]CH₂-.

30. A compound according to Claim 29 wherein L¹ is -CH₂-.

31. A compound according to Claim 18 wherein L¹ has the formula:

-[C(R^5aR^5b)]_mC(O)NH[C(R^6aR^6b)]n-

R^5a, R⁵¹³, R^6a, and R^6b are each independently chosen from hydrogen, methyl, hydroxymethyl, ethyl, wopropyl, /so-butyl, or benzyl.

32. A compound according to Claim 31 wherein L¹ is chosen from: i) -CH₂C(O)NHCH₂-; ii) -CH(CH₃)C(O)NHCH₂-; iii) -CH₂C(O)NHCH(CH₃)-; iv) -CH(CH₃)C(O)NHCH(CH₃)-; v) -CH[CH(CH₃)₂]C(O)NHCH₂-; vi) -CH₂C(O)NHCH[CH(CH₃)_Z]-; vii) -CH[CH(CH₃)₂]C(O)NHCH[CH(CH₃)₂]-; v) -CH[CH(CH₃)₂C(O)NHCH(CH₃)-; vi) -CH(CH₃)C(O)NHCH[CH(CH₃)₂]-; vii) -CH[CH₂CH(CH₃)₂]C(O)NHCH₂-; ix) -CH₂C(O)NHCH[CH₂CH(CH₃)₂]-; x) -CH[CH₂CH(CH₃^]C(O)NHCH(CH₃)-; xi) -CH(CH₃)C(O)NHCH[CH₂CH(CH₃)₂]-; xii) -CH[CH₂CH(CH₃)₂]C(O)NHCH[CH(CH₃)₂]-; xiii) -CH[CH(CH₃)₂]C(O)NHCH[CH₂CH(CH₃)₂]-; xiv) -CH[CH₂CH(CH₃)₂]C(O)NHCH[CH₂CH(CH₃)₂]-; xv) -CH(CH₂C₆H₅)C(O)NHCH₂-; xvi) -CH₂C(O)NHCH(CH₂C₆H₅)-; xvii) -CH(CH₂C₆H₅)C(O)NHCH(CH₃)-; xviii) -CH(CH₃)C(O)NHCH(C₆H₅)-; xix) -CH(CH₂C₆H₅)C(O)NHCH[CH(CH₃)₂]-; xx) -CH(CH₂C₆H₅)C(O)NHCH[CH(CH₃)CH(CH₃)₂]-; xi) -CH[CH(CH₃)CH(CH₃)₂]C(O)NHCH(CH₂C6H₅)-; and xii) -CH[CH(CH₃)₂]C(O)NHCH[CH(CH₃)CH(CH₃)₂]-.

33. A compound according to Claim 18 wherein L¹ is chosen from: i) -CH₂C(O)NHCH₂CH₂SCH₂-; ii) -CH₂C(O)NHCH(CO₂CH₃)CH₂SCH₂-; iii) -CH₂C(O)NH-; iv) -CH₂C(O)NHNCH₃-; v) -C(O)NHCH₂-; or vi) -CH[CH(CH₃)₂]C(O)NHCH₂CH₂-.

34. A composition comprising an effective amount of one or more Akt kinase inhibitors or salts thereof according to any of Claims 1-33.

35. A method for treating cancer comprising administering to a patient in need of treatment an effective amount of one or more compounds according to any of Claims 1-33.

36. A method for treating a cancer chosen from breast cancer, lung cancer, colorectal cancer, and prostate cancer comprising administering to a patient in need of treatment an effective amount of one or more compounds according to any of Claims 1-33.

37. A compound according to any of Claims 1-33, for use in the manufacture of a medicament for the treatment of a cancer chosen from breast cancer, lung cancer, colorectal cancer, and prostate cancer.

38. A compound according to any of Claims 1-33, for use as a medicament.

39. A compound according to any of Claims 1-33, for use as a medicament for treating cancer chosen from breast cancer, lung cancer, colorectal cancer, and prostate cancer.